Changes in Intracellular Na+ following enhancement of late Na+ current in virtual human ventricular myocytes

Abstract

The slowly inactivating or late Na+ current, INa-L , can contribute to the initiation of both atrial and ventricular rhythm disturbances in the human heart. However, the cellular and molecular mechanisms that underlie these pro-arrhythmic influences are not fully understood. At present, the major working hypothesis is that the Na+ influx corresponding to INa-L significantly increases intracellular Na+ , [Na+ ]i ; and the resulting reduction in the electrochemical driving force for Na+ reduces and (may reverse) Na+ /Ca2+ exchange. These changes increase intracellular Ca2+ , [Ca2+ ]i ; which may further enhance INa-L due to calmodulindependent phosphorylation of the Na+ channels. This paper is based on mathematical simulations using the O'Hara et al (2011) model of baseline or healthy human ventricular action potential waveforms(s) and its [Ca2+ ]i homeostasis mechanisms. Somewhat surprisingly, our results reveal only very small changes (≤ 1.5 mM) in [Na+ ]i even when INa-L is increased 5-fold and steady-state stimulation rate is approximately 2 times the normal human heart rate (i.e. 2 Hz). Previous work done using well-established models of the rabbit and human ventricular action potential in heart failure settings also reported little or no change in [Na+ ]i when INa-L was increased. Based on our simulations, the major short-term effect of markedly augmenting INa-L is a significant prolongation of the action potential and an associated increase in the likelihood of reactivation of the L-type Ca2+ current, ICa-L . Furthermore, this action potential prolongation does not contribute to [Na+ ]i increase.