Phase IV Study on New Insights in Remodeling of Diabetic Cardiomyopathy: Gender Difference in Intramyocardial, Molecular and Neuroendocrine Assessment in Response to Chronic Inhibition of Cyclic GMP Phosphodiesterase 5A

DCM is yet unclear and gender differences at baseline and a specific treatment have not been indicated. The study aims to characterize DCM, measuring molecular and neuroendocrine assessment to relate cardiac kinetic. The investigators will perform a randomized, placebo-controlled, double-blind study enrolling 120 diabetic patients with DCM, to evaluate gender responses to 5 months of PDE5Ai. The study will describe gender differences in DCM features. The proposed research will test whether PDE5Ai could become a new target for antiremodeling drugs and to discover a molecular pathways affected by this class of drugs and a network of circulating markers for the early diagnosis, monitoring and treatment of DCM.

In vitro studies have shown that phosphodiesterase 5 overexpression reduces cGMP levels and exacerbates remodeling. The investigators already studied the effects of 3-months daily Inhibition of cGMP hydrolysis through a phosphodiesterase 5A inhibitor (PDE5i) on cardiac remodeling in a cohort of asymptomatic, middle-aged men with type 2 diabetes mellitus (T2DM). CMR imaging revealed that diabetic cardiomyopathy in these patients produced an uncoupling in left ventricular contraction between longitudinal strain, which is reduced, and cardiac axial rotation, which is increased. Characterized DCM at early asymptomatic stages in men, we identified two circulating markers, TGF-beta and MCP-1 increased and significantly related to cardiac kinetic parameters. Then, the investigators found that long-term PDE5i restored coupling by reducing torsion and improving strain. It also reduced the ratio of left ventricular mass to end-diastolic volume that is increased in the presence of concentric hypertrophy. Circulating markers TGF-beta and MCP-1, significantly decreased after PDE5i vs. Placebo.These data suggest that phosphodiesterase 5 inhibition could work as an antiremodeling drug by acting directly on cardiac tissue, independently of other secondary vascular, endothelial, or metabolic effects.

However, these data need to be validated on a wide sample, for a longer duration of treatment, and including women, because of their high vulnerability to diabetic damage with preferential evolution in chronic heart failure, compared to males that frequently have ischemic complications.

T2DM is also considered a state of persistent inflammation that likely plays a role in development cardiovascular disease. Some studies have suggested that inflammation may impair the tissue repair process in diabetes, which appears delayed, unsupervised, and associated with higher levels of circulating classical monocytes.

The interaction between angiogenic cells and the endothelium is still critical for inflammatory cells to move and home in specific tissue sites in various pathological conditions. The Tie2 receptor is highly enriched in the endothelium and actively signals vascular quiescence. It is also expressed by in a unique subset of monocytes, Tie2-expressing monocytes (TEMs), which have been considered crucial for tissue remodeling and repair. Tie2 is stimulated by angiopoietin-1 (Ang1), a protein secreted by peri-endothelial cells and platelets. In the context of inflammation, a paralog of Ang1 called Ang2 competitively inhibits Tie2, normal endothelialcell function depends in part on a tightly regulated balance between Ang1 and Ang2. There is evidence of angiopoietin deregulation T2DM.