Skip Navigation


Rheumatology Advance Access originally published online on March 5, 2008
Rheumatology 2008 47(5):578-583; doi:10.1093/rheumatology/ken078
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
47/5/578    most recent
ken078v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hettema, M. E.
Right arrow Articles by Kallenberg, C. G. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hettema, M. E.
Right arrow Articles by Kallenberg, C. G. M.
Related Collections
Right arrow Systemic Sclerosis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

REVIEWS

Macrovascular disease and atherosclerosis in SSc

M. E. Hettema, H. Bootsma and C. G. M. Kallenberg

Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Correspondence to: M. E. Hettema, Division of Rheumatology and Clinical Immunology, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. E-mail: m.e.hettema{at}int.umcg.nl


   Abstract
Top
 Abstract
Introduction
 Evidence for macrovascular...
 Aetiology
 Summary
 References
 
Atherosclerosis is considered to be a chronic inflammatory disorder. Several autoimmune rheumatic diseases are characterized by premature and accelerated atherosclerosis in which both classical and non-classical risk factors contribute to atherogenesis. SSc is characterized by vasculopathy, and microvascular involvement is common. Macrovascular involvement is considered rare, although increased prevalence of macrovascular disease has been reported as well. Here, we review the literature regarding coronary artery disease, cerebrovascular disease and peripheral arterial disease in SSc. An increased prevalence of distal peripheral artery disease in the digits has been found. The prevalence of coronary artery disease and cerebrovascular disease is not increased, although studies using intima–media thickness of the carotid artery as a marker of early atherosclerosis showed discrepant results. Besides traditional risk factors, as present in the general population, non-traditional risk factors are present in SSc as well, such as increased lipoprotein(a), oxidized LDL, inflammation, vasospasm and endothelial dysfunction. Moreover, markers of vascular damage in atherosclerosis, like antibodies to oxidized LDL, and increased levels of soluble vascular adhesion molecules, have been described in association with vascular damage in SSc. Nevertheless, generalized premature atherosclerosis has not been detected in SSc. Therefore, further research is necessary to assess the prevalence of clinically manifest or subclinical early atherosclerosis in SSc.

KEY WORDS: Macrovascular disease, Atherosclerosis, SSc


   Introduction
Top
 Abstract
 Introduction
Evidence for macrovascular...
 Aetiology
 Summary
 References
 
Atherosclerosis underlying cardiovascular mortality is the leading cause of death in developed countries (WHO Statistical Information System, www.who.int/whosis). Atherosclerosis is a disease of large and medium-sized arteries and can result in ischaemia and infarction. Clinical manifestations include coronary heart disease, stroke and peripheral vascular disease. Atherosclerosis is considered an inflammatory disease, in which, amongst others, monocytes, macrophages and T-cells as well as autoantibodies, autoantigens and cytokines play a role [1, 2]. Several autoimmune diseases, including RA [3–7], SLE [8–13] and WG [14], are characterized by an increased prevalence of atherosclerosis, and consequently, increased cardiovascular morbidity and mortality.

SSc is an autoimmune disorder characterized by widespread vascular involvement. Microvascular abnormalities and RP are well-known as major sites of pathology [15–18], but less attention has been paid to macrovascular abnormalities. Although survival in SSc has improved during the last decades, a recently performed meta-analysis still showed increased standardized mortality ratios. Involvement of major organs, such as heart, lungs and kidneys, was found to be an independent adverse predictor of mortality [19].

In this review, we discuss data on the prevalence and aetiology of macrovascular disease and atherosclerosis in SSc. Evaluation of the prevalence of clinically manifest atherosclerosis in SSc is difficult, as both the prevalence of SSc in the general population and the number of observed cardiovascular events are low. However, early atherosclerosis can be studied in cohorts of patients using standardized techniques. Therefore, we will also review studies describing subclinical, early atherosclerotic changes as assessed by measuring intima–media thickness (IMT) of the carotid artery [20–25]. We searched for original articles in PubMed and Medline published between 1950 and 2007 with the search strategy ‘atherosclerosis OR macrovascular’ in association with ‘systemic sclerosis’. We also used relevant papers retrieved from references of articles found by the search strategy.


   Evidence for macrovascular disease and atherosclerosis in SSc
Top
 Abstract
 Introduction
 Evidence for macrovascular...
Aetiology
 Summary
 References
 
The prevalence of vascular abnormalities in SSc has been considered to be inversely proportional to the size of blood vessels studied [26]. Macrovascular disease was considered extremely rare. Although the heart is one of the major organs involved in SSc [27], coronary arteries were rarely involved in histopathological material [28–31] or in coronary angiography [32]. Even so, in SSc patients admitted to the hospital because of acute myocardial infarction, the odds ratio of having normal coronary arteries was 33.89 compared with the patients admitted from the general population, suggesting microvascular and not macrovascular disease in these patients [33]. Also, cerebrovascular involvement in SSc has rarely been documented, although the opposite has been stated [34]. Only one retrospective cohort study is available, showing no increased prevalence of cerebrovascular disease in 31 female SSc patients compared with matched controls (prevalence 26 vs 19%, RR 1.3 with 95% CI of 0.5, 3.3) [35]. More studies are available regarding peripheral atherosclerotic vascular disease. An increased prevalence of peripheral vascular disease in SSc patients compared with healthy controls (21.7 vs 4.6%) has been observed by Veale et al. [36], using a questionnaire for intermittent claudication, and by Youssef et al. [35], using data available from angiography, Doppler ultrasound or physical examination (prevalence 58 vs 10%, RR 6.0 with 95% CI of 2.0, 18). When angiographic findings of the lower and upper limb in SSc patients were related to cardiovascular risk factors, an association was observed between these risk factors and proximal peripheral artery disease, but not distal peripheral artery disease [37]. Distal peripheral artery disease is present in the digits of many SSc patients, showing a high frequency of digital stenosis and occlusions in the digital arteries of patients. Lesions were most frequently found in the 2nd to 5th proper palmar digital artery, the ulnar artery and the superficial palmar arch [38–41]. As a consequence, digital ischaemia, ulceration or amputation is a well-known, but feared manifestation in SSc [42–44].

Several groups have studied subclinical, early atherosclerosis in SSc. Using IMT of the carotid artery as a marker of early atherosclerosis discrepant results were reported. No differences in IMT or intraluminal diameter of the common carotid artery (CCA) between SSc patients and controls were noted by some authors [45–48], while others found significantly increased IMT values or increased prevalence of carotid artery disease in SSc patients (Table 1) [49–53]. IMT values of the femoral artery in SSc patients and healthy controls were comparable [25, 45]. Nevertheless, large vessel involvement has been suggested in SSc since altered elastic properties of the carotid artery, increased stiffness of the aorta and decreased arterial distensibility have all been reported in SSc patients [45, 54–59]. Another method to assess subclinical atherosclerosis is by means of ankle brachial pressure index (ABPI), which is also the usual non-invasive assessment approach of patients with symptomatic peripheral vascular disease. This technique can also be used to predict cardiovascular disease and mortality [60–62]. ABPI has been used in asymptomatic SSc patients. Ho et al. [50] reported a significantly increased prevalence of peripheral artery disease, but in other studies no differences in ABPI between SSc patients and healthy controls were found [49, 51, 60]. Several other non-invasive tests have been used for the assessment of subclinical early atherosclerosis. Evaluation of heart rate variability has been used for assessing cardiovascular autonomic function, and is found to be a predictor of sudden arrhythmic death, but also of non-arrhythmic cardiac events [63]. The latter can be explained by the influence of heart rate variability on haemodynamic factors, leading to changes in the vascular wall. Evaluation of heart rate variability showed a reduced variability, indicating the presence of autonomic cardiac neuropathy in SSc patients without known cardiac disease [64–67].


View this table:
[in this window]
[in a new window]

  		TABLE 1. Carotid ultrasound studies in SSc

 
In conclusion, an increased prevalence of distal peripheral artery disease is present in SSc. Conflicting results regarding early signs of atherosclerosis are present, but can be explained by methodological differences, such as differences in patients included in the study, comorbidity and non-invasive techniques used.


   Aetiology
Top
 Abstract
 Introduction
 Evidence for macrovascular...
 Aetiology
Summary
 References
 
Traditional risk factors were equally distributed between SSc patients and controls in the aforementioned studies. Hence, other factors beyond traditional cardiovascular risk factors may contribute to any putatively increased prevalence of cardiovascular, cerebrovascular and peripheral vascular disease in SSc.

Lipoprotein profile
Dyslipidaemia, i.e. increased levels of low-density lipoprotein (LDL) cholesterol and triglycerides, and decreased high-density lipoprotein (HDL) cholesterol [68], is an important traditional risk factor for cardiovascular disease. Decreased HDL levels have been detected in patients with limited cutaneous SSc (lcSSc) compared with healthy controls [69]. No studies are available on LDL levels in SSc. However, patients with SSc showed increased susceptibility to oxidation of LDL, a process in which oxidized LDL (OxLDL) is formed [70]. OxLDL is a proatherogenic lipoprotein, which, amongst others, promotes foam cell formation, vascular oxygen radical formation, tissue remodelling, endothelial dysfunction and even vasospasm [71, 72]. Another cardiovascular pathogenic factor is lipoprotein(a) [Lp(a)] [73]. Its exact mechanism is unknown, but [Lp(a)] counterbalances the pro- and anti-coagulant, pro- and anti-inflammatory and vasorelaxing and vasoconstricting properties of the endothelium, in which raised concentrations are linked with atherosclerosis and thrombosis [74, 75]. In patients with SSc, increased concentrations of Lp(a) without further differences in lipid profile in comparison with healthy controls have been found, both in lcSSc and diffuse cutaneous SSc (dcSSc) [76, 77].

Autoantibodies
Increased concentration of antibodies to OxLDL (aOxLDL) have been described in atherosclerosis [78–82]. In young individuals or in early stages of atherosclerosis, low aOxLDL levels have been found [83, 84]. Immunization with OxLDL in experimental animals resulted in a protective effect on the process of atherogenesis leading to increased aOxLDL levels and a reduction in atherosclerosis [85–89]. Increased concentrations of aOxLDL have been found in patients with SSc, particularly in dcSSc [77, 90].

aPLs are present in the APS. APS is clinically characterized by recurrent arterial and venous thrombosis as well as pregnancy losses. These antibodies have pro-coagulant activity and are pro-atherogenic, as has been shown by increased prevalence of cardiovascular disease in patients with APS and SLE [91]. The role of aPLs in vascular manifestatations in SSc is unclear. A prevalence of aCLs and anti-β2-glycoprotein-I antibodies (anti-β2GPI) of 0–40% has been reported in SSc, but no relation of the antibodies with clinical manifestations of the APS was seen [92–99]. However, some studies found an association with pulmonary hypertension, endothelial dysfunction and myocardial ischaemia or necrosis [92, 95, 96]. No association with digital ischaemia was found [97].

Other antibodies present in diseases with vascular damage are the AECAs. These antibodies have been reported in various diseases, such as coronary atherosclerosis, diabetes mellitus, hypertension and autoimmune diseases [100–106]. In WG and SLE, a relation between AECA and disease activity has been found. However, the precise role of AECA is unclear. It is possible that AECAs are an epiphenomenon of vascular damage, or are pathogenic antibodies [107]. AECAs have been detected in 22–85% of SSc patients [108–110]. Differences in detection of AECAs may be ascribed to patient selection and technique used in the laboratory. AECAs are also associated with vascular damage in SSc, such as digital ischaemia, pulmonary hypertension and nail-fold capillary abnormalities [111–114].

Inflammation
Inflammation is a hallmark of systemic autoimmune diseases. Also in SSc, inflammation is present when the disease is active. Disease activity in SSc can be assessed by using the preliminary European Scleroderma Study Group (EScSG) activity indices (a score ranging from 0 to 10). A score >3 denotes active disease [115, 116]. One of the items of this scale is CRP, found to be a strong marker of cardiovascular risk in asymptomatic subjects and subjects with a history of a cardiovascular event [117–122]. Elevated acute-phase reactants have been found especially in dcSSc (41.8%) compared with lcSSc (24.6%), as have been described in the large EULAR Scleroderma Trials and Research (EUSTAR) group database [123]. Therefore, inflammation might play a role in vascular abnormalities in SSc. No data are available concerning acute-phase reactants and atherosclerosis in SSc.

Endothelial dysfunction
Inflammation, autoantibodies, oxLDL and other stimuli allow the endothelium to undergo changes resulting in endothelial cell activation. Endothelial cell activation is an initiating step in atherogenesis [124]. Endothelial function can be assessed non-invasively by means of several methods, based on the inability of dysfunctional endothelium to cause vasodilation of the vessels by its inability to release endothelium-derived vasodilatory mediators. Acetylcholine is used in most studies studying endothelium-dependent vasodilation, as acetylcholine cannot exert its effects in the absence of functional endothelial cells [125]. Endothelium-independent vasodilation can be studied by using glyceryl nitrate, causing vasodilation by direct action on the smooth muscle [126, 127]. Measurement of flow-mediated dilatation (FMD, endothelium-dependent) and endothelium-independent vasodilatation via high ultrasound techniques allowed the detection of endothelial dysfunction in children and adults with risk factors for atherosclerosis [126]. A relationship among endothelial dysfunction, IMT and cardiovascular risk factors has been established [128]. Studies using laser Doppler flowmetry (LDF) [129–133], studies using brachial reactivity via ultrasound [47, 52, 53, 58, 134] and studies using venous occlusion plethysmography [135, 136] show evidence both in favour of, but also against impaired endothelial-dependent as well as endothelial-independent vasodilation in SSc. This might be explained by methodological differences between studies, like differences in sites of measurements or use of a different protocol. Also, endothelial function of conduit arteries has been studied by the assessment of ultrasound-derived FMD of the brachial artery, while LDF has been used for measurement of flow in the microcirculation. Comparison between these two different non-invasive methods has revealed conflicting results [137, 138]. Interestingly, an association between impairments of FMD and increased IMT was found in some [52, 53] but not all studies [47]. Expression of vascular adhesion molecules, such as P-selectin, L-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, is increased in atherosclerosis, but their role in the recruitment, regulation of transmigration and retention of immune cells to atherosclerotic lesions still needs to be clarified [139]. Increased levels of soluble forms of various adhesion molecules in combination with endothelial dysfunction have also been described in SSc, but not in relation to atherosclerosis or macrovascular disease [58, 140–143].

Vasospasm
Autopsy studies of the heart showed focal areas of acute and subacute necrosis in combination with contraction band necrosis in the presence of normal coronary arteries in SSc, even in patients who, prior to death, were known with signs of ischaemic heart disease [28–31]. Bulkley et al. [28, 29] stated that contraction band necrosis was the result of a reperfusion lesion, suggesting that the lesions found at autopsy were the consequence of transient non-perfusion due to arrythmias or RP of the coronary arteries. Cold provocation in patients with SSc resulted in reversible myocardial perfusion abnormalities in a significant proportion of patients [144–146]. Indeed, severe impairment of coronary blood flow, not due to coronary artery stenosis, was found in seven asymptomatic SSc patients using a myocardial multidetector CT [147]. Coronary flow reserve (CFR), a marker of the coronary circulation, is used to evaluate the effects of coronary artery stenosis on coronary microvasculature and myocardial perfusion. Impaired CFR has been found in SSc patients, but no differentiation could be made between vasospasm and structural abnormalities as underlying factors [148–150]. Improvement of myocardial perfusion after administration of oral nifidepine supports the hypothesis of myocardial RP in SSc [151–153]. Coronary vasospasm is also known in the general population as variant angina or Prinzmetal angina. Endothelial dysfunction, as well as local hyperreactivity, play a role in its pathogenesis [154]. Vasospasm, with or without the presence of structural vascular abnormalities, was also seen during digital arteriography in patients with SSc, in whom RP is a common manifestation [40]. Vasospasm has also been observed in patients with SLE, with and without RP, and SSc in cerebral blood flow after a cooling test of the hand [155].


   Summary
Top
 Abstract
 Introduction
 Evidence for macrovascular...
 Aetiology
 Summary
References
 
The immune system is involved in the pathogenesis of atherosclerosis that is considered to be an inflammatory disease. Atherosclerosis is more prevalent and the risk of coronary vascular disease is increased in patients with various autoimmune diseases compared with healthy controls. SSc also is an autoimmune disease, and vascular involvement is frequent. RP is often the first manifestation. The disease is mainly characterized by microvascular involvement, and increasing evidence suggests also macrovascular involvement. Besides traditional risk factors, as in the general population, non-traditional risk factors are present in SSc, such as increased Lp(a), OxLDL, inflammation, vasospasm and endothelial dysfunction. Moreover, markers of vascular damage, like aOxLDL, AECA and increased levels of vascular adhesion molecules are present in SSc. However, clinically manifest atherosclerosis was found to be rare, and studies assessing subclinical, early atherosclerosis showed conflicting results. Cardiovascular involvement is most likely the result of vasospasm of the coronary arteries. Further research is necessary to assess the prevalence of clinically manifest or subclinically early atherosclerosis in SSc, and to explain differences in accelerated atherosclerosis between SSc and other autoimmune rheumatic diseases.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Evidence for macrovascular...
 Aetiology
 Summary
 References
 

  1. Ross R. Mechanisms of disease - Atherosclerosis - An inflammatory disease. N Engl J Med (1999) 340:115–26.[Free Full Text]
  2. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med (2005) 352:1685–95.[Free Full Text]
  3. Alkaabi JK, Ho M, Levison R, Pullar T, Belch JJF. Rheumatoid arthritis and macrovascular disease. Rheumatology (2003) 42:292–7.[Abstract/Free Full Text]
  4. del Rincon I, Williams K, Stern MP, Freeman GL, O’Leary DH, Escalante A. Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects. Arthritis Rheum (2003) 48:1833–40.[CrossRef][Web of Science][Medline]
  5. Gonzalez-Juanatey C, Llorca J, Testa A, Revuelta J, Garcia-Porrua C, Gonzalez-Gay MA. Increased prevalence of severe subclinical atherosclerotic findings in long-term treated rheumatoid arthritis patients without clinically evident atherosclerotic disease. Medicine (2003) 82:407–13.[Medline]
  6. Kumeda Y, Inaba M, Goto H, et al. Increased thickness of the arterial intima-media detected by ultrasonography in patients with rheumatoid arthritis. Arthritis Rheum (2002) 46:1489–97.[CrossRef][Web of Science][Medline]
  7. Wallberg-Jonsson S, Ohman M, Rantapaa-Dahlqvist S. Which factors are related to the presence of atherosclerosis in rheumatoid arthritis? Scand J Rheumatol (2004) 33:373–9.[CrossRef][Web of Science][Medline]
  8. De Leeuw K, Freire B, Smit AJ, Bootsma H, Kallenberg CG, Bijl M. Traditional and non-traditional risk factors contribute to the development of accelerated atherosclerosis in patients with systemic lupus erythematosus. Lupus (2006) 15:675–82.[Abstract/Free Full Text]
  9. Esdaile JM, Abrahamowicz M, Grodzicky T, et al. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum (2001) 44:2331–7.[CrossRef][Web of Science][Medline]
  10. Karrar A, Sequeira W, Block JA. Coronary artery disease in systemic lupus erythematosus: a review of the literature. Semin Arthritis Rheum (2001) 30:436–43.[CrossRef][Web of Science][Medline]
  11. Roman MJ, Shanker B, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med (2003) 349:2399–406.[Abstract/Free Full Text]
  12. Selzer F, Sutton-Tyrrell K, Fitzgerald SG, et al. Comparison of risk factors for vascular disease in the carotid artery and aorta in women with systemic lupus erythematosus. Arthritis Rheum (2004) 50:151–9.[CrossRef][Web of Science][Medline]
  13. Vlachoyiannopoulos PG, Kanellopoulos PG, Ioannidis JPA, Tektonidou MG, Mastorakou I, Moutsopoulos HM. Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study. Rheumatology (2003) 42:645–51.[Abstract/Free Full Text]
  14. De Leeuw K, Sanders JS, Stegeman C, Smit A, Kallenberg CG, Bijl M. Accelerated atherosclerosis in patients with Wegener's granulomatosis. Ann Rheum Dis (2005) 64:753–9.[Abstract/Free Full Text]
  15. Herrick AL. Vascular function in systemic sclerosis. Curr Opin Rheumatol (2000) 12:527–33.[CrossRef][Web of Science][Medline]
  16. Kahaleh MB, Leroy EC. Autoimmunity and vascular involvement in systemic sclerosis (SSc). Autoimmunity (1999) 31:195–214.[Medline]
  17. Kahaleh MB. Vascular involvement in systemic sclerosis (SSc). Clin Exp Rheumatol (2004) 22:S19–23.[Web of Science][Medline]
  18. Leroy EC. Systemic sclerosis. A vascular perspective. Rheum Dis Clin North Am (1996) 22:675–94.[CrossRef][Web of Science][Medline]
  19. Ioannidis JP, Vlachoyiannopoulos PG, Haidich AB, et al. Mortality in systemic sclerosis: an international meta-analysis of individual patient data. Am J Med (2005) 118:2–10.[CrossRef][Web of Science][Medline]
  20. Persson J, Stavenow L, Wikstrand J, Israelsson B, Formgren J, Berglund G. Noninvasive quantification of atherosclerotic lesions. Reproducibility of ultrasonographic measurement of arterial wall thickness and plaque size. Arterioscler Thromb (1992) 12:261–6.[Abstract/Free Full Text]
  21. The ACAPS Group. Rationale and design for the Asymptomatic Carotid Artery Plaque Study (ACAPS). Control Clin Trials (1992) 13:293–314.[CrossRef][Web of Science][Medline]
  22. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation (1986) 74:1399–406.[Abstract/Free Full Text]
  23. Montauban van Swijndregt AD, De Lange EE, De Groot E, Ackerstaff RG. An in vivo evaluation of the reproducibility of intima-media thickness measurements of the carotid artery segments using B-mode ultrasound. Ultrasound Med Biol (1999) 25:323–30.[CrossRef][Web of Science][Medline]
  24. Sramek A, Bosch JG, Reiber JH, Van Oostayen JA, Rosendaal FR. Ultrasound assessment of atherosclerotic vessel wall changes: reproducibility of intima-media thickness measurements in carotid and femoral arteries. Invest Radiol (2000) 35:699–706.[CrossRef][Web of Science][Medline]
  25. Cheng KS, Mikhailidis DP, Hamilton G, Seifalian AM. A review of the carotid and femoral intima-media thickness as an indicator of the presence of peripheral vascular disease and cardiovascular risk factors. Cardiovasc Res (2002) 54:528–38.[Abstract/Free Full Text]
  26. Norton WL, Nardo JM. Vascular disease in progressive systemic sclerosis (scleroderma). Ann Intern Med (1970) 73:317–24.[Abstract/Free Full Text]
  27. Steen V. The heart in systemic sclerosis. Curr Rheumatol Rep (2004) 6:137–40.[Medline]
  28. Bulkley BH, Ridolfi RL, Salyer WR, Hutchins GM. Myocardial lesions of progressive systemic sclerosis. A cause of cardiac dysfunction. Circulation (1976) 53:483–90.[Abstract/Free Full Text]
  29. Bulkley BH, Klacsmann PG, Hutchins GM. Angina pectoris, myocardial infarction and sudden cardiac death with normal coronary arteries: a clinicopathologic study of 9 patients with progressive systemic sclerosis. Am Heart J (1978) 95:563–9.[CrossRef][Web of Science][Medline]
  30. D’Angelo WA, Fries JF, Masi AT, Shulman LE. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med (1969) 46:428–40.[CrossRef][Web of Science][Medline]
  31. Leinwand I, Duryee AW, Richter MN. Scleroderma;based on a study of over 150 cases. Ann Intern Med (1954) 41:1003–41.[Abstract/Free Full Text]
  32. Akram MR, Handler CE, Williams M, et al. Angiographically proven coronary artery disease in scleroderma. Rheumatology (2006) 45:1395–8.[Abstract/Free Full Text]
  33. Derk CT, Jimenez SA. Acute myocardial infarction in systemic sclerosis patients: a case series. Clin Rheumatol (2007) 26:965–8.[CrossRef][Web of Science][Medline]
  34. Averbuch-Heller L, Steiner I, Abramsky O. Neurologic manifestations of progressive systemic sclerosis. Arch Neurol (1992) 49:1292–5.[Abstract/Free Full Text]
  35. Youssef P, Brama T, Englert H, Bertouch J. Limited scleroderma is associated with increased prevalence of macrovascular disease. J Rheumatol (1995) 22:469–72.[Web of Science][Medline]
  36. Veale DJ, Collidge TA, Belch JJF. Increased prevalence of symptomatic macrovascular disease in systemic-sclerosis. Ann Rheum Dis (1995) 54:853–5.[Abstract/Free Full Text]
  37. Dick EA, Aviv R, Francis I, et al. Catheter angiography and angioplasty in patients with scleroderma. Br J Radiol (2001) 74:1091–6.[Abstract/Free Full Text]
  38. Dabich L, Bookstein JJ, Zweifler A, Zarafonetis CJ. Digital arteries in patients with scleroderma. Arteriographic and plethysmographic study. Arch Intern Med (1972) 130:708–14.[Abstract/Free Full Text]
  39. Janevski B. Arteries of the hand in patients with scleroderma. Diagn Imag Clin Med (1986) 55:262–5.
  40. Stucker M, Quinna S, Memmel U, et al. Macroangiopathy of the upper extremities in progressive systemic sclerosis. Eur J Med Res (2000) 5:295–302.[Medline]
  41. Hasegawa M, Nagai Y, Tamura A, Ishikawa O. Arteriographic evaluation of vascular changes of the extremities in patients with systemic sclerosis. Br J Dermatol (2006) 155:1159–64.[CrossRef][Web of Science][Medline]
  42. Merkel PA, Herlyn K, Martin RW, et al. Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon. Arthritis Rheum (2002) 46:2410–20.[CrossRef][Web of Science][Medline]
  43. Chung L, Fiorentino D. Digital ulcers in patients with systemic sclerosis. Autoimmun Rev (2006) 5:125–8.[CrossRef][Web of Science][Medline]
  44. Nihtyanova SI, Brough GM, Black CM, Denton CP. Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis (2008) 67:120–3.[Abstract/Free Full Text]
  45. Cheng KS, Tiwari A, Boutin A, et al. Carotid and femoral arterial wall mechanics in scleroderma. Rheumatology (2003) 42:1299–305.[Abstract/Free Full Text]
  46. Cheng KS, Tiwari A, Boutin A, et al. Differentiation of primary and secondary Raynaud's disease by carotid arterial stiffness. Eur J Vasc Endovasc Surg (2003) 25:336–41.[CrossRef][Web of Science][Medline]
  47. Szucs G, Timar O, Szekanecz Z, et al. Endothelial dysfunction precedes atherosclerosis in systemic sclerosis. Relevance for prevention of vascular complications. Rheumatology (2007) 46:759–62.[Abstract/Free Full Text]
  48. Stafford L, Englert H, Gover J, Bertouch J. Distribution of macrovascular disease in scleroderma. Ann Rheum Dis (1998) 57:476–9.[Abstract/Free Full Text]
  49. Bartoli F, Angotti C, Fatini C, et al. Angiotensin-converting enzyme I/D polymorphism and macrovascular disease in systemic sclerosis. Rheumatology (2007) 46:772–5.[Abstract/Free Full Text]
  50. Ho ML, Veale D, Eastmond C, Nuki G, Belch J. Macrovascular disease and systemic sclerosis. Ann Rheum Dis (2000) 59:39–43.[Abstract/Free Full Text]
  51. Kaloudi O, Basta G, Perfetto F, et al. Circulating levels of Nepsilon-(carboxymethyl)lysine are increased in systemic sclerosis. Rheumatology (2007) 46:412–6.[Abstract/Free Full Text]
  52. Lekakis J, Mavrikakis M, Papamichael C, et al. Short-term estrogen administration improves abnormal endothelial function in women with systemic sclerosis and Raynaud's phenomenon. Am Heart J (1998) 136:905–12.[CrossRef][Web of Science][Medline]
  53. Bartoli F, Blagojevic J, Bacci M, et al. Flow-mediated vasodilation and carotid intima-media thickness in systemic sclerosis. Ann NY Acad Sci (2007) 1108:283–90.[CrossRef][Web of Science][Medline]
  54. Cheng KS, Baker CR, Hamilton G, Hoeks AP, Seifalian AM. Arterial elastic properties and cardiovascular risk/event. Eur J Vasc Endovasc Surg (2002) 24:383–97.[CrossRef][Web of Science][Medline]
  55. Constans J, Gosse P, Pellegrin JL, et al. Alteration of arterial distensibility in systemic sclerosis. J Intern Med (1997) 241:115–8.[CrossRef][Web of Science][Medline]
  56. Gosse P, Taillard J, Constans J. Evolution of ambulatory measurement of blood pressure and parameters of arterial stiffness over a 1-year period in patients with systemic sclerosis: ERAMS study. J Hum Hypertens (2002) 16:627–30.[CrossRef][Web of Science][Medline]
  57. Moyssakis I, Gialafos E, Vassiliou V, et al. Aortic stiffness in systemic sclerosis is increased independently of the extent of skin involvement. Rheumatology (2005) 44:251–4.[Abstract/Free Full Text]
  58. Andersen GN, Mincheva-Nilsson L, Kazzam E, et al. 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 (2002) 46:1324–32.[CrossRef][Web of Science][Medline]
  59. Constans J, Germain C, Gosse P, et al. Arterial stiffness predicts severe progression in systemic sclerosis: the ERAMS study. J Hypertens (2007) 25:1900–6.[CrossRef][Web of Science][Medline]
  60. Wan MC, Moore T, Hollis S, Herrick AL. Ankle brachial pressure index in systemic sclerosis: influence of disease subtype and anticentromere antibody. Rheumatology (2001) 40:1102–5.[Abstract/Free Full Text]
  61. Vogt MT, Cauley JA, Newman AB, Kuller LH, Hulley SB. Decreased ankle/arm blood pressure index and mortality in elderly women. J Am Med Assoc (1993) 270:465–9.[Abstract/Free Full Text]
  62. Thatipelli MR, Pellikka PA, McBane RD, et al. Prognostic value of ankle-brachial index and dobutamine stress echocardiography for cardiovascular morbidity and all-cause mortality in patients with peripheral arterial disease. J Vasc Surg (2007) 46:62–70.[CrossRef][Web of Science][Medline]
  63. Huikuri HV, Mäkikallio T, Airaksinen KEJ, Mitrani R, Castellanos A, Myerburg RJ. Measurement of heart rate variability: a clinical tool or a research toy? J Am Coll Cardiol (1999) 34:1878–83.[Abstract/Free Full Text]
  64. Morelli S, Piccirillo G, Fimognari F, et al. Twenty-four heart period variability in systemic sclerosis. J Rheumatol (1996) 23:643–5.[Web of Science][Medline]
  65. Ferri C, Emdin M, Giuggioli D, et al. Autonomic dysfunction in systemic sclerosis: time and frequency domain 24 hour heart rate variability analysis. Br J Rheumatol (1997) 36:669–76.[Abstract/Free Full Text]
  66. Pancera P, Sansone S, Presciuttini B, et al. Autonomic nervous system dysfunction in sclerodermic and primary Raynaud's phenomenon. Clin Sci (1999) 96:49–57.[CrossRef][Web of Science][Medline]
  67. Di Franco M, Paradiso M, Riccieri V, Basili S, Mammarella A, Valesini G. Autonomic dysfunction and microvascular damage in systemic sclerosis. Clin Rheumatol (2007) 26:1278–83.[CrossRef][Web of Science][Medline]
  68. Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation (2003) 108:2093–8.[Abstract/Free Full Text]
  69. Borba EF, Borges CT, Bonfa E. Lipoprotein profile in limited systemic sclerosis. Rheumatol Int (2005) 25:379–83.[CrossRef][Web of Science][Medline]
  70. Bruckdorfer KR, Hillary JB, Bunce T, Vancheeswaran R, Black CM. Increased susceptibility to oxidation of low-density lipoproteins isolated from patients with systemic sclerosis. Arthritis Rheum (1995) 38:1060–7.[Web of Science][Medline]
  71. Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med (2000) 28:1815–26.[CrossRef][Web of Science][Medline]
  72. Galle J, Hansen-Hagge T, Wanner C, Seibold S. Impact of oxidized low density lipoprotein on vascular cells. Atherosclerosis (2006) 185:219–26.[CrossRef][Web of Science][Medline]
  73. Expert Panel on Detection EaToHBCiA. Executive summary of the third report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). J Am Med Assoc (2001) 285:2486–97.[Free Full Text]
  74. Koschinsky ML. Lipoprotein(a) and the link between atherosclerosis and thrombosis. Can J Cardiol (2004) 20(Suppl B):37B–43B.[Web of Science][Medline]
  75. Lippi G, Guidi G. Lipoprotein(a): an emerging cardiovascular risk factor. Crit Rev Clin Lab Sci (2003) 40:1–42.[CrossRef][Web of Science][Medline]
  76. Lippi G, Caramaschi P, Montagnana M, Salvagno GL, Volpe A, Guidi G. Lipoprotein[a] and the lipid profile in patients with systemic sclerosis. Clin Chim Acta (2006) 364:345–8.[CrossRef][Web of Science][Medline]
  77. Herrick AL, Illingworth KJ, Hollis S, Gomez-Zumaquero JM, Tinahones FJ. Antibodies against oxidized low-density lipoproteins in systemic sclerosis. Rheumatology (2001) 40:401–5.[Abstract/Free Full Text]
  78. Piarulli F, Lapolla A, Sartore G, et al. Autoantibodies against oxidized LDLs and atherosclerosis in type 2 diabetes. Diabetes Care (2005) 28:653–7.[Abstract/Free Full Text]
  79. Salonen JT, Yla-Herttuala S, Yamamoto R, et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet (1992) 339:883–7.[CrossRef][Web of Science][Medline]
  80. Goncalves I, Gronholdt ML, Soderberg I, et al. Humoral immune response against defined oxidized low-density lipoprotein antigens reflects structure and disease activity of carotid plaques. Arterioscler Thromb Vasc Biol (2005) 25:1250–5.[Abstract/Free Full Text]
  81. Faviou E, Vourli G, Nounopoulos C, Zachari A, Onyssiou-Asteriou A. Circulating oxidized low density lipoprotein, autoantibodies against them and homocysteine serum levels in diagnosis and estimation of severity of coronary artery disease. Free Radic Res (2005) 39:419–29.[CrossRef][Web of Science][Medline]
  82. Lopes-Virella MF, Virella G, Orchard TJ, et al. Antibodies to oxidized LDL and LDL-containing immune complexes as risk factors for coronary artery disease in diabetes mellitus. Clin Immunol (1999) 90:165–72.[CrossRef][Web of Science][Medline]
  83. Hulthe J, Wiklund O, Hurt-Camejo E, Bondjers G. Antibodies to oxidized LDL in relation to carotid atherosclerosis, cell adhesion molecules, and phospholipase A(2). Arterioscler Thromb Vasc Biol (2001) 21:269–74.[Abstract/Free Full Text]
  84. Tinahones FJ, Gomez-Zumaquero JM, Garrido-Sanchez L, et al. Influence of age and sex on levels of anti-oxidized LDL antibodies and anti-LDL immune complexes in the general population. J Lipid Res (2005) 46:452–7.[Abstract/Free Full Text]
  85. Palinski W, Miller E, Witztum JL. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci USA (1995) 92:821–5.[Abstract/Free Full Text]
  86. Ameli S, Hultgardh-Nilsson A, Regnstrom J, et al. Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol (1996) 16:1074–9.[Abstract/Free Full Text]
  87. Freigang S, Horkko S, Miller E, Witztum JL, Palinski W. Immunization of LDL receptor-deficient mice with homologous malondialdehyde-modified and native LDL reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. Arterioscler Thromb Vasc Biol (1998) 18:1972–82.[Abstract/Free Full Text]
  88. Chyu KY, Reyes OS, Zhao X, et al. Timing affects the efficacy of LDL immunization on atherosclerotic lesions in apo E (-/-) mice. Atherosclerosis (2004) 176:27–35.[CrossRef][Web of Science][Medline]
  89. Yamashita T, Freigang S, Eberle C, et al. Maternal immunization programs postnatal immune responses and reduces atherosclerosis in offspring. Circ Res (2006) 99:e51–64.[CrossRef][Web of Science][Medline]
  90. Lopez LR, Simpson DF, Hurley BL, Matsuura E. OxLDL/beta2GPI complexes and autoantibodies in patients with systemic lupus erythematosus, systemic sclerosis, and antiphospholipid syndrome: pathogenic implications for vascular involvement. Ann N Y Acad Sci (2005) 1051:313–22.[CrossRef][Web of Science][Medline]
  91. Sherer Y, Shoenfeld Y. Antiphospholipid syndrome, antiphospholipid antibodies, and atherosclerosis. Curr Atheroscler Rep (2001) 3:328–33.[Medline]
  92. Assous N, Allanore Y, Batteux F, et al. Prevalence of antiphospholipid antibodies in systemic sclerosis and association with primitive pulmonary arterial hypertension and endothelial injury. Clin Exp Rheumatol (2005) 23:199–204.[Web of Science][Medline]
  93. Pope JE, Thompson A. The frequency and significance of anticardiolipin antibodies in scleroderma. J Rheumatol (2000) 27:1450–2.[Web of Science][Medline]
  94. Merkel PA, Chang Y, Pierangeli SS, Convery K, Harris EN, Polisson RP. The prevalence and clinical associations of anticardiolipin antibodies in a large inception cohort of patients with connective tissue diseases. Am J Med (1996) 101:576–83.[CrossRef][Web of Science][Medline]
  95. Ihn H, Sato S, Fujimoto M, et al. Measurement of anticardiolipin antibodies by ELISA using beta 2-glycoprotein I (beta 2-GPI) in systemic sclerosis. Clin Exp Immunol (1996) 105:475–9.[CrossRef][Web of Science][Medline]
  96. Picillo U, Migliaresi S, Marcialis MR, Ferruzzi AM, Tirri G. Clinical significance of anticardiolipin antibodies in patients with systemic sclerosis. Autoimmunity (1995) 20:1–7.[Web of Science][Medline]
  97. Herrick AL, Heaney M, Hollis S, Jayson MI. Anticardiolipin, anticentromere and anti-Scl-70 antibodies in patients with systemic sclerosis and severe digital ischaemia. Ann Rheum Dis (1994) 53:540–2.[Abstract/Free Full Text]
  98. Lima J, Fonollosa V, Fernandez-Cortijo J, et al. Platelet activation, endothelial cell dysfunction in the absence of anticardiolipin antibodies in systemic sclerosis. J Rheumatol (1991) 18:1833–6.[Web of Science][Medline]
  99. Passaleva A, Massai G, Matucci-Cerinic M, et al. Immunological abnormalities in a group of patients with limited cutaneous systemic sclerosis and prominent vascular disease. Autoimmunity (1990) 6:283–91.[Medline]
  100. Sebastian JK, Mahr AD, Ahmed SS, et al. Antiendothelial cell antibodies in patients with Wegener's granulomatosis: prevalence and correlation with disease activity and manifestations. J Rheumatol (2007) 34:1027–31.[Abstract/Free Full Text]
  101. Papadopoulos DP, Makris TK, Krespi P, et al. Antiendothelial cell antibody levels in healthy normotensives with high normal blood pressure. Clin Exp Hypertens (2006) 28:663–7.[CrossRef][Web of Science][Medline]
  102. Renaudineau Y, Dugue C, Dueymes M, Youinou P. Antiendothelial cell antibodies in systemic lupus erythematosus. Autoimmun Rev (2002) 1:365–72.[CrossRef][Medline]
  103. Nityanand S, Bergmark C, de Faire U, Swedenborg J, Holm G, Lefvert AK. Antibodies against endothelial cells and cardiolipin in young patients with peripheral atherosclerotic disease. J Intern Med (1995) 238:437–43.[Web of Science][Medline]
  104. D’Cruz DP, Houssiau FA, Ramirez G, et al. Antibodies to endothelial cells in systemic lupus erythematosus: a potential marker for nephritis and vasculitis. Clin Exp Immunol (1991) 85:254–61.[Web of Science][Medline]
  105. Jones DB, Wallace R, Frier BM. Vascular endothelial cell antibodies in diabetic patients. Association with diabetic retinopathy. Diabetes Care (1992) 15:552–5.[Abstract]
  106. George J, Meroni PL, Gilburd B, Raschi E, Harats D, Shoenfeld Y. Anti-endothelial cell antibodies in patients with coronary atherosclerosis. Immunol Lett (2000) 73:23–7.[Web of Science][Medline]
  107. Belizna C, Duijvestijn A, Hamidou M, Cohen Tervaert JW. Antiendothelial cell antibodies in vasculitis and connective tissue disease. Ann Rheum Dis (2006) 65:1545–50.[Abstract/Free Full Text]
  108. Hebbar M, Lassalle P, Delneste Y, et al. Assessment of anti-endothelial cell antibodies in systemic sclerosis and Sjogren's syndrome. Ann Rheum Dis (1997) 56:230–4.[Abstract/Free Full Text]
  109. Ihn H, Sato S, Fujimoto M, et al. Characterization of autoantibodies to endothelial cells in systemic sclerosis (SSc): association with pulmonary fibrosis. Clin Exp Immunol (2000) 119:203–9.[CrossRef][Web of Science][Medline]
  110. Renaudineau Y, Revelen R, Levy Y, et al. Anti-endothelial cell antibodies in systemic sclerosis. Clin Diagn Lab Immunol (1999) 6:156–60.[Medline]
  111. Carvalho D, Savage CO, Black CM, Pearson JD. IgG antiendothelial cell autoantibodies from scleroderma patients induce leukocyte adhesion to human vascular endothelial cells in vitro. Induction of adhesion molecule expression and involvement of endothelium-derived cytokines. J Clin Invest (1996) 97:111–9.[Web of Science][Medline]
  112. Negi VS, Tripathy NK, Misra R, Nityanand S. Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol (1998) 25:462–6.[Web of Science][Medline]
  113. Salojin KV, Le TM, Saraux A, et al. Antiendothelial cell antibodies: useful markers of systemic sclerosis. Am J Med (1997) 102:178–85.[CrossRef][Web of Science][Medline]
  114. Pignone A, Scaletti C, Matucci-Cerinic M, et al. Anti-endothelial cell antibodies in systemic sclerosis: significant association with vascular involvement and alveolo-capillary impairment. Clin Exp Rheumatol (1998) 16:527–32.[Web of Science][Medline]
  115. Valentini G, Della Rossa A, Bombardieri S, et al. European multicentre study to define disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes. Ann Rheum Dis (2001) 60:592–8.[Abstract/Free Full Text]
  116. Valentini G, Bencivelli W, Bombardieri S, et al. European Scleroderma Study Group to define disease activity criteria for systemic sclerosis. III. Assessment of the construct validity of the preliminary activity criteria. Ann Rheum Dis (2003) 62:901–3.[Abstract/Free Full Text]
  117. Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol (1997) 17:1121–7.[Abstract/Free Full Text]
  118. Speidl WS, Graf S, Hornykewycz S, et al. High-sensitivity C-reactive protein in the prediction of coronary events in patients with premature coronary artery disease. Am Heart J (2002) 144:449–55.[CrossRef][Web of Science][Medline]
  119. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation (1998) 97:425–8.[Abstract/Free Full Text]
  120. Koenig W, Sund M, Frohlich M, et al. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation (1999) 99:237–42.[Abstract/Free Full Text]
  121. Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK. C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study. Am Heart J (2002) 144:233–8.[CrossRef][Web of Science][Medline]
  122. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. J Am Med Assoc (1998) 279:1477–82.[Abstract/Free Full Text]
  123. Walker UA, Tyndall A, Czirjak L, et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research Group database. Ann Rheum Dis (2007) 66:754–63.[Abstract/Free Full Text]
  124. Hunt BJ. The endothelium in atherogenesis. Lupus (2000) 9:189–93.[Abstract/Free Full Text]
  125. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature (1980) 288:373–6.[CrossRef][Medline]
  126. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet (1992) 340:1111–5.[CrossRef][Web of Science][Medline]
  127. Matucci Cerinic M, Kahaleh MB. Beauty and the beast. The nitric oxide paradox in systemic sclerosis. Rheumatology (2002) 41:843–7.[Free Full Text]
  128. Corrado E, Muratori I, Tantillo R, et al. Relationship between endothelial dysfunction, intima media thickness and cardiovascular risk factors in asymptomatic subjects. Int Angiol (2005) 24:52–8.[Web of Science][Medline]
  129. Anderson ME, Hollis S, Moore T, Jayson MI, Herrick AL. Non-invasive assessment of vascular reactivity in forearm skin of patients with primary Raynaud's phenomenon and systemic sclerosis. Br J Rheumatol (1996) 35:1281–8.[Abstract/Free Full Text]
  130. Anderson ME, Campbell F, Hollis S, Moore T, Jayson MI, Herrick AL. Non-invasive assessment of digital vascular reactivity in patients with primary Raynaud's phenonenon and systemic sclerosis. Clin Exp Rheumatol (1999) 17:49–54.[Web of Science][Medline]
  131. Khan F, Litchfield SJ, McLaren M, Veale DJ, Littleford RC, Belch JJ. Oral L-arginine supplementation and cutaneous vascular responses in patients with primary Raynaud's phenomenon. Arthritis Rheum (1997) 40:352–7.[Web of Science][Medline]
  132. La Civita L, Rossi M, Vagheggini G, et al. Microvascular involvement in systemic sclerosis: laser Doppler evaluation of reactivity to acetylcholine and sodium nitroprusside by iontophoresis. Ann Rheum Dis (1998) 57:52–5.[Abstract/Free Full Text]
  133. Marasini B, Conciato L. Iontophoretic evaluation of vascular reactivity to acetylcholine in patients with primary Raynaud's phenomenon and systemic sclerosis. Clin Rheumatol (2001) 20:451–2.[CrossRef][Web of Science][Medline]
  134. Sfikakis PP, Papamichael C, Stamatelopoulos KS, et al. Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis. Arthritis Rheum (2007) 56:1985–93.[CrossRef][Web of Science][Medline]
  135. Freedman RR, Girgis R, Mayes MD. Endothelial and adrenergic dysfunction in Raynaud's phenomenon and scleroderma. J Rheumatol (1999) 26:2386–8.[Web of Science][Medline]
  136. Freedman RR, Girgis R, Mayes MD. Abnormal responses to endothelial agonists in Raynaud's phenomenon and scleroderma. J Rheumatol (2001) 28:119–21.[Abstract/Free Full Text]
  137. Gori T, Di SG, Sicuro S, et al. Correlation analysis between different parameters of conduit artery and microvascular vasodilation. Clin Hemorheol Microcirc (2006) 35:509–15.[Web of Science][Medline]
  138. Hansell J, Henareh L, Agewall S, Norman M. Non-invasive assessment of endothelial function - relation between vasodilatory responses in skin microcirculation and brachial artery. Clin Physiol Funct Imaging (2004) 24:317–22.[CrossRef][Web of Science][Medline]
  139. Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol (2007) 27:2292–301.[Abstract/Free Full Text]
  140. Andersen GN, Caidahl K, Kazzam E, et al. Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: findings with the soluble adhesion molecules E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. Arthritis Rheum (2000) 43:1085–93.[CrossRef][Web of Science][Medline]
  141. Cerinic MM, Valentini G, Sorano GG, et al. Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum (2003) 32:285–95.[CrossRef][Web of Science][Medline]
  142. Gruschwitz MS, Hornstein OP, von Den DP. Correlation of soluble adhesion molecules in the peripheral blood of scleroderma patients with their in situ expression and with disease activity. Arthritis Rheum (1995) 38:184–9.[Web of Science][Medline]
  143. Shahin AA, Anwar S, Elawar AH, et al. Circulating soluble adhesion molecules in patients with systemic sclerosis: correlation between circulating soluble vascular cell adhesion molecule-1 (sVCAM-1) and impaired left ventricular diastolic function. Rheumatol Int (2000) 20:21–4.[CrossRef][Web of Science][Medline]
  144. Candell-Riera J, Armandans-Gil L, Simeon CP, et al. Comprehensive noninvasive assessment of cardiac involvement in limited systemic sclerosis. Arthritis Rheum (1996) 39:1138–45.[Medline]
  145. Gustafsson R, Mannting F, Kazzam E, Waldenstrom A, Hallgren R. Cold-induced reversible myocardial ischaemia in systemic sclerosis. Lancet (1989) 2:475–9.[CrossRef][Web of Science][Medline]
  146. Long A, Duffy G, Bresnihan B. Reversible myocardial perfusion defects during cold challenge in scleroderma. Br J Rheumatol (1986) 25:158–61.[Abstract/Free Full Text]
  147. Vacca A, Siotto P, Cauli A, et al. Absence of epicardial coronary stenosis in patients with systemic sclerosis with severe impairment of coronary flow reserve. Ann Rheum Dis (2006) 65:274–5.[Free Full Text]
  148. Kahan A, Nitenberg A, Foult JM, et al. Decreased coronary reserve in primary scleroderma myocardial disease. Arthritis Rheum (1985) 28:637–46.[Web of Science][Medline]
  149. Montisci R, Vacca A, Garau P, et al. Detection of early impairment of coronary flow reserve in patients with systemic sclerosis. Ann Rheum Dis (2003) 62:890–3.[Abstract/Free Full Text]
  150. Sulli A, Ghio M, Bezante GP, et al. Blunted coronary flow reserve in systemic sclerosis: a sign of cardiac involvement in asymptomatic patients. Ann Rheum Dis (2004) 63:210–1.[Free Full Text]
  151. Duboc D, Kahan A, Maziere B, et al. The effect of nifedipine on myocardial perfusion and metabolism in systemic sclerosis. A positron emission tomographic study. Arthritis Rheum (1991) 34:198–203.[Web of Science][Medline]
  152. Kahan A, Devaux JY, Amor B, et al. Nifedipine and thallium-201 myocardial perfusion in progressive systemic sclerosis. N Engl J Med (1986) 314:1397–402.[Abstract]
  153. Vignaux O, Allanore Y, Meune C, et al. Evaluation of the effect of nifedipine upon myocardial perfusion and contractility using cardiac magnetic resonance imaging and tissue Doppler echocardiography in systemic sclerosis. Ann Rheum Dis (2005) 64:1268–73.[Abstract/Free Full Text]
  154. Kawano H, Ogawa H. Endothelial function and coronary spastic angina. Intern Med (2005) 44:91–9.[CrossRef][Web of Science][Medline]
  155. Ferraccioli G, Di Poi E, Di Gregorio F, Giacomuzzi F, Guerra U. Changes in regional cerebral blood flow after a cold hand test in systemic lupus erythematosus patients with Raynaud's syndrome. Lancet (1999) 354:2135–6.[CrossRef][Web of Science][Medline]
Submitted 2 October 2007; revised version accepted 31 January 2008.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Rheumatology (Oxford)Home page
J. J. F. Belch, S. McSwiggan, and C. Lau
Macrovascular disease in systemic sclerosis: the tip of an iceberg?
Rheumatology, October 1, 2008; 47(suppl_5): v16 - v17.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
47/5/578    most recent
ken078v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hettema, M. E.
Right arrow Articles by Kallenberg, C. G. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hettema, M. E.
Right arrow Articles by Kallenberg, C. G. M.
Related Collections
Right arrow Systemic Sclerosis
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?