Late sodium current contributes to diastolic cell Ca2+ accumulation in chronic heart failure

We elucidate the role of late Na+ current (I-NaL) for diastolic intracellular Ca2+ (DCa) accumulation in chronic heart failure (HF). HF was induced in 19 dogs by multiple coronary artery microembolizations; 6 normal dogs served as control. Ca2+ transients were recorded in field-paced (0.25 or 1.5 Hz) fluo-4-loaded ventricular myocytes (VM). I-NaL and action potentials were recorded by patch-clamp. Failing VM, but not normal VM, exhibited (1) prolonged action potentials and Ca2+ transients at 0.25 Hz, (2) substantial DCa accumulation at 1.5 Hz, and (3) spontaneous Ca2+ releases, which occurred after 1.5 Hz stimulation trains in similar to 31% cases. Selective I-NaL blocker ranolazine (10 mu M) or the prototypical Na+ channel blocker tetrodotoxin (2 mu M) reversibly improved function of failing VM. The DCa accumulation and the beneficial effect of I-NaL blockade were reproduced in silico using an excitation-contraction coupling model. We conclude that I-NaL contributes to diastolic Ca2+ accumulation and spontaneous Ca2+ release in HF.