Effect of Sodium Homeostasis on Action Potential Duration Alternans in Cardiac Ventricular Cells

Abstract

Beat-to-beat alternation of action potential (AP) duration (alternans) is a precursor of fatal cardiac arrhythmias. The effect of the time course of intracellular Ca2+ transient on AP duration (APD) alternans was studied extensively, and the Na+/Ca2+ exchanger (INCX) was identified as a major coupling link between Ca2+ alternans and APD alternans. However, the role of Ca2+ -independent factors such as the Na+/K+ pump (INaK) in the coupling between the Ca2+ and AP subsystems has been overlooked.We used computational models of AP and Ca2+ cycling in guinea-pig and canine myocytes to study effects of rate-dependent Na+ homeostasis on APD and the Ca2+ transient. We found that rate-dependent Na+ accumulation increases both the amplitude and frequency range of APD alternans in the guinea-pig, but decreases the amplitude of APD alternans in canine cells. The mechanism is as follows: in canine, Ca2+ and APD alternans are concordant (large Ca2+ is accompanied by long APD) and APD prolongation is due to inward INCX enhancement at a late phase of the AP. INaK enhancement by Na+ accumulation blunts the effect of INCX and decreases APD alternans amplitude. In the guinea pig, alternans are discordant (large Ca2+ transient with short APD) due to enhanced Ca2+ -dependent inactivation of L-type Ca2+ current and increased Ca2+-dependent slow delayed rectifier IKs at high Ca2+. Additional APD shortening by INaK increases the amplitude of the discordant alternans.In conclusion, INaK enhancement due to Na+ accumulation decreases the amplitude of concordant APD-Ca2+ alternans and increases the amplitude of discordant APD-Ca2+ alternans. This mechanistic insight is relevant to arrhythmogenesis in heart failure where INCX is upregulated and INaK downregulated, amplifying APD alternans in larger mammals (canine) and possibly humans.