Decreased flow-mediated dilatation with increased arterial stiffness and thickness as early signs of atherosclerosis in polymyositis and dermatomyositis patients.

Several autoimmune rheumatic diseases have been associated with accelerated atherosclerosis or other different types of vasculopathy depending on the underlying disease, leading to increased cardio- and cerebrovascular disease risk. Polymyositis (PM) and dermatomyositis (DM), members of idiopathic inflammatory myopathies (IIMs), a group of systemic autoimmune diseases are also associated with elevated risk of cardiovascular diseases (CVD). Up until now, no specific data is known on the mechanisms, risk factors, or possible vasculopathy leading to increased CVD risk. The aims of the present study were to assess the flow-mediated dilatation of the brachial artery by a TensioClinic arteriograph and to measure the thickness of carotid artery intima-media, the augmentation index, and the pulse wave velocity using high-resolution ultrasonography in a cohort of PM and DM patients. We also investigated the correlation of these parameters with the traditional risk factors of atherosclerosis and overall cardiovascular status within PM and DM patients. Twenty-seven patients (21 females, six males) with IIMs were enrolled in this study, and 38 healthy individuals matched for sex and age served as controls. We found a decreased flow-mediated dilatation in the brachial artery (6.36 vs. 8.39 %) with increased arterial stiffness and carotid artery thickness in our patients compared to healthy controls. We found significantly decreased flow-mediated dilatation of the brachial artery (5.57 vs. 8.39 %) in DM patients. We also detected a correlation between these parameters and the traditional cardiovascular risk factors, as well as hypertriglyceridemy, hypertension, and peripheral arterial disease. In DM, overall, more vascular abnormalities were found than in PM. Our findings suggest that flow-mediated dilatation of the brachial artery, arterial stiffness, and carotid artery thickness measurements could be beneficial for predicting the CVD risk in myositis patients. Further investigations need to find the potential differences and role of inflammation and immune mechanisms in atherosclerotic processes in DM and PM.

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)-gamma 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.

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.

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.

Endothelial dysfunction precedes atherosclerosis in systemic sclerosis--relevance for prevention of vascular complications.

OBJECTIVES: The pathogenesis of systemic sclerosis (SSc) includes vasculopathy with endothelial dysfunction. The aim of this study was to investigate endothelium-dependent, flow-mediated dilatation (FMD), as well as endothelium-independent, nitroglycerin-mediated dilatation (NMD) of the brachial artery and to assess common carotid intimal-medial thickness (ccIMT) in SSc patients compared with healthy controls. METHODS: FMD and NMD of the brachial artery were determined using high-resolution ultrasound imaging and the values were expressed as percentage change from baseline in 29 SSc patients and 29 healthy controls. The two groups were very similar regarding sex, age and traditional cardiovascular risk factors. In addition, common carotid arteries were assessed by duplex colour ultrasound, ccIMT determined using high resolution ultrasound and expressed in mm thickness in the same patients and controls. Correlations between FMD, NMD, ccIMT, age and the SSc subtype (diffuse or limited form) were analysed. RESULTS: In the 29 SSc patients (mean age: 51.8 yrs), the FMD was significantly lower (4.82 +/- 3.76%) in comparison with the controls (8.86 +/- 3.56%) (P < 0.001). No difference was found in NMD between patients (19.13 +/- 17.68%) and controls (13.13 +/- 10.40%) (P > 0.1). There was a tendency of increased ccIMT in SSc patients (0.67 +/- 0.26 mm) compared with healthy subjects (0.57 +/- 0.09), but this difference was not significant (P = 0.067). A significant, positive correlation between ccIMT and age in SSc (r = 0.470, P = 0.013) was detected, as well as in healthy controls (r = 0.61, P = 0.003), but no correlation was found between FMD and age. In addition, ccIMT, but not FMD and NMD, displayed significant correlation with disease duration (r = 0.472, P = 0.011). NMD displayed significant inverse correlation with the age in SSc patients (r = -0.492, P = 0.012), but not in controls. We did not find any correlation between FMD, NMD, ccIMT and SSc subtype. CONCLUSIONS: There is an impairment of endothelium-dependent vasodilatation indicated by low FMD in SSc. At the same time, the endothelium-independent dilatation assessed by NMD is still preserved giving an opportunity of nitroglycerine therapy. Carotid atherosclerosis indicated by ccIMT may occur at higher ages and after longer disease duration. Thus, the assessment of FMD in the pre-atherosclerotic stage may have a beneficial diagnostic, prognostic and therapeutic relevance.

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.