**9. Other studies showing strong prediction of CV risk by the apo-ratio**

In our previous review from 2006 (3) we commented results from several prospective risk studies all showing an important diagnostic improvement of CV risk using apos and the apo-ratio over conventional lipids most commonly also adjusted for other confounders. The Dutch EPIC-Norfolk study (111) published in 2007 was performed in 1,511 apparently healthy controls and in 869 cases who had developed a non-fatal or fatal MI. They showed that in a head to head analysis of TC/HDL-C ratio versus the apo-ratio the Odds ratio for linear trend for quartiles was non-significant for the lipid-ratio but strongly significant for the apo-ratio, p < 0.006. These analyses were adjusted for sex, age, and time of enrollment and was adjusted for diabetes (yes or no), body mass index, smoking status (yes or no), systolic blood pressure, C-reactive protein level, and log-transformed triglyceride level. The apo-ratio added significant predictive value above that of the Framingham risk score since the area under the receiver-operating characteristic curve was 0.594 for Framingham risk score alone vs. 0.613 for Framingham risk score plus the apo-ratio, p < 0.001. Despite the fact that the difference was strongly significantly in favor of the apo-ratio the authors concluded that this was only a small increase. However, the authors pointed out that the apo-ratio is also useful since it can be applied in non-fasting samples.

The German MONICA/Kora Augsburg study (112) showed that in 1,414 men and 1,436 women without prior MI and a median follow up of 13 years the TC/HDL-C ratio predicted MI risk. In addition, the apo-ratio was significantly related to increased risk of MI adjusted for age, smoking, alcohol, BMI, diabetes and hypertension.

112 Lipoproteins – Role in Health and Diseases

be a biomarker for ICAS in Asian patients with stroke.

**8.4. The ISIS-study relating the apo-ratio to risk of MI** 

previously reviewed results including the AMORIS study (3,44).

also useful since it can be applied in non-fasting samples.

and 7.79, for the fourth quartile versus the first quartile). Patients having more metabolic syndrome components indicating MetS were more likely to have ICAS, advanced ICAS, and a higher apo-ratio (p < 0.001 for all). Thus, a higher apo-ratio is a predictor of ICAS rather than of extracranial atherosclerotic stenosis or no cerebral atherosclerotic stenosis. The apo-ratio might

This ISIS case–control study was conducted among 3,510 acute MI patients (without prior vascular disease, diabetes, or statin use) in UK hospitals and 9,805 controls (60). Relative risks (age, sex, smoking, and obesity-adjusted) were more strongly related to apoB than to LDL-C and, given apoB, more strongly negatively related to apoA-I than to HDL-C. The apo-ratio was substantially more informative about risk than LDL-C/HDL-C, TC/HDL-C, non-HDL-C, and TC. Relative risks within several subgroups of patients showed no clear heterogeneity of effect with respect to sex, smoking, or BMI. The strongest effects were seen in those aged 30-49 years but even at ages 70-79, a 2SD higher apo-ratio was associated with a highly significant (P < 0.00001) relative risk. Furthermore, the apo-ratio, if untreated, is stable over time. Given the usual value of apoB, the usual value of LDL-C (indicating sdLDL particles) the risk was significantly higher. They concluded that single measurements of apoB and apoA-I are more predictive than single measurements of LDL-C and HDL-C and that the apo-ratio is the single best predictor of all lipid fractions is consistent with

**9. Other studies showing strong prediction of CV risk by the apo-ratio** 

In our previous review from 2006 (3) we commented results from several prospective risk studies all showing an important diagnostic improvement of CV risk using apos and the apo-ratio over conventional lipids most commonly also adjusted for other confounders. The Dutch EPIC-Norfolk study (111) published in 2007 was performed in 1,511 apparently healthy controls and in 869 cases who had developed a non-fatal or fatal MI. They showed that in a head to head analysis of TC/HDL-C ratio versus the apo-ratio the Odds ratio for linear trend for quartiles was non-significant for the lipid-ratio but strongly significant for the apo-ratio, p < 0.006. These analyses were adjusted for sex, age, and time of enrollment and was adjusted for diabetes (yes or no), body mass index, smoking status (yes or no), systolic blood pressure, C-reactive protein level, and log-transformed triglyceride level. The apo-ratio added significant predictive value above that of the Framingham risk score since the area under the receiver-operating characteristic curve was 0.594 for Framingham risk score alone vs. 0.613 for Framingham risk score plus the apo-ratio, p < 0.001. Despite the fact that the difference was strongly significantly in favor of the apo-ratio the authors concluded that this was only a small increase. However, the authors pointed out that the apo-ratio is

The German MONICA/Kora Augsburg study (112) showed that in 1,414 men and 1,436 women without prior MI and a median follow up of 13 years the TC/HDL-C ratio predicted In the American Thrombo study and its follow-up (113) both high apoB and low apoA-I predicted risk of re-infarction. In a follow-up they found that apoB was the strongest risk factor in those who manifested the MetS (114). However, in the German GRIPS (115), the results were negative in that LDL-C in multivariate analysis was found to be a stronger determinant of risk than apoB and the apo-ratio. This is, in fact, one of the very few studies to be found that shows LDL-C to be significantly better than apos in predicting risk. In the South Wales Cearphilly studies (116), although significant prediction was seen for apoB and apoA-I, the addition of apos did not improve prediction MI. In both of these two studies the number of events was below 300.

In the Swedish ULSAM studies (117,118) they showed that the risk of MI increased in parallel with increasing values of the apo-ratio. In those who had values for the ratio of <0.67 the incidence of MI was 9.5%, those who had ratios of 0.67–0.86 had an incidence of 17.7%, those with ratios of 0.87–1.23 had an incidence of 30.7%, and those with apo-ratio values >1.24 had an incidence of 44.8%. These risk values correspond well with those found in the AMORIS study (3,44). A risk prediction score was derived from one half of the population sample from the ULSAM cohort including systolic blood pressure, smoking, family history of MI, serum pro-insulin, and the apo-ratio. The score was highly predictive for future MI in the other half of the population that was not used for generating the score. The ULSAM score performed slightly better than the Framingham and PROCAM scores (evaluated as areas under the receiver operating curves; Framingham, 61%; PROCAM, 63%; ULSAM, 66%; p < 0.08). The authors also reported from the 30-year follow up of patients in the ULSAM study that ECG abnormalities were risk markers after the first 20 years of follow up but also that the apo-ratio and blood pressure remained significant risk predictors over three decades (118).

Ingelsson et al. (119) in the US Framingham study found that after a median follow-up of 15.0 years, 291 participants, 198 of whom were men, developed various manifestations of CHD. In multivariate models adjusting for non-lipid risk factors, the apo-ratio predicted CHD (HR per SD increment, 1.39; 95% CI 1.23-1.58 in men and HR, 1.40; 1.16-1.67 in women), but risk ratios were similar for the TC/HDL-C ratio (HR, 1.39; 1.22- 1.58 in men and HR, 1.39; 1.17-1.66 in women) and for LDL-C/HDL-C (HR, 1.35; 1.18-1.54 in men and HR, 1.36; 1.14-1.63 in women). In both genders, models using the apo-ratio were comparable with but not better than that for other lipid ratios. The apo-ratio did not predict CHD risk in a model containing all components of the Framingham risk score including the TC/HDL-C ratio. They concluded that the apo-ratio adds no incremental utility over this lipid ratio. Notably, there were few hard events in this small study, a fact that may restrict the interpretation of the results.

In India Goswami et al. (120) studied 100 patients with MI who were age-matched with 100 healthy control subjects. The exponential value of the regression coefficient beta for the aporatio was 11.9, as compared to 4.4 for the LDL-C/HDL-C ratio, 3.5 for the TC/HDL-C ratio and 2.2 for the TC/HDL-C ratio. The findings suggested that the apo-ratio is a better

discriminator of CAD risk in the atherosclerosis-prone Indian population, than any of the conventional lipid ratios. They suggested that the apo-ratio should be an alternative to other lipid ratios in the risk assessment in patients with CAD.

In a comparative observational study by Agoston-Coldea et al. (121) on 289 subjects were divided into two groups: 144 subjects with old MI, and 145 subjects without CHD, but with CV risk factors. The multivariate analysis indicated that apoB over 1.7 g/L are closely correlated with MI (p = 0.001) independent of age, smoking, diabetes, hypertension, lipid TC/HDL-C and the LDL-C/HDL-C ratio. The protective effect of apoA-I was also significant (p = 0.004) in multivariate analysis. They concluded that the predictive value of the apo-ratio is superior to that of serum lipid fractions and that the apo-ratio therefore should be introduced in current clinical practice.

In the prospective case-cohort study (PREVEND cohort) (122) 6,948 subjects without previous CHD they studied the risk factors predicting major coronary events. The age- and sex-adjusted HR was 1.37 (95% CI, 1.26-1.48) for the apo-ratio and 1.24 (1.18-1.29) for the TC/HDL-C ratio (both p < 0.001). The risks of the two ratios were only marginally attenuated by additional controlling for traditional risk factors TG, hypertension, diabetes, obesity and smoking), hs-CRP and albuminuria.

In a Korean study by Kim et al (123) they studied the association between plasma lipids, and apolipoproteins and coronary artery disease: a cross-sectional study in a low-risk Korean population in 544 subjects. In the lowest quartile of TC, TG and LDL-C, and the highest quartile of HDL-C, only the apo-ratio was associated with CAD in both men and women. They concluded that the apo-ratio is the only variable that differentiates the patients with CAD from those without and, furthermore, gives additional information to that supplied by traditional lipid risk factors in a low-risk Korean population.

Agoston-Coldea et al. (124) studied 208 patients (100 men and 108 women), with and without previous MI by coronary angiography. They showed that the apo-ratio had a stronger correlation with MI than the TC/HDL-C ratio. Multivariate analysis performed with adjustments for conventional risk factors, showed that the levels of apoB, the apo-ratio and Lp(a), are significant independent CV risk factors. Therefore they recommend that the apo-ratio and Lp(a) should be included in clinical practice.
