1. Long-Term Use of Sildenafil in the Therapeutic Management of Heart Failure Marco Guazzi, MD, PhD, FACC, Michele Samaja PhD, Ross Arena, PhD 1, Marco Vicenzi, MD, Maurizio D. Guazzi, MD, PhD 1 : Cardiopulmonary Unit, Heart Failure Unit, Institute of Cardiology, University of Milano 3 : Department of Physical Therapy, Richmond, Virginia J Am Coll Cardiol 2007;50:2136-2144

2. Abnormal skeletal muscle signaling due to stimulation by muscle metabolic byproducts (ergoreflex) is becoming a prominent concept in our quest to understand and treat this disease, and interventions effective in reducing the peripheral stimulus have been repeatedly advocated. Long-Term Use of Sildenafil in Heart Failure Background (1) In HF, much attention has lately been focused on the skeletal muscle as an elicitor of autonomic outflow, a mediator of fatigue, and a source of excessive ventilatory stimulus which leads to breathlessness sensation. > >

3. It is conceivable that muscle reflex contribution to ventilation can be reduced by improving endothelial function and up-regulating muscle perfusion because an endothelium-mediated vasodilation modulates exercise neurogenic vasoconstriction and up-regulates perfusion to working muscles. Sildenafil is a specific inhibitor of type 5 phosphodiesterase (PDE 5 ) that increases cGMP nitric oxide (NO) availability and NO-mediated vasodilation in HF patients. > > Evidence for sildenafil use in HF patients is limited to acute studies showing its ability to improve myocardial contractility, to blunt adrenergic stimulation and to improve pulmonary hemodynamics at rest and on exertion. > Long-Term Use of Sildenafil in Heart Failure Background (2)

4. Aims of the present study were three-fold: 1)To investigate whether an endothelium-mediated modulation of muscle oversignaling is a mechanism whereby sildenafil can reduce exercise hyperventilation and heighten exercise capacity. 2)To assess whether the compound maintains this ability during chronic use without adverse effects. 3)To define whether there is a rational basis for larger, long-term therapeutic trials with PDE5 inhibition in CHF. Long-Term Use of Sildenafil in Heart Failure Objectives

5. Vascular Studies * Ergoreflex test Cardiopulmonary Exercise Test (CPET) 0 90 180 46 CHF patients PLACEBO (3 times/day) SILDENAFIL (50 mg, 3 times/day) Days -2 * : Brachial artery flow mediated dilatation (FMD) Prospective, placebo-controlled, double-blind design Measurements at day -2 were performed at baseline, and those at day -1 were performed after a single oral dose of sildenafil (50 mg) in all participants. Holter monitoring 23 21 20 Long-Term Use of Sildenafil in Heart Failure Study Design

6. Eligibility Criteria: > LVEF  40% > Non-smokers (carboxyhemoglobin < 2%) > No physical limitations to complete a maximal exercise testing Exclusion Criteria: > Systemic hypotension > Therapy with nitrate preparations > Primary lung disease and/or COPD > Diabetes mellitus > Severe renal failure (serum creatinine  3 mg.dL -1 ) 46 male CHF pts in stable NYHA class II to III Long-Term Use of Sildenafil in Heart Failure Study Population

7. Long-Term Use of Sildenafil in Heart Failure Baseline Characteristics

8. Long-Term Use of Sildenafil in Heart Failure Hemodynamics, Vascular, Respiratory Variables and Quality of Life

9. Long-Term Use of Sildenafil in Heart Failure Ergoreflex Assessment p<0.01 vs no occlusion; § p<0.01 versus palcebo

10. Long-Term Use of Sildenafil in Heart Failure Correlation Analyses Between FMD and the Ergoreflex Component of Ventilation

11. Long-Term Use of Sildenafil in Heart Failure Correlation Analyses Between Changes from Baseline in the Ergoreflex and Those in Peak VO2 and VE/VCO2 slope

12. Long-Term Use of Sildenafil in Heart Failure Conclusions In CHF, prolonged use of sildenafil improved the nitric oxide-mediated vasodilation, tempered the peripheral stimulus to hyperventilation, heightened ventilatory efficiency and exercise performance, and was associated with no relevant side effects. Chronic sildenafil seems to be a remedy based on CHF pathophysiology and devoid of remarkable adverse effects. These results suggest that larger long-term trials in CHF patients with utilization of PDE5 inhibition should be considered. > > >