Early mavacamten therapy prevents progression to end-stage hypertrophic cardiomyopathy in a MYBPC3 truncation mouse model

Background Approximately 5-10% of patients with hypertrophic cardiomyopathy (HCM) progress to an end-stage phenotype characterised by left ventricular dilatation, systolic dysfunction, and poor prognosis. No effective therapy currently exists to prevent this progression. While mavacamten, a selective cardiac myosin inhibitor, has established efficacy in obstructive HCM, its potential to prevent progression to end-stage heart failure in HCM remains unknown. Because progression to end-stage HCM in humans requires prolonged observation over decades, appropriate disease models are essential to evaluate preventive strategies. Purpose To investigate whether early pharmacological intervention with mavacamten could suppress disease progression using a novel end-stage HCM mouse model. Methods We generated mice harbouring a human MYBPC3 heterozygous frameshift deletion (c.1777delT; p.S593Pfs*9) identified in our clinical cohort with documented progression to end-stage HCM. Mavacamten (2.5 mg/kg/day) was administered from 8 weeks of age, with fortnightly echocardiographic assessment. Histological evaluations were conducted at predefined time points. In parallel, induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) harbouring a MYBPC3 splice variant (c.2996_3013del; p.G999_Q1004del) were analysed using Seahorse flux assays to evaluate mitochondrial oxygen consumption rate (OCR). Results Mybpc3-mutant mouse model developed progressive left ventricular wall thickening by 6-8 weeks, followed by ventricular dilatation and reduced ejection fraction by 10-12 weeks, faithfully recapitulating human end-stage HCM. Histologically, untreated mice exhibited marked cardiomyocyte hypertrophy, interstitial fibrosis, and sarcomeric disarray. Early mavacamten treatment attenuated left ventricular wall thickening and prevented decline in systolic function. Histologically, cardiomyocyte hypertrophy, fibrosis, and sarcomeric disarray were significantly reduced. In MYBPC3-mutant iPS-CMs, elevated OCR was attenuated by mavacamten, indicating correction of hypercontractility-driven energetic stress. Conclusions Early mavacamten intervention prevented progression to end-stage HCM in a Mybpc3-mutant mouse model by stabilising myosin in the super-relaxed state, reducing hypercontractility and mitigating maladaptive remodelling. Given the impracticality of decades-long preventive trials in humans, this model provides critical evidence supporting early therapeutic intervention in HCM.