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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| control | Placebo Comparator | control patients will be given a placebo |
|
| treatment | Experimental | Ramipril 5 mg treatment group |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebos | Drug | 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. |
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Ade Meidian Ambari, MD, FIHA | Contact | 021-5684085 | 2209 | dr_ade_meidian@yahoo.co.id |
| Name | Affiliation | Role |
|---|---|---|
| Ade Meidian Ambari, MD,FIHA | Universitas Indonesia, RSPJN harapan kita | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ade Meidian Ambari | Recruiting | Jakarta | DKI Jakarta | 1140 | Indonesia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27642098 | Background | Wei Q, Liu H, Liu M, Yang C, Yang J, Liu Z, Yang P. Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure. Sci Rep. 2016 Sep 19;6:33677. doi: 10.1038/srep33677. | |
| 23079082 | Background | Shi Q, Abusarah J, Baroudi G, Fernandes JC, Fahmi H, Benderdour M. Ramipril attenuates lipid peroxidation and cardiac fibrosis in an experimental model of rheumatoid arthritis. Arthritis Res Ther. 2012 Oct 18;14(5):R223. doi: 10.1186/ar4062. |
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| ID | Term |
|---|---|
| D012214 | Rheumatic Heart Disease |
| D008946 | Mitral Valve Stenosis |
| D005355 | Fibrosis |
| ID | Term |
|---|---|
| D012213 | Rheumatic Fever |
| D013290 | Streptococcal Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
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| ID | Term |
|---|---|
| D035061 | Control Groups |
| D017257 | Ramipril |
| ID | Term |
|---|---|
| D015340 | Epidemiologic Research Design |
| D004812 | Epidemiologic Methods |
| D008919 | Investigative Techniques |
| D012107 | Research Design |
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pre post test design with placebo control
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study participants do not know whether they become treatment group or control group the investigator does not know which participant in each group
|
| Ramipril 5Mg Oral Capsule | Drug | 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) |
|
|
| 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 |
| 24335613 | Background | Ciccone MM, Cortese F, Gesualdo M, Riccardi R, Di Nunzio D, Moncelli M, Iacoviello M, Scicchitano P. A novel cardiac bio-marker: ST2: a review. Molecules. 2013 Dec 11;18(12):15314-28. doi: 10.3390/molecules181215314. |
| 32850979 | Background | Ambari AM, Setianto B, Santoso A, Radi B, Dwiputra B, Susilowati E, Tulrahmi F, Doevendans PA, Cramer MJ. Angiotensin Converting Enzyme Inhibitors (ACEIs) Decrease the Progression of Cardiac Fibrosis in Rheumatic Heart Disease Through the Inhibition of IL-33/sST2. Front Cardiovasc Med. 2020 Jul 28;7:115. doi: 10.3389/fcvm.2020.00115. eCollection 2020. |
| 34518254 | Derived | Ambari AM, Setianto B, Santoso A, Radi B, Dwiputra B, Susilowati E, Tulrahmi F, Wind A, Cramer MJM, Doevendans P. Randomised controlled trial into the role of ramipril in fibrosis reduction in rheumatic heart disease: the RamiRHeD trial protocol. BMJ Open. 2021 Sep 13;11(9):e048016. doi: 10.1136/bmjopen-2020-048016. |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D006349 | Heart Valve Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D008722 | Methods |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |