Studies showed that myocardial fibrosis is associated with increased hospitalizations for heart failure and mortality in patients with heart failure with preserved ejection fraction (HFpEF). The mechanisms for deleterious effects of myocardial fibrosis are unclear. Gavin Lewis et.al aimed to determine whether myocardial fibrosis causes changes in cardiovascular structure and function, circulating biomarkers and functional status.


Data was extracted from the PIROUETTE (The Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) trial which was conducted to evaluate the role of pirfenidone, in patients with HFpEF. CMR, echocardiography, electrocardiography, 6-minute walk test, laboratory tests and the Kansas City Cardiomyopathy Questionnaire (KCCQ) were performed at baseline and repeated after 52-weeks of treatment. This medication was associated with a modest reduction in myocardial fibrosis, as assessed by cardiac MRI, compared with placebo.
Mediation analyses of extracted data from above study were conducted in order to determine whether changes in myocardial fibrosis, measured using cardiac MR extracellular volume (ECV) following antifibrotic therapy, caused changes in cardiovascular structure and function, circulating biomarkers and functional status.
A total of 94 patients that were randomized. The mean age of patients was 78 years, and nearly all patients had New York Heart Association functional class II or III symptoms (95%), mean LV ejection fraction of 64% and median NT-proBNP of 1104 pg/ml.

Important observations of this study are
1) Change in myocardial ECV from baseline to week 52 showed a weak positive correlation with change in left ventricular end diastolic volume indexed for body surface area (p=0.039).
2) Change in ECV had a weak inverse correlation with 6 minute walk test distance (p=0.021),
3) Change in ECV had a weak inverse correlation with KCCQ Clinical Summary Score (p=0.045)
4) The magnitude of change in LV ejection fraction associated with treatment with pirfenidone was statistically significant but association was weak.
Limitations of this study are
1) PIROUETTE trial was not powered for secondary outcomes, thus the findings of this study are considered exploratory
2) no adjustment for multiple comparisons was performed therefore false positive results cannot be excluded
Authors concluded that regression of myocardial fibrosis was associated with improvements in functional status in heart failure. The small improvement in left ventricular ejection fraction associated with pirfenidone was not mediated by myocardial fibrosis regression.