Abstract
Background: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease. Endothelial dysfunction represents the earliest stage of atherosclerosis.
Objective: To evaluate the influence of chronic inflammatory state on endothelial function in patients with RA by measuring endothelial reactivity in young patients with RA with low disease activity and without traditional cardiovascular risk factors.
Methods: Brachial flow mediated vasodilatation (FMV), assessed by non-invasive ultrasound, was evaluated in 32 young to middle aged patients with RA (age ⩽59 years), with DAS28 ⩽3.2 and without overt cardiovascular disease, and in 28 age and sex matched controls.
Results: Mean (SD) FMV was significantly lower in patients than in controls (3.2 (1.3)% v 5.7 (2.0)%; p<0.001), inversely related to low density lipoprotein cholesterol (r = -0.45, p<0.05) and C reactive protein (CRP), expressed as the value at the moment of ultrasound evaluation (r = -0.44, p<0.05), as the average of CRP levels evaluated at different times during the disease (r = -0.47, p<0.05), or as the average of ⩾4 determinations multiplied by the disease duration (r = -0.40, p<0.05). In a multivariate regression model, a lower brachial flow mediated vasodilatation was independently predicted by low density lipoprotein cholesterol (ß = -0.40, p<0.05), average CRP levels multiplied by the disease duration (ß = -0.44, p<0.05), and brachial artery diameter (ß = -0.28, p<0.05).
Conclusions: Young to middle aged patients with RA with low disease activity, free from cardiovascular risk factors and overt cardiovascular disease, have an altered endothelial reactivity that seems to be primarily related to the disease associated chronic inflammatory condition.
Full Text
The Full Text of this article is available as a PDF (285.5 KB).
Figure 1 .
Univariate correlation between brachial artery flow mediated vasodilatation and CRP duration, expressed as average CRP in the past year multiplied by the disease duration in years.
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Anderson T. J., Uehata A., Gerhard M. D., Meredith I. T., Knab S., Delagrange D., Lieberman E. H., Ganz P., Creager M. A., Yeung A. C. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995 Nov 1;26(5):1235–1241. doi: 10.1016/0735-1097(95)00327-4. [DOI] [PubMed] [Google Scholar]
- Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
- Bacon P. A., Raza K., Banks M. J., Townend J., Kitas G. D. The role of endothelial cell dysfunction in the cardiovascular mortality of RA. Int Rev Immunol. 2002 Jan-Feb;21(1):1–17. doi: 10.1080/08830180210413. [DOI] [PubMed] [Google Scholar]
- Bergholm Robert, Leirisalo-Repo Marjatta, Vehkavaara Satu, Mäkimattila Sari, Taskinen Marja-Riitta, Yki-Järvinen Hannele. Impaired responsiveness to NO in newly diagnosed patients with rheumatoid arthritis. Arterioscler Thromb Vasc Biol. 2002 Oct 1;22(10):1637–1641. doi: 10.1161/01.atv.0000033516.73864.4e. [DOI] [PubMed] [Google Scholar]
- Björklund Kristina, Lind Lars, Zethelius Björn, Andrén Bertil, Lithell Hans. Isolated ambulatory hypertension predicts cardiovascular morbidity in elderly men. Circulation. 2003 Mar 11;107(9):1297–1302. doi: 10.1161/01.cir.0000054622.45012.12. [DOI] [PubMed] [Google Scholar]
- Celermajer D. S., Sorensen K. E., Gooch V. M., Spiegelhalter D. J., Miller O. I., Sullivan I. D., Lloyd J. K., Deanfield J. E. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992 Nov 7;340(8828):1111–1115. doi: 10.1016/0140-6736(92)93147-f. [DOI] [PubMed] [Google Scholar]
- Chowienczyk P. J., Watts G. F., Cockcroft J. R., Ritter J. M. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992 Dec 12;340(8833):1430–1432. doi: 10.1016/0140-6736(92)92621-l. [DOI] [PubMed] [Google Scholar]
- Clarke R., Daly L., Robinson K., Naughten E., Cahalane S., Fowler B., Graham I. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. 1991 Apr 25;324(17):1149–1155. doi: 10.1056/NEJM199104253241701. [DOI] [PubMed] [Google Scholar]
- Corretti Mary C., Anderson Todd J., Benjamin Emelia J., Celermajer David, Charbonneau Francois, Creager Mark A., Deanfield John, Drexler Helmut, Gerhard-Herman Marie, Herrington David. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002 Jan 16;39(2):257–265. doi: 10.1016/s0735-1097(01)01746-6. [DOI] [PubMed] [Google Scholar]
- Danesh J., Whincup P., Walker M., Lennon L., Thomson A., Appleby P., Gallimore J. R., Pepys M. B. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000 Jul 22;321(7255):199–204. doi: 10.1136/bmj.321.7255.199. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dhillon R., Clarkson P., Donald A. E., Powe A. J., Nash M., Novelli V., Dillon M. J., Deanfield J. E. Endothelial dysfunction late after Kawasaki disease. Circulation. 1996 Nov 1;94(9):2103–2106. doi: 10.1161/01.cir.94.9.2103. [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]
- Haagsma C. J., Blom H. J., van Riel P. L., van't Hof M. A., Giesendorf B. A., van Oppenraaij-Emmerzaal D., van de Putte L. B. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis. 1999 Feb;58(2):79–84. doi: 10.1136/ard.58.2.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hingorani A. D., Cross J., Kharbanda R. K., Mullen M. J., Bhagat K., Taylor M., Donald A. E., Palacios M., Griffin G. E., Deanfield J. E. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation. 2000 Aug 29;102(9):994–999. doi: 10.1161/01.cir.102.9.994. [DOI] [PubMed] [Google Scholar]
- Hürlimann David, Forster Adrian, Noll Georg, Enseleit Frank, Chenevard Rémy, Distler Oliver, Béchir Markus, Spieker Lukas E., Neidhart Michel, Michel Beat A. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002 Oct 22;106(17):2184–2187. doi: 10.1161/01.cir.0000037521.71373.44. [DOI] [PubMed] [Google Scholar]
- Kessler P., Popp R., Busse R., Schini-Kerth V. B. Proinflammatory mediators chronically downregulate the formation of the endothelium-derived hyperpolarizing factor in arteries via a nitric oxide/cyclic GMP-dependent mechanism. Circulation. 1999 Apr 13;99(14):1878–1884. doi: 10.1161/01.cir.99.14.1878. [DOI] [PubMed] [Google Scholar]
- Krause D., Schleusser B., Herborn G., Rau R. Response to methotrexate treatment is associated with reduced mortality in patients with severe rheumatoid arthritis. Arthritis Rheum. 2000 Jan;43(1):14–21. doi: 10.1002/1529-0131(200001)43:1<14::AID-ANR3>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
- Lakatos J., Hárságyi A. Serum total, HDL, LDL cholesterol, and triglyceride levels in patients with rheumatoid arthritis. Clin Biochem. 1988 Apr;21(2):93–96. doi: 10.1016/s0009-9120(88)80094-8. [DOI] [PubMed] [Google Scholar]
- Lima Domingos S. N., Sato Emilia I., Lima Valter C., Miranda Fausto, Jr, Hatta Francisca H. Brachial endothelial function is impaired in patients with systemic lupus erythematosus. J Rheumatol. 2002 Feb;29(2):292–297. [PubMed] [Google Scholar]
- Manzi S., Wasko M. C. Inflammation-mediated rheumatic diseases and atherosclerosis. Ann Rheum Dis. 2000 May;59(5):321–325. doi: 10.1136/ard.59.5.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marchesi S., Lupattelli G., Schillaci G., Pirro M., Siepi D., Roscini A. R., Pasqualini L., Mannarino E. Impaired flow-mediated vasoactivity during post-prandial phase in young healthy men. Atherosclerosis. 2000 Dec;153(2):397–402. doi: 10.1016/s0021-9150(00)00415-9. [DOI] [PubMed] [Google Scholar]
- Molenaar E. T., Voskuyl A. E., Familian A., van Mierlo G. J., Dijkmans B. A., Hack C. E. Complement activation in patients with rheumatoid arthritis mediated in part by C-reactive protein. Arthritis Rheum. 2001 May;44(5):997–1002. doi: 10.1002/1529-0131(200105)44:5<997::AID-ANR178>3.0.CO;2-C. [DOI] [PubMed] [Google Scholar]
- Morgan S. L., Baggott J. E., Lee J. Y., Alarcón G. S. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol. 1998 Mar;25(3):441–446. [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]
- Perticone F., Ceravolo R., Pujia A., Ventura G., Iacopino S., Scozzafava A., Ferraro A., Chello M., Mastroroberto P., Verdecchia P. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001 Jul 10;104(2):191–196. doi: 10.1161/01.cir.104.2.191. [DOI] [PubMed] [Google Scholar]
- Petri M., Roubenoff R., Dallal G. E., Nadeau M. R., Selhub J., Rosenberg I. H. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet. 1996 Oct 26;348(9035):1120–1124. doi: 10.1016/S0140-6736(96)03032-2. [DOI] [PubMed] [Google Scholar]
- Pirro M., Bergeron J., Dagenais G. R., Bernard P. M., Cantin B., Després J. P., Lamarche B. Age and duration of follow-up as modulators of the risk for ischemic heart disease associated with high plasma C-reactive protein levels in men. Arch Intern Med. 2001 Nov 12;161(20):2474–2480. doi: 10.1001/archinte.161.20.2474. [DOI] [PubMed] [Google Scholar]
- Rantapä-Dahlqvist S., Wållberg-Jonsson S., Dahlén G. Lipoprotein (a), lipids, and lipoproteins in patients with rheumatoid arthritis. Ann Rheum Dis. 1991 Jun;50(6):366–368. doi: 10.1136/ard.50.6.366. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Raza K., Thambyrajah J., Townend J. N., Exley A. R., Hortas C., Filer A., Carruthers D. M., Bacon P. A. Suppression of inflammation in primary systemic vasculitis restores vascular endothelial function: lessons for atherosclerotic disease? Circulation. 2000 Sep 26;102(13):1470–1472. doi: 10.1161/01.cir.102.13.1470. [DOI] [PubMed] [Google Scholar]
- Ridker P. M., Buring J. E., Shih J., Matias M., Hennekens C. H. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation. 1998 Aug 25;98(8):731–733. doi: 10.1161/01.cir.98.8.731. [DOI] [PubMed] [Google Scholar]
- Ridker P. M., Cushman M., Stampfer M. J., Tracy R. P., Hennekens C. H. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997 Apr 3;336(14):973–979. doi: 10.1056/NEJM199704033361401. [DOI] [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]
- Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. doi: 10.1038/362801a0. [DOI] [PubMed] [Google Scholar]
- Roubenoff R., Dellaripa P., Nadeau M. R., Abad L. W., Muldoon B. A., Selhub J., Rosenberg I. H. Abnormal homocysteine metabolism in rheumatoid arthritis. Arthritis Rheum. 1997 Apr;40(4):718–722. doi: 10.1002/art.1780400418. [DOI] [PubMed] [Google Scholar]
- Schächinger V., Britten M. B., Zeiher A. M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000 Apr 25;101(16):1899–1906. doi: 10.1161/01.cir.101.16.1899. [DOI] [PubMed] [Google Scholar]
- Svenson K. L., Lithell H., Hällgren R., Selinus I., Vessby B. Serum lipoprotein in active rheumatoid arthritis and other chronic inflammatory arthritides. I. Relativity to inflammatory activity. Arch Intern Med. 1987 Nov;147(11):1912–1916. [PubMed] [Google Scholar]
- Svenson K. L., Lithell H., Hällgren R., Vessby B. Serum lipoprotein in active rheumatoid arthritis and other chronic inflammatory arthritides. II. Effects of anti-inflammatory and disease-modifying drug treatment. Arch Intern Med. 1987 Nov;147(11):1917–1920. [PubMed] [Google Scholar]
- Tuomi T., Heliövaara M., Palosuo T., Aho K. Smoking, lung function, and rheumatoid factors. Ann Rheum Dis. 1990 Oct;49(10):753–756. doi: 10.1136/ard.49.10.753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Urieli-Shoval S., Linke R. P., Matzner Y. Expression and function of serum amyloid A, a major acute-phase protein, in normal and disease states. Curr Opin Hematol. 2000 Jan;7(1):64–69. doi: 10.1097/00062752-200001000-00012. [DOI] [PubMed] [Google Scholar]
- Van Doornum S., McColl G., Jenkins A., Green D. J., Wicks I. P. Screening for atherosclerosis in patients with rheumatoid arthritis: comparison of two in vivo tests of vascular function. Arthritis Rheum. 2003 Jan;48(1):72–80. doi: 10.1002/art.10735. [DOI] [PubMed] [Google Scholar]
- Wolfe F., Mitchell D. M., Sibley J. T., Fries J. F., Bloch D. A., Williams C. A., Spitz P. W., Haga M., Kleinheksel S. M., Cathey M. A. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994 Apr;37(4):481–494. doi: 10.1002/art.1780370408. [DOI] [PubMed] [Google Scholar]
- Yasojima K., Schwab C., McGeer E. G., McGeer P. L. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol. 2001 Mar;158(3):1039–1051. doi: 10.1016/S0002-9440(10)64051-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yoshizumi M., Perrella M. A., Burnett J. C., Jr, Lee M. E. Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life. Circ Res. 1993 Jul;73(1):205–209. doi: 10.1161/01.res.73.1.205. [DOI] [PubMed] [Google Scholar]

