Ventricular remodeling in ischemic heart failure stratifies responders to stem cell therapy

Response to stem cell therapy in heart failure is heterogeneous, warranting a better understanding of outcome predictors. This study assessed left ventricular volume, a surrogate of disease severity, on cell therapy benefit. Small to large infarctions were induced in murine hearts to model moderate, advanced, and end‐stage ischemic cardiomyopathy. At 1 month postinfarction, cardiomyopathic cohorts with comparable left ventricular enlargement and dysfunction were randomized 1:1 to those that either received sham treatment or epicardial delivery of cardiopoietic stem cells (CP). Progressive dilation and pump failure consistently developed in sham. In comparison, CP treatment produced significant benefit at 1 month post‐therapy, albeit with an efficacy impacted by cardiomyopathic stage. Advanced ischemic cardiomyopathy was the most responsive to CP‐mediated salvage, exhibiting both structural and functional restitution, with proteome deconvolution substantiating that cell therapy reversed infarction‐induced remodeling of functional pathways. Moderate cardiomyopathy was less responsive to CP therapy, improving contractility but without reversing preexistent heart enlargement. In end‐stage disease, CP therapy showed the least benefit. This proof‐of‐concept study thus demonstrates an optimal window, or “Goldilocks principle,” of left ventricular enlargement for maximized stem cell‐based cardiac repair. Disease severity grading, prior to cell therapy, should be considered to inform regenerative medicine interventions.