Try our beta test site
IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...

RhEumatiC Heart diseAse Genetics (RECHARGE)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2016 by Brigham and Women's Hospital
Sponsor:
Collaborator:
National University, Rwanda
Information provided by (Responsible Party):
Jochen Daniel Muehlschlegel, MD, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT02118818
First received: April 15, 2014
Last updated: July 27, 2016
Last verified: July 2016
  Purpose

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.


Condition Intervention
Rheumatic Heart Disease
Genetic: Next generation sequencing

Study Type: Observational [Patient Registry]
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Target Follow-Up Duration: 5 Years
Official Title: Next Generation Sequencing Approach to the Study of Rheumatic Heart Disease

Resource links provided by NLM:


Further study details as provided by Brigham and Women's Hospital:

Primary Outcome Measures:
  • 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.


Biospecimen Retention:   Samples With DNA
The investigators are collecting blood for DNA analysis from all subjects as well as heart valve tissue from subjects who undergo cardiac surgery.

Estimated Enrollment: 1000
Study Start Date: February 2014
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2017 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
NO rheumatic heart disease by echo
There will be no intervention. This is an observational trial to examine the differences in genetic variants and gene expression between patients with and without RHD. We will be using next generation sequencing to identify these differences.
Genetic: Next generation sequencing
There will be no intervention. This is an observational trial to examine the differences in genetic variants and gene expression between patients with and without RHD.
Rheumatic heart disease by echo
There will be no intervention. This is an observational trial to examine the differences in genetic variants and gene expression between patients with and without RHD. We will be using next generation sequencing to identify these differences.
Genetic: Next generation sequencing
There will be no intervention. This is an observational trial to examine the differences in genetic variants and gene expression between patients with and without RHD.

Detailed Description:

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 section).

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. Each year, there are >280,000 new cases and almost as many deaths from RHD, with a worldwide prevalence of >15 million, of which almost 20% are children aged 5-14 years. The worldwide mortality from RHD is 1.5% annually, compared with an overall mortality of 0.26% for all other cardiovascular diseases in the US3. 79% of all RHD cases come from less developed countries with the highest prevalence in sub-Saharan Africa and Pacific and indigenous Australia/New Zealand (~3-7 cases per 1,000).

The pathogenesis of RHD is complex with both environmental and genetic factors contributing to its etiology, though molecular mimicry between components of S. pyogenes and human heart tissue appear to be a central problem. A clear correlation exists between disease prevalence and lower socioeconomic status in developing countries, while the disease prevalence in developed countries continues to decline. However, the manifestation of acute rheumatic fever in only a subset of children with untreated throat infection by S. pyogenes, familial clustering, and high concordance of RHD among monozygous twins provides strong evidence for genetic determinants for disease susceptibility. Yet 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.

  Eligibility

Ages Eligible for Study:   5 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
The investigators will include patients aged between 5-40 years in Rwanda presenting with an initial diagnosis of RHD and whose echocardiographic findings meet the criteria for definite RHD. World Heart Federation's criteria for echocardiographic diagnosis of definite RHD will be used, utilizing a combination of pathological criteria and morphological features.
Criteria

Inclusion Criteria:

  • Clinical and echocardiographic signs of RHD using WHF criteria

Exclusion Criteria:

  • Congenital heart disease
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02118818

Contacts
Contact: Jochen D Muehlschlegel, MD, MMSc +1 617 732 7330 jmuehlschlegel@partners.org
Contact: Leon Mutesa, MD PhD +250 78 845 10 13 lmutesa@nur.ac.rw

Locations
Rwanda
University of Rwanda Recruiting
Kigali, Rwanda
Contact: Leon Mutesa, MD, PhD    +250 78 845 10 13    lmutesa@nur.ac.rw   
Principal Investigator: Leon Mutesa, MD, PhD         
Sponsors and Collaborators
Brigham and Women's Hospital
National University, Rwanda
Investigators
Principal Investigator: Jochen D Muehlschlegel, MD MMSc Brigham and Women's Hospital, Harvard Medical School
  More Information

Responsible Party: Jochen Daniel Muehlschlegel, MD, Associate Professor of Anesthesia, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT02118818     History of Changes
Other Study ID Numbers: 2013P002682/BWH
Study First Received: April 15, 2014
Last Updated: July 27, 2016

Additional relevant MeSH terms:
Heart Diseases
Rheumatic Diseases
Rheumatic Heart Disease
Cardiovascular Diseases
Musculoskeletal Diseases
Connective Tissue Diseases
Rheumatic Fever
Streptococcal Infections
Gram-Positive Bacterial Infections
Bacterial Infections

ClinicalTrials.gov processed this record on April 26, 2017