SAR340835, a novel selective NCX inhibitor, improves cardiac function and restores sympathovagal balance in Heart Failure.

In failing hearts, Na+/Ca2+ exchanger (NCX) overactivity contributes to Ca2+ depletion leading to contractile dysfunction. Inhibition of NCX is expected to normalize Ca2+ mishandling, to limit after depolarization-related arrhythmias and to improve cardiac function in heart failure (HF). SAR340835/SAR296968 (NCXi) potently inhibited all NCX isoforms across species with no effect on the native voltage-dependent calcium and sodium currents in vitro. Additionally, it showed in vitro and in vivo anti-arrhythmic properties in several models of early and delayed afterdepolarization-related arrhythmias. Its effect on cardiac function was studied under intravenous infusion at 250 - 750 or 1500 µg/kg/h in dogs either normal or submitted to chronic ventricular pacing at 240 bpm (HF dogs). HF dogs were infused with the reference inotrope dobutamine (10 µg/kg/min i.v.). In normal dogs NCXi increased cardiac contractility (dP/dtmax), stroke volume (SV) and tended to reduce heart rate (HR). In HF dogs NCXi significantly and dose-dependently increased SV from the first dose (+28.5%, +48.8%, +62% at 250, 750 and 1500 µg/kg/h respectively) while increasing significantly dP/dtmax only at 1500 (+33%). Furthermore, NCXi significantly restored sympathovagal balance and spontaneous baroreflex sensitivity (BRS) from the first dose and reduced HR at the highest dose. In HF dogs, dobutamine significantly increased dP/dtmax , SV (+68.8%) but did not change HR, sympathovagal balance nor BRS. Overall, SAR340835 a selective potent NCXi displayed a unique therapeutic profile, combining anti-arrhythmic properties, capacity to restore systolic function, sympathovagal balance and BRS in HF dogs. NCX inhibitors may offer new therapeutic options for acute HF treatment. Significance Statement HF is facing growing health and economic burden. Moreover, patients hospitalized for acute Heart Failure(AHF) are at high risk of decompensation recurrence, and no current AHF therapy definitively improved outcomes. A new potent, selective, NCX inhibitor SAR340835 with anti-arrhythmic properties improved systolic function of failing hearts without creating hypotension, while reducing heart rate and restoring sympathovagal balance. Overall SAR340835 may offer a unique and attractive pharmacological profile for AHF patients as compared to current standard of care such as dobutamine