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Original Investigation
September 2017

Temporal Relation Between Myocardial Fibrosis and Heart Failure With Preserved Ejection FractionAssociation With Baseline Disease Severity and Subsequent Outcome

Author Affiliations
  • 1Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 2UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, Pennsylvania
  • 3Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 4Centre for Imaging Sciences and Biomedical Imaging Institute, University of Manchester, Manchester, England
  • 5Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
  • 6National Heart, Lung, and Blood Institute, Bethesda, Maryland
  • 7Houston Methodist DeBakey Heart and Vascular Center, Houston, Texas
  • 8Center for Clinical Trials and Data Coordination, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
  • 9Department of Cardiology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
  • 10Cardiology Division, Stony Brook University, Stony Brook, New York
  • 11Program of Cardiovascular Diseases, Center for Applied Medical Research, Department of Cardiology and Cardiac Surgery, University Clinic, University of Navarra, Pamplona, Spain
  • 12CIBERCV, Carlos III Institute of Health, Madrid, Spain
  • 13Department of Medicine, Mayo Clinic, Rochester, Minnesota
  • 14Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois
JAMA Cardiol. 2017;2(9):995-1006. doi:10.1001/jamacardio.2017.2511
Key Points

Question  Does myocardial fibrosis occur during the evolution of heart failure with preserved ejection fraction (HFpEF) and is it associated with disease severity and outcome in those with HFpEF or at risk for HFpEF?

Findings  In this cohort study of 410 patients at risk for or with a diagnosis of HFpEF, myocardial fibrosis quantified by extracellular volume was associated with baseline brain-type natriuretic peptide level (disease severity surrogate) in linear regression models, and outcomes of heart failure hospitalization or death in Cox models.

Meaning  Among myriad changes in evolving HFpEF, myocardial fibrosis is prevalent and was associated with disease severity and adverse outcomes, so whether the cells and secretomes mediating myocardial fibrosis represent therapeutic targets in HFpEF warrants further evaluation.

Abstract

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  To investigate whether 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, Setting, and Participants  Observational cohort study from June 1, 2010, to September 17, 2015, with follow-up until December 14, 2015, at a cardiovascular magnetic resonance (CMR) center serving an integrated health system. Consecutive patients with preserved systolic function referred for CMR were eligible. Cardiovascular magnetic resonance was used to exclude patients with cardiac amyloidosis (n = 19).

Exposures  Myocardial fibrosis quantified by extracellular volume (ECV) CMR measures.

Main Outcome and Measures  Baseline BNP; subsequent hospitalization for heart failure or death.

Results  Of 1174 patients identified (537 [46%] female; median [interquartile range {IQR}] age, 56 [44-66] years), 250 were “at risk” for HFpEF given elevated brain-type natriuretic peptide (BNP) level; 160 had HFpEF by documented clinical diagnosis, and 745 did not have HFpEF. Patients either at risk for HFpEF or with HFpEF demonstrated similarly higher prevalence/extent of MF and worse prognosis compared with patients with no HFpEF. Among those at risk for HFpEF or with HFpEF, the actual diagnosis of HFpEF was not associated with significant differences in MF (median ECV, 28.2%; IQR, 26.2%-30.7% vs 28.3%; IQR, 25.5%-31.4%; P = .60) or prognosis (log-rank 0.8; P = .38). Over a median of 1.9 years, 61 patients at risk for HFpEF or with HFpEF experienced adverse events (19 hospitalization for heart failure, 48 deaths, 6 with both). In those with HFpEF, ECV was associated with baseline log BNP (disease severity surrogate) in multivariable linear regression models, and was associated with outcomes in multivariable Cox regression models (eg, hazard ratio 1.75 per 5% increase in ECV, 95% CI, 1.25-2.45; P = .001 in stepwise model) whether grouped with patients at risk for HFpEF or not.

Conclusions and Relevance  Among myriad changes occurring during the apparent evolution of HFpEF where elevated BNP is prevalent, MF was similarly prevalent in those with or at risk for HFpEF. Conceivably, MF might precede clinical HFpEF diagnosis. Regardless, MF was associated with disease severity (ie, BNP) and outcomes. Whether cells and secretomes mediating MF represent therapeutic targets in HFpEF warrants further evaluation.

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