Impact of Myocardial Fibrosis on Cardiovascular Structure, Function and Functional Status in Heart Failure With Preserved Ejection Fraction

Abstract Purpose: Myocardial fibrosis, measured using cardiovascular magnetic resonance extracellular volume (ECV), is associated with adverse outcome in heart failure with preserved ejection fraction (HFpEF), but the mechanisms by which myocardial fibrosis exerts this deleterious effect are unclear. We aimed to determine whether myocardial fibrosis causes changes in cardiovascular structure and function, circulating biomarkers and functional status.Methods: Mediation analyses of data from the PIROUETTE (The Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) trial were conducted using the Baron and Kenny approach under a structural equation modelling framework to estimate average causal mediation effects, in order to determine whether changes in myocardial ECV, absolute myocardial extracellular matrix volume, and myocardial cellular volume (the mediator variables) following antifibrotic therapy, caused changes in cardiovascular structure and function, circulating biomarkers and functional status (the outcome variables).Results: Regression of myocardial fibrosis correlated with improvements in functional status (6-minute walk test distance [r=-0.28, p=0.021] and KCCQ clinical summary score [r=-0.23, P=0.045]). Pirfenidone had significant effects on the mediator variables, but the only outcome variable that demonstrated a treatment effect was left ventricular ejection fraction (LVEF) (p=0.011). The estimated average causal mediation effects of myocardial ECV, absolute myocardial extracellular matrix volume and absolute myocardial cellular volume on LVEF were 6.1%, 21.5%, and 13.7% respectively, none of which were significant (p=0.608, p=0.123 and p=0.186 respectively).Conclusion: Regression of myocardial fibrosis was associated with improvements in functional status. The small improvement in LVEF associated with pirfenidone was not mediated by myocardial fibrosis regression.(PIROUETTE; NCT02932566).