High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are strong predictors of atherosclerosis. Statin-induced changes in the ratio of LDL-C to HDL-C (LDL-C/HDL-C) predicted atherosclerosis progression better than LDL-C or HDL-C alone. However, the best predictor of subclinical atherosclerosis remains unknown. Our objective was to investigate this issue by measuring changes in carotid intima-media thickness (IMT). A total of 1,920 subjects received health examinations in 1999, and were followed up in 2007. Changes in IMT (follow-up IMT/baseline
A low level of high-density lipoprotein cholesterol (HDL-C) is a strong and independent predictor of cardiovascular disease [
Elevated levels of LDL-C/HDL-C or apolipoprotein (apo) B100/A-1 ratios were reported in patients with coronary atherosclerosis [
A periodic epidemiological survey was performed in 1999 in a small farming community in Japan (a cohort of the Seven Countries Study) on the island of Kyushu. As reported previously, the demographic backgrounds of the subjects in this area are similar to those of the Japanese general population [
Eight years later, we performed a follow-up examination. IMT was measured in the same manner as in the original examination. Investigators at re-examination were blinded to the participants’ clinical characteristics and to their baseline IMT values. Changes in IMT were calculated as the value of follow-up IMT divided by baseline IMT, and were expressed as a percentage. Of 1,920 subjects in the original study, baseline lipid profiles were missing in 164 subjects, and follow-up IMT could not be performed in 300 subjects (183 had died, 73 refused the re-examination, 37 were lost to follow-up, and 7 had moved). In the end, complete data sets were available from 1,456 subjects, for a follow-up rate of 75.8%.
Informed consent was obtained from all subjects. The study was approved by the Kurume University Ethics Committee.
The subjects’ medical history, alcohol intake, and smoking habits were ascertained by a questionnaire. Alcohol intake and smoking habits were classified as current habitual use or not. Height and weight were measured, and body mass index (BMI) was calculated as weight (kg) divided by the square of height (m2) as an index of obesity. Waist circumference was measured at the level of the umbilicus in the standing position. Blood pressure (BP) was measured in the right arm twice with a mercury sphygmomanometer after subjects had rested in a supine position for more than 5 minutes. The second BP with the fifth-phase diastolic pressure was used for analysis.
Blood was drawn from the antecubital vein for determinations of glycosylated hemoglobin A1c (HbA1c), lipids profiles (total cholesterol, LDL-C, HDL-C, triglycerides (TG), and remnant-like lipoprotein particle cholesterol (RLP-C), and free fatty acid (FFA)) in the morning after 12-hour fast. Fasting blood samples were centrifuged immediately after collection. Serum total cholesterol, LDL-C, HDL-C, TG, FFA, and creatinine were measured by enzymatic assay method, and RLP-C was measured by an immunoseparation technique using an immunoaffinity gel containing monoclonal antibodies to human apo B100 and apo A-1 [
Results were presented as mean ± standard deviation (SD). Because of skewed distributions, TG, RLP-C, and FFA were log-transformed before data analyses; mean values, and upper and lower 95% confidence limits, were exponentiated and presented as geometric mean ± SD, where the SD was approximated as the difference between the exponentiated confidence limits divided by 3.92, the value of SD in a 95% confidence interval for normally distributed data. Sex, smoking habits, alcohol intake, hypertensive medication, diabetic medication, and hyperlipidemic medication were used as dummy variables.
In order to investigate factors responsible for changes in IMT after 8 years, multiple linear regression analyses were performed with age, sex, and baseline IMT. The mean changes in IMT levels stratified by quartiles of LDL-C/HDL-C ratio were compared using analysis of covariance (ANCOVA) adjusted for age, sex, baseline IMT, and lipid lowering medications. Since subjects with a greater IMT at baseline may exhibit increased changes in IMT, further analysis was performed using the subjects with an IMT less than 1.1 mm at baseline. This subanalysis used the same ANCOVA analysis as described above.
Statistical significance was defined as
Demographic data for the 1,920 subjects at baseline in 1999 are presented in Table
Characteristics of subjects at baseline in 1999.
Men | Women | Total | |
---|---|---|---|
N | 794 | 1126 | 1920 |
Age, years | |||
Systolic blood pressure, mmHg | |||
Diastolic blood pressure, mmHg | |||
Body mass index, kg/m2 | |||
Waist, cm | |||
IMT, mm | |||
Absolute difference of IMT, mm | |||
Total cholesterol, mg/dL | |||
HDL-C, mg/dL | |||
LDL-C, mg/dL | |||
Triglycerides | |||
Non-HDL-C, mg/dL | |||
LDL-C/HDL-C ratio | |||
Total cholesterol/HDL-C ratio | |||
Triglycerides/HDL-C ratio | |||
Triglycerides/LDL-C ratio | |||
Free fatty acid | |||
RLP-C | |||
HbA1c, % | |||
Smoking, % | 38.8 | 2.0 | 17.2 |
Alcohol intake, % | 48.9 | 3.2 | 22.1 |
Hypertensive medication, % | 20.5 | 19.0 | 19.6 |
Diabetic medication, % | 3.9 | 2.6 | 3.1 |
Lipids lowering medication, % | 2.4 | 6.4 | 4.7 |
Association between IMT and variables at baseline in multiple linear regression analysis adjusted for age and sex.
Variables | Standard error | Probability | |
---|---|---|---|
Systolic blood pressure | 0.00158 | 0.0002 | <0.01 |
Diastolic blood pressure | 0.00145 | 0.0003 | <0.01 |
Body mass index | 0.00444 | 0.0013 | 0.01 |
Waist | 0.00119 | 0.0005 | 0.01 |
Total cholesterol | 0.00028 | 0.0001 | 0.02 |
HDL-C | −0.00127 | 0.0003 | <0.01 |
LDL-C | 0.00053 | 0.0001 | <0.01 |
Triglycerides* | 0.00006 | 0.0001 | 0.23 |
Non-HDL-C | 0.00049 | 0.0001 | <0.01 |
LDL-C/HDL-C ratio | 0.02930 | 0.0048 | <0.01 |
Total cholesterol/HDL-C | 0.02083 | 0.0037 | <0.01 |
ratio | |||
Triglycerides/HDL-C ratio* | 0.02034 | 0.0062 | <0.01 |
Triglycerides/LDL-C ratio* | 0.00237 | 0.0078 | 0.76 |
Free fatty acid | 0.00313 | 0.0075 | 0.68 |
RLP-C | 0.01832 | 0.0073 | 0.01 |
HbA1c | 0.01688 | 0.0052 | <0.01 |
Smoking | 0.00632 | 0.0120 | 0.60 |
Alcohol intake | −0.02119 | 0.0114 | 0.06 |
In Table
Relationship between 8-year changes in IMT and variables in multiple linear regression analysis adjusted for age, sex, and baseline IMT.
Variables | Standard error | Probability | |
---|---|---|---|
Systolic blood pressure | 0.07764 | 0.0278 | 0.01 |
Diastolic blood pressure | 0.01312 | 0.0464 | 0.78 |
Body mass index | 0.39651 | 0.1681 | 0.02 |
Waist | 0.16325 | 0.0627 | 0.01 |
Total cholesterol | 0.01204 | 0.0155 | 0.44 |
HDL-C | −0.08175 | 0.0380 | 0.03 |
LDL-C | 0.03103 | 0.0175 | 0.08 |
Triglycerides* | −0.00088 | 0.0060 | 0.88 |
Non-HDL-C | 0.02595 | 0.0156 | 0.10 |
LDL-C/HDL-C ratio | 1.55453 | 0.6466 | 0.02 |
Total cholesterol/HDL-C | 1.06553 | 0.4974 | 0.03 |
ratio | |||
Triglycerides/HDL-C ratio* | 0.80106 | 0.7886 | 0.31 |
Triglycerides/LDL-C ratio* | −1.32504 | 0.9724 | 0.03 |
Free fatty acid* | 0.52784 | 1.0439 | 0.61 |
RLP-C* | 0.23376 | 0.8359 | 0.75 |
HbA1c | 0.55307 | 0.7430 | 0.46 |
Smoking | −0.94243 | 1.6585 | 0.57 |
Alcohol intake | −0.55662 | 1.5202 | 0.71 |
Figure
Relationship between LDL-C/HDL-C ratio and changes in IMT. (a) Data from 1,456 subjects was analyzed by ANCOVA adjusted for age, sex, baseline IMT, and lipids lowering medication. (b) Data from 1,349 subjects with less than 1.1 mm IMT at baseline was analyzed by ANCOVA adjusted for age, sex, baseline IMT, and lipid lowering medications.
In analyses using the receiver operating characteristic (ROC) curve, an LDL-C to HDL-C ratio of 2.3 (area under curve 0.552) showed the strongest association with IMT progression (80.3% sensitivity and 79.3% specificity, data not shown).
This is the first report of a general population or large-scale epidemiological study focusing on the relationship between LDL-C/HDL-C ratio and IMT progression.
In this study, we evaluated changes in IMT by high-resolution carotid ultrasonography but did not measure plaques. It may have been preferable to measure changes in plaques rather than IMT. However, it is very difficult to accurately estimate the changes in plaques because of their complex morphology. In contrast, the evaluation of IMT is relatively simple and accurate. Furthermore, IMT, as an indicator of subclinical atherosclerosis, has been shown to be a strong risk factor for cardiovascular events [
With regard to composite variables that include proatherogenic lipoprotein measurements, data for direct comparisons are limited to studies based on the general population [
A significant association between IMT and proatherogenic lipoprotein measurements was shown in Table
Our data may suggest that elevated LDL/HDL ratio is not just a marker of atherosclerosis but may play a causal role in the pathogenesis of human IMT progression. Another interesting issue to be clarified is the cut-off values of LDL-C/HDL-C for predicting IMT progression. One Japanese investigator [
This study had some limitations. First, the lack of biochemical measurements and medication data in the followup is a major limitation. Second, we did not measure total plaque area. Third, we only examined subjects older than 40 years old. It would be interesting to determine whether LDL-C/HDL-C ratio is a predictor of progression of IMT of the carotid artery in subjects younger than 40 years of age. Fourth, several pharmacological interventions have beneficial effects on prevention of the progression of IMT [
In conclusion, to our knowledge, this is the first epidemiological report in a community cohort to show that LDL-C/HDL-C ratio is a better predictor of carotid IMT progression than HDL-C or LDL-C alone.
This study was supported in part by the Kimura Memorial Heart Foundation, Fukuoka, Japan, and by a Science Frontier Research Promotion Center grant from the Ministry of Education, Science Sports and Culture, Japan. The author are grateful to the members of the Japan Medical Association of Ukiha, the residents of Tanushimaru, and the team of participating physicians for help in performing the health examinations.