A 5-fold enhancement of the late Na+ current in virtual human ventricular myocytes resulted in only a small increase (≤ 1.5 mM) in intracellular Na+ concentration.
In silico simulations of human ventricular myocytes reveal that enhancing the late Na+ current primarily prolongs the action potential rather than significantly increasing intracellular Na+, suggesting pro-arrhythmic effects are indirect.
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 calmodulin-dependent 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.
Cardona et al. (2016) studied Healthy human ventricular myocytes (in silico). Enhancement of Late Na+ Current (INa-L) vs. Baseline INa-L was evaluated on Changes in intracellular Na+ concentration ([Na+]i). A 5-fold enhancement of the late Na+ current in virtual human ventricular myocytes resulted in only a small increase (≤ 1.5 mM) in intracellular Na+ concentration.