Fibroblast to Endothelial Transdifferentiation: A Microvascular Mechanism of Cardiac Recovery

Heart failure affects more than 64 million people worldwide and remains a leading cause of cardiovascular mortality. In a landmark study published in Circulation, Li and colleagues demonstrate that recovery from heart failure, modeled by left ventricular assist device support in humans and pharmacological reversal in mice, is fundamentally a microvascular phenomenon driven in part by mesenchymal to endothelial transition (MEndoT) of cardiac fibroblasts. Integrating single nucleus RNA sequencing, genetic lineage tracing, patient derived nonmyocyte cultures, and functional microsphere perfusion, the authors identify c-Myc as a key molecular mediator of this fibroblast to endothelial fate switch. This commentary appraises the novelty, methodology, principal findings, and limitations of this work, and considers what it may and may not yet tell us about the biology of microvascular aging in the failing heart.