Transmural heterogeneity of repolarization and Ca²⁺ handling in a model of mouse ventricular tissue

Mouse hearts have a diversity of action potentials (APs) generated by the cardiac myocytes from different regions. Recent evidence shows that cells from the epicardial and endocardial regions of the mouse ventricle have a diversity in Ca(2+) handling properties as well as K(+) current expression. To examine the mechanisms of AP generation, propagation, and stability in transmurally heterogeneous tissue, we developed a comprehensive model of the mouse cardiac cells from the epicardial and endocardial regions of the heart. Our computer model simulates the following differences between epicardial and endocardial myocytes: 1) AP duration is longer in endocardial and shorter in epicardial myocytes, 2) diastolic and systolic intracellular Ca(2+) concentration and intracellular Ca(2+) concentration transients are higher in paced endocardial and lower in epicardial myocytes, 3) Ca(2+) release rate is about two times larger in endocardial than in epicardial myocytes, and 4) Na(+)/Ca(2+) exchanger rate is greater in epicardial than in endocardial myocytes. Isolated epicardial cells showed a higher threshold for stability of AP generation but more complex patterns of AP duration at fast pacing rates. AP propagation velocities in the model of two-dimensional tissue are close to those measured experimentally. Simulations show that heterogeneity of repolarization and Ca(2+) handling are sustained across the mouse ventricular wall. Stability analysis of AP propagation in the two-dimensional model showed the generation of Ca(2+) alternans and more complex transmurally heterogeneous irregular structures of repolarization and intracellular Ca(2+) transients at fast pacing rates.