Endocrine Cardiomyopathy in Cushing Syndrome: Response to Cyclic GMP PDE5 inhibitOrs
Condition: Cushing's Syndrome Cardiomyopathy
MeSH terms: Cardiomyopathies; Cushing Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2

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) related to cardiac disease in CS;

        -  miRNA expression [miR-208a, 499, 1, 133, 126, 29, 233, 222, 4454] might relate with left
           ventricular remodeling in CS;
    

Detailed description: 
      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
           echocardiography with Tissue Doppler Imaging and speckle tracking at baseline and after
           PDE5Ai administration.

        -  to measure the effect PDE5Ai of circulating cardiac-inflammatory-metabolic-endothelial
           molecular markers

        -  to measure the effect on bone and body composition

      Patients will be screened at time 0. Follow up visits will take place every 4 weeks during
      treatment for 5 months and 1 month after the end of treatment.

      Diagnostic procedures will include:

        -  physical examination with measurement of anthropometric parameters (weight, waist
           circumference, hip circumference) and vital signs (blood pressure, heart rate);

        -  blood sampling for assessing glucose and lipid metabolism, liver, renal, hematopoietic
           and coagulative function, thyroid and androgen hormones, ACTH and UFC, inflammatory
           parameters (cytokines, monocyte subpopulations) and microRNA;

        -  SF36, FSFI (in women), IEFF e IPSS (in men) questionnaires;

        -  cardiac exam, electrocardiogram and echocardiogram;

        -  MOC with DEXA;

        -  magnetic resonance imaging (MRI) with contrast-enhanced cardiac: T1-mapping for
           assessing cardiac fibrosis; tagging for evaluating kinetic parameters (torsion);

      This is a pilot study proof-of-concept, then 10 patients are sufficient to detect the effect
      of PDE5Ai on cardiac remodeling in CS cardiomyopathy. Estimating a 80% drop-out of the study
      due to the complexity of CS and the related neuro-psychiatric involvement, 18 CS patients
      will be enrolled.

      All variables will be tested for normality. Statistical analyzes will be performed using SPSS
      18.0. The comparison before and after treatment will be made by non parametric Wilcoxon test.
      The investigators will calculate the confidence interval for the prevalence of the effect
      measured by χ2 test or Fisher exact test. The correlation was perfomed by Rho di Spearman.
    

Intervention name(s): Tadalafil
Intervention type(s): Drug
Intervention description(s): Tadalafil 20 mg to be taken orally once daily, for 3 months
Other intervention name(s): Cialis
Intervention MeSH terms: Tadalafil
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Left Ventricular Hypertrophy; Diastolic Dysfunction; Myocardial Fibrosis; Cushing's Syndrome