doi: 10.1161/01.ATV.0000193888.71297.f3
© 2005 American Heart Association, Inc.
Letters to the Editor |
Letter to the Editor
Heparin Cofactor II Levels Do Not Predict the Development of Coronary Heart Disease: The Atherosclerosis Risk in Communities (ARIC) Study
Division of Hematology (T.K.G., D.M.T.), Department of Medicine, Washington University School of Medicine, St. Louis, Mo Division of Hematology and Vascular Biology Research Center (C.W.A., K.K.W.), University of Texas Medical School at Houston
To the Editor:
Heparin cofactor II (HCII) is a plasma glycoprotein that inactivates thrombin rapidly in the presence of dermatan sulfate or heparin.1 Although the presence of thrombin–HCII complexes in normal human plasma indicates that HCII inhibits thrombin in vivo,2 the physiological function of HCII remains unknown. Homozygous HCII-deficient mice develop thrombotic occlusion of the carotid artery faster than wild-type mice after photochemically-induced damage to the endothelium,3 suggesting that HCII might play a role in inhibiting thrombosis after arterial injury. Numerous clinical studies, however, have failed to demonstrate a convincing association between HCII deficiency and arterial or venous thrombosis.4 More recent studies suggest that individuals with higher than average HCII levels are less likely to develop carotid atherosclerosis or in-stent restenosis.5–7
To further investigate the association between plasma HCII and coronary heart disease (CHD), we measured HCII antigen levels in stored plasma samples from the Atherosclerosis Risk in Communities (ARIC) study.8 In this study, 
16 000 middle-aged subjects have been followed for the development of atherosclerotic disease and its sequelae with an average follow-up of 11.7 years. A detailed description of the study population, HCII immunoassay, and statistical methods is available at http://atvb.ahajournals.org.
HCII levels were determined in a total of 760 subjects. Of these, 378 were subjects who developed CHD during follow-up (185 definite or probable myocardial infarction, 36 silent myocardial infarction, 24 definite fatal CHD, and 133 revascularization procedure), and 382 were non-cases selected by stratified sampling. CHD cases and non-cases were similar in age, gender, and race. CHD cases were more likely than non-cases to have diabetes or hypertension, greater cigarette use, lower HDL cholesterol, or higher fibrinogen or white blood cell counts.
The distribution of unadjusted HCII levels in the CHD cases and non-cases is shown in Figure I (available online at http://atvb.ahajournals.org). The weighted mean value of HCII for all subjects was 99.1%. In Cox proportional hazards regression analyses, HCII was not significantly associated with the time to development of CHD after adjustment for the effects of other prognostic factors (P=0.56), including age, gender, race, white blood cell count, hypertension, diabetes, total cholesterol, HDL cholesterol, and cigarette years of smoking (Table). Furthermore, there was no significant association between HCII and the time to development of CHD in the subgroups of Blacks (P=0.114), Whites (P=0.813), males (P=0.712), females (P=0.434), smokers (P=0.624), and nonsmokers (P=0.130) after adjustment for the effects of other prognostic factors. Multiple linear regression analyses conducted using HCII as the outcome variable (Table II, available online at http://atvb.ahajournals.org) showed significant associations with gender (P<0.0001), hypertension (P=0.0059), white blood cell count (P=0.0008), and HDL cholesterol (P=0.0084) after controlling for the effects of other variables.
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In conclusion, we observed no association between plasma HCII levels and development of symptomatic CHD in a large cohort of middle-aged subjects followed prospectively for more than a decade. By contrast, Aihara et al6 found a significant negative association between HCII levels and the severity of early atherosclerotic lesions in the carotid arteries of elderly patients. Whether high HCII levels in elderly patients predict a lower incidence of symptomatic carotid artery disease remains to be determined. The apparent discrepancy between the results of their study and ours may be attributable to differences in the study design (prospective versus cross-sectional), the age of the subjects, or the clinical end point (symptomatic CHD versus early carotid atherosclerosis). The effect of natural variation in plasma HCII levels on atherogenesis, therefore, requires further investigation.
References
- Tollefsen DM. Antithrombin deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001.
- Liu L, Dewar L, Song Y, Kulczycky M, Blajchman MA, Fenton JW 2nd, Andrew M, Delorme M, Ginsberg J, Preissner KT, Ofosu FA. Inhibition of thrombin by antithrombin III and heparin cofactor II in vivo. Thromb Haemost. 1995; 73: 405–412.[Medline] [Order article via Infotrieve]
- He L, Vicente CP, Westrick RJ, Eitzman DT, Tollefsen DM. Heparin cofactor II inhibits arterial thrombosis after endothelial injury. J Clin Invest. 2002; 109: 213–219.[CrossRef][Medline] [Order article via Infotrieve]
- Tollefsen DM. Heparin cofactor II deficiency. Arch Pathol Lab Med. 2002; 126: 1394–1400.[Medline] [Order article via Infotrieve]
- Takamori N, Azuma H, Kato M, Hashizume S, Aihara K, Akaike M, Tamura K, Matsumoto T. High plasma heparin cofactor II activity is associated with reduced incidence of in-stent restenosis after percutaneous coronary intervention. Circulation. 2004; 109: 481–486.
[Abstract/Free Full Text] - Aihara K, Azuma H, Takamori N, Kanagawa Y, Akaike M, Fujimura M, Yoshida T, Hashizume S, Kato M, Yamaguchi H, Kato S, Ikeda Y, Arase T, Kondo A, Matsumoto T. Heparin cofactor II is a novel protective factor against carotid atherosclerosis in elderly individuals. Circulation. 2004; 109: 2761–2765.
[Abstract/Free Full Text] - Schillinger M, Exner M, Sabeti S, Mlekusch W, Amighi J, Handler S, Quehenberger P, Kalifeh N, Wagner O, Minar E. High plasma heparin cofactor II activity protects from restenosis after femoropopliteal stenting. Thromb Haemost. 2004; 92: 1108–1113.[Medline] [Order article via Infotrieve]
- The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators. Am J Epidemiol. 1989; 129: 687–702.
[Abstract/Free Full Text]
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