Metabolic stress and therapeutic response in heart failure associated with congenital heart disease

Heart failure in congenital heart disease (CHD) has no effective treatment besides heart transplantation. While hemodynamic etiology is suggested, here we show hypoplastic left heart syndrome (HLHS), a severe CHD is a mitochondrial disease from analysis of HLHS mice and patient derived induced pluripotent stem cell cardiomyocytes (iPSC-CM). The iPSC-CM from patients suffering heart failure or death, but not those with long-term survival, showed reduced cell proliferation with increased apoptosis, mitochondrial hyperfusion with respiration defect and redox stress. Single cell sequencing showed protein synthesis overload with unfolded protein response. Drugs targeting the mitochondria restored metabolic function and rescued cell proliferation and apoptosis, suggesting new stragegies for heart failure therapy in CHD. Overall design: induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) from 1 healthy control and 3 HLHS patients.