Annals of RSCB Vol. XVII, Issue 1/2012

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1 ENDOTHELIAL DYSFUNCTION IN SYSTEMIC SCLEROSIS A. Caraba 1, Cristina Florea 1, R. Timar 1, Andreea Munteanu 1, Corina Serban 2, Diana Nicoară 3, I. Romoşan 1 UNIVERSITY OF MEDICINE AND PHARMACY VICTOR BABEŞ TIMIŞOARA: 1 DEPARTMENT OF INTERNAL MEDICINE; 2 DEPARTMENT OF PATHOPHYSIOLOGY; 3 SELFMED CLINIQUE TIMISOARA Summary Systemic sclerosis is an autoimmune, inflammatory disease, characterized by extensive fibrosis, vasculopathy, and immunological abnormalities. Among other complications, the patients with systemic sclerosis may develop an accelerated and premature atherosclerosis. Aim: The aim of the present study is represented by the assessment of endothelial function in patients with diffuse systemic sclerosis. Material and methods: The study was performed on two groups of subjects: group A, formed by 10 patients with diffuse systemic sclerosis without overt heart disease, and group B, formed by 10 healthy, sex- and age matched controls. Total cholesterol, HDL, LDL cholesterol, triglycerides, C-reactive protein, and blood pressure were determined in all subjects. Endothelial function was assessed by means of flow-mediated vasodilation on brachial artery, using B-mode ultrasonography, with linear transducer of 10 MHz. All the values were presented as mean ± standard deviation. The statistical analysis was done using Student s t-test, and Pearson test, p < 0,05 was considered statistical significantly. Results: The mean age of patients with systemic sclerosis was 45,16 ± 7,28 years, and the mean length of disease evolution was 6,28 ± 2,68 years. The values of total cholesterol, LDL cholesterol, triglycerides, and blood pressure did not show significant differences between the patients and control subjects (p > 0,05). The value of C reactive protein was significantly higher in sclerodermic patients (p < 0,001). The value of FMD was significantly lower in sclerodermic patients (p < 0,001), being a significant negative correlation between FMD and C reactive protein (p < 0,05). Conclusions: The patients with systemic sclerosis present endothelial dysfunction, the first step in the atherosclerosis development. This disorder is not explained only by the traditional risk factors of atherosclerosis, but by the disease related factors. Key words: atherosclerosis, endothelial dysfunction, systemic sclerosis Introduction Systemic sclerosis represents an autoimmune, inflammatory disease, which is characterized by extensive fibrosis, vasculopathy, and immunological abnormalities (Gilliland, 2005). Among other complications, the patients with systemic sclerosis, especially with diffuse forms, develop an accelerated atherosclerosis, even in the absence of traditional cardiovascular risk factors (Matucci et al, 2003; Shoenfeld et al, 2005). In present, atherosclerosis is considered an immune-mediated inflammatory disease (Shoenfeld et al, 159 alexcaraba@yahoo.com 2001). Some studies showed that interleukin-6 is elevated in the serum of patients with systemic sclerosis, especially those with diffuse skin involvement (Sato et al, 2001; Matsushita et al, 2006). This cytokine has an important role in the acute phase response, chronic inflammation, autoimmunity, endothelial cell function, and fibrogenesis (Matsushita et al, 2006). The first step in the atherosclerosis pathogenesis is represented by the endothelial dysfunction. Endothelial dysfunction may be assessed by biochemical or imaging methods (Caraba et al, 2006; Thijssen et al, 2011).

2 The aim of this study is represented by the assessment of endothelial function in patients with systemic sclerosis, using flowmediated vasodilation of the brachial artery. Material and methods The study was performed on two groups of subjects: group A, formed by 10 patients with diffuse systemic sclerosis without overt heart disease, and group B, formed by 10 healthy sex- and age matched controls. The diagnosis of systemic sclerosis was established based on the criteria of the American College of Rheumatology (Ionescu, 2007). The traditional risk factors for atherosclerosis (diabetes mellitus, hypertension, smoking, chronic kidney disease) were absent. Total cholesterol (Abbott photometry), HDL cholesterol (Abbott photometry), triglycerides (Abbott reactive), C reactive protein (turbidimetry), and blood pressure were determined in all patients. The values of LDL cholesterol was calculated using the formula: LDL cholesterol = total cholesterol-hdl cholesterol-tg/5 (Friedewald et al, 1972). Endothelial function was assessed by means of flow-mediated vasodilation (FMD) on brachial artery, using B-mode ultrasonography (ALOKA ProSound 4000 SSD, linear transducer of 10 MHz). Before the test, the subject was relaxed in a stable room temperature between 20-25ºC. The baseline diameter of brachial artery was measured (D 1 ). Then, ischemia was induced by inflated the pneumatic cuff to a pressure 50 mmhg above systolic one, in order to obliterate the brachial artery. After 5 minutes, the cuff was deflated and the diameter of brachial artery was measured again, after 60 seconds post deflation (D 2 ). FMD was calculated with the formula: FMD (%) = [(D 2 -D 1 )/D 1 ] 100 (Correti et al, 2002; Thijssen et al. 2011). All the values were presented as mean ± standard deviation. The statistical analysis was performed using Student s t- test, and Pearson s test, p < 0,05 was considered statistical significantly. Results The demographic, clinical and biological characteristics of the studied groups are shown in table I. Table I The characteristics of the studied groups Parameter Systemic sclerosis group Control group p (Group A) (Group B) Males/Females 0/10 0/10 NS Mean age (years) 45,16 ± 7,28 42,94 ± 9,18 NS Mean length of 6,28 ± 2, systemic sclerosis evolution (years) Total cholesterol 180,9 ± 43,62 177,55 ± 14,81 NS LDL cholesterol 111,5 ± 30,58 107,3 ± 18,35 NS Triglycerides 137,5 ± 28,55 144,2 ± 17,53 NS C reactive protein 13,4 ± 5,95 3,4 ± 1,11 < 0,001 Systolic blood 121 ± 6,58 117,5 ± 7,90 NS pressure (mmhg) Diastolic blood 71,5 ± 7,83 75,5 ± 7,24 NS pressure (mmhg) FMD (%) 9,31 ± 2,39 14,43 ± 2,22 < 0,

3 In systemic sclerosis group (group A), FMD was significantly reduced than in controls (group B) (figure 1) p < 0,001 In systemic sclerosis patients, it was established a significant negative correlation between FMD and C reactive protein (r = -0,709, p < 0,05) (figure 2) FMD (%) Group A Group B Fig. 1 FMD in the studied groups of subjects Fig. 2 Correlation between FMD and C reactive protein Discussion Atherosclerosis represents a complex, continuum process, considered as an immune-mediated inflammatory one. Subclinical vascular abnormalities (endothelial dysfunction, increase of vascular stiffness) are followed by the vascular lesions (increased arterial intimamedia thickness). After these stages, overt cardiovascular disease appears (Shoenfeld et al, 2001; Tănăsescu et al, 2009). It is known that autoimmune rheumatic diseases are associated with a significant morbidity and mortality due to cardiovascular complications (Shoenfeld et 161 al, 2001). These complications develop insidiously, being generated by the coexistence of traditional risk factors of atherosclerosis with other specific factors related to these autoimmune diseases. In order to prevent the development of these cardiovascular complications, it is very important to identify the first step of atherogenesis (Shoenfeld et al, 2005). Endothelial dysfunction, defined by an abnormal response of the vascular endothelium to vasodilator stimulus, represents the first step in the atherosclerosis development (Tănăsescu et al, 2009). Biochemical and imaging

4 methods are used in order to assess the presence of endothelial dysfunction (Caraba et al, 2006; Thijssen et al, 2011). Systemic sclerosis, an autoimmune rheumatic disease is divided into two major forms: localized and systemic scleroderma. The latter has two categories: limited and diffuse systemic sclerosis (Gilliland, 2005). The diagnosis is established based on the preliminary classification criteria for systemic sclerosis (table II) (Ionescu, 2007). Tab. II Preliminary classification criteria for systemic sclerosis A. Major criterion Scleroderma proximal to the metacarpophalangeal joints B. Minor criteria Sclerodactyly (symmetric skin thickening limited to the finger) Digital pitting scars, loss of finger pad substance Bibasilar pulmonary fibrosis In systemic sclerosis, vascular involvement is not limited only to microvasculature. The studies showed an increased prevalence of macrovascular disease, about 30% of all deaths in systemic sclerosis were attributed to cardiovascular causes (Cypiene et al, 2008; Toms et al, 2011). Matucci et al. described the association between systemic sclerosis and atherosclerosis, identifying intimal thickening, destruction of the internal elastic lamina, and cellular infiltrate in the artery walls (Matucci et al, 2003). The same author showed that in sclerodermic patients, the carotid artery was involved in 64% of studied cases, compared with 35% of control subjects (Matucci et al, 2003). In this study, endothelial dysfunction was assessed by flow-mediated vasodilation (FMD) on the brachial artery. FMD was significantly reduced in systemic sclerosis group (p < 0,001). The studies of Szücs et al. (Szücs et al, 2007), Roustit et al. (Roustit et al, 2008), Rollando et al. (Rollando et al, 2010) identified the existence of endothelial dysfunction in patients with diffuse systemic sclerosis. It was identified a strong negative correlation between C reactive protein and FMD (p < 0,05). Endothelial dysfunction is related to pro-inflammatory cytokines and oxidative stress, which contributes to enhance oxidation of LDL particles (Sherer, Shoenfeld, 2006). In the present study, the degree of inflammation was assessed by means of C reactive protein, which was significantly increased compared with the control group (p < 0,001). Barault et al. reported increased levels of tumor necrosis factoralpha and interleukin-6 in patients with systemic sclerosis (Barault et al, 2010). Several studies showed a correlation between the values of interleukin-6 and C reactive protein (Shovman et al, 2006, Barault et al, 2010). In this study, didn t appear any differences between the mean values of total cholesterol, LDL cholesterol and triglycerides in the systemic sclerosis group and control group. The same results were reported by Toms et al (Toms et al, 2011). But in the presence of inflammation, LDL particles suffer an oxidation, generating oxldl particles, which contribute to the atherosclerosis development (Ngian et al, 2011). Conclusion The patients with systemic sclerosis present endothelial dysfunction, the first step in atherosclerosis development. This disorder is not explained only by the traditional risk factors of atherosclerosis, but by the disease related factors. References Barault, J., Michel, L., Verrecchia, F., Farge, D.: Relationship between cytokine profile and clinical outcomes in patients with systemic sclerosis. Autoimmune Rev., 10, 2, 65-73,

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