Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, KCa1.1, in Sinus Node Function and Arrhythmia Risk.

BACKGROUND: KCNMA1 encodes the α-subunit of the large-conductance Ca2+-activated K+ channel, KCa1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of KCa1.1 are limited, and KCNMA1 has not been investigated as an AF candidate gene. METHODS: The KCNMA1 gene was sequenced in 118 patients with familial AF. The role of KCa1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel KCNMA1 variant was functionally characterized. RESULTS: A complex KCNMA1 variant was identified in 1 kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of KCa1.1 in normal hearts using immunostaining and immunogold electron microscopy. KCa1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the KCa1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the KCa1.1 ortholog, kcnma1b, in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the Drosophila KCa1.1 ortholog, slo, systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of slo-deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human KCNMA1 mutant also showed increased heart period and bursts of action potentials, similar to the KCa1.1 loss-of-function models. CONCLUSIONS: Our data point to a highly conserved role of KCa1.1 in sinus node function in humans, mice, zebrafish, and fly and suggest that KCa1.1 loss of function may predispose to AF.

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.

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.

R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy.

OBJECTIVES: The goal of this study was to characterize a variant in the SCN5A gene that encodes the alpha-subunit of the cardiac sodium channel, Nav1.5, which was identified in 1 large kindred with dilated cardiomyopathy (DCM) and multiple arrhythmias, including premature ventricular complexes (PVCs). BACKGROUND: Treatment guidelines for familial DCM are based on conventional heart failure therapies, and no gene-based interventions have been established. METHODS: Family members underwent clinical evaluation and screening of the SCN5A and LMNA genes. Cellular electrophysiology and computational modeling were used to determine the functional consequences of the mutant Nav1.5 protein. RESULTS: An R222Q missense variant located in a Nav1.5 voltage-sensing domain was identified in affected family members. Patch-clamp studies showed that R222Q Nav1.5 did not alter sodium channel current density, but did left shift steady-state parameters of activation and inactivation. Using a voltage ramp protocol, normalized current responses of R222Q channels were of earlier onset and greater magnitude than wild-type channels. Action potential modeling using Purkinje fiber and ventricular cell models suggested that rate-dependent ectopy of Purkinje fiber origin is the predominant ventricular effect of the R222Q variant and a potential cause of DCM. In R222Q carriers, there were only modest responses to heart failure therapies, but PVCs and DCM were substantially reduced by amiodarone or flecainide, which are drugs that have sodium channel-blocking properties. CONCLUSIONS: The R222Q SCN5A variant has an activating effect on sodium channel function and is associated with reversible ventricular ectopy and DCM. Elucidation of the genetic basis of familial DCM can enable effective gene-targeted therapy to be implemented.

Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk.

OBJECTIVES: The aim of this study was to evaluate the role of cardiac K(+) channel gene variants in families with atrial fibrillation (AF). BACKGROUND: The K(+) channels play a major role in atrial repolarization but single mutations in cardiac K(+) channel genes are infrequently present in AF families. The collective effect of background K(+) channel variants of varying prevalence and effect size on the atrial substrate for AF is largely unexplored. METHODS: Genes encoding the major cardiac K(+) channels were resequenced in 80 AF probands. Nonsynonymous coding sequence variants identified in AF probands were evaluated in 240 control subjects. Novel variants were characterized using patch-clamp techniques and in silico modeling was performed using the Courtemanche atrial cell model. RESULTS: Nineteen nonsynonymous variants in 9 genes were found, including 11 rare variants. Rare variants were more frequent in AF probands (18.8% vs. 4.2%, p < 0.001), and the mean number of variants was greater (0.21 vs. 0.04, p < 0.001). The majority of K(+) channel variants individually had modest functional effects. Modeling simulations to evaluate combinations of K(+) channel variants of varying population frequency indicated that simultaneous small perturbations of multiple current densities had nonlinear interactions and could result in substantial (>30 ms) shortening or lengthening of action potential duration as well as increased dispersion of repolarization. CONCLUSIONS: Families with AF show an excess of rare functional K(+) channel gene variants of varying phenotypic effect size that may contribute to an atrial arrhythmogenic substrate. Atrial cell modeling is a useful tool to assess epistatic interactions between multiple variants.

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.

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.

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.

Left ventricular mechanical assist devices and cardiac device interactions: an observational case series.

BACKGROUND: Nonpulsatile left ventricular assist devices (LVADs) are increasingly used for treatment of refractory heart failure. A majority of such patients have implanted cardiac devices, namely implantable cardioverter-defibrillators (ICDs) or cardiac resynchronization therapy-pacemaker (CRT-P) or cardiac resynchronization therapy-defibrillator (CRT-D) devices. However, potential interactions between LVADs and cardiac devices in this category of patients remain unknown. METHODS: We reviewed case records and device logs of 15 patients with ICDs or CRT-P or CRT-D devices who subsequently had implantation of a VentrAssist LVAD (Ventracor Ltd., Chatswood, Australia) as destination therapy or bridge to heart transplantation. Pacemaker and ICD lead parameters before and after LVAD implant were compared. In addition, ventricular tachyarrhythmia event logs and potential electromagnetic interference reports were evaluated. RESULTS: Right ventricular (RV) sensing decreased in the first 6 months post-LVAD. Mean R-wave amplitude preimplant was 10.9 +/- 5.25 mV compared with 7.2 +/- 3.4 mV during follow-up (P = 0.02). RV impedance also decreased from 642 +/- 240 ohms at baseline to 580 +/- 212 ohms at follow-up (P = 0.007). There was a significant increase in RV stimulation threshold following implantation of the LVAD from 0.8 +/- 0.6 V at baseline to 1.4 +/- 1.0 V in the first 6 months postimplant (P = 0.01). A marked increase in ventricular tachyarrhythmia burden was observed in three patients. One patient displayed electromagnetic interference between the LVAD and defibrillator, resulting in inappropriate defibrillation therapy. CONCLUSIONS: LVADs have a definite impact on cardiac devices in respect with alteration of lead parameters, ventricular tachyarrhythmias, and electromagnetic interference.

Stretch-sensitive KCNQ1 mutation A link between genetic and environmental factors in the pathogenesis of atrial fibrillation?

OBJECTIVES: This study sought to evaluate mutations in genes encoding the slow component of the cardiac delayed rectifier K+ current (I(Ks)) channel in familial atrial fibrillation (AF). BACKGROUND: Although AF can have a genetic etiology, links between inherited gene defects and acquired factors such as atrial stretch have not been explored. METHODS: Mutation screening of the KCNQ1, KCNE1, KCNE2, and KCNE3 genes was performed in 50 families with AF. The effects of mutant protein on cardiac I(Ks) activation were evaluated using electrophysiological studies and human atrial action potential modeling. RESULTS: One missense KCNQ1 mutation, R14C, was identified in 1 family with a high prevalence of hypertension. Atrial fibrillation was present only in older individuals who had developed atrial dilation and who were genotype positive. Patch-clamp studies of wild-type or R14C KCNQ1 expressed with KCNE1 in CHO cells showed no statistically significant differences between wild-type and mutant channel kinetics at baseline, or after activation of adenylate cyclase with forskolin. After exposure to hypotonic solution to elicit cell swelling/stretch, mutant channels showed a marked increase in current, a leftward shift in the voltage dependence of activation, altered channel kinetics, and shortening of the modeled atrial action potential duration. CONCLUSIONS: These data suggest that the R14C KCNQ1 mutation alone is insufficient to cause AF. Rather, we suggest a model in which a "second hit", such as an environmental factor like hypertension, which promotes atrial stretch and thereby unmasks an inherited defect in ion channel kinetics (the "first hit"), is required for AF to be manifested. Such a model would also account for the age-related increase in AF development.

Torsades de pointes in a patient with Kearns-Sayre syndrome: a fortunate finding.

We present a case of a 33-year-old woman with Kearns-Sayre syndrome (KSS) who had a pacemaker implanted for complete heart block postpartum and was found to have torsades de pointes. KSS is a rare encephalomyopathy associated with varying levels of central nervous system involvement, typically resulting in progressive external opthalmoplegia and retinal degeneration. Onset of cardiac conduction disease can be insidious and is a strong predictor of sudden cardiac death. The mainstay of treatment has been the judicious implantation of pacemakers. However, as highlighted in this case, patients who have an underlying cardiomyopathy may be more appropriately treated with an implantable cardioverter defibrillator.

Brugada pattern electrocardiographic changes associated with profound electrolyte disturbance.

Only a few case reports of Brugada pattern ECG changes caused by electrolyte disturbance exist in the literature, all of which lack adequate electrophysiological exclusion (or inclusion) of an underlying Brugada syndrome. This report describes a case of an otherwise healthy 38-year-old man who presented to the hospital with diabetic ketoacidosis, profound electrolyte disturbance, and Brugada pattern ECG changes. Subsequent flecanide drug challenge and electrophysiological studies ruled out an underlying Brugada syndrome.

Ventricular tachycardia following ingestion of a commonly used antihistamine.

This report describes ventricular tachycardia, likely to have been torsade de pointes, following ingestion of the non-sedating antihistamine loratadine. Documentation of the arrhythmia was made possible by the automatic electrogram storage facility of an implanted defibrillator in a patient with no prior history of cardiac arrhythmia.