title: Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging.
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.
  
  
  RESULTS
  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.
  
  
  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.
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannetta
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Isidori
authors.forename: Nicola
authors.initials: N
authors.lastname: Galea
authors.forename: Iacopo
authors.initials: I
authors.lastname: Carbone
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mandosi
authors.forename: Carmine D
authors.initials: CD
authors.lastname: Vizza
authors.forename: Fabio
authors.initials: F
authors.lastname: Naro
authors.forename: Susanna
authors.initials: S
authors.lastname: Morano
authors.forename: Francesco
authors.initials: F
authors.lastname: Fedele
authors.forename: Andrea
authors.initials: A
authors.lastname: Lenzi
mesh_terms: D000368:Aged; D057791:Cardiac Imaging Techniques / Q000379:methods; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000473:pathology*; D005500:Follow-Up Studies; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects; D054159:Torsion, Mechanical; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human