Reduced flow-mediated vasodilation as a marker for cardiovascular complications in lupus patients

Abstract

Systemic lupus erythematosus is associated with accelerated atherosclerosis and increased cardiovascular morbidity and mortality.

Objectives were to determine endothelial dysfunction with a non-invasive method in lupus patients and to analyse correlation with risk factors and atherosclerotic complications.

Sixty-one SLE patients and 26 healthy age- and sex-matched control subjects were entered into the study. The diameters of brachial artery at rest, during reactive hyperaemia, and after glyceril trinitrate administration, as well as the intima-media thickness of the common carotid artery were measured using high-resolution B-mode ultrasonography. Demographic characteristics, lipid profile, paraoxonase activity, concentration of anti-phospholipid antibodies and anti-oxLDL were assessed together with atherosclerotic complications.

The endothelium dependent vasodilation (FMD) was significantly impaired in SLE patients as compared to controls. The absolute difference of vessel diameter (Δd) was 0.25 ± 0.15 mm vs. 0.38 ± 0.16 mm (p = 0.001), and Δd as in percent of the rest diameter was 7.31 ± 5.2% vs. 9.86 ± 3.87% (p = 0.013) in lupus patients and controls, respectively. Nitrate mediated dilation (NMD) did not differ. FMD negatively correlated with age, systolic and diastolic blood pressure in SLE, but did not show significant correlation with the other examined parameters. However, FMD significantly differed between SLE patients with (5.54 ± 4.36%) and without (8.81 ± 5.28%) cardiovascular complications (p = 0.01).

The determination of flow-mediated vasodilation is a useful method to detect endothelial dysfunction in lupus patients, as reduced capacity of brachial artery may distinguish between SLE patients and healthy subjects, as well as lupus patients with and without atherosclerotic vascular complications.

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.