Characteristics associated with growth differentiation factor-15 in HFpEF and the impact of Pirfenidone

Background: GDF-15 is elevated in heart failure with preserved ejection fraction and associates with adverse outcome, but its relationship with myocardial fibrosis and other characteristics remains unclear. We sought to evaluate the effect of pirfenidone, a novel antifibrotic agent, on GDF-15 in heart failure with preserved ejection fraction and identify characteristics that associate with GDF-15 and with change in GDF-15 over one year.
Methods and Results: Amongst patients enrolled (n=107) in the PIROUETTE (Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, GDF-15 was measured at baseline and at prespecified time points in patients randomised (n=94) to pirfenidone or placebo. Response of GDF-15 to pirfenidone and association with baseline patient characteristics were evaluated. Pirfenidone had no impact on circulating GDF-15 at any time point during the 52-week trial period. In multivariable analysis, male sex, diabetes, higher circulating levels of NT-proBNP, lower renal function and shorter 6-minute walk test distance at baseline were associated with baseline log GDF-15. Impaired global longitudinal strain at baseline was the strongest predictor of increased GDF-15 over 52-weeks.
Conclusions: In patients with HFpEF, circulating levels of GDF-15 were unaffected by treatment with pirfenidone and do not appear to be determined by myocardial fibrosis. Circulating GDF-15 was associated with a spectrum of important HF characteristics and it may represent a marker of overall physiological disruption. (PIROUETTE; NCT02932566)