A fragment cut from collagen may not be passive debris. This study finds that endotrophin can stimulate human cardiac fibroblasts to make more type I collagen—the collagen that accumulates during heart fibrosis. Extracellular matrix proteins form the core structure of tissues, and they also serve important structural and cell-regulating functions.

During fibrogenesis, increased degradation and formation of extracellular matrix proteins release new epitopes, and some of these signal to cells. Research has mainly focused on signaling peptides from basement membranes, but emerging research suggests that fibroblast collagens also have signaling functions and can drive self-perpetuating signaling that advances fibrogenesis.

Heart failure with preserved ejection fraction is a heterogeneous clinical syndrome affected by fibrosis and metabolic dysregulation, which increases the risk of adverse outcome. That creates a medical need for circulating biomarkers reflecting tissue fibrosis, alongside current techniques for assessing risk and biological abnormalities.

Molecular insight into the mechanisms driving this syndrome could support novel treatment strategies and a better understanding of disease progression risk. Endotrophin is a type VI collagen-derived fragment whose circulating levels have been associated with an increased risk of adverse outcome in heart failure with preserved ejection fraction.

The central finding is that stimulating human cardiac fibroblasts with endotrophin upregulates synthesis of type I collagen, the main interstitial collagen that accumulates in the myocardium during fibrogenesis. That result provides a possible mechanistic explanation for the relation between circulating endotrophin levels and risk of outcome in heart failure with preserved ejection fraction.

The pro-fibrotic effect of endotrophin was investigated in an in vitro cell system using human cardiac fibroblasts. The cells were treated for three days with transforming growth factor beta or with three concentrations of endotrophin: three hundred, three, or zero point zero three nanomolar.

Type I collagen formation was assessed in the supernatant by an enzyme-linked immunosorbent assay, and differences were evaluated using one-way analysis of variance with Dunnett’s multiple comparison test. The model used human primary cardiac ventricular fibroblasts to investigate the potential relationship between endotrophin and fibrosis.

After endotrophin treatment, type I collagen expression increased fivefold. Type I collagen is the most abundant type of collagen in the myocardium, and its response to endotrophin decreased in a dose-dependent manner across the tested conditions.

This could provide a potential mechanism for endotrophin to drive fibrosis and outcome in heart failure with preserved ejection fraction by directly inducing fibroblast activation after its release. Increased fibroblast activity and endotrophin abundance in the myocardium could lead to impaired heart function, contributing to heart failure with preserved ejection fraction pathogenesis and fibrotic diseases more generally.

Figure one shows that treating human cardiac fibroblasts with TGF-beta or endotrophin for three days increased type one collagen formation, measured in the culture supernatant using the PRO-C1 ELISA. The chart reports a thirty-nine-fold increase with TGF-beta and a five-fold increase with three hundred nanomolar endotrophin versus vehicle, with statistically significant effects for both treatments.

This supports a potential mechanism by which endotrophin could contribute to cardiac fibrosis. The experiment is limited by the simplicity of its cell system. Further studies should examine endotrophin in more complex culture systems and link circulating endotrophin levels to local upregulation in disease-affected tissues.

Further work should also investigate disease-specific tissue expression, explore endotrophin as a causal biomarker, and clarify its pro-fibrotic effects in fibro-inflammatory diseases. The study concludes that endotrophin could increase fibrotic burden in the myocardium by activating cardiac fibroblasts and upregulating type I collagen synthesis.

That conclusion is consistent with the view that increased fibrotic burden is associated with an overall increased risk of outcome in heart failure with preserved ejection fraction and other fibro-inflammatory pathologies. The data provide potential mechanistic insight into how endotrophin may relate to increased risk of outcome in heart failure with preserved ejection fraction and fibro-inflammatory diseases more generally.

Endotrophin increased type I collagen synthesis in human cardiac fibroblasts, suggesting a possible mechanism linking circulating endotrophin with fibrotic burden and adverse outcomes in HFpEF. But the simple cell system means the mechanism still needs testing in more complex models.