Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia disorder that is characterized by emotion- and exercise-induced polymorphic ventricular arrhythmias and may lead to sudden cardiac death (SCD). CPVT plays an important role in SCD in the young and therefore recognition and adequate treatment of the disease are of vital importance. In the past years tremendous improvements have been made in the diagnostic methods and treatment of the disease. In this review, we summarize the clinical characteristics, genetics, and diagnostic and therapeutic strategies of CPVT and describe the most recent advances and some of the current challenges. (Circ J 2016; 80: 1285–1291)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially life-threatening inherited arrhythmia disorder that is characterized by the occurrence of polymorphic ventricular arrhythmias in the setting of a high adrenergic tone such as during physical exercise or strong emotions.¹ CPVT is a rare disease with an estimated prevalence of 1:10,000. Even though it is a rare entity, timely recognition is of vital importance because CPVT plays an important role in sudden cardiac death (SCD) in the young. Indeed, molecular autopsy of SCD cases with a normal autopsy have identified pathogenic putative RYR2 mutations in up to 15% of cases in patients under the age of 40 years.^2,3

The majority of patients present around the age of 10 years with exercise-induced syncopal episodes.⁴ However, atypical cases in which the onset of symptoms starts in the 3rd or 4th decade of life are also recognized. In a small study, this atypical form of CPVT occurred more often in women and in genotype-negative individuals.⁵ In approximately one-third of cases a cardiac arrest is the first symptom of the disease.⁴ When left untreated, patients with CPVT have a mortality rate of 30% before age 40.^6,7

Since the first description of CPVT in 1960 by Berg,⁸ enormous progress has been made in our understanding of the pathogenesis, diagnosis and treatment of the disease. Here, we provide an overview of our current knowledge of CPVT as well as the new challenges.

Clinical Characteristics

Patients with CPVT have a structurally normal heart and a normal 12-lead- ECG at rest.¹ Sinus bradycardia is present in approximately 20% of patients.^9,10 The underlying mechanism of the sinus bradycardia was investigated in a CPVT mouse model. In this model the sinoatrial node cells displayed a continuous calcium leakage, which in turn hampered action potential triggering and decreases the intrinsic baseline heart rate.¹¹ In addition, a prominent U-wave is observed in a subset of patients and may also be related to altered intracellular calcium handling.¹² It is, however, unknown if the presence of a prominent U-wave has any clinical relevance. Supraventricular dysrhythmias such as atrial fibrillation and sick sinus syndrome are present in 16–26% of the patients^1,5,9 and may provoke ventricular arrhythmias in some patients.¹³ In young children, supraventricular arrhythmias can precede the occurrence of the classic CPVT phenotype.¹⁴ These supraventricular arrhythmias are hypothesized to arise from dysfunctional calcium handling in atrial cardiomyocytes (comparable to the ventricular phenotype).^15–17 An alternative hypothesis is that microfibrosis in the sinus node may result in altered electrical impulse generation and propagation and lead to sinus node dysfunction and supraventricular tachyarrhythmias.¹⁸

During exercise testing, isolated and often monomorphic ventricular premature beats (VPBs) typically occur first (Figure 1). When the exercise duration increases, the isolated VPBs may appear in a bigeminal pattern and are usually followed by polymorphic doublets or ventricular arrhythmias that become more complex in nature as the exercise increases and disappear when the exercise is stopped. Of note, in a subset of patients the ventricular arrhythmias already disappear with ongoing exercise.¹⁹ Mildly affected patients may present with only single ventricular ectopic beats or bigeminy. Heart rate at the onset of the ventricular arrhythmias is often reproducible within an individual patient and typically occurs at 110–130 beats/min. The VPBs usually have a coupling interval of approximately 400 ms.⁵ The first VPBs have a predominant left bundle branch block inferior axis (47%) or right bundle branch block superior axis (29%) morphology.⁵ The occurrence of a bidirectional ventricular tachycardia (VT) is highly suggestive of the diagnosis CPVT, but is infrequently observed. This particular type of VT is characterized by 180° rotation of the QRS complex from beat to beat (Figure 1C). Other conditions in which a bidirectional VT can be observed are digitalis intoxication and in Andersen-Tawil patients carrying a KCNJ2 mutation.²⁰ Mechanistically, the bidirectional VT seen in CPVT are thought to originate from the His-Purkinje system.²¹

Figure 1.

Exercise-induced ventricular arrhythmias in a female CPVT patient with a RYR2 mutation. Baseline ECG, 12-lead ECG (2×6 leads), at rest (A). Monomorphic ventricular premature beats during mild exercise (B). Polymorphic ventricular beats, couplets and non-sustained VT at moderate exercise (C). Bidirectional VT during maximal exercise (initial part) and polymorphic VT (final part), which disappears when the exercise is stopped (D). CPVT, catecholaminergic polymorphic ventricular tachycardia.

Diagnosis

CPVT is diagnosed in the presence of a structurally normal heart, normal ECG, and unexplained exercise- or catecholamine-induced bidirectional VT or polymorphic VPBs or VT in an individual <40 years and/or in carriers of a pathogenic mutation in a CPVT-associated gene.²² In addition, CPVT is diagnosed in family members of a CPVT proband who manifests exercise-induced VPBs or VTs in the absence of structural heart disease. Finally, CPVT can also be diagnosed in patients >40 years of age with unexplained exercise- or catecholamine-induced VT in the setting of a structurally normal heart, normal ECG and normal coronary arteries.²²

Exercise testing is the most helpful clinical tool to diagnose CPVT. In asymptomatic relatives of CPVT patients the exercise test has a specificity of 97% and a sensitivity of 50% for predicting the presence of the familial CPVT-associated mutation.^7,9,23 In individuals unable to perform an exercise test, for example very young patients or patients whose symptoms are more emotion-related rather than exercise-related, Holter monitoring can be performed. In addition, Holter monitoring is also useful to detect the presence of supraventricular arrhythmias. However, Holter monitoring is less sensitive than exercise testing.⁵ Epinephrine infusions may also be useful to establish the diagnosis CPVT in patients who cannot perform an exercise test.²² In a study of 36 CPVT patients and 45 unaffected relatives, epinephrine infusion was administered at 0.05 μg·kg^–1·min^–1 for 4 min and accelerated to 0.4 μg·kg^–1·min^–1.²⁴ Here, mean maximum heart rate was significantly lower than the maximum heart rate achieved during exercise testing (101±16 vs. 175±19 beats/min, P<0.05). The overall sensitivity of the epinephrine test was low (28%) and the specificity was high (98%) when compared with exercise testing.

Genetic testing is recommended to confirm the diagnosis in the proband, after which so-called cascade screening can be performed to detect mutation-carrying relatives.²⁵ First-degree relatives of mutation-negative patients with CPVT are recommended to be screened by repeat exercise testing, depending on the age of the relative.²⁶

Electrophysiological and Genetic Background

The familial occurrence of CPVT was already recognized by Berg⁸ in 1960, who described 3 sisters suffering from syncopal episodes during exercise or emotional stress in the absence of structural heart disease. Decades later, Swan and coworkers performed genetic linkage studies in 2 unrelated Finnish families, which revealed a disease-causing locus with an autosomal dominant inheritance pattern on chromosome 1q42–q43.²⁷ Later, the gene encoding the cardiac ryanodine receptor (RYR2) was identified as the disease-causing gene residing on this locus.^28,29 CPVT caused by mutations in RYR2 is also known as CPVT1. Mutations in RYR2 account for approximately 65% of the CPVT cases.²⁶ RyR2 is involved in intracellular calcium hemostasis and plays a role in the excitation-contraction coupling of the heart. Mutations in RYR2 cause a diastolic calcium leakage from the sarcoplasmic reticulum, with a subsequent increase in the cytosolic calcium concentration.³⁰ This increase in cytosolic calcium concentration ultimately activates the electrogenic sodium-calcium exchanger, leading to a transient inward current, resulting in delayed after-depolarizations that in turn can lead to triggered arrhythmias. The diastolic calcium leakage becomes more pronounced in the setting of high β-adrenergic tone.^21,31 The majority of the mutations identified in RYR2 are missense mutations that cause a gain of function. However, loss-of-function mutations in RYR2, such A4860G, have also been reported.^6,32 The mutations cluster in certain areas of RYR2 (so-called “hotspot areas”).³³ Apart from the “classic” CPVT phenotype, mutations in RYR2 have also been linked to adrenergic idiopathic ventricular fibrillation.³⁴ Finally, a deletion of exon 3 of RYR2 has been shown to cause a distinct subtype of CPVT characterized by sinoatrial node and atrioventricular node dysfunction, supraventricular arrhythmias, and dilated cardiomyopathy.³⁵

An autosomal recessive inheritance pattern of CPVT caused by mutations in cardiac calsequestrin (CASQ2) was discovered in a large Bedouin family.³⁶ Mutations in CASQ2 account for approximately 2–5% of the CPVT cases. Cardiac calsequestrin is a calcium-buffering protein within the sarcoplasmic reticulum with an inhibitory effect on RyR2.

A 3rd form of CPVT has initially been linked to chromosome 7p14–p22.³⁷ Extension of the family reallocated the locus to chromosome 4 and further fine mapping identified variants in the TECLR gene in all affected individuals in the original family and in 2 unrelated young individuals (unpublished data). This phenotype is highly malignant and characterized by exercise-induced ventricular arrhythmia and a minor exercise-induced QT-prolongation.³⁷ Based on a candidate gene approach, mutations in the gene encoding triadin (TRDN) were identified in the probands of 2 families in whom no mutations were identified in RYR2 and CASQ2.³⁸ The mutations identified followed an autosomal recessive inheritance pattern. Interestingly, one of the probands in whom a compound heterozygous TRDN mutation was identified also suffered from proximal muscle weakness apart from cardiac arrhythmias.³⁸ This may be explained by the fact that some isoforms of TRDN are also expressed in skeletal muscle tissue. TRDN mutations might cause CPVT by an impaired FKBP12.6–RYR2 interaction or by a reduction of CASQ2.³⁸

Other genes that have been associated with CPVT are CALM1 and CALM2 (encoding calmodulin). A mutation in CALM1 was first identified in a Swedish family that presented with a history of exercise-induced ventricular arrhythmias, syncope, and sudden death.³⁹ Subsequent screening of 63 mutation-negative CPVT cases revealed 1 de novo missense mutation in CALM1 in a female of Iraqi descent who suffered from a cardiac arrest while running at the age of 4 years old. An exercise test without antiarrhythmic drugs revealed exercise-induced polymorphic ventricular arrhythmias.³⁹ Calmodulin is a calcium-binding protein that stabilizes RyR2 and reduces the probability of its opening during diastole.³⁹ Apart from CPVT, mutations in CALM1 have also been associated with congenital long-QT syndrome and idiopathic ventricular fibrillation.^40,41 Mutations in CALM2 have been reported in 2 separate papers^40,42 and have been associated with congenital long-QT syndrome and with overlapping features between congenital long-QT syndrome and CPVT.^40,42

Finally, mutations in the genes ANK2, encoding ankyrin-B, and KCNJ2, encoding the potassium inwardly rectifying channel Kir2.1, are generally associated with the congenital long-QT syndrome types 4 and 7, respectively, but may phenocopy CPVT.^43–45 Approximately one-third of CPVT cases remain gene-elusive to date.²²

Comprehensive genetic testing for RYR2 and CASQ2 is recommended for all patients in whom there is a clinical suspicion (clinical history, family history, exercise testing or epinephrine infusion) for CPVT.²⁶ Mutation-specific cascade screening is recommended for family members of a patient in whom a mutation has been identified.^22,25 Generally, the genetic signal-to-noise ratio for RYR2 (ie, the yield of genetic testing in patients divided by the background rate of genetic variants in healthy individuals) is considered low (20:1).²⁶ In contrast, a more recent study identified RYR2 variants previously associated with CPVT in 1:150 healthy individuals.⁴⁶ These data highlight the importance of a careful clinical evaluation for correct selection of patients in whom CPVT is diagnosed or suspected and DNA testing is considered indicated. In addition, these data show the difficulty of establishing the true pathogenicity of rare variants.

Risk Stratification

Risk stratification for the occurrence of cardiac events in CPVT patients is poorly defined. At present, markers to identify patients at high or low risk of cardiac events are lacking. Being a proband, younger age at the time of the diagnosis, history of an aborted cardiac arrest, and absence of β-blocker therapy have been identified as independent predictors for cardiac events.^4,7,9 One small retrospective study that included 51 CPVT patients evaluated baseline ECGs for the presence of an early repolarization pattern (ERP), hypothesizing that ERP may contribute to the risk for cardiac events.⁴⁷ ERP was present in 23 CPVT patients (45%) and correlated with a higher probability of being symptomatic at presentation.⁴⁷ During exercise testing the presence of non-sustained VT is correlated with a worse outcome.²³ It is, however, important to realize that the exercise test is not fully reliable for predicting future cardiac events. Cases in which no ventricular arrhythmias were observed in patients during exercise testing but who did experience a cardiac arrest have been reported.²³

Similar to other inherited arrhythmia syndromes, genotype-phenotype correlations may also exist in CPVT. An increased odds of NSVT has been observed in patients with a mutation in the C-terminal channel-forming domain of RYR2 when compared to the N-terminal domain.⁹ Even though no robust comparison between patients with CPVT1 and CPVT2 has been made, CPVT2 is considered a more severe phenotype. Up until now, no genes have been identified that modulate the risk of cardiac events in CPVT (modifier genes).

Treatment

General Recommendations

Patients with CPVT are recommended to avoid strenuous exercise and competitive sports.²² In addition, adherence to medication (see next) should be stressed, because in our experience a significant number of breakthrough cardiac events occur in the setting of non-adherence.

β-Blockers

First-line therapy for CPVT consists of β-blockers at the highest tolerable dose.²² Current guidelines recommend treating symptomatic patients (Class I) and mutation-positive phenotype-negative patients (Class IIa) with β-blockers. In order to monitor the efficacy of the prescribed treatment, it is recommended to regularly evaluate the patient by exercise testing. Even though no robust comparison between the efficacy of the different type of β-blockers has been performed, reports indicate that the unselective β-blocker nadolol may be superior to other types of β-blockers.^7,48 Hayashi et al observed lower cardiac event rates in patients treated with nadolol compared with other β-blockers and found that treatment with another type of β -blocker then nadolol was an independent risk factor for cardiac events (hazard ratio 3.12; 95% confidence interval [CI] 1.16–8.38; P=0.02).⁷ Of note, that study did not indicate which type and dose of β-blocker the patients who were not on nadolol were receiving. Furthermore, of the patients who did experience a cardiac event on β-blocker therapy, only one used propranolol and none used metoprolol. Nadolol at a dose >1.5 mg·kg^–1·day^–1 is recommended, as patients treated with doses lower than 1.5 mg/kg were at increased risk of cardiac events. In another study, nadolol was associated with a significant decrease in the ventricular arrhythmia burden during exercise testing compared with other β1-selective β-blockers.⁴⁸ Nadolol was also associated with a lower maximum heart rate and arrhythmia score compared with β1-selective β-blockers. A possible explanation for the favorable effect could be that nadolol has a more pronounced chronotropic effect than other types of β-blockers. In addition, nadolol is typically administered once daily, which may result in improved adherence compared with those types of β-blockers that require more frequent administration. Because nadolol is not available in every country, other types of unselective β-blockers such as propranolol may be a good alternative. However, up to almost 40% of patients experience cardiac events while on β-blocker therapy at 8 years of follow-up.⁴⁹

Flecainide

When β-blockers fail to sufficiently suppress ventricular arrhythmias during exercise testing, or when patients experience a cardiac event while on β-blocker therapy, adding flecainide (a Class Ic antiarrhythmic drug) is the next therapeutic step (Class IIa).²² Figure 2 shows the effect of β-blocker therapy and flecainide added to β-blockers in a CPVT patient. A dose-response effect has been observed and optimal dosing for ventricular arrhythmia suppression in adults is approximately 150–300 mg/day, because doses less than 100 mg/day are associated with a lack of therapeutic response.⁵⁰ In healthy subjects, steady-state levels of flecainide are achieved within 3–5 days, so the efficacy of flecainide can be evaluated after approximately 5 days. In contrast to β-blockers, the side effects of flecainide are mild and rarely lead to discontinuation of therapy.

Figure 2.

ECG recordings during maximal exercise before and after treatment in a female patient with CVPT. At baseline without medication, there are polymorphic non-sustained VTs (A). After metoprolol (100 mg/day), only bigeminal ventricular premature beats are observed (B). With metoprolol (100 mg/day) and flecainide (150 mg/day), there is complete suppression of the ventricular arrhythmias (C). CPVT, catecholaminergic polymorphic ventricular tachycardia.

The efficacy of flecainide was first observed in a CPVT CASQ2 knockout mouse model, showing a reduction of ventricular arrhythmia burden both in vitro and in vivo.⁵¹ This discovery led to the successful treatment of 2 severely affected patients.⁵¹ The first cohort study that assessed the efficacy of flecainide included 33 genotype-positive patients who were either symptomatic on maximally tolerated therapy or had persistent severe ventricular arrhythmias despite maximally tolerated therapy.⁵⁰ Partial or complete suppression of the ventricular arrhythmias was achieved in 76% of patients when comparing the last exercise test before the initiation of flecainide with the first exercise test on a stable dose of flecainide. During a mean follow-up of 20 months, 1 patient suffered from an episode of several appropriate ICD shocks related to confirmed non-compliance.⁵⁰ Similar findings were subsequently observed in patients with CASQ2 mutations and genotype-negative CPVT patients.^52,53 One small study evaluated the efficacy of flecainide as a monotherapy in patients who were either intolerant to or had experienced severe side effects of β-blockers.⁵⁴ None of these patients suffered from treatment failure during a median follow-up of 37 months.⁵⁴ However, routine use of flecainide monotherapy is not recommended because the evidence is scarce.

The proposed underlying mechanism of the action of flecainide is that, apart from the known sodium channel (NaV1.5) blocking effect, flecainide has an additional direct blocking effect on the RyR2 channel.⁵¹ However, this suggested mechanism is opposed by others who have proposed a mechanism that can solely be attributed to the sodium channel-blocking properties of the drug or by interaction with other modulators of RyR2.^55–58

Left Cardiac Sympathetic Denervation (LCSD)

LCSD is a surgical procedure in which the lower two-thirds of the left stellate ganglion, together with the thoracic ganglia T2–T4, are ablated, thereby interrupting the major source of norepinephrine release in the heart.^59,60 The surgery can be subdivided into complete or partial LSCD and is considered partial whenever T1 or T4 is not ablated.⁶¹ The most frequent complication of this surgery is Horner’s syndrome (characterized by miosis, ptosis, and anhidrosis resulting from damaging of the sympathetic nerves), which is reversible in a significant proportion of the patients.⁶² LCSD can be performed in patients who are symptomatic despite maximal medical therapy or are intolerant to or in whom β-blockers are contraindicated (Class IIb).²² In an international cohort consisting of 63 patients undergoing LCSD, the number of patients with cardiac events decreased significantly from 86% (54 of 63) to 21% (13 of 63; P<0.001) during follow-up.⁶¹ In the subgroup of patients who were symptomatic despite optimal medical therapy before LCSD, only one-third had a recurrent cardiac event after LCSD. Mean annual event rates dropped 92%, from 3.4 (95% CI 3.2–3.7) pre-LCSD to 0.5 (95% CI 0.4–0.6) post-LCSD. Patients with a partial LCSD were at increased risk for recurrent events compared with those undergoing complete LSCD.

Implantable Cardioverter-Defibrillator (ICD) Therapy

ICDs are recommended in patients with a diagnosis of CPVT who experience cardiac arrest, recurrent syncope or VTs despite optimal medical therapy (Class I).²² There are, however, significant drawbacks to ICD therapy because several case reports have shown the potential proarrhythmic properties of the ICD. An ICD shock (both inappropriate and appropriate) may cause a subsequent catecholamine release from the pain and fear caused by the ICD shock, which in turn can trigger more ventricular arrhythmias and lead to a ventricular arrhythmic storm.^63,64 Therefore, β-blockers and sometimes flecainide are mandatory in CPVT patients with an ICD to reduce the chances of appropriate and inappropriate shocks. Two independent studies found that shock success was highly dependent on the underlying ventricular arrhythmia. Unsuccessful shocks were frequently observed in cases of polymorphic VT or bidirectional VT, whereas shocks administered for VF were often successful.^65,66 Patients with inherited cardiac arrhythmia disorders are exposed to the potential harm of ICD therapy for a long period of time and are therefore at higher risk. A recent meta-analysis demonstrated that inappropriate ICD shocks are significantly more often observed in patients with CPVT (36% vs. 20%; P=0.04) when compared with other inherited arrhythmia syndromes and most often occurred because of supraventricular tachycardia.⁶⁷ Importantly, 85% of the CPVT patients suffered from ICD-related complications during a mean follow-up of 54±43 months.⁶⁷

Future Perspectives

An exciting new development in the field is gene therapy. Gene therapy directly targets the underlying genetic defect that leads to disease by replacing the mutant DNA with wild-type DNA, leading to restoration of normal gene function. Using a knock-in mouse model harboring the CASQ2^R33Q/R33Q mutation, an adeno-associated viral vector with the wild-type CASQ2 gene was injected into newborn CPVT mice.⁶⁸ This intervention reversed the CPVT phenotype of these mice and was still successful in reversing the phenotype after 1 year of follow-up. These first results seem encouraging and point toward potential future gene therapies.

Conclusions

Even though tremendous progress has been made in the recent years in the diagnosis and treatment of CPVT, additional research is needed. Because a large proportion of the patients still remain mutation negative, gene discovery is an ongoing process. Other important issues that need to be addressed are the development of tools for risk stratification and the discovery of modifier genes of CPVT. Gene therapy is a promising new therapy for patients with CPVT in the future.

Acknowledgments

We acknowledge the support of the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences (CVON 2010-12 PREDICT).

Conflict of Interest

None declared.

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