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


J Am Coll Cardiol. 2012;59(1):9-15. 

In This Article


The PDE5Is improved hemodynamic and clinical parameters in patients with CHF in a number of small trials (Table 1), although efficacy has not been tested in large-scale, long-term placebo-controlled trials. In small placebo-controlled trials of patients with CHF, sildenafil increased oxygen uptake,[3,4] increased cardiac index,[4,5] reduced systemic vascular resistance,[5] reduced aorta stiffness,[5] and improved exercise time,[3] 6-min walk distance,[4] depression scores,[6] and quality of life.[6] The hemodynamic improvements of Sildenafil were maintained at 4 weeks,[7] and the benefits of sildenafil on pulmonary arterial pressure, breathlessness score, and aerobic efficiency persisted at 6 months with a trend to greater improvement.[8]

Small trials in patients with CHF demonstrated the greatest benefit of PDE5Is in patients with secondary PAH and right ventricular failure.[4,9] The utility of PDE5Is in CHF patients without PAH is less clear, emphasizing the lack of large-scale testing.

In normal myocardium the presence of PDE5 is minimal to none. PDE5 expression, however, seems to be increased in a number of myocardial disease states, including chronic myopathies involving myocyte or ventricular hypertrophy. Histologic examination of myocardium from 6 patients with CHF and 6 normal donor hearts revealed PDE5 within the myocardium only in CHF hearts.[10] Myocardial PDE5 expression correlated with markers of oxidative stress.[10] In mouse[10] and rat[11] models, pressure overload resulted in increased myocardial PDE5 levels. Superoxide dismutase blunted the increase in PDE5 and protected against left ventricular hypertrophy and CHF, suggesting that oxidative stress increases PDE5 expression leading to hypertrophy.[10] In human surgical specimens, PDE5 was not expressed in normal myocardium; however, PDE5 and PDE5 messenger ribonucleic acid was upregulated in hypertrophied myocardium, but only in the chamber with pressure overload.[11] Furthermore, sildenafil increased the contractility of hypertrophied myocytes in cell-shortening experiments and in hypertrophied right ventricles in a Langendorff model.[11]

PDE5Is increase cGMP levels, which under normal circumstances would activate protein kinase G, decrease intracellular calcium levels, and reduce contractility. However, in hypertrophied myocardium, protein kinase G activity is inhibited, so cGMP preferentially shifts to its other pathway: inhibition of phosphodiesterase-3.[11] Thus, in hypertrophied myocardium, PDE5Is increase cGMP—which inhibits phosphodiesterase-3—thereby increasing cyclic adenosine monophosphate (cAMP), which activates protein kinase A; this, in turn, increases intracellular calcium and contractility.[11]

Sildenafil seems to induce additional mechanisms that prevent adverse remodeling.[12] To assess the effects of sildenafil on remodeling independent of infarct size, randomized treatment began 3 days after permanent coronary occlusion in a mouse model of myocardial infarction.[12] Compared with placebo, sildenafil preserved left ventricular function and reduced left ventricular dilation. Mice randomized to sildenafil demonstrated significantly less fibrosis, apoptosis, and ventricular hypertrophy. Moreover, sildenafil increased protein kinase G activation (from increased NO availability and cGMP levels), increased the Bcl-2/Bcl-2–associated X protein ratio, and inhibited the RhoA/Rho-kinase pathway (this effect was abolished by a protein kinase G inhibitor). The Rho kinase pathway is pathogenic, and Rho kinase inhibition has previously improved atherosclerosis, post-infarction remodeling, and cardiac hypertrophy.[12] The authors concluded that sildenafil reduced myocardial apoptosis, fibrosis, and hypertrophy through a mechanism that involves protein kinase G activation, Rho kinase inhibition, and increased Blc-2 (anti-apoptotic, see following text).[12]

Further evidence of sildenafil's benefits on reverse remodeling comes from a mouse model of cardiomyopathy induced by pressure overload with aortic banding.[13] Despite sustained pressure overload, sildenafil reversed pre-established maladaptive responses to pressure overload, including eccentric remodeling, maladaptive molecular signaling, hypertrophy, fibrosis, and depression of function.[13,14] In addition, sildenafil improved endothelial-mediated vasodilation in patients with CHF.[15]

In conclusion, in patients with CHF, sildenafil improves numerous hemodynamic and clinical parameters both acutely and chronically. In experimental models, sildenafil also benefits cardiac remodeling, apoptosis, fibrosis, and hypertrophy. The heterogeneous nature of CHF requires large scale, long-term placebo-controlled trials with clinical endpoints to determine efficacy. To date, no studies powered to assess mortality have been completed, and the clinical utility of PDE5Is in CHF remains unclear.