The role of the autonomic system in rate-dependent repolarization changes

Cardiac autonomic effects include modulation of sinus pacemaker rate and of ion fluxes in the working myocardium (atria and ventricles). On the other hand, many of the ionic currents determining action potential duration (APD), including those subject to direct autonomic modulation, are also intrinsically rate dependent. Therefore, autonomic modulation of repolarization can be unambiguously defined only if its rate dependency is considered. A systematic analysis of autonomic modulation of APD rate dependency requires controlling heart rate over a broad range of values while exposing the working myocardium to neural stimulation (or receptor agonists). This is difficult to achieve in humans; therefore, studies in animal species with human-like repolarization (guinea pig, rabbit, cat, dog, pig) would be pivotal for this purpose. Unfortunately, the literature available claims that even the sign of autonomic modulation of repolarization (i.e., APD shortening vs. prolongation) is inconsistent among these species, thus questioning the possibility of generalizing results. Differences are often explained by species specificity of IKs, an important repolarizing current under autonomic modulation. Herein we critically review such literature and come to the tentative conclusion that autonomic modulation of repolarization might depend on action potential contour, rather than reflecting species specificity of individual current components. Moreover, we propose that under physiological conditions, autonomic modulation may serve to stabilize repolarization at its rate-determined course, rather than independently acting to change it.