Viagra for failing hearts

November 18, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Milan, Italy & Richmond, VA

Sildenafil, a type 5 phosphodiasterase inhibitor, was originally designed as a blood pressure medicine before it was found to have beneficial sexual effects. Current research has focused on the role of sildenafil in chronic heart failure. Its main vascular effect is reduction of pulmonary vascular resistance, however in heart failure patients it also has beneficial effects on myocardial contractility, afterload, and endothelial function. A new study, published in the Journal of the American College of Cardiology, has examined the effect of long-term sildenafil treatment on heart failure symptoms and hemodynamic parameters.

The focus of the study is on the hypothesis that abnormalities in the ergo-ventilatory reflex contribute to heart failure pathogenesis. “Ergo-” means work; this reflex is initiated by receptors in skeletal muscle that respond to work done. The response to work is an increase in ventilation and activation of the sympathetic nervous system. In heart failure, this reflex is hyperactive, resulting in excessive ventilatory response and sympathetic activation, muscle weakness and fatigue. The authors hypothesize that sildenafil might improve endothelial function and improve hemodynamics, helping to correct the metabolic derangements which lead to altered ergo-ventilatory responses in patients with heart failure.

Forty-six patients with ischemic or idiopathic heart failure were recruited. All had ejection fraction less than 45%, NYHA functional class II or III, and no evidence of obstructive lung disease by pulmonary function testing. The exclusion criteria was extensive, and included patients with systolic blood pressure >140 or <110, diabetes, lung disease, valvular heart disease, neuromuscular disorders or atrial fibrillation. Participants could not be taking nitrates, aspirin, statins, antioxidant vitamins, or xanthine oxidase inhibitors, as these meds could affect endothelial function or interact with sildenifil’s mechanism of action. Subjects were randomized to receive placebo or oral sildenafil 50 mg three times per day for 180 days.

Baseline characteristics were similar in patients randomized to receive sildenafil or placebo. The two groups has similar ages, BMI, medicine regimens, ejection fractions, systemic and pulmonary pressures, exercise performance, ventilatory efficiency, quality of life, and ergoreflexes. All participants were given a single dose of sildenafil prior after randomization to ensure that the hemodynamic response to sildenafil was similar between groups, which was in fact the case.

At 6 months, sildenafil treatment was associated with in a reduction in pulmonary artery pressure (24 vs. 34 mm Hg, p<0.001), increased peak VO2 (19 vs. 15 ml/min/kg, p<0.001), improved ergo-ventilatory reflex (1.9 vs. 7.5, p<0.001), and improved subjective quality of life measures, including relief of breathlessness and improved emotional function. Sildenafil was tolerated well with flushing as the main side effects. No increased in tachyarrhythmias were observed.

The accompanying editorial by Steven Goldsmith notes a few cautions regarding proceeding with larger studies of PDE-5 inhibition in heart failure, most notably a concern regarding possible inotropic effects. He recalls the experience with PDE-3 inhibitors like milrinone, which actually cause increased mortality with long-term use. As to the ergoreflex hypothesis, they demonstrate improvement in this parameter and improvement in hemodynamics. Which finding is causal is impossible to know; the most that can be said is that their findings are consistent with a role for abnormal ergoreflex in heart failure pathogenesis.

The symptomatic improvement and improved hemodynamics demonstrated in this small study are encouraging. The long list of medicines and comorbidities that were excluded from this trial could pose a hurdle when considering larger trials. Future work should examine whether the benefits of sildenafil are shared by a more typical ischemic heart failure patient who is on optimal medical management including an aspirin, statin, and ACE inhibitor.

1. ''Marco Guazzi, Michele Samaja, Ross Arena, Marco Vicenzi, and Maurizio D. Guazzi. Long-Term Use of Sildenafil in the Therapeutic Management of Heart Failure. J Am Coll Cardiol In Press: November 12, 2007. doi:10.1016/j.jacc.2007.07.078''

2. ''Steven R. Goldsmith. Type 5 Phosphodiesterase Inhibition in Heart Failure: The Next Step. J Am Coll Cardiol In Press: November 12, 2007. doi:10.1016/j.jacc.2007.07.075''