SUM: Endocrine Cardiomyopathy: Response to Cyclic GMP PDE5 Inhibitors in Acromegaly Cardiomyopathy

Sponsor

Andrea M. Isidori (Other)

Overall Status

Unknown status

CT.gov ID

NCT02611336

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Acromegaly Cardiomyopathy	Drug: Tadalafil	Phase 2

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 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, 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Study on New Insights in Remodeling of Endocrine Cardiomyopathies: ASsessmentt of Intramyocardial, Molecular and NeUroendocrine Parameters in Response to Chronic Inhibition of Cyclic GMP Phosphodiesterase 5A in AcroMegaly

Study Start Date :

Jul 1, 2016

Anticipated Primary Completion Date :

Jan 1, 2019

Anticipated Study Completion Date :

Jun 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tadalafil Tadalafil 20 mg to be taken orally once daily, for 5 months	Drug: Tadalafil Tadalafil 20 mg to be taken orally once daily, for 5 months

Arm

Intervention/Treatment

Experimental: Tadalafil

Tadalafil 20 mg to be taken orally once daily, for 5 months

Drug: Tadalafil

Tadalafil 20 mg to be taken orally once daily, for 5 months

Outcome Measures

Primary Outcome Measures

Change of Left ventricular torsion (°) evaluated through Cardiac Magnetic Resonance [before treatment and then 5 months after treatment]

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

age >18 yrs;
patients (men and women) with previous diagnosis of Acromegaly, surgically and/or clinically treated according to current guidelines, with stable parameters of Acromegaly disease in the last 3 months, and with concomitant cardiac hypertrophy and/or diastolic dysfunction developed independently of Acromegaly care and detected by 2D echocardiography
IGF-I levels in the normal range for sex and age
normal blood pressure or controlled hypertension

Exclusion Criteria:

use of thiazolidinediones, or spironolactone; nitrates, doxazosin, terazosin e prazosin;
current use of PDE5 inhibitors or previous (wash out of two months at least);
congenital or valvular cardiomyopathy;
recent ischemic heart disease or revascularization after a myocardial infarction (MI);
contraindications to tadalafil use (hypersensitivity to tadalafil, nitrates use, severe cardiovascular disorders such as unstable angina or severe heart failure, severe hepatic impairment, blood pressure <90/50 mmHg, recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa);
contraindications to CMR.