Improved Heart Fibrosis, Functional Gains Linked in HFpEF Trial

Lisa Kuhns, PhD, for Medscape

February 24, 2022

The study covered in this summary was published on as a preprint and has not yet been peer-reviewed.

Key Takeaways

  • Improvement in markers of myocardial fibrosis in patients with heart failure with preserved ejection fraction (HFpEF) was tied to gains in functional status in an analysis from the PIROUETTE (Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) trial.

  • Regression of myocardial fibrosis on active therapy not associated with the small improvement in cardiac function observed in the trial, which assessed the antifibrosis agent pirfenidone in the setting of HFpEF.

Why This Matters

  • This analysis, together with the phenotyping conducted during PIROUETTE, assessed the impact that myocardial fibrosis has on cardiovascular structure and function.

  • The findings of this analysis provide evidence that myocardial fibrosis plays a mechanistic role in HFpEF.

Study Design

  • Researchers conducted a mediation analysis of data from the PIROUETTE trial.

  • The 94 study participants, with a mean age of 78 years, 46% of whom were female, were randomly assigned to pirfenidone or placebo for 52 weeks.

  • Eligible patients were 40 years or older with signs and symptoms of heart failure, a left ventricular ejection fraction (LVEF) of at least 45%, and elevated natriuretic peptide levels.

  • Most patients (95%) had New York Heart Association functional class II or III symptoms, mean left ventricular ejection fraction was 64%, median NT-proBNP was 1104 pg/mL, and mean myocardial extracellular volume (ECV) was 30.1%.

  • The primary outcome was change in myocardial fibrosis.

  • Analyses were conducted using the Baron and Kenny approach, with a structural equation modeling framework. The authors sought to determine whether changes in myocardial ECV, absolute myocardial extracellular matrix volume, or myocardial cellular volume after antifibrotic therapy led to changes in outcome variables, including cardiovascular structure and function, circulating biomarkers, and functional status.

Key Results

  • Change in myocardial ECV from baseline to week 52 was positively correlated with change in left ventricular end diastolic volume, indexed for body surface area (r, 0.23; P = .039) and inversely correlated with 6-minute walk distance (r, –0.28; P = .021) and Kansas City Cardiomyopathy Questionnaire Clinical Summary score (r, –0.23; P = .045).

  • Pirfenidone had a significant effect on myocardial ECV (–1.21%; P = .009) and absolute myocardial extracellular volume (–3.06 mL; P = .002), but not myocardial cellular volume at the P < .05 level of significance.

  • Pirfenidone demonstrated a treatment effect on LVEF (= .011) but did not show a significant treatment effect with other outcome variables.

  • The average causal mediation effects on LVEF were 6.1% for myocardial ECV, 21.5% for absolute myocardial extracellular matrix volume, and 13.7% for absolute myocardial cellular volume, but none of the effects were significant.


  • The findings are considered exploratory because the PIROUETTE trial was not powered for secondary outcomes.

  • The analyses are considered post hoc because they were not part of the statistical analysis plan for PIROUETTE.

  • An adjustment for multiple comparisons was not performed, so false-positive results are possible.


  • The work was funded by the National Institute for Health Research (United Kingdom), but views expressed in the publication are those of the authors.

  • Equipment used in the study was gifted by Roche Products Limited, but Roche had no involvement in study design, preparation, drafting, or editing of the manuscript.

  • One of the authors has served on advisory boards for Novartis, Boehringer Ingelheim and Lilly Alliance, and AstraZeneca; serves as an advisor for HAYA Therapeutics and PureTech Health; and has received research support from Amicus Therapeutics, Guerbet Laboratories Limited, and Univar Solutions B.V.

This is a summary of a preprint research study, Impact of Myocardial Fibrosis on Cardiovascular Structure, Function and Functional Status in Heart Failure With Preserved Ejection Fraction, written by Gavin Lewis of the University of Manchester Faculty of Biology Medicine and Health, United Kingdom, and colleagues. Preprints from are provided to you by Medscape. This study has not yet been peer-reviewed. The full text of the study can be found on


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