Sanjana Ranganathan

Introduction. Rheumatic heart disease (RHD) is a chronic condition caused by acute rheumatic fever (ARF) and resultant damage to cardiac valves.¹   When a patient is infected with group A Streptococcus, an immune response is triggered which can cause auto-immune reactions against host heart tissue by Streptococcus– specific antibodies in 40-60% of patients.^1,2   Penicillin has largely eradicated RHD in high-income countries, but it remains a significant cause of death and disability in low- and middle-income countries.^1,3,4   Increased  survival of ARF patients is contributing to a rise in RHD incidence later in life.⁴   Because symptoms of RHD present many years after initial infection, the early identification of patients susceptible to disease progression can help improve outcomes through early intervention.⁵   Methods. In methods 1 and 2, genomic DNA was isolated from blood of RHD patients, and polymorphisms of selected genes were genotyped using PCR.^5,6   In method 3, exosomes were harvested from RHD and control groups, and the differential expression profiles of lncRNA and mRNA were analyzed.⁷   In method 4, differential expression of miRNA from tissue and blood samples of control and RHD groups was examined.⁸   In method 5, BALB/c mice were cultivated with RHD-like lesions and differences in expression of NKX2-5 and Smad6 was examined.⁹   Results. Gene polymorphisms of inflammatory cytokines IL-1β, STAT3, STAT5B and TLR5 may play a role in disease progression, and could predispose patients to the development of RHD.⁵  The MMP1 2G allele was also shown to be associated with RHD, indicating that increased expression of this matrix metalloproteinase may cause valvular tissue remodeling through increased extracellular matrix degradation.⁶   Serum-derived exosomes containing lncRNAs and mRNAs showed differential expression between groups, and the functions of the differentially expressed mRNAs were largely metabolic or immune-related.⁷   Differentially-expressed miRNAs include miR-1183 and miR-1299, and these may play a role in cardiomyocyte apoptosis through targeting of the Bcl-2 gene and pulmonary artery remodeling, respectively.⁸   NKX2-5 and Smad-6 are two proteins implicated in RHD development; NKX2-5-null tissue showed more inflammation and advanced development of Aschoff bodies, and Smad-6-null tissue showed increased tissue thickening.⁹   Conclusions. The mechanisms in RHD pathogenesis are complex, and elucidating these pathways could give rise to a diagnostic biomarker that can identify susceptible patients. Gene polymorphisms, RNA expression, and proteins have been explored as potential biomarkers for identifying patients at risk of developing RHD, and in turn reducing the global disease burden.

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