Influence of Abdominal Obesity on the Relationship of Low-Density Lipoprotein Cholesterol with Atherosclerosis and Cardiovascular Risk in Rheumatoid Arthritis

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George A Karpouzas Nicoletta Ronda Matthew J Budoff Sarah R Ormseth


Methods. Coronary artery calcium, number of coronary plaques, and extensive ( 5 plaques) or obstructive (>50% stenosis) disease was evaluated with computed tomography angiography in 150 patients at baseline and 101 patients 6.9±0.4 years later. Cardiovascular events were recorded. Oxidized LDL was measured with monoclonal antibody E06. Serum cholesterol loading capacity on macrophages was measured as intracellular cholesterol content with a fluorometric assay.

Results. Abdominal obesity was not associated with per-patient number of coronary plaques or coronary artery calcium score at baseline. Low LDLc positively associated with number of plaques (b 2.13 [95% confidence interval 1.03 to 3.22]), likelihood of extensive or obstructive plaque (odds ratio 6.58, 95% confidence interval [1.63 to 26.46]), and log-transformed CAC (b 1.90 [0.89 to 2.91]) exclusively in nonobese patients (p-for-interaction <0.001, 0.061, and 0.001 respectively). Low LDLc associated with increased likelihood of >median oxidized LDL and higher ratio of cholesterol loading capacity to LDLc in nonobese patients (p-for-interaction 0.041 and 0.001 respectively). Abdominal obesity negatively associated with likelihood of plaque stenosis progression (odds ratio 0.19 [0.07 to 0.54]). Low LDLc associated with greater likelihood of per-segment plaque formation (OR 4.68 [2.26 to 9.66]) and increased stenotic severity (odds ratio 5.35 [1.62 to 17.67]) only in nonobese patients (p-for-interaction 0.002 and 0.040 respectively). Abdominal obesity was not linked to cardiovascular risk (Hazard Ratio 1.57, 95% confidence interval [0.66-3.73]). Low LDLc associated with higher cardiovascular risk in nonobese (Hazard Ratio 7.94 [1.52 to 41.36]) but not obese patients (p-for-interaction=0.017).

Conclusion. Abdominal obesity was not linked to plaque progression or cardiovascular risk in RA. Only in nonobese patients, low LDLc associated with higher atherosclerosis burden, plaque progression and cardiovascular risk. This may reflect higher oxidation and macrophage cholesterol loading capacity of LDL when LDLc is <70mg/dl.

Keywords: Rheumatoid arthritis, abdominal obesity, oxidized LDL, cholesterol loading capacity, coronary atherosclerosis, cardiovascular risk

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KARPOUZAS, George A et al. Influence of Abdominal Obesity on the Relationship of Low-Density Lipoprotein Cholesterol with Atherosclerosis and Cardiovascular Risk in Rheumatoid Arthritis. Medical Research Archives, [S.l.], v. 12, n. 4, apr. 2024. ISSN 2375-1924. Available at: <>. Date accessed: 27 may 2024. doi:
Research Articles


1. Semb AG, Ikdahl E, Wibetoe G, Crowson C, Rollefstad S. Atherosclerotic cardiovascular disease prevention in rheumatoid arthritis. Nat Rev Rheumatol. 2020;16(7):361-379.
2. Gonzalez A, Maradit Kremers H, Crowson CS, et al. Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients? Ann Rheum Dis. 2008;67(1):64-69.
3. Liao KP, Liu J, Lu B, Solomon DH, Kim SC. Association between lipid levels and major adverse cardiovascular events in rheumatoid arthritis compared to non-rheumatoid arthritis patients. Arthritis Rheumatol. 2015;67(8):2004-2010.
4. Navarro-Millán I, Yang S, DuVall SL, et al. Association of hyperlipidaemia, inflammation and serological status and coronary heart disease among patients with rheumatoid arthritis: data from the National Veterans Health Administration. Ann Rheum Dis. 2016;75(2):341-347.
5. Myasoedova E, Crowson CS, Kremers HM, et al. Lipid paradox in rheumatoid arthritis: the impact of serum lipid measures and systemic inflammation on the risk of cardiovascular disease. Ann Rheum Dis. 2011;70(3):482-487.
6. Giles JT, Wasko MCM, Chung CP, et al. Exploring the lipid paradox theory in rheumatoid arthritis: associations of low circulating low-density lipoprotein concentration with subclinical coronary atherosclerosis. Arthritis Rheumatol. 2019;71(9):1426-1436.
7. Karpouzas GA, Ormseth SR, Ronda N, Hernandez E, Budoff MJ. Lipoprotein oxidation may underlie the paradoxical association of low cholesterol with coronary atherosclerotic risk in rheumatoid arthritis. J Autoimmun. 2022;129:102815.
8. Baker JF, Stokes A, Mikuls TR, et al. Current and early life weight and associations with mortality in rheumatoid arthritis. Clin Exp Rheumatol. 2019;37(5):768-773.
9. Baghdadi LR, Woodman RJ, Shanahan EM, Mangoni AA. The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta-analysis. PLoS One. 2015;10(2):e0117952.
10. Liu Y, Hazlewood GS, Kaplan GG, Eksteen B, Barnabe C. Impact of obesity on remission and disease activity in rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2017;69(2):157-165.
11. England BR, Baker JF, Sayles H, et al. Body mass index, weight loss, and cause-specific mortality in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2018;70(1):11-18.
12. Wolfe F, Michaud K. Effect of body mass index on mortality and clinical status in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(10):1471-1479.
13. Escalante A, Haas RW, del Rincón I. Paradoxical effect of body mass index on survival in rheumatoid arthritis: role of comorbidity and systemic inflammation. Arch Intern Med. 2005;165(14):1624-1629.
14. Kremers HM, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis. Arthritis Rheum. 2004;50(11):3450-3457.
15. Huxley R, Mendis S, Zheleznyakov E, Reddy S, Chan J. Body mass index, waist circumference and waist:hip ratio as predictors of cardiovascular risk--a review of the literature. Eur J Clin Nutr. 2010;64(1):16-22.
16. Swainson MG, Batterham AM, Tsakirides C, Rutherford ZH, Hind K. Prediction of whole-body fat percentage and visceral adipose tissue mass from five anthropometric variables. PLoS One. 2017;12(5):e0177175.
17. Roriz AKC, Passos LCS, de Oliveira CC, Eickemberg M, Moreira P de A, Sampaio LR. Evaluation of the accuracy of anthropometric clinical indicators of visceral fat in adults and elderly. PLoS One. 2014;9(7):e103499.
18. Giles JT, Allison M, Blumenthal RS, et al. Abdominal adiposity in rheumatoid arthritis: association with cardiometabolic risk factors and disease characteristics. Arthritis Rheum. 2010;62(11):3173-3182.
19. Miller YI, Choi SH, Fang L, Tsimikas S. Lipoprotein modification and macrophage uptake: role of pathologic cholesterol transport in atherogenesis. Subcell Biochem. 2010;51:229-251.
20. Lourida ES, Georgiadis AN, Papavasiliou EC, Papathanasiou AI, Drosos AA, Tselepis AD. Patients with early rheumatoid arthritis exhibit elevated autoantibody titers against mildly oxidized low-density lipoprotein and exhibit decreased activity of the lipoprotein-associated phospholipase A2. Arthritis Res Ther. 2007;9:R19.
21. Karpouzas GA, Malpeso J, Choi TY, Li D, Munoz S, Budoff MJ. Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Ann Rheum Dis. 2014;73(10):1797-1804.
22. Aviña-Zubieta JA, Thomas J, Sadatsafavi M, Lehman AJ, Lacaille D. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2012;71(9):1524-1529.
23. Karpouzas GA, Ormseth SR, Hernandez E, Budoff MJ. Biologics may prevent cardiovascular events in rheumatoid arthritis by Inhibiting coronary plaque formation and stabilizing high-risk lesions. Arthritis Rheumatol. 2020;72:1467-1475.
24. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15(4):827-832.
25. Leipsic J, Abbara S, Achenbach S, et al. SCCT guidelines for the interpretation and reporting of coronary CT angiography: a report of the Society of Cardiovascular Computed Tomography Guidelines Committee. J Cardiovasc Comput Tomogr. 2014;8(5):342-358.
26. Andreini D, Pontone G, Mushtaq S, et al. A long-term prognostic value of coronary CT angiography in suspected coronary artery disease. JACC Cardiovasc Imaging. 2012;5(7):690-701.
27. Hou Z hui, Lu B, Gao Y, et al. Prognostic value of coronary CT angiography and calcium score for major adverse cardiac events in outpatients. JACC Cardiovasc Imaging. 2012;5(10):990-999.
28. Peters MJ, Symmons DP, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010;69(2):325-331.
29. Penny WF, Ben-Yehuda O, Kuroe K, et al. Improvement of coronary artery endothelial dysfunction with lipid-lowering therapy: heterogeneity of segmental response and correlation with plasma-oxidized low density lipoprotein. J Am Coll Cardiol. 2001;37(3):766-774.
30. Ronda N, Greco D, Adorni MP, et al. Newly identified antiatherosclerotic activity of methotrexate and adalimumab: complementary effects on lipoprotein function and macrophage cholesterol metabolism. Arthritis Rheumatol. 2015;67(5):1155-1164.
31. Nichol A, Bailey M, Egi M, et al. Dynamic lactate indices as predictors of outcome in critically ill patients. Crit Care. 2011;15(5):R242.
32. Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of Life Lost Due to Obesity. JAMA. 2003;289(2):187-193.
33. Peeters A, Barendregt JJ, Willekens F, et al. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med. 2003;138(1):24-32.
34. Semb AG, Kvien TK, Aastveit AH, et al. Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-related Mortality RISk (AMORIS) Study. Ann Rheum Dis. 2010;69(11):1996-2001.
35. Solomon A, Norton GR, Woodiwiss AJ, Dessein PH. Obesity and carotid atherosclerosis in African black and Caucasian women with established rheumatoid arthritis: a cross-sectional study. Arthritis Res Ther. 2012;14(2):R67.
36. Yoshida T, Hashimoto M, Kawahara R, et al. Non-obese visceral adiposity is associated with the risk of atherosclerosis in Japanese patients with rheumatoid arthritis: a cross-sectional study. Rheumatol Int. 2018;38(9):1679-1689.
37. Robertson J, Porter D, Sattar N, et al. Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis. Ann Rheum Dis. 2017;76(11):1949-1952.
38. Karpouzas GA, Ormseth SR, Hernandez E, Budoff MJ. Impact of cumulative inflammation, cardiac risk factors, and medication exposure on coronary atherosclerosis progression in rheumatoid arthritis. Arthritis Rheumatol. 2020;72(3):400-408.
39. Karpouzas GA, Ormseth SR, Hernandez E, Budoff MJ. The impact of statins on coronary atherosclerosis progression and long-term cardiovascular disease risk in rheumatoid arthritis. Rheumatology (Oxford). 2022;61(5):1857-1866.
40. del Rincón I, Polak JF, O’Leary DH, et al. Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis. Ann Rheum Dis. 2015;74(6):1118-1123.
41. Imahori Y, Mathiesen EB, Morgan KE, et al. The association between anthropometric measures of adiposity and the progression of carotid atherosclerosis. BMC Cardiovasc Disord. 2020;20:138.
42. Herder M, Johnsen SH, Arntzen KA, Mathiesen EB. Risk factors for progression of carotid intima-media thickness and total plaque area: a 13-year follow-up study: the Tromsø Study. Stroke. 2012;43(7):1818-1823.
43. van der Meer IM, Iglesias del Sol A, Hak AE, Bots ML, Hofman A, Witteman JCM. Risk factors for progression of atherosclerosis measured at multiple sites in the arterial tree: the Rotterdam Study. Stroke. 2003;34(10):2374-2379.
44. Molino-Lova R, Macchi C, Gori AM, et al. High sensitivity C-reactive protein predicts the development of new carotid artery plaques in older persons. Nutr Metab Cardiovasc Dis. 2011;21(10):776-782.
45. Karpouzas GA, Bui VL, Ronda N, Hollan I, Ormseth SR. Biologics and atherosclerotic cardiovascular risk in rheumatoid arthritis: a review of evidence and mechanistic insights. Expert Rev Clin Immunol. 2021;17(4):355-374.
46. Karpouzas G, Hernandez E, Budoff M, Ormseth S. The influence of abdominal obesity on the accuracy of cardiovascular risk prediction in rheumatoid arthritis. Med Res Arch. 2023;11(9). doi:10.18103/mra.v11i9.4432
47. Motoyama S, Ito H, Sarai M, et al. Plaque characterization by coronary computed tomography angiography and the likelihood of acute coronary events in mid-term follow-up. J Am Coll Cardiol. 2015;66(4):337-346.
48. Gu H, Gao Y, Wang H, et al. Sex differences in coronary atherosclerosis progression and major adverse cardiac events in patients with suspected coronary artery disease. J Cardiovasc Comput Tomogr. 2017;11(5):367-372.
49. Karpouzas GA, Papotti B, Ormseth SR, et al. Serum cholesterol loading capacity on macrophages is regulated by seropositivity and C-reactive protein in rheumatoid arthritis patients. Rheumatology (Oxford). 2023;62(3):1254-1263.
50. Karpouzas GA, Estis J, Todd J, Budoff MJ. Occult coronary plaque presence and burden predict cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheumatol. 2017;69 (suppl 10).
51. Karpouzas GA, Papotti B, Ormseth S, et al. Serum cholesterol loading capacity on macrophages is linked to coronary atherosclerosis and cardiovascular event risk in rheumatoid arthritis. RMD Open. 2022;8(2):e002411.
52. Patel R, Mikuls TR, Richards JS, Kerr G, Cannon GW, Baker JF. Disease characteristics and treatment patterns in veterans with rheumatoid arthritis and concomitant hepatitis C infection. Arthritis Care Res (Hoboken). 2015;67(4):467-474.
53. Sparks JA, Chang SC, Nguyen US, et al. Weight change during the early rheumatoid arthritis period and risk of subsequent mortality in women with rheumatoid arthritis and matched comparators. Arthritis Rheumatol. 2018;70(1):18-29.
54. Baker JF, Reed G, Kremer J. Weight fluctuation and the risk of cardiovascular events in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2022;74(2):229-235.