Chronic Inhibition of cGMP Phosphodiesterase 5A Improves Diabetic Cardiomyopathy A Randomized, Controlled Clinical Trial Using Magnetic Resonance Imaging With Myocardial Tagging

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. Method 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 [sigma], -12.6 +/- 3.1%; increased left ventricular [LV] torsion [theta], 18.4 +/- 4.6 degrees; 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 (Delta theta: sildenafil, -3.89 +/- 3.11 degrees versus placebo, 2.13 +/- 2.35 degrees; P<0.001) and strain (Delta sigma: 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-beta were the only markers affected by active treatment (Delta monocyte chemotactic protein-1: -75.30 +/- 159.28 pg/mL, P=0.032; Delta transforming growth factor-beta: 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.