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.

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.

Successful ablation of incessant AV reentrant tachycardia in a patient on extracorporeal membrane oxygenation.

We present the first described case of an accessory pathway ablation, requiring a transseptal puncture, performed on ECMO for tachycardia-induced cardiomyopathy in the context of cardiogenic shock. The performance of a transseptal puncture in such a scenario is a feasible option and should be considered if the clinical situation dictates, despite the inherent risks. After ablation of the left lateral pathway the patient was successfully weaned off ECMO and made a complete recovery.

Percutaneous left atrial appendage occlusion with a Watchman device following recurrent stroke on warfarin and rivaroxaban in patient with paroxysmal atrial fibrillation.

The optimal management of recurrent cardioembolic stroke in a patient on oral anticoagulation is controversial. Therapeutic strategies for secondary stroke prevention in such circumstances may include the intensification of oral anticoagulation, the addition of antiplatelet therapy to warfarin, or the use of a non-vitamin K antagonist instead of warfarin. However, there is no evidence to support these interventions, and indeed these strategies are not endorsed by the 2011 Guidelines on the Secondary Prevention of Stroke issued by the American Heart Association/American Stroke Association. Percutaneous occlusion of the left atrial appendage (LAA) has recently emerged as an acceptable non-pharmacological strategy to reduce the risk of cardioembolism in patients who cannot tolerate oral anticoagulation, but there is little evidence to support its use in the context of recurrent stroke despite oral anticoagulation. We present the case of a 66 year-old male with paroxysmal atrial fibrillation who experienced recurrent stroke despite treatment with warfarin initially, and rivaroxaban subsequently. After excluding non-cardioembolic causes of recurrent stroke, we proceeded with percutaneous occlusion of the LAA with a Watchman device. Nine months post-procedure he has not experienced recurrence of neurological symptoms. Our case provides anectodal evidence that catheter-based LAA occlusion can be beneficial in secondary stroke prevention where oral anticoagulation has been problematic.

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.

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.

Quantifying the origins of population variability in cardiac electrical activity through sensitivity analysis of the electrocardiogram.

Altered function of ion channels in the heart can increase the risk of sudden arrhythmic death. Hundreds of genetic variants exist in these cardiac ion channel genes. The challenge is how to interpret the effects of multiple conductance perturbations on the complex multi-variable cardiac electrical system? In theory, sensitivity analysis can address this question. However, to date this approach has been restricted by computational overheads to analysis of isolated cells, which has limited extrapolation to physiologically relevant scales. The goal of this study was to extend existing sensitivity analyses to electrocardiogram (ECG) signals derived from multicellular systems and quantify the contribution of ionic conductances to emergent properties of the ECG. To achieve this, we have developed a highly parallelised simulation environment using unconventional high performance computing architectures to analyse the emergent electrical properties of a multicellular system. This has permitted the first systematic analysis of the molecular basis of the T wave amplitude, revealing important but distinct roles for delayed rectifier and inward rectifier K(+) currents. In addition to quantifying how interactions between multiple ion channels influence ECG parameters we show that these sensitivities are dynamic functions of heart rate. This study provides a significant advance in our understanding both of how individual ion conductances define ECG signals and of epistatic modification of cardiac electrical phenotypes. The parallelised simulation environment we have developed removes the computational roadblock that has limited this approach and so provides the framework for future analysis of more complex tissue and whole organ systems.

Isolated ventricular noncompaction: implications for mechanisms of sudden cardiac death.

We present a case of a young patient, whose first manifestation of isolated ventricular noncompaction (IVNC) was sudden cardiac arrest precipitated by ventricular fibrillation. Furthermore we had the rare opportunity to record the onset of subsequent episodes of ventricular fibrillation-with discussion on the mechanisms of ventricular arrhythmias in IVNC.

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.

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.

Unusual adverse consequence of reverse ventricular remodelling following cardiac resynchronization therapy.

Cardiac resynchronization therapy has been shown to produce reverse ventricular remodelling in patients with severe heart failure. We report an unusual case of T-wave oversensing, most likely as a consequence of reverse ventricular remodelling resulting in change of the implantable cardioverter-defibrillator lead redundancy.

Cardiac sarcoidosis masquerading as arrhythmogenic right ventricular cardiomyopathy.

We present a case of ventricular tachycardia with clinical features suggestive of arrhythmogenic right ventricular cardiomyopathy. However, endomyocardial biopsy revealed non-caseating granulomas diagnostic of cardiac sarcoidosis.

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.

Permanent pacing for late-onset atrioventricular block in patients with heart transplantation: a single center experience.

INTRODUCTION: The incidence, mechanisms, clinical associations, and outcomes in patients with late-onset (>3 months) atrioventricular (AV) block following heart transplantation are not well known. This study will characterize late-onset AV block following cardiac transplantation. METHODS: We retrospectively reviewed our databases to identify patients who required pacemakers for late-onset AV block postheart and heart-lung transplantation from January 1990 to December 2007. Orthotopic heart and heart-lung transplantation were separately analyzed. RESULTS: This study included 588 adults who received cardiac transplants over a 17-year period at our center (519 orthotopic, 64 heart-lung transplants, and five heterotopic heart transplants). Of the 519 patients with orthotopic heart transplant, 39 required pacing (7.5%), 17 (3.3%) within 3 months posttransplant, 11 (2.1%) for late-onset sinus node dysfunction (SND), 11 (2.1%) for late-onset AV block. Also, five patients (7.8%) out of 64 heart-lung transplants required pacemakers, two (3.1%) for late-onset SND, three (4.7%) for late-onset AV block. None of the five patients who underwent heterotopic transplant required cardiac pacing prior to or posttransplant. CONCLUSIONS: Late-onset AV block occurs in 2.4% of patients with orthotopic heart transplant or heart-lung transplant. AV block is predominantly intermittent and, often, does not progress to permanent AV block. There are no predictable factors for its onset.

Secondary r' wave in V(1) as a sign of left-sided antegrade accessory pathway conduction.

A secondary r' wave in V(1) on surface electrocardiogram (ECG) has been described in association with left ventricular preexcitation via an accessory pathway. We present a case that demonstrates the mechanism for this ECG observation.

Expression of a common LQT1 mutation in five apparently unrelated families in a regional inherited arrhythmia clinic.

BACKGROUND: The Inherited Arrhythmia Clinic at the University of Western Ontario services a catchment area of 1.5 million people and follows families with inherited arrhythmia syndromes. METHODS: Patients referred for evaluation of long-QT Syndrome (LQTS) are evaluated with resting and standing ECGs, and treadmill exercise testing. Patients with findings consistent with LQTS are offered comprehensive genetic testing with screening of all first-degree relatives of genotype-positive patients. RESULTS: Among 31 probands with disease-causing LQTS mutations, 5 probands from apparently unrelated families of Irish descent were found to have an identical disease causing transmembrane mutation in KCNQ1 (Leu266Pro). Systematic screening of 33 first-degree relatives of genotype-positive individuals detected 15 unaffected and 18 asymptomatic affected family members. Symptoms in 6 patients occurred later in life than reported LQT1 populations (61 +/- 18 years, range 44-89). In this cohort, several family members presented with cardiac arrest during acute myocardial ischemia (n = 2), sudden death, unexplained drowning, and torsade de pointes during exercise testing. There was no identifiable common relative for this cohort after pedigree construction of the previous 4-7 generations. Affected patients had mild QT prolongation at rest with dramatic QT prolongation with exercise. CONCLUSIONS: Genetic testing in this LQTS population suggests a common KCNQ1 Leu266Pro founder effect, with the descendants clustering in our geographical region even though no common relative has been identified. The observations highlight the utility of genotypic and phenotypic correlation and a specialized clinic.