Improving Prediction of Ischemic Cardiovascular Disease in the General Population Using Apolipoprotein B
The Copenhagen City Heart Study
Background— Apolipoprotein B (apoB) levels predict fatal myocardial infarction. Whether apoB also predicts nonfatal ischemic cardiovascular events is unclear. We tested the following hypotheses: apoB predicts ischemic cardiovascular events, and apoB is a better predictor of ischemic cardiovascular events than low-density lipoprotein cholesterol.
Methods and Results— We studied 9231 asymptomatic women and men from the Danish general population followed prospectively for 8 years and observed the following incident events: ischemic heart disease 591, myocardial infarction 278, ischemic cerebrovascular disease 313, ischemic stroke 229, and any ischemic cardiovascular event 807. Women with apoB in the upper versus the lower tertile had hazard ratios for ischemic heart disease of 1.8 (1.2 to 2.5), for myocardial infarction 2.6 (1.4 to 4.7), and for any ischemic cardiovascular event 1.8 (1.3 to 2.3), and men had hazard ratios for ischemic heart disease of 1.9 (1.5 to 2.6), for myocardial infarction 2.4 (1.5 to 3.6), and for any ischemic cardiovascular event 1.6 (1.3 to 2.1). Women had similar hazard ratios for ischemic cerebrovascular disease and ischemic stroke. ApoB had a higher predictive ability than low-density lipoprotein cholesterol in the prediction of ischemic heart disease, myocardial infarction, any ischemic cardiovascular event, and any nonfatal ischemic cardiovascular event in both genders (P=0.03 to <0.001). Finally, in smokers older than 60 years with systolic blood pressure >160 mm Hg, apoB contributed 11% in women and 15% in men to the increase in absolute 10-year risk from the lower to the upper apoB tertile.
Conclusion— ApoB predicts ischemic cardiovascular events in both genders, and is better than low-density lipoprotein cholesterol in this respect. We suggest that prediction of future ischemic cardiovascular events could be improved by measuring apoB.
Ischemic cardiovascular disease, that is ischemic heart disease (IHD) and ischemic cerebrovascular disease (ICVD), is one of the major causes of hospitalization and death in affluent societies. Because elevated low-density lipoprotein (LDL) cholesterol levels cause atherosclerosis and thus ischemic cardiovascular disease, levels of LDL cholesterol are used for screening to identify individuals at risk of this disease. However, the protein component of LDL particles, apolipoprotein B (apoB), has also been shown to predict fatal myocardial infarction in both genders and nonfatal coronary heart disease in men.1–7 These findings suggest that apoB could be a better predictor of fatal and non-fatal cardiovascular events than LDL cholesterol. A likely explanation for this is that while LDL cholesterol is an estimate of the mass of cholesterol in the LDL fraction only, the value for apoB is a measurement of the total number of atherogenic particles (including LDL, intermediate density lipoprotein, very low density lipoprotein, chylomicrons, and chylomicron remnants), because each of these contain only a single molecule of apoB. Because risk of atherosclerosis appears to be more directly related to the number of circulating atherogenic particles that enter the arterial wall than to the concentrations of cholesterol in these fractions, this suggests that apoB would be a better predictor of risk than the concentrations of cholesterol in the LDL fraction. Thus, whether apoB is a better predictor than LDL cholesterol of IHD, myocardial infarction, ICVD, and ischemic stroke in both genders should be further explored.
We tested the hypothesis that apoB predicts IHD, myocardial infarction, ICVD, and ischemic stroke in women and men from the general population. Furthermore, we compared apoB and LDL cholesterol as predictors of ischemic cardiovascular disease. Finally, we evaluated the absolute 10-year risk of any ischemic cardiovascular event by tertiles of apoB and LDL cholesterol as well as by gender, smoking status, age, and systolic blood pressure. For these purposes we studied 9231 asymptomatic women and men from the Danish general population followed prospectively for 8 years.
Subjects and Methods
The Copenhagen City Heart Study is a prospective cardiovascular study of the Danish general population. An almost equal number of women (55%) and men were stratified into 10-year age groups from 20 to 80 years and older; 99% were white and of Danish descent. At the third examination, 1991 to 1994, 10 135 participated. In the present study, we included 9231 individuals from the 1991 to 1994 examination who had apoB, total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoprotein A1 (apoA1) determined and who were free of ischemic cardiovascular disease at baseline.
Endpoints used in the study were IHD, myocardial infarction, ICVD, ischemic stroke, or any ischemic cardiovascular event; myocardial infarction was a subgroup of IHD and ischemic stroke was a subgroup of ICVD. In participants dying within 3 months after an event, the event was regarded as fatal (99% died within 1 week). Participants were followed from baseline, defined as the date of participation in the 1991 to 1994 examination, until the occurrence of IHD, myocardial infarction, ICVD, ischemic stroke, or any ischemic cardiovascular event or end of 2000, whichever came first. Participants were followed using their unique Central Person Register number and follow-up was 100%.
Information on diagnosis of IHD, myocardial infarction, ICVD, and ischemic stroke (WHO International Classification of Diseases, 8th edition codes 410 to 414, 410, 432 to 435, and 432 to 434, respectively; and 10th edition codes I20 to I25, I21 to I22, I63 to I64, and I63, respectively) was collected and verified until December 31, 2000 by reviewing all hospital admissions and diagnoses entered in the Danish National Hospital Discharge Register, and all causes of death entered in the Danish National Register of Causes of Death, and medical records from hospitals and general practitioners.
IHD was determined on the basis of previous myocardial infarction or characteristic symptoms of stable or unstable angina pectoris based on location, character, and duration of pain, and the relation of pain to exercise. A diagnosis of myocardial infarction required the presence of at least 2 of the following criteria: characteristic chest pain, elevated cardiac enzymes, or electrocardiographic changes indicative of myocardial infarction.
An experienced neurologist reviewed all potential cases of ICVD, that is, ischemic stroke, transient ischemic attack (focal neurological symptoms lasting <24 hour), or amaurosis fugax (transient blindness on one eye only). Possible ischemic stroke events were validated using the WHO definition of stroke: an acute disturbance of focal or global cerebral function with symptoms lasting >24 hour or leading to death with presumably no other reason than of vascular origin. To distinguish between infarction, intracerebral hemorrhages and subarachnoid hemorrhages, either a CT or an MRI scan, autopsy, spinal fluid examination, or surgical description was necessary.
Subjects receiving lipid-lowering medication at baseline were excluded (n=92). Hypertension was defined as use of antihypertensive medication, a systolic blood pressure >140 mm Hg, or a diastolic blood pressure >90 mm Hg at inclusion into the study. Diabetes mellitus was defined as self-reported disease or a nonfasting plasma glucose >11.0 mmol/L at baseline. Smokers were active smokers.
The study was approved by institutional review boards and a Danish ethical committee (No.100.2039/91, Copenhagen and Frederiksberg committee), and was conducted according to the Declaration of Helsinki. Participants gave written informed consent.
Turbidimetric and colorimetric assays were used on fresh samples to measure plasma levels of apoB and apoA1 (nonstandardized assays), total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides.8 LDL cholesterol was calculated when plasma triglycerides were <5 mmol/L (97.4% of individuals) using the equation of Friedewald. Non-HDL cholesterol was total cholesterol−HDL cholesterol.
Data were analyzed using SPSS and Stata. Two-sided P<0.05 was considered significant. Student t-test or Pearson χ2 test was used in 2-group comparisons. Gender- and age-specific tertiles of apoB, total cholesterol, LDL cholesterol, apoB/apoA1, total cholesterol/HDL cholesterol, and non-HDL cholesterol were constructed. Pearson product-moment correlation coefficient, r, was used to assess the relationship between apoB and LDL cholesterol.
Cumulative incidences were plotted using Kaplan-Meier curves and differences between tertiles of apoB examined using log-rank tests. Cox proportional hazards regression models with age as a covariate, with age and LDL cholesterol as covariates, or multifactorially adjusted for age, HDL cholesterol, triglycerides, body mass index, hypertension, diabetes mellitus, and smoking status, were used to estimate hazard ratios for ischemic cardiovascular events by tertiles of apoB, total cholesterol, LDL cholesterol, apoB/apoA1, total cholesterol/HDL cholesterol, and non-HDL cholesterol. In addition, Cox regression was performed with age as time scale, which means that differences in age are automatically adjusted for, as well as with gender-specific tertiles of apoB, total cholesterol, LDL cholesterol, apoB/apoA1, total cholesterol/HDL cholesterol, and non-HDL cholesterol within 10-year age groups.
The predictive ability of apoB, total cholesterol, LDL cholesterol apoB/apoA1, total cholesterol/HDL cholesterol, and non-HDL cholesterol in the prediction of ischemic cardiovascular events was estimated as the area under the curve from receiver operating characteristics curves. Equality of the area under the curves on the receiver operating characteristics plot was tested using the algorithm suggested by DeLong.
The estimated absolute risk of any ischemic cardiovascular event (IHD and ICVD combined) was calculated using the regression coefficients from a Poisson regression model by tertiles of apoB and LDL cholesterol, respectively, age in 3 groups (<40, 40 to 60, and >60 years), smoking status (nonsmoker/smoker), and systolic blood pressure in 3 groups (<140, 140 to 160, and >160 mm Hg) for women and men separately. Absolute risks are presented as estimated incidence rates (number of events/10 years) in percent.
To compare LDL cholesterol and apoB for use in a risk prediction score, all individuals in the population who later developed IHD were first assigned a baseline 10-year risk value using the Framingham coronary heart disease risk prediction score sheet based LDL cholesterol levels.9 This score sheet assigns points for age, LDL cholesterol, HDL cholesterol, blood pressure, diabetes, and smoking status. The points are added up for each individual and converted into a 10-year risk estimate. Subsequently, the same individuals were scored now using exactly the same score system, but substituting the LDL cholesterol score with an apoB score. To compare the 2 tests, values of the LDL cholesterol cut points used in the Framingham risk prediction score sheet were converted to a percentile value in the Copenhagen City Heart Study population and the corresponding value for apoB was used as the apoB cut point (group 1: LDL ≤2.59 mmol/L≫≤15.65 percentile≫apoB ≤63 mg/dL; group 2: LDL 2.60 to 3.36 mmol/L≫15.66 to 39.39 percentile≫apoB 64 to 78 mg/dL; group 3: LDL 3.37 to 4.14 mmol/L≫39.40 to 66.67 percentile≫apoB 79 to 94 mg/dL; group 4: LDL 4.15 to 4.91 mmol/L≫66.68 to 85.86 percentile≫apoB 95 to 110 mg/dL; group 5: LDL ≥4.92 mmol/L≫≥85.87 percentile≫apoB ≥111 mg/dL).
Baseline characteristics of individuals from the general population by diagnostic status at the end of follow-up are shown (supplemental Table I, available online at http://atvb.ahajournals.org). During 8 years of follow-up (63 059 person-years), we observed the following number of incident events: IHD, 591; myocardial infarction, 278; ICVD, 313; ischemic stroke, 229; and any ischemic cardiovascular event, 807. Of the latter, 25% in women and 28% in men were fatal ischemic cardiovascular events. ApoB levels increased as a function of age in 10-year age groups for both women and men (supplemental Figure I). Levels of apoB were positively correlated with those of LDL cholesterol (women: r2=0.78, P=0.000; men: r2=0.70, P=0.000).
Risk of Ischemic Cardiovascular Disease by Tertiles of ApoB
Plots of the cumulative incidence of IHD, myocardial infarction, ICVD, and ischemic stroke, and any ischemic cardiovascular event as a function of follow-up time and apoB in tertiles showed a stepwise increase in cumulative incidence from the lower tertile through the middle to the upper tertile for all end-points except for ICVD and ischemic stroke in men (Figure 1, left panel). In the latter 2 groups, the cumulative incidence for the lower and middle tertiles of apoB were similar, whereas in the upper tertile the cumulative incidence appeared to be increased (ICVD: P=0.01; ischemic stroke: P=0.10). At the age of 70 years, on Kaplan-Meier curves using age as time scale, the difference in cumulative incidence of any ischemic cardiovascular event between the lower and upper tertile of apoB was ≈10% in both genders (Figure 1, right panel). Plots of the cumulative incidence of any ischemic cardiovascular event as a function of follow-up time and apoB in tertiles, and stratified on gender and age <60 or ≥60 years, also showed an increased cumulative incidence in the upper tertile for both age groups; however, the cumulative incidence in the middle tertile was not significantly increased compared with the lower tertile in individuals older than 60 years (supplemental Figure II).
By Cox regression adjusted for age only, women and men with apoB in the upper versus lower tertile had an increased risk of IHD, myocardial infarction, and any ischemic cardiovascular event with hazard ratios ranging from 1.6 (95% CI:1.3 to 2.1) for any ischemic cardiovascular event in men to 2.6 (1.4 to 4.7) for myocardial infarction in women (Table 1). These hazard ratios were similar, after multifactorial adjustment for total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, body mass index, hypertension, diabetes mellitus, and smoking. Women, but not men, with apoB in the upper tertile also had an increased risk of ICVD and ischemic stroke, which became more pronounced after adjustment for other cardiovascular risk factors, with hazard ratios of 2.4 (1.3 to 4.4/4.5) for both ICVD and ischemic stroke (Table 1). Cox regression using age as time scale, or using apoB tertiles determined within 10-year age groups in each gender, gave similar results (data not shown).
Comparison of ApoB and LDL Cholesterol as Predictors of Ischemic Cardiovascular Events
In women, the upper tertiles of apoB, apoB/apoA1, and total cholesterol/HDL cholesterol versus the lower tertiles were associated with an increased risk of both IHD and myocardial infarction, whereas LDL cholesterol and non-HDL cholesterol were associated with an increased risk of myocardial infarction only (Figure 2). In men, the upper tertiles of apoB, total cholesterol, LDL cholesterol, apoB/apoA1, total cholesterol/HDL cholesterol, and non-HDL cholesterol were all associated with increased risks of both IHD and myocardial infarction with the largest hazard ratios for apoB. In women only, the upper tertiles of apoB, total cholesterol, LDL cholesterol, and non-HDL cholesterol were also associated with an increased risk of ICVD and ischemic stroke (borderline for LDL cholesterol and non-HDL cholesterol). Finally, the upper tertiles of all 6 predictors were associated with increased risks of any ischemic cardiovascular event in both genders (Figure 2). When distinguishing between nonfatal and fatal ischemic cardiovascular events, only the upper tertile of apoB versus the lower tertile predicted an increased risk of nonfatal events in both genders, whereas the upper tertiles of apoB, total cholesterol, LDL cholesterol, apoB/apoA1, total cholesterol/HDL cholesterol, and non-HDL cholesterol predicted risk of fatal events in men only (data not shown).
ApoB had a higher predictive ability than LDL cholesterol in the prediction of IHD, myocardial infarction, any ischemic cardiovascular event, and any nonfatal ischemic cardiovascular event in both genders (Table 2), and similar trends were found for apoB versus total cholesterol. ApoB was also a more reliable risk predictor than apoB/apoA1, total cholesterol/HDL cholesterol in the prediction of ICVD and ischemic stroke in women, and of any ischemic cardiovascular event in both genders (Table 2).
Comparing the predictive ability of apoB between strata of age, LDL cholesterol level, body mass index, hypertension, diabetes, and smoking showed that apoB was a better predictor in both women and men younger than 60 years compared with those older than 60 (P=0.0001 and P=0.01, respectively), and in women with a body mass index <25 kg/m2 (P=0.001) and without hypertension (P=0.006; supplemental Table II). There was no interaction between levels of LDL cholesterol and apoB in the prediction of any ischemic cardiovascular event in either gender, suggesting that level of LDL cholesterol did not affect the predictive value of apoB as reported by others1(supplemental Table II).
Maximizing both sensitivity and specificity for prediction of any ischemic cardiovascular event, identified a cut-point for levels of apoB of 90 mg/dL (sensitivity and specificity both 61%) and a cut-point for levels of LDL cholesterol of 3.9 mmol/L (sensitivity and specificity both 60%) (Figure 3).
Absolute 10-Year Risk of Any Ischemic Cardiovascular Event
The lowest absolute 10-year risks of any ischemic cardiovascular event were 0.3% and 0.6%, respectively, in nonsmoking women and men younger than 40 years of age with normal blood pressure and in the lowest apoB tertile (Figure 3). Absolute risks increased with smoking, increasing age, blood pressure, and apoB levels. The highest absolute 10-year risks of any ischemic cardiovascular event were 36% and 55% in smoking women and men older than 60 years of age, with a systolic blood pressure >160 mm Hg, and an apoB level in the upper tertile; incorporating LDL cholesterol instead of apoB, the equivalent highest absolute 10-year risks were 34% and 53% (Figure 3, lower right panel in both genders). Within this group of individuals (smokers, >60 years, and systolic blood pressure >160 mm Hg), apoB contributed 11% and 15% in women and men, respectively, to the increase in 10-year risk between the upper and lower tertiles of apoB.
ApoB Versus LDL Cholesterol by Framingham Coronary Heart Disease Risk Prediction Score
Scoring all individuals who later developed ischemic heart disease using the Framingham coronary heart disease risk prediction score sheet with either LDL cholesterol or apoB, showed similar risk scores in 83% of women and 68% of men (Figure 4). However, in 10% of women and 20% of men apoB assigned a higher risk score than LDL cholesterol, whereas LDL cholesterol assigned a higher score than apoB in 7% of women and 12% of men. Individuals in whom apoB assigned a higher risk score than LDL cholesterol had higher levels of triglycerides and body mass index and reduced LDL cholesterol (supplemental Table III).
In this study of the general population, upper versus lower tertile of apoB predicted an increased risk of IHD, myocardial infarction, and any ischemic cardiovascular event in both women and men, as well as an increased risk of ICVD and ischemic stroke in women. These risk estimates only changed slightly when adjusting for LDL cholesterol, indicating that apoB had predictive value beyond LDL cholesterol. Furthermore, apoB had a higher ability than LDL cholesterol in predicting IHD, myocardial infarction, and any ischemic cardiovascular event in both genders. Because of the overlap in levels of both apoB and LDL cholesterol in individuals with and without ischemic cardiovascular events, it was not possible to select clinically relevant cut-points to separate between these 2 diagnostic groups using levels of apoB or LDL cholesterol alone, emphasizing that apoB and LDL cholesterol values alone should not be used as risk predictors in the general population, but should be combined with information on other risk factors to enable risk stratification.
Several case-control studies have shown that levels of apoB are more strongly associated with the presence of IHD than levels of total or LDL cholesterol.10,11 Among prospective studies, the AMORIS study demonstrated that apoB was a predictor of fatal myocardial infarction even at low LDL cholesterol levels, whereas LDL cholesterol alone was a marginally significant predictor in men, but not in women.1 Similar results were reported the Quebec Cardiovascular Study using coronary events as end-point,2 in The Northwick Park Heart Study,3 for apoB compared with non-HDL cholesterol in prediction of ischemic cardiovascular disease in the Health Professionals Follow-up Study,4 for apoB alone and apoB/apoA1 ratio in prediction of coronary heart disease in the Nurses’ Health Study,5 and for apoB as a predictor of risk of recurrent coronary events.6 In the Women’s Health Study apoB/apoA1 ratio was shown to be only marginally better than total cholesterol/HDL cholesterol ratio in prediction of cardiovascular.7 Novel findings in the present study of a general population sample include that apoB level is a predictor of an increased risk of: (1) ischemic heart disease and myocardial infarction not only in men, but also in women; (2) ICVD and ischemic stroke in women; (3) any ischemic cardiovascular event and any nonfatal ischemic cardiovascular event in both genders; and (4) apoB has a higher predictive ability than LDL cholesterol in the prediction of IHD, myocardial infarction, any ischemic cardiovascular event and any nonfatal ischemic cardiovascular event in both women and men. Taken together, this suggests that prediction of future ischemic cardiovascular events in the general population could be improved in both women and men by measuring apoB.
It could be argued that measurement of non-HDL cholesterol could be equally good at predicting ischemic cardiovascular disease compared with apoB, because non-HDL cholesterol measure the cholesterol content of all apoB-containing lipoproteins. In accordance with this idea, we found that the predictive ability using receiver operating characteristics curves for non-HDL cholesterol was similar to that for apoB for all ischemic cardiovascular disease endpoints studied in both women and men.
From a methodological point of view, the measurement of apoB has been standardized by the International Federation of Clinical Chemistry,12 it has been automated, and fasting samples are not required. The interindividual biological coefficient of variation is lower for apoB than for LDL cholesterol (CV within: 6.9% versus 8.3%; http://www.westgard.com/biodatabase1.htm), making repeated measurements of apoB more reliable in the single patient. Measurement of non-HDL cholesterol is even less reliable, because this measurement depends on variation in measurement of both total cholesterol (CV within: 6.0%) and HDL cholesterol (7.1%).
Although there is abundant evidence that the risk of both coronary and peripheral atherosclerotic cardiovascular disease is directly related to plasma cholesterol levels, the relationship between levels of apoB, total cholesterol, and LDL cholesterol and ICVD and ischemic stroke is not so well-established13–15; however, recent data from the AMORISstudy have shown an association of increased apoB/apoA1 ratio and increased risk of fatal ischemic stroke in both genders.16 In this study we demonstrate that the upper tertiles compared with the lower tertiles of apoB, total cholesterol, LDL cholesterol, and non-HDL cholesterol are all associated with risk of ICVD and apoB and total cholesterol with ischemic stroke in women, but not in men. Furthermore, apoB, total cholesterol, LDL cholesterol, and non-HDL cholesterol all have significant ability in the prediction of ICVD and ischemic stroke in women.
Information on the absolute 10-year risk of any cardiovascular event offers a tool useful in the primary prevention of such events, and can be used to identify patients with asymptomatic or subclinical disease who could potentially benefit from intensive primary prevention efforts. Neither the American Heart Association’s recommendations for risk assessment in asymptomatic individuals based on the Framingham Study,9 nor the recommendations of the First Joint Task Force of the European Societies on Coronary Prevention based on the SCORE project17 have included apoB in their risk assessments. The data from the AMORIS study,1 The Quebec Cardiovascular Study,2 The Northwick Park Heart Study,3 the Women’s Health Study,7 the Nurses’ Health Study,5 and the present study suggests that apoB can contribute further information to better-define cardiovascular disease risk, not only in men but also in women. A likely explanation for this is that while LDL cholesterol is an estimate of the mass of cholesterol in the LDL fraction only, the value for apoB is a measurement of the total number of atherogenic particles in plasma, including LDL, intermediate density lipoprotein, very-low-density lipoprotein particles, chylomicrons, and chylomicron remnants.
A limitation of our study is that apoB was measured at baseline only and not by a standardized assay. It would be interesting to determine whether repeated measures of apoB values over time, ie, as area under curves, could contribute even more information on cardiovascular disease risk. Another limitation is that our risk estimates are obtained from a high-risk white population. Using the estimates of absolute 10-year risks in the individual is therefore limited to areas of the world with similar prevalence of risk factors and underlying rates of cardiovascular events. A minor drawback is that we only have information about use of statins at baseline and not during follow-up. Because both apoB and LDL cholesterol are evaluated in the same population and statin treatment would approximately reduce both to the same degree, this would not alter the main conclusion of the article.
In conclusion, apoB predicts ischemic cardiovascular events in both genders, and is better than LDL cholesterol in this respect. For this reason, we suggest that prediction of future ischemic cardiovascular events could be improved by measuring apoB.
Sources of Funding
This work was supported by The Danish Heart Foundation, The Danish Medical Research Council, Chief Physician Johan Boserup and Lise Boserup’s Fund, Ingeborg and Leo Dannin’s Grant, and the Research Fund at Rigshospitalet, Copenhagen University Hospital.
Original received September 23, 2006; final version accepted November 30, 2006.
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