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Latent Causes of Sudden Cardiac ArrestFree Access

State-of-the-Art Review

J Am Coll Cardiol EP, 8 (6) 806–821
Sections

Central Illustration

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 sufficiently 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 repolarization 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.

Highlights

Recently, there have been significant advances in our understanding of otherwise unexplained cardiac arrest.

This review provides practical recommendations for the evaluation of patients after resuscitated cardiac arrest.

Further research is required to understand the underlying pathophysiology of idiopathic ventricular fibrillation.

Introduction

Inherited arrhythmia syndromes are an important cause of unexplained cardiac arrest and sudden cardiac death (SCD). In this series, we have discussed primary electrical conditions such as long QT syndrome and Brugada syndrome, and arrhythmogenic cardiomyopathy which has a predominant arrhythmic presentation.1-3 In this review, we present a framework for the overall diagnostic evaluation of patients after an episode of resuscitated cardiac arrest, and discuss the less common or “latent” causes of cardiac arrest (Central Illustration, Table 1). A systematic approach is paramount for screening, of the affected individual, and also family members.

Central Illustration
Central Illustration

Clinical Approach to Latent Causes of Sudden Cardiac Arrest

∗Refer to other papers in the series for additional information (Krahn et al1-3). AED = automated external defibrillator; ARVC = arrhythmogenic right ventricular cardiomyopathy; BrS = Brugada syndrome; CPVT = catecholaminergic polymorphic ventricular tachycardia; ECG = electrocardiogram; EP = electrophysiology; ERP = early repolarization pattern; ERS = early repolarization syndrome; ICD = implantable cardioverter-defibrillator; LCSD = left cardiac sympathetic denervation; LQTS = long QT syndrome; MRI = magnetic resonance imaging; PVC = premature ventricular complex; SAECG = signal-averaged electrocardiogram; SCB = sodium channel blocker; SCVF = short-coupled ventricular fibrillation; VF = ventricular fibrillation; VT = ventricular tachycardia.

Table 1 Diagnosis and management summary for latent causes of sudden cardiac arrest

Latent Causes of Cardiac Arrest
Resuscitated Cardiac Arrest & Idiopathic Ventricular Fibrillation
Inpatient ManagementFurther Management
Clinical history

Circumstances of cardiac arrest

History and circumstances of cardiogenic syncope

Family history of SCD

Investigations

ECG (including 12-lead, high-lead and AED rhythm strip)

Cardiac telemetry

Coronary assessment

Echocardiogram

Cardiac MRI

Management

Secondary prevention ICD

Medical therapy directed by diagnostic results

Additional testing

Signal-averaged ECG

Holter monitoring (12-lead if possible)

Exercise stress test

Sodium channel blocker provocation

Genetic testing

Discretionary testing

Coronary spasm provocation

Epinephrine provocation

EP study ± electro-anatomical mapping

Re-evaluation

Every 2-3 years for probands for changes in phenotype and in the setting of evolving understanding of IVF

Family screening

First-degree relatives if identified cause in proband OR in those with suspicious cardiogenic symptoms

Other Recognized Syndromes
CPVTSQTSERSSCVF
Diagnosis

Stress (physical or emotional) induced syncope or cardiac arrest

Bidirectional PVCs during exercise testing

Pathogenic variant in RYR2 or CASQ2 gene

Management

Avoid competitive sports and strenuous exercise

β-blockers in all patients

Flecainide if breakthrough events despite β-blocker therapy

LCSD and/or ICD if breakthrough events despite medical therapy

Primary prevention ICD not indicated

Diagnosis

Baseline QTc ≤330ms

Baseline QTc ≤360ms in patient with otherwise unexplained cardiac arrest OR pathogenic gene variant carrier OR suspicious family history

Management

Medical therapy with quinidine may be considered

Secondary prevention ICD

Primary prevention ICD may be considered in patients with SQTS who have non-sustained VT or cardiogenic syncope

Diagnosis

ERP ECG in patient with otherwise unexplained cardiac arrest

ERP ECG in patient with otherwise unexplained SCD (retrospectively identified)

Management

Avoid hypothermia and β-blockers

Secondary prevention ICD

Primary prevention ICD not indicated

Medical therapy (isoproterenol/quinidine) or catheter ablation may be effective in patients with breakthrough events

Diagnosis

Patient with documented VF or polymorphic VT which is initiated by a PVC with a coupling interval <350ms

Absence of other conditions

Management

Secondary prevention ICD

Medical therapy with quinidine may be effective in patients with breakthrough events

Catheter ablation may be considered for those with breakthrough events despite medical therapy

AED = automated external defibrillator; CPVT = catecholaminergic polymorphic ventricular tachycardia; EP = electrophysiology; ERP = early repolarization pattern; ERS = early repolarization syndrome; ICD = implantable cardioverter defibrillator; IVF = idiopathic ventricular fibrillation; LCSD = left cardiac sympathetic denervation; MRI = magnetic resonance imaging; PVCs = premature ventricular complexes; SCD = sudden cardiac death; SQTS = short QT syndrome; VT = ventricular tachycardia.

Initial Approach to Resuscitated Cardiac Arrest

In patients who present with resuscitated cardiac arrest, the initial evaluation should look to exclude recognized conditions, with various approaches being proposed.4-8 First-line care of the cardiac arrest patient typically identifies coronary artery disease or left ventricular dysfunction in up to 90% of patients.9 Though beyond the scope of this review, potential latent structural causes of cardiac arrest including myocarditis, cardiac sarcoid, coronary anomalies, and mitral valve prolapse should also be excluded.4,10,11

In-hospital evaluation should include a detailed clinical history encompassing circumstances of cardiac arrest including documentation of arrhythmia from an automated external defibrillator (where available), prior episodes of syncope or presyncope (and associated circumstances), substance history,12 and pertinent family history (Table 2).13 Importantly, drug overdose (such as opiates) may result in cardiac arrest, although the arrhythmic contribution to these events is yet to be established.14 Relevant inpatient investigations are repeated 12-lead electrocardiogram (ECG), high-lead ECG for Brugada pattern, bloodwork including electrolytes and cardiac enzymes, coronary assessment, echocardiogram, and cardiac magnetic resonance imaging in those with non-ischemic cardiac arrest. Repeated 12-lead ECG is particularly important as a prolonged QTc shortly after resuscitated cardiac arrest may not necessarily represent underlying long QT syndrome.15,16 Additional testing depending on initial workup results can be arranged after patient discharge, and should include provocation testing (exercise testing and sodium channel blocker challenge), Holter monitoring (if implantable cardioverter-defibrillator [ICD] is not inserted) and possibly signal-averaged ECG. In conjunction with a genetics expert, targeted or broad cardiac panel genetic testing may be considered in the workup of patients with resuscitated cardiac arrest.17,18 Further discretionary testing may be sought in certain instances, such as epinephrine test in patients who are unable to exercise, provocation testing for coronary artery spasm, and electrophysiology study for identification of electroanatomical triggers and substrate abnormalities. It is important to consider an inclusive testing strategy to gather “clues” to latent diagnoses, bearing in mind the limitations of many of our tests,8,19 such as limited specificity of signal-averaged ECG or electrophysiology study.

Table 2 Relevant Clinical History in “Unexplained” Cardiac Arrest

Clinical HistoryRelevant Information
Circumstances of cardiac arrest or syncope

Physical exertion (LQT1, ARVC, CPVT)

Emotional stress

Startle (LQT2)

Fever (BrS)

Rest (BrS, ERS, SCVF)

Vagal stimulation (exclude vasovagal syncope)

Additional history

Exercise level (ARVC, CPVT)

Seizures (LQTS)

Substance history

Proarrhythmic medications

Illicit or recreational drugs

Alcohol

Drugs that prolong QT

Drugs that may induce Brugada

Family history

Sudden death with autopsy reports if available

Circumstances of events in family members

Unexplained drownings

Drivers in motor vehicle accidents

ARVC = arrhythmogenic right ventricular cardiomyopathy; BrS = Brugada syndrome; LQTS = long QT syndrome; SCVF = short-coupled ventricular fibrillation; other abbreviations as in Table 1.

In our experience, application of this framework will allow for identification of the most common inherited arrhythmia syndromes. These include more common conditions such as long QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy, which have been previously described, and the less common conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), early repolarization syndrome (ERS), and short-coupled ventricular fibrillation (SCVF) described in this review.

Catecholaminergic Polymorphic Ventricular Tachycardia

CPVT is a genetic condition whereby disordered intracellular Ca2+ handling results in catecholamine-triggered episodes of malignant ventricular arrhythmias.

Pathophysiology

Under normal circumstances, cardiomyocyte depolarization leads to opening of L-type calcium channels with a resultant influx of Ca2+ during phase 2 of the cardiac action potential (Figure 1).20 The influx of Ca2+ binds to the ryanodine receptor 2 (RYR2), causing further release of Ca2+ from the sarcoplasmic reticulum in a process termed calcium-induced calcium release.20 Various other proteins are important in this process, including calsequestrin 2 (CASQ2, which binds to cytosolic Ca2+ within the sarcoplasmic reticulum), triadin (TRDN, which anchors CASQ2 to RYR2), and calmodulin (CALM, which binds to both RYR2 and L-type calcium channel, regulating sensitivity to Ca2+ levels).21,22 This intracellular cytosolic increase in Ca2+ results in myocyte contraction, which is a critical component of excitation–contraction coupling.20,21

Figure 1
Figure 1

Schematic Representation of IC Calcium Homeostasis

CALM = calmodulin; CASQ2 = calsequestrin; EC = extracellular; IC = intracellular; LTCC = L-type calcium channel; NCX = sodium calcium exchange; PM = plasma membrane; SR = sarcoplasmic reticulum; TRDN = triadin.

Dysregulation of intracellular Ca2+ handling is central to the development of CPVT, with the net effect being an increase in intracellular Ca2+. This could be due to a propensity for RYR2 to inappropriately release Ca2+ from the sarcoplasmic reticulum or an inability for CASQ2 to adequately sequester Ca2+ within the sarcoplasmic reticulum.20-22 The increase in intracellular Ca2+ activates the sodium-calcium exchanger, resulting in intracellular Na+ influx and extracellular Ca2+ efflux.23 This Na+ influx leads to cell membrane activation after an action potential has already occurred, causing delayed after-depolarizations,21 which can result in premature ventricular complexes (PVCs) and trigger malignant ventricular arrhythmias.23 Adrenergic stimulation is thought to potentiate sarcoplasmic/endoplasmic reticulum Ca2+ ATPase–mediated Ca2+ reuptake within the sarcoplasmic reticulum and enhance responsiveness of RYR2, leading to the overload of Ca2+ within the sarcoplasmic reticulum coupled with spontaneous Ca2+ release,21,22 resulting in the clinical phenotype of adrenergic induced ventricular arrhythmias.

Genetic variants in RYR2 and CASQ2 are the most commonly found in CPVT, accounting for 50% to 60% of clinical cases.24 In general, gain-of-function variants in RYR2 result in an autosomal dominant form of CPVT25-27 and loss-of-function variants in CASQ2 result in an autosomal recessive form of CPVT,28,29 although deviations from this are described, including an autosomal dominant form of CASQ2-related CPVT.30,31 Less common genetic substrates for CPVT include variants in TRDN (encoding for triadin), CALM (encoding calmodulin), and TECRL (which plays an important role in calcium handling).32,33

Epidemiology

The prevalence of CPVT is estimated to be ∼1:10,000,34 with an equal sex distribution.35,36 Most index patients are diagnosed in later childhood or adolescence, typically between 10 and 12 years.35,36 CPVT is thought to account for up to 10% of cases with “unexplained” cardiac arrest (after exclusion of coronary artery disease or overt structural disease).4,37 CPVT may be even more prevalent in cases of unexplained SCD, whereby ∼15% of families of unexplained SCD victims are found to have CPVT.38

Diagnosis

The classic clinical manifestation of CPVT is stress (exercise or emotional) induced syncope or cardiac arrest,39,40 although up to 25% of episodes are reported to occur in the setting of normal activity.36 Based on earlier cohorts, ∼30% are diagnosed after an episode of resuscitated cardiac arrest, and an additional 50% will have had syncope.41,42 At the time of diagnosis ∼20% of patients are asymptomatic,42 however this is likely to increase with broader access to genetic testing and an emphasis on cascade screening.

The baseline ECG in CPVT is often normal, aside from a preponderance for sinus bradycardia,43 as are other electrophysiological tests, including signal-averaged ECG and programmed ventricular stimulation.44

The pathognomonic feature of CPVT is exercise-induced polymorphic ventricular arrhythmias, especially bidirectional ventricular tachycardia (VT) (Figure 2).44 In a group of 67 asymptomatic relatives of patients with CPVT, Hayashi et al45 found that exercise testing (positive result being induction of ventricular bigeminy, couplets, or VT) produced a sensitivity of 50% and specificity of 97%. Patients with CPVT may also have more frequent exercise-induced PVCs,46 although this finding would be associated with a lower specificity for diagnosis. Recently, it has been proposed that a burst exercise testing protocol may increase the sensitivity for diagnosis of CPVT compared with standard exercise testing,47 although further validation studies are required. Burst testing should be considered in patients with exertional syncope or cardiac arrest if standard exercise testing is nondiagnostic.

Figure 2
Figure 2

ECG Examples of “Latent” Cardiac Arrest Conditions

CPVT = catecholaminergic polymorphic ventricular tachycardia; ECG = electrocardiogram; ERS = early repolarization syndrome; SC-VF = short-coupled ventricular fibrillation; SQTS = short QT syndrome.

Pharmacologic provocation testing with intravenous epinephrine may also induce ventricular arrhythmias in patients with CPVT. However, this is associated with a lower diagnostic sensitivity44,48 and should not replace the use of exercise testing. In those who are unable to exercise, pharmacologic testing should be considered.

In index patients who manifest a clinical CPVT phenotype, genetic testing is recommended, as this may allow for variant-specific cascade testing for family members. Family members who carry a pathogenic or likely pathogenic variant should undergo detailed phenotypic evaluation, including assessment for syncope and exercise testing. Currently, we would consider likely pathogenic and pathogenic variants in RYR2, CASQ2, TRDN, TECRL, CALM1, CALM2, and CALM3 to be disease-causing in CPVT.32,49,50

Management

Due to the preponderance of reported cardiac events (including syncope and cardiac arrest) during exertion,42 assessment in a specialized cardiogenetic clinic and expert opinion are required with regard to recommendations for physical exercise. Although competitive sports and strenuous physical exercise harbor an increased risk of ventricular arrhythmia, recent recommendations have shifted from general restriction to a more individualized approach focusing on shared decision-making.51,52 Limited real-world data indicate that ongoing athletic participation in patients with CPVT does not result in more cardiac events compared with nonathletes.53 Patients are also advised to limit potential exposures to emotional stress where possible.34,42 Evidence for these recommendations is lacking, and ongoing moderate-level exercise in well-treated patients may offer overall cardiovascular benefits. It has been shown that graduated exercise training in mice may protect against arrhythmic events in CPVT,54 whereas exercise training in humans has been shown to improve aerobic capacity and increase the heart rate threshold required for the development of PVCs.55 Thus, our understanding regarding the role of exercise restriction in CPVT is still evolving.

Pharmacotherapy with β-blockers is recommended in all patients who exhibit a clinical CPVT phenotype and may be considered in those with concealed CPVT (genotype positive, phenotype negative).34 In a cohort of 101 patients with CPVT, Hayashi et al56 found that absence of β-blockers was independently associated with a 5-fold risk increase of significant arrhythmic events. Where possible, nonselective β-blockers (nadolol and propranolol) are preferred. Leren et al57 showed that compared with no therapy, nadolol reduces the severity of exercise induced ventricular arrhythmias, whereas no difference was seen with metoprolol. Adherence is important because most cardiac events after diagnosis are reported in the setting of nonadherence.42,58 Of note, adequate treatment with β-blockers is considered safe during pregnancy, and effective for minimizing cardiac events while pregnant.59

Flecainide is an effective adjunct in patients who experience breakthrough events or continue to have complex ventricular arrhythmias on exercise testing despite optimal β-blocker therapy.42,60-64 In a small, randomized control trial, Kannankeril et al65 showed that flecainide and β-blocker combination therapy was more effective than β-blocker alone in reducing exercise induced ventricular arrhythmias, indicating a possible role for early combined pharmacotherapy. There is also limited evidence suggesting a role for flecainide monotherapy in patients who are truly intolerant of β-blockers.42,60-64 On a cellular level, flecainide is thought to exert its effect on Na+ channels and/or due to a direct effect on RYR2.66-68 In patients requiring additional therapeutic escalation, verapamil may be effective.69

In addition, left cardiac sympathetic denervation should be considered in those who experience breakthrough cardiac events despite optimization and escalation of pharmacotherapy.70,71 Left cardiac sympathetic denervation is effective for reducing cardiac events and ICD shocks.72

The current role for ICD in patients with CPVT is contentious. Although conventionally recommended for patients who have experienced a cardiac arrest event,34 ICD complication rates are particularly high in CPVT cohorts.73 In a recent multicenter international study of 136 CPVT patients diagnosed after an episode of cardiac arrest (and were thus treatment naive), van der Werf et al74 found that ICD insertion was associated with a high complication rate (including inappropriate shocks and lead malfunction), but was not associated with a reduction in subsequent SCD events. Based on the current available data, we would recommend against the use of a primary prevention ICD in patients with CPVT. In untreated patients who experience a cardiac arrest, a shared decision-making discussion is warranted. In principle, refraining from ICD implantation warrants consideration despite the secondary prevention context, because of the efficacy of medical therapy and left cardiac sympathetic denervation, and the risks of ICD in this typically young population. In patients who are adequately managed on pharmacotherapy, but experience a cardiac arrest event, a secondary prevention ICD is recommended. In such cases, left cardiac sympathetic denervation should also be considered. ICD programming parameters in patients with CPVT should consider that treatment of initiating rhythms (bidirectional VT or polymorphic VT) is rarely successful75,76 therefore delayed detection with a single ventricular fibrillation (VF) zone programming is recommended.

Future Directions

Our genetic understanding of CPVT is incomplete, as approximately one-third of clinical cases are not associated with an identifiable genetic variant. The relatively recent recognition of TRDN, CALM, and TECRL gene variants as disease causing should prompt efforts for the identification and association of variants in other Ca2+ handling proteins in the pathophysiology of CPVT. Furthermore, recent work demonstrating polygenic influences in other inherited arrhythmia syndromes77,78 may be translatable to patients with CPVT.

Several emerging treatments show promise in CPVT. Preliminary studies indicate that modulation of sinus rate with atropine or atrial overdrive pacing is beneficial in reducing exercise induced ventricular arrhythmias.79,80 Although the exact mechanism is unclear, it is hypothesized that an increase in sinus rate shortens the subsequent diastolic interval, thereby reducing the likelihood of spontaneous SR Ca2+ release, which in turn triggers ventricular ectopy.80 Molecular therapies offer an exciting prospect for a potential “cure” in CPVT. Adeno-associated viral vector serotype 9 gene transfer has successfully reversed both molecular changes and clinical phenotype in murine models of CPVT,81-86 and more recently in a human induced pluripotent stem cell model of CPVT.86 Other options in development include mitochondrial Ca2+ uptake enhancers87 and a fungal RYR2 antagonist.88

Short QT Syndrome

SQTS is a very rare condition characterized by arrhythmic events in the setting of a short QT interval.

Pathophysiology

The pathophysiologic basis of SQTS is thought to be related to abbreviation of the cardiac action potential duration, most commonly from gain-of-function variants in potassium channels.89 Within published reports, a gene variant is identified in up to 50% of reported cases of SQTS,90 and most frequently affect KCNH2 (SQT1), KCNQ1 (SQT2), KCNJ2 (SQT3), and SLC4A3.90,91 The most common variant is KCNH2, encoding for the delayed rectifier potassium channel KV11.1,92 resulting in greater outward potassium current (IKr) during phase 3 of the action potential. Increased IKr density causes shortening of the action potential duration93-96 with impaired heart rate adaptation,94-96 shortening of the effective refractory period (both atrial and ventricular),95 with subsequent arrhythmogenicity affecting the atrium and ventricle. In addition, variants affecting ion transporters97-99 are also reported to result in clinical SQTS.

Epidemiology

SQTS is a rare condition, and the true prevalence is unknown. A recent systematic review identified a total of 145 published cases of SQTS.90 In cohort studies of patients with resuscitated cardiac arrest and/or SCD, there have been no reported cases of SQTS.4,37,38 Of note, atrial arrhythmias are reported in ∼20% of patients with SQTS.90

Diagnosis

Clinical manifestations of SQTS include cardiac arrest or SCD, cardiogenic syncope, and atrial arrhythmias.90,100,101 Based on current reports, ∼40% of patients in SQTS registries are asymptomatic,90 although this number would be significantly higher if population screening cases were included.

A QTc ≤330 ms on baseline ECG (Figure 2) confers a diagnosis of SQTS,34,102 although a cutoff of ≤315 ms has been suggested in children.103 Currently, the Bazett correction is proposed,102 although consensus is lacking.104 Using a cutoff of QTc ≤330 ms, the prevalence of SQTS within general population–screening ECG studies ranges between 0% and 0.2%,104-108 with generally favorable outcomes in these cases in the absence of other cardiac abnormalities.105-108 In survivors of unexplained cardiac arrest, or those who carry a pathogenic gene variant or have a suspicious family history, a QTc ≤360 ms may confer a diagnosis of SQTS.34

Other changes that have been reported in patients with SQTS include less QTc variation during exercise ECG,109 functional left ventricular abnormalities,110 and abbreviation of both atrial and ventricular effective refractory periods during electrophysiological study.111 However, further validation of these parameters is required. A potentially interesting consideration is that patients with SQTS may have failure of QT-interval prolongation during periods of bradycardia, in a similar vein to those with long QT syndrome exhibiting maladaptive QTc responses during exercise and recovery,112 so resting and nocturnal monitoring is likely the optimal mechanism to detect failed QT prolongation.

Management

Quinidine, and its related compound hydroquinidine, is useful in the pharmacologic management of SQTS.113,114 Quinidine has complex antiarrhythmic properties. Although categorized as a class 1a agent,115 thereby prolonging phase 0 of the action potential, quinidine is also known to inhibit potassium currents throughout the duration of the action potential and ICaL during phase 2 of the action potential.116 Mechanistically, it is thought that inhibition of IKr is important in the antiarrhythmic effect of quinidine in SQTS.117 On a cellular level, this results in prolongation of the action potential duration and effective refractory period,117-119 clinically translating to lengthening of the QT interval and suppression of ventricular arrhythmias.113,114 The side effect profile of quinidine is significant,114 and its use is limited due to a lack of drug availability.120,121 Other potential pharmacotherapy options in SQTS include disopyramide,117,122 ivabradine,123,124 mexiletine,124,125 and ajmaline,124 although clinical experience is limited. In general, pharmacotherapy is reserved for symptomatic patients with SQTS.

Similarly, there are few reports regarding the use of ICD in patients with SQTS.126,127 In patients with SQTS and a history of cardiac arrest, a secondary prevention ICD is indicated.34 A transvenous ICD with atrial pacing capability may theoretically protect from bradycardia-induced ventricular arrhythmia. Inappropriate therapies due to T-wave oversensing may be more prevalent in patients with SQTS.127,128 In those with SQTS and nonsustained VT or cardiogenic syncope, it is reasonable to engage patients in a shared decision-making process regarding a primary prevention ICD. Currently, there is no role for the use of a primary prevention ICD in asymptomatic patients with SQTS.

Early Repolarization Syndrome

ERS is a diagnosis of exclusion involving the presence of an early repolarization pattern (ERP) ECG in an individual with resuscitated cardiac arrest or SCD, in the absence of another identifiable cause. This is an important distinction compared with other primary arrhythmic conditions (such as long QT syndrome or Brugada syndrome) whereby a clinical event is required for the diagnosis of ERS.

Pathophysiology

The pathophysiological understanding of ERS is incomplete. It has been proposed that increased transient outward potassium current (Ito) is a central mechanism.129,130 Owing to heterogenous changes in epicardial Ito, there is localized phase 2 re-entry.131 Clinically, this is manifest as fractionated epicardial electrograms localized to the areas of J-waves with shortening of the action potential duration and the occurrence of PVCs.132,133 Recently, localized epicardial fibrofatty changes have been proposed to contribute to arrhythmogenesis.134 Genetic variants encoding for sodium and potassium channels are reported in association with clinical cases of ERS,135-137 although this link remains tenuous.

Epidemiology

The ERP ECG was initially described in 1936 by Shipley and Hallaran,138 and for a long period thereafter, was thought to be a benign phenomenon.139,140

In 2008, an international collaborative study by Haïssaguerre et al141 found that ERP was significantly more prevalent in 206 patients with otherwise idiopathic VF (31%) compared with 412 control subjects (5%). Contemporaneously, similar findings were shown by Rosso et al,142 and a high prevalence was verified in a registry of patients with cardiac arrest without manifest coronary or structural disease.143 Thus, within a cardiac arrest cohort, the prevalence of ERP is ∼30%.141-144 Interestingly, the presence of ERP within cohorts of patients with an established primary arrhythmic syndrome such as long QT syndrome,145 Brugada syndrome,146,147 CPVT,148 or SQTS149 has been reported to be associated with worse outcomes.

By contrast, the prevalence of ERP within the general population is ∼5%150 being more common in young males, athletes,142 and African Americans.151 Although the presence of ERP appears to be associated with an increased risk of cardiovascular mortality,151,152 its significance is questionable when adjusting for factors such as age, sex, and race.151

Diagnosis

Currently, the diagnosis of ERS is only made in the presence of an ERP ECG in a patient with resuscitated cardiac arrest due to documented VF or polymorphic VT with no other attributable cause; or post-mortem in someone with SCD, negative autopsy, and retrospective recognition of an ERP ECG.34 The ERP ECG is defined as the presence of J-point elevation (end-QRS notch on the downslope of a prominent R-wave) ≥1 mm involving ≥2 leads (excluding V1 to V3), where the QRS duration is <120 ms (Figure 2).141,153-155 It is proposed that the ST segment following the terminal portion of the J-point may indicate “malignant” or “benign” early repolarization (Figure 3)—malignant if the ST segment is downsloping or flat, and benign if the ST segment is upsloping154—although further validation is required. Although the ERP may fluctuate, there is currently no validated provocation test for ERP.

Figure 3
Figure 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 = electrocardiogram.

Management

The management modalities described in the following text are for patients with ERS rather than asymptomatic individuals with ERP ECG. In asymptomatic individuals with ERP ECG, we would advocate for reassurance only.

Conservative measures that may be useful include avoidance of hypothermia, correction of electrolyte disturbances, and avoidance of β-blockers, although evidence for these recommendations are primarily from case reports. Hypothermia, which may be spontaneous or initiated in the post-cardiac arrest care pathway, is reported to induce VF in ERS.156,157 In addition, hypokalemia may also precipitate VF,158 whereas β-blockers can accentuate ECG changes in patients with ERP.159

Pharmacotherapy options in ERS include isoproterenol,159,160 quinidine,161 cilostazol,160,162 and sodium channel blockers.163,164 Mechanistically, it is proposed that inhibition of Ito and augmentation of ICaL are important in reversing the repolarization defects.160 The evidence for pharmacotherapy is limited, arising from small observational studies, and currently do not obviate the need for a secondary prevention ICD in those with ERS.

A secondary prevention ICD is indicated in patients with ERS. Furthermore, catheter ablation of VF triggers may be considered in patients with ERS and recurrent VF. These triggers are reported within the right ventricular outflow tract or Purkinje cells.165

Short-Coupled VF

SCVF is used to describe patients with VF that is initiated by PVCs with a short coupling interval. Of note, SCVF appears to consist of a distinct subset of patients who were previously described to have idiopathic VF.166

Pathophysiology

The pathophysiological basis of SCVF is largely undefined, although it is postulated that overactive Purkinje fiber Ito plays an important role,167 thereby providing mechanistic overlap with Brugada syndrome and early repolarization syndrome.166 Increased function of dipeptidyl-peptidase 6, encoded by the DPP6 gene, may lead to SCVF in some patients through an increase in Ito.168 However, this exploratory gene is predominantly described in the Dutch founder population,168,169 and a genetic basis for SCVF requires further elucidation. Electrophysiological observations in this patient cohort indicates that Purkinje system PVCs in conjunction with localized structural changes are important in the development of VF.170-172

Epidemiology

In 1994, Leenhardt et al173 described a cohort of patients with torsade de pointes and VF that was initiated by a short-coupled PVC. However, only recently has SCVF been recognized as a distinct clinical phenotype in patients with otherwise unexplained cardiac arrest, meaning that its true prevalence is largely undefined. An initial report from CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry) suggests SCVF accounts for at least 6% of unexplained cardiac arrest survivors.166

Diagnosis

Currently, the diagnosis of SCVF is made in patients with documented VF (or polymorphic VT) that is initiated by a PVC with a coupling interval <350 ms (Figure 2).166,173-175 Additional markers of a short-coupled PVC include a prematurity index (ratio of coupling interval to previous RR interval) of ≤0.4,174 which usually occurs within 40 ms of the peak of the preceding T wave.174 Because documentation of a PVC coupling interval is required, the diagnosis of SCVF is made almost exclusively in patients with recurrent VF captured during initial hospitalization or in follow-up on an ICD.166

Management

Patients with SCVF may be more susceptible to electrical storm compared with other patients with unexplained cardiac arrest.166 Medical therapy with quinidine may be effective as first-line therapy in patients with recurrent VF.166 Catheter ablation of PVC triggers may be considered if episodes persist despite optimized medical therapy.170,171,176 These triggers have been reported to occur in various locations, including the Purkinje system,170,171 anterior right ventricle,170,171 and right ventricular outflow tract.175,177

Other Entities

Genetic variants in CALM predominantly manifest as long QT syndrome or CPVT.178 Recently, CALM variants have been associated with idiopathic VF.179-181 In a cohort of 74 patients carrying CALM1, CALM2, or CALM3 variants, the International Calmodulin Registry reported that ∼15% of cases presented with idiopathic VF or SCD.178

Bundle branch re-entry VT is a macro-reentrant arrhythmia involving the left and right bundle branches, which may result in cardiac arrest.182 Although most commonly occurring in association with cardiomyopathy or ischemic heart disease,183 it is also reported in those without evidence of structural heart disease.184,185 Recently, it is suggested that bundle branch re-entry VT in the absence of structural heart disease may have an underlying genetic etiology.186

Finally, widespread and persistent ST-segment depression has been reported in families with otherwise unexplained cardiac arrest that appears to be inherited in an autosomal dominant manner, but without identification of a candidate gene.187

Idiopathic VF

In patients where extensive evaluation does not reveal an underlying etiology, a diagnosis of idiopathic VF is assigned. Importantly, this definition is evolving as more conditions are identified.5

The prevalence of idiopathic VF varies depending on the inclusion criteria of patients, and extent of investigations. Based on a large all-inclusive registry of cardiac arrest patients, which included older patients with coronary artery disease, ∼7% of patients were ultimately considered to have idiopathic VF.188 In more selective cohorts that excluded those with coronary artery disease and dilated cardiomyopathy, ∼40% to 50% of patients are considered to have idiopathic VF after extensive clinical evaluation.4,37,38 The proportion of cases attributable to idiopathic VF is also decreasing over time with the recognition of newer clinical entities and as concealed etiologies become overt.5 In those who are assigned a diagnosis of idiopathic VF after extensive investigations, we would recommend re-evaluation every 2 to 3 years due to our evolving understanding of idiopathic VF and the possibility of age or time dependent penetrance of certain conditions.189

In patients with idiopathic VF, a secondary prevention ICD is indicated. In those with idiopathic VF and an ICD, ∼25% to 30% will have appropriate ICD therapies after 5 years of follow-up,190-193 in contrast with a rate of inappropriate therapies of ∼15%.191,193

Future Directions

Our understanding of the latent causes of cardiac arrest continues to advance, meaning that more entities are now identified and fewer cases are termed idiopathic. This evolution of explaining cardiac arrest is nicely summarized in a recent editorial by van der Ree and Postema.194 The discovery of autoantibodies directed against various cardiac ion channels may provide additional clarity. Thus far, autoantibodies against various potassium channels are shown to influence repolarization and be associated with torsade de pointes,195-197 whereas autoantibodies against the L-type calcium channel are associated with the occurrence of SCD.198

Furthermore, genetic influences in cases of idiopathic VF could be pivotal. Monogenic variants in SCN5A and IRX3 (iroquois homebox, a Purkinje system transcription factor) are reported to cause Purkinje origin PVCs and SCD,199,200 whereas loss-of-function RYR2 variants may cause a distinct VF phenotype coined the calcium release deficiency syndrome.201 Consequently, it may become apparent that oligogenic or polygenic influences may account for a proportion of the current cohort of idiopathic VF patients, in a similar vein to the polygenic influences reported in long QT syndrome and Brugada syndrome.77,78

Conclusions

The systematic and comprehensive evaluation of patients after an episode of resuscitated cardiac arrest is pivotal for identifying etiology and the initiation of targeted management options. Careful review for latent clues to diagnosis should couple with provocation testing and long-term follow-up to facilitate diagnosis and related therapy. An understanding of the predominant primary arrhythmia syndromes is critical for practicing cardiologists and electrophysiologists.

Funding Support and Author Disclosures

The study was supported by the Heart in Rhythm Organization (Dr Krahn, principal investigator) that receives support from the Canadian Institute of Health Research (RN380020–406814). Dr Krahn receives support from the Sauder Family and Heart and Stroke 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 received support from the John and Birthe Meyer Foundation. Dr Tadros has received support from the Canadian Research Chair program. Dr Semsarian is the recipient of National Health and Medical Research Council (NHMRC) Practitioner Fellowship #1154992. Dr Han is supported by a Robert and Elizabeth Albert Travel Grant from the RACP Foundation, Australia. Dr Steinberg has reported that he has no relationships relevant to the contents of this paper to disclose.

Abbreviations and Acronyms

CPVT

catecholaminergic polymorphic ventricular tachycardia

ECG

electrocardiogram

ERP

early repolarization pattern

ERS

early repolarization syndrome

ICD

implantable cardioverter-defibrillator

PVC

premature ventricular complex

SCD

sudden cardiac death

SCVF

short-coupled ventricular fibrillation

SQTS

short QT syndrome

VF

ventricular fibrillation

VT

ventricular tachycardia

References

  • 1. Krahn A.D., Behr E.R., Hamilton R., Probst V., Laksman Z., Han H.-C. "Brugada syndrome". J Am Coll Cardiol EP 2022;8:3: 386-405.

    Google Scholar
  • 2. Krahn A.D., Wilde A.A.M., Calkins H., et al. "Arrhythmogenic right ventricular cardiomyopathy". J Am Coll Cardiol EP 2022;8:4: 533-553.

    Google Scholar
  • 3. Krahn A.D., Laksman Z., Sy R.W., et al. "Congenital long QT syndrome". J Am Coll Cardiol EP. 2022;8:5: 687-706.

    Google Scholar
  • 4. Krahn A.D., Healey J.S., Chauhan V., et al. "Systematic assessment of patients with unexplained cardiac arrest: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER)". Circulation 2009;120:278-285.

    CrossrefMedlineGoogle Scholar
  • 5. Visser M., van der Heijden J.F., Doevendans P.A., Loh P., Wilde A.A., Hassink R.J. "Idiopathic ventricular fibrillation: the struggle for definition, diagnosis, and follow-up". Circ Arrhythm Electrophysiol 2016;9:5: e003817.

    CrossrefGoogle Scholar
  • 6. Haïssaguerre M., Duchateau J., Dubois R., et al. "Idiopathic ventricular fibrillation: role of Purkinje system and microstructural myocardial abnormalities". J Am Coll Cardiol EP 2020;6:591-608.

    Google Scholar
  • 7. Davies B., Roberts J.D., Tadros R., et al. "The Hearts in Rhythm Organization: a Canadian National Cardiogenetics Network". CJC Open 2020;2:652-662.

    CrossrefMedlineGoogle Scholar
  • 8. Alqarawi W., Dewidar O., Tadros R., et al. "Defining idiopathic ventricular fibrillation: a systematic review of diagnostic testing yield in apparently unexplained cardiac arrest". Heart Rhythm 2021;18:7: 1178-1185.

    CrossrefMedlineGoogle Scholar
  • 9. Hayashi M., Shimizu W., Albert C.M. "The spectrum of epidemiology underlying sudden cardiac death". Circ Res 2015;116:1887-1906.

    CrossrefMedlineGoogle Scholar
  • 10. Han H.C., Parsons S.A., Teh A.W., et al. "Characteristic histopathological findings and cardiac arrest rhythm in isolated mitral valve prolapse and sudden cardiac death". J Am Heart Assoc 2020;9: e015587.

    CrossrefGoogle Scholar
  • 11. Yafasova A., Fosbøl E.L., Schou M., et al. "Long-term adverse cardiac outcomes in patients with sarcoidosis". J Am Coll Cardiol 2020;76:767-777.

    View ArticleGoogle Scholar
  • 12. Weeke P.E., Kellemann J.S., Jespersen C.B., et al. "Long-term proarrhythmic pharmacotherapy among patients with congenital long QT syndrome and risk of arrhythmia and mortality". Eur Heart J 2019;40:3110-3117.

    CrossrefMedlineGoogle Scholar
  • 13. Bjune T., Risgaard B., Kruckow L., et al. "Post-mortem toxicology in young sudden cardiac death victims: a nationwide cohort study". Europace 2018;20:614-621.

    CrossrefMedlineGoogle Scholar
  • 14. Simpson T.F., Salazar J.W., Vittinghoff E., et al. "Association of QT-prolonging medications with risk of autopsy-defined causes of sudden death". JAMA Intern Med 2020;180:698-706.

    CrossrefMedlineGoogle Scholar
  • 15. Anilkumar A., Moore E.J., Gall A.J., Sammut E., Barman P. "QTc interval in survivors of out of hospital cardiac arrest". Int J Cardiol 2021;323:118-123.

    CrossrefMedlineGoogle Scholar
  • 16. Cohen R.B., Dai M., Aizer A., et al. "QT interval dynamics and triggers for QT prolongation immediately following cardiac arrest". Resuscitation 2021;162:171-179.

    CrossrefMedlineGoogle Scholar
  • 17. Bagnall R.D., Weintraub R.G., Ingles J., et al. "A prospective study of sudden cardiac death among children and young adults". N Engl J Med 2016;374:2441-2452.

    CrossrefMedlineGoogle Scholar
  • 18. Isbister J.C., Nowak N., Butters A., et al. "“Concealed cardiomyopathy” as a cause of previously unexplained sudden cardiac arrest". Int J Cardiol 2021;324:96-101.

    CrossrefMedlineGoogle Scholar
  • 19. Tadros R., Nannenberg E.A., Lieve K.V., et al. "Yield and pitfalls of ajmaline testing in the evaluation of unexplained cardiac arrest and sudden unexplained death: single-center experience with 482 families". J Am Coll Cardiol EP 2017;3:1400-1408.

    Google Scholar
  • 20. Györke S. "Molecular basis of catecholaminergic polymorphic ventricular tachycardia". Heart Rhythm 2009;6:123-129.

    CrossrefMedlineGoogle Scholar
  • 21. Priori S.G., Chen S.R. "Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis". Circ Res 2011;108:871-883.

    CrossrefMedlineGoogle Scholar
  • 22. Wleklinski M.J., Kannankeril P.J., Knollmann B.C. "Molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia". J Physiol 2020;598:2817-2834.

    CrossrefMedlineGoogle Scholar
  • 23. Blaustein M.P., Lederer W.J. "Sodium/calcium exchange: its physiological implications". Physiol Rev 1999;79:763-854.

    CrossrefMedlineGoogle Scholar
  • 24. Ingles J., Macciocca I., Morales A., Thomson K. "Genetic testing in inherited heart diseases". Heart Lung Circ 2020;29:505-511.

    CrossrefMedlineGoogle Scholar
  • 25. Swan H., Piippo K., Viitasalo M., et al. "Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts". J Am Coll Cardiol 1999;34:2035-2042.

    View ArticleGoogle Scholar
  • 26. Priori S.G., Napolitano C., Tiso N., et al. "Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia". Circulation 2001;103:196-200.

    CrossrefMedlineGoogle Scholar
  • 27. Laitinen P.J., Brown K.M., Piippo K., et al. "Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia". Circulation 2001;103:485-490.

    CrossrefMedlineGoogle Scholar
  • 28. Lahat H., Pras E., Olender T., et al. "A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in Bedouin families from Israel". Am J Hum Genet 2001;69:1378-1384.

    CrossrefMedlineGoogle Scholar
  • 29. Postma A.V., Denjoy I., Hoorntje T.M., et al. "Absence of calsequestrin 2 causes severe forms of catecholaminergic polymorphic ventricular tachycardia". Circ Res 2002;91:e21-e26.

    CrossrefMedlineGoogle Scholar
  • 30. Zhao Y.T., Valdivia C.R., Gurrola G.B., et al. "Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function". Proc Natl Acad Sci U S A 2015;112:E1669-E1677.

    CrossrefMedlineGoogle Scholar
  • 31. Gray B., Bagnall R.D., Lam L., et al. "A novel heterozygous mutation in cardiac calsequestrin causes autosomal dominant catecholaminergic polymorphic ventricular tachycardia". Heart Rhythm 2016;13:1652-1660.

    CrossrefMedlineGoogle Scholar
  • 32. Jabbari J., Jabbari R., Nielsen M.W., et al. "New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia". Circ Cardiovasc Genet 2013;6:481-489.

    CrossrefMedlineGoogle Scholar
  • 33. Devalla H.D., Gélinas R., Aburawi E.H., et al. "TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT". EMBO Mol Med 2016;8:1390-1408.

    CrossrefMedlineGoogle Scholar
  • 34. Priori S.G., Wilde A.A., Horie M., et al. "HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes". Heart Rhythm 2013;10:1932-1963.

    CrossrefMedlineGoogle Scholar
  • 35. Miyake C.Y., Asaki S.Y., Webster G., et al. "Circadian variation of ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia". J Am Coll Cardiol EP 2017;3:1308-1317.

    Google Scholar
  • 36. Roston T.M., Yuchi Z., Kannankeril P.J., et al. "The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry". Europace 2018;20:541-547.

    CrossrefMedlineGoogle Scholar
  • 37. Rucinski C., Winbo A., Marcondes L., et al. "A population-based registry of patients with inherited cardiac conditions and resuscitated cardiac arrest". J Am Coll Cardiol 2020;75:2698-2707.

    View ArticleGoogle Scholar
  • 38. van der Werf C., Hofman N., Tan H.L., et al. "Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: the experience of a tertiary referral center in The Netherlands". Heart Rhythm 2010;7:1383-1389.

    CrossrefMedlineGoogle Scholar
  • 39. Reid D.S., Tynan M., Braidwood L., Fitzgerald G.R. "Bidirectional tachycardia in a child. A study using His bundle electrography". Brit Heart J 1975;37:339-344.

    CrossrefMedlineGoogle Scholar
  • 40. Priori S.G., Napolitano C., Memmi M., et al. "Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia". Circulation 2002;106:69-74.

    CrossrefMedlineGoogle Scholar
  • 41. Sy R.W., Gollob M.H., Klein G.J., et al. "Arrhythmia characterization and long-term outcomes in catecholaminergic polymorphic ventricular tachycardia". Heart Rhythm 2011;8:864-871.

    CrossrefMedlineGoogle Scholar
  • 42. Roston T.M., Vinocur J.M., Maginot K.R., et al. "Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry". Circ Arrhythm Electrophysiol 2015;8:633-642.

    CrossrefMedlineGoogle Scholar
  • 43. van der Werf C., Nederend I., Hofman N., et al. "Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives". Circ Arrhythm Electrophysiol 2012;5:748-756.

    CrossrefMedlineGoogle Scholar
  • 44. Sumitomo N., Harada K., Nagashima M., et al. "Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death". Heart 2003;89:66-70.

    CrossrefMedlineGoogle Scholar
  • 45. Hayashi M., Denjoy I., Hayashi M., et al. "The role of stress test for predicting genetic mutations and future cardiac events in asymptomatic relatives of catecholaminergic polymorphic ventricular tachycardia probands". Europace 2012;14:1344-1351.

    CrossrefMedlineGoogle Scholar
  • 46. Blich M., Marai I., Suleiman M., et al. "Electrocardiographic comparison of ventricular premature complexes during exercise test in patients with CPVT and healthy subjects". Pacing Clin Electrophysiol 2015;38:398-402.

    CrossrefMedlineGoogle Scholar
  • 47. Roston T.M., Kallas D., Davies B., et al. "Burst exercise testing can unmask arrhythmias in patients with incompletely penetrant catecholaminergic polymorphic ventricular tachycardia". J Am Coll Cardiol EP 2021;7:437-441.

    Google Scholar
  • 48. Marjamaa A., Hiippala A., Arrhenius B., et al. "Intravenous epinephrine infusion test in diagnosis of catecholaminergic polymorphic ventricular tachycardia". J Cardiovasc Electrophysiol 2012;23:194-199.

    CrossrefMedlineGoogle Scholar
  • 49. Rehm H.L., Berg J.S., Brooks L.D., et al. "ClinGen--the Clinical Genome Resource". N Engl J Med 2015;372:2235-2242.

    CrossrefMedlineGoogle Scholar
  • 50. Landstrom A.P., Dailey-Schwartz A.L., Rosenfeld J.A., et al. "Interpreting incidentally identified variants in genes associated with catecholaminergic polymorphic ventricular tachycardia in a large cohort of clinical whole-exome genetic test referrals". Circ Arrhythm Electrophysiol 2017;10:4: e004742.

    CrossrefMedlineGoogle Scholar
  • 51. Baggish A.L., Ackerman M.J., Lampert R. "Competitive sport participation among athletes with heart disease: a call for a paradigm shift in decision making". Circulation 2017;136:1569-1571.

    CrossrefMedlineGoogle Scholar
  • 52. Etheridge S.P., Saarel E.V., Martinez M.W. "Exercise participation and shared decision-making in patients with inherited channelopathies and cardiomyopathies". Heart Rhythm 2018;15:915-920.

    CrossrefMedlineGoogle Scholar
  • 53. Ostby S.A., Bos J.M., Owen H.J., Wackel P.L., Cannon B.C., Ackerman M.J. "Competitive sports participation in patients with catecholaminergic polymorphic ventricular tachycardia: a single center's early experience". J Am Coll Cardiol EP 2016;2:253-262.

    Google Scholar
  • 54. Kurtzwald-Josefson E., Hochhauser E., Katz G., et al. "Exercise training improves cardiac function and attenuates arrhythmia in CPVT mice". J Appl Physiol (1985) 2012;113:1677-1683.

    CrossrefMedlineGoogle Scholar
  • 55. Manotheepan R., Saberniak J., Danielsen T.K., et al. "Effects of individualized exercise training in patients with catecholaminergic polymorphic ventricular tachycardia type 1". Am J Cardiol 2014;113:1829-1833.

    CrossrefMedlineGoogle Scholar
  • 56. Hayashi M., Denjoy I., Extramiana F., et al. "Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia". Circulation 2009;119:2426-2434.

    CrossrefMedlineGoogle Scholar
  • 57. Leren I.S., Saberniak J., Majid E., Haland T.F., Edvardsen T., Haugaa K.H. "Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia". Heart Rhythm 2016;13:433-440.

    CrossrefMedlineGoogle Scholar
  • 58. Kawata H., Ohno S., Aiba T., et al. "Catecholaminergic polymorphic ventricular tachycardia (CPVT) associated with ryanodine receptor (RyR2) gene mutations--long-term prognosis after initiation of medical treatment". Circ J 2016;80:1907-1915.

    CrossrefMedlineGoogle Scholar
  • 59. Cheung C.C., Lieve K.V., Roston T.M., et al. "Pregnancy in catecholaminergic polymorphic ventricular tachycardia". J Am Coll Cardiol EP 2019;5:387-394.

    Google Scholar
  • 60. Watanabe H., Chopra N., Laver D., et al. "Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans". Nat Med 2009;15:380-383.

    CrossrefMedlineGoogle Scholar
  • 61. van der Werf C., Kannankeril P.J., Sacher F., et al. "Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia". J Am Coll Cardiol 2011;57:2244-2254.

    View ArticleGoogle Scholar
  • 62. Watanabe H., van der Werf C., Roses-Noguer F., et al. "Effects of flecainide on exercise-induced ventricular arrhythmias and recurrences in genotype-negative patients with catecholaminergic polymorphic ventricular tachycardia". Heart Rhythm 2013;10:542-547.

    CrossrefMedlineGoogle Scholar
  • 63. Khoury A., Marai I., Suleiman M., et al. "Flecainide therapy suppresses exercise-induced ventricular arrhythmias in patients with CASQ2-associated catecholaminergic polymorphic ventricular tachycardia". Heart Rhythm 2013;10:1671-1675.

    CrossrefMedlineGoogle Scholar
  • 64. Padfield G.J., AlAhmari L., Lieve K.V., et al. "Flecainide monotherapy is an option for selected patients with catecholaminergic polymorphic ventricular tachycardia intolerant of β-blockade". Heart Rhythm 2016;13:609-613.

    CrossrefMedlineGoogle Scholar
  • 65. Kannankeril P.J., Moore J.P., Cerrone M., et al. "Efficacy of flecainide in the treatment of catecholaminergic polymorphic ventricular tachycardia: a randomized clinical trial". JAMA Cardiol 2017;2:759-766.

    CrossrefMedlineGoogle Scholar
  • 66. Bannister M.L., Thomas N.L., Sikkel M.B., et al. "The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2". Circ Res 2015;116:1324-1335.

    CrossrefMedlineGoogle Scholar
  • 67. Hwang H.S., Baldo M.P., Rodriguez J.P., Faggioni M., Knollmann B.C. "Efficacy of flecainide in catecholaminergic polymorphic ventricular tachycardia is mutation-independent but reduced by calcium overload". Front Physiol 2019;10:992.

    CrossrefMedlineGoogle Scholar
  • 68. Kryshtal D.O., Blackwell D.J., Egly C.L., et al. "RYR2 channel inhibition is the principal mechanism of flecainide action in CPVT". Circ Res 2021;128:321-331.

    CrossrefMedlineGoogle Scholar
  • 69. Alcalai R., Wakimoto H., Arad M., et al. "Prevention of ventricular arrhythmia and calcium dysregulation in a catecholaminergic polymorphic ventricular tachycardia mouse model carrying calsequestrin-2 mutation". J Cardiovasc Electrophysiol 2011;22:316-324.

    CrossrefMedlineGoogle Scholar
  • 70. Wilde A.A., Bhuiyan Z.A., Crotti L., et al. "Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia". N Engl J Med 2008;358:2024-2029.

    CrossrefMedlineGoogle Scholar
  • 71. Collura C.A., Johnson J.N., Moir C., Ackerman M.J. "Left cardiac sympathetic denervation for the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia using video-assisted thoracic surgery". Heart Rhythm 2009;6:752-759.

    CrossrefMedlineGoogle Scholar
  • 72. De Ferrari G.M., Dusi V., Spazzolini C., et al. "Clinical management of catecholaminergic polymorphic ventricular tachycardia: the role of left cardiac sympathetic denervation". Circulation 2015;131:2185-2193.

    CrossrefMedlineGoogle Scholar
  • 73. Roston T.M., Jones K., Hawkins N.M., et al. "Implantable cardioverter-defibrillator use in catecholaminergic polymorphic ventricular tachycardia: a systematic review". Heart Rhythm 2018;15:1791-1799.

    CrossrefMedlineGoogle Scholar
  • 74. van der Werf C., Lieve K.V., Bos J.M., et al. "Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest". Eur Heart J 2019;40:2953-2961.

    CrossrefMedlineGoogle Scholar
  • 75. Miyake C.Y., Webster G., Czosek R.J., et al. "Efficacy of implantable cardioverter defibrillators in young patients with catecholaminergic polymorphic ventricular tachycardia: success depends on substrate". Circ Arrhythm Electrophysiol 2013;6:579-587.

    CrossrefMedlineGoogle Scholar
  • 76. Roses-Noguer F., Jarman J.W., Clague J.R., Till J. "Outcomes of defibrillator therapy in catecholaminergic polymorphic ventricular tachycardia". Heart Rhythm 2014;11:58-66.

    CrossrefMedlineGoogle Scholar
  • 77. Tadros R., Tan H.L., El Mathari S., et al. "Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores". Eur Heart J 2019;40:3097-3107.

    CrossrefMedlineGoogle Scholar
  • 78. Lahrouchi N., Tadros R., Crotti L., et al. "Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome". Circulation 2020;142:324-338.

    CrossrefMedlineGoogle Scholar
  • 79. Faggioni M., Hwang H.S., van der Werf C., et al. "Accelerated sinus rhythm prevents catecholaminergic polymorphic ventricular tachycardia in mice and in patients". Circ Res 2013;112:689-697.

    CrossrefMedlineGoogle Scholar
  • 80. Kannankeril P.J., Shoemaker M.B., Gayle K.A., Fountain D., Roden D.M., Knollmann B.C. "Atropine-induced sinus tachycardia protects against exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia". Europace 2020;22:643-648.

    CrossrefMedlineGoogle Scholar
  • 81. Denegri M., Bongianino R., Lodola F., et al. "Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age". Circulation 2014;129:2673-2681.

    CrossrefMedlineGoogle Scholar
  • 82. Kurtzwald-Josefson E., Yadin D., Harun-Khun S., et al. "Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models". Heart Rhythm 2017;14:1053-1060.

    CrossrefMedlineGoogle Scholar
  • 83. Bongianino R., Denegri M., Mazzanti A., et al. "Allele-specific silencing of mutant mRNA rescues ultrastructural and arrhythmic phenotype in mice carriers of the R4496C mutation in the ryanodine receptor gene (RYR2)". Circ Res 2017;121:525-536.

    CrossrefMedlineGoogle Scholar
  • 84. Pan X., Philippen L., Lahiri S.K., et al. "In vivo Ryr2 editing corrects catecholaminergic polymorphic ventricular tachycardia". Circ Res 2018;123:953-963.

    CrossrefMedlineGoogle Scholar
  • 85. Liu B., Walton S.D., Ho H.T., et al. "Gene transfer of engineered calmodulin alleviates ventricular arrhythmias in a calsequestrin-associated mouse model of catecholaminergic polymorphic ventricular tachycardia". J Am Heart Assoc 2018;7:10: e008155.

    CrossrefGoogle Scholar
  • 86. Bezzerides V.J., Caballero A., Wang S., et al. "Gene therapy for catecholaminergic polymorphic ventricular tachycardia by inhibition of Ca(2+)/calmodulin-dependent kinase II". Circulation 2019;140:405-419.

    CrossrefMedlineGoogle Scholar
  • 87. Schweitzer M.K., Wilting F., Sedej S., et al. "Suppression of arrhythmia by enhancing mitochondrial Ca(2+) uptake in catecholaminergic ventricular tachycardia models". J Am Coll Cardiol Basic Trans Science 2017;2:737-747.

    View ArticleGoogle Scholar
  • 88. Batiste S.M., Blackwell D.J., Kim K., et al. "Unnatural verticilide enantiomer inhibits type 2 ryanodine receptor-mediated calcium leak and is antiarrhythmic". Proc Natl Acad Sci U S A 2019;116:4810-4815.

    CrossrefMedlineGoogle Scholar
  • 89. Patel C., Yan G.X., Antzelevitch C. "Short QT syndrome: from bench to bedside". Circ Arrhythm Electrophysiol 2010;3:401-408.

    CrossrefMedlineGoogle Scholar
  • 90. El-Battrawy I., Schlentrich K., Besler J., et al. "Sex-differences in short QT syndrome: a systematic literature review and pooled analysis". Eur J Prev Cardiol 2020;27:1335-1338.

    CrossrefMedlineGoogle Scholar
  • 91. Shimizu W., Horie M. "Phenotypic manifestations of mutations in genes encoding subunits of cardiac potassium channels". Circ Res 2011;109:97-109.

    CrossrefMedlineGoogle Scholar
  • 92. Tamargo J., Caballero R., Gómez R., Valenzuela C., Delpón E. "Pharmacology of cardiac potassium channels". Cardiovasc Res 2004;62:9-33.

    CrossrefMedlineGoogle Scholar
  • 93. El-Battrawy I., Lan H., Cyganek L., et al. "Modeling short QT syndrome using human-induced pluripotent stem cell-derived cardiomyocytes". J Am Heart Assoc 2018;7:7: e007394.

    CrossrefGoogle Scholar
  • 94. Guo F., Sun Y., Wang X., et al. "Patient-specific and gene-corrected induced pluripotent stem cell-derived cardiomyocytes elucidate single-cell phenotype of short QT syndrome". Circ Res 2019;124:66-78.

    CrossrefMedlineGoogle Scholar
  • 95. Odening K.E., Bodi I., Franke G., et al. "Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility". Eur Heart J 2019;40:842-853.

    CrossrefMedlineGoogle Scholar
  • 96. Shinnawi R., Shaheen N., Huber I., et al. "Modeling reentry in the short QT syndrome with human-induced pluripotent stem cell-derived cardiac cell sheets". J Am Coll Cardiol 2019;73:2310-2324.

    View ArticleGoogle Scholar
  • 97. Roussel J., Labarthe F., Thireau J., et al. "Carnitine deficiency induces a short QT syndrome". Heart Rhythm 2016;13:165-174.

    CrossrefMedlineGoogle Scholar
  • 98. Thorsen K., Dam V.S., Kjaer-Sorensen K., et al. "Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome". Nat Commun 2017;8:1696.

    CrossrefMedlineGoogle Scholar
  • 99. Gélinas R., Leach E., Horvath G., Laksman Z. "Molecular autopsy implicates primary carnitine deficiency in sudden unexplained death and reversible short QT syndrome". Can J Cardiol 2019;35:1256.e1-1256.e2.

    CrossrefGoogle Scholar
  • 100. Villafañe J., Atallah J., Gollob M.H., et al. "Long-term follow-up of a pediatric cohort with short QT syndrome". J Am Coll Cardiol 2013;61:1183-1191.

    View ArticleGoogle Scholar
  • 101. Mazzanti A., Kanthan A., Monteforte N., et al. "Novel insight into the natural history of short QT syndrome". J Am Coll Cardiol 2014;63:1300-1308.

    View ArticleGoogle Scholar
  • 102. Gollob M.H., Redpath C.J., Roberts J.D. "The short QT syndrome: proposed diagnostic criteria". J Am Coll Cardiol 2011;57:802-812.

    View ArticleGoogle Scholar
  • 103. Suzuki H., Horie M., Ozawa J., et al. "Novel electrocardiographic criteria for short QT syndrome in children and adolescents". Europace 2021;23:12: 2029-2038.

    CrossrefMedlineGoogle Scholar
  • 104. Providência R., Karim N., Srinivasan N., et al. "Impact of QTc formulae in the prevalence of short corrected QT interval and impact on probability and diagnosis of short QT syndrome". Heart 2018;104:502-508.

    CrossrefMedlineGoogle Scholar
  • 105. Anttonen O., Junttila M.J., Rissanen H., Reunanen A., Viitasalo M., Huikuri H.V. "Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population". Circulation 2007;116:714-720.

    CrossrefMedlineGoogle Scholar
  • 106. Miyamoto A., Hayashi H., Yoshino T., et al. "Clinical and electrocardiographic characteristics of patients with short QT interval in a large hospital-based population". Heart Rhythm 2012;9:66-74.

    CrossrefMedlineGoogle Scholar
  • 107. Guerrier K., Kwiatkowski D., Czosek R.J., Spar D.S., Anderson J.B., Knilans T.K. "Short QT interval prevalence and clinical outcomes in a pediatric population". Circ Arrhythm Electrophysiol 2015;8:1460-1464.

    CrossrefMedlineGoogle Scholar
  • 108. Dhutia H., Malhotra A., Parpia S., et al. "The prevalence and significance of a short QT interval in 18,825 low-risk individuals including athletes". Brit J Sports Med 2016;50:124-129.

    CrossrefMedlineGoogle Scholar
  • 109. Giustetto C., Scrocco C., Schimpf R., et al. "Usefulness of exercise test in the diagnosis of short QT syndrome". Europace 2015;17:628-634.

    CrossrefMedlineGoogle Scholar
  • 110. Frea S., Giustetto C., Capriolo M., et al. "New echocardiographic insights in short QT syndrome: more than a channelopathy?"Heart Rhythm 2015;12:2096-2105.

    CrossrefMedlineGoogle Scholar
  • 111. Rollin A., Gandjbakhch E., Giustetto C., et al. "Shortening of the short refractory periods in short QT syndrome". J Am Heart Assoc 2017;6:6: e005684.

    CrossrefMedlineGoogle Scholar
  • 112. Sy R.W., van der Werf C., Chattha I.S., et al. "Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands". Circulation 2011;124:2187-2194.

    CrossrefMedlineGoogle Scholar
  • 113. Mazzanti A., Maragna R., Vacanti G., et al. "Hydroquinidine prevents life-threatening arrhythmic events in patients with short QT syndrome". J Am Coll Cardiol 2017;70:3010-3015.

    View ArticleGoogle Scholar
  • 114. El-Battrawy I., Besler J., Li X., et al. "Impact of antiarrhythmic drugs on the outcome of short QT syndrome". Front Pharmacol 2019;10:771.

    CrossrefMedlineGoogle Scholar
  • 115. Lei M., Wu L., Terrar D.A., Huang C.L. "Modernized classification of cardiac antiarrhythmic drugs". Circulation 2018;138:1879-1896.

    CrossrefMedlineGoogle Scholar
  • 116. Vitali Serdoz L., Rittger H., Furlanello F., Bastian D. "Quinidine--a legacy within the modern era of antiarrhythmic therapy". Pharmacol Res 2019;144:257-263.

    CrossrefMedlineGoogle Scholar
  • 117. Whittaker D.G., Ni H., Benson A.P., Hancox J.C., Zhang H. "Computational analysis of the mode of action of disopyramide and quinidine on hERG-linked short QT syndrome in human ventricles". Front Physiol 2017;8:759.

    CrossrefMedlineGoogle Scholar
  • 118. Milberg P., Tegelkamp R., Osada N., et al. "Reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short QT syndrome". J Cardiovasc Electrophysiol 2007;18:658-664.

    CrossrefMedlineGoogle Scholar
  • 119. Luo C., Wang K., Zhang H. "In silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles". PLoS One 2017;12: e0179515.

    CrossrefGoogle Scholar
  • 120. Viskin S., Wilde A.A., Guevara-Valdivia M.E., et al. "Quinidine, a life-saving medication for Brugada syndrome, is inaccessible in many countries". J Am Coll Cardiol 2013;61:2383-2387.

    View ArticleGoogle Scholar
  • 121. Malhi N., Cheung C.C., Deif B., et al. "Challenge and impact of quinidine access in sudden death syndromes: a national experience". J Am Coll Cardiol EP 2019;5:376-382.

    Google Scholar
  • 122. McPate M.J., Duncan R.S., Witchel H.J., Hancox J.C. "Disopyramide is an effective inhibitor of mutant HERG K+ channels involved in variant 1 short QT syndrome". J Mol Cell Cardiol 2006;41:563-566.

    CrossrefMedlineGoogle Scholar
  • 123. Frommeyer G., Weller J., Ellermann C., et al. "Antiarrhythmic properties of ivabradine in an experimental model of Short-QT- Syndrome". Clin Exp Pharmacol Physiol 2017;44:941-945.

    CrossrefMedlineGoogle Scholar
  • 124. Zhao Z., Li X., El-Battrawy I., et al. "Drug testing in human-induced pluripotent stem cell-derived cardiomyocytes from a patient with short QT syndrome type 1". Clin Pharmacol Ther 2019;106:642-651.

    CrossrefMedlineGoogle Scholar
  • 125. Frommeyer G., Garthmann J., Ellermann C., et al. "Broad antiarrhythmic effect of mexiletine in different arrhythmia models". Europace 2018;20:1375-1381.

    CrossrefMedlineGoogle Scholar
  • 126. Giustetto C., Di Monte F., Wolpert C., et al. "Short QT syndrome: clinical findings and diagnostic-therapeutic implications". Eur Heart J 2006;27:2440-2447.

    CrossrefMedlineGoogle Scholar
  • 127. El-Battrawy I., Besler J., Ansari U., et al. "Long-term follow-up of implantable cardioverter-defibrillators in short QT syndrome". Clin Res Cardiol 2019;108:1140-1146.

    CrossrefMedlineGoogle Scholar
  • 128. Schimpf R., Wolpert C., Bianchi F., et al. "Congenital short QT syndrome and implantable cardioverter defibrillator treatment: inherent risk for inappropriate shock delivery". J Cardiovasc Electrophysiol 2003;14:1273-1277.

    CrossrefMedlineGoogle Scholar
  • 129. Trenor B., Cardona K., Saiz J., Noble D., Giles W. "Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour". J Physiol 2017;595:6599-6612.

    CrossrefMedlineGoogle Scholar
  • 130. Teumer A., Trenkwalder T., Kessler T., et al. "KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern". JCI Insight 2019;4:e131156.

    CrossrefMedlineGoogle Scholar
  • 131. Koncz I., Gurabi Z., Patocskai B., et al. "Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome". J Mol Cell Cardiol 2014;68:20-28.

    CrossrefMedlineGoogle Scholar
  • 132. Zhang J., Hocini M., Strom M., et al. "The electrophysiological substrate of early repolarization syndrome: noninvasive mapping in patients". J Am Coll Cardiol EP 2017;3:894-904.

    Google Scholar
  • 133. Yoon N., Patocskai B., Antzelevitch C. "Epicardial substrate as a target for radiofrequency ablation in an experimental model of early repolarization syndrome". Circ Arrhythm Electrophysiol 2018;11: e006511.

    CrossrefMedlineGoogle Scholar
  • 134. Boukens B.J., Benjacholamas V., van Amersfoort S., et al. "Structurally abnormal myocardium underlies ventricular fibrillation storms in a patient diagnosed with the early repolarization pattern". J Am Coll Cardiol EP 2020;6:1395-1404.

    Google Scholar
  • 135. Watanabe H., Nogami A., Ohkubo K., et al. "Electrocardiographic characteristics and SCN5A mutations in idiopathic ventricular fibrillation associated with early repolarization". Circ Arrhythm Electrophysiol 2011;4:874-881.

    CrossrefMedlineGoogle Scholar
  • 136. Delaney J.T., Muhammad R., Blair M.A., et al. "A KCNJ8 mutation associated with early repolarization and atrial fibrillation". Europace 2012;14:1428-1432.

    CrossrefMedlineGoogle Scholar
  • 137. Takayama K., Ohno S., Ding W.G., et al. "A de novo gain-of-function KCND3 mutation in early repolarization syndrome". Heart Rhythm 2019;16:1698-1706.

    CrossrefMedlineGoogle Scholar
  • 138. Shipley R., Hallaran W. "The four-lead electrocardiogram in two hundred normal men and women". Am Heart J 1936;11:325-345.

    CrossrefGoogle Scholar
  • 139. Kambara H., Phillips J. "Long-term evaluation of early repolarization syndrome (normal variant RS-T segment elevation)". Am J Cardiol 1976;38:157-166.

    CrossrefMedlineGoogle Scholar
  • 140. Bianco M., Bria S., Gianfelici A., Sanna N., Palmieri V., Zeppilli P. "Does early repolarization in the athlete have analogies with the Brugada syndrome?"Eur Heart J 2001;22:504-510.

    CrossrefMedlineGoogle Scholar
  • 141. Haïssaguerre M., Derval N., Sacher F., et al. "Sudden cardiac arrest associated with early repolarization". N Engl J Med 2008;358:2016-2023.

    CrossrefMedlineGoogle Scholar
  • 142. Rosso R., Kogan E., Belhassen B., et al. "J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance". J Am Coll Cardiol 2008;52:1231-1238.

    View ArticleGoogle Scholar
  • 143. Derval N., Simpson C.S., Birnie D.H., et al. "Prevalence and characteristics of early repolarization in the CASPER registry: Cardiac Arrest Survivors With Preserved Ejection Fraction Registry". J Am Coll Cardiol 2011;58:722-728.

    View ArticleGoogle Scholar
  • 144. Malhi N., So P.P., Cheung C.C., et al. "Early repolarization pattern inheritance in the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry (CASPER)". J Am Coll Cardiol EP 2018;4:1473-1479.

    Google Scholar
  • 145. Laksman Z.W., Gula L.J., Saklani P., et al. "Early repolarization is associated with symptoms in patients with type 1 and type 2 long QT syndrome". Heart Rhythm 2014;11:1632-1638.

    CrossrefMedlineGoogle Scholar
  • 146. Sarkozy A., Chierchia G.B., Paparella G., et al. "Inferior and lateral electrocardiographic repolarization abnormalities in Brugada syndrome". Circ Arrhythm Electrophysiol 2009;2:154-161.

    CrossrefMedlineGoogle Scholar
  • 147. Honarbakhsh S., Providencia R., Garcia-Hernandez J., et al. "A Primary prevention clinical risk score model for patients with Brugada syndrome (BRUGADA-RISK)". J Am Coll Cardiol EP 2021;7:210-222.

    Google Scholar
  • 148. Tülümen E., Schulze-Bahr E., Zumhagen S., et al. "Early repolarization pattern: a marker of increased risk in patients with catecholaminergic polymorphic ventricular tachycardia". Europace 2016;18:1587-1592.

    CrossrefMedlineGoogle Scholar
  • 149. Watanabe H., Makiyama T., Koyama T., et al. "High prevalence of early repolarization in short QT syndrome". Heart Rhythm 2010;7:647-652.

    CrossrefMedlineGoogle Scholar
  • 150. Noseworthy P.A., Tikkanen J.T., Porthan K., et al. "The early repolarization pattern in the general population: clinical correlates and heritability". J Am Coll Cardiol 2011;57:2284-2289.

    View ArticleGoogle Scholar
  • 151. Ilkhanoff L., Soliman E.Z., Prineas R.J., et al. "Clinical characteristics and outcomes associated with the natural history of early repolarization in a young, biracial cohort followed to middle age: the Coronary Artery Risk Development in Young Adults (CARDIA) study". Circ Arrhythm Electrophysiol 2014;7:392-399.

    CrossrefMedlineGoogle Scholar
  • 152. Tikkanen J.T., Anttonen O., Junttila M.J., et al. "Long-term outcome associated with early repolarization on electrocardiography". N Engl J Med 2009;361:2529-2537.

    CrossrefMedlineGoogle Scholar
  • 153. Tikkanen J.T., Junttila M.J., Anttonen O., et al. "Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome". Circulation 2011;123:2666-2673.

    CrossrefMedlineGoogle Scholar
  • 154. Obeyesekere M.N., Klein G.J., Nattel S., et al. "A clinical approach to early repolarization". Circulation 2013;127:1620-1629.

    CrossrefMedlineGoogle Scholar
  • 155. Macfarlane P.W., Antzelevitch C., Haissaguerre M., et al. "The early repolarization pattern: a consensus paper". J Am Coll Cardiol 2015;66:470-477.

    View ArticleGoogle Scholar
  • 156. Bastiaenen R., Hedley P.L., Christiansen M., Behr E.R. "Therapeutic hypothermia and ventricular fibrillation storm in early repolarization syndrome". Heart Rhythm 2010;7:832-834.

    CrossrefMedlineGoogle Scholar
  • 157. Federman N.J., Mechulan A., Klein G.J., Krahn A.D. "Ventricular fibrillation induced by spontaneous hypothermia in a patient with early repolarization syndrome". J Cardiovasc Electrophysiol 2013;24:586-588.

    CrossrefMedlineGoogle Scholar
  • 158. Myojo T., Sato N., Nimura A., et al. "Recurrent ventricular fibrillation related to hypokalemia in early repolarization syndrome". Pacing Clin Electrophysiol 2012;35:e234-e238.

    CrossrefMedlineGoogle Scholar
  • 159. Morace G., Padeletti L., Porciani M.C., Fantini F. "Effect of isoproterenol on the “early repolarization” syndrome". Am Heart J 1979;97:343-347.

    CrossrefMedlineGoogle Scholar
  • 160. Patocskai B., Barajas-Martinez H., Hu D., Gurabi Z., Koncz I., Antzelevitch C. "Cellular and ionic mechanisms underlying the effects of cilostazol, milrinone, and isoproterenol to suppress arrhythmogenesis in an experimental model of early repolarization syndrome". Heart Rhythm 2016;13:1326-1334.

    CrossrefMedlineGoogle Scholar
  • 161. Kaneko Y., Horie M., Niwano S., et al. "Electrical storm in patients with Brugada syndrome is associated with early repolarization". Circ Arrhythm Electrophysiol 2014;7:1122-1128.

    CrossrefMedlineGoogle Scholar
  • 162. Iguchi K., Noda T., Kamakura S., Shimizu W. "Beneficial effects of cilostazol in a patient with recurrent ventricular fibrillation associated with early repolarization syndrome". Heart Rhythm 2013;10:604-606.

    CrossrefMedlineGoogle Scholar
  • 163. Kawata H., Noda T., Yamada Y., et al. "Effect of sodium-channel blockade on early repolarization in inferior/lateral leads in patients with idiopathic ventricular fibrillation and Brugada syndrome". Heart Rhythm 2012;9:77-83.

    CrossrefMedlineGoogle Scholar
  • 164. Ahn J., Roh S.Y., Lee D.I., Shim J., Choi J.I., Kim Y.H. "Effect of flecainide on suppression of ventricular fibrillation in a patient with early repolarization syndrome". Heart Rhythm 2016;13:1724-1728.

    CrossrefMedlineGoogle Scholar
  • 165. Nademanee K., Haissaguerre M., Hocini M., et al. "Mapping and ablation of ventricular fibrillation associated with early repolarization syndrome". Circulation 2019;140:1477-1490.

    CrossrefMedlineGoogle Scholar
  • 166. Steinberg C., Davies B., Mellor G., et al. "Short-coupled ventricular fibrillation represents a distinct phenotype among latent causes of unexplained cardiac arrest: a report from the CASPER registry". Eur Heart J 2021;42:29: 2827-2838.

    CrossrefMedlineGoogle Scholar
  • 167. Xiao L., Koopmann T.T., Ördög B., et al. "Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation". Circ Res 2013;112:1310-1322.

    CrossrefMedlineGoogle Scholar
  • 168. Alders M., Koopmann T.T., Christiaans I., et al. "Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation". Am J Hum Genet 2009;84:468-476.

    CrossrefMedlineGoogle Scholar
  • 169. ten Sande J.N., Postema P.G., Boekholdt S.M., et al. "Detailed characterization of familial idiopathic ventricular fibrillation linked to the DPP6 locus". Heart Rhythm 2016;13:905-912.

    CrossrefMedlineGoogle Scholar
  • 170. Haïssaguerre M., Shoda M., Jaïs P., et al. "Mapping and ablation of idiopathic ventricular fibrillation". Circulation 2002;106:962-967.

    CrossrefMedlineGoogle Scholar
  • 171. Haïssaguerre M., Hocini M., Cheniti G., et al. "Localized structural alterations underlying a subset of unexplained sudden cardiac death". Circ Arrhythm Electrophysiol 2018;11: e006120.

    CrossrefGoogle Scholar
  • 172. Haissaguerre M., Cheniti G., Escande W., Zhao A., Hocini M., Bernus O. "Idiopathic ventricular fibrillation with repetitive activity inducible within the distal Purkinje system". Heart Rhythm 2019;16:1268-1272.

    CrossrefMedlineGoogle Scholar
  • 173. Leenhardt A., Glaser E., Burguera M., Nürnberg M., Maison-Blanche P., Coumel P. "Short-coupled variant of torsade de pointes. A new electrocardiographic entity in the spectrum of idiopathic ventricular tachyarrhythmias". Circulation 1994;89:206-215.

    CrossrefMedlineGoogle Scholar
  • 174. Viskin S., Lesh M.D., Eldar M., et al. "Mode of onset of malignant ventricular arrhythmias in idiopathic ventricular fibrillation". J Cardiovasc Electrophysiol 1997;8:1115-1120.

    CrossrefMedlineGoogle Scholar
  • 175. Viskin S., Rosso R., Rogowski O., Belhassen B. "The “short-coupled” variant of right ventricular outflow ventricular tachycardia: a not-so-benign form of benign ventricular tachycardia?"J Cardiovasc Electrophysiol 2005;16:912-916.

    CrossrefMedlineGoogle Scholar
  • 176. Steinfurt J., Nazer B., Aguilar M., et al. "Catheter ablation of short-coupled variant of torsade de pointes". Clin Res Cardiol 2022;111:5: 502-510.

    CrossrefMedlineGoogle Scholar
  • 177. Noda T., Shimizu W., Taguchi A., et al. "Malignant entity of idiopathic ventricular fibrillation and polymorphic ventricular tachycardia initiated by premature extrasystoles originating from the right ventricular outflow tract". J Am Coll Cardiol 2005;46:1288-1294.

    View ArticleGoogle Scholar
  • 178. Crotti L., Spazzolini C., Tester D.J., et al. "Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry". Eur Heart J 2019;40:2964-2975.

    CrossrefMedlineGoogle Scholar
  • 179. Marsman R.F., Barc J., Beekman L., et al. "A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence". J Am Coll Cardiol 2014;63:259-266.

    View ArticleGoogle Scholar
  • 180. Nomikos M., Thanassoulas A., Beck K., et al. "Altered RyR2 regulation by the calmodulin F90L mutation associated with idiopathic ventricular fibrillation and early sudden cardiac death". FEBS Lett 2014;588:2898-2902.

    CrossrefMedlineGoogle Scholar
  • 181. Clemens D.J., Gray B., Bagnall R.D., et al. "Prevalence and phenotypic correlations of calmodulinopathy-causative CALM1-3 variants detected in a multicenter molecular autopsy cohort of sudden unexplained death victims". Circ Genom Precis Med 2020;13: e003032.

    CrossrefGoogle Scholar
  • 182. Balasundaram R., Rao H.B., Kalavakolanu S., Narasimhan C. "Catheter ablation of bundle branch reentrant ventricular tachycardia". Heart Rhythm 2008;5:S68-S72.

    CrossrefMedlineGoogle Scholar
  • 183. Cohen T.J., Chien W.W., Lurie K.G., et al. "Radiofrequency catheter ablation for treatment of bundle branch reentrant ventricular tachycardia: results and long-term follow-up". J Am Coll Cardiol 1991;18:1767-1773.

    View ArticleGoogle Scholar
  • 184. Blanck Z., Jazayeri M., Dhala A., Deshpande S., Sra J., Akhtar M. "Bundle branch reentry: a mechanism of ventricular tachycardia in the absence of myocardial or valvular dysfunction". J Am Coll Cardiol 1993;22:1718-1722.

    View ArticleGoogle Scholar
  • 185. Chen H., Shi L., Yang B., et al. "Electrophysiological characteristics of bundle branch reentry ventricular tachycardia in patients without structural heart disease". Circ Arrhythm Electrophysiol 2018;11: e006049.

    CrossrefGoogle Scholar
  • 186. Roberts J.D., Gollob M.H., Young C., et al. "Bundle branch re-entrant ventricular tachycardia: novel genetic mechanisms in a life-threatening arrhythmia". J Am Coll Cardiol EP 2017;3:276-288.

    Google Scholar
  • 187. Bundgaard H., Jøns C., Lodder E.M., et al. "A novel familial cardiac arrhythmia syndrome with widespread ST-segment depression". N Engl J Med 2018;379:1780-1781.

    CrossrefMedlineGoogle Scholar
  • 188. Waldmann V., Bougouin W., Karam N., et al. "Characteristics and clinical assessment of unexplained sudden cardiac arrest in the real-world setting: focus on idiopathic ventricular fibrillation". Eur Heart J 2018;39:1981-1987.

    CrossrefMedlineGoogle Scholar
  • 189. Vittoria Matassini M., Krahn A.D., Gardner M., et al. "Evolution of clinical diagnosis in patients presenting with unexplained cardiac arrest or syncope due to polymorphic ventricular tachycardia". Heart Rhythm 2014;11:274-281.

    CrossrefMedlineGoogle Scholar
  • 190. Ozaydin M., Moazzami K., Kalantarian S., Lee H., Mansour M., Ruskin J.N. "long-term outcome of patients with idiopathic ventricular fibrillation: a meta-analysis". J Cardiovasc Electrophysiol 2015;26:1095-1104.

    CrossrefMedlineGoogle Scholar
  • 191. Blom L.J., Visser M., Christiaans I., et al. "Incidence and predictors of implantable cardioverter-defibrillator therapy and its complications in idiopathic ventricular fibrillation patients". Europace 2019;21:1519-1526.

    CrossrefMedlineGoogle Scholar
  • 192. Conte G., Belhassen B., Lambiase P., et al. "Out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation in patients with normal electrocardiograms: results from a multicentre long-term registry". Europace 2019;21:1670-1677.

    CrossrefMedlineGoogle Scholar
  • 193. Stampe N.K., Jespersen C.B., Glinge C., Bundgaard H., Tfelt-Hansen J., Winkel B.G. "Clinical characteristics and risk factors of arrhythmia during follow-up of patients with idiopathic ventricular fibrillation". J Cardiovasc Electrophysiol 2020;31:2677-2686.

    CrossrefMedlineGoogle Scholar
  • 194. van der Ree M.H., Postema P.G. "What's in a name? further classification of patients with apparent idiopathic ventricular fibrillation". Eur Heart J 2021;42:29: 2839-2841.

    CrossrefMedlineGoogle Scholar
  • 195. Nakamura K., Katayama Y., Kusano K.F., et al. "Anti-KCNH2 antibody-induced long QT syndrome: novel acquired form of long QT syndrome". J Am Coll Cardiol 2007;50:1808-1809.

    View ArticleGoogle Scholar
  • 196. Li J., Maguy A., Duverger J.E., et al. "Induced KCNQ1 autoimmunity accelerates cardiac repolarization in rabbits: potential significance in arrhythmogenesis and antiarrhythmic therapy". Heart Rhythm 2014;11:2092-2100.

    CrossrefMedlineGoogle Scholar
  • 197. Lazzerini P.E., Yue Y., Srivastava U., et al. "Arrhythmogenicity of Anti-Ro/SSA Antibodies in Patients With Torsades de Pointes". Circ Arrhythm Electrophysiol 2016;9: e003419.

    CrossrefMedlineGoogle Scholar
  • 198. Maguy A., Tardif J.C., Busseuil D., Ribi C., Li J. "Autoantibody signature in cardiac arrest". Circulation 2020;141:1764-1774.

    CrossrefMedlineGoogle Scholar
  • 199. Laurent G., Saal S., Amarouch M.Y., et al. "Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy". J Am Coll Cardiol 2012;60:144-156.

    View ArticleGoogle Scholar
  • 200. Koizumi A., Sasano T., Kimura W., et al. "Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias". Eur Heart J 2016;37:1469-1475.

    CrossrefMedlineGoogle Scholar
  • 201. Sun B., Yao J., Ni M., et al. "Cardiac ryanodine receptor calcium release deficiency syndrome". Sci Transl Med 2021;13:579: eaba7287. https://doi.org/10.1126/scitranslmed.aba7287.

    CrossrefGoogle Scholar

Footnotes

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