ISCHEMIC HEART DISEASE

Leading cause of death worldwide, 7 million per year.

Pathophysiologically related syndromes resulting from myocardial ischemia. Imbalance
between supply and demand.
Decreased oxygen, non removal of metabolites, reduced availability of nutrients.
Ischemia is less well tolerated by the heart than pure hypoxia.
In >90% of the cases, the cause is reduced blood flow due to obstructive atherosclerotic lesions
in the coronary arteries.
Thus IHD is often called coronary artery disease.

Usually presents with one or more clinical syndromes:

 Myocardial infarction
 Angina pectoris
 Chronic heart disease with heart failure
 SCD

EPIDEMIOLOGY –
Death rates have fallen because of:
Prevention – diagnosis of ris factors.
Diagnostic and therapeutic advances.
Pathogenesis of IHD and MI may not be identical because MI occurs only in a small proportion
of patients with IHD.

PATHOGENESIS –
Insufficient coronary perfusion relative to myocardial demand.
Chronic progressive atherosclerotic narrowing of the epicardial coronary arteries and a variable
degree of superimposed acute plaque changes, thrombosis and vasospasm.

Chronic Atherosclerosis: >90% of patients with IHD have atherosclerosis of one or more of the
epicardial coronary arteries.
Fixed obstruction or acute plaque disruption with thrombosis which compromises blood flow.
A fixed lesion of >75% of the lumen is generally required to cause symptomatic ischaemia
precipated by exercise (angina). With this degree of obstruction, compensatory arterial
dilatation is no longer sufficient to meet the needs of myocardial demand.
Obstruction of >90% if the lumen can lead to even inadequate coronary flow at rest.
Slow development of occlusions may stimulate the development of collateral vessels over a
period of time.
Usually in the first several centimeters of the LAD and LCX and along the entire length of the
RCA.
Sometimes the major secondary epicardial branches are also involved.

Acute Plaque Change : Distribution, structure and degree of obstruction.

Acute coronary syndromes – unpredictable and abrupt conversion of a stable atherosclerotic
plaque to an unstable and potentially life threatening atherosclerotic lesion.
Occurs because of rupture, superficial erosion, ulceration, fissuring or deep hemorrhage.
The plaque change causes the formation of a superimposed thrombus that partially or
completely occludes the artery.
These acute lesions are often associated with intralesional inflammation.
Consequences of Myocardial Ischemia: Stable angina – increased myocardial oxygen demand
that outstrips the ability of the stenosed coronary arteries to increase delivery.
Unstable angina – Plaque rupture, partial thrombosis and vasoconstriction.
MI – Total thromoic occlusion and death of cardiac muscle.
SCD – Plaque causes regional myocardial ischemia

ANGINA PECTORIS –

Paroxysmal and usually recurrent attacks of substernal or precordial chest discomfort. That falls
short of inducing myocardial necrosis.
The three overlapping patterns are –
 Stable or typical angina
 Prinzmetals variant angina
 Unstable or crescendo angina.
Not all ischemic events are perceived by patients as in silent angina.
Stable Angina – Typical angina. Imbalance in coronary perfusion. Usually relieved by rest or
nitroglycerines.
Prinzmetals – Coronary artery spasm. Responds to vasodialators.
Unstable Angina – Increasingly frequent pain often of prolonged duration that is precipitated by
progressively lower levels of physical activity or that even occurs at rest. Disruption of
atherosclerotic plaque. Preinfarction angina.

MYOCADIAL INFARCTION –
Death of cardiac muscle due to prolonged ischemia.

Incidence and Risk factors: Age, male sex, Postmenopausal women.

Pathogenesis:
Coronary artery occlusion -
Sudden change in athreromatous plaque.
Subendothelial collagen and necrotic plaque contents are exposed. Adherence and
activation of platelets.
Formation of microthrombi.
Vasospasm
Release of tissue factor and addition to the bulk of the thrombus.
Luminal occlusion.
Resolution of the thrombus over a period of 12 to 24 hours.

If there is no occlusion possibilities are:

 Vasospasm
 Emboli from left atrium or paradoxical emboli.
 Vasculitis, hematological abnormalities, amyloid deposition in vascular wall, vascular
dissection, lowered systemic blood pressure, inadequate myocardial protection
during cardiac surgery.

Myocardial Response –

Coronary arterial occlusion compromises the blood supply to a region of the myocardium
causing ischemia, myocardial dysfunction and potential myocyte death.
Anatomical region is called the area of risk.
Severe ischemia induces loss of contractility in 60 seconds.
Can induce cardiac death.
Early changes are potentially reversible. Only severe ischemia lasting 20 to 30 minutes leads to
irreversible damage to the myocardium.
A key feature that marks the early phases of myocyte necrosis is the disruption of the integrity
of the sarcolemmal membrane that allows intracellular macromolecules to leak out of cells into
the interstitium and ultimately into the microvasculature and lymphatics.
Permanent damage to the heart occurs when the perfusion to the myocardium is severely
reduced for an extended period usually 2 to 4 hours.
Ischemia is most pronounced in the subendocardium. With increasing ischemia, a wavefront of
cell death moves through the myocardium to involve progressively more of the transmural
thickness.
Location, size and specific morphological features depend on:

Location, severity and rte of development

 Size of vascular bed.
 Duration
 Metabolic/ oxygen demands
 Extent of collateral blood vessels
 Presence, site and severity of coronary spasm.
 Heart rate, cardiac rhythm etc.

Dominant artery – Posterior 1/3 of the septum.

Transmual versus Subendocardial infarcts:
Usually transmural infarcts.
Subendocardial or nontransmural infarcts constitute and area of ischemic necrosis that is
limited to the inner 1/3 to ½ of the myocardial wall. Usually the subendocardial region. Occurs
if the clot becomes lysed before complete ischemia. Can also occur due to prolonged severe
reduction in systemic blood flow. Called St or non ST infarcts.
 Morphology:

Evolution of Morphologic Changes in Myocardial Infarction

Time Gross Features Light Microscope Electron Microscope

REVERSIBLE INJURY

0-½ hr None None Ralaxation of myofibrils;

glycogen loss;
mitochondrial swelling

IRREVERSIBLE INJURY

½-4 hr None Usually none; variable waviness of Sarcolemmal disruption;

fibers at border mitochondrial
amorphous densities

4-12 hr Dark mottling Early coagulation necrosis; edema;

(occasional) hemorrhage

12-24 hr Dark mottling Ongoing coagulation necrosis;

pyknosis of nuclei; myocyte
hypereosinophilia; marginal
contraction band necrosis; early
neutrophilic infiltrate

1-3 days Mottling with yellow-tan Coagulation necrosis, with loss of

infarct center nuclei and striations; brisk interstitial
infiltrate of neutrophils

3-7 days Hyperemic border; Beginning disintegration of dead

central yellow-tan myofibers, with dying neutrophils;
softening early phagocytosis of dead cells by
macrophages at infarct border

7-10 days Maximally yellow-tan Well-developed phagocytosis of

and soft, with depressed dead cells; early formation of
 red-tan margins fibrovascular granulation tissue at
margins

10-14 days Red-gray depressed Well-established granulation tissue

infarct borders with new blood vessels and collagen
deposition

2-8 wk Gray-white scar, Increased collagen deposition, with

progressive from border decreased cellularity
toward core of infarct

>2 mo Scarring complete Dense collagenous scar

About 0.1 mm of subendocardium is preserved.

Gross and microscopy depends on the survival of the patient post MI.
2 – 3 hours post infarct – Dip the tissue in triphenyl tetrazolium chloride. A brick red color
comes up in normal myocardium due to preserved LDH.
Wavy fibres occur due to forceful tug of the viable fibres
An additional sublethal change maybe seen at the margins of the infarct. Vacuolar degeneration
or myocytolysis which takes the form of large vacuolar space within cells that probably contain
water.
Healing occurs from the periphery towards the centre.
Infarcts may expend beyond their original boundaries over a period of days to weeks because
of repetitive necrosis of the adjacent regions – called extension.

Infarct modification by reperfusion – Reperfusion injury. Arrhythmias, myocardial hemorrhage,

microvascular injury, prolonged ischemic dysfunction called myocardial stunning.
Reperfusion salvages reversibly injured cells and also alters the morphology of lethally injured
cells.
Reperfusion injury maybe because of oxidative stress, calcium overload and potential
inflammation generated during reperfusion.
Causes endothelial swelling that occludes capillaries and may limit the reperfusion of the
critically injured myocardium.
Myocardium that is subjected to chronic sublethal ischemia may enter into a phase of lowered
metabolism called hibernation.
Preconditioning – repetitive short lived transient severe ischemia may protect the myocardium
against infarction.

Clinical Features –

Molecules include myoglobin, cardiac troponins T and I, the MB fraction of creatine kinase (CK-
MB), lactate dehydrogenase, and many others.
The rate of appearance of these markers in the peripheral circulation depends on several
factors, including their intracellular location and molecular weight, the blood flow and
lymphatic drainage in the area of the infarct, and the rate of elimination of the marker from the
blood.
The most sensitive and specific biomarkers of myocardial damage are cardiac-specific proteins,
particularly Troponins I and T (proteins that regulate calcium-mediated contraction of cardiac
and skeletal muscle). Troponins I and T are not normally detectable in the circulation. Following
an MI, levels of both begin to rise at 2 to 4 hours and peak at 48 hours.
Unchanged levels of CK-MB and troponin over a period of 2 days essentially excludes the
diagnosis of MI.

 Contractile dysfunction. Myocardial infarcts produce abnormalities in left ventricular

function roughly proportional to their size.
 Arrhythmias
 Myocardial rupture. The cardiac rupture syndromes result from softening and
weakening of the necrotic and subsequently inflamed myocardium. They include (1)
rupture of the ventricular free wall (most common), with hemopericardium and cardiac
tamponade); (2) rupture of the ventricular septum (less common), leading to an acute
VSD and left-to-right shunting); and (3) papillary muscle rupture (least common)
 Pericarditis.
 Right ventricular infarction.
 Infarct extension.
 Infarct expansion.
 Mural thrombus.
 Ventricular aneurysm.
 Papillary muscle dysfunction.
 Progressive late heart failure

In addition to the sequence of repair in the infarcted tissues described above, the noninfarcted
segments of the ventricle undergo hypertrophy and dilation; collectively, these changes are
termed ventricular remodeling.

CHRONIC IHD

The designation chronic IHD is used here to describe progressive heart failure as a consequence
of ischemic myocardial damage.
The term ischemic cardiomyopathy is often used by clinicians to describe chronic IHD.
Chronic IHD usually appears postinfarction due to the functional decompensation of
hypertrophied noninfarcted myocardium.
However, in other cases severe obstructive coronary artery disease may present as chronic IHD
in the absence of prior infarction.

Morphology:
Enlarged and heavy hearts with LV dilatation and hypertrophy.
Obstructive coronary atherosclerosis.
Discrete scars representing healed infarcts are present.
Mural endocardium may have patchy fibrous thickenings and mural thrombi maybe present.
Myocardial hypertrophy, diffuse subendocardial vacuolization and fibrosis.

The diagnosis rests largely on the exclusion of other cardiac diseases. Patients with chronic IHD
account for nearly half of cardiac transplant recipients.

SUDDEN CARDIAC DEATH

It is defined as unexpected death from cardiac causes in individuals without symptomatic heart
disease or early after symptom onset (usually within 1 hour).
SCD is usually the consequence of a lethal arrhythmia (e.g., asystole, ventricular fibrillation).
It most frequently occurs in the setting of IHD; in some cases, SCD is the first clinical
manifestation of IHD.

Nonatherosclerotic conditions associated with SCD include

 Congenital structural or coronary arterial abnormalities

 Aortic valve stenosis
 Mitral valve prolapse
 Myocarditis
 Dilated or hypertrophic cardiomyopathy
 Pulmonary hypertension
 Hereditary or acquired cardiac arrhythmias
 Cardiac hypertrophy of any cause (e.g., hypertension)
  Other miscellaneous causes, such as systemic metabolic and hemodynamic alterations,
catecholamines, and drugs of abuse, particularly cocaine and methamphetamine.

Morphology. Marked coronary atherosclerosis with a critical (>75%) stenosis

involving one or more of the three major vessels is present in 80% to 90% of SCD
victims; only 10% to 20% of cases are of nonatherosclerotic origin.
Usually there are high-grade stenoses (>90%); in approximately one half, acute
plaque disruption is observed, and in approximately 25% diagnostic changes of
acute MI are seen. This suggests that many patients who die suddenly are suffering
an MI, but the short interval from onset to death precludes the development of
diagnostic myocardial changes.
Most of these deaths are thought to result from myocardial ischemia-induced
irritability that initiates malignant ventricular arrhythmias.

Heritable conditions associated with SCD are of importance, since they may provide a basis for
intervention in surviving family members.