Overcoming Reverse Rate Dependence in Ventricular Cell Models

Abstract

Reverse rate dependence (RRD) is a problematic property of antiarrhythmic drugs that prolong the action potential duration (APD). The prolongation caused by RRD agents will increase at slow rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmogenesis at slow. The opposite property, forward rate dependence (FRD), would theoretically overcome these parallel problems, yet FRD antiarrhythmics remain elusive. Moreover, there is evidence that RRD is an intrinsic property of perturbations to the action potential (AP). We have addressed the possibility of FRD by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we were able to simultaneously predict the rate-dependent effects on the APD of changes in any of an average of 40 parameters per model. The analysis produced several important results. First, while models often display RRD, a variety of ion current perturbations do in fact produce FRD. Second, additional simulations of FRD perturbations provide mechanistic insight into how FRD behavior can be produced. For instance, increasing L-type calcium conductance (GCaL) is FRD when accompanied by concomitant, indirect, rate-dependent changes in slow delayed rectifier current (IKs). Third, comparisons of results between models revealed that changes in IKs are almost always RRD whereas changes in GCaL or the Na-K pump can potentially be FRD. Fourth, the general capacity for FRD correlates strongly with the degree of rate-dependent change in AP shape. Models that display minimal changes in AP shape with rate have little capacity for FRD whereas models with large shape changes have considerable FRD potential. Overall, this study provides new insight into the determinants of APD rate dependence and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs.