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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Change of Left ventricular torsion (°)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Tadalafil
Tadalafil 20 mg to be taken orally once daily, for 3 months
干预措施: Tadalafil (Drug)
结局指标
主要结局
Change of Left ventricular torsion (°)
时间窗: before treatment and then 3 months after treatment
Change of Left ventricular torsion (°) evaluated through Cardiac Magnetic Resonance
次要结局
- Change of cardiac strain (σ - longitudinal shortening: strain %)(before treatment and then 3 months after treatment)
- Quantification of Myocardial fibrosis(before treatment and then 3 months after treatment)
- Inflammatory indices(before treatment and then 3 months after treatment)
- NT-proBNP(before treatment and then 3 months after treatment)
- Assessment of endothelial function markers(before treatment and then 3 months after treatment)
- Assessment of oxidative stress markers(before treatment and then 3 months after treatment)
- cGMP(before treatment and then 3 months after treatment)
- Correlation analysis(before treatment and then 3 months after treatment)
- Assessment of circulating microRNAs(before treatment)
- Changes of circulating miRNAs(before treatment and then 3 months after treatment)
- Assessment of circulating pro-fibrotic and pro-inflammatory chemokines(before treatment and then 3 months after treatment)
- Body composition(before treatment and then 3 months after treatment)
研究者
Andrea M. Isidori
MD - PhD
University of Roma La Sapienza