Identifying and Preventing Rheumatic Heart Valve Disease Progression
BACKGROUND: Rheumatic heart valve disease (RHD) is the cumulative result of autoimmune valve damage triggered by streptococcal pharyngitis that leads to valve inflammation, fibrosis and dysfunction. Our work in valve disease indicates the possibility of prevention and reversibility of inflammatory and fibrotic valve tissue changes using the angiotensin receptor blocker Losartan.
GAP: In early RHD disease, penicillin (PCN) is given to prevent the development of further infection-initiated immune events that compound to valve inflammation and fibrosis. No currently known and used RHD treatment, however, directly targets valve tissue inflammation and fibrosis.
HYPOTHESIS: The anti-inflammatory and anti-fibrotic agent Losartan added to standard PCN prophylaxis will limit and potentially stop RHD progression and prevent valve dysfunction.
METHODS: Children will be screened by Echocardiography (Echo) which allows detection of clinically undetected early subclinical RHD and disease progression risk stratification. Children with RHD will be randomized to PCN plus placebo versus PCN plus Losartan in a two-arm double-blind prospective randomized trial design and followed clinically and by Echo every 6 months for a total of 24 months.
RESULTS: Preliminary studies of valves from patients with RHD who needed surgery show inflammatory and fibrotic changes with increased expression of transforming growth factor (TGF)-β. Our preliminary model studies of another fibrosing valve disease show that these features can be reduced by treatment with losartan, which inhibits TGF-β.
IMPACT: RHD is the most common acquired cardiovascular disease in children, and about 80–85% of children younger than 15 years old (around 2 billion) live in areas where RHD is endemic. Resulting valve dysfunction leads to heart failure, atrial fibrillation, stroke, maternal mortality and need for costly surgical or procedural therapies. If targeting the inflammatory and fibrotic RHD valve tissue processes with a low-risk, FDA-approved medication proves successful, we will have established a novel secondary prevention approach for RHD that should ultimately help to reduce RHD morbidity and mortality.
Optional/Additional Comments: This project involves collaboration with investigators at the Federal University of Minas Gerais in Brazil who have established a strong framework for Echo screening to detect children with early subclinical RHD and their follow-up.