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Rheumatology Advance Access originally published online on January 23, 2007
Rheumatology 2007 46(5):759-762; doi:10.1093/rheumatology/kel426
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

G. Szucs*, O. Tímár1,*, Z. Szekanecz1, H. Dér1, G. Kerekes1, S. Szamosi, Y. Shoenfeld2, G. Szegedi3 and P. Soltész1

Division of Rheumatology, and 1Cardiovascular Unit, Third Department of Medicine, University of Debrecen Medical and Health Science Center, Debrecen, Hungary, 2Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel and 3Research Center for Autoimmune Diseases, Hungarian Academy of Sciences, Debrecen, Hungary.

Correspondence to: Z. Szekanecz, 3rd Department of Internal Medicine, Rheumatology Division, University of Debrecen, Medical and Health Science Center, Hungary, Móricz Zs krt. 22., H-4004 Debrecen, Hungary.E-mail: szekanecz{at}iiibel.dote.hu


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
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.

KEY WORDS: Systemic sclerosis, Endothelial dysfunction, Atherosclerosis, Flow-mediated vasodilatation, Nitrate-mediated vasodilatation, Intima-media thickness


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Systemic sclerosis (SSc) is associated with chronic inflammation, fibrosis and obliterative vasculopathy within the skin and visceral organs. The microvasculature is primarily affected, however, large-vessel disease also occurs in SSc [1–6]. Accelerated atherosclerosis has been described in some patients with SSc [7]. This occurred despite of the absence of classical vascular risk factors. In ulnar artery biopsies, intimal thickening and transmural lymphocytic infiltrates were detected without the presence of atherosclerotic plaques [6]. Macrovascular disease was observed in 58% of patients with limited cutaneous SSc (lcSSc) [2, 4]. Intermittent claudication, cardiovascular disease (CVD) and cerebrovascular disease were detected in 22%, 15% and 6.5% of SSc patients, respectively [7]. Angiography demonstrated rigidity of various arteries [6]. Increased intimal-medial thickness of the common carotid artery (ccIMT) has been described in 64% of SSc patients [3, 6, 8]. Carotid elasticity [9] and coronary flow reserve [10] are also abnormal in SSc.

Early endothelial dysfunction has been described in rheumatoid arthritis (RA) and lupus (reviewed in [3, 4]). However, there are very few studies assessing flow-mediated (FMD) or nitrate-mediated vasodilatation (NMD) in SSc. FMD measured on the brachial artery at rest and during reactive hyperaemia indicates endothelium-dependent vasodilatation, while NMD assessed after administration of sublingual nitroglycerin, is an indicator of endothelium-independent vasodilatation [8, 11]. Twelve patients with SSc and Raynaud's phenomenon (RP) were investigated and both FMD and NMD were reduced in the patients in comparison to controls [8].

Pathogenic factors involved in SSc-associated vascular damage include increased low density lipoprotein (LDL), homocysteine and C reactive protein (CRP) production [3, 12, 13]. We have recently described the association of 5,10-methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism with homocysteine, vitamin B12 production and macrovascular abnormalities in SSc [14]. We also detected increased serum adhesion molecule levels in SSc patients with macrovascular disease [15].


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Forty consecutive SSc patients were screened for inclusion and exclusion criteria described further and 29 patients were eligible for the study. All patients fulfilled the American College of Rheumatology (ACR) criteria for SSc [16, 17]. SSc patients included 25 females and 4 males with a mean age (±S.D.) of 51.8 ± 10.0 yrs (range: 31–69 yrs). The mean disease duration (DD) was 9.43 ± 3.78 yrs (range: 2–23 yrs). Nineteen patients had lcSSc and 10 had dcSSc. DD was based on the onset of RP or awareness of numbness, puffiness, or sclerosis of fingers. Pulmonary fibrosis was diagnosed using high resolution computed tomography (HR-CT) and pulmonary function tests. Oesophageal involvement was assessed by barium swallow test. Cardiac involvement including relaxation and/or conduction disturbances, right ventricular hypertrophy were assessed by echocardiography. Pulmonary arterial hypertension (PAH) was present if the estimated right ventricular systolic pressure exceeded 35 mmHg. Renal manifestations included glomerulopathy or tubulopathy confirmed by histology. For comparison, we studied 29 healthy control subjects (23 females and 6 males) recruited from 35 consecutive healthy individuals including hospital visitors and employees. Twenty-nine out of 35 met the inclusion criteria. Their mean age was 49.3 ± 9.6 yrs (range: 25–69 yrs). Traditional risk factors for CVD, such as age, body mass index (BMI), plasma lipid levels, as well as systolic and diastolic blood pressure were assessed. Members of the control group were individually matched with the 29 SSc patients according to age and traditional cardiovascular risk factors.

Exclusion criteria included known CVD, diabetes mellitus, cigarette smoking, obesity (BMI ≥ 30), vasculitis, infection and renal failure (serum creatinine ≥ 117 mmol/l). All patients and controls were fasting and had not used alcohol, tobacco, antioxidants and vasoactive drugs within the past 24 h.

A written consent was obtained from each individual according to the Declaration of Helsinki. In addition, this study has been approved by the local ethics committee of our university.

Brachial FMD and NMD
Brachial FMD and NMD were assessed as described elsewhere [11]. Briefly, ultrasound examination was performed on the right arm using 10 MHz linear array transducer (HP Sonos 5500) by a trained assessor after 30 min resting in a temperature-controlled room (baseline FMD). In order to assess FMD, reactive hyperaemia was induced by release of a pneumatic cuff around the forearm inflated to suprasystolic pressure for 4.5 min. After deflation, the maximal flow velocity and the arterial diameter was recorded for 90 min. After 15 min of recovery to the baseline diameter (baseline NMD), 400 µg sublingual nitroglycerine was administered and NMD was assessed. FMD and NMD values were expressed as percentage change from baseline value.

ccIMT
ccIMT measurements were carried out as described by others [18]. Briefly, a duplex utrasound system (HP Sonos 5500, 10 MHz) was used to record the common carotid arteries. The offline measurements were performed 1 cm proximal to the carotid bulb in the far wall. The ccIMT was defined as the distance between the first and second echogenic lines from the lumen taking the average of 10 measurements on both sides and ccIMT values were expressed in mm.

Statistical analysis
Data are expressed as the mean ± S.D. Statistical analysis was carried out by paired two-tailed t-test. Correlations were determined using the Pearson correlation coefficient. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
All patients had RP, and 13 (44.8%) had digital ulcers. Nineteen patients (65.5%) had pulmonary fibrosis or PAH. Cardiac abnormalities described above were observed in 19 patients (65.5%). Twenty-one patients (72.4%) had gastrointestinal and 3 patients (10.3%) had renal manifestations. Thirteen, mostly diffuse cutaneous SSc (dcSSc) patients (44.8%) had anti-topoisomerase I antibody, while 3 patients (10.3%) were positive for anti-centromere antibody.

The SSc patient group and the control group were very similar with regards to age (51.8 vs 49.3 yrs), systolic (135.6 vs 133.3 mmHg) and diastolic blood pressure (86.2 vs 84.8 mmHg), plasma levels of total cholesterol (5.39 vs 5.45 mmol/l), LDL-C (3.63 vs 3.13 mmol/l), HDL-C (1.47 vs 1.68 mmol/l) and triglyceride (1.24 vs 1.39 mmol/l), as well as BMI (22.8 vs 24.7 kg/m2). Differences in any of these parameters between SSc patients and controls were non-significant.

Regarding therapy, 20 patients received ACE inhibitors, 17 calcium channel blockers and 3 ß-blockers. There was no difference in risk factors, FMD, NMD or ccIMT between SSc patients taking any of these drugs vs patients receiving none of these drugs. None of the patients received parenteral prostanoids during the last 6 weeks before the study (data not shown).

FMD in SSc patients was significantly lower (4.82 ± 3.76%) compared with controls (8.86 ± 3.56%) (P < 0.001). However, no difference was found in NMD between SSc patients (19.13 ± 17.68%) and controls (13.13 ± 10.40%) (P = 0.129). ccIMT was non-significantly higher in SSc (0.67 ± 0.26 mm) compared with controls (0.57 ± 0.09) (P = 0.067) (Table 1).


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  		TABLE 1. FMD, NMD and ccIMT in SSc and controlsa

 
No differences in FMD, NMD or ccIMT values between lcSSc vs dcSSc subgroups or between patients with digital ulcers vs those without ulcers were found (data not shown).

FMD, NMD and ccIMT values were analysed in relationship with age in controls, as well as with age, DD, clinical manifestations and autoantibodies in SSc patients. Only ccIMT showed a significant correlation with age in controls (r = 0.610; P = 0.003). Neither FMD (r = –0.264, P = 0.082) nor NMD (r = 0.032, P = 0.870) correlated with age in controls (Table 2). In SSc patients, ccIMT also showed a significant correlation with age (r = 0.470; P = 0.013) and DD (r = 0.472, P = 0.011). In contrast to controls, in SSc, NMD displayed an inverse correlation with age (r = –0.492; P = 0.012), however, NMD did not correlate with DD (r = –0.222, P = 0.287). FMD did not correlate with age in SSc (r = –0.364, P = 0.052) or DD (r = 0.039, P = 0.842) (Table 2). In addition, FMD, NMD and ccIMT did not correlate with each other, and with the presence or absence of any organ manifestations, or with autoantibody positivity (data not shown).


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  		TABLE 2. Correlations between certain parameters

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
Accelerated atherosclerosis and CVD is a major cause of morbidity and mortality in autoimmune patients including RA and lupus [3, 4]. Assessing risk for future cardiovascular events include ultrasensitive CRP measurements, determination of brachial or coronary FMD, carotid calcium content or ccIMT [11,18–22].

Little information is available regarding endothelial dysfunction in SSc. Primarily the microvasculature is affected in SSc leading to RP and renal vasculopathy. However, the damage of large vessels may also occur in 50–60% of SSc patients [1–7]. Impaired coronary flow reserve has been described in SSc [10]. CVD may occur in as much as 6–15% of SSc patients [7].

The pathology of macrovascular disease includes large vessel occlusion and transmural inflammation of the vessel wall leading to tissue damage [6]. Traditional Framingham risk factors may influence the determination of vascular function. In this study, there was no difference between SSc patients and controls regarding these factors. In addition, SSc is generally not associated with elevated blood pressure [23].

The assessment of ccIMT is an indicator of atherosclerosis. The carotid artery is involved in 64% of SSc patients [6] and increased ccIMT has been reported in SSc [3, 8]. Here we also found somewhat increased ccIMT in 29 SSc patients (0.67 mm) compared with 29 controls (0.57). Thus, there is a tendency of carotid atherosclerosis in our SSc patients, which may become more pronounced with age. In addition, increased ccIMT was associated with longer DD.

Although early endothelial dysfunction has been described in RA and lupus (reviewed in [3, 4]), there is only limited information available in SSc. While brachial FMD indicates endothelium-dependent vasodilatation, NMD is a marker of endothelium-independent vasodilatation [8, 11, 18]. We found a significantly impaired FMD in SSc patients (4.8%) vs controls (8.9%), while NMD was preserved in SSc patients (19.1%) and controls (13.1%). We found a significant inverse correlation between age and NMD indicating, that NMD may also become impaired at higher age. Neither FMD nor NMD correlated with DD suggesting that the early impairment of FMD is associated with SSc-specific early events and not with long-term disease. Lekakis et al. [8] reported impaired FMD and NMD in 12 patients with either SSc or RP. Unfortunately, authors did not separate SSc from RP. Andersen et al. [24] found similar FMD and NMD in 24 SSc patients compared with controls. However, their patient population also included mixed connective tissue disease (MCTD) patients. Here we studied solely SSc patients. In addition, due to mostly technical reasons (only two highly trained assessors, time-consuming assessment, etc.), we could only include 29 patients and 29 controls, which may be a limitation during data interpretation. However, our data may be confirmed in a future study involving higher number of patients.

Thus, our middle-aged SSc patients represent a population, where there is only a tendency of carotid atherosclerosis, but the impairment of FMD already shows abnormal endothelium-dependent vasodilatation. At the same time, the preserved NMD gives us a possibility, to introduce nitroglycerin treatment or nitric-oxide donor agents in order to decrease cardiovascular risk. As ccIMT was positively, while NMD was inversely, correlated with age, more prominent atherosclerosis and abnormal NMD may develop in elderly patients. The correlation between ccIMT and DD suggests that impaired FMD may precede atherosclerosis in SSc. Our group found similar results in undifferentiated connective tissue disease (UCTD), which is a very early phase of systemic autoimmune diseases [25].

In conclusion, brachial FMD may be useful to assess early macrovascular alterations in SSc, while ccIMT indicates manifest atherosclerosis. Furthermore, preserved NMD indicates that early vasoprotective therapy may be beneficial in SSc.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported by research grants T 032947 (G. S.), T 048541 (Z.S.) and T 046517 (P.S.) from the National Foundation for Scientific Research (OTKA); a Bolyai Research Grant (P.S.) and a research grant from the Hungarian Academy of Sciences (G. Szegedi).

The authors have declared no conflicts of interest.


   Notes
 
*Contributed equally to this work. Back


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Veale DJ, Collidge TA, Belch J. (1995) Increased prevalence of symptomatic macrovascular disease in systemic sclerosis. Ann Rheum Dis 54:853–5.[Abstract/Free Full Text]
  2. Ho M, Veale DJ, Eastmond C, Nuki G, Belch J. (2000) Macrovascular disease in systemic sclerosis. Ann Rheum Dis 59:39–43.[Abstract/Free Full Text]
  3. Shoenfeld Y, Gerli R, Doria A, et al. (2005) Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 112:3337–47.[Free Full Text]
  4. Sherer Y and Shoenfeld Y. (2006) Mechanisms of disease: atherosclerosis in autoimmune diseases. Nature Clin Pract Rheumatol 2:1–8.[CrossRef]
  5. LeRoy CE. (1996) Systemic sclerosis: a vascular perspective. Rheum Dis Clin N Am 22:675.[CrossRef][Web of Science][Medline]
  6. Matucci Cerinic M, Fiori G, Grenbaum E, Shoenfeld Y. (2003) Macrovascular disease in systemic sclerosis. In Furst D and Clements P (Eds.). Systemic sclerosis(Lippincott Williams and Wilkins, Baltimore, MD) pp. 241.
  7. Matucci-Cerinic M, Valentini G, Sorano GG, et al. (2003) Blood coagulation, fibrinolysis and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum 32:285–92.[CrossRef][Web of Science][Medline]
  8. Lekakis J, Mavrikakis M, Papamichael C, et al. (1998) Short-term estrogen administration improves abnormal endothelial function in women with systemic sclerosis and Raynaud's phenomenon. Am Heart J 136:905–12.[CrossRef][Web of Science][Medline]
  9. Cheng KS, Tiwari A, Boutin A, et al. (2003) Carotid and femoral arterial wall mechanics in scleroderma. Rheumatology 42:1299–305.[Abstract/Free Full Text]
  10. Sulli A, Ghio M, Bezante GP, et al. (2004) Blunted coronary flow reserve in systemic sclerosis. Rheumatology 43:505–9.[Abstract/Free Full Text]
  11. Corretti MC, Anderson TJ, Benjamin EJ, et al. (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery. J Am Coll Cardiol 39:257–65.[Abstract/Free Full Text]
  12. Marasini B, Casari S, Bestetti A, et al. (2000) Homocysteine concentration in primary and systemic sclerosis associated Raynaud's phenomenon. J Rheumatol 27:2621–3.[Web of Science][Medline]
  13. Herrick A and Matucci Cerinic M. (2001) The emerging problem of oxidative stress and the role of antioxidants in systemic sclerosis. Clin Exp Rheumatol 19:1–4.[Web of Science][Medline]
  14. Szamosi S, Csiki Z, Szomják E, Szolnoki E, et al. Plasma homocysteine levels, the prevalence of methylenetetrahydrofolate reductase gene C677T polymorphism and macrovascular disorders in systemic sclerosis. J Rheumatol in press.
  15. Szucs G, Szomják E, Csiki Z, et al. (2002) Correlation between the level of serum soluble endothel adhesion molecules, endothelium-associoated cytokines and homocysteine level in patients with systemic sclerosis, atherosclerosis obliterans and primary Raynaud syndrome. Ann Rheum Dis 61:Suppl 1, 403.
  16. Subcommittee for scleroderma criteria of the American Rheumatism Association diagnostic and therapeutic criteria committee. (1980) Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23:581–90.[Web of Science][Medline]
  17. LeRoy EC, Black C, Fleischmajer R, et al. (1988) Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 15:202–5.[Web of Science][Medline]
  18. Kanters SDJM, Algra A, van Leeuwen MS, Banga JD. (1997) Reproducibility of in vivo carotid intima-media thickness measurements. Stroke 28:665–71.[Abstract/Free Full Text]
  19. Gordon PA, George J, Khamashta MA, Harats D, Hughes G, Shoenfeld Y. (2001) Atherosclerosis and autoimmunity. Lupus 4:249–52.
  20. George J, Afek A, Gilburd B, Harats D, Shoenfeld Y. (2000) Autoimmunity in atherosclerosis: lessons from experimental models. Lupus 3:223–27.
  21. Neunteufl T, Katzenschlager R, Hassan A, et al. (1997) Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 129:111–8.[CrossRef][Web of Science][Medline]
  22. Schachinger V and Zeiher AM. (2000) Atherosclerosis-associated endothelial dysfunction. Z Kardiol 89:70–4.[Medline]
  23. Zakopoulos NA, Kotsis VT, Gialafos EJ, et al. (2003) Systemic sclerosis is not associated with clinical or ambulatory blood pressure. Clin Exp Rheumatol 21:199–204.[Web of Science][Medline]
  24. Andersen GN, Mincheva-Nilsson L, Kazzam E, et al. (2002) Assessment of vascular function in systemic sclerosis: indications of the development of nitrate tolerance as a result of enhanced endothelial nitric oxide production. Arthritis Rheum 46:1324–32.[CrossRef][Web of Science][Medline]
  25. Kerekes G, Bodolay E, Sipka S, et al. (2005) Endothelial dysfunction and early atherosclerosis in undifferentiated collagenosis. Hung Med J (Orv Hetil) 146:791–5.
Submitted 20 April 2006; revised version accepted 30 November 2006.
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M. E. Hettema, H. Bootsma, and C. G. M. Kallenberg
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