In Silico Investigation into Cellular Mechanisms of Cardiac Alternans in Myocardial Ischemia

Myocardial ischemia is associated with pathophysiological conditions such as hyperkalemia, acidosis, and hypoxia. These physiological disorders may lead to changes on the functions of ionic channels, which in turn form the basis for cardiac alternans. In this paper, we investigated the roles of hyperkalemia and calcium handling components played in the genesis of alternans in ischemia at the cellular level by using computational simulations. The results show that hyperkalemic reduced cell excitability and delayed recovery from inactivation of depolarization currents. The inactivation time constant 𝜏𝑓 of L-type calcium current (𝐼CaL) increased obviously in hyperkalemia. One cycle length was not enough for 𝐼CaL to recover completely. Alternans developed as a result of 𝐼CaL responding to stimulation every other beat. Sarcoplasmic reticulum calcium-ATPase (SERCA2a) function decreased in ischemia. This change resulted in intracellular Ca (Ca𝑖) alternans of small magnitude. A strong Na+-Ca2+ exchange current (𝐼NCX) increased the magnitude of Ca𝑖 alternans, leading to APD alternans through excitation-contraction coupling. Some alternated repolarization currents contributed to this repolarization alternans.