The relationship between plasma proadrenomedullin level and severity of the disease in patients with isolated rheumatic mitral stenosis.

OBJECTIVE: In this study, we aimed to determine the plasma proadrenomedullin (ProADM) levels in patients with rheumatic mitral stenosis (MS), to evaluate the relationship between ProADM levels and the echocardiographic parameters that represent the severity of stenosis and symptoms, and to compare the ProADM and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, which is a well-known marker for rheumatic MS. METHODS: Our study included 53 consecutive patients with isolated rheumatic MS and 45 volunteers with similar age and gender features. Patients with MS were divided into two groups based on the presence of an indication for intervention. Detailed echocardiographic examinations were performed on all participants, and blood samples were collected to detect the NT-proBNP and ProADM levels. RESULTS: NT-proBNP and ProADM levels were significantly higher in the rheumatic MS group compared with the control group. In rheumatic MS groups, patients with an indication for intervention had higher levels of NT-proBNP and ProADM compared with patients without an indication for intervention. Moreover, NT-proBNP and ProADM levels were found to be significantly correlated with echocardiographic parameters, which revealed the severity of stenosis in various degrees. Both parameters increased as the New York Heart Association (NYHA) class increased, and this increase had a statistical significance. Additionally, the cut-off values of both parameters (NT-proBNP: 119.9 pg/mL, ProADM: 6.15 nmol/L) could detect patients with an indication for intervention with high sensitivity and specificity rates. NT-proBNP was found to be slightly more effective in this regard. CONCLUSION: The increased NT-proBNP and ProADM levels in patients with isolated rheumatic MS can help clinicians in distinguishing patients with an indication for intervention by providing additional information to echocardiography.

Systemic cytokines, chemokines and growth factors reveal specific and shared immunological characteristics in infectious cardiomyopathies.

Heart disease is a major cause of death worldwide. Chronic Chagas cardiomyopathy (CCC) caused by infection with Trypanosoma cruzi leading to high mortality in adults, and rheumatic heart disease (RHD), resulting from infection by Streptococcus pyogenes affecting mainly children and young adults, are amongst the deadliest heart diseases in low-middle income countries. Despite distinct etiology, the pathology associated with both diseases is a consequence of inflammation. Here we compare systemic immune profile in patients with these cardiopathies, to identify particular and common characteristics in these infectious heart diseases. We evaluated the expression of 27 soluble factors, employing single and multivariate analysis combined with machine-learning approaches. We observed that, while RHD and CCC display higher levels of circulating mediators than healthy individuals, CCC is associated with stronger immune activation as compared to RHD. Despite distinct etiologies, univariate analysis showed that expression of TNF, IL-17, IFN-gamma, IL-4, CCL4, CCL3, CXCL8, CCL11, CCL2, PDGF-BB were similar between CCC and RHD, consistent with their inflammatory nature. Network analysis revealed common inflammatory pathways between CCC and RHD, while highlighting the broader reach of the inflammatory response in CCC. The final multivariate model showed a 100% discrimination power for the combination of the cytokines IL-12p70, IL-1Ra, IL-4, and IL-7 between CCC and RHD groups. Thus, while clear immunological distinctions were identified between CCC and RHD, similarities indicate shared inflammatory pathways in these infectious heart diseases. These results contribute to understanding the pathogenesis of CCC and RHD and may impact the design of immune-based therapies for these and other inflammatory cardiopathies that may also share immunological characteristics.

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.

Evaluating Vitamin D levels in Rheumatic Heart Disease patients and matched controls: A case-control study from Nepal.

BACKGROUND: Diagnosis and treatment for Rheumatic Heart Disease (RHD) is inaccessible for many of the 33 million people in low and middle income countries living with this disease. More knowledge about risk factors and pathophysiologic mechanisms involved is needed in order to prevent disease and optimize treatment. This study investigated risk factors in a Nepalese population, with a special focus on Vitamin D deficiency because of its immunomodulatory effects. METHODS: Ninety-nine patients with confirmed RHD diagnosis and 97 matched, cardiac-healthy controls selected by echocardiography were recruited from hospitals in the Central and Western region of Nepal. Serum 25(OH)D concentrations were assessed using dried blood spots and anthropometric values measured to evaluate nutritional status. Conditional logistic regression analysis was used to define association between vitamin D deficiency and RHD. RESULTS: The mean age of RHD patients was 31 years (range 9-70) and for healthy controls 32 years (range 9-65), with a 4:1 female to male ratio. Vitamin D levels were lower than expected in both RDH and controls. RHD patients had lower vitamin D levels than controls with a mean s-25(OH)D concentration of 39 nmol/l (range 8.7-89.4) compared with controls 45 nmol/l (range 14.5-86.7) (p-value = 0.02). People with Vitamin D insufficiency had a higher risk (OR = 2.59; 95% CI: 1.04-6.50) of also having RHD compared to people with Vitamin D concentrations >50 nmol/l. Body mass index was significantly lower in RHD patients (22.6; 95% CI, 21.5-23.2) compared to controls (24.2; 95% CI, 23.3-25.1). CONCLUSION: RHD patients in Nepal have lower Vitamin D levels and overall poor nutritional status compared to the non-RHD controls. Longitudinal studies are needed to explore the causality between RHD and vitamin D level. Future research is also recommended among Nepali general population to confirm the low level of vitamin D as reported in our control group.

Implication of d-dimer in rheumatic severe mitral stenosis - A tertiary centre study.

BACKGROUND: In rheumatic mitral stenosis (MS), left atrial (LA) thrombus and LA spontaneous echo contrast (LA SEC) reflect hypercoagulability. The study focuses on whether D-dimer levels predict the existence of LA thrombus and SEC in patients with severe MS. METHODS: 95 consecutive patients with severe MS referred for transesophageal echocardiogram (TEE) between July 2011 and March 2012 to evaluate LA thrombus prior to balloon mitral valvotomy (BMV) were included in the study. D-Dimer levels in these patients were observed. RESULTS: Out of the 95 patients, 15 (15.8%) had LA thrombus and 52 patients had LA SEC (54.7%). Any correlation between D-Dimer levels and existence (or non-existence) of LA thrombus was not noticed from the receiver operating characteristics (ROC) curve with an area of .535. For patients with LA SEC, the D-Dimer levels were found to be considerably higher (776 ± 866 µg/L vs. 294 ± 331 µg/L, p = .001). An ideal cut-off level of 393 µg/L for diagnosing LA SEC was illustrated by the ROC curve with a sensitivity of 63.4%, specificity of 83.72%, positive predictive value of 82.5% and a negative predictive value of 65.45%. CONCLUSIONS: D-dimer levels were not representative of the presence or absence of LA thrombus in patients with severe MS. Nonetheless, this study demonstrated the substantial link between D-Dimer level and LA SEC. If a D-Dimer level of 400 µg/L or higher is taken as positive, it has high specificity and positive predictive value for diagnosing LA SEC.

CD4+ T cells and TGFß1/MAPK signal pathway involved in the valvular hyperblastosis and fibrosis in patients with rheumatic heart disease.

The aim of this study was to investigate the roles of CD4+ T cells and transforming growth factor beta (TGFß1) in the pathological process of valvular hyperblastosis and fibrosis of patients with rheumatic heart disease (RHD). A total of 151 patients were enrolled, among whom, 78 patients were with RHD, and 73 were age and gender matched RHD negative patients. Blood samples and valve specimens were collected for analysis. Pathological changes and collagen fibers contents of valves were analyzed using HE and Masson staining. Percentage of peripheral blood CD4+ T cells was tested through flow cytometry. TGFß1 level in serum were identified by ELISA. CD4+ T cells infiltration and expression of TGFß1, p-p38, p-JNK, p-ERK in valves were detected by immunohistochemistry. The mRNA and protein levels of p38, JNK, ERK, TGFß1, I-collagen and α-SMA were detected by qRT-PCR and western blotting, respectively. The heart valve tissues of RHD patients showed higher degrees of fibrosis, calcification and lymphocytes infiltration, which were mainly CD4+ T cells. In addition, compared with control group, RHD patients had more total CD4+ T cells in peripheral blood and valve tissues. Expression of TGFß1, phosphorylation of JNK and p38, and synthesis of I-collagen in valve tissues of RHD patients were also significantly increased. Furthermore, we found a strong positive correlation between TGFß1 expression and phosphorylation of JNK and p38. CD4+ T cells, and fibrogenic cytokine TGFß1, which activate the intracellular MAPK signaling pathway may participate in the fibrosis of heart valve in RHD patients.

The risk of intramuscular haematoma is low following injection of benzathine penicillin G in patients receiving concomitant anticoagulant therapy.

The use of intramuscular injections is widely recommended to be avoided in patients who are prescribed anticoagulant agents, both oral and parenteral due to concerns of haematoma. Benzathine penicillin G (BPG), administered via intramuscular injection, is a vital treatment component for patients with rheumatic heart disease. BPG must be administered long term (for at least a decade) as part of treatment and alternative options to intramuscular injection are currently limited. Many of these patients with rheumatic heart disease will also require long term or lifelong anticoagulation. Our retrospective, single centre study of 48 adult and paediatric hospitalised patients, 29 of which were receiving concomitant anticoagulants, demonstrates no significant bleeding complications from intramuscular administration of BPG on the day of intramuscular injection and for 7 days post injection or until hospital discharge. In the absence of practical alternatives for patients with rheumatic heart disease, our local data supports continuing intramuscular injection of BPG in patients with rheumatic heart disease receiving anticoagulant medication.Letter to the editor.

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.

The neutrophil-to-lymphocyte ratio and mean platelet volume can be associated with severity of valvular involvement in patients with acute rheumatic carditis.

OBJECTIVE: The aim of the study was to investigate the association between the severity of acute rheumatic carditis (ARC) and the neutrophil-lymphocyte ratio (NLR) and mean platelet volume (MPV). METHODS: Paediatric patients diagnosed with ARC between 2010 and 2016 and age- and gender-matched controls were retrospectively analysed. At the time of diagnosis, we reviewed the demographic features obtained: echocardiographic data, complete blood count reports, acute-phase reactants, including C-reactive protein, and erythrocyte sedimentation rate values. The patient group was further divided into two subgroups according to the degree of valvular regurgitation, which included those with severe and those with mild-to-moderate valvular regurgitation. RESULTS: The number of cases with ARC and age- and gender-matched controls were 120 and 50, respectively. The mean age of the patients was 12.25 ± 2.89 (range: 7-18) years. NLR, MPV, anti-streptolysin-O, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), haemoglobin level, and white blood cell (WBC) and neutrophil count were significantly higher in patients with acute carditis compared with the controls (p < 0.001). NLR was found to have a significantly positive correlation with CRP (r = 0.177, p = 0.001), ESR (r = 0.81, p = 0.03) and WBC count ( r = 0.47, p = 0.001). Moreover, we found a positive correlation between NLR and severity of valvular regurgitation (r = 0.34, p < 0.001), and a negative correlation between MPV and severity of valvular regurgitation ( r = -0.38, p < 0.05) in our patients. In multiple linear regression analysis, severe valvular regurgitation was associated with NLR (0.51; 95% CI: 0.32-0.68; p = 0.006) and MPV ( -0.78; 95% CI: -0.72 to -0.98; p = 0.008). CONCLUSIONS: NLR and MPV are novel inflammatory markers and simple, rapid and easily accessible prognostic parameters that can be associated with severity of valvular involvement in patients with ARC.

Relationship of cardiac biomarkers with white matter hyperintensities in cardioembolic stroke due to atrial fibrillation and/or rheumatic heart disease.

White matter hyperintensities (WMHs), which are common in elderly people and contribute to age-related disability, can coexist with cardiac injury. It remains unclear whether cardiac biomarkers are associated with WMHs.To investigate this question, we prospectively recruited patients with cardioembolic stroke due to atrial fibrillation (AF) and/or rheumatic heart disease (RHD). Four cardiac biomarkers were measured: myoglobin, high-sensitivity cardiac troponin T (hs-cTnT), creatine kinase-MB, and terminal pro-brain natriuretic peptide. WMHs in periventricular and deep white matter were assessed separately.In the entire sample of 171 patients, 120 (70.2%) presented with WMHs, of whom 18 (10.5%) presented with moderate to severe deep white matter hyperintensities (DWMH) and 55 (32.2%) presented with moderate to severe periventricular hyperintensities (PVH). Risk of moderate to severe PVH, after adjusting for confounders, was 2.460-fold higher in patients with high myoglobin levels than in those with low levels, and the risk was 2.608-fold higher in patients with high hs-cTnT levels than in those with low levels. There were no significant associations between any of the 4 cardiac biomarkers and moderate to severe DWMH.This prospective observational study provides new evidence of the potential relationship of cardiac biomarkers with WMHs in patients with cardioembolic stroke due to AF and/or RHD. We found that elevated myoglobin levels and high hs-TnT levels were independently associated with the presence of moderate to severe PVH. Further studies are required to test our findings and explore whether cardiac biomarkers contribute directly to WMHs pathogenesis.

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.

The association of plasma high-sensitivity C-reactive protein level with rheumatic heart disease: The possible role of inflammation.

BACKGROUND: Currently, it is not clear whether recurrent traumatic events lead to progression of rheumatic heart disease (RHD) after the incident of acute rheumatic fever or a persistent inflammatory state at the site of the valves. The aim of this study was to assess the possible association between plasma high sensitive C Reactive Protein (hs-CRP) level as an indicator of inflammation and RHD. MATERIALS & METHODS: Ninety patients with RHD and 90 healthy controls who had undergone complete echocardiographic examination were enrolled in this cross-sectional study. A score was given to each patient according to the severity of valvular involvement. Plasma hs-CRP level was checked for each patient by ELISA method twice with two-week interval, and the mean hs-CRP was calculated. RESULTS: The mean plasma hs-CRP level in the case group was significantly higher compared to its level in the control group (2.59±4.82 and 0.55±0.43 in the case and control groups respectively, p<0.001). There was also a strong association between the level of plasma hs-CRP and the severity of rheumatic valvular involvement (p<0.001). CONCLUSION: The mean plasma hs-CRP level seems to have a significant association with RHD and its severity. Further studies are needed to determine the cause and effect relationship.

Immune System Activation in Rheumatic Heart Disease.

OBJECTIVE: To assess activation of immune system in rheumatic heart disease (RHD) patients in the form of AECA, ACL and anti GBM antibodies. STUDY DESIGN: Descriptive, observational study. PLACE AND DURATION OF STUDY: Department of Immunology, University of Health Sciences (UHS), Lahore, and Outpatient Department, Punjab Institute of Cardiology, from February 2015 to January 2016. METHODOLOGY: Clinically suspected patients of RHD and confirmed by echocardiography were included. AECA, ACL and anti GBM antibodies were investigated in the sera of RHD patients. RESULTS: Eighty-six RHD patients were included in the study; the mean age of the patients was 30 ±9.3 years. Among these patients, 59 (68.6%) were females and 27 (31.4%) were males. AECA was most commonly detected autoantibody i.e. in 17 (19.8%) patients; whereas, ACL was detected in only 2 (2.3%) subjects. Another 2 (2.3%) patients had both AECA and ACL antibodies. AGBM was not detected in any of the patients. ACL was seen in females with isolated MR. AECA were seen in mixed valvular heart disease patients. CONCLUSION: Immune system gets activated in RHD patients leading to formation of different antibodies, and they are also related to the type of lesion. ACL antibodies are present in females with isolated mitral regurgitation, while AECA are present in both the genders with mixed valvular heart disease. Anti GBM antibodies are not seen in RHD patients.

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.

Sickening or Healing the Heart? The Association of Ficolin-1 and Rheumatic Fever.

Rheumatic fever (RF) and its subsequent progression to rheumatic heart disease (RHD) are chronic inflammatory disorders prevalent in children and adolescents in underdeveloped countries, and a contributing factor for high morbidity and mortality rates worldwide. Their primary cause is oropharynx infection by Streptococcus pyogenes, whose acetylated residues are recognized by ficolin-1. This is the only membrane-bound, as well as soluble activator molecule of the complement lectin pathway (LP). Although LP genetic polymorphisms are associated with RF, FCN1 gene's role remains unknown. To understand this role, we haplotyped five FCN1 promoter polymorphisms by sequence-specific amplification in 193 patients (138 with RHD and 55, RF only) and 193 controls, measuring ficolin-1 serum concentrations in 78 patients and 86 controls, using enzyme-linked immunosorbent assay (ELISA). Patients presented lower ficolin-1 serum levels (p < 0.0001), but did not differ according to cardiac commitment. Control's genotype distribution was in the Hardy-Weinberg equilibrium. Four alleles (rs2989727: c.-1981A, rs10120023: c.-542A, rs10117466: c.-144A, and rs10858293: c.33T), all associated with increased FCN1 gene expression in whole blood or adipose subcutaneous tissue (p = 0.000001), were also associated with increased protection against the disease. They occur within the *3C2 haplotype, associated with an increased protection against RF (OR = 0.41, p < 0.0001) and with higher ficolin-1 levels in patient serum (p = 0.03). In addition, major alleles of these same polymorphisms comprehend the most primitive *1 haplotype, associated with increased susceptibility to RF (OR = 1.76, p < 0.0001). Nevertheless, instead of having a clear-cut protective role, the minor c.-1981A and c.-144A alleles were also associated with additive susceptibility to valvar stenosis and mitral insufficiency (OR = 3.75, p = 0.009 and OR = 3.37, p = 0.027, respectively). All associations were independent of age, sex or ethnicity. Thus, minor FCN1 promoter variants may play a protective role against RF, by encouraging bacteria elimination as well as increasing gene expression and protein levels. On the other hand, they may also predispose the patients to RHD symptoms, by probably contributing to chronic inflammation and tissue injury, thus emphasizing the dual importance of ficolin-1 in both conditions.

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.