Author + information
- Received March 13, 2014
- Revision received May 6, 2014
- Accepted May 19, 2014
- Published online August 12, 2014.
- Brian R. Lindman, MD, MSCI∗∗ (, )
- Victor G. Dávila-Román, MD∗,
- Douglas L. Mann, MD∗,
- Steven McNulty, MS†,
- Marc J. Semigran, MD‡,
- Gregory D. Lewis, MD‡,
- Lisa de las Fuentes, MD, MS∗,
- Susan M. Joseph, MD∗,
- Justin Vader, MD, MS∗,
- Adrian F. Hernandez, MD, MHS† and
- Margaret M. Redfield, MD§
- ∗Washington University School of Medicine, St. Louis, Missouri
- †Duke University School of Medicine, Durham, North Carolina
- ‡Harvard University School of Medicine, Boston, Massachusetts
- §Mayo Clinic, Rochester, Minnesota
- ↵∗Reprint requests and correspondence:
Dr. Brian R. Lindman, Washington University School of Medicine, Cardiovascular Division, Campus Box 8086, 660 South Euclid Avenue, St. Louis, Missouri 63110.
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.
Objectives 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)
- diabetes mellitus
- exercise capacity
- heart failure with preserved ejection fraction
- left ventricular structure
This study was supported by National Institutes of Healthhttp://dx.doi.org/10.13039/100000002 grants U10HL084904 (data coordinating center), U10HL084907 (to Dr. Redfield), and U10HL110309 (to Drs. Dávila-Román, Mann, de las Fuentes, Joseph, and Vader). Dr. Lindman was supported by K23 HL116660 and Washington University Institute of Clinical and Translational Sciences grants UL1 TR000448 and KL2 TR000450 from the National Center for Advancing Translational Sciences of the National Institutes of Health. Dr. Dávila-Román was supported in part by the Barnes-Jewish Hospital Foundation. Dr. Lindman is a consultant for Gerson Lehrman Group Research; and has received research support from BG Medicine and Roche Diagnostics. Dr. Hernandez has financial relationships with Bristol-Myers Squibb, Novartis, and GlaxoSmithKline in the form of research grants to his institution. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received March 13, 2014.
- Revision received May 6, 2014.
- Accepted May 19, 2014.
- American College of Cardiology Foundation