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

Abstract

BACKGROUND: Cardiac alternans is promoted by heart failure (HF)-induced calcium (Ca) cycling abnormalities. Late sodium current (I) is enhanced in HF and promotes Caoverload; however, mechanisms underlying an antiarrhythmic effect of Iblockade in HF remain unclear. OBJECTIVE: The purpose of this study was to determine whether ranolazine suppresses cardiac alternans in HF by normalizing Cacycling. METHODS: Transmural dual optical mapping of Catransients 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 Catransient alternans (Ca-ALT) was compared at baseline and with ranolazine (5-10 &#x3bc;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 Caoverload, 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 &#xb1; 0.02) compared to normal (0.44 &#xb1; 0.02; P <.05) and was normalized by ranolazine (0.36 &#xb1; 0.05; P <.05), representing a complementary mechanism by which Iblockade 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 Imay reverse impaired Cacycling to mitigate cardiac alternans, representing a mechanism underlying the antiarrhythmic benefit of Iblockade in HF.