Chronic Inhibition of Cyclic GMP Phosphodiesterase 5A Improves Diabetic Cardiomyopathy: A Randomized, Controlled Clinical Trial using Magnetic Resonance Imaging with Myocardial Tagging
Background—Cyclic-GMP-Phosphodiesterase (PDE5) protein is upregulated in myocardial hypertrophy. However, it has never been ascertained if PDE5 inhibition exerts an anti-remodeling effect in non-ischemic heart disease in humans. We explored the cardioreparative properties of a selective PDE5A 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 non-ischemic, non-failing diabetic cardiomyopathy [reduced circumferential strain, σ: -12.6±3.1%, increased left ventricular (LV) torsion, θ: 18.4±4.6 and increased LV mass-to-volume ratio: 2.1±0.5g/mL], were randomized to receive sildenafil or placebo (100 mg/day). At baseline, the metabolic indices were correlated with torsion, strain, NT-proBNP, VEGF, MCP1 and blood pressure. After three months, sildenafil produced a significant improvement compared to placebo in LV torsion (Δθ: Sildenafil -3.89±3.11 vs. Placebo 2.13±2.35, p <0.001) and strain (Δσ: Sildenafil -3.30±1.86% vs. 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). MCP1 and TGF-β were the only markers affected by active treatment (ΔMCP1: -75.30±159.28 pg/mL, p=0.032; ΔTGF-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 PDE5 inhibition, at this stage, has an anti-remodeling 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 Information—clinicaltrial.gov; Identifier: NCT00692237.
- cardiac magnetic resonance imaging
- diabetes mellitus type 2
- diabetic diastolic heart failure
- phosphodiesterase inhibitors heart failure
- Received August 30, 2011.
- Accepted March 26, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited