Recovery From Heart Failure: Microvascular Mechanisms

BACKGROUND: Heart failure (HF) is a significant global health problem. Left ventricular assist device (LVAD) implantation serves as a bridge for patients awaiting heart transplantation. Intriguingly, LVAD support often improves cardiac histology and function, sometimes enough to avoid transplantation after LVAD removal. However, the cellular programs underlying this recovery remain unclear. METHODS: Myocardial tissues were obtained from patients with HF at the time of LVAD implantation (pre LVAD) and explantation (post LVAD) for histological analysis and single-nucleus RNA sequencing. A murine model of HF recovery, combined with lineage tracing studies, was employed to define cellular sources of vascular repair. Cardiac function, fibrosis, and vascular density were assessed using echocardiography, histology, and fluorescent microsphere perfusion. A patient-derived cardiac nonmyocyte culture system was established to interrogate mechanisms of cell fate regulation. RESULTS: Post-LVAD myocardial tissues exhibited reduced fibrosis and increased capillary density compared with pre-LVAD samples. Across samples, fibroblast abundance was inversely correlated with endothelial cell abundance, consistent with enhanced angiogenesis during recovery. Single-nucleus RNA sequencing identified a fibroblast subset predisposed to undergo mesenchymal-to-endothelial transition, acquiring an endothelial cell identity. Additionally, nonmyocytes from pre-LVAD hearts proliferated poorly and failed to form vascular structures, whereas nonmyocytes from post-LVAD hearts displayed greater proliferation and angiogenesis capacity, forming vessel-like structures, reinforcing the association of HF recovery with angiogenic reprogramming. Mechanistically, knockdown of c-Myc (cellular myelocytomatosis oncogene) by small interfering RNA shifted post-LVAD nonmyocytes to a pre-LVAD-like state, while c-Myc overexpression by mRNA in pre-LVAD cells induced a post-LVAD-like phenotype, implicating c-Myc as 1 contributor to this fate switch. A model of HF recovery in mice mimicked the histological and functional changes in patients, with physiological evidence of increased microvascular perfusion, associated with a fibroblast-to-endothelial transition, documented by lineage tracing. CONCLUSIONS: HF recovery involves reduced fibrosis and enhanced microvascularization, partly driven by fibroblast-to-endothelial cell fate transition. c-Myc functions as 1 regulator of this transition, offering a mechanistic entry point to develop regenerative therapies in HF.