Action potential and contractility changes in [Na+]i overloaded cardiac myocytes:: A simulation study

Sodium overload of cardiac cells can accompany various pathologies and induce fatal cardiac arrhythmias. We investigate effects of elevated intracellular sodium on the cardiac action potential (AP) and on intracellular calcium using the Luo-Rudy model of a mammalian ventricular myocyte. The results are: 1) During rapid pacing, AP duration (APD) shortens in two phases, a rapid phase without Na+ accumulation and a slower phase that depends on [Na+](i). 2) The rapid APD shortening is due to incomplete deactivation (accumulation) of I-Ks. 3) The slow phase is dire to increased repolarizing currents I-NaK and reverse-mode I-NaCa, secondary to elevated [Na+](i). 4) Na+-overload slows the rate of AP depolarization, allowing time for greater I-Ca(L) activation; it also enhances reverse-mode I-NaCa. The resulting increased Ca2+ influx triggers a greater [Ca2+](i) transient. 5) Reverse-mode I-NaCa alone can trigger Ca2+ release in a voltage and [Na+](i)-dependent manner. 6) During I-NaK block, Na+ and Ca2+ accumulate and APD shortens due to enhanced reverse-mode I-NaCa; contribution of I-K(Na) to APD shortening is negligible. By slowing AP depolarization thence velocity) and shortening APD, Na+-overload acts to enhance inducibility of reentrant arrhythmias. Shortened APD with elevated [Ca2+], (secondary to Na+-overload) also predisposes the myocardium to arrhythmogenic delayed afterdepolarizations.