Arrhythmogenic cardiac alternans in heart failure is suppressed by late sodium current blockade by ranolazine

BACKGROUND Cardiac alternans is promoted by heart failure (HF)-induced calcium (Ca2+) cycling abnormalities. Late sodium current (I-Na,I- L) is enhanced in HF and promotes Ca2+ overload; however, mechanisms underlying an antiarrhythmic effect of I-Na,I- L blockade in HF remain unclear. OBJECTIVE The purpose of this study was to determine whether ranolazine suppresses cardiac alternans in HF by normalizing Ca2+ cycling. METHODS Transmural dual optical mapping of Ca2+ transients and action potentials was performed in wedge preparations from 8 HF and 8 control (normal) dogs. Susceptibility to action potential duration alternans (APD-ALT) and Ca2+ transient alternans (Ca-ALT) was compared at baseline and with ranolazine (5-10 mu M). RESULTS HF increased APD-and Ca-ALT compared to normal (both P<. 05), and ranolazine suppressed APD-and Ca-ALT in both groups (P<. 05). The incidence of spatially discordant alternans (DIS-ALT) was increased by HF (8/8) compared to normal (4/8; P<. 05), and ranolazine decreased DIS-ALT in HF (4/8; P<. 05). Not only did ranolazine mitigate HF-induced Ca2+ overload, it also attenuated APD-ALT to Ca-ALT gain (amount of APD-ALT produced by Ca-ALT). In HF, APD-ALT to Ca-ALT gain was significantly increased (0.55 +/- 0.02) compared to normal (0.44 +/- 0.02; P<. 05) and was normalized by ranolazine (0.36 +/- 0.05; P<. 05), representing a complementary mechanism by which I-Na,I- L blockade suppressed cardiac alternans. CONCLUSION Ranolazine attenuated arrhythmogenic cardiac alternans in HF, both by suppressing Ca-ALT and decreasing the coupling gain of APD-ALT to Ca-ALT. Blockade of I-Na,I- L may reverse impaired Ca2+ cycling to mitigate cardiac alternans, representing a mechanism underlying the antiarrhythmic benefit of I-Na,I- L blockade in HF.