• Barry A Borlaug, Gregory D Lewis, Steven E McNulty, Marc J Semigran, Martin LeWinter, Horng Chen, Grace Lin, Anita Deswal, Kenneth B Margulies, and Margaret M Redfield.
• From the Department of Medicine, Division of Cardiology, Mayo Clinic, Rochester, MN (B.A.B., H.C., G.L., M.M.R.); Department of Medicine, Massachusetts General Hospital, Boston (G.D.L., M.J.S.); Department of Medicine, Duke Clinical Research Institute, Durham, NC (S.E.M.); Department of Medicine, Cardiology Unit, University of Vermont College of Medicine, Burlington (M.L.W.); Department of Medicine, Michael E. DeBakey VA Medical Center and Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); and Department of Medicine, University of Pennsylvania, Translational Research Center, Philadelphia (K.B.M.). borlaug.barry@mayo.edu.
• Circ Heart Fail. 2015 May 1;8(3):533-41.

BackgroundEarly studies showed beneficial effects of phosphodiesterase 5 inhibitors on cardiovascular function in heart failure (HF) patients, but the RELAX trial observed no improvement in exercise capacity with sildenafil treatment in subjects with HF and preserved ejection fraction.Methods And ResultsA subgroup of participants in the RELAX trial (n=48) underwent comprehensive noninvasive cardiovascular assessment before and after treatment with sildenafil or placebo in a prospective ancillary study. Left ventricular contractility was assessed by peak power index and stroke work index. Systemic arterial load was assessed by arterial elastance (Ea) and right ventricular afterload by pulmonary artery systolic pressure. Endothelial function was assessed by reactive hyperemia index after upper arm cuff occlusion. Compared with placebo (n=25), sildenafil (n=23) decreased Ea (-0.29±0.28 mm Hg/mL versus +0.02±0.29, P=0.008) and tended to improve reactive hyperemia index (+0.30±0.45 versus -0.17±0.30, P=0.054). In contrast, left ventricular contractility was reduced by 11% to 16% with sildenafil compared with placebo (ΔPWR/EDV -52±70 versus +0±40 mm Hg/s, P=0.006; ΔSW/EDV +0.3±5.8 versus -6.0±5.1 mm Hg, P=0.04). Sildenafil had no effect on pulmonary artery systolic pressure.ConclusionsIn subjects with HF and preserved ejection fraction, sildenafil displayed opposing effects on ventricular and vascular function. We speculate that beneficial effects of phosphodiesterase 5 inhibitors in the systemic vasculature and endothelium were insufficient to improve clinical status or that the deleterious effects on left ventricular function offset any salutary vascular effects, contributing to the absence of benefit observed with sildenafil in subjects with HF and preserved ejection fraction in the RELAX trial.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.© 2015 American Heart Association, Inc.

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