Human cardiac myofibroblasts in late-stage heart failure (HF) are not terminally differentiated, but actually retain the capacity for dedifferentiation, according to a new study published in JACC. This finding highlights the potential of antifibrotic therapies targeting myofibroblasts to possibly reverse fibrosis in patients with end-stage HF.

The adverse remodelling process in the heart that precedes the onset of HF involves increased fibrosis, which contributes to both impaired diastolic filling and contractile dysfunction. “Mechanistic insights from animal studies suggest that fibrosis can be prevented or treated, while human data are so far very limited,” comments Karin Sipido, lead investigator of the study. The authors thus designed a study to characterize human cardiac myofibroblasts involved in late-stage HF, and to examine whether their phenotype in end-stage HF can be reversed.

Fibroblasts were isolated from explanted hearts from transplant recipients with end-stage HF (n = 27) and without HF (n = 17). The number of myofibroblasts was higher in end-stage HF hearts than in non-HF hearts, and the majority of fibroblastic cells in the end-stage HF hearts were myofibroblasts, some of which remained proliferative. Importantly, these myofibroblasts had a gene expression profile that was associated with a high turnover of matricellular proteins, and expressed high levels of pro-fibrotic cytokines. Inhibition of transforming growth factor-β signalling in end-stage-HF myofibroblasts in vitro promoted their dedifferentiation to a less activated state.

Taken together, these in vitro data highlight the potential reversibility of the myofibroblast phenotype in late-stage HF. “We will further explore the molecular signalling pathways that determine differentiation and dedifferentiation of human cardiac fibroblasts, distinguishing those that are responsible for scar and those for interstitial fibrosis,” concludes Sipido.