Clinical Trial: REmodelling in Diabetic CardiOmapathy: Gender Response to PDE5i InhibiTOrs

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: Phase IV Study on New Insights in Remodeling of Diabetic Cardiomyopathy: Gender Difference in Intramyocardial, Molecular and Neuroendocrine Assessment in Response to Chron

Brief Summary: Pathophysiology of diabetic cardiomyopathy (DCM) is yet unclear and gender differences at baseline and a specific treatment have not been indicated. The investigators already demonstrated the positive impact of phosphodiesterase type 5A (PDE5A) inhibition in men. The investigators' study aims to characterize DCM, measuring molecular and neuroendocrine assessment to relate to intramyocardial metabolism and cardiac kinetic. The investigators will perform a randomized, placebo-controlled, double-blind study enrolling 164 diabetic patients (females and males) with DCM, to evaluate gender responses to 6 months of PDE5A inhibitors (PDE5Ai). The investigators' 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 prediction of response to treatment of DCM.

Detailed Summary:

Pathophysiology of diabetic cardiomyopathy (DCM) is yet unclear and gender differences at baseline and a specific treatment have not been indicated. The investigators demonstrated the positive impact of phosphodiesterase type 5A (PDE5A) inhibition in men. The investigators' study aims to characterize DCM, measuring molecular and neuroendocrine assessment to relate to intramyocardial metabolism and cardiac kinetic. The investigators will perform a randomized, placebo-controlled, double-blind study enrolling 164 diabetic patients (females and males) with DCM, to evaluate gender responses to 6 months of PDE5A inhibitors (PDE5Ai). The investigators' 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.

The investigators will allow identifying a cluster of cardiovascular, metabolic and oxidative stress markers and miRNAs, whose variations together correlate with the DCM evolution and the prediction of risk and response to treatment.

The investigators will evaluate if PDE5Ai could become a new target for antiremodeling drugs; if the mechanism of action is direct on cardiac tissue, independently of other secondary effects and gender related difference.

Type 2 diabetes mellitus is associated with cardiac remodeling that may occur independently of ischemic heart disease, hypertension, or macrovascular complications.

In vitro studies have shown that phosphodiesterase 5 overexpression reduces cGMP levels and exacerbates remodeling. The investigators already studied the effects
Sponsor: University of Roma La Sapienza

Current Primary Outcome: Change from Baseline in Left Ventricular torsion (°) at 3 and 6 months [ Time Frame: 0 , + 3 months, + 6 months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Change from baseline in longitudinal shortening (Strain %) at 3 and 6 months [ Time Frame: time 0, +3 months, + 6 months ]
  Change of cardiac strain (longitudinal shortening: strain %), and of parameters of cardiac geometry and performance assessed through CMR with tagging before and after treatment and gender differences
• Change from baseline in Myocardial fibrosis at 3 and 6 months [ Time Frame: time 0, + 3 months, + 6 motnhs ]
  Quantification of Myocardial fibrosis assessed with T1-mapping to establish a new parametersfor the characterization of DCM and treatment efficacy, assessed through CMR before and after treatment and gender differences
• Change from baseline in Circulating microRNAs at 3 and 6 months [ Time Frame: Time 0, + 3 months, + 6 months ]

  Assessment of circulating microRNAs from plasma and white blood cells (miR208, 499, 1, 133, 29, 223, 222) and correlation of their levels to basal torsion, strain and fibrosis (molecular markers predictors of disease).

  Evaluation of miRNAs before and after treatment and and gender differences

• Change from baseline in Circulating pro-fibrotic and pro-inflammatory chemokines at 3 and 6 months [ Time Frame: Time 0, + 3 months, + 6 months ]
  Assessment of circulating pro-fibrotic and pro-inflammatory chemokines (MCP-1 and TGF-beta) and correlation to torsion, strain and fibrosis at time 0 and after treatment (markers predictors of disease progression and treatment efficacy) and differences in genders
• Markers predictor of answer to treatment [ Time Frame: Time 3 and 6 months ]
  Correlation of basal miRNAs and chemokines to cardiac parameters assessed through CMR after treatment (markers predictor of answer to treatment) and differences in genders
• Therapeutic efficacy markers [ Time Frame: Time 3 and 6 months ]
  Changes of circulating miRNAs from plasma and whit blood cells (miR208, 499, 1, 133, 29, 223, 222), after treatment (therapeutic efficacy measure) and changes in circulating chemokines. These results will be related to changes measured in cardiac torsion, strain, fibrosis and geometry (CMR). Gender differences will be analyzed
• Risk of progression to heart failure [ Time Frame: Time 3 and 6 months ]
  Stratification of patients in subgroup with respect to kinetic parameters (strain and torsion), cardiac fibrosis, geometry (LV mass and index of concentricity) and performance and metabolic parameters to identify patients at risk of progression to heart failure and differences in genders

Original Secondary Outcome: Same as current

Information By: University of Roma La Sapienza

Dates:
Date Received: February 26, 2013
Date Started: May 2014
Date Completion: March 2018
Last Updated: July 7, 2014
Last Verified: July 2014