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(Circulation. 1995;91:23-27.)
© 1995 American Heart Association, Inc.

Articles

Anti-Cardiolipin Antibodies and Risk of Myocardial Infarction in a Prospective Cohort of Middle-Aged Men

Outi Vaarala, MD; Matti Mänttäri, MD; Vesa Manninen, MD; Leena Tenkanen, PhD; Marja Puurunen; Kimmo Aho, MD; Timo Palosuo, MD

From the National Public Health Institute (O.V., M.P., K.A., T.P.); and the First Department of Medicine (M.M., V.M., L.T.), University of Helsinki, Finland.

Correspondence to Outi Vaarala, MD, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.

	Abstract

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Background Data concerning the relation between anti-phospholipid (aPL) antibodies and myocardial infarction in subjects without evidence of overt autoimmune disease are conflicting. All published studies have been performed on survivors of myocardial infarction or in patients with established coronary heart disease. The purpose of the present study was to determine whether the presence of aPL antibodies, namely, anti-cardiolipin (aCL) antibodies, carries a risk for myocardial infarction in a prospective cohort.

Methods and Results The sera to be studied were drawn at entry from middle-aged dyslipidemic men (non–high-density lipoprotein cholesterol, 5.2 mmol/L) participating in the Helsinki Heart Study, a 5-year coronary primary prevention trial with gemfibrozil. Samples were tested for IgG-class antibodies to cardiolipin by an ELISA. The risk was estimated with logistic regression analysis using a nested case-control design with 133 patients (myocardial infarction or cardiac death) and 133 control subjects, matched for treatment (gemfibrozil/placebo) and geographical area. The aCL antibody level, as expressed in optical density units, was significantly higher in patients than in control subjects (0.417 versus 0.361; P<.005). Subjects with the antibody level in the highest quartile of distribution had a relative risk for myocardial infarction of 2.0 (95% confidence interval, 1.1 to 3.5) compared with the remainder of the population. This risk was independent of confounding factors, such as age, smoking, systolic blood pressure, low-density lipoprotein (LDL), and high-density lipoprotein. There was a correlation between the levels of aCL antibodies and antibodies to oxidized LDL (r=.40, P<.001), and their joint effect was additive for the risk.

Conclusions In a prospective cohort of healthy middle-aged men, the presence of a high aCL antibody level is an independent risk factor for myocardial infarction or cardiac death. Antibodies to cardiolipin and oxidized LDL may, at least in part, represent cross-reactive antibody populations.

Key Words: lipoproteins • antibodies • thrombosis • infarction

	Introduction

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Antibodies binding to anionic phospholipids, such as cardiolipin, are associated with a clinical syndrome characterized in particular by venous and arterial thrombosis, recurrent abortion, and thrombocytopenia.¹ Although the anti-phospholipid (aPL) antibody syndrome was first described in patients with systemic lupus erythematosus (SLE), it is now generally accepted that there is a group of patients in whom high titers of aPL antibodies, usually IgG class, and thrombotic features occur without clinical manifestations of SLE. On the other hand, aPL antibodies may transiently appear during many infections and in association with several drugs without any association with thrombosis.²

Hamsten et al³ observed an increased prevalence of patients with elevated anti-cardiolipin (aCL) antibody levels in a highly selected series of young patients with myocardial infarction. Furthermore, high titers of these antibodies appeared to serve as a marker of high risk for recurrent cardiovascular events. In accordance with this, Klemp et al⁴ reported an association between elevated levels of aCL antibodies and ischemic heart disease. After these reports, there have been three studies on myocardial infarction or ischemic heart disease in which the frequency of elevated aCL antibodies was not appreciably higher in patients than in control subjects, and such antibodies were not predictive for subsequent cardiovascular complications.^{5 6 7} All of these studies were performed on survivors of myocardial infarction or in patients with established coronary heart disease. In the present report, we investigated the association between aCL antibodies and the risk of myocardial infarction in a cohort of initially healthy middle-aged dyslipidemic men.

	Methods

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Patient Population
The Helsinki Heart Study was a double-blind, randomized coronary primary prevention trial with gemfibrozil among dyslipidemic (non–high-density lipoprotein cholesterol, 5.2 mmol/L) middle-aged men. The study population was selected by screening from a cohort of 19 000 male employees in private and government-owned industries.⁸ Gemfibrozil treatment was associated with a 34% reduction in the incidence of coronary heart disease during the 5-year double-blind period,^{9 10} and the favorable trend is continuing during the extended open-label follow-up.¹¹

A total of 140 of 4081 subjects in the Helsinki Heart Study population had a cardiac end point, either cardiac death or nonfatal myocardial infarction, during the double-blind study period. For the present study, serum drawn at baseline in 1981 through 1982 and preserved at -20°C was available from 133 patients with cardiac end points (26 cardiac deaths and 107 nonfatal myocardial infarctions). A control subject without an end point was selected for each patient using drug treatment (gemfibrozil/placebo) and the clinic in the study organization as matching variables. The differences in classic coronary risk factors in patients and control subjects are given in Table 1.

View this table: [in this window] [in a new window]   Table 1. Baseline Risk Factor Levels in Helsinki Heart Study Case-Control Population

Antibody Assays
Cardiolipin-binding antibodies were detected by ELISA as previously described.¹² The analyses were done blinded without knowledge of the case-control status. The assay was standardized using reference sera prepared by the Lupus Research Laboratory, Rayne Institute, St Thomas Hospital. Briefly, polystyrene plates (Nunc) were coated with cardiolipin (Sigma Chemical Co) at a concentration of 48 µg/mL in ethanol. Human serum albumin (HSA) solution (Finnish Red Cross Blood Transfusion Service) diluted to 1% in phosphate-buffered saline (PBS) was used as a ß₂-glycoprotein I–containing blocking solution. The presence of human ß₂-glycoprotein I in HSA solution was demonstrated by immunoblotting using polyclonal anti–ß₂-glycoprotein I antibodies (Boehringer Mannheim). Serum samples were analyzed in duplicate at a serum dilution of 1:50 in 0.2% HSA-PBS. Alkaline phosphatase–conjugated rabbit anti-human IgG (Jackson ImmunoResearch) in 0.2% HSA-PBS was used as the second antibody. The results were expressed as optical density (OD) units.

Antibodies to oxidized low-density lipoprotein (LDL) were detected by ELISA as previously described,¹² and data on the occurrence of these antibodies are reported elsewhere.¹³

Statistical Analysis
The differences in continuous baseline variables were estimated using either t test or ANOVA. The ² test was applied to class variables. For the study of associations between aCL antibody levels and classic risk factors, Pearson's correlation coefficients were calculated. A logistic regression analysis (EGRET, Statistics and Epidemiology Research Corp) was used to study the associations between the aCL antibody level and coronary heart disease. The joint effects of the antibody and other risk factors (lipid levels, smoking, and leukocyte count) on coronary risk were also studied. A new variable was added to the model representing the combinations of categories of aCL antibodies (highest quartile/others) and the other risk factor, eg, LDL (highest tertile/others). This approach is similar to a stratified analysis, except that all combinations of LDL and aCL antibody levels are simultaneously present in the calculations.

	Results

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The mean level of aCL antibodies, as measured in OD units, was significantly higher in patients than in control subjects (0.417±0.173 versus 0.361±0.139, P<.005). The Figure illustrates the frequency distributions of aCL antibodies in patients and control subjects. Fifteen patients and two control subjects had antibody levels of >0.650 OD unit. The total number of fatal cases was 26, and only 4 of these had an antibody level of >0.650 OD unit; 3 of these had a fatal event and 1 nonfatal case later died of reinfarction. Thus, the case-fatality rate in subjects with high titers of aCL antibodies was not different from that of the remainder of the population.

View larger version (112K): [in this window] [in a new window]   Figure 1. Bar graph of distribution of anticardiolipin antibodies in patients (n=133) and control subjects (n=133).

The aCL antibody levels were higher in smokers than in nonsmokers (0.409±0.165 versus 0.370±0.142, P<.05) and only 13 of 42 patients (31%) with elevated aCL antibody levels (highest quartile) were nonsmokers.

There was a relatively close correlation between the levels of aCL antibodies and antibodies against oxidized LDL (r=.40, P<.001). The association with lipid levels disclosed a variable pattern. In patients, the correlation coefficients between the antibody levels and lipids were .15 (P=.08) for LDL, .09 (P=.3) for HDL cholesterol, and -.21 (P<.03) for triglycerides (TG). The corresponding coefficients in control subjects were .24 (P<.005) for LDL, -.14 (P=.09) for HDL, and -.07 (P=.2) for TG. In logistic regression analysis, the risk associated with aCL antibody level when used as a continuous variable was significant (P<.03) and independent of confounding factors such as age, smoking, systolic blood pressure, LDL, and HDL. When tertile distribution of the antibody was in the model and the risk in the lowest tertile was used as reference, the odds ratios (ORs) in the middle and high tertiles were 1.4 (95% confidence interval [CI], 0.7 to 2.6) and 1.8 (95% CI, 0.9 to 3.3). An increased risk at conventional significance level (P<.04) was found only in the highest quartile (OR, 2.0; 95% CI, 1.1 to 3.5) of the aCL antibody distribution.

When considered jointly, both elevated aCL antibodies (OR, 2.3; 95% CI, 1.0 to 5.3) and high LDL (OR 3.0; 95% CI 1.5-5.8) had an independent contribution to coronary risk. Simultaneous elevation of both of these produced no additional risk (OR, 2.7; 95% CI, 1.1 to 6.2). A similar risk pattern was detected for the joint effect of elevated aCL antibody and low HDL with no additional risk in the combination category. However, a different pattern was found for the joint effect of the antibody and TG, with the increased risk in the joint category only (Table 2). Simultaneous elevations of aCL antibodies and antibodies against oxidized LDL resulted in an increased risk that was close to additive (Table 3). A similar pattern was found in joint effects with elevated leukocyte count (WBC; highest tertile). The OR was 2.0 (95% CI, 0.9 to 4.2) in the elevated-antibody-only category and 2.2 (95% CI, 1.1 to 4.2) in the elevated-WBC-only category, whereas OR was 3.2 (95% CI, 1.2 to 8.9) in the joint category. The increment in risk associated with simultaneous smoking and elevated aCL antibody was close to multiplicative in statistical terms (Table 4).

View this table: [in this window] [in a new window]   Table 2. Joint Effect of Anti-Cardiolipin Antibodies and Serum Triglycerides on Coronary Risk in the Helsinki Heart Study Case-Control Population

View this table: [in this window] [in a new window]   Table 3. Joint Effect of Anti-Cardiolipin Antibodies and Antibody Against Oxidized LDL on Coronary Risk in the Helsinki Heart Study Case-Control Population

View this table: [in this window] [in a new window]   Table 4. Joint Effect of Anti-Cardiolipin Antibodies and Smoking on Coronary Risk in the Helsinki Heart Study Case-Control Population

	Discussion

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In the present study, the aCL antibody levels were significantly higher in patients developing a cardiac end point than in control subjects. The relative risk in the highest quartile of the distribution was twofold compared with the remainder of the study population, and the risk was independent of classic coronary risk factors.

Thus, the results of our prospective study are in agreement with two earlier works,^{3 4} but they disagree with findings of three other studies of the prevalence of aCL antibodies in patients with myocardial infarction or coronary artery disease.^{5 6 7} There may be several reasons for these discrepancies. First, our report was prospective and the participants were free of coronary artery disease at entry, whereas all other studies included survivors of myocardial infarction or patients with established ischemic heart disease. Second, there are differences in the study populations. For example, our study subjects had been selected on the basis of high LDL cholesterol concentration, whereas those investigated by Hamsten et al³ were <45 years old.

Third, differences in test techniques may be involved. There is evidence that aPL antibodies in patients with SLE are directed against an antigenic complex containing not only anionic phospholipids but also a plasma apolipoprotein H (ß₂-glycoprotein I).¹⁴ On the other hand, aCL antibodies occurring in infectious diseases appear to bind to pure anionic phospholipids.¹⁵ In our assay, HSA was used as a blocking buffer and serum diluent. The blocking buffer contains as an impurity ß₂-glycoprotein I. However, this kind of cofactor-containing ELISA also detects aCL antibodies independent of the cofactor. Others had used bovine serum,^{4 6} or there was no exogenous source of cofactor,³ or information on the composition of the blocking buffer was not given.^{5 7}

We have shown earlier that the IgG class aCL antibody level was marginally higher in patients with ischemic heart disease than in community-based healthy control subjects and that there was a statistically significant increase in the antibody level as observed in paired specimens taken after myocardial infarction.¹⁶ Others, too, have documented a rise in the aCL antibody level after myocardial infarction,⁶ possibly due to an immunological response to tissue necrosis.

It is commonly believed that only clearly elevated aPL antibodies are clinically significant. Thus, in a recent population-based case-control study, there was an increased risk of deep venous thrombosis or pulmonary embolism appearing above the 98th percentile of aCL antibody distribution of the control subjects.¹⁷ However, our data appear to indicate that even lower levels might carry an excess risk.

Because aCL antibodies in healthy subjects were shown to predict myocardial infarction, it is possible that at least in some instances they could be directly involved in the pathogenesis of thrombotic events. Causality speculations based on statistical interactions are highly questionable. However, in light of the accumulated experimental and clinical evidence, this circumstantial evidence could be interpreted to support a role for aPL antibodies in the thrombogenesis rather than in the pathogenesis of atherosclerosis. In particular, the interactions between aCL antibodies and smoking, leukocyte count, or TG support this conclusion, since all of these coronary risk factors are known to be associated with hypercoagulative stages.^{18 19 20} Several different mechanisms for the involvement of aPL antibodies in thrombogenesis have been proposed.²¹ For example, aPL antibodies may bind to the membranes of thrombocytes or of vascular endothelial cells and alter the function of these cells. However, the antibodies are directed against phospholipid components that are normally not exposed in the outer membrane leaflet of inactivated platelets or intact endothelial cells. Thus, some primary change in the membrane is needed before the action of aPL antibodies. The observation that aCL antibodies in patients with SLE (in contrast to infection-associated aCL antibodies) bind to a complex of cardiolipin and ß₂-glycoprotein I (apolipoprotein H) rather than to a cardiolipin alone¹⁴ has aroused the idea that aCL antibodies may interfere in vivo with the function of ß₂-glycoprotein I, which is, among other things, an inhibitor of the intrinsic pathway of coagulation. On the other hand, there is accumulating evidence to suggest that infections can play a role in the pathogenesis of coronary heart disease.²² A transient aCL antibody response takes place in a variety of bacterial and viral infections, and elevated levels can persist in many chronic infections, notably syphilis.² Thus, it is possible that aCL antibodies in our study subjects reflect some chronic infection, for example, chlamydial infection, which has been associated with coronary heart disease.^{23 24 25} Actually, antibodies against chlamydial lipopolysaccharide may cross-react with anionic phospholipids in ELISA.²⁶

We have demonstrated a cross-reaction between aCL antibodies and antibodies against oxidized LDL in patients with SLE.¹² Such a cross-reaction was by no means unexpected taking into account the structural similarity between the LDL molecule and the complex consisting of cardiolipin and ß₂-glycoprotein I (apolipoprotein H). Antibodies against oxidized LDL have been associated with the progression of carotid atherosclerosis.²⁷ As described in detail elsewhere,¹³ the present sera were also tested for antibodies against oxidized LDL. A clear association was noted between the presence of these two antibody moieties. Despite this, both antibodies had an independent contribution to coronary risk, and their joint effect was additive in statistical terms. Nevertheless, it is possible that part of the effect of aPL antibodies could be mediated via a cross-reacting property directed against oxidized LDL.

	Acknowledgments

 
This work was supported by grants from the Paavo Nurmi Foundation, Helsinki (M.M.), and from the Foundation for Nutrition Research, Helsinki (O.V.).

Received March 21, 1994; accepted July 31, 1994.

	References

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				F. L Ruberg and J. Loscalzo Prothrombotic determinants of coronary atherothrombosis Vascular Medicine, November 1, 2002; 7(4): 289 - 299. [Abstract] [PDF]

				J. K. Pai, G. C. Curhan, C. C. Cannuscio, N. Rifai, P. M. Ridker, and E. B. Rimm Stability of Novel Plasma Markers Associated with Cardiovascular Disease: Processing within 36 Hours of Specimen Collection Clin. Chem., October 1, 2002; 48(10): 1781 - 1784. [Full Text] [PDF]

				R. L. Brey, C. L. Stallworth, D. L. McGlasson, M. A. Wozniak, R. J. Wityk, B. J. Stern, M. A. Sloan, R. Sherwin, T. R. Price, R. F. Macko, et al. Antiphospholipid Antibodies and Stroke in Young Women * Editorial Comment Stroke, October 1, 2002; 33(10): 2396 - 2401. [Abstract] [Full Text] [PDF]

				J. T. Cvetkovic, S. Wallberg-Jonsson, E. Ahmed, S. Rantapaa-Dahlqvist, and A. K. Lefvert Increased levels of autoantibodies against copper-oxidized low density lipoprotein, malondialdehyde-modified low density lipoprotein and cardiolipin in patients with rheumatoid arthritis Rheumatology, September 1, 2002; 41(9): 988 - 995. [Abstract] [Full Text] [PDF]

				D. Erkan, Y. Yazici, M. G. Peterson, L. Sammaritano, and M. D. Lockshin A cross-sectional study of clinical thrombotic risk factors and preventive treatments in antiphospholipid syndrome Rheumatology, August 1, 2002; 41(8): 924 - 929. [Abstract] [Full Text] [PDF]

				J. S. Levine, D. W. Branch, and J. Rauch The Antiphospholipid Syndrome N. Engl. J. Med., March 7, 2002; 346(10): 752 - 763. [Full Text] [PDF]

				Y Sherer and Y Shoenfeld Atherosclerosis Ann Rheum Dis, February 1, 2002; 61(2): 97 - 99. [Abstract] [Full Text] [PDF]

				E. Svenungsson, K. Jensen-Urstad, M. Heimburger, A. Silveira, A. Hamsten, U. de Faire, J. L. Witztum, and J. Frostegard Risk Factors for Cardiovascular Disease in Systemic Lupus Erythematosus Circulation, October 16, 2001; 104(16): 1887 - 1893. [Abstract] [Full Text] [PDF]

				R. L. Brey, R. D. Abbott, J. D. Curb, D. S. Sharp, G. W. Ross, C. L. Stallworth, and S. J. Kittner {beta}2-Glycoprotein 1-Dependent Anticardiolipin Antibodies and Risk of Ischemic Stroke and Myocardial Infarction: The Honolulu Heart Program Stroke, August 1, 2001; 32(8): 1701 - 1706. [Abstract] [Full Text] [PDF]

				D. Pratico, R. K. Tangirala, S. Horkko, J. L. Witztum, W. Palinski, and G. A. FitzGerald Circulating autoantibodies to oxidized cardiolipin correlate with isoprostane F2{alpha}-VI levels and the extent of atherosclerosis in ApoE-deficient mice: modulation by vitamin E Blood, January 15, 2001; 97(2): 459 - 464. [Abstract] [Full Text] [PDF]

				A. Mustafa, S. Nityanand, L. Berglund, H. Lithell, and A. K. Lefvert Circulating Immune Complexes in 50-Year-Old Men as a Strong and Independent Risk Factor for Myocardial Infarction Circulation, November 21, 2000; 102(21): 2576 - 2581. [Abstract] [Full Text] [PDF]

				A. Bili, A. J. Moss, C. W. Francis, W. Zareba, L. F. M. Watelet, I. Sanz, f. t. T. Factors, and R. C. E. Investigators Anticardiolipin Antibodies and Recurrent Coronary Events : A Prospective Study of 1150 Patients Circulation, September 12, 2000; 102(11): 1258 - 1263. [Abstract] [Full Text] [PDF]