Altomare C, Bartolucci C, Sala L, Bernardi J, Mostacciuolo G, Rocchetti M, Severi S, Zaza A. IKr impact on repolarization and its variability assessed by dynamic-clamp. Circulation: Arrhythmia and Electrophysiology. 2015 Jun 23:CIRCEP-114.

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.

In single guinea-pig myocytes, endogenous IKr was replaced by modelled IKr (mIKr) by Dynamic-Clamp (DC) at a cycle length of 1 s. mIKr 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) IKr blockade increased SD1 more than expected by its dependency on APD; 2) mIKr completely reversed APD and SD1 changes caused by IKr 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 mIKr, they significantly increased SD1; 5) changes in maximal conductance resulted in a pattern similar to that of activation shifts.

The largest effect on repolarization and its stability are expected from changes in IKr inactivation. APD is less sensitive to changes in other IKr gating parameters, which are better revealed by SD1 changes. SD1 may be more sensitive than APD in detecting IKr-dependent repolarization abnormalities.