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

Abstract

IntroductionRheumatic 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 analysisThis 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 disseminationThe 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 numberNCT03991910.

Myocardial fibrosis in rheumatic heart disease: emerging concepts and clinical implications

“…Myocardial fibrosis in RHD is greatly influenced by angiotensin II, TGF-β, and the MAPK signaling pathway, as discussed previously ( 3 , 34 ). By inhibiting angiotensin II, ACE inhibitors are thought to be effective at targeting this pathway ( 3 , 8 , 75 ). ACE inhibitors reduce inflammation and fibrosis by lowering IL-6 and TNF-α ( 76 ), and also trigger the apoptosis of cardiac fibroblasts, which generate pathological ECM components for myocardial fibrosis ( 3 , 34 ).…”

“…This modifies our understanding of selecting the best course of treatment for the patients ( 6 ). It is also predicted to be an important indicator to evaluate medication therapy ( 8 ).…”

“…Myocardial fibrosis in RHD was noticed decades ago ( 1 , 2 ). However, its role in clinical settings has not been explored sufficiently ( 8 ). Research progress surrounding this area of expertise is relatively slow compared to other cardiovascular problems such as coronary artery disease or heart failure.…”

Effect of Dapagliflozin on Patients with Rheumatic Heart Disease Mitral Stenosis

“…Previous studies have tried several drugs to inhibit fibrosis. However, the results are inconsistent, and these drugs have not yet become standard therapy [ 26 , 27 , 28 ]. Therefore, new approaches and treatments are needed to prevent RHD progression, and perhaps to improve LA function.…”

Editorial: New challenges with the management of rheumatic heart disease

“…Although ACE inhibitor is considered hemodynamically safe and effective in patients with rheumatic MR ( 10 ), recent valvular guidelines have not yet recommended the use of ACE inhibitor in the medical management of MS ( 11 , 12 ). This interesting theory needs to be studied further to prove the protective effect on the progression of valve deterioration in RHD, and the authors have been doing an on-going randomized controlled trial to prove this theory ( 13 ). If positive results are consistently found, this may become a breakthrough and change the medical management strategy in rheumatic MS patients.…”