Does targeting hypercontractility and oxidative stress through myosin inhibition reduce arrhythmic risk in hypertrophic cardiomyopathy models?
This preclinical study demonstrates a mechanistic link between hypercontractility, mitochondrial reactive oxygen species, and creatine kinase dysfunction in HCM, suggesting myosin inhibition may restore energy balance and reduce arrhythmic risk.
BACKGROUND: disrupt CK function in HCM. METHODS: sensitizer EMD-57033, the CK inhibitor 1-fluoro-2,4-dinitrobenzene (DNFB), and the myosin inhibitor MYK-581, a mavacamten derivative. RESULTS: levels and triggered cellular arrhythmias. This mitochondrial oxidation was independently confirmed in mito-roGFP2-Orp1 cardiomyocytes exposed to DNFB. Mitochondrial-targeted catalase-overexpressing mice were protected from DNFB-induced oxidative stress and arrhythmogenic events. CONCLUSIONS: This study reveals a mechanistic link between hypercontractility, mitochondrial reactive oxygen species, and CK dysfunction in HCM, perpetuating a cycle of energetic dysfunction. Targeting hypercontractility and oxidative stress through myosin inhibition offers a strategy to restore energy balance and reduce arrhythmic risk in HCM.
Xu et al. (Mon,) studied this question.