Autoantibodies to Phosphorylcholine and Cardiovascular Outcomes in Patients with Acute Coronary Syndromes in the ATLAS ACS-TIMI 46 Trial

Overview

Journal J Thromb Thrombolysis

Specialty Cardiology & Vascular Diseases

Date 2013 Jul 18

PMID 23860881

Citations 8

Authors

Bram J Geller

Jessica L Mega

David A Morrow

Jianping Guo

Elaine B Hoffman

C Michael Gibson

Christian T Ruff

Affiliations

Soon will be listed here.

Abstract

Atherogenesis is a complex inflammatory process stemming from the accumulation and oxidation of low density lipoproteins (LDL). IgM autoantibodies against phosphorylcholine (anti-PC) bind to the PC epitope on oxidized LDL (OxLDL), inhibiting the uptake of oxLDL by macrophages in atherosclerotic lesions. Anti-PC autoantibodies have been reported to be protective against atherothrombosis. We investigated the relationship of anti-PC concentrations with cardiovascular outcomes in patients with acute coronary syndromes (ACS). We measured anti-PC levels within 7 days of an ACS in 3,356 patients enrolled in the ATLAS ACS-TIMI 46 trial, a randomized dose ranging study of rivaroxaban versus placebo. The primary endpoint was death, myocardial infarction (MI), stroke, or severe recurrent ischemia (SRI) requiring revascularization during 6 months. The median baseline anti-PC concentration was 40.9 U/mL (25th, 75th percentiles: 25.4, 67.4). There was no significant association between anti-PC levels and the primary endpoint (Q1: 6.8 %, Q2: 4.2 %, Q3: 7.8 %, Q4: 5.4 %, p-trend = 0.87), all-cause mortality (Q1: 1.4 %, Q2: 0.7 %, Q3: 2.4 %, Q4: 0.9 %, p-trend = 0. 96), or any of the other individual endpoint components (MI: p-trend = 0.87, Stroke: p-trend = 0.43, SRI: p-trend = 0.66). Using the previously reported anti-PC cutpoint of 17 U/mL did not reveal a significant relationship between anti-PC concentrations and cardiovascular outcomes (<17 U/mL: 8.1 % vs. ≥17 U/mL: 5.8 %; p = 0.11). Similarly, evaluation of anti-PC as a continuous variable did not reveal a significant association (p = 0.30). In this study of patients early after ACS undergoing intensive secondary preventive therapy, IgM anti-PC titers did not exhibit a significant relationship with cardiovascular outcomes.

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References

Frostegard J . Low level natural antibodies against phosphorylcholine: a novel risk marker and potential mechanism in atherosclerosis and cardiovascular disease. Clin Immunol. 2009; 134(1):47-54. DOI: 10.1016/j.clim.2009.08.013. View

Libby P, Ridker P, Hansson G . Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009; 54(23):2129-38. PMC: 2834169. DOI: 10.1016/j.jacc.2009.09.009. View

ODonoghue M, Morrow D, Sabatine M, Murphy S, McCabe C, Cannon C . Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial.... Circulation. 2006; 113(14):1745-52. DOI: 10.1161/CIRCULATIONAHA.105.612630. View

de Faire U, Frostegard J . Natural antibodies against phosphorylcholine in cardiovascular disease. Ann N Y Acad Sci. 2009; 1173:292-300. DOI: 10.1111/j.1749-6632.2009.04748.x. View

Weismann D, Binder C . The innate immune response to products of phospholipid peroxidation. Biochim Biophys Acta. 2012; 1818(10):2465-75. PMC: 3790971. DOI: 10.1016/j.bbamem.2012.01.018. View

Sjoberg B, Su J, Dahlbom I, Gronlund H, Wikstrom M, Hedblad B . Low levels of IgM antibodies against phosphorylcholine-A potential risk marker for ischemic stroke in men. Atherosclerosis. 2008; 203(2):528-32. DOI: 10.1016/j.atherosclerosis.2008.07.009. View

Caligiuri G, Khallou-Laschet J, Vandaele M, Gaston A, Delignat S, Mandet C . Phosphorylcholine-targeting immunization reduces atherosclerosis. J Am Coll Cardiol. 2007; 50(6):540-6. DOI: 10.1016/j.jacc.2006.11.054. View

Caidahl K, Hartford M, Karlsson T, Herlitz J, Pettersson K, de Faire U . IgM-phosphorylcholine autoantibodies and outcome in acute coronary syndromes. Int J Cardiol. 2012; 167(2):464-9. DOI: 10.1016/j.ijcard.2012.01.018. View

Wu R, de Faire U, Lemne C, Witztum J, Frostegard J . Autoantibodies to OxLDL are decreased in individuals with borderline hypertension. Hypertension. 1999; 33(1):53-9. DOI: 10.1161/01.hyp.33.1.53. View

10.

Lopes-Virella M, Virella G, Orchard T, Koskinen S, Evans R, Becker D . Antibodies to oxidized LDL and LDL-containing immune complexes as risk factors for coronary artery disease in diabetes mellitus. Clin Immunol. 1999; 90(2):165-72. DOI: 10.1006/clim.1998.4631. View

11.

Chou M, Hartvigsen K, Hansen L, Fogelstrand L, Shaw P, Boullier A . Oxidation-specific epitopes are important targets of innate immunity. J Intern Med. 2008; 263(5):479-88. DOI: 10.1111/j.1365-2796.2008.01968.x. View

12.

Silverman G, Gronwall C, Vas J, Chen Y . Natural autoantibodies to apoptotic cell membranes regulate fundamental innate immune functions and suppress inflammation. Discov Med. 2009; 8(42):151-6. View

13.

Gronlund H, Hallmans G, Jansson J, Boman K, Wikstrom M, de Faire U . Low levels of IgM antibodies against phosphorylcholine predict development of acute myocardial infarction in a population-based cohort from northern Sweden. Eur J Cardiovasc Prev Rehabil. 2009; 16(3):382-6. DOI: 10.1097/HJR.0b013e32832a05df. View

14.

Hartvigsen K, Chou M, Hansen L, Shaw P, Tsimikas S, Binder C . The role of innate immunity in atherogenesis. J Lipid Res. 2008; 50 Suppl:S388-93. PMC: 2674727. DOI: 10.1194/jlr.R800100-JLR200. View

15.

Boullier A, Friedman P, Harkewicz R, Hartvigsen K, Green S, Almazan F . Phosphocholine as a pattern recognition ligand for CD36. J Lipid Res. 2005; 46(5):969-76. DOI: 10.1194/jlr.M400496-JLR200. View

16.

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(2):269-74. DOI: 10.1161/01.atv.21.2.269. View

17.

Tsimikas S, Palinski W, Witztum J . Circulating autoantibodies to oxidized LDL correlate with arterial accumulation and depletion of oxidized LDL in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2001; 21(1):95-100. DOI: 10.1161/01.atv.21.1.95. View

18.

Chang M, Binder C, Miller Y, Subbanagounder G, Silverman G, Berliner J . Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J Exp Med. 2004; 200(11):1359-70. PMC: 2211955. DOI: 10.1084/jem.20031763. View

19.

Horkko S, Bird D, Miller E, Itabe H, Leitinger N, Subbanagounder G . Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest. 1999; 103(1):117-28. PMC: 407862. DOI: 10.1172/JCI4533. View

20.

Su J, Georgiades A, Wu R, Thulin T, de Faire U, Frostegard J . Antibodies of IgM subclass to phosphorylcholine and oxidized LDL are protective factors for atherosclerosis in patients with hypertension. Atherosclerosis. 2005; 188(1):160-6. DOI: 10.1016/j.atherosclerosis.2005.10.017. View