Chronic Inhibition of cGMP Phosphodiesterase 5A Improves Diabetic Cardiomyopathy

Abstract

Background—cGMP phosphodiesterase type 5 protein is upregulated in myocardial hypertrophy. However, it has never been ascertained whether phosphodiesterase type 5 inhibition exerts an antiremodeling effect in nonischemic heart disease in humans. We explored the cardioreparative properties of a selective phosphodiesterase type 5 inhibitor, sildenafil, in a model of diabetic cardiomyopathy.Methods and Results—Fifty-nine diabetic men (60.3±7.4 years) with cardiac magnetic resonance imaging consistent with nonischemic, nonfailing diabetic cardiomyopathy (reduced circumferential strain [σ], −12.6±3.1; increased left ventricular [LV] torsion [θ], 18.4±4.6°; and increased ratio of LV mass to volume, 2.1±0.5 g/mL) were randomized to receive sildenafil or placebo (100 mg/d). At baseline, the metabolic indices were correlated with torsion, strain, N-terminal pro–B-type natriuretic peptide, vascular endothelial growth factor, monocyte chemotactic protein-1, and blood pressure. After 3 months, sildenafil produced a significant improvement compared with placebo in LV torsion (Δθ: sildenafil, −3.89±3.11° versus placebo, 2.13±2.35°;P<0.001) and strain (Δσ: sildenafil, −3.30±1.86 versus placebo, 1.22±1.84;P<0.001). Sildenafil-induced improvement of LV contraction was accompanied by consistent changes in chamber geometry and performance, with a 6.5±11 improvement in mass-to-volume ratio over placebo (P=0.021). Monocyte chemotactic protein-1 and transforming growth factor-β were the only markers affected by active treatment (Δmonocyte chemotactic protein-1: −75.30±159.28 pg/mL,P=0.032; Δtransforming growth factor-β: 5.26±9.67 ng/mL,P=0.009). No changes were found in endothelial function, afterload, or metabolism.Conclusions—The early features of diabetic cardiomyopathy are LV concentric hypertrophy associated with altered myocardial contraction dynamics. Chronic phosphodiesterase type 5 inhibition, at this stage, has an antiremodeling effect, resulting in improved cardiac kinetics and circulating markers. This effect is independent of any other vasodilatory or endothelial effects and is apparently exerted through a direct intramyocardial action.Clinical Trial Registration—URL:http://www.clinicaltrials.gov. Unique identifier: NCT00692237.