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 (60.3Ϯ7.4 years) with cardiac magnetic resonance imaging consistent with nonischemic, nonfailing diabetic cardiomyopathy (reduced circumferential strain [], Ϫ12.6Ϯ3.1%; increased left ventricular [LV] torsion [], 18.4Ϯ4.6°; and increased ratio of LV mass to volume, 2.1Ϯ0.5 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 (⌬: sildenafil, Ϫ3.89Ϯ3.11°versus placebo, 2.13Ϯ2.35°; PϽ0.001) and strain (⌬: sildenafil, Ϫ3.30Ϯ1.86% versus placebo, 1.22Ϯ1.84%; PϽ0.001). Sildenafil-induced improvement of LV contraction was accompanied by consistent changes in chamber geometry and performance, with a 6.5Ϯ11% improvement in mass-to-volume ratio over placebo (Pϭ0.021). Monocyte chemotactic protein-1 and transforming growth factor-␤ were the only markers affected by active treatment (⌬monocyte chemotactic protein-1: Ϫ75.30Ϯ159.28 pg/mL, Pϭ0.032; ⌬transforming growth factor-␤: 5.26Ϯ9.67 ng/mL, Pϭ0.009). 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. (Circulation. 2012;125:2323-2333.) Key Words: cardiac magnetic resonance imaging Ⅲ diabetes mellitus type 2 Ⅲ diabetic diastolic heart failure Ⅲ fibrosis Ⅲ phosphodiesterase inhibitors heart failure I nhibition of phosphodiesterase type 5 (PDE5) exerts a relaxant effect on the smooth muscle cells of the trabecular structures of the corpora cavernosa, resulting in improved erections. More recently, PDE5 inhibitors have been claimed to offer cardioprotective effects. In vitro and in vivo studies in mice have shown that cGMP and its downstream protein kinase G are signals common to most pathways activated in cardiac hypertrophy. 1 Low levels of PDE5 protein and cGMP-mediated activation of protein kinase G have been found in unstimulated hearts. 2 However, in isolated mouse cardiomyocytes tr...

Six months of daily treatment with vardenafil improves parameters of endothelial inflammation and of hypogonadism in male patients with type 2 diabetes and erectile dysfunction: a randomized, double-blind, prospective trial

“…Data from the literature demonstrate an FMD improvement after chronic (13,24,25,26,27) and acute sildenafil administration in diabetic men (28). By using vardenafil, here, we demonstrate that FMD improves during treatment.…”

The safety and efficacy of Avanafil, a new 2ndgeneration PDE5i: comprehensive review and meta-analysis

“…In addition, recent data have documented that long-term treatment with PDE5is might improve underlying organic comorbidities, providing a general health benefit although ED cure is not possible. [56][57][58] A drug ensuring a more natural profile of action and lower incidence of side effects could theoretically guarantee lower dropout, higher ED recovery, or successful improvement of ED (Box 2). Longer studies and head-tohead trials are advisable to better clarify these points.…”

Cyclic GMP-Dependent Signaling in Cardiac Myocytes

“…75 Giannetta et al reported anti-remodeling effects and improved cardiac kinetics from 3 months sildenafil treatment in diabetic cardiomyopathy patients. 76 These results suggest that PDE5 inhibition is a promising new approach to treating various human heart diseases. A large placebo-controlled multicenter trial (RELAX, NCT00763867) led by NIH is ongoing to test sildenafil efficacy in heart failure patients with preserved ejection fraction.…”