Endocrine Cardiomyopathy: Response to Cyclic GMP PDE5 Inhibitors in Acromegaly Cardiomyopathy - Full Text View

Purpose

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	Intervention	Phase
Acromegaly Cardiomyopathy	Drug: Tadalafil	Phase 2


Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

MedlinePlus related topics: Cardiomyopathy

Drug Information available for: Tadalafil

Genetic and Rare Diseases Information Center resources: Acromegaly

U.S. FDA Resources

Further study details as provided by Andrea M. Isidori, University of Roma La Sapienza:

Primary Outcome Measures:

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

Secondary Outcome Measures:

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


Estimated Enrollment:	15
Study Start Date:	November 2015
Estimated Study Completion Date:	April 2017
Estimated Primary Completion Date:	April 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

Show Detailed Description

Eligibility


Ages Eligible for Study:	18 Years to 75 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02611336

Contacts


Contact: Elisa Giannetta, MD - Phd	+39 3471482262	elisa.giannetta@uniroma1.it
Contact: Andrea M. Isidori, MD - Phd	+39 0649970540	andrea.isidori@uniroma1.it

Sponsors and Collaborators

Andrea M. Isidori

Investigators


Principal Investigator:	Elisa Giannetta, MD - Phd	Sapienza University of Rome, Policlinico Umberto I, Department of Experimental Medicine

More Information

Publications:

Giannetta E, Isidori AM, Galea N, Carbone I, Mandosi E, Vizza CD, Naro F, Morano S, Fedele F, Lenzi A. Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation. 2012 May 15;125(19):2323-33. doi: 10.1161/CIRCULATIONAHA.111.063412. Epub 2012 Apr 11.

Bernardo BC, Weeks KL, Pretorius L, McMullen JR. Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther. 2010 Oct;128(1):191-227. doi: 10.1016/j.pharmthera.2010.04.005. Epub 2010 May 12. Review.

Montgomery RL, Hullinger TG, Semus HM, Dickinson BA, Seto AG, Lynch JM, Stack C, Latimer PA, Olson EN, van Rooij E. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation. 2011 Oct 4;124(14):1537-47. doi: 10.1161/CIRCULATIONAHA.111.030932. Epub 2011 Sep 6.

Fichtlscherer S, Zeiher AM, Dimmeler S. Circulating microRNAs: biomarkers or mediators of cardiovascular diseases? Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2383-90. doi: 10.1161/ATVBAHA.111.226696. Review.

Baseler WA, Thapa D, Jagannathan R, Dabkowski ER, Croston TL, Hollander JM. miR-141 as a regulator of the mitochondrial phosphate carrier (Slc25a3) in the type 1 diabetic heart. Am J Physiol Cell Physiol. 2012 Dec 15;303(12):C1244-51. doi: 10.1152/ajpcell.00137.2012. Epub 2012 Oct 3.

Grasso LF, Colao A. Left ventricular synchronicity in acromegaly. Endocrine. 2013 Aug;44(1):1-2. doi: 10.1007/s12020-013-0005-0. Epub 2013 Jun 27.


Responsible Party:	Andrea M. Isidori, MD - PhD, University of Roma La Sapienza
ClinicalTrials.gov Identifier:	NCT02611336 History of Changes
Other Study ID Numbers:	SUM 2015-004498-34 ( EudraCT Number )
Study First Received:	November 18, 2015
Last Updated:	November 18, 2015

Keywords provided by Andrea M. Isidori, University of Roma La Sapienza:


Left Ventricular Hypertrophy Diastolic Dysfunction Myocardial Fibrosis Acromegaly

Additional relevant MeSH terms:


Cardiomyopathies Acromegaly Heart Diseases Cardiovascular Diseases Bone Diseases, Endocrine Bone Diseases Musculoskeletal Diseases Hyperpituitarism Pituitary Diseases Hypothalamic Diseases Brain Diseases	Central Nervous System Diseases Nervous System Diseases Endocrine System Diseases Tadalafil Vasodilator Agents Phosphodiesterase 5 Inhibitors Phosphodiesterase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Urological Agents

ClinicalTrials.gov processed this record on July 14, 2017

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