Krystien V.V. Lieve

Flecainide monotherapy is an option for selected patients with catecholaminergic polymorphic ventricular tachycardia intolerant of β-blockade

Gareth J. Padfield, MBChB, PhD, Leenah AlAhmari, Krystien V.V. Lieve, MD, Tasneem AlAhmari, Thomas M. Roston, MD, Arthur A. Wilde, MD, PhD, FHRS, Andrew D. Krahn, MD, FHRS, Shubhayan Sanatani, MD, FHRS From Heart Rhythm Services, University of British Columbia, Vancouver, British Columbia, Canada, The Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands, and The Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, King Saud University, Jeddah, Kingdom of Saudi Arabia.

Inherited ion channel diseases: a brief review.

Ion channelopathies are diseases caused by dysfunctional ion channels that may lead to sudden death. These diseases can be either acquired or inherited. The main phenotypes observed in patients carrying these heritable arrhythmia syndromes are congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. In the recent years, tremendous progress has been made in the recognition, mechanisms, and treatment of these diseases. The goal of this review is to provide an overview of the main phenotypes, genetic underpinnings, risk stratification, and treatment options for these so-called cardiac ion channelopathies.

Prognostic value of post-procedural aPTT in patients with ST-elevation myocardial infarction treated with primary PCI

Unfractionated heparin is the most commonly used anticoagulant in ST-elevation myocardial infarction (STEMI) and its effect can be monitored with activated partial thromboplastin time (aPTT). However, the optimal aPTT range during heparin therapy after primary percutaneous coronary intervention (PCI) is yet to be defined. A mean aPTT was calculated of all aPTT measurements in the first 24 hours after pPCI in a total of 1,876 STEMI patients. Mean aPTT measurements were stratified into four categories; < 1.5 times the upper limit of normal (ULN), 1.5 - 2.0 times ULN (the therapeutic group), 2.01 - 3.99 times ULN, and ≥ 4 times ULN. Compared to patients with a therapeutic aPTT, patients with aPTTs < 1.5 times ULN had no increase in recurrent ischaemic events and had similar rates of bleeding complications. Patients with a mean aPTT ≥ 4 times ULN had higher rates recurrent ischaemic and haemorrhagic complications. After multivariable analyses, aPTT ratios ≥ 4 times ULN were no longer associated with recurrent ischaemic events, but remained a strong predictor of severe and moderate bleeding (hazard ratio [HR] 4.64, p = 0.016 and HR 2.27, p = 0.052). In conclusion, in 1,876 STEMI patients treated with pPCI, low aPTTs in the first 24 hours after PCI were not associated with an increase in ischaemic events, whereas high aPTT values were associated with more frequent bleeding complications. These results indicate no clear benefit as well as a safety concern with heparin treatment after primary PCI.

The Role of Flecainide in the Management of Catecholaminergic Polymorphic Ventricular Tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but severe genetic cardiac arrhythmia disorder, with symptoms including syncope and sudden cardiac death due to polymorphic VT or ventricular fibrillation typically triggered by exercise or emotions in the absence of structural heart disease. The cornerstone of medical therapy for CPVT is β-blockers. However, recently flecainide has been added to the therapeutic arsenal for CPVT. In this review we summarise current data on the efficacy and role of flecainide in the treatment of CPVT.

Cardiorenal axis and arrhythmias: Will renal sympathetic denervation provide additive value to the therapeutic arsenal?

Disruption of sympathetic tone may result in the occurrence or maintenance of cardiac arrhythmias. Multiple arrhythmic therapies that intervene by influencing cardiac sympathetic tone are common in clinical practice. These vary from pharmaceutical (β-blockers, angiotensin-converting enzyme inhibitors, and calcium antagonists) to percutaneous/surgical (cardiac sympathetic denervation) interventions. In some patients, however, these therapies have insufficient prophylactic and therapeutic capabilities. A safe and effective additional therapy wherein sympathetic drive is further attenuated would be expedient. Recently, renal sympathetic denervation (RSD) has been subject of research for various sympathetic nervous system-related diseases. By its presumed afferent and efferent sympatholytic effects, RSD might indirectly attenuate sympathetic outflow via the brain to the heart but might also reduce systemic catecholamine excretion and might therefore reduce catecholamine-sensitive arrhythmias. RSD is subject of research for various sympathetically driven arrhythmias, both supraventricular and ventricular. In this review, we give an overview of the rationale behind RSD as potential therapy in mediating arrhythmias that are triggered by a disrupted sympathetic nervous system and discuss the presently available results from animal and human studies.

Gain-of-function mutation in SCN5A causes ventricular arrhythmias and early onset atrial fibrillation

BACKGROUND Mutations in SCN5A, the gene encoding the α-subunit of the cardiac sodium channel (NaV1.5), are associated with a broad spectrum of inherited cardiac arrhythmia disorders. The purpose of this study was to identify the genetic and functional determinants underlying a Dutch family that presented with a combined phenotype of ventricular arrhythmias with a likely adrenergic component, either in isolation or in combination with a mildly decreased heart function and early onset (<55years) atrial fibrillation. METHODS AND RESULTS We performed next generation sequencing in the proband of a two-generation Dutch family and demonstrated a novel missense mutation in SCN5A-(p.M1851V) which co-segregated with the clinical phenotype in the family. We functionally evaluated the putative genetic defect by patch clamp electrophysiological studies in human embryonic kidney cells transfected with mutant or wild-type Nav1.5. The current inactivation was slower and recovery from inactivation was faster in SCN5A-M1851V channels. The voltage dependence of inactivation was shifted towards more positive potentials and consequently, a larger TTX-sensitive window current was observed in SCN5A-M1851V channels. Furthermore, a higher upstroke velocity was observed for the SCN5A-M1851V channels, while the depolarization voltage was more negative, both indicating increased excitability. CONCLUSIONS This mutation leads to a gain-of-function mechanism based on increased channel availability and increased window current, fitting the observed clinical phenotype of (likely adrenergic-induced) ventricular arrhythmias and atrial fibrillation. These findings further expand the range of cardiac arrhythmias associated with mutations in SCN5A.

Linking the heart and the brain: Neurodevelopmental disorders in patients with catecholaminergic polymorphic ventricular tachycardia

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. OBJECTIVE The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. METHODS We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. RESULTS Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. CONCLUSION Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.

Beta-blockers in the treatment of catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary inherited arrhythmia syndrome with bidirectional or polymorphic ventricular arrhythmias and associated symptoms under conditions of increased sympathetic activity as its signature feature. Ever since CPVT was first described, the typical circumstances of exercise of emotion during occurrence of symptoms and the efficacy of beta-blocker therapy have been recognized. Today, beta-blockers are the mainstay of therapy for patients with clinical manifestations of CPVT. However, arrhythmic event rates in these patients on beta-blocker therapy are substantial, which underscores the importance of effective second-line therapeutic options such as flecainide and left cardiac sympathetic denervation. Betablockers probably also are protective in carriers of a familial CPVT-causing mutation with no signs of CPVT (concealed mutation carriers), although the natural history of these individuals and the efficacy of beta-blockers on their prognosis have not been studied. Multiple factors affect an eventual favorable response to beta-blockers. The most important factors are nonadherence and the type and dosage of beta-blocker. For example, in a recently published large cohort of 226 children with CPVT, 82 arrhythmic events occurred in children on beta-blocker monotherapy or a beta-blocker combined with a calcium channel blocker or flecainide. Poor adherence contributed to 48% of these events. In addition to the general major public health problem of medication nonadherence, the adverse effects of beta-blocker therapy in children or young adults with CPVT often have a significantly impact on patient quality of life and reinforce nonadherence or require dose adjustment or beta-blocker discontinuation. In our patient population of CPVT patients who were identified through cascade screening, significant adverse effects were reported in 29%. Adverse events led to discontinuation of initial

Inherited Arrhythmias: Brugada Syndrome and Early Repolarisation Syndrome

In this chapter a detailed overview on Brugada syndrome and the early repolarisation syndrome is presented. These two disease entities are associated with malignant arrhythmias and sudden death in otherwise healthy young adults and even children. We discuss their history, clinical perspectives (including patient characteristics and epidemiology), the pathway to the diagnosis, pathophysiological mechanisms (including genetic associations) and review clinical risk stratification and treatment. With this chapter we aim to provide a thorough insight in the knowledge base that has developed in these entities in the past decades and we specifically included current debates and uncertainties that are relevant to daily practice and influence our judgements. Undoubtedly our understanding of these syndromes will continue to develop and influence the management of patients and their families in the coming years. Relevant topics for future research in these syndromes are likewise provided. We sincerely hope that this chapter is of practical use for al health care professionals and researchers in this field and that it will contribute to a better understanding and care for affected patients and their families.

Implantable cardioverter-defibrillator use in catecholaminergic polymorphic ventricular tachycardia: A systematic review

BACKGROUND The implantable cardioverter-defibrillator (ICD) may be associated with a high risk of complications in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). However, ICDs in this population have not been systematically evaluated. OBJECTIVE The purpose of this study was to characterize the use and outcomes of ICDs in CPVT. METHODS We conducted a systematic review using Embase, MEDLINE, PubMed, and Google Scholar to identify studies that included patients with CPVT who had an ICD. RESULTS Fifty-three studies describing 1429 patients with CPVT were included. In total, 503 patients (35.2%) had an ICD (median age 15.0 years; interquartile range 11.0-21.0 years). Among ICD recipients with a reported medication status, 96.7% were prescribed β-blockers and 13.2% flecainide. Sympathetic denervation was performed in 23.2%. Nearly half of patients received an ICD for primary prevention (47.3%), and 12.8% were prescribed optimal antiarrhythmic therapy. During follow-up, 40.1% had ≥1 appropriate shock, 20.8% experienced ≥1 inappropriate shock, 19.6% had electrical storm, and 7 patients (1.4%) died. An ICD-associated electrical storm was implicated in 4 deaths. Additional complications such as lead failure, endocarditis, or surgical revisions were observed in 96 of 296 patients (32.4%). A subanalysis of the 10 studies encompassing 330 patients with the most detailed ICD-related data showed similar trends. CONCLUSION In this population with CPVT, ICDs were common and associated with a high burden of shocks and complications. The reliance on primary prevention ICDs, and poor uptake of adjuvant antiarrhythmic therapies, suggests that improved adherence to guideline-directed management could reduce ICD use and harm.