title: Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology.
abstract: BACKGROUND
  Various pathways have been implicated in the pathogenesis of heart failure (HF) with preserved ejection fraction (HFPEF). Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF).
  
  
  RESULTS
  This study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα) axis in community-based cohorts of HFPEF patients (n = 100), HFREF patients (n = 100) and healthy controls (n = 50). Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2), and a non-TNFα cytokine, interleukin-6 (IL-6), in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF.
  
  
  CONCLUSIONS
  Inflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Brendan N
authors.initials: BN
authors.lastname: Putko
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Zuocheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lo
authors.affiliation: Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Todd
authors.initials: T
authors.lastname: Anderson
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Harald
authors.initials: H
authors.lastname: Becher
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.affiliation: Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000368:Aged; D000085962:Angiotensin-Converting Enzyme 2; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology*; D006334:Heart Function Tests; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood*; D013318:Stroke Volume; D014463:Ultrasonography
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2