A longitudinal study of antibody responses to selected host antigens in rheumatic fever and rheumatic heart disease.

Introduction. Group A streptococci can trigger autoimmune responses that lead to acute rheumatic fever (ARF) and rheumatic heart disease (RHD).Gap Statement. Some autoantibodies generated in ARF/RHD target antigens in the S2 subfragment region of cardiac myosin. However, little is known about the kinetics of these antibodies during the disease process.Aim. To determine the antibody responses over time in patients and healthy controls against host tissue proteins - cardiac myosin and peptides from its S2 subfragment, tropomyosin, laminin and keratin.Methodology. We used enzyme-linked immunosorbent assays (ELISA) to determine antibody responses in: (1) healthy controls; (2) patients with streptococcal pharyngitis; (3) patients with ARF with carditis and (4) patients with RHD on penicillin prophylaxis.Results. We observed significantly higher antibody responses against extracellular proteins - laminin and keratin in pharyngitis group, patients with ARF and patients with RHD when compared to healthy controls. The antibody responses against intracellular proteins - cardiac myosin and tropomyosin were elevated only in the group of patients with ARF with active carditis. While the reactivity to S2 peptides S2-1-3, 8-11, 14, 16-18, 21-22 and 32 was higher in patients with ARF, the reactivity in the RHD group was high only against S2-1, 9, 11, 12 when compared to healthy controls. The reactivity against S2 peptides reduced as the disease condition stabilized in the ARF group whereas the reactivity remained unaltered in the RHD group. By contrast antibodies against laminin and keratin persisted in patients with RHD.Conclusion. Our findings of antibody responses against host proteins support the multistep hypothesis in the development of rheumatic carditis. The differential kinetics of serum antibody responses against S2 peptides may have potential use as markers of ongoing cardiac damage that can be used to monitor patients with ARF/RHD.

The prognostic value of postoperative blood glucose in non-diabetic patients with rheumatic heart disease.

BACKGROUND: Blood glucose (BG) is a risk factor of adverse prognosis in non-diabetic patients in several conditions. However, a limited number of studies were performed to explore the relationship between postoperative BG and adverse outcomes in non-diabetic patients with rheumatic heart disease (RHD). METHODS: We identified 1395 non-diabetic patients who diagnosed with having RHD, and underwent at least one valve replacement and preoperative coronary angiography. BG was measured at admission to the intensive care unit (ICU) after surgery. The association of postoperative BG level with in-hospital and one-year mortality was accordingly analyzed. RESULTS: Included patients were stratified into four groups according to postoperative BG level's (mmol/L) quartiles: Q1 (< 9.3 mmol/L, n = 348), Q2 (9.3-10.9 mmol/L, n = 354), Q3 (10.9-13.2 mmol/L, n = 341), and Q4 (≥ 13.2 mmol/L, n = 352). The in-hospital death (1.1% vs. 2.3% vs. 1.8% vs. 8.2%, P < 0.001) and MACEs (2.0% vs. 3.1% vs. 2.6% vs. 9.7%, P < 0.001) were significantly higher in the upper quartiles. Postoperative BG > 13.0 mmol/L was the best threshold for predicting in-hospital death (area under the curve (AUC) = 0.707, 95% confidence interval (CI): 0.634-0.780, P < 0.001). Multivariate logistic regression analysis indicated that postoperative BG > 13.0 mmol/L was an independent predictor of in-hospital mortality (adjusted odds ratio (OR) = 3.418, 95% CI: 1.713-6.821, P < 0.001). In addition, Kaplan-Meier curve analysis showed that the risk of one-year death was increased for a postoperative BG > 13.2 (log-rank = 32.762, P < 0.001). CONCLUSION: Postoperative BG, as a routine test, could be served as a risk measure for non-diabetic patients with RHD.

Circulating cytokines predict severity of rheumatic heart disease.

BACKGROUND: Rheumatic heart disease (RHD) is associated with inflammation that damages cardiac valves, often requiring surgical interventions. The underlying mechanisms involved in the disease progression are not completely understood. This study aimed to evaluate cytokine plasma levels in patients with RHD as possible markers of disease severity. METHODS AND RESULTS: Eighty-nine patients with RHD, age of 41 years ±11.5 years, were prospectively enrolled. RHD severity was defined as valve dysfunction that required invasive intervention, either valve repair or replacement. Peripheral blood samples were collected from all patients for cytokine measurements. The patients were followed up to look at adverse clinical events defined as either the need for valve intervention or death. At baseline, 64 (71.9%) patients had previously undergone valve intervention, whereas 25 patients had stable clinical presentation. Patients with severe RHD displayed higher levels of inflammatory cytokines than patients with stable disease. Cluster analysis showed segregation of severe and stable RHD based on IL-6/TNF-α and IL-6/IL-17A, respectively. IL-6 and TNF-α expression were positively correlated in severe but not in stable RHD patients. During a median follow-up of 23 months, 16 patients (18%) had an adverse outcome. IL-10 at baseline (HR 1.24, 95% CI 1.08-1.43, p = 0.003), and IL-4 (HR 1.12, 95% CI 1.01-1.24, p = 0.041) were predictors of events during the follow-up. CONCLUSIONS: High levels of cytokines are associated with severity of RHD. The co-regulated expression of IL-6 and TNF-α is associated with severe valve dysfunction, whereas high IL-10 and IL-4 levels predicted subsequently adverse outcome.

Effect of Fast Cardioplegic Arrest Induced by Adenosine on Cardiac Troponin Levels After Heart Valve Surgery.

BACKGROUND: Cellular injury is not avoidable with current cardioplegic solutions. The effect of adenosine on reducing cardiac injury post-surgery is controversial. The objective of the current study is to evaluate the effect of fast cardioplegic arrest induced by adenosine on high sensitive cardiac troponin I after heart valve surgery. METHODS: Forty-five (45) patients with rheumatic heart diseases underwent heart valve surgery using conventional approach through median sternotomy. They were classified into two groups, group I (n=21) patients received 0.25mg/kg adenosine into the aortic root just after aortic cross-clamping and before infusion of the cold hyperkalaemic crystalloid cardioplegia via antegrade route and group II (n=24) who received cold crystalloid hyperkalaemic cardioplegia without adenosine. Cardiac troponin I was measured preoperatively and on postoperative days 0, 3 and 7. RESULTS: There was no significant difference between both groups in the demographic, preoperative and operative data. Adenosine significantly reduced arrest time. Postoperative high sensitive cardiac troponin I increased significantly in both groups compared to the preoperative levels and the rise continued till postoperative day 3. Troponin levels were significantly lower in the adenosine group compared to the control at all measurements. The clinical outcomes were non-significant different between groups. CONCLUSIONS: Using adenosine in inducing fast cardioplegic arrest in heart valve surgery after aortic cross clamp and prior to infusion of the cold cardioplegia had significantly decreased postoperative cardiac troponin levels which was used as a proxy for cellular injury compared to the control group.

Relationship of serum HLA-B alleles and TNF-α with rheumatic heart disease

Background/aim: Acute rheumatic fever and rheumatic heart disease are major causes of morbidity and mortality in developing countries. Genetic studies have determined that the immune response in rheumatic heart disease is genetically controlled and that there is a close relationship between the gene of concern and the class II human leukocyte antigen (HLA) gene. The aim of this study was to evaluate the relationship of serum HLA-B alleles and tumor necrosis factor alpha (TNF-α) with rheumatic heart disease. Materials and methods: A total of 50 consecutive patients with rheumatic heart disease and 50 controls were enrolled in the study. HLA alleles were analyzed using sequence-specific primer-polymerase chain reaction and nucleotide sequencing. Results: The HLA-B35 allele was significantly more common in patients with rheumatic heart disease than the control group (P = 0.043). The HLA-B44 allele was significantly more common in control patients than in patients with rheumatic heart disease (P = 0.014). There was a significant inverse correlation between high-sensitivity C-reactive protein and mitral valve area (P = 0.001). There was no correlation between TNF-α levels and mitral valve area (P = 0.066). Conclusion: Our findings confirmed the association between HLA-B alleles and rheumatic heart disease.

Evaluation of serum 25-hydroxyvitamin D levels in calcific rheumatic mitral stenosis- A cross sectional study.

BACKGROUND AND AIM OF THE STUDY: Rheumatic mitral stenosis (RMS) is an autoimmune, progressive destructive valve disease occurring as a sequele of streptococcal infection. Epidemiological studies support an association of vitamin D deficiency with initial susceptibility and severity of autoimmune diseases. The aim of the present study was to assess serum level of 25 hydroxyvitamin D in subjects of RMS and assess if any correlation exists with serum levels of vitamin D and severity of disease along with calcification assessed semi-quantitatively by echocardiography by applying Wilkins score. METHOD: Fifty five patients of RMS without any calcification of the valves (Group A) assessed by echocardiography along with fifty five patients of RMS with mild to moderately calcified valves (Group B, Wilkins calcium score 1 or 2) and 55 patients with severely calcified valves (Group C, Wilkins calcium score 3 or 4) were enrolled for the study. All subjects underwent clinical, echocardiographic, and biochemical evaluation. The total Wilkins score, Wilkins calcium score along with serum level of 25 hydroxyvitamin D was evaluated in all the patients. RESULTS: The median serum level of 25 hydroxyvitamin D was significantly lower in Group B (20.4ng/ml, p<0.001) and group C (11.4ng/ml, p<0.001) compared to Group A patients (27.9ng/ml). Similarly serum level of 25 hydroxyvitamin D in Group C patients were significantly less than Group B patients (p<0.001). A significant inverse correlation was identified between serum level of 25 hydroxyvitamin D and total Wilkins score (r=-0.65, p<0.001) as well as Wilkins calcium score (r=-0.69, p<0.001). But no correlation was identified between 25 hydroxyvitamin D levels and other echocardiographic parameters of RMS. CONCLUSION: Our study showed a significantly lower level of 25 hydroxyvitamin D in subjects of RMS with severely damaged and calcified valves as compared to those with less severely damaged non-calcified valves and it correlated with both Wilkins score and Wilkins calcification score. Thus a link may exist between vitamin D deficiency (an immunomodulator) and severity of autoimmune injury on the valves.

Comprehensive microRNA profiling reveals potential augmentation of the IL1 pathway in rheumatic heart valve disease.

BACKGROUND: Valvular heart disease is a leading cause of cardiovascular mortality, especially in China. More than a half of valvular heart diseases are caused by acute rheumatic fever. microRNA is involved in many physiological and pathological processes. However, the miRNA profile of the rheumatic valvular heart disease is unknown. This research is to discuss microRNAs and their target gene pathways involved in rheumatic heart valve disease. METHODS: Serum miRNA from one healthy individual and four rheumatic heart disease patients were sequenced. Specific differentially expressed miRNAs were quantified by Q-PCR in 40 patients, with 20 low-to-moderate rheumatic mitral valve stenosis patients and 20 severe mitral valve stenosis patients. The target relationship between certain miRNA and predicted target genes were analysis by Luciferase reporter assay. The IL-1ß and IL1R1 expression levels were analyzed by immunohistochemistry and western blot in the mitral valve from surgery of mitral valve replacement. RESULTS: The results showed that 13 and 91 miRNAs were commonly upregulated or downregulated in all four patients. Nine miRNAs, 1 upregulated and 8 downregulated, that had a similar fold change in all 4 patients were selected for quantitative PCR verification. The results showed similar results from miRNA sequencing. Within these 9 tested miRNAs, hsa-miR-205-3p and hsa-miR-3909 showed a low degree of dispersion between the members of each group. Hsa miR-205-3p and hsa-miR-3909 were predicted to target the 3'UTR of IL-1ß and IL1R1 respectively. This was verified by luciferase reporter assays. Immunohistochemistry and Western blot results showed that the mitral valve from rheumatic valve heart disease showed higher levels of IL- 1ß and IL1R1 expression compared with congenital heart valve disease. This suggested a difference between rheumatic heart valve disease and other types of heart valve diseases, with more inflammatory responses in the former. CONCLUSION: In the present study, by next generation sequencing of miRNAs, it was revealed that interleukin 1ß and interleukin 1 receptor 1 was involved in rheumatic heart diseases. And this is useful for diagnosis and understanding of mechanism of rheumatic heart disease.

Assessment of myocardial fibrosis by late gadolinium enhancement imaging and biomarkers of collagen metabolism in chronic rheumatic mitral regurgitation.

BACKGROUND: In chronic rheumatic mitral regurgitation (CRMR), involvement of the myocardium in the rheumatic process has been controversial. Therefore, we sought to study the presence of fibrosis using late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR) and biomarkers of collagen turnover in CRMR. METHODS: Twenty-two patients with CRMR underwent CMR and echocardiography. Serum concentrations of matrix metalloproteinase- 1 (MMP-1), tissue inhibitor of MMP-1 (TIMP- 1), MMP-1-to-TIMP-1 ratio, procollagen III N-terminal pro-peptide (PIIINP) and procollagen type IC peptide (PIP) were measured. RESULTS: Four patients had fibrosis on LGE-CMR. PICP and PIIINP concentrations were similar to those of the controls, however MMP-1 concentration was increased compared to that of the controls (log MMP-1 3.5 ± 0.7 vs 2.7 ± 0.9, p = 0.02). There was increased MMP-1 activity as the MMP-1-to- TIMP-1 ratio was higher in CRMR patients compared to the controls ( -1.2 ± 0.6 vs -2.1 ± 0.89, p = 0.002). CONCLUSIONS: Myocardial fibrosis was rare in CRMR patients. CRMR is likely a disease characterised by the predominance of collagen degradation rather than increased synthesis and myocardial fibrosis.

Serum glial cell line-derived neurotrophic factor levels and postoperative cognitive dysfunction after surgery for rheumatic heart disease.

OBJECTIVE: Postoperative cognitive dysfunction is an important complication of cardiac surgery with poor outcomes. Serum glial cell line-derived neurotrophic factor levels are decreased in patients with Alzheimer's disease, but the association between glial cell line-derived neurotrophic factor levels and postoperative cognitive dysfunction is poorly understood. The present study aimed to investigate the prognostic value of postoperative serum glial cell line-derived neurotrophic factor levels to predict postoperative cognitive dysfunction in patients with rheumatic heart disease undergoing heart valve replacement. METHODS: This was a prospective observational study of 80 patients undergoing elective heart valve replacement surgery from June 2015 to June 2016 at the Affiliated Hospital of Southeast Medical University. Cognitive functions were assessed 1 day before and 7 days after surgery. Serum glial cell line-derived neurotrophic factor levels were measured by an enzyme-linked immunosorbent assay before (T1) and 1 (T2), 2 (T3), and 7 (T4) days after surgery. Perioperative parameters were evaluated to assess the relationship between glial cell line-derived neurotrophic factors and postoperative cognitive dysfunction. RESULTS: Postoperative cognitive dysfunction was identified in 38 patients (47.5%) 7 days after surgery. Average glial cell line-derived neurotrophic factor levels at 2 and 7 days after surgery in the postoperative cognitive dysfunction group were lower than in the nonpostoperative cognitive dysfunction group at the same time points (P < .001). ΔGlial cell line-derived neurotrophic factor (T1-T3) and Δglial cell line-derived neurotrophic factor (T1-T4) were identified as good predictors of postoperative cognitive dysfunction with threshold for postoperative cognitive dysfunction detection of 49.10 and 60.90, respectively. CONCLUSIONS: The perioperative glial cell line-derived neurotrophic factor levels in patients with postoperative cognitive dysfunction were lower than in patients without postoperative cognitive dysfunction. Glial cell line-derived neurotrophic factor could be an effective predictor for the occurrence of postoperative cognitive dysfunction. The results reveal a potentially important role of decreased glial cell line-derived neurotrophic factor levels in postoperative cognitive dysfunction, with possible treatment targets.

High sensitive C-reactive protein and interleukin 6 in atrial fibrillation with rheumatic mitral stenosis from Indian cohort.

INTRODUCTION: Presence of chronic low grade inflammation has often been implicated in the etiology of atrial fibrillation (AF). Whether pre-existing inflammatory state promotes AF or initiation of AF activates inflammation is a dilemma among clinicians. This study investigates the role of high sensitive C reactive protein (hs-CRP) and interleukin 6 (IL-6) in AF with rheumatic mitral stenosis (Rh-MS) as markers of chronic inflammation. METHODS: This case control cohort included sixty five (n=65) Rh-MS patients having other valve lesions as trivial to mild. Out of them twenty nine (n=29; group C) had baseline AF and rest were normal sinus rhythm (NSR). A 24h holter recording was done in NSR patients to diagnose paroxysmal AF/tachyarrhythmia forming group B (n=12) and not having any tachyarrhythmia were designated as NSR; group A (n=24). RESULTS: hs-CRP and IL6 showed statistically significant increase in group C (permanent AF) compared to group A (95% CI: 4.2-0.9, p=0.007; 95% CI: 1.2-0.89; p=0.05 respectively), while it was non significant between group A and group B (p>0.05). A weak positive correlation was observed with hs-CRP and left atrial volume index (LAVi) (r=0.45, p=0.06) in AF group as compared to NSR group. 68.2% of patients in AF group (27/41) had moderate to severe spontaneous echo contrast (SEC) as compared to 37.5% (10/24) in NSR group. CONCLUSION: Increased hs-CRP and IL-6 levels in the paroxysmal and permanent AF group may favour the hypothesis that low grade chronic inflammation could be the cause of atrial fibrillation than a consequence.

Serum uric acid as a simple risk factor in patients with rheumatic heart disease undergoing valve replacement surgery.

BACKGROUND: We evaluated the relationship between admission serum uric acid (SUA) and in-hospital and one-year mortality after valve replacement surgery (VRS) for patients with rheumatic heart disease (RHD). METHODS: One-thousand five-hundred thirty-six consecutive patients with RHD undergoing VRS were divided into 4 groups based on the quartiles of SUA on admission. The association between SUA and adverse outcomes was analyzed. RESULTS: The in-hospital mortality (2.1% vs 2.6% vs 5.3% vs 7.7%, p<0.001) and postoperative acute kidney injury (AKI) (52.0% vs 52.6% vs 61.6% vs 63.3%, p=0.001) increased from the lowest to the highest SUA quartiles. SUA levels were negatively correlated with eGFR value (r=-0.426, p<0.001) and positively correlated with C-reactive protein value (r=0.103, p<0.001). ROC analysis showed that SUA had good predictive value for in-hospital death (AUC=0.665, p<0.001) and was similar to Euro score (Z=0.966, p=0.334). Multiple logistic regression analysis showed that SUA was independently associated with in-hospital (OR=1.21, 95% CI: 1.06, 1.37, p=0.004) and one-year mortality (HR=1.17, 95% CI: 1.05, 1.29, p=0.003). Kaplan-Meier analysis demonstrated that the cumulative rate of one-year mortality after surgery was higher in patients with SUA>7.3mg/dl (Log-rank=21.1, p<0.001). CONCLUSIONS: Admission SUA could be used as a preoperative risk assessment factor in RHD patients who underwent VRS.

A novel approach for characterizing variations in serum peptides in rheumatic heart disease.

BACKGROUND & OBJECTIVES: Acute rheumatic fever and rheumatic heart disease (RHD) are important public health problems in developing countries. In this study, peptidomic analyses on RHD patients and healthy individuals were performed to characterize variations in serum peptide levels using label-free quantitation approaches. METHODS: Blood samples were obtained from 160 healthy controls and 160 RHD patients. Of the 448 identified peptides, 272 were analyzed by two label-free mass spectrometry methods, the spectral count and spectral index. RESULTS: There were 38 proteins and 95 peptides with significant (adjusted P<0.001) differences in the abundance of peptides between healthy controls and RHD patients, including multiple peptides derived from histone H2B, villin-like protein, complement C4-B and motile sperm domain containing protein-2. The levels of 10 peptides were upregulated, and 85 peptides were downregulated in patients compared to controls. In addition, in patients, the levels of four proteins were upregulated and 34 were downregulated compared to controls. INTERPRETATION & CONCLUSIONS: This study shows that detection of significant changes in serum peptides reflects the difference between RHD patients and healthy controls. This label-free method may be helpful for clinicians to treat RHD patients during the perioperative period.

Prognostic value of hypoalbuminemia for adverse outcomes in patients with rheumatic heart disease undergoing valve replacement surgery.

High-risk patients with rheumatic heart disease (RHD) who were undergoing valve replacement surgery (VRS) were not identified entirely. This study included 1782 consecutive patients with RHD who were undergoing VRS to explore the relationship between hypoalbuminemia and adverse outcomes and to confirm whether hypoalbuminemia plays a role in risk evaluation. A total of 27.3% of the RHD patients had hypoalbuminemia. In-hospital deaths were significantly higher in the hypoalbuminemic group than in the non-hypoalbuminemic group (6.6% vs 3.1%, P = 0.001). Hypoalbuminemia was an independent predictor of in-hospital death (OR = 1.89, P = 0.014), even after adjusting for the Euro score. The addition of hypoalbuminemia to Euro score enhanced net reclassification improvement (0.346 for in-hospital death, P = 0.004; 0.306 for 1-year death, p = 0.005). A Kaplan-Meier curve analysis revealed that the cumulative rate of 1-year mortality after the operation was higher in patients with a new Euro score ≥6. These findings indicated that hypoalbuminemia was an independent risk factor for in-hospital and 1-year mortality after VRS in patients with RHD, which might have additive prognostic value to Euro score.

Parameters indicative of persistence of valvular pathology at initial diagnosis in acute rheumatic carditis: the role of albumin and CD19 expression / Parâmetros indicativos de persistência de patologia valvular no diagnóstico inicial de cardite reumática aguda: o papel da albumina e da expressão de CD19

Abstract Objective: The aim of this study is to define the predictors of chronic carditis in patients with acute rheumatic carditis (ARC). Methods: Patients diagnosed with ARC between May 2010 and May 2011 were included in the study. Echocardiography, electrocardiography, lymphocyte subset analysis, acute phase reactants, plasma albumin levels, and antistreptolysin-O (ASO) tests were performed at initial presentation. The echocardiographic assessments were repeated at the sixth month of follow-up. The patients were divided into two groups according to persistence of valvular pathology at 6th month as Group 1 and Group 2, and all clinical and laboratory parameters at admission were compared between two groups of valvular involvement. Results: During the one-year study period, 22 patients had valvular disease. Seventeen (77.2%) patients showed regression in valvular pathology. An initial mild regurgitation disappeared in eight patients (36.3%). Among seven (31.8%) patients with moderate regurgitation initially, the regurgitation disappeared in three, and four patients improved to mild regurgitation. Two patients with a severe regurgitation initially improved to moderate regurgitation (9.1%). In five (22.8%) patients, the grade of regurgitation [moderate regurgitation in one (4.6%), and severe regurgitation in 4 (18.2%)] remained unchanged. The albumin level was significantly lower at diagnosis in Group 2 (2.6 ± 0.48 g/dL). Lymphocyte subset analysis showed a significant decrease in the CD8 percentage and a significant increase in CD19 percentage at diagnosis in Group 2 compared to Group 1. Conclusion: The blood albumin level and the percentage of CD8 and CD19 (+) lymphocytes at diagnosis may help to predict chronic valvular disease risk in patients with acute rheumatic carditis.

Resumo Objetivo: Definir os preditores da cardite crônica em pacientes com cardite reumática aguda (CRA). Métodos: Os pacientes diagnosticados com CRA entre maio de 2010 e maio de 2011 foram incluídos no estudo. Foram feitos os testes de ecocardiografia, eletrocardiograma, uma análise do subgrupo de linfócitos, provas de fase aguda, níveis de albumina plasmática, antiestreptolisina-O (ASO) na manifestação inicial. As avaliações ecocardiográficas foram repetidas no 6º mês de acompanhamento. Os pacientes foram divididos em dois grupos de acordo com a persistência da patologia valvular no 6º mês como Grupo 1 e Grupo 2 e todos os parâmetros clínicos e laboratoriais na internação foram comparados entre dois grupos de comprometimento valvular. Resultados: Durante o período do estudo de um ano, 22 pacientes apresentaram doença valvular; 17 (77,2%) apresentaram regressão da patologia valvular. Houve desaparecimento de regurgitação moderada inicial em oito pacientes (36,3%). Entre sete (31,8%) pacientes com regurgitação moderada inicialmente, a regurgitação desapareceu em três e quatro apresentaram melhoria para regurgitação leve. Dois pacientes com regurgitação grave inicialmente apresentaram melhoria para regurgitação moderada (9,1%). Em cinco (22,8%) pacientes o grau de regurgitação (regurgitação moderada em um [4,6%] e regurgitação grave em quatro [18,2]) continuou inalterado. O nível de albumina foi significativamente menor no diagnóstico no Grupo 2 (2,6 ± 0,48 gr/dL). A análise do subgrupo de linfócitos mostrou uma redução significativa no percentual de CD8 e um aumento significativo no percentual de CD19 no Grupo 2 em comparação com o Grupo 1. Conclusão: O nível de albumina no sangue e o percentual de linfócitos CD8 e CD19 (+) no diagnóstico podem ajudar a prever risco de doença valvular crônica em pacientes com cardite reumática aguda.

Prevalence of rheumatic heart disease in patients with recurrent tonsillitis and elevated anti-streptolysin O titers.

INTRODUCTION: Patients with elevated anti-streptolysin O (ASO) titers (ASOT) and recurrent tonsillitis episodes are known to be at higher risk for rheumatic heart disease (RHD). However, there is no data regarding prevalence of RHD in this high risk population. In this study, we aimed to screen ambulatory patients with elevated ASOT and recurrent tonsillitis episodes using echocardiography for identification of RHD. We hypothesized that prevalence of RHD is higher in this patient group compared to general population. METHODS: 102 patients (10.33 ± 4.01 years, 50.98% female) who were diagnosed with recurrent tonsillitis and had elevated ASOT were included this study. Echocardiographic evaluation was performed by an experienced cardiologist. RESULTS: Echocardiographic examination revealed definite RHD in 2/102 (1.96%) patients and borderline RHD in 3/102 (2.94%) patients. CONCLUSION: Our study demonstrates a high prevalence of RHD in patients with recurrent tonsillitis episodes and high ASOT. Screening with echocardiography is beneficial to improve the detection rates of subclinical RHD in such high-risk populations.

Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.

Role of Natural Autoantibodies in Ugandans With Rheumatic Heart Disease and HIV.

BACKGROUND: Rheumatic heart disease (RHD) and HIV are prevalent diseases in sub-Saharan Africa, but little is known about their potential interrelationships. The objective of this study was to assess the prevalence of protective natural autoantibodies among patients with RHD in Uganda, and to determine whether the levels of these autoantibodies are affected by HIV status. METHODS: Participants were grouped according to RHD and HIV status. The three control groups (RHD - HIV -, RHD - HIV +, RHD + HIV -) were age-matched to the RHD + HIV + participants. All participants underwent HIV testing and echocardiography to evaluate for RHD. Natural autoantibody levels reactive with phosphorylcholine (PC) and malondialdehyde (MDA) were measured. FINDINGS: We enrolled 220 participants; 21 with both RHD and HIV. Ages ranged from 10 to 60 years, with female predominance (144/220, 65%). After adjusting for age and gender, HIV infection and RHD were each associated with low IgM anti-PC (HIV: p < 0.0001 and RHD: p = 0.01). A distinct HIV ∗ RHD interaction was identified (p = 0.045) with increased IgG anti-MDA levels in HIV infected subjects without RHD, whereas IgG anti-MDA levels were decreased in HIV infected subjects with RHD. INTERPRETATION: We found that HIV and RHD are associated with alterations in natural autoantibody responses previously linked to an increased risk for atherosclerosis and autoimmune inflammatory disease.

IL-10 and ET-1 as biomarkers of rheumatic valve disease.

OBJECTIVE: To evaluate the immunological profile and gene expression of endothelin-1 (ET-1) in mitral valves of patients with rheumatic fever originated from a reference service in cardiovascular surgery. METHODS: This was a quantitative, observational and cross-sectional study. Thirty-five subjects (divided into four groups) participated in the study, 25 patients with chronic rheumatic heart disease and ten control subjects. The mean age of the sample studied was 34.5 years. Seventeen of them (48.58%) were male and 18 (51.42%) were female. Inflammatory cytokines (TNF-α, IL-4 and IL-10) were measured and ten mitral valves of patients who underwent first valve replacement were collected for determination of gene expression of endothelin-1 by real time PCR. RESULTS: Among the groups studied (patients vs. controls), there was a statistically significant difference in IL-10 levels (P=0.002), and no differences in other cytokines. Expression of endothelin-1 was observed in 70% of samples. Quantitatively, average of ET-1 expression was 62.85±25.63%. CONCLUSION: Inflammatory cytokine IL-10 participates in the maintenance of chronicity of rheumatic fever in patients who underwent valve replacement and those who are undergoing medical treatment. The expression of endothelin-1 in heart valve lesions in patients undergoing mitral valve replacement confirms its association with inflammatory activity in rheumatic fever.

IL-10 and ET-1 as biomarkers of rheumatic valve disease / IL-10 e ET-1 como biomarcadores de doença valvar reumática

Objective: To evaluate the immunological profile and gene expression of endothelin-1 (ET-1) in mitral valves of patients with rheumatic fever originated from a reference service in cardiovascular surgery. Methods: This was a quantitative, observational and cross-sectional study. Thirty-five subjects (divided into four groups) participated in the study, 25 patients with chronic rheumatic heart disease and ten control subjects. The mean age of the sample studied was 34.5 years. Seventeen of them (48.58%) were male and 18 (51.42%) were female. Inflammatory cytokines (TNF-α, IL-4 and IL-10) were measured and ten mitral valves of patients who underwent first valve replacement were collected for determination of gene expression of endothelin-1 by real time PCR. Results: Among the groups studied (patients vs. controls), there was a statistically significant difference in IL-10 levels (P=0.002), and no differences in other cytokines. Expression of endothelin-1 was observed in 70% of samples. Quantitatively, average of ET-1 expression was 62.85±25.63%. Conclusion: Inflammatory cytokine IL-10 participates in the maintenance of chronicity of rheumatic fever in patients who underwent valve replacement and those who are undergoing medical treatment. The expression of endothelin-1 in heart valve lesions in patients undergoing mitral valve replacement confirms its association with inflammatory activity in rheumatic fever. .

Objetivo: Avaliar o perfil imunológico e a expressão gênica de endotelina-1 em valvas mitrais de pacientes com febre reumática, originados de um serviço de referência em cirurgia cardiovascular. Métodos: Este foi um estudo quantitativo, observacional e transversal. Trinta e cinco indivíduos (divididos em quatro grupos) participaram do estudo, 25 deles com doença cardíaca reumática crônica, além de 10 controles. A média de idade da amostra estudada foi de 34,5 anos. Dezessete (48,58%) dos indivíduos eram homens, e 18 (51,42%) eram mulheres. Foram medidas algumas citocinas inflamatórias (TNF-α, IL-4 e IL-10) e coletadas 10 valvas mitrais de pacientes que se submeteram a primeira troca valvar para determinação da expressão gênica de endotelina-1 pelo PCR real-time. Resultados: Entre os grupos estudados (pacientes e controles), observou-se diferença estatisticamente significante em relação aos níveis de IL-10 (P=0,002), sem diferenças nas outras citocinas. Em relação à endotelina-1, foi observada sua expressão em 70% das amostras. Quantitativamente, a expressão média de endotelina-1 foi de 62,85±25,63%. Conclusão: A citocina inflamatória IL-10 participa da manutenção da cronicidade da febre reumática em pacientes que se submeteram a troca valvar e naqueles que estão em tratamento médico. A expressão de endotelina-1 nas lesões em valvas cardíacas de pacientes que foram submetidos à troca valvar mitral confirma sua relação com a atividade inflamatória na febre reumática. .