Comprehensive Analyses of Ventricular Myocyte Models Identify Targets Exhibiting Favorable Rate Dependence

Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP). The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD) antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz) and fast (2 Hz) rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, rate-dependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal rate-dependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of AP duration rate dependence, and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs.Author Summary: Several drugs intended to treat cardiac arrhythmias have failed because of unfavorable rate-dependent properties. That is, the drugs fail to alter electrical activity at fast heart rates, where this would be beneficial, but they do affect electrical activity at slow rates, where this is unwanted. In targeted studies, several agents have been shown to exhibit these unfavorable properties, suggesting that these rate-dependent responses may be intrinsic to ventricular muscle. To determine whether drugs with desirable rate-dependent properties could be rationally designed, we performed comprehensive and systematic analyses of several heart cell models. These analyses calculated the rate-dependent properties of changes in any model parameter, thereby generating simultaneously a large number of model predictions. The analyses showed that targets with favorable rate-dependent properties could indeed be identified, and further simulations uncovered the mechanisms underlying these behaviors. Moreover, a quantitative comparison of results obtained in different models provided new insight in why a given drug applied to different species, or to different tissue types, might produce different rate-dependent behaviors. Overall this study shows how a comprehensive and systematic approach to heart cell models can both identify novel targets and produce more general insight into rate-dependent alterations to cardiac electrical activity.