Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity.

Background: Ischemic heart disease is associated with dual risk for atrial and ventricular arrhythmias.

Objective: We examined whether selectively targeting late sodium channel current (INa) with GS-458967 (hereafter GS967) can reduce cardiac electrical instability and compared its effects to a clinically relevant dose of flecainide.

Methods: Electrode catheters were positioned on the left atrial appendage and left ventricle of anesthetized pigs to monitor repolarization alternans and electrocardiographic heterogeneity before and during left circumflex coronary artery stenosis (75% flow reduction) before and after GS967 (0.

Inhibition of I(f) in the atrioventricular node as a mechanism for dronedarone's reduction in ventricular rate during atrial fibrillation.

Background: In clinical trials, dronedarone lowers ventricular rate during atrial fibrillation (AF). This agent was recently demonstrated to inhibit If in the sinoatrial node.

Objective: The purpose of this study was to examine whether dronedarone inhibits If at the atrioventricular (AV) node to reduce ventricular rate during AF by slowing conduction at the AV node.

Dronedarone's inhibition of If current is the primary mechanism responsible for its bradycardic effect.

Introduction: The mechanism(s) whereby dronedarone reduces sinus rate are not well understood, although L-type calcium channel antagonism, beta-adrenergic blockade, and inhibition of If are plausible.

Methods And Results: In anesthetized pigs, we compared the effects of dronedarone to the prototypical If inhibitor, ivabradine, and the L-type calcium channel antagonist diltiazem on heart rate, mean arterial blood pressure (MAP), and contractility. Dronedarone's effects on the phenylephrine-induced rise in MAP and on the chronotropic response to isoproterenol were also investigated.