Apolipoprotein A-II is a negative risk indicator for cardiovascular and total mortality: findings from the Ludwigshafen risk and cardiovascular health study.
Article Type:
Letter to the editor
Cardiac patients (Health aspects)
Infection control (Health aspects)
Medical research (Health aspects)
Medicine, Experimental (Health aspects)
Winkler, Karl
Hoffmann, Michael M.
Seelhorst, Ursula
Wellnitz, Britta
Boehm, Bernhard O.
Winkelmann, Bernhard R.
Marz, Winfried
Scharnagl, Hubert
Pub Date:
Name: Clinical Chemistry Publisher: American Association for Clinical Chemistry, Inc. Audience: Academic Format: Magazine/Journal Subject: Chemistry Copyright: COPYRIGHT 2008 American Association for Clinical Chemistry, Inc. ISSN: 0009-9147
Date: August, 2008 Source Volume: 54 Source Issue: 8
Product Code: 8000200 Medical Research; 9105220 Health Research Programs; 8000240 Epilepsy & Muscle Disease R&D NAICS Code: 54171 Research and Development in the Physical, Engineering, and Life Sciences; 92312 Administration of Public Health Programs

Accession Number:
Full Text:
To the Editor:

Apolipoprotein A-II (apoA-11) [1] was recently shown by Birjmohun and coworkers to be inversely associated with future risk for coronary artery disease in 912 cases and 1635 controls (1). This finding is important, because prior data have suggested that apoA-II has poor antiatherogenic properties and may even be proatherogenic. We now confirm and extend the antiatherogenic association of apoA-II to cardiac and total mortality on the basis of data collectd after 8 years of follow-up in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, which is investigating patients who underwent elective coronary angiography (2).

Complete clinical and biochemical data from 3261 participants in the LURIC study are available. For these study participants, 752 deaths were recorded, and causes of death were obtained from official death certificates. Death from cardiac causes was re corded in 431 cases. Patients with (n = 2535) and without (n = 726) coronary artery disease presented with mean (SD) apoA-II concentrations of 0.44 (0.10) and 0.41 (0.09) g/L (P < 0.001), respectively. To examine the effect of apoA-II on cardiac and total mortality, we used Cox proportional hazards regression models to calculate hazard ratios (HRs). The data of the LURIC trial showed that apoA-II concentrations were negatively associated with cardiac death (HR 0.95,95% CI 0.94-0.96; P < 0.001) and total mortality (HR 0.96, 95% CI 0.95-0.96; P < 0.001). For further risk assessment, quartile ranges of apoA-II concentrations measured in study participants without coronary artery disease were defined as [less than or equal to] 0.37 g/L (reference), 0.37-0.43 g/L, 0.430.50 g/L, and [greater than or equal to] 0.50 g/L. The unadjusted HR for cardiac death of the fourth vs the reference quartile was 0.38 (95% CI 0.27-0.52; P < 0.001), and the HR per SD increase of apoA-II was 0.60 (95% CI 0.54-0.67; P for trend <0.001). However, in contrast to the findings of Birjmohun et al., we found that HRs of the fourth vs first quartile were 0.26 (95% CI 0.140.50; P < 0.001) for females (n = 990) and 0.45 (95% CI 0.31-0.64; P < 0.001) for males (n = 2271). For the total population, adjustment for age, sex, and body mass index; use of lipid-lowering drugs; presence of hypertension, diabetes, smoking, and/or alcohol consumption; and concentrations of triglycerides, LDL- and HDL cholesterol, and apoA-I resulted in HRs per SD increase of apoA-II of 0.66 (95% CI 0.57-0.78; P for trend <0.001) for cardiac death and 0.77 (95% CI 0.68-0.86; P for trend <0.001) for total mortality, respectively. If sensitive C-reactive protein was included, the HRs for the second and third quartile vs the 1st quartile remained significant only for cardiac death: 0.77 (95% CI 0.59-1.00; P = 0.047) and 0.69 (95% CI 0.50-0.96; P = 0.027), respectively, with an HR per SD increase of apoA-II of 0.71 (95% CI 0.61-0.84; P for trend <0.001). After inclusion of N-terminal pro-B-type natriuretic peptide (3) into the model, however, the HRs for apoA-II were no longer found to be statistically significant.

Thus, the presented data from the LURIC trial clearly support the negative association of apoA-II with coronary artery disease and extend these findings to cardiac and total mortality. In contrast to the data reported by Birjmohun et al., our data indicate that this effect occurs in patients of both sexes, with an even more pronounced effect in females. When we included sensitive C-reactive protein in the analysis, the second and third quartile of apoA-II remained associated with cardiac death. However, further inclusion of N-terminal pro-B-type natriuretic peptide completely abolished the risk association of apoA-II. These findings support the hypothesis that apoA-II has a pathophysiological effect as an antiatherogenic apolipoprotein. Nevertheless, the usefulness of including apoA-II in risk stratification strategies is questionable because of the availability of more powerful risk markers, such as sensitive C-reactive protein and N-terminal pro-B-type natriuretic peptide.

Grant/Funding Support: None declared.

Financial Disclosures: None declared.

Acknowledgments: We thank the members of the LURIC study team who were involved in patient recruitment or sample and data handling and the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany.


(1.) Birimohun RS, Dallinga-Thie GM, Kuivenhoven JA, Stroes ES, Otvos JD, Wareham NJ, et al. Apolipoprotein A-II is inversely associated with risk of future coronary artery disease. Circulation 2007;116:2029-35.

(2.) Winkelmann BR, Marz W, Boehm BO, Zotz R, Hager J, Hellstem P, Senges J. Rationale and design of the LURIC study: a resource for functional genomics, pharmacogenomics and longterm prognosis of cardiovascular disease. Pharmacogenomics 2001;2:51-73.

(3.) Marz W, Tiran B, Seelhorst U, Wellnitz B, Bauersachs J, Winkelmann BR, Boehm BO. N-terminal pro-B-type natriuretic peptide predicts total and cardiovascular mortality in individuals with or without stable coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health Study. Clin Chem 2007;53:1075-83.

[1] Nonstandard abbreviations: apoA-II, apolipoprotein A-II; LURIC, Ludwigshafen Risk and Cardiovascular Health; HR, hazard ratio.

Karl Winkler [2] *

Michael M. Hoffmann [2]

Ursula Seelhorst [3]

Britta Wellnitz [3]

Bernhard O. Boehm [4]

Bernhard R. Winkehnann [5]

Winfried Marz [6]

Hubert Scharnagl [7]

[2] Department of Clinical Chemistry University Medical Center Freiburg, Germany

[3] LURIC Study Nonprofit LLC Freiburg, Germany

[4] Division of Endocrinology Department of Medicine University Hospital Ulm, Germany

[5] Cardiology Group Frankfurt-Sachsenhausen, Germany

[6] Synlab Center of Laboratory Diagnostics Heidelberg, Germany

[7] Department of Clinical Chemistry University of Graz Graz, Austria

* Address correspondence to this author at: Department of Clinical Chemistry University of Freiburg Hugstetter Str. 55 79106 Frieburg, Germany

Fax +49 761 270 3444

E-mail karl.winkler@uniklinik-freiburg.de

DOI: 10.1373/clinchem.2008.103929
Gale Copyright:
Copyright 2008 Gale, Cengage Learning. All rights reserved.