Cellular Basis of Biventricular Hypertrophy and Arrhythmogenesis in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsade de Pointes

Abstract

Background-In the dog with chronic complete atrioventricular block (AVB), torsade de pointes arrhythmias (TdP) can be induced reproducibly by class III antiarrhythmic agents. In vivo studies reveal important electrophysiological alterations of the heart at 5 weeks of AVB, resulting in increased proarrhythmia. Autopsy studies indicate the presence of biventricular hypertrophy. In this study, the cellular basis of proarrhythmia and hypertrophy in chronic AVB was investigated. Methods and Results-From chronic-AVB dogs with increased heart weights and TdP, left midmyocardial and right ventricular myocytes were isolated by enzymatic dispersion. These myocytes were significantly larger than sinus rhythm (SR) controls. In chronic AVB, the action potential spike-and-dome configuration was preserved. However, the action potential duration (APD) at 95% and 50% of repolarization of the left midmyocardium was significantly larger in chronic AVB than in SR, with little change in the right ventricle, causing enhanced interventricular dispersion of repolarization at slow pacing rates. Treatment with the class III agent almokalant increased the APD to a much larger extent in chronic-AVB than in SR myocytes and resulted in a higher incidence of early afterdepolarizations (EADs). EADs had their takeoff potential between Ϫ35 and 0 mV. There was no evidence that spontaneous sarcoplasmic reticulum Ca 2ϩ release underlies these EADs. Conclusions-In

Downregulation of Delayed Rectifier K + Currents in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsades de Pointes

“…Transmembrane action potential recordings in isolated myocytes indicate that the prolonged ventricular repolarization of chronic AVB is an intrinsic abnormality, which is amplified by class III antiarrhythmic drugs. 7 In addition, action potential prolongation is more pronounced in left (LV) than right (RV) ventricular myocytes, supporting the in vivo finding of increased regional dispersion of repolarization.…”

“…5 Electrical remodeling is accompanied by the development of biventricular hypertrophy. 5,7 Approximately 15% of the chronic-AVB dog population dies suddenly, often during circumstances of excitement (eg, during feeding or ambulation). Transmembrane action potential recordings in isolated myocytes indicate that the prolonged ventricular repolarization of chronic AVB is an intrinsic abnormality, which is amplified by class III antiarrhythmic drugs.…”

Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block

“…5 The increase of APD in AVB myocytes was 10% to 30% in the LV (depending on the cycle length) under baseline conditions. 4 There was a 50% reduction of I Ks and no change of I Kr in the LV. This I Ks reduction was considered the cause of APD prolongation in the LV.…”

“…1 In the dog model with AVB, it has been demonstrated that APD differences between left midmyocardial and right ventricular myocytes cause an enhanced spatial inhomogeneity of repolarization. 4 Additional and more extensive experimental studies will be required to clarify interventricular and transmural changes of ionic currents as well as APD in AVB rabbits.…”

“…2 In the model, the bradycardia-induced volume overload causes biventricular hypertrophy and heterogeneous prolongation of the ventricular action potential. [3][4][5][6] Significant reduction of the slow component of the delayed rectifier K ϩ current (I Ks ) in both ventricles and that of the rapid component (I Kr ) in the RV were demonstrated. 5 TdP was easily induced in the canine model by class III antiarrhythmic drugs (eg, d-sotalol and almokalant) and programmed stimulation, 2,7 but documented spontaneous TdP episodes and the incidence of sudden cardiac death were relatively rare.…”