Recovery from Heart Failure is a Vascular Recovery

Abstract Heart failure (HF) remains a major cause of morbidity and mortality worldwide, with limited treatment options. Heart transplantation is an end stage option but limited by donor availability. Left-ventricular assist device (LVAD) implantation serves as a bridging strategy for patients awaiting a transplant. Intriguingly, LVAD support (typically for 6-12 months before heart transplantation) is often associated with some level of improvement in cardiac function and histology. In rare cases, LVAD support can improve cardiac function sufficiently to avoid heart transplantation after LVAD removal. The underlying mechanisms of this improvement in cardiac function are not understood. Here, we provide evidence that the improvement in cardiac function post-LVAD is associated with a reduction in fibrosis and an increase in capillary density. This heart failure recovery (HFR) is also associated with an angiogenic cell fate transition. We observed a distinct pro-angiogenic phenotype of cardiac non-myocytes isolated from post-LVAD hearts. Single-nuclei RNA sequencing of pre- and post-LVAD cardiac tissue reveals a fibroblast subtype that undergoes mesenchymal to endothelial transition (MEndoT), potentially facilitating HFR. In a murine model of HFR, lineage tracing studies confirm that MEndoT is associated with the increase in capillary density and perfusion during HFR. In summary, our results support the new concept that HFR is associated with a reduction in interstitial cardiac fibrosis, an increase in capillary density and perfusion, that is due in part to an angiogenic cell fate transition. Our work represents a shift in the conceptual framework regarding mechanisms of HFR, and a new therapeutic avenue for exploration.