**3.1. ApoB production, circulation and distribution**

ApoB-100 is produced in the liver and apoB-48 is synthesized in the gut (3,12). ApoB-100 is the dominating protein in plasma compared with minute amounts of apoB-48 even in the postprandial state. In most conditions, more than 90% of all apoB in blood is found in LDL. There are excellent reviews of how apoB-100 assembles VLDL in the liver, more details on VLDL composition (12), and some comments on the genetics of apoB (30-33). ApoB is present in VLDL, IDL large buoyant LDL, and small dense LDL (sdLDL), with one molecule of apoB in each of these atherogenic particles (1). Importantly, apoB does not occur on HDL particles. Thus, total apoB reflects the total number of potentially atherogenic particles **(Figure 1).** This is principally different from non-HDL-C which indicates the total mass of C. ApoB produced in the liver stabilizes and allows the transport of C and TG in plasma VLDL, IDL, large buoyant LDL and sdLDL**.** ApoB also serves as the ligand for the apoB and apoB,E receptors thereby facilitating uptake of C in peripheral tissues and in the liver as reviewed (2,3,12). ApoB may provoke atherogenesis since it can be entrapped in the arterial wall of the coronary arteries and also as exemplified by findings in femoral plaques (12,34,35) where it may be modified, oxidized and glucosylated and therefore also contribute in the process of plaque formation. In this process LDL-C with apoB infiltrates the arterial wall and many factors like adhesion molecules, cytokines, growth factors are involved in oxidation processes leading to inflammation and growth of plaques unless HDL bound apoA-I can neutralize these processes (see elsewhere in this paper). Interestingly, already in 1976 Hoff presented data showing that apoB and apoA-I were found in the arterial wall of the coronary and carotid arteries as well as in the aorta (35). Olofsson et al (12) discuss the intra-arterial metabolism of apoB and apoA-I and also Fogelstrand and Borén (36).

#### **3.2. Plasma levels of apoB and target values for therapy**

The levels of apoB in plasma may vary from 0.2 to above 3 g/L, with highest values for those with hereditary hypercholesterolemias. In the "normal case" the values for males and females do not differ much. Reference values have been published by Cantois et al. already in 1996 (37). The values slowly increase from childhood to adult life (2,3). Those who live to ages above 75 years commonly have relatively low apoB values since those with higher values may have died due to various CV events. During lipid-lowering therapy apoB targets have been recommended to be < 0.90 g/L for those at moderate risk and < 0.80 for those at a high risk, see further below (3,9,11,38). Values should be given in two decimals.

#### **3.3. ApoB versus LDL-C and risk for CV events**

One of the first publications on clinical risks during the course of myocardial infarction (MI) related to apoB and also to apoA-I was presented by Avogaro already in 1978 (39,40). In 1980 Sniderman et al. presented data indicating that hyperapoB with normal C levels was related to coronary atherosclerosis (41). Since then many reports have been published indicating that apoB is involved in atherogenesis and its complications like MI. In 1996 Lamarche et al. (42) showed that apoB was strongly associated with onset of coronary heart disease in 2,155 men aged 45–76 years followed for 5 years (Quebec Cardiovascular Study). The predictive effect of apoB remained after adjustment for TG, HDL-C and TC/HDL-C. ApoA-I was protective, but not as strong as the harmful apoB in multivariate analysis. In the 10-year follow up of the Atherosclerosis Risk in Communities (ARIC) study, apoB was measured in 12,339 middle-aged participants (43) and had predictive power above that of LDL-C, TG and HDL-C. However, despite strong univariate associations for apoB and LDL-C, apoB did not contribute to risk prediction in subgroups with elevated TG, with lower LDL-C, or with high apoB relative to LDL-C. This may be due to the error for apoB determination which was estimated at 17% which is considerably higher than the approximate 5% that is common in most recent trials.

98 Lipoproteins – Role in Health and Diseases

**3. Physiological and pathophysiological aspects of apoB** 

ApoB-100 is produced in the liver and apoB-48 is synthesized in the gut (3,12). ApoB-100 is the dominating protein in plasma compared with minute amounts of apoB-48 even in the postprandial state. In most conditions, more than 90% of all apoB in blood is found in LDL. There are excellent reviews of how apoB-100 assembles VLDL in the liver, more details on VLDL composition (12), and some comments on the genetics of apoB (30-33). ApoB is present in VLDL, IDL large buoyant LDL, and small dense LDL (sdLDL), with one molecule of apoB in each of these atherogenic particles (1). Importantly, apoB does not occur on HDL particles. Thus, total apoB reflects the total number of potentially atherogenic particles **(Figure 1).** This is principally different from non-HDL-C which indicates the total mass of C. ApoB produced in the liver stabilizes and allows the transport of C and TG in plasma VLDL, IDL, large buoyant LDL and sdLDL**.** ApoB also serves as the ligand for the apoB and apoB,E receptors thereby facilitating uptake of C in peripheral tissues and in the liver as reviewed (2,3,12). ApoB may provoke atherogenesis since it can be entrapped in the arterial wall of the coronary arteries and also as exemplified by findings in femoral plaques (12,34,35) where it may be modified, oxidized and glucosylated and therefore also contribute in the process of plaque formation. In this process LDL-C with apoB infiltrates the arterial wall and many factors like adhesion molecules, cytokines, growth factors are involved in oxidation processes leading to inflammation and growth of plaques unless HDL bound apoA-I can neutralize these processes (see elsewhere in this paper). Interestingly, already in 1976 Hoff presented data showing that apoB and apoA-I were found in the arterial wall of the coronary and carotid arteries as well as in the aorta (35). Olofsson et al (12) discuss the

intra-arterial metabolism of apoB and apoA-I and also Fogelstrand and Borén (36).

high risk, see further below (3,9,11,38). Values should be given in two decimals.

The levels of apoB in plasma may vary from 0.2 to above 3 g/L, with highest values for those with hereditary hypercholesterolemias. In the "normal case" the values for males and females do not differ much. Reference values have been published by Cantois et al. already in 1996 (37). The values slowly increase from childhood to adult life (2,3). Those who live to ages above 75 years commonly have relatively low apoB values since those with higher values may have died due to various CV events. During lipid-lowering therapy apoB targets have been recommended to be < 0.90 g/L for those at moderate risk and < 0.80 for those at a

One of the first publications on clinical risks during the course of myocardial infarction (MI) related to apoB and also to apoA-I was presented by Avogaro already in 1978 (39,40). In 1980 Sniderman et al. presented data indicating that hyperapoB with normal C levels was related to coronary atherosclerosis (41). Since then many reports have been published indicating that apoB is involved in atherogenesis and its complications like MI. In 1996 Lamarche et al. (42) showed that apoB was strongly associated with onset of coronary heart

**3.2. Plasma levels of apoB and target values for therapy** 

**3.3. ApoB versus LDL-C and risk for CV events** 

**3.1. ApoB production, circulation and distribution** 

Importantly, apoB has been found to have a stronger relation with CV risk than LDL-C in several other studies as reported in coming sections. These include the AMORIS study (44), especially at low values of LDL-C (see below), the Thrombo Study (45), the Thrombo Metabolic Syndrome Study (46), the Northwick Park Heart Study (47), the Nurses' Health Study (48) and amongst patients with type 2 diabetes in the Health Professionals Follow-up Study (49).

In the Copenhagen City Heart Study Benn et al. (50) studied 9,231 asymptomatic women and men from the Danish general population followed prospectively for 8 years and observed the following incident events: ischemic heart disease 591, MI 278, ischemic cerebrovascular disease 313, ischemic stroke 229, and any ischemic CV event 807. ApoB, adjusted for multiple common confounding risk factors, had a higher predictive ability than LDL-C in all these various ischemic events (p < 0.03 to < 0.001). They suggested that prediction of future ischemic cardiovascular events could be improved by measuring apoB.

**Figure 2.** The AMORIS study; apoB, non-HDL-C and LDL-C (x-axis, deciles) versus risk of myocardial infarction (Odds Ratio) (y-axis) in males (left) and females (right).

In addition, in the placebo groups of several major statin clinical trials such as 4S (51), AFCAPS/TexCAPS (52,53) and LIPID (54) apoB was more informative than LDL-C as an index of the risk of CV events. Taken together, this strongly indicates that apo B is superior to LDL-C in recognizing the risk of CV disease and effects of statin therapy. Additional results (55) also favor apoB over LDL-C, and others are also reported in the section on the apo-ratio below. Such major studies are the AMORIS (3,44,56,57). In our study we found the steepest risk-relationship for MI with increasing values of apoB followed by non-HDL-C and the lowest increase in relation to LDL-C values with similar risk progressions for men and women **(Figure 2 and Figure 3 left).** Also in the INTERHEART (58,59) and ISIS-studies (60) as well as those summarized in the ERFC-meta-analyses (8,10) apoB was strongly related to risk of MI. In meta-analyses similar strong findings for apoB versus LDL-C are summarized by a large number of international scientists and clinicians in more detail (4,13,61,62).
