Lupus (2009) 18, 522529

http://lup.sagepub.com

PAPER

Arterial wall dysfunction in systemic lupus erythematosus

A Cypiene1,2, M Kovaite2, A Venalis1, J Dadoniene1, R Rugiene1, Z Petrulioniene2, L Ryliskyte2 and A Laucevicius2
1Institute

of Experimental and Clinical Medicine at Vilnius University, Lithuania; and 2Department of Cardiovascular Medicine, Vilnius University; Centre of Cardiology and Angiology, Vilnius University Hospital Santariskiu Klinikos, Vilnius, Lithuania

Carotid-radial pulse wave velocity (PWV), aortic augmentation index (AIx) and endotheliumdependent flow-mediated dilatation (FMD) have been repeatedly showed to be related to premature atherosclerosis and cardiovascular diseases in different settings of population. The increased arterial stiffness and endothelium dysfunction may add to premature aging of the arteries in systemic lupus erythematosus (SLE) patients. Still data about arterial stiffness and endothelium function in inflammatory rheumatic diseases are not well described. The aim of this study was to determine the PWV, its derivate marker AIx and FMD and factors possibly influencing them in young SLE women without significant organ damage. Thirty women between 23 and 55 years with an established SLE diagnosis and 66 healthy women were consequently included in the study and both groups were comparable according to age, body mass index (BMI), serum lipid profile and creatinine. PWV was determined by measuring carotid-radial pulse wave transit time with the help of applanation tonometry and AIx, its derivate marker, was calculated as a difference between two waveform peaks expressed as a percentage of the pulse pressure. The FMD was performed by obtaining the repeated scans of the brachial artery at rest and during reactive hyperemia. In SLE women, PWV and AIx were significantly higher and FMD was not different from controls. In linear multiple stepwise regression analysis if patients and controls were both considered, PWV was weakly related to mean blood pressure (MBP), AIx was mostly predicted by age and MBP and FMD was predicted by the diameter of blood vessel, BMI, high density lipoproteins. If the sole SLE setting was analyzed, PWV was not related to any of the pending parameters, AIx turned out to be related to organ damage measured by Systemic Lupus International collaborative Clinics (SLICC) index and age, and FMD obtained strong and significant relation with vessel diameter, and BMI, and disease duration. Regardless of the small number of study group patients, we can state that controlling for MBP and taking measures towards organ damage prevention can partially slow down the process of early atherosclerosis in SLE patients. Lupus (2009) 18, 522529. Key words: arterial stiffness; atherosclerosis; endothelial function; systemic lupus erythematosus

Introduction
The increased arterial stiffness has been recognized as an independent risk factor for cardiovascular disease and measuring it could become an important routine assessment of patients in daily cardiology practice.1 Carotid-radial pulse wave velocity (PWV), aortic augmentation index (AIx) and endothelium-dependent flow-mediated dilatation have been repeatedly showed to be related to premature atherosclerosis and cardiovascular diseases increasing risk for them.18 There is now evidence that arterial stiffness is a predictor for cardiovascular events in the general
Correspondence to: Alma Cypiene, Experimental and Clinical medicine Research Institute at Vilnius University, Zygimantu 9, Vilnius, LT-01102. Email: alma@salmija.lt Received 10 January 2008; accepted 10 October 2008
2009 SAGE Publications Los Angeles, London, New Delhi and Singapore

population, in patients with hypertension, impaired glucose tolerance and coronary artery disease, and even in patients with end-stage renal disease, but had no independent predictive value in the healthy elderly patients of the Rotterdam study.3,911 According to Laurent and Boutouyrie, aortic stiffness has an independent predictive value for all-cause and cardiovascular mortality, cardiovascular disease, fatal and nonfatal coronary events and fatal strokes in patients with various levels of cardiovascular risk.10 Nevertheless, data about arterial stiffness and endothelium function in inflammatory rheumatic diseases are not consistent and their prognostic value is not well established.58,1223 Large number of publications summarized by Laurent in 2006 presented an extended list of conditions that may alter the artery elasticity. Age is playing the major independent role among them, but others are also important. They
10.1177/0961203308099625

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include physiological conditions, genetic and classical risk factors and inflammatory diseases as well.24 Several studies dealing with inflammatory and noninflammatory diseases demonstrated that C-reactive protein and a number of circulating and endothelium derived factors, including nitric oxide, von Willebrand factor (vWF), excess of adhesive molecules, endothelin-1, may influence large arteries elasticity providing so-called functional regulation of arterial stiffness.2527 Not only active chemical compounds but also disease itself may harm endothelium. In particular, SLE was shown to be an independent risk factor for endothelium dysfunction in women.15 Inflammation itself or adding to traditional cardiovascular risk factors may contribute to premature manifestation of atherosclerosis in systemic lupus erythematosus (SLE) patients.4,12,13,1519,2123 Arterial stiffness and endothelium function may serve as a valuable preclinical measure to be counted in the follow-up of these patients prior to a potential cardiovascular event. Two major estimates of vascular function, in particular augmentation index (AIx), indicating systemic arterial stiffness and flow-mediated dilatation (FMD), the parameter of endothelial function and to less extend carotid-radial pulse wave velocity (PWV), the parameter of regional arterial stiffness, have intensively been explored during last decade in different ways in rheumatic patients.48,1221 This study deals not only with systemic but with regional stiffness as well while classical studies and earlier studies encounter systemic and local stiffness. The increase of PWV, and AIx and reduced FMD goes in parallel with increased vascular stiffness, diminished elasticity and compliance of the arteries, and should be monitored and considered for treatment early before major cardiovascular events occur. Despite increasing interest in noninvasive functional tests of the arteries, no normal measures have been proposed until now for carotid-radial PWV evaluation in the healthy population. For carotid-femoral PWV, a threshold more than 12 m/s has been related to higher risk of coronary artery disease in hypertensive patients.28 So-called normal values of AIx are assessed individually for particular patient adjusting for age, blood pressure, height, weight and gender and the individual values of AIx can variate from around 20% in young athletes to about 40% in elderly hypertensive patients, but no normal ranges for healthy population for carotidradial PWV have been established until now. The normal individual values of FMD are described by equation encountering age and resting diameter of brachial artery,29,30 but no population data are available either. FMD cutoff point to predict high coronary heart dis-

ease risk was found to be lower than 4.5% in the study by Schroeder29 and lower that 6.5% in the study by Ryliskyte, et al.30 As no data for healthy population for arterial stiffness is available, the comparisons between disease and control group should be interpreted with caution. The aim of this study was to determine the carotidradial pulse wave velocity (PWV), aortic augmentation index (AIx) as a derivate marker of arterial wall dysfunction and endothelium-dependent flowmediated dilatation (FMD) and factors possibly influencing them in young SLE women without significant organ damage.

Patients and methods

Study population Thirty women between 23 and 55 years with an established SLE diagnosis (the 1982 revised criteria for the classification of SLE)31 were recruited from the Department of Rheumatology and examined at the Department of Cardiology and Angiology of Vilnius university hospital. In addition to demographical data, the disease activity index was assessed by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score,32 damage by Systemic Lupus International Collaborative Clinics (SLICC) damage index,33 and Raynaud syndrome, and antiphosholipid syndrome, and current therapy documented. Renal impairment was considered when proteinuria was more than 0.5 g up to 3.4 g per 24 h and/or haematuria more than five erythrocytes in the visual area. Blood samples were obtained in the morning after 12 h fasting, for the following tests: erythrocyte sedimentation rate, high-sensitivity C-reactive protein (hsCRP) by immunonephelometry, serum lipid profile, serum glucose and creatinine. Sixty-six healthy women aged between 19 and 55 years were consequently involved in the study when they were undergoing the preventive inspection at the same hospital. Subjects were excluded from the study in cases of a previous history of coronary artery disease or stroke, arrhythmias, infectious diseases, neoplasia, kidney or liver insufficiency, smoking or alcohol abuse. Hypertension (defined by blood pressure > 140/ 90 mm Hg), history of high hyperlipidaemia (total cholesterol > 6.2 mmol/L, low-density lipoprotein cholesterol (LDL) > 4.1 mmol/L) or obesity (body mass index (BMI) > 30 kg/m2) and diabetes mellitus (fasting glucose 7.0 mmol) were also considered as exclusion criteria. Approval was obtained from the
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Lithuanian Bioethics Committee, and a written informed consent was obtained from each participant. Non-invasive assessment of arterial stiffness Subjects were refrained from eating, drinking alcohol, coffee or tea at least 12 h prior to the study. To insure the stability of the measurement, the test of arterial stiffness was performed in the supine position after 10 min resting in a quiet, temperature controlled room (2224 C) in the early morning hours. Blood pressure was recorded in the left arm using an automatic blood pressure monitor. Pulse wave velocity (PWV) was determined by measuring the carotid-to radial pulse wave transit time. Carotid and radial pulse waves were obtained non-invasively by applanation tonometry using highfidelity micromanometer (Sphygmocor (v.7.01) AtCor Medical Pty. Ltd 19992002). Pulse waves obtained consecutively from the radial and carotid arteries were referenced to a simultaneously recorded ECG, and transit time was computed from the time difference between the carotid and radial waveforms. The distance between the surface markings of the sternal notch and the radial artery was used to estimate the difference in path between the carotid and radial arteries, and PWV adjusted for MBP was calculated. AIx (AIx adjusted for the heart rate 75 bpm) was calculated from radial pulse waves of non-dominant arm.34,35 Validated transfer function from peripheral pulse wave analysis was used to generate a corresponding central waveform. From this aortic AIx was calculated by using the integrated software. The systolic part of the central arterial waveform is characterized by two pressure peaks. The first peak is caused by left ventricular ejection, whereas the second peak is a result of pulse wave reflection. The difference between both pressure peaks reflects the degree to which central arterial pressure is augmented by wave reflection. AIx, a measure of systemic arterial stiffness, is calculated as the difference between the second and the first systolic peaks expressed as a percentage of pulse pressure. Flow-mediated dilatation measurement The endothelium-dependent flow-mediated dilatation test in a brachial artery was performed according to the method described by Celermajer, et al. and adapted according to international recommendations2,36 and technical equipment of our department.37 The brachial artery diameter was measured on B-mode imaging by the ultrasound system (Logiq 7, General Electric) with a high-resolution 12 MHz linear-array transducer.
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The computerized software program for image acquisition (CVI Acquisition) and semi-automatic analysis software were used (Vascular Analysis Tools (Vascular Converter CVI and Brachial Analyzer), Medical Imaging Application, 19982003 LLC Iowa City, Iowa 52246, USA). The arterial diameter was measured between the intima/lumen interfaces of the anterior and posterior wall at the end of diastole (synchronized with the beginning of the R wave on the continuously recorded ECG). Scans were taken in the longitudinal plane 18 cm above the antecubital fossa. Measurements were performed at rest and during reactive hyperaemia. In all, 1015 resting scans were obtained and resting arterial flow velocity was measured by means of a pulsed doppler signal at the 60 angle to the vessel, with the range gate in the centre of the artery. Increased flow was induced by the inflation of a pneumatic tourniquet to a 100 mmHg suprasystolic pressure for 5 min. A second scan was taken continuously for 3 min after cuff deflation, including a repeated flow velocity measurement within the first 15 s. after cuff release. During image acquisition, a stereotactic probe-holding device was used to insure the hand stability. Statistical analysis Data were analysed using SPSS software for Windows (version 11.0, Chicago, Illinois, USA). Continuous variables were compared with a help of t-test and for proportions Fishers exact test or chi-square test were used when appropriate. If normality assumption was violated, non-parametric Mann-Whitney U-test was used for continuous variables. To explore the relationship between arterial wall parameters and independent clinical and laboratory measures, two models of linear multiple stepwise regression analysis were considered. First model included the whole set of patients and binary variable indicating presenceabsence of SLE. Second model included only SLE group and disease-related variable SLEDAI, SLICC damage index, disease duration, renal impairment, Raynaud syndrome and antiphospholipid syndrome. In both cases, adjustments were made for additional factors. To avoid multicolinearity, cholesterol was excluded from the analyses as it was in significant correlation with the lipids (r > 0.7) and height being a compound of BMI. The variable entered stepwise selection model if its significance was less or equal to 0.05 and was excluded from the model if its significance was greater than 0.1. Variables considered for the model were supposed to have influence on dependent variable based on similar studies and our clinical experience. A full list of independent variables is presented under each

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linear regression model table. Level of significance was set to 0.05.

Results
Cardiovascular risk factors profile and arterial wall parameters in SLE women Demographical and clinical characteristics of 30 SLE women (aged 37.33 9.22 years) and 66 controls women (aged 37.45 8.69 years) are presented in Table 1. The mean disease activity was 18.4 (8.17) and considered to be mild and the median of damage index assessed by SLICC damage index was 1.0 (IQR 2.0). Seven women experienced Raynaud syndrome and six were diagnosed with antiphospholipid syndrome. It is noteworthy that nine women had renal impairment encountering proteinuria and haematuria but without important renal insufficiency. Twenty eight were on steroids from the start of disease and 14 were taking immunosuppressants (12 of them used azathioprine, 1-metotrexate, 1-cyclophosphamide), for at least one month before the examination of arterial functioning. In addition, 17 were taking hydrochloroquine together with immunosuppressants and 11 nonsteroidal antiinflammatory drugs. Therefore, to control the disease activity, all patients were on two or more medications concomitantly. In addition, eight patients were treated with ACE inhibitors, four with beta blockers and three with Ca channel blockers. Both groups were age, height, BMI homogenous and total cholesterol, high-density lipoprotein (HDL), LDL and creatinine were comparable. MBP

was significantly higher in the SLE women when compared to the controls following mean triglycerides levels (TG) and median hsCRP. The direct comparison of PWV, AIx and FMD between groups showed that PWV and AIx were significantly elevated in SLE while FMD did not. Influence of different risk factors on arterial wall parameters in the SLE and control groups To evaluate relationship of arterial stiffness and SLE, the stepwise multiple linear regression analysis was applied for the whole set of study population. Full list of independent predictors for PWV and AIx consisted of age, BMI, MBP, LDL, HDL, TG, log transformed hsCRP, creatinine and presence or absence of disease. For FMD, MBP was replaced with diameter of blood vessel. It was shown that SLE as disease did not have an impact on any measures of arterial wall functional parameters. MBP was the only one variable that might be related to the PWV (R2 = 0.076, adjusted R2 = 0.065, P = 0.010) though its influence was very mild. AIx was predicted importantly and significantly by age and MBP (R2 = 0.576, adjusted R2 = 0.566, P < 0.001) and FMD (R2 = 0.260, adjusted R2 = 0.232, P < 0.001)) was predicted by diameter of blood vessel, HDL and BMI (Table 2). Influence of different risk factors on arterial wall parameters in the SLE cohort To find out whether the disease-related variables may have an impact on arterial wall parameters, the same statistical approach was considered but the set of

Table 1 Clinical characteristics and arterial wall parameters between systemic lupus erythematosus (SLE) patients and control groups
Variable Age Height (cm) BMI (kg/m2) Mean blood pressure Total cholesterol High density lipoprotein Low density lipoprotein Triglycerides (mmol/L) C-reactive protein (mg/L)a Creatinine (mmol/L) SLEDAI SLICC damage indexa Disease duration (years) Renal impairment Raynaud syndrome Antiphospholipid syndrome Pulse wave velocity m/s Augmentation index % Flow-mediated dilatation %
aMedian

SLE group (n = 30) 37.33 (9.22) 166.43 (6.16) 23.20 (3.75) 95.57 (11.37) 5.26 (1.37) 1.44 (0.49) 2.93 (0.96) 1.99 (1.00) 3.20 [3.05;4.47] 71.18 (10.59) 18.40 (8.17) 1.00 [0;2.0] 8.01 (7.72) 9 (30%) 7 (23.3%) 6 (20%) 8.70 (1.88) 20.53 (12.40) 9.25 (5.15)

Controls (n = 66) 37.45 (8.69) 166.78 (5.53) 23.95 (3.39) 88.65 (9.55) 4.92 (0.84) 1.53 (0.33) 2.98 (0.68) 0.89 (0.52) 0.59 [0.29;1.35] 67.00 (9.30) 8.03 (1.18) 13.50 (10.14) 9.69 (3.29)

P value 0.951 0.782 0.336 0.003 0.218 0.310 0.777 <0.001 <0.001 0.064

0.036 0.004 0.670

[interquartile range] is reported.

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Table 2 Influence of different risk factors on arterial wall parameters in systemic lupus erythematosus (SLE) and control groupsa
Dependent variable PWV = 0.076, adjusted = 0.065, P = 0.010) AIx (R2 = 0.576, adjusted R2 = 0.566, P < 0.001) FMD (R2 = 0.260, adjusted R2 = 0.232, P < 0.001) (R2 R2 Predictor MBP Age MBP Diameter HDL BMI Regression coefficient 0.037 0.610 0.482 5.746 2.154 0.399 SE 0.014 0.097 0.081 1.220 0.990 0.125 Beta 0.275 0.478 0.450 0.480 0.210 0.323 P value 0.010 <0.001 <0.001 <0.001 0.033 0.002

aFull

list of independent predictors for PWV and AIx consisted of age, BMI, mean blood pressure, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG), log transformed C-reactive protein (hsCRP), creatinine and SLE coding: 0 absent, 1 present. For FMD MBP was replaced with diameter of blood vessel.

patients was restricted to SLE patients. The variable indicating presence or absence of SLE was removed from the list of independent predictors while SLEDAI, disease duration, SLICC damage index, renal impairment, Raynaud and antiphospholipid syndrome were added. In SLE patients, AIx was found to be related to age and SLICC (R2 = 0.567, adjusted R2 = 0.508; P < 0.001). PWV in SLE cohort was not related to any of pending parameters. FMD (R2 = 0.714, adjusted R2 = 0.673; P < 0.001) obtained strong and significant relation with vessel diameter, and BMI, and disease duration (Table 3). Other disease-related variables like renal impairment, Raynaud syndrome and antiphospholipid syndrome did not turn out to be important in predicting arterial stiffness or endothelial damage.

Discussion
Premature atherosclerosis has been repeatedly shown to be prevalent and the age of onset reduced in SLE patients when compared to matched population.13,23 The risk to develop coronary artery disease is five to eight times higher and is closely related to more frequent clinically important vascular events38,39 and higher mortality in this population subset.40 In addition, atherosclerotic vascular events are major contri-

butors to the clinical presentation of late-stage lupus.22 Although coronary artery sclerosis is a major cause of morbidity and poor outcome in patients with SLE, still little is known about its pathogenesis.23 This study showed that two markers of arterial wall dysfunction, namely aortic AIx (the parameter of systemic arterial stiffness) and to a less extent increased carotid-radial PWV (the indicator of diminished regional vessel flexibility, but not FMD), were increased in young SLE women with no history of cardiovascular disease and no severe organ damage when compared to healthy controls. It may be assumed that impaired arterial stiffness plays an independent pathogenetic role in atherosclerosis41 and may be responsible for premature atherosclerosis in SLE and atherosclerotic lesions. Higher frequency of cardiovascular events occurring earlier cannot be solely explained by traditional risk factors. It may be hypothesized that inflammation or side effects of the treatment added to traditional risk factors may initiate early atherosclerotic lesions through enhanced stiffening of the arteries. To avoid the summing effect of traditional and disease-related risk factors, this study compares young SLE women group without traditional risk factors and presumably without atherosclerosis with a healthy control group. Organ insufficiency was also considered as exclusion criteria for this study.

Table 3 Influence of different risk factors on arterial wall parameters in SLE cohorta
Dependent variable PWVb AIx(R2 = 0.567, adjusted R2 = 0.508, P < 0.001) FMD (R2 = 0.714, adjusted R2 = 0.673, P < 0.001) Predictor SLICC Age Diameter Disease duration BMI Regression coefficient 3.458 0.529 11.511 0.265 0.547 SE 1.291 0.210 1.658 0.081 0.223 Beta 0.414 0.380 0.868 0.403 0.315 P value 0.014 0.019 <0.001 0.004 0.023

aFull

list of independent predictors for PWV and AIx consisted of age, BMI, mean blood pressure, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (TG), log transformed C-reactive protein (CRP), creatinine, SLEDAI, disease duration, SLICC damage index, renal impairment, Raynaud syndrome and antiphospholipid syndrome. For FMD MBP was replaced with diameter of blood vessel. bNone of variables entered the final model.
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Despite well matching groups, AIx was obviously increased in SLE group, meaning increased artery stiffness in this group and not to say about FMD. In multivariate regression model, age and MBP were found to be associated with AIx if both, patients and controls, were considered. In the cohort of solely SLE patients disease damage index and age remains as the most important predicting factors for AIx. Our study echoes with Laurent study that proved aging and the blood pressure being the two major determinants of arterial stiffness.41 Based on this we think that monitoring and controlling of the MBP should be started from the beginning of disease and measures should be taken to prevent organ damage in this disease, since MBP and SLICC appears independent and potentially treatable influencing factor of functional status of arteries. Our data is in harmony with the results from the studies focusing on SLE and arterial wall functioning, namely study of Brodszki, et al.,42 Roman, et al.,4 Selzer, et al.21 These studies demonstrated an increased arterial stiffness and signs of premature vascular ageing in SLE patients without manifest cardiovascular disease and without significant atherosclerotic lesions.42 The authors conclude that other mechanisms beside atherosclerosis might be involved in the pathogenesis of arterial stiffening in SLE patients. The association of arterial stiffening with disease duration and circulating levels of C-reactive protein and IL-6 implicates chronic inflammation as important mediator of this process.4 SLE-specific variables were more important among younger women than in senior ones when traditional risk factors and age add to the context of disease.21 The study of Bjarnegard, et al. did not found differences in AIx (34 vs 33%) and brachial PWV (8.4 vs 8.5 m/s) in lupus women compared to controls.6 Nevertheless, the authors concluded that women with SLE have increased stiffness of their elastic central arteries judging on aortic PWV (9.8 vs 8.2 m/s) that was still higher in SLE women and was positively associated to CRP and complement factor 3.12 Other inflammatory diseases were also investigated within aspect of structural and functional reformation of the arteries, namely rheumatoid arthritis (RA) was thoroughly approached but the data are still controversial. In the study of Klocke, et al., the AIx of middle aged RA patients (mean age 42 years) was significantly higher in the RA group than in the control group (26.2 versus 18.9%; P = 0.028).26 In the study of Maki-Petaja27 where the mean age of study population was about 57 years, no difference was found in AIx between the RA (n = 77) and the control (n = 142) groups, 27% and 26%, P = 0.4, respectively,

although the carotid-radial PWV was found 8.6 m/s in RA patients and 8.15 m/s in controls; P = 0.02. In the study of Cypiene, et al.,28 comparison of the arterial wall parameters of 68 RA patients aged about 40 years has shown that the mean AIx (22.66 versus 10.49%; P < 0.001) was significantly higher in RA patients while carotid-radial PWV did not differ between the groups (8.42 vs 8.21 m/s; P = 0.315). In the study by Roman4 comparing arterial stiffness index between SLE and RA, and control subjects the values of arterial stiffness were significantly greater in SLE and RA patient populations than in the control group. It may be concluded from the above mentioned studies that differences in AIx and PWV are more prominent in younger ages when inflammation plays the major role and less prominent in older years when age adds to the profile of influencing factors. Aging of the arteries is more pronounced in central elastic arteries whose function is reflected by AIx, whereas the stiffness of muscular arteries reflected by PWV changes little with age.41,43 In the load-bearing media of elastic arteries, the orderly arrangement of elastic fibers and laminae is gradually lost over time, and thinning, splitting, fraying and fragmentation are observed. The degeneration of elastic fibres is associated with an increase in collagenous material and often accompanied by calcium deposition in ground substance and in degenerate elastic fibbers.41 It may be assumed that alterations in arterial wall parameters occur earlier in SLE patients than in matched population and the differences become less prominent with aging and becoming exposed to increasing number of traditional risk factors similarly for SLE patients and population. It is not known whether it manifests the same to all rheumatic diseases. Studies dealing with RA found age and disease factor much more important than MBP factor, which was found above others in SLE studies.14,44 Several studies approaching endothelial function of the brachial artery in SLE women differently from our findings indicate impaired FMD.1519 The patients enrolled in the quoted studies were either older, or smokers or diseased with other important diseases like diabetes or coronary artery disease, which may result in alterations of FMD. Likewise, in the study by Johnson, et al. corresponding values for lupus patients with subclinical coronary artery disease and no disease were 11 and 9.6%, respectively.17 It may be assumed that differently from AIx increasing early in the disease, the endothelial dysfunction may evolve later in the course of disease. This may be supported by the finding of disease duration factor inversely correlating with FMD in linear regression model in this study; with increasing disease duration the FMD
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decreases. Interestingly, not SLE itself, not even SLEDAI as a composite measure of disease activity or renal impairment had any impact on artery wall functioning. Concomitantly, Raynaud syndrome or antiphospholipid syndrome had no impact on arterial wall or endothelium as well. Moreover, TG and hsCRP, which are commonly considered as predictors of cardiovascular risk in general population45 and were significantly higher in SLE group, did not show any influence to AIx or FMD. Our findings come along with the study by Lima, et al. where endothelium-dependent dilatation was not related to anticardiolipin antibodies, hypertension history, Raynauds phenomenon, SLE disease activity score, vasculitis and even antimalar use.18 This study did not omit number of limitations. Though controlling the mean blood pressure seems logical to prevent from artery stiffening, some other important factors may be missing and their influence underestimated. In particular, treatment may play a crucial role to prevent endothelial damage and it was not assessed properly in this study. The vascular reactivity and improvement of endothelium dependent and independent vasodilation as an effect of corticosteroids was demonstrated in Tani, et al. study for SLE patients after administration of 20 mg of 6-metilprednisolone.16 The effect of treatment has been addressed in the publications of Bhagat and Vallace46 were hydrocortisone (100 mg) and high doses of aspirin (1000 mg) was shown to protect the cytokine influenced endothelial dysfunction on healthy volunteers aged 19-40. It may be assumed that hydrochloroquine may also play a significant role on artery functioning as Selzer, et al. study found no use of hydrochloroquine associated with increased PWV.21 Regarding the importance of treatment, the influence of biological therapy on arteries functioning was clearly demonstrated by the reduction of carotidradial PWV in young RA patients undergoing the treatment with infliximab in our hospital.6,7 Based on this, treatment effects may be extremely important in SLE patients as well. This study did not address endothelial derived factors namely, vWF though it may be linked to endothelial dysfunction, but antiphospholipid syndrome was not. Second, the impact of disease on arterial functioning may be clearer and more accurate when compared to other rheumatic diseases in direct comparisons. From the data acquired in our department, although not suitable for direct comparisons, because of unmatched epidemiological variables, systemic sclerosis group showed prominently increased arterial stiffness and poor endothelium functioning when compared to rheumatoid arthritis, SLE and vasculitis. Finally, this study is a small one to get
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to any strong conclusion and may not catch the differences where they really exist. Nevertheless, we believe that our findings are consistent with the number of studies, and may add to the knowledge of dysfunction of arteries occurring early in disease that may lead to premature atherosclerosis and serious clinical problems in young SLE patients.

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