Ryanodine receptor 2 mutations in catecholaminergic polymorphic ventricular tachycardia: From molecular mechanisms to precision medicine

A rare case of tetralogy of Fallot with catecholaminergic polymorphic ventricular tachycardia

Ventricular arrhythmias and sudden cardiac death

Although structural heart disease remains the predominant substrate for ventricular arrhythmia, channelopathies including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndrome (ERS) are less common but important contributing entities. These etiologies require specific therapies potentially contrary to empirical management of arrhythmias associated with structural heart disease. Conventional therapy including antiarrhythmic drug therapy may not only fail to resolve unstable arrhythmias but worsen them. Additionally, channelopathy patients with implantable cardioverter defibrillators (ICD) and arrhythmic storms represent a major challenge, and the acute care team needs to be cognizant of unique circumstances that require specific acute therapies beyond empirical advanced life support algorithm recommendations.1 Successful and considered acute management of ventricular arrhythmias is contingent on a number of variables, including knowledge of the cardiac substrate or potential substrate; form, mechanism, and precipitants of ventricular arrhythmias; and acute effect of potential therapies. In the longer term, an understanding of the natural history of the channelopathy along with the efficacy of long-term therapy will lead to superior outcomes. This review will present the risk of ventricular arrhythmias associated with these uncommon entities, the evolving understanding of the mechanism of arrhythmia, and the mechanistic basis of therapies along with a clinical approach to summarize the evidence pertaining to acute and long-term management. Patients with a prolonged QT interval are at risk of sudden cardiac death (SCD) due to Torsade de Pointes (TdP; Figure 1). Most patients with congenital LQTS are asymptomatic and diagnosed incidentally on electrocardiogram screening or following family screening. However, syncope, aborted SCD, or SCD may be the first presentation. Most arrhythmic events in congenital LQT1 occur during physical or emotional stress, at rest or in association with sudden auditory stimulation in LQT2, and during sleep or rest in LQT3 …

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder causing life-threatening arrhythmias whenever sympathetic activity increases. β-Βlockers are the mainstay of therapy; when they fail, implantable cardioverter-defibrillators (ICDs) are used but often cause multiple shocks. Preliminary results with flecainide appear encouraging. We proposed left cardiac sympathetic denervation (LCSD) as useful additional therapy, but evidence remains anecdotal. We report 63 patients with CPVT who underwent LCSD as secondary (n=54) or primary (n=9) prevention. The median post-LCSD follow-up was 37 months. The 9 asymptomatic patients remained free of major cardiac events. Of the 54 patients with prior major cardiac events either on (n=38) or off (n=16) optimal medical therapy, 13 (24%) had at least 1 recurrence: 0 patients had an aborted cardiac arrest, 2 patients had syncope only, 10 patients had ≥1 appropriate ICD discharges, and 1 patient died suddenly. The 1- and 2-year cumulative event-free survival rates were 87% and 81%. The percentage of patients with major cardiac events despite optimal medical therapy (n=38) was reduced from 100% to 32% (P<0.001) after LCSD, and among 29 patients with a presurgical ICD, the rate of shocks dropped by 93% from 3.6 to 0.6 shocks per person per year (P<0.001). Patients with an incomplete LCSD (n=7) were more likely to experience major cardiac events after LCSD (71% versus 17%; P<0.01) than those with a complete LCSD. LCSD is an effective antifibrillatory intervention for patients with CPVT. Whenever syncope occurs despite optimal medical therapy, LCSD could be considered the next step rather than an ICD and could complement ICDs in patients with recurrent shocks.

Objective: To report the case of a successful pregnancy outcome in a severely symptomatic woman affected by catecholaminergic polymorphic ventricular tachycardia (CPVT) carrier of a novel variant in ryanodine receptor 2 (RYR2) followed by a review of the current literature. Case(s): A 27-year-old primigravida affected by CPVT was referred to our tertiary care hospital after an implantable cardioverter defibrillator (ICD) shock. The patient also received medical treatment with metoprolol and flecainide. A healthy baby was born by Cesarean section at 31 weeks after the onset of preterm labor and premature rupture of membranes. CPVT is a rare inherited cardiac condition characterized by episodic polymorphic ventricular arrhythmias with a structurally normal heart. These are usually triggered by exercise or emotional stress and can lead to syncope or even sudden cardiac death. Treatment of this condition comprises betablockers in isolation or in addition to other antiarrhythmics, left cardiac sympathetic denervation and/or ICD. Conclusion: This case illustrates the importance of a multidisciplinary approach in this clinical scenario and the benefits of an optimization of the medical treatment, and demonstrates that, even in severely affected patients, a successful pregnancy is possible under close control. However, the risk of arrhythmic events and the course of pregnancy remain largely unknown in patients with CPVT, and further investigation is needed.

Inherited arrhythmia syndromes (IAS) are a group of rare disorders that result from genetic mutations in several genes including congenital long QT syndrome, Brugada syndrome (BrS), short QT syndrome, and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Affected individuals may have various symptoms including sudden cardiac death (SCD). Few reports have highlighted long QT syndrome from the Arbian Gulf region. The current study aims to describe demographics of children and adults with inherited arrhythmia syndromes; report the presenting clinical features, genetic mutations and management strategies. This is a descriptive retrospective study that included Omani children and adults with inherited arrhythmia syndromes who were diagnosed and treated at the National Heart Centre (NHC) of the Royal Hospital, between 2006 and 2022. Data collected include patient demographics, geographical distribution, clinical features, genetic reports and management strategies. A total of one hundred and six Omani patients were included. Sixty-six (62.3 %) were males, and 71 (67 %) were adults at diagnosis and 35 (33 %) were children. Three inherited arrhythmia syndromes were found including Long QT, Brugada and catecholaminergic polymorphic ventricular tachycardia (CPVT) and these accounted for 58 (54.7 %), 39 (36.8 %) and 9 (8.5 %), respectively. Seventy-six (71.7 %) of the patients were from consanguineous families. The clinical features varied based on the type of arrhythmia. The treatment modalities constituted of beta blockers and antiarrhythmics, implantable cardioverter defibrillators (ICDs), pacemakers, and left sympathetic ganglionectomy (LSGs). Seventy-one individuals (66.9 %) underwent genetic testing. It is important to highlight that 36 (50.7 %) individuals were with pathogenic or likely pathogenic variants and 13 (18.3 %) individuals were with variants of uncertain significance (VUS) in different IAS related genes. The current study is the first comprehensive study on the inherited arrhythmia syndromes in Oman and the Arabian Gulf countries. It provides insight about the demographic, clinical and genetic profile of the most common IAS in the region, hence helping in early detection of different types of IAS types and prevention of sudden cardiac death in patients and their relatives. Continuous research efforts in the genetic and cellular mechanisms underlying these disorders will help to identify potential targets for improved disease-specific treatments.

IntroductionTreating therapy-resistant patients with inherited arrhythmia syndromes can be difficult and left cardiac sympathetic denervation (LCSD) might be a viable alternative treatment option. We provide an overview of the indications and outcomes of LCSD in patients with inherited arrhythmia syndromes in the only tertiary referral centre in the Netherlands where LCSD is conducted in these patients.MethodsThis was a retrospective study, including all patients with inherited arrhythmia syndromes who underwent LCSD in our institution between 2005 and 2013. LCSD involved ablation of the lower part of the left stellate ganglion and the first four thoracic ganglia.ResultsSeventeen patients, 12 long-QT syndrome (LQTS) patients (71 %) and 5 catecholaminergic polymorphic ventricular tachycardia (CPVT) patients (29 %), underwent LCSD. Most patients (94 %) were referred because of therapy-refractory cardiac events. In 87 % the annual cardiac event rate decreased. However, after 2 years the probability of complete cardiac event-free survival was 59 % in LQTS and 60 % in CPVT patients. Two patients (12 %) had major non-reversible LCSD-related complications: one patient suffered from a Harlequin face post-procedure and one severely affected LQT8 patient died the day after LCSD due to complications secondary to an arrhythmic storm during the procedure.ConclusionLSCD for inherited arrhythmia syndromes, which is applied on a relatively small scale in the Netherlands, reduced the cardiac event rate in 87 % of the high-risk patients who had therapy-refractory cardiac events, while the rate of major complications was low. Therefore, LSCD seems a viable treatment for patients with inherited arrhythmia syndromes without other options for therapy.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by VT induced by adrenergic stress in the absence of structural heart disease and high incidence of sudden cardiac death. Two causative genes of CPVT have been identified: RYR2, encoding cardiac ryanodine receptor (RyR2) Ca2+ release channel, and CASQ2, encoding cardiac calsequestrin. A mutation in RYR2 or CASQ2 is identified in approximately 60% of patients with CPVT. Mutations in these two genes destabilize the RyR2 Ca2+ release channel complex in sarcoplasmic reticulum and result in spontaneous Ca2+ release through RyR2 channels leading to delayed after depolarization, triggered activity, and bidirectional/polymorphic VT. Implantable cardioverter defibrillators (ICDs) are recommended for prevention of sudden death in patients with CPVT. However, painful shocks can trigger further adrenergic stress and arrhythmias, and deaths have occurred despite appropriate ICD shocks. Treatment with β-adrenergic blockers reduces arrhythmia burden and mortality, but is not completely effective. The beneficial effects of Ca2+ channel blocker verapamil in combination with β-blocker have been reported, but the role of verapamil has not been well assessed. Because Ca2+ leakage through RyR2 channel is a common mechanism of CPVT, RyR2 channel block may have a therapeutic effect. We discovered that flecainide directly inhibits RyR2 channels and prevent CPVT. Left cardiac sympathetic denervation may be an effective alternative treatment in combination with ICD, especially for patients whose arrhythmias are not controlled by medication.

Inherited arrhythmia syndromes encompass several different diseases, including long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), and progressive cardiac conduction system disease (PCCD).1 The heart is typically structurally normal with no evidence of disease macroscopically. They are an important cause for sudden cardiac death in the young, and an autopsy is typically negative.2,3 Ventricular arrhythmias are caused by mutations of ion channels and their interacting proteins, predominantly involving potassium, sodium, and calcium handling.4 Genetic studies have identified the specific genetic abnormalities that underpin these diseases, even permitting diagnosis in the deceased using postmortem genetic testing (the molecular autopsy).3 Most arrhythmia syndromes are inherited in an autosomal dominant manner, such that first-degree family members have a 50% chance of inheriting the disease. Identification of the mutation allows for predictive genetic testing in other living family members.4 Variable penetrance is common in all arrhythmia syndromes, the same mutation in the same family causing wide variation in phenotype.4 This suggests that other factors such as genetic modifiers and environmental factors may influence the phenotype. This review will highlight the latest developments in understanding the genetic basis of inherited arrhythmia syndromes and discusses the new opportunities and challenges faced with evolving genetic technologies including determining pathogenicity and the utility of large genetic databases. Finally, we will discuss newly described entities that continue the evolving theme of genetic syndromes with phenotypic overlap. Early views that a single genotype associates with a particular phenotype continue to be challenged by our greater understanding of the genotype–phenotype relationship. ### Long QT Syndrome Congenital LQTS is diagnosed in the presence of a prolonged corrected QT (QTc) interval after secondary causes (eg, QT-prolonging medications or electrolyte abnormalities) are excluded.1 The 2013 Heart Rhythm …

Since the early descriptions almost four decades ago1, 2, there has been considerable expansion in the knowledge base for catecholaminergic polymorphic ventricular tachycardia (CPVT), with identification of underlying genetic mutations3, 4 and a better understanding of mechanisms leading to ventricular arrhythmias5, 6. However, as a malignant entity predisposing mostly young, apparently healthy individuals to sudden cardiac arrest (SCA), CPVT continues to pose a management challenge to the clinical cardiologist, often compounded by emotionally fraught situations. Risk stratification for CPVT remains problematic, particularly since long-term follow-up data in adequate numbers of patients is hard to obtain in this rare entity; yet clinical experience suggests fairly high event rates in diagnosed subjects7. The therapeutic approach to CPVT relies mainly on countering sympathetic stimulation as the key trigger of arrhythmia in this syndrome. Beta blockers have conventionally been the cornerstone of management with sizeable reductions in arrhythmia burden; unfortunately breakthrough events despite beta blocker therapy are not uncommon8. Side effects such as lethargy related to beta-blockade also result in non-compliance in this young population9. Calcium channel blockers such as verapamil have limited efficacy10 and the class Ic agent flecainide has shown some promise11 though long-term data are lacking. At the present time, implantable cardioverter defibrillators (ICDs) are advocated for those with sustained VT/syncope or aborted cardiac arrest despite beta blockers12. However, concerns have been raised about the possibility of VT storm and death due to the sympathetic surge following ICD shocks13 as well as the relatively high rate of inappropriate shocks and device complications in these young patients14. Left cardiac sympathetic denervation (LCSD) has emerged as an alternative approach to sympathetic blockade and has been effectively used in other inherited arrhythmia syndromes such as the long QT syndrome15. While scattered reports of the success of LCSD in abolishing arrhythmia in CPVT exist16, 17, recommendation for its adoption as standard therapy has been hampered by lack of data on long-term efficacy.

Introduction: Treatment options for patients with recurrent ventricular arrhythmias (VAs) refractory to pharmacotherapy and/or ablation are minimal. Although left cardiac sympathetic denervation (LCSD) is well established in long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), LCSD’s role in idiopathic ventricular fibrillation (IVF) is less clear. Here, we report our single-center experience regarding the early outcomes of LCSD in patients with IVF. Hypothesis: To determine the efficacy of LCSD on reducing VAs in IVF patients refractory to conventional therapy. Methods: A retrospective analysis of the electronic health record of patients with IVF between January 2000 to April 2023 was performed. Cardiac event rates [defined as arrhythmic syncope/seizure, appropriate implantable cardioverter defibrillator (ICD) therapy, sudden cardiac arrest (SCA), or sudden cardiac death (SCD)] before and after LCSD for each patient were calculated and a Wilcoxon signed rank test was performed. Results: In total, 94 patients (41% female) were classified as IVF. Overall, 15/94 patients (16%) had LCSD due to refractory VAs (60% male; mean age at LCSD 36 ± 20 years) despite beta-blocker treatment (100%) or combined drug therapy (67%). In total, 14 patients (15%) had an electrophysiology study performed before LCSD of which 10 (67%) had VAs ablation. All patients had a structurally normal heart and genetic testing performed in 14/15 patients (93%) confirmed absence of genetic cardiomyopathies and channelopathies. SCA was the sentinel event in 10 of 15 patients (67%); 14 patients (93%) had an ICD in place. The average follow-up time after LCSD was 3 ± 4 years. The VA event rate before LCSD was 4 ± 3 events per year and was reduced to 1 ± 3 per year (p&lt;0.04) after LCSD. Patients had a median of 3.2 less events per year after LCSD (p=0.02) with 7 patients (47%) having no post-LCSD recurrences thus far while 3 (20%) patients were deemed LCSD non-responders with no reduction of event rate. Conclusions: LCSD represents a substrate-independent, anti-fibrillatory treatment option for patients with life-threatening, genetic arrhythmias. While not curative, the early outcomes of LCSD for patients with medically refractory IVF are promising.

<i>Circulation Research</i> Thematic Synopsis

Arrhythmic Risk and Clinical Features in Catecholaminergic Polymorphic Ventricular Tachycardia: Results From a Multicenter Study in Korea.

RyR2 Gain-of-Function and Not So Sudden Cardiac Death

Drs Moss and McDonald1 described left cardiac sympathetic denervation (LCSD) to prevent arrhythmia and sudden death in long QT syndrome (LQTS) nearly 45 years ago. In the past 15 years, there has been an increased focus on LCSD. The resurgence in interest is probably because of the presence of larger studies that demonstrate its potential use, increased technical proficiency with thoracoscopic surgery, and additional focus on channelopathy research. The 2013 consensus statement for management of patients with primary arrhythmia syndromes offered a class I recommendation for LCSD in high-risk patients with LQTS when implantable cardioverter–defibrillator (ICD) therapy is refused or contraindicated and when β-blockers were ineffective or contraindicated.2 In the consensus document, LCSD in catecholaminergic polymorphic ventricular tachycardia (CPVT) was limited to a class IIB recommendation after recurrent arrhythmia or shocks on β-blockers or when β-blockers are contraindicated. However, even after the consensus document, some authors have advocated a wider application. For example, an international group of authors concluded this year, “Whenever syncope occurs despite optimal medical therapy, LCSD could be considered the next step rather than an ICD and could complement ICDs in patients with recurrent shocks.”3 Article see p 1151 LCSD is not first-line therapy for either LQTS or CPVT. β-adrenergic receptor blocker (β-blocker) therapy has remained the first option for LQTS and CPVT.2,4 β-blockers are effective in both diseases and the value of medication compliance has been dramatically illustrated in LQT1.5,6 Other medication regimens have been proposed, depending on clinical circumstances and genotype. However, no pharmacological treatment has eliminated mortality risk in either disease. In fact, the same studies that demonstrate the effectiveness of β-blockers caution that their protection is imperfect. ICDs remain a backstop against lethal arrhythmias in these diseases. Although …