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Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. Based on the underlying genetic defect, LQTS has been subdivided into different subtypes. Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype–phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. Nevertheless, despite these great advancements in the LQTS field, large gaps in knowledge still exist. For example, up to 25% of LQTS cases still remain genotype elusive, which hampers proper identification of family members at risk, and it is still largely unknown what determines the large variability in disease severity, where even within one family an identical mutation causes malignant arrhythmias in some carriers, while in other carriers, the disease is clinically silent. In this review, we summarise the current evidence available on the diagnosis, clinical management and therapeutic strategies in LQTS. We also discuss new scientific developments and areas of research, which are expected to increase our understanding of the complex genetic architecture in genotype-negative patients, lead to improved risk stratification in asymptomatic mutation carriers and more targeted (gene-specific and even mutation-specific) therapies.

Contains fulltext : 225390.pdf (Publisher’s version ) (Open Access) BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (ICD) was designed to avoid complications related to the transvenous ICD lead by using an entirely extrathoracic placement. Evidence comparing these systems has been based primarily on observational studies. METHODS: We conducted a noninferiority trial in which patients with an indication for an ICD but no indication for pacing were assigned to receive a subcutaneous ICD or transvenous ICD. The primary end point was the composite of device-related complications and inappropriate shocks; the noninferiority margin for the upper boundary of the 95% confidence interval for the hazard ratio (subcutaneous ICD vs. transvenous ICD) was 1.45. A superiority analysis was prespecified if noninferiority was established. Secondary end points included death and appropriate shocks. RESULTS: A total of 849 patients (426 in the subcutaneous ICD group and 423 in the transvenous ICD group) were included in the analyses. At a median follow-up of 49.1 months, a primary end-point event occurred in 68 patients in the subcutaneous ICD group and in 68 patients in the transvenous ICD group (48-month Kaplan-Meier estimated cumulative incidence, 15.1% and 15.7%, respectively; hazard ratio, 0.99; 95% confidence interval [CI], 0.71 to 1.39; P = 0.01 for noninferiority; P = 0.95 for superiority). Device-related complications occurred in 31 patients in the subcutaneous ICD group and in 44 in the transvenous ICD group (hazard ratio, 0.69; 95% CI, 0.44 to 1.09); inappropriate shocks occurred in 41 and 29 patients, respectively (hazard ratio, 1.43; 95% CI, 0.89 to 2.30). Death occurred in 83 patients in the subcutaneous ICD group and in 68 in the transvenous ICD group (hazard ratio, 1.23; 95% CI, 0.89 to 1.70); appropriate shocks occurred in 83 and 57 patients, respectively (hazard ratio, 1.52; 95% CI, 1.08 to 2.12). CONCLUSIONS: In patients with an indication for an ICD but no indication for pacing, the subcutaneous ICD was noninferior to the transvenous ICD with respect to device-related complications and inappropriate shocks. (Funded by Boston Scientific; PRAETORIAN ClinicalTrials.gov number, NCT01296022.).

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Background We aimed to determine the mutation yield and clinical applicability of “molecular autopsy” following sudden arrhythmic death syndrome (SADS) by validating and utilizing low-cost high-throughput technologies: Fluidigm Access Array PCR-enrichment with Illumina HiSeq 2000 next generation sequencing (NGS). Methods We validated and optimized the NGS platform with a subset of 46 patients by comparison with Sanger sequencing of coding exons of major arrhythmia risk-genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RYR2). A combined large multi-ethnic international SADS cohort was sequenced utilizing the NGS platform to determine overall molecular yield; rare variants identified by NGS were subsequently reconfirmed by Sanger sequencing. Results The NGS platform demonstrated 100% sensitivity for pathogenic variants as well as 87.20% sensitivity and 99.99% specificity for all substitutions (optimization subset, n = 46). The positive predictive value (PPV) for NGS for rare substitutions was 16.0% (27 confirmed rare variants of 169 positive NGS calls in 151 additional cases). The overall molecular yield in 197 multi-ethnic SADS cases (mean age 22.6 ± 14.4 years, 68% male) was 5.1% (95% confidence interval 2.0–8.1%), representing 10 cases carrying pathogenic or likely pathogenic risk-mutations. Conclusions Molecular autopsy with Fluidigm Access Array and Illumina HiSeq NGS utilizing a selected panel of LQTS/BrS and CPVT risk-genes offers moderate diagnostic yield, albeit requiring confirmatory Sanger-sequencing of mutational variants. Electronic supplementary material The online version of this article (10.1186/s12872-019-1154-8) contains supplementary material, which is available to authorized users.

Objective: The aim of the current study was to determine the contemporary incidence, risk factors and prognosis of heart failure (HF) after ST-elevation myocardial infarction (STEMI). Methods: We used the Arrhythmia Genetics in the Netherlands observational cohort study to identify patients with a first STEMI from 2001 onwards (n=1459). HF during follow-up was defined as hospitalisation for HF or an outpatient clinic visit for HF. Cox regression was performed to estimate the relationship between baseline covariates and the onset of HF. Results: Follow-up was completed for 1360 (93.2%) patients with an overall median follow-up time of 6.7 years, 1232 (90.6%) of these patients had undergone primary percutaneous coronary intervention (PCI). A total of 85 patients (6.3%) developed HF during follow-up. HF cases were significantly older at their index MI (59.9 vs 57.2 years, P

Summary Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4–38·2) and of interleukin 6 by 14·6% (10·7–18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9–9·1) and of fibrinogen by 1·0% (0·7–1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8–5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

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.

Background— The characteristic ECG pattern of ST-segment elevation in V 1 and V 2 in the Brugada syndrome is dynamic; it is often intermittently present in affected individuals and can be unmasked by sodium channel blockers, including antiarrhythmic drugs and tricyclic antidepressants. We report here 2 patients who developed the Brugada ECG pattern after administration of lithium, a commonly used drug not previously reported to block cardiac sodium channels. Methods and Results— Lithium induced transient ST-segment elevation (type 1 Brugada pattern) in right precordial leads at therapeutic concentrations in 2 patients with bipolar disorder. Lithium withdrawal in the patients resulted in reversion to type 2 or 3 Brugada patterns or resolution of ST-T abnormalities. In Chinese hamster ovary cells transfected with SCN5A , which encodes the cardiac sodium channel, lithium chloride caused concentration-dependent block of peak I Na at levels well below the therapeutic range (IC 50 of 6.8±0.4 μmol/L). Conclusions— The widely used drug lithium is a potent blocker of cardiac sodium channels and may unmask patients with the Brugada syndrome.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by the occurrence of adrenergically induced polymorphic ventricular arrhythmias. Mutations in the cardiac ryanodine receptor (RYR2) underlie the majority of CPVT cases and show an autosomal dominant inheritance pattern. Mutations in RYR2 and other genes involved in CPVT cause spontaneous diastolic calcium release from the sarcoplasmatic reticulum (SR), which eventually lead to triggered arrhythmias. CPVT is usually diagnosed by use of exercise testing. β-blockers are the mainstay of drug therapy in CPVT, whereas flecainide and left cardiac sympathetic denervation can be added or performed in patients with significant ventricular arrhythmias or arrhythmic events on β-blocker therapy.

In this second edition of Electrical Disease of the Heart, our goal was to embrace and highlight the explosion of knowledge that our field has witnessed since the publication of the first edition of this book. Building on the success of our first edition, our approach continues to be one of bridging basic and clinical science in an attempt to meaningfully advance our understanding of heart disease and identify the knowledge gaps that exist. The book is organized into 77 chapters in 2 volumes. Each chapter includes up-to-date results of studies aimed at providing an understanding of the electrical function of the heart in health and disease, established and evidence- based knowledge of clinical outcomes, areas of controversy, and future trends. Our goal is to provide a contemporary and succinct distillation of the state of the art. Although many of the chapters are highly sub-specialized, this book is designed for a broad audience, ranging from medical and graduate students to clinicians and scientists. The book is the result of a collaboration that has brought together the skills and perspectives of researchers, scientists, and clinicians. We are deeply indebted to our associate editors and to all of the authors for their valuable contributions.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare, potentially lethal inherited arrhythmia syndrome characterized by stress or emotion-induced ventricular arrhythmias. CPVT was first described in 1960, while the genetic basis underlying this syndrome was discovered in 2001. The past decade has seen substantial advances in understanding the pathophysiology of CPVT. In addition, significant advances have been made in elucidating clinical characteristics of CPVT patients and new treatment options have become available. Here, we review current literature on CPVT to present state-of-the-art knowledge on the subject of the genetic basis, pathophysiology, clinical presentation, diagnosis, treatment and prognosis.

In the past 3 decades, the congenital long-QT syndrome (LQTS) has emerged as an important paradigm for understanding arrhythmogenesis. An understanding of the electrophysiological basis of arrhythmias in LQTS has now merged with new molecular genetics, solving some problems and raising new ones both in clinical management and in basic arrhythmia mechanisms (for review, see Roden and Spooner1 ). In this scientific evolution, the international LQT registry has proved to be of paramount importance. Since 1979, data from this registry have proved to be of great value for the diagnosis, prognosis, and management of LQT patients and their relatives, and in more recent years, data from the registry represent a reliable source for attempts to correlate phenotype with genotype and vice versa. We now understand that LQTS can arise as a result of mutations in multiple genes, each encoding an ion channel structural unit. Because ion channels have different time and voltage characteristics, it is tempting to speculate that the clinical presentation may be gene specific, and indeed emerging data support this idea (Table⇓). Phenotypical differences in genetically distinct forms of LQTS may include every aspect of the clinical presentation, ie, the ECG appearance of the ST-T–wave patterns and arrhythmias, symptoms that trigger arrhythmias, QT dynamics during exercise or other triggers, efficacy of different treatment modalities, and the clinical course of affected patients (Table⇓). View this table: Table 1. Clinical Characteristics in Common Forms of LQTS A gene-differentiating potential has indeed been shown for symptom-related triggers: swimming and acoustic stimuli typically trigger events in LQT1 and LQT2 patients, respectively.2 3 4 5 QT dynamics during exercise vary between genotypes,6 7 and data from the registry have suggested that the clinical course (age of onset, prognosis, etc) relies to some extent on the underlying gene defect.8 Finally, gene-specific ST-T …

The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers.

Several arrhythmia syndromes that for long were considered idiopathic are now known to have a genetic basis and are caused by mutations in genes primarily encoding ion channels. Mutations in cardiac ion channels lead to abnormal ionic current characteristics via mechanisms, such as defective channel gating or reduction in sarcolemmal channel expression. This results in the electrocardiogram (ECG) features or arrhythmogenesis in the inherited arrhythmia syndromes. The genetic basis for most arrhythmia syndromes is heterogeneous (a given disorder may be caused by mutations in different genes) and evidence for further genetic heterogeneity exists. It is becoming increasingly clear that therapy should take the type of gene affected into consideration (gene-specific therapy). Considerable heterogeneity may exist in disease manifestation (both in severity as well as differences in disease features) among family members carrying the same mutation.

Background— The electrocardiographic short QT-interval syndrome forms a distinct clinical entity presenting with a high rate of sudden death and exceptionally short QT intervals. The disorder has recently been linked to gain-of-function mutation in KCNH2 . The present study demonstrates that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene. Methods and Results— A 70-year man presented with idiopathic ventricular fibrillation. Both immediately after the episode and much later, his QT interval was abnormally short without any other physical or electrophysiological anomalies. Analysis of candidate genes identified a g919c substitution in KCNQ1 encoding the K + channel KvLQT1. Functional studies of the KvLQT1 V307L mutant (alone or coexpressed with the wild-type channel, in the presence of IsK) revealed a pronounced shift of the half-activation potential and an acceleration of the activation kinetics leading to a gain of function in I Ks . When introduced in a human action potential computer model, the modified biophysical parameters predicted repolarization shortening. Conclusions— We present an alternative molecular mechanism for the short QT-interval syndrome. Functional and computational studies of the KCNQ1 V307L mutation identified in a patient with this disorder favor the association of short QT with mutation in KCNQ1 .

In recent years, research on the genetic basis of inherited cardiac channelopathies, namely the Long QT syndrome, the Brugada syndrome, and more recently catecholamine-induced polymorphic ventricular tachycardia, has initiated an increased understanding of the molecular blueprints of myocardial electrical function. The electrophysiological analysis of naturally-occurring mutant ion channels associated with these disorders provides insight, not only into mechanisms of disease but also, for instance, into the biophysical properties of the native channel, its pharmacology, its association with other subunits and its contribution to the myocardial action potential. This, in turn, should ultimately enable more specific pharmacological intervention in the management of these syndromes and other related and possibly more common arrhythmias.

Background — Congenital long QT syndrome (LQTS), a cardiac ion channel disease, is an important cause of sudden cardiac death. Prolongation of the QT interval has recently been associated with sudden infant death syndrome, which is the leading cause of death among infants between 1 week and 1 year of age. Available data suggest that early onset of congenital LQTS may contribute to premature sudden cardiac death in otherwise healthy infants. Methods and Results — In an infant who died suddenly at the age of 9 weeks, we performed mutation screening in all known LQTS genes. In the surface ECG soon after birth, a prolonged QTc interval (600 ms 1/2 ) and polymorphic ventricular tachyarrhythmias were documented. Mutational analysis identified a missense mutation (Ala1330Pro) in the cardiac sodium channel gene SCN5A , which was absent in both parents. Subsequent genetic testing confirmed paternity, thus suggesting a de novo origin. Voltage-clamp recordings of recombinant A1330P mutant channel expressed in HEK-293 cells showed a positive shift in voltage dependence of inactivation, a slowing of the time course of inactivation, and a faster recovery from inactivation. Conclusions — In this study, we report a de novo mutation in the sodium channel gene SCN5A , which is associated with sudden infant death. The altered functional characteristics of the mutant channel was different from previously reported LQTS3 mutants and caused a delay in final repolarization. Even in families without a history of LQTS, de novo mutations in cardiac ion channel genes may lead to sudden cardiac death in very young infants.