IKr Impact on Repolarization and Its Variability Assessed by Dynamic Clamp

Background - Repolarization and its stability are exquisitely sensitive to IKr features. Information on the relative importance of specific IKr abnormalities is missing and would assist in the evaluation of arrhythmogenic risk. Methods and Results - In single Guinea-pig myocytes, endogenous IKr was replaced by modeled IKr (mIKr) by dynamic clamp (DC) at a cycle length of 1 s. mI Kr parameters were systematically modified, and the resulting changes in action potential duration (APD) and its short term variability (SD1) were measured. We observed that (1) I Kr blockade increased SD1 more than expected by its dependency on APD; (2) mI Kr completely reversed APD and SD1 changes caused by I Kr blockade; (3) repolarization was most sensitive to inactivation shifts, which affected APD and SD1 concordantly; (4) activation shifts of the same magnitude had marginal impact on APD, but only when reducing mI Kr, they significantly increased SD1; (5) changes in maximal conductance resulted in a pattern similar to that of activation shifts. Conclusions - The largest effect on repolarization and its stability are expected from changes in I Kr inactivation. APD is less sensitive to changes in other I Kr gating parameters, which are better revealed by SD1 changes. SD1 may be more sensitive than APD in detecting I Kr -dependent repolarization abnormalities.