Temporal relation between myocardial fibrosis and heart failure with preserved ejection fraction: Association with baseline disease severity and subsequent outcome

Importance: Among myriad changes occurring during the evolution of heart failure with preserved ejection fraction (HFpEF), cardiomyocyte-extracellular matrix interactions from excess collagen may affect microvascular, mechanical, and electrical function.
Objective: We hypothesized myocardial fibrosis (MF) is similarly prevalent both in those with HFpEF and those at risk for HFpEF, similarly associating with disease severity and outcomes.
Design: Observational cohort study from June 1, 2010 to September 17, 2015, followed until December 14, 2015.
Setting: Cardiovascular magnetic resonance (CMR) center serving an integrated health system.
Participants: Consecutive patients with preserved systolic function referred for CMR (n=1174). We identified 3 groups: 1) “at risk” for HFpEF (n=250) given elevated B-type natriuretic peptide (BNP); 2) HFpEF (n=160) by documented clinical diagnosis (e.g., signs, symptoms, or prior hospitalization for heart failure (HHF)); 3) no HFpEF (n=745). CMR excluded cardiac amyloidosis (n=19).
Exposure: MF quantified by extracellular volume (ECV) CMR measures.
Main Outcome Measure: Baseline BNP; subsequent HHF or death.
Results: Patients either at risk for HFpEF or with HFpEF mostly had elevated BNP and demonstrated similarly higher prevalence/extent of MF and worse prognosis compared to patients with no HFpEF who fared significantly better. Among those at risk for HFpEF or with HFpEF, the actual diagnosis of HFpEF did not associate with significant differences in MF or prognosis. Over a median of 1.9 years, 61 patients at risk for HFpEF or with HFpEF experienced adverse events (19 HHF, 48 deaths, 6 with both). In those with HFpEF, ECV associated with baseline log BNP (disease severity surrogate) in multivariable linear regression models, and associated with outcomes in multivariable Cox regression models (e.g., HR 1.75 per 5% increase in ECV, 95%CI 1.25-2.45, p=0.001 in stepwise model) whether grouped with patients at risk for HFpEF or not.
Conclusion and Relevance: Among myriad changes occurring during the apparent evolution of HFpEF where elevated BNP is prevalent, MF appears similarly prevalent in those with or at risk for HFpEF. Conceivably, MF might precede clinical HFpEF diagnosis. Regardless, MF associates with disease severity (i.e., BNP) and outcomes. Whether cells and secretomes mediating MF represent therapeutic targets in HFpEF warrants further evaluation.