Endocrine Cardiomyopathy: Response to Cyclic GMP PDE5 Inhibitors in Acromegaly Cardiomyopathy
Condition: Acromegaly Cardiomyopathy
MeSH terms: Acromegaly; Cardiomyopathies
Study type: Interventional
Phase: Phase 2

Summary: 
      Pathophysiology of acromegaly 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 Acromegaly
      cardiomyopathy.

      The proposed research will test whether phosphodiesterase 5A inhibition could become a new
      target for antiremodeling drugs and to discover molecular pathways affected by this class of
      drugs and a network of circulating markers (miRNA) for the early diagnosis of acromegaly
      cardiomyopathy.

      We 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 acromegaly

        -  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 (LV) remodeling in Acromegaly;

        -  there are neuroendocrine (e.g. natriuretic peptides), metabolic markers and chemokines
           (e.g. MCP-1, TGF-ß) related to cardiac disease in Acromegaly;

        -  miRNA expression [miR-208a, 499, 1, 133, 126, 29, 233, 222, 4454] might relate with LV
           remodeling in Acromegaly.
    

Detailed description: 
      Mechanisms of action and evolutionary progression of acromegaly cardiomyopathy are not yet
      been well elucidated and a specific treatment has not been identified. Our study aims to
      characterize the acromegaly 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 Acromegaly treated patients that developed cardiac hypertrophy and/or
      diastolic dysfunction independently of Acromegaly care accorded by current guidelines. We
      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 acromegaly
      cardiomyopathy parameters measured at CMR and 2D-ecocardiography.

      The Primary Objective is to evaluate the effect of PDE5Ai on left ventricular (LV) remodeling
      (kinetic parameters: strain and torsion), geometry and performance measured by cine Cardiac
      Magnetic Resonance (CMR) with tagging technique and contrast-enhanced and 2D echocardiography
      with Tissue Doppler Imaging and speckle tracking in patients with Acromegaly and related
      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 3 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, GH and IGFI, 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 Acromegaly cardiomyopathy. Estimating a 50% drop-out of
      the study due to the complexity of Acromegaly and the related complications that will induce
      patients to leave the study, 15 acromegaly 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
      comparison between the groups of patients will be made by Mann-Withey test. The comparison
      between prevalence will be performed 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; Acromegaly