This study examined the effects of cardiac shockwave therapy (SWT) on heart function in patients with ischemic cardiomyopathy. The researchers found that SWT activates Toll-like receptor 3 (TLR3), which plays a key role in reprogramming cardiac fibroblasts into endothelial-like cells. In both human cells and a mouse model, SWT increased the expression of endothelial markers and led to the formation of vessel-like structures. In mice with coronary artery occlusion, SWT promoted fibroblast-to-endothelial transdifferentiation, reduced scar size, and improved left ventricular function. Single-cell RNA sequencing confirmed the presence of a distinct population of fibroblasts transitioning toward an endothelial phenotype. Chromatin analysis showed that SWT increased DNA accessibility in over 1,700 genomic regions, supporting the concept of epigenetic remodeling. Overall, SWT appears to enhance myocardial repair by activating innate immune signaling and promoting vascular regeneration. These findings suggest that SWT could become a valuable noninvasive therapy for improving perfusion and function in ischemic hearts.