Association of Interleukin-6 With the Progression of Carotid Atherosclerosis A 9-Year Follow-Up Study Shuhei Okazaki, MD; Manabu Sakaguchi, MD; Kaori Miwa, MD; Shigetaka Furukado, MD; Hiroshi Yamagami, MD; Yoshiki Yagita, MD; Hideki Mochizuki, MD; Kazuo Kitagawa, MD Background and Purpose—Limited information is available on the long-term effects of interleukin-6 (IL-6) on systemic atherosclerosis. The purpose of the present study was to clarify the relationship between chronic elevation of IL-6 and the long-term progression of carotid atherosclerosis. Methods—We prospectively evaluated 210 patients with ≥1 vascular risk factors for 9.0±1.0 years. Carotid mean-maximal intima-media thickness (mmIMT), the serum high-sensitivity C-reactive protein (hs-CRP) level, and the serum IL-6 level were measured at baseline and every 3 years. The associations between the progression of mmIMT and the long-term average levels of hs-CRP and IL-6 were analyzed. Results—Carotid mmIMT increased throughout the study period (0.031±0.026 mm/y). Baseline mmIMT was significantly associated with baseline hs-CRP (P=0.002) and baseline IL-6 (P80% of the participants underwent carotid ultrasonography measurements every 3 years, and we verified the linear progression of the average mmIMT throughout the study period. In conclusion, the results of the present study indicate that chronic elevation of the serum IL-6 level is associated with the progression of atherosclerosis in patients with vascular risk factors. These findings warrant further investigation of IL-6 as a quantitative maker and a potential therapeutic target for accelerated atherosclerosis.
Acknowledgments We thank C. Ito and K. Nishiyama for their secretarial assistance.
Sources of Funding This work was supported by Japan Society for the Promotion of Science KAKENHI Grant No. 24790882 and in part by the Ministry of Health, Labour, and Welfare of Japan (H14-023, H15-020, H16003, H17-001, and H22-006).
Disclosures None.
References 1. Lamon BD, Hajjar DP. Inflammation at the molecular interface of atherogenesis: an anthropological journey. Am J Pathol. 2008;173:1253–1264. 2. Schuett H, Luchtefeld M, Grothusen C, Grote K, Schieffer B. How much is too much? Interleukin-6 and its signalling in atherosclerosis. Thromb Haemost. 2009;102:215–222. 3. Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008;8:802–815. 4. van der Valk FM, van Wijk DF, Stroes ES. Novel anti-inflammatory strategies in atherosclerosis. Curr Opin Lipidol. 2012;23:532–539. 5. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012;379:1214–1224. 6. Kitagawa K, Hougaku H, Yamagami H, Hashimoto H, Itoh T, Shimizu Y, et al; OSACA2 Study Group. Carotid intima-media thickness and risk of cardiovascular events in high-risk patients. Results of the Osaka Follow-Up Study for Carotid Atherosclerosis 2 (OSACA2 Study). Cerebrovasc Dis. 2007;24:35–42. 7. Sakaguchi M, Kitagawa K, Nagai Y, Yamagami H, Kondo K, Matsushita K, et al. Equivalence of plaque score and intima-media thickness of carotid ultrasonography for predicting severe coronary artery lesion. Ultrasound Med Biol. 2003;29:367–371. 8. Yamagami H, Kitagawa K, Hoshi T, Furukado S, Hougaku H, Nagai Y, et al. Associations of serum IL-18 levels with carotid intima-media thickness. Arterioscler Thromb Vasc Biol. 2005;25:1458–1462. 9. Okazaki S, Furukado S, Abe Y, Tanaka M, Miwa K, Yamagami H, et al. Association of inflammatory markers and carotid intima-media thickness with the risk of cardiovascular events in high-risk patients. Cerebrovasc Dis. 2010;30:180–187. 10. Rothwell PM, Gibson RJ, Slattery J, Sellar RJ, Warlow CP. Equivalence of measurements of carotid stenosis. A comparison of three methods on 1001 angiograms. European Carotid Surgery Trialists’ Collaborative Group. Stroke. 1994;25:2435–2439. 11. Teramoto T, Sasaki J, Ueshima H, Egusa G, Kinoshita M, Shimamoto K, et al. Risk factors of atherosclerotic diseases. Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention of atherosclerosis cardiovascular diseases for Japanese. J Atheroscler Thromb. 2007;14:267–277. 12. Salonen R, Salonen JT. Progression of carotid atherosclerosis and its determinants: a population-based ultrasonography study. Atherosclerosis. 1990;81:33–40. 13. Chambless LE, Folsom AR, Davis V, Sharrett R, Heiss G, Sorlie P, et al. Risk factors for progression of common carotid atherosclerosis: the Atherosclerosis Risk in Communities Study, 1987-1998. Am J Epidemiol. 2002;155:38–47. 14. van der Meer IM, Iglesias del Sol A, Hak AE, Bots ML, Hofman A, Witteman JC. Risk factors for progression of atherosclerosis measured at multiple sites in the arterial tree: the Rotterdam Study. Stroke. 2003;34:2374–2379. 15. Moody WE, Edwards NC, Chue CD, Ferro CJ, Townend JN. Arterial disease in chronic kidney disease. Heart. 2013;99:365–372. 16. Shah AS, Dolan LM, Kimball TR, Gao Z, Khoury PR, Daniels SR, et al. Influence of duration of diabetes, glycemic control, and traditional cardiovascular risk factors on early atherosclerotic vascular changes
Downloaded from http://stroke.ahajournals.org/ at BIBLIOTHEQUE DE L'UNIV LAVAL on January 26, 2015
Okazaki et al IL-6 and Carotid Atherosclerosis Progression 2929 in adolescents and young adults with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2009;94:3740–3745. 17. Sutton-Tyrrell K, Alcorn HG, Wolfson SK Jr, Kelsey SF, Kuller LH. Predictors of carotid stenosis in older adults with and without isolated systolic hypertension. Stroke. 1993;24:355–361. 18. Psaty BM, Furberg CD, Kuller LH, Borhani NO, Rautaharju PM, O’Leary DH, et al. Isolated systolic hypertension and subclinical cardiovascular disease in the elderly. Initial findings from the Cardiovascular Health Study. JAMA. 1992;268:1287–1291. 19. Lorenz MW, Karbstein P, Markus HS, Sitzer M. High-sensitivity C-reactive protein is not associated with carotid intima-media progression: the carotid atherosclerosis progression study. Stroke. 2007;38:1774–1779. 20. Sander K, Horn CS, Briesenick C, Sander D; INVADE Study Group. High-sensitivity C-reactive protein is independently associated with early carotid artery progression in women but not in men: the INVADE Study. Stroke. 2007;38:2881–2886. 21. Sander D, Schulze-Horn C, Bickel H, Gnahn H, Bartels E, Conrad B. Combined effects of hemoglobin A1c and C-reactive protein on the progression of subclinical carotid atherosclerosis: the INVADE study. Stroke. 2006;37:351–357. 22. Hashimoto H, Kitagawa K, Hougaku H, Shimizu Y, Sakaguchi M, Nagai Y, et al. C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis. Circulation. 2001;104:63–67. 23. Lee WY, Allison MA, Kim DJ, Song CH, Barrett-Connor E. Association of interleukin-6 and C-reactive protein with subclinical carotid atherosclerosis (the Rancho Bernardo Study). Am J Cardiol. 2007;99:99–102. 24. Thakore AH, Guo CY, Larson MG, Corey D, Wang TJ, Vasan RS, et al. Association of multiple inflammatory markers with carotid intimal
medial thickness and stenosis (from the Framingham Heart Study). Am J Cardiol. 2007;99:1598–1602. 25. van der Meer IM, de Maat MP, Bots ML, Breteler MM, Meijer J, Kiliaan AJ, et al. Inflammatory mediators and cell adhesion molecules as indicators of severity of atherosclerosis: the Rotterdam Study. Arterioscler Thromb Vasc Biol. 2002;22:838–842. 26. Chapman CM, Beilby JP, McQuillan BM, Thompson PL, Hung J. Monocyte count, but not C-reactive protein or interleukin-6, is an independent risk marker for subclinical carotid atherosclerosis. Stroke. 2004;35:1619–1624. 27. Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M, et al. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol. 1999;150:341–353. 28. Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med. 2008;5:e78. 29. Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA. 1987;84:7251–7255. 30. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340:115–126. 31. Lorenz MW, Polak JF, Kavousi M, Mathiesen EB, Völzke H, Tuomainen TP, et al; PROG-IMT Study Group. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet. 2012;379:2053–2062.
Downloaded from http://stroke.ahajournals.org/ at BIBLIOTHEQUE DE L'UNIV LAVAL on January 26, 2015
Association of Interleukin-6 With the Progression of Carotid Atherosclerosis: A 9-Year Follow-Up Study Shuhei Okazaki, Manabu Sakaguchi, Kaori Miwa, Shigetaka Furukado, Hiroshi Yamagami, Yoshiki Yagita, Hideki Mochizuki and Kazuo Kitagawa Stroke. 2014;45:2924-2929; originally published online August 19, 2014; doi: 10.1161/STROKEAHA.114.005991 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/45/10/2924
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Acknowledgments We thank C. Ito and K. Nishiyama for their secretarial assistance.
Sources of Funding This work was supported by Japan Society for the Promotion of Science KAKENHI Grant No. 24790882 and in part by the Ministry of Health, Labour, and Welfare of Japan (H14-023, H15-020, H16003, H17-001, and H22-006).
Disclosures None.
References 1. Lamon BD, Hajjar DP. Inflammation at the molecular interface of atherogenesis: an anthropological journey. Am J Pathol. 2008;173:1253–1264. 2. Schuett H, Luchtefeld M, Grothusen C, Grote K, Schieffer B. How much is too much? Interleukin-6 and its signalling in atherosclerosis. Thromb Haemost. 2009;102:215–222. 3. Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008;8:802–815. 4. van der Valk FM, van Wijk DF, Stroes ES. Novel anti-inflammatory strategies in atherosclerosis. Curr Opin Lipidol. 2012;23:532–539. 5. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012;379:1214–1224. 6. Kitagawa K, Hougaku H, Yamagami H, Hashimoto H, Itoh T, Shimizu Y, et al; OSACA2 Study Group. Carotid intima-media thickness and risk of cardiovascular events in high-risk patients. Results of the Osaka Follow-Up Study for Carotid Atherosclerosis 2 (OSACA2 Study). Cerebrovasc Dis. 2007;24:35–42. 7. Sakaguchi M, Kitagawa K, Nagai Y, Yamagami H, Kondo K, Matsushita K, et al. Equivalence of plaque score and intima-media thickness of carotid ultrasonography for predicting severe coronary artery lesion. Ultrasound Med Biol. 2003;29:367–371. 8. Yamagami H, Kitagawa K, Hoshi T, Furukado S, Hougaku H, Nagai Y, et al. Associations of serum IL-18 levels with carotid intima-media thickness. Arterioscler Thromb Vasc Biol. 2005;25:1458–1462. 9. Okazaki S, Furukado S, Abe Y, Tanaka M, Miwa K, Yamagami H, et al. Association of inflammatory markers and carotid intima-media thickness with the risk of cardiovascular events in high-risk patients. Cerebrovasc Dis. 2010;30:180–187. 10. Rothwell PM, Gibson RJ, Slattery J, Sellar RJ, Warlow CP. Equivalence of measurements of carotid stenosis. A comparison of three methods on 1001 angiograms. European Carotid Surgery Trialists’ Collaborative Group. Stroke. 1994;25:2435–2439. 11. Teramoto T, Sasaki J, Ueshima H, Egusa G, Kinoshita M, Shimamoto K, et al. Risk factors of atherosclerotic diseases. Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention of atherosclerosis cardiovascular diseases for Japanese. J Atheroscler Thromb. 2007;14:267–277. 12. Salonen R, Salonen JT. Progression of carotid atherosclerosis and its determinants: a population-based ultrasonography study. Atherosclerosis. 1990;81:33–40. 13. Chambless LE, Folsom AR, Davis V, Sharrett R, Heiss G, Sorlie P, et al. Risk factors for progression of common carotid atherosclerosis: the Atherosclerosis Risk in Communities Study, 1987-1998. Am J Epidemiol. 2002;155:38–47. 14. van der Meer IM, Iglesias del Sol A, Hak AE, Bots ML, Hofman A, Witteman JC. Risk factors for progression of atherosclerosis measured at multiple sites in the arterial tree: the Rotterdam Study. Stroke. 2003;34:2374–2379. 15. Moody WE, Edwards NC, Chue CD, Ferro CJ, Townend JN. Arterial disease in chronic kidney disease. Heart. 2013;99:365–372. 16. Shah AS, Dolan LM, Kimball TR, Gao Z, Khoury PR, Daniels SR, et al. Influence of duration of diabetes, glycemic control, and traditional cardiovascular risk factors on early atherosclerotic vascular changes
Downloaded from http://stroke.ahajournals.org/ at BIBLIOTHEQUE DE L'UNIV LAVAL on January 26, 2015
Okazaki et al IL-6 and Carotid Atherosclerosis Progression 2929 in adolescents and young adults with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2009;94:3740–3745. 17. Sutton-Tyrrell K, Alcorn HG, Wolfson SK Jr, Kelsey SF, Kuller LH. Predictors of carotid stenosis in older adults with and without isolated systolic hypertension. Stroke. 1993;24:355–361. 18. Psaty BM, Furberg CD, Kuller LH, Borhani NO, Rautaharju PM, O’Leary DH, et al. Isolated systolic hypertension and subclinical cardiovascular disease in the elderly. Initial findings from the Cardiovascular Health Study. JAMA. 1992;268:1287–1291. 19. Lorenz MW, Karbstein P, Markus HS, Sitzer M. High-sensitivity C-reactive protein is not associated with carotid intima-media progression: the carotid atherosclerosis progression study. Stroke. 2007;38:1774–1779. 20. Sander K, Horn CS, Briesenick C, Sander D; INVADE Study Group. High-sensitivity C-reactive protein is independently associated with early carotid artery progression in women but not in men: the INVADE Study. Stroke. 2007;38:2881–2886. 21. Sander D, Schulze-Horn C, Bickel H, Gnahn H, Bartels E, Conrad B. Combined effects of hemoglobin A1c and C-reactive protein on the progression of subclinical carotid atherosclerosis: the INVADE study. Stroke. 2006;37:351–357. 22. Hashimoto H, Kitagawa K, Hougaku H, Shimizu Y, Sakaguchi M, Nagai Y, et al. C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis. Circulation. 2001;104:63–67. 23. Lee WY, Allison MA, Kim DJ, Song CH, Barrett-Connor E. Association of interleukin-6 and C-reactive protein with subclinical carotid atherosclerosis (the Rancho Bernardo Study). Am J Cardiol. 2007;99:99–102. 24. Thakore AH, Guo CY, Larson MG, Corey D, Wang TJ, Vasan RS, et al. Association of multiple inflammatory markers with carotid intimal
medial thickness and stenosis (from the Framingham Heart Study). Am J Cardiol. 2007;99:1598–1602. 25. van der Meer IM, de Maat MP, Bots ML, Breteler MM, Meijer J, Kiliaan AJ, et al. Inflammatory mediators and cell adhesion molecules as indicators of severity of atherosclerosis: the Rotterdam Study. Arterioscler Thromb Vasc Biol. 2002;22:838–842. 26. Chapman CM, Beilby JP, McQuillan BM, Thompson PL, Hung J. Monocyte count, but not C-reactive protein or interleukin-6, is an independent risk marker for subclinical carotid atherosclerosis. Stroke. 2004;35:1619–1624. 27. Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M, et al. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol. 1999;150:341–353. 28. Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB, et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med. 2008;5:e78. 29. Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA. 1987;84:7251–7255. 30. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340:115–126. 31. Lorenz MW, Polak JF, Kavousi M, Mathiesen EB, Völzke H, Tuomainen TP, et al; PROG-IMT Study Group. Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet. 2012;379:2053–2062.
Downloaded from http://stroke.ahajournals.org/ at BIBLIOTHEQUE DE L'UNIV LAVAL on January 26, 2015
Association of Interleukin-6 With the Progression of Carotid Atherosclerosis: A 9-Year Follow-Up Study Shuhei Okazaki, Manabu Sakaguchi, Kaori Miwa, Shigetaka Furukado, Hiroshi Yamagami, Yoshiki Yagita, Hideki Mochizuki and Kazuo Kitagawa Stroke. 2014;45:2924-2929; originally published online August 19, 2014; doi: 10.1161/STROKEAHA.114.005991 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/45/10/2924
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Stroke is online at: http://stroke.ahajournals.org//subscriptions/
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