**12. The apo-ratio and relations to atherosclerosis, vascular functions and inflammation**

In many clinical conditions coronary arteriography, carotid ultrasound (CIMT), endothelial function, calcium scoring (CAC) and even more recently Intra Vascular Ultrasound (IVUS) studies of the coronary arteries has been related to lipid- and apo-abnormalities. Coronary and femoral plaques also contain apos (34-36). Many of these studies indicate that apos are more closely related to the amount of atherosclerosis than conventional lipids. Relevant studies are commented below.

In the Uppsala PIVUS study by Andersson et al. (145) the prevalence of carotid plaque was investigated. In 942 free living 70 year old men (n = 469) and women (n = 473) an ultrasound was performed. A plaque was defined by at least 50% increase of the intima-media thickness (IMT). Plaques were slightly more prevalent in men (n = 322) than in women (n = 293). Individuals with plaques had significantly higher the apo-ratio (p = 0.013), LDL-C/HDL-Cratio (p = 0.04), LDL-C (p = 0.02), higher levels of fasting blood glucose (p = 0.02), Framingham risk score (p < 0.0001), higher levels of systolic blood pressure, (p < 0.0001), and also a higher average of pack-years of cigarette smoking (p = 0.008) after adjustment for gender and statin use. No significant differences were seen for HDL-C, diastolic blood pressure or BMI. The inflammatory markers oxidized LDL, TNF alpha, and leucocyte count as well as insulin resistance (HOMA) were increased.

In another subsample of 70 years old men (n = 124) and women (n = 123) who did not use lipid-lowering drugs from the PIVUS study (146) were investigated whether the amount of visceral (VAT) or subcutaneous adipose tissue (SAT) independently of the other can determine the apo-ratio. VAT and SAT areas were assessed using magnetic resonance imaging. Their adipose tissue areas were related to their levels of apoB, apoA-I and the aporatio. ApoA-I levels were independently related to the VAT area (r = −0.33, p < 0.0001) whereas the apoB levels were not (r = 0.102, p = 0.07). The VAT area was independently significantly (r = 0.25, p = 0.001) related to the apo-ratio in the multiple regression analysis whereas the SAT area was not. This observation may indicate that VAT is metabolically active possibly through decreased adiponectin levels. The VAT metabolism seems more related to abnormalities in the apo-ratio which also may be a consequence of abnormal glucose-insulin metabolism as discussed above in other studies on the MetS.

118 Lipoproteins – Role in Health and Diseases

**inflammation** 

studies are commented below.

as well as insulin resistance (HOMA) were increased.

Carnevale-Schianca et al. (143) enrolled 616 patients with normal glucose tolerance (NGT) (273 men and 343 women), and measured insulin resistance, lipid profile, the apo-ratio and the factors compounding the MetS. An unfavorable apo-ratio (> 0.90 for males and > 0.80 for females) was present in 13.9 % of 108 patients with LDL-C < 100 mg/dL. Compared to subjects with lower apo-ratio, they had more elements of MetS and their lipid profile strongly correlated with high CV risk. In NGT individuals with LDL-C < 100 mg/dL, a higher apo-ratio indicated an atherogenic lipid profile, suggesting that LDL-C alone is insufficient to define CV risk. This study demonstrates that the apo-ratio is at least complementary to LDL-C in

Wen et al. (144) measured high sensitive hsCRP, apoB, apoA-I, and the profiles of coronary angiograms, echocardiography and oral glucose tolerance tests (OGTT)s as well as traditional risk factors in 1,757 cardiology patients. The hsCRP or the apo-ratio were significantly correlated with the presence and severity of angiographic profiles, the levels of left ventricular (LV) ejection fraction, LV mass and LV mass index, and the presence of abnormal OGTT. The combination of the apo-ratio and hsCRP had greater correlation with abnormal glucose metabolism than its individual components in patients with normal

**12. The apo-ratio and relations to atherosclerosis, vascular functions and** 

In many clinical conditions coronary arteriography, carotid ultrasound (CIMT), endothelial function, calcium scoring (CAC) and even more recently Intra Vascular Ultrasound (IVUS) studies of the coronary arteries has been related to lipid- and apo-abnormalities. Coronary and femoral plaques also contain apos (34-36). Many of these studies indicate that apos are more closely related to the amount of atherosclerosis than conventional lipids. Relevant

In the Uppsala PIVUS study by Andersson et al. (145) the prevalence of carotid plaque was investigated. In 942 free living 70 year old men (n = 469) and women (n = 473) an ultrasound was performed. A plaque was defined by at least 50% increase of the intima-media thickness (IMT). Plaques were slightly more prevalent in men (n = 322) than in women (n = 293). Individuals with plaques had significantly higher the apo-ratio (p = 0.013), LDL-C/HDL-Cratio (p = 0.04), LDL-C (p = 0.02), higher levels of fasting blood glucose (p = 0.02), Framingham risk score (p < 0.0001), higher levels of systolic blood pressure, (p < 0.0001), and also a higher average of pack-years of cigarette smoking (p = 0.008) after adjustment for gender and statin use. No significant differences were seen for HDL-C, diastolic blood pressure or BMI. The inflammatory markers oxidized LDL, TNF alpha, and leucocyte count

In another subsample of 70 years old men (n = 124) and women (n = 123) who did not use lipid-lowering drugs from the PIVUS study (146) were investigated whether the amount of visceral (VAT) or subcutaneous adipose tissue (SAT) independently of the other can determine the apo-ratio. VAT and SAT areas were assessed using magnetic resonance

identifying a more correct CV risk profile of asymptomatic NGT subjects.

fasting glucose, and was an independent predictor for coronary artery disease.

Schmidt and Wikstrand (147) reported that in a multi-variable analysis including all baseline variables only the apo-ratio (p = 0.003) and serum insulin (p = 0.026) were significantly related to IMT composite progression rate indicating that the apo-ratio is an important risk factor for predicting atherosclerotic progression rate during very long-term follow-up in clinically healthy middle-aged men.

Reis et al (148) have studied factors that may influence MetS and development of obesity. They performed weighted Pearson partial correlation coefficients for waist circumference, log-transformed leptin, and insulin vs. metabolic, inflammatory, and thrombogenic CV risk factors among men and women aged 40 years and older, NHANES III. They found that apoB was positively correlated with waist, leptin and insulin both in men and women, whereas apoA-I was significantly and negatively related to these risk markers. These findings may indicate that the apo-ratio can summarize the lipid abnormalities into one number. The results were adjusted for age, ethnicity, smoking, physical activity, alcohol intake and time of fasting.

Junyent et al. (149) assessed carotid intima-media thickness (CIMT) and plaque in relation to classical risk factors and apoA-I and apoB levels in 131 unrelated patients with familial hypercholesterolemia (FCHL), 27 with prior CVD and 190 age- and sex-matched control subjects. By multivariate analysis in a model with all risk factors, inclusive of the MetS, independent associations of CIMT were age, the apo-ratio, systolic blood pressure, fasting glucose, family history of CVD and TC/HDL-C ratio (r2 = 0.475, p < 0.001). The strongest determinant of IMT was the apo-ratio (β = 0.422, p < 0.001). The findings support the atherogenicity of the lipid phenotype in FCHL beyond associated risk factors. They also have implications for diagnosis and management of CVD risk in this condition.

Vladimirova-Kitova et al. (150) have found that carriers of a LDL-receptor defective gene have a higher carotid IMT and apo-ratio than non-carriers, whereas no difference between the groups was found with respect to the level of other lipid parameters, ADMA, total homocysteine, cell adhesion molecules, and % flow mediated dilation. Thus the apo-ratio is a predictor of IMT in carriers of this LDL-receptor gene.

Dahlen et al. (151) performed the CARDIPP-1 primary care study a study in 247 patients with type 2 diabetes, aged 55-66 years. They found that there was a significant association between the apo-ratio and CIMT in middle-aged patients with in type 2 diabetes. The association was independent of conventional lipids, hsCRP, glycaemic control and use of statins.

In the study by Rasouli et al. (152) 138 men and 126 women aged 40-70 years, were classified as CAD cases or controls, according to the results of coronary angiography. The severity of CAD was scored on the basis of the number and extent of lesions in coronary arteries. The results indicate that the apo-ratio, apoB and Lp(a) are independent risk factors for CAD and are superior to any of the cholesterol ratios. They suggested using the apo-ratio as the best marker of CAD in clinical practice.

Smith et al. (153) compared the body composition and the apo-ratio in migrant Asian Indians white Caucasians in Canada. Indian men and women had a higher apo-ratio than Caucasians (p = 0.0003)]. Of interest, there were also significant correlations between the apo-ratio and WHR in all groups, except the Indian women.

Both in children and adults obesity either defined by BMI or waist/hip ratio has been found to be directly related to apoB and the apo-ratio, and indirectly to apoA-I levels (154-156).

In the Cardiovascular Risk in Young Finns Study (157) they measured CIMT and brachial endothelial function in 879 subjects. They determined whether apoB and apoA-I measured in childhood and adolescence could predict atherosclerosis in adulthood. In subjects aged 12 to 18 years at baseline, apoB and the apo-ratio were directly (p < 0.001) related and apoA-I was inversely (p = 0.01) related with adulthood IMT. In subjects aged 3 to 18 years at baseline, apoB (p = 0.02) and the apo-ratio (p < 0.001) were inversely related, and apoA-I (p = 0.003) was directly related to adulthood flow mediated dilatation. Adjustment for age, gender, blood pressure, BMI, TG, insulin, CRP and brachial diameter at baseline did not change these relations. The apo-ratio measured in adolescence was stronger than the LDL-C/HDL-C or non-HDL-C/HDL-C ratios (c-values, 0.623 vs. 0.569, p = 0.03) in predicting increased CIMT in adulthood. The authors concluded that apoB and apoA-I measured in children and adolescents reflect an abnormal lipoprotein profile that may predispose to the development of subclinical atherosclerosis later in life. These markers are therefore useful in pediatric lipid risk assessment.

In a cross-sectional and 6-year prospective data from the cardiovascular risk in young Finns study (aged 24 to 39 years) (158) they studied metabolic risk variable MetS and their associations with CIMT. ApoB, CRP, and type II secretory phospholipase A2 enzyme activity were significantly higher and apoA-I lower in subjects with MetS (n = 325) than in subjects without MetS (n=858) indicating that the apo-ratio may summarize the risk into one number. In prospective analysis both MetS and high apoB predicted (p < 0.0001) incident high CIMT. The association between MetS and incident high CIMT was attenuated by about 40% after adjustment with apoB. Adjustments with apoA-I, CRP, or type II secretory phospholipase A2 did not diminish the association. Thus, the atherogenicity of MetS in this population assessed by incident high CIMT is mainly mediated by elevated apoB, but not inflammatory markers.

In the Swedish study Wallenfeldt et al. studied the relationships between abnormalities in lipoprotein concentrations in 338 apparently healthy 58-year-old men with manifestations of the MetS (159). Those who had an apo-ratio > 0.74, irrespective of blood pressure and smoking, had a significant progression (untreated) of the IMT values of the carotids over a 3-year period. Thus CIMT is a non-invasive simple, sensible and useful method to follow dynamic progression of atherosclerosis. Furthermore, the level of the apo-ratio is a strong predictor of these atherosclerotic changes in the arterial wall. Thus, values of the apo-ratio > 0.74 may alert the treating doctor to the need of adequate lipid-lowering therapy.

120 Lipoproteins – Role in Health and Diseases

marker of CAD in clinical practice.

pediatric lipid risk assessment.

inflammatory markers.

apo-ratio and WHR in all groups, except the Indian women.

In the study by Rasouli et al. (152) 138 men and 126 women aged 40-70 years, were classified as CAD cases or controls, according to the results of coronary angiography. The severity of CAD was scored on the basis of the number and extent of lesions in coronary arteries. The results indicate that the apo-ratio, apoB and Lp(a) are independent risk factors for CAD and are superior to any of the cholesterol ratios. They suggested using the apo-ratio as the best

Smith et al. (153) compared the body composition and the apo-ratio in migrant Asian Indians white Caucasians in Canada. Indian men and women had a higher apo-ratio than Caucasians (p = 0.0003)]. Of interest, there were also significant correlations between the

Both in children and adults obesity either defined by BMI or waist/hip ratio has been found to be directly related to apoB and the apo-ratio, and indirectly to apoA-I levels (154-156).

In the Cardiovascular Risk in Young Finns Study (157) they measured CIMT and brachial endothelial function in 879 subjects. They determined whether apoB and apoA-I measured in childhood and adolescence could predict atherosclerosis in adulthood. In subjects aged 12 to 18 years at baseline, apoB and the apo-ratio were directly (p < 0.001) related and apoA-I was inversely (p = 0.01) related with adulthood IMT. In subjects aged 3 to 18 years at baseline, apoB (p = 0.02) and the apo-ratio (p < 0.001) were inversely related, and apoA-I (p = 0.003) was directly related to adulthood flow mediated dilatation. Adjustment for age, gender, blood pressure, BMI, TG, insulin, CRP and brachial diameter at baseline did not change these relations. The apo-ratio measured in adolescence was stronger than the LDL-C/HDL-C or non-HDL-C/HDL-C ratios (c-values, 0.623 vs. 0.569, p = 0.03) in predicting increased CIMT in adulthood. The authors concluded that apoB and apoA-I measured in children and adolescents reflect an abnormal lipoprotein profile that may predispose to the development of subclinical atherosclerosis later in life. These markers are therefore useful in

In a cross-sectional and 6-year prospective data from the cardiovascular risk in young Finns study (aged 24 to 39 years) (158) they studied metabolic risk variable MetS and their associations with CIMT. ApoB, CRP, and type II secretory phospholipase A2 enzyme activity were significantly higher and apoA-I lower in subjects with MetS (n = 325) than in subjects without MetS (n=858) indicating that the apo-ratio may summarize the risk into one number. In prospective analysis both MetS and high apoB predicted (p < 0.0001) incident high CIMT. The association between MetS and incident high CIMT was attenuated by about 40% after adjustment with apoB. Adjustments with apoA-I, CRP, or type II secretory phospholipase A2 did not diminish the association. Thus, the atherogenicity of MetS in this population assessed by incident high CIMT is mainly mediated by elevated apoB, but not

In the Swedish study Wallenfeldt et al. studied the relationships between abnormalities in lipoprotein concentrations in 338 apparently healthy 58-year-old men with manifestations of the MetS (159). Those who had an apo-ratio > 0.74, irrespective of blood pressure and smoking, had a significant progression (untreated) of the IMT values of the carotids over a In a Japanese study (160) sixty-six type 2 diabetic patients with carotid atherosclerosis and 66 age- and sex-matched patients without carotid atherosclerosis were compared. They concluded that the combination of apoB and HOMA-R is a superior marker of carotid atherosclerosis compared with LDL-C alone in patients with type 2 diabetes.

Kim et al. (161) have studied 757 stroke patients undergoing coronary artery bypass grafting. They found that prevalence of asymptomatic carotid stenosis > 50% and > 70% was 26.4 % and 8.6%, respectively. In multivariate analysis, plasma levels of the apo-ratio and homocysteine were independently associated with carotid stenosis. Receiver operating characteristic curve (ROC) analysis indicated area under the curve values of 0.708 (the aporatio), 0.678 (Lp(a)), and 0.689 (homocysteine).

Ajeganova et al. (162) have studied patients with rheumatoid arthritis (RA) that commonly are affected by premature atherosclerosis including development of xanthomas. They studied 114 patients, age 50.6 years, 68.4% women, with recent RA (< 12 months after symptoms onset) and they were assessed at 0, 3, 12, 24 and 60 months after RA diagnosis. Plaque detection was positively associated with age and smoking (ever). After adjustment, a longitudinal approach demonstrated an independent positive prediction of CIMT by the aporatio (p = 0.030), but negative prediction by apoA-I (p = 0.047). Higher levels of the proatherogenic apo-ratio and apoB and low anti-PC (IgM antibodies against phosphorylcholine) were independently associated with bilateral carotid plaque p = 0.002, 0.026 and 0.000, respectively). Both baseline and longitudinal levels of other inflammatory/disease-related factors failed to show significant associations with the study outcomes.
