Action potential wavelength restitution predicts alternans and arrhythmia in murine Scn5a(+/-) hearts.

Reductions in cardiac action potential wavelength, and the consequent wavebreak, have been implicated in arrhythmogenesis. Tachyarrhythmias are more common in the Brugada syndrome, particularly following pharmacological challenge, previously modelled using Scn5a(+/-) murine hearts. Propagation latencies and action potential durations (APDs) from monophasic action potential recordings were used to assess wavelength changes with heart rate in Langendorff-perfused wild-type (WT) and Scn5a(+/-) hearts.

Antithrombotic therapy in atrial fibrillation: aspirin is rarely the right choice.

Atrial fibrillation, the commonest cardiac arrhythmia, predisposes to thrombus formation and consequently increases risk of ischaemic stroke. Recent years have seen approval of a number of novel oral anticoagulants. Nevertheless, warfarin and aspirin remain the mainstays of therapy.

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.

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 (RyR2(p/s)) and homozygous (RyR2(s/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 RyR2(p/s) and RyR2(s/s) hearts as compared to WTs.

Risk stratification for sudden cardiac death.

Recent advances in pharmacological and device-based therapies have provided a range of management options for patients at risk of sudden cardiac death (SCD). Since all such interventions come with their attendant risks, however, stratification procedures aimed at identifying those who stand to benefit overall have gained a new degree of importance. This review assesses the value of risk stratification measures currently available in clinical practice, as well as of others that may soon enter the market.

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).

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.

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.

Criteria for arrhythmogenicity in genetically-modified Langendorff-perfused murine hearts modelling the congenital long QT syndrome type 3 and the Brugada syndrome.

The experiments investigated the applicability of two established criteria for arrhythmogenicity in Scn5a+/Delta and Scn5a+/- murine hearts modelling the congenital long QT syndrome type 3 (LQT3) and the Brugada syndrome (BrS). Monophasic action potentials (APs) recorded during extrasystolic stimulation procedures from Langendorff-perfused control hearts and hearts treated with flecainide (1 microM) or quinidine (1 or 10 microM) demonstrated that both agents were pro-arrhythmic in wild-type (WT) hearts, quinidine was pro-arrhythmic in Scn5a+/Delta hearts, and that flecainide was pro-arrhythmic whereas quinidine was anti-arrhythmic in Scn5a+/- hearts, confirming clinical findings. Statistical analysis confirmed a quadratic relationship between epicardial and endocardial AP durations (APDs) in WT control hearts.

Restitution analysis of alternans and its relationship to arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts.

Alternans and arrhythmogenicity were studied in hypokalaemic (3.0 mM K(+)) Langendorff-perfused murine hearts paced at high rates. Epicardial and endocardial monophasic action potentials were recorded and durations quantified at 90% repolarization.

A quantitative analysis of the effect of cycle length on arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts.

The clinically established proarrhythmic effect of bradycardia and antiarrhythmic effect of lidocaine (10 microM) were reproduced in hypokalaemic (3.0 mM K(+)) Langendorff-perfused murine hearts paced over a range (80-180 ms) of baseline cycle lengths (BCLs). Action potential durations (at 90% repolarization, APD(90)s), transmural conduction times and ventricular effective refractory periods (VERPs) were then determined from monophasic action potential records obtained during a programmed electrical stimulation procedure in which extrasystolic stimuli were interposed following regular stimuli at successively decreasing coupling intervals.

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.

The contribution of refractoriness to arrhythmic substrate in hypokalemic Langendorff-perfused murine hearts.

The clinical effects of hypokalemia including action potential prolongation and arrhythmogenicity suppressible by lidocaine were reproduced in hypokalemic (3.0 mM K(+)) Langendorff-perfused murine hearts before and after exposure to lidocaine (10 muM). Novel limiting criteria for local and transmural, epicardial, and endocardial re-excitation involving action potential duration (at 90% repolarization, APD(90)), ventricular effective refractory period (VERP), and transmural conduction time (Deltalatency), where appropriate, were applied to normokalemic (5.