Ranolazine prevents pressure overload‐induced cardiac hypertrophy and heart failure by restoring aberrant Na⁺ and Ca²⁺ handling

Abstract

Background Cardiac hypertrophy and heart failure are characterized by increased late sodium current and abnormal Ca2+ 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). Ca2+ 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.

Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy

“…Additionally, it was previously shown that laminopathic cardiomyocytes are highly sensitive to apoptosis ( Ho et al, 2011 ; Lee et al, 2017 ), which could over the years contribute to the development of severe cardiac fibrosis that is typical in cardiac laminopathy patients ( van Tintelen et al, 2007b ; Fontana et al, 2013 ; Tobita et al, 2018 ). A corollary of these intriguing hypotheses is that medical interventions during the early phases of the disease, such as the use of calcium antagonists (such as our use of verapamil here) and/or anti-apoptotic agents ( Lee et al, 2014 ; Nie et al, 2018 ), may be able to prevent the development of heart failure in cardiac laminopathy patients.…”

Mechanisms for the transition from physiological to pathological cardiac hypertrophy

“…Cytosolic or intracellular Ca 2+ overload and exhausted Ca 2+ stores disturb protein folding, leading to an unfolded protein response and endoplasmic reticulum (ER) stress (Hayashi and Su 2007). In the failing heart, ER-initiated stress has been reported to contribute to cardiomyocyte apoptosis (Nie et al 2019). Intracellular Ca 2+ overload within cardiomyocytes may be involved in the transition from adaptive cardiac hypertrophy to pathological cardiac hypertrophy.…”

“…Along with the effects of cytosolic Ca 2+ overload previously discussed, intracellular Ca 2+ overload within cardiomyocytes contributes to the activation of pro-hypertrophic signaling pathways that stimulate the progression of pathological cardiac hypertrophy. Elevated levels of intracellular Ca 2+ lead to increased binding of Ca 2+ with inactive calmodulin (CaM) to form active CaM (Nie et al 2019). Active CaM initiates signaling pathways involving Ca 2+ /CaM/CaMKII/myocyte enhancer factor-2 (MEF-2) and Ca 2+ /CaM/CaMKII/calcineurin/nuclear factor of activated T-cells (NFAT), which are pro-hypertrophic signaling pathways (Zhang et al 2007).…”

Challenges and Opportunities for Therapeutic Targeting of Calmodulin Kinase II in Heart

“…Late Na + current, through the actions of the sodium Ca 2+ exchanger, may impact intracellular Ca 2+ , contributing to further activation of CaMKII as well as driving the incidence of arrhythmogenic DADs. Ranolazine has been used successfully in rodents and large animals to block these changes and prevent the development of hypertrophy, HF, and arrhythmias (Rastogi et al, 2008;Figueredo et al, 2011;Glynn et al, 2015;Liang et al, 2016;Ellermann et al, 2018;Nie et al, 2019). However, results from clinical trials have been mixed with data supporting that ranolazine is safe with questionable efficacy in preventing AF recurrence (RAFAELLO trial), ventricular tachycardia (VT) or ventricular fibrillation (VF) following implantation of cardioverter defibrillator (RAID trial), or improving functional capacity in hypertrophic cardiomyopathy (RESTYLE-HCM trial) (De Ferrari et al, 2015;Bengel et al, 2017;Olivotto et al, 2018;Zareba et al, 2018).…”