Human Genetics of Cardiac Arrhythmias.

Inherited forms of cardiac arrhythmias mostly are rare diseases (prevalence <1:2000) and considered to be either "primary electrical heart disorders" due to the absence of structural heart abnormalities or "cardiac ion channel disorders" due to the myocellular structures involved. Precise knowledge of the electrocardiographic features of these diseases and their genetic classification will enable early disease recognition and prevention of cardiac events including sudden cardiac death.The genetic background of these diseases is complex and heterogeneous. In addition to the predominant "private character" of a mutation in each family, locus heterogeneity involving many ion channel genes for the same familial arrhythmia syndrome is typical. Founder pathogenic variants or mutational hot spots are uncommon. Moreover, phenotypes may vary and overlap even within the same family and mutation carriers. For the majority of arrhythmias, the clinical phenotype of an ion channel mutation is restricted to cardiac tissue, and therefore, the disease is nonsyndromic.Recent and innovative methods of parallel DNA analysis (so-called next-generation sequencing, NGS) will enhance further mutation and other variant detection as well as arrhythmia gene identification.

Molecular Pathways and Animal Models of Arrhythmias.

Arrhythmias account for over 300,000 annual deaths in the United States, and approximately half of all deaths are associated with heart disease. Mechanisms underlying arrhythmia risk are complex; however, work in humans and animal models over the past 25 years has identified a host of molecular pathways linked with both arrhythmia substrates and triggers. This chapter will focus on select arrhythmia pathways solved by linking human clinical and genetic data with animal models.

Pro-arrhythmic effects of gain-of-function potassium channel mutations in the short QT syndrome.

The congenital short QT syndrome (SQTS) is a rare condition characterized by abbreviated rate-corrected QT (QTc) intervals on the electrocardiogram and by increased susceptibility to both atrial and ventricular arrhythmias and sudden death. Although mutations to multiple genes have been implicated in the SQTS, evidence of causality is particularly strong for the first three (SQT1-3) variants: these result from gain-of-function mutations in genes that encode K+ channel subunits responsible, respectively, for the IKr, IKs and IK1 cardiac potassium currents. This article reviews evidence for the impact of SQT1-3 missense potassium channel gene mutations on the electrophysiological properties of IKr, IKs and IK1 and of the links between these changes and arrhythmia susceptibility. Data from experimental and simulation studies and future directions for research in this field are considered. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Genome Editing and Inherited Cardiac Arrhythmias.

Inherited arrhythmic disorders are a group of heterogeneous diseases predisposing to life-threatening arrhythmias and sudden cardiac death. Their diagnosis is not always simple due to incomplete penetrance and genetic heterogeneity. Furthermore, the available treatments are usually invasive and merely preventive. Genome editing and especially CRISPR/Cas9 technologies have the potential to correct the genetic arrhythmogenic substrate, thereby offering a cure for these fatal diseases. To date, genome editing has allowed reproducing cardiac arrhythmias in vitro, providing a robust platform for variant pathogenicity, mechanistic, and drug-testing studies. However, in vivo approaches still need profound research regarding safety, specificity, and efficiency of the methods.

Exercise in the Genetic Arrhythmia Syndromes - A Review.

Provide a brief summary of your article (100-150 words; no references or figures/tables). The synopsis appears only in the table of contents and is often used by indexing services such as PubMed. Genetic arrhythmia syndromes are rare, yet harbor the potential for highly consequential, often unpredictable arrhythmias or sudden death events. There has been historical uncertainty regarding the correct advice to offer to affected patients who are reasonably wanting to participate in sporting and athletic endeavors. In some cases, this had led to abundantly cautious disqualifications, depriving individuals from participation unnecessarily. Societal guidance and expert opinion has evolved significantly over the last decade or 2, along with our understanding of the genetics and natural history of these conditions, and the emphasis has switched toward shared decision making with respect to the decision to participate or not, with patients and families becoming better informed, and willing participants in the decision making process. This review aims to give a brief update of the salient issues for the busy physician concerning these syndromes and to provide a framework for approaching their management in the otherwise aspirational or keen sports participant.

Identification through action potential clamp of proarrhythmic consequences of the short QT syndrome T618I hERG 'hotspot' mutation.

The T618I KCNH2-encoded hERG mutation is the most frequently observed mutation in genotyped cases of the congenital short QT syndrome (SQTS), a cardiac condition associated with ventricular fibrillation and sudden death. Most T618I hERG carriers exhibit a pronounced U wave on the electrocardiogram and appear vulnerable to ventricular, but not atrial fibrillation (AF). The basis for these effects is unclear. This study used the action potential (AP) voltage clamp technique to determine effects of the T618I mutation on hERG current (IhERG) elicited by APs from different cardiac regions. Whole-cell patch-clamp recordings were made at 37 °C of IhERG from hERG-transfected HEK-293 cells. Maximal IhERG during a ventricular AP command was increased ∼4-fold for T618I IhERG and occurred much earlier during AP repolarization. The mutation also increased peak repolarizing currents elicited by Purkinje fibre (PF) APs. Maximal wild-type (WT) IhERG current during the PF waveform was 87.2 ± 4.5% of maximal ventricular repolarizing current whilst for the T618I mutant, the comparable value was 47.7 ± 2.7%. Thus, the T618I mutation exacerbated differences in repolarizing IhERG between PF and ventricular APs; this could contribute to heterogeneity of ventricular-PF repolarization and consequently to the U waves seen in T618I carriers. The comparatively shorter duration and lack of pronounced plateau of the atrial AP led to a smaller effect of the T618I mutation during the atrial AP, which may help account for the lack of reported AF in T618I carriers. Use of a paired ventricular AP protocol revealed an alteration to protective IhERG transients that affect susceptibility to premature excitation late in AP repolarization/early in diastole. These observations may help explain altered arrhythmia susceptibility in this form of the SQTS.

Diagnosis and management of short QT syndrome.

Establishing a definition of short QT syndrome (SQTS), including symptomatology and QT-interval duration, is still a work in progress. However, it is clear , that SQTS is a rare, life-threatening, inherited heart disease presenting as sudden cardiac death (SCD) or aborted SCD in 34% and a family history of SCD in 15%. Genetic testing is important in diagnosing the disease, but to date a causative mutation is found in <25%. A benign variety of the disease has been observed in children with atrial fibrillation and a KCNH2-V141M mutation, and recently a mutation in the cardiac Cl/HCO3 exchanger AE3 was found to cause SQTS. Issues related to measuring and correcting the QT interval for heart rate has made it difficult to rely entirely on QT duration for the diagnosis of SQTS. In order to establish the diagnosis on firmer grounds, symptoms, family history, and genetic testing need to be considered. Although the benefit of insertion of an implantable cardioverter-defibrillator as secondary prophylaxis against SCD in a patient with SQTS is well documented, the benefit as primary prophylaxis is controversial and not proven by solid data. In 2 recent similar studies involving 115 patients with approximately 5 years of follow-up, insertion of an implantable cardioverter-defibrillator in 40 patients saved the lives of 12, 11 who had presented with cardiac arrest and 1 with syncope. No appropriate shocks were delivered in any patients who did not have a history of either syncope or cardiac arrest. Currently quinidine is the only drug that has undergone any clinical testing.

Investigations on effect of taurine-magnesium coordination compound against SQT2 in isolated hearts of guinea pig / 中国药理学通报

Aim To investigate the effect of taurine-magnesium coordination compound (TMCC) on elec-trocardiogram of isolated guinea pig hearts, hoping to describe a primary research on its characteristic of anti-short QT syndrome. Methods The isolated guinea pig heart was retrograde perfused using Langendorff tech-nique. In order to determine the effects of TMCC on QT interval, transmural dispersion of repolarization, effective refractory period, instability of RR interval and instability of QT interval in the presence of potassi-um channel opener pinacidil, the electrocardiogram of isolated guinea pig hearts was recorded using Biopac physiological recorder. Results The shortened QT in-terval and the effective refractory period induced by pinacidil could be prolonged by TMCC; the increased transmural dispersion of repolarization induced by pinacidil could be decreased by TMCC; the increased instability of RR and QT interval induced by pinacidil could be decreased by TMCC. Conclusion TMCC has the effects of anti-SQT2 by prolonging the QT inter-val and the effective refractory period, reducing the transmural dispersion of repolarization and instability.

Channelopathies, genetic testing and risk stratification.

The cardiac channelopathies are a group of diseases with (disease-) specific electrocardiographic (ECG) characteristics and a disease-specific risk of sudden cardiac death (SCD). This group includes the Long QT Syndromes (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Brugada Syndrome (BrS), Short QT Syndromes (SQTS), and Early Repolarization Syndrome (ERS). In the past 2 decades the genetic basis for these disease entities has largely been unraveled and that, together with the identification of the genetic basis of the cardiomyopathies, has paved the way for the complete new field of Cardiogenetics. By virtue of the identification of the genetic underpinning of a given disease, presymptomatic carriers of the genetic aberrancy can be identified and timely treatment can be installed. In addition, it has become clear that the pathophysiological substrate of some diseases previously considered to be one disease is not identical, and this has led to gene-specific treatment in some and complete new treatment, based on the newly developed insight, in others. Finally, the genetic information proved to be important in the prediction of risk on lethal ventricular arrhythmias of affected individuals and that is the topic of this brief review.

Modelling the effects of chloroquine on KCNJ2-linked short QT syndrome.

A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of short QT syndrome (SQT3), which is associated with increased susceptibility to arrhythmias and sudden death. Anti-malarial drug chloroquine was reported as an effective inhibitor of Kir2.1 channels. Using biophysically-detailed human ventricle computer models, this study assessed the effects of chloroquine on SQT3. The ten Tusscher et al. model of human ventricular cell action potential was modified to recapitulate functional changes in the inward rectifier K+ current (IK1) due to heterozygous and homozygous forms of the D172N mutation. Mutant formulations were incorporated into multi-scale models. The blocking effects of chloroquine on ionic currents were modelled using IC50 and Hill coefficient values from literatures. Effects of chloroquine on action potential duration (APD), effective refractory period (ERP) and pseudo-ECGs were quantified. It was shown that chloroquine caused a dose-dependent reduction in IK1, prolonged APD, and decreased the maximum voltage heterogeneity. Chloroquine prolonged QT interval and declined the T-wave amplitude. Although chloroquine reduced tissue's temporal vulnerability, it increased the minimum substrate size necessary for sustaining re-entry. The actions of chloroquine decreased arrhythmia risk, due to the reduced tissue vulnerability, prolonged ERP and wavelength of re-entrant excitation waves, which in combination prevented and terminated re-entry in the tissue models. In conclusion, the results of this study provide new evidence that the anti-arrhythmic effects of chloroquine on SQT3 and, by extension, to the possibility that chloroquine may be a potential therapeutic agent for SQT3 treatment.

Role of Genetic Testing in Patients with Ventricular Arrhythmias in Apparently Normal Hearts.

Ventricular arrhythmias without structural heart disease are responsible for ∼35% of patients who have sudden cardiac death before the age of 40 years. Molecular autopsy and/or cardiological investigation of nearby family members often reveals the diagnosis and genetic testing can be helpful in family screening and risk stratification in disease carriers. Extended gene panels can be screened in a short period of time at low cost. A multidisciplinary team of (genetically) specialized clinicians is necessary to judge all the available details and to decide on the significance of the variant and further strategies.

Prognostic significance of ambulatory ECG monitoring for ventricular arrhythmias.

Ventricular arrhythmia can be detected in ambulatory ECG monitoring in individuals with or without cardiac disease, and its prognostic value varies, depending on the underlying condition. The use of continuous or intermittent ambulatory ECG monitoring can be helpful for diagnosis when there is a high pre-test probability of identifying a transient arrhythmia. In addition, Holter monitoring can be used for risk stratification of patients, in the context of the prognostic value of non-sustained ventricular arrhythmias in various clinical settings, as discussed in detail.

The structure and function of KCNQ1 channel / 中国药理学通报

The paper concluded systematically the progress of study on KCNQ1 in recent years.Firstly,the structure of ? subunit or ? subunit and its interaction between each other were explained in the paper.Secondly,the physiological function of complex KCNQ1/KCNE was interviewed,such as many kinds of inherited cardiac arrhythmias induced by mutation of KCNQ1 or KCNE and secretion of KCNQ1 in different epithelial cells.Eventually,the paper introduced the study of antagonists and agonists on KCNQ1 channel.