Unveiling Specific Triggers and Precipitating Factors for Fatal Cardiac Events in Inherited Arrhythmia Syndromes

Abstract

Patients with inherited arrhythmia syndromes, such as long QT syndrome, Brugada syndrome, early repolarization syndrome, catecholaminergic polymorphic ventricular tachycardia, and their latent forms, are at risk for fatal arrhythmias. These diseases are typically associated with genetic mutations that perturb cardiac ionic currents. The analysis of cardiac events by genotype-phenotype correlation studies has revealed that fatal arrhythmias in some genotypes are triggered by physical or emotional stress, and those in the others are more likely to occur during sleep or at rest. Thus, the risk stratification and management of affected patients differ strikingly according to the genetic variant of the inherited arrhythmia syndrome. Risk stratification may be further refined by considering the precipitating factors, such as drugs, bradycardia, electrolyte disturbances, fever, and cardiac memory. Moreover, an increasing number of studies imply that the susceptibility of fatal arrhythmias in patients with acute coronary syndrome or takotsubo cardiomyopathy is at least partly ascribed to the genetic variants causing inherited arrhythmia syndromes. In this article, we review the recent advances in the understanding of the molecular genetics and genotype-phenotype correlations in inherited arrhythmia syndromes and consider the triggers and precipitating factors for fatal arrhythmias in these disorders. Further studies to explore the triggers and precipitating factors specific to the genotypes and diseases are needed for better clinical management. (Circ J 2015; 79: 1185–1192)

Since the identification of the genes for long QT syndrome (LQTS) manifesting as syncope and sudden cardiac death (SCD), an increasing number of new genes associated with a new group of syndrome, called the inherited arrhythmia syndromes, have been discovered. Those include LQTS, Brugada syndrome (BrS), early repolarization syndrome (ERS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) etc, and the term “channelopathies” defines the inherited arrhythmia syndromes caused by mutations of the genes encoding cardiac ion channel proteins or their modifiers that regulate cardiac ion channels.

Patients with an inherited arrhythmia syndrome are at variable risk for SCD and need to be managed according to risk stratification that includes the genotype of the disease. Current pharmacological treatments are not always successful in preventing cardiac events and an implantable cardioverter defibrillator (ICD) is the only option for high-risk patients; therefore, risk stratification is a critical step in clinical management. In particular, the identification of triggers and precipitating factors for fatal arrhythmias is effective for predicting cardiac events and reducing the risk for SCD.

This review will focus on the genetic basis and the triggers or precipitating factors for fatal arrhythmias in inherited arrhythmia syndromes, including their latent forms. Recent studies points to an important role for genetic variants of ion channels in patients with acute coronary syndrome (ACS) or takotsubo cardiomyopathy accompanying fatal arrhythmias.

Inherited Arrhythmia Syndromes

LQTS

LQTS is a genetically heterogeneous disorder characterized by QT interval prolongation on ECG and polymorphic VT, torsades de pointes (TdP), leading to syncope and SCD. Since the discovery of 3 causative genes (KCNQ1 for LQT1; KCNH2 for LQT2; SCN5A for LQT3) in 1995 and 1996,^1–3 to date at least 13 genes for LQTS have been identified (Table 1).^4–6 Most of them encode cardiac ion channels or their modifiers. The first 3 LQTS (LQT1–3) account for approximately 75% of clinically definite LQTS, and the other genes account for only 5% of cases.

Table 1. Responsible Genes and Their Altered Functions in Inherited Arrhythmia Syndromes

	Gene	Protein	Function
LQTS
LQT1	KCNQ1	Kv7.1	↓ IKs
LQT2	KCNH2	Kv11.1	↓ IKr
LQT3	SCN5A	Nav1.5	↑ INa
LQT4	ANKB	Ankyrin	↓ Na/K, ATPase
LQT5	KCNE1	MinK	↓ IKs
LQT6	KCNE2	MiRP1	↓ IKr
LQT7	KCNJ2	Kir2.1	↓ IK1
LQT8	CACNA1C	Cav1.2	↑ ICa
LQT9	CAV3	Caveolin-3	↑ INa
LQT10	SCN4B	Navβ4	↑ INa
LQT11	AKAP9	Yotiao	↓ IKs
LQT12	SNTA1	Syntrophin-α1	↑ INa
LQT13	KCNJ5	Kir3.4	↓ IK-Ach
LQT	CALM1	Calmodulin	↓ Ca2+ binding to proteins
LQT	CALM2	Calmodulin	↓ Ca2+ binding to proteins
BrS
BrS1	SCN5A	Nav1.5	↓ INa
BrS2	GPD1-L	GPD1-L	↓ INa
BrS3	CACNA1C	Cav1.2	↓ ICa
BrS4	CACNB2b	Cavβ2b	↓ ICa
BrS5	SCN1B	Navβ1	↓ INa
BrS6	KCNE3	MiRP2	↑ Ito
BrS7	SCN3B	Navβ3	↓ INa
BrS8	KCNJ8	Kir6.1	↑ IK-ATP
BrS9	CACNA2D1	Cavα2d	↓ ICa
BrS10	KCND3	Kv4.3	↑ Ito
BrS11	MOG1	MOG1	↓ INa
BrS12	ABCC9	SUR2A	↑ IK-ATP
ERS
ERS1	KCNJ8	Kir6.1	↑ IK-ATP
ERS2	CACNA1C	Cav1.2	↓ ICa
ERS3	CACNB2b	Cavβ2b	↓ ICa
ERS4	CACNA2D1	Cavα2d	↓ ICa
ERS5	ABCC9	SUR2A	↑ IK-ATP
ERS6	SCN5A	Nav1.5	↓ INa
CPVT
CPVT1	RYR2	Ryanodine receptor	↑ Ca2+ release from SR
CPVT2	CASQ2	Calsequestrin-2	↑ Ca2+ release from SR
CPVT3	KCNJ2	Kir2.1	↓ IK1
CPVT4	TRDN	Triadine
CPVT5	CALM1	Calmodulin	↓ Ca2+ binding to proteins
CPVT6	CALM2	Calmodulin	↓ Ca2+ binding to proteins

Modified with permission from Mizusawa Y, et al⁶ and Antzelevitch C.²⁰ BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; ERS, early repolarization syndrome; LQTS, long QT syndrome; SR, sarcoplasmic reticulum.

KCNQ1 and KCNH2 encode the α-subunit of the slow component (I_Ks) and rapid components (I_Kr), respectively, of the delayed rectifier potassium currents.^7,8 SCN5A encodes the α-subunit of the cardiac voltage-gated sodium channels (sodium currents: I_Na).³ A decrease of the outward currents (I_Ks, I_Kr) or an increase of the inward currents (I_Na) in ventricular myocytes causes a delay of repolarization, thus leading to prolongation of the QT interval on ECG (Figure 1). TdP is thought to be triggered by ventricular action potential (AP) phase 2 early afterdepolarization under conditions of a prolonged QT interval.⁴ Because the I_Ks activates very slowly on depolarization and is increased by sympathetic activation, its net repolarizing current can accumulate at higher heart rates, thus contributing to QT adaptation during tachycardia. Loss-of-function of the I_Ks by KCNQ1 mutations can theoretically cause QT prolongation, especially during tachycardia. Indeed, cardiac events in LQT1 mostly occur during physical exertion or emotional stress, typically during swimming (Table 2).⁹ The I_Kr rapidly activates but is suppressed by strong depolarization because of its inward rectification property.⁸ Emotional stress and sudden auditory stimuli are major triggers for cardiac events in LQT2 (Table 2).^9,10 Moreover, female patients with LQT2 have an increased risk of cardiac events during the postpartum period.¹¹ In contrast to LQT1 and LQT2, cardiac events in LQT3 patients mainly occur during sleep or at rest (Table 2).⁹ In this manner, the triggers for fatal arrhythmias in LQTS differ strikingly among the genotypes.

Figure 1.

Mechanisms of prolongation of repolarization and QT interval, and contributed ionic currents associated with major types of long QT syndrome (LQT1–3). (A) Schematic representation of the ventricular action potential, (B) surface ECG lead, and (C) ionic currents. Loss-of-function of I_Ks and I_Kr, or gain-of-function of I_Na can theoretically cause prolongation of repolarization and the QT interval (red lines). The dotted red line in (A) indicates early afterdepolarization.

Table 2. Typical Triggers for Fatal Arrhythmias and Appropriate Medical Therapy in Inherited Arrhythmia Syndromes

	Typical trigger	Medical therapy
LQT1	Exercise, swimming	β-blockers
LQT2	Emotion, auditory stimuli, postpartum period	β-blockers, potassium supplement
LQT3	Sleep, rest	(β-blockers), mexiletine
BrS	Sleep, rest, fever	Isoproterenol infusion, quinidine, bepridil, cilostazol
ERS	Sleep, rest	Isoproterenol infusion, quinidine, bepridil, cilostazol
CPVT	Exercise	β-blockers, flecainide

Abbreviations as in Table 1.

β-blocker therapy (propranolol or nadolol but not metoprolol) is extremely effective for patients with LQT1,^12,13 and also partly effective in patients with LQT2,¹³ but efficacy is controversial in patients with LQT3.¹⁴ Mexiletine, which blocks persistent I_Na, can shorten the QT interval and may be effective in LQT3.¹⁵ The appropriate guidance to avoid specific triggers for fatal arrhythmias should be given to genotyped LQTS patients. In LQT1, excessive physical stress, especially swimming, should be avoided. In LQT2, the use of items that cause sudden noises such as alarm clocks and ringing telephones should be avoided. LQTS patients who experience aborted cardiac arrest or are resistant to optimal medical therapy are indicated for ICD. Left cardiac sympathetic denervation (LCSD) is another therapeutic option for patients at high risk.¹⁶

BrS

BrS is a hereditable disorder characterized by ST segment elevations in the right precordial ECG leads, associated with a high incidence of syncope or SCD because of fatal arrhythmias, which mostly affects adult males.^4,17

The transient outward potassium current (I_to), which is abundant in the right ventricular epicardium compared with the endomyocardium, has been postulated to contribute to the pathogenesis of BrS. The presence of a prominent I_to-mediated AP notch in the right ventricular epicardium but not endomyocardium causes a transmural voltage gradient manifested as a J-point elevation on the right precordial ECG leads.¹⁸ An additional decrease of the inward currents (I_Na, I_Ca: Ca currents) or increase of the outward currents (I_to and I_K-ATP: ATP-sensitive potassium channels) during the early phase of the AP can theoretically lead to an increased transmural voltage gradient, manifesting as the Brugada ECG pattern and phase 2 reentry.¹⁸ Since the first identification of a causative SCN5A mutation in 1998,¹⁹ BrS has been linked to mutations in genes that perturb cardiac ionic currents contributing to the early phase of the AP (Table 1).^4,5,20,21 Mutations in SCN5A that cause loss-of-function of the I_Na have accounted for the major form of BrS in approximately 20% of cases, and other gene mutations account for approximately 10%; thus, approximately 70% of BrS cases remain to be genetically elucidated.

In contrast to LQTS, the knowledge about the genotype-phenotype correlation in BrS is limited. Cardiac events in BrS patients mostly occur during sleep or at rest (Table 2).²² ICD is the only available treatment for preventing SCD. Isoproterenol infusion, which increases the I_Ca and suppresses the I_to by insufficient recovery from inactivation with increasing heart rate, is useful for suppressing the electrical storm of ventricular fibrillation (VF).²² Quinidine and bepridil, which have an inhibitory effect on I_to, and cilostazol, a phosphodiesterase III inhibitor that increases I_Ca through elevation of cAMP, have been shown to be effective to some extent as adjunctive therapy in cases of frequent ICD shocks (Table 2).^23–25

ERS

The ER or J wave is characterized by ≥0.1 mV J-point elevation in 2 contiguous inferior and/or lateral ECG leads. The prevalence of ER in the general population is highly variable and ranges from 1% to 13%.²⁶ An ER pattern was long thought to be a benign ECG manifestation. However, Haissaguerre et al demonstrated an association between ER and idiopathic VF in 2008,²⁷ and the combination is now defined as ERS.²⁰

As with BrS, a higher epicardial I_to relative to the endocardium, as well as other ionic currents contributing to the early phase of the AP, have been implicated as important mediators of ER. ERS shares similar ECG characteristics, clinical characteristics and risk factors with BrS.²⁰ Most patients with ERS experience arrhythmic events during sleep or at rest (Table 2). Of note, the genetic basis for ERS overlaps that for BrS (Table 1).²⁰ The presence of ER on ECG is associated with electrical storm in patients with BrS.²⁸ Akin to BrS, VF can be suppressed to some extent by quinidine, bepridil, cilostazol, and isoproterenol infusion or with pacing at increasingly rapid rates (Table 2).^25,29,30

CPVT

CPVT is a hereditable disorder characterized by adrenergic-induced bidirectional and polymorphic VT without structural heart diseases, leading to syncope and SCD.^31,32

RYR2 (encoding the cardiac ryanodine receptor), CAQS2 (encoding cardiac calsequestrin), KCNJ2 (encoding I_K1: inwardly rectifying potassium currents), TRDN (encoding the junctional protein triadine) have been identified as causative genes for CPVT (Table 1).^5,32,33 Recently, mutations in 2 (CALM1 and CALM2) of 3 genes (CALM1–3) encoding identical peptide sequences for the essential Ca²⁺-signaling protein calmodulin were reported to be associated with malignant forms of LQTS, CPVT and idiopathic VF.^34,35

In CPVT, cytosolic Ca²⁺ overload in ventricular myocytes or Purkinje cells generates inward currents thorough the Na⁺/Ca²⁺ exchanger, leading to membrane depolarization called delayed afterdepolarization (DAD). If Ca²⁺ overload under adrenergic conditions is sufficient to bring DAD to a threshold, it induces full AP, manifesting as ventricular ectopies on ECG.³² Exercise or catecholamine infusion can easily induce an arrhythmic burden in patients with CPVT.^31,36 Therefore, exercise should be limited in affected patients. β-blocker therapy can reduce the arrhythmia burden and death, so is the first choice for CPVT, but is not completely effective.³¹ Patients with CPVT resistant to β-blocker therapy should be considered for flecainide (Table 2).³⁷ Combined therapy with LCSD can be also considered. ICD should be the last intervention because the device can potentially have proarrhythmic effects because discharges could prove disastrous by evoking a self-induced vicious circle.³²

Precipitating Factors for Fatal Arrhythmias

Several factors are known to be precipitators for cardiac events in patients with inherited arrhythmia syndromes or their latent forms (Table 3). Combinations of precipitating factors can increase the risk of fatal arrhythmias. Gene-specific or mutation site-specific precipitating factors may also be present.

Table 3. Precipitating Factors for Fatal Arrhythmias Associated With Inherited Arrhythmia Syndromes and Their Latent Forms

Precipitating factor	Phase	Fatal arrhythmia	Phenotype	Responsible gene and mutation/variant
Drugs		TdP	LQTS	LQTS-causing genes (≤40%)
		VF	BrS
Bradyarrhythmias		TdP	LQTS	LQTS-causing genes (17–28%); common in KCNH2 but rare inKCNQ1
Hypokalemia		TdP	LQTS	LQTS-causing genes
Fever		VF	BrS	SCN5A
		TdP	LQTS	KCNH2 (S5-pore region)
ACS	Acute	Electrical storm		SCN5A G400A
	Subacute	TdP	LQTS	KCNH2 R744X, SCN5A E446K, KCNH2 K897T, KCNQ1 G643S
Takotsubo cardiomyopathy	Acute	VF
	Subacute	TdP	LQTS	KCNH2 V115-A121dup
Cardiac memory		TdP	LQTS	KCNH2

ACS, acute coronary syndrome; TdP, torsades de pointes; VF, ventricular fibrillation. Other abbreviations as in Table 1.

Drugs

Not only QT-prolonging antiarrhythmic drugs, such as quinidine and sotalol, but also other non-antiarrhythmic drugs, such as antihistamines, antibiotics and antipsychotics, exhibit marked QT prolongation and development of TdP (drug-induced LQTS (dLQTS)).³⁸ (refer to www.qtdrugs.org). QT prolongation is mainly caused by the I_Kr-blocking effect of the culprit drug. After a washout period, the QT interval usually returns to within the normal range in patients with dLQTS.

Mutations or variants in the LQTS-causing genes, including KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A, have been identified in up to 40% of patients with dLQTS (Table 3).^39–43 Of note, functional analysis revealed that KCNQ1 or KCNH2 mutations identified in dLQTS showed no dominant-negative suppression or only a relatively mild decreased current density compared with those identified in congenital LQTS (cLQTS).⁴² Drugs that have an I_Kr-blocking effect lead to further reductions of the repolarizing currents in patients with a latent genetic background of mildly reduced repolarizing currents, thus unmasking dLQTS. Interestingly, colleagues have reported that K⁺ channel regulator-1 (KCR1), homologous to yeast α-1,2-glucosyltransferase ALG10, protects KCNH2 currents from pharmacological block by QT-prolonging antiarrhythmic drugs through enhancing of cellular glycosylation by acting as an α-1,2-glucosyltransferase.^44,45 They demonstrated that the common variant KCR1 I447V, less common in patients with dLQTS than in control subjects, reduced the drug sensitivity of KCNH2 to dofetilide, whereas the KCR1 E33D variant identified in a patient with VF and significant QT prolongation increased it through reduced α-1,2-glucosyltransferase activity.^44,46 Common variants of NOS1AP have been reported to be associated with a significant increase in the risk of dLQTS.⁴⁷ Also, common variants in drug metabolism pathways may also predispose to dLQTS in a drug-specific fashion.

In the case of dLQTS, QT-prolonging drugs and those interfering with their metabolism must be promptly discontinued. Intravenous magnesium sulfate is the initial therapy of choice regardless of serum level. Serum potassium, which paradoxically increases the I_Kr, should be maintained in the high-normal range. Because drug-induced TdP is pause-dependent, as with other acquired LQTS, temporal cardiac pacing is highly effective in preventing recurrence of TdP. If temporal cardiac pacing is not available or while preparing for it, isoproterenol infusion should be considered to increase heart rate.

On the other hand, many drugs, including antiarrhythmic drugs, psychotropic drugs, and anesthetic drugs, have been reported to induce the Brugada ECG and/or fatal arrhythmias in patients with BrS (refer to www.brugadadrugs.org).⁴⁸ Patients with BrS should be advised not to use these drugs or to use them only under controlled conditions.

Bradyarrhythmias

Between 5% and 30% of patients with complete atrioventricular block (AVB) develop TdP.⁴⁹ Patients with AVB-induced TdP display an abnormally prolonged QT interval at slower heart rates than do those without TdP, though, in general, the slower the heart rate, the longer repolarization.³⁸

KCNQ1, KCNH2, KCNE2 and SCN5A mutations have been reported in approximately 17–28% patients with bradycardia-induced LQTS (Table 3).^49–51 Of note, the KCNH2 mutation has been the most common, but KCNQ mutation is quite rare compared with cLQTS. Only a single KCNQ1 mutation, G272V, had been reported to date.⁵¹ The functional consequences of KCNQ1 and KCNH2 mutations are loss-of-function of each current (I_Ks, I_Kr), with milder suppression than in cLQTS.^49,51

Electrolyte Disturbances

Electrolyte disturbances such as hypokalemia, hypocalcemia and hypomagnesemia, especially hypokalemia, are major precipitating factors for TdP.³⁸ Hypokalemia-induced LQTS can be present in all LQTS genotypes (Table 3). Hypokalemia is thought to decrease KCNH2/ I_Kr currents because of enhanced channel block by Na⁺ and enhanced voltage-dependence of KCNH2 channel inactivation,^52,53 and increased internalization and degradation of KCNH2 channels in the plasma membrane, thus prolonging the QT interval.⁵⁴ Conversely, elevated serum potassium within the normal-high range by long-term oral potassium administration results in improvement in repolarization in patients with LQT2, and is thus considered as adjunctive therapy in LQT2 (Table 2).⁵⁵

Fever

Fever has been reported as a precipitating factor for fatal arrhythmias in both BrS and LQTS (Table 3). In some BrS patients, fever unmasks the Brugada ECG and also triggers fatal arrhythmias.⁵⁶ A representative case is shown in Figure 2. Cellular electrophysiological studies using a patch-clamp method have demonstrated that SCN5A mutations (eg, V1340I, F1344S, D1714G) impair cardiac sodium channel gating more severely at higher temperatures, leading to further I_Na reduction during fever.^57–59 Thus, pronounced reduction of I_Na during fever is thought to increase arrhythmogenicity in BrS patients.

Figure 2.

Fever-induced coved-type ST elevations and frequent premature ventricular contractions in a patient with Brugada syndrome. 12-lead ECG recorded at (A) normal body temperature (36.2℃) and (B) in a febrile state (38.5℃).

Concerning LQTS, although the QT interval in healthy people is usually shortened during fever, A558P, T613M and F640V mutations of KCNH2 have been reported as associated with prolongation of the QT interval and development of TdP during fever.^60,61 We also recently identified a G584S mutation in KCNH2, which has been previously identified in patients with mild phenotype,⁶² in a female patient with dLQTS who developed TdP during fever.⁶³ Of note, these mutations converge at the S5-Pore region in KCNH2 (Figure 3), a region that has been postulated to be related to voltage-dependent inactivation of KCNH2 channels.^64,65 Functional analysis has demonstrated that wild-type (WT) KCNH2 increased current amplitudes when temperature is elevated, but mutants (A558P, F640V) did not much increase current amplitudes compared with the WT, possibly because of its faster inactivation rate at elevated temperature, which suggested that the failure of an increase of I_Kr might be the cause of QT prolongation and TdP during fever.⁶⁰ These findings make us aware of the importance of reducing body temperature by timely use of antipyretics.

Figure 3.

Location of KCNH2 mutations associated with fever-induced long QT syndrome in a predicted topology of KCNH2. Red filled circles indicate the mutation sites.

ACS

ACS is often accompanied by the development of fatal arrhythmias during its acute phase. Despite successful resuscitation from aborted SCD, fatal arrhythmias sometimes occur incessantly, the so-called electrical storm. A novel SCN5A G400A mutation has been identified in a patient who experienced electrical storm during the acute phase of myocardial infarction (MI) (Table 3).⁶⁶ Myocardial ischemia and subsequent reperfusion result in increased production of reactive oxygen species (ROS), which induced a wide range of modifications to cellular lipids, nucleic acids and proteins, and the cardiac sodium channel is 1 of the proteins that can be modified by ROS.⁶⁷ Besides reduction of I_Na by SCN5A mutation, further reduction of the I_Na in the setting of ACS may cause pronounced slowed conduction and prolonged refractoriness in the ventricular myocardium, leading to the formation of a substrate for reentry. Therefore, indigenous I_Na reduction may contribute to electrical storm during the acute phase of ACS.

On the other hand, a rare form of fatal arrhythmia, which is associated with excessive QT prolongation and has the characteristics of pause-dependent TdP (ACS-TdP), was reported to occur during the subacute phase of ACS (3–11 days after presentation) in 8 (1.8%) of 434 patients.⁶⁸ Crotti et al reported that 2 (15%) of 13 Caucasian patients with ACS-TdP were found to carry LQTS mutations (KCNH2 R744X, SCN5A E446K) (Table 3).⁶⁹ Additionally, 9 (82%) of the remaining 11 patients carried the KCNH2 K897T variant, which is commonly present in an allele frequency of 35% in Caucasians but is rare in Asians. We have previously reported a patient with ACS-TdP, in whom we identified a KCNQ1 G643S variant.⁷⁰ Carriers of the variant are at higher risk for fatal arrhythmias in the presence of appropriate precipitating factors such as bradycardia and hypokalemia, and the variant shows mild reduction of the KCNQ1/KCNE1 (I_Ks) channels,⁷¹ although the allele frequency of the variant in Asians is approximately 6–10%.⁷² A rat experimental model of MI showed that downregulation of potassium channel gene expression (ERG, KCNE1, KCNQ1) and the potassium currents (I_Kr, I_Ks) occurs in surviving myocytes from the infarct zone 2 days after MI.⁷³ This suggests that major repolarizing currents (ie, I_Kr and I_Ks) may be reduced in the actual setting of the subacute phase of ACS in humans. Therefore, it is conceivable that patients with genetic variants, such as KCNQ1 G643S and KCNH2 K897T, would be at higher risk of TdP in the presence of additional reduction of repolarizing currents during the subacute phase of ACS.

Takotsubo Cardiomyopathy

Takotsubo cardiomyopathy is characterized by transient ventricular dysfunction in the absence of coronary artery disease and accompanied by repolarization abnormalities, including T-wave inversions and QT prolongation. It is commonly triggered by severe emotional or physical stress.⁷⁴ The exact underlying mechanisms of the disease remain unclear; however, it is believed that ventricular dysfunction and subsequent repolarization abnormalities result from catecholamine-mediated myocardial toxicity.

Madias et al reported that 8 (8.6%) of 93 total patients with takotsubo cardiomyopathy developed TdP or VF.⁷⁵ The QT interval became pronouncedly prolonged over the 24–48 h after presentation, and most cases of TdP or VF occurred during the subacute phase of the disease. The initiation pattern of TdP exhibits characteristics of pause-dependent LQTS. A novel duplication mutation (V115-A121dup) in the Per-Arnt-Sim domain of KCNH2 has been identified in a patient with takotsubo cardiomyopathy who experienced excessive QT prolongation and syncope (Table 3),⁷⁶ suggesting that patients with LQTS have a higher risk of TdP when experiencing takotsubo cardiomyopathy.

Cardiac Memory

Cardiac memory is characterized by an altered T wave (marked inversion of T-wave polarity with QT prolongation) on the surface ECG during normal ventricular activation following altered electrical activation such as left bundle branch block, ventricular preexcitation and right ventricular pacing.⁷⁷ Although cardiac memory is usually considered benign, cessation of long-lasting ventricular pacing has induced T-wave polarity changes with marked QT prolongation after a normal ventricular activation pattern, followed by TdP in a LQT2 patient (Table 3).⁷⁸ Therefore, apart from patients with pause-dependent TdP, unnecessary ventricular pacing should be avoided in LQTS patients. Conversely, in LQTS patients with ventricular pacing, the appearance of occasional spontaneous normal rhythm should be inhibited.

Besides those mentioned, other factors such as congestive heart failure, nervous system injury, starvation, female sex etc are also known as precipitating factors for fatal arrhythmias.³⁸

Conclusions

In this review, we have highlighted the triggers and precipitating factors for fatal arrhythmias in patients with inherited arrhythmia syndromes, including their latent forms, in which clinical phenotypes become manifest under specific conditions (drugs, bradycardia, electrolyte disturbances, fever, ACS, takotsubo cardiomyopathy, and cardiac memory). At present, risk stratification is based on clinical phenotype, including episodes of syncope, findings of the surface ECG and electrophysiological study, and family history for SCD, and the yield of genetic testing is not sufficient to determine the risk for future events. Further studies to unmask the potential triggers and precipitating factors for fatal cardiac events in patients carrying genetic variants associated with inherited arrhythmia syndromes is urgently required to improve the risk stratification process.

Acknowledgments

This work was supported by JSPS KAKENHI Grant Number 26461056.

Disclosures

None.

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