Severe Rheumatic Heart Disease Research Articles

Association of IL-4 (intron 3) and IL-10 (-1082) gene polymorphisms with risk of mitral valve disease in children with rheumatic heart disease.

Aim Rheumatic heart disease is an inflammatory disease of cardiac tissue. The underlying pathogenic mechanisms highlight a complex interplay of immunological, genetic, and environmental factors. The aim of the present study was to investigate whether IL-4 (intron 3) and IL-10 (-1082) gene polymorphisms could be associated with susceptibility and/or severity of rheumatic heart disease among patients from the Egyptian population. Materials and methods A cohort of 140 Egyptian children with rheumatic heart disease and 100 healthy controls were enrolled in this case-control study. Genotyping for IL-4 (intron 3) and IL-10 (-1082) gene polymorphisms was carried out for all patients using a polymerase chain reaction-based analysis. No significant difference in the distribution of genotypes and allelic frequencies between rheumatic heart disease cases and controls for IL-4 (intron 3) (p=0.17; OR 1.07, 95% CI 0.82-3.74) and IL-10 (-1082) (p=0.49; OR 1.03, 95% CI 0.65-2.71) gene polymorphisms was observed. Further categorisation of patients into mitral valve disease and combined valve disease subgroups showed that cases with mitral valve disease have significantly higher frequency of the RP2 allele of IL-4 (intron 3) (p=0.03; OR 2.98, 95% CI 1.93-6.15) and the G allele of IL-10 (-1082) (p=0.04; OR 2.14, 95% CI 1.62-4.95) when compared with controls. Discussion Our study shows that IL-4 (intron 3) and IL-10 (-1082) gene polymorphisms are not significantly associated with susceptibility to rheumatic heart disease, but they might play a role in the pathogenesis of patients with mitral valve disease.

Secondary prophylaxis in rheumatic fever: is it time to change?

Background Carditis and rheumatic chronic heart disease are the most serious complications of Acute Rheumatic Fever. Nowadays prevention of recurrent episodes of group A b-hemolytic streptococcal pharyngitis is the most effective method to prevent the development of severe rheumatic heart disease. However the evidence of these guidelines are weak and result from studies conducted more than 50 years ago [1]. To detect rate of Carditis related to Acute Rheumatic Fever found at follow up and to find a relationship with clinical data at diagnosis and compliance to prophylaxis.

Incidental histological diagnosis of acute rheumatic myocarditis: case report and review of the literature.

Rheumatic fever (RF) remains endemic in many countries and frequently causes heart failure due to severe chronic rheumatic valvular heart disease, which requires surgical treatment. Here, we report on a patient who underwent an elective surgical correction for mitral and aortic valvular heart disease and had a post-operative diagnosis of acute rheumatic carditis. The incidental finding of Aschoff bodies in myocardial biopsies is frequently reported in the nineteenth-century literature, with prevalences as high as 35%, but no clinical or prognostic data on the patients is included. The high frequency of this finding after cardiac surgery in classical reports suggests that these patients were not using secondary prophylaxis for RF. We discuss the clinical diagnosis of acute rheumatic myocarditis in asymptomatic patients and the laboratorial and imaging methods for the diagnosis of acute rheumatic carditis. We also discuss the prognostic implications of this finding and review the related literature.

Epidemiology, Clinical Profile and Cardiac Remodeling of Severe Rheumatic Heart Disease in Malaysia

Rheumatic heart disease (RHD) is the most common cause of valvular heart disease and heart failure in the developing world and a major global public health challenge. However, there is little data on severe RHD in Southeast Asia. We first defined both the epidemiology and clinical profile of severe RHD (defined as requiring valve surgery or PTMC) that presented to the largest academic cardiology hospital in Malaysia from 2010 through 2012. We then defined, by echocardiography, the adverse cardiac remodeling in this severe RHD population and examined the short term, reverse cardiac remodeling that occurred post-surgical or PTMC relief of the valvular disease.

Signal transducers and activators of transcription (STATs) gene polymorphisms related with susceptibility to rheumatic heart disease in north Indian population

Rheumatic heart disease (RHD) is the most serious complication of heart that comprises inflammatory reactions in heart valves. Cytokines play a critical role in triggering inflammatory reactions and they activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway. Altered signals of STATs play important roles in the balance between proinflammatory and anti-inflammatory cytokines in inflammatory diseases. The aim of the present study was to investigate for the association of polymorphisms related with STAT genes, i.e. STAT3 (rs4796793 C/G) and STAT5b (rs6503691 C/T) with the pathogenesis of RHD. This case–control association study involved 300 healthy controls and 400 RHD patients from North Indian Population. We categorized RHD patients into two subgroups based on involvement of heart valves, mitral valve lesion alone (MVL), and combined valve lesions including mitral valve (CVL). Genotyping was done by RFLP/Taqman probes. We observed that STAT3 CG and GG genotypes were significantly associated with RHD (p=0.030 and p=0.014 respectively), STAT5b CT and TT genotypes were also significantly associated with RHD (p≤0.001). Haplotype analysis revealed that minor alleles of both the variants (Grs4796793Trs6503691) were significantly associated (p<0.0001) with increased risk of the disease susceptibility irrespective of gender or age of onset of the disease. However, the polymorphisms were not involved in severity of RHD as both MVL and CVL patients were equally affected. STAT Grs4796793Trs6503691 carriers may have reduced production of STAT3 leading to damage of heart valves. Thus, STAT genes polymorphisms may be useful markers for the identification of individuals with high risk of RHD in the susceptible population.

O086 Does HIV infection modify the risk of RHD? Initial echocardiographic screening experience at the Joint Clinical Research Centre in Kampala, Uganda

Introduction: The prevalence of rheumatic heart disease (RHD) is estimated tobe 10-fold higher in developing than indevelopednations; however, accurate epidemiological data is limited by the lack of echocardiography to detect subclinical RHD. Because of the immunologic basis of RHD, there is reason to suspect that HIV/AIDS may affect the prevalence and/or severity of RHD. Objectives: To describe the prevalence of subclinical RHD among HIV-infected children in Kampala, Uganda and to compare our findings with previously published and unpublished studies from Uganda. Methods: This was a cross-sectional study of HIV-infected children enrolled in care at the Joint Clinical Research Centre in Kampala. Screening echocardiograms were performed by two physician-sonographers trained in RHD screening using 2012 World Heart Federation criteria. All children with abnormal screening echocardiograms were referred for a confirmatory echocardiogram at the Uganda Heart Institute. Clinical information including age, gender, CD4 count, and use of antiretroviral therapy was obtained by chart review. Results: Screening echocardiograms were performed on 266 children (see Table). Thirteen children(4.9%) had a positive screen for definite or borderline RHD of the mitral valve and none was positive for aortic valve disease. The overall prevalence of 4.9% (definite and borderline RHD) is higher than the published prevalence of 1.5% (definite, probable, or possible RHD) among 5,000 similarly aged Kamapla school children, and higher than the 0.7% prevalence (definiteonly) inapreviousunpublished studyof 285HIV-infected childrenonART inKampala.

PT431 Role of care co-ordination and case conferencing in managing pre and post operative challenges in the NT remote indigenous patients with severe rheumatic heart disease

Cardiac surgery in Indigenous Australians poses many challenges, particularly to the Indigenous patients who live in more remote communities where access to specialist physicians, surgeons and Echocardiography is problematic. Other problems encountered are late presentation, associated co-morbidities and difficulties with medication adherence, especially anticoagulation. Indigenous patients have a significantly higher prevalence of diabetes, chronic kidney disease, hypertension and smoking. Long term studies have shown significantly worse outcome for Indigenous patients following valve or coronary bypass surgery. There is an increased need for valve sparing surgery to avoid the need for anticoagulation. Surgeons need to be better acquainted with the local circumstances of each patient in planning surgery. There may be a case for selected referral centres for rheumatic heart disease surgery in Indigenous patients in order to increase case volume and expertise of individual surgeons.

Increased Prevalence of Severe Rheumatic Heart Disease Requiring Early Valve Replacement Surgery and Fragmented Germ Cells

Background: Patients requiring valve replacement at a younger age, for rheumatic heart disease was apparently increasing after the new age practice of contraception. Methods: In 2012, data of patients referred to tertiary care hospital from two cardiology screening camps conducted in the community, were analyzed for the severity of presentation of rheumatic heart disease and associated contraception status by dividing into the three age groups—20 - 35 years, 36 - 50 years, >51 years; ~400 patients attended the camps; 31 female and 2 male patients were referred to the tertiary care hospital for further evaluation and categorized treatment, including valve replacement surgeries; among the 33 referred patients, belonging to the three age groups, the data were analyzed for [if any] correlation of contraception status with severe rheumatic heart disease. 8 randomly chosen males, of the 3 age groups, from a different community, whose life partners had undergone sterilization, were assessed for their serum testosterone levels. Results: Among 20 - 35 years, 7 female patients with contraception required valve replacement surgeries [p 51 years, 3 female and 2 male patients without contraception received medical treatment only [p

Role of Care Co-ordination and Case Conferencing in Managing Pre and Post Operative Challenges in the NT Remote Indigenous Patients with Severe Rheumatic Heart Disease

William J. Martin*, Gabriela Minigo, Joanne Keeble, Peta Tipping, Melita McKinnon, Ruijie Liu, Gordon Smyth, Jonathan Carapetis, Ian Wicks Inflammation Division, Walter & Eliza Hall Institute of Medical Research, Melbourne, Menzies School of Health Research, Darwin, Bioinformatics Division, Walter & Eliza Hall Institute of Medical Research, Melbourne, Telethon Institute for Child Health Research, Perth, Inflammation Division, Walter & Eliza Hall Institute, Rheumatology Unit, Royal Melbourne Hospital, Melbourne, Australia

Commentary on Remond et al.

<b>Commentary on <scp>R</scp>emond <i>et al</i>.</b>

Oral health of patients with severe rheumatic heart disease

In order to determine whether adequate attention is paid to the maintenance of good oral health in patients at risk of developing infective endocarditis, we studied 44 black patients with severe rheumatic heart disease before they had cardiac surgery. Plaque and gingival index scores were calculated and panoramic radiographs were done in all patients. There were 17 males and 27 females (mean age: 30.6 years). The plaque and gingival index scores were classified as poor in 31.8 and 54.6% of patients, respectively. Panoramic radiographic findings included caries in 56.8% of patients, peri-apical pathology in 18.1% and retained roots in 22.7% of patients. This study demonstrates that inadequate attention is paid to the maintenance of good oral health in patients with severe rheumatic heart disease. The oral and dental care of patients at risk of developing infective endocarditis needs to be improved.

Rheumatic fever in New Zealand

Acute rheumatic fever and its sequel rheumatic heart disease remain major unsolved problems in New Zealand, causing significant morbidity and premature death. The disease burden affects predominantly indigenous Māori and Pacific Island children and young adults. In the past decade these ethnic disparities are even widening. Secondary prophylaxis using 28-day intramuscular penicillin has been the mainstay of disease control. In the greater Auckland region, audit shows community nurse-led penicillin delivery rates of 95% and recurrence rates of less than 5%. The true penicillin failure rate of 0.07 per 100 patient years supports 4 weekly penicillin rather than more frequent dose regimens. Landmark primary prevention research has been undertaken supporting sore throat primary prevention programmes in regions with very high rheumatic fever rates. Echocardiographic screening found 2.4% previously undiagnosed rheumatic heart disease in socially disadvantaged children. Combined with secondary prevention, echocardiography screening has the potential to reduce the prevalence of severe rheumatic heart disease.

Optimising echocardiographic screening for rheumatic heart disease in New Zealand: not all valve disease is rheumatic

Echocardiography detects a greater prevalence of rheumatic heart disease than heart auscultation. Echocardiographic screening for rheumatic heart disease combined with secondary prophylaxis may potentially prevent severe rheumatic heart disease in high-risk populations. We aimed to determine the prevalence of rheumatic heart disease in children from an urban New Zealand population at high risk for acute rheumatic fever. To optimise accurate diagnosis of rheumatic heart disease, we utilised a two-step model. Portable echocardiography was conducted on 1142 predominantly Māori and Pacific children aged 10-13 years. Children with an abnormal screening echocardiogram underwent clinical assessment by a paediatric cardiologist together with hospital-based echocardiography. Rheumatic heart disease was then classified as definite, probable, or possible. Portable echocardiography identified changes suggestive of rheumatic heart disease in 95 (8.3%) of 1142 children, which reduced to 59 (5.2%) after cardiology assessment. The prevalence of definite and probable rheumatic heart disease was 26.0 of 1000, with 95% confidence intervals ranging from 12.6 to 39.4. Portable echocardiography overdiagnosed rheumatic heart disease with physiological valve regurgitation diagnosed in 28 children. A total of 30 children (2.6%) had non-rheumatic cardiac abnormalities, 11 of whom had minor congenital mitral valve anomalies. We found high rates of undetected rheumatic heart disease in this high-risk population. Rheumatic heart disease screening has resource implications with cardiology evaluation required for accurate diagnosis. Echocardiographic screening for rheumatic heart disease may overdiagnose rheumatic heart disease unless congenital mitral valve anomalies and physiological regurgitation are excluded.

Rheumatic Heart Disease in Indigenous Populations—New Zealand Experience

Rheumatic fever continues unabated among the indigenous Māori and Pacific Island New Zealanders. Ethnic disparities have increased in the past decade. The major success story for disease control has been secondary penicillin prophylaxis with 28-day intramuscular benzathine penicillin with high penicillin delivery rates and low recurrence rates. A landmark study for primary prevention of acute rheumatic fever for group A streptococcal pharyngitis was published in 2009. New Zealand has helped establish the role of echocardiography in acute rheumatic fever, with subclinical carditis incorporated into guidelines as a major criterion of rheumatic fever in high prevalence regions. The rates of mitral valve repair for rheumatic heart disease (RHD) are currently greater than 90% in the children's cardiac unit but remain low in adult cardiac units in New Zealand. This is particularly relevant to women of child bearing age where New Zealand data has shown that pregnancy outcomes for mothers with prosthetic valves on warfarin are poor. There are new initiatives to prevent severe RHD using portable echocardiography by screening school aged children. The prevalence of definite RHD was 2.4% in a large cohort of socially disadvantaged children in South Auckland studied in 2007-2008. Cost benefit models of screening need to be developed. Ongoing research involves international consensus standardisation of RHD patterns, and the need to define the natural history of subclinical RHD.

Percutaneous closure of a large peri-prosthetic left ventricular pseudoaneurysm in a high-risk surgical candidate

A 71-year-old woman presented with increasingly severe congestive cardiac failure 6 months after dual aortic/mitral bioprosthetic valve replacement for severe rheumatic valvular heart disease. Echocardiography showed the presence of a...

Gene Polymorphisms of TNF-α−308, IL-10−1082, IL-6−174, and IL-1RaVNTR Related to Susceptibility and Severity of Rheumatic Heart Disease

Rheumatic heart disease (RHD) is an inflammatory disease of the heart tissues caused by interactive immune, genetic, and environmental factors. The objective of this study is to test for the association of polymorphisms related to cytokine genes with susceptibility and severity of RHD among affected children from the Nile Delta region of Egypt. The study included 50 children with chronic RHD (29 males and 21 females), with a mean age of 12.2 years, in addition to 98 healthy unrelated controls. Cases were further classified on the basis of echocardiographic findings into those with only mitral valve disease (MVD) or multivalvular lesions (MVLs) and also as mild, moderate, or severe valve lesions. For all cases and controls, DNA was extracted and amplified using polymerase chain reaction with sequence-specific primers for detection of single nucleotide polymorphisms (SNPs) in the promoter regions of cytokine genes tumor necrosis factor (TNF)-alpha(-308 )G/A, interleukin (IL)-10(-1082 )G/A, and IL-6(-174 )G/C as well as a variable number of tandem repeats (VNTRs) in intron 2 of the IL-1Ra gene. All cases showed a significantly higher frequency of homozygous genotypes of TNF-alpha(-308 )A/A [odds ratio (OR) = 5.7, p < 0.001], IL-10(-1082) A/A (OR = 3.1, p < 0.05), IL-10(-1082) G/G (OR = 5.2, p < 0.05), and IL-1Ra A1/A1 (OR = 2.2, p < 0.05). Cases with MVD showed higher frequencies of genotypes TNF-alpha(-308 )A/A, G/G; IL-10(-1082) G/G; and IL-1Ra(VNTR) A1/A1 (p < 0.05). Cases with MVL showed a significantly higher frequency of homozygous A/A genotype of both TNF-alpha(-308 )(OR = 10.6, p < 0.05) and IL-10(-1082) (OR = 5.2, p < 0.05). The same was observed for cases with severe valve lesions. On the other hand, all studied groups showed significantly lower frequency of heterozygous genotypes of TNF-alpha(-308 )G/A, IL-10(-1082) G/A, and IL-1Ra(VNTR) A1/A2. No significant difference was found regarding the frequency of IL-6(-174 )G/C polymorphisms in total cases or subgroups compared to controls (p > 0.05). Predisposition to RHD is influenced by genetic factors including cytokine gene polymorphisms, with possible susceptibility to severe disease with multivalvular affection among cases with composite polymorphism (TNF-alpha(-308 )A/A and IL-10(-1082) A/A) and (TNF-alpha(-308 )A/A and IL-10(-1082) G/G).

T Cell Response in Rheumatic Fever: Crossreactivity Between Streptococcal M Protein Peptides and Heart Tissue Proteins

Molecular mimicry between streptococcal and human proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic fever (RF) and rheumatic heart disease (RHD). In this review we focus on the studies on genetic susceptibility markers involved in the development of RF/RHD and molecular mimicry mediated by T cell responses of RHD patients against streptococcal antigens and human tissue proteins. We identified several M protein epitopes recognized by peripheral T cells of RF/RHD patients and by heart tissue infiltrating T cell clones of severe RHD patients. The regions of the M protein preferentially recognized by human T cells were also recognized by murine T cells. By analyzing the T cell receptor (TCR) we observed that some Vbeta families detected on the periphery were oligoclonal expanded in the heart lesions. These results allowed us to confirm the major role of T cells in the development of RHD lesions.

Tumor Necrosis Factor-α Gene G-308A and G-238A Polymorphisms are Not Associated with Rheumatic Heart Disease in Taiwan

Purpose. The aim of this study was to test whether tumor necrosis factor (TNF)-α gene polymorphisms could be used as markers of susceptibility or severity of rheumatic heart disease (RHD) among the Chinese population in Taiwan. Methods. A group of 115 patients with RHD diagnosed by echocardiography, and another group of 103 age and sex-matched normal control subjects were studied. TNF-α gene G-308A and G-238A polymorphisms were identified by polymerase chain reaction-based restriction analysis. Results. There was no significant difference in the distribution of genotypes and allelic frequencies of the TNF-α gene G-308A and G-238A polymorphisms between RHD patients and controls. Further categorization of RHD patients into mitral valve disease and combined valve disease subgroups also revealed no statistical difference in these gene polymorphisms when compared with controls. Conclusions. These findings suggest that the TNF-α gene G-308A and G-238A polymorphisms are not suitable genetic markers for RHD in Taiwan Chinese.

Rheumatic Fever: HowS. pyogenes-Primed Peripheral T Cells Trigger Heart Valve Lesions

The pathogenesis of rheumatic fever (RF) is related to autoimmune humoral and cellular responses against human tissues triggered by Streptococcus pyogenes. CD4(+) T cells are the ultimate effectors of chronic heart lesions in rheumatic heart disease (RHD). Heart-infiltrating CD4(+) T cell clones are able to recognize heart tissue and streptococcal antigens by molecular mimicry. The streptococcal M5(81-103) region, an immunodominant region, was recognized by both intralesional and peripheral T cell clones (62% and 38%, respectively). Peripheral T lymphocytes from Brazilian patients with severe RHD preferentially recognized the M5(81-96) peptide, in the context of HLA-DR7(+) and DR53(+) molecules. HLA-DR7 seems to be related to the development of multiple valvular lesions in RHD patients from different countries. In addition, the fact that peripheral and intralesional T cells recognized the M5(81-103) region points to this region as one of the streptococcal triggers of autoimmune reactions in RHD. T cell repertoire analysis from peripheral and intralesional T cell lines derived from RHD patients showed several oligoclonal expansions of BV families. Major expansions were found in the heart lesions, suggesting that such T cell populations preferentially migrate from the periphery to the heart. Some cross-reactive intralesional T cell clones displayed the same T cell receptor (TCR) BVBJ and CDR3 sequences, showing a degenerate pattern of antigen recognition. Heart tissue-infiltrating cells from myocardium and valvular tissue produced TNF-alpha, IFN-gamma, IL-10, and IL-4, whereas few cells from valvular tissue produced IL-4, showing that the lack of regulation in the valves could be responsible for the permanent and progressive valvular lesions.

How an autoimmune reaction triggered by molecular mimicry between streptococcal M protein and cardiac tissue proteins leads to heart lesions in rheumatic heart disease

Molecular mimicry between microbial antigens and host tissue is suggested as a mechanism for post-infectious autoimmune disease. In the present work we describe the autoimmune reactions of two severe rheumatic heart disease (RHD) patients, through an analysis of heart-infiltrating T-cell repertoire, antigen recognition, and cytokine production induced by specific antigens. T-cell clones derived from oligoclonally expanded T cells in the heart cross-recognized M5 peptides, heart tissue-derived proteins, and myosin peptides. We show, using binding affinity assays, that an immunodominant streptococcal peptide (M5(81–96)) is capable of binding to the HLA-DR53 molecule. The same peptide was recognized by an infiltrating T-cell clone from a patient carrying HLA-DR15, DR7, and DR53 molecules. This suggests that this peptide is probably presented to T cells in the context of the HLA-DR53 molecule. Cross-reactive heart-infiltrating T cells activated by the M5 protein and its peptides and by heart tissue-derived proteins produced predominantly inflammatory cytokines. Interleukin (IL)-4 was produced in small amounts by mitral valve intralesional T-cell lines and clones. Altogether, these results suggest that mimicry between streptococcal antigens and heart-tissue proteins, combined with high inflammatory cytokine and low IL-4 production, leads to the development of autoimmune reactions and cardiac tissue damage in RHD patients.