Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events
2006; Elsevier BV; Volume: 48; Issue: 2 Linguagem: Inglês
10.1194/jlr.m600361-jlr200
ISSN1539-7262
AutoresSotirios Tsimikas, Emmanouil S. Brilakis, Ryan J. Lennon, Elizabeth R. Miller, Joseph L. Witztum, Joseph P. McConnell, Kenneth S. Kornman, Peter B. Berger,
Tópico(s)Adipokines, Inflammation, and Metabolic Diseases
ResumoThe relationship between autoantibodies to oxidized low density lipoprotein (OxLDL) and coronary artery disease (CAD) remains controversial. IgM and IgG OxLDL autoantibodies to malondialdehyde (MDA)-modified LDL, copper oxidized low density lipoprotein (CuOxLDL), and oxidized cholesterol linoleate (OxCL), as well as apolipoprotein B-100 immune complexes (apoB-ICs), were measured in 504 patients undergoing clinically indicated coronary angiography. Patients were followed for cardiovascular events for a median of 4 years. In univariate analysis, IgM OxLDL autoantibodies and IgM apoB-ICs were inversely associated with the presence of angiographically determined CAD, whereas IgG OxLDL autoantibodies and IgG apoB-ICs were positively associated. In logistic regression analysis, compared with the first quartile, patients in the fourth quartile of IgM OxLDL autoantibodies and apoB-ICs showed a lower probability of angiographically determined CAD (>50% diameter stenosis). Odds ratios and (95% confidence intervals) were as follows: MDA-LDL, 0.51 (0.32–0.82; P = 0.005); CuOxLDL, 0.63 (0.39–1.01; P = 0.05); OxCL, 0.63 (0.39–1.01; P = 0.05); and apoB-IC, 0.55 (0.34–0.88; P = 0.013). These relationships were accentuated in the setting of hypercholesterolemia, with the highest IgM levels showing the lowest risk of CAD for the same level of hypercholesterolemia. Multivariable analysis revealed that neither IgM or IgG OxLDL autoantibodies nor apoB-ICs were independently associated with angiographically determined CAD or cardiovascular events. In conclusion, IgG and IgM OxLDL biomarkers have divergent associations with CAD in univariate analysis but are not independent predictors of CAD or clinical events. The relationship between autoantibodies to oxidized low density lipoprotein (OxLDL) and coronary artery disease (CAD) remains controversial. IgM and IgG OxLDL autoantibodies to malondialdehyde (MDA)-modified LDL, copper oxidized low density lipoprotein (CuOxLDL), and oxidized cholesterol linoleate (OxCL), as well as apolipoprotein B-100 immune complexes (apoB-ICs), were measured in 504 patients undergoing clinically indicated coronary angiography. Patients were followed for cardiovascular events for a median of 4 years. In univariate analysis, IgM OxLDL autoantibodies and IgM apoB-ICs were inversely associated with the presence of angiographically determined CAD, whereas IgG OxLDL autoantibodies and IgG apoB-ICs were positively associated. In logistic regression analysis, compared with the first quartile, patients in the fourth quartile of IgM OxLDL autoantibodies and apoB-ICs showed a lower probability of angiographically determined CAD (>50% diameter stenosis). Odds ratios and (95% confidence intervals) were as follows: MDA-LDL, 0.51 (0.32–0.82; P = 0.005); CuOxLDL, 0.63 (0.39–1.01; P = 0.05); OxCL, 0.63 (0.39–1.01; P = 0.05); and apoB-IC, 0.55 (0.34–0.88; P = 0.013). These relationships were accentuated in the setting of hypercholesterolemia, with the highest IgM levels showing the lowest risk of CAD for the same level of hypercholesterolemia. Multivariable analysis revealed that neither IgM or IgG OxLDL autoantibodies nor apoB-ICs were independently associated with angiographically determined CAD or cardiovascular events. In conclusion, IgG and IgM OxLDL biomarkers have divergent associations with CAD in univariate analysis but are not independent predictors of CAD or clinical events. Oxidative modification of LDL is postulated to be one of the earliest events in the initiation of atherogenesis (1Tsimikas S. Glass C. Steinberg D. Witztum J.L. Chien K.R. Lipoproteins, lipoprotein oxidation and atherogenesis. In Molecular Basis of Cardiovascular Disease. A Companion to Braunwald's Heart Disease. W. B. Saunders Company, Philadelphia, PA2004: 385-413Google Scholar, 2Navab M. Ananthramaiah G.M. Reddy S.T. Van Lenten B.J. Ansell B.J. Fonarow G.C. Vahabzadeh K. Hama S. Hough G. Kamranpour N. Thematic review series. The pathogenesis of atherosclerosis. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J. Lipid Res. 2004; 45 (et al.): 993-1007Google Scholar). Oxidized low density lipoprotein (OxLDL) is present in aortas of human fetuses of hypercholesterolemic mothers (3Palinski W. Napoli C. The fetal origins of atherosclerosis: maternal hypercholesterolemia and cholesterol-lowering or antioxidant treatment during pregnancy influence in utero programming and postnatal susceptibility to atherogenesis. FASEB J. 2002; 16: 1348-1360Google Scholar) even before macrophage foam cell formation, in progressing atherosclerotic lesions of animal models (4Torzewski M. Shaw P.X. Han K.R. Shortal B. Lackner K.J. Witztum J.L. Palinski W. Tsimikas S. Reduced in vivo aortic uptake of radiolabeled oxidation-specific antibodies reflects changes in plaque composition consistent with plaque stabilization. Arterioscler. Thromb. Vasc. Biol. 2004; 24: 2307-2312Google Scholar), and within human vulnerable plaques (5Ehara S. Ueda M. Naruko T. Haze K. Itoh A. Otsuka M. Komatsu R. Matsuo T. Itabe H. Takano T. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation. 2001; 103 (et al.): 1955-1960Google Scholar, 6Nishi K. Itabe H. Uno M. Kitazato K.T. Horiguchi H. Shinno K. Nagahiro S. Oxidized LDL in carotid plaques and plasma associates with plaque instability. Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1649-1654Crossref PubMed Scopus (341) Google Scholar). Conceptually, OxLDL is not a single defined chemical entity but represents a variety of modifications of both the lipid and protein components of LDL after the initiation of lipid peroxidation. The resulting oxidized lipid and oxidized lipid-protein adducts are not only proinflammatory (7Berliner J.A. Subbanagounder G. Leitinger N. Watson A.D. Vora D. Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc. Med. 2001; 11: 142-147Crossref PubMed Scopus (152) Google Scholar) but also are recognized as foreign by the immune system and therefore are highly immunogenic (8Binder C.J. Shaw P.X. Chang M.K. Boullier A. Hartvigsen K. Horkko S. Miller Y.I. Woelkers D.A. Corr M. Witztum J.L. The role of natural antibodies in atherogenesis. J. Lipid Res. 2005; 46: 1353-1363Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). Although autoantibodies to OxLDL epitopes correlate well with atherosclerosis in animal models (9Palinski W. Tangirala R.K. Miller E. Young S.G. Witztum J.L. Increased autoantibody titers against epitopes of oxidized LDL in LDL receptor-deficient mice with increased atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1569-1576Google Scholar, 10Tsimikas S. Palinski W. Witztum J.L. 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: 95-100Google Scholar, 11Cyrus T. Praticó D. Zhao L. Witztum J.L. Rader D.J. Rokach J. FitzGerald G.A. Funk C.D. Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein E-deficient mice. Circulation. 2001; 103: 2277-2282Google Scholar), an ongoing controversy exists regarding whether OxLDL autoantibodies are markers of cardiovascular disease and/or have a causative role in either the progression of or protection against the development of atherosclerosis in humans (12Shoenfeld Y. Wu R. Dearing L.D. Matsuura E. Are anti-oxidized low-density lipoprotein antibodies pathogenic or protective? Circulation. 2004; 110: 2552-2558Google Scholar). Much of this controversy is fueled by many factors, including measurement of different OxLDL epitopes, underpowered studies and incomplete assessment of different OxLDL autoantibodies, differences among patient cohorts, comparison of different vascular areas, and lack of standardization of antigens and assays. In this large cross-sectional study of 504 patients, we evaluated a comprehensive panel of both IgG and IgM OxLDL autoantibodies to a wide array of OxLDL epitopes, including malondialdehyde (MDA)-LDL, copper oxidized low density lipoprotein (Cu-OxLDL), and oxidized cholesterol linoleate (OxCL), as well as apolipoprotein B-100 immune complexes (apoB-ICs), and their relationship to angiographically determined coronary artery disease (CAD). The patient cohort included 504 patients (>97% Caucasian), age 26–75 years, undergoing clinically indicated coronary angiography at the Mayo Clinic from June 1998 to January 1999 and has been described previously (13Tsimikas S. Brilakis E.S. Miller E.R. McConnell J.P. Lennon R.J. Kornman K.S. Witztum J.L. Berger P.B. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 2005; 353: 46-57Crossref PubMed Scopus (590) Google Scholar). The initial study was designed to assess genetic polymorphisms in cardiovascular risk assessment. Therefore, patients with well-established risk factors or risk equivalents, such as diabetes mellitus and smoking history of >50 pack years, as well as prior revascularization procedures, were excluded. This study was approved by the Mayo Clinic Institutional Review Board, and all subjects provided written informed consent. Aliquots of blood in EDTA-containing tubes were collected before coronary angiography and frozen at −70°C until analyses were performed. Four hundred sixty-six patients (92.5%) were contacted by a follow-up questionnaire or by telephone in September 2002 [median follow-up of 4.0 years (interquartile range, 3.9–4.2 years)]. The remaining 38 patients either refused to participate in the follow-up (n = 18) or could not be contacted (n = 20). The medical records of the patients who had an event were obtained and reviewed to ascertain the type of event or the cause of death. The follow-up events of these patients were described previously (14Brilakis E.S. McConnell J.P. Lennon R.J. Elesber A.A. Meyer J.G. Berger P.B. Association of lipoprotein-associated phospholipase A2 levels with coronary artery disease risk factors, angiographic coronary artery disease, and major adverse events at follow-up. Eur. Heart J. 2005; 26: 137-144Google Scholar) and consisted of 20 deaths (6 cardiac), 14 myocardial infarctions, 26 coronary revascularizations (15 percutaneous intervention only, 9 coronary artery bypass surgery only, and 2 with both), and 10 strokes. Coronary angiograms were analyzed as described previously (13Tsimikas S. Brilakis E.S. Miller E.R. McConnell J.P. Lennon R.J. Kornman K.S. Witztum J.L. Berger P.B. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 2005; 353: 46-57Crossref PubMed Scopus (590) Google Scholar) and divided into those revealing normal coronary arteries [smooth arteries with either no stenosis or with diameter stenosis (DS) ⩽ 10%], mild disease (DS 10–50% in one or more coronary arteries), one-vessel (⩾50% DS in a single coronary artery or its major branches), two-vessel, and three-vessel disease. Total cholesterol, HDL cholesterol (HDL-C), and triglycerides were determined on a COBAS MIRA system. LDL cholesterol (LDL-C) was estimated from the Friedewald formula. High-sensitivity C-reactive protein (hsCRP) was measured as described previously (15McConnell J.P. Branum E.L. Ballman K.V. Lagerstedt S.A. Katzmann J.A. Jaffe A.S. Gender differences in C-reactive protein concentrations—confirmation with two sensitive methods. Clin. Chem. Lab. Med. 2002; 40: 56-59Google Scholar). Hypercholesterolemia was defined as total cholesterol ⩾ 250 mg/dl or LDL ⩾ 150 mg/dl, or ongoing treatment with lipid-lowering agents in patients for whom pretreatment lipid values could not be determined. Fibrinogen was measured by an immunoturbidimetric method using reagents from Kamiya Biomedical Co. on a Roche COBAS MIRA chemistry analyzer (absorbance, 700 nm). Lipoprotein-associated lipoprotein lipase A2 mass was measured with a commercial kit (Diadexus, Inc., South San Francisco, CA). Total plasma homocysteine was measured after reduction of the disulfide bonds by high-pressure liquid chromatography. Chemiluminescence ELISAs were used to measure IgG and IgM autoantibodies to MDA-LDL, Cu-OxLDL, OxCL, and apoB-IC as described previously (16Tsimikas S. Bergmark C. Beyer R.W. Patel R. Pattison J. Miller E. Juliano J. Witztum J.L. Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes. J. Am. Coll. Cardiol. 2003; 41: 360-370Google Scholar, 17Tsimikas S. Witztum J.L. Miller E.R. Sasiela W.J. Szarek M. Olsson A.G. Schwartz G.G. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial. Circulation. 2004; 110: 1406-1412Google Scholar). OxLDL-E06, measuring the oxidized phospholipid content on apoB particles, was measured as described previously (13Tsimikas S. Brilakis E.S. Miller E.R. McConnell J.P. Lennon R.J. Kornman K.S. Witztum J.L. Berger P.B. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 2005; 353: 46-57Crossref PubMed Scopus (590) Google Scholar, 17Tsimikas S. Witztum J.L. Miller E.R. Sasiela W.J. Szarek M. Olsson A.G. Schwartz G.G. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial. Circulation. 2004; 110: 1406-1412Google Scholar). Continuous variables with symmetric distributions are summarized as means ± SD and are compared by Student's t-test. Those with skewed distributions are summarized as medians and interquartile ranges and compared with the Mann-Whitney rank sum test. Discrete covariates are summarized as frequencies and group percentages and are compared using Pearson's Chi-square test. Spearman's correlation coefficient was used to measure the linear association between the rank values of OxLDL autoantibodies and apoB-IC and clinical and laboratory variables. The association between OxLDL autoantibodies and CAD was assessed using logistic regression analysis. The laboratory values were collapsed into quartiles and assigned a value from 1 to 4. These values were then used in the logistic regression models. There was no evidence of a nonlinear trend over quartiles in any model. Models with OxLDL autoantibodies and hypercholesterolemia assume additivity between the two variables; there was no evidence of an interaction in any such model. Multiple logistic regression was used to estimate the partial associations between OxLDL autoantibodies and CAD adjusting for age, sex, smoking history, hypertension, LDL-C, HDL-C, log(triglycerides), and log(hsCRP). The baseline clinical characteristics, indications for coronary angiography, and lipid parameters of the study cohort have been described previously (13Tsimikas S. Brilakis E.S. Miller E.R. McConnell J.P. Lennon R.J. Kornman K.S. Witztum J.L. Berger P.B. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 2005; 353: 46-57Crossref PubMed Scopus (590) Google Scholar). For the purposes of this analysis, patients were dichotomized as those with 50% DS, and baseline characteristics are shown in Table 1 . There were 233 patients with nonobstructive CAD ( 50% DS). Of these, 122 patients had angiographically normal coronary arteries, 111 had mild CAD (10–50% DS), and 85, 80, and 106 had one-, two-, and three-vessel CAD, respectively (⩾50% DS). As expected, patients with obstructive CAD were more likely to be older and male and had a higher frequency of hypertension and dyslipidemia (Table 1). Indications for angiography reflected typical clinical indications as described previously (13Tsimikas S. Brilakis E.S. Miller E.R. McConnell J.P. Lennon R.J. Kornman K.S. Witztum J.L. Berger P.B. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 2005; 353: 46-57Crossref PubMed Scopus (590) Google Scholar).TABLE 1Baseline clinical and laboratory characteristics of patients with no or mild angiographically determined CAD and those with obstructive CAD (>50% DS)VariableNo/Mild CAD (n = 233)CAD (n = 271)PAge, years57.6 ± 11.362.2 ± 10.2<0.001Female, n (%)131 (56%)62 (23%)<0.001Hypertension, n (%)89 (38%)143 (53%)0.001Current smoker, n (%)17 (7%)23 (8%)0.62Prior myocardial infarction, n (%)9 (4%)68 (25%)<0.001Congestive heart failure, n (%)44 (19%)15 (6%)<0.001Family CAD history, n (%)51 (22%)77 (28%)0.09Hypercholesterolemia, n (%)96 (41%)190 (70%)<0.001Treated with statin, n (%)35 (15%)107 (39%)<0.001Body mass index29.0 ± 6.329.6 ± 4.80.24Creatinine, median (Q1, Q3)1.1 (1.0, 1.2)1.2 (1.0, 1.3)<0.001Total cholesterol, mg/dl203.8 ± 41.9210.5 ± 47.10.10Triglycerides, median (Q1, Q3)150.0 (109.0, 202.0)157.0 (114.0, 213.0)0.13HDL cholesterol, mg/dl52.4 ± 16.344.0 ± 11.5<0.001LDL cholesterol, mg/dl117.7 ± 34.5130.2 ± 37.4 50% DS versus <50% DS and also as no CAD (angiographically normal arteries) versus any CAD (Table 2 ). In both analyses, IgM autoantibody levels to MDA-LDL, Cu-OxLDL, and OxCL as well as IgM apoB-IC were significantly lower in patients with obstructive versus nonobstructive CAD as well as any CAD versus no CAD (Table 2). In contrast, IgG autoantibody levels to Cu-OxLDL were higher in patients with obstructive versus nonobstructive CAD and any CAD versus no CAD (Table 2). The other IgG measures were not statistically significantly different among groups. Analyzing the data according to the extent of disease (no disease, mild disease, and one-, two-, or three-vessel disease) showed similar results (Table 3 ).TABLE 2Association between OxLDL autoantibodies and apoB-IC levels and the presence of CADParameterNo/Mild CAD (n = 233)Obstructive CAD (n = 271)PNo CAD (n = 122)Any CAD (n = 382)PIgMMDA-LDL16.1 (10.8, 23.0)13.9 (9.3, 19.9)0.01616.7 (11.7, 23.5)14.6 (9.6, 20.3)0.010Cu-OxLDL5.2 (3.0, 7.6)4.3 (2.8, 6.9)0.0375.5 (3.3, 7.8)4.5 (2.8, 7.2)0.019OxCL2.7 (1.7, 4.5)2.2 (1.3, 3.7)0.0223.0 (1.8, 4.6)2.3 (1.4, 3.9)0.007ApoB-IC6.7 (4.0, 9.8)5.5 (3.5, 8.5)0.0067.2 (4.3, 11.1)5.7 (3.7, 8.5) 50% DS. Open table in a new tab TABLE 3Association between OxLDL autoantibodies and apoB-IC levels and the extent of CADParameterNone (n = 122)Mild (n = 111)One Vessel (n = 85)Two Vessel (n = 80)Three Vessel (n = 106)PIgMMDA-LDL16.7 (11.7, 23.5)15.4 (9.9, 21.2)12.9 (8.7, 19.9)14.4 (11.0, 20.0)14.1 (9.1, 19.6)0.027Cu-OxLDL5.5 (3.3, 7.8)4.8 (2.8, 7.3)3.7 (2.7, 6.9)4.5 (3.0, 7.1)4.5 (2.8, 6.8)0.030OxCL3.0 (1.8, 4.6)2.4 (1.6, 4.0)2.5 (1.5, 3.6)2.4 (1.5, 4.1)2.1 (1.2, 4.0)0.028ApoB-IC7.2 (4.3, 11.1)6.0 (4.0, 8.4)5.2 (3.2, 8.5)5.5 (3.7, 8.2)5.4 (3.4, 8.5)0.017IgGMDA-LDL4.4 (3.3, 6.0)5.1 (3.4, 7.2)4.4 (3.3, 5.9)4.4 (3.2, 7.1)4.8 (3.7, 7.0)0.18Cu-OxLDL2.4 (1.7, 3.6)2.7 (1.9, 4.2)2.8 (1.9, 3.8)2.6 (2.0, 3.8)3.1 (2.2, 4.5)0.010OxCL0.8 (0.6, 1.1)0.7 (0.6, 1.1)0.7 (0.6, 1.2)0.8 (0.6, 1.2)0.8 (0.6, 1.1)0.28ApoB-IC5.0 (3.6, 6.9)5.1 (3.9, 6.8)5.2 (3.7, 7.0)5.1 (3.8, 7.1)5.7 (4.2, 7.3)0.027All OxLDL marker values are in relative light units × 103. Open table in a new tab ApoB-IC, apolipoprotein B-100 immune complex; Cu-OxLDL, copper oxidized low density lipoprotein; MDA, malondialdehyde; OxCL, oxidized cholesterol linoleate; OxLDL, oxidized low density lipoprotein. All OxLDL marker values are median and (interquartile range) and expressed as relative light units × 103. Obstructive CAD is defined as >50% DS. All OxLDL marker values are in relative light units × 103. The association between OxLDL measures and obstructive CAD was also assessed using logistic regression analysis. Compared with the lowest quartile, the highest quartiles of all three types of IgM OxLDL autoantibodies and IgM apoB-ICs were associated with significantly or nearly significantly decreased odds ratio (OR) for obstructive CAD (Table 4 ), ranging in OR from 0.51 to 0.63. In contrast, no such relationships were noted with IgG OxLDL autoantibodies and apoB-ICs, except for a trend for IgG Cu-OxLDL autoantibodies (OR, 1.54; P = 0.07).TABLE 4Odds ratios and (95% confidence intervals) for obstructive CAD (>50% DS) according to quartiles of IgM and IgG OxLDL markersQuartilePatient GroupIIIIIIIVP for TrendIgMMDA-LDL1.000.80 (0.68, 0.94)0.64 (0.46, 0.87)0.51 (0.32, 0.82)0.005Cu-OxLDL1.000.86 (0.73, 1.00)0.73 (0.53, 1.01)0.63 (0.39, 1.01)0.05OxCL1.000.86 (0.73, 1.00)0.73 (0.54, 1.01)0.63 (0.39, 1.01)0.05ApoB-IC1.000.82 (0.70, 0.96)0.67 (0.49, 0.92)0.55 (0.34, 0.88)0.013IgGMDA-LDL1.000.99 (0.84, 1.16)0.97 (0.71, 1.33)0.96 (0.60, 1.54)0.87Cu-OxLDL1.001.16 (0.99, 1.35)1.34 (0.97, 1.83)1.54 (0.96, 2.48)0.07OxCL1.001.04 (0.89, 1.21)1.08 (0.79, 1.48)1.12 (0.70, 1.79)0.64ApoB-IC1.001.13 (0.96, 1.32)1.27 (0.93, 1.74)1.43 (0.89, 2.29)0.14Cutoff values (relative light units) for each quartile are as follows: IgM MDA-LDL (I, 21,270), IgM Cu-OxLDL (I, 7,331), IgM OxCL (I, 4,062), IgM apoB-IC (I, 9,003); IgG MDA-LDL (I, 6,662), IgG Cu-OxLDL (I, 4,047), IgM OxCL (I, 1,135), IgM apoB-IC (I, 6,991). Open table in a new tab Cutoff values (relative light units) for each quartile are as follows: IgM MDA-LDL (I, 21,270), IgM Cu-OxLDL (I, 7,331), IgM OxCL (I, 4,062), IgM apoB-IC (I, 9,003); IgG MDA-LDL (I, 6,662), IgG Cu-OxLDL (I, 4,047), IgM OxCL (I, 1,135), IgM apoB-IC (I, 6,991). These relationships were further evaluated by determining ORs for obstructive CAD in patients with and without hypercholesterolemia using the lowest quartiles of OxLDL markers without hypercholesterolemia as the reference point. In the absence of hypercholesterolemia, the OR for obstructive CAD decreased progressively with increasing levels of IgM MDA-LDL autoantibodies and IgM apoB-IC (Fig. 1A ). In the presence of hypercholesterolemia, quartile 1 of all IgM autoantibodies and apoB-ICs had an OR of ∼3.3 for CAD, consistent with a strong association between hypercholesterolemia and obstructive CAD. However, the OR decreased progressively with increasing levels of IgM autoantibodies and apoB-ICs. In contrast, the OR for obstructive CAD tended to increase progressively with increasing levels of IgG OxLDL autoantibody and IgG apoB-ICs, particularly Cu-OxLDL (Fig. 1B).Fig. 1.Odds ratio (OR) for the presence of >50% diameter stenosis (DS) for IgM (A) and IgG (B) autoantibodies to oxidized low density lipoprotein (OxLDL) and apolipoprotein B-100 immune complexes (apoB-ICs) in the presence or absence of hypercholesterolemia. Cu-OxLDL, copper oxidized low density lipoprotein; MDA, malondialdehyde; OxCL, oxidized cholesterol linoleate.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In general, IgM autoantibodies and IgM apoB-ICs were modestly inversely correlated with age, serum creatinine, and homocysteine but positively associated with HDL-C (Table 5 ). No correlations were noted between hsCRP and any IgM and IgG OxLDL autoantibodies, except for a weak inverse correlation with OxCL IgG (R = −0.09, P = 0.04). Weak but statistically significant correlations were noted between OxLDL-E06 and IgG MDA-LDL (R = 0.10, P = 0.021), IgG apoB-IC (R = 0.12, P = 0.009), IgM apoB-IC (R = 0.10, P = 0.026), IgG Cu-OxLDL (R = 0.12, P = 0.008), and IgM Cu-OxLDL (R = 0.09, P = 0.041). There were also no statistically significant correlations between any OxLDL autoantibodies and apoB-ICs with total cholesterol, triglycerides, fibrinogen, or lipoprotein-associated lipoprotein lipase A2.TABLE 5Spearman correlation rank coefficients between OxLDL autoantibodies and apoB-ICs and clinical and laboratory variablesParameterAgeCreatinineLDL CholesterolHDL CholesterolHomocysteineC-Reactive ProteinIgMMDA-LDL−0.13 (0.003)−0.14 (0.002)−0.02 (0.72)0.10 (0.03)−0.10 (0.03)0.08 (0.09)Cu-OxLDL−0.19 (<0.001)−0.11 (0.01)−0.08 (0.06)0.11 (0.01)−0.11 (0.010)0.02 (0.69)OxCL−0.17 (<0.001)−0.13 (0.003)−0.03 (0.56)0.11 (0.02)−0.14 (0.002)0.02 (0.58)ApoB-IC−0.27 (<0.001)−0.12 (0.009)−0.09 (0.04)0.11 (0.01)−0.14 (0.002)−0.04 (0.41)IgGMDA-LDL0.16 (<0.001)0.03 (0.46)−0.01 (0.86)0.003 (0.94)0.08(0.06)0.004 (0.92)Cu-OxLDL0.13 (0.004)0.07 (0.14)0.02 (0.66)−0.07 (0.11)0.07 (0.12)−0.03 (0.52)OxCL0.07 (0.11)0.07 (0.11)0.04 (0.36)−0.05 (0.31)0.12 (0.006)−0.09 (0.04)ApoB-IC0.09 (0.04)0.11 (0.02)−0.04 (0.32)−0.15 (<0.001)0.09 (0.05)−0.06 (0.20)Values shown are R and (P). Open table in a new tab Values shown are R and (P). There were strong correlations among all IgG classes of OxLDL autoantibodies and apoB-ICs as well as among all classes of IgM autoantibodies and IgM apoB-ICs. Less strong correlations were noted between IgG and IgM classes (Table 6 ).TABLE 6Spearman rank correlations (above diagonal) and P values (footnotes) among OxLDL autoantibodies and apoB-ICsIgGIgMParameterMDA-LDLCu-OxLDLOxCLApoB-ICMDA-LDLCu-OxLDLOxCLApoB-ICIgGMDA-LDL—0.66aP < 0.001.0.54aP < 0.001.0.48aP < 0.001.0.14bP < 0.01.0.16bP < 0.01.0.16bP < 0.01.0.12bP < 0.01.Cu-OxLDL—0.50aP < 0.001.0.59aP < 0.001.0.08cP < 0.05.0.120.11bP < 0.01.0.05OxCL—0.38aP < 0.001.0.16aP < 0.001.0.18aP < 0.001.0.27aP < 0.001.0.18aP < 0.001.ApoB-IC—0.020.040.030.03IgMMDA-LDL—0.81aP < 0.001.0.77aP < 0.001.0.74aP < 0.001.Cu-OxLDL—0.77aP < 0.001.0.82aP < 0.001.OxCL—0.76aP < 0.001.ApoB-IC—a P < 0.001.b P < 0.01.c P < 0.05. Open table in a new tab In multivariable analysis, age, LDL-C, smoking history, and hypertension were independent predictors of obstructive CAD, whereas female gender and HDL-C were independently associated with reduced risk of obstructive CAD (Fig. 2 ). There was no significant association between OxLDL measures and cardiovascular events in patients 60 years old. None of the IgG or IgM OxLDL measures or hsCRP was an independent predictor of obstructive CAD. There was no significant relationship between the OxLDL autoantibodies or apoB-IC variables and follow-up events after adjustment for covariates. Table 7 shows the event rates at years 1, 2, and 3 for each OxLDL variable above and below its respective median value and documents no independent association of these markers at each time point. In addition, there was no association based on whether patients were categorized as none/mild CAD versus obstructive CAD (>50% DS).TABLE 7Association between OxLDL autoantibodies and apoB-IC levels (above or below the median value) and the combined events of death, myocardial infarction, and stroke during the follow-up periodParameter1 Year2 Years3 YearsPIgM MDA-LDL⩽15,0847 (3.0)11 (4.7)14 (6.0)0.36>15,0847 (3.0)11 (4.7)14 (6.1)IgM Cu-OxLDL⩽4,5766 (2.6)10 (4.3)12 (5.2)0.22>4,5768 (3.4)12 (5.2)16 (6.9)IgM OxCL⩽2,4527 (3.0)11 (4.7)13 (5.6)0.68>2,4527 (3.0)11 (4.8)15 (6.5)IgM apoB-IC⩽5,8608 (3.4)12 (5.1)15 (6.4)0.80>5,8606 (2.6)10 (4.3)13 (5.7)IgG MDA-LDL⩽4,5068 (3.4)14 (6.0)17 (7.3)0.81>4,5066 (2.6)8 (3.5)11 (4.8)IgG Cu-OxLDL⩽2,7317 (3.0)12 (5.1)15 (6.4)0.42>2,7317 (3.0)10 (4.3)13 (5.7)IgG OxCL⩽780.85 (2.1)12 (5.2)14 (6.0)0.90>780.89 (3.9)10 (4.3)14 (6.1)IgG apoB-IC⩽5,2008 (3.4)13 (5.6)16 (6.8)0.40>5,2006 (2.6)9 (3.9)12 (5.2)CADNone/mild3 (1.5)6 (3.0)7 (3.5)0.20Obstructive11 (4.2)16 (6.1)21 (8.1)OxLDL values are in relative light units and are presented as number (percent). Open table in a new tab OxLDL values are in relative light units and are presented as number (percent). This study assessed the relationship between both IgG and IgM OxLDL markers and angiographically determined CAD. In univariate analysis, a positive relationship of angiographically determined CAD with IgG Cu-OxLDL was present, whereas an inverse relationship existed between IgM OxLDL autoantibodies and IgM apoB-ICs, with ∼40–50% reduction in the probability of the presence of >50% DS. However, in multivariable analysis tak
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