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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Rheumatic Heart Disease; ACE Inhibitor; Mitral Stenosis; Rheumatic Mitral Stenosis; Fibrosis; Heart
• Intervention / Treatment: Drug: Placebos; Drug: Ramipril 5Mg Oral Capsule

Detailed Description

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

• Study Type: Interventional
• Enrollment (Anticipated): 66
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ade Meidian Ambari, MD, FIHA; Phone Number: 2209 021-5684085; Email: dr_ade_meidian@yahoo.co.id

Study Locations

• Indonesia
  • DKI Jakarta
    • Jakarta, DKI Jakarta, Indonesia, 1140
      • Recruiting
      • Ade Meidian Ambari
      • Contact: Ade Meidian Ambari, MD,FIHA; Phone Number: 2209 021-5684085; Email: dr_ade_meidian@yahoo.co.id

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

1. Patients with congenital heart disease
2. patients with non-mitral valve surgery
3. patients with coronary artery bypass surgery
4. patients who refuse to join this study.
5. adults aged over 65 years or older
6. pregnant women
7. patients with autoimmune disease.
8. Patients with persistent hypotension (systolic blood pressure (BP) < 100 mm Hg)
9. severe aortic stenosis (aortic valve orifice < 0.75 cm2 )
10. chronic renal dysfunction with serum creatinine > 2.5 mg/ dL,
11. known ACEI intolerance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: control; control patients will be given a placebo	Drug: Placebos; 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.; Other Names: control group
Experimental: treatment; Ramipril 5 mg treatment group	Drug: Ramipril 5Mg Oral Capsule; 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); Other Names: treatment group

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Indonesia University
• Investigators: Principal Investigator: Ade Meidian Ambari, MD,FIHA, Universitas Indonesia, RSPJN harapan kita

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2019
• Primary Completion (Anticipated): August 8, 2024
• Study Completion (Anticipated): August 8, 2024

Study Registration Dates

• First Submitted: June 17, 2019
• First Submitted That Met QC Criteria: June 18, 2019
• First Posted (Actual): June 19, 2019

Study Record Updates

• Last Update Posted (Actual): August 16, 2021
• Last Update Submitted That Met QC Criteria: August 13, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: ST2; Rheumatic Heart Disease; ramipril; Mitral Stenosis; Rheumatic Mitral Stenosis; Valve Fibrosis
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Infections; Musculoskeletal Diseases; Connective Tissue Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Streptococcal Infections; Gram-Positive Bacterial Infections; Pathological Conditions, Anatomical; Heart Valve Diseases; Rheumatic Fever; Fibrosis; Heart Diseases; Rheumatic Diseases; Constriction, Pathologic; Mitral Valve Stenosis; Rheumatic Heart Disease; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Ramipril
• Other Study ID Numbers: RamiRHeD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No