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

Cardiac alternans is promoted by heart failure (HF)-induced calcium (Ca²⁺) cycling abnormalities. Late sodium current (I_Na,L) is enhanced in HF and promotes Ca²⁺ overload; however, mechanisms underlying an antiarrhythmic effect of I_Na,L blockade in HF remain unclear.

The purpose of this study was to determine whether ranolazine suppresses cardiac alternans in HF by normalizing Ca²⁺ cycling.

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 μM).

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,L blockade suppressed cardiac alternans.

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,L may reverse impaired Ca²⁺ cycling to mitigate cardiac alternans, representing a mechanism underlying the antiarrhythmic benefit of I_Na,L blockade in HF.