Na/K pump regulation of cardiac repolarization: Insights from a systems biology approach

The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the Systems Biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most\ud important ionic mechanisms in regulating key properties of cardiac repolarization and its rate-dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies

CaMKII-dependent regulation of cardiac Na(+) homeostasis.

Na(+) homeostasis is a key regulator of cardiac excitation and contraction. The cardiac voltage-gated Na(+) channel, NaV1.5, critically controls cell excitability, and altered channel gating has been implicated in both inherited and acquired arrhythmias. Ca(2) (+)/calmodulin-dependent protein kinase II (CaMKII), a serine/threonine kinase important in cardiac physiology and disease, phosphorylates NaV1.5 at multiple sites within the first intracellular linker loop to regulate channel gating. Although CaMKII sites on the channel have been identified (S516, T594, S571), the relative role of each of these phospho-sites in channel gating properties remains unclear, whereby both loss-of-function (reduced availability) and gain-of-function (late Na(+) current, INa L) effects have been reported. Our review highlights investigating the complex multi-site phospho-regulation of NaV1.5 gating is crucial to understanding the genesis of acquired arrhythmias in heart failure (HF) and CaMKII activated conditions. In addition, the increased Na(+) influx accompanying INa L may also indirectly contribute to arrhythmia by promoting Ca(2) (+) overload. While the precise mechanisms of Na(+) loading during HF remain unclear, and quantitative analyses of the contribution of INa L are lacking, disrupted Na(+) homeostasis is a consistent feature of HF. Computational and experimental observations suggest that both increased diastolic Na(+) influx and action potential prolongation due to systolic INa L contribute to disruption of Ca(2) (+) handling in failing hearts. Furthermore, simulations reveal a synergistic interaction between perturbed Na(+) fluxes and CaMKII, and confirm recent experimental findings of an arrhythmogenic feedback loop, whereby CaMKII activation is at once a cause and a consequence of Na(+) loading

25 years of basic and translational science in EP Europace: novel insights into arrhythmia mechanisms and therapeutic strategies.

In the last 25 years, EP Europace has published more than 300 basic and translational science articles covering different arrhythmia types (ranging from atrial fibrillation to ventricular tachyarrhythmias), different diseases predisposing to arrhythmia formation (such as genetic arrhythmia disorders and heart failure), and different interventional and pharmacological anti-arrhythmic treatment strategies (ranging from pacing and defibrillation to different ablation approaches and novel drug-therapies). These studies have been conducted in cellular models, small and large animal models, and in the last couple of years increasingly in silico using computational approaches. In sum, these articles have contributed substantially to our pathophysiological understanding of arrhythmia mechanisms and treatment options; many of which have made their way into clinical applications. This review discusses a representative selection of EP Europace manuscripts covering the topics of pacing and ablation, atrial fibrillation, heart failure and pro-arrhythmic ventricular remodelling, ion channel (dys)function and pharmacology, inherited arrhythmia syndromes, and arrhythmogenic cardiomyopathies, highlighting some of the advances of the past 25 years. Given the increasingly recognized complexity and multidisciplinary nature of arrhythmogenesis and continued technological developments, basic and translational electrophysiological research is key advancing the field. EP Europace aims to further increase its contribution to the discovery of arrhythmia mechanisms and the implementation of mechanism-based precision therapy approaches in arrhythmia management

Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus.

This is the final version of the article. It first appeared from Hindawi via https://doi.org/10.1155/2016/2848759Diabetes is a common endocrine disorder with an ever increasing prevalence globally, placing significant burdens on our healthcare systems. It is associated with significant cardiovascular morbidities. One of the mechanisms by which it causes death is increasing the risk of cardiac arrhythmias. The aim of this article is to review the cardiac (ion channel abnormalities, electrophysiological and structural remodelling) and extracardiac factors (neural pathway remodelling) responsible for cardiac arrhythmogenesis in diabetes. It is concluded by an outline of molecular targets for future antiarrhythmic therapy for the diabetic population.GT was awarded a BBSRC Doctoral Training Award at the University of Cambridge for his PhD

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

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Effects of ageing on pro-arrhythmic ventricular phenotypes in incrementally paced murine Pgc1β-/- hearts

A range of chronic clinical conditions accompany cardiomyocyte energetic dysfunction and constitute independent risk factors for cardiac arrhythmia. We investigated pro-arrhythmic and arrhythmic phenotypes in energetically deficient C57BL mice with genetic ablation of the mitochondrial promoter peroxisome proliferator activated receptor-γ coactivator-1β (Pgc-1β), a known model of ventricular arrhythmia. Pro-arrhythmic and cellular action potential (AP) characteristics were compared in intact Langendorff-perfused hearts from young (12-16 week) and aged (>52 week), WT and Pgc-1β-/- mice. Simultaneous electrocardiographic and intracellular microelectrode recordings were made through successive trains of 100 regular stimuli at progressively incremented heart rates. Aged Pgc-1β-/- hearts displayed an increased incidence of arrhythmia compared to other groups. Young and aged Pgc-1β-/- hearts showed higher incidences of alternans in both AP activation (maximum AP upshoot velocity (dV/dt)max and latency), recovery (action potential duration (APD90) and resting membrane potential (RMP)) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (dV/dt)max and increased AP latency values in the Pgc-1β-/- hearts. APs observed prior to termination of the protocol showed lower (dV/dt)max and longer AP latencies, but indistinguishable APD90 and RMPs in arrhythmic compared to non-arrhythmic hearts. APD restitution analysis showed that Pgc-1β-/- and WT hearts showed similar limiting gradients. However, Pgc-1β-/- hearts had shortened plateau AP wavelengths, particularly in aged Pgc-1β-/- hearts. Pgc-1β-/- hearts therefore show pro-arrhythmic instabilities attributable to altered AP conduction and activation rather than recovery characteristics.We acknowledge the financial support from the Medical Research Council (MR/M001288/1); the Wellcome Trust (105727/Z/14/Z); the British Heart Foundation (PG/14/79/31102 and PG/15/12/31280), Sudden arrhythmic death syndrome (SADS) UK; The McVeigh Benefaction and by the Fundamental Research Grant Scheme (FRGS/2/2014/SKK01/PERDANA/02/1), Ministry of Education, Malaysia

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Heart failure (HF) is associated with elevated sympathetic tone and mechanical load. Both systems activate signaling transduction pathways that increase cardiac output, but eventually become part of the disease process itself leading to further worsening of cardiac function. These alterations can adversely contribute to electrical instability, at least in part due to the modulation of Ca2+ handling at the level of the single cardiac myocyte. The major aim of this review is to provide a definitive overview of the links and cross talk between β-adrenergic stimulation, mechanical load, and arrhythmogenesis in the setting of HF. We will initially review the role of Ca2+ in the induction of both early and delayed afterdepolarizations, the role that β-adrenergic stimulation plays in the initiation of these and how the propensity for these may be altered in HF. We will then go onto reviewing the current data with regards to the link between mechanical load and afterdepolarizations, the associated mechano-sensitivity of the ryanodine receptor and other stretch activated channels that may be associated with HF-associated arrhythmias. Furthermore, we will discuss how alterations in local Ca2+ microdomains during the remodeling process associated the HF may contribute to the increased disposition for β-adrenergic or stretch induced arrhythmogenic triggers. Finally, the potential mechanisms linking β-adrenergic stimulation and mechanical stretch will be clarified, with the aim of finding common modalities of arrhythmogenesis that could be targeted by novel therapeutic agents in the setting of HF