Henrietta Dér

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.

Impaired endothelial function and increased carotid intima-media thickness in association with elevated von Willebrand antigen level in primary antiphospholipid syndrome

Primary antiphospholipid syndrome (APS) is characterized by venous or arterial thrombotic events and/or recurrent abortions, fetal death, preeclasmpsia, eclampsia in the presence of anticardiolipin antibodies or lupus anticoagulant, in the absence of accompanying diseases. Antiphospholipid antibodies can activate endothelial cells, and were recently implicated in atherosclerosis. To assess potential endothelial impairment and early signs of atherosclerosis, flow-mediated (endothelium-dependent) and nitrate-mediated (endothelium independent) vasodilation, as well as von Willebrand factor antigen level and carotid artery intima-media thickness (IMT) were measured in patients with primary antiphospholipid syndrome and in healthy controls. Flow-mediated vasodilation in patients with primary APS was significantly lower than that of controls (3.43 ± 2.86% versus 7.96 ± 3.57%; P < 0.0001). We also found significantly higher von Willebrand antigen levels in patients with primary APS than in the control group (157.91 ± 52.45% versus 125.87 ± 32.8%; P = 0.012). Moreover, carotid artery IMT was significantly larger in the primary APS group compared to controls (0.714 ± 0.2 mm versus 0.58 ± 0.085 mm; P = 0.0037). Our results reflect ongoing endothelial damage and accelerated atherosclerosis in patients with primary APS, and suggest that vasoprotective therapy may be beneficial in the treatment of these patients. Lupus (2007) 16, 497—503.

Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction

OBJECTIVES To describe how certain peripheral immune parameters reflect the inflammatory alterations in patients with primary APS. METHODS Twenty-eight patients with newly diagnosed primary APS were studied. The control group included 26 patients with stable coronary disease and 38 healthy individuals. Peripheral blood lymphocyte subgroups were quantified, intracellular cytokines were measured by flow cytometry, soluble cytokines and auto-antibodies were assessed using ELISA. Endothelial dysfunction was evaluated by measuring endothelium-dependent (flow-mediated; FMD) vasodilation. Carotid duplex ultrasound was performed to quantify the carotid artery intima-media thickness (IMT). Stiffness parameters, augmentation index (AIx) and pulse wave velocity (PWV) were assessed by TensioClinic technology. RESULTS Serum IL-4 and IL-6 levels were significantly higher in APS. CD4+IL10+ and CD8+IL10+ cell percentages in APS were significantly increased compared with controls. Th 0 and T cytotoxic 0 cell percentages were significantly decreased in patients compared with controls. FMD in APS was significantly lower, while IMT was higher than that of controls. FMD showed strong association with stiffness parameters, AIx and PWV. A significant negative linear correlation was detected between PWV and CD8+IL10+ cell percentages and significant positive linear correlation was found between PWV and CD8+IL10- cell percentage. CONCLUSION In APS, the orchestrated pro-inflammatory cascade can eventually result in endothelial dysfunction, leading to the characteristic vascular abnormalities of the disease.

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.

Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease

IntroductionThe aim of the present study was to investigate the association between cardiovascular risk factors and endothelial dysfunction in patients with mixed connective tissue disease (MCTD) and to determine which biomarkers are associated with atherosclerotic complications, such as cardiovascular disease.MethodsFifty MCTD patients and 38 healthy age-matched and sex-matched controls were enrolled in this study. In order to describe endothelial dysfunction, we assessed flow-mediated dilation (FMD), nitrate-mediated dilation (NMD) and carotid artery intima-media thickness (IMT). We investigated FMD of the brachial artery after reactive hyperemia and NMD after sublingual nitroglycerin administration, while the IMT of the common carotid artery was determined by ultrasound. Anti-U1 ribonucleoprotein (anti-U1RNP) antibodies, anti-cardiolipin (anti-CL) antibodies, anti-endothelial cell antibody (AECA) and endothelial cell markers, such as soluble thrombomodulin (TM) and von Willebrand factor antigen (vWFAg), were assessed.ResultsThe endothelium-dependent vasodilation (FMD) was significantly impaired in patients with MCTD, as compared with controls (%FMD: 4.7 ± 4.2% vs. 8.7 ± 5.0%; P < 0.001), while the percentage NMD did not differ (%NMD: 14.3 ± 6.6% vs. 17.1 ± 6.7%; P = 0.073). Mean carotid IMT values were higher in patients than in controls (IMT: MCTD, 0.64 ± 0.13 mm vs. controls, 0.53 ± 0.14 mm; P < 0.001). FMD negatively correlated with disease duration, the levels of apolipoprotein A1, the paraoxonase-1 activity, and systolic blood pressure in MCTD patients. The percentage FMD was significantly lower in MCTD patients with cardiovascular diseases (CVD), than in those without CVD (%FMD: 3.5 ± 2.9 vs. 5.8 ± 4.8, P < 0.0002), while percentage NMD did not differ between patients with and without CVDs. Serum levels of autoantibodies (anti-U1RNP, AECA and anti-CL) were significantly higher in MCTD patients and differed between MCTD patients with and without CVD. Endothelial cell markers such as soluble TM (12.2 ± 8.1 ng/ml vs. 3.2 ± 1.3 ng/ml; P < 0.001) and vWFAg (224.1 ± 115% vs. 89.4 ± 27.1%, P < 0.001) were the highest in MCTD patients with CVD.ConclusionsFMD is a reliable sensitive marker of endothelial cell dysfunction in MCTD. Beside the traditional risk factors, anti-U1RNP, AECA and anti-CL antibodies may be important not only in the pathogenesis of MCTD but in the induction of endothelial cell activation, and may play crucial roles in the development of early atherosclerosis in MCTD.

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.

The autoimmune features of vasculopathies

In the development of atherosclerotic plaques we can identify three autoantigens, the pathological value of which has been proven by experimental and clinical data. These antigens are the 60 kDa heat-shock-protein, beta2-glycoprotein I and oxidized LDL. They have role in the antigen-specific T-cell differentiation processes, moreover, against these antigens autoantibodies are produced, which have prothrombotic activity, leading to the acceleration of atherosclerosis. In autoimmune diseases besides these factors other mechanisms are present, which lead to the development of autoimmune vasculopathies. The current review gives an overview of these vasculopathies.

Vasculopathiák autoimmun vonatkozásai

In the development of atherosclerotic plaques we can identify three autoantigens, the pathological value of which has been proven by experimental and clinical data. These antigens are the 60 kDa heat-shock-protein, beta2-glycoprotein I and oxidized LDL. They have role in the antigen-specific T-cell differentiation processes, moreover, against these antigens autoantibodies are produced, which have prothrombotic activity, leading to the acceleration of atherosclerosis. In autoimmune diseases besides these factors other mechanisms are present, which lead to the development of autoimmune vasculopathies. The current review gives an overview of these vasculopathies.

[Cardiovascular actions of a standardized polyphenol concentrate on patients undergoing coronary bypass grafting: a randomized, double-blind, placebo-controlled study].

In this study the authors analyzed the action of Flavon Max product on the cardiovascular system of patients with severe coronary disease. Two randomized, double-blind, placebo controlled trials were carried out using impedance-cardiography, arteriography, vascular Doppler and biochemical laboratory methods. The results demonstrate that Augmentation Index measured with arteriography and C reactive protein (CRP) levels were significantly ameliorated after 2 x 2 months Flavon Max therapy. In conclusion, this product is beneficial as adjuvant in the treatment of atherosclerotic coronary disease.

Multiplex obliterative vascular disease. Challenge in diagnostics and in treatment

UNLABELLED Currently, peripheral arterial disease is an underdiagnosed disorder. Several modifiable and non-modifiable risk factors have role in its development and progression. As system disorder it might be a part and an important predictor of fatal cardio- and cerebrovascular events. CASE REPORT The authors describe the case of a 73-year-old male with multilocational vascular disorder, with simultaneously occurring carotid disease, critical limb ischaemia with aorto-bifemoral bypass, multiple infarction with mechanical complication, inoperable coronary disease and with implantable cardioverter defibrillator for ventricular arrhythmia. CONCLUSION Peripheral arterial disease affects the whole vascular system and can progress into serious cardiac and cerebral manifestations causing the patients death inspite of comprehensive treatment.