A new approach to measure the contribution of restitution to repolarization alternans

Several studies suggest link between repolarization alternans and arrhythmia. A potential target for minimization of alternans amplitude is pharmacological flattening of restitution function, which links a diastolic interval (DI) and subsequent action potential duration (APD). While our recent studies have shown that DI dependent restitution is not a necessary mechanism for alternans, in circumstances of nearly invariant activation intervals, restitution contributes to alternans. Determination of the degree to which restitution contributes to alternans during stable alternans, which requires determination of the gain between DI and APD, is not possible because it always is unity. We propose that the rate of change of alternans along the length of the tissue may provide an estimate of the degree to which restitution contributes to alternans amplitude. We conducted experiments with swine to demonstrate the above approach. In a linear strand of tissue, we paced such that DIs for successive activations were invariant at one end, which eliminates the restitution dependent mechanism of alternans at this end. Due to conduction delays, at the distal end, both restitution dependent and independent mechanisms manifest. Action potentials recorded from right ventricular endocardial tissue from swine (n = 3D3) showed an average difference in amplitudes of alternans between the two ends to be 11.99, 25.49, and 39.37 msec. Rates of change of alternans amplitude as a function of distance, computed using linear interpolation, were 0.36, 1.69 and 0.97. We propose that this rate of change may provide an indirect measure of degree of contribution of restitution to alternans and thus may be useful in evaluating therapeutic approaches to minimize its amplitude.