title: Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study.
abstract: BACKGROUND
  The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) study was a multicenter, randomized trial of sildenafil versus placebo in heart failure with preserved ejection fraction (HFpEF) with rigorous entry criteria and extensive phenotypic characterization of participants.
  
  
  OBJECTIVE
  The aim of this study was to characterize clinical features, exercise capacity, and outcomes in patients with HFpEF with or without diabetes and gain insight into contributing pathophysiological mechanisms.
  
  
  METHODS
  The RELAX study enrolled 216 stable outpatients with heart failure, an ejection fraction ≥ 50%, increased natriuretic peptide or intracardiac pressures, and reduced exercise capacity. Prospectively collected data included echocardiography, cardiac magnetic resonance, a comprehensive biomarker panel, exercise testing, and clinical events over 6 months.
  
  
  RESULTS
  Compared with nondiabetic patients (n = 123), diabetic HFpEF patients (n = 93) were younger, more obese, and more often male and had a higher prevalence of hypertension, renal dysfunction, pulmonary disease, and vascular disease (p < 0.05 for all). Uric acid, C-reactive protein, galectin-3, carboxy-terminal telopeptide of collagen type I, and endothelin-1 levels were higher in diabetic patients (p < 0.05 for all). Diabetic patients had more ventricular hypertrophy, but systolic and diastolic ventricular function parameters were similar in diabetic and nondiabetic patients except for a trend toward higher filling pressures (E/e') in diabetic patients. Diabetic patients had worse maximal (peak oxygen uptake) and submaximal (6-min walk distance) exercise capacity (p < 0.01 for both). Diabetic patients were more likely to have been hospitalized for heart failure in the year before study entry (47% vs. 28%, p = 0.004) and had a higher incidence of cardiac or renal hospitalization at 6 months after enrollment (23.7% vs. 4.9%, p < 0.001).
  
  
  CONCLUSIONS
  HFpEF patients with diabetes are at increased risk of hospitalization and have reduced exercise capacity. Multimorbidity, impaired chronotropic reserve, left ventricular hypertrophy, and activation of inflammatory, pro-oxidative, vasoconstrictor, and profibrotic pathways may contribute to adverse outcomes in HFpEF patients with diabetes. (Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure [The RELAX Study]; NCT00763867).
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri. Electronic address: blindman@dom.wustl.edu.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lindman
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Dávila-Román
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
authors.affiliation: Duke University School of Medicine, Durham, North Carolina.
authors.forename: Steven
authors.initials: S
authors.lastname: McNulty
authors.affiliation: Harvard University School of Medicine, Boston, Massachusetts.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Semigran
authors.affiliation: Harvard University School of Medicine, Boston, Massachusetts.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewis
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Lisa
authors.initials: L
authors.lastname: de las Fuentes
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Joseph
authors.affiliation: Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Justin
authors.initials: J
authors.lastname: Vader
authors.affiliation: Duke University School of Medicine, Durham, North Carolina.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Hernandez
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Redfield
mesh_terms: D000368:Aged; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000175:diagnosis* / Q000188:drug therapy / Q000453:epidemiology; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate
keywords: biomarkers; diabetes mellitus; exercise capacity; heart failure with preserved ejection fraction; left ventricular structure
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