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apoA-I levels
International Congress Series 1262 (2004) 203 – 206
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Hypercholesterolemia and hypertriglyceridemia—greatest cardiac risk in subjects with high apoB/apoA-I levels Go¨ran Walldius a,b,*, Are Aastveit c, Ingmar Jungner d a
King Gustaf V Research Institute, Karolinska Institute, Stockholm, Sweden b AstraZeneca, SE-431 83 Molndal, Sweden c Department of Mathematical Sciences, Agricultural University of Norway, As, Norway d CALAB Research, Stockholm and Karolinska Institute, Stockholm, Sweden
Abstract. Hypercholesterolemia and hypertriglyceridemia are risk factors for cardiovascular disease. The potentially atherogenic very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), large buoyant, and small dense low-density lipoprotein (LDL) particles are all transported by apolipoprotein (apo) B, one protein per particle. The anti-atherogenic HDL contains apoA-I. In the apolipoprotein-related mortality risk (AMORIS) study, 98,722 males and 76,831 females aged 20 – 80 years were investigated at health check-ups. They were followed for 98 months, and 1267 males and 586 females died from myocardial infarction. The aim of the study is to investigate if apoB and apoA-I are more closely related to cardiac risk than lipids. The most common lipid phenotype in those who died was combined hypercholesterol- and hypertriglyceridemia (type IIB, 48%), followed by isolated hypercholesterolemia (type IIA, 40%). However, irrespective of lipid phenotype, and also in subjects with normal lipids, the highest CV risk was seen in those with a high apoB/apoA-I (>0.9 in males, >0.8 in females) compared with those with values below these cut-points. It is concluded that the balance of apoB/apoA-I is a simple and precise indicator strongly reflecting CV risk irrespective of lipid levels or combinations of lipids. D 2004 Published by Elsevier B.V. Keywords: Apolipoprotein B; Apolipoprotein A-I; Cholesterol; Triglycerides; Myocardial infarction
1. Introduction Hypercholesterolemia due to high levels of low-density lipoprotein (LDL) cholesterol (C), hypertriglyceridemia often associated with low values of high-density lipoprotein (HDL)-C, and especially combined hyperlipidemias are all associated with increased risk of cardiovascular morbidity and mortality. The potentially atherogenic lipoprotein particles very low density (VLDL), intermediate density (IDL), large buoyant LDL, and small
* Corresponding author. AstraZeneca, SE-431 83 Molndal, Sweden. Tel.: +46-31-776-2678; fax: +46-31776-3802. E-mail address: [email protected] (G. Walldius). 0531-5131/ D 2004 Published by Elsevier B.V. doi:10.1016/j.ics.2003.12.033
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dense LDL all contain one apolipoprotein (apo) B per particle, whereas the antiatherogenic HDL particles contain apoA-I, the major apolipoprotein that can remove excess cholesterol from peripheral tissues and transport it back to the liver in the reverse cholesterol transport. New data from our apolipoprotein-related mortality risk (AMORIS) study [1] and other prospective data [2], as well as results from lipid-lowering trials, indicate that the higher the values for the ratio, i.e., the balance between apoB/apoA-I, the greater is the risk of suffering from a cardiac event [2]. The objective of the present AMORIS report is to analyse if an abnormal apoB/apoA-I balance can identify those at greatest risk of a fatal acute myocardial infarction (AMI) irrespective of their lipid levels and their lipid phenotypes. 2. Materials and methods In the AMORIS study, we have followed prospectively 98,722 males and 76,831 females from under 20 to above 80 years of age at entry for in average 98 months. The subjects were investigated at health check-ups, and no patients were hospitalized or investigated in acute situations. All details on the design, laboratory, and statistical methods have been described previously [1,3]. In the present report, the results from the cohort of individuals above 40 years of age at entry are presented. The subjects were classified in different lipid phenotypes based on TC cut levels of 5.0 mmol/l and TG cut levels of 1.5 mmol/l. Thus, isolated hypercholesterolemia is indicated as type IIA subjects, isolated hypertriglyceridemia as type IV subjects, and combined hyperlipidemias as type IIB subjects. Normal individuals (N) had lipid levels below both cut values. Prevalence numbers for the different lipid phenotypes are given. The subjects were also categorized according to their apoB/apoA-I ratio. The cut values chosen were 0.9 for males and 0.8 for females. These cut-points were chosen based on the cumulative curves for apoB/apoA-I values corresponding to about the 25th percentile of those dying from an AMI. 3. Results At entry into the study, the most common lipid phenotype was type IIA, which occurred in about 45% of the males and in 58% of the females. The corresponding numbers for type IIB were 39% and 25%, respectively. Isolated hypertriglyceridemia, i.e., type IV, was uncommon—below 5% in both genders. At the follow-up, 1243 males and 586 females died from AMI. A total of 48% of all subjects suffering a fatal AMI had type IIB hyperlipidemia, and above 40% had type IIA hypercholesterolemia. Type IV occurred only in 2 –4% of the subjects and in only 8% of males and 6% of females with normal TC and TG levels. The highest risks were seen in subjects with type IIB hyperlipidemia, similar in both genders with p < 0.0001, compared with subjects having normal lipid levels. AMI risk was also higher in type IIA subjects, p < 0.0001 for both genders, as well as for subjects with type IV hypertriglyceridemia, p < 0.004 for males, and p < 0.005 for females. In all subjects, males and females pooled, irrespective of their lipid phenotype, the risk was significantly greater in those having a high apoB/apoA-I value with a mean value of about 1 or higher, compared with those with a low value, p < 0.0001 for all phenotypes
G. Walldius et al. / International Congress Series 1262 (2004) 203–206
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Fig. 1. Cardiac risk (deaths/1000 obs.yrs.) in relation to lipid phenotypes and levels of apoB/apoA-I.
(Fig. 1). Also in subjects with normal lipids, those with a high apoB/apoA-I ratio had a greater risk, p < 0.0003. However, although they were comparatively few, the greatest risk was observed in type IV subjects having a high ratio, p < 0.0002 vs. normals with a high ratio. The greatest number of AMI cases (n = 784) was found in subjects with a high apoB/ apoA-I and type IIB. Their risk factor was double that of normals with a high apoB/apoAI, p < 0.0001. Notably, subjects with type IIA and a high ratio did not have a greater risk than normals with a high ratio despite 2-mmol/l higher TC values in type IIA subjects. In fact, many of type IIA subjects had a high apoA-I and a fairly normal apoB (Fig. 1), indicating a proportionally high contribution of HDL-C in this cohort. 4. Discussion Although isolated hypercholesterolemia was more prevalent in the population, combined hyperlipidemia of type IIB was the most common abnormality in those suffering a fatal AMI. The difference in the risk of dying from AMI was somewhat bigger for subjects with type IIA hypercholesterolemia than for those with normal lipids, but the difference was not as big as that for individuals with combined hyperlipidemia or isolated hypertriglyceridemia. Although few individuals had isolated hypertriglyceridemia, they experienced a great risk, especially those with a high apoB/apoA-I ratio. The greatest risk of dying from AMI, irrespective of lipid phenotype, was obtained in subjects having a high ratio apoB/apoA-I compared with those having a low ratio. In addition, in those with normal lipid levels, the risk was greater in those with a high apoB/ apoA-I ratio than those having a low ratio. Notably, individuals with type IIA and a high ratio did not differ in risk vs. those with normal lipids and a high ratio.
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G. Walldius et al. / International Congress Series 1262 (2004) 203–206
The present findings confirm and extend our previous AMORIS results showing that the apoB/apoA-I ratio has additional predictive value above that of TC and TG irrespective of age and gender [1,2]. The present results show that apoB/apoA-I has a superior predictive value not only above the lipid levels as such, but also in subjects with different, and commonly occurring lipid phenotypes. This is further illustrated in those with normal lipid levels and a high apoB/apoA-I ratio. In conclusion, our results indicate that the balance in apoB/apoA-I is a simple and informative risk indicator that is valid in both genders of all ages and largely independent on the lipid levels and lipid profiles or phenotypes. Since apoB and apoA-I methods are internationally standardized [3] and can be measured with low errors, CV 3 –5%, they are cheap and insensitive to the nutritional state; these risk indicators should be used also in the clinical routine. In fact, new international guidelines now recognize these apolipoproteins as new important cardiovascular risk markers [4]. In addition, cut levels, at least for apoB, have been proposed [5]. Since apoB and apoA-I are also at least as good or, in fact, better markers of lipid-lowering treatment by statins [2], apoB, apoA-I, and especially the balance of apoB/apoA-I will become important predictors of cardiac risk and targets for lipid-lowering therapy. References [1] G. Walldius, I. Jungner, I. Holme, A.H. Aastveit, W. Kolar, E. Steiner, High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study, Lancet 358 (2001) 2026 – 2033. [2] A.D. Sniderman, C.D. Furberg, A. Keech, J.E. Roeters van Lennep, J. Frohlich, I. Jungner, G. Walldius, Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment, Lancet 361 (2003) 777 – 780. [3] I. Jungner, S.M. Marcovina, G. Walldius, I. Holme, W. Kolar, E. Steiner, Apolipoprotein B and A-I values in 147 576 Swedish males and females, standardized according to the World Health Organization—International Federation of Clinical Chemistry First International Reference Materials, Clin. Chem. 44 (1998) 1641 – 1649. [4] International Atherosclerosis Society, Harmonized clinical guidelines on prevention of atherosclerotic vascular disease, Executive Summary, 2003, 1 – 23, http://[email protected]. [5] S.M. Grundy, Low-density lipoprotein, non-high density lipoprotein, and apolipoprotein B as targets of lipid lowering therapy, Circulation 106 (2002) 2526 – 2529.
www.ics-elsevier.com
Hypercholesterolemia and hypertriglyceridemia—greatest cardiac risk in subjects with high apoB/apoA-I levels Go¨ran Walldius a,b,*, Are Aastveit c, Ingmar Jungner d a
King Gustaf V Research Institute, Karolinska Institute, Stockholm, Sweden b AstraZeneca, SE-431 83 Molndal, Sweden c Department of Mathematical Sciences, Agricultural University of Norway, As, Norway d CALAB Research, Stockholm and Karolinska Institute, Stockholm, Sweden
Abstract. Hypercholesterolemia and hypertriglyceridemia are risk factors for cardiovascular disease. The potentially atherogenic very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), large buoyant, and small dense low-density lipoprotein (LDL) particles are all transported by apolipoprotein (apo) B, one protein per particle. The anti-atherogenic HDL contains apoA-I. In the apolipoprotein-related mortality risk (AMORIS) study, 98,722 males and 76,831 females aged 20 – 80 years were investigated at health check-ups. They were followed for 98 months, and 1267 males and 586 females died from myocardial infarction. The aim of the study is to investigate if apoB and apoA-I are more closely related to cardiac risk than lipids. The most common lipid phenotype in those who died was combined hypercholesterol- and hypertriglyceridemia (type IIB, 48%), followed by isolated hypercholesterolemia (type IIA, 40%). However, irrespective of lipid phenotype, and also in subjects with normal lipids, the highest CV risk was seen in those with a high apoB/apoA-I (>0.9 in males, >0.8 in females) compared with those with values below these cut-points. It is concluded that the balance of apoB/apoA-I is a simple and precise indicator strongly reflecting CV risk irrespective of lipid levels or combinations of lipids. D 2004 Published by Elsevier B.V. Keywords: Apolipoprotein B; Apolipoprotein A-I; Cholesterol; Triglycerides; Myocardial infarction
1. Introduction Hypercholesterolemia due to high levels of low-density lipoprotein (LDL) cholesterol (C), hypertriglyceridemia often associated with low values of high-density lipoprotein (HDL)-C, and especially combined hyperlipidemias are all associated with increased risk of cardiovascular morbidity and mortality. The potentially atherogenic lipoprotein particles very low density (VLDL), intermediate density (IDL), large buoyant LDL, and small
* Corresponding author. AstraZeneca, SE-431 83 Molndal, Sweden. Tel.: +46-31-776-2678; fax: +46-31776-3802. E-mail address: [email protected] (G. Walldius). 0531-5131/ D 2004 Published by Elsevier B.V. doi:10.1016/j.ics.2003.12.033
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G. Walldius et al. / International Congress Series 1262 (2004) 203–206
dense LDL all contain one apolipoprotein (apo) B per particle, whereas the antiatherogenic HDL particles contain apoA-I, the major apolipoprotein that can remove excess cholesterol from peripheral tissues and transport it back to the liver in the reverse cholesterol transport. New data from our apolipoprotein-related mortality risk (AMORIS) study [1] and other prospective data [2], as well as results from lipid-lowering trials, indicate that the higher the values for the ratio, i.e., the balance between apoB/apoA-I, the greater is the risk of suffering from a cardiac event [2]. The objective of the present AMORIS report is to analyse if an abnormal apoB/apoA-I balance can identify those at greatest risk of a fatal acute myocardial infarction (AMI) irrespective of their lipid levels and their lipid phenotypes. 2. Materials and methods In the AMORIS study, we have followed prospectively 98,722 males and 76,831 females from under 20 to above 80 years of age at entry for in average 98 months. The subjects were investigated at health check-ups, and no patients were hospitalized or investigated in acute situations. All details on the design, laboratory, and statistical methods have been described previously [1,3]. In the present report, the results from the cohort of individuals above 40 years of age at entry are presented. The subjects were classified in different lipid phenotypes based on TC cut levels of 5.0 mmol/l and TG cut levels of 1.5 mmol/l. Thus, isolated hypercholesterolemia is indicated as type IIA subjects, isolated hypertriglyceridemia as type IV subjects, and combined hyperlipidemias as type IIB subjects. Normal individuals (N) had lipid levels below both cut values. Prevalence numbers for the different lipid phenotypes are given. The subjects were also categorized according to their apoB/apoA-I ratio. The cut values chosen were 0.9 for males and 0.8 for females. These cut-points were chosen based on the cumulative curves for apoB/apoA-I values corresponding to about the 25th percentile of those dying from an AMI. 3. Results At entry into the study, the most common lipid phenotype was type IIA, which occurred in about 45% of the males and in 58% of the females. The corresponding numbers for type IIB were 39% and 25%, respectively. Isolated hypertriglyceridemia, i.e., type IV, was uncommon—below 5% in both genders. At the follow-up, 1243 males and 586 females died from AMI. A total of 48% of all subjects suffering a fatal AMI had type IIB hyperlipidemia, and above 40% had type IIA hypercholesterolemia. Type IV occurred only in 2 –4% of the subjects and in only 8% of males and 6% of females with normal TC and TG levels. The highest risks were seen in subjects with type IIB hyperlipidemia, similar in both genders with p < 0.0001, compared with subjects having normal lipid levels. AMI risk was also higher in type IIA subjects, p < 0.0001 for both genders, as well as for subjects with type IV hypertriglyceridemia, p < 0.004 for males, and p < 0.005 for females. In all subjects, males and females pooled, irrespective of their lipid phenotype, the risk was significantly greater in those having a high apoB/apoA-I value with a mean value of about 1 or higher, compared with those with a low value, p < 0.0001 for all phenotypes
G. Walldius et al. / International Congress Series 1262 (2004) 203–206
205
Fig. 1. Cardiac risk (deaths/1000 obs.yrs.) in relation to lipid phenotypes and levels of apoB/apoA-I.
(Fig. 1). Also in subjects with normal lipids, those with a high apoB/apoA-I ratio had a greater risk, p < 0.0003. However, although they were comparatively few, the greatest risk was observed in type IV subjects having a high ratio, p < 0.0002 vs. normals with a high ratio. The greatest number of AMI cases (n = 784) was found in subjects with a high apoB/ apoA-I and type IIB. Their risk factor was double that of normals with a high apoB/apoAI, p < 0.0001. Notably, subjects with type IIA and a high ratio did not have a greater risk than normals with a high ratio despite 2-mmol/l higher TC values in type IIA subjects. In fact, many of type IIA subjects had a high apoA-I and a fairly normal apoB (Fig. 1), indicating a proportionally high contribution of HDL-C in this cohort. 4. Discussion Although isolated hypercholesterolemia was more prevalent in the population, combined hyperlipidemia of type IIB was the most common abnormality in those suffering a fatal AMI. The difference in the risk of dying from AMI was somewhat bigger for subjects with type IIA hypercholesterolemia than for those with normal lipids, but the difference was not as big as that for individuals with combined hyperlipidemia or isolated hypertriglyceridemia. Although few individuals had isolated hypertriglyceridemia, they experienced a great risk, especially those with a high apoB/apoA-I ratio. The greatest risk of dying from AMI, irrespective of lipid phenotype, was obtained in subjects having a high ratio apoB/apoA-I compared with those having a low ratio. In addition, in those with normal lipid levels, the risk was greater in those with a high apoB/ apoA-I ratio than those having a low ratio. Notably, individuals with type IIA and a high ratio did not differ in risk vs. those with normal lipids and a high ratio.
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G. Walldius et al. / International Congress Series 1262 (2004) 203–206
The present findings confirm and extend our previous AMORIS results showing that the apoB/apoA-I ratio has additional predictive value above that of TC and TG irrespective of age and gender [1,2]. The present results show that apoB/apoA-I has a superior predictive value not only above the lipid levels as such, but also in subjects with different, and commonly occurring lipid phenotypes. This is further illustrated in those with normal lipid levels and a high apoB/apoA-I ratio. In conclusion, our results indicate that the balance in apoB/apoA-I is a simple and informative risk indicator that is valid in both genders of all ages and largely independent on the lipid levels and lipid profiles or phenotypes. Since apoB and apoA-I methods are internationally standardized [3] and can be measured with low errors, CV 3 –5%, they are cheap and insensitive to the nutritional state; these risk indicators should be used also in the clinical routine. In fact, new international guidelines now recognize these apolipoproteins as new important cardiovascular risk markers [4]. In addition, cut levels, at least for apoB, have been proposed [5]. Since apoB and apoA-I are also at least as good or, in fact, better markers of lipid-lowering treatment by statins [2], apoB, apoA-I, and especially the balance of apoB/apoA-I will become important predictors of cardiac risk and targets for lipid-lowering therapy. References [1] G. Walldius, I. Jungner, I. Holme, A.H. Aastveit, W. Kolar, E. Steiner, High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study, Lancet 358 (2001) 2026 – 2033. [2] A.D. Sniderman, C.D. Furberg, A. Keech, J.E. Roeters van Lennep, J. Frohlich, I. Jungner, G. Walldius, Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment, Lancet 361 (2003) 777 – 780. [3] I. Jungner, S.M. Marcovina, G. Walldius, I. Holme, W. Kolar, E. Steiner, Apolipoprotein B and A-I values in 147 576 Swedish males and females, standardized according to the World Health Organization—International Federation of Clinical Chemistry First International Reference Materials, Clin. Chem. 44 (1998) 1641 – 1649. [4] International Atherosclerosis Society, Harmonized clinical guidelines on prevention of atherosclerotic vascular disease, Executive Summary, 2003, 1 – 23, http://[email protected]. [5] S.M. Grundy, Low-density lipoprotein, non-high density lipoprotein, and apolipoprotein B as targets of lipid lowering therapy, Circulation 106 (2002) 2526 – 2529.