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

• 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
• Subjects: Aged; Associated diseases and complications; Biological and medical sciences; Blood and lymphatic vessels; Cardiac Imaging Techniques - methods; Cardiology. Vascular system; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Diabetes Mellitus, Type 2 - complications; Diabetes. Impaired glucose tolerance; Diabetic Cardiomyopathies - drug therapy; Diabetic Cardiomyopathies - pathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Follow-Up Studies; Humans; Hypertrophy, Left Ventricular - drug therapy; Hypertrophy, Left Ventricular - pathology; Magnetic Resonance Imaging - methods; Male; Medical sciences; Middle Aged; Phosphodiesterase 5 Inhibitors - administration & dosage; Phosphodiesterase 5 Inhibitors - adverse effects; Piperazines - administration & dosage; Piperazines - adverse effects; Purines - administration & dosage; Purines - adverse effects; Sildenafil Citrate; Sulfones - administration & dosage; Sulfones - adverse effects; Torsion, Mechanical; Treatment Outcome; Ventricular Remodeling - drug effects; Endocrinopathy; Type 2 diabetes; Heart failure; phosphodiesterase inhibitors heart failure; Cardiomyopathy; cardiac magnetic resonance imaging; Metabolic diseases; 3',5'-GMP; Cardiovascular disease; Myocardial disease; Nuclear magnetic resonance imaging; Chronic; Heart disease; Fibrosis; diabetic diastolic heart failure; Tagging; diabetes mellitus type 2
• DOI: 10.1161/CIRCULATIONAHA.111.063412
• EISSN: 1524-4539
• ISSN: 0009-7322

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.