Emboli Paru
Emboli Paru
Emboli Paru
6, 2022
PUBLISHED BY ELSEVIER
STATE-OF-THE-ART REVIEW
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.
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.
*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
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022 Krahn et al 809
JUNE 2022:806–821 Latent Causes of Sudden Cardiac Arrest
T A B L E 1 Diagnosis and management summary for latent causes of sudden cardiac arrest
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
810 Krahn et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022
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
812 Krahn et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022
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
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022 Krahn et al 813
JUNE 2022:806–821 Latent Causes of Sudden Cardiac Arrest
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
814 Krahn et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022
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.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022 Krahn et al 815
JUNE 2022:806–821 Latent Causes of Sudden Cardiac Arrest
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
816 Krahn et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022
REFERENCES
1. Krahn AD, Behr ER, Hamilton R, Probst V, 2. Krahn AD, Wilde AAM, Calkins H, et al. 3. Krahn AD, Laksman Z, Sy RW, et al. Congenital
Laksman Z, Han H-C. Brugada syndrome. J Am Coll Arrhythmogenic right ventricular cardiomyopathy. long QT syndrome. J Am Coll Cardiol EP.
Cardiol EP. 2022;8(3):386–405. J Am Coll Cardiol EP. 2022;8(4):533–553. 2022;8(5):687–706.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022 Krahn et al 817
JUNE 2022:806–821 Latent Causes of Sudden Cardiac Arrest
4. Krahn AD, Healey JS, Chauhan V, et al. Sys- 482 families. J Am Coll Cardiol EP. 2017;3:1400– primary arrhythmia syndromes. Heart Rhythm.
tematic assessment of patients with 1408. 2013;10:1932–1963.
unexplained cardiac arrest: Cardiac Arrest Sur-
20. Györke S. Molecular basis of catecholamin- 35. Miyake CY, Asaki SY, Webster G, et al. Circa-
vivors With Preserved Ejection Fraction Registry
ergic polymorphic ventricular tachycardia. Heart dian variation of ventricular arrhythmias in cate-
(CASPER). Circulation. 2009;120:278–285.
Rhythm. 2009;6:123–129. cholaminergic polymorphic ventricular
5. Visser M, van der Heijden JF, Doevendans PA, tachycardia. J Am Coll Cardiol EP. 2017;3:1308–
21. Priori SG, Chen SR. Inherited dysfunction of
Loh P, Wilde AA, Hassink RJ. Idiopathic ventricular 1317.
sarcoplasmic reticulum Ca2þ handling and
fibrillation: the struggle for definition, diagnosis,
arrhythmogenesis. Circ Res. 2011;108:871–883. 36. Roston TM, Yuchi Z, Kannankeril PJ, et al. The
and follow-up. Circ Arrhythm Electrophysiol.
clinical and genetic spectrum of catecholaminergic
2016;9(5):e003817. 22. Wleklinski MJ, Kannankeril PJ, Knollmann BC.
polymorphic ventricular tachycardia: findings from
Molecular and tissue mechanisms of catechol-
6. Haïssaguerre M, Duchateau J, Dubois R, et al. an international multicentre registry. Europace.
aminergic polymorphic ventricular tachycardia.
Idiopathic ventricular fibrillation: role of Purkinje 2018;20:541–547.
J Physiol. 2020;598:2817–2834.
system and microstructural myocardial abnormal-
37. Rucinski C, Winbo A, Marcondes L, et al.
ities. J Am Coll Cardiol EP. 2020;6:591–608. 23. Blaustein MP, Lederer WJ. Sodium/calcium
A population-based registry of patients with
exchange: its physiological implications. Physiol
7. Davies B, Roberts JD, Tadros R, et al. The Hearts inherited cardiac conditions and resuscitated car-
Rev. 1999;79:763–854.
in Rhythm Organization: a Canadian National Car- diac arrest. J Am Coll Cardiol. 2020;75:2698–2707.
diogenetics Network. CJC Open. 2020;2:652–662. 24. Ingles J, Macciocca I, Morales A, Thomson K.
38. van der Werf C, Hofman N, Tan HL, et al.
8. Alqarawi W, Dewidar O, Tadros R, et al. Defining Genetic testing in inherited heart diseases. Heart
Diagnostic yield in sudden unexplained death and
idiopathic ventricular fibrillation: a systematic re- Lung Circ. 2020;29:505–511.
aborted cardiac arrest in the young: the experience
view of diagnostic testing yield in apparently un- 25. Swan H, Piippo K, Viitasalo M, et al. Arrhythmic of a tertiary referral center in The Netherlands.
explained cardiac arrest. Heart Rhythm. disorder mapped to chromosome 1q42-q43 causes Heart Rhythm. 2010;7:1383–1389.
2021;18(7):1178–1185. malignant polymorphic ventricular tachycardia in
39. Reid DS, Tynan M, Braidwood L, Fitzgerald GR.
9. Hayashi M, Shimizu W, Albert CM. The spectrum structurally normal hearts. J Am Coll Cardiol.
Bidirectional tachycardia in a child. A study using
of epidemiology underlying sudden cardiac death. 1999;34:2035–2042.
His bundle electrography. Brit Heart J. 1975;37:
Circ Res. 2015;116:1887–1906. 26. Priori SG, Napolitano C, Tiso N, et al. Muta- 339–344.
10. Han HC, Parsons SA, Teh AW, et al. Charac- tions in the cardiac ryanodine receptor gene
40. Priori SG, Napolitano C, Memmi M, et al.
teristic histopathological findings and cardiac ar- (hRyR2) underlie catecholaminergic polymorphic
Clinical and molecular characterization of patients
rest rhythm in isolated mitral valve prolapse and ventricular tachycardia. Circulation. 2001;103:
with catecholaminergic polymorphic ventricular
sudden cardiac death. J Am Heart Assoc. 2020;9: 196–200.
tachycardia. Circulation. 2002;106:69–74.
e015587. 27. Laitinen PJ, Brown KM, Piippo K, et al. Muta-
41. Sy RW, Gollob MH, Klein GJ, et al. Arrhythmia
11. Yafasova A, Fosbøl EL, Schou M, et al. Long- tions of the cardiac ryanodine receptor (RyR2)
characterization and long-term outcomes in cate-
term adverse cardiac outcomes in patients with gene in familial polymorphic ventricular tachy-
cholaminergic polymorphic ventricular tachy-
sarcoidosis. J Am Coll Cardiol. 2020;76:767–777. cardia. Circulation. 2001;103:485–490.
cardia. Heart Rhythm. 2011;8:864–871.
12. Weeke PE, Kellemann JS, Jespersen CB, et al. 28. Lahat H, Pras E, Olender T, et al. A missense
42. Roston TM, Vinocur JM, Maginot KR, et al.
Long-term proarrhythmic pharmacotherapy mutation in a highly conserved region of CASQ2 is
Catecholaminergic polymorphic ventricular tachy-
among patients with congenital long QT syndrome associated with autosomal recessive
cardia in children: analysis of therapeutic strate-
and risk of arrhythmia and mortality. Eur Heart J. catecholamine-induced polymorphic ventricular
gies and outcomes from an international
2019;40:3110–3117. tachycardia in Bedouin families from Israel. Am J
multicenter registry. Circ Arrhythm Electrophysiol.
Hum Genet. 2001;69:1378–1384.
13. Bjune T, Risgaard B, Kruckow L, et al. Post- 2015;8:633–642.
mortem toxicology in young sudden cardiac death 29. Postma AV, Denjoy I, Hoorntje TM, et al.
43. van der Werf C, Nederend I, Hofman N, et al.
victims: a nationwide cohort study. Europace. Absence of calsequestrin 2 causes severe forms of
Familial evaluation in catecholaminergic poly-
2018;20:614–621. catecholaminergic polymorphic ventricular tachy-
morphic ventricular tachycardia: disease pene-
cardia. Circ Res. 2002;91:e21–e26.
14. Simpson TF, Salazar JW, Vittinghoff E, et al. trance and expression in cardiac ryanodine
Association of QT-prolonging medications with 30. Zhao YT, Valdivia CR, Gurrola GB, et al. receptor mutation-carrying relatives. Circ
risk of autopsy-defined causes of sudden death. Arrhythmogenesis in a catecholaminergic poly- Arrhythm Electrophysiol. 2012;5:748–756.
JAMA Intern Med. 2020;180:698–706. morphic ventricular tachycardia mutation that
44. Sumitomo N, Harada K, Nagashima M, et al.
15. Anilkumar A, Moore EJ, Gall AJ, Sammut E, depresses ryanodine receptor function. Proc Natl
Catecholaminergic polymorphic ventricular tachy-
Barman P. QTc interval in survivors of out of Acad Sci U S A. 2015;112:E1669–E1677.
cardia: electrocardiographic characteristics and
hospital cardiac arrest. Int J Cardiol. 2021;323:118– 31. Gray B, Bagnall RD, Lam L, et al. A novel het- optimal therapeutic strategies to prevent sudden
123. erozygous mutation in cardiac calsequestrin cau- death. Heart. 2003;89:66–70.
16. Cohen RB, Dai M, Aizer A, et al. QT interval ses autosomal dominant catecholaminergic
45. Hayashi M, Denjoy I, Hayashi M, et al. The
dynamics and triggers for QT prolongation imme- polymorphic ventricular tachycardia. Heart
role of stress test for predicting genetic muta-
diately following cardiac arrest. Resuscitation. Rhythm. 2016;13:1652–1660.
tions and future cardiac events in asymptomatic
2021;162:171–179. 32. Jabbari J, Jabbari R, Nielsen MW, et al. New relatives of catecholaminergic polymorphic ven-
17. Bagnall RD, Weintraub RG, Ingles J, et al. exome data question the pathogenicity of genetic tricular tachycardia probands. Europace. 2012;14:
A prospective study of sudden cardiac death variants previously associated with catecholamin- 1344–1351.
among children and young adults. N Engl J Med. ergic polymorphic ventricular tachycardia. Circ
46. Blich M, Marai I, Suleiman M, et al. Electro-
2016;374:2441–2452. Cardiovasc Genet. 2013;6:481–489.
cardiographic comparison of ventricular premature
18. Isbister JC, Nowak N, Butters A, et al. “Con- 33. Devalla HD, Gélinas R, Aburawi EH, et al. complexes during exercise test in patients with
cealed cardiomyopathy” as a cause of previously TECRL, a new life-threatening inherited CPVT and healthy subjects. Pacing Clin Electro-
unexplained sudden cardiac arrest. Int J Cardiol. arrhythmia gene associated with overlapping physiol. 2015;38:398–402.
2021;324:96–101. clinical features of both LQTS and CPVT. EMBO
47. Roston TM, Kallas D, Davies B, et al. Burst
Mol Med. 2016;8:1390–1408.
19. Tadros R, Nannenberg EA, Lieve KV, et al. exercise testing can unmask arrhythmias in pa-
Yield and pitfalls of ajmaline testing in the eval- 34. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/ tients with incompletely penetrant catecholamin-
uation of unexplained cardiac arrest and sudden APHRS expert consensus statement on the diag- ergic polymorphic ventricular tachycardia. J Am
unexplained death: single-center experience with nosis and management of patients with inherited Coll Cardiol EP. 2021;7:437–441.
818 Krahn et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022
48. Marjamaa A, Hiippala A, Arrhenius B, et al. catecholaminergic polymorphic ventricular tachy- resuscitated from sudden cardiac arrest. Eur Heart
Intravenous epinephrine infusion test in diagnosis cardia. J Am Coll Cardiol. 2011;57:2244–2254. J. 2019;40:2953–2961.
of catecholaminergic polymorphic ventricular
62. Watanabe H, van der Werf C, Roses-Noguer F, 75. Miyake CY, Webster G, Czosek RJ, et al. Effi-
tachycardia. J Cardiovasc Electrophysiol. 2012;23:
et al. Effects of flecainide on exercise-induced cacy of implantable cardioverter defibrillators in
194–199.
ventricular arrhythmias and recurrences in young patients with catecholaminergic poly-
49. Rehm HL, Berg JS, Brooks LD, et al. ClinGen– genotype-negative patients with catecholamin- morphic ventricular tachycardia: success depends
the Clinical Genome Resource. N Engl J Med. ergic polymorphic ventricular tachycardia. Heart on substrate. Circ Arrhythm Electrophysiol. 2013;6:
2015;372:2235–2242. Rhythm. 2013;10:542–547. 579–587.
50. Landstrom AP, Dailey-Schwartz AL, 63. Khoury A, Marai I, Suleiman M, et al. Flecainide 76. Roses-Noguer F, Jarman JW, Clague JR, Till J.
Rosenfeld JA, et al. Interpreting incidentally therapy suppresses exercise-induced ventricular Outcomes of defibrillator therapy in catechol-
identified variants in genes associated with cate- arrhythmias in patients with CASQ2-associated aminergic polymorphic ventricular tachycardia.
cholaminergic polymorphic ventricular tachycardia catecholaminergic polymorphic ventricular tachy- Heart Rhythm. 2014;11:58–66.
in a large cohort of clinical whole-exome genetic cardia. Heart Rhythm. 2013;10:1671–1675.
77. Tadros R, Tan HL, El Mathari S, et al. Predicting
test referrals. Circ Arrhythm Electrophysiol.
64. Padfield GJ, AlAhmari L, Lieve KV, et al. Fle- cardiac electrical response to sodium-channel
2017;10(4):e004742.
cainide monotherapy is an option for selected blockade and Brugada syndrome using polygenic
51. Baggish AL, Ackerman MJ, Lampert R. patients with catecholaminergic polymorphic risk scores. Eur Heart J. 2019;40:3097–3107.
Competitive sport participation among athletes ventricular tachycardia intolerant of b-blockade.
78. Lahrouchi N, Tadros R, Crotti L, et al. Trans-
with heart disease: a call for a paradigm shift in Heart Rhythm. 2016;13:609–613.
ethnic genome-wide association study provides
decision making. Circulation. 2017;136:1569–1571.
65. Kannankeril PJ, Moore JP, Cerrone M, et al. insights in the genetic architecture and heritability
52. Etheridge SP, Saarel EV, Martinez MW. Exer- Efficacy of flecainide in the treatment of cate- of long QT syndrome. Circulation. 2020;142:324–
cise participation and shared decision-making in cholaminergic polymorphic ventricular tachy- 338.
patients with inherited channelopathies and car- cardia: a randomized clinical trial. JAMA Cardiol.
79. Faggioni M, Hwang HS, van der Werf C, et al.
diomyopathies. Heart Rhythm. 2018;15:915–920. 2017;2:759–766.
Accelerated sinus rhythm prevents catecholamin-
53. Ostby SA, Bos JM, Owen HJ, Wackel PL, 66. Bannister ML, Thomas NL, Sikkel MB, et al. ergic polymorphic ventricular tachycardia in mice
Cannon BC, Ackerman MJ. Competitive sports The mechanism of flecainide action in CPVT does and in patients. Circ Res. 2013;112:689–697.
participation in patients with catecholaminergic not involve a direct effect on RyR2. Circ Res.
80. Kannankeril PJ, Shoemaker MB, Gayle KA,
polymorphic ventricular tachycardia: a single 2015;116:1324–1335.
Fountain D, Roden DM, Knollmann BC. Atropine-
center’s early experience. J Am Coll Cardiol EP.
67. Hwang HS, Baldo MP, Rodriguez JP, induced sinus tachycardia protects against
2016;2:253–262.
Faggioni M, Knollmann BC. Efficacy of flecainide in exercise-induced ventricular arrhythmias in pa-
54. Kurtzwald-Josefson E, Hochhauser E, Katz G, catecholaminergic polymorphic ventricular tachy- tients with catecholaminergic polymorphic ven-
et al. Exercise training improves cardiac function cardia is mutation-independent but reduced by tricular tachycardia. Europace. 2020;22:643–648.
and attenuates arrhythmia in CPVT mice. J Appl calcium overload. Front Physiol. 2019;10:992.
81. Denegri M, Bongianino R, Lodola F, et al. Sin-
Physiol (1985). 2012;113:1677–1683.
68. Kryshtal DO, Blackwell DJ, Egly CL, et al. gle delivery of an adeno-associated viral construct
55. Manotheepan R, Saberniak J, Danielsen TK, RYR2 channel inhibition is the principal mechanism to transfer the CASQ2 gene to knock-in mice
et al. Effects of individualized exercise training in of flecainide action in CPVT. Circ Res. 2021;128: affected by catecholaminergic polymorphic ven-
patients with catecholaminergic polymorphic 321–331. tricular tachycardia is able to cure the disease from
ventricular tachycardia type 1. Am J Cardiol. birth to advanced age. Circulation. 2014;129:2673–
69. Alcalai R, Wakimoto H, Arad M, et al. Pre-
2014;113:1829–1833. 2681.
vention of ventricular arrhythmia and calcium
56. Hayashi M, Denjoy I, Extramiana F, et al. Inci- dysregulation in a catecholaminergic polymorphic 82. Kurtzwald-Josefson E, Yadin D, Harun-Khun S,
dence and risk factors of arrhythmic events in ventricular tachycardia mouse model carrying et al. Viral delivered gene therapy to treat cate-
catecholaminergic polymorphic ventricular tachy- calsequestrin-2 mutation. J Cardiovasc Electro- cholaminergic polymorphic ventricular tachycardia
cardia. Circulation. 2009;119:2426–2434. physiol. 2011;22:316–324. (CPVT2) in mouse models. Heart Rhythm. 2017;14:
1053–1060.
57. Leren IS, Saberniak J, Majid E, Haland TF, 70. Wilde AA, Bhuiyan ZA, Crotti L, et al. Left
Edvardsen T, Haugaa KH. Nadolol decreases the cardiac sympathetic denervation for catechol- 83. Bongianino R, Denegri M, Mazzanti A, et al.
incidence and severity of ventricular arrhythmias aminergic polymorphic ventricular tachycardia. Allele-specific silencing of mutant mRNA rescues
during exercise stress testing compared with b1- N Engl J Med. 2008;358:2024–2029. ultrastructural and arrhythmic phenotype in mice
selective b-blockers in patients with catechol- carriers of the R4496C mutation in the ryanodine
71. Collura CA, Johnson JN, Moir C, Ackerman MJ.
aminergic polymorphic ventricular tachycardia. receptor gene (RYR2). Circ Res. 2017;121:525–536.
Left cardiac sympathetic denervation for the
Heart Rhythm. 2016;13:433–440.
treatment of long QT syndrome and catechol- 84. Pan X, Philippen L, Lahiri SK, et al. In vivo Ryr2
58. Kawata H, Ohno S, Aiba T, et al. Catechol- aminergic polymorphic ventricular tachycardia editing corrects catecholaminergic polymorphic
aminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery. Heart ventricular tachycardia. Circ Res. 2018;123:953–
(CPVT) associated with ryanodine receptor (RyR2) Rhythm. 2009;6:752–759. 963.
gene mutations–long-term prognosis after initia-
72. De Ferrari GM, Dusi V, Spazzolini C, et al. 85. Liu B, Walton SD, Ho HT, et al. Gene transfer
tion of medical treatment. Circ J. 2016;80:1907–
Clinical management of catecholaminergic poly- of engineered calmodulin alleviates ventricular
1915.
morphic ventricular tachycardia: the role of left arrhythmias in a calsequestrin-associated mouse
59. Cheung CC, Lieve KV, Roston TM, et al. Preg- cardiac sympathetic denervation. Circulation. model of catecholaminergic polymorphic ventric-
nancy in catecholaminergic polymorphic ventric- 2015;131:2185–2193. ular tachycardia. J Am Heart Assoc. 2018;7(10):
ular tachycardia. J Am Coll Cardiol EP. 2019;5:387– e008155.
73. Roston TM, Jones K, Hawkins NM, et al.
394.
Implantable cardioverter-defibrillator use in cate- 86. Bezzerides VJ, Caballero A, Wang S, et al.
60. Watanabe H, Chopra N, Laver D, et al. Fle- cholaminergic polymorphic ventricular tachy- Gene therapy for catecholaminergic polymorphic
cainide prevents catecholaminergic polymorphic cardia: a systematic review. Heart Rhythm. ventricular tachycardia by inhibition of Ca(2þ)/
ventricular tachycardia in mice and humans. Nat 2018;15:1791–1799. calmodulin-dependent kinase II. Circulation.
Med. 2009;15:380–383. 2019;140:405–419.
74. van der Werf C, Lieve KV, Bos JM, et al.
61. van der Werf C, Kannankeril PJ, Sacher F, et al. Implantable cardioverter-defibrillators in previ- 87. Schweitzer MK, Wilting F, Sedej S, et al. Sup-
Flecainide therapy reduces exercise-induced ven- ously undiagnosed patients with catecholamin- pression of arrhythmia by enhancing mitochon-
tricular arrhythmias in patients with ergic polymorphic ventricular tachycardia drial Ca(2þ) uptake in catecholaminergic
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022 Krahn et al 819
JUNE 2022:806–821 Latent Causes of Sudden Cardiac Arrest
ventricular tachycardia models. J Am Coll Cardiol 103. Suzuki H, Horie M, Ozawa J, et al. Novel model of short QT syndrome. J Cardiovasc Elec-
Basic Trans Science. 2017;2:737–747. electrocardiographic criteria for short QT syn- trophysiol. 2007;18:658–664.
drome in children and adolescents. Europace.
88. Batiste SM, Blackwell DJ, Kim K, et al. Un- 119. Luo C, Wang K, Zhang H. In silico assessment
2021;23(12):2029–2038.
natural verticilide enantiomer inhibits type 2 rya- of the effects of quinidine, disopyramide and E-
nodine receptor-mediated calcium leak and is 104. Providência R, Karim N, Srinivasan N, et al. 4031 on short QT syndrome variant 1 in the human
antiarrhythmic. Proc Natl Acad Sci U S A. 2019;116: Impact of QTc formulae in the prevalence of short ventricles. PLoS One. 2017;12:e0179515.
4810–4815. corrected QT interval and impact on probability
120. Viskin S, Wilde AA, Guevara-Valdivia ME,
and diagnosis of short QT syndrome. Heart.
89. Patel C, Yan GX, Antzelevitch C. Short QT et al. Quinidine, a life-saving medication for Bru-
2018;104:502–508.
syndrome: from bench to bedside. Circ Arrhythm gada syndrome, is inaccessible in many countries.
Electrophysiol. 2010;3:401–408. 105. Anttonen O, Junttila MJ, Rissanen H, J Am Coll Cardiol. 2013;61:2383–2387.
Reunanen A, Viitasalo M, Huikuri HV. Prevalence
90. El-Battrawy I, Schlentrich K, Besler J, et al. 121. Malhi N, Cheung CC, Deif B, et al. Challenge
and prognostic significance of short QT interval in
Sex-differences in short QT syndrome: a system- and impact of quinidine access in sudden death
a middle-aged Finnish population. Circulation.
atic literature review and pooled analysis. Eur J syndromes: a national experience. J Am Coll Car-
2007;116:714–720.
Prev Cardiol. 2020;27:1335–1338. diol EP. 2019;5:376–382.
106. Miyamoto A, Hayashi H, Yoshino T, et al.
91. Shimizu W, Horie M. Phenotypic manifesta- 122. McPate MJ, Duncan RS, Witchel HJ,
Clinical and electrocardiographic characteristics of
tions of mutations in genes encoding subunits of Hancox JC. Disopyramide is an effective inhibitor
patients with short QT interval in a large hospital-
cardiac potassium channels. Circ Res. 2011;109:97– of mutant HERG Kþ channels involved in variant 1
based population. Heart Rhythm. 2012;9:66–74.
109. short QT syndrome. J Mol Cell Cardiol. 2006;41:
107. Guerrier K, Kwiatkowski D, Czosek RJ, 563–566.
92. Tamargo J, Caballero R, Gómez R, Spar DS, Anderson JB, Knilans TK. Short QT in-
Valenzuela C, Delpón E. Pharmacology of cardiac terval prevalence and clinical outcomes in a pe- 123. Frommeyer G, Weller J, Ellermann C, et al.
potassium channels. Cardiovasc Res. 2004;62:9– diatric population. Circ Arrhythm Electrophysiol. Antiarrhythmic properties of ivabradine in an
33. 2015;8:1460–1464. experimental model of Short-QT- Syndrome. Clin
Exp Pharmacol Physiol. 2017;44:941–945.
93. El-Battrawy I, Lan H, Cyganek L, et al. 108. Dhutia H, Malhotra A, Parpia S, et al. The
Modeling short QT syndrome using human- prevalence and significance of a short QT interval 124. Zhao Z, Li X, El-Battrawy I, et al. Drug testing
induced pluripotent stem cell-derived car- in 18,825 low-risk individuals including athletes. in human-induced pluripotent stem cell-derived
diomyocytes. J Am Heart Assoc. 2018;7(7): Brit J Sports Med. 2016;50:124–129. cardiomyocytes from a patient with short QT
e007394. syndrome type 1. Clin Pharmacol Ther. 2019;106:
109. Giustetto C, Scrocco C, Schimpf R, et al.
642–651.
94. Guo F, Sun Y, Wang X, et al. Patient-specific Usefulness of exercise test in the diagnosis of
and gene-corrected induced pluripotent stem cell- short QT syndrome. Europace. 2015;17:628–634. 125. Frommeyer G, Garthmann J, Ellermann C,
derived cardiomyocytes elucidate single-cell et al. Broad antiarrhythmic effect of mexiletine in
110. Frea S, Giustetto C, Capriolo M, et al. New
phenotype of short QT syndrome. Circ Res. different arrhythmia models. Europace. 2018;20:
echocardiographic insights in short QT syndrome:
2019;124:66–78. 1375–1381.
more than a channelopathy? Heart Rhythm.
95. Odening KE, Bodi I, Franke G, et al. Transgenic 2015;12:2096–2105. 126. Giustetto C, Di Monte F, Wolpert C, et al.
short-QT syndrome 1 rabbits mimic the human Short QT syndrome: clinical findings and
111. Rollin A, Gandjbakhch E, Giustetto C, et al.
disease phenotype with QT/action potential diagnostic-therapeutic implications. Eur Heart J.
Shortening of the short refractory periods in short
duration shortening in the atria and ventricles and 2006;27:2440–2447.
QT syndrome. J Am Heart Assoc. 2017;6(6):
increased ventricular tachycardia/ventricular
e005684. 127. El-Battrawy I, Besler J, Ansari U, et al. Long-
fibrillation inducibility. Eur Heart J. 2019;40:842–
term follow-up of implantable cardioverter-
853. 112. Sy RW, van der Werf C, Chattha IS, et al.
defibrillators in short QT syndrome. Clin Res
Derivation and validation of a simple exercise-
96. Shinnawi R, Shaheen N, Huber I, et al. Cardiol. 2019;108:1140–1146.
based algorithm for prediction of genetic testing
Modeling reentry in the short QT syndrome with
in relatives of LQTS probands. Circulation. 128. Schimpf R, Wolpert C, Bianchi F, et al.
human-induced pluripotent stem cell-derived
2011;124:2187–2194. Congenital short QT syndrome and implantable
cardiac cell sheets. J Am Coll Cardiol. 2019;73:
cardioverter defibrillator treatment: inherent risk
2310–2324. 113. Mazzanti A, Maragna R, Vacanti G, et al.
for inappropriate shock delivery. J Cardiovasc
Hydroquinidine prevents life-threatening
97. Roussel J, Labarthe F, Thireau J, et al. Carni- arrhythmic events in patients with short QT syn- Electrophysiol. 2003;14:1273–1277.
tine deficiency induces a short QT syndrome. Heart
drome. J Am Coll Cardiol. 2017;70:3010–3015. 129. Trenor B, Cardona K, Saiz J, Noble D, Giles W.
Rhythm. 2016;13:165–174.
114. El-Battrawy I, Besler J, Li X, et al. Impact of Cardiac action potential repolarization revisited:
98. Thorsen K, Dam VS, Kjaer-Sorensen K, et al. antiarrhythmic drugs on the outcome of short QT early repolarization shows all-or-none behaviour.
Loss-of-activity-mutation in the cardiac chloride- syndrome. Front Pharmacol. 2019;10:771. J Physiol. 2017;595:6599–6612.
bicarbonate exchanger AE3 causes short QT syn-
115. Lei M, Wu L, Terrar DA, Huang CL. Modernized 130. Teumer A, Trenkwalder T, Kessler T, et al.
drome. Nat Commun. 2017;8:1696.
classification of cardiac antiarrhythmic drugs. Cir- KCND3 potassium channel gene variant confers
99. Gélinas R, Leach E, Horvath G, Laksman Z. culation. 2018;138:1879–1896. susceptibility to electrocardiographic early repo-
Molecular autopsy implicates primary carnitine larization pattern. JCI Insight. 2019;4:e131156.
116. Vitali Serdoz L, Rittger H, Furlanello F,
deficiency in sudden unexplained death and
Bastian D. Quinidine–a legacy within the modern 131. Koncz I, Gurabi Z, Patocskai B, et al. Mecha-
reversible short QT syndrome. Can J Cardiol.
era of antiarrhythmic therapy. Pharmacol Res. nisms underlying the development of the elec-
2019;35:1256.e1–1256.e2.
2019;144:257–263. trocardiographic and arrhythmic manifestations of
100. Villafañe J, Atallah J, Gollob MH, et al. Long- early repolarization syndrome. J Mol Cell Cardiol.
117. Whittaker DG, Ni H, Benson AP, Hancox JC,
term follow-up of a pediatric cohort with short QT 2014;68:20–28.
Zhang H. Computational analysis of the mode of
syndrome. J Am Coll Cardiol. 2013;61:1183–1191.
action of disopyramide and quinidine on hERG- 132. Zhang J, Hocini M, Strom M, et al. The elec-
101. Mazzanti A, Kanthan A, Monteforte N, et al. linked short QT syndrome in human ventricles. trophysiological substrate of early repolarization
Novel insight into the natural history of short QT Front Physiol. 2017;8:759. syndrome: noninvasive mapping in patients. J Am
syndrome. J Am Coll Cardiol. 2014;63:1300–1308. Coll Cardiol EP. 2017;3:894–904.
118. Milberg P, Tegelkamp R, Osada N, et al.
102. Gollob MH, Redpath CJ, Roberts JD. The Reduction of dispersion of repolarization and 133. Yoon N, Patocskai B, Antzelevitch C. Epicar-
short QT syndrome: proposed diagnostic criteria. prolongation of postrepolarization refractoriness dial substrate as a target for radiofrequency
J Am Coll Cardiol. 2011;57:802–812. explain the antiarrhythmic effects of quinidine in a ablation in an experimental model of early
820 Krahn et al JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022
repolarization syndrome. Circ Arrhythm Electro- polymorphic ventricular tachycardia. Europace. ventricular fibrillation and Brugada syndrome.
physiol. 2018;11:e006511. 2016;18:1587–1592. Heart Rhythm. 2012;9:77–83.
134. Boukens BJ, Benjacholamas V, van 149. Watanabe H, Makiyama T, Koyama T, et al. 164. Ahn J, Roh SY, Lee DI, Shim J, Choi JI,
Amersfoort S, et al. Structurally abnormal High prevalence of early repolarization in short QT Kim YH. Effect of flecainide on suppression of
myocardium underlies ventricular fibrillation syndrome. Heart Rhythm. 2010;7:647–652. ventricular fibrillation in a patient with early
storms in a patient diagnosed with the early repolarization syndrome. Heart Rhythm. 2016;13:
150. Noseworthy PA, Tikkanen JT, Porthan K,
repolarization pattern. J Am Coll Cardiol EP. 1724–1728.
et al. The early repolarization pattern in the gen-
2020;6:1395–1404.
eral population: clinical correlates and heritability. 165. Nademanee K, Haissaguerre M, Hocini M,
135. Watanabe H, Nogami A, Ohkubo K, et al. J Am Coll Cardiol. 2011;57:2284–2289. et al. Mapping and ablation of ventricular fibrilla-
Electrocardiographic characteristics and SCN5A tion associated with early repolarization syn-
151. Ilkhanoff L, Soliman EZ, Prineas RJ, et al.
mutations in idiopathic ventricular fibrillation drome. Circulation. 2019;140:1477–1490.
Clinical characteristics and outcomes associated
associated with early repolarization. Circ Arrhythm
with the natural history of early repolarization in a 166. Steinberg C, Davies B, Mellor G, et al. Short-
Electrophysiol. 2011;4:874–881.
young, biracial cohort followed to middle age: the coupled ventricular fibrillation represents a
136. Delaney JT, Muhammad R, Blair MA, et al. Coronary Artery Risk Development in Young distinct phenotype among latent causes of unex-
A KCNJ8 mutation associated with early repolari- Adults (CARDIA) study. Circ Arrhythm Electro- plained cardiac arrest: a report from the CASPER
zation and atrial fibrillation. Europace. 2012;14: physiol. 2014;7:392–399. registry. Eur Heart J. 2021;42(29):2827–2838.
1428–1432.
152. Tikkanen JT, Anttonen O, Junttila MJ, et al. 167. Xiao L, Koopmann TT, Ördög B, et al. Unique
137. Takayama K, Ohno S, Ding WG, et al. A de Long-term outcome associated with early repo- cardiac Purkinje fiber transient outward current b-
novo gain-of-function KCND3 mutation in early larization on electrocardiography. N Engl J Med. subunit composition: a potential molecular link to
repolarization syndrome. Heart Rhythm. 2019;16: 2009;361:2529–2537. idiopathic ventricular fibrillation. Circ Res.
1698–1706. 2013;112:1310–1322.
153. Tikkanen JT, Junttila MJ, Anttonen O, et al.
138. Shipley R, Hallaran W. The four-lead elec- Early repolarization: electrocardiographic pheno- 168. Alders M, Koopmann TT, Christiaans I, et al.
trocardiogram in two hundred normal men and types associated with favorable long-term Haplotype-sharing analysis implicates chromo-
women. Am Heart J. 1936;11:325–345. outcome. Circulation. 2011;123:2666–2673. some 7q36 harboring DPP6 in familial idiopathic
139. Kambara H, Phillips J. Long-term evaluation 154. Obeyesekere MN, Klein GJ, Nattel S, et al. ventricular fibrillation. Am J Hum Genet. 2009;84:
of early repolarization syndrome (normal variant A clinical approach to early repolarization. Circu- 468–476.
RS-T segment elevation). Am J Cardiol. 1976;38: lation. 2013;127:1620–1629. 169. ten Sande JN, Postema PG, Boekholdt SM,
157–166. et al. Detailed characterization of familial idio-
155. Macfarlane PW, Antzelevitch C,
140. Bianco M, Bria S, Gianfelici A, Sanna N, Haissaguerre M, et al. The early repolarization pathic ventricular fibrillation linked to the DPP6
Palmieri V, Zeppilli P. Does early repolarization in pattern: a consensus paper. J Am Coll Cardiol. locus. Heart Rhythm. 2016;13:905–912.
the athlete have analogies with the Brugada syn- 2015;66:470–477. 170. Haïssaguerre M, Shoda M, Jaïs P, et al.
drome? Eur Heart J. 2001;22:504–510. Mapping and ablation of idiopathic ventricular
156. Bastiaenen R, Hedley PL, Christiansen M,
141. Haïssaguerre M, Derval N, Sacher F, et al. Behr ER. Therapeutic hypothermia and ventricular fibrillation. Circulation. 2002;106:962–967.
Sudden cardiac arrest associated with early repo- fibrillation storm in early repolarization syndrome. 171. Haïssaguerre M, Hocini M, Cheniti G, et al.
larization. N Engl J Med. 2008;358:2016–2023. Heart Rhythm. 2010;7:832–834. Localized structural alterations underlying a sub-
142. Rosso R, Kogan E, Belhassen B, et al. J-point 157. Federman NJ, Mechulan A, Klein GJ, set of unexplained sudden cardiac death. Circ
elevation in survivors of primary ventricular Krahn AD. Ventricular fibrillation induced by Arrhythm Electrophysiol. 2018;11:e006120.
fibrillation and matched control subjects: inci- spontaneous hypothermia in a patient with early 172. Haissaguerre M, Cheniti G, Escande W,
dence and clinical significance. J Am Coll Cardiol. repolarization syndrome. J Cardiovasc Electro- Zhao A, Hocini M, Bernus O. Idiopathic ventricular
2008;52:1231–1238. physiol. 2013;24:586–588. fibrillation with repetitive activity inducible within
143. Derval N, Simpson CS, Birnie DH, et al. 158. Myojo T, Sato N, Nimura A, et al. Recurrent the distal Purkinje system. Heart Rhythm. 2019;16:
Prevalence and characteristics of early repolari- ventricular fibrillation related to hypokalemia in 1268–1272.
zation in the CASPER registry: Cardiac Arrest Sur- early repolarization syndrome. Pacing Clin Elec- 173. Leenhardt A, Glaser E, Burguera M,
vivors With Preserved Ejection Fraction Registry. trophysiol. 2012;35:e234–e238. Nürnberg M, Maison-Blanche P, Coumel P. Short-
J Am Coll Cardiol. 2011;58:722–728. coupled variant of torsade de pointes. A new
159. Morace G, Padeletti L, Porciani MC, Fantini F.
144. Malhi N, So PP, Cheung CC, et al. Early Effect of isoproterenol on the “early repolariza- electrocardiographic entity in the spectrum of
repolarization pattern inheritance in the Cardiac tion” syndrome. Am Heart J. 1979;97:343–347. idiopathic ventricular tachyarrhythmias. Circula-
Arrest Survivors With Preserved Ejection Fraction tion. 1994;89:206–215.
160. Patocskai B, Barajas-Martinez H, Hu D,
Registry (CASPER). J Am Coll Cardiol EP. 2018;4: 174. Viskin S, Lesh MD, Eldar M, et al. Mode of
Gurabi Z, Koncz I, Antzelevitch C. Cellular and
1473–1479. onset of malignant ventricular arrhythmias in
ionic mechanisms underlying the effects of cil-
145. Laksman ZW, Gula LJ, Saklani P, et al. Early ostazol, milrinone, and isoproterenol to suppress idiopathic ventricular fibrillation. J Cardiovasc
repolarization is associated with symptoms in pa- arrhythmogenesis in an experimental model of Electrophysiol. 1997;8:1115–1120.
tients with type 1 and type 2 long QT syndrome. early repolarization syndrome. Heart Rhythm. 175. Viskin S, Rosso R, Rogowski O, Belhassen B.
Heart Rhythm. 2014;11:1632–1638. 2016;13:1326–1334. The “short-coupled” variant of right ventricular
146. Sarkozy A, Chierchia GB, Paparella G, et al. 161. Kaneko Y, Horie M, Niwano S, et al. Electrical outflow ventricular tachycardia: a not-so-benign
Inferior and lateral electrocardiographic repolari- storm in patients with Brugada syndrome is asso- form of benign ventricular tachycardia?
zation abnormalities in Brugada syndrome. Circ ciated with early repolarization. Circ Arrhythm J Cardiovasc Electrophysiol. 2005;16:912–916.
Arrhythm Electrophysiol. 2009;2:154–161. Electrophysiol. 2014;7:1122–1128.
176. Steinfurt J, Nazer B, Aguilar M, et al. Catheter
147. Honarbakhsh S, Providencia R, Garcia- 162. Iguchi K, Noda T, Kamakura S, Shimizu W. ablation of short-coupled variant of torsade de
Hernandez J, et al. A Primary prevention clinical Beneficial effects of cilostazol in a patient with pointes. Clin Res Cardiol. 2022;111(5):502–510.
risk score model for patients with Brugada syn- recurrent ventricular fibrillation associated with
177. Noda T, Shimizu W, Taguchi A, et al. Malig-
drome (BRUGADA-RISK). J Am Coll Cardiol EP. early repolarization syndrome. Heart Rhythm.
nant entity of idiopathic ventricular fibrillation and
2021;7:210–222. 2013;10:604–606.
polymorphic ventricular tachycardia initiated by
148. Tülümen E, Schulze-Bahr E, Zumhagen S, 163. Kawata H, Noda T, Yamada Y, et al. Effect of premature extrasystoles originating from the right
et al. Early repolarization pattern: a marker of sodium-channel blockade on early repolarization ventricular outflow tract. J Am Coll Cardiol.
increased risk in patients with catecholaminergic in inferior/lateral leads in patients with idiopathic 2005;46:1288–1294.
JACC: CLINICAL ELECTROPHYSIOLOGY VOL. 8, NO. 6, 2022 Krahn et al 821
JUNE 2022:806–821 Latent Causes of Sudden Cardiac Arrest
178. Crotti L, Spazzolini C, Tester DJ, et al. 186. Roberts JD, Gollob MH, Young C, et al. 194. van der Ree MH, Postema PG. What’s in a
Calmodulin mutations and life-threatening cardiac Bundle branch re-entrant ventricular tachycardia: name? further classification of patients with
arrhythmias: insights from the International novel genetic mechanisms in a life-threatening apparent idiopathic ventricular fibrillation. Eur
Calmodulinopathy Registry. Eur Heart J. 2019;40: arrhythmia. J Am Coll Cardiol EP. 2017;3:276–288. Heart J. 2021;42(29):2839–2841.
2964–2975.
187. Bundgaard H, Jøns C, Lodder EM, et al. 195. Nakamura K, Katayama Y, Kusano KF,
179. Marsman RF, Barc J, Beekman L, et al. A novel familial cardiac arrhythmia syndrome with et al. Anti-KCNH2 antibody-induced long QT
A mutation in CALM1 encoding calmodulin in fa- widespread ST-segment depression. N Engl J Med. syndrome: novel acquired form of long QT
milial idiopathic ventricular fibrillation in child- 2018;379:1780–1781. syndrome. J Am Coll Cardiol. 2007;50:1808–
hood and adolescence. J Am Coll Cardiol. 2014;63: 1809.
259–266. 188. Waldmann V, Bougouin W, Karam N, et al.
196. Li J, Maguy A, Duverger JE, et al.
Characteristics and clinical assessment of unex-
180. Nomikos M, Thanassoulas A, Beck K, et al. Induced KCNQ1 autoimmunity accelerates car-
plained sudden cardiac arrest in the real-world
Altered RyR2 regulation by the calmodulin F90L diac repolarization in rabbits: potential
setting: focus on idiopathic ventricular fibrilla-
mutation associated with idiopathic ventricular significance in arrhythmogenesis and
tion. Eur Heart J. 2018;39:1981–1987.
fibrillation and early sudden cardiac death. FEBS antiarrhythmic therapy. Heart Rhythm. 2014;11:
Lett. 2014;588:2898–2902. 189. Vittoria Matassini M, Krahn AD, Gardner M, 2092–2100.
et al. Evolution of clinical diagnosis in patients
181. Clemens DJ, Gray B, Bagnall RD, et al. Prev- 197. Lazzerini PE, Yue Y, Srivastava U, et al.
presenting with unexplained cardiac arrest or
alence and phenotypic correlations of Arrhythmogenicity of Anti-Ro/SSA Antibodies in
syncope due to polymorphic ventricular tachy-
calmodulinopathy-causative CALM1-3 variants Patients With Torsades de Pointes. Circ Arrhythm
cardia. Heart Rhythm. 2014;11:274–281.
detected in a multicenter molecular autopsy Electrophysiol. 2016;9:e003419.
cohort of sudden unexplained death victims. Circ 190. Ozaydin M, Moazzami K, Kalantarian S, Lee H,
Genom Precis Med. 2020;13:e003032. Mansour M, Ruskin JN. long-term outcome of 198. Maguy A, Tardif JC, Busseuil D, Ribi C, Li J.
patients with idiopathic ventricular fibrillation: a Autoantibody signature in cardiac arrest. Circula-
182. Balasundaram R, Rao HB, Kalavakolanu S, tion. 2020;141:1764–1774.
meta-analysis. J Cardiovasc Electrophysiol.
Narasimhan C. Catheter ablation of bundle branch
2015;26:1095–1104.
reentrant ventricular tachycardia. Heart Rhythm. 199. Laurent G, Saal S, Amarouch MY, et al.
2008;5:S68–S72. 191. Blom LJ, Visser M, Christiaans I, et al. Inci- Multifocal ectopic Purkinje-related premature
dence and predictors of implantable cardioverter- contractions: a new SCN5A-related cardiac
183. Cohen TJ, Chien WW, Lurie KG, et al. Radio-
defibrillator therapy and its complications in channelopathy. J Am Coll Cardiol. 2012;60:144–
frequency catheter ablation for treatment of
idiopathic ventricular fibrillation patients. Euro- 156.
bundle branch reentrant ventricular tachycardia:
pace. 2019;21:1519–1526.
results and long-term follow-up. J Am Coll Cardiol. 200. Koizumi A, Sasano T, Kimura W, et al. Genetic
1991;18:1767–1773. defects in a His-Purkinje system transcription
192. Conte G, Belhassen B, Lambiase P, et al. Out-
factor, IRX3, cause lethal cardiac arrhythmias. Eur
184. Blanck Z, Jazayeri M, Dhala A, Deshpande S, of-hospital cardiac arrest due to idiopathic ven-
Heart J. 2016;37:1469–1475.
Sra J, Akhtar M. Bundle branch reentry: a mecha- tricular fibrillation in patients with normal elec-
nism of ventricular tachycardia in the absence of trocardiograms: results from a multicentre long- 201. Sun B, Yao J, Ni M, et al. Cardiac ryanodine
myocardial or valvular dysfunction. J Am Coll term registry. Europace. 2019;21:1670–1677. receptor calcium release deficiency syndrome. Sci
Cardiol. 1993;22:1718–1722. Transl Med. 2021;13(579):eaba7287. https://doi.
193. Stampe NK, Jespersen CB, Glinge C,
185. Chen H, Shi L, Yang B, et al. Electrophysio- Bundgaard H, Tfelt-Hansen J, Winkel BG. Clinical org/10.1126/scitranslmed.aba7287
logical characteristics of bundle branch reentry characteristics and risk factors of arrhythmia dur-
ventricular tachycardia in patients without struc- ing follow-up of patients with idiopathic ventric-
tural heart disease. Circ Arrhythm Electrophysiol. ular fibrillation. J Cardiovasc Electrophysiol. KEY WORDS inherited, sudden death,
2018;11:e006049. 2020;31:2677–2686. ventricular arrhythmia