Serum levels of anti-apolipoprotein A-1 auto-antibodies and myeloperoxidase as predictors of major adverse cardiovascular events after carotid endarterectomy

Nicolas Vuilleumier; Fabrizio Montecucco; Giovanni Spinella; Sabrina Pagano; Maria Bertolotto; Bianca Pane; Aldo Pende; Katia Galan; Pascale Roux-Lombard; Christophe Combescure; Franco Dallegri; François Mach; Domenico Palombo

doi:10.1160/TH12-10-0714

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 109(04): 706-715
DOI: 10.1160/TH12-10-0714

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Serum levels of anti-apolipoprotein A-1 auto-antibodies and myeloperoxidase as predictors of major adverse cardiovascular events after carotid endarterectomy

Nicolas Vuilleumier^*

¹Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva , Switzerland

²Department of Human Protein Science, Geneva Faculty of Medicine, Geneva, Switzerland

,

Fabrizio Montecucco^*

³Division of Cardiology Department of Internal Medicine, University of Geneva, Geneva, Switzerland

⁴First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy

,

Giovanni Spinella

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy

,

Sabrina Pagano

¹Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva , Switzerland

²Department of Human Protein Science, Geneva Faculty of Medicine, Geneva, Switzerland

,

Maria Bertolotto

⁴First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy

,

Bianca Pane

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy

,

Aldo Pende

⁴First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy

,

Katia Galan

³Division of Cardiology Department of Internal Medicine, University of Geneva, Geneva, Switzerland

,

Pascale Roux-Lombard

¹Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva , Switzerland

⁶Division of Immunology and Allergy, Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland

,

Christophe Combescure

⁷CRC & Division of clinical-epidemiology, Department of health and community medicine, University of Geneva & University Hospitals of Geneva, Geneva, Switzerland

,

Franco Dallegri

⁴First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Genoa, Italy

,

François Mach^#

³Division of Cardiology Department of Internal Medicine, University of Geneva, Geneva, Switzerland

,

Domenico Palombo^#

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy

› Author Affiliations

Abstract

Summary

We aimed at challenging the prognostic accuracies of myeloperoxidase (MPO) and antibodies anti-apolipoprotein A-1 (anti-apoA-1 IgG), alone or in combination, for major adverse cardiovascular events (MACE) prediction, one year after carotid endarterectomy (CEA). In this prospective single centre study, 178 patients undergoing elective CEA were included. Serum anti-apoA-1 IgG and MPO were assessed by enzyme-linked immunosorbent assay prior to the surgery. Post-hoc determination of the MPO cut-off was performed by receiver operating characteristics (ROC) analyses. MACE was defined by the occurrence of fatal or non-fatal acute coronary syndromes or stroke during one year follow-up. Prognostic accuracy of anti-apoA-1 IgG was assessed by ROC curve analyses, survival analyses and reclassification statistics. During follow-up, 5% (9/178) of patients presented a MACE, and 29% (52/178) were positive for anti-apoA-1 IgG. Patients with MACE had higher median MPO and anti-apoA-1 IgG levels at admission (p=0.01), but no difference for the 10-year global Framingham risk score (FRS) was observed (p=0.22). ROC analyses indicated that both MPO and anti-apoA-1 IgG were significant predictors of subsequent MACE (area under the curve [AUC]: 0.75, 95% confidence interval [95%CI]: 0.61–0.89, p=0.01; and 0.74, 95%CI: 0.59–90; p=0.01), but combining anti-apoA-1 IgG positivity and MPO>857 ng/ml displayed the best predictive accuracy (AUC: 0.78, 95%CI: 0.65–0.91; p=0.007). It was associated with a poorer MACE-free survival (98.2% vs. 57.1%; p<0.001, LogRank), with a positive likelihood ratio of 13.67, and provided incremental predictive ability over FRS. In conclusion, combining the assessment of anti-apoA-1 IgG and MPO appears as a promising risk stratification tool in patients with severe carotid stenosis.

Keywords

Autoantibodies - myeloperoxidase - atherosclerosis - major adverse cardiovascular events - carotid stenosis

Full Text

References

References
1 Packard Libby RR. Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clin Chem 2008; 54: 24-38.
2 Blasi C. The autoimmune origin of atherosclerosis. Atherosclerosis 2008; 201: 17-32.
3 Roux-Lombard P, Pagano S, Montecucco F. et al. Auto-antibodies as Emergent Prognostic Markers and Possible Mediators of Ischemic Cardiovascular Diseases. Clin Rev Allergy Immunol 2013; 44: 84-89.
4 Dinu AR, Merrill JT, Shen C. et al. Frequency of antibodies to the cholesterol transport protein apolipoprotein A1 in patients with SLE. Lupus 1998; 07: 355-360.
5 Batuca JR, Ames PR, Isenberg DA. et al. Antibodies toward high-density lipoprotein components inhibit paraoxonase activity in patients with systemic lupus erythematosus. Ann NY Acad Sci 2007; 1108: 137-146.
6 Ames PR, Matsuura E, Batuca JR. et al. High-density lipoprotein inversely relates to its specific autoantibody favoring oxidation in thrombotic primary antiphospholipid syndrome. Lupus 2010; 19: 711-716.
7 Vuilleumier N, Bratt J, Alizadeh R. et al. Anti-apoA-1 IgG and oxidized LDL are raised in rheumatoid arthritis (RA): potential associations with cardiovascular disease and RA disease activity. Scand J Rheumatol 2010; 39: 447-453.
8 Vuilleumier N, Bas S, Pagano S. et al. Anti-apolipoprotein A-1 IgG predicts major cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheum 2010; 62: 2640-2650.
9 Vuilleumier N, Rossier MF, Pagano S. et al. Anti-apolipoprotein A-1 IgG as an independent cardiovascular prognostic marker affecting basal heart rate in myocardial infarction. Eur Heart J 2010; 31: 815-823.
10 Keller PF, Pagano S, Roux-Lombard P. et al. Autoantibodies against apolipoprotein A-1 and phosphorylcholine for diagnosis of non-ST-segment elevation myocardial infarction. J Intern Med 2012; 271: 451-462.
11 Montecucco F, Vuilleumier N, Pagano S. et al. Anti-Apolipoprotein A-1 auto-antibodies are active mediators of atherosclerotic plaque vulnerability. Eur Heart J 2011; 32: 412-421.
12 Srivastava R, Yu S, Parks BW. et al. Autoimmune-mediated reduction of high-density lipoproteincholesterol and paraoxonase 1 activity in systemic lupus erythematosus-prone gld mice. Arthritis Rheum 2011; 63: 201-211.
13 Zheng L, Nukuna B, Brennan ML. et al. Apolipoprotein A-I is a selective target for myeloperoxidasecatalysed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest 2004; 114: 529-541.
14 Undurti A, Huang Y, Lupica JA. et al. Modification of high density lipoprotein by myeloperoxidase generates a proinflammatory particle. J Biol Chem 2009; 284: 30825-30835.
15 Chang LT, Chua S, Sheu JJ. et al. Level and prognostic value of serum myeloperoxidase in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ J 2009; 73: 726-731.
16 Mocatta TJ, Pilbrow AP, Cameron VA. et al. Plasma concentrations of myeloperoxidase predict mortality after myocardial infarction. J Am Coll Cardiol 2007; 49: 1993-2000.
17 Nicholls SJ, Tang WH, Brennan D. et al. Risk prediction with serial myeloperoxidase monitoring in patients with acute chest pain. Clin Chem 2011; 57: 1762-1770.
18 North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325: 445-453.
19 D’Agostino Sr RB, Vasan RS, Pencina MJ. et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008; 117: 743-753.
20 DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988; 44: 837-845.
21 Pencina MJ, D’Agostino Sr RB, D’Agostino Jr RB. et al. Evaluating the added predictive ability of a newmarker: from area under The ROC curve to reclassification and beyond. StatMed 2008; 27: 157-172.
22 Exner M, Minar E, Mlekusch W. et al. Myeloperoxidase predicts progression of carotid stenosis in states of low high-density lipoprotein cholesterol. J Am Coll Cardiol 2006; 47: 2212-2218.
23 Nendaz MR, Perrier A. Théorème de Bayes et rapports de vraisemblance. Rev Mal Respir 2004; 21: 394-397.
24 Rossier MF, Pagano S, Python M. et al. Antiapolipoprotein A-1 IgG chronot-ropic effects require nongenomic action of aldosterone on L-type calcium channels. Endocrinology 2012; 153: 1269-1278.
25 Pagano S, Satta N, Werling D. et al. Anti-apolipoprotein A-1 IgG in patients with myocardial infarction promotes inflammation through TLR2/CD14 complex. J Intern Med 2012; 272: 344-357.
26 Shao B, Oda MN, Bergt C. et al. Myeloperoxidase impairs ABCA1-dependent cholesterol efflux through methionine oxidation and site-specific tyrosine chlorination of apolipoprotein A-I. J Biol Chem 2006; 281: 9001-9004.
27 Shih J, Datwyler SA, Hsu SC, Matias MS, Pacenti DP, Lueders C, Mueller C, Danne O, Möckel M. Effect of collection tube type and preanalytical handling on myeloperoxidase concentrations. Clin Chem 2008; 54: 1076-1079.
28 Schindhelm RK, van der Zwan LP, Teerlink T, Scheffer PG. Myeloperoxidase: a useful biomarker for cardiovascular disease risk stratification?. Clin Chem 2009; 55: 1462-1470.
29 Pencina MJ, D’Agostino Sr RB, D’Agostino Jr RB, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008; 27: 157-172.