Ian N. Sabir

Ventricular arrhythmogenesis: Insights from murine models

Ventricular arrhythmias are the key underlying cause of sudden cardiac death, a common cause of mortality and a significant public health burden. Insights into the electrophysiological basis of such phenomena have been obtained using a wide range of recording techniques and a diversity of experimental models. As in other fields of biology, the murine system presents both a wealth of opportunities and important challenges when employed to model the human case. This article begins by reviewing the extent to which the murine heart is representative of that of the human. It then presents a novel physiological classification of mechanisms of arrhythmogenesis, critically assessing the extent to which the study of murine hearts has offered worthwhile insights.

Dispersions of repolarization and ventricular arrhythmogenesis : Lessons from animal models

Sudden cardiac death resulting from ventricular arrhythmogenesis is a leading cause of mortality in the developed world, accounting for up to 400,000 deaths per year in the US alone. Within the past forty years we have taken considerable leaps forward in our understanding of the causes and mechanisms underlying cardiac arrhythmias, particularly in the setting of inherited and acquired dysfunctions in ionic currents which constitute human long QT syndrome (LQTS). Impaired repolarization seen in LQTS commonly gives rise to an altered dispersion of repolarization, which is considered to provide the functional substrate necessary for the perpetuation of lethal arrhythmias. This review examines the bases for arrhythmias arising from repolarization heterogeneities and explores the applicability of the genetically amenable mouse for the study of arrhythmias arising from such mechanisms.

Mouse models of human arrhythmia syndromes

Sudden cardiac death stemming from ventricular arrhythmogenesis is one of the major causes of mortality in the developed world. Congenital and acquired forms of long QT syndrome (LQTS) are in turn associated with life threatening arrhythmias. Over the past decade our understanding of arrhythmogenic mechanisms in the setting of these diseases has increased greatly due to the creation of a number of animal models. Of these, the genetically amenable mouse has proved to be a particularly powerful tool. This review summarizes the congenital and acquired LQTS and describes the various mouse models that have been created to further probe arrhythmogenic mechanisms.

Oral anticoagulants for Asian patients with atrial fibrillation

Anticoagulation is the most-important intervention to prevent stroke in patients with atrial fibrillation (AF). Despite a lower point prevalence of AF in Asian communities and Asian countries than in other populations, individuals of Asian ethnicity are at a disproportionately high risk of stroke and have greater consequent mortality. Warfarin and other vitamin K antagonists are conventionally used for anticoagulation, and demonstrably reduce the risk of stroke and all-cause mortality in patients with AF. The use of warfarin in Asian countries is suboptimal, primarily owing to the universal challenge of achieving controlled anticoagulation with an unpredictable drug as well as concerns about the particularly high-risk of haemorrhage in Asian patients. Instead, antiplatelet therapy has been favoured in Asian communities, this strategy is neither safe nor effective for stroke prevention in these individuals. The non-vitamin K antagonist, oral anticoagulant drugs offer a solution to this challenge. The direct thrombin inhibitor dabigatran, and the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, have demonstrated noninferiority to warfarin in the prevention of stroke and systemic embolism in international, randomized, controlled trials. Importantly, some of these drugs are also associated with a significantly lower incidence of major haemorrhage, and all result in lower rates of intracranial haemorrhage and haemorrhagic stroke than warfarin. In this article, we review the use of the non-vitamin K antagonist anticoagulants in the management of AF in Asian populations.

Action potential wavelength restitution predicts alternans and arrhythmia in murine Scn5a+/− hearts

•  Mice which are haploinsufficient in the Scn5a+/− gene have reduced cardiac sodium channel (Nav1.5) density and are used to model the Brugada syndrome. •  Conduction velocity restitution showed lower initial values and earlier points of failure during incremental pacing in the murine Scn5a+/− right ventricle (RV) epicardium particularly when treated with flecainide. •  The broadness of the conduction velocity restitution function was a poor indicator of arrhythmia or alternans. Conduction velocity alternans occurred abruptly and was more marked in the flecainide‐treated Scn5a+/− RV epicardium. •  Introduction of wavelength restitution yielded functions that converged to a common instability condition in contrast to action potential duration (APD) or conduction velocity restitution. •  This occurred at significantly lower heart rates in Scn5a+/− RV epicardium following flecainide or quinidine challenge, corresponding to a smaller total wavelength (basic cycle distance) resulting from a reduction in conduction velocity. •  Wavelength restitution was superior at predicting alternans than either APD or conduction velocity restitution.

Alternans in Genetically Modified Langendorff-Perfused Murine Hearts Modeling Catecholaminergic Polymorphic Ventricular Tachycardia

The relationship between alternans and arrhythmogenicity was studied in genetically modified murine hearts modeling catecholaminergic polymorphic ventricular tachycardia (CPVT) during Langendorff perfusion, before and after treatment with catecholamines and a β-adrenergic antagonist. Heterozygous (RyR2p/s) and homozygous (RyR2s/s) RyR2-P2328S hearts, and wild-type (WT) controls, were studied before and after treatment with epinephrine (100 nM and 1 μM) and propranolol (100 nM). Monophasic action potential recordings demonstrated significantly greater incidences of arrhythmia in RyR2p/s and RyR2s/s hearts as compared to WTs. Arrhythmogenicity in RyR2s/s hearts was associated with alternans, particularly at short baseline cycle lengths. Both phenomena were significantly accentuated by treatment with epinephrine and significantly diminished by treatment with propranolol, in full agreement with clinical expectations. These changes took place, however, despite an absence of changes in mean action potential durations, ventricular effective refractory periods or restitution curve characteristics. Furthermore pooled data from all hearts in which arrhythmia occurred demonstrated significantly greater alternans magnitudes, but similar restitution curve slopes, to hearts that did not demonstrate arrhythmia. These findings thus further validate the RyR2-P2328S murine heart as a model for human CPVT, confirming an alternans phenotype in common with murine genetic models of the Brugada syndrome and the congenital long-QT syndrome type 3. In contrast to these latter similarities, however, this report demonstrates the dissociation of alternans from changes in the properties of restitution curves for the first time in a murine model of a human arrhythmic syndrome.

Transient alterations in transmural repolarization gradients and arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts

Clinical hypokalaemia is associated with acquired electrocardiographic QT prolongation and arrhythmic activity initiated by premature ventricular depolarizations and suppressed by lidocaine (lignocaine). Nevertheless, regular (S1) pacing at a 125 ms interstimulus interval resulted in stable waveforms and rhythm studied using epicardial and endocardial monophasic action potential (MAP) electrodes in Langendorff‐perfused murine hearts whether under normokalaemic (5.2 mm K+) or hypokalaemic (3.0 mm K+) conditions, in both the presence and absence of lidocaine (10 μm). Furthermore, the transmural gradient in repolarization time, known to be altered in the congenital long‐QT syndromes, and reflected in the difference between endocardial and epicardial MAP duration at 90% repolarization (ΔAPD90), did not differ significantly (P > 0.05) between normokalaemic (5.5 ± 4.5 ms, n= 8, five hearts), hypokalaemic (n= 8, five hearts), or lidocaine‐treated normokalaemic (n= 8, five hearts) or hypokalaemic (n= 8, five hearts) hearts. However, premature ventricular depolarizations occurring in response to extrasystolic (S2) stimulation delivered at S1S2 intervals between 0 and 22 ± 6 ms following recovery from refractoriness initiated arrhythmic activity specifically in hypokalaemic (n= 8, five hearts) as opposed to normokalaemic (n= 25, 14 hearts), or lidocaine‐treated hypokalaemic (n= 8, five hearts) or normokalaemic hearts (n= 8, five hearts). This was associated with sharp but transient reversals in ΔAPD90 in MAPs initiated within the 250 ms interval directly succeeding premature ventricular depolarizations, from 3.3 ± 5.6 ms to −31.8 ± 11.8 ms (P < 0.05) when they were initiated immediately after recovery from refractoriness. In contrast the corresponding latency differences consistently remained close to the normokalaemic value (−1.6 ± 1.4 ms, P > 0.05). These findings empirically associate arrhythmogenesis in hypokalaemic hearts with transient alterations in transmural repolarization gradients resulting from premature ventricular depolarizations. This is in contrast to sustained alterations in transmural repolarization gradients present on regular stimulation in long‐QT syndrome models.

Cardiac Arrhythmia: A Simple Conceptual Framework

This review presents a simple trigger-substrate model of arrhythmogenesis and its application to the generation of reentrant ventricular arrhythmias. We demonstrate its broad applicability to the understanding of arrhythmic phenomena in a wide range of both hereditary and acquired arrhythmic disorders.

Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome.

The gain-of-function Scn5a+/DeltaKPQ mutation in the cardiac Na(+) channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The K(ATP) channel-opener nicorandil (20muM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Delta hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD(90)) that (2) restored transmural repolarization gradients, DeltaAPD(90). Scn5a+/Delta hearts showed longer epicardial but not endocardial APD(90)s, giving shorter DeltaAPD(90)s than WT hearts. Nicorandil reduced epicardial APD(90) in both Scn5a+/Delta and WT hearts thereby increasing DeltaAPD(90). (3) Reduced epicardial critical intervals for re-excitation; Scn5a+/Delta hearts showed greater differences between APD(90) and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD(90) alternans. Scn5a+/Delta hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Delta hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Delta hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Delta and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Delta and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil.

DPP-IV inhibitors: Beyond glycaemic control?

Dipeptidyl-peptidase-IV (DPP-IV) inhibitors are a new class of oral hypoglycaemic agents recently approved for the management of type 2 diabetes mellitus. Early data suggested that they had a positive impact on the cardiovascular system: treatment appeared to result in improvements in cardiac performance, blood pressure and lipid levels. However, recent clinical findings bring this into question. Our understanding of the physiological actions of these agents is complicated by the fact that DPP-IV has a wide range of substrates in addition to glucagon-like peptide 1. Indeed, DPP-IV inhibition alters concentrations of a wide variety of cytokines and neuropeptides. A deeper understanding of the physiological effects of these drugs as well as their true impact on cardiovascular risk is needed before consideration can be given to extending their use beyond the treatment of diabetes.