Why the study?
Cardiac hypertrophy and heart failure feature increased late sodium current and abnormal Ca2+ handling, prompting investigation into whether late sodium current inhibition with ranolazine affects pressure overload-induced cardiac hypertrophy and heart failure.
Does ranolazine prevent pressure overload-induced cardiac hypertrophy and heart failure in mice?
Does ranolazine prevent pressure overload-induced cardiac hypertrophy and heart failure in mice?
Ranolazine prevents pressure overload-induced cardiac hypertrophy and heart failure in a mouse model by restoring Na+ and Ca2+ handling and inhibiting downstream hypertrophic pathways and ER stress.
Should not yet change HF practice; leaves open whether ranolazine prevents human pressure-overload hypertrophy.
Background Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca 2+ handling. Ranolazine, a selective inhibitor of the late sodium current, can reduce sodium accumulation and Ca 2+ overload. In this study, we investigated the effects of ranolazine on pressure overload‐induced cardiac hypertrophy and heart failure in mice. Methods and Results Inhibition of late sodium current with the selective inhibitor ranolazine suppressed cardiac hypertrophy and fibrosis and improved heart function assessed by echocardiography, hemodynamics, and histological analysis in mice exposed to chronic pressure overload induced by transverse aortic constriction (TAC). Ca 2+ imaging of ventricular myocytes from TAC mice revealed both abnormal SR Ca 2+ release and increased SR Ca 2+ leak. Ranolazine restored aberrant SR Ca 2+ handling induced by pressure overload. Ranolazine also suppressed Na + overload induced in the failing heart, and restored Na + ‐induced Ca 2+ overload in an sodium‐calcium exchanger (NCX)‐dependent manner. Ranolazine suppressed the Ca 2+ ‐dependent calmodulin (CaM)/CaMKII/myocyte enhancer factor‐2 (MEF2) and CaM/CaMKII/calcineurin/nuclear factor of activated T‐cells (NFAT) hypertrophy signaling pathways triggered by pressure overload. Pressure overload also prolonged endoplasmic reticulum (ER) stress leading to ER‐initiated apoptosis, while inhibition of late sodium current or NCX relieved ER stress and ER‐initiated cardiomyocyte apoptosis. Conclusions Our study demonstrates that inhibition of late sodium current with ranolazine improves pressure overload‐induced cardiac hypertrophy and systolic and diastolic function by restoring Na + and Ca 2+ handling, inhibiting the downstream hypertrophic pathways and ER stress. Inhibition of late sodium current may provide a new treatment strategy for cardiac hypertrophy and heart failure.
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Nie et al. (2018) studied this question.
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