OUP user menu

Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments

Christian van der Werf, Aeilko H. Zwinderman, Arthur A.M. Wilde
DOI: http://dx.doi.org/10.1093/europace/eur277 175-183 First published online: 5 September 2011

This article has a correction. Please see:

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by bidirectional or polymorphic ventricular arrhythmias under conditions of increased sympathetic activity in young patients with structurally normal hearts. Patients with CPVT are at high risk of developing life-threatening ventricular arrhythmias when untreated. A wide variety of arrhythmic event rates on conventional therapy, with β-blockers as the cornerstone, has been reported. Here, we systematically review all available studies describing the efficacy of β-blocker therapy for prevention of arrhythmic events in CPVT. Because of heterogeneity between the studies, a random-effects meta-analysis model was used to assess the efficacy of β-blocker therapy in preventing any arrhythmic event [syncope, aborted cardiac arrest (ACA), and sudden cardiac death (SCD)], near-fatal arrhythmic events (ACA and SCD), and fatal arrhythmic events. Eleven studies including 403 patients, of whom 354 (88%) had a β-blocker prescribed, were identified. Mean follow-up ranged from 20 months to 8 years. Estimated 8-year arrhythmic, near-fatal, and fatal event rates were 37.2% [95% confidence interval (CI): 16.6–57.7], 15.3% (95% CI: 7.4–23.3), and 6.4% (95% CI: 3.2–9.6), respectively. In addition, we review the recent developments in alternate chronic treatment options for CPVT patients, including calcium channel blockers, flecainide, left cardiac sympathetic denervation, and implantable cardioverter defibrillators. A new treatment strategy is proposed, including a stepwise addition of the alternate treatment options to β-blockers in patients who do not respond sufficiently to this first-line therapy. Finally, future developments in chronic treatment options and acute treatment options of ventricular arrhythmias are discussed.

  • Catecholaminergic polymorphic ventricular tachycardia
  • Syncope
  • Aborted cardiac arrest
  • Sudden cardiac death
  • Treatment
  • Therapy
  • Adrenergic β-antagonists
  • Calcium channel blockers
  • Flecainide
  • Sympathectomy

Introduction

The hallmark of the inherited arrhythmia syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT) includes bidirectional or polymorphic ventricular arrhythmias under conditions of increased sympathetic activity in young patients with structurally normal hearts and a normal 12-lead electrocardiogram.1,2 Mutations in the genes encoding the cardiac ryanodine-calcium release channel (RYR2) or, infrequently, cardiac calsequestrin (CASQ2) are identified in ∼60% of patients meeting the precise definition of CPVT.3,4 These genes encode proteins that are involved in the release of calcium from the sarcoplasmic reticulum (SR) and mutations therein result in inappropriate calcium leak from the SR,57 leading to cytosolic calcium overload generating delayed afterdepolarizations, triggered activity, and ventricular arrhythmias, particularly under conditions of increased β-adrenergic tone.8,9 We described a third locus in a small consanguineous family, but at present the causal gene in this locus is unknown.10

The differential diagnosis in a patient with suspected CPVT can include Andersen–Tawil syndrome (which can mimic the CPVT phenotype),11 and long QT syndrome type 1 (which is associated with exercise-induced arrhythmic events as well). In addition, mutations in the RYR2 gene have also been identified in patients with discrete abnormalities of the right ventricle.12 Whether this fits the diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy is subject to discussion.

Catecholaminergic polymorphic ventricular tachycardia is considered to be a malignant inherited arrhythmia syndrome. Indeed, in untreated patients 8-year overall arrhythmic event rates of 58% and fatal or near-fatal event rates of 25% have been reported.13 The risk of arrhythmic events is considered to be higher in patients with aborted cardiac arrest (ACA),13 and in patients carrying recessively inherited CASQ2 mutations.14,15 However, it has become apparent that mutation-carrying CPVT patients with no ventricular arrhythmias during exercise testing (so-called silent mutation carriers) are at risk of arrhythmic events as well.13,16

In this review we first systematically assess the efficacy of β-blocker therapy, which is considered the cornerstone of chronic CPVT therapy. Secondly, alternate pharmacologic and non-pharmacologic treatment options are discussed and a new treatment approach in CPVT patients is proposed. This review concludes with a glimpse at future therapeutic developments and acute management strategies in CPVT.

β-Blocker therapy

Ever since CPVT was first described, the strong relationship between ventricular tachycardia (VT) and β-adrenergic activation as well as the efficacy of β-blocker therapy were recognized.1719 As a consequence, CPVT patients are advised to be cautious with practicing (competitive) sports, including swimming.20

In the first comprehensive CPVT series published by Leenhardt et al.2 in 1995, it became apparent that β-blockers were the most effective drug therapy for reducing ventricular arrhythmias during exercise testing or Holter monitoring and preventing arrhythmic events. In subsequently published series, the range of arrhythmic events on β-blocker therapy has been variable.

Eleven studies describing a total of 403 CPVT patients were included in our systematic analysis on the overall efficacy of β-blocker therapy in CPVT (see Supplementary material and Table 1).2,13,15,16,21,2328 As expected, mean age of patients in these studies was relatively young and no apparent gender predominance could be observed. Two-hundred and sixty-seven (66%) patients were symptomatic when CPVT was diagnosed, and 255 (63% of total) patients harboured a mutation in RYR2, whereas 32 (8%) patients carried a CASQ2 mutation.

View this table:
Table 1

Summary of the studies selected

StudyYear publishedNumber of patients (probands/relatives)Age at diagnosis (years)aMaleNumber of symptomatic patientsRYR2 mutation/CASQ2 mutation/no mutation identified/genetic testing not performedNumber of patients on β-blocker therapyDaily β-blocker doseTherapy on top of β-blocker (number of patients)Follow-up duration (years)aNumber of patients with arrhythmic events on β-blocker therapyNumber of patients with near-fatal arrhythmic events on β-blocker therapyFatal arrhythmic event rateMinimal number of patients with arrhythmic events related to poor compliance
Leenhardt et al.2199521 (20/1)9.9 ± 412 (57%)20 (95%)0/0/0/2121 (100%)Nadolol 40–80 mgNone7 (2–16)b3 (14%)2 (9%)2 (9%)1
Swan et al.21199914 (from 2 families)25 ± 119 (64%)9 (64%)14/0/0/0c14 (100%)Not reportedNone8 ± 61 (7%)1 (7%)0Not reported
Lahat et al.15/Katz et al.22d2001/200925 (from 12 families)9 ± 8e4 (31%)e20 (80%)0/25/0/025 (100%)Mostly propranolol 4.8 mg/kgICD (6)5.2 (5–11)b8 (32%)4 (16%)4 (16%)2e
Bauce et al.23200243 (from 8 families)31 ± 2023 (53%)28 (65%)43/0/0/026 (60%)Acebutolol 200–400 mg, atenolol 100 mgICD (1)6.5 (0.5–14)b000Not reported
Priori et al.24200243 (30/13)Not reported15 (35%)29 (67%)23/0/20/019 (83%)/20 (100%)fNadolol 1–2 mg/kg, metoprolol 1–3 mg/kg, propranolol 3–4 mg/kgICD (12)3.3 ± 2.4/4.3 ± 2.5f7 (37%)/11 (55%)fNot reportedNot reportedNot reported
Sumitomo et al.25200329 (25/4)10.3 ± 6.113 (45%)27 (93%)Not reported28 (97%)Propranolol 52 ± 42, 64 ± 37, and 56 ± 24 mghVerapamil (3), mexiletine (2)6.8 ± 4.9Not reportedg9 (32%)4 (14%)1
Postma et al.26200554 (12/42)12 (4–51)22 (49%)26 (58%)54/0/0/050 (93%)Nadolol 1–2 mg/kg, metoprolol 50–100 mg, propranolol 3–4 mg/kgICD (2)2 (2–37)2 (4%)2 (4%)1 (2%)1
Hayashi et al.132009101 (50/51)15 ± 1054 (53%)61 (60%)72/7/16/681 (80%)Nadolol 1.6 ± 0.9 mg/kgVerapamil (6), ICD (16)7.9 ± 4.927 (33%)13 (16%)5 (6%)6
Celiker et al.27200916 (13/3)10.6 ± 3.511 (69%)12 (75%)1/0/0/1515 (94%)Propranolol 2–4 mg/kgVerapamil (4), ICD (4)2.5 ± 2.07 (47%)6 (40%)3 (20%)1
Haugaa et al.16201030 (6/24)32 (6–75)15 (50%)11 (37%)30/0/0/030 (100%)Metoprolol 125 ± 50 mg, nadolol 77 ± 34 mgICD (3)1.8 (1.1–24)1 (3%) 1 (3%)1 (3%)Not reported
Sy et al.28201127 (16/11)35 (5–72)9 (33%)24 (89%)18/0/4/525 (93%)Atenolol 25–100 mg, nadolol 20–80 mg, bisoprolol 2.5–10 mg; mean equivalent bisoprolol dose = 8 mgVerapamil (3), flecainide (5), LCSD (1), ICD (15)6.2 ± 5.78 (32%)5 (20%)2 (8%)0
  • ICD, implantable cardioverter defibrillator; LCSD, left cardiac sympathetic denervation.

  • aMean ± standard deviation or median (range), unless otherwise indicated.

  • bMean (range).

  • cDisorder mapped to chromosome 1q42–q43, which contains the RYR2 gene.

  • dLahat et al.'s15 is the original paper, but Katz et al.22 contain additional follow-up data. Therefore all data were derived from Katz et al.22, unless it was not reported.

  • eData from Lahat et al.15 (n = 13).

  • fRYR2 mutation carriers and genotype-negative patients, respectively.

  • gOnly the number of patients uncontrolled by β-blocker therapy, including dizziness and persistent ventricular tachycardia [18 (64%)] is reported.

  • hDaily β-blocker dose in sudden cardiac death, controlled, and uncontrolled cases, respectively.

Out of the 403 patients, 354 (88%) had a β-blocker prescribed during follow-up and/or at time of an arrhythmic event (if any). Mean or median follow-up durations ranged from 20 months to 8 years. Ten studies reported the proportion of CPVT patients experiencing an arrhythmic event, which ranged from 0 to 55% (Table 1).2,13,15,16,21,23,24,2628 The estimated overall 4- and 8-year arrhythmic event rates were 18.6% [95% confidence interval (CI): 8.3–28.9] and 37.2% (95% CI: 16.6–57.7), respectively (Figure 1 and Table 2).

View this table:
Table 2

Event rates including all studies and excluding studies with low or unknown β-blocker doses

Studies includedFour-year event ratesEight-year event rates
ArrhythmicNear-fatalFatalArrhythmicNear-fatalFatal
All studies18.6% (8.3–28.9)7.7% (3.7–11.7)3.2% (1.6–4.8)37.2% (16.6–57.7)15.3% (7.4–23.3)6.4% (3.2–9.6)
Sumitomo et al.25 excluded (low β-blocker doses)18.6% (8.3–28.9)6.3% (2.8–9.8)3.0% (1.3–4.6)37.2% (16.6–57.7)12.5% (5.5–19.5)5.9% (2.6–9.2)
Sumitomo et al.25and Swan et al.21 excluded (low or unknown β-blocker doses)20.3% (9.3–31.3)6.9% (2.8–11.0)3.1% (1.4–4.9)40.6% (18.6–62.6)13.8% (5.7–22.0)6.3% (2.7–9.8)
  • Values are proportion (95% CI).

Figure 1

Arrhythmic event curves. The red line and its corresponding area indicate the proportion of patients with arrhythmic events and its corresponding 95% confidence interval based on a random-effects meta-analysis model. The green data points represent the arrhythmic event rates of the individual studies (Table 1). The area of each data point is proportional to its number of patients and statistical weight. The two groups included in the study by Priori et al. (RYR2 mutation carriers and genotype-negative CPVT patients) are displayed separately, because data for the total study population are not provided.

Ten studies2,13,15,16,21,23,2528 reported the proportion of near-fatal and fatal arrhythmic events, ranging from 0 to 40% and 0 to 20%, respectively (Table 1). Estimated 4- and 8-year near-fatal arrhythmic event rates were 7.7% (95% CI: 3.7–11.7) and 15.3% (95% CI: 7.4–23.3), respectively (Figure 2 and Table 2). Fatal events occurred in 3.2% (95% CI: 1.6–4.8) at 4-year and 6.4% (95% CI: 3.2–9.6) at 8-year follow-up (Figure 3 and Table 2).

Figure 2

Near-fatal arrhythmic event curves. The red line and its corresponding area indicate the proportion of patients with near-fatal arrhythmic events and its corresponding 95% confidence interval based on a random-effects meta-analysis model. The green data points represent the near-fatal arrhythmic event rates of the individual studies (Table 1). The area of each data point is proportional to its number of patients and statistical weight.

Figure 3

Fatal arrhythmic event curves. The red line and its corresponding area indicate the proportion of patients with fatal arrhythmic events and its corresponding 95% confidence interval based on a random-effects meta-analysis model. The green data points represent the fatal arrhythmic event rates of the individual studies (Table 1). The area of each data point is proportional to its number of patients and statistical weight.

A few important factors may influence these results, so caution should be taken in interpretation of these data. First, in one Japanese study25 daily β-blocker doses were significantly lower compared with the other studies that reported β-blocker doses, which might explain the high near-fatal and fatal event rates in that study. In addition, β-blocker doses were not reported in one study.21 Arrhythmic event rates excluding the Japanese study only and excluding both studies with low or unknown β-blocker doses are displayed in Table 2. No significant differences were observed.

Second, six studies described that at least one arrhythmic event could be attributed to poor drug compliance in general or at the time of the arrhythmic event (Table 1). Although drug compliance is one of the factors influencing drug efficacy, it could imply that ventricular arrhythmias were actually well controlled in these patients when they did take their β-blocker.

Lastly, in eight studies a minority of patients were treated with verapamil and/or flecainide, and/or underwent left cardiac sympathetic denervation (LCSD) and/or implantable cardioverter defibrillator (ICD) implantation in addition to β-blocker.13,16,2328 Thus, the estimated event rates are not event rates on β-blocker exclusively, and the actual event rates on β-blockers only may be underestimated due to these additional treatment measures.

Unfortunately, it was not possible to study β-blocker efficacy in specific subgroups, such as age, gender, mutation status, and symptomatic vs. asymptomatic patients, due to the low number of patients and lack of reported data.

The study by Song et al.,29 which included 10 non-genotyped CPVT patients in their single-centre study on ventricular tachycardia in children, was not included because the exact follow-up duration of this subgroup was not described. Although details on β-blocker therapy were not described either, their population seemed to remain symptomatic on β-blocker therapy. In addition to the four children who suffered ACA (n = 2) or sudden cardiac death (SCD; n = 2), some others were not well-controlled either, as three of them underwent LCSD, including one ICD patient who experienced electrical storm after panicking after an ICD shock. The appropriateness of the ICD shock is not described.

Conversely, in the study by Allouis et al.30 all nine CPVT patients who received β-blocker therapy were asymptomatic during an unknown follow-up duration.

Alternate chronic treatment options

Calcium channel blockers

Since calcium influx through the L-type calcium channels incites the so-called (increased) calcium-dependent calcium release through the defective or inappropriately regulated RYR2, the rationale for treating CPVT patients with the L-type calcium channel blocker verapamil is apparent.31 Moreover, the negative inotropic effect of verapamil could also positively contribute.

Swan et al.32 studied the efficacy of verapamil infusion (0.2 mg/kg of body weight) on top of β-blocker therapy in reducing the ventricular arrhythmia burden during exercise testing in six CPVT patients carrying a RYR2 mutation. Verapamil significantly decreased the number of ventricular premature beats (VPBs) during the entire exercise test as well as the longest ventricular salvo, and increased the ventricular arrhythmia threshold rate as compared with the exercise tests before verapamil infusion and after a wash-out period.

Rosso et al.33 treated six non-genotyped CPVT patients with exercise-induced ventricular ectopy despite maximally tolerated β-blocker doses with 240 mg verapamil daily (2–3 mg/kg body weight in children). After 1–2 weeks on combination therapy, exercise testing was repeated and a significant improvement in several ventricular arrhythmia parameters was observed. During short-term follow-up, two patients who had several episodes of syncope while on β-blocker therapy experienced one episode on combination therapy, whereas the other four patients (including one patient with multiple ICD shocks before verapamil was started) remained event-free. However, long-term verapamil did not prevent arrhythmic events in these patients.34 Three of these patients had clinically significant ventricular arrhythmias during 37 ± 6 months of follow-up.

Recently, Katz et al.35 studied the efficacy of several antiarrhythmic drugs in CASQ2 mutant mice and concluded that verapamil was most effective in reducing ventricular arrhythmias induced by exercise and epinephrine infusion. Subsequently, 11 young CPVT patients homozygous for the CASQ2D307H mutation who remained symptomatic despite being treated with maximally tolerated doses of propranolol received the maximally tolerated dose of verapamil treatment. After 1 week, combination treatment resulted in a decrease in ventricular arrhythmia burden at exercise testing in five patients. Alcalai et al.36 also observed an important effect of verapamil in reducing ventricular arrhythmias in their CASQ2 deficient mouse models.

In none of the three studies was a negative inotropic effect of verapamil observed, as the maximum heart rate was similar before and after verapamil in all studies.

Hayashi et al.13 reported four patients who remained event free during 1.6 ± 0.6 years after verapamil was added to β-blocker therapy, but the indications for adding verapamil were not specified. Based on these data as well as our37,38 and others'25,2729 experiences, verapamil has not proven to be Columbus' egg in CPVT patients with continuous ventricular arrhythmias and/or symptoms on β-blocker therapy who require additional treatment. However, verapamil may be beneficial in some of these patients and/or in CPVT patients carrying a (specific) CASQ2 mutation.

Flecainide

An important new development in this field has been the discovery of the RYR2 blocking properties of the Class 1c antiarrhythmic agent flecainide, which thereby can directly target ‘the molecular defect’ in CPVT.37,39 After promising results in in vitro and in vivo studies in (ventricular myocytes from) a CASQ2 knockout mouse model, flecainide was tested in two highly symptomatic CPVT patients (one RYR2 mutation and one CASQ2 mutation carrying patient).37 Flecainide dramatically reduced the ventricular arrhythmia burden during exercise testing in these patients.

Next, the efficacy of flecainide was retrospectively evaluated in our relatively large multicentre study consisting of 33 mutation carrying CPVT patients.38 Flecainide had been started in these patients because of persistent physical or emotional stress-induced ventricular arrhythmias and/or persistent symptoms, while on β-blocker monotherapy or combined with calcium channel blockers. In 22 (76%) patients flecainide suppressed exercise-induced ventricular arrhythmias either partially (n = 8) or completely (n = 14). Importantly, proarrhythmia as a result of flecainide was not observed. Median daily flecainide dose in patients in whom a decrease in ventricular arrhythmia burden was observed was 150 mg [2.3 mg/kg body weight; range: 100–300 mg (1.5–4.5 per kg body weight)]. As a proportion of patients treated did not receive optimal β-blocker therapy (most often because of side-effects), a subgroup analysis was performed in patients who did receive optimal conventional therapy. Flecainide significantly improved the ventricular arrhythmia parameters in this subgroup to a similar extent as in the total study population, supporting the concept that flecainide's point of action is independent from the degree of β-adrenergic receptor block.

During a median follow-up of 20 months (range: 12–40) no arrhythmic events occurred, except for one patient who experienced ICD shocks for polymorphic ventricular arrhythmias, which was associated with very low flecainide levels. The study also included an RYR2 mutation carrier who presented with exercise-induced VT in 1981, and in whom flecainide has successfully suppressed exercise-induced ventricular arrhythmias ever since.

Our findings were recently supported by a case of a female CPVT patient who did not tolerate β-blocker therapy and was successfully treated with flecainide,40 and a case of a severely symptomatic RYR2 mutation carrying 11-year-old boy.41 A concomitant advantage of treatment flecainide may be its efficacy in preventing supraventricular arrhythmias, which are associated with CPVT.2,28,42

Flecainide will probably play an important role in the treatment of CPVT patients. Yet, as previously commented,43 some issues are still unresolved, such as flecainide's efficacy in preventing arrhythmic events long term, its efficacy in genotype-negative CPVT patients, and whether flecainide could serve as first-line therapy (combined with β-blockers or even as monotherapy). Currently, a randomized clinical trial comparing flecainide on top of β-blocker vs. β-blocker monotherapy is ongoing to test the effect of flecainide prospectively (http://clinicaltrials.gov: NCT01117454).

Left cardiac sympathetic denervation

Decades before the efficacy of LCSD in CPVT patients was first reported,44 its beneficial results in patients with angina pectoris,45,46 long QT syndrome,47,48 and post-myocardial infarction patients at high risk of SCD49 had been recognized. In this first publication on its efficacy in CPVT, the excellent follow-up results in three young CPVT patients in whom ventricular arrhythmias could not be controlled by β-blocker therapy were reported, including two patients with a very long follow-up duration (20 and 10 years).44 This was followed by one case report50 and two case series,51,52 all using video-assisted thoracoscopic LSCD. Atallah et al.51 described the results of LCSD in four CPVT patients who received recurrent ICD discharges for ventricular tachycardia (n = 3) or rapidly conducted supraventricular tachycardia (n = 1) despite optimal drug therapy. One patient experienced one arrhythmic storm with recurrent ICD discharges in the first 8h after the procedure, and remained event-free for the next 2 years. In the other three patients, there were no ventricular arrhythmias up to 2 months post-procedure. Collura et al.52 published the results of LCSD in two severely symptomatic CPVT patients. One patient experienced recurrent post-operative ventricular arrhythmias leading to an extended hospital stay, but thereafter no other arrhythmic events occurred during 15 months of follow-up.

One case report suggested that the maximum benefit from LCSD may be several months instead of directly after the procedure,53 whereas another case showed that bilateral cardiac sympathetic denervation may (also) be effective.50 Pharmacologic sympathectomy using a high thoracic epidural catheter may be considered before performing LCSD to get information on its potential effectiveness.54

In the 14 CPVT patients treated with LCSD that were collected by Odero et al.,55 the result was favourable in 13 (93%). Although these initial results are encouraging, long-term follow-up has only been available in one more patient, who had a drastic decrease in appropriate ICD discharges during a 10-year follow-up.56 Hence, more data on the long-term efficacy of LCSD are required to determine its exact place in the therapeutic strategy in CPVT patients, including if the procedure's initial beneficial effects persist long term, and thus whether LCSD should be combined with drug therapy and/or ICD implantation.

The drawbacks of LCSD include potential complications, such as a transient or persistent Horner's syndrome and pneumothorax, but the incidence of these complications is very low.55 Also, at the moment LCSD is not universally available, as an expert surgeon and dedicated instrumentation are required.

Implantable cardioverter defibrillators

In the 2006 ACC/AHA/ESC Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention for Sudden Cardiac Death, a Class I recommendation was given for implantation of an ICD in addition to β-blocker therapy for CPVT patients who are survivors of ACA.57 A Class IIa recommendation was given for ICD implantation in CPVT patients with syncope and/or documented sustained VT despite β-blocker therapy.57 More recently, the Heart Rhythm UK Statement on Clinical Indications for ICDs in Adult Patients with Familial Sudden Cardiac Death Syndromes concurred with these recommendations, while adding LCSD as a therapeutic consideration before ICD implantation.58

However, ICDs have been implanted much more liberal by the cardiological community before and after these guidelines were published. This was most probably caused by the high mortality rates in untreated CPVT patients and in CPVT patients with β-blocker therapy reported in the first case series,2,24,25 which gave CPVT a highly malignant reputation. Potentially this is a worrisome development, because ICDs may have harmful effect in CPVT patients. A least five cases have been described showing that both appropriate and inappropriate ICD shocks can trigger catecholamine release, subsequently resulting in multiple shocks, arrhythmic storm, and death,28,5961 and as such ICD therapy does have a proarrhythmic potential. In a recent case report LCSD was performed simultaneously with ICD implantation to reduce the risk of such a fatal event.62

In addition, many CPVT patients are young, in whom ICD implantation can lead to significant complications,63 and because of the increased prevalence of supraventricular arrhythmias, CPVT patients with an ICD are at increased risk of receiving inappropriate ICD shocks. In the series by Celiker et al.27 the number of patients (n = 3) with appropriate ICD shocks was equal to the number of patients with inappropriate ICD shocks because of sensing errors (n = 2), lead fracture (n = 1, one of the patients with sensing errors), and lead migration. All four patients who received an ICD required psychological support because of signs of depression and anxiety. Inappropriate shocks can probably partly be prevented by careful ICD programming, e.g. with one ventricular fibrillation zone with a detection interval of 240 b.p.m. and (exceptionally) long detection intervals.

Given these serious drawbacks and the discovery of promising treatment alternatives on top of β-blocker therapy, we propose a more conservative approach for ICD implantation in CPVT patients, probably even with regard to those who were diagnosed with CPVT after experiencing ACA (see Proposed treatment strategy).

Definition of failure of therapy

As ICD implantation is recommended in CPVT patients with syncope and/or documented sustained VT despite β-blocker therapy,57 one may conclude that this imposes pharmacological failure. However, one study has had the statistical power to identify independent predictors for arrhythmic events in patients treated with β-blockers. Predictors were treatment with β-blockers other than nadolol [Hazard ratio (HR): 3.12; 95% CI: 1.16–8.38; P= 0.02], and a younger age at diagnosis (HR: 0.31 per decade; 95% CI: 0.14–0.69; P = 0.004).13 In addition, the presence of couplets or more successive VPBs during exercise testing were significantly associated with future arrhythmic events (sensitivity 0.62; specificity 0.67).13 The association between provokable VT and risk of arrhythmic events was supported by the observations by Sy et al.,28 who reported arrhythmic event rates of 36% in 22 CPVT patients with VT induced by exercise testing or epinephrine challenge and 0% in 5 patients without provokable VT.

Yet, overall insufficient data are available to reliably identify high-risk patients. Indeed, persistent symptoms or VTs despite therapy should be considered a sign of treatment failure. Furthermore, albeit not perfectly predictive, it seems reasonable to intensify treatment with couplets or more successive VPBs during exercise testing, whereas solitary VPBs can probably be accepted.

Another important issue that may require a change in therapy of a CPVT patient is the presence of side-effects. In this relatively young patient population, fatigue and other side-effects of β-blockers may cause serious limitations in daily life and jeopardize therapeutic compliance.

Proposed treatment strategy

First, it is important to conclude that there is a lack of data to identify CPVT patients with such a low risk of arrhythmic events that would make treatment unnecessary. Thus, all phenotypically and/or genotypically diagnosed CPVT patients should receive appropriate therapy, although in clinical practice exceptions are (and probably can safely be) made in asymptomatic patients over ∼60 years of age who are newly diagnosed by cascade screening.

Second, advising against participation in competitive sports and emphasizing the great importance of drug compliance are essential. In addition, CPVT patients should be informed that the use of sympathomimetic agents is contraindicated.

The first step in treating a CPVT patient should be a β-blocker in the highest tolerable dose, preferably nadolol.13 Verapamil may be added to β-blocker therapy, but addition of flecainide is preferred and more effective when β-blocker therapy fails (step 2).38 In patients resistent to combination therapy with β-blocker and flecainide, either LCSD should be performed or an ICD should be implanted (step 3). Left cardiac sympathetic denervation may be preferred when an expert surgeon is available to perform this procedure. To date it is unknown which pharmacologic regiment should be followed after a succesfull procedure, so it is recommended to continue β-blocker therapy.

Every next step and/or change in drug type or dose should probably be carefully monitored by exercise testing, and, if necessary and possible, Holter monitoring or ICD interrogation.

Future developments

Apart from the previously described developments that are being more widely introduced into patient care currently, some other treatment modalities may become available or may be introduced on a larger scale in CPVT patients in the near future.

The Class 1c antiarrhythmic agent propafenone may be another effective mechanism-based treatment option in difficult-to-treat CPVT patients. Propafenone succesfully prevented further ICD shocks and exercise-induced CPVT in a patient from Turkey, who remained severely symptomatic after maximal drug therapy and LCSD.64 Because flecainide is not available in Turkey, propafenone was successfully attempted in this patient. Subsequent in vitro and in vivo studies showed that propafenone had similar RYR2 blocking properties to flecainide.64 As propafenone also contains β-receptor blocking properties, it may be an ideal drug in CPVT.

Dantrolene65 and the newly synthesized compounds S10766 and K201 (JTV519)7,67 are also RYR2 channel inhibitors and prevented exercise- and epinephrine-induced ventricular arrhythmias in CPVT mouse models. In addition, KN93, an inhibitor of calcium/calmodulin-dependent protein kinase II, was recently described as preventing ventricular arrhythmia in a CPVT mouse model.68

Another interesting observation is the CPVT patient in whom the selective serotonin reuptake inhibitor paroxetine combined with β-blocker therapy prevented ICD shocks during 2 years of follow-up, while this patient received two ICD shocks in the previous 6 months while treated with β-blocker only.69 However, the exact underlying mechanism of action remains to be clarified.

Finally, pulmonary vein isolation (PVI) aimed to reduce supraventricular arrhythmias was successfully performed in a CPVT patient.70 This patient received inappropriate ICD shocks due to atrial fibrillation with a rapid ventricular response and therefore underwent PVI, which also decreased the number of VTs and PVCs on Holter registration. Pulmonary vein isolation may have decreased the sympathetic innervation, and may be an additional treatment option in patients resembling the case described.

Acute treatment

The most critical step in the acute management of sustained VT, VT storm or ventricular fibrillation in a CPVT patient (in the absence of correctable inciting factors) may be to recognize that it concerns a CPVT patient, and the subsequent instruction to discontinue the standard epinephrine infusion in a resuscitation setting. Intravenous β-blocker therapy is considered first choice, analogous to ventricular tachycardia storm of other etiology.57 General anaesthesia is probably the last resort when β-blocker therapy is not effective.

In one case report adenosine triphosphate and verapamil were effective in terminating epinephrine-induced VT during electrophysiological study.71

Conclusions

Although the majority of CPVT patients are well controlled by β-blocker therapy, arrhythmic event rates on β-blocker therapy remain significant, but current data are imprecise. The exact arrhythmic event rates in different subgroups as well as factors that help to identify individuals at high and low risk may be identified in larger cohorts, for instance by setting up a multicentre CPVT patient registry. For patients who are thought to be at high risk of arrhythmic events or actually experience arrhythmic events despite β-blocker therapy, several effective alternatives have become available and more may become available in the near future. These alternatives could diminish the number of ICD implantations in CPVT patients. Yet, this can only be achieved by propagating the new developments in this field to the cardiological community.

Conflict of interest: none declared.

Funding

This work was supported by ZorgOnderzoek Nederland Medische Wetenschappen (ZonMW, grant 120610013 to C.W. and A.A.M.W.), and by the Fondation Leducq Trans-Atlantic Network of Excellence, Preventing Sudden Death (grant 05-CVD-01 to A.A.M.W.).

Acknowledgements

We thank P.J. Kannankeril for critical reading of the manuscript.

References

View Abstract