Inheritable Arrhythmia Research Articles

Paradigm shifts in the genetics of inherited arrhythmias: Using next-generation sequencing technologies to uncover hidden etiologies

Long QT syndrome (LQTS), a rare inheritable arrhythmia first described by Romano andWard et al. in the 1960s, is characterized by the prolongation of the QT interval on surface ECGs and an increased risk of potentially fatal ventricular arrhythmias, especially torsade de pointes [1]. In 1995, after years of extensive clinical investigation and linkage analysis, several research groups, including Keating et al., successfully identified three distinct LQTS phenotypes (LQT1, LQT2, and LQT3) associated with mutations in genes encoding plasma membrane ion channels (KCNQ1, KCNH2, and SCN5A, respectively) [2–4]. These seminal studies motivated further extensive genetic screening in LQTS patients using a candidate gene approach and functional analyses of the mutant genes. These efforts provided evidence that ion channel genes represent the genetic basis for several other arrhythmogenic syndromes that occur in the structurally intact heart, often referred to as idiopathic ventricular fibrillation. At present, 13 genes responsible for LQTS have been identified. Approximately 90% of the genotyped LQTS subjects belong to the three major subtypes (LQT1-3) [5] in which numbers of distinct genotype-specific clinical characteristics have been demonstrated, including T-wave morphology [6], triggers for cardiac events [7], response to the epinephrine provocation test [8] and drug therapy [9]. Genetic testing for known arrhythmia susceptibility genes has become the standard-of-care for a number of disorders, including LQTS. Considering the remarkable progress of research in this area, there is no doubt that 1995 was the year in which genetic technologies experienced a paradigm shift with respect to both the understanding and clinical management of inherited arrhythmias. However, it should be noted that despite the rapid progress in understanding the genetic basis, the etiology still remains unknown in approximately 20% of LQTS conditions [10]. Therefore, additional studies are needed to reveal the missing heritable factors associated with these syndromes. Traditionally, DNA sequence information has been elucidated using Sanger sequencing, but this method is limited by the amount of DNA that can be processed at a given time and by the read length (average 800 base pairs). Although the Human Genome Project completed the sequencing of the entire human genome in 2001 using Sanger sequencing, it took 13 years of effort at an estimated cost of $2.7 billion. Now, next-generation sequencing (NGS), a revolutionary new genetic technology, has enabled whole genomes to be sequenced over a period of a few days at projected costs of less than $10,000. This technology involves massively parallel sequencing of clonally amplified or single DNA molecules that are spatially separated in a flow cell. To date, the genes responsible for disease in more than 3000 Mendelian disorders have yet to be identified. NGS opens up exciting new possibilities of discovering the genes associated with these monogenic disorders. Classical strategies involve linkage analysis in families with known shared genetic heritage by identifying candidate genomic regions encompassing the gene

Fever and the electrocardiogram: What about Brugada syndrome?

In 2000, colleagues from Spain appreciated that fever could evoke malignant arrhythmias in Brugada syndrome and in the years thereafter many more examples have been reported.1–5 Brugada syndrome is an inheritable arrhythmia syndrome associated with a characteristic electrocardiogram (ECG; type-1 or coved-type Brugada ECG). The pathophysiological mechanisms underlying Brugada syndrome are not yet resolved but may include depolarization or repolarization abnormalities.6 Although most patients with Brugada syndrome will not have arrhythmias during follow-up, some patients are extremely symptomatic and may die suddenly or have repetitive malignant ventricular arrhythmias.

Characterisation of familial idiopathic ventricular fibrillation linked to DPP6

Purpose: Idiopathic ventricular fibrillation (IVF) is a rare but notoriously difficult to manage arrhythmia syndrome as there are no clinical identifiers to establish the risk for a premature cardiac arrest. However, we recently uncovered a link between familial IVF and a risk haplotype on the new arrhythmia gene DPP6 on chromosome 7q36 in several related IVF families. DPP6 is putatively involved in the Ito current in heart. In this study we characterise both the extended bench and bedside evaluations in IVF linked to DPP6. Methods: We studied 235 carriers and 267 non-carriers of the DPP6 risk haplotype. Clinical parameters and a combination of all cause mortality and cardiac arrest were evaluated. Additional expression studies in human cardiac tissue samples and adenovirus-mediated gene transfer studies in cultured canine Purkinje cells and cardiomyocytes were performed. Results: Successfully resuscitated patients did not have any sign of other inheritable arrhythmia syndromes. Recorded IVF was always initiated by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall. Ablation of extrasystole preceding Purkinje potentials and/or the administration quinidine led to suppression of subsequent arrhythmias. Carriers and non-carriers had normal and similar electrocardiographic and echocardiographic indices. Cardiac MRI showed a trend to slightly larger right ventricular volumes in carriers, but these were still within normal limits and not clinically useful. Death and/or cardiac arrest occurred in 84 carriers and 10 non-carriers. Median survival of carriers was 68 years (p<0.01 vs non-carriers), with events starting from age 16 with a worse phenotype in males (median survival 59 vs 82 years, p<0.01 vs females). Biopsy studies uncovered DPP6 mRNA overexpression in carriers (p<0.01 vs controls). Studies in non-diseased explanted human hearts revealed higher DPP6 mRNA expression in Purkinje fibers than in other regions (p<0.01 vs ventricular myocardium) while DPP6-overexpression significantly increased Ito density in canine Purkinje cells (∼52%, p<0.05 vs control) but not in cardiomyocytes, further underpinning the importance of the Purkinje network in the DPP6 risk haplotype. Conclusions: A new arrhythmia gene DPP6 is linked to familial IVF and shows a malignant phenotype. Our results point to a pivotal role of DPP6 overexression in Purkinje fibers eliciting short-coupled extrasystoles which trigger IVF. For the first time, only genetic predisposition can be used as a risk-marker for future events in IVF.

542 Current Practices Regarding the Investigation of Sudden Unexpected Death in the Young (SUDY) in Canada

542 Current Practices Regarding the Investigation of Sudden Unexpected Death in the Young (SUDY) in Canada

Familial Brugada syndrome unmasked by carbon monoxide intoxication

We describe a patient with carbon monoxide intoxication and lactic acidosis that uncovered typical Brugada syndrome (BrS) electrocardiogram (ECG). Further screening ECG in his family members confirmed familial BrS. Carbon monoxide intoxication with metabolic acidosis may uncover an inheritable arrhythmia syndrome that may put the patient and his family members at risk for a sudden death.

Wearable Defibrillator in Congenital Structural Heart Disease and Inherited Arrhythmias

Patients with congenital structural heart disease (CSHD) and inherited arrhythmias (IAs) are at high risk of ventricular tachyarrhythmias and sudden cardiac death. The present study was designed to evaluate the short- and long-term outcomes of patients with CSHD and IA who received a wearable cardioverter-defibrillator (WCD) for the prevention of sudden cardiac death. The study population included 162 patients with CSHD (n = 43) and IA (n = 119) who were prospectively followed up in a nationwide registry from 2005 to 2010. The mortality rates were compared using Kaplan-Meier survival analysis. The mean age of the study patients was 38 ± 27 years. The patients with CSHD had a greater frequency of left ventricular dysfunction (ejection fraction <30%) than did the patients with IA (37% vs 5%, respectively; p = 0.002). The predominant indication for WCD was pending genetic testing in the IA group and transplant listing in the CSHD group. Compliance with the WCD was similar in the 2 groups (91%). WCD shocks successfully terminated 3 ventricular tachyarrhythmias in the patients with IA during a median follow-up of 29 days of therapy (corresponding to 23 appropriate WCD shocks per 100 patient-years). No arrhythmias occurred in the patients with CSHD during a median follow-up of 27 days. No patients died while actively wearing the WCD. At 1 year of follow-up, the survival rates were significantly lower among the patients with CSHD (87%) than among the patients with IA (97%, p = 0.02). In conclusion, our data suggest that the WCD can be safely used in high-risk adult patients with IA and CSHD. Patients with IA showed a greater rate of ventricular tachyarrhythmias during therapy but significantly lower long-term mortality rates.

732 Current practices regarding the clinical care and management of families affected by sudden unexpected death in the young (SUDY) in Canada

Sudden unexpected death in the young (SUDY) refers to the non-traumatic sudden unexpected death of a healthy individual under the age of 40 years in whom no cause of death is identified. As many as 35% of cases of autopsy-negative SUDY are due to the presence of inheritable arrhythmia substrates (IAS). There is a high probability that surviving family members may be affected. In the absence of national standards, strategies to improve diagnosis and care of these individuals are urgently needed. We developed a questionnaire for electrophysiologists to obtain information on current clinical practices and challenges.

Brugada syndrome and right ventricular conduction delay: What else?

In the past decades, we have gained enormous knowledge about the epidemiology and pathophysiologic mechanisms underlying inheritable arrhythmia syndromes such as Brugada syndrome and long QT syndrome. However, this has not made clinical decision-making easy when we are confronted with presymptomatic patients and their family members. The booming number of case reports and (smaller) series on these syndromes often resulted in a fast growing number of presymptomatic patients being uncovered and treated with invasive and complication-sensitive therapy such as implantable cardioverter-defibrillators at a young age. In particular, this scenario is true for Brugada syndrome. Meanwhile, both risk stratification in Brugada yndrome and its underlying pathophysiologic mechanisms ecame heavily disputed among experts, further complicatng clinical decision-making. The latter is fueled by the iscussion on whether Brugada syndrome is a depolarizaion (ie, conduction) disorder or a repolarization disorder. This distinction is important for understanding the pathophysiologic mechanisms underlying Brugada syndrome and recently has resulted in specific treatment options for symptomatic Brugada syndrome patients. All of these issues urge physicians worldwide to keep in mind that (1) strict diagnostic criteria should be followed; (2) patients need either to be discussed with a specialized center, or be referred especially when invasive treatment is considered (excellent example for long QT syndrome); (3) noninvasive therapy, such as advising against the use of certain drugs and treatment of fever when appropriate, should be extensively used; and (4) patients should receive adequate (family) counseling.

Familial Brugada syndrome uncovered by hyperkalaemic diabetic ketoacidosis

We describe a case of diabetic ketoacidosis with concomitant hyperkalaemia that uncovered a typical Brugada syndrome electrocardiogram (ECG). Further provocation testing in the patient and his son confirmed familial Brugada syndrome. Diabetic ketoacidosis with hyperkalaemia may uncover an inheritable arrhythmia syndrome that may put the patient and his/her next of kin at risk for a sudden death, irrespective of diabetes mellitus.

Founder mutations in the Netherlands: familial idiopathic ventricular fibrillation and DPP6

In this part of a series on founder mutations in the Netherlands, we review familial idiopathic ventricular fibrillation linked to the DPP6 gene. Familial idiopathic ventricular fibrillation determines an intriguing subset of the inheritable arrhythmia syndromes as there is no recognisable phenotype during cardiological investigation other than ventricular arrhythmias highly associated with sudden cardiac death. Until recently, it was impossible to identify presymptomatic family members at risk for fatal events. We uncovered several genealogically linked families affected by numerous sudden cardiac deaths over the past centuries, attributed to familial idiopathic ventricular fibrillation. Notably, ventricular fibrillation in these families was provoked by very short coupled monomorphic extrasystoles. We were able to associate their phenotype of lethal arrhythmic events with a haplotype harbouring the DPP6 gene. While this gene has not earlier been related to cardiac arrhythmias, we are now able, for the first time, to identify and to offer timely treatment to presymptomatic family members at risk for future fatal events solely by genetic analysis. Therefore, when there is a familial history of unexplained sudden cardiac deaths, a link to the DPP6 gene may be explored as it may enable risk evaluation of the remaining family members. In addition, when closely coupled extrasystoles initiate ventricular fibrillation in the absence of other identifiable causes, a link to the DPP6 gene should be suspected.

HCN-related channelopathies

HCN channels are the molecular subunits of native funny (f-) channels of cardiac pacemaker cells and neurons. Although funny channels were first functionally described in cardiac cells in the late 1970s, cloning of HCN channels, of which four subunits are known today (HCN1-4), had to wait some 20 years to be accomplished, which delayed the investigation of HCN-related channelopathies. In cardiac pacemaker cells, the main function of f-channels is to contribute substantially to the generation of spontaneous activity of pacemaker cells and control of heart rate. Given this role in cardiac rhythm, it is natural to expect that defective f-channels (or their molecular correlates HCN4 channels) might be responsible for inheritable forms of cardiac arrhythmogenic diseases. Indeed, the recent search for HCN4-related inheritable arrhythmias has resulted in the finding of four different mutations of the hHcn4 gene, which have been reported to be associated with bradycardia and/or more complex arrhythmic conditions. In neurons, HCN channels display a variety of functions including the regulation of excitability, dendritic integration, plasticity, motor learning, generation of repetitive firing, and others. Defective HCN channels may therefore in principle also contribute to pathological conditions in the nervous system. While full evidence for neuronal HCN channelopathies is not yet available, several indications point to a link between temporal lobe and absence epilepsies and altered distribution of HCN1/HCN2 isoforms. Here we briefly review the current knowledge of HCN-related channelopathies in the heart and the brain.

Ventricular tachycardia and aggravation of Brugada ECG pattern in a patient with coronary artery disease and combined amiodarone and betablocker therapy

A. Castel Hospital Clinic Thorax Institute Villarroel 17008036 Barcelona, Spain Tel.: +34 /932275722 Fax: +34 /932279868 E-Mail: acastel@gmx.de Sirs: Brugada syndrome is defined as a typical ECG pattern that predisposes individuals with structurally normal hearts to ventricular arrhythmias and sudden cardiac death. It is an inheritable arrhythmia syndrome first described in 1992 by Brugada & Brugada [1] that can be linked to mutations in myocardial ion channel mutations in 20% of patients. Typical electrocardiograms show ST segment elevation in the precordial leads V1 to V3, with morphology of the QRS complex resembling a right bundle branch block [2]. We report on a case with underlying coronary artery disease, presenting with a defibrillator shock due to ventricular tachycardia under amiodarone and beta-blocker therapy and a Brugada type ECG pattern. Possible interferences by these drugs and suitable therapeutic actions are discussed.

Biology of cardiac arrhythmias: ion channel protein trafficking.

The mechanisms underlying normal and abnormal cardiac rhythms are complex and incompletely understood. Through the study of uncommon inheritable arrhythmia syndromes, including the long QT and Brugada syndromes, new insights are emerging. At the cellular and tissue levels, we now recognize that ion channel current is the sum of biophysical (gating, permeation), biochemical (phosphorylation, etc), and biogenic (biosynthesis, processing, trafficking, and degradation) properties. This review focuses on how heart cells process ion channel proteins and how this protein trafficking may be altered in some cardiac arrhythmia diseases. In this review, we honor Dr Harry A. Fozzard, a modern pioneer in cardiac arrhythmias, cell biology, and molecular electrophysiology. As a scientist and physician, his writings and mentorship have served to foster a generation of investigators who continue to bring this complex field toward greater scientific understanding and impact on humankind.