3: Department of Physical Therapy, Richmond, Virginia 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 J Am Coll Cardiol 2007;50:2136-2144 1: Cardiopulmonary Unit, Heart Failure Unit, Institute of Cardiology, University of Milano 3: Department of Physical Therapy, Richmond, Virginia Thank you very much Dr

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. > 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. What we know on sildenafil and CHF is that several beneficial effects of sildenafil have been demonstrated following acute administration, and these effects were observed in patients thought to be

Long-Term Use of Sildenafil in Heart Failure Background (2) > 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 (PDE5) that increases cGMP nitric oxide (NO) availability and NO-mediated vasodilation in HF patients. What we know on sildenafil and CHF is that several beneficial effects of sildenafil have been demonstrated following acute administration, and these effects were observed in patients thought to be > 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 Objectives Aims of the present study were three-fold: To investigate whether an endothelium-mediated modulation of muscle oversignaling is a mechanism whereby sildenafil can reduce exercise hyperventilation and heighten exercise capacity. To assess whether the compound maintains this ability during chronic use without adverse effects. To define whether there is a rational basis for larger, long-term therapeutic trials with PDE5 inhibition in CHF. What we know on sildenafil and CHF is that several beneficial effects of sildenafil have been demonstrated following acute administration, and these effects were observed in patients thought to be optimally treated with medical therapy. The effects have been shown to be directed to the heart such as an improvement in LV contractility through… and circulation with a specific effect on both pulmonary and systemic hemodynamic by endothelial-mediated effect In additional acute administration of sildenafil has been shown to be able to reduce sympathetic nervous system activation (neural discharge to the muscles). For the potential combination of all these effects sildenafil improves aerobic efficiency.

Long-Term Use of Sildenafil in Heart Failure Study Design Vascular Studies * Ergoreflex test Cardiopulmonary Exercise Test (CPET) 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. -1 Holter monitoring 23 21 20 The study design was organized as follows: 1 day before randomization patients underwent a non-invasive hemodynamic evaluation and a specific assessement of their quality of life, vascular function as endothelial responsiveness by measuring the flow-mediated brachial artery dilatation, ergoreflex test and cardiopulmonary exercise testing and results were taken as baseline. Then patients were discharged and a 6 month double-blind trial of sildenafil (23 patients) vs placebo (23 patients) was began. At 3 and 6 months measurements of all variables that were assessed at baseline were repeated.

Long-Term Use of Sildenafil in Heart Failure Study Population 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 This is a prospective, placebo controlled and double-blind trial We studied 46 CHF patients in stable class II to III NYHA selected according to the following eligibility criteria: -Significant LV systolic dysfunction (EF40%) -Non-smokers -No physical limitations to complete a maximal CPET Exclusion criteria were: -presence of systemic hypotension -documentation of primary lung disease and COPD -evidence of severe renal failure

Long-Term Use of Sildenafil in Heart Failure Baseline Characteristics Here are reported the baseline characteristics of the patients population. Controls are patients randomized to placebo and study patients are those who were randomized to sildenafil. The two group were similar on age, LVEF and pulmonary arterial pressure. There was also a quite similar quality of life score, endothelial vascular function and exercise performance. All patients were receiving renin agiotensis system inhibitors, most of them ACE-inhibitors and most of them were also receiving beta-blockers.

Long-Term Use of Sildenafil in Heart Failure Hemodynamics, Vascular, Respiratory Variables and Quality of Life Here are reported the baseline characteristics of the patients population. Controls are patients randomized to placebo and study patients are those who were randomized to sildenafil. The two group were similar on age, LVEF and pulmonary arterial pressure. There was also a quite similar quality of life score, endothelial vascular function and exercise performance. All patients were receiving renin agiotensis system inhibitors, most of them ACE-inhibitors and most of them were also receiving beta-blockers.

Long-Term Use of Sildenafil in Heart Failure Ergoreflex Assessment Here are reported changes observed in flow-mediated endothelial response and sildenafil induced a statistical improvement a 3 months that was sustained and mantained at 6 months. p<0.01 vs no occlusion; § p<0.01 versus palcebo

Long-Term Use of Sildenafil in Heart Failure Correlation Analyses Between FMD and the Ergoreflex Component of Ventilation Here are reported changes observed in flow-mediated endothelial response and sildenafil induced a statistical improvement a 3 months that was sustained and mantained at 6 months.

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 Here are reported changes observed in flow-mediated endothelial response and sildenafil induced a statistical improvement a 3 months that was sustained and mantained at 6 months.

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. > > What we know on sildenafil and CHF is that several beneficial effects of sildenafil have been demonstrated following acute administration, and these effects were observed in patients thought to be