Cardiac Uses of Phosphodiesterase-5 Inhibitors

Bryan G. Schwartz, MD; Laurence A. Levine, MD; Gary Comstock, MD; Vera J. Stecher, PhD; Robert A. Kloner, MD, PhD

Disclosures

J Am Coll Cardiol. 2012;59(1):9-15. 

In This Article

Abstract and Introduction

Abstract

Phosphodiesterase-5 inhibitors (PDE5Is) improve erectile function by enhancing nitric oxide availability in the penis and its supplying vasculature, resulting in vasodilation and increased blood flow. PDE5Is might benefit cardiovascular diseases because phosphodiesterase-5 is also located elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. PDE5Is are approved for pulmonary arterial hypertension, given that they improved several hemodynamic and clinical parameters in large randomized trials. Initial evidence suggests that PDE5Is benefit patients with congestive heart failure and secondary pulmonary hypertension. PDE5Is seem to improve hemodynamic and clinical parameters in patients with high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. In climbers with prior episodes of HAPE, PDE5Is prevented HAPE in 2 small randomized trials. In small randomized trials of PDE5Is, patients with Raynaud's phenomenon demonstrated improved blood flow, fewer symptoms and frequency of attacks, and resolution of digital ulcers. In addition to enhancing vasodilation, PDE5Is seem to protect the myocardium through complex pathways that involve nitric oxide, cyclic guanosine monophosphate, protein kinase G, extracellular-signal-regulated kinase, B-cell lymphoma protein-2, and Rho kinase inhibition. In animal models of acute myocardial infarction, PDE5Is consistently reduced infarct size indicating cardioprotection and PDE5Is also promote reverse remodeling and reduce myocardial apoptosis, fibrosis, and hypertrophy. PDE5Is might also benefit patients with treatment-resistant hypertension, preeclampsia, or peripheral arterial disease. This review presents the pathophysiology and trial data with regard to the use of PDE5Is for cardiac diseases.

Introduction

Phosphodiesterase-5 inhibitors (PDE5Is) are widely used for erectile dysfunction, making sildenafil and tadalafil among the 75 most popular prescription drugs dispensed in the United States. Phosphodiesterase type 5 (PDE5), however, is not confined to the human penis; it is found elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. In fact, the PDE5I sildenafil was originally investigated for its potential in treating angina. The PDE5Is demonstrated only marginal benefit for angina in clinical trials, but patients did demonstrate the peculiar "side effect" of improved erections. After extensive clinical trials and years of experience in treating erectile dysfunction, PDE5Is now have a proven safety record: they do not increase cardiovascular events (even in patients with coronary artery disease or congestive heart failure) and are safe in combination with most other medications (contraindicated with all nitrates, use with caution with alpha-blockers, might require dose adjustments with drugs that alter the cytochrome P450 3A4 metabolic pathway).[1] Reviewed elsewhere,[2] sildenafil and tadalafil have been approved for use in patients with pulmonary arterial hypertension (PAH) and are now prescribed as first-line therapy for many such patients. Initial investigation suggests that PDE5Is might benefit other cardiovascular diseases, including congestive heart failure (CHF), myocardial infarction, altitude sickness, hypertension, and Raynaud's phenomenon. This review will explore the data and theory with regard to the use of PDE5Is in cardiovascular diseases other than PAH.

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