The association between systemic lupus erythematosus and valvular heart disease: an extensive data analysis.

BACKGROUND: Association between antiphospholipid syndrome in systemic lupus erythematosus (SLE) and valvular heart disease (VHD) is well reported, but relatively few studies have been carried out to establish the linkage between VHD and SLE itself. We aimed to investigate link between VHD and SLE and to evaluate the association of diverse factors with VHD among these patients in a large-scale population-based study. MATERIALS AND METHODS: We used the databases of the largest state-mandated health service organization in Israel. All SLE patients were included (n = 5018) as well as their age and sex-matched controls (n = 25 090), creating a cross-sectional population-based study. Medical records of all subjects were analysed for documented VHD and the presence of antiphospholipid antibodies (aPLs). A logistic regression model was carried out to evaluate the diverse factors including SLE and aPLs as independent risk factors for VHD. RESULTS: Valvular heart disease were found to be more frequent among SLE group when compared to controls (aortic stenosis, 1·08% vs. 0·35% respectively, P < 0·001; aortic insufficiency, 1·32% vs. 0·29% respectively, P < 0·001; mitral stenosis, 0·74% vs. 0·21% respectively, P < 0·001; mitral insufficiency, 1·91% vs. 0·39% respectively, P < 0·001). Male sex, hypertension, aPLs and SLE were found to be significant independent risk factors for VHD. CONCLUSION: All VHD are more prevalent among SLE patients when compared to controls. SLE and aPLs are independent risk factor for VHD (OR of 2·46 and 1·7, respectively). Physicians must be aware of such significant association, and routine echocardiography should be considered in SLE patients regardless of their aPL status.

Predicting outcome after percutaneous balloon mitral commissurotomy : Role of neutrophil-lymphocyte ratio.

BACKGROUND: The value of the neutrophil-lymphocyte ratio (NLR) along with the severity of mitral stenosis (MS) in predicting the outcome of percutaneous balloon mitral commissurotomy (PBMC) has not been studied. PATIENTS AND METHODS: Patients with severe MS undergoing PBMC between 2013 and 2014 in a university hospital were prospectively enrolled. Complete blood cell count was obtained upon admission and NLRs were calculated. The correlations between NLR with immediate PBMC success and restenosis in 1 year were evaluated. RESULTS: In all, 102 patients (80 women) with a mean age of 44.5 ± 13.1 years were enrolled in the study. NLR on admission was 2.6 ± 0.8 and mitral valve area (MVA) was 0.89 ± 0.18 cm2. Patients with a lower MVA at baseline had a higher NLR (p = 0.016). The rate of immediate success was 63 % for PBMC. There was no difference in NLR between patients with regard to early and late failures, as well as those who developed restenosis of the valve. Smaller valve area and the rate of valvular dilatation during PBMC were the only independent factors that predicted early and late failure, respectively. CONCLUSION: NLR at the time of treatment was not useful in predicting procedural outcome or restenosis during follow-up of patients undergoing PBMC.

Plasma levels of tumor necrosis factor-alpha and its receptors in patients with mitral stenosis and sinus rhythm undergoing percutaneous balloon valvuloplasty.

This study aimed to determine whether plasma levels of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptor (sTNF-R) increases in rheumatic mitral stenosis (MS) patients with sinus rhythm and to examine the effect of percutaneous mitral balloon valvuloplasty (PMBV) on these parameters. Twenty-six patients with MS and sinus rhythm (study group, 20 female, mean age 33 +/- 8 years), who were scheduled for PMBV, and a well-matched control group consisting of 21 healthy volunteers (15 female, mean age 35 +/- 6 years) were enrolled in the study. Tumor necrosis factor-alpha and sTNF-R levels were compared between study patients and controls, and between peripheral and left atrium (LA) blood. Changes in TNF alpha and sTNF-R levels 24 h and 4 weeks after PMBV were analyzed. Significantly higher baseline TNF-alpha and sTNF-R levels were noted in the study group. In the study group, TNF-alpha and its receptors were also found to be higher in LA blood than in baseline peripheral blood. After PMBV, mitral valve area (MVA) increased and transmitral pressure gradient decreased significantly. At the 24th hour after PMBV, the TNF-alpha level decreased from 29.61 +/- 12.22 pg/ml to 22.42 +/- 8.81 pg/ml (P < 0.0001) and at the 4th week, from 22.42 +/- 8.81 pg/ml to 18.92 +/- 7.37 pg/ml (P < 0.0001). Similar reductions were observed in the sTNF-R level. Regression analysis between the difference in sTNF-R level measured 24 h after and before PMBV and the difference in MVA measured 24 h after and before PMBV showed a significant direct relationship between these variables. This study suggests that isolated rheumatic MS without atrial fibrillation is accompanied by increased TNF-alpha and sTNF-R level. The successful PMBV establishes a significant reduction in TNF-alpha and its receptors, probably due to improved postprocedural hemodynamic parameters.

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.

Antiphospholipid Antibodies and Heart Valve Disease in Systemic Lupus Erythematosus.

Evaluation of antiphospholipid antibodies (aPL) and correlation with heart valve abnormalities among patients with systemic lupus erythematosus (SLE). Nested case-control study was conducted with 70 patients with SLE selected from a longitudinal database based on levels of aPL and presence or absence of valve disease by echocardiogram. Valvular abnormalities observed were regurgitation (52), other (14), artificial valves (4), stenosis (2), thickening (2) and no Libman-Sacks endocarditis (0). The mitral valve was the most commonly affected (30 abnormalities), followed by the tricuspid (20 abnormalities). Multivariate logistic regression for those with and without an aPL value ≥20 units/mL, adjusted for disease duration and age, showed significant differences for any valve abnormality (odds ratio [OR] = 3.1; 95% CI: 1.0-8.9; P = 0.041) and individually for the tricuspid valve (OR = 3.3; 95% CI: 1.0-11.1; P = 0.052) but not for the mitral valve (OR = 2.1; 95% CI: 0.68-6.45; P = 0.195). Levels of aPL ≥20 units/mL showed no association with aortic (P = 0.253), pulmonic (P = 1.000), tricuspid (P = 0.127), or mitral (P = 0.249) valve abnormalities. Levels of aPL correlate with certain valvular abnormalities among patients with SLE.

Circulating CD4+CD25+ T cells in rheumatic mitral stenosis.

BACKGROUND AND AIM OF THE STUDY: Autoimmunity plays an essential role in the pathogenesis of rheumatic heart disease. Although the ongoing rheumatic process has been demonstrated with high levels of inflammatory markers, the cellular mechanism(s) of autoimmunity have not yet been investigated. The study aim was to examine levels of circulating CD4+CD25+ T cells in patients with rheumatic mitral stenosis, and to evaluate the relationship between regulatory CD4+CD25+ T-cell count and clinical and echocardiographic measures. METHODS: A total of 42 patients with mitral stenosis was enrolled into the study, and 27 normal age- and gender-matched healthy subjects served as controls. All patients and controls underwent clinical, electrocardiographic, echocardiographic and laboratory evaluation. T-cell levels were determined with flow cytometry using monoclonal fluorescein isothiocyanate-labeled anti-CD4 and phycoerythrin-labeled anti-CD25 antibodies. RESULTS: The circulating CD4+CD25+ T-cell count was significantly lower in patients with mitral stenosis than in controls (231 +/- 120 versus 372 +/- 180 per mm3; p = 0.001). The percentage ratio of CD4+CD25+ T cells to total leukocytes and lymphocytes was significantly lower in patients with mitral stenosis than in controls (2.9 +/- 1.5 versus 5.2 +/- 2.1; p < 0.001, and 11.2 +/- 5.6 versus 14.8 +/- 5.6; p = 0.011, respectively). In addition, a significant negative correlation was identified between the erythrocyte sedimentation rate and circulating CD4+CD25+ T-cell count (Spearman rho = -0.414; p = 0.006). No correlation was found between CD4+CD25+ T-cell count and clinical and echocardiographic parameters in patients with mitral stenosis. CONCLUSION: A decrease in CD4+CD25+ T cell numbers in mitral stenosis patients might suggest a role for cellular autoimmunity in a smoldering rheumatic process.

Increased M1 Macrophages Infiltration Is Associated with Thrombogenesis in Rheumatic Mitral Stenosis Patients with Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia. In patients with AF, the role of macrophage subsets in thrombogenesis is unclear. In the present study, we analyzed the role of M1 and M2 macrophages and related cytokines in thrombogenesis of AF. Immunohistochemistry, Western blot, and TUNEL assay were used to detect M1/M2 macrophage infiltration, the expression pattern of IL-1ß and inflammasome components, and apoptosis of cardiomyocytes in 71 specimens obtained from the left atrial appendage of patients with rheumatic mitral stenosis (MS) with or without thrombosis. We demonstrated that proinflammatory M1 macrophages were predominant in the atrium of MS patients with AF and thrombus. NLRP3 inflammasomes and IL-1ß, which are primarily functional in macrophages, were activated in those patients. We also showed that increased cell death was associated with thrombogenesis in MS patients. These data indicate that infiltration of M1 macrophages and over-activation of NLRP3 inflammasomes may play a role in progressive atrial inflammation and thrombogenesis in rheumatic mitral stenosis patients with AF.

Changes in the expression of Th17 cell-associated cytokines in the development of rheumatic heart disease.

BACKGROUND: Autoimmunity plays a critical role in the development of rheumatic heart disease (RHD). Recent studies have linked Th17 cells to the autoimmune mechanism associated with RHD. This study aimed to investigate changes in Th17 cell-related cytokine expression in acute and chronic RHD. METHODS: We established a Lewis rat model of experimental RHD, which was induced by inactivated Group A streptococci and complete Freund's adjuvant. After 7- and 24-week intervention treatments, we measured serum levels of interleukin-17 (IL-17) and IL-6, key cytokines associated with Th17 cells, using a Luminex liquichip method, and levels of IL-17 and IL-6 in heart tissues using immunohistochemical assays. Moreover, expression levels of IL-17, IL-21, IL-6, and IL-23 in mitral valve tissues of human RHD patients were also measured using immunohistochemistry. RESULTS: Compared with the normal control group, serum IL-17 and IL-6 concentrations were significantly increased, and the expression levels of IL-17 and IL-6 in the mitral valve were also significantly increased in 7- or 24-week RHD rats (P<.017). Compared with the control group, expression of IL-17, IL-21, IL-6, and IL-23 in mitral valve tissues was significantly increased in RHD patients (P<.05). CONCLUSIONS: Our study suggested that the increased expression of Th17 cell-associated cytokines might play an important role in the pathogenesis and development of RHD.

Corticosteroid and immune responses to cardiac surgery.

Serum corticosteroid-binding globulin (CBG) and cortisol levels as well as subsets of circulating immunocompetent cells (ICCs) were measured during cardiac surgery. Closed heart surgery (closed mitral commissurotomy) resulted in an elevation of cortisol levels (up to 32 +/- 5 micrograms/dL by the end of the surgery) with no changes in CBG and ICC levels observed. Open heart surgery (open reconstruction of the mitral valve) in surface-induced hypothermia (without extracorporeal bypass) caused a dramatic drop in CBG activity (from 250 +/- 17 microM before the beginning of anesthesia to 198 +/- 15 microM by the end of cooling (just before cardiac arrest) and 158 +/- 13 microM after 30 min of reperfusion), whereas cortisol levels were only slightly elevated by the end of cooling, and a significant increase (up to 17 +/- 2 micrograms/dL) was observed only at the end of the surgery (60 min of reperfusion and warming). Similar to CBG, a significant decline in circulating ICC contents occurred in response to cooling and circulatory arrest.

The effect of pentoxifylline on the lung during cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) produces an inflammatory response due to the interaction of blood with a foreign body surface. The lungs are most affected by this inflammatory response. Pentoxifylline (PTX), a phosphodiesterase inhibitor and an inhibitor of leukocyte activation, is used to minimize damage in lungs where leukocytes play an important role. Twenty patients with mitral valve stenosis with planned mitral valve surgery were included in the study. The ten patients receiving pentoxifylline (PTX group) were administered 400 mg PTX orally TID for 3 days preoperatively and, following anesthetic induction, a 300 mg PTX infusion was given. The ten patients receiving no PTX were the control group (CT). Platelet and leukocyte counts, mean pulmonary arterial pressure (mPAP), pulmonary capillary wedge pressure (PCWP), cardiac index (CI), pulmonary vascular resistance (PVR), alveolar-arterial PO2 gradient (AaDO2) were measured just before and after CPB, and 2 h postoperatively. The number of the leukocytes increased in the blood samples drawn 15 min after CPB in both groups and 2 h postoperatively showed no statistical change. The number of platelets had decreased significantly at the end of the CPB in both groups and, 2 h postoperatively, there was a further decrease in the blood count in the control group (P < 0.05). There was no significant difference in either the preoperative or postoperative PAP, PAWP, and CI. Pulmonary vascular resistance increased in both groups following the CPB (CT, before: 136 +/- 44, after: 177 +/- 94 dyne. sec.cm-5; PTX, before: 151 +/- 82, after 182 +/- 43 dynes.sec.cm-5). Two hours postoperatively, a considerable increase continued in the control group (CT 219 +/- 170 dynes.sec. cm-5), while there was an insignificant increase in the PTX group (PTX 193 +/- 51 dynes.sec.cm-5) (P < 0.05). The alveolar-arterial PO2 gradient increased after the CPB in both groups but a moderate decrease was observed 2 h postoperatively. In lung biopsy specimens taken before and after the CPB, there was marked leukocyte sequestration in the control group, whereas the number of leukocytes was seen to be insignificant in the PTX group (P < 0.005). This dosage regimen of PTX inhibits the postoperative increase in PVR and greatly minimized leukocyte sequestration in the lung due to CPB.

[Antibodies to polysaccharides of group A Streptococcus in patients with rheumatism after mitral commissurotomy]. / Antitela k polisakharidu Streptokoka gruppy A u bol'nykh revmatizmom, perenesshikh mitral'nuiu komissurotomiiu.

Gel precipitation was employed to detect antibodies to the A-polysaccharide specific antigenic determinant in blood serum of 131 patients with different versions of rheumatic fever. 21 patients with non-rheumatic myocarditis, 25 convalescents following quinsy, and 58 donors. It was established that high titers of antibodies to A-polysaccharide in patients with protracted and latent rheumatic fever correlate with the clinical and morphological signs of the process activity. Elevation of the antibody titers after mitral commissurotomy made to 107 patients was recorded only in those with exacerbation or activation of rheumatic fever. During the first year after mitral commissurotomy as well as at the preoperative period, the titers of antibodies to A-polysaccharide in patients with protracted rheumatic fever were higher than in those with latent and inactive disease patterns.

[The microcirculatory function and immune status indices of patients with rheumatic heart defects combined with pulmonary hypertension]. / Sostoianie mikrogemotsirkuliatsii i nekotorykh pokazatelei immunnogo statusa u bol'nykh revmaticheskimi porokami serdtsa v sochetanii s legochnoi gipertenziei.

Blood microcirculation and immunity were studied in 52 patients with rheumatic valve disease associated with pulmonary hypertension. The most pronounced changes were observed in patients with "active" pulmonary hypertension. Microcirculatory and immune disorders are likely to be pathogenetical factors aggravating prognosis of pulmonary hypertension.

[Dynamics of the cellular and humoral immunity indices before and after closed commissurotomy]. / Dinamika pokazatelei kletochnogo i gumoral'nogo immuniteta u bol'nykh do i posle zakrytoi komissurotomii.

The state of the cellular and humoral immunity was studied in patients with acquired valvular disease of rheumatic etiology who were subjected to closed commissurotomy. It was established that the patients whose postoperative course was complicated by a suppuration of the wound had low levels of T-lymphocytes, immunoglobulins in their peripheral blood in the postoperative period. A dramatic elevation of the content of immunoglobulins of all classes on the 7th day of the postoperative period is considered to be the evidence of the development of an infectious process.

Association of neutrophil-lymphocyte ratio with the presence and severity of rheumatic mitral valve stenosis.

The aim of the study is to investigate the association between the severity of rheumatic mitral valvular disease (RMVD) and the neutrophil-lymphocyte ratio (NLR). A total of 227 patients were enrolled in the study and divided into 3 groups. Patients in group 1 had rheumatic mitral stenosis (RMS), those in group 2 had RMVD without stenosis, and those in group 3 served as the control group. Group 1 was further divided into 2 groups, severe mitral stenosis (MS) and mild to moderate MS. The NLR was significantly higher in patients with severe MS when compared to those with mild to moderate MS (P = .002) while lymphocyte count was lower (P = .034). Using a cutoff level of 2.56, the NLR predicted severe RMS with a sensitivity of 75% and specificity of 74%. In conclusion, as an inexpensive, simple, and accessible marker of inflammation, the NLR may be useful in predicting the presence and severity of MS in patients with RMVD.

Regulated upon activation, normal T-cell expressed and secreted chemokine and interleukin-6 in rheumatic pulmonary hypertension, targets for therapeutic decisions.

BACKGROUND: Recent studies have highlighted the possible influence of chemokines and cytokines on several types of pulmonary arterial hypertension (PAH). Increasing interest has also been focussed on their role as a cause of post-cardiopulmonary bypass (CPB) organ dysfunction. HYPOTHESIS: Chemokines and cytokines are involved in the pathobiology of rheumatic PAH. METHODS: Serum levels of the chemokine, regulated upon activation, normal T-cell expressed and secreted (RANTES) and the cytokine interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA) in 35 patients with rheumatic mitral valve disease and 10 matched healthy subjects (control group). Eleven patients (31.4%) had severe pulmonary hypertension. Subsequently, 23 patients underwent mitral valve replacement. The relation of RANTES and IL-6 circulating level with postoperative organ dysfunction was analysed through multiple organ dysfunction score (MODS). RESULTS: Patients with severe PAH have a significantly higher mean serum level of RANTES compared with other patients (6138.6+/-3543.8 pg/ml vs 1818.2+/-475.2 pg/ml, p=0.0003). The serum level of IL-6 in the patients was statistically different from that of the control (378+/-50.8 pg/ml vs 262+/-90.5 pg/ml, respectively, p=0.002). Patients who required postoperative inotropes had higher preoperative and post-CPB levels of both RANTES and IL-6. While patients with postoperative lung dysfunction had higher levels of IL-6 preoperatively and post-CPB and lower levels of RANTES post-CPB. CONCLUSIONS: RANTES and IL-6 should be investigated as potential therapeutic targets in the control of rheumatic PAH. Improved understanding of the contribution of RANTES and IL-6 to adverse postoperative complications can lead to improved patient outcome.