Abstract Body: Background
Drug-induced and genetic cardiomyopathies, including dilated cardiomyopathy (DCM), represent major causes of heart failure. Current heart failure therapies primarily manage hemodynamics but do not directly target cardiomyocytes to prevent mitochondrial and sarcomeric damages.
Research Questions
Does a novel compound identified through a screening using in vitro iPSC-derived cardiac cells and tissues provide therapeutic benefit in in vivo Doxorubicin (DOX)-induced cardiomyopathy and DCM mouse models?
Goals
To evaluate the in vivo cardioprotective efficacy, mechanism of action, and translational potential of a newly identified candidate drug in a DOX-induced cardiomyopathy and DCM mouse model.
Methods
Therapeutic efficacy of the compound (10mg/kg, oral administration) was evaluated in mouse models of DOX-induced cardiomyopathy (5-day administration)and genetic dilated cardiomyopathy (DCM;TPM1 mutation) (2-week administration). Assessments included survival, echocardiography, and pharmacokinetics. Mechanistic pathways were investigated using gene expression analysis.

Results
In the DOX-induced model, the compound significantly improved survival (Hazard ratio 0.373, 95% CI 0.188 to 0.740, logrank p<0.01) with improved cardiac function (FS%; DOX vs treated=38.5 vs 43.9, p<0.01). Histological analyses demonstrated reduced apoptosis, preserved sarcomere integrity, and improved mitochondrial morphology. The compound also improved cardiac function in a DCM model (FS%; DCM vs treated=24.7 vs 30.4, p<0.05). Gene expression profiling in both models revealed restored calcium handling, metabolic programs, and homeostasis-related pathways, suggesting mitochondrial protection and restoration of cellular homeostasis as central mechanisms underlying the therapeutic effects of the compound.
Conclusion
A novel compound identified using in vitro human cardiac tissue platform confers robust cardioprotection in both DOX-induced and genetic DCM models by restoring mitochondrial function and cardiomyocyte homeostasis. These findings support further translational development of this therapy for cardiomyopathy.