Clinical Chemistry 54: 1325-1330, 2008.
First published June 12, 2008; 10.1373/clinchem.2008.103234
(Clinical Chemistry. 2008;54:1325-1330.)
© 2008 American Association for Clinical Chemistry, Inc.
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Lipids, Lipoproteins, and Cardiovascular Risk Factors |
Increased Plasma Apolipoprotein C-III Concentration Independently Predicts Cardiovascular Mortality: The Hoorn Study
Peter G. Scheffer1,4,a,
Tom Teerlink1,4,
Jacqueline M. Dekker2,
Griët Bos2,
Giel Nijpels2,
Michaela Diamant3,4,
Piet J. Kostense5,
Coen D. A. Stehouwer6 and
Robert J. Heine3,4
1 Metabolic Laboratory, Department of Clinical Chemistry, VU University Medical Center, Amsterdam;2
EMGO Institute, VU University Medical Center, Amsterdam;3
Department of Endocrinology/Diabetes Center, VU University Medical Center, Amsterdam;4
Institute for Cardiovascular Research, VU University Medical Center, Amsterdam;5
Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam;6
Department of Medicine, Division of General Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands.
aAddress correspondence to this author at: VU University Medical Center, Department of Clinical Chemistry, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. Fax +31-204443895; e-mail p.scheffer{at}vumc.nl.
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Abstract
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Background: Hypertriglyceridemia is a cardiovascular risk factor. Apolipoprotein C-III (apoC-III) is an important determinant of the catabolic rate of triglyceride-rich lipoproteins. The aim of this study was to investigate the prognostic value of plasma apoC-III concentrations for cardiovascular mortality.
Methods: We performed this prospective study in 2244 subjects (ages 49–77 years) who participated in the Hoorn Study. During a mean follow-up of 15 years, 504 individuals died: 231 of cardiovascular disease, 180 of cancer, and 93 of other causes. Cardiovascular disease risk factors and plasma apoC-III concentrations were measured at baseline.
Results: The age- and sex-adjusted plasma apoC-III concentration was prospectively associated with cardiovascular mortality (P < 0.001). After adjustment for traditional risk factors, including fasting triglycerides, the hazard ratio (95% CI) for cardiovascular death between the highest and the lowest quartile of apoC-III was 1.85 (1.02–3.38). High concentrations of apoC-III did not appear to be associated with noncardiovascular mortality.
Conclusions: In this general population cohort, a high apoC-III concentration in plasma, independently of fasting triglycerides and other traditional risk factors, predicts cardiovascular mortality.
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Introduction
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Increased plasma triglyceride concentrations are associated with increased coronary heart disease (CHD)1
risk (1). Apolipoprotein C-III (apoC-III) resides on the surface of triglyceride-rich lipoproteins (2) but is also present on HDL particles (3) and remnant-like particles (4). ApoC-III retards the clearance of triglyceride-rich apoB-containing lipoproteins by inhibiting lipoprotein lipase (LPL), and as such plays a pivotal role in the catabolism of triglycerides (5). The presence of apoC-III on triglyceride-rich lipoproteins has also been shown to influence their fate by suppression of direct removal of these lipoproteins from the circulation and enhancement of their conversion to smaller and denser particles (6). In addition, apoC-III containing VLDL and LDL have been shown to increase monocyte adhesion to the endothelium by inducing expression of vascular cell adhesion molecule-1 in endothelial cells (7) and activating β1 integrin in monocytes (8). Furthermore, apoC-III enhances the binding of apoB-containing lipoproteins to vascular proteoglycans (9). Taken together, these factors are strong indications that apoC-III promotes atherosclerosis not only by impairing catabolism of triglyceride-rich lipoproteins, but also by stimulating vascular retention of lipoproteins and endothelial activation. The cardiovascular risk associated with apoC-III concentrations has been previously investigated in several high-risk populations, e.g., patients with type 2 diabetes (10)(11), postmyocardial infarction (12), CHD (13), and the metabolic syndrome (14). Only two of these studies examined the cardiovascular risk of apoC-III prospectively, and in both studies apoC-III was measured in isolated lipoproteins rather than whole plasma (11)(12). The aim of the present study was to examine the predictive value of plasma apoC-III concentrations for cardiovascular mortality during 15 years of follow-up in a population-based study.
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Materials and Methods
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subjects
All subjects were participants of the Hoorn Study, a population-based cohort study of glucose metabolism and diabetes complications, as described (15). Briefly, in 1989, a random sample of 50- to 75-year-old individuals was taken from the population register of Hoorn in the Netherlands. Of the 3552 individuals invited to take part in the study, 2540 participated (71.5%), of whom 56 non-Caucasians were excluded, resulting in 2484 participants at baseline. For the present study, we excluded subjects with missing information regarding the cause of death (n = 65) or plasma apoC-III concentration (n = 158) and those who were lost to follow up (n = 17). Consequently, the study population consisted of 2244 subjects, 1031 men and 1213 women. All participants, except known type 2 diabetes patients, took a 75-g oral glucose tolerance test. Subjects with impaired glucose metabolism (impaired fasting glucose or impaired glucose tolerance) or known or newly diagnosed type 2 diabetes (16) were grouped together in the abnormal glucose metabolism category and compared with subjects with normal glucose metabolism. The study was approved by the Ethical Review Committee of the VU University Medical Center. Informed consent was obtained from all participants.
follow-up and definition of cardiovascular mortality
In 1995, the population register of Hoorn was checked for the vital status of all participants, and since then a prospective registration was continued. For the current analyses, we used follow-up data until January 2005. Causes of death were extracted from the medical records of the general practitioner and the local hospital, and mortality was coded according to the International Classification of Diseases, Ninth Revision (ICD-9). Cardiovascular mortality was defined as diseases of the circulatory system (ICD codes 390–459) or sudden death (ICD 798). Sudden death was defined as death occurring within 1 h after onset of symptoms or unwitnessed death, in which a cardiovascular origin could not be excluded. For the present study, cases of CHD mortality were defined as those with ICD codes 410–414 (ischemic heart disease) or 798 (sudden death). Of those who had moved out of Hoorn (7.8%), vital status was checked in the population registers of the cities where the subjects had moved. Seventeen subjects (0.7%) were lost to follow-up.
methods
During the baseline examination, blood samples were taken and plasma was stored at –80 °C until analyzed. Plasma glucose concentration was determined with a glucose dehydrogenase method (Merck); triglycerides, total cholesterol, and HDL cholesterol were measured by enzymatic techniques (Roche); LDL cholesterol was calculated according to Friedewald’s formula; and apoC-III concentration was measured in plasma by an immunoturbidimetric assay (Daiichi) on a Cobas Mira analyzer (ABX Diagnostics). The intra- and interassay CVs were 1.7% and 2.7%, respectively. Blood pressure was measured at the right upper arm after 5 min of rest in seated subjects, using a random-zero sphygmomanometer (Hawksley-Gelman Ltd), taking the mean of duplicate measurements. Anthropometric data were obtained from all subjects after removal of heavy outer clothing. Body mass index (BMI) and waist-to-hip ratio were calculated by dividing weight by height squared, and waist circumference by hip circumference, respectively. Cardiovascular history and lifestyle habits, including smoking, were assessed by questionnaire.
statistical analysis
Baseline characteristics are shown as mean (SD). Because plasma apoC-III and triglyceride concentrations had a skewed distribution, the median and interquartile ranges are presented. We explored associations between apoC-III and several variables by Spearman correlation analysis. We calculated follow-up duration from the date of baseline examinations to date of death, date of loss to follow-up, or to January 1, 2005. With, on average, 15 years of follow-up and 504 deaths, we obtained hazard ratios and 95% CIs (across quartiles) of baseline apoC-III concentrations for mortality from Cox proportional hazard models. We first adjusted for age and sex, and then we added glucose metabolism and HDL or LDL cholesterol or triglycerides to the model. Finally, we adjusted the association between apoC-III and cardiovascular disease (CVD) mortality for the above variables and other known cardiovascular risk markers in a so-called fully adjusted model. P values <0.05 (2-tailed) were considered statistically significant. All analyses were done with SPSS version 12.0.1.
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Results
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The baseline characteristics of the study population classified on the basis of quartiles of apoC-III concentrations are shown in Table 1
. ApoC-III concentrations were positively associated with several cardiovascular risk factors, whereas no significant linear trends were observed across quartiles of apoC-III for age and smoking at baseline. In the highest apoC-III quartile, there were more individuals with an abnormal glucose metabolism (impaired glucose metabolism or type 2 diabetes). Likewise, the apoC-III concentration was higher in subjects with an abnormal glucose metabolism than in individuals with a normal glucose metabolism (median 103.1 and 98.2 mg/L, respectively; P < 0.01). Women had a somewhat higher plasma apoC-III concentration than men (medians 100.5 and 97.5 mg/L, respectively; P < 0.01).
As illustrated in Table 2
, apoC-III concentration was strongly associated with fasting plasma concentrations of total cholesterol, LDL cholesterol, and triglycerides, but less strong correlations were found with HDL cholesterol. In general, the observed correlations were similar in individuals with normal or abnormal glucose metabolism (Table 2
). In contrast to the normal glucose metabolism group, a significant inverse relationship was found between apoC-III and age in abnormal glucose metabolism, and blood pressure was positively correlated to apoC-III in normal glucose metabolism but not abnormal glucose metabolism.
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Table 2. Spearman correlations between apoC-III and clinical and biochemical variables in the whole study group and in individuals with normal (NGM) and abnormal glucose metabolism (AGM).
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During the follow-up period of 15 years, 504 individuals died: 231 of cardiovascular disease, 180 of cancer, and 93 of other causes. Subjects who died from cardiovascular disease during follow-up had higher concentrations of apoC-III than those who survived (median 103.5 and 98.9 mg/L, respectively; P < 0.01). In the entire group, we observed a significantly increased cardiovascular mortality risk with increasing plasma concentrations of apoC-III after adjustment for age and sex (hazard ratio per 10 mg/L apoC-III increase, 1.10 [95% CI 1.06–1.14]; P < 0.001). In comparison, the risk of all-cause mortality associated with apoC-III concentrations was somewhat less (1.06 [1.03–1.09]; P < 0.001). In contrast, no statistically significant prognostic relationship was found for apoC-III concentrations and noncardiovascular mortality (1.03 [0.98–1.07]; P = 0.27) or cancer-related mortality (1.03 [0.98–1.09]; P = 0.21). The risk of cardiovascular mortality associated with increased apoC-III concentrations was not found to differ between subjects with normal and abnormal glucose metabolism (P for interaction 0.88). The event-free survival during 15 years of follow-up for cardiovascular mortality according to quartiles of apoC-III is illustrated in Fig. 1
. The cardiovascular risk increased significantly across quartiles of apoC-III (P < 0.05). Table 3
shows the hazard ratios per quartile of apoC-III concentrations for cardiovascular mortality. After adjustment for age and sex, a significant hazard ratio for cardiovascular mortality (including sudden death) was reached at the highest quartile of apoC-III. As illustrated in Fig. 2
, the sex- and age-adjusted estimated risk for CHD mortality in the highest quartile was also significantly increased (2.8 [1.43–5.51]; P < 0.01). In contrast, mortality risk of cancer was not found to be significantly increased in the highest quartile of apoC-III. Additional adjustment for glucose metabolism and HDL cholesterol did not change the association between plasma apoC-III and cardiovascular mortality (Table 3
). After further adjustment for LDL cholesterol or triglycerides, the risk estimates were slightly attenuated. In the fully adjusted model, however, both the trend across quartiles and the hazard ratio for the fourth quartile of apoC-III remained statistically significant. In this model, LDL cholesterol was significantly associated with increased risk (hazard ratio per 1 mmol/L increase, 1.20 [1.06–1.35]), but triglycerides were not and HDL had borderline significance (hazard ratios per 1 mmol/L 0.48 [0.13–1.76] and 0.55 [0.30–1.01], respectively).
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Figure 1. Kaplan–Meier survival plot for cardiovascular mortality according to quartiles (Q1 to Q4) of plasma apolipoprotein C-III.
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Figure 2. Hazard ratios and 95% confidence intervals adjusted for sex and age for mortality according to highest compared to lowest quartile of plasma apolipoprotein C-III.
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Discussion
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Our prospective study clearly shows that high plasma concentrations of apolipoprotein C-III contribute to cardiovascular mortality risk, independent of other risk factors or glucose metabolism status. This study also demonstrates that the average plasma apoC-III concentration is higher in postmenopausal women compared than in men of similar age, as well as in individuals with abnormal glucose metabolism.
An enhanced production rate of triglyceride-rich lipoproteins, as seen in subjects with hepatic insulin resistance, is an important factor contributing to cardiovascular disease. Obese men with insulin resistance were demonstrated to have higher concentrations of plasma apoC-III and triglyceride-rich lipoproteins and a lower estimated fractional catabolic rate of these particles (17). In addition to the increased synthesis, a reduced catabolic rate of apoC-III–containing particles appears to contribute to the dyslipidemia observed in insulin-resistant individuals. Because apoC-III inhibits LPL-mediated triglyceride hydrolysis (5), a reduced catabolic rate of apoC-III–containing lipoproteins might be a major factor contributing to dyslipidemia in type 2 diabetes.
This large, 15-year follow-up, population-based cohort study with well-characterized subjects allowed us to assess the prognostic value of apoC-III concentration for cardiovascular mortality among subjects with normal and abnormal glucose metabolism. Earlier studies have demonstrated that the adverse lipid profile is similar for subjects with impaired glucose metabolism and subjects with type 2 diabetes (18). Hence, subjects with impaired glucose tolerance and those with type 2 diabetes were taken together in the analyses. In addition, we have pooled all subjects in survival analysis to increase statistical power, because associations between apoC-III and several variables were similar in all subjects and those with a normal glucose metabolism (Table 2
). Moreover, the observed predictive value of apoC-III for CVD mortality risk was independent of glucose metabolism (Table 3
) and additional analyses, in which subjects with normal and impaired glucose metabolism and type 2 diabetes were considered separately, yielded similar results (data not shown).
Lipid-lowering medication may have modified our results because statins have been shown to lower apoC-III (19). We did not exclude subjects using lipid-lowering medication because this number of subjects was very small (1.4% at baseline), and their exclusion did not substantially alter our results (data not shown). It is likely that the use of lipid-lowering drugs substantially increased during the relatively long follow-up period, resulting in lowering of both apoC-III concentrations and CVD risk. Therefore, the hazard ratios reported in the present study probably underestimate the real risk associated with high apoC-III.
Several studies have prospectively and retrospectively investigated the role of apoC-III in cardiovascular risk. In a subset of the Cholesterol and Recurrent Events (CARE) trial, a prospective, nested case-control study in patients with myocardial infarction, the plasma concentrations of apoC-III in VLDL and LDL were more strongly associated with CHD risk than plasma triglycerides (12). In a population with a high prevalence of the metabolic syndrome (42%), the association between apoC-III and prevalent CHD has been studied cross-sectionally (14). In men, but not in women, both total apoC-III and apoC-III in the non-HDL-cholesterol subfraction were associated with prevalent CHD, independent of LDL- and HDL-cholesterol concentrations. Two relatively small studies showed that apoC-III is a cardiovascular risk factor in type 2 diabetic patients. In 242 diabetes patients with previous myocardial infarction, apoC-III–containing LDL prospectively predicted recurrent coronary events, independently of other lipids (11). Another study showed that triglycerides and apoC-III concentrations were independent cardiovascular risk factors in 188 patients with type 2 diabetes (10). In contrast, in a study with 30 type 2 diabetes patients and 30 subjects without diabetes, matched for plasma triglyceride concentrations, the subjects with diabetes had concentrations of apoC-III–containing VLDL similar to those of subjects without diabetes (2). This study suggested that plasma triglyceride concentration, and not type 2 diabetes, determined apoC-III concentration.
In subjects with normal triglyceride concentrations, apoC-III is mostly contained in HDL during the fasting state and is transferred to VLDL after a meal (10). In hypertriglyceridemic subjects, however, the majority of apoC-III is carried on VLDL during fasting (20). Although it has been shown recently that total apoC-III concentrations do not change postprandially (21), it cannot be excluded that an even stronger association with cardiovascular mortality risk could be obtained by measuring apoC-III in separate lipoprotein fractions instead of whole plasma. Indeed, apoC-III concentrations in VLDL and LDL, but not in HDL, were positively associated with the risk of recurrent coronary events (12). At first sight, the fact that we only measured apoC-III in plasma might be considered as a limitation of the present work. However, Cohn et al. (22) recently demonstrated that total plasma apoC-III was not affected by frozen storage. In contrast, storage of plasma leads to alterations in the lipoprotein distribution of apoC-III. For example, HDL apoC-III concentrations were 25% to 65% higher in samples after storage, depending on the method of isolation (22).
In accordance with its role as an inhibitor of lipoprotein lipase, we observed a strong correlation between concentrations of apoC-III and fasting triglycerides. The association between apoC-III and CVD risk was slightly attenuated after adjustment for fasting triglycerides. Remarkably, however, in the fully adjusted Cox model apoC-III remained significantly associated with CVD risk, independent of traditional risk factors, including fasting triglycerides. A possible explanation may be that apoC-III is a determinant not only of fasting concentrations of triglycerides, but also of the postprandial increase in triglycerides. Recent studies have shown that increased nonfasting triglycerides are associated with increased risk of cardiovascular events (23)(24). The latter study provided evidence that, at least in women, postprandial triglyceride concentrations may be superior to fasting concentrations for assessment of cardiovascular risk (24).
In conclusion, in a population-based cohort study, we observed that a high apoC-III concentration is a strong and independent predictor of cardiovascular mortality risk. Our results support an important role of triglyceride-rich lipoproteins, as reflected by apoC-III concentrations, in cardiovascular disease.
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Acknowledgments
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Grant/Funding Support: Merck & Co., Inc. is kindly acknowledged for the financial support of the determinations of apoC-III concentration in plasma.
Financial Disclosures: None declared.
Acknowledgments: We thank the colleagues of the Westfries Gasthuis, the participating general practitioners, and the staff of the Population Register of the city of Hoorn for their cooperation with this study. We also thank Regina Last for carefully searching the medical records for evidence of cardiovascular mortality, and we gratefully acknowledge Eric J. M. Wever for technical support.
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Footnotes
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1 Nonstandard abbreviations: CHD, coronary heart disease; apoC-III, apolipoprotein C-III; ICD-9, International Classification of Diseases, Ninth Revision; BMI, body mass index; CVD, cardiovascular disease. 
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Abstract
Introduction
