ReviewReduced flow-mediated vasodilation as a marker for cardiovascular complications in lupus patients
Introduction
Systemic lupus erythematosus (SLE) is a chronic inflammatory, autoimmune disorder. Life expectancy of lupus patients has increased in the past ten years, as such, accelerated atherosclerosis with consequent cardio- and cerebrovascular events have become the major causes of morbidity and mortality in lupus patients [1], [2], [3], [4]. In one such study SLE women aged 44–50 had 7.5-fold increased risk to develop coronary heart disease compared with controls, even after adjusting for classical risk factors [5]. Since SLE-related cardiovascular diseases could give insights into the nature of autoimmunity in atherosclerosis in general there is increased focus on autoimmune rheumatic diseases with chronic inflammation. In addition to traditional risk factors, such as smoking, obesity, hypertension, diabetes and dyslipidemia, disease specific factors such as steroid therapy, chronic renal failure, inflammation and autoimmune reactions may also account for enhanced atherosclerosis in lupus [6].
Immune-inflammatory processes have evidenced to play important role in the pathogenesis and progression of atheroma formation and plaque rupture. T cell, monocyte-macrophage, and cytokine influx to vessel wall have been confirmed [7], [8], [9], [10], [11]. Furthermore, atherogenesis has been suggested to be an autoimmune disease, based on animal experiments indicating that adoptive transfer of beta2-glycoprotein I-reactive lymphocytes to LDL receptor-deficient mice enhances early atherosclerosis [12].
Endothelial dysfunction represents the earliest stage of atherosclerosis. It is characterized by an impaired capacity of arterial vessels to dilate in response to different stimuli that induce release of nitric oxide (NO) [13]. A reduction of endothelial NO bioavailability, induced by the exposure to increased oxidative stress, is considered the main determinant of endothelial dysfunction [14], [15]. In the 1990’s, a high-frequency ultrasonographic imaging of the brachial artery was developed to assess endothelium-dependent flow-mediated vasodilation. The technique provokes the release of NO in response to increasing flow, and to the consequent shear stress, resulting in vasodilation which can be measured as an index of vasomotor function. This phenomenon is designated flow-mediated vasodilation (FMD). Vessel response to direct effect of NO, that is nitrate mediated vasodilation (NMD), is endothelium independent. As numerous factors affect flow-mediated vascular reactivity, including temperature, food, drugs, and sympathetic stimuli, an international consensus for the standardisation of technique has been developed [16].
Paraoxonase (PON1) is an important enzyme of the endogenous antioxidant systems. The PON1 activity was shown to be reduced and associated with atherosclerotic events in lupus patients [17], [18], [19], [20]. This may be an additional factor leading to oxidative stress, enhancing modification of plasma lipids [21], [22]. Increased anti-oxLDL level may refer to this process. Besides oxidised low-density lipoprotein and heat shock proteins, antiphospholipid antibodies (aPL) are considered as possible antigens initiating inflammatory processes in atherosclerosis [22], [23], [24]. These factors are highly supposed to influence FMD.
Another method to characterise quantitatively atherosclerotic processes is the measurement of intima-media thickness (IMT) of common carotid artery by high-resolution ultrasonography [25]. Evidences indicate correlation between IMT and cardiovascular diseases, especially with coronary heart disease [26], [27]. In a previous study, IMT in lupus patients showed the strongest correlation with the fact of having lupus [28]. This observation also suggests shared pathogenic pathways in SLE and atherosclerosis.
The aim of the present study was to measure endothelial dysfunction in lupus patients and healthy subjects with a non-invasive method. Our goal was also to find correlation between flow-mediated vasodilation of brachial artery and risk factors together with atherosclerotic complications in lupus patients.
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Patients
Sixty-one unselected patients (52 women and 9 men) were entered into the study. All of them fulfilled four or more of the revised American College of Rheumatology (ACR) criteria for the classification of systemic lupus erythematosus [29]. The age of patients (mean ± SD) was 45.2 ± 14.7 year. Disease duration was 10.2 ± 7.6 years (mean ± SD). Twenty-six age- and sex-matched healthy subjects served as controls. The mean serum lipid concentrations were similar between SLE and control groups. Patients with
Flow- and nitrate-mediated vasodilation in SLE patients and normal controls
Traditional risk factors, serum lipid parameters and blood pressure did not differ in patients with SLE as compared to a sex- and age-matched healthy control group (Table 1). Diabetic, obese patients and smokers were excluded.
Endothelium dependent vasodilation (FMD), representing endothelial dysfunction, was reduced in lupus patients as compared to controls. The difference was significant when FMD was expressed as the absolute dilation (d2–d1) in mm, and also when dilation was expressed
Discussion
Systemic lupus erythematosus is a chronic inflammatory autoimmune disease and as such, lupus is associated with accelerated atherosclerosis [32], [33]. Traditional and non-traditional risk factors, including atherogen lipid profile, obesity, smoking, diabetes, hypertension, antiphospholipid antibodies, enhanced lipid peroxidation and inflammation are related to atherosclerotic and atherothrombotic complications [23], [24]. However, despite the extensive scientific efforts the underlying
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