Meta-Analysis of Genome-Wide Association Studies Reveals Genetic Mechanisms of Supraventricular Arrhythmias.

BACKGROUND: Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT). METHODS: We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies. RESULTS: Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate NKX2-5 and TTN as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of NKX2-5 and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate SCN5A, SCN10A, and TTN/CCDC141. Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals. CONCLUSIONS: Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.

Coronary Artery Fistula Involving the RCA, LAD, and the Main Pulmonary Artery.

We present a case of a complex congenital coronary artery fistula between the right coronary artery, left anterior descending artery, and the main pulmonary artery complicated by massive aneurysms and a left-to-right shunt. We highlight the multimodality approach to assessment and the importance of individualized management of complex coronary fistulas.

Action Potential Morphology Accurately Predicts Proarrhythmic Risk for Drugs With Potential to Prolong Cardiac Repolarization.

BACKGROUND: Drug-induced or acquired long QT syndrome occurs as a result of the unintended disruption of cardiac repolarization due to drugs that block cardiac ion channels. These side effects have been responsible for the withdrawal of a range of drugs from market and are a common reason for termination of the development of new drugs in the preclinical stage. Existing approaches to risk prediction are expensive and overly sensitive meaning that recently there have been renewed efforts, largely driven by the comprehensive proarrhythmic assay initiative, to develop more accurate methods for allocation of proarrhythmic risk. METHODS: In this study, we aimed to quantify changes in the morphology of the repolarization phase of the cardiac action potential as an indicator of proarrhythmia, supposing that these shape changes might precede the emergence of ectopic depolarizations that trigger arrhythmia. To do this, we describe a new method of quantifying action potential morphology by measuring the radius of curvature of the repolarization phase both in simulated action potentials, as well as in action potentials measured from induced pluripotent stem cell-derived cardiomyocytes. Features derived from the curvature signal were used as inputs for logistic regressions to predict proarrhythmic risk. RESULTS: Optimal risk classifiers based on morphology were able to correctly classify risk to drugs in the comprehensive proarrhythmic assay initiative panels with very high accuracy (0.9375) and outperformed conventional metrics based on action potential duration at 90% repolarization, triangulation, and charge movement (qNet). CONCLUSIONS: Analysis of action potential morphology in response to proarrhythmic drugs improves prediction of torsadogenic risk. Furthermore, morphology metrics can be measured directly from the action potential, potentially eliminating the burden of undertaking complex screens of potency and drug-binding kinetics against multiple cardiac ion channels. As such, this method has the potential to improve and streamline regulatory assessment of proarrhythmia in preclinical drug development.

Management of the arrhythmic manifestations of cardiac sarcoidosis.

Cardiac sarcoidosis (CS) is characterised by a high burden of arrhythmic manifestations and cardiac electrophysiologists play an important role in both the diagnosis and management of this challenging condition. CS is characterised by the formation of noncaseating granulomas within the myocardium, which can subsequently lead to fibrosis. Clinical presentations of CS are varied and depend on the location and extent of granulomas. Patients may present with atrioventricular block, ventricular arrhythmias, sudden cardiac death or heart failure. CS is being increasing diagnosed through use of advanced cardiac imaging, however endomyocardial biopsy is often still required to confirm the diagnosis. Due to the low sensitivity of fluoroscopy-guided right ventricular biopsies, three-dimensional electro-anatomical mapping and electrogram-guided biopsies are being investigated as a means to improve diagnostic yield. Cardiac implantable electronic devices are often required in the management of CS, either for pacing or for primary or secondary prevention of ventricular arrhythmias. Catheter ablation for ventricular arrythmias may also be required, although this is often associated with high recurrence rates due to the challenging nature of the arrhythmogenic substrate. This review will explore the underlying mechanisms of the arrhythmic manifestations of CS, provide an overview of current clinical practice guidelines, and examine the important role that cardiac electrophysiologists play in managing patients with CS.

The diagnostic role of T wave morphology biomarkers in congenital and acquired long QT syndrome: A systematic review.

INTRODUCTION: QTc prolongation is key in diagnosing long QT syndrome (LQTS), however 25%-50% with congenital LQTS (cLQTS) demonstrate a normal resting QTc. T wave morphology (TWM) can distinguish cLQTS subtypes but its role in acquired LQTS (aLQTS) is unclear. METHODS: Electronic databases were searched using the terms "LQTS," "long QT syndrome," "QTc prolongation," "prolonged QT," and "T wave," "T wave morphology," "T wave pattern," "T wave biomarkers." Whole text articles assessing TWM, independent of QTc, were included. RESULTS: Seventeen studies met criteria. TWM measurements included T-wave amplitude, duration, magnitude, Tpeak-Tend, QTpeak, left and right slope, center of gravity (COG), sigmoidal and polynomial classifiers, repolarizing integral, morphology combination score (MCS) and principal component analysis (PCA); and vectorcardiographic biomarkers. cLQTS were distinguished from controls by sigmoidal and polynomial classifiers, MCS, QTpeak, Tpeak-Tend, left slope; and COG x axis. MCS detected aLQTS more significantly than QTc. Flatness, asymmetry and notching, J-Tpeak; and Tpeak-Tend correlated with QTc in aLQTS. Multichannel block in aLQTS was identified by early repolarization (ERD30% ) and late repolarization (LRD30% ), with ERD reflecting hERG-specific blockade. Cardiac events were predicted in cLQTS by T wave flatness, notching, and inversion in leads II and V5 , left slope in lead V6 ; and COG last 25% in lead I. T wave right slope in lead I and T-roundness achieved this in aLQTS. CONCLUSION: Numerous TWM biomarkers which supplement QTc assessment were identified. Their diagnostic capabilities include differentiation of genotypes, identification of concealed LQTS, differentiating aLQTS from cLQTS; and determining multichannel versus hERG channel blockade.

Splinters in the fingernails, heart and brain: thromboembolic complications of non-bacterial thrombotic endocarditis despite treatment with a direct-acting oral anticoagulant.

Non-bacterial thrombotic endocarditis (NBTE) is a rare condition characterized by non-infectious vegetations affecting the cardiac valves. Although systemic thromboembolism is a commonly associated condition, antiphospholipid syndrome is less common. Nevertheless, treatment generally involves long-term anticoagulation. We report a case of a patient with previously undiagnosed NBTE who suffered systemic thromboembolic events despite pre-existing treatment with a direct-acting oral anticoagulant.

Ventricular Arrhythmias in Cardiac Amyloidosis: A Review of Current Literature.

Cardiac Amyloidosis is an infiltrative cardiomyopathy which occurs secondary to deposition of mis-folded protein in the myocardium, with the two most common subtypes being AL amyloidosis and TTR amyloidosis. The pathogenesis of the disease is multifaceted and involves a variety of mechanisms including an inflammatory response cascade, oxidative stress and subsequent separation of myocyte fibrils. Cardiac Amyloidosis frequently results in congestive cardiac failure and arrhythmias, from a disruption in cardiac substrate with subsequent electro-mechanical remodelling. Disease progression is usually demonstrated by development of progressive pump failure, which may be seen with a high arrhythmic burden, usually portending a poor prognosis. There is a paucity of literature on the clinical implications of ventricular arrhythmias in the context of cardiac amyloidosis. The important diagnostic investigations for these patients include transthoracic echocardiography, cardiac magnetic resonance imaging and an electrophysiology study. Whilst there are no robust management guidelines, studies have indicated benefits from contemporary pharmacological therapy and case-by-case catheter ablation. There are novel directed therapies available for TTR amyloidosis that have shown to improve overall survival. The role of ICD therapy in cardiac amyloidosis is controversial, with benefits seen predominantly in early phases of the disease process. The only definitive surgical therapy includes heart transplantation, but is largely indicated for progressive decompensated heart failure (Figure 1). Further large-scale studies are required to better outline management paradigms for treating ventricular arrhythmias in cardiac amyloidosis.

The Unpaceable Heart.

This is a case of flecainide toxicity in a patient with a permanent pacemaker. This case not only highlights the effects of flecainide toxicity on surface electrocardiography but how toxicity effects pacemaker function and its ability to transvenously pace the heart. The report provides some discussion of the management options for flecainide toxicity. (Level of Difficulty: Beginner.).

Heritability of ECG Biomarkers in the Netherlands Twin Registry Measured from Holter ECGs.

INTRODUCTION: The resting ECG is the most commonly used tool to assess cardiac electrophysiology. Previous studies have estimated heritability of ECG parameters based on these snapshots of the cardiac electrical activity. In this study we set out to determine whether analysis of heart rate specific data from Holter ECGs allows more complete assessment of the heritability of ECG parameters. METHODS AND RESULTS: Holter ECGs were recorded from 221 twin pairs and analyzed using a multi-parameter beat binning approach. Heart rate dependent estimates of heritability for QRS duration, QT interval, Tpeak-Tend and Theight were calculated using structural equation modeling. QRS duration is largely determined by environmental factors whereas repolarization is primarily genetically determined. Heritability estimates of both QT interval and Theight were significantly higher when measured from Holter compared to resting ECGs and the heritability estimate of each was heart rate dependent. Analysis of the genetic contribution to correlation between repolarization parameters demonstrated that covariance of individual ECG parameters at different heart rates overlap but at each specific heart rate there was relatively little overlap in the genetic determinants of the different repolarization parameters. CONCLUSIONS: Here we present the first study of heritability of repolarization parameters measured from Holter ECGs. Our data demonstrate that higher heritability can be estimated from the Holter than the resting ECG and reveals rate dependence in the genetic-environmental determinants of the ECG that has not previously been tractable. Future applications include deeper dissection of the ECG of participants with inherited cardiac electrical disease.

Accelerated graft dysfunction in heart transplant patients with persistent atrioventricular conduction block.

AIMS: Bradyarrhythmia following heart transplantation is common-∼7.5-24% of patients require permanent pacemaker (PPM) implantation. While overall mortality is similar to their non-paced counterparts, the effects of chronic right ventricular pacing (CRVP) in heart transplant patients have not been studied. We aim to examine the effects of CRVP on heart failure and mortality in heart transplant patients. METHODS AND RESULTS: Records of heart transplant recipients requiring PPM at St Vincent's Hospital, Sydney, Australia between January 1990 and January 2015 were examined. Patient's without a right ventricular (RV) pacing lead or a follow-up time of <1 year were excluded. Patients with pre-existing abnormal left ventricular function (<50%) were analysed separately. Patients were grouped by pacing dependence (100% pacing dependent vs. non-pacing dependent). The primary endpoint was clinical or echocardiographic heart failure (<35%) in the first 5 years post-PPM. Thirty-three of 709 heart transplant recipients were studied. Two patients had complete RV pacing dependence, and the remaining 31 patients had varying degrees of pacing requirement, with an underlying ventricular escape rhythm. The primary endpoint occurred significantly more in the pacing-dependent group; 2 (100%) compared with 2 (6%) of the non pacing dependent group (P < 0.0001 by log-rank analysis, HR = 24.58). Non-pacing-dependent patients had reversible causes for heart failure, unrelated to pacing. In comparison, there was no other cause of heart failure in the pacing-dependent group. CONCLUSIONS: Permanent atrioventricular block is rare in the heart transplant population. We have demonstrated CRVP as a potential cause of accelerated graft failure in pacing-dependent heart transplant patients.

Impact of Implantable Cardioverter Defibrillators on Survival of Patients with Centrifugal Left Ventricular Assist Devices.

BACKGROUND: Both implantable cardioverter defibrillators (ICDs) and left ventricular assist devices (LVADs) have a positive impact on survival in the heart failure population. We sought to determine whether these positive effects on survival are additive or whether LVAD therapy supersedes ICD therapy. METHOD: We analyzed survival data of patients implanted with nonpulsatile LVADs between October 2004 and March 2013. Survival in patients with ICDs (n = 64) was compared to those without ICDs (n = 36). Patients exited the study at the time of heart transplantation or death. RESULTS: A total of 100 patients underwent LVAD implantation during this time. Patients had a mean follow-up time of 364 ± 295 days. Death occurred in 15 (38%) patients in the no ICD group versus 18 (30%) in the ICD group. Univariate analysis demonstrated a marginal early survival benefit at up to 1 year post-LVAD implant in the ICD cohort; however, at time points greater than 1 year there was no statistically significant benefit in ICD therapy in LVAD patients (P = 0.56). Multivariate analysis did not show any significant predictor of survival. There were no patients who died of sudden cardiac death. There was no significant difference in the time to heart transplantation (443 days ± 251 no ICD vs 372 days ± 277 ICD, P = 0.37). CONCLUSION: The benefit of ICD therapy in the setting of continuous flow LVAD therapy is uncertain. Although prolonged ventricular arrhythmias (VAs) may potentially impact on patient survival, LVAD therapy is beneficial in prevention of sudden cardiac death due to VAs.

Multiscale cardiac modelling reveals the origins of notched T waves in long QT syndrome type 2.

The heart rhythm disorder long QT syndrome (LQTS) can result in sudden death in the young or remain asymptomatic into adulthood. The features of the surface electrocardiogram (ECG), a measure of the electrical activity of the heart, can be equally variable in LQTS patients, posing well-described diagnostic dilemmas. Here we report a correlation between QT interval prolongation and T-wave notching in LQTS2 patients and use a novel computational framework to investigate how individual ionic currents, as well as cellular and tissue level factors, contribute to notched T waves. Furthermore, we show that variable expressivity of ECG features observed in LQTS2 patients can be explained by as little as 20% variation in the levels of ionic conductances that contribute to repolarization reserve. This has significant implications for interpretation of whole-genome sequencing data and underlies the importance of interpreting the entire molecular signature of disease in any given individual.