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Original Investigation
March 2018

Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction

Author Affiliations
  • 1Department of Cardiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
  • 2Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston
  • 3Inova Heart and Vascular Institute, Falls Church, Virginia
  • 4Department of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts
  • 5Cardiovascular Research Center, Massachusetts General Hospital, Boston
  • 6Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
  • 7Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
  • 8Ciccarone Center for the Prevention of Heart Disease, The Johns Hopkins University, Baltimore, Maryland
  • 9Division of Hematology/Oncology, Department of Medicine, University of Vermont Larner College of Medicine, Burlington
  • 10Department of Medicine, Johns Hopkins Medical Institutions, The Johns Hopkins University, Baltimore, Maryland
  • 11Department of Cardiology, Heart and Vascular Institute, Johns Hopkins Medical Institutions, The Johns Hopkins University, Baltimore, Maryland
  • 12Division of Cardiovascular Medicine, Keck School of Medicine of University of Southern California, Los Angeles
  • 13Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  • 14Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
  • 15Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland
  • 16Center of Research on Psychology in Somatic Diseases, Department of Medical and Clinical Psychology, Tilburg University, Tilburg, the Netherlands
  • 17Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 18Framingham Heart Study, Framingham, Massachusetts
  • 19Cardiovascular Medicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
  • 20Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, Massachusetts
  • 21Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
  • 22Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle
  • 23Kaiser Permanente Washington Health Research Institute, Seattle
  • 24Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
  • 25Department of Biostatistics, University of Washington, Seattle
  • 26Department of Family Medicine and Public Health, University of California, San Diego, La Jolla
  • 27Division of Cardiology, Department of Medicine, Rutgers New Jersey Medical School, Newark
  • 28Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 29Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina
  • 30Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina
JAMA Cardiol. 2018;3(3):215-224. doi:10.1001/jamacardio.2017.4987
Key Points

Question  What cardiovascular biomarkers are associated with the development of heart failure with preserved vs reduced ejection fraction?

Findings  Among 22 756 participants enrolled in 4 longitudinal community-based cohorts, several biomarkers of renal dysfunction, endothelial dysfunction, and inflammation, in addition to natriuretic peptides and high-sensitivity troponin, were associated with incident heart failure with reduced ejection fraction. By contrast, only natriuretic peptides and urinary albumin to creatinine ratio were associated with heart failure with preserved ejection fraction.

Meaning  These findings highlight the need for future studies focused on identifying novel biomarkers of heart failure with preserved ejection fraction.

Abstract

Importance  Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood.

Objective  To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population.

Design, Setting, and Participants  This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017.

Exposures  The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6.

Main Outcomes and Measures  Development of incident HFpEF and incident HFrEF.

Results  Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF.

Conclusions and Relevance  Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.

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