Clinical Trial: RhEumatiC Heart diseAse Genetics

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational [Patient Registry]

Official Title: Next Generation Sequencing Approach to the Study of Rheumatic Heart Disease

Brief Summary:

Rheumatic fever (RF) is an autoimmune disease that is mediated by the cellular and humoral immune response that follows an untreated pharyngeal Streptococcus pyogenes infection. The most serious complication is rheumatic heart disease (RHD), one of the most common problems facing children and young adults worldwide, which leads to chronic valvular lesions. It is estimated that 60% of all acute rheumatic fever cases will develop RHD.

The pathogenesis of RHD is complex with both environmental and genetic factors contributing to its etiology. The investigators know little about the genetic etiology, cellular events and modifiers of progression of RHD, and there exists a wide range of disease severity and progression to severe valve pathology.

Thus, the investigators will study the genetics of RHD in Rwanda, a country with a very high incidence of RHD, using a combination of next-generation targeted exome capture, transcriptomics, and expressed quantitative trait loci (eQTL) analysis.


Detailed Summary:

There are an estimated 2.4 million children between 5 and 14 years of age affected by RF and/or RHD in developing countries of the world, approximately one million of whom live in sub-Saharan Africa (>40%) (1). A systematic review of prevalence studies found exceptionally high rates of RHD in sub-Saharan Africa, with the highest level found at 30.4 cases per 1000 children in Mozambique (2,3,4,5). At present, no specific treatment for rheumatic heart disease exists other than for its complications, including heart failure, atrial fibrillation, ischemic embolic events, and infective endocarditis. Medical treatment (other than antibiotic prophylaxis) has shown little evidence of slowing the progression of the disease. Medical heart failure treatment is given when patients become symptomatic, and includes mainly β blockers, angiotensin converting- enzyme inhibitor therapies, or a combination of both, as tolerated, and symptomatic treatments such as diuretics. Patients with atrial fibrillation need rate or rhythm control and anticoagulation with warfarin if at high risk of embolic complications. Rheumatic heart disease is a major cause of infective endocarditis in African countries.

North American and European guidelines have considerably reduced the number of heart disorders needing antibiotic prophylaxis to prevent infective endocarditis. Whether guidelines issued from developed regions can be safely applied to developing countries is debatable, and further studies are warranted. Pregnancy in patients with rheumatic heart disease is a challenge, and is associated with high morbidity and mortality. Antenatal consultation with support from cardiology and obstetrics clinics should be done to Provide contraception, counseling, treatment planning before start of pregnancy, and planning for patients with moderate to severe disease who are already pregnant (e.g. caesarean s
Sponsor: Brigham and Women's Hospital

Current Primary Outcome: Echocardiographic signs of rheumatic heart disease [ Time Frame: 3 years ]

All patients enrolled will have had an echocardiogram of their heart to assess for signs of rheumatic heart disease according to WHF criteria. The investigators will perform next generation sequencing on their tissue samples and perform a combination of whole exome or genotyping array on their DNA samples. The goal is to identify variants in those patients with severe disease compared to age, gender, socioeconomic, geographically matched controls without echocardiography signs of RHD.


Original Primary Outcome: Same as current

Current Secondary Outcome:

Original Secondary Outcome:

Information By: Brigham and Women's Hospital

Dates:
Date Received: April 15, 2014
Date Started: February 2014
Date Completion: July 2018
Last Updated: July 27, 2016
Last Verified: July 2016