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

Abstract

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 τ f of L-type calcium current (I CaL) increased obviously in hyperkalemia. One cycle length was not enough for I CaL to recover completely. Alternans developed as a result of I CaL 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 (I NCX) increased the magnitude of Cai alternans, leading to APD alternans through excitation-contraction coupling. Some alternated repolarization currents contributed to this repolarization alternans.

Exploring Impaired SERCA Pump-Caused Alternation Occurrence in Ischemia

“…We used it to obtain the Ca 2+ uptake rate per pump and multiplied a scale factor to calculate I up . The appropriate coefficient was determined by comparing the I up amplitude produced by the original ORd epi cell model and the Ca 2+ uptake rate per pump at steady state under normal conditions (this method was described in detail in our previous study [11]). The SERCA pump model incorporates the regulation effect of phospholamban (PLB) on Ca 2+ uptake.…”

“…The link between ischemia and alternans has been extensively explored [10]. Our previous simulations identified that hyperkalaemia, one component of ischemia, results in depolarization alternans [11]. Other two ischemic components, hypoxia and acidosis, lead to repolarization alternans by causing instabilities in calcium cycling [4, 11, 12].…”

“…Our previous simulations identified that hyperkalaemia, one component of ischemia, results in depolarization alternans [11]. Other two ischemic components, hypoxia and acidosis, lead to repolarization alternans by causing instabilities in calcium cycling [4, 11, 12]. Ca 2+ alternans in ischemia can be taken as the arrhythmic triggers leading to afterdepolarization and also as the substrate facilitating reentry by inducing electrical alternans [4].…”

“…Alternans depends on instabilities of membrane voltage ( V m ) [13] or/and intracellular Ca 2+ handling [1, 7, 9, 14–20], due to their bidirectional couplings [3, 9, 21]. For the latter, it is known that the Ca 2+ handling includes Ca 2+ influx and efflux [16], and its abnormality can arise from the dysfunction of sarcoplasmic reticulum (SR) calcium transport ATPase (SERCA) [11, 13, 14], ryanodine receptor (RyR2) [1, 4, 7, 14, 16], and Ca 2+ leak [13]. Under ischemic conditions, both the Ca 2+ release current ( I rel ) [4] and the Ca 2+ uptake current ( I up ) decrease [4, 22] to facilitate the formation of Ca 2+ alternans in an interactive manner.…”

One-dimensional Simulation of Alternating Conduction under Hyperkalaemic Conditions

“…Previous studies [2,6] point out the important effect of I CaL on blocks, but yet they don ' t explain how it associates with conduction delay under hyperkalaemic conditions. In addition, I CaL plays an important role in alternans occurring in the single cell under hyperkalaemic conditions [14].…”