Clinical Trial: Endocrine Cardiomyopathy in Cushing Syndrome: Response to Cyclic GMP PDE5 inhibitOrs

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: Study on New Insights in Remodeling of Endocrine Cardiomyopathies: Intramyocardial, Molecular and Neuroendocrine Assessment in Response to Chronic Inhibition of Cyclic GMP Phosphodiesterase 5A in

Brief Summary:

Pathophysiology of Cushing's Syndrome (CS) cardiomyopathy is yet unclear and a specific treatment have not been indicated. It was already demonstrated the positive impact of phosphodiesterase type 5A (PDE5A) inhibition in several models of cardiomyopathy and in a model of endocrine cardiomyopathy due to type 2 diabetes mellitus. In this patients with diabetic cardiomyopathy it was demonstrated an improvement in cardiac kinetic, geometry and performance parameters and reduction of the ambulatory measurement of waist circumference.

This represents the first study that evaluate heart remodeling and performance changes and metabolic/immunological/molecular parameters after 5-months of Tadalafil 20 mg in Cushing's Syndrome cardiomyopathy. The proposed research will test whether phosphodiesterase 5A inhibition could become a new target for anti-remodeling drugs and to discover molecular pathways affected by this class of drugs and a network of circulating markers (miRNA) for the early diagnosis of Cushing's Syndrome cardiomyopathy.

The investigators hypothesize that:

  • the signal molecules cGMP and cAMP could underlie the hypertrophic/profibrotic triggers related to this model of endocrine cardiomyopathy and that chronic inhibition of PDE5, activating cGMP signaling pathways, could improve cardiac remodeling due to CS;
  • PDE5 inhibition could have a role in lipolytic regulation;
  • neuroendocrine (e.g. natriuretic peptides) and metabolic markers and chemokines (e.g. MCP-1, TGF-ß) might relate with left ventricular remodeling in CS;
  • there are neuroendocrine (e.g. natriuretic peptides), metabolic markers and chemokines (e.g. MCP-1, TGF-ß) relat

    Detailed Summary:

    Mechanisms of action and evolutionary progression of Cushing's Syndrome (CS) cardiomyopathy are not yet been well elucidated and a specific treatment has not been identified. Our study aims to characterize the CS cardiomyopathy in terms of measuring the cardiac kinetic and performance parameters (tagged Cardiac Magnetic Resonance Imaging), fibrosis (T1-mapping technique). Our study will evaluate if PDE5A inhibition could become a new target for antiremodeling drugs in CS treated patients that developed cardiac hypertrophy and/or diastolic dysfunction independently of CS care accorded by current guidelines. The investigators also will explore the potential mechanisms of action of PDE5Ai: if exerted on cardiac tissue directly and contemporary also on other secondary pathways (analyzing vascular, endothelial, or metabolic markers).

    A multidisciplinary approach will allow identifying a cluster of cardiovascular (NT-ProBNP, TGFb, MCP1) and metabolic indices, oxidative stress markers (iNOS, COX2, ROS, RANTES) and miRNAs, whose variations will analyze together with the CS cardiomyopathy parameters measured at CMR and 2D-echocardiography.

    The Primary Objective is to evaluate the effects of PDE5Ai on Left Ventricular (LV) remodeling (kinetic and geometry parameters) at cine cardiac magnetic resonance (CMR) with tagging technique and contrast-enhanced and/or at 2D echocardiography with Tissue Doppler Imaging and speckle tracking in patients with CS cardiomyopathy

    Secondary Objectives :

    • to measure the effect of PDE5Ai on LV fibrosis at T1-mapping CMR at baseline and after PDE5Ai administration.
    • to measure the effect of PDE5Ai on cardiac performance at cine CMR and at 2D
      Sponsor: Andrea M. Isidori

      Current Primary Outcome: Change of Left ventricular torsion (°) evaluated through Cardiac Magnetic Resonance [ Time Frame: Baseline and 5 months after treatment ]

      Original Primary Outcome: Same as current

      Current Secondary Outcome:

      • Change of cardiac strain (σ - longitudinal shortening: strain %) evaluated through Cardiac Magnetic Resonance [ Time Frame: Baseline and 5 months after treatment ]
      • Quantification of Myocardial fibrosis assessed with T1-mapping through Cardiac Magnetic Resonance [ Time Frame: Baseline and 5 months after treatment ]
      • Assessment of inflammatory indices (TGF-beta, MCP1) [ Time Frame: Baseline and 5 months after treatment ]
      • Assessment of endothelial function markers (ET-1, VEGF) [ Time Frame: Baseline and 5 months after treatment ]
      • Assessment of cardiac remodeling indices (NT-proBNP) [ Time Frame: Baseline and 5 months after treatment ]
      • Assessment of oxidative stress markers (iNOS, COX2, ROS, P Selectin, ICAM1) in monocytes [ Time Frame: Baseline and 5 months after treatment ]
      • Assessment of plasmatic levels of cGMP [ Time Frame: Baseline and 5 months after treatment ]
      • Correlation of biochemical parameters with cardiac parameters assessed through Cardiac Magnetic Resonance [ Time Frame: Baseline and 5 months after treatment ]
      • Assessment of circulating microRNAs from plasma and white blood cells (miR208, 499, 1, 133, 29, 223, 222, 4454) and correlation of their levels to basal torsion, strain and fibrosis. [ Time Frame: Baseline ]
      • Changes of circulating miRNAs from plasma and white blood cells (miR208, 499, 1, 133, 29, 223, 222, 4454) [ Time Frame: Baseline and 5 months after treatment ]
      • Assessment of circulating pro-fibrotic and pro-inflammatory chemokines (MCP-1 and TGF-beta) and correlation to torsion, strain and fibrosis [ Time Frame: Baseline and 5 months after treatment ]
      • Change of parameters of body composition evaluated by MOC with total body DEXA scan [ Time Frame: Baseline and 5 months after treatment ]


      Original Secondary Outcome: Same as current

      Information By: University of Roma La Sapienza

      Dates:
      Date Received: November 16, 2015
      Date Started: November 2015
      Date Completion: April 2017
      Last Updated: November 20, 2015
      Last Verified: November 2015