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.