Alternative Hypothesis to Explain Disease Progression in Rheumatic Heart Disease

Karthikeyan, Ganesan; Fung, Erik; Foo, Roger

doi:10.1161/circulationaha.120.050955

Cited by 10 publications

(18 citation statements)

References 5 publications

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“…For example there is previous work showing that myocarditis remained in its active phase in patients with ARF, months after the disease ventured into the quiescent phase [ 48 ] suggesting that continuous valve damage may occur in a similar fashion in chronic RHD patients, with evidence of a continuum of inflammation due to the presence of high levels of CRP [ 49 ]. Elsewhere Karthikeyan and colleagues have suggested that a major driver of persistent inflammation and progression of valve disease may be related to the hemodynamic burden and turbulence created by transvalvular pressure gradients across damaged valves [ 50 ]. Of interest, Rifaie et al reported that high concentrations of inflammatory markers present in the sera of patients with chronic rheumatic valvular heart disease subsequently disappeared after administration of anti-inflammatory drugs [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Data-independent acquisition mass spectrometry in severe rheumatic heart disease (RHD) identifies a proteomic signature showing ongoing inflammation and effectively classifying RHD cases

et al. 2022

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Background Rheumatic heart disease (RHD) remains a major source of morbidity and mortality in developing countries. A deeper insight into the pathogenetic mechanisms underlying RHD could provide opportunities for drug repurposing, guide recommendations for secondary penicillin prophylaxis, and/or inform development of near-patient diagnostics. Methods We performed quantitative proteomics using Sequential Windowed Acquisition of All Theoretical Fragment Ion Mass Spectrometry (SWATH-MS) to screen protein expression in 215 African patients with severe RHD, and 230 controls. We applied a machine learning (ML) approach to feature selection among the 366 proteins quantifiable in at least 40% of samples, using the Boruta wrapper algorithm. The case–control differences and contribution to Area Under the Receiver Operating Curve (AUC) for each of the 56 proteins identified by the Boruta algorithm were calculated by Logistic Regression adjusted for age, sex and BMI. Biological pathways and functions enriched for proteins were identified using ClueGo pathway analyses. Results Adiponectin, complement component C7 and fibulin-1, a component of heart valve matrix, were significantly higher in cases when compared with controls. Ficolin-3, a protein with calcium-independent lectin activity that activates the complement pathway, was lower in cases than controls. The top six biomarkers from the Boruta analyses conferred an AUC of 0.90 indicating excellent discriminatory capacity between RHD cases and controls. Conclusions These results support the presence of an ongoing inflammatory response in RHD, at a time when severe valve disease has developed, and distant from previous episodes of acute rheumatic fever. This biomarker signature could have potential utility in recognizing different degrees of ongoing inflammation in RHD patients, which may, in turn, be related to prognostic severity.

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Section: Discussionmentioning

confidence: 99%

Data-independent acquisition mass spectrometry in severe rheumatic heart disease (RHD) identifies a proteomic signature showing ongoing inflammation and effectively classifying RHD cases

et al. 2022

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“…The treatment is challenging, and the outcomes are poor. 3 , 4 If rheumatic fever occurs repeatedly, it often causes severe damage to the endocardium, especially the endocardial tissue of the mitral valve, mechanical damage caused by turbulent flow, and platelet accumulation. 5 , 6 , 7 RVHD should be diagnosed early, and targeted treatment should be carried out as soon as possible to improve outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…Severe cases are often characterized by non‐purulent inflammation, heart failure, pulmonary edema, and hemoptysis. The treatment is challenging, and the outcomes are poor 3,4 . If rheumatic fever occurs repeatedly, it often causes severe damage to the endocardium, especially the endocardial tissue of the mitral valve, mechanical damage caused by turbulent flow, and platelet accumulation 5‐7 .…”

Section: Introductionmentioning

confidence: 99%

Hsa_circ_0003748 promotes disease progression in rheumatic valvular heart disease by sponging miR‐577

Zhang

Yuan-fu

et al. 2022

Clinical Laboratory Analysis

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The diagnosis and treatment of rheumatic valvular heart disease (RVHD) require substantial improvements. Studies found that circular RNAs (circRNAs) are involved in the progression of cardiovascular diseases. We screened target hsa_circ_0003748 by circRNA microarrays uploaded to a database. We used fluorescence in situ hybridization to determine the cellular location of hsa_circ_0003748. A dual‐luciferase reporter gene assay revealed that has_circ_0003748 might bind the miRNA miR‐577. In hVIC cells (an RVHD cell line), Cell Counting Kit‐8, Transwell, and flow cytometry assays measured proliferation, migration, and cell cycle and apoptosis, respectively. We found that hsa_circ_0003748 was localized in the cytoplasm; hsa_circ_0003748 promoted the proliferation and migration of hVIC cells, arrested the cell cycle in the G2/M phase, and inhibited apoptosis. These phenomena may result from hsa_circ_0003748 promoting RVHD after sponging miR‐577. Bioinformatic analysis revealed that hsa_circ_0003748 might affect RVHD progression by affecting transcription and the MAPK signaling pathway, the Ras signaling pathway, the cAMP signaling pathway, the Rap1 signaling pathway, and other signaling pathways.

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“…These mechanisms and how they work together and produce disease are yet to be completely understood and new biomarkers identified. In addition to the mimicry between streptococci and heart, RHD may be caused or exacerbated by release of collagen from damaged tissues (3,46), development of anti-myosin and anti-collagen antibodies (47) and collagen reactive T cells (48), as well as a fibrotic response to elevated transforming growth factor beta-1 (TGF-β1) in RHD tissues (49). To explain the left sided mitral valve association with heart valve injury, an alternate hypothesis has been proposed suggesting that initial group A streptococcal infection provokes inflammatory signaling (TNFα and IL-6), inducing epigenetic changes that prime gene expression in the endothelial and interstitial cells of cardiac valves (49).…”

mentioning

confidence: 99%

“…Epigenetic priming of valve tissue and exposure to hemodynamic stress attributable to transvalvular pressure gradients (TVPGs) are necessary prerequisites for the initiation and progression of valve disease. Acute valvulitis and progression to RHD preferentially occur in the valves exposed to high TVPGs (49). The valves that are normally not exposed to high 10.3389/fcvm.2022.919700 hemodynamic stress only develop lesions characteristic of RHD when exposed to elevated TVPGs.…”

mentioning

confidence: 99%

IgG2 rules: N-acetyl-β-D-glucosamine-specific IgG2 and Th17/Th1 cooperation may promote the pathogenesis of acute rheumatic heart disease and be a biomarker of the autoimmune sequelae of Streptococcus pyogenes

Kirvan

Canini²,

Swedo³

et al. 2023

Front. Cardiovasc. Med.

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Antecedent group A streptococcal pharyngitis is a well-established cause of acute rheumatic fever (ARF) where rheumatic valvular heart disease (RHD) and Sydenham chorea (SC) are major manifestations. In ARF, crossreactive antibodies and T cells respond to streptococcal antigens, group A carbohydrate, N-acetyl-β-D-glucosamine (GlcNAc), and M protein, respectively, and through molecular mimicry target heart and brain tissues. In this translational human study, we further address our hypothesis regarding specific pathogenic humoral and cellular immune mechanisms leading to streptococcal sequelae in a small pilot study. The aims of the study were to (1) better understand specific mechanisms of pathogenesis in ARF, (2) identify a potential early biomarker of ARF, (3) determine immunoglobulin G (IgG) subclasses directed against GlcNAc, the immunodominant epitope of the group A carbohydrate, by reaction of ARF serum IgG with GlcNAc, M protein, and human neuronal cells (SK-N-SH), and (4) determine IgG subclasses deposited on heart tissues from RHD. In 10 pediatric patients with RHD and 6 pediatric patients with SC, the serum IgG2 subclass reacted significantly with GlcNAc, and distinguished ARF from 7 pediatric patients with uncomplicated pharyngitis. Three pediatric patients who demonstrated only polymigrating arthritis, a major manifestation of ARF and part of the Jones criteria for diagnosis, lacked the elevated IgG2 subclass GlcNAc-specific reactivity. In SC, the GlcNAc-specific IgG2 subclass in cerebrospinal fluid (CSF) selectively targeted human neuronal cells as well as GlcNAc in the ELISA. In rheumatic carditis, the IgG2 subclass preferentially and strongly deposited in valve tissues (n = 4) despite elevated concentrations of IgG1 and IgG3 in RHD sera as detected by ELISA to group A streptococcal M protein. Although our human study of ARF includes a very small limited sample set, our novel research findings suggest a strong IgG2 autoantibody response against GlcNAc in RHD and SC, which targeted heart valves and neuronal cells. Cardiac IgG2 deposition was identified with an associated IL-17A/IFN-γ cooperative signature in RHD tissue which displayed both IgG2 deposition and cellular infiltrates demonstrating these cytokines simultaneously. GlcNAc-specific IgG2 may be an important autoantibody in initial stages of the pathogenesis of group A streptococcal sequelae, and future studies will determine if it can serve as a biomarker for risk of RHD and SC or early diagnosis of ARF.

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Alternative Hypothesis to Explain Disease Progression in Rheumatic Heart Disease

Cited by 10 publications

References 5 publications

Data-independent acquisition mass spectrometry in severe rheumatic heart disease (RHD) identifies a proteomic signature showing ongoing inflammation and effectively classifying RHD cases

Data-independent acquisition mass spectrometry in severe rheumatic heart disease (RHD) identifies a proteomic signature showing ongoing inflammation and effectively classifying RHD cases

Hsa_circ_0003748 promotes disease progression in rheumatic valvular heart disease by sponging miR‐577

IgG2 rules: N-acetyl-β-D-glucosamine-specific IgG2 and Th17/Th1 cooperation may promote the pathogenesis of acute rheumatic heart disease and be a biomarker of the autoimmune sequelae of Streptococcus pyogenes

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