Advances in Cardiac Disease
Advances in Cardiac Disease
Advances in Cardiac Disease
DIAGNOSIS OF CORONARY
ATHEROSCLEROSIS
Edited by Suna F. Kiraç
Advances in the Diagnosis of Coronary Atherosclerosis
Edited by Suna F. Kiraç
Published by InTech
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Preface IX
Coronary artery disease (CAD) and its consequences are the most important morbidity
and mortality reasons in the developed and developing countries. Advanced imaging
techniques (intravascular ultrasound, MR and CT angiography, SPECT/CT, PET/CT,
PET/MRI) and novel serologic biomarkers (C-reactive protein, interleukin 6, matrix
metalloproteinase, P-selectin, intracellular adhesion molecule 1 and tumor necrosis
factor ) provide early diagnosis of CAD and protect patients from hard cardiac
events. Non-invasive techniques are being widely used in the diagnosis and
management while conventional CAG is still the most commonly performed test in the
cases at high risk. Following the first cardiac catheterization performed, first selective
CAG has been reported at the end of 1950's. Patient specific and procedure-related
complications range widely from minor ones with short term sequelae to life
threatening events that may cause irreversible end-point if urgent treatment is not
adequately provided. The important risk factors for complications are older age, renal
insufficiency, uncontrolled diabetes mellitus, morbid obesity, and iodine allergy.
However, operator skills and the type of invasive procedure being performed remain
as the most important predictors to undesired outcomes. The risk-to-benefit ratio of
the CAG should be considered carefully on an individual basis.
Coronary CTA and CMRA among advanced imaging systems offer anatomical
informations not only for coronary vessels but also for peripheral vascular structures,
and assessment of the left and right ventricular functions is possible in same image
series. Quantified coronary artery calcification and many post-processing images (2-D
images and the different 3-D rendering images such as volume rendering, multiplanar
reformation, partial maximum intensity projection, curved multiplanar reformation)
should be evaluated to increase diagnostic accuracy. High calcification level signs
atherosclerotic changes in the coronary arteries, but is not specific for luminal
obstruction. Because the absence of detectable calcium deposition has a high negative
predictive value for CAD, CAC value is a significant predictive determinant for
prognosis in asymptomatic patients. As with coronary angiography, myocardial
perfusion abnormality may not be detected even there is coronary lesion causing a
luminal narrowing of greater than 50 % defined by CTA and MRA. In asymptomatic
and intermediate likelihood patients, assessment of myocardial perfusion by single
photon emission computed tomography (SPECT) or positron emission tomography
(PET) appears to be valuable even when coronary arteries are normal in angiography.
X Preface
If gated study is added, left ventricular systolic and diastolic functions can be
investigated simultaneously with myocardial perfusion. This field includes a overview
of molecular targeted imaging, permeability of the coronary vessel wall, and
interventional coronary MR. Recent developments in the field of ultrasonography
have allowed us to objectively quantify global and regional ventricular function, and
also, to get real-time evaluation of coronary walls and calcium load of atherosclerotic
plaques. While we achieve more knowledge about atherosclerotic lesions by IVUS,
tissue Doppler imaging has attempted us to assess myocardial function.
On the other hand, radiation exposure is the most limited factor for CTA and MPS
gated SPECT procedures and needs particular attention. Ionizing radiation doses,
hazardous effects and general radiation protection principles should be known for
optimal protection of the patients. Mainly radiation safety rules, various techniques
and equipments that may be used to reduce patient and staff radiation exposure
during diagnostic and therapeutic procedures especially cardiac interventional
fluoroscopic procedures have been detailed discussed in this book. In this field cardiac
MR, which is a powerful non-invasive technique for the simultaneously assessment of
coronary artery anatomy and function, has a great promise as a radiation-free method.
But, it currently lays behind CTA for noninvasive coronary angiography because of
some limitation factors such as metallic implants and equipment design.
Selection of the most appropriate diagnostic test in special situations such as chronic
kidney disease (CKD) and diabetes mellitus is an other important issue. Although
coronary angiography is a valuable tool, the major challenges with coronary
angiography relate to when it is appropriate to perform and what the risks are
associated with the procedure. Because renal function may be more and more impair
with contrast agents used during CAG, and sometimes dialysis may be needed.
Therefore, stress echocardiography, MRA and nuclear cardiac tests are often
recommended to rule out the presence of CAD in those patients and the presence of
any risk factor must be assessed on an individual basis in order to prevent for a soft or
hard local or systemic complications. Contrast induced nephropathy (CIN) remains an
important clinical issue in these patients, pre-treatment with theophylline combined
with volume expansion using sodium bicarbonate; acetylcysteine; use of the lowest
possible dose of contrast material (CM), and ISO-osmolar CM or low osmolar CM are
advised to prevent CIN. Contrast induced nephropathy is diagnosed if a rapid renal
dysfunction is occurred after CM administration without obviously any other cause of
acute kidney insufficiency. Serum creatinine (sCr) is the standard marker for detecting
CIN; however little changes in sCr after CM exposure may be seen but it is not
considered clinically relevant. Therefore, glomerular filtration rate which usually
measured by creatinine clearance is usually accepted as the most accurate method for
the assessment of kidney function. But, even in patients with stable sCr the GFR may
significantly be declined. Recently more sensitive markers (Cystatin-C and
Neutrophilic gelatinase associated lipocaline) than sCr for GFR have been developed
and validated. Cystatin-C is presented as more accurate marker than sCr for
predicting renal function. Readers will get detailed discussions about advantages,
Preface XI
Suna F. Kıraç
Pamukkale University, Faculty of Medicine, Denizli
Turkey
1
Mechanisms of Disease:
Novel Polymorphisms in
Coronary Artery Disease
Asghar Ghasemi1, Morteza Seifi2 and Mahmood Khosravi3
1Tabriz Health Center
2Department of Iranian Legal Medicine Organization
3Hematology Department of Medicine Faculty,
1. Introduction
Coronary artery disease (CAD) is one of the most common cardiovascular diseases and has
a high incidence of morbidity and mortality. CAD is a major public health problem in
developing and developed countries and its increasing prevalence is a cause of considerable
concern in the medical community worldwide (He et al., 2005). CAD involves genetic and
environmental factors and their interaction with each other. Traditional risk factors account
for at most one-half of the prevalence of CAD (Zdravkovic et al., 2002). Despite attempts to
establish the molecular and genetic determinants that could account for variations in CAD
(Zdravkovic et al., 2002), the etiology and complex multigenic basis of atherosclerosis is still
not completely understood.
Completion of the sequencing of the human genome was a monumental achievement (Venter
et al., 2001). Molecular researchers now take for granted the information provided by the
sequence, however the clinical applications are not immediately obvious. A limitation of the
Human Genome Project was that it produced only a single “reference” sequence. But in order
to identify new disease causing mechanisms and cures for disease, we need to go beyond the
“reference” and characterize the differences between our genomes, and in turn the effect that
these differences have. The Human HapMap consortium (Frazer et al., 2007) and recent
genome-wide association studies (GWAS) have set out to capture the interindividual
differences that are associated with disease processes, including coronary artery disease.
The association between genetic variations and CAD have been reviewed in several
previous manuscripts (Lanktree et al., 2008), but in our knowledge so far there has been no
study in the field of association between novel gene variations and CAD; therefore we
focused on introducing some novel polymorphisms and their relationships with CAD.
the interactions between multiple genetic and environmental factors (Wright & Hastie, 2001;
Reich & Lander, 2001). Although the total genetic contribution to CAD risk can be
quantified, the determination of the size and number of contributing effects is impossible
without identifying all CAD susceptibility genes. The multiple risk factors for CAD
themselves have their own genetic architecture. The heritabilities of some of the risk factors
for CAD are considerable - total cholesterol (40 to 60%), HDL-cholesterol (45 to 75%), total
triglycerides (40 to 80%), body mass index (25 to 60%), systolic blood pressure (50 to 70%),
Lp(a) levels (90%), homocysteine levels (45%), type 2 diabetes (40 to 80%), fibrinogen (20 to
50%) (Lusis et al., 2004). Also, as CAD is rare before the age of 50 yr, it is unlikely to have an
effect on reproductive success and hence less likely to have been subject to direct
evolutionary selection pressure. Variants that confer susceptibility or protection for CAD
might therefore have evolved neutrally in the past, and so could present at a wide range of
frequencies.
This is the basis of the Common Disease/Common Variant (CDCV) hypothesis which holds
that the genetic variants underlying complex traits occur with a relatively high frequency
(>1%), have undergone little or no selection in earlier populations and are likely to date back
to >100,000 years ago (Lander et al., 1996).The other competing model is the Common
Disease Rare Variant hypothesis, with an inverse relationship between the magnitude of
genetic effect and allele frequency (Pritchard et al., 2001). This model argues that diseases
are common because of highly prevalent environmental influences, not because of common
disease alleles in the population (Wright & Hastie, 2001). A review of candidate gene
associations and recent genome wide association study results support the importance of
common alleles in CAD. At odds with this, rare allelic variants of three candidate genes
(ABCA1, APOA1, LCAT) that influence HDL levels, were jointly found to make a
substantial contribution to the population distribution of HDL levels (Cohen et al., 2004;
Frikke-Schmidt et al., 2004). The most likely scenario would be that the allelic spectrum of
the disease variants is the same as the general spectrum of all disease variants. Under this
neutral model, although most susceptibility variants are rare with minor allele frequencies
(MAF) <1 per cent, variants with MAF>1 per cent would account for more than 90 per cent
of the genetic differences between individuals. It is plausible that these common variants
might contribute significantly to those common diseases in which susceptibility alleles
might not be under intense negative selection.
This approach is more directed than is the genome-scan linkage approach, but it is limited
by our incomplete knowledge of disease mechanisms and thus may miss important
causative genes. It is worth noting that whereas in linkage analyses “disease” alleles are
tracked in families, genetic association is a phenomenon of populations and association
studies compare populations of subjects with and without the disease of interest (Bernhard
et al., 2000).
2007) The WTCCC study identified 24 genetic variants associated with at least one of these
complex diseases and helped to clarify key methodological issues, setting the stage for the
more than 400 GWAS that were to follow. These GWAS have so far identified more than 250
loci at which common variants influence the predisposition to diseases that are common
(i.e., diabetes, autoimmune diseases, and several types of cancer), an achievement that by far
outweighed that of the previous decade of genetic studies. Results are available in the
catalogue of published GWAS prepared by the National Cancer Institute (NCI)-National
Human Genome Research Institute (NHGRI). (Hindorff et al., 2010) The genetic variants
that can be identified by GWAS are common variants (with at least 5% frequency in the
population) and have a low effect size; the conferred relative risks, as expressed by odds
ratio, usually range between 1.1 and 1.5. These results confirm the views that the genetic
predisposition to common diseases consists of the combined effect of numerous common
genetic variants, each of a small effect size. However, it should be noted that GWAS identify
regions of the genome (loci) rather than variants of specific genes. Indeed, the specific
variant(s) identified by GWAS may simply represent the signal of one or more hidden
variant(s) (not typed in the arrays used in GWAS). Limitations of GWAS need to be
mentioned. First, these studies need very large samples of cases and controls. Second, DNA
and data quality control procedures and statistical analysis need to be carried out by expert
centers. Third, the overall cost of GWAS, ranging from hundreds of thousands to millions of
US dollars, is prohibitive for most research groups worldwide. And finally, even after and in
spite of all quality control procedures, there is still the chance that the results of GWAS
include false-positive results, so that an independent replication of these results is still
important even after testing thousands of individuals (Pier et al., 2010)
der Meer et al., (Van der Meer et al., 2004) found a clear association of G allele of the -1793
C/G polymorphism in the VWF gene with an increased risk of Coronary heart disease.
ChREBP gene or hepatocytes treated with siRNA to reduce ChREBP expression cannot
induce lipogenic gene expression in response to carbohydrate (Iizuka et al., 2004; Dentin et
al., 2004). In hepatocytes prepared from ChREBP null mice, the induction can be restored by
the addition of a ChREBP expression vector (Ishii et al., 2004). Thus, ChREBP is essential for
regulating lipogenic gene expression. However, it has previously reported that ChREBP
requires an interaction partner, Mlx, to efficiently bind to ChoRE sequences and exert its
functional activity (Stoeckman et al., 2004). Mlx is a basic helix-loop helix/leucine zipper
protein that heterodimerizes with several partners, including ChREBP; MondoA, a paralog
of ChREBP expressed predominantly in skeletal muscle; and the repressors Mad1, Mad4,
and Mnt (Billin et al., 2000; Billin et al., 1999; Meroni et al., 2000). Expressing a dominant
negative form of Mlx in hepatocytes completely inhibits the glucose response of a number of
lipogenic enzyme genes, including PK, S14, ACC, and FAS (Ma et al., 2005). This inhibition
is rescued by overexpressing ChREBP but not MondoA. Therefore, Mlx is an obligatory
partner of ChREBP in regulating glucose-responsive lipogenic enzyme genes.
Recently, SNPs localized within the MLXIPL (MLX intracting protein like; ChREBP,
carbohydrate response element binding protein) loci have been associated with plasma
triglycerides (Kooner et al., 2008; Kathiresan et al., 2008). The most significant association
was described for the rs3812316 SNP (C771G, His241Gln); the CC genotype was associated
with elevated TGs. The identified SNP is located at evolutionary conserved domain
responsible for glucose dependent activation of MLXIPL. After activation and binding to the
MLX, the complex increases the transcription of genes involved, among others, in
lipogenesis and triglyceride synthesis. Since, elevated plasma triglycerides (TG) are an
independent risk factor for cardiovascular disease development (Sarwar et al., 2007) and
MLXIPL loci have been associated with plasma triglycerides, this gene might be a novel
genetic risk factor for coronary artery disease ( Pan et al., 2009)
4.2 Resistin
Resistin is a 10 kDa protein composed of 94 amino acids. It was cloned in 2001 and was
shown to be a thiazolidinedione (TZD)-regulated cytokine expressed in adipose tissue (Wolf
et al., 2004). The effect of resistin on insulin action has been extensively investigated in
laboratory models. It was shown to be involved in hepatic glucose and lipid metabolism and
appears to play a pivotal role in hepatic insulin resistance (IR) induced by high-fat diet
(Rajala et al., 2003). Resistin was suggested to affect endothelial function and the migration
of vascular smooth muscle cells (Cohen & Horel., 2009), which are regarded as key
pathophysiological mechanisms of atherosclerosis. Further, resistin has been noted to play a
vital role in increasing the level of very low density lipoprotein (VLDL) and low density
lipoprotein (LDL) in an obese person (Rizkalla et al., 2009) which is directly atherogenic.
Resistin induces increases in MCP-1 and sVCAM-1 expression in vascular endothelial cells
which suggest a possible mechanism that contribute to atherogenesis (Cohen & Horel.,
2009). Recent reports indicate that resistin promotes proliferation of VSMC that occurs
through both ERK 1/2 and Akt signalling pathways (Calabro et al., 2004). Thus resistin is
noted to enhance VSMC migration, which is a known component of athermanous plaque
synthesis (Verma et al., 2003). Resistin promotes foam cell formation via dysregulation of
scavenger receptors (SR-A) and ATP-binding cassette transporter-A1 (ABCA1) (Lee et al.,
2009) through PPAR gamma. In atherosclerosis, increased level of resistin causes elevation
of soluble TNF-_ receptor 2, IL-6 and lipoprotein-associated phospholipase A2 (Lp- PLA2)
(Reilly et al., 2005).
Mechanisms of Disease: Novel Polymorphisms in Coronary Artery Disease 7
With respect to the reported resistin variants, the mostly extensively studied has been the
promoter variant SNP-420C>G. Functional binding studies have been done with stimulatory
proteins (Sp)-1 and 3, which bind to the promoter. Their binding has been described to be
influenced by SNP-420C>G. Sp-1 and 3 were discovered to bind efficiently only to the G-
allele sequence and after binding to increase the activity of the promoter. (Chung et al.,
2005). It seems likely that the more active promoter with the SNP-420C>G G allele is the
reason for several observations of higher plasma resistin concentration in the G allele
carriers (Yamauchi et al., 2008). However, in contrast to these studies, it has also been
reported that the genotypes of SNP-420C>G do not influence the plasma resistin
concentration in Italian subjects (Norata et al., 2007). Furthermore in a small study of
polycystic ovary syndrome patients noassociation was detected between SNP-420C>G
genotype and the serum level of resistin (Escobar-Morreale et al., 2006).
Recent studies have shown that the resistin levels are significantly correlated with coronary
artery calcification and are predictive of coronary atherosclerosis in humans (Mohty et al.,
2009). Previous studies described the association among this -420 (C>G) polymorphism, the
resistin levels and cardiovascular risk factors (Ukkola et al., 2006; Norata et al., 2007)
However, the association between the serum resistin levels and CHD seemed to be negative,
and might be controversial for this polymorphism and CAD. (Norata et al., 2007; Kunnari et
al. 2005) Differences in the cohorts might explain the different results, depending on which
ethnic group was tested (Menzaghi et al., 2006; Hivert et al., 2009). Indeed, methodological
limitations in the commercially available ELISA assays might also result in variations among
serum levels, which might cause difficulties when comparing results from different
publications.
4.3 Renalase
The kidney, in addition to maintaining fluid and electrolyte homeostasis, performs essential
endocrine functions (Peart et al., 1977). Patients with end-stage renal disease are at high risk
for cardiovascular events, even when provided optimal renal replacement therapy (Go et al.,
2004; Anavekar et al., 2004). It has been suggested that failure to replicate the endocrine
functions of the kidney may contribute to this risk, in association with heightened
sympathetic tone (Joles & Koomans 2004; Neumann et al., 2004; Wolfe et al., 1999). Renalase,
a flavin adenine dinucleotide-dependent amine oxidase that is secreted into the blood by the
kidney, metabolizes circulating catecholamines, and is deficient in chronic kidney disease
(Xu et al., 2005). Excess catecholamines promote the activity, secretion, and synthesis of
renalase, providing a novel pathway of negative feedback homeostatic control (Li et al.,
2008). In rodents, parenteral administration of renalase lowers blood pressure, heart rate,
and cardiac contractility (Xu J, Desir GV 2007). During cardiac ischemia in rats, infusion of
recombinant renalase reduces myocardial infarct size whereas neonatal nephrectomy leads
to elevated sympathetic nervous system activity, renalase deficiency, and cardiac
hypertrophy (Desir 2008; Ghosh et al., 2008). Human renalase is encoded by a 311Kbp gene
with 10 exons located on chromosome 10q23.33. The major isoform of renalase contains 342
amino acids comprising a signal peptide (amino acids 1–17), a flavin-adenine dinucleotide
(FAD) binding domain (amino acids 4–45), and a monoamine oxidase domain (amino acids
75–342). Evidence exists for at least four alternatively- spliced isoforms of renalase (Desir,
2009). The most common isoform (renalase1) is encoded by exons 1–4, 6–7, and 9. It is the
predominant human renalase protein detectable in plasma, kidney, heart, skeletal muscle,
8 Advances in the Diagnosis of Coronary Atherosclerosis
and liver. The functional significance of the spliced isoforms is not known. It has weak AA
similarities to MAO-A and MAO-B and distinct substrate specificity and inhibitor profile,
which indicates that it represents a new class of FAD-containing monoamine oxidases.
MAO-A and MAO-B are FAD containing, mitochondrial enzymes that metabolize
intracellular catecholamines. MAO-A and MAO-B have overlapping substrate specificity;
catabolize neurotransmitters such as epinephrine, norepinephrine, serotonin, and
dopamine; and are specifically inhibited by clorgyline and deprenyl, respectively.
Polyamine oxidase, the other known FAD-containing oxidase, is an intracellular oxidase
that metabolizes spermine and spermidine and regulates cell growth (Jalkanen & Salmi,
2001). Unlike MAO-A and MAO-B, which are anchored through the carboxyl terminus to
the outer mitochondrial membrane (Binda et al., 2002) and confined to intracellular
compartments, renalase is secreted into the blood, where it is detectable by Western blotting.
Amine oxidase activity has been measured in human plasma and is believed to be mediated
by vascular adhesion protein 1 (VAP-1), a copper-containing semicarbazide-sensitive amine
oxidase that is secreted by smooth muscle cells, adipocytes, and endothelial cells (Salmi &
Jalkanen, 2001). VAP-1’s substrate specificity and inhibitor profile are very different from
that of renalase. It metabolizes benzylamine and methylamine and is inhibited by
semicarbazide and hydroxylamine. Therefore, renalase is the only known amine oxidase
that is secreted into blood and that metabolizes circulating catecholamines. While the
hypotensive effect of renalase can be fully accounted for by the observed decrease in
contractility and heart rate, we cannot categorically exclude the possibility that renalase’s
effect may be partly receptor mediated.
A common missense polymorphism in the flavin-adenine dinucleotide-binding domain of
human renalase (Glu37Asp) has recently been described. This is the only reported common
coding single-nucleotide polymorphism in the renalase gene, and was recently found to be
associated with essential hypertension (Zhao et al., 2007). Whether common genetic
variation at this locus affects cardiac structure, function, and ischemia in humans is not
known.
4.4 P-selectin
P-selectin (GMP-140; granule membrane protein-140) is an adhesion molecule which
mediates the interaction of activated endothelial cells or platelets with leukocytes. The
selectin family of adhesion molecules also comprises E- and L-selectin. The genes coding for
the three selectins are clustered on chromosome 1q21–q24 (Watson et al., 1990). The P-
selectin gene spans >50 kb and contains 17 exons, most of which encode structurally distinct
domains. P-selectin is stored in a-granules of platelets and the Weibel–Palade bodies of
vascular endothelial cells (McEver et al., 1989) it rapidly shifts from the membranes of
secretory granules to the surface of platelets and endothelial cells upon stimulation by
oxidized low density lipoprotein (LDL) (Vora et al., 1997), oxygen radicals (Patel et al.,
1991), thrombin (Lorant et al., 1991), cytokines and various other stimuli (Zimmermann, et
al., 1990). P-selectin is required for efficient recruitment of neutrophils in acute and chronic
inflammation (Johnson, R.C., et al. 1995) and recently has been shown to bind T cells on
vascular endothelial cells. These properties suggest that P-selectin could contribute to
atherogenesis (Hansson, G.K. , 1989, Libby, P. and Hansson, G.K.,1991). Actually, P-selectin
expression has been demonstrated to be significantly increased in endothelium overlying
atherosclerotic plaques, and it is focally expressed in the aorta of hypercholesterolemic
Mechanisms of Disease: Novel Polymorphisms in Coronary Artery Disease 9
rabbits. It has been reported that P-selectin-deficient mice on an atherogenic diet develop
significantly smaller fatty streaks than non-deficient mice (Johnson, R.C., et al. 1997). In
humans, plasma P selectin levels have been shown to be increased in diabetic patients, in
patients with unstable angina, post-angioplasty restenosis and after coronary artery spasm
(Kaikita, K. , 1995).
Recent study that genotyped 5 single nucleotide polymorphisms (SNPs) in P-selectin (SELP)
(V168M, S290N, N592D, V599L, T715P), 2 SNPs (M62I, S273F) in P-selectin glycoprotein
ligand-1 (SELPLG), 5 SNPs in CD40LG (−3459A>G, −122A>C, −123A>C, 148T>C, intr4–
13T>C), the H558R SNP in SCN5A, and rs2106261 in ZFHX3. In addition, length
polymorphisms in SELPLG (36bp-tandem repeat) and CD40LG (CA-repeat) were genotyped
by PCR methods. None of the gene polymorphisms showed significant differences between
AMI patients and healthy controls. Among patients with a history of VF (Ventricular
fibrillation), however, the SELP 168M variant showed a significantly higher prevalence as
compared with patients without VF. This was the first description of an association of the
SELP gene variant 168M with primary VF during acute MI. This variant may be a novel
polymorphism for evaluating the susceptibility for VF in the setting of acute MI. (Elmas, 2010)
4.5 KDR
Kinase insert domain-containing receptor/fetal liver kinase-1, also called VEGFR2 (KDR), is
expressed in a wide variety of cells such as endothelial progenitor cells (EPCs), endothelial
cells, and primitive and more mature hematopoietic cells. Kinase insert domain-containing
receptor/ fetal liver kinase-1 is required for the differentiation of EPCs and for the
movement of EPCs from the posterior primitive streak to the yolk sac, a precondition for the
subsequent formation of blood vessels (Shalaby et al., 1997). Studies with KDR knockout
mice have found that KDR plays critical roles in the development and formation of blood
vessel networks (Fong et al., 1995). Vascular endothelial growth factor binds to 2 tyrosine
kinase receptors, VEGF receptor-1 (VEGFR1, Flt-1) and KDR, in endothelial cells. The
mitogenic and chemotactic effects of VEGF are mediated mainly through KDR in
endothelial cells VEGF receptor signal transduction which is activated through
autophosphorylation of tyrosine residues in the cytoplasmic kinase domain of KDR. This
event is followed by activation of downstream signaling pathways such as mitogen-
activated protein kinases, Akt and eNOS, which are essential for migration and proliferation
of endothelial cells, thereby stimulating angiogenesis (Matsumoto & Claesson-Welsh, 2001).
After vascular endothelial growth factor (VEGF) binding to KDR, multiple early signaling
cascades are activated in EPCs and in endothelial cells. An array of biological activities are
subsequently elicited in vivo and in vitro, including angiogenesis, endothelial survival,
proliferation, migration, and increased production of nitric oxide and prostaglandin I2
(Gerber et al., 1994). Dysregulated vessel growth is implicated in the pathogenesis of a wide
variety of diseases, including proliferative retinopathies, tumors, rheumatoid arthritis,
atherosclerosis, as well as CHD. (Dimmeler et al., 2001; Rehman et al., 2004; Werner et al.,
2002). The variation of KDR gene may change the biological function of KDR. Bioinformatic
analysis showed that the single nucleotide polymorphism (SNP) -604T/C (rs2071559) leads
to structural alteration of the binding site for transcriptional factor E2F (involving in cell
cycle regulation, interacting with Rb p107 protein) in KDR gene promoter region, which
may alter KDR expression. Exonic polymorphisms SNP1192G/A (rs2305948, in exon 7) and
SNP1719A/T (rs1870377, in exon 11) are located in the third and fifth NH2-terminal IG-like
10 Advances in the Diagnosis of Coronary Atherosclerosis
domains within the extracellular region, which are important for ligand binding, and result
in nonsynonymous amino acid changes at residue 297V/I and 472H/Q, respectively. It is
showed that patients carrying the KDR mutations are more susceptible to CHD. The higher
CHD risk could be due to downregulation of the VEGF/KDR signaling pathway. However,
the angiogenesis preceded by VEGF/KDR signaling pathway could be decreased due to low
KDR activity. The SNP-604T/C decreases mRNA levels of KDR and both SNP1192G/A and
SNP1719T/A resulted in slight but significant decrease in the VEGF binding efficiency to
KDR. One can speculate that the decrease in KDR function is correlated with vascular
dysfunction, including endothelial cell damage, impaired endothelial cell survival,
decreased antiapoptotic effects of VEGF, and abnormal vascular repair. All of these can
promote the progression of atherosclerotic disease. A previous study has suggested that -
907T/C, -11903G/A, and -18487A/T (now called SNP-604, SNP1192, and SNP1719,
respectively) have no significant association with the development of coronary artery lesion
in Japanese subjects with Kawasaki disease (Kariyazono et al., 2004). The differences
between the studies could be due to the different pathologic mechanism between the
coronary artery lesion with Kawasaki disease and CHD, different genetic background of the
populations as well as the sample size in different studies. (Schmidt-Lucke et al., 2005). The
genotype frequencies of the 3 SNPs from the HapMap data were similar to others. The
rs2071559 can capture rs7667298 (exon_1, untranslated). No linkage disequilibrium was
found in rs2305948 with other SNPs in HapMap CHB data. The rs1870377 (exon_11) can
capture rs10016064 (intron_13), rs17085265 (intron_21), rs3816584 (intron_16), rs6838752
(intron_17), rs1870379 (intron_15), rs2219471 (intron_20), rs1870378 (intron_15), rs13136007
(intron_13), and rs17085262 (intron_21). The results showed that 2 blocks were captured by
SNP-604 (rs2071559) and SNP1719 (rs1870377), respectively, and SNP1192 (rs2305948) were
associated with CHD.
6. Conclusion
Studying only one SNP may be an overly simplistic method in investigating a complex
disease such as CAD. Complex traits such as CAD, more large databases of high-quality
Mechanisms of Disease: Novel Polymorphisms in Coronary Artery Disease 11
genetic and clinical data need to be established and since genes and environmental factors
are both involved in this disease; environmental causes and gene-environment interactions
must be carefully assessed. These results will provide clues to the involvement and
investigation of novel candidate genes in association studies. Large replication studies with
different ethic samples are needed to investigate whether there are ethnic differences in the
influence of novel polymorphisms on coronary artery disease. This issue should be
investigated with different ethnic samples in the future. Therefore studies with large sample
size of coronary artery disease and different ethnicity will be welcome to help elucidate the
interconnection between novel genetics and pathogenesis of coronary artery disease.
7. Abbreviations
ABCA1: ATP-binding cassette transporter 1
ACC: acetyl-CoA carboxylase
ALOX5AP: Arachidonate 5-lipoxygenase-activating protein.
APOA1: Apolipoprotein A1
CAD: Coronary artery disease
LCAT: Lecithin-cholesterol acyltransferase
CHD: Coronary heart disease
ChoRE: Carbohydrate response element
ChREBP: Carbohydrate response element binding protein
ELISA: Enzyme-linked immunosorbent assay
EPCs: Endothelial progenitor cells
ERK 1/2 : Extracellular signal-regulated kinases1/2
FAD: Flavin-adenine dinucleotide
FAS: Fatty acid synthase
GWAS: Genome-wide association Studies
HDL: High-density lipoprotein
KDR: Kinase insert domain-containing receptor
Lp- PLA2: Lipoprotein-associated phospholipase A2
Mad1: Mitotic arrest deficient-like 1
Mad4: Mitotic arrest deficient-like 4
MAO-A: L-Monoamine oxidases A
MAO-B : L-Monoamine oxidases B
MEF2A: Myocyte enhancer factor 2A
MlX: Max-like x protein
PPAR: Peroxisome proliferator-activated receptors
PK : Pyruvate kinase
siRNA: Small interfering RNA
SNPs: Single nucleotide polymorphisms
Sp1: stimulatory proteins 1
SR-A: Scavenger receptors A
TNF: Tumor necrosis factors
VAP-1: vascular adhesion protein 1
VCAM-1: Vascular cell adhesion protein 1
VF: Ventricular fibrillation
VLDL: Very low density lipoprotein
VWF: Von Willebrand factor
12 Advances in the Diagnosis of Coronary Atherosclerosis
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18 Advances in the Diagnosis of Coronary Atherosclerosis
1. Introduction
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) belongs to the TNF
ligand superfamily. As the name suggests, TRAIL was identified and cloned based on its
sequence homology to the extracellular domain of TNF ligand family members (Pitti et al.,
1996; Wiley et al., 1995). Human TRAIL consists of 281 amino acids. TRAIL is a type II
transmembrane protein with a short intracellular amino-terminal domain and an extracellular
carboxy-terminal domain (Fig. 1). TRAIL is cleaved by cysteine proteases from the cell surface
to form a soluble ligand, and when released soluble TRAIL is measurable in human blood.
TRAIL contains cysteine residue (Cys 230) that interacts with the zinc ion, resulting in the
formation of a TRAIL homotrimer (Hymowitz et al., 1999) (Fig. 1). This trimerization is
necessary for TRAIL to bind to its receptors and to exert optimal biological activity, as is
described below. (Hao et al., 2004; Johnstone et al., 2008; Wang, 2008; Wu et al., 2004).
TRAIL binds to five different receptors found on a variety of cells. Of these receptors, two,
TRAIL-R1 (DR4) and TRAIL-R2 (DR5), contain a cytoplasmic death domain and trigger
TRAIL-induced apoptosis. Two decoy receptors lacking a functional death domain, TRAIL-
R3 (DcR1) and TRAIL-R4 (DcR2), compete with TRAIL-R1 and TRAIL-R2 for TRAIL
binding, possibly antagonizing apoptotic signaling. In addition, osteoprotegerin (OPG) is a
fifth soluble decoy receptor. Briefly, the TRAIL apoptosis pathway is initiated by the
binding of a TRAIL trimer to TRAIL-R1 or TRAIL-R2, which leads to receptor trimerization.
This receptor conformational change recruits the adaptor protein Fas-associated death
domain (FADD) through the death domains (DD) of each protein. Subsequently, FADD
interacts with caspase-8 and/or -10 through the death effector domain (DED) of each
protein, resulting in the assembly of a death-inducing signaling complex (DISC). In the type
I pathway, extrinsic signals proteolytically activate caspase-8 and/or -10 followed by
stimulation of effector caspase-3 and -7, the key mediators of apoptosis, triggering
apoptosis. In the type II intrinsic pathway, however, apoptotic commitment requires an
amplification step involving the mitochondrial pathway triggered by caspase-8-dependent
cleavage of the Bid protein to its active form, t-Bid (Corallini et al., 2006; Hao et al., 2004;
Testa, 2010; Wang, 2008). Since TRAIL-R3, TRAIL-R4, and OPG lack intracellular functional
20 Advances in the Diagnosis of Coronary Atherosclerosis
portions, it is conceivable that they do not mediate apoptosis (Fig. 2.). However, even
binding of TRAIL to death receptors such as TRAIL-R1 or TRAIL-R2 can antagonize
apoptosis and induce cell proliferation under certain conditions in some cells. For example,
TRAIL-R1 and TRAIL-R2 recruit receptor-interacting protein (RIP) through their DD, which
can activate nuclear factor B (NFB). RIP-mediated NFB activation appears to induce cell
proliferation by TRAIL (Hao et al., 2004). TRAIL triggers recruitment of cellular FLICE-like
inhibitory protein (cFLIP) to DISC through their DED in some instances. Some cFLIPs
appear to prevent TRAIL-induced apoptosis (Hao et al., 2004; Wang, 2008). TRAIL
stimulation also recruits phosphoprotein enriched in diabetes (PED) to the DISC. This
process inhibits downstream caspase activation in some cases (Hao et al., 2004) (Fig. 2.).
Therefore, two contradictory steps should be considered when determining the biological
effects of TRAIL besides simple apoptotic signaling. First, TRAIL has death receptors
(TRAIL-R1 and TRAIL-R2) and antagonized decoy receptors (TRAIL-R3, TRAIL-R4, and
OPG) at the cell surface level. Second, these death receptors can counteract apoptotic
signaling at the intracellular level in certain contexts. Thus, TRAIL signaling is very
complicated.
Cysteine proteases
Transmembrane
Domain Receptor Binding Region
1 18 38 114 281
Cys 230
Soluble TRAIL
Zn
Formation of homotrimer
TRAIL consists of 281 amino acids with a transmembrane domain that separates the short intracellular
and extracellular domains. The extracellular domain of TRAIL is cleaved and released into the
bloodstream. TRAIL forms a homotrimer through interactions between zinc ions and each cysteine
residue.
Fig. 1. The Structure of TRAIL.
TRAIL has attracted clinical attention as a promising agent for the treatment of cancer since
it can induce apoptosis in various tumor cells without having any toxic effects on normal
cells (Finnberg and El-Deiry, 2008; Wang, 2008; Wu et al., 2004). Apart from high
expectations in the field of cancer, TRAIL also exhibits diverse biological effects on the
immune system, hematopoiesis, and metabolic disorders, including diabetes (Afford and
Multifunctional Role of TRAIL in Atherosclerosis and Cardiovascular Disease 21
Adams, 2005; Benito-Martin et al., 2009; Corallini et al., 2006; Testa, 2010; Vaccarezza et al.,
2007). Recently, the involvement of TRAIL in atherosclerosis and cardiovascular diseases
has been at the forefront of research efforts (Corallini et al., 2008; Kavurma and Bennett,
2008; Martin-Ventura et al., 2007). In this review, we focus on the role of TRAIL in the
cardiovascular system.
OPG
TRAIL-R1
TRAIL-R2 TRAIL-R3 TRAIL-R4
DD
DD
DD
FADD
DD
DD
RIP
cFLIP
DISC
PED
DED
DED
DED
DED
DED
Mitochondria
Type II
DED
DED
DED
Bid
Caspase-8, 10
Type I
Caspase-3, 7
apoptosis
Among the five known TRAIL receptors, TRAIL-R1 and –R2 can induce intracellular apoptotic signaling.
Upon binding of TRAIL to TRAIL-R1 or –R2, a death-inducing signaling complex (DISC) is formed
through the recruitment of Fas-associated death domain (FADD), and subsequently results in the
activation of caspase-8/10. In the type I intrinsic pathway, this activation is sufficient to conduct apoptosis
through downstream effector caspases. On the other hand, activated Bid by caspase-8 amplifies apoptotic
signaling through the mitochondria, which is a necessary step to induce effective downstream signaling in
the type II extrinsic pathway. In addition to this activation process, it appears that at least a few other
factors, such as receptor-interacting protein (RIP), cellular FLICE-like inhibitory protein (cFLIP), and
phosphoprotein enriched in diabetes (PED), are antagonistic to TRAIL-induced apoptosis.
Fig. 2. TRAIL receptors and downstream apoptotic signaling.
the direct effects of TRAIL on each cellular component in the arterial wall. We will then
discuss how TRAIL can act on the cardiovascular system based on evidence from animal
models. Subsequently, we try to make causal inferences relating to TRAIL’s role in
cardiovascular diseases from cross-sectional and longitudinal clinical studies in humans.
Finally, we report our recent clinical findings and debate whether TRAIL could be a
common biomarker that reflects early to advanced stage atherosclerotic changes.
2.1 Effects of TRAIL on cellular components in the arterial wall (in vitro findings)
Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are the principal cellular
components of the normal arterial wall. Immune-inflammatory infiltrates such as activated
T lymphocytes and macrophages play crucial roles in the onset and development of
atherosclerosis (Libby, 2002; Weyand et al., 2008). This process is triggered and exacerbated
by complicated interactions between modified lipoproteins and various cellular
components. Since TRAIL and its receptors are expressed in both physiological and
pathological arterial walls (Corallini et al., 2008; Kavurma and Bennett, 2008; Martin-
Ventura et al., 2007; Schoppet et al., 2004), it is hypothesized that TRAIL signaling could
regulate vascular wall homeostasis and morbid atherosclerosis. TRAIL is expressed in each
cellular component, both in resident cells (ECs, VSMCs) and in infiltrating cells (T
lymphocytes and macrophages) (Corallini et al., 2008; Kavurma and Bennett, 2008). To
determine the role of TRAIL in atherosclerosis, we must first determine the effects of TRAIL
on each cellular component based on results from in vitro studies.
ECs are located on the intima, which separates the blood stream from the vascular wall. In
addition, these cells have a critical function not only as a simple barrier but also as a
dynamic organ. Thus, ECs can regulate vascular tone, inflammation, thrombosis, and
vascular remodeling. Balanced homeostasis in ECs protects against atherosclerosis while
disruption of endothelial function results in the initiation and development of
atherosclerosis (Sandoo et al., 2010). Human ECs, both human umbilical vein ECs
(HUVECs) and human dermal microvascular ECs (HDMECs), express death receptors,
TRAIL-R1 and TRAIL-R2. As expected, TRAIL could induce apoptosis in ECs, although this
phenomenon was not observed in every cell (Li et al., 2003). This study also found that
apoptosis in ECs could be reduced by treatment with caspase inhibitors and by transfection
of dominant-negative FADD, suggesting the involvement of a FADD-caspase 8 pathway in
this apoptotic process (Li et al., 2003). Subsequently, Secchiero et al. showed that both
HUVECs and primary human aortic ECs express death TRAIL-R1, -R2 and decoy TRAIL-R3,
-R4. As predicted, the removal of serum and endothelial cell growth factor (tropic
withdrawal) from the cell culture system led to apoptosis. Surprisingly, TRAIL protected
HUVECs from tropic withdrawal-induced apoptosis. Activation of phosphatidylinositol 3-
kinase (PI3K)/Akt pathway by TRAIL appears to be involved in this anti-apoptotic action.
In addition to this unexpected anti-apoptotic property, TRAIL stimulated proliferation of
ECs in an ERK 1/2 dependent manner in this cell system (Secchiero et al., 2003). It has also
been reported that TRAIL alone can increase HUVEC cell proliferation (Alladina et al.,
2005). As reported above (Secchiero et al., 2003), inhibition of the PI3K/Akt pathway
sensitizes EC cells to TRAIL-induced apoptosis (Alladina et al., 2005). More detailed
investigations have found that inhibition of PI3K/Akt leads to activation of both extrinsic
and intrinsic apoptotic pathways and appears to sensitize HUVECs to TRAIL-induced
apoptosis by concurrent down-regulation of anti-apoptotic cFLIPs and Bcl-2 (Alladina et al.,
Multifunctional Role of TRAIL in Atherosclerosis and Cardiovascular Disease 23
2005). Taken together, these results suggest that the effects of TRAIL on ECs appear to
depend on cell culture conditions. Aside from cell apoptosis/proliferation, ECs have a
protective role against atherosclerosis by producing nitric oxide (NO), one of the most
important vasoactive factors. NO, a potent vasodilator, has antithrombotic and anti-
inflammatory activity (Sandoo et al., 2010). Interestingly, TRAIL stimulates NO production
through activation of endothelial NO synthase (eNOS) in HUVECs (Zauli et al., 2003). In
particular, eNOS trafficking appears to be involved in TRAIL-induced eNOS activation.
TRAIL can translocate eNOS from the cell membrane to the cytoplasm in HUVECs (Di
Pietro et al., 2006). However, microtubule disruption with nocodazole inhibits the eNOS
activity induced by TRAIL, suggesting that translocation of eNOS through cytoskeletal
reorganization may be necessary for TRAIL-induced NO production (Di Pietro et al., 2006).
NO synthesis with cytoskeletal alteration by TRAIL is possibly linked to the migration of
HUVECs stimulated by TRAIL treatment (Zauli et al., 2003).
In terms of atherosclerosis, attachment of blood leukocytes to ECs is recognized as the first
step in the initiation of this phenomenon (Libby, 2002). It is probable that TRAIL regulates
this process as well. An adhesion assay using co-cultured HUVECs and HL-60 leukocytes
showed that TRAIL increased the binding of leukocytes to ECs (Li et al., 2003). A later report
reproduced the pro-adhesive activity of TRAIL, although its effect was much less than that
of pro-inflammatory cytokines such as TNF and interleukin-1 (Secchiero et al., 2005).
When TRAIL and pro-inflammatory cytokines were evaluated at the same time, TRAIL pre-
treatment showed reverse inhibition of TNF and IL 1 induced HL-60 leukocyte
adhesion to HUVECs. This inhibitory effect of TRAIL on cell attachment was mediated by
down-regulation of the inflammatory chemokines CCL8 and CXCL10, which were
stimulated by TNF (Secchiero et al., 2005). In particular, TRAIL-R1 and TRAIL-R2
contributed to the TRAIL-induced down-regulation of chemokine release (Secchiero et al.,
2005). Again, TRAIL has multiple context-dependent effects. At any rate, TRAIL may play
an important role in EC function, both physiologically and pathologically.
Another physiological cellular component is the VSMCs, which are mainly localized in the
media and constitute the vascular structure. Once VSMCs are transformed, however, they
proliferate and migrate, contributing to the development of atherosclerosis (Ross, 1993). In
advanced atheromatous plaques, apoptosis of VSMCs in the fibrous cap may be involved in
plaque rupture. The former transformation exacerbates atherosclerosis (Libby, 2002),
whereas the latter leads to poorer outcome (Clarke et al., 2006). TRAIL participates in the
apoptosis and proliferation of VSMCs as well as ECs. For example, plaque-derived CD4 T
cells expressing TRAIL induce apoptosis of VSMCs, probably through the interaction of
TRAIL with TRAIL-R2 (Sato et al., 2006). On the other hand, TRAIL has been reported to act
on human and rat VSMCs as an anti-apoptotic factor through TRAIL-R1 and –R2 (Secchiero
et al., 2004). TRAIL promotes proliferation and migration of VSMCs through activation of
ERK (Secchiero et al., 2004). Furthermore, Kavurma et al. reported that TRAIL stimulated
proliferation of human VSMCs, although it induced apoptosis at high concentrations
(Kavurma et al., 2008). Interestingly, they showed the importance of insulin-like growth
factor-1 (IGF-1), one of the most potent growth factors, in TRAIL-induced proliferation of
VSMCs. Thus, TRAIL up-regulates expression of the IGF-1 receptor in an NFB-dependent
manner (Kavurma et al., 2008). It is thus too soon to decide whether TRAIL causes apoptosis
or proliferation in VSMCs, even in vitro.
In addition to the seemingly contradictory findings in ECs and VSMCs, a few reports have
suggested that TRAIL has a pro-apoptotic effect on inflammatory lymphocytes (Janssen et
24 Advances in the Diagnosis of Coronary Atherosclerosis
al., 2005) and macrophages (Kaplan et al., 2000). In either case, TRAIL appears to have
multiple functions in both physiological and pathological cells under various conditions. As
described previously, the existence of five different types of TRAIL receptors and the cross-
talk among multiple post-receptor signaling pathways may explain these diverse effects. On
the basis of in vitro findings, it is very difficult to speculate the impact of TRAIL on
atherosclerotic lesions in vivo, although the in vitro findings clearly indicate the involvement
of the TRAIL/TRAIL receptor system in atherogenesis. In the next section, we try
summarizing and discussing whether TRAIL protects against or exacerbates atherosclerosis
in ways aside from its function as a mere pro-apoptotic factor.
2.2 Role of TRAIL in atherosclerosis and vascular injury (in vivo findings)
With regard to the role of TRAIL in the vascular wall, Secchiero et al. first demonstrated
compelling in vivo findings using diabetic apolipoprotein E (apoE)-null mice that mimic the
atherosclerotic lesions observed in humans (Secchiero et al., 2006). That is, intraperitoneal
administration of recombinant human TRAIL into these mice resulted in a transient high
concentration of TRAIL and subsequent protection against the development of
atherosclerosis (Secchiero et al., 2006). Secchiero et al. carefully investigated the effects of
TRAIL on in vivo atherosclerotic lesions using an adeno-associated virus containing TRAIL
to ensure a low but sustained expression of TRAIL, similar to physiological conditions.
TRAIL again attenuated the development of atherosclerotic plaques, even under these
conditions (Secchiero et al., 2006). One of the mechanisms responsible for this effect may be
selective apoptosis of infiltrating macrophages in plaque lesions. At the same time,
increased VSMC levels were also observed in the fibrous caps of the atherosclerotic lesions.
This increase may contribute to stabilization of the atherosclerotic plaques (Secchiero et al.,
2006). Therefore, TRAIL appears to act as a protective factor against atherosclerosis in vivo.
Subsequently, Kavurma’s group showed the direct effects of TRAIL on VSMCs in vivo. They
have already reported that TRAIL stimulates VSMC proliferation in vitro (Kavurma et al.,
2008). To prove this using an in vivo model, they used a cuff-induced vascular injury method
in TRAIL-null mice. In wild-type mice, this procedure can induce VSMC proliferation and
intimal thickening in response to vascular injury. However, TRAIL-null mice were protected
from neointimal formation and displayed reduced VSMC proliferation, suggesting a
significant role for TRAIL in VSMC proliferation in vivo (Chan et al., 2010). Although this
report showed the direct effects of TRAIL on VSMCs, the lack of atherogenic factors
involved in the formation of vascular lesions should be studied further. Very recently, it has
been reported that TRAIL attenuates the development of atherosclerosis using TRAIL
(TRAIL −/−)/apoE (apoE −/−) double-knockout mice (Watt et al., 2011). TRAIL −/− apoE
−/− mice had significantly larger atheromatous lesions compared with apoE −/− control
mice at 8 weeks. The larger lesions in TRAIL −/− apoE −/− mice appeared to be due to an
increase in the number of lesional VSMCs, suggesting the anti-atherogenic action of TRAIL.
Intriguingly, the difference in atheromatous lesion size among these mice became smaller at
12 weeks. In contrast to Secchiero’s findings, the lack of TRAIL had no effect on the
macrophage content in the atheromatous lesions. There are still unsolved and controversial
issues with regard to the precise mechanisms by which TRAIL acts on the arterial wall.
However, TRAIL at least appears to protect against atherogenic lesions as a whole in vivo.
first study demonstrated that serum TRAIL levels were significantly lower in patients with
acute coronary syndrome (ACS) compared with those with stable angina and normal
coronary arteries (Michowitz et al., 2005). Subsequently, Schoppet et al. found a tendency
for serum TRAIL levels to be lower in patients with coronary artery disease (CAD)
compared with subjects without CAD, although this difference was not significant. To
further investigate this relationship, we examined serum TRAIL levels in 285 subjects who
underwent coronary angiography for suspected CAD. Interestingly, we found that serum
TRAIL levels were inversely associated with the severity of CAD (Mori et al., 2010). In
particular, TRAIL levels in patients with severe three-vessel disease (VD) were significantly
lower than in those without CAD (Mori et al., 2010). Moreover, TRAIL was an independent
and negative contributor for the presence of CAD (Mori et al., 2010). Taken together, these
results suggest that lower TRAIL levels may reflect the advancement of CAD.
In addition to cross-sectional findings, recent studies have also suggested that TRAIL can be
a protective predictor against cardiovascular prognosis. As previously reported (Michowitz
et al., 2005), Secchiero et al. showed that serum TRAIL levels were significantly lower in
patients with acute myocardial infarction (AMI) at baseline (within 24 hours from
admission) compared with healthy subjects (Secchiero et al., 2009). Interestingly, serum
TRAIL levels at baseline were significantly lower in patients with in-hospital adverse events
compared with those who did not experience these events (Secchiero et al., 2009).
Subsequently, they observed that serum TRAIL levels in AMI patients gradually recovered
at discharge. Furthermore, low TRAIL levels at discharge were associated with an increased
incidence of cardiac death and heart failure in the 12-month follow-up (Secchiero et al.,
2009). The prognostic value of TRAIL was also examined in 351 patients with advanced
heart failure (HF). Again, low serum TRAIL levels were related to a worse prognosis. The
risk of mortality dropped by 70% in the highest quartile of TRAIL levels, suggesting that
TRAIL is a strong inverse predictor of mortality in patients with advanced HF (Niessner et
al., 2009). In addition, the role of TRAIL as a more general predictor of mortality and not
limited to patients with AMI or advanced HF was investigated by a large prospective
population-based study of older people (Volpato et al., 2011). Baseline TRAIL levels were
inversely related to all-cause mortality over a period of six years (Volpato et al., 2011). As
expected, more detailed analyses revealed that the prognostic effect of TRAIL levels was
strong and highly significant in subjects with prevalent cardiovascular diseases (Volpato et
al., 2011). These findings expand on the predictive ability of TRAIL at a population level
with a longer follow-up period. Moreover, Secchiero et al. focused not only on TRAIL but
also on OPG. As was described earlier, OPG is a soluble neutralizing receptor for TRAIL. In
contrast to TRAIL, it is known that serum OPG levels are positively associated with the
presence and severity of CAD and are inversely correlated with prognosis (Abedin et al.,
2007; Jono et al., 2002; Kiechl et al., 2004; Omland et al., 2008; Rhee et al., 2005; Schoppet et
al., 2003). In this context, both TRAIL and OPG were evaluated at the same time. The
researchers found that the OPG/TRAIL ratio was significantly higher in patients with acute
AMI who developed HF during the follow-up period (Secchiero et al., 2010). The increase in
OPG, which is a decoy TRAIL receptor, may act against TRAIL and thus negate its
protective effects on the cardiovascular system. Thus, an unbalanced OPG/TRAIL ratio may
be a more accurate predictor of prognosis after AMI.
Fig. 3. The association of TRAIL with endothelial function in 109 healthy subjects.
Flow-mediated dilatation (FMD) was used to evaluate endothelial function in 109 healthy
subjects. There was no correlation between serum TRAIL levels and FMD (ρ = −0.128, p = 0.148).
28 Advances in the Diagnosis of Coronary Atherosclerosis
3. Conclusions
Recent emerging evidence has suggested the definite involvement of TRAIL in
cardiovascular diseases. Taken together, these results have shown that lower serum TRAIL
levels appear to be associated with worse prognosis in patients with CAD and HF. One of
most important question is why TRAIL levels are lower in such conditions. It is necessary to
investigate how TRAIL is produced and cleared in humans in future studies. In addition, to
confirm the direct effects of TRAIL on cardiovascular diseases, administration of
recombinant TRAIL may be a powerful approach. In fact, recombinant TRAIL induces
apoptosis in a wide variety of tumor cells and prevents tumor progression and metastasis in
the field of cancer therapy (Johnstone et al., 2008; Wang, 2008; Wu et al., 2004). Further
studies are needed to address these problems.
4. Acknowledgment
This review was supported in part by a Grant-in-Aid for scientific research (No. 20591068)
from the Japan Society for the Promotion of Science (to ME and KM). The authors thank Dr.
Naoya Kawano, Dr. Hidenori Koyama, Ms. Yuko Kikukawa, Ms. Hisako Fujii, Dr. Sanae
Fukuda, Mr. Hidekichi Tokai, Dr. Yoshinobu Hirayama, and Dr. Yasuyoshi Watanabe for
their help with the study to investigate the association between TRAIL levels and FMD in
healthy subjects (Fig. 3).
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3
1. Introduction
Since the first serendipitous selective coronary angiography was performed by pediatric
cardiologist Dr. Mason Sones in 1958 during ventriculography and aortography (Sones et
al., 1959), invasive coronary angiography has become well established as the diagnostic gold
standard for coronary artery disease.
Coronary angiography provides definitive information of “luminology” (radiographic
outline using a contrast agent) of the coronary arteries. It is the standard with which other
diagnostic modalities are compared. Millions are performed annually worldwide. Whilst the
risk of coronary angiography of complications is very low in experienced hands the
procedure is invasive and, requires dedicated infrastructure and expense. There are certain
specific indications for coronary angiography. The general indication for a coronary
angiography is to define the coronary artery anatomy. More detailed guidelines for
coronary angiography date back to 1999 from the American College of Cardiology (Scanlon
et al., 1999). This of course predated the enormous technological advancement over the past
decade, the development in computed tomography coronary angiography, the widespread
adoption of coronary stenting, the improvement afforded by drug eluting stents, and the
availability of new antiplatelet therapy that enhanced the safety of all coronary
interventions.
This chapter examines the appropriate indications for invasive coronary angiography in the
current era, assesses the role of non invasive CT coronary angiography, and incorporates the
emerging adjunctive role in the management of patients undergoing percutaneous cardiac
structural interventions. Case vignettes are included in this chapter to illustrate the
indications and use of coronary angiography in the current era.
It must be stressed whilst guidelines do provide recommendations regarding the indications
for invasive coronary angiography, many more complex clinical and non clinical factors
exist for each individual patient and the clinician must exercise clinical acumen to proceed
to perform an invasive diagnostic and/or therapeutic procedure.
epicardial arteries, with a spatial resolution that is still superior to other non-invasive
imaging modalities. There are however limitations to coronary angiography. Aside from the
obvious invasive nature and attendant risks, it provides only a projection of the lumen
outlined by contrast and hence no information on the extent of atheroma contained within
the vessel wall or the functional significance of the stenosis which can only be inferred. Both
of these limitations can be overcome by the use of intravascular modalities such as
intravascular ultrasound, optical coherence tomography and fractional flow reserve
assessment. When combined with these adjuncts, coronary angiography serves as a
formidable tool in guiding revascularization strategies, with a body of scientific data that
has been well validated to provide long term prognostic benefit.
The guiding principle in determining the indication behind the decision to undertake
coronary angiography in a given patients is similar to that underpinning the decision to
undertake any invasive investigations in medicine. The decision to proceed is based on that
the knowledge gained from the investigation outweighs the perceived risk, that the result
will benefit the patient, in that it will likely change management and the available treatment
option will improve symptoms and/or prognosis. The risks and complications of coronary
angiography are covered elsewhere in this book and this chapter will focus on the
indications of coronary angiography. Relative and absolute contraindications are also
covered briefly.
The indications for coronary angiography have been divided into the follow clinical
categories:
1. Coronary artery disease
1. Stable pattern
i. suspected coronary artery disease
ii. known coronary artery disease
2. Unstable pattern
i. Acute coronary syndrome with unstable haemodynamics or rhythm
ii. Unstable angina and Non-ST elevation MI
iii. ST elevation MI
iv. Out of hospital cardiac arrest
3. Special considerations
i. Congestive cardiac failure
ii. Preoperative assessment for non cardiac surgery
iii. The value of non invasive computed tomography coronary angiography
4. Relative and absolute contraindications
2. Prelude to structural cardiac disease/valvular heart disease intervention
3. Case vignettes of the use of coronary angiography in the contemporary era
investigation of congestive cardiac failure, pre-valvular surgery and the emerging role of
computed tomography coronary angiography will be covered too.
3.1.1 Coronary artery disease – stable pattern – suspected coronary artery disease
The assessment of patients with symptoms suggestive of coronary artery disease (CAD)
depends on three key factors: the clinical assessment of the quality of symptoms, the clinical
risk profile, and the presence of existing abnormalities on surface electrocardiogram
suggestive of CAD.
The ACC/AHA guidelines on exercise testing (Gibbons, 2002) provide classification of
symptoms as typical, atypical angina and non-anginal chest pain (table 1). It is well known
symptoms alone have a poor predictive value and differ between males and females
(Hemingway et al, 2006, 2008). Combined with the underlying clinical risk profile however,
a more reliable pre-test probability on CAD can be generated (table 2).
Table 2. Pretest probability of coronary artery disease based on age, sex and symptoms
(adapted from Gibbons et al, 2002)
The resting surface electrocardiogram (ECG) is important in the initial evaluation of the
patient for two reasons. First, it provides a screening tool to assess for remote infarctions
(Ammar et al 2004; Michael et al, 2007), with changes such as pathological Q waves, and other
36 Advances in the Diagnosis of Coronary Atherosclerosis
non-specific ST segment and T wave changes. Second, any such changes may guide the choice
of the appropriate functional study. The presence of a left bundle branch block, for example,
essentially renders exercise stress electrocardiography uninterpretable and confounds
assessment of stress echocardiography or perfusion studies (La Canna et al, 1992).
Non-invasive tests such as exercise or pharmacological stress studies form an important
pathway in the diagnostic algorithm. The value of a functional study cannot be
overemphasized in patients with atypical or noncardiac chest pains. A negative functional
study, such a negative treadmill test to 12 minutes on the Bruce protocol, provides sufficient
prognostic information to negate any further investigations (Myers et al 2002; Marshall et al,
2010). The ischaemic burden as determined from imaging tests also provides pertinent
guidance as to the appropriateness of revascularization. A substudy (Shaw et al 2008) of the
COURAGE trial (Boden et al, 2007), which showed no benefit of PCI over optimized medical
therapy, did show mortality and MI benefit with revascularizing patients with >10%
ischaemic myocardial burden. A well executed functional study may also assist in
localizing the appropriate territory for revascularization, especially in the setting of multi-
vessel intermediate lesions.
Patients with positive stress tests, especially with high risk features (table three), suggestive
of significant ischaemic burden, should proceed to coronary angiography for risk
stratification with a view to possible percutaneous or surgical revascularization. Indeed, of
the indications of coronary angiography outlined in the ACC guideline for stable angina, a
positive stress test with high risk features carries the highest level of evidence (Level A)
compared to all other indications (level B to C).
Noninvasive test results predicting high risk for adverse outcome (> 3% annual mortality rate)
Severe resting left ventricular dysfunction (LVEF <35%)
High-risk treadmill score (score -11)
Severe exercise induced left ventricular dysfunction (exercise LVEF <35%)
Stress-induced large perfusion defect (particularly if anterior)
Stress-induced moderate-size multiple perfusion defects
Large, fixed perfusion defect with left ventricular dilatation or increased lung uptake
Stress-induced moderate-size perfusion defect with left-ventricular dilatation or increased
lung uptake
Echocardiographic wall motion abnormality (involving >2 segments) developing at low
dose of dobutamine ( 10mg/kg/min) or at a low heart rate (<120bpm)
Stress echocardiographic evidence of extensive ischaemia
with a view to revascularization for symptomatic benefit. As outlined in the ESC guideline
on myocardial revascularization (Wijns et al, 2010), patients deemed to have a high pretest
probability of coronary disease are advised against (IIIA and IIIB recommendations) non-
invasive tests but to proceed to coronary angiography (IA recommendation). Patients
intolerant of non-invasive testings, or with left ventricular dysfunction, could be considered
for coronary angiography. Cardiac transplant patients continue to form an important group
of the patients in whom coronary angiography is routinely performed for follow up for
transplant vasculopathy. It continues to be a class II recommendation for patients awaiting
organ transplant aged 40 years or older.
3.1.2 Coronary artery disease – stable pattern – known coronary artery disease
There is no role for surveillance routine coronary angiography in stable asymptomatic patients
with known CAD, previous coronary interventions or coronary bypass surgery, unless as
part of a research protocol. Patients who have documented coronary artery disease and
previous interventions or CABG, who have developed recurred or worsening symptoms,
coronary angiography is indicated and may be combined with percutaneous
revascularization. It is reasonable to proceed to coronary angiography directly in these
patients. Whilst functional non-invasive tests will still provide localizing data for inducible
ischaemia, intravascular testing modalities such as intravascular ultrasound, optical
coherence tomography and fractional flow reserve testing allow a robust evidence based
approach to guide any revascularization (Tonino et al 2009; Pijls et al 2007).
Cardiogenic shock
haemodynamic instability - severe hypotension on ischaemia
Recurrent/Persistent ischaemia and/or chest pain
Instability in cardiac rhythm e.g. major ventricular arrhythmia
3.2.2 Acute coronary syndromes – unstable angina and non ST elevation acute
coronary syndromes (non STEACS)
Non STEACS is the most frequent presentation of acute coronary syndromes and carries at
least as poor an outcome as STEACS (Chan et al 2009, Polonski et al, 2010). It is
recommended (ESC and ACC class I recommendation) that patients who presented with
non STEACS should be treated with an invasive strategy of coronary angiography. This is
especially for patients with evidence of ischaemia on ECG or biomarkers, the two most
38 Advances in the Diagnosis of Coronary Atherosclerosis
benefited most from an early invasive strategy, this group of high risk patients would
benefit from prompt (<24 hours) coronary angiography.
transferred to the PCI-capable centre. Established logistics and personnel arrangement must
be in place for this to take place.
In patients with successful thrombolysis, the timing of transfer to a PCI-capable facility and
the timing of angiography have been addressed in several contemporary trials and meta-
analyses. Several recent meta-analyses (Borgia et al, 2010; Desch et al, 2008; Savio et al, 2010)
which included studies such as CARESS-AMI (Di Mario et al, 2009), TRANSFER-AMI
(Cantor et al, 2010) and NORDISTEMI (Bøhmer et al, 2009), demonstrated that early transfer
to a PCI capable facility is associated with a significant reduction in the combined endpoint
of 30 day mortality, re-infarction, ischaemia. The benefit appears to be driven most by a
reduction of re-infarction and ischaemia. Current ESC and ACC guidelines recommend this
pharmacoinvasive strategy, or “drip and ship” strategy, the prompt transfer of
thrombolyzed patients to a PCI capable hospital within 24 hours.
The timing of coronary angiography deserves special mention. In stable patients
successfully thrombolyzed, having been transferred to a PCI capable facility, coronary
angiography and PCI should be deferred until 3 to 24 hours after thrombolysis. Whilst
immediate coronary angiography appears attractive a proposition, evidence from
“facilitated PCI” suggests otherwise. Facilitated PCI is a strategy of immediate angiography
and PCI after pharmacotherapy such as upstream full or half dose thrombolytic therapy,
with or without glycoprotein IIb/IIIa inhibitor. Several trials have addressed this question.
ASSENT-4 (ASSENT-4 investigators, 2006), assessing tenecteplase then PCI compared to
primary PCI, showed increased rates of ischaemic and bleeding complications with
facilitated PCI, and FINESSE (Ellis et al, 2008, reduced reteplace and abciximab then PCI vs.
abciximab then PCI vs. PCI) showed no difference in the mortality, ventricular function or
cardiogenic shock but excess bleeding. A meta-analysis (Keeley et al, 2006) of 18 trials over 3
decades showed no benefit of facilitated PCI over primary PCI. There is currently no data to
recommend the use of “facilitated” PCI. Pharmacoinvasive strategy is encouraged but
facilitated PCI is not.
Coronary angiography should be performed prior to definitive surgical treatment for
mechanical complications of any myocardial infarction (e.g. ventricular septal defect, acute
mitral regurgitation or ventricular aneurysm). There are some situation however where the
delays associated with angiography may outweigh the benefits of defining the coronary
anatomy. For example angiography should not delay emergent surgical treatment of VSD
and shock or aortic dissection.
hypothermia (Bernard et al, 2002; Wolfrum et al, 2008) should be incorporated as part of the
treatment strategy for those undergoing immediate angiography.
Surgical risk estimate (adapted from Boersma et al, 2005) – risk of MI and cardiac death at
30 days
Low risk <1% Intermediate risk 1-5% High risk >5%
Breast Abdominal Aortic and major
vascular surgery
Dental Carotid Peripheral vascular
surgery
Endocrine Peripheral arterial angioplasty
Eye Endovascular aneurysm repair
Reconstructive Head and neck surgery
Orthopaedic – minor e.g. Neurological/major
knee orthopaedic
Urologic – minor Pulmonary/renal/liver
transplant
Urologic – major
Table 7. Risk of adverse cardiac events in different surgical scenarios
Indications for Coronary Angiography 43
Patients who have stable angina or are asymptomatic can generally proceed with surgery.
Patients who have worsening symptoms of ischaemia probably deserve further assessment,
namely in the form of functional studies, prior to elective surgery. The same indications for
coronary angiography and/or intervention should apply here as would be in the non-
surgical setting. The cardiac risks of the particular operation should be assessed. It is a class
I recommendation (Poldermans et al, 2009) that pre-operative coronary angiography be
performed in acute coronary syndromes as well as in patients with angina refractory to
medical therapy. Pre-operative angiography is not recommended in cardiac-stable patients
undergoing low-risk and even intermediate risk surgery.
Evidence of improved outcome with revascularization prior to surgery however is lacking.
There is little data pertaining to the benefit of revascularization in patients undergoing non
cardiac vascular surgery, a subset of surgical patients known for high cardiac co-morbidity.
One study (McFalls et al, 2004 - Coronary Artery Revascularization Prophylaxis CARP
study) on stable CAD patients with preserved LV failed to demonstrate improved outcome
with prophylactic revascularization compared to optimized medical therapy. Another study
(Poldermans et al, 2007 - DECREASE-V pilot study), assessed the same concept on complex
CAD with impaired LV systolic function, and reached the same conclusion. This was despite
75% of these cases having three vessel or left main coronary artery disease. On the currently
limited available data, prophylactic revascularization cannot be recommended.
Guidelines on the appropriateness of CTCA (Taylor et al, 2010) published in 2010 attempted
to address the use of this rapidly evolving technology. The indications chosen mirrored that
of invasive coronary angiography. In view of its high sensitivity, CTCA is particularly
suited to low to intermediate risk patients in the setting of stable symptomatic patients, low
risk acute coronary syndromes and heart failure patients. Patients with normal CTCA
findings convey a very low risk of future cardiac events and cardiac mortality (Hulten et al,
2011). Patients at high risk of coronary artery disease are advised against CTCA as this
represents hindrance to timely diagnosis and management of CAD with the additional risk
of contrast and radiation. It has no role in the preoperative assessment of non-cardiac
surgery. It is deemed appropriate in the assessment of graft patency for symptomatic
patients with previous CABG. To reflect the emerging role of left main stenting, CTCA has
been deemed appropriate as a means for routine follow up screening of left main stent(s) in
asymptomatic patients.
Unless the limitations of CTCA can be sufficiently improved upon, it is likely CTCA will
continue to be utilized in a complementary role to invasive coronary angiography in the
assessment of CAD. Of course the major advantage of angiography remains the ability to
proceed on to coronary intervention as part of the imaging procedure.
Fig. 2a. Angiography with a 5 French Judkins Left 5 catheter through a CoreValve ®
bioprosthesis
Indications for Coronary Angiography 49
This demonstrated patent grafts as previously noted but progression in his PDA disease
(Figure 2b). Percutaneous, or surgical, treatment remained an unfavourable prospect and he
was successfully treated with intensified medical therapy with CCS (Canadian
Cardiovascular Society) I angina. Coronary angiography can be safely performed through
CoreValve struts but care must be exercised with the choice and manipulation of catheters.
Fig. 2b. Severe native posterior descending artery disease not amenable to percutaneous
treatment
Case Three – percutaneous treatment of left main stenosis and aortic stenosis
A 76 year old male with severe aortic stenosis was referred for possible percutaneous
treatment due to his high surgical risk. Assessment for TAVI entailed a coronary angiogram,
aortogram and an iliofemoral angiogram (Figure 3a). Coronary angiography revealed a
significant left main stenosis (Figure 3b) which on intravascular ultrasound measured 5.8
mm2. A multidisciplinary heart team assessed the data and concluded surgical treatment to
be prohibitively high risk. The patient then underwent left main stenting with a drug eluting
stent under IVUS guidance. Satisfactory stent expansion was attained with a final diameter
of 4.5mm (Figure 3c). The patient then proceeded to a successful TAVI (CoreValve®)
implant and continued to enjoy excellent symptom relief at six months.
50 Advances in the Diagnosis of Coronary Atherosclerosis
Coronary angiography, and arterial (aortic, iliac, and femoral) assessment, form an integral
part of TAVI assessment. Elderly patients with severe aortic stenosis often have severe co-
existing coronary artery disease as well as peripheral vascular disease as demonstrated by
this case. Optimizations of the coronary status, as well as an appreciation of the peripheral
vasculature, are absolutely paramount to a successful TAVI implant and to avoid vascular
complications.
Fig. 3a. Tortuous aorta and iliac arteries, important information for TAVI transfemoral
access.
Indications for Coronary Angiography 51
Fig. 3c. Drug eluting stent deployment in left main guided by IVUS
Case Four – anomalous coronary artery
A 63 year old male underwent coronary angiography after being successfully thrombolyzed
for an inferior STEACS, 24 hours after his original pain onset. Coronary angiography via his
right femoral artery showed a normal left coronary system but the origin of the right
coronary artery (RCA) was not in the usual sinus. An Amplatz left catheter 2 (AL2)
eventually revealed (Figure 4a) an anomalous RCA from the opposite sinus (ACAOS). A
95% stenosis in the mid RCA was found and after trying various catheters, an EBU (extra
back up) 3.5 guiding catheter (Medtronic ®), traditionally a left coronary catheter, made it
possible for a successful intervention and the placement of a coronary stent (Figure 4b and
4c). A CTCA (Figure 4d) was performed to ascertain the course of the RCA and confirmed
ACAOS. Percutaneous coronary intervention in anomalous coronary arteries required
innovative use of guiding catheters.
Indications for Coronary Angiography 53
Fig. 4a. Right coronary artery injection with a 5Fr AL2 catheter showing an anomalous right
coronary origin with impossible selective engagement
54 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 4b. A 6Fr EBU catheter used to engage the anomalous origin. Traditional right coronary
catheters would not have been useful.
Indications for Coronary Angiography 55
Fig. 4c. Successful placement of a drug eluting stent in the mid RCA with no residual
stenosis.
56 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 4d. CTCA 3D reconstruction shows the origin and course of the anomalous right
coronary artery clearly and defines its ante-aortic course.
Case Five – CTCA in graft assessment
A 69 year old male developed atypical chest pain 12 months after his coronary bypass graft
(LIMA-LAD; RA-ramus; SVG-OM1). During the initial angiographic assessment he
underwent IVUS of his left main and left anterior descending artery indeterminate lesions.
IVUS showed his LM to be 5.44mm2 and LAD 3.96mm2. These were thought be suggest
significant stenoses. To investigate his current atypical chest pain an MPS (Figure 5a) was
performed which showed no inducible ischaemia or symptoms. A CTCA (Figure 5b) was
performed which however suggested possible occluded LIMA graft. A coronary angiogram
and graft study (Figure 5c and 5d) confirmed this finding that the LIMA graft had become
atretic and normal coronary flow seen in the LAD. His other grafts were patent as was
shown on the CTCA. This case demonstrated the value of CTCA in identifying graft patency
and position, often facilitating the location of the graft anastomosis at the aorta. The atypical
symptoms, patent coronary arteries and grafts, correlated well with his negative functional
study. The LIMA-LAD graft probably underwent atresia as a result of no physiological
implication to his intermediate LM and LAD lesions even though the diameters measured
fulfilled conventional criteria for significant lesions.
Indications for Coronary Angiography 57
Fig. 5b. Position of two aortic grafts demonstrated clearly on CTCA. No LIMA flow
demonstrated.
Indications for Coronary Angiography 59
Fig. 5c. LAD artery with no obvious proximal stenosis and normal coronary flow.
60 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 6a. Distal left main eccentric stenosis and ostial circumflex stenosis.
62 Advances in the Diagnosis of Coronary Atherosclerosis
6. Conclusion
Coronary angiography remains the most accurate diagnostic modality for coronary artery
disease. It provides a definitive assessment of coronary artery lumen and provides an
avenue to percutaneous intervention. It is pivotal in the treatment on unstable or acute
coronary syndromes and life saving in cardiogenic shock and STEACSs. Indications for
invasive coronary angiography have changed incrementally over the decade since
ACC/AHA guidelines on the topic were published. The advent of noninvasive CTCA has
changed the landscape for the diagnosis of CAD but CTCAs seem destined only for the low
to intermediate risk patients. Coronary angiography also serves a pivotal role in the
burgeoning field of percutaneous structural cardiac interventions, especially percutaneous
valve implants.
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Indications for Coronary Angiography 67
1. Introduction
Diagnostic cardiac catheterization is recommended whenever it is clinically important to
define the presence of cardiac disease that cannot be evaluated adequately by noninvasive
techniques. Because the risk of a major complication from cardiac catheterization is less than
1% with mortality of less than 0.08%, many doctors can perform the catheterization safely
now. We discuss the history of coronary angiography.
2. X-ray
We must talk about X-rays, at first, when we discuss the history of coronary angiography.
In 1895, Roentgen discovered the x-rays. In 1896, X-rays of fractures had been obtained and
published. Walter B. Cannon observed the movements of the opaque mass in the stomach
and subsequently with mixing bismuth subnitrate described the nature and site of peristaltic
activity in cats as seen on the fluoroscopic screen.
Walsh published “The Röntgen Rays in Medical Work. New York: William Wood, 1898.” He
reproduced a chest film that clearly showed the position and dimensions of the heart and
describe a number of cardiac and aortic conditions that he visualized radiographically. The
radiograph in his book required an exposure time of 20 minutes, with the tube only 30
inches (76 cm) from the radiographic plate (Figure 1).
3. Angiogram
Visualization of human blood vessels was achieved in January 1896, during the month after
the announcement of Roentgen’s discovery, when Haschek and Lindenthal injected
Teichmann’s mixture, composed mainly of calcium carbonate, into the blood vessels of an
amputated hand. A published photograph of their original roentgenogram clearly showed
the potential of the method for visualizing the vascular bed (Figure 2).
Morton who was a pioneer American radiologist wrote a text entitled “The X-ray, or,
Photography of the Invisible and Its Value in Surgery. New York: American Technical
* Hidetaka Iida, Hiroaki Takeshita, Takanori Kusuyama, Hitoshi Kanamitsu, Hideya Mitsui,
Fig. 1. The chest film from “The Röntgen Rays in Medical Work”.
Book Company. 1896.” In this book, his remarks concerning contrast studies are
intriguing.
In teaching the anatomy of the blood vessels, the X-ray opens out a new and feasible
method. The arteries and veins of dead bodies may be injected with a substance opaque to
the X-ray and thus, their distribution may be more accurately followed than by any possible
dissection. The feasibility of this method applies equally well to the study of the structures
and organs of the dead body. To a certain extent, therefore, X-ray photography may replace
both dissection and vivisection, and in the living body, the location and size of a hollow
organ may be ascertained by causing the subject to drink a harmless fluid more or less
opaque to the X-ray, or an effervescing mixture which will cause distention, and then taking
the picture.
In 1920, a radiographic atlas devoted only to the systemic arteries of the body was published
in England, “The X-ray atlas of the systemic arteries of the body. London: Balliere, Tindall,
and Cox, 1920,” by Orrin. The reproductions showed blood vessels in cadavers with great
clarity (Figure 3).
In 1910, Franek and Alwens introduced a suspension of bismuth and oil into the hearts of
dogs and rabbits directly through the large veins and observed the passage of droplets from
the heart into the lungs. In 1922, the work of Sicard and Forestier represented the next major
History of Coronary Angiography 71
advance, when they used Lipiodol, an early oil-based contrast medium, to study the
bronchial tree and then the spinal subarachnoid space. In 1923, they injected 5 ml of
Lipiodol into the femoral vein of a dog and, with the aid of fluoroscopy, watched droplets
move with increasing speed from the iliac vein into the heart. The Lipiodol was then
pulverized by ventricular contraction, thrown with great speed into the pulmonary artery
and finally spread as multiple emboli into the small vessels of the lungs, disappearing in 10-
12 minutes. Nextly, they repeated the experiment with human subjects, in whom they
carefully observed the course of the opaque oil from the antecubital vein to the pulmonary
capillaries. They reported that the patients coughed as the oil reached the lungs but suffered
no other ill effects.
In 1923, Berberich and Hirsch reported the first arteriograms and venograms obtained in
human subjects, using 20% strontium bromide (Figure 4). In 1924, Brooks described the
intraarterial injection of sodium iodide as a means of showing vessels of the lower
extremities in humans (Figure 5).
In 1928, Moniz et al. described carotid angiography and its application to the study of
cerebral lesions (Figure 6).
Fig. 2. A roentgenogram made by Haschek and Lindenthal after the injection of Teichman’s
mixture into the blood vessels of an amputated hand (Haschek E. Lindenthal O’F. A
contribution to the practical use of the photography according to Röntgen. Wien Klin
Wochenschr 1896:9:63.).
72 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 4. Venographic studies obtained by Berberich and Hirsch in 1923. They injected 20%
strontium bromide into the veins of the upper extremity (Berberich J Munchen Klin
Wochenschr 1923;49:2226).
74 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 5. The first femoral arteriogram obtained in a human subject. Brooks used sodium
iodide as a means of demonstrating the vessels of the lower extremities in 1924(Brooks B.
Intraarterial injection of sodium iodide. JAMA 1924; 82:1016.).
History of Coronary Angiography 75
4. Cardiac catheterization
As Andre Cournand remarked in his Nobel lecture of Decenber, 11th, 1956
(http://nobelprize.org/nobel_prizes/medicine/laureates/). Cournand and his colleagues
led us into a new era in the understanding of cardiac function in humans. According to
Cournand, cardiac catheterization was performed and so named by Claude Bernard in
1844. The subject was a horse, and both the right and left ventricles were entered by
retrograde approach from the jugular vein and carotid artery.
His careful application of scientific method to the study of cardiac physiology using the
cardiac catheter demonstrated the enormous value of this technical innovation. An era of
investigation of cardiovascular physiology in animals then followed, resulting in the
development of many important techniques and principles (pressure manometry, the Fick
cardiac output method), which awaited direct application to the patient with heart
disease.
76 Advances in the Diagnosis of Coronary Atherosclerosis
In 1928, Werner Forssmann, having practiced on a cadaver, inserted a 65 cm catheter into his
own antecubital vein until he felt that it had reached the right atrium [1] (Figure 7). With the
catheter dangling from his arm, he walked through a hospital basement to the radiographic
room. There he obtained a roentgenogram that confirmed his belief that the catheter tip had
in fact reached the right atrium.
During the next 2 years, Forssmann continued to perform catheterization studies including
six additional attempts to catheterize himself. Bitter criticism, based on an unsubstantiated
belief in the danger of his experiments, caused Forssmann to turn his attention to other
concerns, and he eventually pursed another catheter-related career as a urologist.
Nevertheless, for his contribution and foresight he shared the Nobel Prize in Medicine with
Andre Cournand and Dickinson Richards in 1956. Forssmann’s primary goal in his
catheterization studies was to develop a therapeutic technique for the direct delivery of
drugs into the heart.
He wrote, “If cardiac action cases suddenly, as is seen in acute shock or in the heart disease,
or during anesthesia or positioning, one is forced to deliver drugs locally. In such cases the
intracardiac injection of drugs may be life saving. However, this may be a dangerous
procedure because of many incidents of laceration of coronary arteries and their branches
leading to cardiac tamponade, and death. Because of such incidents, one often waits until
the very last moment and valuable time is wasted. Therefore I started to look for a new way
to approach the heart, and I catheterized the right side of the heart through the venous
system.”
Others, however, appreciated the potential of using Forssmann’s technique as a diagnostic
tool. In 1930, Klein reported 11 right heart catheterizations, including passage to the right
ventricle and measurement of cardiac output using Fick’s principle. In 1932, Padillo and
coworkers reported that right heart catheterization and measurement of cardiac output in
two subjects. Except for these few early studies, application of cardiac catheterization to
study the circulation in normal and disease states was fragmentary until the work of Andre
Cournand and Dickinson Richards, who separately and in collaboration produced a
remarkable series of investigations of right heart physiology in humans [2]. In 1947, Dexter
reported his studies on congenital heart disease and passed the catheter to the distal
pulmonary artery, describing “the oxygen saturation and source of pulmonary capillary
blood” obtained from the pulmonary artery wedge position [3]. Subsequent studies from
Dexter’s laboratory [4] and by Werko elaborated the use of this pulmonary artery wedge
position and reported that pressure measured at this position was a good estimate of
pulmonary venous and left atrial pressure. During this exciting early period, catheterization
was used to investigate problems in cardiovascular physiology by McMichael and Sharpey-
Shafer in England. Lenegre and Maurice in Paris and Warren, Stead, Bing, Dexter,
Cournand and others in the United States [5-9].
Further developments came rapidly in the 1950s and 1960s. Retrograde left heart
catheterization was first reported by Zimmerman and others [10] and Limon-Lason and
Bouchard in 1950. The percutaneous (rather than cut-down) technique was developed by
Seldinger in 1953 and was soon applied to cardiac catheterization of both the left and right
heart chambers [11]. Trans-septal catheterization was first developed by Ross [12] and
Cope [13] in 1959 and quickly became accepted as a standard technique. Selective
coronary angiography was reported by Sones and others in 1959 and was perfected to
History of Coronary Angiography 77
remarkable excellence over the ensuing years [14]. Coronary angiography was modified
for a percutaneous approach by Ricketts and Abrams [15] in 1962 and Judkins [16] in 1967.
In 1970, Swan and Ganz introduced a practical balloon-tipped, flow-guided catheter
technique enabling the application of catheterization outside the laboratory [17]. Better
radiographic imaging techniques and less toxic radiographic contrast agents have been
developed progressively, as many numbers of diagnostic catheterizations has performed
(Figure 8).
In 1977, Grüntzig and others introduced the technique of balloon angioplasty, known as
percutaneous transluminal coronary angioplasty (PTCA) [18].
Fig. 7. The first documented cardiac catheterization. At age 25, while receiving clinical
instruction in surgery at Eberswalde, Werner Forssmann passed a catheter 65 cm through
one of his left antecubital veins until its tip entered the right atrium. He then walked to the
radiology department where this roentgenogram was taken (Klin Wochenschr 1929;8:2085.
Springer-Verlag, Berlin, Heidelberg, New York).
78 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 8. Normal coronary angiogram. Left panel: left coronary artery. Right Panel: right
coronary artery.
6. Conclusion
Medicine moves so fast that its evolution tends to be forgotten. In particularly, techniques
that have become an integral part of the standard device of diagnosis or therapy are passed
History of Coronary Angiography 79
to each new generation of physicians and trainees. We perform them without their having
sense of efforts involved in the initial development of those techniques.
In this one decade, we would be astonished at how far the field has come and how much
information can be gathered on the structure and function of the heart from diagnostic
imaging. A century is a short time in the history of medicine, but it has been an eventful
lifetime.
7. References
[1] Shapiro, S.M. et al. (1997) Primary pulmonary hypertension: improved long-term effects
and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol,
Vol.30, No.2, pp. 343-349
[2] Cournand, A. et al. (1945) Measurement Of Cardiac Output In Man Using The Technique
Of Catheterization Of The Right Auricle Or Ventricle. J Clin Invest, Vol. 24, No.1,
pp. 106-116
[3] Dexter, L. et al. (1947) Studies Of Congenital Heart Disease. Ii. The Pressure And Oxygen
Content Of Blood In The Right Auricle, Right Ventricle, And Pulmonary Artery In
Control Patients, With Observations On The Oxygen Saturation And Source Of
Pulmonary "Capillary" Blood. J Clin Invest, Vol. 26, No. 3, pp. 554-560
[4] Hellems, H.K. et al. (1949) Pulmonary capillary pressure in man. J Appl Physiol, Vol. 2,
No. 1, pp. 24-29
[5] Bing, R.J. et al. (1947) Catheterization of the coronary sinus and the middle cardiac vein
in man. Proc Soc Exp Biol Med, Vol. 66, No. 1, pp. 239
[6] Bing, R.J. et al. (1947) Physiological studies in congenital heart disease. Bull Johns Hopkins
Hosp, Vol. 80, No.2, pp. 107-120
[7] Burchell, H.B. et al. (1948) Cardiac catheterization in the diagnosis of various cardiac
malformations and diseases. Mayo Clin Proc, Vol. 23, No. 22, pp. 481-487
[8] Stead, E.A., Jr. and Warren, J.V. (1947) Cardiac output in man; an analysis of the
mechanisms varying the cardiac output based on recent clinical studies. Arch Med
Interna, Vol. 80, No. 2, pp. 237-248
[9] Stead, E.A., Jr. et al. (1948) Cardiac output in congestive heart failure; an analysis of the
reasons for lack of close correlation between the symptoms of heart failure and the
resting cardiac output. Am Heart J, Vol. 35, No.4, pp. 529-541
[10] Zimmerman, H.A. et al. (1950) Catheterization of the left side of the heart in man.
Circulation, Vol. 1, No. 3, pp. 357-359
[11] Seldinger, S.I. (1953) Catheter replacement of the needle in percutaneous
arteriography; a new technique. Acta radiol 39 (5), 368-376
[12] Ross, J., Jr. (1959) Transeptal left heart catheterization: a new method of left atrial
puncture. Ann Surg, Vol. 149, No. 3, pp. 395-401
[13] Cope, C. (1959) Technique for transseptal catheterization of the left atrium; preliminary
report. J Thorac Surg, Vol. 37, No. 4, pp. 482-486
[14] Ryan, T.J. (2002) The coronary angiogram and its seminal contributions to
cardiovascular medicine over five decades. Circulation, Vol. 106, No. 6, pp. 752-756
[15] Ricketts, H.J. and Abrams, H.L. (1962) Percutaneous selective coronary cine
arteriography. JAMA, Vol. 181, pp. 620-624
[16] Judkins, M.P. (1967) Selective coronary arteriography. I. A percutaneous transfemoral
technic. Radiology, Vol. 89, No.5, pp. 815-824
80 Advances in the Diagnosis of Coronary Atherosclerosis
[17] Swan, H.J. et al. (1970) Catheterization of the heart in man with use of a flow-directed
balloon-tipped catheter. N Engl J Med, Vol. 283, No. 9, pp. 447-451
[18] Gruntzig, A.R. et al. (1979) Nonoperative dilatation of coronary-artery stenosis:
percutaneous transluminal coronary angioplasty. N Engl J Med, Vol. 301, No. 2, pp.
61-68
[19] Bargeron, L.M., Jr. et al. (1977) Axial cineangiography in congenital heart disease.
Section I. Concept, technical and anatomic considerations. Circulation, Vol. 56, No.
6, pp. 1075-1083
5
Coronary Angiography -
Physical and Technical Aspects
Maria Anna Staniszewska
Medical University of Lodz, Department of
Medical Imaging Techniques
Poland
1. Introduction
Diseases of coronary system and heart are the main reason of deaths in highly civilized
population. Then the appropriate diagnostic methods and treating of early disorders are
very important for a population health care. As the imaging techniques play a great role in
good diagnosis they are intensively used and developed. Among the most commonly used
methods is coronary angiography, which involves coronary vessels visualization during
exposure to x-rays, after filling them up with contrast agents.
There are two versions of the procedure:
CCA – conventional coronary angiography, performed under control of x-ray unit with C-arm,
CTA - CT angiography, performed under control of computerized tomography (CT scanner).
2. CCA
2.1 Description of the procedure
A patient lies in a supine position on the table which is a part of the C-arm unit. The x-ray
tube moves rotationally in two perpendicular planes (horizontal and vertical); it makes
possible any needed type of projection. (The most common projections are: LAO,
LAO/Cranial, LAO/Caudal, RAO). The principal current-voltage parameters are chosen
automatically.
Good practice rules require keeping the x-ray tube under the table. This allows avoiding an
unnecessary irradiation of the staff and makes the doses to a patient lower.
To visualize coronary vessels a contrast agent is administered intravenously. intravenously:
first a thin catheter is introduced the brachial artery or the femoral artery (there are two
alternative access routes) and its movement is traced by fluoroscopy and observed on
monitor by the operator.
(Physiological parameters of a patient of patient are permanently monitored during the
procedure.)
The operating team consists of 3 to 4 persons: usually there are an operator (with assistant if
necessary), instrumenting nurse and anaesthetic nurse. All the staff remind around the
patient table and thus may be exposed to quite high doses of radiation. (There are mainly
scattered x-rays). The most exposed member of the team is the operator: the doses registered
for such persons may achieve the highest level measured for occupational exposures [1,2].
82 Advances in the Diagnosis of Coronary Atherosclerosis
Patient exposure results mainly from the primary x-ray beam which covers a part of the
back surface (the area of left shoulder) by the most time of the procedure. The remaining
parts of the patient’s body are exposed rather to scattered radiation.
The images created during the procedure can be registered in three ways:
a. Real-time images (fluoroscopic images) observed only by the operator,
b. Some chosen moments of the procedure recorded in radiography mode (so-called
acquisition),
c. Long periods of exposure can be recorded in so-called “cine-mode” (if this mode is
implemented in the x-ray system).
The results of CCA procedure are analyzed by cardiologists during its performance and also
retrospectively afterwards.
Most of x-ray units used nowadays in cardiology are equipped with the digital image
recording system. They are two types of them: (1) image intensifier based systems and (2)
flat-panel fluoroscopy systems.
The first one uses conventional technology: the output screen of image intensifier is
projected in a video camera or a CCD camera to produce an electronic information. (In the
previously used conventional image intensifier analogue system the output screen had been
projected on the film by optical lens).
In the flat-panel systems signals created by x-rays are electronic and are thus recorded
simultaneously.
(The fundamental difference between “analogue” and “digital” systems concerns to way of
image archiving (i.e. film or electronic information). The both systems produce the “real-
time” image, although the flat-panel systems create the image by dividing the primarily
detected signal. That is why the modern x-ray system has much higher output capacity and
thus higher doses are possible).
inversely proportional to the diameter of the image intensifier. The entrance dose to skin
may locally achieved values exceeding the threshold of deterministic effects and the skin
injuries of patients undergoing interventional procedures are reported [5].
Generally, exposure of the patients during CCA procedures is extremely non-uniform:high
doses are received on a small are of the back while the remaining parts of the body
practically stay out of the primary beam. Although effective dose is not a good measure of
radiation risk for that, this quantity is used after all. The measurable quantities, i.e. entrance
surface dose (or air kerma) and DAP, have more practical meaning. These quantities are
proportional to each other:
DAP = EAKc. S
where EAKc –the entrance air kerma in the centre of the beam, S – mean value of incident x-
ray beam are (on patient’s skin).
(Both values are averaged over the total exposure time, because their varies from one
projection to another.)
DAP (and EAKc) values have to be displayed on the monitors of x-ray system and should be
registered in the patient record. (Especially when EAKc>1Gy and exceeds the threshold of
deterministic skin effects.)
As the doses to patients in CCA are affected by a number of factors the range of their values
is very wide. The examples are presented in Table 1 and Table 2.
To keep the radiation risk to patients on an acceptable level and control it the reference
levels are introduced also for interventional cardiology procedures (like for another
radiological procedures).
dose(s) to the hands. The protective aprons used by the staff in interventional procedures
should have Pb-equivalent of 0.35mm.
As the doses to staff in CCA are affected by a number of factors the range of their values is
very wide (the same concerns patients) and many studies were performed to evaluate them.
The range of the doses shows the results given in the paper from the USA [18], where on
the basis of the rich collection of published data the exposure for operators in
cardiovascular procedures from the early 1970’s through the present was analyzed. The
range of effective doses from 0.02μSv to 38 μSv per one cardiac diagnostic catheterization
procedure was found.
Another survey had been performed by European research group SENTINEL in a sample of
European cardiac centres and the results have been published recently [19]. According to
this study the results for the first operator are as follows:
a. annual effective dose: median 1.3mSv, third quartile 1.4mSv,
b. equivalent dose over the apron: median 11.1mSv, third quartile 14mSv.
Although the above values are rather low it should be underlined that they may be many
times higher (even up the annual limits) , especially for inexperienced staff or in a case of
clinically difficult patient.
3. CTA
A very dynamic development computerized tomography (CT) Which occurred during last
decade creates quite new possibilities for this imaging method. The rotation time below one
second together with a rich software allow applying CT to diagnostics of dynamic
physiological processes and quickly moving objects (organs). On the other hand, increasing
frequency of heart diseases in population linked the health needs With technological
achievements in the CT technique to implement this imaging method to cardiology.
Although traditional (conventional) coronary x-ray diagnostics remain a gold standard
these procedures are invasive and resulted in high radiation doses both to patients and to
staff. Therefore CT procedures became an alternative and comfortable method for heart
diagnosis.
For technological reasons the possibilities of CT are limited to diagnostics, without further
therapeutic activity (i.e. angioplasty). However, cardiovascular CT plays an increasingly
important role in planning for cardiovascular interventions (those are performed under C-
arm x-ray units).
Improvements in spatial and temporal resolution, scan time, scan range and advanced
image postprocessing (very important in clinical practice) have made CT angiography (CTA)
an excellent tool for identifying patients in need of invasive therapy and for mapping out
the best percutaneous or surgical approach. In some cases CTA provides complementary
information to conventional angiography (CCA).
As coronary disease is jointed with calcification of coronary arteries evaluation of this
process is a good indicator of pathology. CTA gives possibility to display calcifications (3D)
and to assess them quantitatively: it is so-called “calcium scoring”.
Although history of CTA had begun with four-slice scanners, the real development came
with 64-slice scanners with appropriate combination of spatial and temporal resolution.
Generally, the heart can be imaged well if its structures do not move significantly during the
scanning time. This condition is fulfilled during the diastolic phase of cardiac cycle. For
Coronary Angiography - Physical and Technical Aspects 87
selection of the proper phase for CT images recording ECG gating (triggering) is applied.
Additionally, to collect sufficient image data the table speed should not exceed v= SC . fH
and pitch should not exceed p=fH. trot,
where SC- total collimation width (CT primary beam), fH- frequency of heart, trot- rot1ation time.
(For example: if trot=0.5sec and fH=60bpm then p≤0.5 )
The main benefit from CTA is the evaluation of cardiac structure and function. That
concerns coronary anomalies, right and left ventricular function, left ventricular ejection
fraction and myocardial viability assessment, when the results of other modalities are
inadequate [1,2].
According the American College of Cardiology Foundation (ACCF) the principal
indications to cardiac CT are as follows [3]:
- low and intermediate pretest probability of obstructive coronary artery disease (CAD),
- noncontrast CT calcium scoring for patients at intermediate risk of coronary heart
disease, and for low-risk patients with a family history of disease,
- coronary CT is especially recommended for patients with reduced left ventricular
ejection fraction at low or intermediate pretest probability of disease,
- preoperative CT angiography for both heart surgery and noncoronary indications in the
setting of risk of CAD.
It should be underlined that imaging possibilities of each CT scanner are determined by its
technical configuration (number of detectors, generator, etc.) but even more by the installed
version of software.
The principal algorithms for image post-processing are [4]:
- curved and multiplanar reformats (MPR),
- shaded-surface display (SSD),
- maximum intensity projection (MIP),
- volume rendering (VR).
The axial images produced by hardware (so-called row data) are essential and should be
used but reformatted images may improve lesion detection and classification (particularly
coronal and oblique views). The axial images and MPRs are used for diagnosis and the SSD
and MIPs are for display purposes.
The results of CTA are evaluated or consulted by a cardiologist.
3.2 Dosimetry in CT
Because of special exposure system CT needs the special dosimetry quantities, i.e.: dose-
length-product (DLP) and computed-tomography-dose- index (CTDI).
CTDI is treated as an estimation of mean absorbed dose to the whole scanned volume. This
quantity also evaluates the level of radiation risk for given procedure at assumed exposure
parameters.
CTDI is calculated automatically by scanner software on the basis the selected exposure
parameters and is displayed on CT monitor. The DLP is then computed as a product of
CTDI (averaged over the whole scan length) and the scan length: such value is displayed on
CT monitor after the examination is completed.
Independently, CTDI can be computed on the basis of measurements performed for particular
dosimetric phantoms. For that purpose DLP is measured using special pencil-shaped
chamber (external probe) to summarize the dose from incident photons during the tube
rotation on the whole length of scanned object. (This is also performed during the
acceptance or constancy Quality Control (QC) tests for CT scanner.)
Final evaluation of risk to patient in CT procedures is based on the effective dose. As in the
other radiological techniques this quantity can be estimated theoretically (Monte Carlo
simulation) or experimentally (TL dosimeters inside the anthropomorphic phantom).
Additionally – the effective dose obtained in the particular procedure can be estimated
indirectly:
Eff= k . DLP
where DLP – value for the procedure, k – transition coefficient for the examined body part
(computed theoretically). The above evaluation is applied for adult patients only.
For coronary examinations the transition coefficient k=0.014 mSv.mGy-1.cm-1 is used which
corresponds to the chest as the examined region [5].
The problem of doses in CTA is considered only for patients as the staff is out of radiation area.
Table 3. The effect of tube voltage and heart rate on absorbed doses [mGy] in CTA
(according to [8]).
90 Advances in the Diagnosis of Coronary Atherosclerosis
2. Doses to patients in CTA procedures covering the chest are distributed more uniformly
and are dependent on the scanner configuration and protocol of the procedure.
CCA CTA
1st manufacturer: 0.9 – 1.4 16-slice scanner: 5.4
2nd manufacturer: 1.3 – 3.2 64-slice scanner: 23.1
(The both scanners made by 1st
3rd manufacturer: 6.2 – 18.8
manufacturer.)
Table 6. Absorbed doses [mGy] to patients in CTA (both CT scanners made by 1st
manufacturer)
92 Advances in the Diagnosis of Coronary Atherosclerosis
5. References
5.1 References for CCA
[1] International Commission on Radiological Protection, Publication 85, Avoidance of
Radiation Injuries from Medical Interventional Procedures, 2001.
[2] Vano E, Gonzales L, Guibelalde E, et al:Radiation exposure to medical staff in
interventional and cardiac radiology. Br.J.Radio., 71,954-960,1998.
[3] International Commission on Radiological Protection, Publication 60, Recommendations
of the International Commission on Radiological Protection, 1991.
[4] International Commission on Radiological Protection, Publication 103, The 2007
Recommendations of the International Commission on Radiological Protection,
2007.
[5] Vano E, Arranz L, Sastre JM, et al: Dosimetric and radiation protection considerations
based on some cases of patient skin injuries in interventional cardiology.
Br.J.Radiol., 71, 510-516, 1998.
[6] Bor D, Olgar T, Toklu T, et al.: Patient doses and dosimetric evaluations in interventional
cardiology. Physica Medica, 25,31-42, 2009.
[7] Maccia C: An optimization study of cardiac interventional radiology procedures: an
experience in France. ERPET in Madrid, p.113-119, 1997.
[8] Hansson B, Karambatsakidou A: Relagtionships between entrance skin dose, effective
dose and dose area product for patients in diagnostic and interventional cardiac
procedures. Radia.Prot.Dosimetry. 90: 141-144, 2000.
[9] Van de Putte S, Verhaegen F, Taeymans Y, et al.: Correlation of patient skin doses in
cardiac interventional radiology with dose-are product. Br.J.Radiol. 73: 504-513,
2000.
[10] Clark AL, Brennan AG, Robertson LJ, et al.:Factors affecting patient radiation exposure
during routine coronary angiography in a tertiary referral centre. Br.J.Radiol. 73:
184-189, 2000.
[11] McFadden SL, Money RB, Shepherd PH: X-ray dose and associated risks from
radiofrequency catheter ablation procedures. Br.J.Radio. 75: 253-265,
2002.
[12] Delichas MG, Psarrakos K, Molyvda Athanassopoulou E, et al.:Radiation doses to
patients undergoing coronary angiography and percutaneuos transluminal
coronary angioplasty. Radiat.Prot.Dosimetry.103(2):149-154, 2003.
[13] Sandborg M, Fransson SG, PetterssonH: Evaluation of patient and staff absorbed doses
during coronary angiography and intervention by femoral and radial artery access
routes. Eur.Radiol. 14(4):653-658, 2004.
[14] Leung KC, Martin CJ: Effective doses for coronary angiography. Br.J.Radiol. 69:426-
431, 1996.
[15] Tsapaki V, Kottou S, Kollaros N, et al.: Dose performance evaluation of a charge
coupled device and a flat-panel digital fluoroscopy system recently installed in
an interventional cardiology laboratory. Radiat.Prot.Dosimetry. 111(3): 297-
304,2004.
Coronary Angiography - Physical and Technical Aspects 93
[16] Chida K, Fuda K, Saito H, et al.: Patient skin dose in cardiac interventional procedures:
conventional fluoroscopy versus pulsed fluoroscopy. Catheter Cardiovasc
Interv.69(1):115-121, 2007.
[17] International Commission on Radiological Protection, Publication 75, General
Principles of Monitoring for Radiation Protection of Workers, 1997.
Kim KP, Miller DL, Balter S, et al.: Occupational radiation doses to operators performing
cardiac catheterization procedures. Health Phys. 94(3):211-227,2008.
[18] Padovani R: Optimisation of patient and staff exposure in interventional radiology. In:
Radiation Protection in Medical Physics, edited by Y.Lemoigne and A.Caner,
Springer in Cooperation with NATO Public Diplomacy Division, The Netherlands,
2011.
[12] Ropers D, Baum U, Polite K, et.al. Detection of coronary artery stenoses with thin-slice
multi-detector row spiral computed tomography and multiplanar reconstruction.
Circulation 2003. 107:664-666.
[13] Staniszewska MA, Jazwinski J: MSCT and C-arm units: doses to patients in the chest
angiography procedures. Pol.J.Radiol. 73(1):43-49, 2008.
6
Procedural Techniques
of Coronary Angiography
Jasmin Čaluk
BH Heart Center Tuzla
Bosnia-Herzegovina
1. Introduction
Coronary angiography is an invasive diagnostic procedure in which radiocontrast is injected
into the coronary arteries under X-ray guidance in order to display the coronary anatomy
and possible luminal obstruction. Despite the advances in other diagnostic methods, it
remains to be "the golden standard" of coronary disease diagnostics. Although today the
complication rate is far lower than previously, the possibility of complication still exists, and
an invasive cardiologist must be able to complete the procedure flawlessly, and to
competently deal with complications, should they occur. In order to be able to do that,
he/she must master the proper techniques in performing the coronary angiography
procedure, and be comfortable with all the available access-sites.
2. Cath lab
The procedure is performed in a specifically designed room, very much resembling the
operating room, called the catheterization laboratory, or cath lab (Fig.1). Recordings are made
using a special X-ray machine, called cardioangiograph (Fig.1). Today, these machines are
completely digitalized, enabling superb picture quality, with the lowest possible radiation
doses, and some additional features, such as precise measurements and quantifications of the
recorded angiograms, connections to additional devices, such as intravascular ultrasound,
easy and large-capacity data storage etc. It is convenient to have a wide choice of spare
catheters, multi-packs, guidewires, coronary angioplasty ballons, coronary stents, and other
equipment in the cath lab itself, so it can be used without time-delay. The space should be
intuitively organized, and the spare devices, sterile gowns, gloves, drapes etc. must be easily
accesible. Defibrillator, endotracheal tubes, temporary pacemakers and leads, oxygen supply,
and other cardiopulmonary resuscitation equipment must be held in the cath lab at all times.
Just outside of the cath lab is the control-station with monitors for angiogram, patient data,
electrocardiogram (ECG), haemodynamics etc (Fig.2). Modern cardioangiographs allow for
data analysis both from the control station outside the cath lab, as well as from within the cath
lab, using specifically designed control-commands at the table.
procedure, the patient lays down in supine position on the cardioangiograph table, and is
prepared for the procedure in sterile conditions (Fig.3).
- a J-shaped guidewire,
- diagnostic catheters for coronary angiography; start with the most common JL4 and JR4
with angulated pigtail if left ventriculography and/or aortography is planned,
- a three-outlet manifold which is to be connected to pressure transducer, saline solution
container, and radiocontrast container on side-outlets, to the syringe for radiocontrast
application on the proximal end, and with its distal end to diagnostic/therapeutic
catheters during the procedure.
During the procedure, the patient must be monitored by several systems, and the ECG is
absolutely essential. The patient also must have an ECG recording done just before the
procedure actually starts. For practical reasons, during the angiography itself, there is really
no need to apply the precordial leads, since the basic four electrodes can provide enough
information for ECG monitoring during coronary angiography and percutaneous coronary
interventions (PCI). Four electrodes should be placed on the calf or thigh and on the
shoulders or upper arms (Watson & Hunter, 2011).
The area of the puncture site must be shaved, disinfected, then anesthetized, and only then
punctured. The center of the field for shaving and disinfection is the puncture site. The
disinfection is performed starting at the center, and spiraling outwards, at least twice, using
Betadine. Thereafter, the site is wiped off with a third swab. If the procedure is planned to
be performed via the femoral artery, than both right and left groins must be shaved and
disinfected, in case that the operator must switch to contralateral artery. Only after the
disinfection of the puncture site, the patient is covered with a sterile drape. Most centers
today use single-use pre-packed sterile drapes. These drapes have openings conveniently
placed at the location of patient's left and right inguinal area (Fig.5, Fig. 6).
Fig. 5. Sterile drape openings in patient's inguinal area, femoral pulse palpation
4. Catheter menu
Coronary angiography is performed with the use of specifically designed diagnostic
catheters. More than 95% of all procedures can be completed using catheters Judkins left 4
(JL4), and Judkins right 4 (JR4). Also, a pigtail catheter is used for obtaining left
ventriculogram, if it is recorded. Usually the catheters come pre-packed in a sterile
envelope, in which JL4, JR4 and pigtail catheters are present. Diagnostic catheters are more
elastic than the catheters used for PCI, and can be manipulated into the coronary ostium.
However, sometimes the anatomy of the aortic arch and coronary ostia requires the use of
different types of catheters. Today, the catheter menu is abundant with different versions,
and at least one of the available catheters will be able to adequately cannulate even the most
difficult and distorted coronary ostia (Fig.7). It is necessary to know the shapes of those
catheters in order to choose the appropriate-ones for certain anatomical variants.
Therapeutic (guiding) catheters are somewhat stiffer and do not forgive an imperfect
position, because the insertion of interventional equipment (coronary guidewires,
angioplasty balloons, stents etc.) creates much more backforce than does the radiocontrast
injection. Therefore, an unstable catheter with inadequate backup will be frequently
displaced out of the coronary ostium. This is why coronary stenting, even more than
diagnostic coronary angiography, requires the use of dedicated guiding catheters.
5. Arterial puncture
The standard technique of arterial puncture used today is Seldinger technique (Powell &
Moxey, 2011), cleverly developped by Sven-Ivar Seldinger, a Swedish radiologist, in 1953.
The procedure of arterial puncture is performed as follows: firstly, at the site of arterial
puncture, an appropriate pulse has to be palpated in order to locate the artery (Fig.5). A
local anesthesia is applied, usually with 10-15 ml of 1% or 2% lidocaine for local infiltration
of the skin and subcutaneous tissues. Then, a percutaneous puncture of the desired vessel
with a hollow beveled tapered-tip needle is made. The pointy tip at the distal end of the
needle is the first one in contact with the skin, and subsequently with the artery, while the
distal needle opening faces upwards. The needle is held in the operator's hand like a pencil,
at an angle of 30º-45º against the surface of the skin. Arterial puncture is made by advancing
the needle to the site of the arterial pulse. An experienced operator will usually feel when
the needle has punctured the arterial wall. A correct arterial puncure is confirmed by the
pulsatile back-flow of the bright-red blood from the proximal end of the needle (Fig.8).
It is not necessary to have a syringe attached to the needle during arterial puncture, because
the arterial pressure will produce a pulsatile jet of blood when the needle tip reaches the
arterial lumen. If the backflow is slow and barely pulsatile (or seems to be continuous,
without pulsations), and the blood is dark-red, the needle tip has punctured the vein. In
certain circumstances, however, even correct arterial puncture may resemble venous
puncture: shock, hypotension, severe bradycardia, very low oxygen saturation, cardiac
arrest and/or resuscitation etc.
After the arterial puncture, an atraumatic, curved-tipped guide wire (J-wire with moveable
inner core) is passed through the needle and advanced into the artery (Fig.9). The needle is
then removed, leaving the guide wire in the vessel. The site of puncture at the skin level is
usually widened by a couple of milimetres using a small and shallow cut by a surgical
scalpel, an 11-mm or 15-mm blade to facilitate the passage of the arterial sheath. The sheath
Procedural Techniques of Coronary Angiography 101
with a plastic dilator inside of it is advanced over the guide wire, and into the artery. The
dilator is removed, leaving the sheath in the vessel, and a haemostatic valve prevents
bleeding through the sheath. It also provides access for the passage of catheters and other
devices into the vessels, with no blood loss. The side arm of the sheath is aspirated and
injected with heparinized saline before the advancement of catheters. During arterial
puncture and sheath placement, the patient may develop a vasovagal reaction due to
puncture and vessel manipulation, which will manifest as hypotension and bradycardia.
Atropine IV usually swiftly reverts the condition, and sometimes elevation of patient's legs
and high-rate saline infusion with oxygen supplementation should be implemented
additionally. The technique of direct arterial approach, with the preparation and direct
visualization of the artery at the puncture site is today very rarely used, and therefore
discussed elsewhere.
Fig. 8. Pulsatile back-flow of the bright-red blood from the proximal end of the needle
Fig. 9. J-wire is passed through the needle and advanced into the artery
Procedural Techniques of Coronary Angiography 103
6. Vascular access
6.1 Femoral approach
Preferences of particular access sites vary in different centers, but the most commonly used
are right femoral and right radial artery. The percutaneous transfemoral approach has been
routinely used for cardiac catheterization and coronary angioplasty (Kwac et al, 2010). Right
transfemoral approach is favoured because of the larger artery diameter, and therefore the
possibility to insert larger arterial sheaths, catheters and bulkier devices, in comparison with
the transradial approach. If there is a peripheral vascular problem, the left femoral, or right
or left radial or brachial approaches can be used. The femoral approach is the most
comfortable access for the operator. Its main disadvantage is the time-delay after the
angiography and before mobilizing the patient. After the femoral pulse is palpated (Fig.5)
and local anesthesia applied, the puncture of the femoral artery is performed some 2 cm
below the inguinal ligament (Fig.10), at the punctum maximum of the pulse. The inguinal
ligament is attached to spina illiaca anterior superior on one end, and with the pubic bone on
the other (Fig.10). This makes determining of its anatomical location easier, because
overlapping skin crease in obese patients can be located more distally, thus deceptively
making the less experienced operators prone to puncturing too distally. Puncture through
the ligament itself will make the haemostasis very difficult, because the ligament is a firm
structure which precludes adequate pressure application against the artery after
angiography.
Fig. 10. Inguinal area anatomy; 1 – spina iliaca anterior superior, 2 – inguinal ligament, 3 –
skin crease, 4 – common femoral artery, 5 – common femoral vein, 6 – femoral nerve, 7 –
deep femoral artery, 8 – saphenous vein, 9 – pubic bone, 10 – superficial femoral artery, 11 –
sartorius muscle, 12 – abductor longus muscle
104 Advances in the Diagnosis of Coronary Atherosclerosis
that renegotiating the wire through this spasm-prone and often tortuous vessel can be
avoided. Some population studies have shown that patients prefer radial access because of
early ambulation (Cooper et al, 1999) and some cardiologists also strongly prefer it.
However, one should bear in mind that the most important indication for PCI today is acute
myocardial infarction. This important setting must be considered when discussing the
preffered vascular access, because this is the primary circumstance in which PCI improves
survival. It can be expected that difficulties with radial approach and conversion to femoral
approach may delay time to reperfusion, jeoppardizing the lives of critically ill patients,
especially those in cardiogenic shock, requiring intra-aortic balloon pump, for example. So
the question is: with the increased use of radial approach, should it become the new
standard of care, especially regarding emergency interventions for acute myocardial
infarction, and can primary PCI (pPCI) be routinely performed through radial
approach?And the answer is: No. As for the setting of acute myocardial infarction (AMI),
Vorobcsuk et al (2009) performed a systematic review and meta-analysis of 12 trials
comparing the radial versus the femoral approach. They found no significant difference in
the time to reperfusion between the two groups but found access site failure when
transradial approach was used, which contributed to longer procedure times (Jolly et al,
2009). Recent systematic reviews and meta-analyses of trials in the acute setting of ST-
elevation AMI, where time is of the essence, have shown radial access to be associated with
a 10% crossover rate increasing "time to reperfusion" in the individual case (Vorobcsuk et al,
2009). Those trials usually excluded unstable patients in cardiogenic shock requiring
additional treatment options, such as intra-aortic balloon pumps, central venous access or
temporary pacing. These patients are automatically treated using femoral access as it is
more convenient and appropriate to use one access site. In some circumstances these
patients arrest on the table necessitating cardiopulmonary resuscitation, and femoral access
is simply easier and less fiddly under difficult circumstances (Patterson & Foale, 2011).
Radial artery puncture can only be attempted once. If that attempt fails, the morbidity
associated with access site crossover occurs, including the risk of radial artery occlusion, but
also the need for double site post-procedural care (Stella et al, 1997). The radial approach
therefore increases procedure times, not only because of the steep learning curve to this
technically more challenging approach. Radial artery anomalies are also relatively common
and are a cause of transradial procedure failure even for experienced radial operators (Lo et
al, 2009). Even when operators achieve equal procedural times using radial and femoral
approach, there is still significantly greater fluoroscopy time with radial approach PCI.
Inevitably an increase in the irradiation of staff and patient follows (Brasselet et al, 2008).
Femoral access is easier for training, not limited by anomalous radial artery anatomy, and
allows for both left and right mammary arterial bypass graft evaluation. It is also convenient
if a venous puncture is necessary for obtaining haemodynamic measurements. In these
circumstances, an adjecent femoral vein puncture requires "same-site" postprocedural
management. Surely this does not mean that the transradial technique should be dismissed
as a cardiology fashion. It should be learned because it has certain advantages in diagnostic
coronary angiography and elective PCI, it is associated with an earlier patient discharge, and
can be applied in circumstances of severe aortoiliac disease which precludes the use of
femoral approach. However, in primary PCI, the current enthusiasm for using transradial
approach is not sufficiently justified in evidence, and especially not justified enough to
dismiss the femoral route from current training programmes.
106 Advances in the Diagnosis of Coronary Atherosclerosis
hydrophilic coating. Also, when advancing the catheter, the proximal part of the J-wire has
to be visible on the outside of the catheter and secured by the operator's hand (Fig.11), as to
avoid embolization of the J-wire into the patient's circulation. That would require an
emergency vascular surgical procedure to remove the J-wire from the patient's aorta. Under
the X-ray guidance, the guidewire tip is advanced up to the ascending aorta, and into the
aortic root. Holding it in place, the coronary diagnostic catheter is advanced over the
guidewire until it reaches the ascending aorta.
After the catheter reaches the Valsalva sinus in the aorta, the guidewire is withdrawn
leaving the catheter in place. The outside portion of the catheter is connected to a manifold
(Fig.12). The manifold is on the other side connected to the syringe (or an automated
injection-device) for radiocontrast application, and on its side arms to the saline infusion, to
the transducer for invasive blood-pressure monitoring, and to a radiocontrast container
from which radiocontrast is taken into the syringe. Through the manifold, the operator
controls the contrast injection, blood pressure, injections of heparinized saline if necessary,
etc. To ensure that there is no air or clot within the coronary catheter, a syringe is connected
to the catheter to aspirate and discard at least some 5 ml of blood. This is the approximate
volume of the catheter lumen. Some operators instead just allow a small ''bleed back'' from
the catheter, after which the catheter is connected to the three-port manifold.
Fig. 11. Through the arterial sheath and over the guidewire, the first coronary diagnostic
catheter is introduced into the artery; note the proximal end of the wire outside of the
catheter
When connecting the catheter to the manifold, it is important to connect using the fluid-
against-fluid method, i.e. to let the blood back-bleed from the catheter, and at the same time
to allow saline flush from the manifold. This manner of connecting the catheter to the
manifold prevents air embolism from air bubbles from within the catheter, or from within
the manifold.
108 Advances in the Diagnosis of Coronary Atherosclerosis
catheter, and thereafter advance the catheter tip downwards and into the LMCA ostium.
This, on the other hand, carries some risk of scratching the surface of the aortic endothelium
and embolizing atheromas if they are located in catheter's path. If the catheter tip is at the
level of the ostium, but not within the ostium itself, it is usually easily inserted into the
ostium by a clockwise or counter-clockwise torque. An injection of 5-10 ml of contrast close
to the expected location of the coronary ostium reveals the position of the catheter tip within
the aortic root and facilitates a precise cannulation. If the aorta is dilated, a JL5 or JL6
catheters may be required, while in small individuals, or with small aortic arches, a JL3.5 or
even JL3 catheters may be used to cannulate the left coronary artery. Multiple recordings are
taken from diffrerent perspectives. The optimal positions for recording the left coronary
artery are discussed later in the chapter.
replaces the blood in the coronaries, with a continuous back-flow into the aortic root. A
weak injection may appear as a pulsatile contrast flow with filling-defects, and fail to
display the coronary lumen adequately. It sometimes causes the operator to declare a
coronary stenosis existence in a place where only a simple contrast filling defect exists. On
the contrary, a too-forceful injection can, in extreme cases, cause a coronary dissection,
although this event is extremely rare today. If there is no contrast back-flow to the aortic
root, or if the back-flow is inadequate, there may be an ostial lesion present.
RAO-cranial, RAO-caudal, LAO (left anterior oblique), LAO-cranial, and LAO-caudal. These
positions are also defined by angles to cranial or caudal, and angles to the left or to the right.
These angles may vary depending on patients' anatomy, coronary anatomy, position of the
heart etc.
of all human hearts. The PLA and the PDA have several smaller branches, e.g. the posterior
septal perforators originating from the PDA. In the crux region, the atrioventricular node
artery origins from the RCA, and passes vertically upward towards the AV-node. This is
why ischemia in the region of RCA at the time of an acute inferior-wall myocardial
infarction can be associated with different degrees of heart block.
8.2 The best projections for evaluating the left coronary artery
Left caudal view (LAO-caudal, or "spider" view) is excellent for evaluation of the LMCA
and its bifurcation into the LAD and CX, or trifurcation into the LAD, CX and intermediate
branch if it exists (Di Mario and Sutaria, 2005). Interventionalists use it in many cases for
wiring the LAD or the CX. It forshortens the mid and the distal segment of the LAD, and
should not be used to evaluate these segments, although it can pretty nicely separate LAD
from diagonals and septals. Also, it can be very useful in viewing ostia of high marginal
branches, and therefore is used for wiring these branches too. It is usually done in 25-40º
caudal and 30-50º to the left.
Left cranial (LAO-cranial) view is very good for showing the ostium of the LMCA, but
considerably forshortens the proximal half of the LAD. It is convenient for separating the
diagonals and the septals from the LAD, though, and can be used to guide the guidewire
into and from these branches during interventions. The CX and its high-originating
branches are not appreciated well in this projection, but if the CX is dominant, this
projection can be useful to depict the very distal parts of the CX.
Cranial (AP-cranial) projection displays the ostium of the LMCA (Di Mario and Sutaria,
2005), similarly to the LAO-cranial view. Although some operators use it to intervene on the
proximal LAD, the aouthor's opinion is that the overlap of the CX is too distracting, and that
there are better projections for interventions and evaluation of the proximal LAD than the
AP-cranial. This projection can be useful for evaluating the mid and distal segments of the
LAD and diagonals' take-off, although the diagonal ostia can be overlapped with the main-
course LAD. The CX in this view often looks confusing for the inexperienced operator,
especially in its proximal and mid segments, but if it is dominant, this can be a very useful
projection for evaluating the very distal portions of the CX.
Caudal (AP-caudal) is a very good projection for evaluation of the LMCA, its bifurcation (or
in some cases trifurcation), ostial LAD, and the intire CX if it is not dominant. This is the
author's favourite projection for interventions on the CX. It can be useful for ostial stent
placement in the LAD, similarly to LAO-caudal. Some operators prefere wiring of the
marginal branches in RAO-caudal, but in that projection, the marginal ostia are often
overlapped with the main course CX. The author feels that AP-caudal is the best projection
for evaluating the CX in its entirety, including the marginal ostia, meaning that this
projection is also probably the best for wiring those too. It is especially good for treating
bifurcational lesions on CX + marginals, but in author's experience also good for treating
bifurcation lesions on LMCA + LAD + CX, along with the spider-view. However, if the CX
is anatomically dominant, the distal portions of the artery will usually overlap with 3rd
marginal branch, PLA and/or PDA. For these, in the case of CX dominance, the cranial
projections should be used.
Right cranial (RAO-cranial) projection is the most useful if it is performed with increased
cranial angulation of 30º, or in some cases even more. This projection shows nicely the mid
Procedural Techniques of Coronary Angiography 113
part of the LAD with the take-offs of diagonal branches and can in most instances be very
useful for treating bifurcation lesions within the LAD + diagonals. Sometimes, the diagonal
ostia will overlap, and LAO-cranial, LAO-caudal or AP-cranial will be better for that
purpose. If the LMCA is very short, even proximal and ostial LAD can be nicely appreciated
in steep RAO-cranial. The CX can be appreciated in this view only if it is dominant, and that
goes only for its most distal parts. The proximal and the mid segment of the CX cannot be
adequately evaluated in this view.
Right caudal (RAO-caudal) view is very good for evaluating the distal LAD. The proximal
and the mid part of the LAD are overlapped with diagonals in most cases, so this should be
taken into consideration when evaluating LAD in RAO-caudal. Still, some stenoses of the
LAD can only be seen here, so it requires operator's attention. The LMCA is displayed in
this view, although the bifurcation itself is being overlapped in most patients by the ostial
segments of the LAD and the CX. The CX artery can be nicely evaluated in RAO-caudal, but
to be sure, the AP-caudal should always be taken.
Left lateral is rarely used today. It can be useful to display LIMA-LAD anastomosis, the mid
and the distal portions of the LAD, and to separate the LAD from the diagonals, LAD being
the closest to the sternum. Pure RAO is rarely used today, since it does not display any of
the LCA segments ideally, except it can be useful for evaluating the distal LAD. Pure LAO is
very useful for cannulation of both LCA and RCA, but is not very useful in evaluating LCA
or its branches, so it is not being routinely used for LCA today. Straight AP is also not an
ideal projection for evaluation of the LCA, and for any of the segments, there are many more
useful projections.
8.3 The best projections for evaluating the right coronary artery
Many operators believe that two projections can be quite enough for evaluation of the RCA
since it has less complex anatomy in comparison to the LCA. The RCA can be viewed nicely
in LAO, but even better in LAO-caudal, which is better than the former one in displaying
the crux. The crux with the bifurcation of the RCA into the PLA and the PDA is also very
nicely displayed in AP-cranial, and in some cases in RAO-cranial projection. Some operators
use only simple LAO and RAO to evaluate the RCA. Left cranial (LAO-cranial) displays best
the proximal and the distal RCA and is very good for displaying the crux. It can also be
pretty good for displaying the PLA and the PDA (Di Mario and Sutaria, 2005). Cranial (AP-
cranial), sometimes with just a small angulation to the right (5-10º) is very good for
displaying the crux, the PLA and the PDA. The mid-RCA is best displayed in lateral and the
RAO-view, but in most cases, LAO can be sufficient for this segment also.
standard JR4, or JR3.5, sometimes JR3 catheter. The origin of the graft to the RCA is usually
in the ascending aorta, just above the sinotubular junction. The cannulation is performed by
placing the catheter high in the ascending aorta, applying clockwise-rotation, and, at the
same time, pushing the catheter a bit downwards. If Judkins catheters are inadequate, RCB
(right coronary bypass) catheter can also be used for cannulating the SVG (saphenous vein
graft) to RCA.
The JR4 or JR3.5 catheters can also be used to cannulate all the other bypass grafts. Those
grafts' origins are usually located higher in the ascending aorta, just beneath the arch. If the
grafts for LAD, diagonals, intermediate, and obtuse marginals are unreachable with JR
catheter, an LCB (left coronary bypass), or an AL catheter can be used. If grafts cannot be
found selectively, an aortography in LAO position can be used to determine their origin,
position, or stumps if they are occluded. For obtaining a proper evaluation, after
aortography, a selective cannulation of the grafts should be reattempted.
Left internal mammary arterial graft can be cannulated using the IMA (internal mammary
artery) catheter, but JR4, JR3.5, JR3, or short tip JR can also be used in certain situations. The
ostium of the left internal mammary artery (LIMA) is engaged in 50° LAO position,
although sometimes it can be viewed better from AP or RAO 40° position. First in 50° LAO,
a J-wire is passed into the left subclavian artery, beyond LIMA. Than the IMA catheter is
passed over the wire, also beyond the LIMA origin. Then, from the position best suited for
the operator (AP, LAO 50°, or RAO 40°), the catheter is slowly withdrawn, rotating the tip
counterclockwise. Small test-injections are needed to display the ostium of the LIMA. The
angiography should be performed from several positions, especially paying attention to the
distal anastomosis with the LAD, since this position is the one most prone to iatrogenic
injury from manipulation during the grafting procedure, thus being the most prone to
developing a significant stenosis. A 90° left-lateral position is almost mandatory in
displaying LIMA-LAD graft, since it is very good to depict the distal anastomosis.
For cannulating the right interior mammary artery (RIMA), the brachicephalic artery is
engaged, J-wire is advanced distally to the RIMA origin, from the right subclavian to the
right axillary artery. The IMA catheter is advanced also distally over the wire. In the LAO
50° projection, after removing the J-wire, the catheter is slowly withdrawn, and with
occasional test-injections engaged into the RIMA ostium.
The right gastroepiploic artery has been used for coronary bypass, although very rarely.
Surgeons sometimes use it when mammary arteries and saphenous vein grafts are
unavailable. It is cannulated by first entering the hepatic artery using the cobra catheter. The
operator must then advance a hidrophylic guidewire into the gastroduodenal artery, and
then into the right gastroepiploic artery. Selective angiography of the letter will be enabled
by switching the catheter, usually to right Judkins (Di Mario and Sutaria, 2005). The
procedure is performed very rarely, and because of the unusual anatomy for the invasive
cardiolgist, can be time-consuming.
9.1 Haemostasis
Haemostasis is an important practical matter. Complications from diagnostic cardiac
catheterization are rare, but if they happen, those related to haemostasis are the most
common ones. When a patient comes out of the hospital after coronary angiography or
coronary stenting, and gets a groin haematoma, he/she will most likely quickly forget the
top-notch, several million euros costing equipment used during the procedure, as well as
the skills of the operator who performed sometimes very difficult intervention, but will
remember a large haematoma, and often complain about it to his family, neighbours, and
friends. Therefore, it is very important to adequately perform haemostasis, not only for
obvious medical, but also for "public-relation" reasons. The details of haemostasis and its
possible complications are discussed elsewhere. However, there are a few points that need
to be noted. Haemostasis may be difficult if the patient is obese, if there is high blood
pressure (always try to regulate the blood pressure prior to sheath removal), or if clotting
time is prolonged. If there is no vital indication, coronary angiography should be avoided if
INR is >1.6, otherwise, the sheath should be sutured and removed upon achieving a more
appropriate INR value. A significant aortic regurgitation with pulsus celer et altus can also
make the post-sheath-removal hold difficult.
Large sheaths create bigger holes in the arterial wall, so the bigger the sheath diameter, the
more difficult haemostasis will be. The patients who frequently elevate intra-abdominal
pressure by sneezing, coughing or performing Valsalva maneuvers can prolong bleeding
from the vascular access site. Same is true for restless patients, so those sometimes need to
be sedated and observed by a nurse. In order to facilitate the haemostasis process,
haemostatic devices have been developed, such as: collagen plugs, external pressure
devices, vascular clips, external C clamps, topical haemostatic accelerators etc.
echocardiograms, avoiding left ventriculography spares the patient from additional contrast
administration, which is especially important if the patient already has impaired renal
function. Also, without left ventriculography there is less radiation both for the patient and
for the operator. If the patient is in heart failure or cardiogenic shock, every additional
volume intake can prove to be risky for his/her condition. However, some operators and
some centers prefer to perform the left ventriculography, especially if there is doubt about
echocardiography findings, or if there is no echocardiography finding available.
In order to perform the left ventriculoghaphy, the operator advances the pigtail catheter
over a J-wire to the aortic root. The author's choice is usually the angled version of the
pigtail catheter. The J-wire is withdrawn into the catheter, with the J-wire tip just inside the
catheter tip to add to the catheter stiffness in order to successfully pass over the aortic valve.
The position of the digital flat-panel detector or the image intensifier is in RAO 30°. The
catheter with the wire inside of it is advanced farther, so that the body of the catheter
"bounces off" the aortic valve, and the distal curve faces upwards. Then the catheter is
rotated in a clockwise fashion, being at the same time slowly withdrawn. This causes the
catheter to rotate, and when the aortic valve opens, slip through the aortic ostium and into
the left ventricle. If there are difficulties to pass the catheter into the left ventricle this way,
the catheter tip is withdrawn into the ascending aorta, and the valve is probed with the J-
wire. When the wire passes into the ventricular cavity, the catheter is advanced into the
ventricle over the wire. Sometimes, a Glidewire with hydrophyllic coating must be used to
pass the aortic valve, especially if there is a tight aortic stenosis. Also, sometimes it might be
easier to pass the valve with a Judkins right coronary catheter.
The catheter is then held with the tip in the middle of the ventricle. The proximal end of the
catheter is connected to the injector after it has been adequately aspirated and flushed.
Through the automated injector, some 35–50 ml of contrast is injected into the ventricle at
the rate of 12-15 ml/s, delineating the left ventricular cavity and displaying the left ventricle
contractility. Intracavitary thrombi can be seen as hypodensities or filling-defects of contrast
within the left ventricle. Mitral regurgitation, if exists, can be seen and semi-quantified,
using degrees from 1 to 4, with 4 being the most severe. Care must be taken when advancing
the pigtail catheter into the left ventricle, because the mechanical contact with endocardium
can provoke premature ventricular beats, even ventricular tachicardia. It can also provoke a
complete heart block if the patient already has a right bundle-branch block, and the catheter
irritates the left bundle-branch upon contact with left ventricular endocardium. If there are
foreign masses within the left ventricle, such as thrombi or vegetations, those can be
fragmented and embolized into systemic circulation, causing potentially catastrophic
outcomes. A combination of a fragile myocardium and too vigorous catheter manipulation
can cause myocardial rupture with fatal cardiac tamponade and refractory shock.
Entanglement of the catheter into the chordae tendineae of the mitral valve or hooking the
catheter tip on a mitral cusp can result in seemingly severe mitral regurgitation, so care
must be taken to avoid this. In exceptional circumstances, catheter tip can theoretically rip a
mitral cusp or break up a chorda or two, causing acute mitral regurgitation of various
degree, thus complicating the left ventriculography.
After the ventriculography, the catheter is connected to manifold to record pressures in the
left ventricle. Upon withdrawal of the catheter over the aortic valve, pressure curves in the
aorta are also noted, and pressure values recorded. The systolic pressures in the aorta and
Procedural Techniques of Coronary Angiography 117
the left ventricle are noted for transvalvular aortic pressure gradient. Care must be taken not
to declare aortic stenosis in patients with previously unrecognized hypertrophic obstructive
cardiomyopathy with high pressure-gradients across the left ventricular outflow tract,
which may mimic the haemodynamics of aortic stenosis, with pressure gradients between
the middle of the left ventricle and the ascending aorta.
Calculation of the left ventricular ejection fraction (LVEF) is usually performed using the
software already incorporated into the imaging review station. Some operators use the semi-
quantitative eye-ball method in LVEF estimation, which has, when used by experienced
operators, shown a surprisingly good correlation with the actual value of LVEF measured
invasively in several studies. The software calculates LVEF by subtracting left ventricular
end-systolic volume from the left ventricular end-diastolic volume.
Mastering the left ventriculography is important as the transfemoral – transcatheter aortic
valve implantation is being performed increasingly. For severely stenosed aortic valves, it
may be easier to pass the valve using an AL catheter and a Glidewire.
10.2 Aortography
Aortography is defined as a radiographic recording of injection of a large volume of
radiocontrast into the aortic root. Most commonly, some 50 ml of radiocontrast, at a rate
of 15-25 ml/sec with a 0.5 sec linear rise is used. The catheter of choice is a sidehole
catheter, usually the pigtail shape. The best projection for estimation of aortic
regurgitation is LAO 45°. Aortic regurgitation is semi-quantified and described in degrees
from 1 to 4, much like mitral regurgitation. If the patient is subjected to invasive
diagnostics because of suspected coarctation of aorta, the coarctation will be best visible if
aortography is performed in LAO 20° position. Using the pressure monitoring, the
gradient across the coarctation can also be measured. For evaluation of a suspected patent
ductus arteriosus, the shot is usually taken at a very steep LAO projection. Aortography is
usually done for evaluating the ascending aorta for dilation or aneurysm, and/or aortic
regurgitation. The J-wire and the catheter are positioned in the ascending aorta, inside the
root or at the level of sinotubular junction. Anatomy and dimensions of the ascending
aorta and aortic arch are noted, as well as aortic regurgitation (if such a disorder exists),
and/or aorto-coronary bypass grafts, also if they exist. Care must be taken that the
catheter does not protrude back into the left ventricle during injection, which can make
quantification of the aortic regurgitation difficult.
11. Conclusion
Invasive cardiologists today generally continue their education and become
interventionalists. Anyone who wants to become a good interventionalist must be able to
routinely perform diagnostic coronary angiography and to be able to solve the problems
that might occur during the procedure. Therefore, the techniques of performing coronary
angiography must be mastered by an invasive cardiologist. That creates the conditions for
swift procedures, informative findings, purposefull conclusions and further
recommendations, and last, but not least, the maximum safety for the patient. However,
even with most carefully conducted coronary angiograms, there can be false readings. This
is especially true for less experienced operators, who can sometimes misinterprete the
118 Advances in the Diagnosis of Coronary Atherosclerosis
finding, thus affecting the final recommendation for further treatment. These pitfalls may
be: inadequate number of projections, ostial coronary occlusions without visible stumps,
superselective injection, e.g. especially if LAD and CX have (almost) separate ostia, catheter
induced coronary spasm, congenital coronary anomalies, pulsatile injection of radiocontrast
with filling defects mimicking coronary atherosclerotic obstruction, myocardial bridging –
the key to recognize it is the fact that the lumen normalizes upon muscle relaxation, i.e.
during diastole. Today, coronary angiogram projections must be observed by the operator in
the context of future percutaneous coronary intervention. The lesions are not assessed only
as significant or non-significant, but are evaluated regarding their length, their position
regarding side-branches and other caracteristics important for the possible intervention.
Therefore, it is of paramount importance to adequately display the coronary arteries and
their lesions, in appropriate projections, with an adequate number of different views, still
remaining rational regarding radiation and contrast medium consumption. Interventional
procedures in cardiology today have expanded beyond the treatment of coronary artery
disease. We are witnessing a technopharmacological improvement which enabled the
interventional, catheter-based treatment of valvular heart disease, closure of interatrial and
interventricular septal defects, relief of aortic coarctations, interventional treatment of
hypertrophic obstructive cardiomyopathies, paravalvular leak closure, left atrial appendage
closure, peripheral vascular disease treatment etc, and the basis for performing any of the
interventional procedures, especially percutaneous coronary interventions, is mastering
coronary angiography first.
12. References
Brasselet C, Blanpain T, Tassan-Mangina S, Deschildre A, Duval S, Vitry F, Gaillot-Petit
N, Clément JP, Metz D. (2008) Comparison of operator radiation exposure with
optimized radiation protection devices during coronary angiograms and ad hoc
percutaneous coronary interventions by radial and femoral routes. Eur Heart J 2008
Jan;29(1), pp. 63-70, ISSN 0195-668x
Chen CW, Lin CL, Lin TK, Lin CD. (2006) A simple and effective regimen for prevention of
radial artery spasm during coronary catheterization. Cardiology. 2006;105(1): pp. 43-
7, ISSN 1878-5409
Conti CR, Levin DC, Grossman W. (1980). Coronary Angiography, In: Cardiac catheterization
and angiography, Grossman W, pp. 147-169, Lea & Febiger, ISBN 0-8121-0712-4,
Philadelphia, Pa, USA
Cooper CJ, El-Shiekh RA, Cohen DJ, Blaesing L, Burket MW, Basu A, Moore JA. (1999).
Effect of transradial access on quality of life and cost of cardiac catheterization: a
randomized comparison. Am Heart J 1999 Sep;138(3 Pt 1): pp. 430-6, ISSN 0002-
8703
Di Mario C & Sutaria N. (2995). Coronary angiography in the angioplasty era: projections
with a meaning. Heart 20052005;91: pp. 968-976, ISSN 1355-6037
Gonzalez A, Rahimtoola SH, Kulick DL. (1991). Technique of Vascular Access, In: Techniques
and Applications in Interventional Cardiology, Kulick DL and Rahimtoola SH, pp. 1-18,
MosbyYear Book, ISBN 0-8151-7048-3, St. Louis, MO, USA
Procedural Techniques of Coronary Angiography 119
Watson S & Hunter J. (2011) Cath Lab Staff Duties, In: Invasive Cardiology: a manual for cath
lab personnel, 3rd Edition, Watson S & Gorski KA, pp. 119-129, Jones & Bartlett
Learning, ISBN 978-0-7637-6468-5, Sudbury, MA, USA.
7
1. Introduction
Since Wilhelm Röntgen reported his novel discovery of the X- Ray in 1895(Röntgen, 1898 as
cited in Weinmann etal., 2005), the Diagnostic imaging has been an integral part of
medicine. He was decorated by the second class of Prussian crown medal and he was also
awarded the first physic Nobel Prize at 1901. Levy- Dorn was another pioneer in radiology
who understood the potential importance of X-ray in medicine and opened a daily private
office for medical examination with X-ray in 1896 just one year after innovation of X-ray by
Röntgen. He pointed to the danger of this method to the living organism very early
(Hierholzer K & Hierholzer J 1997; Nitze, 1895; as cited in Hierholzer K & Hierholzer J, 2002)
Since X-rays are not sufficiently absorbed by soft tissue, contrast media (CM) is used to
highlight organs or pathologies. Osborne etal reported that inorganic Iodine enhanced the
urinary tracts X-ray images (Osborn etal., 1923). But the most important contributor to the
field of urological imaging came from the field of agriculture when A Binz and C Räth, two
scientists from the Berlin agricultural college synthesized a new organic iodinated molecule
"Selectan"(Binz & Räth 1928 as cited in Hierholzer K & Hierholzer J, 2002), and a research
fellow used this agent in clinical investigations. (Swick 1929a, 1929b as cited in Hierholzer K
& Hierholzer J, 2002; Weinmann etal., 2005).
In 1928 an urologist, Forssmann, used one of these agents in his own coronary arteries
(Hricak & Barbarive 1984).This was an unexpected methodological contribution of
urological research to cardiology.
From 1929 on, serial production of Uroselectan was established. This agent was a big step
forward in safety, because ionic iodide (Sodium Iodide and Lithium Iodide) cannot be used
in a clinical setting. In the early 1950s, a new generation of iodinated agents was launched,
which were derivatives of triiodinated benzoic acid, e.g. diatrizoate (Urografin etc.). These
agents became standard in diagnostic imaging for the next 30 years and are still widely used
in many countries. Almen suggested that non-ionic molecules could reduce osmolality
(Almen, 1969, as cited in Weinmann etal., 2005), an idea that was the basis of safer
compounds that entered routine clinical use in the 1980s. Water-soluble, non-ionic iodinated
contrast agents are now the workhorses in contrast based imagings. More than 90% of
contrasts media are used in western countries are non-ionic CM.
There are two main complications of contrast media. The aim of this chapter is to discuss
these two major side effects of CM. the most important of these two complication is contrast
induced nephropathy (CIN) which will be described in details and the other is anaphylaxis
reactions to the CM which will be mentioned briefly at the end of the chapter.
122 Advances in the Diagnosis of Coronary Atherosclerosis
amount of iodine
Type Name osmolality ionicity mono/dimer viscosity
iodine ratio
(mosm/kg water) mg/mL mPa.sec at 370c
dialysis. But it is not known whether the increased level of Cystatin-C is due to the
decreased GFR or it is released from atherosclerotic plaques during angiography .If
Cystatin-C increases by more than 10% within 24 hours, then it is a good marker of CIN
occurrence and further events. But an increase of less than 10% from baseline will rule out
the diagnosis of CIN and the patient can be discharged without any caution (Briguori etal.,
2010).There is no study to evaluate the validity of Cystatin-C in earlier time. Cystatin-C has
to be better validated in different situations.
NGAL is also an early diagnostic biomarker of acute kidney injury, but studies for
validating this biomarker in CIN are limited. It’s specificity and sensitivity in diagnosis of
CIN in children has been identified (Hirsch etal., 2007).
The most accurate method for measuring GFR is radionuclide techniques which are
expensive and labor-intensive. The Cockcroft-Gault or MDRD equations are useful for the
calculation of GFR in clinic.
The problem with Studies, regarding CIN is that nearly in all these studies contrast
nephropathy is defined by serum creatinine increment which is a soft outcomes value. If
hard outcomes like the need for dialysis, readmission, other clinical complications and death
are considered, it may cause better understanding the nature of AKI including CIN and
therefore its better management. It may also be more useful if RIFLE classification is taken
into account rather than Acute Kidney Injury Network criteria for better definition of CIN.
Further studies should be done to validate this classification for CIN diagnosis.
The differential diagnosis of CIN is cholesterol atheroemboli, volume depletion and
interstitial nephritis.
2.3 Incidence
CIN is the third cause of AKI in hospitalized patients. The cumulative incidence of CIN is
10% of all AKI (Tepel etal., 2006). The incidence of CIN in patients without any risk factor is
0.6-2.3%, but in high risk patients it will be raised up to 90% (McCullough etal., 2006A ;
Toprak & Cirit 2002). In two studies in 1979 and 2002, CIN was the third cause of in-hospital
AKI (Nash etal., 2002). These studies showed no change in the incidence of CIN in this
period (12% in 1979 and 11% in 2002).
Three factors increase the incidence of CIN in future: 1) increase in burden of CKD, 2)
Increase in incidence of diabetes, and 3) increase in diagnostic and therapeutically measures
requiring CM.
The incidence of CIN is dependent on the renal function. With serum creatinine more than
1.3mg/dl and more than 1 mg/dl in men and women respectively the risk of CIN will
significantly increase (Lamiere etal., 2006). It has been shown that by increasing serum
creatinine from 1.2 to 2.9mg/dl the risk of CIN increases from 4% to 20% (Barrett etal.,
1992;). The incidence of CIN in patients with serum creatinine of 3 mg/dl with or without
diabetes is more than 30%.In another study the risk of CIN in patients with serum creatinine
equal to1.5mg/dl was 8%, but with serum creatinine of 6.8mg/dl the risk of CIN has been
increased to 92% (McCullough etal.,1997). In patients with normal renal function, even in
the presence of diabetes or other risk factors the incidence of CIN is less than 2% ( Lamiere
etal., 2006). The incidence of CIN in diabetic patients with normal serum creatinine is 3.7%
(Rihal etal., 2002).In patient with severe renal failure and diabetes the need to dialysis will
be increase to 12% if CIN develops after CM exposure (Manske etal.,1990).
With regards to coronary angiography the incidence of CIN after this procedure has been
reported to be 3-14%. Only 2% of patients without diabetes and with serum creatinine of 1.1
mg/dl will develop CIN after coronary angiography (McCullough etal.,1997; Rihal etal., 2002).
125
Risks and Complication of Coronary Angiography: Contrast Related Complications
contrast that is being used for coronary angiography (Marenzi etal., 2006b). Old age
(Iokavou etal., 2003), hypovolemia (McCullough etal., 2006B) and hypotension are other risk
factors of CIN. Hypovolemia is among few risk factors which are preventable and should be
corrected promptly before starting the procedure. The medications that cause extra-cellular
contraction like diuretics or cause vascular tonicity changes like non-steroidal anti-
inflammatory drugs (NSAIDS) may be involved in development of CIN or at least may
increase the severity of the disease. The use of angiotensin converting enzyme inhibitors
(ACIs) or angiotensin receptor blockers (ARBs), while the blood pressure is in normal range
are not considered contraindicated and could be continued.
2.6 Type of CM
The safety of a contrast agent depends in large part on the amount of CM that must be
administered. The body’s ability to tolerate any substance depends on the amount given.
Even isotonic saline is toxic at very large doses. High dosages that disturb the ionic and
osmotic balance in the body will elicit adverse reactions without exhibiting a direct
interaction with other molecules (chemotoxicity). This kind of toxicity is based on the
osmotic activity of the agent or, more precisely, on the osmotic load (mosmol/kg body
weight). The important properties of a CM that determine its nephrotoxicity are: osmolality,
volume, and repeated use, route of use, viscosity and Ionicity.
Here we briefly review the role of each of the properties of a CM in the development of
CIN.
127
Risks and Complication of Coronary Angiography: Contrast Related Complications
3. Pathogenesis
The primary mechanism of CIN is Ischemia and direct tubular toxicity of CM to epithelial
tubular cells.In experimental studies, after contrast infusion there is an early brief
vasodilatation of renal vasculature, followed by a long term vasoconstriction (Arakawa etal.,
1996; Seeliger etal., 2007). This biphasic response has not been evident in human and mostly
increase of renal blood flow has been shown (Weisberg etal.,1992). These studies carried out
the direct measurement of blood flow by hemodilution techniques. Nevertheless, if renal
blood flow is measured directly by an intra-renal artery guide-wire, no difference of blood
flow could be detected at the time of ventriculography, while subsequently by further CM
infusion, the blood flow is decreased by3.7-39.5% from base (Mockel etal., 2008).Although
these studies showed mild to moderate decrease of renal blood flow after exposure to CM,
these findings nevertheless cannot describe the longitudinal decrement of GFR in CIN
patients.
the low oxygen pressure in this part of nephron is not related to the osmolality of CM (Liss
etal., 1998). Administration of A1 adenosin receptor antagonists could not humiliate the
decreased oxygen tension (Liss etal., 2004), but it seems that prostaglandins and nitric oxide
could counteract vasoconstrictor effect of CM (Agmon etal., 1994). In animals, nitric oxide
depletion has an effective role in vasoconstriction (Agmon etal., 1994; Ribeiro etal., 2004).
3.4 Others
In experimental studies CM can decrease capillary blood flow by decreasing the velocity of
erythrocytes and increasing the red blood cells aggregation. HOCM also decreases
erythrocyte volume and alters its membrane deformability. Recently hemeoxygenase
activator is introduced as a pathomechanism of CIN development. Hemeoxygenase inhibits
ROS production, suppresses pro-apoptotic proteins, activate anti-apoptotic proteins and has
anti-inflammatory and vasodilatory effects. In future this enzyme may play an important
role in CIN prophylaxis in human.
4. Prophylaxis
If CIN happens, the management is supportive, and because the time of insult is known the
best measure is prophylaxis. Although in many studies, meta-analysis and systematic
reviews have focused on prophylactic measures of CIN, nevertheless there is no an
evidence-based guideline for clinical use.
130 Advances in the Diagnosis of Coronary Atherosclerosis
No general consensus is present about the prophylactic measures of CIN other than
stopping nephrotoxic agents, hydration and use of the lowest possible volume of CM and
not using HOCM. Published guidelines are according to limited studies on very heterogenic
patients. So they cause more confusion rather than better understanding and enlightment of
the issue of CIN to provide the best reliable prophylactic measures. Probably the European
Society of Urogenital Radiology (ESUR) guideline is yet valid (Morcos etal.,1999) and
further studies within last 13 years have not been demoted its validity.
etal., 2003; Duong etal., 2005; Dzgoeva etal., 1995, Isenbarger etal., 2003; Kshirsagar etal.,
2004; Liu etal., 2005; Nallamothu etal., 2004; Onbasili etal., 2007; Pannu etal., 2004; Spargias
et al., 2004; Zagler etal., 2006). Some of these studies showed that there is no positive effect
for NAC in prevention of CIN (Onbasili etal., 2007; Spargias et al., 2004). On the other hand
some meta-analyses showed effectiveness of NAC but the most of these meta- analyses had
inconclusive results (Bagshaw etal., 2006; Nallamothu, 2004). In conclusion although huge
data is available, the role of NAC in preventing CIN is moot yet. This discrepancy may be
due to bias in the publishing of studies with positive results, so these studies should be
considered with skepticism (Fishbane etal., 2008).
In a study on patients with myocardial infarction high dose intravenous NAC (1200mg) was
effective in prevention of CIN (Marenzi etal., 2006b). Surprisingly no patient in this study
had received fluid for volume expansion. An interesting but confusing issue in studies about
NAC is the decrement of serum creatinine after CM exposure (Baker etal., 2003; Drager etal.,
2004; Kay etal., 2003; Marenzi etal., 2006b). Probably NAC can decrease serum creatinine
directly without affecting renal function (Drager etal., 2004). In this study the GFR of
patients who were taken NAC four days before CM exposure was significantly higher than
those patients were taken NAC only for two days. Interestingly this study and study of
Hoffmann and coworkers showed that NAC may decrease serum creatinine in patients that
had not received CM (Hoffmann etal., 2004). There are concerns that NAC with increasing
tubular secretion of creatinine decreases the serum creatinine without any change in GFR. A
recent meta-analysis found that NAC was more protective than saline infusion and the
authors recommended the use of NAC because of its low cost, availability and paucity of
side effects (Cigarroa etal., 1989). In contrast to this recommendation which is based on
safety of the NAC, there is a report of anaphylactic reaction in 3-6% of patients receiving
intra-venous NAC (Kanter, 2006).
Briefly, NAC may increase GFR in normal patients and restore GFR in high risk patients for
CIN. But it is not known whether these effects are due to direct protective effect of NAC on
kidney or it is due to alteration in creatinine metabolism. Some studies reported good effect
of NAC while others did not find such positive effects.
In conclusion, there is no agreement about the NAC. Otherwise there is no guideline about
the route of administration of NAC or the dose or the time of its administration. There is an
important question whether its effect on serum creatinine is real or spurious. It is obvious
that we need more good designed RCTs to solve these controversies.
incidence of CIN (Cigarroa etal., 1989; Manske etal., 1990), but there is no magical dose of
contrast to believe that below that dose, the CIN will not occur. The renal function is an
important limiting factor for dose of CM. In study of Laskey etal. it was reported that if the
volume of CM exceeded 3.7 times of creatinine clearance, the risk of CIN will be higher
(Laskey eal., 2002). So the absolute value of contrast volume may be too low. There are 2
formulas for calculating relatively the safe volume of CM according to renal function.
ml
5 contrast media
kg
dose of CM mg (1)
serumcreatinine ( )
dl
Or,
4.5.1 Theophylin
High level of adenosin is a possible mechanism for occurrence of CIN. It causes afferent
arteriole vasoconstriction (Haller etal., 2004; Pflueger etal., 2000). Theophylin is a non
specific antagonist of adenosin receptor, so it may theoretically be beneficial. Studies about
the theophylin like studies of NAC are not conclusive. Few studies showed effectiveness
of theophylin or aminophylin in prevention of CIN , but in a meta-analysis no positive effect
of this drug was shown (Bagshaw & Ghali, 2005). So the routine use of theophylin is not
recommended. In a study on patients in ICU, infusion of 200mg theophylin half an hour
before contrast exposure was superior to NAC (Huber etal., 2006) but arythmogenesity of
theophylin is a problem in coronary artery disease. It is possible that in the future,
theophylin is replaced by a selective adenosin receptor antagonist with less toxicity and
more effectiveness than theophylin in CIN prophylaxis protocols (Pflueger etal., 2000).
4.5.4 Trimetazidine
This novel pharmacologic agent interferes with different metabolic pathways. It can prevent
Ischemia-reperfusion injuries. In a RCT it was effective in preventing CIN (Onbasili etal.,
2007).
4.5.5 Erythropoietin
Erythropoietin may have some role in CIN prophylaxis. Its effect has been shown in some
studies (Yokomaku etal., 2008).
4.7.3 Metformin
Metformin causes lactic acidosis in patients with renal failure. Otherwise uncontrolled
diabetes is a risk factor of CIN. There is no RCT about metformin and CIN. It is
recommended to continue the use of the drug until the night before the procedure (Bailey
etal., 1996). Others have suggested the continuation of metformin in patients with normal
renal function. If metformin is stopped, it is better to start it again when the physician is sure
that CIN has not been happened.
4.7.4 Diuretics
Use of furosemide, manitol and endothelial receptor antagonists were associated with
increased risk of CIN (Anto etal., 1981; Solomon etal., 1994; Weisberg etal., 1994).Forced
diuresis increases the risk of CIN. Although there is no RCT about diuretics, nevertheless it
is not theoretically rational to expand the volume from one hand and to contract it from the
other hand. So it is recommended to discontinue diuretics 12 hours before the procedure
and to restart it 24 hours after that.
4.7.5 Manitol
Like diuretics it may increase the risk of CIN in patients with forced diuresis (Solomon etal.,
1994). The problem is raised in neurosurgical patients on manitol. It is suggested to stop the
drugs several hours before CM administration and to monitor the hydration status of the
patients very carefully (Erley, 2006)
Up to the present time there are two popular scoring models. Both of which have been
introduced at 2004 and provide good tools for estimating the odds of the CIN. They are
more or less similar with few differences in the terms of risk factors and scoring. According
to the data of 8357 PCI patients, Mehran et al. determined the independent predictive factors
of CIN and provided a scoring model for estimating potential risk of patients (Mehran etal.,
2004). Bartholomew et al. also suggested another risk stratification model at the same year
(Bartholomew etal., 2004). They evaluated the data of 2047 patients and determined the risk
factors and their risk scoring. Table 3 shows these two models comparatively.
According to Mehran's model the risk score of less than 5 is associated with 7.2% risk of CIN
and nearly no patients need dialysis (0.04%) but risk score more than 16 will increase the
risk of CIN up to 57.7% and need to dialysis to 12.6%.
Bartholomew et al. reported no patients with risk score of less than 1 developed CIN and
CIN had occurred in 25% of patients with risk score more than 9.
In regards to risk stratification models, some factors are not predictable before the procedure
(like need to balloon pump or volume of contrast), so according to these models it is
impossible to estimate the exact reliable and accurate risk of CIN in every patient.
6. Recommendations
Until more accurate and universally accepted guidelines are developed, following
recommendations which are based on different studies are useful in preventing CIN.The
important issue is how to find the patients at risk before imaging procedures. There are
some recommendations in this regard.
The American Radiology College (ARC) has suggested the measurement of serum creatinine
in all patients who are suspected of having renal disease or those at risk of nephrotoxicity
before the procedure (The committee on drugs and contrast media of the American College
of Radiology, 2010). The patients at risk are those with a positive answer to any of the
following statements: history of renal disease (including tumor or transplantation), familial
history of renal disease, on diabetes therapy, having paraproteinemia disorders, having
137
Risks and Complication of Coronary Angiography: Contrast Related Complications
2. Delaying the procedure in volume depleted patients or those who have blood
circulation collapse or patients with CHF until stability of hemodynamic is achieved.
3. Infusion of 0.45% salin in patients at risk of volume overload.
4. If the time to procedure is less than 6 hours (in emergent angiography) a simultaneous
administration of oral and IV Fluid with the dose of 3 ml/kg/hour and maximum 300cc
fluid/hour is recommended. The fluid administration should be started one hour
before procedure. After procedure the fluid is continued with the rate of 1 ml/kg/hr for
12 hours.
5. Use of NAC 1200mg twice daily in the day and day after the procedure. In emergency
situations use of 1200mg intravenous bolus of NAC instead of first oral dose is
appropriate.
6. Measurement of serum creatinine 24-48 hours after procedure in patients with
moderate and severe risk factors
7. Anaphylactic reactions
Anaphylactic reactions to CM are well known from the early use of these agents. These
reactions are dermal allergic type reactions, edema, pulmonary edema, angina pectoris,
arrhythmia and hypertension crisis. Mostly these side effects are mild and there is no need
to treatment. The occurrence of the serious side-effects is within 20 minutes of CM
administration. They are exhibited by nausea and vomiting, urticaria, pulmonary edema,
bronchospasm, laryngospasm, hypotension, tachycardia, vaso-vagal responses and seizure.
In last decade the reactions to CM have significantly decreased from 5-12% to 0.2-0.7%
(Sayol & Bush, 2011). It may be due to shift from HOCM to LOCM and IOCM. Anaphylactic
reaction to HOCM is more than LOCM. Ionicity is also a cause of reaction to these agents
and nonionic monomers are less anaphylactic. These reactions are either chemotoxic or
Anaphylactic (Idio or nonidiosynchratic).The chemotoxic reaction is related to
physicochemical property of CM and its severity is dependent on the dose and
concentration of the agent.
The mechanisms of anaphylactic reaction are not well understood. Histamine, Leukotriens,
Basophiles and prostaglandins may be mediators of this type reaction. It is unlike that
antigen- antibody interaction plays any role.
Aging, history of allergy and asthma and previous history of reaction to CM, are the risk
factors of anaphylactic reactions. The patients with CKD, cardiovascular disease and
epilepsy are also at increased risk. Beta blockers may increase the threshold and severity of
anaphylactic reactions (Kadivar & McClennan, 2010).
139
Risks and Complication of Coronary Angiography: Contrast Related Complications
9. Conclusion
Contrast agents are associated with many complications. There are two more prevalent and
important complications related to contrast media: allergic reactions and CIN. The allergic
reactions are preventable by knowing the high risk patients and premedication with steroids
and antihistamines.
The most important complication of contrast agents is CIN, which is usually a mild to
moderate AKI that is rapidly recovered. But it could be associated with increased significant
morbidity and mortality. There is no treatment for developed CIN, so it should be
prevented by some measures. The proved modalities for prevention of CIN are saline
administration, the lowest possible dose of CM, and use of IOCM or LOCM.
All patients at risk should be evaluated carefully before the procedures with CM and the
risk factors should be stratified according to available risk stratification models.
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147
Risks and Complication of Coronary Angiography: Contrast Related Complications
Complications of Cardiac
Catetherization
Mariano García-Borbolla1, Rafael García-Borbolla2
and Begoña Balboa3
1Hospital Virgen Macarena
2Hospital
de Jerez
3Hospital Virgen del Rocio
Spain
1. Introduction
Cardiac catheterization was primarily a diagnostic procedure that was used to evaluate
hemodynamics, ventricular function, and coronary anatomy. However, the introduction of
improved angioplasty equipment and new interventional devices in the 1980s made
catheterization an important tool in the treatment of cardiovascular disease.
Although diagnostic catheterization and percutaneous coronary intervention are done by
skin puncture rather than incision, and under local rather than general anesthesia, they can
cause a variety of adverse events, ranging from minor problems without long-term sequelae
to major complications requiring immediate corrective action. Furthermore, newer
interventional procedures may be associated with different and, in some cases, more
frequent complications.
2. Major complications
The risk of producing a major complication (death, myocardial infarction, or major
embolization) during diagnostic cardiac catheterization is generally well below 1 percent. As
a result, the risk-to-benefit ratio still favors performing this procedure as a part of the
evaluation of potentially fatal or lifestyle limiting cardiac disease.
The risk of an adverse event, for the individual patient, is dependent upon demographics,
cardiovascular anatomy, clinical circumstances including comorbidities, the experience of
the operator, and the type of procedure being performed (table 1 A-C) [1]. Severe peripheral
artery disease is a risk factor for all of the major complications.
2.1 Death
Death following diagnostic cardiac catheterization is now rare. Compared with the 1 percent
mortality rate seen in the 1960s, the second registry of the Society for Cardiac Angiography
revealed that the procedural mortality had fallen to 0.1 percent in the more than 200,000
patients catheterized between 1984 and 1987 [2].
High-risk subgroups have been identified in multiple large series [1-9]:
150 Advances in the Diagnosis of Coronary Atherosclerosis
Percent
Mortality 0.11
Myocardial infarction 0.05
Cerebrovascular accident 0.07
Arrhythmia 0.38
Vascular complications 0.43
Contrast reaction 0.37
Hemodynamic complications 0.26
Perforation of heart chamber 0.28
Other complications 0.28
Total of major complications 1.70
Noto, TJ Jr, Johnson, LW, Krone, R, et al. Cardiac catheterization 1990: A report of the Registry of the
Society for Cardiac Angiography and Interventions (SCA&I). Cathet Cardiovasc Diagn 1991; 24:75.
Table 1. (A): Risk of cardiac catheterization and coronary angiography (based on 59,792
patients)
PTCA: percutaneoas transluminal coronary angioplasty; CABG: coronary artety bypass graft.
Scanlon, PJ, Faxon, DP, Audet, AM, et al, J Am Coll Cardiol 1999; 33:1756.
Table 1. (C): Relative contraindications to coronary angiography
Patients with valvular heart disease, chronic kidney disease, diabetes mellitus requiring
insulin therapy, peripheral artery disease, cerebrovascular disease, and pulmonary
insufficiency all appear to have an increased incidence of death and major
complications from cardiac catheterization. Mortality is especially high in those with
preexisting renal insufficiency who have further deterioration of renal function within
48 hours after the procedure, particularly when dialysis is required [10].
A similar increase in risk is seen with severe disease of the left main coronary artery
(compared to single vessel disease) and with a left ventricular ejection fraction (LVEF)
below 30 percent (compared to an LVEF above 50 percent).
Age above 60 years and below one year and women have an increased mortality rate
after catheterization.
New York Heart Association functional class IV is associated with an almost tenfold
increase in mortality compared with classes I and II (table 2).
152 Advances in the Diagnosis of Coronary Atherosclerosis
Risk Factors*
Age ≥75 years
Black race
Female sex
Prior history of stroke
Systolic blood pressure ≥160 mmHg
Weight ≤65 kg for women or ≤80 kg for men
INR >4 or PT >24•
Use of alteplase (versus other thrombolytic agent)
Risk score Rate of intracranial hemorrhage, percent
0 or 1 0.69
2 1.02
3 1.63
4 2.49
≥5 4.11
* Each risk factor is worth 1 point if present, 0 points if absent. Points are added to determine the risk
score.
• INR: international normalized ratio; PT: prothrombin time.
Brass, LM, Lichtman, JH, Wang, Y, et al. Intracranial hemorrhage associated with thrombolytic therapy
for elderly patients with acute myocardial infarction: results from the cooperative cardiovascular
project. Stroke 2000; 31:1802.
Table 3. Cooperative cardiovascular project risk model for intracranial hemorrhage with
thrombolytic therapy
154 Advances in the Diagnosis of Coronary Atherosclerosis
Meticulous attention to technical factors such as wire and catheter exchanges is mandatory
in all patients, regardless of risk. Transient neurologic deficits may also result from the
injection of high osmolar contrast agents into the carotid or vertebral arteries. The majority
of patients with a periprocedural stroke have an unfavorable neurologic outcome and, in
one study, the in-hospital mortality was 32 percent [11].
These problems may include acute thrombosis, distal embolization, dissection or poorly
controlled bleeding (which may be manifested as free hemorrhage or contained hematoma
in the femoral or retroperitoneal areas), pseudoaneurysm, or arteriovenous fistula.
Hemorrhage and hematoma are usually evident within 12 hours after the procedure by
virtue of local discomfort, hypotension, or falling hematocrit, which lead to confirmatory
noninvasive testing (ultrasound or CT). In contrast, other complications such as
pseudoaneurysm and arteriovenous fistula may not become apparent for days to weeks
afterward.
device (OR 0.71) and toward more complications with the VasoSeal and Perclose devices
(OR 1.85 and 1.51, respectively).
For reports limited to PCI, there were no significant differences between APCDs and
mechanical compression overall. However, there was a significant increase in vascular
complications with the VasoSeal device (OR 2.52).
Closure devices also increase the risk of local infection or endarteritis [25,26]. Although this
complication is infrequent (0.3 percent in one series) [26], it can be serious when it occurs.
Consideration should be given to periprocedural antibiotics in immunocompromised
patients following prolonged arterial access or when sterility has been breached when a
closure device is used. It may also be prudent for the operator to change gloves prior to
using an arterial closure device. (See 'Infection' below.) An angiogram of the femoral artery
should be performed prior to use of an APCD. Use ofclosure devices should be avoided if a
hematoma has formed during the procedure, or in the presence of severe iliofemoral
vascular disease, and when the access site is below the bifurcation of the superficial and
profunda femoral arteries.
an excessive estimated risk from a femoral approach (eg, severe peripheral artery disease,
large abdominal aortic aneurysm, morbid obesity) [37].
The results of the modified Allen test can be altered by a number of factors, including
overextension of the wrist, skin tension over the ulnar artery, and operator error. As a result,
an appreciable number of false positive and false negative results have been reported [38].
As an alternative, many centers use a more direct assessment of blood flow to the thumb
during radial artery occlusion, which can be accomplished with pulse oximetry and
plethysmography [38,40].
The traditional modified Allen test was compared to pulse oximetry and plethysmography
in a consecutive series of 1010 patients referred for diagnostic cardiac catheterization [38].
The modified Allen test was considered abnormal if palmar blanching persisted for ≥10
seconds after release of ulnar compression. Plethysmography was observed for two minutes
during radial artery compression. Plethysmography was characterized as follows:
A: no change in the amplitude of the pulse tracing during compression
B: reduction in amplitude with compression
C: loss of pulse tracing with initial compression, but recovery of flow during two
minutes of compression (signifying development of collateral flow)
D: loss of pulse tracing with no recovery
Patients in categories A, B and C were considered to have a patent ulnopalmar arch, and
therefore eligible for radial catheterization.
The modified Allen test was abnormal in significantly more patients than plethysmography
(6.3 versus 1.5 percent). The authors concluded that plethysmography more accurately
demonstrates the adequacy of the ulnopalmar arch, and that the modified Allen test may
unnecessarily exclude some patients from radial artery catheterization. However, the
number of patients who underwent radial artery catheterization was not reported, and the
value of either test for predicting ischemic complications following radial artery
catheterization was not assessed.
4. Arrhythmias
A variety of arrhythmias and conduction disturbances can occur during catheterization. The
most common, ventricular premature beats, may be induced by catheter introduction into
the right or left ventricle, and are generally without clinical importance or impact.
Atrial flutter is generally well tolerated and can be treated with burst atrial pacing, or
electrical or pharmacologic cardioversion. Atrial fibrillation, on the other hand, can cause
clinical sequelae in the setting of a rapid ventricular response or if the loss of atrial systole
results in hypotension, as in a patient with mitral stenosis or diastolic ventricular
dysfunction. Synchronized cardioversion should be performed immediately in patients who
are hemodynamically unstable.
4.3 Bradycardia
Bradycardia commonly occurs during coronary angiography, most often at the end of the
injection of ionic contrast into the right coronary artery. Forceful coughing helps to clear the
contrast, support perfusion, and restore normal cardiac rhythmtachycardia or fibrillation is
rare complications of catheterization, occurring in 0.4 percent of cases in the second registry of
the Society for Cardiac Angiography [2]. These arrhythmias may result from excess catheter
manipulation or, more commonly, from intracoronary contrast injection. This complication
occurs more commonly when ionic and hyperosmolar contrast agents are used.
Vasovagal reactions, which can include bradycardia, hypotension, yawning, and/or sweating,
are seen in up to 3 percent of patients, particularly if they have pain or are anxious [2]. These
reactions may occur with palpation or compression of the artery prior to needle access.
Treatment usually consists of volume administration, atropine (0.5 to 1.0 mg intravenously),
and removal of the painful stimulus. Patients with critical coronary or valvular disease may
undergo irreversible decompensation from vagally-mediated hypotension. As a result, rapid
reversal of hypotension is crucial in this setting.
6. Allergic reactions
Allergic reactions during catheterization may be precipitated by three agents: the local
anesthetic, the contrast agent, or protamine sulfate.
6.3 Protamine
Allergic reactions to protamine sulfate occur occasionally, more often in insulin-dependent
diabetic patients who have received NPH insulin (which contains protamine) in the past [1].
The rapid administration of protamine sulfate can also provoke back pain of unknown
etiology.
In current practice, protamine is rarely administered. Most diagnostic catheterizations are
done without heparin anticoagulation and in most interventional procedures the heparin is
either allowed to wear off over the next two to three hours prior to sheath removal, or the
sheath is removed in the fully anticoagulated state using an arterial closure device.
7. Atheroembolism
During the process of cardiac catheterization, atheromatous debris is often scraped from the
aortic wall. This debris can cause systemic embolization, including cutaneous, renal, retinal,
cerebral, and gastrointestinal emboli (photo 1 and photo 2 and photo 3). To minimize the
risk of stroke or visual impairment, arterial catheter exchanges are best performed over a
wire in the descending aorta at the level of the diaphragm (for closed loop catheters) and in
the ascending aorta for angiographic catheters. Once arterial access has been obtained, the
practice of readvancing the guidewire through the infrarenal aorta rather than exchanging it
through a catheter should be avoided.
Blue toes are a classic manifestation of peripheral embolization of atheromatous material from proximal
arterial sources (eg, aorta); the pedal pulses are often normal. This patient, who has a 30-year history of
type 1 diabetes and severe peripheral vascular disease, presented with foot pain and discoloration.
Cholesterol microemboli from the aorta were suspected to be the cause.
Photo 1. Blue toe syndrome
Complications of Cardiac Catetherization 163
The high rate of release of atheromatous debris was illustrated in a series of 1000 patients
undergoing percutaneous coronary intervention: 51 percent had aortic atheromatous
material retrieved from the catheter after back flow of blood [43]. There were no associated
in-hospital ischemic complications, probably due to sufficient withdrawal of blood
containing the debris prior to the injection of contrast.
The reported incidence of atheroembolic events varies from 0.6 to 0.9 percent in
retrospective studies to 1.4 to 1.9 percent in prospective series [44].
Patient with lupus and anti-phospholipid antibodies with livedo reticularis (manifested by a reddish-
cyanotic, reticular pattern of the skin) which has resulted in ulcer formation (arrows).
Photo 2. Livedo reticularis
The clinical features of atheroembolism after diagnostic cardiac catheterization were
examined in a prospective evaluation of 1786 patients ≥40 years of age [45]. The following
observations were made:
25 patients (1.4 percent) were diagnosed with atheroembolism; 12 had cutaneous signs
(eg, "blue toes" syndrome, livedo reticularis) (photo 1 and photo 2) and 16 had acute
renal failure that was considered to be atheroembolic in origin because it persisted for
at least two weeks (while contrast nephropathy typically reverses within the first week).
Eosinophil counts were significantly higher in patients suffering from atheroembolism
both before and after catheterization.
Four patients with atheroembolism died in hospital (16 percent); all had progressive
renal dysfunction. The mortality rate was much lower (0.5 percent) in the patients
without atheroembolism.
164 Advances in the Diagnosis of Coronary Atherosclerosis
prefer the use of iso-osmolal agents (approximately 290 mosmol/kg) rather than low osmolal
agents (500 to 850 mosmol/kg) because of a lower risk of contrast nephropathy.
The 2007 focused update of the ACC/AHA/SCAI 2005 PCI guidelines recommended the use
of iso-osmolal in preference to low osmolal agents in patients with chronic kidney disease [47].
9. Infection
Cardiac catheterization procedures are performed using sterile technique. Thus, both local
infection and bacteremia are rare and endocarditis prophylaxis during cardiac
catheterization is not recommended for patients with valvular disease. Infection is
approximately 10 times more common with the brachial approach compared to the femoral
approach (0.6 versus 0.06 percent) [2-7].
Infection control guidelines for the cardiac catheterization laboratory were updated in 2006
by the Society for Cardiovascular Angiography and Interventions [48]. These guidelines
emphasize the importance of handwashing caps, gowns, gloves, and masks to protect the
patient against bacterial infection, and measures such as eye wear and vaccination for
hepatitis B to protect laboratory personnel.
12. Conclusions
Cardiac catheterization is a common proceduce with very low incidence of complications
nowadays. We can consider different kind of adverse events. On the one hand, the events
166 Advances in the Diagnosis of Coronary Atherosclerosis
related with the artery access, that are the most common, like haematoma, pseudoaneurysm
or dissection. On the other hand, we can observe complications more severe like
embolizations, renal failure or allergic reactions. Death is an uncommon complication, with
a is generally well below 1 percent. It is very important to know the potential adverse
events of these procedures in order to be aware to prevent it as better as possible.
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9
1. Introduction
Since its introduction several decades ago, coronary angiography and intervention has
become a widely and ever increasingly popular diagnostic and therapeutic modality.
However, it is not devoid of occasional systemic and local complications, and their
immediate detection and management are crucial to achieving a favourable clinical course.
This chapter focuses on the mechanism, diagnosis and treatment of the inherent risks of
coronary angiography and intervention.
2. Systemic complications
Coronary angiography and intervention comprise local procedures performed via a
percutaneous vascular approach. Untoward hemodynamic and systemic hormonal changes
and toxic effects of the contrast agents used might occur during and after procedures.
Patient’s general status, comorbid conditions and degree of systemic atherosclerosis are the
most important factors predisposing to the development of systemic complications.
Effective pre-procedural preparation and immediate proper treatment help prevent event
occurrence and its subsequent deterioration to permanent sequelae.
aggravate heart failure when present. In the past 60 years, high–osmolar contrast media
with osmolarity 5∼8 times higher than that of plasma have been replaced by low-osmolar
contrast media having osmolarity 2∼3 times higher than that of plasma.
pruritus, dizziness, mild dyspnea, nausea and vomiting and these are usually self-limiting
and resolving with minimal medical therapy. In severe cases, symptoms such as
hypotension, bronchospasm, laryngeal edema, abdominal cramps, pulmonary edema,
syncope, and serious arrhythmias can occur and lead to death and therefore require
intensive treatment. In patients who are at high risk of an anaphylactoid reaction to contrast
media, H1 antihistamines and corticosteroids prior to the administration of ionic contrast
may be useful in preventing anaphylactoid reactions to contrast agents (Delaney et al 2006).
The treatment of anaphylactoid reactions depends on the severity of symptoms and clinical
findings. Monitoring of the respiratory status and oxygen concentration is very important. If
mild bronchospasm occurs, patient can be treated with oxygen supplementation and/or
bronchodilator inhalation. In moderate cases, 0.1-0.3 mL of 1:1000 epinephrine should be
subcutaneously administered carefully, especially in patients with cardiac disease. In more
severe cases, 1 mL of 1:10,000 epinephrine can be administered intravenously for 5 minutes,
which can be repeated every 10 minutes. Additionally, antihistamines may be administered.
Hypotension is another serious side effect of contrast agents. Immediate oxygen
supplementation and isotonic fluid supplement is necessary, and if ineffective, dopamine at
an infusion rate of 2-20 μgm/kg/min can be administered.
2.3 Stroke
The cerebral embolism rate associated with coronary angiography is dependent on the
clinical characteristics of the patients, catheterization methods, imaging modalities for the
diagnosis, and clinical severity. In one series, silent ischemic cerebral lesions detected by
diffusion-weighted MRI were found in 5-22% patients after cardiac catheterization (Hamon
et al 2006, Busing et al 2005). After diagnostic coronary angiography via femoral approach,
stroke occurred in 0.11%, with a persistent neurological defect in only 0.04% (Ammann et al
2003). Although radial access for coronary angiography is more prone than femoral access to
generating more particulate cerebral microemboli which can pass the right middle cerebral
artery, femoral and radial access are associated with similar rates of stroke.
3. Local complications
Local vascular puncture and closure necessary in all catheterization procedures can cause a
variety of local complications, ranging from minor problems resolving with time to major
complications with long-term sequelae. For the individual patient, the risk is dependent
upon cardiovascular anatomy, the experience of the operator, and the type of procedure
being performed. Immediate detection and proper treatment is vital for the prevention of
catastrophic events.
risk factors are old age, female gender, high blood pressure, use of large sized sheaths, long
procedural times and use of anticoagulants and glycoprotein IIb/IIIa receptor antagonists
before or after procedures. Many arterial closure devices are available as an alternative to
traditional mechanical compression. Although these devices have the potential to reduce the
time to hemostasis, facilitate patient mobilization and decrease hospital length of stay, the
incidence of access-site-related complications is similar or somewhat higher compared with
mechanical compression (Nikolsky et al 2004, Biancari et al 2010). Local bleeding is
transformed to hematoma, which spontaneously resolves in 1∼2 weeks in small hematomas,
or in several weeks or months in large hematomas. Table 4 describes the general
recommendations for postprocedural hemostasis after femoral artery access listed in the
American College of Cardiology/Society for Cardiac Angiography and Interventions
Clinical Expert Consensus Document on Cardiac Catheterization Laboratory Standards
(Bashore et al 2001).
Situation Recommendation
Following hemostatic closure device 1–2 h recumbent in position of comfort,
then ambulate 3 30 min before discharge
Following removal of venous sheath 1 h with leg straight, then ambulate 3 30
min before discharge
Following removal of femoral arterial
sheath (ACT ,175 s)
Manual compression 10–20 min (until hemostasis achieved)
Clamp 15 min to 1 h to achieve hemostasis
Bedrest Leg straight, slight head elevation X 2–6 h
Ambulation 30 min to 1 h before discharge
Table 4. General recommendations regarding postprocedural hemostasis after prior femoral
artery access(Bashore et al. 2001)
3.2 Pseudoaneurysm
After removal of the sheath and compression, the puncture site is surrounded and blocked
by local hematoma. Inappropriate compression favours come-and-go blood flow between
artery lumen and aneurysm surrounded by hematoma. Femoral peudoaneurysm is the
second most common complication occurring in 0.1% to 0.2% of diagnostic angiograms and
3.5% to 5.5% of interventional procedures (Demirbas et al 2005, Kronzon 1997). If hemostasis
is achieved using manual compression, the pseudoaneurysm rate is higher in superficial
femoral artery than common femoral artery access, however rates are similar when using
closure devices (Gutzeit et al 2011). In patients with acute coronary syndrome who are
undergoing emergency angiography and possible intervention, pseudoaneurysm rate
needing closure is lower in radial compared with femoral angiography (HR 0·30, 95% CI
0·13—0·71; p=0·006) (Jolly et al 2011). Small femoral pseudoaneurysm is usually filled with
clots and does not require treatment, however, larger femoral pseudoaneurysms may lead
to secondary complications including rupture, local pain and compression of the adjacent
femoral vein or nerve (Kronzon 1997). Color Doppler ultrasonography is the best diagnostic
tool with a positive diagnostic rate of 95%, however other imaging modalities such as 3-
dimentional CT angiography and angiography are useful. Using color-Doppler
ultrasonography, flow inside the aneurysm sac and the “to-and-fro flow” at the neck of the
lesion is definitely diagnostic. Application of good external compression after sheath
Diagnosis and Management of Complications of Invasive Coronary Angiography 175
removal, selecting a small-bore introducer and sheath removal at a low activated clotting
time (<200 sec) are important factors preventing pseudoaneurysm. Ultrasonography guided
compression of the communicating canal of the pseudoaneurysm stops the blood flow and
leads to clotting and obliteration with a success rate of 84-93% in patients without
anticoagulation (Lange et al 2001, Gabriel et al 2007, Schaub et al 1994). Ultrasound-guided
thrombin injection is another effective means with a success rate of 97-100% (Schneider et al
2009, Weinmann et al 2002). Other endovascular approaches, such as stent graft repair and
coil embolization, are also available. Open surgical repair should be considered after non-
surgical procedure failure.
Fig. 1. Doppler ultrasonography image showing a flow jet from superficial femoral artery to
pseudoaneurysm surrounded by huge hematoma
Fig. 3. Angiographic findings of pseudoaneurysm before (A) and after (B) coil embolization.
Fig. 4. Contrast-enhanced CT scan showing retropelvic hematoma one day after coronary
angiography via right femoral artery
3.5 Spasm
Arterial spasm near the puncture site occurs when arterial size is too small for the sheath.
The transradial approach for coronary angiography or angioplasty is increasingly being
used as an alternative to femoral access due to its low rate of local complications. Arterial
spasm is the most common complication of this technique especially in female patients. Use
of hydrophilic coated sheath, but not long sheath, reduces the incidence of radial artery
spasm during transradial coronary procedures (Rathore et al 2010). Intra-arterial or
subcutaneous infusion of nitroglycerin reduces arterial spasm and facilitates introduction of
catheters (Candemir et al 2009).
4. Conclusion
It is critical to make every attempt at minimizing occurrence of complications during and
after coronary angiography and interventional procedures; beyond operator’s experience
and the patient factors noted, this involves care and attentiveness. The impact of improved
understanding and techniques in intervention should be added to management
considerations. Coronary angiography and intervention is continuously evolving and
knowledge acquired through clinical experience and availability of new devices should
therefore allow safer procedures in the future.
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10
1. Introduction
Radiologic procedures such as coronary angiography utilizing intravascular contrast media
(CM) injections are being widely applied for diagnostic and therapeutic purposes. These led
to a parallel increase in the incidence of contrast-induced nephropathy (CIN). Renal failure
requiring dialysis after contrast media administration is associated with a 40% in-hospital
mortality rate and has a 2-year mortality rate of 80%. Approximately $180 million are spent
annually to manage CIN in the US. The large number of patients who are severely affected
by CIN underscores the importance of addressing known risk factors and preventions for
CIN. Patients at risk for CIN can often be identified with a routine medical history, physical
examination and laboratory analysis before the procedure. Two of the major risk factors of
CIN are pre-existing renal failure and diabetes mellitus. After the high-risk patient
population has been identified and risk factors addressed, the next step in preventing CIN is
the use of different prophylactic therapies. The following chapter provides an overview of
current risk factors and preventive methods of CIN.
requiring greater amount of CM, defective prostaglandin synthesis, and the presence of
renovascular disease. Furthermore, hypovolemia is very common in elderly patients. In a
prospective study in which elderly patients (≥70 years) were subjected to cardiac
catheterization, 11% developed CIN (Rich & Crecelius, 1990). In another study, CIN
incidence was 17% in elderly patients (>60 years) as compared with 4% in younger patients
(Kohli et al., 2000). In 208 patients with acute myocardial infarction who underwent
coronary intervention, it was found that an age of ≥75 years was an independent risk for
CIN (OR=5.28, p=0.0009) (Marenzi et al., 2004).
Gender
In a retrospective study of 8628 patients who underwent PCI, female sex was an
independent predictor of CIN (OR=1.4, p<0.0001). One-year outcome analyses by gender
showed a higher mortality among females than among males in a cohort of CIN patients
(14% vs 10%, p=0.05) (Iakovou et al., 2003). The findings of this study contradict those of a
previous randomized controlled trial of ionic vs nonionic CM, in which a multivariate
analysis identified male gender as an independent risk factor for CIN (Rudnick et al., 1995).
Whether female gender is truly an independent predictor of CIN will require further
confirmatory studies.
Pre-existing renal disease
The major risk factor for CIN is a GFR<60 ml/min/1.73 m2. Chronic kidney disease is
associated with decreased vasodilatory response, which is important in developing CIN,
and in patients with renal insufficiency, the clearance of CM is slower than in normal
subjects. In a study of 7586 patients who underwent coronary intervention, CIN developed
in 22.4% of the patients who had serum creatinine levels of 2.0 to 2.9 mg/dl and in 30.6% of
those with serum creatinine levels of 3.0 mg/dl or higher, compared with 2.4% of patients
with serum creatinine levels <1.1 mg/dl ( Rihal et al., 2002). Two other studies (Moore et al.,
1992; Barrett et al., 1992) reported that the incidence of CIN increased from 4% to 20% as the
baseline serum creatinine increased from 1.2 to 2.9 mg/dl. In another study, the incidence of
CIN increased from 8% to 92% as the serum creatinine increased from 1.5 to 6.8 mg/dl.
Furthermore, the probability of CIN requiring dialysis increases from 0.04% to 48% as the
baseline GFR decreases from 50 to 10 ml/min (McCullough et al., 1997).
Diabetes mellitus
Patients with diabetes constitute an important group at high risk of developing CIN.
Patients with diabetic nephropathy and a mean serum creatinine of 6.8 mg/dl had a 92%
incidence of CIN after coronary angiography (Weinrauch et al., 1977). Patients with diabetes
who have advanced chronic renal failure because of causes other than diabetic nephropathy
are at significantly higher risk of developing CIN like diabetic nephropathy. On the other
hand, studies have shown that when pre-existing renal disease is present, patients with and
without diabetes are similarly at risk of CIN, which correlates with the degree of renal
disease. Some authors have suggested that DM in the absence of nephropathy, particularly
in insulin-dependent patients with diabetes, is associated with an increased risk of CIN
(McCullough et al., 1997; Toprak 2007). In a study, it was found that the incidence of CIN
was rather low (2%) in patients with neither diabetes nor azotemia, significantly higher
(16%) in individuals with diabetes but preserved renal function, and much higher (38%) in
patients who had both diabetes and azotemia (Lautin et al., 1991). In another study, the
incidence of CIN was found to be 2% in patients without diabetes and 3.7% in patients with
Coronary Angiography and Contrast-Induced Nephropathy 185
diabetes with a baseline creatinine of 1.1 mg/dl or less (OR=1.86, p=0.005). When renal
function is mildly impaired (serum creatinine level 1.2 to 1.9 mg/dl), the risk of CIN in
patients with diabetes mellitus increases to 4.5% (OR=2.42, p<0.001) ( Rihal et al., 2002).
Other studies have failed to corroborate this connection (Parfrey et al., 1989). However,
given that, those with diabetes alone were found to be at slightly higher risk of CIN than the
general population.
Pre-diabetes
In a study of 421 patients who underwent coronary angiography with renal insufficiency,
we presented that pre-DM increase the incidence of CIN 2.1-fold in comparison to patients
with normal fasting glucose (NFG) but pre-DM is not as strong as DM as a risk of
developing CIN. CIN occurred in 20% of the DM (RR=3.6, p=0.001), 11.4% of the pre-DM
(RR 2.1, p=0.314) and 5.5% of the NFG group. The decrease of GFR was higher in DM and
pre-DM (p=0.001 and p=0.002, respectively). Length of hospital stay was 2.45 ± 1.45 day in
DM, 2.27 ± 0.68 day in pre-DM, and 1.97 ± 0.45 day in NFG (p<0.001, DM vs. NFG and
p=0.032, pre-DM vs. NFG). The rate of major adverse cardiac events was 8.7% in DM, 5% in
pre-DM, and 2.1% in NFG (P=0.042, DM vs. NFG). Hemodialysis was required in 3.6% of
DM, and 0.7% in pre-DM (P=0.036, DM vs. NFG), and the total number of hemodialysis
sessions during 3 months was higher in DM and pre-DM (P<0.001). Serum glucose ≥124
mg/dl was the best cut-off point for prediction of CIN (Toprak et al., 2007).
Congestive heart failure and reduced left ventricular ejection fraction
Studies have shown that reduced left ventricular ejection fraction (LVEF) (≤49%) and
advanced congestive heart failure are independent risk factors for CIN. In a study, Dangas
et al. showed that LVEF below 40% is an independent predictor of CIN (Dangas et al., 2005).
We have previously reported that if the LVEF is greater than 30%, this condition does not
show any significant effect on the development of CIN (Toprak et al., 2003). In a study it was
shown that congestive heart failure was an independent risk for CIN (OR=1.53, p=0.007)
(Rihal et al., 2002). In a cohort study it was found that congestive heart failure is a risk for
CIN in patients who underwent PCI (OR=2.2, p<0.0001) (Bartholomew et al., 2004).
Hypertension
Hypertension has been categorized as a risk factor for CIN in some research. In a study of
8628 patients who underwent percutaneous interventions, hypertension was found to be an
independent predictor of CIN (OR=1.2, p=0.0035) (Iakovou et al., 2003). In another cohort
study, hypertension was a risk for CIN in patients who underwent PCI (OR=2.0, p=0.0001)
(Bartholomew et al., 2004).
ACE Inhibitors and angiotensin receptor blockers
ACE inhibitors have been identified as a risk factor for CIN because of their potential to
reduce renal function. On the other hand, some small studies have shown that the
nephrotoxicity of CM may be reduced because of decreased renal vasoconstriction by
inhibition of angiotensin II. In a randomized controlled study with 71 patients with diabetes
who underwent coronary angiography randomized to captopril or control, 25-mg captopril
was given three times daily. There was a significant decrease in CIN in the patients who
received captopril compared with the control group (6% vs 29%, respectively, p<0.02)
(Gupta et al., 1999). We have performed a randomized controlled study in 80 patients with
serum creatinine below 2 mg/dl who underwent coronary angiography. Captopril was
186 Advances in the Diagnosis of Coronary Atherosclerosis
reduced production of nitric oxide (Yang et al., 2004). Altered nitric oxide-dependent renal
vasodilatation, which is important in the pathogenesis of CIN, is prevalent in
hypercholesterolemia.
Hyperuricemia
It has been suggested that tubular obstruction by uric acid plays a role in the pathogenesis
of CIN. In a prospective cohort study we evaluated 266 patients who undergoing elective
coronary angiography and we found that patients with hyperuricemia are at risk of
developing CIN (OR=4.71, p=0.019). CIN occurred in 15.1% of the hyperuricemic group and
2.9% of the normouricemic group (p<0.001). Length of hospital stay (p<0.001) and CIN
requiring renal replacement therapy (p=0.017) were significantly higher in hyperuricemic
group. Serum uric acid 7 mg/dl in males and 5.9 mg/dl in females were found the best
cut-off value for prediction of CIN (Toprak et al., 2006).
Multivessel coronary involvement, peripheral vascular disease, and renal artery stenosis
Factors related to accelerated or diffuse atherosclerosis are linked to the development of
CIN. The treatment of multivessel disease, challenging chronic total occlusions and
extensively diseased coronary segments, may require high doses of CM for providing an
optimal image quality, thus enhancing the potential toxic effects on the renal function. If a
patient has multivessel coronary involvement, the other vessels in the body, such as the
renal artery, can be involved. In a study of 177 patients who underwent cardiac
catheterization, subjects were also evaluated for renal artery stenosis. Coronary artery
disease was detected in 110 patients (62%), and significant renal artery stenosis was detected
in 19 patients (11%). Using multivariate analysis, it was found that the extent of coronary
artery disease was an independent predictor of renal artery stenosis (Weber-Mzell et al.,
2002). In a study a total of 5571 patients who underwent PCI were evaluated for CIN risk
factors, and it was found that multivessel coronary involvement was only a univariate
predictor of CIN (p=0.003) (Mehran et al., 2004). In two other cohort studies it was found
that peripheral vascular disease is a risk for CIN in patients who underwent PCI (OR=1.9,
p<0.0001 and OR=1.71, p=0.001, respectively) (Bartholomew et al., 2004; Rihal et al., 2002).
In a study a total of 219 non-diabetic patients who underwent coronary angiography we
have found that multivessel coronary involvement is a risk for CIN (OR=3.24, p=0.038)
(Toprak et al., 2006).
Hypovolemia
Decreased effective circulating volume and reduced renal perfusion potentiate renal
vasoconstriction after administration of intravascular CM. The toxic effects of CM on the
renal tubular lumen may be exacerbated in hypovolemia. At present the most convincing
preventive procedure of CIN is adequate hydration with isotonic saline or sodium
bicarbonate, and intravenous hydration seems to have better results than does oral
hydration. Before angiography, the volume status of patients can be assessed through the
inferior vena cava index, mean atrial pressure, noninvasive pulmonary-capillary wedge
pressure or bioimpedance spectroscopy (Toprak & Cirit, 2005).
Renal transplantation
Patients with renal transplantation may be at a higher risk of CIN due to concomitant use of
cyclosporine and higher prevalence of diabetes and renal insufficiency. In a study, 33
patients with a functioning renal allograft who underwent different contrast studies, the
incidence of CIN was 21.2% (Ahuja et al., 2000).
188 Advances in the Diagnosis of Coronary Atherosclerosis
(Mueller et al., 2005). Most studies have found that hydration alone is better than hydration
combined with a diuretic. In a study, 78 patients with serum creatinine >1.6 mg/dl were
randomized to three groups: hydration alone, hydration with mannitol and hydration with
furosemide. Half-isotonic saline was used for hydration. CIN occurred in 11%, 28% and 40%
of patients in the three groups, respectively (p=0.02), thus showing that forced diuresis is of
no benefit in preventing CIN. In a meta-analysis it was found that the administration of
sodium bicarbonate is superior to the administration of saline alone in the prevention of
CIN (Solomon et al., 1994). However, further controlled clinical trials are needed due to
significant study heterogeneity and publication bias. The effectiveness of sodium
bicarbonate treatment to prevent CIN in high-risk patients remains uncertain.
N-acetylcysteine
It had been postulated that antioxidant N-acetylcysteine (NAC) might scavenge oxygen free
radicals, thus attenuate the cytotoxic effects of CM. NAC may also have direct vasodilating
effects on the kidneys through an increase in the biologic effects of nitric oxide. Tepel et al.
were evaluated the effects of NAC (600 mg orally twice daily), at first time, in 83 patients
undergoing computed tomography. Two percent of the patients in the NAC group had CIN
versus 21% in the placebo group (p=0.01) (Tepel et al., 2000). Since then, a number of trials
have been published. Results from these trials have been inconsistent. In a randomized,
placebo-controlled study it was found that NAC is protective against CIN Fifty-four patients
were randomized to receive either 600 mg of NAC twice daily for 4 doses or placebo. The
incidence of CIN was 8% in the NAC group versus 45% in the placebo group (p=0.005)
(Diaz-Sandoval et al., 2002). In addition to oral administration, intravenous administration
of NAC to protect against CIN has also been evaluated. In a study, Baker et al. randomly
assigned 80 patients to receive either NAC infusion (n=41) versus saline infusion (n=39).
CIN developed in only 2 (5%) of patients in the NAC group compared with 8 (21%) in the
saline group (p=0.04) (Baker et al., 2003). The authors concluded that NAC infusion protects
against CIN. In a meta-analysis, evaluating more than 800 patients at high risk of
developing CIN also documented a positive impact of NAC prophylaxis on CIN (Birck et
al., 2003). In another meta-analysis, nine randomized controlled trials were included and the
difference in mean change in creatinine between the NAC treated group and controls was -
0.27 mg/dl. The relative risk of developing CIN was 0.43 in subjects randomized to NAC.
They suggest that NAC helps prevent declining renal function and CIN (Liu et al., 2005). In
contrast to these reports, some studies failed to find a significant effect of NAC on the
occurrence of CINA total of 183 patients with preexisting renal insufficiency undergoing
contrast study were randomly assigned to receive NAC at a dose of 600 mg twice daily on
the day before and the day of the contrast study plus saline infusion or saline alone. The
incidence of CIN was 6.5% in the NAC group versus 11% in the control group (p=0.22)
(Briguori et al., 2002). In a multi centric double blind clinical trial 156 patients undergoing
coronary angiography or percutaneous coronary intervention with creatinine clearance <50
ml/min were randomly assigned to receive N-acetylcysteine 600 mg orally twice daily for
two days or placebo. Sixteen patients developed CIN. Eight of 77 patients (10.4%) in the
NAC group and eight of 79 patients (10.1%) in the placebo group (p=1.00). No difference
was observed in the change in endogenous creatinine clearance, p=0.28). They concluded
that oral NAC did not prevent CIN in patients at low to moderate risk undergoing cardiac
catheterisation with ionic low osmolality CM (Gomes et al., 2005). In another study, 50
patients undergoing elective diagnostic coronary angiography with serum creatinine values
Coronary Angiography and Contrast-Induced Nephropathy 193
above 1.3 mg/dl were included and CIN was detected in 3 of 25 patients (12%) in the NAC
group and 2 of 25 patients (8%) in the control group (p>0.05). It was detected that in patients
planned to undergo elective diagnostic coronary angiography with renal dysfunction, oral
NAC and hydration before the procedure was not more effective than hydration alone in the
prevention of CIN (Gulel et al., 2005). A direct renoprotective effect of NAC remains
questionable. To date, only a few trials described the effects of NAC not only on serum
creatinine but also on clinical end points. The serum creatinine can be decrease in
administration of NAC without renoprotective effect. In a prospective study, NAC was
given at a dose of 600 mg every 12 h for a total of four doses to the volunteers with a normal
renal function who did not receive contrast agent. There was a significant decrease of the
mean serum creatinine (p<0.05) and a significant increase of the GFR (p<0.02), whereas the
cystatin C concentration did not change significantly (Hoffmann et al., 2004). In patients
undergoing emergency diagnostic procedures, in whom a full hydration protocol is not
possible, an abbreviated hydration regimen plus oral or intravenous administration of NAC
can be recommended. NAC may be of benefit mostly in high-risk patients. If NAC is to be
used as a preventative measure, it should be given at a dose of 600 mg orally twice daily on
the day before and day of the procedure.
Ascorbic acid
Prophylactic oral administration of ascorbic acid may protect against CIN. In a randomized,
placebo-controlled trial in 231 patients with serum creatinine concentration ≥1.2 mg/dl who
undergoing coronary angiography showed that the use of ascorbic acid was associated with
a significant reduction in the rate of CIN. CIN occurred in 11 of the 118 patients (9%) in the
ascorbic acid group and in 23 of the 113 patients (20%) in the placebo group (OR=0.38;
p=0.02) (Spargias et al., 2004). Further prospective studies are needed to validate these
preliminary results.
Fenoldopam
Fenoldopam mesylate is a selective dopamine-1 receptor agonist that produces systemic,
peripheral and renal arterial vasodilatation. Several investigators have reported a positive
impact of fenoldopam against CIN in small studies. In a placebo-controlled, double-blind,
multicenter trial, 315 patients with creatinine clearance of less than 60 ml/min were
randomized to receive fenoldopam infusion [0.05 µg/kg/min titrated to 0.1 µg/kg/min
(n=157)] or matching placebo (n=158). CIN occurred in 33.6% of patients in the
fenoldopam group compared with 30.1% of patients in the placebo group (p=0.61) (Stone
et al., 2003). The authors concluded that fenoldopam did not protect against CIN. In 2
other large studies comparing fenoldopam with NAC treatment with fenoldopam either
had a similar, non significant effect as that of NAC or was inferior to it (Allaqaband et al.,
2002; Briguori et al., 2004). Therefore, the routine use of fenoldopam cannot be
recommended at the present time.
Adenosine antagonists
CM stimulate the intrarenal secretion of adenosine, which binds to the renal adenosine
receptor and acts as a potent vasoconstrictor, reducing renal blood flow and increasing the
generation of oxygen free radicals as it is metabolized to xanthine and hypoxanthine.
Theophylline and aminophylline, adenosine antagonists, have also been studied in the
prevention of CIN in a number of trials. Studies with these agents have used varying doses
and dosage forms and yielded conflicting results (Erley et al., 1999; Kapoor et al., 2001).
194 Advances in the Diagnosis of Coronary Atherosclerosis
Based on the conflicting information found in clinical studies, adenosine antagonists should
not be routinely used in patients as a preventative measure at this time.
Calcium channel blockers
The calcium channel antagonists verapamil and diltiazem have been found to attenuate the
renal vasoconstrictor response after exposure to CM. However, when the efficacy of the
felodipine, nitrendipine and nifedipine was evaluated, results were inconsistent. Two small
studies performed the use of sublingual nifedipine given prior to contrast administration.
Patients (n=20) who received sublingual nifedipine did not have a significant increase in
serum creatinine, while those in the placebo group did (Rodicio et al., 1990). In another
study, patients (n=30) who received nifedipine had an increase in renal plasma flow
following administration of contrast, while patients in the placebo group had a decrease in
renal flow (Russo et al., 1990). One other study showed that nitrendipine use cause a
significant reduction in the GFR in the placebo group compared to little or no change in GFR
in the nitrendipine group (Neumayer et al., 1989). In another study, 27 patients with normal
to moderately reduced renal function underwent femoral angiography randomized to
receive either oral felodipine or placebo. Patients in the felodipine group had a significant
increase in serum creatinine from baseline, while patients in the placebo group did not
demonstrate a similar increase (Spangberg-Viklund et al., 1996). More large-scale trials are
needed before calcium channel blockers can be routinely recommended in patients prior to
contrast administration.
Prostaglandin E1
PGE1 has vasodilatory effects that may be beneficial in preventing CIN. In one study, 130
patients were randomly assigned to receive either placebo or one of three doses of PGE1. The
increase in serum creatinine level was smaller in all of the three PGE1 groups than in the
placebo group, but the difference was significant only in the medium-dose (20 ng/kg/min)
of PGE1 group (Koch et al., 2000). More studies need to be done to better understand the role
of prostaglandin E1, but results from this pilot study appear promising.
Atrial natriuretic peptide (ANP)
ANP may prevent CIN by increasing renal blood flow. In a study, ANP was included in one
of the four arms. In which dopamine, mannitol, and ANP caused an increase in CIN in
diabetic patients as compared to saline alone (Weisberg et al., 1994). In another trial patients
were randomized to one of four treatment arms: fluid alone or one of three doses of ANP.
Results showed no statistically significant differences in the incidence of CIN between any of
the four treatment arms (Kurnik et al., 1998) Based on these results and the limited clinical
data, ANP cannot be advocated in the prevention of CIN.
Endothelin antagonists
Endothelin-1 is a potent endogenous vasoconstrictor, is thought to play a role in the
development of CIN. Endothelin-1 has two primary receptors. In animal studies, endothelin-
A antagonists were shown to reduce the incidence of CIN (Liss et al., 2003). However, in a
randomized study of 158 patients, the use of a mixed endothelin-A and B antagonist was
associated with a significantly higher incidence of CIN than was placebo (56% vs. 29%,
p=0.002) (Wang et al., 2000). Endothelin antagonists currently have no role in prevention of
CIN.
Coronary Angiography and Contrast-Induced Nephropathy 195
Low-dose of dopamine
At low doses (1-3 mcg/kg/min), dopamine activates two types of dopamine (DA) receptors,
DA-1 and DA-2. Activation of the DA-1 receptor results in an increase in natriuresis and
renal blood flow. Since dopamine, at low doses, is believed to be more selective for the DA-1
receptors, it has been investigated in the prevention of CIN. Kapoor et al. randomized 40
patients with diabetes scheduled to undergo a coronary angiography to either dopamine or
placebo control. None of the patients in the dopamine group developed CIN compared to
50% of patients receiving placebo (Kapoor et al., 2002). In another prospective, randomized
trial, Hans et al. evaluated 55 patients (40% had diabetes) with chronic renal insufficiency.
Patients were randomized to receive dopamine or an equal volume of saline. The group
receiving dopamine had a significantly lower incidence of CIN as compared to the control
group (Hans et al., 1998). In contrast to the trials showing a potential benefit of dopamine,
other studies have failed to demonstrate this benefit. Abizaid et al. performed a randomized,
prospective study involving patients with renal insufficiency who underwent coronary
angioplasty. Patients were randomized to continue with the saline, receive aminophylline in
addition to the saline, or receive dopamine plus saline. In the dopamine plus saline group,
50% of patients developed CIN, while only 30% of the patients in the saline-alone group
developed CIN. This difference did not reach statistical significance, but it appeared that use
of dopamine might worsen outcomes (Abizaid et al., 1999). Low-dose dopamine use cannot
be supported at this time.
Statins
Whether additional benefits can be achieved with the use of statin in decreasing the risk of
CIN remains undetermined. In a recent meta analysis of randomised controlled trials
comparing statin pretreatment with non-statin pretreatment for the prevention of CIN, it
was found that, the incidence of CIN was not significantly lower in statin pretreatment
group as compared with control group (RR=0.76, p=0.30) (Zhang et al., 2011). The current
cumulative evidence suggests that statin pretreatment may neither prevent CIN nor reduce
the need for renal replacement therapy.
Hemofiltration and hemodialysis
Currently available data do not support use of prophylactic hemodialysis for prevention of
CIN. In a trial of 113 patients, reported that CIN occurred in 24% of the hemodialysis group
as compared with 16% of non-hemodialysis group (Vogt et al., 2001). Clinically relevant
events also were not different in two groups. Only continuous venovenous hemofiltration
has been shown to protect against CIN. In a study, 114 patients with chronic renal failure
undergoing percutaneous coronary intervention were divided in two groups: 56 patients
received normal saline and 58 patients underwent hemofiltration at a rate of 1000 ml/h
(Marenzi et al., 2003). Hemofiltration seems to have a protective effect, including significant
reduction in in-hospital and 1-year mortality compared with routine hydration. The
mechanisms of this benefit are not clear. Further studies are needed to confirm the results of
this trial.
New types of contrast medias
Gadolinium-enhanced magnetic resonance coronary angiography is a non-invasive method
for evaluation of coronary arteries. It has been suggested that gadolinum-based CM could
be used in stead of iodinated CM for radiological examinations in patients with significant
196 Advances in the Diagnosis of Coronary Atherosclerosis
renal impairment. However, its use has been questioned on the basis of reports of
nephrotoxicity and its association with nephrogenic systemic fibrosis, a rare and serious
syndrome that involves fibrosis of skin, joints, eyes, and internal organs. In a study by
Hoffmann et al. the effect of gadopentetate dimeglumine (iodine-based CM) was studied in
181 patients with normal renal function and the effect of gadolinium was studied in 198
patients with pre-excisting renal failure. There was no statistically significant change in
serum creatinine concentration after gadopentetate dimeglumine. In contrary, serum
creatinine levels decreased significantly after the administration of gadolinium (p<0.01)
(Hoffmann et al., 2005). In a retrospective study, the safety of gadolinium was evaluated in
91 patients with stage 3 and 4 renal failure who underwent angiographic MRI procedures.
Eleven of 91 patients developed CIN (12.1%) (Ergun et al., 2006). In another randomized
study gadobutrol, a gadolinium-based CM, was compared with standard iohexol, an
iodinated CM, in 21 patients with renal dysfunction. The incidence of CIN was 50% in
gadobutrol group and 45% in iohexol group (p=0.70). In this study, gadolinium showed no
benefit over iohexol in patients with severely impaired renal function (Erley et al., 2004).
More studies need to be done to better understand the role of gadolinum on CIN.
Ultrasound contrast agents are micro-bubbles which produce acoustic enhancement. They
are pharmacologically almost inert and safe.
3. Conclusion
The development of CIN is associated with adverse outcomes including prolonged
hospitalization, the potential need for renal replacement therapy, and most important,
increased mortality. The treatment of established CIN is limited to supportive measures and
dialysis. For this reason, screening for high-risk patients before CM including cardiac
procedures and taking the appropriate prophylactic regimens is important in reducing CIN.
Pre-existing renal dysfunction, especially when secondary to diabetic nephropathy, is the
most important risk factor. Extra cellular volume expansion and use of low osmolar CM are
the two most effective measures to prevent CIN. Acetylcysteine may use in high-risk
patients, but this finding has not been uniform or always demonstrated by currently
available trials.
4. References
Abizaid, AS., Clark, CE., Mintz, GS., Dosa, S., Popma, JJ., Pichard, AD., Satler, LF., Harvey,
M., Kent, KM., & Leon, MB. (1999). Effects of Dopamine and Aminophylline on
Contrast-Induced Acute Renal Failure after Coronary Angioplasty in Patients with
Preexisting Renal Insufficiency. The American Journal of Cardiology, Vol.83, No.2,
(January 1999), pp.260-263, ISSN 0002-9149
Ahuja, TS., Niaz, N., & Agraharkar, M. (2000). Contrast-Induced Nephrotoxicity in Renal
Allograft Recipients. Clinical Nephrology, Vol.54, No.1, (July 2000), pp.11-14, ISSN
0301-0430
Allaqaband, S., Tumuluri, R., Malik, AM., Gupta, A., Volkert, P., Shalev, Y., & Bajwa, TK. (2002).
Prospective Randomized Study of N-Acetylcysteine, Fenoldopam, and Saline for
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11
1. Introduction
Cardiovascular disease, mostly coronary artery disease (CAD), remains an important cause
of morbidity and mortality in patients with any degree of renal dysfunction. Presently,
according to the United States Renal Data System, the size of the population with chronic
kidney disease (CKD) stage V reached a new high in 2008, with almost 550,000 patients
under treatment (U.S. Renal Data System, 2010). Sadly, it is expected that half of them will
die from cardiovascular disease; moreover, it is noteworthy that even patients with less
advanced stages of CKD are at greater risk of death from CAD than of reaching the final
stages of renal failure that would eventually require renal replacement therapy (Sarnak et
al., 2003). In these patients, about 50% to 60% of all cardiovascular deaths are due to acute
myocardial infarction, sudden death, or ischemic heart disease (Herzog et al., 2008).
The interplay between CKD and CAD is a very complex one and can only be partly
explained by the fact that patients with CKD share many of the so-called traditional risk
factors also linked to CAD, such as long-standing diabetes, hypertension, low levels of
HDL-cholesterol, and hypertriglyceridemia (McCullough, 2002a). Additionally, a pro-
inflammatory state and high oxidative stress levels are usually seen in patients with
advanced CKD, which may contribute to accelerated atherosclerosis, plaque instability,
acute coronary syndromes, and myocardial fibrosis (Yerkey et al., 2004). The result of this
clustering of traditional and nontraditional risk factors may explain the epidemiological
observation that patients with CKD stage V have more than a 10-fold increased risk of death
from CAD than a patient with 5 Framingham risk scores (McCullough, 2002b).
The prevalence of CAD in CKD patients undergoing dialysis varies with such factors as age,
diabetic status, time of follow-up, and the diligence with which CAD is investigated. In a
group of 4,024 new dialysis patients, including 44% with diabetes, 32% had a history of
CAD (Foley, 2003), which is conceivably more than 3 times the figure corresponding to CAD
in the general population (Levey & Eknoyan, 1999). The prevalence of angiographically
confirmed CAD, on the other hand, defined as luminal reduction >50%, ranges from 24% in
low-risk patients to 85% in older, diabetic patients (Goldsmith & Covic, 2001). Nevertheless,
most of these data originated from studies in which coronary angiography was performed
only in patients with clinical evidence and/or noninvasive studies suggestive of CAD,
204 Advances in the Diagnosis of Coronary Atherosclerosis
2.1 The challenge of referring patients with CKD for coronary angiography
Tables 1 and 2 show the most recent guidelines for coronary angiography to establish the
diagnosis in patients with suspected angina and for risk stratification in patients with chronic
stable angina, respectively (Fraker Jr et al., 2007).
Invasive coronary angiography has received a Class I indication for patients with known or
possible angina pectoris who have survived sudden cardiac death. For risk stratification in
patients with chronic stable angina, coronary angiography should be performed in: a)
patients with disabling (Canadian Cardiovascular Society classes III and IV) stable angina
despite medical therapy; b) patients with high-risk criteria on noninvasive testing; c)
patients with angina and symptoms and signs of heart failure; d) patients with clinical
characteristics indicating a high likelihood of severe CAD.
Coronary angiography is
indicated to establish the Level of
Comment for Patients with CKD
diagnosis of CAD in patients with Evidence
suspected angina in those with…
Known or possible angina pectoris
Survival rates much lower than rates
who have survived sudden cardiac B
for the general population
death
Coronary angiography is
indicated for risk stratification in Level of
Comment for Patients with CKD
patients with chronic CAD in Evidence
those with…
Disabling chronic stable angina Uncommon clinical presentation for
B
despite medical therapy patients with CKD
High-risk criteria on noninvasive
Lower sensitivity than that in the
testing regardless of angina B
general population
severity
Angina who have survived sudden
Survival rates much lower than those
cardiac death or serious ventricular B
in the general population
arrhythmia
May be confused with hypertensive
Angina and symptoms and signs of cardiomyopathy, fluid overload,
C
congestive heart failure
subdialysis
Clinical characteristics that indicate Lower specificity than that in the
C
a high likelihood of severe CAD general population
Table 2. Class I indications of the AHA/ACC Guidelines for coronary angiography for risk
stratification in patients with chronic stable angina. Modified from Fraker Jr, et al. (2007).
206 Advances in the Diagnosis of Coronary Atherosclerosis
Although these guidelines have been extensively tested and validated in the general
population, for patients with CKD the data supporting that approach is less robust. The
main pitfalls of applying the same criteria recommended for patients with normal renal
function to patients with CKD are briefly described below.
with a sensitivity and negative predictive value between 70% and 80% (Herzog et al., 1999;
Ferreira et al., 2007). However, the utility of this test is limited, because dobutamine often
increases blood pressure, causing interruption of the test in about 15% of patients.
Until a few years ago, magnetic resonance imaging (MRI) had been used for assessment of
myocardial function and detection of myocardial ischemia and scar tissue in patients with
CKD (Andrade et al., 2009). Myocardial stress perfusion studies performed with MRI
adequately detected CAD, and there was a good correlation between these results and those
from coronary angiography and radionuclide studies (Andrade et al., 2004). Unfortunately,
further development of this imaging modality was halted, because of the description of a
serious complication related to the use of gadolinium-based contrast media in patients with
CKD, called nephrogenic systemic fibrosis (Grobner, 2006). Thus, starting in 2007, the
United States Food and Drug Administration issued a boxed warning about this
progressive, debilitating and, occasionally fatal condition recommending that the use of
gadolinium-based contrast agents should be avoided in patients with acute or chronic renal
insufficiency with a glomerular filtration rate < 30mL/min/1.73m2.
2.1.2.3 Coronary angiotomography
Multidetector-row computed tomography (MDCT) has been recently applied to the
detection of CAD in patients with ESRD (Rosário et al., 2010). This method allows not only
the detection of coronary calcifications but also the detailed visualization of the arterial wall
and lumen, and therefore, may become an alternative to coronary angiography. Experience
with this method in patients with CKD is still very limited.
2.1.2.4 Clinical implications
Thus, referring patients with CKD for coronary angiography is not an easy task (De Lima et
al., 2010; Lentine et al., 2010). One could be very “conservative,” only referring patients with
overt, unequivocal symptoms of angina or extensive myocardial ischemia on noninvasive
testing to undergo coronary angiography.
This approach would most likely yield a prohibitively large number of “false negatives,”
meaning that many patients with significant CAD will be deemed free of disease. It is quite
easy to see the clinical implications of such an approach, especially for renal transplant
candidates. Alternatively, one could be very “aggressive” and refer all patients with CKD
stages IV or V for coronary angiography. We would be able to diagnose every single patient
with CAD in adopting this strategy. The downside is that coronary angiography is a
somewhat risky, costly procedure and as many as 50% to 60% of all patients will have no
significant CAD at all and, therefore, will not be further referred for coronary interventions
(percutaneous or surgical). Finally, patients still not on renal replacement therapy might not
only not benefit from this strategy but might also have worsening of their residual renal
function because of the contrast-induced nephropathy.
As a matter of fact, it is still unclear whether the benefits outweigh the harms of routine
screening and prophylactic revascularization to prevent coronary artery disease (CAD) in
asymptomatic kidney transplant candidates. To help clarify that issue, an ongoing
randomized clinical trial is being performed to study the effect of CAD screening on major
adverse cardiac events (Kasiske et al., 2011).
CKD regarding the presence and severity of CAD is, based on the previous considerations,
which additional patients should be referred for coronary angiography, especially those
asymptomatic patients being assessed before renal transplantation.
In a previous study, we sought to determine the clinical predictors more closely related to
CAD in 301 renal transplant candidates treated by hemodialysis (Gowdak et al, 2007). CAD
(> 70% stenosis) was found in 45% of patients, and the clinical variables significantly
associated with CAD were diabetes, peripheral vascular disease, and previous myocardial
infarction. More important, the prevalence of CAD increased with the number of clinical
predictors from 26% (none) to 100% (all present), while the incidence of events increased 2-,
4-, and 6-fold in those with diabetes, peripheral vascular disease, or previous myocardial
infarction, respectively (p < .0001). This approach would allow reducing the prevalence of
unnecessary angiography from 55% (when all patients undergo angiography) to 26%.
However, we believe that missing the diagnosis of CAD in one-fourth of patients is still not
totally satisfactory.
Another approach should be to restrict the use of coronary angiography as a predictive tool
of cardiovascular events in patients with CKD in which this strategy is powerful enough to
discern between patients at high- and low-risk, comparatively to either clinical stratification
alone or to noninvasive testing. We compared the efficacy of clinical stratification,
noninvasive testing, and coronary angiography in predicting cardiovascular events in
patients with CKD being considered as potential renal transplant candidates (De Lima et al.,
2006; Gowdak et al., 2008). We were able to show that, for patients considered at low-risk for
CAD (age < 50 years, with no diabetes, and no history of cardiovascular disease), additional
noninvasive or invasive testing, added no capability in predicting cardiovascular events
beyond that given by clinical stratification. On the other hand, for patients at high-risk for
CAD, defined by the presence of any 2 risk factors combined (age 50 years or diabetes or
cardiovascular disease), noninvasive testing failed to identify patients at higher risk for
cardiovascular events; indeed, the finding of significant CAD by angiography (luminal
stenosis 70%) was the strongest predictor of events. For patients at intermediate-risk for
CAD, defined by the presence of any single risk factor alone, noninvasive testing was a good
tool in identifying patients at higher risk of events, should an abnormal myocardial
perfusion scan be found. Figure 1 shows the proposed algorithm for risk stratification of
CAD in renal transplant candidates.
either in absolute terms (0.5 to 1.0mg/dL) or as a proportional rise in SCr of 25% to 50%
above the baseline value (Gleeson & Bulugahapitiya, 2004).
NON-INVASIVE
TESTING
NEGATIVE POSITIVE
CORONARY ANGIOGRAPHY
Fig. 1. Proposed algorithm for coronary angiography in patients with CKD awaiting renal
transplantation.
210 Advances in the Diagnosis of Coronary Atherosclerosis
The increase in SCr seen in patients with contrast-induced AKI is associated with a
significant increase in the risk of death. In a large retrospective study comprising over 16,000
patients undergoing procedures, those who developed contrast-induced AKI had a 5.5-fold
increased risk of death during hospitalization (Levy et al., 1996). Another study with more
than 7,000 patients confirmed the short-term worse prognosis in patients with AKI but
extended the greater risk of death up to 5 years after the procedure: the mortality rates at 1
year after development of contrast-induced AKI (12.1%) and at 5 years (44.6%) were higher
compared with rates of 3.7% and 14.5%, respectively, in patients who did not develop
contrast-induced AKI, indicating that the increased risk of death persisted in the long term
(Rihal et al., 2002).
Besides the increased mortality, contrast-induced AKI also poses a high morbidity risk. Its
occurrence has been linked to late cardiovascular events after percutaneous coronary
intervention (such as myocardial infarction), bleeding requiring transfusion, and vascular
complications. As a consequence of more serious adverse events, the in-hospital stay is
longer with an estimated US$10,000 to US$12,000 added to the final bill during the first year
(Subramanian et al., 2007).
proteinuria gout
Table 3. A brief 7-item survey to identify patients at higher risk for AKI.
with the lowest risk of contrast-induced AKI. Iodixanol (an iso-osmolar contrast media) has
been shown to have the lowest risk for contrast-induced AKI in patients with CKD and
diabetes mellitus compared with low-osmolar contrast media (McCullough et al. 2006b). The
American College of Cardiology/American Heart Association guidelines for the management of
acute coronary syndromes in patients with CKD listed the use of iso-osmolar contrast media
as a class I, Level of Evidence: A recommendation. The National Kidney Foundation Kidney
Disease Outcome Quality Initiative guidelines have also recommended use of iso-osmolar
contrast media in renal dialysis patients to minimize the chances of volume overload and
complications before the next dialysis session.
Higher contrast volumes (100 mL) are associated with higher rates of contrast-induced
AKI in patients at risk. However, even small (30 mL) volumes of iodinated contrast in
very high-risk patients can cause contrast-induced AKI and acute renal failure requiring
dialysis, suggesting the absence of a threshold effect (Manske et al., 1990). As a general
rule, the volume of contrast received should not exceed twice the baseline level of eGFR in
mL.
Finally, intraarterial administration of iodinated contrast appears to pose a greater risk of
contrast-induced AKI above that with intravenous administration.
4.3 Strategies to further reduce the risk of contrast-induced Acute Kidney Injury
4.3.1 Volume expansion
Adequate intravenous volume expansion with isotonic crystalloid (1.0–1.5 mL/kg/h) for 3–
12 h before the procedure and continued for 6–24 h afterwards can lessen the probability of
contrast-induced AKI in patients at risk (Mueller et al., 2002). Achieving a good urine output
(150 mL/h) in the 6h after the procedure has been associated with reduced rates of AKI in
one study. The data on oral as opposed to intravenous volume expansion as a contrast-
induced AKI prevention measure are insufficient.
However, NAC as an antioxidant has been shown to lower rates of AKI and mortality after
primary PCI in 1 trial. The recently published REMEDIAL (Renal Insufficiency Following
Contrast Media Administration) trial suggested that the use of volume supplementation
with sodium bicarbonate together with NAC was more effective than NAC alone in
reducing the risk of AKI (Briguori et al., 2007; Brown et al., 2009). Dosing of NAC has varied
in the trials; however, the most successful approach has been with 1,200 mg orally twice a
day on the day before and after the procedure.
4.3.2.3 Other agents
Fenoldopam, dopamine, calcium-channel blockers, atrial natriuretic peptide, and L-arginine
have not been shown to be effective in the prevention of contrast-induced AKI. Furosemide,
mannitol, and an endothelin receptor antagonist are potentially detrimental (Stacul et al.,
2006).
In general, cardiovascular patients undergoing procedures with iodinated contrast have
either high risk for atherosclerosis or have the anatomic presence of disease. Therefore, the
vast majority of patients should be on statin therapy with a common low-density lipoprotein
cholesterol target of <70 mg/dL. Several studies have demonstrated that patients continuing
on statins during cardiovascular procedures including PCI and coronary artery bypass
grafting have lower rates of AKI (Khanal et al., 2005). All small, randomized trials published
to date support this concept as well. Preservation of endothelial function at the level of the
glomerulus and reductions in systemic inflammatory factors are postulated mechanisms by
which statins may have renoprotective effects.
4.3.2.4 Dialysis and hemofiltration
Prophylactic hemodialysis or hemofiltration has not been validated as an effective strategy,
even when carried out within 1 h or simultaneously with contrast administration.
Hemofiltration, however, performed 6 h before and 12 to 18 h after contrast deserves
consideration, given reports of reduced mortality and need for hemodialysis in the
postprocedure period in very high-risk patients (Marenzi et al., 2003).
4.3.2.5 Withdrawal of additional nephrotoxic drugs
Despite the lack of more robust data in this area, it is a reasonable practice to withhold
nonsteroidal anti-inflammatory drugs, calcineurin inhibitors, high-dose loop diuretics,
aminoglycosides, and other nephrotoxic agents if possible for several days before contrast
exposure (McCullough, 2008). It is routine practice to withhold metformin before all contrast
procedures, not because metformin itself is nephrotoxic but because in the setting of AKI if
metformin is continued, lactic acidosis can develop leading to systemic complications and
death. As a general rule, metformin should not be restarted until the clinician is confident
that the patient has not developed AKI.
5. Conclusion
Patients with chronic kidney disease are at high-risk for CAD and, therefore, coronary
angiography is very often needed to establish the diagnosis and severity of CAD. The major
challenges in this regard are how to select those patients more likely to have significant
CAD, in the absence of typical symptoms suggestive of CAD or myocardial perfusion
defects disclosed by noninvasive testing. Moreover, the possibility of contrast-induced acute
kidney injury should signal the need for a careful and more judicious decision-making
approach by the cardiologist, working in tandem with the nephrologist, when trying to
establish the risk-benefit ratio for each patient being considered for invasive assessment.
Having decided that an invasive procedure is clearly needed, all preventive and therapeutic
measurements should be applied to minimize the risk of worsening residual renal function.
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12
1. Introduction
Cardiomyopathies are a group of heart diseases that influence muscles directly and are not
related to congenital, valvular, and pericardial diseases (Salehifar et al., 2008).
Cardiomyopathies are usually classified on the basis of structural or functional causes. Thus,
dilated cardiomyopathy is characterized by an enlarged ventricular chamber size and
reduced cardiac contractility, hypertrophic cardiomyopathy is characterized by hypertrophy
of the ventricular walls and increased cardiac performance and finally the restrictive form is
characterized by stiff ventricular walls which restrict diastolic filling of the ventricle while
systolic performance is not impaired (Ammash et al., 2000; Dec & Fuster ,1994). The
classification by the American Heart Association Scientific Statement panel divides
cardiomyopathy into primary and secondary causes (Maron et al., 2006).In this classification
primary cardiomyopathies are subdivided into genetic, mixed and acquired groups.
2. Dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is characterized by enlargement of one or both ventricles
accompanied by impaired myocardial systolic function.DCM is the most common
cardiomyopathy. Patients with DCM usually have symptoms and signs of congestive heart
failure and there are many cardiac and systemic causes leading to DCM. However, in about
50 percent or more of the patients with DCM, the etiology can not be identified. Thus, the
patient is called as having an idiopathic DCM (Felker et al., 2000).
therapy or it can be due to spontaneous reverse remodeling. On the other hand, the clinical
stability of some patients deteriorates suddenly and the hemodynamic situation requires
inotropic or mechanical support (Teuteberg et al.,2006).
2.2 Etiology
DCM is the major cause of congestive heart failure (CHF).Other most frequent specific
Cardiomyopathies causing CHF include ischemic or hypertensive cardiomyopathies and
nonsystolic heart failure (Owan et al.,2006).In DCM after excluding the specific disease
about 50 percent is called idiopathic DCM( Felker et al., 2000).However, some of these
idiopathic DCM cases are caused by genetic abnormalities or some environmental etiologies
that are not diagnosed at the time of primary presentation and with more imaging or
molecular evaluation, many of these idiopathic cases will have a specific etiology.
2.5.1 Electrocardiography
Nonspecific electrocardiographic changes include sinus tachycardia, interventricular
conduction delay and poor R progression and left bundle branch block. Other
electrocardiographic abnormalities such as ST segment and T wave abnormalities may also
be seen. Patients may show a wide spectrum of supraventricular and ventricular
arrhythmia.
2.5.2 Echocardiography
By two-dimensional echocardiography ventricular size and function are usually evaluated.
Doppler echocardiography is helpful to evaluate valvular stenosis or regurgitation and
restrictive filling patterns. Dobutamine stress echocardiography is helpful to differentiate
ischemic from idiopathic DCM and also to assess contractile reserve of myocardium.
3. Ischemic cardiomyopathy
When myocardial dysfunction is secondary to occlusion of the coronary arteries, the term
ischemic CMP is used and is the most common cause of heart failure. Based on the
pathophysiological processes ischemic CMP may be classified into three groups. The first
one is called myocardial hibernation. In this form of ischemic CMP a reduced coronary flow
will result in persistent contractile dysfunction and revascularization procedures will
usually restore myocardial function, at least partially. Myocardial stunning is the second
form of ischemic CMP. In this form the contractile dysfunction of the viable myocardium is
transient and is usually caused by reduced sensitivity of contractile proteins to calcium.
222 Advances in the Diagnosis of Coronary Atherosclerosis
Finally in the third type, the contractile dysfunction is secondary to irreversible cell death of
the myocardium.
4.2 Complications
Cardiac catheterization also is a safe procedure, potentially has some complications. In
patients with left ventricular thrombus or aortic valve endocarditis it is better to avoid
inserting catheters into the left heart. Catheter induced arrhythmia is another potential
complication of right or left heart. Right or left bundle branch blocks may occur if the
catheter is placed in the right ventricular outflow tract or crossed the aortic valve,
respectively. Thus, patients with right or left bundle branch block are at potential risk of
developing complete heart block during cardiac catheterization. Renal failure, contrast
reactions, vascular complications are the more common complications of cardiac
catheterization. The incidence of cerebrovascular accident, myocardial infarction, and death
is less than 1 percent. Other rare complications include infection, chamber or vessel
perforation, cholesterol embolism, air embolism, and radiation -induced skin injury.
motion of the tricuspid annulus toward the right atrium at the onset of the ventricular
systole. The distance of the “c” from the “a” is the same as the PR interval in the
electrocardiogram and first degree atrioventricular block produces a more visible “c” wave.
The “x” descent represents the decrease of the right atrial pressure in ventricular systole
which is followed by the “v” wave in atrial diastole when the right atrium is filled by
venous return. The peak of the “v” wave occurs at the end of ventricular systole when the
right atrium is maximally filled and is at the same time of T wave on the electrocardiogram.
The final “y” descent represents the rapid emptying of the right atrium at the initial part of
ventricular diastole when the tricuspid valve opens. As shown in Figure 2 the normal right
ventricular systolic pressure is 20 to 30mmHg, and normal right ventricular end-diastolic
pressure is 0 to 8 mmHg. The right ventricular pressure normally consists of a rapid rise of
pressure followed by a decline during ventricular contraction and then rapid downward
motion with ventricular relaxation. At the beginning of diastole the pressure is low and with
ventricular filling increases gradually.
During right heart catheterization the pulmonary capillary wedge pressure (PCWP)
waveform is usually evaluated. The pressure waveform is better to obtain with an end-
hole catheter. The end-hole catheter obstructs the antegrade flow into the pulmonary
artery, so it reflects the left atrial pressure, or the PCWP. This pressure can be obtained by
a Swan-Ganz catheter in the pulmonary artery. By inflating the balloon of this catheter
and obstructing the flow, the PCWP is obtained. The normal mean pressure of the PCWP
is about 2 to 14mmHg and consists of positive “a” and “v” and negative “x” and “y”
waves (Fig.4).
septal approach can be helpful. During some interventional procedures such as mitral
balloon valvuloplasty, percutaneous mitral valve repairs with clips, some electrophysiologic
procedures, and placement of a percutaneous left ventricular assist device may require trans
-septal puncture.
Fig. 7. Normal concomitant waveform of right ventricle and left ventricular in systole
Fig. 10. Left ventricular pressure waveform in a patient with severe left ventricular
dysfunction which have a triangular appearance
Another presentation of severely reduced left ventricular contractility is the appearance of
pulsus alternans on the aortic or left ventricular pressure waveform (Fig 11).
Ambulatory patients with dilated CMP may have a relatively low normal resting cardiac
output and a modest elevation in both right-and left-sided filling pressures. However, in
advanced stages of heart failure, the systemic vascular resistance rises significantly in response
to the reduced cardiac output. Also, in advanced heart failure in dilated CMP patients
Cardiac Catheterization and Coronary Angiography in Patients with Cardiomyopathy 229
biventricular failure is usually characteristic. The right atrial pressure waveform will
demonstrate steep “x” and “y” descents indicative of severe volume overload and right
ventricular systolic and diastolic dysfunction. Kussmaul sign, i.e., absence of the normal
respiratory fall in the right atrial pressure is common and as a result of tricuspid regurgitation
the “y” descent is steep. The PCWP waveform may demonstrate a prominent “v” wave. The
left ventricular pressure waveform is characterized by an elevation in pressure throughout
early diastole. The arterial tracing may show a narrow pulse pressure (pulsus parvus).
Fig. 11. Aortic pressure tracing in a patient with severe left ventricular dysfunction pulsus
alternans
In patients with right-sided heart failure similar to left heart failure, pulsus alternans may be
present in right-sided pressure waveforms (Fig 12).
Fig. 12. Pulsus alternans in the right ventricular wave form in a patient with right-sided
heart failure
In the case of tricuspid regurgitation secondary to pulmonary hypertension as in primary
tricuspid regurgitation a prominent “v” wave on the right atrial waveform may appear (Fig
13) and in severe cases of tricuspid regurgitation ventricularization of the right atrial
waveform may occur (Fig 14).
230 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 13. Prominent “v” wave in the right atrial pressure in a patient with severe tricuspid
regurgitation
Fig. 14. Ventricularization of the right atrial waveform in a patient with severe tricuspid
regurgitation
In patients with hypertrophic obstructive cardiomyopathy the systolic anterior motion of
the mitral valve obstructs the left ventricular outflow tract causing a pressure gradient
between the left ventricle and aorta (Fig 15). And the aorta pressure waveform may show
the characteristic pattern of spike and dome configuration (Fig 16). In some cases the
gradient may be absent at rest but can be provoked by decreasing the preload.
Fig. 15. Simultaneous left ventricular and aortic pressure waveform in a patient with
hypertrophic obstructive cardiomyopathy which shows significant pressure gradients at rest
Cardiac Catheterization and Coronary Angiography in Patients with Cardiomyopathy 231
6. Left ventriculography
Left ventriculography is performed during a left heart catheterization to assess left
ventricular function. Left ventriculography can also be helpful to identify the presence of
mitral regurgitation, ventricular septal defect, and left ventricular hypertrophy. In patients
with high pulmonary capillary wedge pressure or left ventricular end-diastolic pressure the
injection of contrast may impose the patient to the risk of acute pulmonary edema. In
addition, in patients with a mobile left ventricular thrombus seen on echocardiography it is
better not to perform left ventriculography. Left ventriculography is commonly performed
by a power injector and a pigtail catheter positioned in the mid ventricle.
For assessment of ventricular systolic function, ejection fraction is calculated via left
ventriculography. Usually computer-based software is applied and the left ventricular end-
diastolic and end-systolic contours are traced. Diastolic and systolic areas can be determined
and based on the assumptions regarding the geometry of the heart, ventricular volumes are
calculated and then the left ventricular ejection fraction can be calculated. Furthermore, in
patients with coronary artery disease, regional left ventricular function can be assessed.
Based on the distribution of the coronary arteries the left ventricle is divided into some
segments. The contractions of the segments are evaluated. If the contraction of each segment
is reduced it is classified as “hypokinetic” and if there is no contraction it is called
“akinetic”. Finally, if during systole the segment moves outward it is called “dyskinetic”. In
patients with hypertrophic cardiomyopathy, because of excessive hypertrophy, in left
ventriculography cavity obliteration and a small ventricular end-systolic volume are
commonly seen. In these patients if ventricular outflow tract obstruction also is present,
systolic anterior motion of the mitral valve can be noted. Interestingly, in apical form of
hypertrophic cardiomyopathy the ventriculogram appears with a “spade” – shaped contour.
In patients with apical ballooning syndrome who have transient severe left ventricular
dysfunction in the absence of coronary artery disease left ventriculography shows aneurysm
of the left ventricle which predominantly affects the apex of the heart.
7. Right ventriculography
Right ventriculography is usually indicated in congenital heart disease. However, right
ventriculography in adults may be helpful in the diagnosis of right ventricular dysplasia
and determination of right ventricular systolic function. In patients with arrhythmogenic
right ventricular dysplasia several findings associated with this disorder have been noted.
However, there is no pathognomonic feature in right ventriculography in these patients.
232 Advances in the Diagnosis of Coronary Atherosclerosis
8. Coronary angiography
Coronary angiography is considered the gold standard for diagnosing coronary artery
disease and can be useful to differentiate ischemic from dilated forms of cardiomyopathies.
During coronary angiography the dominant vessel and also the vascular territories for each
artery can be identified. Obstructive coronary artery disease is usually defined by
angiography when a greater than 50% diameter narrowing is seen. When the lesions narrow
the lumen by more than 70%, they are generally believed to be hemodynamically significant.
However, there are some limitations regarding the usefulness of coronary angiography in
diagnosing coronary artery disease. Coronary angiography only assesses the arterial lumen,
while atherosclerosis is a disease of the arterial wall. There may be a substantial amount of
plaque in the arterial wall before it is evident by angiography. Thus, a normal coronary
arteriogram does not exclude the presence of coronary artery disease. Second, there is a
wide range of interobserver variability in interpreting the coronary arteriogram of a patient.
Third, depending on the image quality, the operator technique, patient body habitus, the
vessel tortuosity, and the presence of overlapping segments, the ability of the angiography
to assess a lesion may be affected. Finally, for identification of a luminal narrowing a
reference normal segment of the vessel is usually used for comparison. In patients with
diffuse coronary lesions, a true normal segment is not present and the arterial lumen may
appear uniform.
Ischemic cardiomyopathy results following severe coronary artery disorders and usually
angiography must be performed for proper diagnosis (Shokrzadeh et al., 2008). Coronary
atherosclerosis usually causes narrowing of the lumen of the coronary arteries in advanced
stages. In the early stages of atherosclerosis, compensatory enlargement of the artery
maintains the coronary artery lumen. Thus, coronary angiography which only assesses the
arterial lumen can not detect the early stages of atherosclerosis. However, techniques such
as intravascular ultrasound provide images of arterial wall and detect coronary
atherosclerosis in earlier stages. Coronary atherosclerosis can be detected anywhere along
the course of the artery.
There are many indications for performing coronary angiography. For example, in different
clinical situations such as myocardial infarction, acute coronary syndromes stable angina,
patients with valvular or congenital heart diseases coronary angiography may be useful to
define coronary artery anatomy. However, coronary angiography should not be performed
in patients who do not want to undergo revascularization, patients with severe left
ventricular dysfunction in whom revascularization is not likely to improve ventricular
function, patients with acute bleeding, unexplained fever, and in patients with severe
coagulopathy.
9. Conclusion
Cardiac catheterization is performed in patients with heart failure to assess the etiology, to
evaluate the hemodynamic status of the patient, and to define therapeutic responses. While
the major part of the hemodynamic evaluation is assessed in the supine state, exercise
conditions can also be evaluated. After hemodynamic evaluation of the patient angiography
should be performed to define the coronary anatomy and if needed left ventriculography to
assess ventricular contractility. Ventriculography is also helpful to define ventricular size
and mitral regurgitation, although most patients will have had complete echocardiographic
study prior to catheterization. In the absence of coronary artery disease to explain
Cardiac Catheterization and Coronary Angiography in Patients with Cardiomyopathy 233
10. Acknowledgement
I wish to thank Dr Safoora Masoumi for her help in providing this chapter.
11. References
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Bishay, ES., McCarthy, PM., Cosgrove, DM., Hoercher, KJ., Smedira, NG., Mukherjee, D.,
White, J., & Blackstone, EH.(2000). Mitral valve surgery in patients with severe left
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234 Advances in the Diagnosis of Coronary Atherosclerosis
1. Introduction
Contrast-induced nephropathy (CIN) is an injury to the kidney as a result of exposure to
intravascular iodinated contrast medium. It represents an increasing health care burden and
challenge as the frequency of diagnostic imaging and interventional studies increase,
particularly among populations at risk of developing CIN. As the population ages,
decreased renal function and increased atherosclerotic cardiovascular disease become more
prevalent. An increasing incidence of obesity with resultant metabolic syndrome and/or
type 2 diabetes mellitus also increases the population at risk for CIN (Toprak et al., 2006).
Coronary artery disease is a major complication of type 2 diabetes mellitus. Thus, patients
with type 2 diabetes mellitus often require coronary angiography and coronary intervention
and are at risk of CIN.
results from the administration of contrast medium. CIN carries short-term and long-term
mortality. Acute renal failure after coronary intervention is associated with a 36% in-
hospital mortality rate and a 19% 2-year survival rate. Thus, understanding why patients
with type 2 diabetes are at increased risk of CIN and controlling factors to decrease the risk
of CIN, has major short- and long-term benefits to patients with type 2 diabetes (Nikolsky et
al., 2004). Most clinical studies on CIN have mainly been in patients with type 2 diabetes
mellitus rather than type 1 diabetes mellitus and, thus, the remarks in this chapter will be
confined to patients with type 2 diabetes kidney disease.
In patients with normal GFR, the risk of CIN is likely less, not only because of more rapid
clearance of contrast medium from the kidney (less time for generation of oxygen-free
radicals), but, presumably, because of the presence of a variety of endogenous vasodilators
that protect against renal ischemia, including prostaglandins (E2 and I2), atrial natriuretic
peptide and nitric oxide. In patients with GFR of less than 60 mL/min/1.73 m2, the risk of
CIN increases with prolonged clearance of contrast medium.
In summary, patients with type 2 diabetes mellitus appear to be at increased risk of CIN, not
only because chronic renal disease is common in these patients, but also because there
appears to be a greater vasoconstriction of the renal afferent arterioles to intrarenal
adenosine and suppressed nitric oxide bioavailability in the kidney due to endothelial
dysfunction (Komers & Anderson, 2003). Recent reports indicate that severe renal
dysfunction need not be present to create a risk of CIN in diabetic patients with measured
creatinine clearance of 100 mL/min and receiving proper hydration (Hardiek et al., 2008).
medullary ischemia, and dipyridamole that blocks the normal cellular uptake of adenosine
resulting in a greater renal adenosine – mediated vasconstrictive response.
In patients with type 2 diabetes mellitus requiring elective angiography, nonsteroidal anti-
inflammatory medicines, diuretics and dipyridamole should be held prior to the procedure.
While nonsteroidal anti-inflammatory medications are considered the cornerstone for
managing the pain of osteoarthritis and other painful conditions, recent meta-analysis
indicate significantly increased risk of myocardial infarction, stroke or death from
cardiovascular disease compared to placebo with the chronic use of these medications.
Contrary to some previous reports, the current meta-analysis found no suggestion that this
increased cardiovascular risk is specific to cyclo-oxygenase-2 inhibitors. Data were available
for naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib and lumiracoxib.
Overall, naproxen appeared to be the least harmful nonsteroidal anti-inflammatory
medication in terms of cardiovascular outcomes. Risks were greatest with ibuprofen,
diclofenac, etoricoxib and lumiracoxib. Thus, chronic use of nonsteroidal anti-inflammatory
medications in patients with type 2 diabetes who are at increased cardiovascular risk is
discouraged. In regard to dipyridamole, recent data suggests superiority of clopidogrel over
dipyridamole in patients who have suffered a cerebral vascular accident. Increasingly
clopidogrel rather than dipyridamole is the recommended antiplatelet agent in addition to
81 mg aspirin in patients with type 2 diabetes after transient ischemic attacks or cerebral
vascular accidents. Thus, if the patient with type 2 diabetes mellitus needs emergency
angiography, the risk of dipyridamole contributing to CIN would no longer exist.
Patients with type 2 diabetes mellitus have a significantly greater risk of macrovascular
disease, including coronary heart disease, stroke and peripheral vascular disease, in addition
to the microvascular complications, such as retinopathy, neuropathy and nephropathy.
Despite evidence of benefit for reduction of microvascular disease with glycemic control, to
date, there is no such evidence for the role of glycemic control in macrovascular event
reduction. In newly diagnosed patients with type 2 diabetes, besides initiation of diet, exercise
and weight reduction, metformin is usually the recommended initial therapy unless
contraindicated, such as renal disease (serum creatinine greater than 1.5 mg/dL in males and
greater than 1.4 mg/dL in females). Although not relevant to CIN prevention, metformin
should be temporarily discontinued at the time of or prior to use of contrast medium or major
surgical procedures and withheld for 48 hours after the procedure. Metformin should be
restarted after renal function has been reevaluated and found to be normal (Goergen et al.,
2010). While the mortality rate for patients who develop lactic acidosis can be quite high, the
actual number of people dying from metformin-induced lactic acidosis after contrast medium
exposure is quite low using these guidelines.
Cigarette smoking is the most common cause of preventable morbidity and mortality in
developed countries. In addition to it being a major risk factor for cardiovascular disease,
lung disease and cancer, cigarette smoking is now recognized as an important independent
risk factor of chronic kidney disease, including diabetic nephropathy, by increasing the rate
of transition from microalbuminuria to proteinuria and promoting the progression to end-
stage renal disease (Phisitkul et al., 2008). Furthermore, a recent cross-sectional analysis of
participants in the National Health and Nutrition Examination Survey demonstrated a
strong association between exposure to secondhand smoke and proteinuria, suggesting that
passive smokers are also at increased risk of chronic kidney disease (Obert et al., 2011).
Several clinical and experimental studies have demonstrated the role of transforming
growth factor-beta in the pathogenesis of chronic kidney disease, including diabetic
Contrast-Induced Nephropathy in Patients with Type 2 Diabetes Mellitus
and Coronary Artery Disease: Update and Practical Clinical Applications 239
nephropathy. This cytokine is largely profibrotic and plays a significant role in diabetic
nephropathy by increasing the production of extracellular matrix proteins, including
fibronectin and collagen, in the glomerulus. It is also known that one cigarette paralyzes the
ability of the endothelium to make nitric oxide for up to 24 hours. Thus, patients with type 2
diabetes mellitus should be counseled to discontinue smoking. Emphasizing that
recommendation prior to elective angiography may decrease the incidence of CIN.
Another class of medication that warrants discussion in the long-term treatment of patients
with type 2 diabetes mellitus, not only for the long-term metabolic advantages, but also
because of the risk of CIN is beta-blocker therapy. Both nonselective and selective
traditional beta-blockers have been shown to increase insulin resistance, facilitate weight
gain of approximately 1 kilogram per six months and worsen hypertriglyceridemia by
approximately 13%. In contrast, carvedilol in hypertensive diabetic patients has been found
to have a neutral effect on insulin resistance, weight and triglycerides (Bakris et al., 2004).
This favorable metabolic profile also suggests that carvedilol is a better choice compared to
traditional beta-blockers in these high risk patients. Recent trials emphasize the class
heterogeneity that exists for beta-blockers and provide a strong basis for preferred use of
carvedilol in patients with type 2 diabetes. Carvedilol is a unique molecule that combines
the properties of a nonspecific beta-blocker and a specific alpha-1-blocker in a ratio of 2:3.
Carvedilol also possesses antioxidant properties. In hypertensive diabetic patients,
carvedilol compared to metoprolol tartrate has been shown to reduce existing
microalbuminuria and to decrease the risk of progression to microalbuminuria. These
results suggest improved endothelial function and may be related to improvement in insulin
resistance or an effect on oxidant stress in the kidney. Thus, in patients with type 2 diabetes
mellitus that require beta-blocker therapy, carvedilol has become the recommended beta-
blocker. There are also data to suggest that carvedilol compared to traditional beta-blockers
attenuates CIN. Proposed mechanisms include unopposed alpha-medicated renal
vasoconctriction causing more ischemia when on traditional beta-blockers and/or improved
endothelial function due to the antioxidant properties of carvedilol.
There are other medicines that may attenuate the risk of CIN. Calcium-channel blocking
medications attenuate both the magnitude and duration of renal vasoconstriction after
contrast medium administration (Russo et al., 1990). In patients with type 2 diabetes
mellitus and hypertension and/or angina requiring calcium-channel blocking medications,
these medications should be continued if contrast medium administration is planned.
The adenosine receptor antagonists, theophylline and aminophylline, attenuate the decrease
in GFR seen after contrast medium. Since patients with type 2 diabetes mellitus have an
increased reactivity to intrarenal adenosine, theophylline prior to contrast medium
administration warrants special consideration. The kidney responds to contrast media-
induced stress with a tubuloglomercular feedback response which is largely medicated by
adenosine when less than 100 mL of contrast medium is administered. This mechanism has
been confirmed by both animal and clinical studies. Pretreatment with long-acting
theophylline 3 mg/kg orally at least 30 minutes before contrast medium administration and
12 hours later in addition to hydration has been shown to attenuate the depression of
creatinine clearance. It is critical that theophylline be administered before contrast medium
injection, but prolonged treatment after angiography is unnecessary. Theophylline
prophylaxis is effective, safe, and inexpensive. This dose of theophylline is manyfold greater
than the minimum dose required to block renal vascular adenosine receptors and is well
below that shown to affect renal cyclic nucleotide phosphodiesterase activity (Vassallo &
240 Advances in the Diagnosis of Coronary Atherosclerosis
Lipsky, 1998). This dose of theophylline causes transient plasma theophylline levels of 7
mcg/mL which is below therapeutic levels required for treatment of asthma and unlikely to
cause serious gastrointestinal, neurological, or cardiovascular adverse effects (Cooling, 1993;
Shannon, 1999).
Adenosine receptor antagonists, theophylline and aminophylline, prophylaxis to attenuate
CIN has not been strongly adopted except in patients at high risk for CIN. Some controlled
trials have shown a significant reduction in the risk for CIN while others have shown no
reduction (Abizaid et al., 1999; Erley et al., 1999; Erley et al., 1994; Gandhi et al., 1992; Huber
et al., 2001; Huber et al., 2002; Huber et al., 2003; Kolonko et al., 1998; Shammas et al., 2001).
However, these studies have been limited by small sample size, variation in timing and
dosage of drug administration, and variation in the definition of CIN. Three meta-analyses
have dealt specifically with the clinical use of theophylline for the prevention of CIN. Each
of these gave extensive information concerning the way that the papers which were
included were chosen, exactly what factors were chosen for matching across studies and
which factors did not match. In addition, statistics were presented which addressed the
concerns about selection bias and efforts were made to adjust for non-matching factors to
the extent possible. No attempt will be made to describe each of these studies completely,
however, we will give some summary information concerning each of them. One meta-
analysis identified 10 studies in which theophylline was used for the prevention of CIN (Ix
et al., 2004). Of the ten, seven were found to fulfill all the inclusion criteria and these
constituted the final sample for the analysis. The studies included were reported between
1994 and 2003 and included a number of different protocols for the administration of the
theophylline. The final conclusion reached by these investigators was that the prophylactic
administration of theophylline appears to protect against contrast-induced declines in
kidney function. They also reported that “the protective benefits appeared robust regardless
of the study design, form or volume of contrast medium delivered, and the presence or
absence of intravenous volume expansion.” The investigators did indicate that they were
unable to determine (given the available data) if theophylline reduced the number of
patients who experienced large increases in serum creatinine concentrations or required
dialysis. Another meta-analysis identified nine studies which met the study criteria for their
protocol (Bagshaw & Ghali, 2005). Their conclusion was that the data they considered
indicated that there is promising evidence supporting the use of theophylline for the
prevention of CIN but the evidence is still not conclusive. They suggested that what was
required to answer this question was a larger, well designed clinical trial for confirmation
and assessment of risks before theophylline could be recommended routinely for the
prevention of CIN. They also noted from their analysis of these papers that such a trial
should include a hydration protocol and the routine use of low or iso-osmolar nonionic
contrast media since those are now the current standards of care. These two meta-analyses
focused primarily on theophylline and a comparison of the choices of papers from the two
studies shows that seven papers included in the initial meta-analysis were also included in
the nine chosen by the second meta-analysis. The latter authors included two papers which
were in the same search time frame as the initial meta-analysis but were not selected under
that study protocol. A third meta-analysis covered a number of drugs aimed at reducing the
incidence of CIN (Kelly et al., 2008). The primary drug considered was N-acetylcysteine
with theophylline being more secondary to the study. Only six of the studies considered
dealt primarily with theophylline. Of the six considered, five were part of the set of studies
considered by the second meta-analysis while four of them coincided with those used in the
Contrast-Induced Nephropathy in Patients with Type 2 Diabetes Mellitus
and Coronary Artery Disease: Update and Practical Clinical Applications 241
initial meta-analysis. The sixth paper which was unique to this analysis appeared in 2006
which was out of the range of years covered by the other two papers. One of the six papers
common to both was not included by the initial meta-analysis. The conclusion of this paper
with respect to the efficacy of theophylline was that it produced a large risk reduction but
did not achieve statistical significance. Of these three meta-analyses, the first two are most
comparable. Both reach the same conclusion. Each of these papers used slightly different
statistical methods. Both contained a thorough discussion of the selection criteria used to
choose the papers included and measures to check for selection bias. The general
conclusions were favorable with the hypothesis that theophylline is protective against CIN.
Unfortunately, neither group of authors was willing to report a definitive answer. There are
some areas where the studies under review by these authors differed. One was in the area
of how the theophylline was administered: as a fixed dose regardless of body weight or as a
dose adjusted per kilogram of body weight. The broad conclusion reached is that a large,
carefully designed clinical trial needs to be conducted to reach a final conclusion. The trial
should be stratified according to ancillary risk factors such as age and diabetes. In addition,
the effect of the dosing protocol and hydration methods needs to be considered. Finally,
since it is known that certain beverages like coffee and tea also block adenosine vascular
receptors, a study testing the benefit of theophylline should exclude other xanthine
exposure during the time before contrast medium administration and for the 48 hours after
while the subject is being followed.
Studies suggest two mechanisms by which intrarenal adenosine contributes to CIN. Early
depression of renal function after contrast medium exposure is caused by A1 receptor-
mediated renal afferent arteriolar vasoconstriction and A2 receptor-mediated efferent
arteriolar vasodilatation resulting in decreased glomerular perfusion pressure. Later
depression of renal function after contrast medium exposure is caused by oxygen-free
radical production, in part, due to intrarenal adenosine catabolism to xanthine.
Pretreatment with theophylline may attenuate CIN by maintaining GFR such that contrast
medium is cleared from the kidney more rapidly, thus, decreasing direct cytotoxic effects
from contrast medium and decreasing the potential for intrarenal adenosine-mediated
oxygen-free radical production. Pretreatment with allopurinol has also been shown to
attenuate CIN. To be effective, it is crucial to administer allopurinol at least 24 hours prior to
exposure to contrast medium. Pretreatment allows time for production of oxypurinol, the
chief metabolite of allopurinol, which is a much more potent xanthine oxidase inhibitor.
Allopurinol administered in this fashion was renally protective. Decreasing renal xanthine
oxidase decreases the catabolism of intrarenal adenosine to xanthine resulting in decreased
oxygen-free radical production and less renal tubular cell injury.
Patients with type 2 diabetes mellitus are usually on angiotensin-converting enzyme
inhibitors, angiotensin II receptor blockers and/or direct renin inhibitor to decrease the
progression of renal disease. Whether these agents need to be held or should be continued
when contrast medium is administered requires clinical judgment. Intrarenal angiotensin II
enhances adenosine-mediated vasoconstriction so theoretically blockade of the renin-
angiotensin system should attenuate the risk of CIN. In support of this concept,
preprocedure angiotensin-converting enzyme inhibitor use has been shown to lower the risk
for CIN in patients with chronic renal disease (Dangas et al., 2005). Another clinical trial
showed that periprocedural captopril, compared with an untreated control group, reduced
the risk of CIN in patients with type 2 diabetes mellitus (Gupta et al, 1999). However, if an
unstable patient has low cardiac output or hypotension, renin-angiotensin system blockade
242 Advances in the Diagnosis of Coronary Atherosclerosis
dopamine, atrial natriuretic peptide and L-arginine have not been shown to be effective.
Potentially beneficial strategies for attenuating CIN include theophylline, allopurinol,
ascorbic acid, oral and intravenous N–acetylcysteine, hemodialysis of contrast medium and
venous capture of contrast medium.
In regard to pretreatment approaches to limit oxygen-free radical injury following contrast
medium, four pharmacologic approaches warrant further study with adequately powered,
appropriately designed, randomized trials of high-risk diabetic patients, perhaps combined
with theophylline pretreatment. One of these is isotonic sodium bicarbonate solution with
the length of post-procedure treatment determined by the volume of contrast medium
administered. Maintaining an alkaline environment should decrease oxygen-free radical
formation in the renal tubule. As discussed above, one source of oxygen-free radical
production after contrast medium is the catabolism of intrarenal adenosine to xanthine.
Allopurinol, a xanthine oxidase inhibitor, 4 mg/kg orally daily starting 24 hours before
administration of contrast medium has shown benefit. This dose of allopurinol, if given 24
hours before elective procedures, is metabolized into oxypurinol which is a more effective
xanthine oxidase inhibitor than allopurinol. This 24-hour pretreatment approach has been
shown to attenuate the fall in GFR after contrast medium exposure. Besides limiting oxygen-
free radical formation, allopurinol may also protect the kidney from contrast medium
exposure by its ability to inhibit adenine nucleotide degradation (thus, preservation of
adenine nucleotide is required for recovery from renal injury). Allopurinol has also been
found to markedly decrease the vasodilatation response to intravenous adenosine in the
renal vasculature. Less adenosine-mediated efferent renal arteriolar vasodilatation would
preserve glomerular perfusion pressure. In view of the possible role of oxidase stress and
oxygen-free radical generation in CIN, ascorbic acid as an antioxidant warrants further
study (Spargias et al., 2004). N-acetylcysteine, as an antioxidant and renal vasodilator, has
not been shown to be consistently effective when given orally (Solomon, 2009). Perhaps a
larger oral dose is needed or intravenous administration may be required. Allopurinol,
ascorbic acid and N-acetylcysteine, if proven beneficial, require pretreatment and would be
less helpful in diabetic patients requiring emergency diagnostic and/or interventional
contrast medium usage.
To decrease the risk of CIN requires careful patient screening and selection, adequate
patient hydration, limiting the volume of contrast medium administered and choosing a
safe, non-ionic, low osmolar contrast agent. Based on comparisons of contrast media in
proximal renal tubular cell culture and in recent robust head-to-head prospective clinical
trials in high risk patients, however, iso-osmolar iodixanol and low-osmolar iopamidol are
comparable and appear to be the contrast agents of choice to reduce renal risk for CIN.
The direct cellular toxicities of commonly used contrast medium have been compared in
renal proximal tubular cells in culture (Hardiek et al., 2001). All contrast media, whether
high-osmolar or iso-osmolar, ionic or non-ionic, stress renal proximal tubular cells. When
renal proximal tubular cells in culture are exposed to contrast media, they respond by
increasing extracellular adenosine concentrations because of the depletion of adenosine
triphosphate due to osmotic load and the large size of contrast medium molecules. The renal
toxicity from the direct effects of contrast medium is reversible, as has been shown in vitro in
studies in which renal tubular cells respond to contrast media exposure by decreasing the
activity of mitochondrial enzymes without altering viability. While all contrast medium may
reduce mitochondrial enzyme activity, differences among agents are seen with iopamidol
and iodixanol being the least toxic and the two ionic contrast media, ioxaglate and
244 Advances in the Diagnosis of Coronary Atherosclerosis
diatrizoate, being the most toxic. The lesser the depression of mitochondrial function, the
more rapidly renal proximal tubular cells can recover after contrast medium has been
eliminated from the kidney suggesting that iopamidol and iodixanol are the least
nephrotoxic molecules when studied in cell culture.
Earlier clinical trials comparing contrast medium risk in patients with type 2 diabetes for
CIN had limitations that prevented valid conclusions: the studies were not blinded, the
number of patients was small, the timing of outcome assessment was unclear, or the patients
received contrast intra-arterially and/or intravenously. With proper hydration and
identification of high-risk patients, the incidence of CIN after intra-arterial contrast medium
administration is about 10%. More recent trials in high-risk diabetic patients given contrast
medium intravenously suggest that the incidence of CIN is about 5%. More recent trials
have been head-to-head, robust and prospective in high-risk patients with chronic renal
failure (eGFR 59-20 mL/min) with intra-arterial contrast medium administration. Based on
animal studies, concern about osmotoxicity in the pathogenesis of CIN emerged which led
to the development of low-osmolar, and, later, iso-osmolar contrast medium. Of interest, in
human prospective trials and meta-analysis, no specifically significant differences in
nephrotoxicity between high-osmolar (1,400-2,000 mOsm/kg) and non-ionic low-osmolar
(600-800 mOsm/kg) contrast have been found in patients with normal renal function
(Solomon, 2005). Clinical trials published in the 1990s, however, showed that use of high-
osmolar ionic monomer diatrizoate in patients with chronic renal disease who were
undergoing coronary angiography had a higher incidence of CIN than that associated with
non-ionic low-osmolar contrast medium. In general, lower osmolar contrast medium has
now replaced diatrizoate for routine clinical use. It is less clear whether there are
appreciable differences among various non-ionic low-osmolar contrast medium regarding
the incidence of CIN. Because individual contrast medium has specific effects on renal
tubular cells, head-to-head studies are required to compare the safer contrast medium in at
risk patients undergoing angiography. With the development of the non-ionic iso-osmolar
dimer, iodixanol, subsequent studies have evaluated whether a further reduction in
osmolality would result in still more protection against CIN. In the first of these
comparative studies ((Nephrotoxicity of High-Risk Patient Study of Iso-osmolar and Low-
Osmolar Non-ionic Contrast Medium (NEPHRIC)) 129 patients with diabetes with chronic
renal failure (baseline eGFR of 48 mL/min) and serum creatinine levels 1.5-3.5 mg/dL were
randomized to the low-osmolar contrast medium iohexol or the iso-osmolar contrast
medium, iodixanol (Aspelin et al., 2003). A higher rate of CIN defined as a serum creatinine
rise of greater than 0.5 mg/dL after angiography was noted after iohexol (26.2%) than after
iodixanol (3.1%).
Since the publication of NEPHRIC, subsequent prospective randomized trials involving
high-risk patients with renal insufficiency and diabetes and the intra-arterial administration
of contrast medium have not consistently found a lower incidence of CIN associated with
iso-osmolar contrast medium. In general, a benefit favoring the non-ionic iso-osmolar dimer,
iodixanol, is seen compared with the non-ionic low-osmolar monomer iohexol or the ionic
low-osmolar dimer, ioxaglate. In contrast, when comparing non-ionic low-osmolar
monomers, iopamidol or ioversol, in high-risk patients with iso-osmolar iodixanol, no
additional protective effect is seen. There have been no head-to-head comparisons of iohexol
with any other non-ionic, low-osmolar contrast agents in high-risk patients undergoing
intra-arterial administration of contrast. Based on a recent systematic review of
angiographic contrast medium in high-risk patients, however, the likely explanation of the
Contrast-Induced Nephropathy in Patients with Type 2 Diabetes Mellitus
and Coronary Artery Disease: Update and Practical Clinical Applications 245
NEPHRIC findings is that low-osmolar, iohexol, appears to be more nephrotoxic than other
low-osmolar contrast media, such as iopamidol and ioversol. Furthermore, a systematic
review of angiographic contrast media in high-risk patients found no statistically significant
difference in the risk of CIN between low-osmolar iopamidol and iso-osmolar iodixanol
(Solomon, 2005). These comparisons in low-osmolar and iso-osmolar contrast medium
administered intra-arterially in high-risk patients suggest that each molecules safety must
be based on robust clinical trials. These data also suggest that physical and/or chemical
properties of each molecule, other than osmolarity, are implicated in the pathogenesis of
CIN. Given this incidence of CIN, prospective randomized trials need larger patient
populations to be properly powered to be certain of the conclusions. The recently published
Cardiac Angiography in Renally-Impaired Patients (CARE) study fits these criteria by being
a multicenter, double-blind, randomized study designed to prospectively compare the
incidence of CIN after intra-arterial administration of low-osmolar iopamidol or iso-osmolar
iodixanol in 414 patients with moderate to severe chronic kidney disease (eGFR of 20-59
mL/min/1.73 m2) who underwent coronary angiography or percutaneous coronary
intervention (Solomon et al., 2007). All patients received intravenous sodium bicarbonate
prophylaxis. The primary endpoint was a post-dose serum creatinine increase of greater
than 0.5 mL/dL over baseline. The renal effects of these two agents were comparable with
no significant difference in occurrence of CIN and no significant difference in occurrence of
CIN in the subgroup of chronic kidney disease patients with diabetes. More recently, a
multicenter, randomized double-blind trial comparing the renal effects of non-ionic, iso-
osmolar iodixanol versus non-ionic, low-osmolar iopamidol in 526 patients with impaired
baseline renal function and diabetes undergoing diagnostic and/or therapeutic coronary
angiography procedures was completed (Laskey et al., 2009). This trial showed overall rate
of CIN in patients with chronic kidney disease and diabetes undergoing coronary
angiographic procedures was 10.5%. There was no significant difference between iodixanol
and iopamidol in either peak increase in serum creatinine or risk of CIN.
The renal effects of iodixanol and iopamidol are comparable in high-risk diabetic patients
requiring contrast medium for diagnostic studies or intervention. The non-renal differences
between these contrast agents should be considered when selecting an agent and when
obtaining informed patient consent, however. Using a contrast medium with a higher iodine
concentration per milliliter, such as iopamidol which has 370 mg/mL compared to iodixanol
which has 320 mg/mL iodine content, may allow for a smaller volume to be used
intravenously without sacrificing image quality. The higher iodine concentration of
iopamidol may make complex plaques easier to appreciate during coronary angiography
and intervention. Other considerations are that iodixanol is threefold more likely to cause
contrast-induced delayed skin reactions compared to iopamidol. After percutaneous
coronary intervention with bare-metal or drug-eluting stent placement, cardiac patients
require antiplatelet therapy with clopidogrel, which may cause a rash within 5 to 7 days of
treatment initiation, a timeline similar to that for delayed contrast-induced skin reactions. In
clinical trials with clopidogrel, skin reactions are noted in 4.2% of patients. The choice of a
contrast molecule, such as iopamidol, that is less likely to cause a delayed contrast-induced
skin reaction makes decisions regarding the discontinuation of clopidogrel less frequent and
more definitive. Finally, iopamidol is less expensive than iodixanol.
Gadolinium-based contrast agents were introduced, partly, because of the discovery that
iodine-based contrast medium could cause CIN. However, recent reports suggest that
gadolinium-based agents may also be nephrotoxic. Furthermore, after exposure to
246 Advances in the Diagnosis of Coronary Atherosclerosis
of sodium bicarbonate because normally there is little bicarbonate in the urine. Even a small
increase in serum bicarbonate of 1 to 2 mEq/L will result in the ‘dumping’ of bicarbonate
into the urine in most patients (Solomon, 2009). Such a change in serum is easily obtained
with the infusion rate recommended. Sodium bicarbonate therapy is readily available,
inexpensive, and safe. The question is whether it is efficacious for prevention of CIN. Of
particular clinical interest from recent meta-analysis was the finding that sodium
bicarbonate therapy is most effective in patients who experienced urgent or emergency
contrast medium exposure (Meier et al., 2009). Presumably this selects a group of patients
who are less likely to receive any other form of prophylaxis for CIN. This is of great
potential importance for the emergency room and cardiac catheterization laboratory.
Sodium bicarbonate therapy was also most effective in those receiving low osmolality
contrast media compared with iso-osmolality contrast media. Low osmolality contrast is
increasingly chosen because of its safety, lower costs, and higher iodine content. It has also
been found that the addition of N-acetylcysteine to fluid expansion with sodium bicarbonate
showed no additional reduction in the rate of CIN after the intra-arterial administration of
iopamidol or iodixanol to high-risk patients with type 2 diabetes mellitus and chronic
kidney disease (Staniloae et al., 2009).
CIN needs to be redefined using markers of kidney injury that are sensitive, specific, and
predictive of adverse outcomes (Solomon, 2009). This will enable investigators to better
address the question of how to attenuate this condition in the future. The most important
question to be answered is whether prevention of kidney injury results in a change in short-
and long-term adverse outcomes. Using iopamidol has been associated with a reduction in
long-term adverse events (Solomon et al., 2007). The recent meta-analyses found that despite
a reduction in the incidence of CIN, sodium bicarbonate therapy had no benefit on the need
for dialysis or mortality (Meier et al., 2009). No matter how available, inexpensive, and safe
a potential preventive therapy, to find an important role in clinical therapeutics, it must
improve the ‘downstream’ adverse outcomes, an as yet elusive goal for the prevention and
treatment of CIN (Solomon, 2009).
3. Conclusions
In summary, CIN remains an important clinical challenge in patients with type 2 diabetes
mellitus with coronary artery disease. Reducing the incidence of CIN requires recognizing
high risk patients, such as patients with type 2 diabetes mellitus. Long-term risk factor
modification should improve endothelial function so a more normal renal compensatory
response will occur should contrast medium administration be required. Lowest volume of
iopamidol needed would appear to be the contrast agent of choice. In patients with type 2
diabetes mellitus, pretreatment with theophylline to block adenosine-mediated renal
vasoconstriction combined with volume expansion with sodium bicarbonate to limit
oxygen-free radical generation is a rational approach based on existing data. Appropriately
designed robust randomized clinical trials combining pharmacologic approaches aimed at
both the renal vasoconstriction and the oxygen-free radical generation are needed to confirm
that this is the best preventive strategy in patients with type 2 diabetes mellitus.
4. Acknowledgement
Special thanks to Marcey R. Ervin and Sandy Sledge for preparation of the manuscript.
Contrast-Induced Nephropathy in Patients with Type 2 Diabetes Mellitus
and Coronary Artery Disease: Update and Practical Clinical Applications 249
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14
1. Introduction
Coronary angiography through selective injection of radiopaque contrast agent into the
coronary arteries is currently the gold standard for evaluating coronary artery disease
(CAD). Subjective visual estimation of lesion severity has been shown to be inadequate due
to high degrees of intraobserver and interobserver variability (Topol & Nissen, 1995). Since
the late 1980s methods and algorithms for quantitative coronary angiography (QCA) have
been developed in order to objectively quantify the extent of CAD (Serruys et al., 1984).
Furthermore, validation of specific QCA measurements associated with clinical outcomes
has led to their incorporation into various scoring systems and trials endpoint.
2. Two-dimensional QCA
This technique is based on contrast coronary angiograms obtaining parameters that quantify
objectively the coronary lumen measuring the significance of a coronary stenosis. Notably, a
single coronary angiography image gives only a two-dimensional (2D) radiographic image
while coronary arteries can be highly tortuous three-dimensional structures thus at least two
projections orthogonal to each other and both perpendicular to the analyzed coronary
segment are necessary to obtain the most complete data to avoid foreshortening or
underestimation of stenosis severity.
Most of the systems available nowadays are based on vessel edge detection algorithms to
designate the arterial lumen on conventional coronary angiograms providing, therefore, the
assessment of the lesion in an operator-independent way exploiting specific and dedicated
software. The earliest form of quantitative angiography was the application of calipers to
visually estimate percent diameter stenosis. In 1971 Gensini and colleagues described an
electronic caliper system in which the arterial borders of the lesion and normal segments are
manually defined by moving cursors (Gensini et al., 1971). In the years several generations
256 Advances in the Diagnosis of Coronary Atherosclerosis
of QCA systems have been developed based on edge detection algorithms to improve
measurement accuracy. First-generation algorithms have been introduced at the beginning
of the Eighties (Mancini et al., 1987; Reiber et al., 1985) improving the reliability of coronary
measurements (Spears et al., 1983); the main pitfall of these first generation systems was the
overestimation of the diameters of small vessels (Herrington et al., 1993a), an issue which
was improved in the second generation systems (diameter approximation \1.2 mm) and
producing more reliable results at the low end of the spectrum of vessel size (Hausleiter et
al., 1997). In more recent years cardiovascular X-ray imaging systems are equipped with
flat-panel (FP) detectors (Spahn et al., 2003) replacing the combination of image intensifier
and charge-couple device camera providing better image quality and enabling further image
enhancement. Novel QCA third-generation system which took advantage of digital flat-
panel (FP) detectors instead of the conventional image intensifier systems were better able to
determine smaller diameter vessels (Van Herck et al., 2004) and analyze complex lesion
morphology with irregular borders (Van der Zwet & Reiber, 1994). However differences in
results using FP systems compared with classic image intensifier-based imaging systems
were shown to be clinically not significant (Tuinenburg et al., 2006). In the common clinical
practice there are different computer systems for QCA that have been validated: among
them the most commonly employed are CAAS (PIE Medical, Maastricht, The Netherlands)
and QAngio XA (Medis, Leiden, The Netherlands) (Garrone et al., 2009).
3. Three-dimensional QCA
Currently, 2-dimensional (2D) QCA is the most commonly used and validated form of QCA.
However, 2D angiography technology has limitations because of vessel overlap and vessel
foreshortening during image acquisition. This is especially problematic in more complex
lesions such as bifurcations. 3D angiography utilizes standard 2D angiographic images
obtained at least 30 degrees apart and with minimal vessel overlap, and reconstructs 3D
images. Several 3D QCA programs are now available: among them the most commonly
employed are CardiOp-B (Paieon Medical Ltd. Park Afek, Israel) and CAAS 5 (Pie medical
Imaging, Maastricht, The Netherlands, and Medis, Leiden, The Netherlands) (Ng & Lansky,
2011). In these systems, the user defines the area of interest by defining the proximal end,
distal end and area of stenosis. However, the systems differ in their calibration methods.
CardiOp-B requires the operator to input the size of the catheter in the image into the
program, whereas the Medis and CAAS 5 systems automatically calibrates the images using
DICOM (Digital Imaging and Communications in Medicine) information embedded in the
angiographic images (Gradaus et al., 2006; Ramcharitar et al., 2008a). Once the image is
created, operators can manipulate the images by zooming in or rotating the image. This
allows the operator to have a better understanding of coronary anatomy and could also help
the operator find an optimal angle to image of a vessel for an intervention (Dvir et al., 2005;
Agostoni et al., 2008). An example of coronary after reconstructed with CardiOp-B system is
shown in figure 1.
3D QCA programs have been validated (Schuurbiers et al., 2009; Tsuchida et al., 2007) and
are now available to provide information of vessel size, percent diameter stenosis, minimal
lumen diameter, bifurcation angle and other QCA values. It was thought that 3D QCA
would have improved accuracy by resolving problems with vessel foreshortening and out of
plane magnification. However, comparisons of 3D QCA programs to conventional 2D QCA
programs have shown mixed results regarding the accuracy of this technology (Ramcharitar
Quantitative Coronary Angiography in the Interventional Cardiology 257
et al., 2008a; Dvir et al., 2005; Tsuchida et al., 2007; Meerkin et al., 2010; Wellnhofer et al.,
1999; Tu et al., 2010). One small study has compared the two current 3D QCA programs
using phantom models demonstrated that the CAAS 5 system may be more accurate than
the CardiOp-B system (Ramcharitar et al., 2008a).
Fig. 1. Reconstruction with 3-D CardiOp-B system of proximal left anterior descending
artery.
are the accuracy of QCA analysis and reliability of the algorithm for the automated
detection and reconstruction of the lumen edges. That is why it is also important that the
coronary images are obtained when the patient is in deep inspiration, which increases the
radiotransparent lung fields surrounding the heart and thus the possibility that the stenosis
is in front of this radiotransparent field. It is also important that the distal tip of the coronary
angiography catheter is present in the sequence, at least in the initial frames.
Indeed, the tip of the catheter, whose diameter in French or millimeters is known, is the
basic tool for calibration (i.e., to estimate the proportion between pixels in the digitalized
images and mm of length). Finally, intracoronary nitroglycerine (e.g., 200 μg) might be
administered to obtain coronary vasodilatation and avoid to mistakenly confounding
vasospasm with atherosclerotic processes.
After choosing the appropriate run, a single static image (i.e., frame) is selected which
should be chosen in end-diastole, when coronaries tend to “stretch” along their course on
the released heart muscle without being subject to contraction or squeezing, even in the case
of intra-myocardial course. Regardless of the type of software, the analysis proceeds
similarly and the following steps consist in: digitization, image calibration and arterial
automatic contour detection. Advances have been made to each of these steps over the last
several decades. The process of digitization from cine film using cine video converter is
obsolete and it has been replaced by digital systems with direct digital input to a video
camera. The analogic video output signal is modified electronically and results in a greater
contrast difference in the parts with high X-ray absorption and lower contrast differences in
areas with low X-ray absorption, significantly improving image quality. Image calibration is
often done with contrast-filled injection catheters (Figure 2), and can be problematic due to
variable image quality and out-of-plane magnification that can be overcome by using
biplane calibration.
A central line is usually then drawn by hand along the stretch of the catheter tip and the
software automatically recognizes its margins by using specific algorithms that, by means of
digital images, recognize the change from radiopaque pixels (black or dark grey) to radio-
transparent pixels (light grey or white) according to a densitometric analysis. The software
then transforms every pixel into a square with sides characterized by known dimensions
(mm). This parameter is then employed to measure the coronary segment of interest that
must be focused on the stenosis or lesion undergoing treatment. The proximal and distal
coronary segments should be relatively free of disease and are referred to as reference
segments. Afterwards, a central line is traced manually and the software automatically
recognizes the margins of the coronary segment under consideration taking advantage of
the automatic contour detection .
This procedure determines the vessel edge based on the weighted sum of the first and
second derivative functions of the brightness values of scanlines perpendicular to the
centerline, which in turn undergoes an analysis that determines the optimal contour path
along the segment (Figure 3).
Fig. 3. After having traced a central line the software recognizes the margins elaborating
automatically the contours.
A further step allows, always automatically, the reconstruction of the hypothetically normal
coronary lumen. An algorithm then creates a line of the coronary margin that interpolates
the coronary segment considered free from illness located proximally and distally to the
region of interest with the ones of the region of interest. The algorithm then reconstructs the
reference coronary segments (i.e., those apparently free from disease) (Figure 4).
This technique is essentially based on the calculation of a mean value of the diameters of the
lumen in the segments of reference located upstream and downstream to the lesion. It
appears thus clear the importance of including two coronary segments in the QCA analysis,
one proximal and one distal to the target segment and both angiographically-free from
significant disease. These steps produce different parameters, some measured directly and
others derived with interpolation techniques.
260 Advances in the Diagnosis of Coronary Atherosclerosis
5. Parameters
Coronary lesions can be assessed qualitatively and quantitatively, in terms of severity of the
lesion itself. The qualitative evaluation is based on the visual estimation of the lesion and it
depends very much on the operator’s experience. The quantitative evaluation, based on
QCA, allows instead to obtain numeric parameters that are much more independent from
the operator acquiring the images or the one performing the analyses. The coronary
parameters of major interest are summarized in Table 1.
Range
Parameter commonly Meaning
used
Minimal Luminal Diameter The smallest lumen diameter in the segment
0–6.00 mm
(MLD) of interest
Reference Vessel Diameter The averaged diameter of the coronary
1.5–6.0 mm
(RVD) assumed without atherosclerotic disease
Length of the stenosis as measured by 2 points
where the coronary margins change direction,
Lesion length 0–60.0 mm creating a shoulder between the
angiographically normal subsegment and the
diseased subsegment
Acute gain 0–4.0 mm Post-procedural MLD – pre-procedural MLD
Late loss (LL) 0.10 to 3.00 Post-procedural MLD – MLD at follow-up
Diameter stenosis (DS) 0–100% (RVD-MLD)/RVD
DS >50% at follow-up coronary angiography
Binary restenosis (BR) Yes or no
in the treated coronary segment
Table 1. Main parameters obtained with QCA (adapted from Garrone et al., 2009)
Quantitative Coronary Angiography in the Interventional Cardiology 261
Additional tool of QCA are also available, indeed it is possible analysis of the stent edges
after stent implantation. In fact, the radiopaque stent can generally be visualized during
angiographic sequence when the contrast medium has not yet been injected in the coronary
vessel. By comparing this image with the frame selected for the QCA analysis, it is possible
to determine the two edges, proximal and distal, of the implanted stent. The software then
enables to mark the edges with a line transversal to the vessel lumen in order to
automatically calculate the segment where the stent has been implanted and to calculate the
5-mm segments that lie proximal and distal to the stent. Therefore, it is possible to
determine MLD and DS for each one of the three segments considered.
Several angiographic phenomena can bias QCA and lead to overestimation or
underestimation of QCA parameters such as acute or chronic thrombus, extensive calcium
deposits, dissections, diffuse disease, and slow flow, therefore it is of paramount importance
to add a qualitative analysis for lesion features to any QCA analysis (Garrone et al., 2009).
6. Applications
QCA can be employed in clinical practice during diagnostic coronary angiography (online),
to have an objective and independent parameter for the assessment of stenosis severity as
the human eye does not have the resolution capability of software. Usually, visual
interpretation of the severity of a coronary stenosis is expressed in intervals of percentage of
stenosis while QCAproduces a single specific measure for DS, improving the accuracy and
reproducibility of the severity assessment (Kalbfleisch et al., 1990). It has been shown that
the visual assessment tends to underestimate stenoses<50% and to overestimate those >50%
(Fleming et al., 1991) therefore the online use of QCA assessing the lesion length and RVD
might allow to obtain objective parameters to decide which specific measures (mainly
diameter and length) of the device (e.g., balloon or stent) should be chosen.
In the field of clinical research QCA allows serial analysis of the same coronary segment
over time in an indipendent way. In trials on coronary devices typically at least three QCA
runs are performed, one before treatment, another immediately after treatment, and a final
one at angiographic follow-up, after a respecified time.
In recent years late luminal loss and binary restenosis have taken an important role in
several studies aimed at evaluating PCI devices, in particular, stents. These values, more
specific and more prevalent of the clinically relevant end-point of target lesion
revascularization (TLR), allow researchers to compare different types of devices in clinical
trials, with greater statistical power, and thus with fewer patients. In fact, late luminal loss is
a continuous parameter and is in itself statistically more powerful and precise, while binary
restenosis, despite being a value present or absent as the TLR, occurs with an incidence
roughly two times higher than the incidence of TLR. Therefore QCA can reduce the number
of patients needed in a clinical trial to obtain significant differences between different
devices.
Another interesting application is the study of plaque progression/regression that is based
on at least two QCA runs made over a pre-specified interval of time, usually at least 1 year.
The change in MLD of the coronary segments of interest is quantified after a given
pharmacologic regimen that purports to act on the development or progression
ofatherosclerotic disease.
262 Advances in the Diagnosis of Coronary Atherosclerosis
8.2 Bifurcations
With the expanding practice of stenting coronary bifurcation lesions worldwide , the need
for reliable, standardized and reproducible quantitative bifurcation analyses became
apparent. A fundamental challenge in assessing bifurcations using quantitative methods is
in acquiring the entire bifurcation lesion without significant foreshortening or vessel and
side branch overlap. While current QCA standards require a minimum of two orthogonal
views more than 30° apart, optimal visualization of the bifurcation lesion (parent vessel and
side branch) is typically available in one best single view. When QCA is applied using a
standard operating procedure, i.e. by including in the analyzed segment the proximal main
vessel (PMV) and distal main vessel (DMV), the RVD function takes an average of the
‘‘normal’’ segments of the proximal and distal vessel. Tapering, however, causes the
proximal RD and thus the percentage diameter reduction of lesions proximal to the
bifurcation to be underestimated, while the distal RD and %DS of lesions distal to the
bifurcation will be overestimated. If on-line QCA is used for guidance during a procedure,
this can lead to inappropriate balloon selection, with significant under sizing of balloons
used for dilatation of the proximal segment and equally, over sizing of balloons used for the
distal segment of the main vessel (MV). The operator must manually redraw the proximal
segment within the MV and is forced to tediously correct for the contours of the lesion, a
possible source of inaccuracy and subjectivity. Even with optimal angiographic views, the
main issues of conventional QCA in the analysis of bifurcation lesions are: defining the true
reference vessel size of both the parent vessel and its side branch; the assessment of side-
branch (SB) stenoses when truly ostial. In the non-diseased state, the RD of the main vessel
is reduced from proximal to distal relative to the side branch. It has been shown that the
change in RD of the main vessel across the side branch is a function of the size of the PMV,
the DMV and that of the SB. Murray was the first to describe the mother/daughter-vessel
relations in vascular bifurcations, in terms of a cost function: i.e., the sum of function power
loss and metabolic power dissipation proportional to blood flow. Murray described the
optimal conditions for vascular bifurcation, known as Murray’s law, which states that the
cube of the radius of the mother vessel equals the sum of the cubes of the radii of the
daughter vessels: Dm3=Dd13+Dd23 (Murray, 1926). Afterwards, a simplified equation relating
the size of the proximal and distal main vessel and the side branch, in the non-diseased
state, has been described by a constant [D1= 0.687 (D2 + D3 + …)] (Kassab, 2006; Kamiya &
Takahashi, 2007) such that the reference size of any one segment can always be derived if
the two other segment sizes are known (Finet et al., 2007). Standard QCA algorithms are
designed to detect vessel contours assuming minimal vessel tapering; thus, the reference
vessel dimensions are inherently inaccurate when applied to bifurcation lesions. Several
techniques have been used to attempt to overcome this limitation but remain problematic
(Lansky et al., 2009).
Fig. 5. T-shape model (A) and Y-shape model (B) showing the segments, proximal delimiter,
and sections terminology. For each model, the segment generated four segments that
represent the building blocks of the models. A) Using the T-shape model, the arterial and
reference diameters of the ostium of the side branch and the whole main section (including
the transition within the bifurcation core) can be accurately determined. B) Using the Y-
shape model, the arterial and reference diameters up to the carinal point and in the distal 1
and 2 sections can be determined accurately.
Quantitative Coronary Angiography in the Interventional Cardiology 265
The particular advantage of these models is that they combine the proximal and two distal
vessel segments with the bifurcation core, resulting in a total of two or three sections, all
derived from one analysis procedure, such that each of these sections has its own diameter
function and associated parameter data.
Step 1. Contour detection. Three path-line points have to be selected to define the arterial
bifurcation segment: a start point in the proximal parent vessel (PV), and end points
in the distal PV and the SB. From these points, two pathlines are constructed
followed by the automated detection of the arterial contours of all three vessel
segments using an algorithm.
Step 2. Lesions analysis. The bifurcation core is defined automatically as the area between
the first diameter of the distal PV segment, and the interpolated contour between
the proximal and distal PV segments.
In the T Bifurcation model, the proximal and distal PV and core segments are combined to
define the first section and the SB segment forms the second section. For the entire PV
section the arterial diameter function is calculated following the conventional Medis
straight analysis approach, while for the SB section the Medis ostial analysis approach is
followed.
For the Y bifurcation model, the core segment is defined as the area between the
automatically determined proximal boundaries of the proximal segment and the carinal
point. Excluding the core segment, three sections are defined with each arterial diameter
functions calculated using the conventional straight analysis approach.
Step 3. Result reporting. The results of the bifurcation analysis are reported individually for
the proximal segment (combining the proximal PV and core segments), the distal
PV segment, the SB segment, and the ‘‘combined lesion’’ results (combined
proximal, core, and distal PV). Conventional angiographic parameters will be
reported including the obstruction, reference, minimum, maximum, and mean
diameters and areas, the percent diameter and area stenosis, as well as the vessel
and lesion lengths.
The Pie Medical Analysis Principles: CAAS 5 QCA bifurcation methodology. In this
system the bifurcated vessel is considered to be a single entity, including the central
bifurcation area divided in 10 segments when stented (Ramcharitar S, 2008) (Figure 6).
In this analysis, the segments 1, 4 and 6 are 5 mm beyond the stent edge. The main
vessel stent is divided at the carina as that proximal and distal corresponding to
segments 2 and 3 respectively, with the side branch stent confined to segment 5. The
central portion, segment 7 is an independent region called the Polygon of Confluence
(POC) that is unique to the bifurcation and represents a new quantification modality.
Segment 8 is an ostial region of side branch including 5 mm distal from the end of
bifurcation. The CAAS 5 quantitative analysis of bifurcations can be summarized in six
steps:
1. Contour detection, that is performed in a semi-automated process employing either
manually drawn initial pathline, or three user-defined points (one at the proximal side
of the main vessel and two at both distal ends of the bifurcated branches). The
algorithm automatically calculates path lines and the contours. The software assumes
the bifurcated vessel is a single object delineated by a left, middle and right contour,
specifically making no further assumptions.
266 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 7. Polygon of confluence and point of bifurcation in CAAS system (Adapted from
Ramcharitar, 2008b)
4. Determination diameter and reference values within the bifurcation. Traditional diameter
measurements can also be obtained. However, unlike the branches where the diameter
measurements are determined by the distance between left and right border, it is not
straightforward inside the POC. In order to derive such data within the POC the
“Minimum Freedom” approach must be employed. In this approach shortest distances
between a centreline point and the boundaries are determined, and the distance
between these points used as best estimate for the diameter within the POC for that
location along the centreline. The MLD at the bifurcation can be found using this
approach by walking through points along the termini of the bifurcation to the centre
point within the polygon of confluence. The reference diameter outside the POC is
determined from the edges of the ‘healthy’ part of the vessel. It is based only on the
characteristics of the branch itself as in the CAAS single vessel software.
5. Determining the bifurcation angulation. For the calculation of the angles between the
arterial branches, a method that employs lines derived from the circle used for the
definition of the “POC” can be used. The intersection positions of the circle with the
centrelines are used as the centres for new circles. These new circles have the same
radius as the circle within the “POC” and are not dependent on the mean vessel
diameter of the specific branch.
6. Report. Different versions of the bifurcation analysis software are available for clinical
and core lab use. Available analysis methods include automatic reference obstruction
analysis, local reference analysis, user defined subsegments as well as the 10
segmental analysis method to analyse the stented bifurcations, post-procedure and at
follow-up.
programs dedicated for 3-dimensional QCA, only two software packages are dedicated for
bifurcation analysis: The CardiOp-B system (Dvir et al., 2007; Galassi et al., 2010) and the
recent CAAS 5 QCA 3D bifurcation software (Onuma et al., 2011).
CAAS 3-D QCA, while following the already described algorithm based on vessel size
adjusted vectors, calculates BA values in 3-D space without overlap, therefore theoretically
more precisely than 2-D QCA. On the other hand, in CardiOp-B angle values were
computed between the weighted vectors of direction of the respective vessel segments. The
weighted vector is calculated as the sum of two vectors, each of them connecting the
bifurcation point with distal points along the vessel centre line, distant by 5 mm and 10 mm,
respectively. This algorithm was employed in a recent substudy of the SYNTAX trial, the
first ever to describe the 3-D angulation of the left main before and after intervention and its
impact on 1-year clinical outcome (Girasis et al., 2010a). When it comes to the quantification
of stenosis, CardiOp-B provides diameter-derived and cross-sectional (densitometric) data
together with the lesion length; lesion markers can be manipulated, in order to relocate the
region of interest across the main vessel or from the PMV into the SB. (Figure 8)
Fig. 8. An example of coronary bifurcation lesion reconstructed with 3D- CardiOp-B software.
Quantitative Coronary Angiography in the Interventional Cardiology 269
In CAAS 5, a 3-D model of the central bifurcation area is constructed taking into account the
fact that the contour information obtained from the 2-D projections may contain vessel
overlap, since the bifurcated vessel might be partly obscured in at least one of the
projections. To overcome this problem the 3-D cross-section shape is created using virtual
vessel contours by virtue of information derived outside the bifurcation region (Onuma,
2011).
Cross-sectional area values are calculated on the assumption that the vessel has an elliptical
cross section based on the luminal diameters from the two different 2-D projections; this
elliptical cross-section is the primary measured parameter. The equivalent luminal diameter,
minimum luminal diameter and maximal luminal diameter curves are calculated based on a
circularity assumption. Reference vessel lines, up to the entrance of the POC and within the
POC, are based on the 2-D approach adapted to 3-D.
So far, there is not direct comparison between these two QCA bifurcation software
packages, both of which recostruct from two projections, thus the issue of overlapping
vessels in tortuous bifurcation lesions may still be a problem. Particularly, there are two
special challenging situations in QCA analysis: a diffusely diseased bifurcation region
with no apparent healthy reference and an ostial stenosis in a short left main trunk
(Girasis, 2010 b). Based on the scaling laws of Murray (Murray, 1926) and Finet (Finet,
2007), the size of any bifurcation vessel segment could be determined, if the reference of
the other two vessel segments is known. This is not the case in a diffusely diseased
bifurcation region; however, extrapolation of the reference of the PMV even on the basis
of less accurate RVD values for the DMV and SB could avoid a gross underestimation of
the PMV true size (Girasis, 2010 b).
In the case of an ostial stenosis in a short left main stem, both contour detection and
sizing could be challenging. Manual contour corrections would not be unreasonable,
especially if there is overlap with the angiographic catheter. For the RVD determination,
either a user-defined reference outside the obstructions boundaries but within the left
main, or a value back-calculated from the distal branches reference values can be chosen
(Girasis, 2010 b).
Altough 3-D new techniques allow more extensive analyses for coronary bifurcations, there
are several limitations such as reproducibility, accuracy and standard reference values for
special lesion subsets that need further studies.
9. Conclusion
Although QCA was born more than 20 years ago and still burden well established
limitations, it remains a useful tool in clinical research, whereas its role in clinical practice
is mainly complementary to standard coronary angiography and other imaging
techniques, such as computed tomography (CT), intravascular ultrasound (IVUS), virtual
histology and optical coherence tomography. In recent years QCA has advanced to
provide more accurate measurements and descriptions of the coronary vascular tree and
still continues to evolve as 3D coronary angiographic techniques provide more detailed
descriptions of complex lesions such as bifurcations, eccentric lesions and chronic total
occlusions. However standard values in these lesions will need to be determined and
validated.
270 Advances in the Diagnosis of Coronary Atherosclerosis
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15
1. Introduction
1.1 Importance of methods for scoring coronary angiograms to reflect extent and
severity of CAD
Despite advances in modern medicine, the early detection of patients with obstructive
coronary lesions remains an unresolved problem due to frequently occurring atypical,
painless, and asymptomatic clinical variants of ischemic heart disease. For example, 80 to
90% of sudden cardiac deaths occur with a background of significant coronary artery
disease (Zipes, 1998) and sudden death is often the first presentation of the cardiac
disease. It is estimated that sudden death occurs in 33% to 70% of cardiac disease patients
(Davies, 2000). In addition, an acute myocardial infarction (MI) usually develops in
patients with multi-vessel coronary disease (Goldstein et al., 2000), while angiographic
studies have shown that an acute MI may develop in coronary segments having only
slight or moderate stenosis. It is well known that a ruptured atheromatous plaque in the
coronary artery can initiate intracoronary thrombosis and occlusion with the subsequent
development of an acute MI. However, plaque rupture with platelet activation and
thrombus formation are more recognized as the key events in the pathogenesis of acute
coronary syndrome than are the extent and severity of the coronary artery disease (CAD).
Additionally, the symptoms of myocardial ischemia may not be caused by obstructive
lesions in the coronary arteries at all. Myocardial ischemia may occur not only due to
decreased blood flow through epicardial coronary arteries, but also because of the
increased oxygen demand in patients with myocardial hypertrophy or hyperfunction.
Myocardial hypertrophy may be the cause of cardiac arrhythmias due to coronary
insufficiency in hypertensive patients. However, even in the absence of obstructive CAD,
hypertensive patients frequently have angina or may show electrocardiographic
abnormalities suggestive of myocardial ischemia due to coronary insufficiency (Vogt et
al., 1992).
In this era of great achievements in cardiology, we are still in need of a convenient and
informative coronary arteries analysis system that would allow us to quantitatively estimate
the size and severity of atherosclerotic CAD and myocardial ischemia burden.
274 Advances in the Diagnosis of Coronary Atherosclerosis
et al., 1999, 2000, 2002; Korosoglou et al., 2007; Kunadian et al., 2009). Until recently, it
was assumed that the blood flow in the non-culprit arteries in patients with acute
coronary syndromes was normal. However, according to the data of Gibson et al., (2000)
the coronary flow in the non-involved arteries in acute MI was, in fact, 40% slower than
normal. It was also noted that the slower flow throughout all three arteries in acute MI
could be associated not only with the extensive damage of microvasculature circulation
but also might be the result of more extensive damage of non-culprit epicardial arteries.
Greater lesion complexity might also be associated with poorer epicardial and myocardial
perfusion.
usual flow to the left ventricle in each coronary vessel (Leaman et al., 1981) and according to
the flow to muscle mass rather than to the actual volume of flow (Brandt et al., 1977;
Gensini, 1983). However, it is difficult to accurately assess the coronary artery blood supply
zones due to variable coronary artery dominance and multiple branching options. Still some
authors tend to offset the impact of longevity of stenosis (Dodge et al., 1992) on myocardial
blood flow.
However, the determined angiographic CAD scores in most cases had a poor correlation
with the severity of angina pectoris and myocardial function. Therefore, the development of
new coronary scoring methods needs a different approach from those which have been
previously adopted for the accounting of coronary obstructions only.
2.2 Technique for determination of summarized caliber of coronary arteries and left
ventricle mass
It is well established that the development and progression of CAD involves three
processes: the reduction of the total caliber of coronary arteries, the increase in myocardium
weight, and the deterioration of left ventricular pump function. Therefore, we have sought
to create a specific coronary lesion scoring system which would avoid the subjectivity in the
determination of degree of stenosis and in the selection of normal reference diameter which
is highly variable and dependant on multiple variants in coronary dominance and
branching.
The severity of the coronary lesion was expressed by the sum of residual calibers of all
coronary arteries in the selected level. The extent of the coronary lesion was expressed by
the calculation of the summarized caliber of three levels (Fig. 1). The narrowest diameters of
the selected segments were used to calculate the coronary caliber expressed by coronary
square area (CSA = 0.785 × D2). The assessment of the SCCA at the first coronary branching
level included the sum of the cross-sectional areas at the narrowest points of the 1st and 5th
segments, at the second level – the areas of the 2nd, 6th, and 11th segments, and at the third
level – the areas of the 3rd, 7th , 9th, 12th , and 13th segments. The average of the arterial
calibers at each level was considered to be the SCCA.
The computer-assisted calculating algorithm for SCCA is very simple, and coronary
diameters can be measured using a quantitative analysis program readily available in
almost every modern angiographic unit. We measured the narrowest diameters of each
coronary segment in at least two projections of video images. In cases of uncommon
variants of coronary dominance or branching, we also measured and summed all segments
of the trunk below its second bifurcation.
Contrasting of the left ventricle was performed while the patient was taking a deep breath at
the right anterior oblique 30˚ body position. We performed a quantitative analysis of the
ventriculographic data using the radial method (Fig. 2). We computed the end-systolic and
diastolic volumes and estimated the myocardial mass by determining the wall thickness of
the left ventricle. The end-systolic and end-diastolic volumes were calculated using the
equation for spherical formations:
Fig. 1. A scheme of 15 segments of the coronary tree proposed by the American Heart
Association which was used to calculate the summarized caliber of coronary arteries
(SCCA). The cross-sectional areas in the narrowest points of the segments at each level were
added together to represent the coronary caliber at one of the three coronary tree levels:
above the first bifurcation, below the first bifurcation, or below the second bifurcation of the
right and left coronary arteries. The average of the arterial calibers at the three levels was
considered to be the average SCCA.
We calculated the left ventricular mass using the thickness (h) of the anterior wall of the left
ventricle using the following equation:
in patients with decreased SCCA and low LVEF (due to the presence of post-infarction
myocardial scars) the ratio did not show the inadequacy between the blood supply and
demand and masked the poor prognosis for these patients. Both the diminished SCCA
and the lowered LVEF may equally increase risk in patients. Therefore, the compound of
ACI and LVEF was labeled angiographic prognostic index (API). It was calculated using
this equation:
3. Results
3.1 Calculation of angiographic coronary index using autopsy data
The necropsy study consisted of the following parts: 1) performance of the post-mortem
coronary angiography (Fig. 3A); 2) the longitudinal excision of contrasted coronary artery
trunks from the myocardial tissue and cutting them into 10 mm-long pieces for microscopic
analysis, and 3) the division of the myocardial mass of both ventricles (with and without
fatty tissues) into three parts according to the supply regions of the right coronary artery,
the circumflex branch and the anterior descending artery (Fig. 3B).
A B
performed using the methodology for the determination of SCCA. The second step was
supplemented by weighing the different parts of the myocardium, by calculation of the
coronary caliber, and by the assessment of the three separate ACIs for each coronary
artery.
The examination of the arterial cuts revealed the diffuse nature of the obstructive lesions in
patients who died suddenly or died after complications of chronic heart disease. In the
control group of younger patients, the slight narrowing (less than 50%) covered only 5.9 -
8.1% of the coronary artery length. In the second control group of older patients, the same
lesions covered 9.8 to 13.3% of coronary artery length. However, in patients who died from
CAD, the total length of the obstructed segments covered from 73.6% to 91.6% of coronary
artery length; furthermore, one-half of the segments had less than 50% narrowing. This
means that the quantitative estimation of the degree of stenosis using the referential normal
adjacent segment for calculation may often be incorrect.
The assessment of the coronary artery diameter without the calculation of the degree of
stenosis is more objective. The SCCA in control patients was almost the same at each level
and there were no significant differences between the control groups. However, the
difference between each level SCCA of the two groups of died patients, from one side, and
of the three control groups, from other side, was noticed (Table 1). These findings are a
consequence of differences in the size, location, and severity of obstruction in CAD patients.
At the same time the decrease in SCCA with the simultaneous increase in myocardial
weight was fixed in patients who died from sudden coronary death or from CAD
complications (Table 2).
the fourth and the fifth groups with CAD was significantly smaller, and the ACI was
consequently low, also.
and left coronary arteries. Coronarograms performed in the left and right anterior oblique
30˚ views are shown in the upper part of the figure. The views are most informative in
understanding the branching peculiarities of both coronary arteries supplying the posterior
and inferior walls of the left ventricle. A percept used to calculate the amount of myocardial
tissue supplied by the right and left coronary arteries is shown in the lower part of the
picture. This approach was chosen according the information obtained from post-mortem
studies. The whole myocardial tissue (mass) was assigned 20 conceptual mass units. Five
units were assigned to the right ventricle, another five to the septum (3 units to the anterior
and 2 units to the posterior septum), and the remaining 10 units were assigned to the mass
of the left ventricle divided into ten equal parts.
the variant of the left dominance), 6:14; 7:13; 8:12; 9:11, and 10:10 (potentially, the variant of
the right dominance).
Fig. 5. The quantitative expression of coronary dominance: A, 12:8; B, 9:11; C, 6:14; D, 4:16.
The usage of the right-to-left myocardial mass ratio allowed us to define the coronary
dominance variants more precisely (Fig. 5). Dividing control patients into the six groups
(according to the most common coronary dominance variants) allowed us to obtain
significant differences in segment diameters of the circumflex branch of the left coronary
artery and the right coronary artery between all groups. However, there was no statistical
difference between all groups according to the segments of the left anterior descending
artery, because the caliber of these segments is more stable with respect to the variations in
coronary dominance.
We have identified the four most frequent variants of coronary branching (Fig. 6) while
using these topographic schemes for a more thorough analysis of the coronary supply
zones. It is interesting to note that the following four variants of coronary branching had
the exact same ratio of coronary dominance determined by the myocardial supply zones.
However, the correlation between the caliber of the coronary segments and the size of their
myocardial supply zones was found to be very high (г = 0.96) despite the variability of
coronary dominance and branching. This finding shows the fundamental importance of
assessing the contiguous segments to estimate the real degree of stenosis, because diameters
of adjacent arterial segments usually visible in coronarograms may be diminished because
of the diffuse obstructive changes in adjacent coronary arteries, and it becomes very difficult
to decide whether the particular segment is damaged or not. Therefore, the assessment of
the coronary lesion score using SCCA appears to be more objective; it does not require
consideration of the coronary dominance and branching. At the same time, the location and
degree of atherosclerotic obstructions may be detected automatically by measuring the
diameter of the narrowest point in every segment at several levels. Therefore, to increase the
accuracy of coronary scoring, it is important to calculate the SCCA in a higher number of
levels.
Summarized Coronary Artery Caliber and Left Ventricle
Mass for Scoring of Cardiac Ischemia: Diagnostic and Prognostic Value 285
Fig. 6. The most frequent variants of coronary branching: A, common (6:14); B, left anterior
descending dominance (6:14); C, trifurcation (6:14); and D, marginal (6:14).
2) the degree (weight) of stenosis for each segment regarding the three types of coronary
dominancy, and 3) the average SCCA. The comparative analysis of different scoring
methods showed that the lowest correlation was observed between the methods that were
based on different coronary scoring principles. For example, Friesinger index has only
moderate correlation with ACI (r = -0.45). The correlation between Gensini index and ACI
was only insignificantly better (r = -0.54). However, the correlation between Friesinger and
Gensini indexes was high (r = 0.84).
Class of ACI
No. of SCCA, AAI
Angina (SCCA / LV mass) API (ACI+EF)
pts. mm2 (ACI /LVEF)
Pectoris
1˚ 49 23.4 ±1.0 0.68 ± 0.03 1.0 ± 0.06 0.78 ± 0.07
2˚ 21 18.0 ± 1.1 0.49 ± 0.04 0.8 ± 0.08 0.45 ± 0.08
3˚ 22 13.2 ± 0.7* 0.39 ± 0.05 0.6 ± 0.03 0.23.9 ± 0.14
1 vs. 2 0.001 0.001 0.019 0.006
P 1 vs. 3 0.001 0.013 0.007 0.007
2 vs. 3 0.005 0.009 0.05 0.05
Table 3. ACMS in patients with different functional class of angina pectoris.
All angiographic characteristics were worse in patients with typical angina (2nd group)
compared to patients with atypical chest pain (1st group). Similar significant differences
were discovered between the 1st and 3rd groups of patients who did not have the post-
infarction angina. The patients who did not have the post–infarction angina also had worse
average SCCA, ACI, and anginal index. It is interesting that there were no differences in
ACMS between patients in the 2nd (typical angina) and 3rd groups (no post-MI angina).
Summarized Coronary Artery Caliber and Left Ventricle
Mass for Scoring of Cardiac Ischemia: Diagnostic and Prognostic Value 287
Average
Character of No. of ACI AAI API
SCCA,
anginal pain pts. (SCCA / LV mass) (ACI /LVEF) (ACI+EF)
mm2
0.71 ±
1˚ atypical AP 49 27.3 ± 1.2 71.1 ± 4.1 1.0 ± 0.05
0.07
0.48 ±
2˚ typical AP 21 20.8 ± 1.2 57.2 ± 2.9 0.83 ± 0.06
0.05
3˚ disappeared
22 22.9 ± 2.2 48.7 ± 4.4 1.33 ± 0.1 0.63 ± 0.1
post-MI AP
1 vs. 2 0.001 0.009 0.05 0.05
P 1 vs. 3 0.05 0.001 0.05
2 vs. 3 0.004
Table 4. Angiographic characteristics of myocardial supply in patients with different
character of anginal pain. The statistical significance of the differences in angiographic
characteristics between the three different characters of anginal pain is shown in the lower
part of the table.
However, the difference in the angiographic anginal index between these three groups
existed not because of the difference in SCCA but because of the difference in left-
ventricular ejection fraction that was evidently lower in post-MI patients. Furthermore,
there was no inadequacy between the diminished SCCA and the diminished left-ventricular
ejection fraction in post-infarction patients.
3.3.2 Interrelation between clinical forms of coronary artery disease and angiographic
characteristics of myocardial supply
We have studied the levels of ACMS in patients divided into groups according to the
different clinical forms of ischemic heart disease. The values of different ACMS obtained
from patients with different clinical diagnoses of ischemic heart disease are shown in Table
5. The SCCA was highest in control patients and lowest in patients with multivessel CAD.
The SCCA of all patients groups with CAD was lower compared with the groups without
CAD. This consistent pattern was observed in the comparison of patients according to ACI,
except that the ACI was the same in patients with one vessel disease and in patients with
myocardial hypertrophy. The same regularity was noted between groups compared
according to AAI and API. The anginal syndrome was expressed mostly in patients with
multi-vessel disease. The AAI and API were equally expressed between patients with one-
vessel disease and patients with myocardial hypertrophy.
The various ACMS in patients with different clinical forms of myocardial infarction are
shown in table 6. The 1st group included patients with myocardial infarction without ST
segment elevation (NSTEMI). The 2nd group included patients with ST elevation myocardial
infarction (STEMI).
After comparing both groups of patients, we noticed that NSTEMI and STEMI were
significantly different according to AAI and API only. The SCCA and ACI differed
insignificantly. The API was worse in NSTEMI patients. Similar findings confirm the studies
of other authors.
288 Advances in the Diagnosis of Coronary Atherosclerosis
Table 6. ACMS in groups of patients with different clinical forms of myocardial infarction.
Myocardial
ACI
infarction No. of SCCA, AAI API
LVEF (SCCA /
in pts. mm2 (ACI /LVEF) (ACI+EF)
LV mass)
anamnesis
Death
during the 1.04 ±
7 20.7 ± 8.2 0.53 ± 0.03 0.51 ± 0.04 0.98 ± 0.03
3rd year 0.05
(1st group)
Death
during the 0.60 ±
5 22.7 ± 6.6 0.29 ± 0.03 0.31 ± 0.05 1.07 ± 0.05
2nd year 0.08
(2nd group)
Death
during the 1.03 ±
6 14.3 ± 0.1 0.67 ± 0.04 0.36 ± 0.06 0.53 ± 0.06
1st year 0.09
(3rd group)
1 vs. 2 0.001 0.05 0.001
P 1 vs. 3 0.001
2 vs. 3 0.001 0.001 0.01
Table 7. ACMS in patients who died within three years.
All 18 patients were divided into 3 groups: the 1st group (n = 7) consisted of patients who
died during the third year of investigation, the 2nd group (n = 5) of patients who died during
the second year of investigation, and the 3rd group (n = 6) of patients who died during the
first year of investigation. Patients who died during the first year after coronarography had
the most diminished average SCCA, but their left-ventricular ejection fraction was normal.
These patients usually experienced a sudden coronary death. However, the patients who
died later, during the 2nd year after investigation, had not only a lower ACI but also a lower
left-ventricular ejection fraction. They usually died from heart failure. It is interesting to
point out that these patients had a worse API and a normal AAI. They did not have typical
anginal symptoms. The patients with a lower ACI and a decreased LVEF lived slightly
longer despite the fact that they had clinical symptoms of heart failure but they were treated
more intensively. It is very important to emphasize that inadequacy between ACI and
ejection fraction, when left ventricular hypertrophy has developed, increases the risk for
sudden cardiac death. This is a consequence of expressed multi-vessel CAD in patients with
viable myocardial hypertrophy. In patients who survived three years, the left-ventricular
ejection fraction, ACI and API were better. Therefore, we believe that the survival and death
of patients with CAD can be better predicted with the help of ACMS. The product of both
angiographic criteria (the ACI expressing the supply adequacy to the myocardial mass and
the anginal index expressing the adequacy of supply to the functional requirements) could
be the most informative prognostic index of survival in CAD. The product of ACI and
ACI/EF could be named the angiographic outcome index (AOI). Mathematically, it can be
calculated using the following equation:
290 Advances in the Diagnosis of Coronary Atherosclerosis
AOI = ACI × (ACI / EF) = (SCCA / LVM) × (SCCA / LVM) / EF = SCCA2 / LVM2 × EF (5)
In the equation above the ACI stands for the angiographic coronary index, AOI –
angiographic outcome index, SCCA -- summarized caliber of coronary arteries (mm2), LVM
– mass of the left ventricle (g), and EF – ejection fraction of the left ventricle. The AOI was
statistically different in all three groups of patients who died during the 1st, 2nd, or 3rd year
after intervention. It was subsequently 0.1 ± 0.03, 0.33 ± 0.02, and 0.5 ± 0.02 (p < 0.009, p <
0.001, and p < 0.007).
4. Discussion
The quantification of coronary stenosis is an important practice in cardiology from both a
clinical and a research standpoint. In the recent past, there have been several imaging
methods which could differently characterize the size and severity of obstructive CAD:
coronary angiography, computed tomography, magnetic resonance imaging, and
intravascular ultrasound. Various techniques with differing degrees of sophistication were
used to measure the amount of luminal narrowing. Each method has provided new
opportunities for a more thorough understanding of the pathogenesis of ischemic heart
disease and variability of clinical picture. Angiography, performed with the use of digital
techniques, has been shown to have significant advantages over the above-listed techniques
due to its excellent reproducibility and accuracy (Funabaschi et al., 2003; Kalbfleisch et al.,
1990; Molloi et al., 2001). However, for the effective computerized assessment of coronary
lesion scores, we need to develop programs which can help to determine the size and
severity of CAD more accurately. To achieve this aim, the proposed SCCA assessment
system could be useful both theoretically and practically. Let us compare this innovative
system to other methods of analysis.
All scoring systems have been based on percentage of stenosis evaluation using the
“normal” diameter in the adjacent coronary segment. The validity of this reference is in
question because coronary atherosclerosis is often diffuse and the adjacent segment could
also be narrowed (Marcus et al., 1983; Seiler et al., 1992). In addition, serial segmental
narrowing representing a type of diffuse disease is not taken into account because of the
absence of a true normal reference segment. To assess the severity of diffuse CAD (with or
without segmental narrowing) it is necessary to know what the normal arterial lumen size
would be at each segment in the absence of coronary atherosclerosis. Various authors have
attempted to solve this problem in different ways (Kucher et al., 2001; Seiler et al., 1992).
Kucher et al. (2001) showed that in a population without cardiac disease, women have
smaller coronary artery size even after normalization for left ventricular mass. The existence
of a gender difference in coronary artery size remains controversial.
Our search for a “normal” diameter at each segment showed that the successful solution to
this problem is impossible due to high variability in coronary dominance and branching.
However, our experience and several other experimental and clinical reports (Dodge et al.,
1992; Roberts C & Roberts W, 1980; Seiler et al., 1992) have shown a direct relationship
between the coronary artery lumen size and the myocardial mass supplied by this artery.
Therefore, the variability in coronary diameter and its direct relationship to myocardial mass
have led us to propose a methodology which could be used to assess the degree and cause of
any imbalance between residual coronary diameter and the supplied myocardial mass.
Summarized Coronary Artery Caliber and Left Ventricle
Mass for Scoring of Cardiac Ischemia: Diagnostic and Prognostic Value 291
An analysis of patients with intact coronary arteries and increased myocardial mass showed
that the SCCA can increase along with the degree of myocardial hypertrophy, especially if
this process takes place at a young age. This phenomenon does not disturb the balance
between SCCA and left ventricular mass. Therefore, the ratio remains normal. In cases of
myocardial hypertrophy in older populations where the process of atherosclerosis has
begun, the SCCA does not increase in conjunction with myocardial mass. This relative
discrepancy is well illustrated by the lowering of the angiographic coronary index. Similar
findings have been described by Marcus et al., (1983). Myocardial ischemia is frequently
observed in patients with cardiac hypertrophy even when the conduit coronary arteries are
normal (Fig. 7.2 and 7.3). Recent studies indicate that impaired coronary reserve in
hypertrophied hearts probably occurs because the growth of the coronary bed does not keep
pace with increase of cardiac mass (Fig. 7.4). The imbalance between vascular proliferation
and muscle growth is probably most severe when the cardiac hypertrophy is caused by
pressure overload or atherosclerotic infiltration (Fig. 7.5). These observations suggest that
abnormalities in the coronary microcirculation which accompany cardiac hypertrophy play
a significant role in the pathogenesis of the complications associated with cardiac
hypertrophy.
The diminishing ACI in people without blockage of epicardial coronary arteries usually is
associated with the onset of typical or atypical anginal symptoms. Syndrome X can be
associated with chest pain and chest discomfort in people who do not show signs of
obstruction in the larger coronary arteries. No one knows exactly what causes Syndrome X
and it is unlikely to have a single cause. Today, we speculate that Syndrome X may be
caused by microvascular dysfunction. A large majority of women have typical anginal
symptoms which are not associated with the presence of atherosclerotic plaques. Scientists
speculate that the blood vessels in these women are diffusely abnormal and smaller than in
males (Kucher et al., 2001). It is possible that the diminishing ACI is a causative factor in the
development of Syndrome X.
Additionally, the relationship between the angiographic coronary index and the functional
status of the left ventricle expressed by ejection fraction may specify the adequacy of
myocardial supply to myocardial functional demands. First, the inadequacy of myocardial
supply with the inadequacy of myocardial nutritional requirements may lead to the
occurrence of ischemic pain and its severity. The relationship between the angiographic
coronary index and the ejection fraction we named the angiographic anginal index, because
we found a strong negative correlation between this index and the intensity of angina.
Recent techniques have revealed new characteristics and expanded our understanding of
painless or silent myocardial ischemia. These techniques include treadmill exercise testing;
radioisotope techniques, including ejection fraction studies, stress thallium scintigraphy,
and tomographic imaging. These new noninvasive tests should be used to detect transient
ischemia, estimate its severity, and measure patient's risk for adverse coronary events
especially in patients with painless or silent myocardial ischemia (Selwyn, 1990). Usage of
anginal angiographic index in clinical practice can facilitate the selection of such high-risk
patients with silent ischemia. Patients with diabetes, chronic renal insufficiency and other
coexisting diseases have an increased prevalence of coronary artery disease with silent
myocardial ischemia, complex ventricular arrhythmias, atrial fibrillation, and left
ventricular hypertrophy (Das et al., 2006; Chipkin et al., 1987). These risk factors for
cardiovascular morbidity and mortality contribute to the increased incidence of
292 Advances in the Diagnosis of Coronary Atherosclerosis
cardiovascular morbidity and mortality seen in patients with the above mentioned
concomitant diseases (Selwyn, 1990). It is also important to stress that the energy needs of
the left ventricle are not always proportional to the ejection fraction. LVEF can be
permanently reduced due to post-infarction scar development, but the LVEF may
temporarily decrease due to inadequate blood supply to the heart muscle. This phenomenon
is known as myocardial hibernation (Camici et al., 2008). In both situations with the
disappearance of anginal pain the occurrence of symptomatic heart failure can manifest
with the clinical symptoms of ischemic cardiomyopathy (Felker et al., 2002).
The prognostic capabilities of different coronary scores were confirmed by several authors
(Friesinger et al., 1970; Graham et al., 1999; Korosoglou et al., 2007; Ringqvist 1983). The
complex angiographic coronary index, anginal index, and left-ventricular ejection fraction
are more informative for predicting CAD outcomes. It was shown that only an increase in
LV mass in initially healthy persons with essential hypertension resulted in more
complications and deaths (Koren et al., 1991). Differently determined left ventricular
hypertrophy is an important prognostic marker in patients with or without coronary artery
disease (Ghali et al., 1992). It was shown that only reduced LVEF has a clear predictive value
in patients without known obstructive CAD. Reduced LVEF was related to sudden death
from the absolute presence of CAD as well as the increased number of vessels with
obstruction (Min et al., 2010).
4.1 Limitations
We have measured the lumen areas of different segments at their narrowest points on
coronarograms in this study. Very small measurements sometimes cannot be done without
interpretative errors; however, the margin of error is not high. The possibility of
underestimating the impact of a single expressed lesion on the diminishing SCCA could be a
limitation of this method. It is well known that such single-culprit lesions may cause the
development of acute myocardial infarction. However, the main goal of this quantitative
analysis system is to assess the total real size and severity of the epicardial coronary lesion
using the SCCA as a coronary score.
5. Conclusion
The most important advantage of this SCCA calculation system is that it provides an easier
and more objective assessment of an angiographic coronary lesion score in patients with a
wide spectrum of CAD, ranging from a minimal stenosis to extensive diffuse involvement of
the coronary arteries. The SCCA as a coronary lesion score is simple and easily interpreted;
it gives no reason for interpretative differences. First, the estimation of the average SCCA
does not require a precise assessment of stenosis degree, coronary dominance, or branching
peculiarities. Second, it provides the possibility to analyze the relationship between
coronary score and myocardial function what implies a correlation between myocardial
supply and demand. In addition, this quantitative analysis system can give more diagnostic
and prognostic information about the real mechanisms of myocardial ischemia, the
character of angina pectoris, and the possible risk for occurrence of life threatening
complications. Furthermore, the technique for interpretation of angiographic data and
computation of quantitative characteristics has been considerably facilitated.
6. Acknowledgment
I would like to thank the staff of the Department of Clinical Pathology, Lithuanian
University of Health Sciences for their valuable assistance in performing post-mortem
examinations.
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16
1. Introduction
In this chapter we will discuss the woven coronary artery which is one of the most
interesting coronary arterial anomalies. Although it is difficult to estimate the real incidence
of coronary artery anomalies due to the difficulty in specific identification, it is
approximately %0.3 - %1.3. The main reasons of underestimation of coronary artery
anomalies may be that, in many individuals; don’t lead to symptoms, morbidity, or
mortality (Friedman & Silverman, 2010).
AVR: aortic valve replacement, MVC: mitral valve commissurotomy, CHF: Congestive heart failure,
LAD: left anterior descending artery, RCA: right coronary artery, LCA: left coronary artery, AMI: acute
miyocardial infarction, LCXA: Left circumflex artery
Table 1. The summary of the demographic and clinical data of the patients with woven
coronary artery in the literature.
Woven Coronary Artery 299
5. Differential diagnosis
In differential diagnosis of woven coronary artery the important criteria is the absence of
coronary artery disease history of the patient with normal stress tests such as treadmill,
echocardiography and myocardial scintigraphy. The patient with a woven coronary artery
anomaly usually demonstrates normal coronary reserve during stress test.
Woven Coronary Artery 301
Fig. 1A. and B. Right coronary angiography showed proximal thin channels and distal
reanastomosis
This is dependent on normal blood flow distal to the anomalous segment (Kursaklıoglu et
al., 2006; Yıldırım et al., 2010; İyisoy et al., 2010). In woven coronary artery anomaly, normal
blood flow can be maintained distal to the anomalous segment, therefore coronary blood
reserve is not disturbed with stress tests, especially myocardial perfusion imaging (İyisoy et
al., 2101). Even if there is clinical evidence of myocardial infarction or angina pectoris in a
patient with woven coronary artery, coronary angiography should be repeated to eliminate
other coronary artery pathologies. Radiologically, the examination and the interpretation of
the angiographic image are crucial to prevent misdiagnosis of the woven coronary arteries.
In this coronary anomaly, although the filling is defective, flow is normal; which
differentiates this structure from other pathologies such as intracoronary thrombus, stenosis
or dissection.
302 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 1C. Diagram of the right woven coronary artery showing proximal thin channels (TC)
and distal reanastomosis (DRA)
6. Associated diseases
Up to now, woven coronary artery cases have only been reported as isolated coronary artery
anomaly (Sane et al., 1988; Berman et al.1990; Gregorini et al., 1995; Martuscelli et al., 2000;
Kursaklıoglu et al., 2006; Kaya et al., 2006; İyisoy et al., 2010). Only in the case report of
Yıldırım et al., (2010) the woven coronary artery was described as the part of a systemic
disease, Kawasaki disease, in an infant patient of nine months old. In this patient, routine
echocardiographic evaluation of coronary arteries revealed aneurysm of the left coronary
artery, leading to an angiographic study in which a woven right coronary artery was
detected coincidentally. In fact there is also a tendency for the development of thrombus in
Kawasaki disease and this condition should not be confused with woven coronary artery
(Yıldırım et al., 2010). For this reason, the pediatric and adult cardiologists should be aware
that woven coronary artery may accompany Kawasaki Disease and they should perform
coronary angiography to distinguish real thrombus from this coronary anomaly.
7. Treatment
Woven coronary artery is an anatomic abnormality and it doesn’t disturb cardiac functions
at all. Therefore it is not necessary to treat this anomaly. However other coronary artery
Woven Coronary Artery 303
8. Conclusion
Angiographic examination of the patients with suspected coronary artery pathologies
should be performed carefully to make differential diagnosis of dissection, thrombosis
stenosis and woven coronary artery. The catheter angiography scenes should be evaluated
repeatedly not to misinterpret the coronary artery pathologies. Such a detailed evaluation
and definitive diagnosis is important to reduce the risk of unnecessary percutaneous
coronary interventions, which expose the patients to several complications. Woven coronary
artery does not need treatment but follow-up is required as there are only a few reports
about the progress of this rare event. Advanced studies are needed on this unknown entity
to demonstrate its detailed pathology. Even though this anomaly appears to be a benign
coronary anomaly without any major adverse cardiovascular events, we need more data to
figure out its exact natural history.
9. Acknowledgment
As the current collected data about the woven coronary arteries has been provided from a
very limited number of cases, we believe that the embryology, pathophysiology, clinical
feature and the prognosis of this rare coronary anomaly will be explained better with
advanced studies.
10. References
Berman AD, Kim D, Baim DS.(1990) ’’Woven’’ right coronary artery: case report and
therapeutic implications. Cathet Cardiovasc Diagn ; 21:258–259.
Gregorini L, Perondi R, Pomidossi G, Saino A, Bossi IM, Zanchetti A. (1995). Woven left
coronary artery disease. Am J Cardiol ;75(4): 311-2.
Friedman AH and Silverman NH. Congenital anomalies of the coronary artery. (2010)
Pediatric Cardiology In Anderson RH, Baker EJ, Penny D, Redington, AN, Rigby ML,
Wernovsky G. (third edition), Churchill Livingstone and Elsevier, Philadelphia
pp:933-943
Iyisoy A, Celik T, Yuksel UC, Isik E. Woven right coronary artery: a case report and review
of the literature. Clin Cardiol. 2010;33:43-45.
Kaya D, Kilit C, Onrat E. (2006)An uncommon congenital anomaly of coronary arteries
misdiagnosed as intracoronary thrombus: woven coronary artery disease. Anadolu
Kardiol Derg. 6:383-384.
Kursaklioglu H, Iyisoy A, Celik T. (2006) Woven coronary artery: a case report and review of
literature. Int J Cardiol 113(1) 121-3.
Martuscelli E, Romeo F, Giovannini M, Nigri A. (2000) Woven coronary artery:
differential diagnosis with diffuse intracoronary thrombosis. Ital Heart J.
1(4):306-7.
304 Advances in the Diagnosis of Coronary Atherosclerosis
Matherne GP and Lim DS. Congenital anomalies of the coronary vessels and the aortic
root (2008). Moss and Adams’ Heart Disease in Infant, Children and
Adolescents including the Fetus and Young Adult. In Allen HD, Driscoll DJ,
Shaddy Re, Feltes TE. (seventh edition) Lippincott Williams & Wilkins,
Philadelphia. Pp:702-715.
Sane DC, Vidaillet JH Jr. (1988) Woven right coronary artery: a previously undescribed
congenital anomaly. Am J Cardiol 61(13):1158.
Tomanek RJ.(1996) Formation of the coronary vasculature: A brief review. Cardiovasc Res 31
Spec No: E46-51
Tomanek RJ. (2005) Formation of the coronary vasculature during development.
Angiogenesis 8:273-284
Yıldırım A, Oğuz D, Olguntürk R (2010). Woven Right and Aneurysmatic Left Coronary
Artery Associated with Kawasaki Disease in a 9-month-old Patient. Cardiol Young
20:342-344.
17
1. Introduction
Image post-processing is defined as the process of integrating a series of axial images into a
form that is often easier to interpret than the sections themselves. The source transverse section
is a fundamental image for interpretation. However, because of the complexity of coronary
anatomy, interpreters must review coronary CT angiography interactively on workstations
capable of 3-dimensional (3D) displays. The 3D data set can be reformatted according to the
needs of the investigator using several types of post-processing algorithms. Coronary artery
interpretation includes assessment of calcium scoring on non-contrast image and coronary
angiography on enhanced image. Non-coronary cardiovascular findings and extra-cardiac
findings should be reviewed in addition to recognize primary and secondary comorbid
pathology and to identify findings that lead to alternative non-cardiovascular diagnoses. The
ultimate objective of post-processing and interpretation is to convey diagnostic information to
the treating physician with as much clarity and accuracy as possible. Interpretation times
vary, usually depending on the image quality and the user’s experience and knowledge of
cardiac CT and the individual workstation. Normally, experienced users usually spend no
more than 10 minutes segmenting and interpreting cardiac CT studies.
2. Post-processing technique
The source transverse sections are the primary tools for interpretation of coronary CT
angiography examinations. Post-processing imaging is performed from reconstructed axial
images and is useful in allowing clinically relevant information to be extracted from large
number of axial images. In addition, the diagnostic accuracy of axial images (86% sensitive
and 78% accurate) for the detection of coronary stenosis is low compared with combination
of post-processing techniques (98% sensitive and 94% accurate) (Jinzaki et al, 2009). Thus,
the review of 3D displays is necessary for the coronary artery interpretation due to the
complexity of coronary anatomy. These include volume rendering, multiplanar reformation,
thin-slab maximum intensity projection, curved multiplanar reformation, angiographic
view, and plaque-loaded angiographic view. A post-processing image which enables the
evaluation of coronary artery disease with fewer images and one that is understandable to
the third person is preferable.
axial plane but also in orthogonal (coronal and sagittal) or oblique planes that better follow
the arterial course in the thorax. The slice thickness can be modified, and a thick slab may be
helpful in visualizing tortuous coronary artery. MPR is a simple algorithm which can be
rendered quickly and accurately on any image-processing workstations. The distance
measurements in MPR are accurate. Different structures in MPR are accurate and do not
overlap. There is no loss of voxel value information due to threshold.
MPRs are best suited for evaluation of the individual cardiac chambers, aorta (Fig. 1), and
pulmonary vasculature with cardiac CT. MPRs are also well suited for selective evaluation
of a coronary short segment. If a narrowing is suspected on axial views, display in coronal
or sagittal orientations can confirm the presence of a stenosis (Fig. 2).
The disadvantage of MPR is that only short segments can be analyzed at a time due to the
nonlinear pathway of the coronary arteries. Thus, MPR requires the creation of numerous
images in different planes at every suspected location of coronary stenosis. Furthermore, it
is less suited for displaying the length of an artery. Grading of a stenosis is not advisable
with coronal, sagittal, or oblique reconstructions alone, because of partial averaging
(Johnson et al, 2010).
a) b) c)
Fig. 2. Multiplanar reconstruction of coronary stenosis
Image Post-Processing and Interpretation 307
When a narrowing (arrow) is suspected on axial views (a), multiplanar reformation can be
used to set the planes (b, c) in an orientation that matches one of the coronary short
segments.
a) b) c)
Fig. 3. Thin-slab maximum intensity projection of coronary stenosis
When a narrowing (arrow) is suspected on axial views (a), the use of thin-slab maximum
intensity projection (b) increases the overview of each coronary artery. Thin-slab maximum
intensity projection enables creation of a vascular map (c) quickly without modification of
several parameters.
308 Advances in the Diagnosis of Coronary Atherosclerosis
a) b)
Fig. 4. Curved multiplanar reformation of the coronary arteries.
The vessel can be seen in a long length with this technique. Fig. 4a demonstrates a
multiplanar reformation of the entire right coronary artery, including a segment of
posterolateral marginal branch. The atrio ventricular node artery (arrow) would require a
second reconstruction to follow that artery. The left anterior descending (b), with multiple
diagonal branches, often needs multiple reconstructions to demonstrate its entire course.
Curved MPR with coronary CT angiography has been reported with high sensitivity and
specificity (Achenbach et al., 1998). Significant stenosis and occlusions of the coronary
arteries can be visualized with an accuracy that exceeds 90%, since the CT value is
preserved, making it fairly easy to delineate calcifications from the lumen. Recognition of
calcifications with either higher or lower density than inner lumen contrast is very difficult
with VR, somewhat better with MIP, and best with MPR. In addition, curved MPR is used to
identify and quantify the degree of stenosis without being hindered by partial averaging
(Fig. 5). This method is also useful in delineating the morphology of plaque and its effect on
the lumen and adjacent vessel wall. Furthermore, the distance measurements in the curved
MPR images represent the true distance. Overall, curved MPR, because they can be
rendered quickly and convey all the information about the different CT densities within the
vessel, is an extremely useful tool to evaluate contrast-enhanced CT angiography data.
Image Post-Processing and Interpretation 309
The drawback of curved MPR is that only one vessel can be visualized in one image and that
side branches are not depicted unless separate reconstructions are rendered for every side
branch (Achenbach et al., 1998). Angiographic view is better in evaluating multiple
branches. Furthermore, accurate assessment for stenosis requires correct centerline
placement. Since the quality and ability of the computer workstation for tracking the vessel
depends on border definition and overall image quality, off-axis centerline placement may
happen, which result in misinterpretation of stenosis. Thus, curved MPR requires some
editing in most cases. This commonly occurs in the presence of heavy arterial calcification
and at the site of origin of branch.
a)
b) c) d)
Fig. 5. Curved multiplanar reformation for coronary artery stenosis
Coronary stenosis (arrow) is demonstrated in the proximal segment of the right coronary
artery. The observer can always create a plane orthogonal to the direction of the vessel,
which allows the evaluation of the configuration of plaque and grading of a stenosis. The
three orthogonal planes are at the level of a proximal normal lumen (b), a significant
stenosis (c), and a distal normal lumen (d), respectively.
VR provides an excellent overview of the cardiac and vascular anatomy, such as defining
the course of coronary anomalies (Fig. 7a), the presence and course of coronary bypass
grafts (Fig. 7b), the analysis of thoracic cardiovascular anatomy and congenital heart disease
(Fig. 7c). Because VR creates volumetric 3D representations with the illusion of spatial
integrity, it is helpful for surgeons to understand the anatomic complexity before surgery,
and for teaching purposes and as illustrations for patients.
It is controversial whether VR can be used for the assessment of coronary stenosis. One
study using 16 slice CT compared 3D VRs with combination of techniques including axial
images, MPRs, and curved MPRs and MIPs. Sensitivity (63% vs 74%), specificity (80% vs
76%), and accuracy (78% vs 75%) were not significantly different between VR and the
combination of techniques, respectively (Cordeiro et al., 2006). However, the diameter of
vessels and the apparent thickness of the vessel lumen are dependent on threshold or
transparency settings and the computer algorithm that is used to subtract non-vascular
structures with VR (Ferencik et al., 2007) (Fig. 8). Furthermore, the overlap of cardiac veins
on coronary arteries often hinders the coronary artery stenosis at the overlapped segment on
VR (Fig. 9). Another disadvantage of VR is that due to its use of threshold or transparency
setting which obscure the lower attenuation structures, the visualization of smaller vessel
may be inferior compared with other displaying methods (Johnson et al, 2010). VR also
requires several angles to evaluate the entire coronary artery (Fig. 6).
a) b)
c) d)
Fig. 6. Volume rendering of the coronary arteries.
Volume rendering provides an excellent overview of coronary anomalies, the course of
coronary bypass grafts, and congenital heart disease
a. Coronary anomalies: both coronary arteries originate from left coronary cusp (stent is
placed in the proximal segment of left descending artery).
b. Bypass grafts: right internal thoracic artery (RITA) graft communicate with the left
descending artery and left internal thoracic artery (LITA) graft communicate with
obtuse marginal branch.
Image Post-Processing and Interpretation 311
c. Major aortopulmonary collateral artery in patients with Tetralogy of Fallot (red: aortic
arch, yellow: right pulmonary artery arising from aorta, green: left pulmonary arteries
arising from ductus arteriosus).
a) b) c)
Fig. 7. Volume rendering of cardiac and vascular anatomy
Volume rendering allows an easy overview of coronary artery anatomy. It assists
significantly in understanding the topography of coronary vessels and position of the lesion
in coronary tree. Dedicated projections for each of the three main vessels are performed. The
proximal and middle segment of the RCA is visualized in a view from the right side (a). The
distal segment of the RCA is visualized in a right caudal view (b). The left anterior
descending artery is visualized in a left anterior view (c). The left circumflex artery is
visualized in a left cranial view and a left view (d).
a) b) c)
Fig. 8. The affect of modifying threshold and opacity setting on volume rendering
Coronary stenosis (arrow) is suspected in the proximal segment of left descending artery in
the image with high opacity setting (a), while it is difficult to detect coronary stenosis in the
image with low opacity setting (b). Significant coronary stenosis (c: arrow) is seen in curved
MPR at the same location suspected in volume rendering with high opacity setting. The
diameter of coronary artery is also modified by changing the threshold and opacity setting.
312 Advances in the Diagnosis of Coronary Atherosclerosis
a) b) c)
Fig. 9. Overlapped coronary vein on volume rendering
Coronary stenosis in the proximal left circumflex artery (arrow) is hindered by overlapped
great cardiac vein on volume rendering (a), while it is well visualized on angiographic view
(b: arrow) and curved MPR (c: arrow).
a) b) c)
Fig. 10. Angiographic view
Image Post-Processing and Interpretation 313
Angiographic view image clearly demonstrates the distribution of coronary artery stenosis
(long arrow) and coronary calcifications (short arrows) in one image. This resembles the
images of coronary angiography and is understandable by third parties. Angiographic view
image (a) and coronary angiography (b, c) shows considerable consistency in the detection
of coronary artery stenosis (long arrows).
a) b) c)
d) e) f)
g) h) i)
Fig. 11. Angiographic view divided into right and left coronary artery
Angiographic view image divided into right and left coronary artery enables viewing the
coronary arteries with the same angle as CAG. We create three directions in RCA [a: left
anterior oblique (LAO) 45 and cranial angulations (CRA) 0, b: LAO 20 and CRA 30, c: right
anterior oblique (RAO) 30 and CRA 0) and 6 directions in LCA (d: LAO 0 and CRA 30, e:
LAO 45 and CRA 25, f: RAO 20 and CRA 40, g: RAO 30 and caudal angulations (CAU) 30, h:
RAO 0 and CAU 30, i: LAO 50 and CAU 30].
314 Advances in the Diagnosis of Coronary Atherosclerosis
The advantage of AGV image is that it clearly demonstrates the distribution of high-density
lesions, such as coronary calcifications and stents, and coronary artery stenosis in a single
image, making it easier to be understood when viewed by any third party. Because the
structures are displayed based upon their brightness, calcium and metal are easily
distinguished from the contrast-enhanced lumen. For the detection of coronary stenosis,
AGV was equally sensitive (98%) and accurate (91%) to a combination of conventional
techniques, including interactive MIP and MPR as well as preset curved MPRs
(98%sensitive, 94% accurate) (Jinzaki et al., 2009). AGV is also better for displaying small-
caliber segments as described in thin-slab MIP. Furthermore, AGV divided into right and
left coronary artery enables viewing the lesion with the same angle as CAG, and the
detection of best angle of the lesion prior to PCI (Fig. 12). Collateral arteries are also well
visualized in AGV. The whole collateral arteries are demonstrated with AGV in less images
than volume rendering, since AGV is a projection image (Fig. 13). Thus, AGV would be
useful for explaining the severity of disease to the patient, as a guide for the reading due to
its high diagnostic accuracy, and in the discussion of the treatment strategy in conference.
Fig. 12. The detection of best angle of the lesion prior to PCI
The coronary stenosis (arrow) is best visualized in the view of RAO 30 and CAU 30
(middle). This information will help cardiologists in discussing treatment strategy and
reduce the number of CAG image acquisitions.
a) b)
Fig. 13. Angiographic view in case with collateral vessels
In patients with chronic total occlusion of RCA, collateral vessels are seen between left
descending artery and posterior descending artery (yellow arrows), left circumflex artery
and posterolateral artery (blue arrows). These collateral vessels are well demonstrated in
one image with angiographic view (a), while the whole collateral arteries are not visualized
in one image with volume rendering (b).
Image Post-Processing and Interpretation 315
a) b) c) d)
Fig. 14. Plaque-loaded Angiographic View of multiple non-calcified plaques
Curved MPR of the right coronary artery (a) demonstrates the non-stenotic non-calcified
plaques (arrows), which are assigned blue in color-coded image (b). The angiographic view
image (c) demonstrates the lumen of the entire coronary artery. The color-coded image in
curved MPR is re-formatted into a MIP image and merged with the Angiographic View
image. The Plaque-loaded Angiographic View image (d) demonstrates the lumen and
multiple plaques (arrows) of coronary arteries in one image.
a) b)
Fig. 15. Plaque-loaded Angiographic View of chronic totally occlusion
An angiographic view image (a) could not provide the information of the occluded lesion.
The Plaque-loaded Angiographic View image (b) demonstrates the overview of the tortuous
vessel (arrows) in the occluded lesion.
3. Image interpretation
At the beginning of interpretation, an overview of the data set should be performed to
detect artifacts, gross abnormalities and the presence of non-coronary cardiac or extra-
cardiac abnormalities. Coronary artery interpretation is then performed using post-
processing images
Image Post-Processing and Interpretation 317
3.1.1 Artifact
“Artifact” can be defined as any discrepancy between the reconstructed Hounsfield values
in the image and the true attenuation coefficients of the object in such a way that these
discrepancies are clinically significant or relevant as judged by the radiologist (Hsieh, J.,
2003). Artifacts of coronary CT angiography were classified into three categories (Table 2).
The first is cardiac motion-related artifact (Choi et al., 2004). This is caused by many factors,
including a heart rate greater than 70–75 beats per minute during imaging acquisition,
variations in heart rate during breath holding (Fig 16), arrhythmia, and inappropriate
selection of pitch or reconstruction window. Artifacts are classified into two patterns:
motion blurring or stepladder effects. Blurring occurs when movement in the cardiac
structure of interest exceeds the temporal resolution of scanning, either because of a fast
heart rate or because of an inappropriate selection of the reconstruction window for the
particular coronary artery. Stepladder artifacts are due to motion occurring between
reconstruction of sequential heartbeats. The easiest way of reducing cardiac motion artifacts
is to lower the heart rate by the prior administration of-blocker. Customized reconstructions
at a different cardiac phase may be successful by either adjusting the phase of reconstruction
or removing data from undesirable beats.
a) b)
Fig. 16. Stepladder artifact due to changing heart rate during CT acquisition.
Volume-rendered image (a) shows a severe motion-related artifact (arrows) caused by
acceleration in heart rate toward the end of the breath hold. Selection of an optimal
reconstruction window reduced the artifact (b).
The second is voluntary motion that is generally preventable with careful instruction of the
patient (Choi et al., 2004). Artifacts due to breathing (Fig 17) or body motion are distinctive
because they affect the bones of the anterior or lateral chest wall in addition to the coronary
arteries; these are less likely to be correctable by additional reconstructions. Oxygen
supplementation may help dyspneic patients hold their breaths for a longer period.
The third is high-attenuating artifact (Choi et al., 2004). High-attenuating artifact includes,
blooming artifacts, beam hardening artifacts and streaking artifacts. Blooming artifact is a
result of partial-volume effects, causing the status that small high-contrast objects appear
larger than they are. These artifacts commonly make calcified plaque (Fig 18a) and stents
appear to narrow the lumen more than they actually do. Use of appropriate reconstruction
filters may reduce these artifacts. Beam hardening presents as dark banding between dense
objects. These are also seen in calcified plaque and stents (Fig 18b). Streaking artifact is a
kind of reconstruction artifact due to undersampling, photon starvation, motion, beam
Image Post-Processing and Interpretation 319
a) b)
Fig. 17. Stepladder artifact due to breathing
Sagittal maximum intensity projection image (a) and coronal MPR image (b) show a
severe respiration-related artifact in the anterior chest wall (arrow) and at the diaphragm
(arrow).
a) b) c)
Fig. 18. High-attenuating artifacts
a. Blooming artifact caused by severe coronary calcifications that interfere with the
evaluation of luminal stenosis.
b. Beam hardening artifacts caused by coronary stent that prevents accurate evaluation of
the stent lumen.
c. Metal artifacts caused by surgical clips.
a) b)
Fig. 20. Non-coronary cardiac findings
a. Focal thinning of myocardial wall due to ventricular diverticula (arrow)
b. Thrombus in ventricular chamber (arrow)
a) b)
Fig. 21. Interpretation of axial images
Myocardial bridge of coronary artery (a: arrow) is often easily noticed in axial images. The
diagnosis of coronary stenosis is easy in the lesions located in the segment running the
cranio-caudal direction (b: arrow), however difficult in the lesions located in the segment
running horizontal to the axial section.
should be evaluated further for vessel wall morphology and composition using curved
MPR. Further evaluation could be omitted in branch vessels with no stenotic lesions on
AGV, since the negative predictive value of AGV is very high (99%) and evaluating multiple
diagonal branches or obtuse marginal branches is time-consuming with curved MPR or
other methods. However, even if stenotic lesion is not detected in three main arteries on
AGV, we recommend reconstructing curved MPR of these arteries to evaluate non-stenotic
non-calcified plaque, which may be missed on AGV. This is because acute myocardial
infarction is frequently related to a segment that was not significantly stenosed at previous
angiography (Littele, et al., 1988, Giroud et al., 1992). Acute coronary occlusions leading to
myocardial infarction tend to cluster in predictable "hot spots" within the proximal third of
the coronary arteries (Wang et al., 2004). Identification of low attenuation plaques in these
high-risk zones for acute coronary occlusions will be important for potentially locally
directed preventive strategies.
Fig. 22. Workflow of post-processing and interpretation for coronary artery evaluation
Step 1. Overview of coronary artery on angiographic view
Step 2. Quantitative evaluation of coronary lesions detected on angiographic view
Step 3. Evaluation of three main arteries using curved MPR and no further evaluation in
branch vessels without stenotic lesions on angiographic view
324 Advances in the Diagnosis of Coronary Atherosclerosis
a) b) c)
Fig. 23. Low attenuation plaque and spotty calcification
Curved MPR demonstrates significant stenosis in left descending artery (a: arrow). The
lesion is accompanied with spotty calcification (b: arrow) and area < 30HU (c: arrow).
a) b) c)
Fig. 24. Positive remodeling
Non-calcified plaque (a: long arrows) in right coronary artery is positively remodeled as
compared with the normal coronary segment proximal to the lesion (short arrows). The
diameter was 4.3 mm in normal segment (b) and 4.9 mm in the lesion (c). Remodeling index
was 1.14.
326 Advances in the Diagnosis of Coronary Atherosclerosis
c. Total occlusions
PCI of CTO has a lower success rate than PCI of non-occluded coronary stenosis. Failure of
guide-wire crossing the occluded lesion is the main cause of unsuccessful PCI of CTO.
Coronary CT angiography may provide useful information for selecting patients suitable for
PCI of CTO (Soon et al., 2007). It can show the collateral supply in the distal vessel beyond
the occlusion (Fig. 13). The proximal and distal ends of an occluded segment can be
distinctively seen on coronary CT angiography. Therefore, the occlusion length can be
measured on CCTA (Fig. 24). Mollet et al. also reported that CTO lesion length > 15 mm
measured on CT was associated with higher failure rate of PCI (Mollet et al., 2005). Heavy
calcification of CTO has been reported to be an independent predictor of failed PCI of CTO
(Noguchi et al., 2000). The exact location of calcified plaque on the image of coronary CT
angiography may help the interventionist to steer the guide wire away from the calcified
lesion that is not well seen on conventional angiography. PLAG images are able to
demonstrate the overview of occluded lesion, which are helpful in providing the roadmap
for interventionists during the process of wiring the occluded vessel (Fig. 15).
a) b)
Fig. 25. CT evaluation of chronic total occlusion
The total occlusion is seen in the distal segment of right coronary artery on thin-slab MIP
images (a: arrows). The occlusion length can be measured on stretched MPR (b). Calcified
plaque is also well visualized.
Image Post-Processing and Interpretation 327
4. Conclusion
Many post-processing images are available for the evaluation of coronary artery. The
interpreter should know the advantage and disadvantage of each post-processing
image, and perform the incorporative review of the 2D images and the different 3D
renderings.
5. References
Achenbach, S., Moshage, W., Ropers, D., & Bachmann, K. (1998). Curved multiplanar
reconstructions for the evaluation of contrast-enhanced electron beam CT of the
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Achenbach, S., Giesler, T., Ropers, D., Ulzheimer, S., Anders, K., Wenkel, E., Pohle, K.,
Kachelriess, M., Derlien, H., Kalender, WA., Daniel, WG., Bautz, W., & Baum, U.
(2003). Comparison of image quality in contrast-enhanced coronary-artery
visualization by electron beam tomography and retrospectively electrocardiogram-
gated multislice spiral computed tomography. Invest Radiol, Vol.38, No.2, (Feb
2003), pp. 119–128.
Busch, S., Johnson, TR., Nikolaou, K., von Ziegler, F., Knez, A., Reiser, MF., & Becker, CR.
(2007). Visual and automatic grading of coronary artery stenoses with 64-slice CT
angiography in reference to invasive angiography. Eur Radiol, Vol.17, No. 6, (Jun
2007), pp.1445-1451.
Cademartiri, F; Mollet, NR & Nieman, K. (2005). Image post-processing, In Computed
Tomography of the Coronary Arteries, Feyter PJ & Krestin GP, (ed.), 27-46, Taylor &
Francis, New York
Calhoun, PS., Kuszyk, BS., Heath, DG., Carley, JC., & Fishman, EK. (1999). Three-
dimensional volume rendering of spiral CT data: theory and method. Radiographics,
Vol.19, No.3, (May-Jun 1999), pp. 745-764.
Cheng, V., Gutstein, A., Wolak, A., Suzuki, Y., Dey, D., Gransar, H., Thomson, LEJ., Hayes,
SW., Friedman, JD., & Berman, DS. (2008). Moving beyond binary grading of
coronary arterial stenoses on coronary computed tomographic angiography:
insights for the imager and referring clinician. J Am Coll Cardiol Imaging, Vol.1, No.
4, (Jul 2008), pp. 460-471.
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Choi, HS., Choi, BW., Choe, KO., Cho,i D., Yoo, KJ., Kim, MI., & Kim, J. (2004). Pitfalls,
artifacts, and remedies in multi- detector row CT coronary angiography.
Radiographics, Vol.24, No.3, (May-Jun 2004), pp. 787-800.
Choi, JW., Seo, JB., Do, KH., Choi, SI., Lee, W., Ko, SM., Lee, SH., Lee, JS., Song, JW., Song,
KS., & Lim, TH. (2006). Comparison of transaxial source images and 3-plane, thin-
slab maximal intensity projection images for the diagnosis of coronary artery
stenosis with using ECG-gated cardiac CT. Korean J Radio,l Vol.7, No.1, (Jan-Mar
2006), pp. 20-27.
Cordeiro, MA., Lardo, AC., Brito, MS., Rosário Neto, MA., Siqueira, MH., Parga, JR., Avila,
LF., Ramires, JA., Lima, JA., & Rochitte, CE. (2006). CT angiography in highly
calcified arteries: 2D manual vs. modified automated 3D approach to identify
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516.
Ferencik, M., Moselewski, F., Ropers, D., Hoffmann, U., Baum, U., Anders, K., Pomerantsev,
EV., Abbara, S., Brady, TJ., & Achenbach, S.(2003). Quantitative parameters of
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Moselewski, F., Daniel, WG., & Achenbach, S. (2007). Diagnostic accuracy of image
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Image Post-Processing and Interpretation 329
1. Introduction
Coronary angiography is an invasive technique for imaging the coronary artery lumen and
remains one of the most accurate methods for diagnosing coronary artery disease.
Furthermore, this invasive technique is the standard method for guiding revascularization
procedures such as percutaneous coronary intervention (PCI) and coronary-artery bypass
graft (CABG), as well as for guiding stent placement during PCI. However, the degree of
coronary stenosis is usually decided by visual estimation of the percentage diameter
narrowing using the proximal assumed normal arterial as a reference. There is 20% variation
among readings of experienced angiographers, and the same angiographer may even render
a different interpretation at a time remote from the first reading. Borderline stenosis, or
angiographic narrowing of 40 to 70%, does not always correspond to abnormal physiology
and myocardial ischemia (1,2). For such lesions, noninvasive or direct physiological
measurements of impaired flow validate the decision to initiate revascularization therapy.
Though quantitative coronary angiography can be reproduced for assessment of coronary
stenosis, the inability to determine the functional severity of coronary stenosis remains a
limitation of coronary angiography.
Intracoronary physiological parameters have been introduced to assess functional coronary
lesion severity during cardiac catheterization. Measurement of coronary flow reserve (CFR;
coronary flow velocity response to adenosine) and fractional flow reserve (FFRmyo;
coronary pressure-derived with adenosine) provide information about functional severity
(3). Furthermore, FFRmyo, which is calculated from coronary pressure measurements, is an
invasive index used to identify a stenosis responsible for reversible ischemia (4,5,6).
For most patients with stable angina, the goal of treatment is complete, or nearly complete
elimination of anginal chest pain and return to normal activities with a functional capacity
corresponding to Canadian Cardiovascular Society (CCS) class I angina. This goal should be
accomplished with minimal side effects, as well as with a reduced risk of mortality (7). The
332 Advances in the Diagnosis of Coronary Atherosclerosis
topics of this chapter encompass the activities of daily life and functional stenosis in patients
with angiographically demonstrated stenosis.
2. Functional severity
For coronary angiographic assessment employing cardiac catheterization, it should be noted
that the stenotic lumen is compared to a nearby angiographically normal lumen, which may
still show diffuse atherosclerotic disease. Furthermore, lesions containing diffuse,
concentric, symmetrical disease, remodeling, or dissection, will be underestimated when
disease severity is assessed (Fig.1). CFR and FFRmyo, which provide information about
functional severity, can be performed during cardiac catheterization.
(A) Stenosis can be visualized from multiple angles. (B) Stenosis can be viewed as indicated by the
white arrow, but is normally visualized as indicated by the black arrow. Stricture necessitates changing
the angle. (C) Vascular conduits appear normal at all angles despite the existence of stenosis.
Fig. 1. Angiographic images and vascular conduits
CFR reflects both epicaudal and microvascular disease but does not identify these entities by
itself (8,9). Intra-coronary flow velocity can be measured with a 0.014-inch doppler guide
wire during baseline measurements and maximum hyperemia which is induced by
administering adenosine. CFR was calculated as the ratio of hyperemic to baseline of the
average peak velocity (10,11). CFR can also be measured with a temperature sensor-tipped
Novel Insights Into Stenosis on Coronary Angiography–Outline
of Functional Assessment of Stable Angina Patients with Angiographic Stenosis 333
guidewire, as the ratio of the inverse mean transit times obtained by thermodilution curves
at baseline and during hyperemia (12,13,14). The parameters of CFR show agreement at a
cut-off value of 2.0 (11,15).
On the other hand, FFRmyo is an accurate functional index of epicaudal stenosis (4,5). Intra-
coronary pressure can be measured with a 0.014-inch pressure-monitoring guidewire, which
was first calibrated, then set to be equal with the aortic pressure in the guiding catheter, and
finally positioned distal to the coronary lesion. Mean aortic and distal pressures were
obtained during baseline measurements, and FFRmyo was calculated as the ratio of the
mean distal pressure to the mean aortic pressure during maximum hyperemia (3,4,5).
Although a previous report emphasized the importance of combining pressure and flow
velocity measurements to evaluate coronary lesion severity and microvascular involvement
(11), FFRmyo is a reliable index of the functional severity of coronary stenosis, and an
FFRmyo value of 0.75 distinguishes stenoses associated with inducible ischemia from those
that are not. Indeed, in patients with stable chest pain, the most important prognostic factor
is the occurrence of myocardial ischemia reflected by an FFRmyo of < 0.75 (5,6, Fig.2).
In the case on the left, angiographic stenosis was 56% in the left circumflex branch (LCX) by quantitave
coronary angiography (A). During adenosine infusion, the wire was pulled back to track coronary
pressure from the far distal LCX to the catheter, and after crossing the lesion produced a change in
coronary pressure (FFRmyo = 0.58).
Likewise, in the case shown on the right, angiographic stenosis was 46% in left anterior descending
branch (LAD) by quantitative coronary angiography (C), and FFRmyo = 0.70 (D)
Fig. 2. Representative case of FFRmyo
334 Advances in the Diagnosis of Coronary Atherosclerosis
Even when treated with PCI, the clinical outcomes of these patients are significantly worse
than those of patients with functionally insignificant stenoses (FFRmyo 0.75) (16,17). When
FFRmyo was used to divide patients into a group in which stenosis was most likely to be
physiologically significant (FFRmyo < 0.75) and a group in which it was not, the overlap
between the 2 groups in terms of angiographic severity was so large that it suggested
angiography (16,17) could not be used to predict the absence or presence of inducible
ischemia in individual patients (4,18, Fig.3). In fact, however, in patients with multivessel
coronary artery disease undergoing PCI with drug eluting stents, routine measurement of
FFR in addition to angiographic guidance, as compared with PCI guided by angiography
alone, results in a significant reduction in major adverse events (19).
(A) The percent stenosis is likely to be physiological; FFRmyo. (B) The overlap between stenosis and
FFRmyo was large.
3. Functional capacity
The factors contributing to impaired exercise capacity appear to be multifactorial and
include increasing age, sedentary lifestyle, depression, obesity and other comorbidities as
well as impaired cardiovascular function. Poor exercise capacity is generally considered to
be a predictor of mortality in patients with ischemic heart disease as well as all cause
mortality (20,21). Traditional exercise tests such as the treadmill test or walking distance in 6
minutes are well-known methods for measurement of exercise capacity.
Additionally, self-assessed questionnaires, such as the Duke Activity Status INDEX (DASI)
(22), the Specific Activity Questionnaire (SAQ) (23) and the Veterans Specific Activity
Questionnaire (VSAQ) (24), can also measure exercise capacity as a well validated measure
of functional capacity that can be expressed as metabolic equivalents (METs) and have been
shown to correlate with adverse outcomes. Self-assessed questionnaires can be a simple and
easy tool that contributes to the global risk assessment (10).
The cardiopulmonary exercise test (CPX) is useful for measurement of excise capacity
employing various parameters at each stage in a series of exercises (Fig.4). A symptom-limited
incremental exercise test is usually performed using an upright, electromagnetically braked
cycle ergometer or treadmill with measurement of breath-by-breath VO2, carbon dioxide
Novel Insights Into Stenosis on Coronary Angiography–Outline
of Functional Assessment of Stable Angina Patients with Angiographic Stenosis 335
production (VCO2) and minute ventilation (VE). This evaluates peak VO2, oxygen uptake at
the anaerobic threshold (AT) and so on. A 12-lead electrocardiogram (ECG) and heart rate
were continuously monitored throughout the test, and cuff blood pressure was measured
every minute using an automatic manometer. CPX testing is more useful than self-assessed
health status, which is subjective and can vary among patients depending upon symptom
complexity and the unique perceptions, expectations and preferences of individuals (7).
0.542, p < 0.05). A previous study showed stable angina patients with impaired functional
capacity as assessed by a CPX test to likely have reduced FFRmyo. The present study also
showed that an FFRmyo value of 0.75 reflects stenoses associated with inducible ischemia
and hence appears to correspond to a peak VO2 value of 15.0. A cut-off value of FFRmyo of
0.75 nearly matched the exercise capacity value (peak VO2; 15 ml/kg/min) improvement
with PCI. As noted above, exercise capacity in patients with stable angina reflects functional
rather than angiographic stenosis. Exercise training can improve myocardial perfusion, as
revealed by myocardial scintigraphy, as well as maximal exercise capacity (27). Therefore,
that study suggested that it may be possible to improve FFRmyo by increasing exercise
capacity through training.
(A) There is no correlation between angiographic stenosis and peak VO2. However, there is a positive
correlation between FFRmyo and peak VO2 (B). (Source: Circ J 2009;73: 2308–2314)
Fig. 5. Relationship between exercise capacity and stenosis.
A 58-year-old woman presented with unstable angina. Coronary angiography revealed 99%
stenosis of the right coronary artery (RCA#3), and 75% stenosis (#11) and 90% stenosis (#12)
of the left circumflex branch (LCX). She received stent implantation to #3 in the emergent
stage (Fig.6). Thallium-201 scintigraphy with adenosine revealed ischemia in the LCX area
(Fig.7A). PCI was recommended, but the patient refused because the condition was
asymptomatic in her daily life. This patient did not wish to undergo revascularization of the
LCX and continue to receive cardiac rehabilitation (physical training at AT level). Peak VO2
increased from13.3 ml/kg/min (Fig.4) to 16.8 ml/kg/min. Thallium-201 scintigraphy
(Fig.7B) with adenosine documented improved myocardial perfusion distal to the LCX.
(Ischemia area reduced from 13.7% to 8.75%)
There was (A) 99% stenosis of the right coronary artery (RCA #3) and a (B) stent was implanted. Left coronary
angiongraphy revealed 75% stenosis (#11) and 90% stenosis (#12) of the left circumflex branch (LCX).
Fig. 6. Coronary angiographies of case repor
Fig. 7. Bull’s eye image from thallium-201 single-photon emission computed tomography
(A) pre-training (ischemic area 13.7%), and (B) post-training (ischemic area 8.75%)
Novel Insights Into Stenosis on Coronary Angiography–Outline
of Functional Assessment of Stable Angina Patients with Angiographic Stenosis 339
of the ultrasound backscattered signal from a small volume of tissue using fast Fourier
transform measured in decibels (dB) (32). IB-IVUS is a useful method for analyzing coronary
plaque tissue (Fig.9), which accurately and quantitatively differentiates among calcification,
dense fibrosis, fibrosis and lipid components (33). IB-IVUS results previously suggested that
classifying plaques as vulnerable or stable using this technique is an effective means of
predicting acute coronary syndrome. When evaluated using IB-IVUS, plaques are deemed
vulnerable when the lipid area is > 65% and the fibrotic area is < 25% (30). Thus, functional
stenosis and tissue characterization may be linked to clinical outcome. Previously, we
assessed the relationship between functional stenosis and the characterization of plaque
tissue using FFRmyo and IB-IVUS (18).
The initial image was constructed by tracing the lumen and the external elastic membrane. In the color-
coded map, red is calcification, yellow and green are fibrosis, and blue represents the lipid pool.
Fig. 9. Representative IB-IVUS images
We studied 17 lesions showing 75%-stenosis visually by coronary angiography in 17 stable
angina patients (64.2+/-9.1 years old, 11 males). We found no correlation between FFRmyo
and %DS (r = -0.354, p = 0.166, Fig.3B). Nor was there a correlation between FFRmyo and
plaque burden (r = -0.241, p = 0.359, Fig.1B), or between FFRmyo and minimum lumen
cross-sectional area (r = -0.002, p = 0.995). Likewise, neither %DS nor plaque burden
correlated with the tissue characterization values (Figs.10A). There was no correlation
between FFRmyo and %CA (calcification area) (r = -0.068, p = 0.799). By contrast, we
observed a significant positive correlation between FFRmyo and %F (r = 0.620 p = 0.0067),
and a significant negative correlation between FFRmyo and %LP (lipid pool area) (r = -0.524,
p = 0.0293) (Fig.10B).
Our previous findings indicate that the tissue characteristics of coronary plaques in
intermediate lesions affect functional stenosis. Fibrous tissue and FFRmyo also correlate
positively. Lipid pool and FFRmyo correlate negatively. The apparently contradictory
results obtained in this study might be explained by the progression of human
atherosclerotic lesions leading to increasing fibrosis and stenosis. Distal pressure,
additionally, decreases with the severity of coronary narrowing in the epicardial arteries,
Novel Insights Into Stenosis on Coronary Angiography–Outline
of Functional Assessment of Stable Angina Patients with Angiographic Stenosis 341
(A) There was no correlation between angiographic stenosis and tissue characterization (B). There was a
significant positive correlation between FFRmyo and fibrosis, and a significant negative correlation
between FFRmyo and the lipid pool: ▲, %CA = percent calcification area; □, %F = percent fibrotic area;
●, %LP = percent lipid pool area. (Source: J. Cardiol; 2010 ;55,296—302)
Fig. 10. Relationship between stenosis and tissue characterization
Our studies showed that angina patients with reduced FFRmyo are likely to have reduced
functional capacity, and that the tissue characteristics of coronary plaques in intermediate
lesions affect functional stenosis. According to these studies, high exercise capacity in
patients with stable angiographic stenosis is linked to the stability of coronary plaques.
Another report on coronary computed tomographic angiography indicated that coronary
342 Advances in the Diagnosis of Coronary Atherosclerosis
plaque characteristics were identified in patients with progressively reduced exercise times,
and that functional ischemia was more severe in those with mixed plaque. (36)
Thus, though coronary angiography is one of the most accurate methods for diagnosing
coronary artery disease, comprehensive assessment of health status is necessary for stable
angina patients with angiographic stenosis.
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19
1. Introduction
Radiation exposure is a concern for those who participate in the practice of interventional
cardiology. However, many cardiologists are unaware that they may be exposing patients
to relatively high levels of radiation during cardiac catheterization procedures.
Interventional cardiology techniques are highly appreciated for its less invasive character
than surgery. A wide range of interventions, from diagnosis to treatment of heart and
coronary specific disorders are performed in both adults and children. Interventional
cardiology procedures can involve significant radiation exposure. Therefore, it is essential to
reduce the radiation dose as far as possible, by keeping an adequate image quality for
diagnostic and therapeutic purposes. Over the last years, introduction of new technologies
like flat-panel detectors have revolutionized fluoroscopy imaging. Most of the digital
detectors can potentially be used at lower doses. In practice, technical optimization studies
are rarely reported (especially for cardiac catheterization laboratories), notwithstanding the
fact that optimal settings could be very different from the optimal settings with the
traditional image intensifier systems.
This chapter is structured in three parts. The first part focuses on background notions
concerning X-ray production, radiation quantities and units, personal health risks and
concepts of radiation protection. The second part reviews the radiation exposure in
cardiovascular practice. The last part presents optimization strategies of image quality and
radiation dose and recommendations for limiting radiation exposures.
positioning of medical devices within the patient. Cineangiography mode (shortly cine
mode) is the acquisition of a series of high definition dynamic images. It is mainly used to
image vessels injected with contrast media. The necessity of obtaining high contrast and
sharp edge definition with low noise images requires higher radiation dose rates. The basic
components of a fluoroscopic imaging chain are shown in Figure 1. The chain is composed
by an X-ray tube and generator, which are capable to produce a stable X-ray output over
long exposure times, a detector mounted opposite the X-ray tube, capable of dynamic
imaging, digital image processing and storage facilities, and a display system capable for
viewing real-time or recorded digital image series.
Fig. 2. X-ray detector technology. On the left, image intensifier (II) technology. On the right,
flat-panel indirect detector (FD) technology.
There is a common consensus that FDs provides advantages in terms of image quality and
dose efficiency comparing with II technology. Advantages include image uniformity, no
geometrical distortions, no veiling glare and vignetting, wider dynamic range and better
ergonomics for patient accessibility. On the other hand, for FDs, system noise remains a
limiting factor and performance is rather limited for low exposure levels. (Holmes et at.,
2004; Seibert, 2006; Davies et al., 2007).
measurement of the total exposure of the patient. The DAP-meter is a flat large-area
ionization chamber mounted at the exit window of the X-ray tube and intercepts the entire
useful beam. In interventional cardiology, we work also with other quantities that influence
radiation dose. One of them is fluoroscopy time, which can be adopted as starting unit in a
quality assurance program (for comparison between operators, centers, procedures, for the
evaluation of protocols, and for the evaluation of operator skills). Other quantity is the
number of acquired cineangiographic images or number of series.
Entrance skin dose (ESD) includes the scatter from the patient. ESD = D*BF, where
backscatter factor ranges from 1.2-1.4 as a function of field size. The SI unit for ESD is the
Gray (Gy). Values of absorbed dose to tissue, compared with to air, will vary by a few
percent depending on the exact composition of the medium that is taken to represent soft
tissue. To evaluate the dose inside the patient’s body, we use the mean absorbed dose in a
tissue or organ, DT, in fact the energy deposited in the organ divided by the mass of that
organ. Organ doses cannot be measured on real patients. They can be measured in
anthropomorphic phantoms simulating examinations or by dedicated software tools that
simulates the interaction of X-rays on mathematical or realistic phantoms.
measurements on the patient with large area detectors (films and TLDs array), and (d) by
portal monitoring with area or point/area detectors. The new cardiac X-ray systems are
able to display on the monitors dosimetric parameters at the interventional reference
point (IRP). The IRP is the reference point intended to be representative of the position of
the patient’s skin at the entrance site of the X-ray beam during an interventional
procedure. For fluoroscopic systems with an isocentre, the IRP is located along the central
ray of the X-ray beam at a distance of 15 cm from the isocentre in the direction of the focal
spot (Figure 3).
Radiation exposure of the different organs and tissues in the body results in different
probabilities of harm and different severity. The combination of probability and severity of
harm is called detriment. For instance in young patients, organ doses may significantly
increase the risk of radiation-induced cancer in later life. The equivalent dose (H) is the
absorbed dose multiplied by a dimensionless radiation weighting factor, wR, which
expresses the biological effectiveness of a given type of radiation. H D wR . The SI unit of
H is the Sievert (Sv). For X-rays, the wR is 1 so H is equal to D. The mean equivalent dose in
a tissue or organ HT is the energy deposited in the organ divided by the mass of that organ.
To reflect the detriment from stochastic effects due to the equivalent doses in the different
organs and tissues of the body, the equivalent dose is multiplied by a tissue weighting
factor, wT. The equivalent doses to organs and tissues weighted by the relative wT are
summed over the whole body to give the effective dose, E. The SI unit of E is also the Sievert
(Sv). E T wT HT . Till 2007 the tissue weighting factors of ICRP Publication 60 were
used. A recent estimation of those factors was published in ICRP report 103. Main
differences between publications for tissue weighting factors, wT are presented in Table 1.
Stochastic risk is calculated multiplying effective dose by a risk factor specific for sex and
age at the exposure.
Figure 3 illustrates the dosimetry terminology used in interventional cardiology. To
summarize, the biological effects and risks from ionizing radiation are divided into
deterministic and stochastic effects. Deterministic effects have a dose threshold, and the
intensity of the effect increases with increasing dose. Stochastic effects include cancer and
genetic risk. Probability of stochastic risks increases with increasing dose, but the intensity
of the effect is not a function of the absorbed dose. For personnel working in cardiac
catetherization laboratories, the major worries about radiation exposure are the potential
risk of cancer, cataracts, and genetic birth defects of pregnant staff if the appropriate
protective measures are not used. For patients, deterministic effects can be produced by
high doses of fluoroscopic X-rays. In addition, stochastic effects can appear on patients
with repeated interventional cardiac procedures, especially if are performed in young
population.
Risks of exposure to ionizing radiation are contra balanced by the need for and potential
benefit for a patient to have a cardiac interventional procedure. In fact medical use of
radiation is a unique situation in which patients are intentionally irradiated. The risk should
be minimised by utilizing techniques and procedures that keep exposure to a level As Low
As Reasonably Achievable (ALARA principle). The principle of ALARA is the axiom for all
radiation workers. Its successful implementation in catheterization laboratory require
understanding of factors responsible for levels of radiation exposure and applying
optimized procedures to obtain the medical diagnostic or therapeutic goal with minimum
radiation risks.
350 Advances in the Diagnosis of Coronary Atherosclerosis
procedures, usually the total DAP for whole procedure is documented. Sometimes, the
DAP for the fluoroscopy part (DAPfluoro) and the DAP for the cineangiography part of a
procedure (DAPcine) are indicated. Some authors propose additional technical quantities
like the total fluoroscopy time of a procedure, the total number of acquired images, the
number of series of acquired images, the mean number of images per series in a
procedure. Dosimetry quantities for stochastic risk evaluation are organ equivalent
doses to organ/tissue and effective dose. These quantities are indicators of overall
exposure in the assessment of stochastic effects of radiation exposure for population. Use
of these quantities allows us to compare exposures from different types of procedure,
radiation type, and radiation quality, and irradiation geometry. From effective dose, using
correct risk coefficients (ICRP Report 103), we can estimate the detriment of individuals or
population from medical exposure. Dosimetry for deterministic effects focuses on skin
dose assessment. For complex interventional cardiology procedures, the knowledge of
irradiated skin area is important with respect to the potential for deterministic effects of
radiation exposure. Different methodologies are used to express the maximal skin dose
(MSD): off-line or on-line calculation, direct measurements on the patient with point
detectors (TLDs or solid state detectors), direct measurements on the patient with the area
detectors (TLD array and film) or by portal monitoring with point or area detectors.
Unfortunately not all methods are feasible for routine work, specially the on-line ones. An
alternative approach on two levels can be used. The first level able to prevent
deterministic effects is using a threshold. This can be fluoroscopy time or a measurable
quantity like DAP, able to alert the operator that a certain value of skin dose,
corresponding to a threshold for deterministic effects can be reached. The second level to
assess MSD requires specific methods. In case of electrophysiology procedures where
stationary fields are used, electronic point detectors or computational methods able to
assess skin dose distribution can be employed.
We will present a summary of published patient doses in interventional cardiology. Any
attempt to compare published studies must be performed with circumspection due to the lack
of standardization of data acquisition and the uncontrolled variables (equipment differences,
radiographic technique, complexity of procedure, patient characteristics (size, age, sex).
values for interventional cardiology procedures vary considerably. This can be attributed to
procedural complexity, examination technique, use of radiation-reducing techniques,
operator experience, workload, and catheterization laboratory examination. For example,
Broadhead et al, 1997 compared patient dosimetry between single intensifier system and
biplane image intensifier system, and found that the biplane system provides greater
imaging capability but with increased dose. DAP for CA is 47.7 vs. 23.4 Gycm² (biplane vs.
single system), and for PCI is 72.2 vs. 51.6 Gycm².
(Efstathopoulos et al., 2003, Kuon et al., 2004). Mean DAP for fluoroscopy and image
acquisition calculated from the values reported in these studies are 18% DAP fluoroscopy
and 81% DAP image acquisition for CA procedures. For PCIs, DAP is 41% from fluoroscopy
and 59% from image acquisition. The patient radiation doses vary widely among published
studies. These differences are related to patient, procedure, X-ray equipment and physician.
3.2 Patient radiation doses radiation doses during electrophysiology studies and
pacemaker implantations
Cardiac electrophysiology is a subdiscipline of interventional cardiology that is focused on
elucidating, diagnosing, and treating the electrical problems of the heart. The procedures are
performed by invasive intracardiac catheter recordings of spontaneous activity as well as of
cardiac responses to programmed electrical stimulation. These studies are performed to
evaluate abnormal electrocardiograms and to assess complex arrhythmias. Typically
therapeutic procedures are radiofrequency catheter ablations (RFCA). Patient doses are also
influenced by the type of procedures. Diagnostic electrophysiological study (EPS) relies
mainly on fluoroscopy. For therapeutic procedures, we can find different categories: RFCA
without angiographic images using contrast medium, RFCA with angiographic images
using contrast medium and RFCA of atrial fibrillation (AF) (Dragusin et al., 2005). The
dosimetric data of this study is presented in Table 4. In the case of therapeutic examinations,
354 Advances in the Diagnosis of Coronary Atherosclerosis
the radiation doses varied according to the location of the tachycardia. Ablations in which
contrast medium is used to take images need more radiation exposure. RFCA of atrial
fibrillation had longer examination times and yielded the maximum radiation doses.
16.5, 12, 16, 18, 21, 20 minutes for fluoroscopy time and 9, 14, 12, 18, 22, 19 acquisition series.
The effective doses for each patient were estimated using PCXMC software (STUK, Finland).
The 25th, 50th and 75th percentile per each age group for diagnostic procedure is presented in
Figure 4 and for therapeutic procedures is presented in Figure 5.
ray systems, performing diagnostic and interventional procedures with shorter fluoroscopic
times, and using effective shielding to protect from radiation.
it is evident that the poorest image quality corresponds to the fluoroscopy mode and the
better image quality corresponds to acquisition mode with maximum detector entrance dose
(240 nGy/frame).
0,1
0,1 1,0 10,0
Fig. 6. Contrast-detail curves for CDRAD phantom for fluoroscopy mode and cine mode for
different detector entrance doses.
10
9 cm
13 cm
17 cm
21 cm
0,1
0,1 1 10
Fig. 7. Contrast-detail curves for CDRAD phantom for cine mode (15 frames/second; 170
nGy/frame) and different simulated patient thicknesses.
The improvement in image quality between settings is not very clearly visible because of the
small changes in detector dose levels. Differences between detector dose settings are not
significan (a factor of 2.4 between the minimum 100 nGy and maximum 240 nGy). This
implies a little change in threshold contrast. Despite of the limitation of this study, the
authors observed that just a simple change of the detector entrance dose from a superior to a
next inferior setting (i.e. from 170 nGy/frame to 140 nGy/frame) will not dramatically
change image quality. This simple action would potentially reduce the patient skin dose
between 14-19% depending of the size of the patient. The limitation of the use of contrast
detail phantoms consists of the difficulty to link with clinical image quality requirements. In
particular for interventional cardiology, visualization of moving structures, visualization
and grading of subtle lesions or anatomical structures during the passage of a contrast agent
and the tracing of small catheters on the moving heart, implies the use of test objects that
Optimization of Radiation Dose and Image Quality in Cardiac Catheterization Laboratories 359
Fig. 8. (Left) Synthetic Arterial Model (SAM) integrated into phantom body. (Right) Close-
up view of the heart model with coronary grooves highlighted
In this experiment were studied the effect of four technical variable of the X-ray equipment
with an anticipated influence on image quality: tube voltage (kV), additional Copper
filtration (mm Cu), detector entrance dose and dynamic density optimization (DDO). The
last variable is particular to Siemens cardiac catheterization systems equipped with flat
panel detector and is a image quality (post processing) parameter that works in real-time by
harmonizing the distribution of gray steps in the image. The X-ray filming of the phantom
allows the cardiologist to track the contrast agent circulation, to identify coronary lesions
and evaluate their visibility in rapport with anatomical structures. In this study four
calcified structures in the coronary arteries were used to simulate stenotic lesions. The first
lesion was located on the proximal left anterior descending (LAD) segment, the second on
the mid LAD segment, the third on the proximal circumflex segment (Cx) and the fourth on
the distal Cx segment. Typical radiographic images, with indication of the lesions, are
presented in Figure 9.
360 Advances in the Diagnosis of Coronary Atherosclerosis
Fig. 9. X-ray images of the heart phantom under different experimental conditions. L1 to L4
indicate the location of simulated lesions.
The contrast media (Iodine) was injected in the phantom using the hand technique and a 6F
catheter. 15 to 20 ml of iodine was used at the same flow rates and the image sequence is
started a few seconds after the injection. For full characterization of the lesions, sets of two
coronary angiograms from two viewing angle were recorded: RAO 30° and LAO
40°/CAUD20° (where RAO the right anterior oblique view, LAO the left anterior oblique
direction and CAUD the caudal inclination). The duration of the angiograms was 5 seconds
and was acquired at a rate of 15 frames/second. The angiograms were presented in a
random order to eight interventional cardiologists (4 experienced interventional cardiologist
and 4 residents). The observers were asked to subjectively assess the visibility of each
simulated lesion and to give an overall score for each angiogram by using a five-point scale:
1 = not visible; 2 = poor visibility; 3 = acceptable visibility; 4 = good visibility and 5 = very
good visibility. The evaluation of angiograms is presented in terms of image quality (IQ)
scores. For every angiogram entrance skin dose was measured and an effective dose was
estimated. Mean IQ scores ranged from 1.68 to 4.88. The highest IQ scores were obtained for
the angiograms acquired with tube potential 80 kV, no added Cu filters, DDO 60%, RAO
and LAO views and the highest entrance detector dose that has been used in the present
study, namely 170 nGy/frame. Radiation doses (entrance skin dose approximately 40 mGy
and effective dose of 1 mSv) were estimated for angiograms acquired at 15 frames/second,
detector field-of-view 20 cm, and a length of 5 s. The following parameters improved the IQ
factor significantly: a change in tube potential from 96 to 80 kV, detector entrance dose from
100 nGy/frame to 170 nGy/frame, the absence of Copper filtration. DDO variable which is a
post-processing parameter should be carefully evaluated because it alters the quality of the
images independently of radiation exposure settings. The SAM anthropomorphic phantom
has the advantage of visualization of stenotic lesions during the injection of a contrast agent
and using an anatomical background. In the future, this phantom could potentially bridge
the gap between physics tests and the clinical reality in the catheterization laboratory.
Future generation of phantoms should simulate the beating heart.
Optimization of X-ray equipment settings through experimental measurements is necessary,
mainly when it involves new equipment or technology. The acceptance of optimized
settings that affects image quality and radiation dose has to be accompanied by the training
of the user. Authors of this work have experience in this area. In our center in Luxembourg
Optimization of Radiation Dose and Image Quality in Cardiac Catheterization Laboratories 361
70,0 66,1
CA CA+PCI
60,0
50,9
50,0
43,0
DAP (Gycm²)
40,0
30,0
21,9
20,0 17,0
14,8
10,0
0,0
II before course II after course FD - new system
Fig. 10. Mean DAP patient values with II before and after training course and with FD for
CA and PCI examinations.
Based on the survey of patient doses, we were able to establish reference levels (RL) for
common interventional procedures. These indicators are DAP, fluoroscopy time and
number of images, and give to the operator somehow the guideline of good and normal
practice. Of course, higher doses might occur if the clinical status of the patient justifies the
corresponding exposures to ionizing radiations. The goal to use RL is to control the level of
optimization of the procedures. Once the dose indicators are collected, the RL are
established as third quartile (75% percentile) of the distribution of observed data. In our
center, INCCI Luxembourg, local RL values for CA procedures are: 23 Gycm² for DAP, 5
minutes for fluoroscopy time and 617 images. For PCI procedures, the RL values are 44
Gycm² for DAP, 15.5 minutes for fluoroscopy time and 1163 images. Our values were
compared with reference levels at European level proposed by the SENTINEL consortium
(Padovani et al., 2008). The data was collected from nine European centers, 672 CA and 662
PCI procedures. Comparison of our local reference values with the European values are
shown in Figure 11 for CA procedures and in Figure 12 for PCI procedures.
362 Advances in the Diagnosis of Coronary Atherosclerosis
45
30
15
0
KAP [Gycm²] CF (x100) FT [min]
Fig. 11. Comparison of diagnostic reference levels for CA procedures between INCCI (local
RL) and European study
75
60
45
30
15
0
KAP [Gycm²] CF (x100) FT [min]
Fig. 12. Comparison of diagnostic reference levels for PCI procedures between INCCI (local
RL) and European study
Strictly comparison between both studies is difficult to perform, because we do not have
complete information about how the X-ray cardiac systems in the European study were
configured. Also, we do not know if the cardiologist’s experience and training education in
radiation protection is uniform between centers.
Probably one of the factors that explain the difference is the configuration of the X-ray
equipment for fluoroscopy mode. In our center the pulse rate is 6 pulses/s (low dose mode),
where in European study, centers that submitted data work usually with 12.5 frames/s (for
II systems) and 15 pulses/s (for FD systems). Our clinical experience shows that there is
possible to optimize protocols when using new technology with little compromise on image
quality but with benefit in reducing radiation dose levels to the patient.
5. Conclusion
Optimization of radiation dose - image quality and implementation of ALARA principle in
catheterization laboratories are tasks that involve all actors: interventional cardiologists,
auxiliary staff, medical physicist, and applications specialists. However, in daily practice
Optimization of Radiation Dose and Image Quality in Cardiac Catheterization Laboratories 363
some tactics for radiation dose reduction and image quality improvement should be known
by all interventional cardiologists. We create a list of little steps that have an impact in
radiation safety in daily practice.
Use the lowest acceptable clinical protocols during fluoroscopy and cineangiography. Pulsed
fluoroscopy and cineangiography at lowest radiation level should be used. If the equipment
allows, different protocols must be created and used in function on the type of structure that
is being imaged (venous vs. arterial, fast-moving vs. slow-moving).
Correct placement of the patient in the isocenter on the table. Having the patient correct
positioned in the isocenter facilitates keeping the heart at the center of the X-ray field. In this
way there is no need of prolonged fluoroscopy to adjust the patient’s position with each
change in angiographic projection.
Avoid the use of fluoroscopy to make changes to the patient position or collimators. Fluoroscopy
should be used very briefly to check the patient position. Movements to the correct position
should be avoided by using fluoroscopy constantly. Modern units have “virtual” markers
that enable the positioning of the collimators. The correct position of collimators should be
checked by brief fluoroscopy rather then constant visualization.
Remove unnecessary instruments and body parts from the X-ray field. Presence of the patient’s
arm, operator’s hands or any external instruments should never be visible on a cardiac
study. These structures or objects result in an overall increase in radiation dose to the patient
because of the demand of AEC system to compensate with increased radiation output.
Minimize the number of angiograms. Limit the number of projections to provide an overview
of the status of the coronary arterial tree and indentify the ideal projections to be used for
coronary angioplasty. Always performs test injection of a small amount of contrast material
using fluoroscopy prior to acquiring an angiogram. This approach prevents the wasted
angiogram that is taken with the catheter inadvertently wedged deeply in a vessel. Also
fluoroscopy of test injection can aid in determining the correct magnification mode. Keep in
mind that few seconds of fluoroscopy and little quantity of contrast material are less
irradiating the patient than a full wasted angiogram. During complicated interventions,
limit the use of magnification, because of the substantial increase in radiation dose.
Keep the detector (II or FD) as close to the patient as possible. The X-ray tube should be as far
away as possible. If the detector is far from patient, the input doses will be higher and the
scatter radiation increases.
Decrease beam on time. This is probably one of the most important rules. Fluoroscopy must
not be applied when discussing or doing other manoeuvre. If the eye is not on the screen,
the foot should not be on the fluoroscopic pedal. Use stored images rather than live images
for studying the case.
Use angiographic projections that reduce operator exposure whenever possible. For right oblique
projections, the X-ray tube moves away from the operator, while for left anterior oblique
projection moves it closer. Kuon et al., 2004 published an interesting paper focused on
identification of less-irradiation tube angulations in invasive cardiology. Di Mario & Sutaria,
2005 published a review of techniques to obtain optimal views of all segments of the
coronary arterial system.
Remove anti-scatter grid when imaging small children. New cardiac X-ray systems have
possibility to remove the grid. In pediatric patients a significant reduction in radiation dose
is possible without compromising image quality.
Know your own cardiac X-ray equipment and its features. Work with radiation physicist, the
manufacturer to regularly test and maintain the equipment in optimal working conditions.
364 Advances in the Diagnosis of Coronary Atherosclerosis
Ensure protection of laboratory staff. Before starting fluoroscopy, ensure that everyone in the
room use radiation protection shielding. Ask of laboratory staff to keep distance during cine
angiography. Remember the inverse square law: doubling the distance from a point source
reduces the radiation exposure to one-quarter. Keep the proper use and storage of lead
aprons. Aprons that are not proper storage might develop cracks, compromising their
effectiveness. Always use personal dosimeters.
Technology of X-ray cardiac system is continuously adapting and optimization of radiation
doses with less compromise on image quality is possible. On the other side, activity in
cardiac catheterization laboratories increases and more complex procedures are performed.
All the actors involved in catheterization laboratory should be trained and familiar with the
basic principles of radiation safety. Developing a radiation safety culture should be a
priority. Attention to the simple rules of radiation safety and the planning of an
interventional procedure should enable the interventional cardiologist to produce high
quality images at low radiation level to the patient.
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366 Advances in the Diagnosis of Coronary Atherosclerosis
1. Introduction
The volume of diagnostic or therapeutic procedures in cardiology that require the use of
ionizing radiation is increasing constantly. Currently, technological developments offer the
possibility of exploring not only the cardiac function (measurement of ejection fraction, for
example) but also the state of coronary and great vessels. In fact, the management of
patients with heart disease often requires the use of investigative techniques using X-rays.
For example 3.85 million cardiac catheterizations were performed in the United States in
2002 (Einstein et al., 2007). In Switzerland the last national survey on the exposure of the
population by medical radiology revealed that nearly 34 000 coronary angiographies and
more than 18 000 coronary dilatations were performed in 2008. They are associated to 65%
of the collective dose related to interventional radiology and 8% to that related to all medical
X-rays (Samara et al. 2011).
The increase in radiological examinations using ionizing radiation has been mentioned for
several years not only in medical journals for professionals but also in the press addressing
the general public. For example, in its edition of 17 June, 2007, the New York Times
questioned the public opinion about the justification of the increasing number of CT
examinations.
While most examinations deliver relatively low doses and thus add only a low risk to the
procedure itself, there are situations where doses exceed the dose level where an excess risk
of death from cancer has been demonstrated. In addition, some complex procedures may
result in the occurrence of deterministic effects such as burns to the skin.
The substantial increase of fluoroscopy-guided procedures in cardiology over the past few
years has been accompanied by a parallel growth in concern for patient radiation safety and
for the safety of the operators who perform these procedures. Thus, radiation safety has
become a major issue in radiology departments.
The aim of this chapter is:
- to recall the effects of ionizing radiation on the human body and the radiological risks;
- to introduce the dosimetric quantities (basic and operational) commonly used to
quantify those risks;
- to briefly present the principles of radiation protection;
- to provide the tools (actions and means) necessary for operational radiation protection.
368 Advances in the Diagnosis of Coronary Atherosclerosis
HT = Σ R wR . DT,R
HT has the same dimension as DT (J kg-1), but is expressed in sievert (Sv).
As shown in table 2, X-rays or gamma rays are taken as reference radiation and wR is
therefore equal to unity. Thus, an adsorbed dose of 1 mGy is equivalent to a dose equivalent
of 1 mSv
E = Σ T wT . HT = Σ T,R wT . wR . DT,R
where wT is the tissue weighting factor (see table 3).
lymphatic nodes, muscle, oral mucosa, pancreas, prostate, small intestine, spleen, thymus,
uterus/cervix.
Table 3. Tissue weighting factors
3.1 Justification
The first principle of radiation protection is justification. No exposure is acceptable unless its
usefulness is demonstrated. In the medical practice any radiological modality or procedure
has to be justified. It should be properly indicated to the diagnostic or therapeutic case. In
other words it should be demonstrated that no other non-irradiating non invasive modality
can give the same diagnostic or therapeutic results. In order to implement the justification
principle, learned society in several countries (USA, UK, France, Switzerland and others)
worked out referral guides in order to indicate which radiological modality/examination is
suited to which diagnostic or therapeutic case.
3.2 Optimization
The second principle of radiation protection is optimization. When the exposure to radiation
is justified, an effort must be engaged in order to keep the radiation dose delivered as low as
reasonably achievable (ALARA principle). If justification reflects the will “to do the right
thing”, optimisation reflects the will “to do it right”. In the medical practice the principle of
optimization is implemented in different ways contributing together to lower the radiation
doses to the patients and to the staff. The quality control of the X-ray unit is important to
make sure the optimal settings are used. The auditing of the protocols used for each
radiological procedure allows producing the quantity and quality of images sufficient to the
diagnostic or therapeutic goal, with an optimum trade-off between image quality and
radiation dose, and no unnecessary irradiation of the patient and staff. The use of protecting
means contribute to cut down the radiation (direct or scattered) that is not useful in the
imaging process. Training, informing, using diagnostic reference levels, all this helps spread
a culture of optimization.
3.3 Limitation
The third principle of radiation protection is dose limitation in order to avoid excessive
exposure of an individual. The ICRP recommends a set of dose limits for the general public
and for people exposed in the course of their occupation (ICRP 103, 2007). The principle of
dose limitation applies to health professionals (physicians, radiographers, medical
physicists, etc.) but it does not apply to the patient. The sound benefit (diagnostic or
therapeutic) from X-rays use implies that higher doses of radiation are tolerated as long as
the radiological procedure is justified and optimized.
It is worth mentioning that the exposure of staff is not due to X-ray leakage from the X-ray
tube of the fluoroscopy unit. Exposure to the staff is due to the X-ray scatter that is produced
when the X-ray beam interacts with the tissues of the patient. Thus, the higher the dose to
the skin of the patient the higher the amount of scattered radiation produced. From this,
patient and staff exposure are interlinked. One should always remember that the patient is
the main source of exposure of the staff. Therefore optimizing the patient dose will improve
the staff radiation protection.
4.1 Patient
Patient dose can be quite high but deterministic effects should never be a surprise to the
operator. Avoiding as much as possible the appearance of deterministic effects (short term
radiological complications) the operator should also minimize the stochastic effects (long
term radiological complications).
4.2 Personnel
The X-ray beam enters the patient and interacts with the tissue. Some radiation will be
absorbed in the patient and thus deposit energy to that patient. The transmitted radiation
will impinge the image amplifier to produce images. Unfortunately, the X-ray interaction
within the patient will also create scattered radiation emitted all around the patient which
will expose the staff to ionizing radiations.
The dose the staff might receive when being at one meter from the patient is approximately
0.1% of the skin dose delivered to that patient when the size of the X-ray beam is large
(typically 400 cm2). For example if the skin dose rate is equal to 40 mGy.min-1, ambient dose
rate at one meter from the patient can be estimated to 2.5 mSv.h-1 (natural background of
0.0001-0.0002 mSv.h-1). During cine runs the skin dose rate can reach 1 Gy.min-1 which
implies a higher dose rate to the staff during this type of acquisition. The ratio between
patient skin dose and staff dose is dependent on the size of the X-ray beam. The larger the
field size the higher the ratio. It is thus important to always reduce the size of the X-ray
beam to its strict minimum. Expressed in terms of DAP one can take 0.3% of the DAP (DAP
expressed in Gy.cm2 and E in mSv). Thus when a cardiologist has delivered a DAP of 60
Gy.cm2 he might have received over his/her lead apron a dose of 0.2 mSv.
4.2.1 Shielding
Shielding allows the staff to be isolated from scattered radiation produced by the X-ray
interaction in the patient. Barriers used for shielding may be fixed to the unit, movable or
worn by individuals. The amount of radiation attenuated by a material depends on the
elemental composition of the material, its thickness and the energy of the radiation passing
through it. As an example, the transmission through 0.5 mm of lead is 3.2% at 100kV and
0.36% at 70 kV (Yaffe & Mawdsley, 1991).
To reduce the operator exposure, one should begin by creating a sort of booth with
shielding devices around him or herself. To do so, an articulated ceiling leaded screen
lengthened by a leaded flap beside the table, or a mobile barrier as the one shown in Figure
1, together with a longitudinal protection adjacent to the table can be used (Kuon et al.
2002). Each shield should be at least 0.5 mm lead equivalent. The operator has then to
complete his or her protection by wearing a lead apron, which should be adjusted to his or
her size. Concerning the lead equivalent content, most of the aprons are either 0.5 or 0.35
mm lead equivalent. The use of a 0.35 mm instead of a 0.5 mm lead equivalent reduces
weight by about 30%, but increases the transmission of scattered radiation of almost a factor
of 2 at 90 kV. However, Marshall in an experimental study showed that at 90 kV, wearing a
0.35 mm lead equivalent apron with an additional 0.35 mm lead equivalent thyroid shield
resulted in a factor 2 greater reduction in effective dose than can be achieved by wearing a
0.55 mm lead equivalent apron alone (Marshall & Faulkner, 1993). Some aprons are made of
composite materials which offers equivalent shielding properties but which are significantly
less heavy than aprons containing lead as shield material (Yaffe & Mawdsley, 1991).
Figure 1 presents one way the operator can insulate himself from the scatter produced by
the patient when the examination is performed in the chest area with a femoral access. One
Protection of the Patient and the Staff from Radiation
Exposure During Fluoroscopy-Guided Procedures in Cardiology 375
should always remember that it is at the surface where the X-ray beam enters the patient
that the scatter dose rate is at its highest level. One should shield himself from that
particular spot.
Figure 2 summarizes the efficiency of the shielding devices presented in Figure 1 for various
tube-image amplifier orientations. It can be seen that an operator can significantly decrease
his or her exposure when a shielding device is placed in such a way that the operator is as
much as possible shielded from scattered radiation (Kuon et al., 2002). Unfortunately this is
not always possible, as in the case of biliary drainage for example. In such a case, staff
exposure is mainly controlled by the optimisation of patient exposure, the distance from the
scatter source and personal shielding (Williams, 1997).
Fig. 1. Example of operator shielding with various devices (1 leaded glass, 2 and 3 leaded
curtains, 4 leaded wall; 1 and 4 being on a mobile barrier)
To improve protection against cataract (which is a deterministic effect of ionising radiation),
a 0.5 mm lead equivalent eyeglass should be used to reduce exposure to the lens by 10% to
65% (Nicholson, 1995). Finally, gloves made of composite material and offering the same
tactile perception than regular chirurgical ones are available. Unfortunately, they offer a
limited protection since they usually reduce dose by a factor less than 2 (Vaño & Guibelalde,
1997; Balter, 2001).
Protection
Sv/h device
2000
without
1000
+
200
ambient dose rate
200
device (1+2)
100
20 +
10
10 device (3+4)
personal
0.1
shielding
Fig. 2. Mean ambient dose rate to the operator (Sv.h-1) for different tube-image amplifier
orientations. The dose rate corresponds to an examination in the cardiac area of a Rando
phantom, representative of a 70 kg standard patient, the operator being at about 1 m from
the central beam impinging the phantom (situation presented in Figure 1). Without any
radiation protection device, the dose rate is in the range of 2 to 0.2 mSv.h-1. As expected, the
LAO angulations are the ones which potentially deliver the highest dose to the operator.
The addition of the protection devices 1 and 2 allows a reduction of the ambient dose rate at
operator’s level by a factor of 10. A further reduction is obtained by completing the
shielding with devices 3 and 4. Finally, the use of personal shielding devices (i.e. lead apron,
thyroid shield and leaded glasses) reduces the ambient dose rate to about 0.1 Sv.h-1
(adapted from Kuon et al., 2002).
X Ray tube
Image Amplifier
Primary
Radiation Scattered
Radiation
Primary
Radiation
Scattered
Image Amplifier Radiation
X Ray tube
Fig. 3. The schematics show the influence of the tube-image amplifier orientation on the
operator’s exposure. When the tube is below the table, exposure to the legs and the lower
part of the abdomen is the highest. When the tube is above the table, exposure to the face,
neck and chest is the highest.
Protection of the Patient and the Staff from Radiation
Exposure During Fluoroscopy-Guided Procedures in Cardiology 377
5. Conclusion
Several recently published studies showed that there is a high potential to reduce radiation
doses to the patient and subsequently to enhance radiation safety for the staff. The aim of
this chapter was to introduce the effects of ionizing radiation and the radiological risks, and
to present various methods that may be used to reduce patient and personnel exposure
during fluoroscopy-guided procedures in cardiology, such as the reduction of patient
exposure, the increase of the distance from the source of scatter, and the shielding.
Every effort needs to be made in order to reduce patient and staff exposure as much as
possible, not for legal purposes but simply for workers health. This applies in particular in
the field of interventional radiology where exposure to the staff is potentially very high.
Dose reduction to the staff can be reduced by the optimisation of patient exposure. Thus the
introduction of the diagnostic reference levels (DRL) will certainly improve the control of
staff exposure. Moreover, the application of simple rules, such as the ones mentioned in this
contribution, allow radiologists to use fluoroscopy units minimising their exposure as much
as possible. The respect of these rules allow also to improve the protection of other medical
staff present near the patient and who are less familiar with radiation protection.
6. References
Einstein, A.J.; Moser, K.W., Thompson R.C., Cerqueira M.D., Henzlova M.J. (2007).
Radiation dose to patients from cardiac diagnostic imaging. Circulation, 116:1290-
1305
Samara, E.; Aroua, A., Vader, J.-P., Trueb, Ph., Bochud, F., Verdun, F.R. (2011). Exposure of
the Swiss Population by Radiodiagnostics: 2008 Review. Health Physics, submitted
Suzuki, S.; Furui, S., Isshiki, T. (2008). Patients' skin dose during percutaneous coronary
intervention for chronic total occlusion. Catheter Cardiovasc Interv, 71:160-164
Jacobi, W.; (1975). The concept of effective dose – a proposal for the combination of organ
doses Radiat Environ Biophys, 12:101-109
ICRP 26 (1977). International Commission on Radiological Protection: The recommendations
of the international commission on radiological protection. ICRP Publication 26,
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ICRP 90 (1990). International Commission on Radiological Protection: The recommendations
of the international commission on radiological protection. ICRP Publication 90,
Elsevier
378 Advances in the Diagnosis of Coronary Atherosclerosis