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Th1/Th2 imbalance, measured by circulating and intracytoplasmic inflammatory cytokines : Immunological alterations in acute coronary syndrome and stable coronary artery disease

To describe how peripheral immune‐parameters reflect the inflammatory alterations of the atherosclerotic plaques in coronary atherosclerosis. We measured general inflammatory markers C‐reactive protein (CRP) and granulocyte activity, lymphocyte subpopulations and their state of activation, evaluated circulating Th1/Th2‐type cytokines, and specific intracytoplasmic cytokines. We investigated the association of immune‐parameters with disease outcome and mortality. Thirty‐three patients with acute coronary syndrome (ACS), 62 with stable coronary artery disease (CAD) and 58 healthy controls were studied. Peripheral blood lymphocyte subgroups were quantified by flow cytometry, soluble cytokines and autoantibodies were assessed using enzyme‐linked immunosorbent assay (ELISA), while intracellular cytokine levels were measured by flow cytometry after intracellular staining. We found elevated levels of CRP and granulocyte activity in ACS versus CAD (P < 0.001, P = 0.017, respectively). Natural killer (NK) cell percentages were elevated, while percentage of T cells to the total lymphocyte count was slightly decreased in ACS compared to controls (P < 0.0001, P = 0.012, respectively). Both forms of coronary atherosclerosis showed significantly higher percentages of activated T cells than controls when stained for the activation markers HLA‐DR3 and CD69+ (ACS: P < 0.0001, P = 0.002, CAD: P < 0.0001, P = 0.018, respectively). IL‐1, IL‐4 and IL‐10 proved significantly higher in ACS versus controls (P = 0.036, P = 0.01, P < 0.0001 respectively). Th1 to Th2 ratio shifted towards a Th1 dominance in both diseases. Both general proinflammatory markers and activated T cells signify CAD. The orchestrated proinflammatory cascade eventually leads to the development of the disease.

Assessment of IgG antibodies to oxidized LDL in patients with acute coronary syndrome

Objectives. Circulating IgG antibodies to oxidized low-density lipoprotein (anti-oxLDL) have been implicated in the development of atherosclerotic plaques. In this study, we investigated the prognostic value of IgG anti-oxLDL antibodies in patients with acute coronary syndrome (ACS). Methods. In total 54 patients with ACS and 41 matched healthy controls were involved in this prospective study. Serum IgG anti-oxLDL levels were assessed by ELISA. Results. Higher IgG anti-oxLDL levels were found in patients with ACS versus controls (22.8 ± 23.3 vs. 7.5 ± 5.27 EU/ml, p < 0.0001). IgG anti-oxLDL concentrations were significantly higher in ACS patients with unstable clinical complications (circulatory insufficiency, malignant arrhythmias, recurring ischaemic pain, positive stress-test, need for urgent coronary intervention or sudden cardiac death) versus those without such complications (30.0 vs. 11.7 EU/ml, p < 0.001). Twelve patients (22%) were taking statins. Patients on statins had a significant reduction in clinical complications (33%) versus patients not receiving statin therapy (61%). IgG anti-oxLDL levels were also different in these two groups (11.4 vs. 25.8 EU/ml, respectively; p = 0.03). Serum IgG anti-oxLDL levels correlated with the subsequent development of unstable coronary events. Levels of anti-oxLDL significantly decreased in response to statin therapy, independently of its lipid-lowering effect. Conclusions. Anti-oxLDL antibodies are involved in ACS. The association of anti-oxLDL with unstable clinical complications may indicate the role of this antibody in plaque destabilization.

Evaluation of antibodies to oxidized low-density lipoprotein and assessment of C-reactive protein in acute coronary syndrome and stable coronary artery disease

The aim was to measure the level of antibodies to oxidized LDL (oxLDL) and C-reactive protein (CRP) in the serum of patients with acute coronary syndrome (ACS). The results were correlated with data obtained from patients with stable coronary artery disease (stable CAD) and healthy controls. Thirty-three patients with ACS and 62 stable CAD patients were enrolled in the study. Fifty healthy individuals served as controls. The evaluation of anti-oxLDL autoantibodies was performed by ELISA, while CRP levels were measured by turbidimetry. The level of antibodies to oxLDL was significantly higher in both groups of patients with ACS and stable CAD compared to controls. The comparison between the acute and stable groups showed that anti-oxLDL levels were higher in the acute group, but because of high SD, the difference was not significant. By performing group analysis, anti-oxLDL levels were found to be significantly higher in ACS patients with unstable clinical state (circulatory insufficiency, malignant arrhythmias, recurring ischemic pain, need for urgent coronary intervention and death). CRP level in patients with ACS was significantly higher than in those with stable CAD. A positive correlation was found between anti-oxLDL antibodies and CRP levels both in patients with ACS and stable CAD. The association between the two biomarkers was stronger in the ACS group. In conclusion, our findings support the notion that the presence of antibodies to oxLDL, a plaque-specific antigen, plays a major role as a predictor of complicated manifestations of ACS.

Plasma homocysteine levels, the prevalence of methylenetetrahydrofolate reductase gene C677T polymorphism and macrovascular disorders in systemic sclerosis: risk factors for accelerated macrovascular damage?

The purpose of this study was to investigate plasma homocysteine (Hcy) levels in patients with systemic sclerosis (SSc) and to study the association between plasma Hcy, C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), and the clinical manifestations in SSc. Associations of Hcy level, C677T MTHFR polymorphism, and macrovascular diseases were investigated in 152 patients with SSc and 58 controls. No significant differences in Hcy levels and MTHFR genotypes were found in SSc patients compared to controls or in SSc patients with limited cutaneous compared to diffuse disease. Significantly higher Hcy concentration was observed in patients with macroangiopathy/thromboembolic events compared to patients without such clinical manifestations (p < 0.05). There was significant correlation between age and macrovascular disorders, between Hcy level and the disease duration (r = 0.164; p < 0.05). Seventy-one percent of patients with macrovascular disorders had MTHFR polymorphism. In addition, 45% of patients with hyperhomocysteinemia had pulmonary hypertension. The presence of MTHFR C677T mutation influences the incidence of macrovascular abnormalities in SSc patients. Elevated Hcy levels may be associated with disease duration and the evolution of macrovascular disorders and pulmonary hypertension in SSc.

Elevated factor XIII level and the risk of peripheral artery disease

The prothrombotic state resulting from the elevation of certain clotting factors and suppression of fibrinolysis contribute to the risk of atherothrombotic diseases. Peripheral artery disease (PAD) has been associated with elevated plasma fibrinogen concentration, increased plasminogen activator

Association of HELLP syndrome with primary antiphospholipid syndrome—a case report

Authors present the first Hungarian case of a young pregnant woman with the association of antiphospholipid syndrome (APS) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. After the onset of severe preeclampsia, the pregnancy was terminated but the patient’s condition continued to worsen. New symptoms of APS, including deep vein thrombosis and ischemic nervus opticus lesion, developed in the patient followed by the onset of acute respiratory distress syndrome, which required respiratory therapy. Intensive treatment with plasmapheresis, high-dose intravenous immunoglobulin, high-dose corticosteroids, cyclophosphamide, and anticoagulants eventually led to full recovery. There have been only few scattered reports in the literature on the association of HELLP syndrome and APS, which was successfully managed with the combination of various immunosuppressive and immunomodulatory treatment modalities.

Polymorphism of clotting factors in Hungarian patients with Raynaud's phenomenon

Patients with primary Raynauds phenomenon may have a genetically determined risk for clotting factors that predispose them to aberrant microvascular thrombosis. We investigated the prevalence of factor V substitution of G to A at position 1691 (FVLeiden), prothrombin G20210A, and methyltetrahydrofolate reductase C677T mutations in these patients. Two hundred (158 women, 42 men, mean age of 42.4 ± 13.7 years) consecutive patients with primary Raynauds phenomenon and 200 age-sex-matched healthy controls of Hungarian origin were included in a case–control study. The prevalence of methyltetrahydrofolate reductase C677T homozygous among patients was significantly lower than in the control group (odds ratio 0.4, 95% confidence interval 0.2–0.9, P < 0.05). The prevalence of other thrombosis-associated alleles did not differ between patients with primary Raynauds phenomenon and control subjects. FVLeiden, prothrombin G20210A, and polymorphism, prothrombin G20210A mutations have no apparent effect on the etiology of primary Raynauds phenomenon.

Immunological parameters, including CXCL8 (IL-8) characterize cerebro- and cardiovascular events in patients with peripheral artery diseases.

The most commonly occurring atherosclerotic manifestations are peripheral artery diseases (PAD). Immune‐mediated processes contribute to the development of atherosclerosis, and affect the diseases outcome. The aim of the present study was to assess various immune‐competent cells, cytokines and chemokines in patients with PAD and to evaluate whether the base immunological values reflect the subsequent development of cardio/cerebrovascular symptoms. One hundred sixty patients with PAD were followed‐up for 42 months. At the time of enrolment, we determined blood lymphocyte subpopulations, both T‐helper (Th)1/Th2‐type intracytoplasmic cytokines and soluble cytokines, chemokines. Intracellular cytokines were measured on phorbol‐myristate‐acetate‐ and ionomycine‐ stimulated cells. Lymphocyte subgroups were quantified by flow cytometry, soluble cytokines by ELISA and intracellular cytokine levels were measured by flow cytometry. The ankle‐brachial index (ABI), indicator of atherosclerosis, was also evaluated. The clinical results were correlated with the immune‐parameters to assess the input of immune‐inflammatory events in the propagation of vascular manifestation. CD4+ T‐cell proportions in patients with PAD with cerebro‐ cardio‐vascular manifestations were decreased, which further reduced in patients with fatal outcome. Of circulating chemokines, IL‐8 (CXCL‐8) was increased in patients with subsequent cerebro‐ cardio‐vascular manifestations, compared to those without the symptoms, and further raised in patients with fatal outcome. The percentage of interferon (IFN)‐γ positive cells showed clear negative correlation with ABI. We conclude that altered peripheral lymphocyte subsets and cytokine/chemokine imbalance play important roles in the proinflammatory cascade and reflect disease severity in patients with PAD.

Platelet Volume Indices in Peripheral Artery Disease

This study aimed to assess the relationship between platelet volume indices (PVI) and peripheral artery disease (PAD). Platelet count (PLT), platelet distribution width (PDW), platelet large cell ratio (P-LCR), and mean platelet volume (MPV) were studied in adult patients with PAD. Two hundred ninety two patients were divided into two groups according to Fontaine classification. Group-1 contained 183 patients with stage I and II with mild symptoms, and the remaining 109 patients referred to the group-2 with severe symptoms. Blood samples were analyzed in a Sysmex SF3000 for platelet indices. There were no significant differences between patients in group-1 and group-2 in terms of PVI (P > 0.05). No significant correlation was identified between severity of peripheral vascular disease and PVI in patients with PAD. PVI seem not to associate with severity of PAD.

The effect of FXIII-A Val34Leu genotype on the risk of peripheral arterial disease.

Plasma coagulation factor XIII (FXIII) is a tetrameric zymogen consisting of two potentially active A subunits (FXIII-A) and two carrier/inhibitory B subunits [1]. It is activated by the combined action of Ca2þ and thrombin. By hydrolyzing the peptide bond of Arg37-Gly38 in FXIII-A, thrombin cleaves off the activation peptide from the N-terminal part of the molecule, and then in the presence of Ca2þ FXIII-B dissociates and the dimer of FXIII-A becomes an active transglutaminase (FXIIIa). FXIIIa cross-links fibrin g-chains into dimers and fibrin a-chains into high-molecular-weight polymers. This way it strengthens fibrin clots and makes them more resistant against shear stresses. FXIIIa also attaches a2 plasmin inhibitor to fibrin and protects newly formed fibrin from the prompt elimination by plasmin. Plasminogen activator inhibitor 2, thrombin activable fibrinolysis inhibitor, and plasminogen are also substrates of FXIIIa, which is now considered as one of the key regulators of fibrinolysis [2].