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

Abstract

Background-Acquired QT prolongation enhances the susceptibility to torsades de pointes (TdP). Clinical and experimental studies indicate ventricular action potential prolongation, increased regional dispersion of repolarization, and early afterdepolarizations as underlying factors. We examined whether K ϩ -current alterations contribute to these proarrhythmic responses in an animal model of TdP: the dog with chronic complete atrioventricular block (AVB) and biventricular hypertrophy. Methods and Results-The whole-cell K ϩ currents I TO1 , I K1 , I Kr , and I Ks were recorded in left (LV) and right (RV) ventricular midmyocardial cells from dogs with 9Ϯ1 weeks of AVB and controls with sinus rhythm. I TO1 density and kinetics and I K1 outward current were not different between chronic AVB and control cells. I Kr had a similar voltage dependence of activation and time course of deactivation in chronic AVB and control. I Kr density was similar in LV myocytes but smaller in RV myocytes (Ϫ45%) of chronic AVB versus control. For I Ks , voltage-dependence of activation and time course of deactivation were similar in chronic AVB and control. However, I Ks densities of LV (Ϫ50%) and RV (Ϫ55%) cells were significantly lower in chronic AVB than control. Conclusions-Significant downregulation of delayed rectifier K ϩ current occurs in both ventricles of the dog with chronic AVB. Acquired TdP in this animal model with biventricular hypertrophy is thus related to intrinsic repolarization defects. (Circulation. 1999;100:2455-2461.)

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

“…This I Ks reduction was considered the cause of APD prolongation in the LV. 5 In the present study, we found a 52% to 120% prolongation of the QT interval and a 20% to 60% increase in APD in the LV myocytes from the rabbit model. The 50% decrease of I Kr in addition to the 55% decrease of I Ks observed in our study may explain the more pronounced prolongation of the AP compared with that in the dog model.…”

“…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.…”

“…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.…”

“…[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. 8 In this study, we have produced a chronic AVB model in the rabbit for the first time.…”

Torsades de pointes during complete atrioventricular block: Genetic factors and electrocardiogram correlates

“…Mechanistically, it has been reported that during bradyarrhythmias, downregulation of the repolarizing currents -rapid and slow delayed rectifier K + currents (I Kr and I Ks , respectively) -results in QT interval prolongation and TdP (15)(16)(17)(18). These findings were based on canine and rabbit models of chronic complete AV block that showed reduction in I Kr and I Ks , and altered L-type Ca 2+ current, with other currents (inward Na + current, transient outward K + current and inward rectifier K + current) remaining normal (15,16,18).…”