Conduction abnormalities and ventricular arrhythmogenesis: The roles of sodium channels and gap junctions.

This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.ijcha.2015.10.003Ventricular arrhythmias arise from disruptions in the normal orderly sequence of electrical activation and recovery of the heart. They can be categorized into disorders affecting predominantly cellular depolarization or repolarization, or those involving action potential (AP) conduction. This article briefly discusses the factors causing conduction abnormalities in the form of unidirectional conduction block and reduced conduction velocity (CV). It then examines the roles that sodium channels and gap junctions play in AP conduction. Finally, it synthesizes experimental results to illustrate molecular mechanisms of how abnormalities in these proteins contribute to such conduction abnormalities and hence ventricular arrhythmogenesis, in acquired pathologies such as acute ischaemia and heart failure, as well as inherited arrhythmic syndromes.GT received a BBSRC Doctoral CASE Studentship at the Department of Biochemistry, University of Cambridge, in conjunction with Xention Discovery, for his Ph.D. studies. This manuscript is based, in part, on the doctoral thesis of GT. GT thanks Dr. Antony Workman of University of Glasgow, and Prof. Sarah Lummis, of University of Cambridge, for their helpful comments on an earlier draft of his thesis. We also thank two anonymous expert reviewers who have provided insightful comments and helpful suggestions which we have used to improve our original manuscript

Ventricular anti-arrhythmic effects of heptanol in hypokalaemic, Langendorff-perfused mouse hearts.

This is the final version of the article. It first appeared from Spandidos Publications via http://dx.doi.org/10.3892/br.2016.577Ventricular arrhythmic and electrophysiological properties were examined during normokalaemia (5.2 mM [K+]), hypokalaemia (3 mM [K+]) or hypokalaemia in the presence of 0.1 or 2 mM heptanol in Langendorff-perfused mouse hearts. Left ventricular epicardial or endocardial monophasic action potential recordings were obtained during right ventricular pacing. Hypokalaemia induced ventricular premature beats (VPBs) in 5 of 7 and ventricular tachycardia (VT) in 6 of 7 hearts (P0.05), reducing excitation wavelengths (λ, CV × VERP) from 7.9±1.1 to 5.1±0.3 mm (P0.001). Heptanol (0.1 mM) prevented VT, restored effective refractory period (ERP) to 45.2±2.9 msec without altering CV or APD, returning λ to control values (P>0.05) and CI to 8.4±3.8 msec (P0.05), returning λ and CI to control values (P>0.05). Anti-arrhythmic effects of heptanol during hypokalaemia were explicable by ERP changes, scaling λ and CI.GT was supported by a Wellcome Trust Vacation Scholarship, Trinity Hall, Cambridge, a Biotechnology and Biological Sciences Research Council (BBSRC) CASE Studentship and Xention Discovery. The experiments were conducted in the laboratory of Dr. Andrew Grace and Prof. Christopher Huang at the University of Cambridge, whose funding was provided by the British Heart Foundation, the Medical Research Council, the Wellcome Trust and the BBSRC

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

Gap junction inhibition by heptanol increases ventricular arrhythmogenicity by reducing conduction velocity without affecting repolarization properties or myocardial refractoriness in Langendorff-perfused mouse hearts.

This is the final version of the article. It first appeared from Spandidos via https://doi.org/ 10.3892/mmr.2016.5738In the current study, arrhythmogenic effects of the gap junction inhibitor heptanol (0.05 mM) were examined in Langendorff-perfused mouse hearts. Monophasic action potential recordings were obtained from the left ventricular epicardium during right ventricular pacing. Regular activity was observed both prior and subsequent to application of heptanol in all of the 12 hearts studied during 8 Hz pacing. By contrast, induced ventricular tachycardia (VT) was observed after heptanol treatment in 6/12 hearts using a S1S2 protocol (Fisher's exact test; P0.05). Consequently, excitation wavelengths (λ; CV x ERP) were reduced from 9.1±0.6 to 6.5±0.6 mm (P0.05). Together, these observations demonstrate for the first time, to the best of our knowledge, that inhibition of gap junctions alone using a low heptanol concentration (0.05 mM) was able to reduce CV, which alone was sufficient to permit the induction of VT using premature stimulation by reducing λ, which therefore appears central in the determination of arrhythmic tendency.GT was awarded a BBSRC Doctoral Training Award at the University of Cambridge

Mechanisms of Electrical Activation and Conduction in the Gastrointestinal System: Lessons from Cardiac Electrophysiology.

This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fphys.2016.00182The gastrointestinal (GI) tract is an electrically excitable organ system containing multiple cell types, which coordinate electrical activity propagating through this tract. Disruption in its normal electrophysiology is observed in a number of GI motility disorders. However, this is not well characterized and the field of GI electrophysiology is much less developed compared to the cardiac field. The aim of this article is to use the established knowledge of cardiac electrophysiology to shed light on the mechanisms of electrical activation and propagation along the GI tract, and how abnormalities in these processes lead to motility disorders and suggest better treatment options based on this improved understanding. In the first part of the article, the ionic contributions to the generation of GI slow wave and the cardiac action potential (AP) are reviewed. Propagation of these electrical signals can be described by the core conductor theory in both systems. However, specifically for the GI tract, the following unique properties are observed: changes in slow wave frequency along its length, periods of quiescence, synchronization in short distances and desynchronization over long distances. These are best described by a coupled oscillator theory. Other differences include the diminished role of gap junctions in mediating this conduction in the GI tract compared to the heart. The electrophysiology of conditions such as gastroesophageal reflux disease and gastroparesis, and functional problems such as irritable bowel syndrome are discussed in detail, with reference to ion channel abnormalities and potential therapeutic targets. A deeper understanding of the molecular basis and physiological mechanisms underlying GI motility disorders will enable the development of better diagnostic and therapeutic tools and the advancement of this field.Croucher Foundatio

Restitution analysis of alternans using dynamic pacing and its comparison with S1S2 restitution in heptanol-treated, hypokalaemic Langendorff-perfused mouse hearts.

This is the final version of the article. It first appeared from Spandidos Publications via https://doi.org/10.3892/br.2016.659Action potential duration (APD) and conduction velocity restitution explain the dependence of these parameters on the previous diastolic interval (DI). It is considered to be an adaptive mechanism for preserving diastole at fast heart rates. Hypokalaemia is known to induce ventricular arrhythmias that could be prevented by heptanol, the gap junction uncoupler, mediated through increases in ventricular refractory period (VERP) without alterations in APDs. The present study investigated alternans and restitution properties during normokalaemia, hypokalaemia alone or hypokalaemia with heptanol (0.1 mM) in Langendorff-perfused mouse hearts using a dynamic pacing protocol. APD90 alternans were elicited in the epicardium and endocardium during normokalaemia. Hypokalaemia increased the amplitudes of epicardial APD90 alternans when basic cycle lengths (BCLs) were ≤65 msec, which was associated with increases in maximum APD90 restitution gradients, critical DIs and APD90 heterogeneity. Heptanol (0.1 mM) did not exacerbate or reduce the APD90 alternans or alter these restitution parameters further. By contrast, endocardial APD90 alternans did not show increases in amplitudes during hypokalaemia at short BCLs studied, and restitution parameters were also unchanged. This was true whether in the presence or absence of 0.1 mM heptanol. The study demonstrates that anti-arrhythmic effects of heptanol exerted during hypokalaemia occurred despite exacerbation of APD90 alternans. This would suggest that even in the presence of arrhythmogenic APD90 alternans, arrhythmias could still be prevented by influencing VERP alone. Restitution data obtained here by dynamic pacing were compared to previous data from S1S2 pacing.GT was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Grant at the University of Cambridge

Monophasic action potential recordings: which is the recording electrode?

This is the final version of the article. It first appeared from De Gruyter via https://doi.org/10.1515/jbcpp-2016-0007The aim of this article is to provide an overview of current debate on the monophasic action potential (MAP) recording technique, specifically whether the depolarizing or the reference electrode is responsible for recording the MAP waveform. A literature search was made using key words including monophasic action potential, MAP, electrophysiological basis, recording electrode, depolarizing electrode, contact electrode, indifferent electrode, and reference electrode. References from articles were screened for additional relevant papers. Articles published by the different experimental groups claim that depolarizing electrode, but not reference electrode, records MAPs from the myocardium. This can be more accurately described when considering biophysical theory, which states that MAP is a bipolar signal with contributions from not only the depolarizing electrode but also remote activation at the reference electrode. It is not meaningful to claim that one is the recording electrode because potential differences must be measured between two points in space. Nevertheless, the MAP technique is useful for assessing the local electrical activity of the myocardium in contact with the depolarizing electrode. It is important to have the recording electrode in close proximity with the reference electrode to minimize contamination from far-field signals.GT was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) CASE Doctoral Training Award at the University of Cambridge

Molecular and Electrophysiological Mechanisms Underlying Cardiac Arrhythmogenesis in Diabetes Mellitus

Diabetes 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

Electrophysiological Mechanisms of Bayés Syndrome: Insights from Clinical and Mouse Studies.

This is the final version of the article. It first appeared from Frontiers via https://doi.org/10.3389/fphys.2016.00188Bayés syndrome is an under-recognized clinical condition characterized by inter-atrial block (IAB). This is defined electrocardiographically as P-wave duration > 120 ms and can be categorized into first, second and third degree IAB. It can be caused by inflammatory conditions such as systemic sclerosis and rheumatoid arthritis, abnormal protein deposition in cardiac amyloidosis, or neoplastic processes invading the inter-atrial conduction system, such as primary cardiac lymphoma. It may arise transiently during volume overload, autonomic dysfunction or electrolyte disturbances from vomiting. In other patients without an obvious cause, the predisposing factors are diabetes mellitus, hypertensive heart disease, and hypercholesterolemia. IAB has a strong association with atrial arrhythmogenesis, left atrial enlargement (LAE), and electro-mechanical discordance, increasing the risk of cerebrovascular accidents as well as myocardial and mesenteric ischemia. The aim of this review article is to synthesize experimental evidence on the pathogenesis of IAB and its underlying molecular mechanisms. Current medical therapies include anti-fibrotic, anti-arrhythmic and anti-coagulation agents, whereas interventional options include atrial resynchronization therapy by single or multisite pacing. Future studies will be needed to elucidate the significance of the link between IAB and atrial tachyarrhythmias in patients with different underlying etiologies and optimize the management options in these populations.GT was awarded a BBSRC Doctoral Training Award at the University of Cambridge for his PhD

Cardiac dynamics: Alternans and arrhythmogenesis

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