Work

Mechanical stretch reduces fibroblast activation in heart failure with reduced ejection fraction

Year: 2025

Type: article

Abstract: AIMS: Elevated hemodynamic load in heart failure (HF) activates fibroblasts and increases collagen deposition, but normalization of load (as occurs with current nonpulsatile left ventricular assist device (LVAD) support) does not reverse fibroblast activation or fibrosis, attributable to a persistently altered fibroblast phenotype. We hypothesized that the combination of reduced load and cyclic stretch in vitro (equivalent to pulsatile LVAD therapy in vivo) would attenuate fibroblast activation. METHODS AND RESULTS: Myocardium from subjects with HF (n = 15) with reduced ejection fraction (HFrEF) and from unused donor hearts (control, n = 5) was used to assess collagen content and for human cardiac fibroblasts (HCF) isolation. HCFs were cultured on substrates with stiffness representing normal (1 kPa) or HFrEF (10 kPa) myocardium and were exposed to 48 hours of cyclic stretch or left unstretched. Alterations in protein production and transcriptional expression in control and HFrEF fibroblasts were assessed. Collagen content was significantly greater in HFrEF tissue than control (6.7% vs 2.1%, p < 0.01). In contrast to control, HFrEF HCFs showed no difference in collagen 1α(I), TIMP1, and αSMA production on 1 vs 10 kPa substrates without cyclic stretch; however, HFrEF HCFs with cyclic stretch produced less collagen1α(I), TIMP1, and αSMA on 1 kPa but not 10 kPa substrates (all p < 0.01). Bulk ribonucleic acid sequencing analysis identified dysregulated pathways in force sensing/signaling in HFrEF HCFs, that, on 1 kPa with stretch, were altered towards that of controls. CONCLUSION: These novel results in primary HCFs demonstrate that normalized substrate stiffness combined with cyclic stretch attenuated HCF activation and identified associated mechanistic pathways for reversing fibroblast phenotype in patients with HF.

Source: The Journal of Heart and Lung Transplantation

DOI: 10.1016/j.healun.2025.12.021