The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients

Study Overview
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Brief Summary
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Objective propose: to investigate the effect of Ramipril in suppressing ST2 (suppression of tumorigenicity 2) in the cardiac mitral valve in patients with Rheumatic Heart Disease. We hypothesized that we hypothesized that ramipril will improve rheumatic mitral valve fibrosis through the downregulation of ST2.

Detailed Description
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The efficacy of secondary prevention is limited in the prevention of RHD progression. For this reason, new strategies and therapies are needed to prevent the progression of RHD. Neutralizing inflammatory cytokines or antagonizing their receptor function has been considered as a useful therapeutic strategy to treat autoimmune diseases. In this respect, new therapies targeting ST 2 and their receptors as studied in some autoimmune diseases may promise a new approach for patients with RHD. Angiotensin II induces the upregulation of Transforming growth factor β (TGF-β) and latter the binding of IL-33 to sST2 and not to the natural ligand (ST2L). The binding of IL-33 to sST2 will cause fibrogenesis even more. Thus, ACEI is hypothesized to attenuate this vicious cycle through the inhibition of Angiotensin II and consequently increase Bradykinin that furtherly inhibits fibrosis through the negative regulation of angiotensin II activity in Mitogen Activator Protein Kinase (MAPK) pathways through the suppression of the Ca2+ response and the Na+ transportACE inhibitor were agents with anti-fibrosis effects. The investigators keen to investigate the effect of Ramipril in suppressing ST2 expression as biomarkers of fibrosis in cardiac mitral valve in patients with Rheumatic Heart Disease in the National Cardiac Center Harapan Kita hospital Jakarta Indonesia. This study was designed as a randomized clinical trial. Patients with mitral stenosis valvular dysfunction due to rheumatic process planned for cardiac valve replacement surgery were given Ramipril or placebo for a minimum of 12 weeks (3 months). ST2 expression will be analyzed as the fibrosis biomarker in the mitral valve. This study will be conducted in the Department of Cardiology and Vascular Medicine, University Indonesia, National Cardiac Center Harapan Kita Hospital, Jakarta, Indonesia from June 2019

Official Title
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Randomised Controlled Trial Into the Role of Ramipril in Fibrosis Reduction in Rheumatic Heart Disease: The RamiRHeD Trial Protocol

Conditions
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Rheumatic Heart Disease, Mitral Stenosis, Rheumatic Mitral Stenosis, Fibrosis; Heart, ACE Inhibitor

Intervention / Treatment
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* Drug: Placebos
* Drug: Ramipril 5Mg Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with mitral valve stenosis or a combination aged more than 18 years undergo cardiac valve replacement operation with or without a tricuspid valve repair, patients with systolic blood pressure (SBP) ≥ 100 mmHg and diastolic blood pressure (DBP) ≥ 60 mmHg passed in medication phase without side effect minimum 4 weeks until operation schedule Exclusion Criteria: Patients with congenital heart disease patients with non-mitral valve surgery patients with coronary artery bypass surgery patients who refuse to join this study. adults aged over 65 years or older pregnant women patients with autoimmune disease. Patients with persistent hypotension (systolic blood pressure (BP) < 100 mm Hg) severe aortic stenosis (aortic valve orifice < 0.75 cm2 ) chronic renal dysfunction with serum creatinine > 2.5 mg/ dL, known ACEI intolerance.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: pre post test design with placebo control
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: control<br>control patients will be given a placebo | Drug: Placebos<br>* the control group will be given placebo inside a capsule, so study participant won't be able to know the drug and doses inside the capsule (for masking). Placebo will be given until 5 days prior to Mitral valve replacement surgery.<br>* Other names: control group;|
| Experimental: treatment<br>Ramipril 5 mg treatment group | Drug: Ramipril 5Mg Oral Capsule<br>* the treatment group will be given each Ramipril 2,5 mg inside a capsule as an initial dose, for 2 weeks. If there is no serious adverse effect in the observation period of 2 weeks, Ramipril 5 mg inside a capsule will be given for the next weeks until 5 days before the mitral valve surgery date. Study participant won't be able to know the drug and doses inside the capsule (for masking)<br>* Other names: treatment group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ST2 expression in mitral valve tissue and papillary muscle | expression of ST2 in mitral valve tissue, using immunohistochemistry method | a year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ST2 Plasma concentration | plasma level of ST2 measured by ELISA | a year | 
| NT-proBNP concentration (pg/ml) | concentration of NT-proBNP, plasma markers for cardiac dysfunction. | a year | 
| NYHA class | related symptoms will be graded in class I to IV according to NYHA. | a year | 
| cardiovascular mortality | Study participants will be followed up until 1 year after the surgery for any mortality that is caused by progression of the cardiac disease | 1 year | 
| All-cause mortality | Study participants will be followed up until 1 year after the surgery for mortality of any cause. | 1 year | 
| End diastolic dimension | The diameter across a ventricle at the end of diastole, if not else specified then usually referring to the transverse (left-to-right) internal (luminal) distance, excluding thickness of walls, although it can also be measured as the external distance. | 1 year | 
| End systolic dimension | The diameter across a ventricle at the end of systole, if not else specified then usually referring to the transverse (left-to-right) internal (luminal) distance, excluding thickness of walls, although it can also be measured as the external distance. | 1 year | 
| Mitral valve area | mitral valve area is the area of mitral valve, measured by the Gorlin formula MVA (cm2) = (CO ÷ DFP) ÷ (38.0 x MPG) where MVA is the mitral valve area, CO is cardiac output, DFP is the diastolic flow period, 38.0 is the constant and MPG is pressure gradient. | 1 year | 
| Mitral valve gradient | mitralvalve graient is a echocardiographic parameters of the pressure gradient in the mitral valve | 1 year | 
| Tricuspid maximal velocity (Vmax) | Tricuspid maximal velocity (Vmax) is the echocardiographic parameters of the maximal velocity in tricuspid valve annulus | 1 year | 
| Tricuspid regurgitation severity | TRicuspid regurgitation severity is classified ad mild, moderate, and severe, according to European Association of Echocardiography measurement year 2010 for Tricuspid Valve regusrgitation severity. | 1 year | 
| Ejection fraction | echocardiographic parameter to asses ventricular function | 1 year | 
| TAPSE (tricuspid annular plane systolic excursion) | echocardiography parameter to asses right ventricular function | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatic Heart Disease, Mitral Stenosis, Rheumatic Mitral Stenosis, Valve Fibrosis, ramipril, ST2