Chronically altered ventricular activation causes pro-arrhythmic cardiac electrical remodelling in the chronic AV block dog model.

Aims: Altered ventricular activation (AVA) causes intraventricular mechanical dyssynchrony (MD) and impedes contraction, promoting pro-arrhythmic electrical remodelling in the chronic atrioventricular block (CAVB) dog. We aimed to study arrhythmogenic and electromechanical outcomes of different degrees of AVA.

Methods And Results: Following atrioventricular block, AVA was established through idioventricular rhythm (IVR; n = 29), right ventricular apex (RVA; n = 12) pacing or biventricular pacing [cardiac resynchronization therapy (CRT); n = 10].

Effects of K201 on repolarization and arrhythmogenesis in anesthetized chronic atrioventricular block dogs susceptible to dofetilide-induced torsade de pointes.

The novel antiarrhythmic drug K201 (4-[3-{1-(4-benzyl)piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine monohydrochloride) is currently in development for treatment of atrial fibrillation. K201 not only controls intracellular calcium release by the ryanodine receptors, but also possesses a ventricular action that might predispose to torsade de pointes arrhythmias. The anti- and proarrhythmic effects of K201 were investigated in the anesthetized canine chronic atrioventricular block model.

Late na(+) current inhibition by ranolazine reduces torsades de pointes in the chronic atrioventricular block dog model.

Objectives: This study investigated whether ranolazine reduces dofetilide-induced torsades de pointes (TdP) in a model of long QT syndrome with down-regulated K(+) currents due to hypertrophic remodeling in the dog with chronic atrioventricular block (cAVB).

Background: Ranolazine inhibits the late Na(+) current (I(NaL)) and is effective against arrhythmias in long QT3 syndromes despite its blocking properties of the rapid component of delayed rectifying potassium current.

Methods: Ranolazine was administered to cAVB dogs before or after TdP induction with dofetilide and electrophysiological parameters were determined including beat-to-beat variability of repolarization (BVR).

The canine model with chronic, complete atrio-ventricular block.

Proarrhythmic susceptibility to drug-induced Torsades de Pointes is restricted to individuals with a predisposed phenotype characterized by a reduced repolarization reserve. Additional factors are often involved in a further impairment of repolarization, possibly culminating with dangerous ventricular polymorphic tachyarrhythmias. Drugs that block repolarizing currents represent such an additional hit.

Cellular basis for triggered ventricular arrhythmias that occur in the setting of compensated hypertrophy and heart failure: considerations for diagnosis and treatment.

Malignant ventricular tachyarrhythmias are common among patients with hypertrophy and heart failure, and these arrhythmias can initiate by triggered activity. Abnormal repolarization and disturbed calcium handling due to remodeling processes are common features of the hypertrophied and failing heart that conspire to facilitate triggering events. These changes have a different cellular origin in compensated hypertrophy as compared with failure, which underscores the complexity of mechanisms that predispose the remodeled heart to arrhythmias.

High-septal pacing reduces ventricular electrical remodeling and proarrhythmia in chronic atrioventricular block dogs.

Objectives: This study was designed to analyze the relevance of ventricular activation patterns for ventricular electrical remodeling after atrioventricular (AV) block in dogs.

Background: Bradycardia is thought to be the main contributor to ventricular electrical remodeling after complete AV block. However, an altered ventricular activation pattern or AV dyssynchrony may also contribute.

Beat-to-beat variability of repolarization: a new parameter to determine arrhythmic risk of an individual or identify proarrhythmic drugs.

Hypertrophy and heart failure are associated with an enhanced propensity for cardiac arrhythmias and a high mortality rate. Altered repolarization might play a role in the occurrence of these ventricular arrhythmias. Beat-to-beat variability of repolarization duration (BVR) has been proposed as a parameter for detection of an unstable, and less controlled repolarization process that precedes the actual tachyarrhythmia.

Proarrhythmic electrical remodelling is associated with increased beat-to-beat variability of repolarisation.

Objective: Acquired long-QT syndrome in combination with increased beat-to-beat variability of repolarisation duration (BVR) is associated with lethal torsades de pointes arrhythmias (TdP) in dogs with remodelled heart after atrioventricular block (AVB). We evaluated the relative contributions of bradycardia and ventricular remodelling to proarrhythmic BVR with and without pharmacological I(Kr) block in order to identify the individual at risk.

Methods: Three groups of dogs were used: sinus rhythm dogs (n = 12), dogs with acute AVB (n = 8), and dogs with >3 weeks chronic AVB (n = 27).

Atrial-specific drug AVE0118 is free of torsades de pointes in anesthetized dogs with chronic complete atrioventricular block.

Background: The novel compound AVE0118 has been shown to prevent and terminate persistent atrial fibrillation. AVE0118 blocks I(Kur), I(KAch), and I(to), leading to prolongation of atrial repolarization with no change in ventricular repolarization. This finding suggests that AVE0118 may be devoid of proarrhythmic side effects.