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

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 phosph...

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Published in:Circulation (New York, N.Y.) Vol. 125; no. 19; pp. 2323 - 2333
Main Authors: GIANNETTA, Elisa, ISIDORI, Andrea M, GALEA, Nicola, CARBONE, Iacopo, MANDOSI, Elisabetta, VIZZA, Carmine D, NARO, Fabio, MORANO, Susanna, FEDELE, Francesco, LENZI, Andrea
Format: Journal Article
Language:English
Published: Hagerstown, MD Lippincott Williams & Wilkins 15-05-2012
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Summary: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. 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. 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.
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ISSN:0009-7322
1524-4539
DOI:10.1161/CIRCULATIONAHA.111.063412