Skip to main content
SpringerLink
Log in

Low levels of natural IgM antibodies against phosphorylcholine are independently associated with vascular remodeling in patients with coronary artery disease

  • Original Paper
  • Published:
Clinical Research in Cardiology Aims and scope Submit manuscript

Abstract

Low anti-phosphorylcholine (PC) IgM plasma levels have been associated with increased incidence of adverse events in coronary artery disease (CAD). The underlying mechanisms are unclear. We hypothesized that atheroprotection mediated by anti-PC IgM antibodies is associated with reduced vascular remodeling and therefore tested whether anti-PC IgM plasma levels independently predict vascular remodeling. In a prospective cross-sectional study, anti-PC IgM plasma levels were measured in 175 consecutive patients with suspected CAD undergoing cardiac computed tomography angiography. Plaque morphology was thoroughly analyzed. Vascular remodeling was defined by a change in the vessel diameter at the plaque site in comparison to the reference segment proximal to the lesion (reference diameter) of ≥10 %. Mean age of the patients was 64.8 ± 10.7 years, 48.6 % were female. In 98 patients CAD was diagnosed, 57 (58.2 %) of which displayed non-obstructive CAD (stenosis <50 %), whereas 41 (41.8 %) exhibited obstructive CAD (stenosis ≥50 %). In 34 of 98 (34.7 %) CAD patients vascular remodeling was present. Mean anti-PC IgM levels did not differ between patients with and without CAD (70.8 ± 52.7 vs. 69.1 ± 55.1 U/mL). However, anti-PC IgM levels were significantly lower in CAD patients compared to those without vascular remodeling (46.6 ± 31.6 vs. 73.3 ± 58.5 U/mL, P = 0.024). Using multivariate logistic regression, anti-PC IgM plasma levels independently predicted coronary vascular remodeling (HR 0.322, 95 % confidence interval 0.121–0.856, P = 0.023). In conclusion, low anti-PC IgM levels are independently associated with coronary vascular remodeling. These findings may represent the link between in vitro studies demonstrating atheroprotective effects of anti-PC IgM and clinical data demonstrating that low anti-PC IgM levels are associated with adverse outcome in CAD patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Ajeganova S, Ehrnfelt C, Alizadeh R, Rohani M, Jogestrand T, Hafström I, Frostegård J (2011) Longitudinal levels of apolipoproteins and antibodies against phosphorylcholine are independently associated with carotid artery atherosclerosis 5 years after rheumatoid arthritis onset—a prospective cohort study. Rheumatology 50:1785–1793. doi:10.1093/rheumatology/ker204

    Article  CAS  PubMed  Google Scholar 

  2. Andrassy M, Volz HC, Schuessler A, Gitsioudis G, Hofmann N, Laohachewin D, Wienbrandt AR, Kaya Z, Bierhaus A, Giannitsis E, Katus HA, Korosoglou G (2012) HMGB1 is associated with atherosclerotic plaque composition and burden in patients with stable coronary artery disease. PLoS One 7:e52081. doi:10.1371/journal.pone.0052081

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Binder C (2010) Natural IgM antibodies against oxidation-specific epitopes. J Clin Immunol 30:56–60. doi:10.1007/s10875-010-9396-3

    Article  Google Scholar 

  4. Bischoff B, Hein F, Meyer T, Hadamitzky M, Martinoff S, Schomig A, Hausleiter J (2009) Impact of a reduced tube voltage on CT angiography and radiation dose: results of the PROTECTION I study. JACC Cardiovasc Imaging 2:940–946. doi:10.1016/j.jcmg.2009.02.015

    Article  PubMed  Google Scholar 

  5. Caidahl K, Hartford M, Karlsson T, Herlitz J, Pettersson K, de Faire U, Frostegård J (2013) IgM-phosphorylcholine autoantibodies and outcome in acute coronary syndromes. Int J Cardiol 167:464–469. doi:10.1016/j.ijcard.2012.01.018

    Article  PubMed  Google Scholar 

  6. Caligiuri G, Khallou-Laschet J, Vandaele M, Gaston A-T, Delignat S, Mandet C, Kohler HV, Kaveri SV, Nicoletti A (2007) Phosphorylcholine-targeting immunization reduces atherosclerosis. J Am Coll Cardiol 50:540–546

    Article  CAS  PubMed  Google Scholar 

  7. Cho HJ, Shashkin P, Gleissner CA, Dunson D, Jain N, Lee JK, Miller Y, Ley K (2007) Induction of dendritic cell-like phenotype in macrophages during foam cell formation. Physiol Genomics 29:149–160

    Article  CAS  PubMed  Google Scholar 

  8. de Faire U, Frostegård J (2009) Natural antibodies against phosphorylcholine in cardiovascular disease. Ann N Y Acad Sci 1173:292–300. doi:10.1111/j.1749-6632.2009.04748.x

    Article  PubMed  Google Scholar 

  9. de Faire U, Su J, Hua X, Frostegård A, Halldin M, Hellenius M-L, Wikström M, Dahlbom I, Grönlund H, Frostegård J (2010) Low levels of IgM antibodies to phosphorylcholine predict cardiovascular disease in 60-year old men: Effects on uptake of oxidized LDL in macrophages as a potential mechanism. J Autoimmun 34:73–79. doi:10.1016/j.jaut.2009.05.003

    Article  PubMed  Google Scholar 

  10. De Metrio M, Milazzo V, Marenzi G (2012) Serum vitamin D concentration status and its correlation with early biomarkers of remodeling following acute myocardial infarction. Clin Res Cardiol Off J Ger Card Soc 101:771–772. doi:10.1007/s00392-012-0457-x

    Article  Google Scholar 

  11. Faria-Neto JR, Chyu K-Y, Li X, Dimayuga PC, Ferreira C, Yano J, Cercek B, Shah PK (2006) Passive immunization with monoclonal IgM antibodies against phosphorylcholine reduces accelerated vein graft atherosclerosis in apolipoprotein E-null mice. Atherosclerosis 189:83–90

    Article  CAS  PubMed  Google Scholar 

  12. Ferencik M, Schlett CL, Ghoshhajra BB, Kriegel MF, Joshi SB, Maurovich-Horvat P, Rogers IS, Banerji D, Bamberg F, Truong QA, Brady TJ, Nagurney JT, Hoffmann U (2012) A computed tomography-based coronary lesion score to predict acute coronary syndrome among patients with acute chest pain and significant coronary stenosis on coronary computed tomographic angiogram. Am J Cardiol 110:183–189. doi:10.1016/j.amjcard.2012.02.066

    Article  PubMed Central  PubMed  Google Scholar 

  13. Fischer-Rasokat U, Honold J, Seeger FH, Fichtlscherer S, Schachinger V, Dimmeler S, Zeiher AM, Assmus B (2012) Early remodeling processes as predictors of diastolic function 5 years after reperfused acute myocardial infarction and intracoronary progenitor cell application. Clin Res Cardiol Off J Ger Card Soc 101:209–216. doi:10.1007/s00392-011-0382-4

    Article  Google Scholar 

  14. Fiskesund R, Stegmayr B, Hallmans G, Vikström M, Weinehall L, de Faire U, Frostegård J (2010) Low levels of antibodies against phosphorylcholine predict development of stroke in a population-based study from Northern Sweden. Stroke 41:607–612. doi:10.1161/strokeaha.109.558742

    Article  CAS  PubMed  Google Scholar 

  15. Galkina EV, Ley K (2009) Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol 27:165–197. doi:10.1146/annurev.immunol.021908

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ (1987) Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 316:1371–1375

    Article  CAS  PubMed  Google Scholar 

  17. Glass CK, Witztum JL (2001) Atherosclerosis. The road ahead. Cell 104:503–516

    Article  CAS  PubMed  Google Scholar 

  18. Gleissner CA, Leitinger N, Ley K (2007) Effects of native and modified low-density lipoproteins on monocyte recruitment in atherosclerosis. Hypertension 50:276–283. doi:10.1161/HYPERTENSIONAHA.107.089854

    Article  CAS  PubMed  Google Scholar 

  19. Gleissner CA, Sanders JM, Nadler J, Ley K (2008) Upregulation of aldose reductase during foam cell formation as possible link among diabetes, hyperlipidemia, and atherosclerosis. Arterioscler Thromb Vasc Biol 28:1137–1143. doi:10.1161/ATVBAHA.107.158295

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Grönlund H, Hallmans G, Jansson JH, Boman K, Wikström M, de Faire U, Frostegård J (2009) 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 16:382–386. doi:10.1097/HJR.0b013e32832a05df

    Article  PubMed  Google Scholar 

  21. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ (2004) Implications of recent clinical trials for the National cholesterol education program adult treatment panel III guidelines. Circulation 110:227–239

    Article  PubMed  Google Scholar 

  22. Hadamitzky M, Distler R, Meyer T, Hein F, Kastrati A, Martinoff S, Schömig A, Hausleiter J (2011) Prognostic Value of Coronary Computed Tomographic Angiography in Comparison With Calcium Scoring and Clinical Risk Scores. Circ Cardiovasc Imaging 4:16–23. doi:10.1161/circimaging.110.955351

    Article  PubMed  Google Scholar 

  23. Hernando L, Corros C, Gonzalo N, Hernandez-Antolin R, Banuelos C, Jimenez-Quevedo P, Bernardo E, Fernandez-Ortiz A, Escaned J, Macaya C, Alfonso F (2013) Morphological characteristics of culprit coronary lesions according to clinical presentation: insights from a multimodality imaging approach. Int J Cardiovasc Imaging 29:13–21. doi:10.1007/s10554-012-0043-3

    Article  PubMed  Google Scholar 

  24. Hoefer IE, Sels JW, Jukema JW, Bergheanu S, Biessen E, McClellan E, Daemen M, Doevendans P, de Groot P, Hillaert M, Horsman S, Ilhan M, Kuiper J, Pijls N, Redekop K, van der Spek P, Stubbs A, van de Veer E, Waltenberger J, van Zonneveld AJ, Pasterkamp G (2013) Circulating cells as predictors of secondary manifestations of cardiovascular disease: design of the CIRCULATING CELLS study. Clin Res Cardiol Off J Ger Card Soc 102:847–856. doi:10.1007/s00392-013-0607-9

    Article  CAS  Google Scholar 

  25. Hoffmann U, Moselewski F, Nieman K, Jang I-K, Ferencik M, Rahman AM, Cury RC, Abbara S, Joneidi-Jafari H, Achenbach S, Brady TJ (2006) Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by multidetector computed tomography. J Am Coll Cardiol 47:1655–1662

    Article  PubMed  Google Scholar 

  26. Kearney JF (2000) Immune recognition of OxLDL in atherosclerosis. J Clin Investig 105:1683–1685. doi:10.1172/JCI10426

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Khalili H, Talasaz AH, Salarifar M (2012) Serum vitamin D concentration status and its correlation with early biomarkers of remodeling following acute myocardial infarction. Clin Res Cardiol Off J Ger Card Soc 101:321–327. doi:10.1007/s00392-011-0394-0

    Article  CAS  Google Scholar 

  28. Korosoglou G, Lehrke S, Mueller D, Hosch W, Kauczor HU, Humpert PM, Giannitsis E, Katus HA (2011) Determinants of troponin release in patients with stable coronary artery disease: insights from CT angiography characteristics of atherosclerotic plaque. Heart 97:823–831. doi:10.1136/hrt.2010.193201

    Article  PubMed  Google Scholar 

  29. Korosoglou G, Mueller D, Lehrke S, Steen H, Hosch W, Heye T, Kauczor H-U, Giannitsis E, Katus H (2010) Quantitative assessment of stenosis severity and atherosclerotic plaque composition using 256-slice computed tomography. Eur Radiol 20:1841–1850. doi:10.1007/s00330-010-1753-3

    Article  PubMed  Google Scholar 

  30. Kroner ES, van Velzen JE, Boogers MJ, Siebelink HM, Schalij MJ, Kroft LJ, de Roos A, van der Wall EE, Jukema JW, Reiber JH, Schuijf JD, Bax JJ (2011) Positive remodeling on coronary computed tomography as a marker for plaque vulnerability on virtual histology intravascular ultrasound. Am J Cardiol 107:1725–1729. doi:10.1016/j.amjcard.2011.02.337

    Article  PubMed  Google Scholar 

  31. Lewis MJ, Malik TH, Ehrenstein MR, Boyle JJ, Botto M, Haskard DO (2009) Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 120:417–426. doi:10.1161/circulationaha.109.868158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Lok DJ, Lok SI, Bruggink-Andre de la Porte PW, Badings E, Lipsic E, van Wijngaarden J, de Boer RA, van Veldhuisen DJ, van der Meer P (2013) Galectin-3 is an independent marker for ventricular remodeling and mortality in patients with chronic heart failure. Clin Res Cardiol Off J Ger Card Soc 102:103–110. doi:10.1007/s00392-012-0500-y

    Article  CAS  Google Scholar 

  33. Motoyama S, Kondo T, Sarai M, Sugiura A, Harigaya H, Sato T, Inoue K, Okumura M, Ishii J, Anno H, Virmani R, Ozaki Y, Hishida H, Narula J (2007) Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol 50:319–326

    Article  PubMed  Google Scholar 

  34. Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, Naruse H, Ishii J, Hishida H, Wong ND, Virmani R, Kondo T, Ozaki Y, Narula J (2009) Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 54:49–57. doi:10.1016/j.jacc.2009.02.068

    Article  PubMed  Google Scholar 

  35. Palinski W, Hörkkö S, Miller E, Steinbrecher UP, Powell HC, Curtiss LK, Witztum JL (1996) Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma. J Clin Investig 98:800–814. doi:10.1172/JCI118853

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH (1997) Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973–979. doi:10.1056/NEJM199704033361401

    Article  CAS  PubMed  Google Scholar 

  37. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J, Committee obotAHAS, Stroke Statistics Subcommittee, Disease ObotAHAH, Stroke Statistics Writing Group (2011) Heart disease and stroke statistics—2011 Update: a report from the American Heart Association. Circulation 123:e18–209. doi:10.1161/CIR.0b013e3182009701

    Article  PubMed  Google Scholar 

  38. Shashkin P, Dragulev B, Ley K (2005) Macrophage differentiation to foam cells. Curr Pharm Des 11:3061–3072

    Article  CAS  PubMed  Google Scholar 

  39. Shmilovich H, Cheng VY, Tamarappoo BK, Dey D, Nakazato R, Gransar H, Thomson LE, Hayes SW, Friedman JD, Germano G, Slomka PJ, Berman DS (2011) Vulnerable plaque features on coronary CT angiography as markers of inducible regional myocardial hypoperfusion from severe coronary artery stenoses. Atherosclerosis 219:588–595. doi:10.1016/j.atherosclerosis.2011.07.128

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Sinning C, Kieback A, Wild PS, Schnabel RB, Ojeda F, Appelbaum S, Zeller T, Lubos E, Schwedhelm E, Lackner KJ, Debus ES, Munzel T, Blankenberg S, Espinola-Klein C (2014) Association of multiple biomarkers and classical risk factors with early carotid atherosclerosis: results from the Gutenberg Health Study. Clin Res Cardiol Off J Ger Card Soc 103:477–485. doi:10.1007/s00392-014-0674-6

    Article  CAS  Google Scholar 

  41. Sjöberg BG, Su J, Dahlbom I, Grönlund H, Wikström M, Hedblad B, Berglund G, de Faire U, Frostegård J (2009) Low levels of IgM antibodies against phosphorylcholine—a potential risk marker for ischemic stroke in men. Atherosclerosis 203:528–532. doi:10.1016/j.atherosclerosis.2008.07.009

    Article  PubMed  Google Scholar 

  42. Sobel M, Moreno KI, Yagi M, Kohler TR, Tang GL, Clowes AW, Zhou X-HA, Eugenio E (2013) Low levels of a natural IgM antibody are associated with vein graft stenosis and failure. J Vasc Surg 58:997–1005. doi:10.1016/j.jvs.2013.04.042

    Article  PubMed Central  PubMed  Google Scholar 

  43. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL (1989) Beyond Cholesterol. N Engl J Med 320:915–924. doi:10.1056/NEJM198904063201407

    Article  CAS  PubMed  Google Scholar 

  44. Su J, Georgiades A, Wu R, Thulin T, de Faire U, Frostegård J (2006) Antibodies of IgM subclass to phosphorylcholine and oxidized LDL are protective factors for atherosclerosis in patients with hypertension. Atherosclerosis 188:160–166

    Article  CAS  PubMed  Google Scholar 

  45. Virmani R, Burke AP, Farb A, Kolodgie FD (2002) Pathology of the unstable plaque. Prog Cardiovasc Dis 44:349–356

    Article  PubMed  Google Scholar 

  46. Whelton PK (1994) Epidemiology of hypertension. Lancet 344:101–106. doi:10.1016/S0140-6736(94)91285-8

Download references

Acknowledgments

We thank Nadine Wambsganss for excellent technical assistance.

Conflict of interest

Göran Conradson works for Athera.

Author information

Authors and Affiliations

  1. Department of Cardiology, University Hospital, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Christian A. Gleissner, Christian Erbel, Julia Haeussler, Mohammadreza Akhavanpoor, Gabriele Domschke, Fabian Linden, Andreas O. Doesch, Sebastian J. Buss, Nina P. Hofmann, Gitsios Gitsioudis, Hugo A. Katus & Grigorios Korosoglou

  2. Athera Biotechnologies, Fogdevreten 2A, 171 65, Solna, Sweden

    Göran Conradson

  3. DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany

    Hugo A. Katus

Authors
  1. Christian A. Gleissner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Erbel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julia Haeussler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammadreza Akhavanpoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gabriele Domschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fabian Linden
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Andreas O. Doesch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Göran Conradson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sebastian J. Buss
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nina P. Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gitsios Gitsioudis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hugo A. Katus
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Grigorios Korosoglou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Christian A. Gleissner or Grigorios Korosoglou.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 111 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gleissner, C.A., Erbel, C., Haeussler, J. et al. Low levels of natural IgM antibodies against phosphorylcholine are independently associated with vascular remodeling in patients with coronary artery disease. Clin Res Cardiol 104, 13–22 (2015). https://doi.org/10.1007/s00392-014-0750-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00392-014-0750-y

Keywords

Search

Navigation