This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Rationale for this study is provided by proven benefits of PDE-5 inhibition in patients with pulmonary hypertension, emerging evidence of benefit in HF with systolic dysfunction in pre-clinical and early clinical studies, seminal studies in animal models of pressure overload suggesting unique activation of cardiac PDE-5 in pressure overload hypertrophy and animal studies suggesting that PDE-5 up-regulation mediates hypo-responsiveness to natriuretic peptides and contributes to sodium retention in HF. In aggregate, these studies suggest PDE-5 inhibition may provide beneficial effects on the heart, peripheral vasculature, pulmonary vasculature, kidney and neuroendocrine function. Such multi-system effects suggest the potential for PDE-5 inhibition to ameliorate several key pathophysiological perturbations and thus, improve exercise capacity and clinical status in DHF. Study Design: This is a double-blind, placebo controlled study testing the hypothesis that chronic PDE-5 inhibition (Sildenafil) improves exercise capacity and clinical status in patients with heart failure (HF) and normal ejection fraction (diastolic HF, DHF). The study also measures the effect of this therapy on key pathophysiological parameters which are postulated to impact clinical status and exercise performance in DHF. Intervention: PDE-5 inhibition (Sildenafil) vs Placebo (20 mg tid for 12 weeks followed by 60 mg tid for 12 weeks).
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