Randomised controlled trial into the role of ramipril in fibrosis reduction in rheumatic heart disease: the RamiRHeD trial protocol

Abstract

Introduction: Rheumatic heart disease (RHD) is a major burden in developing countries and accounts for 80% of all people living with the disease, where it causes most cardiovascular morbidity and mortality in children and young adults. Chronic inflammation and fibrosis of heart valve tissue due to chronic inflammation in RHD will cause calcification and thickening of the impacted heart valves, especially the mitral valve. This fibrogenesis is enhanced by the production of angiotensin II by increased transforming growth factor β expression and later by the binding of interleukin-33, which is known to have antihypertrophic and antifibrotic effects, to soluble sST2. sST2 binding to this non-natural ligand worsens fibrosis. Therefore, we hypothesise that ACE inhibitors (ACEIs) would improve rheumatic mitral valve stenosis.

Methods and analysis: This is a single-centre, double-blind, placebo-controlled, randomised clinical trial with a pre-post test design. Patients with rheumatic mitral stenosis and valve dysfunction will be planned for cardiac valve replacement operation and will be given ramipril 5 mg or placebo for a minimum of 12 weeks before the surgery. The expression of ST2 in the mitral valve is considered to be representative of cardiac fibrosis. Mitral valve tissue will be stained by immunohistochemistry to ST2. Plasma ST2 will be measured by ELISA. This study is conducted in the Department of Cardiology and Vascular Medicine, Universitas Indonesia, National Cardiac Center Harapan Kita Hospital, Jakarta, Indonesia, starting on 27 June 2019.

Ethics and dissemination: The performance and dissemination of this study were approved by the ethics committee of National Cardiovascular Center Harapan Kita with ethical code LB.02.01/VII/286/KEP.009/2018.

Trial registration number: NCT03991910.

Keywords: cardiology; cardiothoracic surgery; valvular heart disease.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Hypothesis. Molecular mimicry is a defence mechanism of group A Streptococcus to avoid immune cells. This mechanism allows immune cells to generate autoimmunity against protein the lining of endothelial cells and causing chronic inflammation and valvular damage. Continuous process of chronic inflammation leads to valvular thickening and fibrosis, which is mediated by the angiotensin II. Angiotensin II increase TGF-β expression and cause IL-33 to bind with sST2, and subsequently cause damage and fibrosis to the valvular tissue even more, which later will end with rheumatic heart failure. ACEI is hypothesised to counteract these processes by decreasing angiotensin II conversion from angiotensin I. ACEI, ACE inhibitor; IL, interleukin; TGF-β, transforming growth factor β.

Figure 2

Research flowchart. TGF-β, transforming growth factor β.