Emboli Paru

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO.
6, 2022
ª 2022 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
STATE-OF-THE-ART REVIEW
Latent Causes of Sudden Cardiac Arrest

Andrew D. Krahn, MD,a Jacob Tfelt-Hansen, MD, DMSC,b,c Rafik Tadros, MD, PHD,d Christian Steinberg, MD,e
Christopher Semsarian, MBBS, PHD, MPH,f Hui-Chen Han, MBBS, PHDa,g
ABSTRACT
Inherited arrhythmia syndromes are a common cause of apparently unexplained cardiac arrest or sudden cardiac death.
These include long QT syndrome and Brugada syndrome, with a well-recognized phenotype in most patients with suf-
ficiently severe disease to lead to cardiac arrest. Less common and typically less apparent conditions that may not be
readily evident include catecholaminergic polymorphic ventricular tachycardia, short QT syndrome and early repolari-
zation syndrome. In cardiac arrest patients whose extensive testing does not reveal an underlying etiology, a diagnosis of
idiopathic ventricular fibrillation or short-coupled ventricular fibrillation is assigned. This review summarizes our current
understanding of the less common inherited arrhythmia syndromes and provides clinicians with a practical approach to
diagnosis and management. (J Am Coll Cardiol EP 2022;8:806–821) © 2022 by the American College of Cardiology
Foundation.
I nherited arrhythmia syndromes are an important

cause of unexplained cardiac arrest and sudden
cardiac death (SCD). In this series, we have dis-
cussed primary electrical conditions such as long QT
INITIAL APPROACH TO RESUSCITATED
CARDIAC ARREST
In patients who present with resuscitated cardiac

syndrome and Brugada syndrome, and arrhythmo- arrest, the initial evaluation should look to exclude
genic cardiomyopathy which has a predominant recognized conditions, with various approaches be-
arrhythmic presentation. 1-3 In this review, we ing proposed. 4-8 First-line care of the cardiac arrest
present a framework for the overall diagnostic evalu- patient typically identifies coronary artery disease or
ation of patients after an episode of resuscitated car- left ventricular dysfunction in up to 90% of patients. 9
diac arrest, and discuss the less common or Though beyond the scope of this review,
“latent” causes of cardiac arrest (Central Illustration, potential latent structural causes of cardiac arrest
Table 1). A systematic approach is paramount for including myocarditis, cardiac sarcoid, coronary
screening, of the affected individual, and also family anomalies, and mitral valve prolapse should also be
members. excluded.4,10,11
From the aCenter for Cardiovascular Innovation, Heart Rhythm Services, Division of Cardiology, University of British Columbia,
Vancouver, British Columbia, Canada; bThe Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rig-
shospitalet, Copenhagen, Denmark; cDepartment of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen,
d
Copenhagen, Denmark; Cardiovascular Genetics Center, Montreal Heart Institute, Department of Medicine, Université de
Montréal, Montreal, Québec, Canada; eInstitut universitaire de cardiologie et pneumologie de Québec (IUCPQ-UL), Laval Uni-
versity, Inherited Arrhythmia Services, Départment of Cardiology and Cardiac Surgery, Québec, Canada; fAgnes Ginges Centre for
Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; and the gVictorian
Heart Institute, Monash University, Clayton, Victoria, Australia.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received August 27, 2021; revised manuscript received December 9, 2021, accepted December 29, 2021.
ISSN 2405-500X/$36.00 https://doi.org/10.1016/j.jacep.2021.12.014

JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022 Krahn et al 807
JUNE 2022:806–821 Latent Causes of Sudden Cardiac Arrest
In our experience, application of this ABBREVIATIONS

HIGHLIGHTS AND ACRONYMS
framework will allow for identification of the
Recently, there have been significant most common inherited arrhythmia syn-
CPVT = catecholaminergic
advances in our understanding of other- dromes. These include more common condi- polymorphic ventricular
wise unexplained cardiac arrest. tions such as long QT syndrome, Brugada tachycardia
syndrome, and arrhythmogenic cardiomyop- ECG = electrocardiogram

This review provides practical recom-
athy, which have been previously described, ERP = early repolarization
mendations for the evaluation of patients
and the less common conditions such as pattern
after resuscitated cardiac arrest.
catecholaminergic polymorphic ventricular ERS = early repolarization
Further research is required to under- tachycardia (CPVT), short QT syndrome syndrome
(SQTS), early repolarization syndrome (ERS), ICD = implantable

stand the underlying pathophysiology of
cardioverter-defibrillator
idiopathic ventricular fibrillation. and short-coupled ventricular fibrillation
PVC = premature ventricular
(SCVF) described in this review.
complex
In-hospital evaluation should include a detailed
SCD = sudden cardiac death
clinical history encompassing circumstances of car- CATECHOLAMINERGIC POLYMORPHIC
SCVF = short-coupled
diac arrest including documentation of arrhythmia VENTRICULAR TACHYCARDIA ventricular fibrillation
from an automated external defibrillator (where SQTS = short QT syndrome
available), prior episodes of syncope or presyncope CPVT is a genetic condition whereby disor- VF = ventricular fibrillation
(and associated circumstances), substance history, 12 dered intracellular Ca 2þ handling results in
VT = ventricular tachycardia
and pertinent family history (Table 2). 13 Impor- catecholamine-triggered episodes of malig-
tantly, drug overdose (such as opiates) may result in nant ventricular arrhythmias.
cardiac arrest, although the arrhythmic contribution
to these events is yet to be established. 14 Relevant PATHOPHYSIOLOGY. Under normal circumstances,
inpatient investigations are repeated 12-lead electro- cardiomyocyte depolarization leads to opening of L-
cardiogram (ECG), high-lead ECG for Brugada pattern, type calcium channels with a resultant influx of Ca 2þ
bloodwork including electrolytes and cardiac en- during phase 2 of the cardiac action potential
zymes, coronary assessment, echocardiogram, and (Figure 1).20 The influx of Ca 2þ binds to the ryanodine
cardiac magnetic resonance imaging in those with receptor 2 (RYR2), causing further release of Ca2þ
non-ischemic cardiac arrest. Repeated 12-lead ECG is from the sarcoplasmic reticulum in a process termed
particularly important as a prolonged QTc shortly calcium-induced calcium release. 20 Various other
after resuscitated cardiac arrest may not necessarily proteins are important in this process, including cal-
represent underlying long QT syndrome. 15,16 Addi- sequestrin 2 (CASQ2, which binds to cytosolic Ca 2þ
tional testing depending on initial workup results can within the sarcoplasmic reticulum), triadin (TRDN,
be arranged after patient discharge, and should which anchors CASQ2 to RYR2), and calmodulin
include provocation testing (exercise testing and so- (CALM, which binds to both RYR2 and L-type calcium
dium channel blocker challenge), Holter monitoring channel, regulating sensitivity to Ca 2þ levels).21,22
(if implantable cardioverter-defibrillator [ICD] is not This intracellular cytosolic increase in Ca2þ results
inserted) and possibly signal-averaged ECG. In in myocyte contraction, which is a critical component
conjunction with a genetics expert, targeted or broad of excitation–contraction coupling.20,21
cardiac panel genetic testing may be considered in Dysregulation of intracellular Ca 2þ handling is
the workup of patients with resuscitated cardiac ar- central to the development of CPVT, with the net ef-
rest.17,18 Further discretionary testing may be sought fect being an increase in intracellular Ca2þ. This could
in certain instances, such as epinephrine test in pa- be due to a propensity for RYR2 to inappropriately
tients who are unable to exercise, provocation testing release Ca2þ from the sarcoplasmic reticulum or an
for coronary artery spasm, and electrophysiology inability for CASQ2 to adequately sequester Ca 2þ
study for identification of electroanatomical triggers within the sarcoplasmic reticulum.20-22 The increase
and substrate abnormalities. It is important to in intracellular Ca2þ activates the sodium-calcium
consider an inclusive testing strategy to gather exchanger, resulting in intracellular Na þ influx and
“clues” to latent diagnoses, bearing in mind the lim- extracellular Ca2þ efflux. 23 This Naþ influx leads to
8,19
itations of many of our tests, such as limited cell membrane activation after an action potential has
specificity of signal-averaged ECG or electrophysi- already occurred, causing delayed after-de-
ology study. polarizations, 21 which can result in premature
808 Krahn et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022
Latent Causes of Sudden Cardiac Arrest JUNE 2022:806–821
C E NT R AL IL L U STR AT IO N Clinical Approach to Latent Causes of Sudden Cardiac Arrest
Krahn AD, et al. J Am Coll Cardiol EP. 2022;8(6):806–821.
*Refer to other papers in the series for additional information (Krahn et al1-3). AED ¼ automated external defibrillator; ARVC ¼ arrhythmogenic right ventricular
cardiomyopathy; BrS ¼ Brugada syndrome; CPVT ¼ catecholaminergic polymorphic ventricular tachycardia; ECG ¼ electrocardiogram; EP ¼ electrophysiology;
ERP ¼ early repolarization pattern; ERS ¼ early repolarization syndrome; ICD ¼ implantable cardioverter-defibrillator; LCSD ¼ left cardiac sympathetic denervation;
LQTS ¼ long QT syndrome; MRI ¼ magnetic resonance imaging; PVC ¼ premature ventricular complex; SAECG ¼ signal-averaged electrocardiogram; SCB ¼ sodium
channel blocker; SCVF ¼ short-coupled ventricular fibrillation; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.
ventricular complexes (PVCs) and trigger malignant (which plays an important role in calcium
ventricular arrhythmias.23 Adrenergic stimulation is handling).32,33
thought to potentiate sarcoplasmic/endoplasmic re-
ticulum Ca 2þ ATPase–mediated Ca 2þ reuptake within EPIDEMIOLOGY. The prevalence of CPVT is esti-
the sarcoplasmic reticulum and enhance responsive- mated to be w1:10,000,34 with an equal sex distri-
ness of RYR2, leading to the overload of Ca 2þ
within bution. 35,36 Most index patients are diagnosed in later
the sarcoplasmic reticulum coupled with sponta- childhood or adolescence, typically between 10 and 12
neous Ca2þ release,21,22 resulting in the clinical years. 35,36 CPVT is thought to account for up to 10% of
phenotype of adrenergic induced ventricular cases with “unexplained” cardiac arrest (after exclu-
arrhythmias. sion of coronary artery disease or overt structural
Genetic variants in RYR2 and CASQ2 are the most disease).4,37 CPVT may be even more prevalent in
commonly found in CPVT, accounting for 50% to 60% cases of unexplained SCD, whereby w15% of families
of clinical cases. 24 In general, gain-of-function vari- of unexplained SCD victims are found to have
ants in RYR2 result in an autosomal dominant form of CPVT.38
25-27
CPVT and loss-of-function variants in CASQ2 DIAGNOSIS. The classic clinical manifestation of
result in an autosomal recessive form of CPVT, 28,29 CPVT is stress (exercise or emotional) induced syn-
although deviations from this are described, cope or cardiac arrest, 39,40 although up to 25% of
including an autosomal dominant form of CASQ2- episodes are reported to occur in the setting of normal
related CPVT.30,31 Less common genetic substrates activity. 36 Based on earlier cohorts, w30% are diag-
for CPVT include variants in TRDN (encoding for tri- nosed after an episode of resuscitated cardiac arrest,
adin), CALM (encoding calmodulin), and TECRL and an additional 50% will have had syncope.41,42 At
T A B L E 1 Diagnosis and management summary for latent causes of sudden cardiac arrest
Latent Causes of Cardiac Arrest
Resuscitated Cardiac Arrest & Idiopathic Ventricular Fibrillation
Inpatient Management Further Management
Clinical history Additional testing

Circumstances of cardiac arrest Signal-averaged ECG
History and circumstances of cardiogenic syncope Holter monitoring (12-lead if possible)
Family history of SCD Exercise stress test
Investigations Sodium channel blocker provocation
ECG (including 12-lead, high-lead and AED rhythm strip) Genetic testing
Cardiac telemetry Discretionary testing
Coronary assessment Coronary spasm provocation
Echocardiogram Epinephrine provocation
Cardiac MRI EP study electro-anatomical mapping
Management Re-evaluation
Secondary prevention ICD Every 2-3 years for probands for changes in phenotype and in the setting of
Medical therapy directed by diagnostic results evolving understanding of IVF
Family screening
First-degree relatives if identified cause in proband OR in those with suspicious
cardiogenic symptoms
Other Recognized Syndromes
CPVT SQTS ERS SCVF
Diagnosis Diagnosis Diagnosis Diagnosis

Stress (physical or emotional) Baseline QTc #330ms ERP ECG in patient with other- Patient with documented VF or
induced syncope or cardiac arrest Baseline QTc #360ms in patient wise unexplained cardiac arrest polymorphic VT which is initi-
Bidirectional PVCs during exer- with otherwise unexplained car- ERP ECG in patient with other- ated by a PVC with a coupling
cise testing diac arrest OR pathogenic gene wise unexplained SCD (retro- interval <350ms
Pathogenic variant in RYR2 or variant carrier OR suspicious spectively identified) Absence of other conditions
CASQ2 gene family history Management Management
Management Management Avoid hypothermia and Secondary prevention ICD
Avoid competitive sports and Medical therapy with quinidine b-blockers Medical therapy with quinidine
strenuous exercise may be considered Secondary prevention ICD may be effective in patients
b-blockers in all patients Secondary prevention ICD Primary prevention ICD not with breakthrough events
Flecainide if breakthrough events Primary prevention ICD may be indicated Catheter ablation may be
despite b -blocker therapy considered in patients with SQTS Medical therapy (isoproterenol/ considered for those with
LCSD and/or ICD if breakthrough who have non-sustained VT or quinidine) or catheter ablation breakthrough events despite
events despite medical therapy cardiogenic syncope may be effective in patients with medical therapy
Primary prevention ICD not breakthrough events
indicated
AED ¼ automated external defibrillator; CPVT ¼ catecholaminergic polymorphic ventricular tachycardia; EP ¼ electrophysiology; ERP ¼ early repolarization pattern; ERS ¼ early repolarization syndrome;
ICD ¼ implantable cardioverter defibrillator; IVF ¼ idiopathic ventricular fibrillation; LCSD ¼ left cardiac sympathetic denervation; MRI ¼ magnetic resonance imaging; PVCs ¼ premature ventricular
complexes; SCD ¼ sudden cardiac death; SQTS ¼ short QT syndrome; VT ¼ ventricular tachycardia.
the time of diagnosis w20% of patients are asymp- Recently, it has been proposed that a burst exercise
tomatic, 42 however this is likely to increase with testing protocol may increase the sensitivity for
broader access to genetic testing and an emphasis on diagnosis of CPVT compared with standard exercise
cascade screening. testing,47 although further validation studies are
The baseline ECG in CPVT is often normal, aside required. Burst testing should be considered in pa-
from a preponderance for sinus bradycardia, 43 as are tients with exertional syncope or cardiac arrest if
other electrophysiological tests, including signal- standard exercise testing is nondiagnostic.
averaged ECG and programmed ventricular Pharmacologic provocation testing with intrave-
stimulation.44 nous epinephrine may also induce ventricular ar-
The pathognomonic feature of CPVT is exercise- rhythmias in patients with CPVT. However, this is
induced polymorphic ventricular arrhythmias, espe- associated with a lower diagnostic sensitivity 44,48 and
cially bidirectional ventricular tachycardia (VT) should not replace the use of exercise testing. In
(Figure 2).44 In a group of 67 asymptomatic relatives those who are unable to exercise, pharmacologic
of patients with CPVT, Hayashi et al45 found that testing should be considered.
exercise testing (positive result being induction of In index patients who manifest a clinical CPVT
ventricular bigeminy, couplets, or VT) produced a phenotype, genetic testing is recommended, as this
sensitivity of 50% and specificity of 97%. Patients may allow for variant-specific cascade testing for
with CPVT may also have more frequent exercise- family members. Family members who carry a path-
induced PVCs,46 although this finding would be ogenic or likely pathogenic variant should undergo
associated with a lower specificity for diagnosis. detailed phenotypic evaluation, including
Pharmacotherapy with b-blockers is recommended

T A B L E 2 Relevant Clinical History in “Unexplained”
Cardiac Arrest
in all patients who exhibit a clinical CPVT phenotype
and may be considered in those with concealed CPVT
Clinical History Relevant Information
(genotype positive, phenotype negative). 34 In a
Circumstances of Physical exertion (LQT1, ARVC, CPVT)
cardiac arrest or Emotional stress cohort of 101 patients with CPVT, Hayashi et al56
syncope Startle (LQT2) found that absence of b-blockers was independently
Fever (BrS)
Rest (BrS, ERS, SCVF) associated with a 5-fold risk increase of significant
Vagal stimulation (exclude vasovagal arrhythmic events. Where possible, nonselective b -
syncope)
blockers (nadolol and propranolol) are preferred.
Additional history Exercise level (ARVC, CPVT)
Seizures (LQTS) Leren et al 57 showed that compared with no therapy,
Substance history Proarrhythmic medications nadolol reduces the severity of exercise induced
Illicit or recreational drugs
ventricular arrhythmias, whereas no difference was
Alcohol
Drugs that prolong QT seen with metoprolol. Adherence is important
Drugs that may induce Brugada
because most cardiac events after diagnosis are re-
Family history Sudden death with autopsy reports if
available ported in the setting of nonadherence.42,58 Of note,
Circumstances of events in family adequate treatment with b-blockers is considered
members
Unexplained drownings safe during pregnancy, and effective for minimizing
Drivers in motor vehicle accidents cardiac events while pregnant.59
Flecainide is an effective adjunct in patients who
ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; BrS ¼ Brugada syn-
drome; LQTS ¼ long QT syndrome; SCVF ¼ short-coupled ventricular fibrillation; experience breakthrough events or continue to have
other abbreviations as in Table 1.
complex ventricular arrhythmias on exercise testing
despite optimal b -blocker therapy. 42,60-64 In a small,
randomized control trial, Kannankeril et al 65 showed
that flecainide and b -blocker combination therapy
assessment for syncope and exercise testing.
was more effective than b-blocker alone in reducing
Currently, we would consider likely pathogenic and
exercise induced ventricular arrhythmias, indicating
pathogenic variants in RYR2, CASQ2, TRDN, TECRL,
a possible role for early combined pharmacotherapy.
CALM1, CALM2, and CALM3 to be disease-causing in
32,49,50 There is also limited evidence suggesting a role for
CPVT.
flecainide monotherapy in patients who are truly
MANAGEMENT. Due to the preponderance of re- intolerant of b-blockers. 42,60-64 On a cellular level,
ported cardiac events (including syncope and cardiac flecainide is thought to exert its effect on Naþ chan-
arrest) during exertion,42 assessment in a specialized nels and/or due to a direct effect on RYR2.66-68 In
cardiogenetic clinic and expert opinion are required patients requiring additional therapeutic escalation,
with regard to recommendations for physical exer- verapamil may be effective.69
cise. Although competitive sports and strenuous In addition, left cardiac sympathetic denervation
physical exercise harbor an increased risk of ventric- should be considered in those who experience
ular arrhythmia, recent recommendations have shif- breakthrough cardiac events despite optimization
ted from general restriction to a more individualized and escalation of pharmacotherapy.70,71 Left cardiac
approach focusing on shared decision-making.51,52 sympathetic denervation is effective for reducing
Limited real-world data indicate that ongoing ath- cardiac events and ICD shocks.72
letic participation in patients with CPVT does not The current role for ICD in patients with CPVT is
result in more cardiac events compared with non- contentious. Although conventionally recommended
athletes.53 Patients are also advised to limit potential for patients who have experienced a cardiac arrest
exposures to emotional stress where possible.34,42 event,34 ICD complication rates are particularly high
Evidence for these recommendations is lacking, and in CPVT cohorts. 73 In a recent multicenter interna-
ongoing moderate-level exercise in well-treated pa- tional study of 136 CPVT patients diagnosed after an
tients may offer overall cardiovascular benefits. It has episode of cardiac arrest (and were thus treatment
been shown that graduated exercise training in mice naive), van der Werf et al74 found that ICD insertion
54
may protect against arrhythmic events in CPVT, was associated with a high complication rate
whereas exercise training in humans has been (including inappropriate shocks and lead malfunc-
shown to improve aerobic capacity and increase the tion), but was not associated with a reduction in
heart rate threshold required for the development of subsequent SCD events. Based on the current avail-
PVCs.55 Thus, our understanding regarding the role of able data, we would recommend against the use of a
exercise restriction in CPVT is still evolving. primary prevention ICD in patients with CPVT. In
F I G U R E 1 Schematic Representation of IC Calcium Homeostasis
CALM ¼ calmodulin; CASQ2 ¼ calsequestrin; EC ¼ extracellular; IC ¼ intracellular; LTCC ¼ L-type calcium channel; NCX ¼ sodium calcium
exchange; PM ¼ plasma membrane; SR ¼ sarcoplasmic reticulum; TRDN ¼ triadin.
untreated patients who experience a cardiac arrest, a Several emerging treatments show promise in
shared decision-making discussion is warranted. In CPVT. Preliminary studies indicate that modulation
principle, refraining from ICD implantation warrants of sinus rate with atropine or atrial overdrive pacing
consideration despite the secondary prevention is beneficial in reducing exercise induced ventricular
context, because of the efficacy of medical therapy arrhythmias. 79,80 Although the exact mechanism is
and left cardiac sympathetic denervation, and the unclear, it is hypothesized that an increase in sinus
risks of ICD in this typically young population. In rate shortens the subsequent diastolic interval,
patients who are adequately managed on pharmaco- thereby reducing the likelihood of spontaneous SR
therapy, but experience a cardiac arrest event, a Ca 2þ release, which in turn triggers ventricular
secondary prevention ICD is recommended. In such ectopy.80 Molecular therapies offer an exciting pros-
cases, left cardiac sympathetic denervation should pect for a potential “cure” in CPVT. Adeno-associated
also be considered. ICD programming parameters in viral vector serotype 9 gene transfer has successfully
patients with CPVT should consider that treatment of reversed both molecular changes and clinical pheno-
initiating rhythms (bidirectional VT or polymorphic type in murine models of CPVT,81-86 and more
75,76
VT) is rarely successful therefore delayed detec- recently in a human induced pluripotent stem cell
tion with a single ventricular fibrillation (VF) zone model of CPVT.86 Other options in development
programming is recommended. include mitochondrial Ca2þ uptake enhancers87 and a
fungal RYR2 antagonist. 88
FUTURE DIRECTIONS. Our genetic understanding of
CPVT is incomplete, as approximately one-third of
SHORT QT SYNDROME
clinical cases are not associated with an identifiable
genetic variant. The relatively recent recognition of
SQTS is a very rare condition characterized by
TRDN, CALM, and TECRL gene variants as disease
arrhythmic events in the setting of a short QT
causing should prompt efforts for the identification
interval.
and association of variants in other Ca2þ handling
proteins in the pathophysiology of CPVT. Further- PATHOPHYSIOLOGY. The pathophysiologic basis of
more, recent work demonstrating polygenic in- SQTS is thought to be related to abbreviation of the
fluences in other inherited arrhythmia syndromes77,78 cardiac action potential duration, most commonly
may be translatable to patients with CPVT. from gain-of-function variants in potassium
F I G U R E 2 ECG Examples of “Latent” Cardiac Arrest Conditions
CPVT ¼ catecholaminergic polymorphic ventricular tachycardia; ECG ¼ electrocardiogram; ERS ¼ early repolarization syndrome; SC-VF ¼ short-
coupled ventricular fibrillation; SQTS ¼ short QT syndrome.
channels.89 Within published reports, a gene variant ventricular),95 with subsequent arrhythmogenicity
90
is identified in up to 50% of reported cases of SQTS, affecting the atrium and ventricle. In addition, vari-
and most frequently affect KCNH2 (SQT1), KCNQ1 ants affecting ion transporters 97-99 are also reported
90,91
(SQT2), KCNJ2 (SQT3), and SLC4A3. The most to result in clinical SQTS.
common variant is KCNH2, encoding for the delayed EPIDEMIOLOGY. SQTS is a rare condition, and the
rectifier potassium channel KV 11.1,92 resulting in true prevalence is unknown. A recent systematic re-
greater outward potassium current (I Kr ) during phase view identified a total of 145 published cases of
3 of the action potential. Increased I Kr density causes SQTS. 90 In cohort studies of patients with resusci-
shortening of the action potential duration 93-96 with tated cardiac arrest and/or SCD, there have been no
impaired heart rate adaptation,94-96 shortening of the reported cases of SQTS.4,37,38 Of note, atrial arrhyth-
effective refractory period (both atrial and mias are reported in w20% of patients with SQTS.90
F I G U R E 3 Early Repolarization Patterns
Top ECG shows “malignant” early repolarization in a patient post cardiac arrest. There is J-point elevation, followed by a horizontal ST segment (inset). Bottom ECG
shows “benign” early repolarization in a screening ECG. There is J-point elevation followed by upsloping ST segment (inset). Note that the ST segment is measured
100 ms from the terminal portion of the J-point (arrow). ECG ¼ electrocardiogram.
DIAGNOSIS. Clinical manifestations of SQTS include Other changes that have been reported in patients
cardiac arrest or SCD, cardiogenic syncope, and atrial with SQTS include less QTc variation during exercise
arrhythmias.90,100,101 Based on current reports, w40% ECG, 109 functional left ventricular abnormalities, 110
90
of patients in SQTS registries are asymptomatic, and abbreviation of both atrial and ventricular effec-
although this number would be significantly higher tive refractory periods during electrophysiological
if population screening cases were included. study. 111 However, further validation of these pa-
A QTc #330 ms on baseline ECG (Figure 2) confers a rameters is required. A potentially interesting
diagnosis of SQTS,34,102 although a cutoff of #315 ms consideration is that patients with SQTS may have
has been suggested in children.103 Currently, the failure of QT-interval prolongation during periods of
Bazett correction is proposed, 102 although consensus bradycardia, in a similar vein to those with long QT
is lacking. 104 Using a cutoff of QTc #330 ms, the syndrome exhibiting maladaptive QTc responses
prevalence of SQTS within general population– during exercise and recovery,112 so resting and
screening ECG studies ranges between 0% and nocturnal monitoring is likely the optimal mechanism
0.2%,104-108 with generally favorable outcomes in to detect failed QT prolongation.
these cases in the absence of other cardiac abnor-
malities.105-108 In survivors of unexplained cardiac MANAGEMENT. Quinidine, and its related compound
arrest, or those who carry a pathogenic gene variant hydroquinidine, is useful in the pharmacologic man-
or have a suspicious family history, a QTc #360 ms agement of SQTS. 113,114 Quinidine has complex anti-
may confer a diagnosis of SQTS. 34 arrhythmic properties. Although categorized as a
class 1a agent,115 thereby prolonging phase 0 of the arrhythmogenesis. 134 Genetic variants encoding for
action potential, quinidine is also known to inhibit sodium and potassium channels are reported in as-
potassium currents throughout the duration of the sociation with clinical cases of ERS,135-137 although
action potential and I CaL during phase 2 of the action this link remains tenuous.
potential. 116 Mechanistically, it is thought that inhi- EPIDEMIOLOGY. The ERP ECG was initially described
bition of I Kr is important in the antiarrhythmic effect in 1936 by Shipley and Hallaran, 138 and for a long
of quinidine in SQTS. 117 On a cellular level, this re- period thereafter, was thought to be a benign
sults in prolongation of the action potential duration phenomenon. 139,140
and effective refractory period, 117-119 clinically trans- In 2008, an international collaborative study by
lating to lengthening of the QT interval and sup- Haïssaguerre et al141 found that ERP was significantly
pression of ventricular arrhythmias.113,114 The side more prevalent in 206 patients with otherwise idio-
effect profile of quinidine is significant,114 and its use pathic VF (31%) compared with 412 control subjects
is limited due to a lack of drug availability. 120,121 (5%). Contemporaneously, similar findings were
Other potential pharmacotherapy options in SQTS shown by Rosso et al,142 and a high prevalence was
include disopyramide,117,122 ivabradine,123,124 mex- verified in a registry of patients with cardiac arrest
iletine, 124,125 and ajmaline, 124 although clinical expe- without manifest coronary or structural disease. 143
rience is limited. In general, pharmacotherapy is Thus, within a cardiac arrest cohort, the prevalence
reserved for symptomatic patients with SQTS. of ERP is w30%.141-144 Interestingly, the presence of
Similarly, there are few reports regarding the use of ERP within cohorts of patients with an established
ICD in patients with SQTS.126,127 In patients with SQTS primary arrhythmic syndrome such as long QT syn-
and a history of cardiac arrest, a secondary preven- drome,145 Brugada syndrome,146,147 CPVT,148 or
34
tion ICD is indicated. A transvenous ICD with atrial SQTS 149
has been reported to be associated with
pacing capability may theoretically protect from worse outcomes.
bradycardia-induced ventricular arrhythmia. Inap- By contrast, the prevalence of ERP within the
propriate therapies due to T-wave oversensing may general population is w5% 150 being more common in
be more prevalent in patients with SQTS.127,128 In young males, athletes, 142 and African Americans. 151
those with SQTS and nonsustained VT or cardiogenic Although the presence of ERP appears to be associ-
syncope, it is reasonable to engage patients in a ated with an increased risk of cardiovascular mortal-
shared decision-making process regarding a primary ity,151,152 its significance is questionable when
prevention ICD. Currently, there is no role for the use adjusting for factors such as age, sex, and race. 151
of a primary prevention ICD in asymptomatic patients
DIAGNOSIS. Currently, the diagnosis of ERS is only
with SQTS.
made in the presence of an ERP ECG in a patient with
EARLY REPOLARIZATION SYNDROME resuscitated cardiac arrest due to documented VF or
polymorphic VT with no other attributable cause; or
ERS is a diagnosis of exclusion involving the presence post-mortem in someone with SCD, negative autopsy,
of an early repolarization pattern (ERP) ECG in an and retrospective recognition of an ERP ECG.34 The
individual with resuscitated cardiac arrest or SCD, in ERP ECG is defined as the presence of J-point eleva-
the absence of another identifiable cause. This is an tion (end-QRS notch on the downslope of a prominent
important distinction compared with other primary R-wave) $1 mm involving $2 leads (excluding V 1 to
arrhythmic conditions (such as long QT syndrome or V 3), where the QRS duration is <120 ms
Brugada syndrome) whereby a clinical event is (Figure 2).141,153-155 It is proposed that the ST segment
required for the diagnosis of ERS. following the terminal portion of the J-point may
indicate “malignant” or “benign” early repolarization
PATHOPHYSIOLOGY. The pathophysiological under-
(Figure 3)—malignant if the ST segment is down-
standing of ERS is incomplete. It has been proposed
sloping or flat, and benign if the ST segment is
that increased transient outward potassium current
129,130 upsloping154 —although further validation is required.
(I to ) is a central mechanism. Owing to heterog-
Although the ERP may fluctuate, there is currently no
enous changes in epicardial I to, there is localized
131 validated provocation test for ERP.
phase 2 re-entry. Clinically, this is manifest
as fractionated epicardial electrograms localized MANAGEMENT. The management modalities described
to the areas of J-waves with shortening of the in the following text are for patients with ERS rather
action potential duration and the occurrence of than asymptomatic individuals with ERP ECG. In
PVCs.132,133 Recently, localized epicardial fibrofatty asymptomatic individuals with ERP ECG, we would
changes have been proposed to contribute to advocate for reassurance only.
Conservative measures that may be useful include prevalence is largely undefined. An initial report from
avoidance of hypothermia, correction of electrolyte CASPER (Cardiac Arrest Survivors With Preserved
disturbances, and avoidance of b-blockers, although Ejection Fraction Registry) suggests SCVF accounts
evidence for these recommendations are primarily for at least 6% of unexplained cardiac arrest
from case reports. Hypothermia, which may be survivors. 166
spontaneous or initiated in the post-cardiac arrest
DIAGNOSIS. Currently, the diagnosis of SCVF is
care pathway, is reported to induce VF in ERS.156,157
made in patients with documented VF (or poly-
In addition, hypokalemia may also precipitate VF, 158
morphic VT) that is initiated by a PVC with a coupling
whereas b-blockers can accentuate ECG changes in
interval <350 ms (Figure 2).166,173-175 Additional
patients with ERP.159
markers of a short-coupled PVC include a prematurity
Pharmacotherapy options in ERS include isopro-
index (ratio of coupling interval to previous RR in-
terenol,159,160 quinidine,161 cilostazol,160,162 and so-
terval) of #0.4,174 which usually occurs within 40 ms
dium channel blockers.163,164 Mechanistically, it is
of the peak of the preceding T wave.174 Because
proposed that inhibition of I to and augmentation of
documentation of a PVC coupling interval is required,
I CaL are important in reversing the repolarization de-
the diagnosis of SCVF is made almost exclusively in
fects. 160 The evidence for pharmacotherapy is
patients with recurrent VF captured during initial
limited, arising from small observational studies, and
hospitalization or in follow-up on an ICD.166
currently do not obviate the need for a secondary
prevention ICD in those with ERS. MANAGEMENT. Patients with SCVF may be more
A secondary prevention ICD is indicated in patients susceptible to electrical storm compared with other
with ERS. Furthermore, catheter ablation of VF trig- patients with unexplained cardiac arrest. 166 Medical
gers may be considered in patients with ERS and therapy with quinidine may be effective as first-line
recurrent VF. These triggers are reported within the therapy in patients with recurrent VF.166 Catheter
165
right ventricular outflow tract or Purkinje cells. ablation of PVC triggers may be considered if episodes
persist despite optimized medical therapy. 170,171,176
SHORT-COUPLED VF These triggers have been reported to occur in
various locations, including the Purkinje sys-
SCVF is used to describe patients with VF that is tem,170,171 anterior right ventricle,170,171 and right
initiated by PVCs with a short coupling interval. Of ventricular outflow tract.175,177
note, SCVF appears to consist of a distinct subset of
patients who were previously described to have OTHER ENTITIES
idiopathic VF.166
Genetic variants in CALM predominantly manifest as
PATHOPHYSIOLOGY. The pathophysiological basis
long QT syndrome or CPVT.178 Recently, CALM vari-
of SCVF is largely undefined, although it is postulated
ants have been associated with idiopathic VF.179-181 In
that overactive Purkinje fiber I to plays an important
a cohort of 74 patients carrying CALM1, CALM2, or
role,167 thereby providing mechanistic overlap with
CALM3 variants, the International Calmodulin Reg-
Brugada syndrome and early repolarization syn-
istry reported that w15% of cases presented with
drome.166 Increased function of dipeptidyl-peptidase
idiopathic VF or SCD.178
6, encoded by the DPP6 gene, may lead to SCVF in
Bundle branch re-entry VT is a macro-reentrant
some patients through an increase in Ito .168 However,
arrhythmia involving the left and right bundle
this exploratory gene is predominantly described in
branches, which may result in cardiac arrest. 182
the Dutch founder population,168,169 and a genetic
Although most commonly occurring in association
basis for SCVF requires further elucidation. Electro-
with cardiomyopathy or ischemic heart disease,183 it
physiological observations in this patient cohort in-
is also reported in those without evidence of struc-
dicates that Purkinje system PVCs in conjunction with
tural heart disease. 184,185 Recently, it is suggested
localized structural changes are important in the
that bundle branch re-entry VT in the absence of
development of VF. 170-172
structural heart disease may have an underlying ge-
EPIDEMIOLOGY. In 1994, Leenhardt et al 173 described netic etiology.186
a cohort of patients with torsade de pointes and VF Finally, widespread and persistent ST-segment
that was initiated by a short-coupled PVC. However, depression has been reported in families with other-
only recently has SCVF been recognized as a distinct wise unexplained cardiac arrest that appears to be
clinical phenotype in patients with otherwise unex- inherited in an autosomal dominant manner, but
plained cardiac arrest, meaning that its true without identification of a candidate gene. 187
IDIOPATHIC VF Furthermore, genetic influences in cases of idio-

pathic VF could be pivotal. Monogenic variants in
In patients where extensive evaluation does not SCN5A and IRX3 (iroquois homebox, a Purkinje system
reveal an underlying etiology, a diagnosis of idio- transcription factor) are reported to cause Purkinje
pathic VF is assigned. Importantly, this definition is origin PVCs and SCD,199,200 whereas loss-of-function
5
evolving as more conditions are identified. RYR2 variants may cause a distinct VF phenotype
The prevalence of idiopathic VF varies depending coined the calcium release deficiency syndrome.201
on the inclusion criteria of patients, and extent of Consequently, it may become apparent that oligo-
investigations. Based on a large all-inclusive registry genic or polygenic influences may account for a pro-
of cardiac arrest patients, which included older pa- portion of the current cohort of idiopathic VF patients,
tients with coronary artery disease, w7% of patients in a similar vein to the polygenic influences reported in
were ultimately considered to have idiopathic VF. 188 long QT syndrome and Brugada syndrome.77,78
In more selective cohorts that excluded those with
coronary artery disease and dilated cardiomyopathy, CONCLUSIONS
w40% to 50% of patients are considered to have
idiopathic VF after extensive clinical evalua- The systematic and comprehensive evaluation of pa-
tion.4,37,38 The proportion of cases attributable to tients after an episode of resuscitated cardiac arrest is
idiopathic VF is also decreasing over time with the pivotal for identifying etiology and the initiation of
recognition of newer clinical entities and as con- targeted management options. Careful review
cealed etiologies become overt. 5 In those who are for latent clues to diagnosis should couple with prov-
assigned a diagnosis of idiopathic VF after extensive ocation testing and long-term follow-up to facilitate
investigations, we would recommend re-evaluation diagnosis and related therapy. An understanding
every 2 to 3 years due to our evolving understand- of the predominant primary arrhythmia syndromes
ing of idiopathic VF and the possibility of age or time is critical for practicing cardiologists and
dependent penetrance of certain conditions. 189 electrophysiologists.
In patients with idiopathic VF, a secondary pre-
vention ICD is indicated. In those with idiopathic VF FUNDING SUPPORT AND AUTHOR DISCLOSURES
and an ICD, w25% to 30% will have appropriate ICD
therapies after 5 years of follow-up,190-193 in contrast The study was supported by the Heart in Rhythm Organization (Dr
Krahn, principal investigator) that receives support from the Cana-
with a rate of inappropriate therapies of w15%.191,193
dian Institute of Health Research (RN380020–406814). Dr Krahn re-
ceives support from the Sauder Family and Heart and Stroke
FUTURE DIRECTIONS Foundation Chair in Cardiology (Vancouver, BC), the Paul Brunes
Chair in Heart Rhythm Disorders (Vancouver, BC), and the Paul
Albrechtson Foundation (Winnipeg, MB). Dr Tfelt-Hansen has
Our understanding of the latent causes of cardiac ar- received support from the John and Birthe Meyer Foundation.
rest continues to advance, meaning that more entities Dr Tadros has received support from the Canadian Research Chair
are now identified and fewer cases are termed idio- program. Dr Semsarian is the recipient of National Health and Medical
Research Council (NHMRC) Practitioner Fellowship #1154992. Dr Han
pathic. This evolution of explaining cardiac arrest is
is supported by a Robert and Elizabeth Albert Travel Grant from the
nicely summarized in a recent editorial by van der RACP Foundation, Australia. Dr Steinberg has reported that he has no
194
Ree and Postema. The discovery of autoantibodies relationships relevant to the contents of this paper to disclose.
directed against various cardiac ion channels may
provide additional clarity. Thus far, autoantibodies ADDRESS FOR CORRESPONDENCE: Dr Andrew D.
against various potassium channels are shown to in- Krahn, Center for Cardiovascular Innovation, Heart
fluence repolarization and be associated with torsade Rhythm Services, Division of Cardiology, University
de pointes, 195-197 whereas autoantibodies against the of British Columbia, 211-1033 Davie Street, Vancouver,
L-type calcium channel are associated with the British Columbia V6E 1M7, Canada. E-mail: akrahn@
occurrence of SCD. 198 mail.ubc.ca. Twitter: @HeartsInRhythm.
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JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO.

ª 2022 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

Latent Causes of Sudden Cardiac Arrest

I nherited arrhythmia syndromes are an important

In patients who present with resuscitated cardiac

ISSN 2405-500X/$36.00 https://doi.org/10.1016/j.jacep.2021.12.014

In our experience, application of this ABBREVIATIONS

syndrome, and arrhythmogenic cardiomyop- ECG = electrocardiogram

Further research is required to under- tachycardia (CPVT), short QT syndrome syndrome

(SQTS), early repolarization syndrome (ERS), ICD = implantable

Latent Causes of Sudden Cardiac Arrest JUNE 2022:806–821

C E NT R AL IL L U STR AT IO N Clinical Approach to Latent Causes of Sudden Cardiac Arrest

Krahn AD, et al. J Am Coll Cardiol EP. 2022;8(6):806–821.

Latent Causes of Cardiac Arrest

Resuscitated Cardiac Arrest & Idiopathic Ventricular Fibrillation

Inpatient Management Further Management

Clinical history Additional testing

Other Recognized Syndromes

CPVT SQTS ERS SCVF

Diagnosis Diagnosis Diagnosis Diagnosis

Latent Causes of Sudden Cardiac Arrest JUNE 2022:806–821

Pharmacotherapy with b-blockers is recommended

F I G U R E 1 Schematic Representation of IC Calcium Homeostasis

Latent Causes of Sudden Cardiac Arrest JUNE 2022:806–821

F I G U R E 2 ECG Examples of “Latent” Cardiac Arrest Conditions

F I G U R E 3 Early Repolarization Patterns

Latent Causes of Sudden Cardiac Arrest JUNE 2022:806–821

Latent Causes of Sudden Cardiac Arrest JUNE 2022:806–821

IDIOPATHIC VF Furthermore, genetic inﬂuences in cases of idio-

Latent Causes of Sudden Cardiac Arrest JUNE 2022:806–821

Latent Causes of Sudden Cardiac Arrest JUNE 2022:806–821

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