LAUSR

Heart failure (HF) affects over 6 million people, enhances arrhythmogenesis and is associated with elevated intracellular [Na] ([Na]i), which impacts Ca handling via Na/Ca exchange. HF myocytes exhibit increased late Na current (INaL), typically insufficient to explain the rise in [Na]i. However, in HF there is also an increase in diastolic Na influx (INaDiast) that is tetrodotoxin (TTX) sensitive. INaL is known to be activated by CaMKII and blocked by the selective INaL inhibitors ranolazine and GS967. To test whether the elevated INaDiast in HF has the same sensitivities to CaMKII and INaL inhibitors, we studied freshly isolated ventricular myocytes from HF and control rabbits. We measured [Na]i and unidirectional Na-influx rate upon acute Na/K-ATPase blockade. Ranolazine (10 µM) inhibited INaDiast in HF myocytes (by 58.5%), consistent with INaDiast in HF being mediated via an INaL-like current. GS967, tested in control myocytes, also inhibited INaDiast. Application of CaMKII blocker, KN-93 (1 µM) reduced INaDiast in HF, but not control myocytes. We also measured INaDiast under voltage clamp, as shifts in holding current (Ihold) at diastolic Vm upon acute addition of INaL blockers. In control myocytes TTX induced −7.5pA IHold, but in HF myocytes the TTX-sensitive IHold was −25.4 pA at −80mV. This agrees with INaDiast measured using Na dyes. INaDiast could be via a window INa. However, the V1/2 of the INa steady state activation and inactivation curves were shifted in HF by −3.8mV and −7.2mV, respectively, and intermediate INa inactivation was also enhanced in HF. Both of these effects make window INa current unlikely to mediate INaDiast. INaL measured in AP-clamp was increased by ∼50% in HF. We suggest that INaDiast in HF has drug sensitivities like INaL during the AP, but produces inward current at diastolic potentials that can explain the rise in [Na]i.