Cardiac repolarization: insights from mathematical modeling and electrocardiographic imaging (ECGI)

Cardiac repolarization is a complex rate dependent process. At the cellular level, it depends on a delicate dynamic balance of ion channel currents. At the heart level, it is spatially heterogeneous, leading to spatial gradients of potential and excitability. This article provides insights into the molecular mechanisms of the delayed rectifiers I(Kr) (rapid) and I(Ks) (slow) that underlie effective function of these channels as repolarizing currents during the cardiac action potential (AP). We also provide noninvasive images of cardiac repolarization in humans. Methodologically, computational biology is used to simulate ion channel function and to incorporate it into a model of the cardiac cell. ECG imaging (ECGI) is applied to normal subjects and Wolff-Parkinson-White (WPW) patients to obtain epicardial maps of repolarization. The simulations demonstrate that I(Kr) and I(Ks) generate their peak current late during the AP, where they effectively participate in repolarization. I(Kr) maximizes the current by fast inactivation and gradual recovery during the AP. I(Ks) does so by generating an available reserve of channels in closed states from which the channels can open rapidly. ECGI shows that in the human heart, normal repolarization epicardial potential maps are static with 40 ms dispersion between RV and LV. In WPW, ECGI located the accessory pathway(s) and showed a large base-to-apex repolarization gradient that resolved to normal one month post-ablation, demonstrating presence of "cardiac memory". We conclude that computational biology can provide a mechanistic link across scales, from the molecular functioning of ion channels to the cellular AP. ECGI can noninvasively image human cardiac repolarization and its alteration by disease and interventions. This property makes it a potential tool for noninvasive risk stratification and evaluation of treatment by drugs and devices.