Abstract
Background: Several autoimmune disorders are complicated by excess cardiovascular disease. In addition to traditional risk factors, non-traditional risk factors such as endothelial activation and excessive vascular remodelling might be determinants of the progression of atherosclerosis in patients with an autoimmune disease.
Objective: To evaluate whether patients with Wegener's granulomatosis (WG) have an increased prevalence of atherosclerosis and to determine predisposing factors.
Methods: 29 WG patients (19 men; mean (SD) age, 53 (14) years) with inactive disease and 26 controls (16 men; age 53 (15) years) were studied. Common carotid intima–media thickness (IMT) was measured by ultrasound. In all individuals traditional risk factors for cardiovascular disease were determined. High sensitivity C reactive protein (hsCRP) was measured. Endothelial activation was assessed by measuring thrombomodulin, vascular cell adhesion molecule-1, and von Willebrand factor. As a marker of vascular remodelling matrix metalloproteinases (MMP-3 and MMP-9) and TIMP-1 were measured.
Results: IMT was increased in WG patients compared with controls (p<0.05). No differences in traditional risk factors and endothelial activation markers between patients and controls were found. Levels of hsCRP, MMPs, and TIMP-1 were increased in WG patients (p<0.05).
Conclusions: Increased IMT found in WG patients cannot be explained by an increased prevalence of traditional risk factors. Although endothelial activation markers in WG patients with inactive disease were not increased, the raised levels of hsCRP, MMPs, and TIMP-1 suggest that enhanced inflammation and excessive vascular remodelling are contributing factors in the development of accelerated atherosclerosis in WG.
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- Albert Michelle A., Glynn Robert J., Ridker Paul M. Plasma concentration of C-reactive protein and the calculated Framingham Coronary Heart Disease Risk Score. Circulation. 2003 Jun 30;108(2):161–165. doi: 10.1161/01.CIR.0000080289.72166.CF. [DOI] [PubMed] [Google Scholar]
- Alkaabi J. K., Ho M., Levison R., Pullar T., Belch J. J. F. Rheumatoid arthritis and macrovascular disease. Rheumatology (Oxford) 2003 Feb;42(2):292–297. doi: 10.1093/rheumatology/keg083. [DOI] [PubMed] [Google Scholar]
- Ara J., Mirapeix E., Arrizabalaga P., Rodriguez R., Ascaso C., Abellana R., Font J., Darnell A. Circulating soluble adhesion molecules in ANCA-associated vasculitis. Nephrol Dial Transplant. 2001 Feb;16(2):276–285. doi: 10.1093/ndt/16.2.276. [DOI] [PubMed] [Google Scholar]
- Booth A. D., Jayne D. R. W., Kharbanda R. K., McEniery C. M., Mackenzie I. S., Brown J., Wilkinson I. B. Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation. 2004 Mar 22;109(14):1718–1723. doi: 10.1161/01.CIR.0000124720.18538.DD. [DOI] [PubMed] [Google Scholar]
- Booth A. D., Wallace S., McEniery C. M., Yasmin, Brown J., Jayne D. R. W., Wilkinson I. B. Inflammation and arterial stiffness in systemic vasculitis: a model of vascular inflammation. Arthritis Rheum. 2004 Feb;50(2):581–588. doi: 10.1002/art.20002. [DOI] [PubMed] [Google Scholar]
- Del Rincón Inmaculada, Williams Ken, Stern Michael P., Freeman Gregory L., O'Leary Daniel H., Escalante Agustín. Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects. Arthritis Rheum. 2003 Jul;48(7):1833–1840. doi: 10.1002/art.11078. [DOI] [PubMed] [Google Scholar]
- Esdaile J. M., Abrahamowicz M., Grodzicky T., Li Y., Panaritis C., du Berger R., Côte R., Grover S. A., Fortin P. R., Clarke A. E. Traditional Framingham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus. Arthritis Rheum. 2001 Oct;44(10):2331–2337. doi: 10.1002/1529-0131(200110)44:10<2331::aid-art395>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- Faia Kerrie L., Davis Wendell P., Marone Adele J., Foxall Thomas L. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in hamster aortic atherosclerosis: correlation with in-situ zymography. Atherosclerosis. 2002 Feb;160(2):325–337. doi: 10.1016/s0021-9150(01)00590-1. [DOI] [PubMed] [Google Scholar]
- Filer A. D., Gardner-Medwin J. M., Thambyrajah J., Raza K., Carruthers D. M., Stevens R. J., Liu L., Lowe S. E., Townend J. N., Bacon P. A. Diffuse endothelial dysfunction is common to ANCA associated systemic vasculitis and polyarteritis nodosa. Ann Rheum Dis. 2003 Feb;62(2):162–167. doi: 10.1136/ard.62.2.162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Galis Zorina S., Khatri Jaikirshan J. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002 Feb 22;90(3):251–262. [PubMed] [Google Scholar]
- Gonzalez-Juanatey Carlos, Llorca Javier, Testa Ana, Revuelta Javier, Garcia-Porrua Carlos, Gonzalez-Gay Miguel A. Increased prevalence of severe subclinical atherosclerotic findings in long-term treated rheumatoid arthritis patients without clinically evident atherosclerotic disease. Medicine (Baltimore) 2003 Nov;82(6):407–413. doi: 10.1097/01.md.0000101572.76273.60. [DOI] [PubMed] [Google Scholar]
- Hoffman G. S., Kerr G. S., Leavitt R. Y., Hallahan C. W., Lebovics R. S., Travis W. D., Rottem M., Fauci A. S. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992 Mar 15;116(6):488–498. doi: 10.7326/0003-4819-116-6-488. [DOI] [PubMed] [Google Scholar]
- Howard G., Sharrett A. R., Heiss G., Evans G. W., Chambless L. E., Riley W. A., Burke G. L. Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound. ARIC Investigators. Stroke. 1993 Sep;24(9):1297–1304. doi: 10.1161/01.str.24.9.1297. [DOI] [PubMed] [Google Scholar]
- Kai H., Ikeda H., Yasukawa H., Kai M., Seki Y., Kuwahara F., Ueno T., Sugi K., Imaizumi T. Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes. J Am Coll Cardiol. 1998 Aug;32(2):368–372. doi: 10.1016/s0735-1097(98)00250-2. [DOI] [PubMed] [Google Scholar]
- Khreiss Tarek, József Levente, Potempa Lawrence A., Filep János G. Conformational rearrangement in C-reactive protein is required for proinflammatory actions on human endothelial cells. Circulation. 2004 Mar 29;109(16):2016–2022. doi: 10.1161/01.CIR.0000125527.41598.68. [DOI] [PubMed] [Google Scholar]
- Leavitt R. Y., Fauci A. S., Bloch D. A., Michel B. A., Hunder G. G., Arend W. P., Calabrese L. H., Fries J. F., Lie J. T., Lightfoot R. W., Jr The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum. 1990 Aug;33(8):1101–1107. doi: 10.1002/art.1780330807. [DOI] [PubMed] [Google Scholar]
- Libby Peter, Ridker Paul M., Maseri Attilio. Inflammation and atherosclerosis. Circulation. 2002 Mar 5;105(9):1135–1143. doi: 10.1161/hc0902.104353. [DOI] [PubMed] [Google Scholar]
- Luqmani R. A., Bacon P. A., Moots R. J., Janssen B. A., Pall A., Emery P., Savage C., Adu D. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994 Nov;87(11):671–678. [PubMed] [Google Scholar]
- Matsuyama Akifumi, Sakai Naohiko, Ishigami Masato, Hiraoka Hisatoyo, Kashine Susumu, Hirata Ayumu, Nakamura Tadashi, Yamashita Shizuya, Matsuzawa Yuji. Matrix metalloproteinases as novel disease markers in Takayasu arteritis. Circulation. 2003 Sep 2;108(12):1469–1473. doi: 10.1161/01.CIR.0000090689.69973.B1. [DOI] [PubMed] [Google Scholar]
- Montauban van Swijndregt A. D., De Lange E. E., De Groot E., Ackerstaff R. G. 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 Mar;25(3):323–330. doi: 10.1016/s0301-5629(98)00183-5. [DOI] [PubMed] [Google Scholar]
- Muller Kobold A. C., van Wijk R. T., Franssen C. F., Molema G., Kallenberg C. G., Tervaert J. W. In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener's granulomatosis and microscopic polyangiitis. Clin Exp Rheumatol. 1999 Jul-Aug;17(4):433–440. [PubMed] [Google Scholar]
- Nomoto Kazumiki, Oguchi Sumito, Watanabe Ikuyoshi, Kushiro Toshio, Kanmatsuse Katsuo. Involvement of inflammation in acute coronary syndromes assessed by levels of high-sensitivity C-reactive protein, matrix metalloproteinase-9 and soluble vascular-cell adhesion molecule-1. J Cardiol. 2003 Nov;42(5):201–206. [PubMed] [Google Scholar]
- Orbe J., Fernandez L., Rodríguez J. A., Rábago G., Belzunce M., Monasterio A., Roncal C., Páramo José A. Different expression of MMPs/TIMP-1 in human atherosclerotic lesions. Relation to plaque features and vascular bed. Atherosclerosis. 2003 Oct;170(2):269–276. doi: 10.1016/s0021-9150(03)00251-x. [DOI] [PubMed] [Google Scholar]
- Pasceri V., Willerson J. T., Yeh E. T. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000 Oct 31;102(18):2165–2168. doi: 10.1161/01.cir.102.18.2165. [DOI] [PubMed] [Google Scholar]
- Posthumus M. D., Limburg P. C., Westra J., van Leeuwen M. A., van Rijswijk M. H. Serum matrix metalloproteinase 3 in early rheumatoid arthritis is correlated with disease activity and radiological progression. J Rheumatol. 2000 Dec;27(12):2761–2768. [PubMed] [Google Scholar]
- Ridker P. M., Hennekens C. H., Buring J. E., Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000 Mar 23;342(12):836–843. doi: 10.1056/NEJM200003233421202. [DOI] [PubMed] [Google Scholar]
- Ridker Paul M., Rifai Nader, Rose Lynda, Buring Julie E., Cook Nancy R. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002 Nov 14;347(20):1557–1565. doi: 10.1056/NEJMoa021993. [DOI] [PubMed] [Google Scholar]
- Roman Mary J., Shanker Beth-Ann, Davis Adrienne, Lockshin Michael D., Sammaritano Lisa, Simantov Ronit, Crow Mary K., Schwartz Joseph E., Paget Stephen A., Devereux Richard B. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med. 2003 Dec 18;349(25):2399–2406. doi: 10.1056/NEJMoa035471. [DOI] [PubMed] [Google Scholar]
- Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115–126. doi: 10.1056/NEJM199901143400207. [DOI] [PubMed] [Google Scholar]
- Shimokawa H. Primary endothelial dysfunction: atherosclerosis. J Mol Cell Cardiol. 1999 Jan;31(1):23–37. doi: 10.1006/jmcc.1998.0841. [DOI] [PubMed] [Google Scholar]
- Simantov R., Lo S. K., Gharavi A., Sammaritano L. R., Salmon J. E., Silverstein R. L. Antiphospholipid antibodies activate vascular endothelial cells. Lupus. 1996 Oct;5(5):440–441. doi: 10.1177/096120339600500521. [DOI] [PubMed] [Google Scholar]
- Sorbi D., French D. L., Nuovo G. J., Kew R. R., Arbeit L. A., Gruber B. L. Elevated levels of 92-kd type IV collagenase (matrix metalloproteinase 9) in giant cell arteritis. Arthritis Rheum. 1996 Oct;39(10):1747–1753. doi: 10.1002/art.1780391019. [DOI] [PubMed] [Google Scholar]
- Stegeman C. A., Tervaert J. W., Huitema M. G., de Jong P. E., Kallenberg C. G. Serum levels of soluble adhesion molecules intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin in patients with Wegener's granulomatosis. Relationship to disease activity and relevance during followup. Arthritis Rheum. 1994 Aug;37(8):1228–1235. doi: 10.1002/art.1780370818. [DOI] [PubMed] [Google Scholar]
- Szmitko Paul E., Wang Chao-Hung, Weisel Richard D., de Almeida John R., Anderson Todd J., Verma Subodh. New markers of inflammation and endothelial cell activation: Part I. Circulation. 2003 Oct 21;108(16):1917–1923. doi: 10.1161/01.CIR.0000089190.95415.9F. [DOI] [PubMed] [Google Scholar]
- Tchetverikov I., Lard L. R., DeGroot J., Verzijl N., TeKoppele J. M., Breedveld F. C., Huizinga T. W. J., Hanemaaijer R. Matrix metalloproteinases-3, -8, -9 as markers of disease activity and joint damage progression in early rheumatoid arthritis. Ann Rheum Dis. 2003 Nov;62(11):1094–1099. doi: 10.1136/ard.62.11.1094. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tziakas Dimitrios N., Chalikias Georgios K., Parissis John T., Hatzinikolaou Eleni I., Papadopoulos Elias D., Tripsiannis Grigorios A., Papadopoulou Evropi G., Tentes Ioannis K., Karas Spilios M., Chatseras Dimitrios I. Serum profiles of matrix metalloproteinases and their tissue inhibitor in patients with acute coronary syndromes. The effects of short-term atorvastatin administration. Int J Cardiol. 2004 Apr;94(2-3):269–277. doi: 10.1016/j.ijcard.2003.05.013. [DOI] [PubMed] [Google Scholar]
- Van Bortel L. M., Vanmolkot F. H., van der Heijden-Spek J. J., Bregu M., Staessen J. A., Hoeks A. P. Does B-mode common carotid artery intima-media thickness differ from M-model? Ultrasound Med Biol. 2001 Oct;27(10):1333–1336. doi: 10.1016/s0301-5629(01)00448-3. [DOI] [PubMed] [Google Scholar]
- Vlachoyiannopoulos P. G., Kanellopoulos P. G., Ioannidis J. P. A., Tektonidou M. G., Mastorakou I., Moutsopoulos H. M. Atherosclerosis in premenopausal women with antiphospholipid syndrome and systemic lupus erythematosus: a controlled study. Rheumatology (Oxford) 2003 May;42(5):645–651. doi: 10.1093/rheumatology/keg182. [DOI] [PubMed] [Google Scholar]
- de Groot E., Jukema J. W., Montauban van Swijndregt A. D., Zwinderman A. H., Ackerstaff R. G., van der Steen A. F., Bom N., Lie K. I., Bruschke A. V. B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Am Coll Cardiol. 1998 Jun;31(7):1561–1567. doi: 10.1016/s0735-1097(98)00170-3. [DOI] [PubMed] [Google Scholar]
- van Leeuwen M. A., van Rijswijk M. H., Westra J., de Jong H. J., Marrink J. C-reactieve proteïne; een dure bezinking? Ned Tijdschr Geneeskd. 1986 Aug 2;130(31):1391–1395. [PubMed] [Google Scholar]