Circulating Endotrophin Predicts Myocardial Fibrosis Burden and Is Sensitive to Antifibrotic Therapy

Novel collagen-derived circulating peptides, such as endotrophin, have been proposed as biomarkers of myocardial fibrosis.

We aimed to determine the effect of pirfenidone, an antifibrotic agent, on circulating levels of these peptides, and their association with cardiovascular magnetic resonance extracellular volume (ECV).

In the PIROUETTE (Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, novel collagen-derived circulating peptides (PRO-C3, C3M, CTX-III, endotrophin, PRO-C6, and C6M) were measured at baseline and at prespecified time points in patients with ECV ≥27% randomized (n = 94) to pirfenidone or placebo. Baseline peptide levels were also measured in patients with ECV <27% who were not randomized (n = 13).

Treatment with pirfenidone was associated with a significant reduction in log endotrophin (P = 0.034), with a treatment effect seen from 13 weeks. After multivariable adjustment there were significant albeit modest associations between change in myocardial ECV and change in log endotrophin (R²: 0.14; P = 0.031), and baseline ECV and baseline log endotrophin (R²: 0.30; P = 0.022). Pirfenidone had no effect on the levels of other collagen-derived circulating peptides, and there were no associations between their levels and change in myocardial ECV or baseline ECV.

In patients with heart failure with preserved ejection fraction, treatment with pirfenidone was associated with a sustained reduction in circulating levels of endotrophin from 13 weeks. Circulating endotrophin was also independently associated with both baseline myocardial ECV and change in myocardial ECV. Endotrophin shows high potential as a circulating biomarker reflective of myocardial fibrosis burden and sensitive to change in myocardial fibrosis over time.