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

• Status: Unknown status
• Trial end date: 2019-06-01
• Target enrollment: 0
• Participant gender: All

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;

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Andrea M. Isidori
• Treatments: Tadalafil

Criteria

Inclusion Criteria:

• age>18 yrs;

• patients (men and women) with previous diagnosis of Cushing Syndrome (CS), surgically and/or clinically treated according to current guidelines, with stable parameters of CS disease in the last 3 months, and with concomitant cardiac hypertrophy and/or diastolic dysfunction developed independently of CS care and detected by 2D echocardiography;

• urinary free cortisol (UFC) 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.