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the Honolulu Epidemiology Research Unit, Field Studies and Clinical Epidemiology Scientific Research Group, Epidemiology and Biometry Program, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Hawaii (C.M.B., D.S.S.); the Division of Biostatistics, University of Virginia School of Medicine, Charlottesville (R.D.A.); the Division of Clinical Epidemiology, Department of Medicine, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu (J.D.C., B.L.R.); and the Honolulu Heart Program, Kuakini Medical Center (J.D.C., B.L.R., K.Y.), Hawaii.
| Abstract |
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240 mg/dL: 6.7%; HDL cholesterol <35 mg/dL: 6.4%; LDL cholesterol
160 mg/dL: 5.5%; triglycerides
200 mg/dL: 18.7%), while prevalence of desirable total (<200 mg/dL) and HDL cholesterol (
60 mg/dL) concentrations was more common (62.7% and 23.7%, respectively). Mean levels of total cholesterol, LDL cholesterol, and triglyceride decreased significantly with increasing age (P<.001), while mean HDL cholesterol level increased slightly (P<.05). After univariate analyses of potential correlates, multiple linear regression models were used to identify variables independently associated with each of the lipids. After adjustment for other variables, levels of fibrinogen and hematocrit were positively associated and insulin, white blood cell count, and use of diabetic medication were negatively associated with total cholesterol. Correlates for LDL cholesterol were similar but also included vital capacity (positive relation) and alcohol (negative relation). Heart rate, physical activity, alcohol, and hematocrit were positively associated with HDL cholesterol; body mass index, subscapular skinfold thickness, glucose, fibrinogen, white blood cell count, and hypertension were negatively associated. Factors associated with triglycerides tended to be similar, yet the direction of relations was reversed. Age-adjusted total cholesterol levels were significantly lower in men who had coronary surgery, thromboembolic stroke, and hemorrhagic stroke but were higher in those with peripheral vascular disease. Lower HDL cholesterol levels were found in men with prevalent angina, angioplasty, definite myocardial infarction, thromboembolic stroke, and peripheral vascular disease. LDL cholesterol and triglycerides showed fewer significant relations with these conditions. Findings indicate that elderly Japanese-American men have a favorable lipid profile, except for elevated triglyceride levels, relative to levels in other populations of older Americans and that a number of cardiovascular risk factors and diseases are strongly associated with lipids in elderly men. These analyses also identify several modifiable factors that may favorably influence lipid and lipoprotein levels in the elderly.
Key Words: Asian Americans cardiovascular diseases cholesterol lipoproteins triglycerides
| Introduction |
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240 mg/dL) levels of total cholesterol, as well as the prevalence of low levels of HDL cholesterol (<35 mg/dL), high LDL cholesterol (
160 mg/dL), and high triglyceride (
200 mg/dL), and potential differences in these proportions across different ethnic groups. Assessments of lipid and lipoprotein correlates in elderly minority populations have also been infrequent. Several previous studies have identified generalized and regional obesity, hypertension, glucose intolerance, medication use, and lifestyle variables such as physical activity, smoking, and alcohol consumption as factors that may influence lipid and lipoprotein levels.1 17 18 19 20 21 22 In addition, factors such as fibrinogen, insulin, vital capacity, and red and white cell indices have often not been included as potential correlates of lipids.
A recent reexamination of over 3700 participants from the Honolulu Heart Program (HHP) provided the opportunity to examine cross-sectionally the distribution and potential correlates of lipids and lipoproteins in this population-based cohort of Japanese-American men who now exceed 70 years of age. In addition to identifying factors that were independently associated with these lipids, relations between lipids and prevalent cardiovascular disease were also examined.
| Methods |
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Study Population
Among 8006 men examined at baseline, 3845 subjects completed the reexamination or extended telephone interview at the 25-year follow-up between 1991 and 1993. Eighty percent of the men alive at that time were examined (n=3741), a majority in a clinic setting (86%) and a smaller proportion at home (13%) or in a nursing home (1%). Fasting blood specimens were provided by 3573 subjects. A total of 394 men who reported taking lipid-lowering medication and an additional 135 men who fasted <12 hours were excluded from the analyses. The study population consisted of 3044 men, most of whom had lipid and lipoprotein measurements (3043 for total cholesterol, 3036 for HDL cholesterol, 2972 for LDL cholesterol, and 3038 for triglycerides).
Lipid Determinations
After a recommended overnight fast of at least 12 hours, collection of blood specimens, and separation of plasma, standard enzymatic measurements of total cholesterol, HDL cholesterol, and triglycerides were performed using the same laboratory and methods used in the Cardiovascular Health Study (CHS).1 27 Total and HDL cholesterol and triglyceride analyses were performed using an Olympus Demand System (Olympus Corp) and were standardized according to the Centers for Disease Control.27 LDL cholesterol was calculated for subjects with triglyceride levels
400 mg/dL based on the Friedewald method.28
Measurement of Other Variables
Standard methods used in data collection were consistent with previous examinations.25 Briefly, an index of physical activity was based on the number of hours spent in five activity levels weighted by the estimated oxygen required.29 Dietary data were not collected at this examination. Hypertension was defined as blood pressure
160/95 mm Hg based on an average of two readings or reported use of antihypertensive medication. Spirometry was performed using American Thoracic Society recommendations30 and was consistent with methods used in the CHS.31
Waist and hip circumference, fibrinogen, and fasting and 2-hour glucose and insulin concentrations were also measured for the first time. Plasma fibrinogen concentrations were measured with a clot-based end point using a BBL fibrometer (Becton Dickinson).27 A standard oral glucose tolerance test was completed by 2133 subjects who fasted
12 hours. Glucose was measured using a glucose oxidase method (University of Vermont), and insulin was measured using a double antibody radioimmunoassay method32 at the University of Washington after storage at -70°C for up to 2 years.
Prevalent Cardiovascular Disease
Prevalent manifestations of clinical and subclinical cardiovascular disease were determined on the basis of information from the current examination and a comprehensive hospital-based surveillance system in existence since 1965.25 26 Angina was considered present if it was identified by hospital surveillance or was diagnosed by a physician at any examination. Criteria for a definite myocardial infarction included a clinically apparent event based on electrocardiographic and cardiac enzyme evidence identified through surveillance, a silent event detected by electrocardiograms at any examination, or a temporal change in electrocardiograms diagnostic of myocardial infarction. Definite and probable thromboembolic and hemorrhagic strokes were identified by hospital surveillance as described previously.26 33 Coronary surgery and angioplasty were ascertained by questionnaire. Peripheral vascular disease was identified using a ratio of blood pressures measured by a Doppler device in the ankle to that in the arm (ankle/brachial index <0.9).
Statistical Analysis
Since the distribution of triglycerides was skewed, a log10 transformation was used, and its antilogarithm was calculated for presentation of mean values. Tests of trend in mean lipid levels across age were determined from a general linear-models procedure.34 Pearson correlation coefficients were used in assessing potential associations of continuous variables with lipids. These associations were further confirmed by comparing mean levels of these lipids across quintiles of continuous correlates (data not presented). Relations between lipids and potential categorical correlates including prevalent cardiovascular disease were also investigated using a general linear model.34 35 On the basis of these results, multiple linear regression analysis with and without stepwise selection was used to identify factors independently associated with each lipid and lipoprotein. In the case of regional obesity measures, subscapular skinfold thickness was included instead of waist circumference, since multivariate associations with lipids were slightly stronger; results for lipid correlates other than these obesity measures were unchanged regardless of which measure was used.
To illustrate the magnitude of associations between potential correlates and these lipids and lipoproteins, the absolute difference in lipid concentration associated with a specified change in the level of each correlate was estimated from these multivariate models. A difference between the 80th and 20th percentiles was selected for continuous independent variables. In the case of triglycerides, the predicted mean log10 triglyceride concentration was calculated at the 80th and 20th percentiles for a specific independent variable using mean levels of each variable in the model and their respective regression coefficients. The antilogarithms of these two predicted mean log10 triglyceride values were then calculated to express these values in their original units (mg/dL), and the difference between these two antilogarithms provided the estimated difference in triglyceride level associated with the difference between the 80th and 20th percentiles for each risk factor.
| Results |
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Age-specific and overall prevalences of adverse and desirable lipid concentrations based on the NCEP screening recommendations are presented in Table 2
. A high total cholesterol level defined as
240 mg/dL was observed in 6.7% of this population (desirable levels <200 mg/dL were found in 62.7%). A low level of HDL cholesterol was found in 6.4%, while a desirable level (
60 mg/dL) was present in 23.7% of the subjects. High LDL levels (
160 mg/dL) were found in 5.5% (desirable levels <130 mg/dL occurred in 75.7%), and high triglyceride levels (
200 mg/dL) were seen in 18.7% of subjects. The combination of low HDL (<35 mg/dL) and high triglyceride (
200 mg/dL) levels was observed in 3.7% of the men. In general, trends in prevalence associated with age were similar to although somewhat less consistent than those observed for mean lipid concentrations.
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A number of previously confirmed and relatively new potential correlates of these lipids were examined. Pearson correlation coefficients are presented in Table 3
for continuous variables. In general, correlation coefficients were similar in size and direction for total and LDL cholesterol, while those for HDL cholesterol and log10 triglycerides were opposite in direction but similar in magnitude, with a few exceptions. Education, blood pressure, heart rate, and pack-years of smoking were directly and significantly associated with triglycerides but not with HDL cholesterol, while alcohol (directly) and fibrinogen (inversely) were significantly associated with HDL cholesterol but not with triglycerides. The strongest correlations involved measures of obesity, fat distribution, and fasting insulin with HDL cholesterol (r=-.28 to -.37) and triglycerides (r=.26 to .41). Correlations for waist/hip ratio and subscapular/triceps thickness ratio were weaker than waist circumference and subscapular skinfold thickness, respectively (data not shown). Both fasting and postchallenge measures of glucose and insulin were strongly associated with HDL cholesterol and triglycerides but not with total and LDL cholesterol. Physical activity was positively associated with HDL cholesterol and inversely associated with triglycerides. Also of interest were the positive associations of fibrinogen and hematocrit with total and LDL cholesterol, the positive relation of hematocrit and white blood cell count with triglycerides, and the inverse associations of fibrinogen, hematocrit, and white blood cell count with HDL cholesterol.
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Associations of categorical variables with lipids are shown in Table 4
. Subjects with hypertension had significantly higher age-adjusted mean total cholesterol, LDL cholesterol, and triglyceride concentrations and significantly lower HDL cholesterol concentrations than subjects without hypertension. Subjects who reported antihypertensive medication had significantly lower mean HDL cholesterol levels and higher triglyceride levels, but levels of total and LDL cholesterol were similar to those not taking antihypertensive medication. Men who took diabetic medication had significantly lower total and HDL cholesterol levels and higher triglyceride levels than those not taking medication. Current smokers had significantly elevated triglyceride levels relative to never smokers. Total cholesterol levels were somewhat higher, but not significantly, in current compared with never smokers, and past smokers tended to have intermediate levels of total cholesterol and triglycerides.
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Factors that were associated significantly with these four lipids were examined in separate multiple linear regression models to identify variables independently associated with these lipids. In general, results were similar when a stepwise selection process was used. To assess the magnitude of these associations in a comparable manner, the influence of a difference in each independent continuous variable (80th minus 20th percentile) and discrete variable on lipid concentrations was estimated from regression coefficients (Table 5
). For example, a difference of 94 mg/dL in fibrinogen level (80th minus 20th percentile) was associated with a 7.1 mg/dL increase in total cholesterol level after adjusting for other factors. Most factors associated with total cholesterol had a relatively small impact on the predicted difference in mean concentration when considered separately. Differences were perhaps more notable for fibrinogen (7.1 mg/dL), hematocrit (10.5 mg/dL), and use of diabetic medication (-7.7 mg/dL); these factors plus fasting insulin and white blood cell count were independently associated with total cholesterol (P<.05).
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These same factors, along with forced vital capacity (positive) and alcohol (inverse), were independently associated with LDL cholesterol. Correlates of HDL cholesterol included heart rate, physical activity, alcohol, body mass index, subscapular skinfold, fasting glucose, fibrinogen, hematocrit, white blood cell count, and hypertension (all P<.01; all inversely related except heart rate, physical activity, alcohol, and hematocrit). Body mass index appeared to have the largest association with HDL concentration. A decrease of 5.4 mg/dL in HDL was predicted by an increase of 5.23 kg/m2 (80th minus 20th percentile) in body mass index.
In addition to the correlates identified for HDL cholesterol, pack-years of smoking, fasting insulin, and diabetic medication but not physical activity, alcohol, and fibrinogen were independently associated with triglycerides. For example, a difference between the 80th and 20th percentiles of 9.5 mm in subscapular skinfold thickness was associated with an increase in triglyceride concentration of 9.9 mg/dL. Similarly, increases of 12.0 and 10.4 mg/dL in triglyceride levels corresponded to increases of 5.23 kg/m2 in body mass index and 6.9% in hematocrit, respectively (80th minus 20th percentile).
Cross-sectional associations between lipids and prevalent manifestations of cardiovascular disease were also examined (Table 6
). Age-adjusted total cholesterol levels were significantly lower in subjects who underwent coronary artery bypass surgery and in those who had thromboembolic stroke and hemorrhagic stroke compared with subjects who did not have these treatments or disorders. Differences were relatively small except for hemorrhagic stroke, in which case subjects had a 20 mg/dL lower cholesterol level than those without a stroke. In contrast, subjects with peripheral vascular disease had elevated total cholesterol levels. Patterns were similar for LDL cholesterol, but differences were smaller and less often significant. Significantly lower HDL cholesterol concentrations were observed in men who had angina, angioplasty, coronary surgery, definite myocardial infarction, thromboembolic stroke, and peripheral vascular disease than in those who did not have these conditions or treatments. Triglyceride concentrations tended to be higher for subjects with each of the cardiovascular manifestations except hemorrhagic stroke than for those without; however, only peripheral vascular disease showed a statistically significant relation.
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| Discussion |
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The limited information available from other population-based studies on the prevalence of adverse lipid and lipoprotein concentrations defined by NCEP guidelines is consistent with differences in mean concentrations. Age-specific and overall comparisons demonstrated that elevated total cholesterol levels (
240 mg/dL) occurred three to four times less frequently in men from the HHP than in men from the CHS (6.7% versus 24%, respectively).1 Age-specific proportions of men from the Iowa Rural Health Study who had a high total cholesterol level were also higher (18% for 71 to 79 years, 12% for 80 to 89, and 5% for 90+) than for men from the HHP.4 Results from the National Health and Nutrition Examination Surveys conducted between 1976 and 1980 and between 1988 and 1991 showed that the percentage of persons aged 20 to 74 years with high total cholesterol levels declined from 26% to 20%.3
In addition to an actual decline in both mean total cholesterol and in the proportion with high levels over time suggested by national data, it is possible that selective survival could lead to some of the cross-sectional decline with increasing age observed in the present study. Subjects with elevated total and LDL cholesterol, as well as those with a dyslipidemic pattern of low HDL and high triglyceride levels, may be at greater risk of cardiovascular mortality, thus leaving a smaller proportion of surviving subjects with adverse lipid and lipoprotein concentrations at the time of examination. As demonstrated by Newschaffer et al,38 both differential mortality and a true decline in total cholesterol levels with increasing age may account for cross-sectional associations of lipids with age. Consistent with both of these influences, a larger proportion of a random sample of this cohort exhibited adverse lipid levels at a younger age.39 Among subjects aged 51 to 72 years in 1970 to 1972 who were free of cardiovascular disease and were not taking lipid-lowering medication, 30% had total cholesterol
240 mg/dL, 17% had HDL cholesterol <35 mg/dL, and 23% had triglycerides >200 mg/dL compared with 6.7%, 6.4%, and 18.7%, respectively, from the current larger cohort.
Reasons for relatively lower total and LDL cholesterol levels yet higher HDL cholesterol and triglyceride levels among these elderly Japanese-American men are not clear. It is possible that a diet higher in carbohydrate and lower in fat could contribute to these differences, as recently suggested in a comparison of persons residing in Mexico City with Mexican Americans from San Antonio.37 It is also possible that beneficial effects of alcohol intake on HDL cholesterol levels40 41 42 and perhaps physical activity could account for some of the elevation in HDL cholesterol in this population, while a relatively high prevalence of diabetes and impaired glucose tolerance43 and possibly antihypertensive treatment might contribute to both low HDL cholesterol and high triglyceride levels. Similarly, because lipid levels may be influenced by adiposity,17 a more optimal lipid profile (lower total and LDL cholesterol and higher HDL cholesterol) in the HHP cohort may also be explained by their relatively lean body composition.
Previous investigations of Japanese men of the same age living in Japan, Hawaii, and California (Ni-Hon-San Study) conducted nearly 30 years ago44 45 46 are unique in that they provide the opportunity to compare risk factors such as serum lipid levels in subjects with differing lifestyles but similar genetic backgrounds. Mean total cholesterol and triglyceride levels were notably lower in men from Japan compared with men in Hawaii who had much higher but intermediate levels and men from California who had the highest levels overall.46 Composition of the diet also differed considerably, with Japanese men in Japan eating less protein and fat and more carbohydrate than Japanese men in Hawaii and California. Evidence from these studies is consistent with the concept that some aspects of lifestyle such as diet and physical activity or other environmental factors may influence serum lipid levels.
Studies that examine potential determinants of lipid concentrations are numerous; however, those that explore factors associated with lipid levels among the elderly and in minority groups using population-based designs are far less frequent. In this study, generalized obesity and excesses in localized body fat distribution (eg, waist circumference and subscapular skinfold thickness) were strongly associated with elevated levels of total cholesterol, LDL cholesterol, and triglycerides and lower levels of HDL cholesterol, consistent with previous studies.17 18 19 20 36 47 Several additional factors were confirmed as correlates of lipids in this study. As in other investigations, physical activity,18 20 alcohol,1 4 18 19 20 21 40 41 42 47 48 blood pressure,49 and diabetes or impaired glucose intolerance22 50 have been associated with lipid levels in general and with HDL cholesterol in particular.
Several less frequently examined factors were also found to be correlates of lipids in this study. Associations with lipids were relatively weak and were consistent, in general, with findings from previous studies for heart rate,51 vital capacity,52 smoking,21 47 and insulin.1 18 53 54 55 In this study, no association of smoking with HDL cholesterol was observed, consistent with findings from the CHS,1 while others have shown a negative relation.18 19 20 Although 2-hour insulin was not included in the multivariate assessment because of limited sample size, univariate results were similar to those for elderly men from the CHS in whom associations involving HDL cholesterol were negative and those involving triglycerides were positive.1 The association of fibrinogen with lipid levels was somewhat larger and the direction of relations was consistent with several other studies.56 57 Hematocrit also had a relatively strong association with total and LDL cholesterol after adjustment for other variables, consistent with previous findings in young adults.47 58 Results from several large epidemiological studies have also shown associations between white blood cell count and lipids and lipoproteins.47 59 60 61
Lipids and lipoproteins were also associated cross-sectionally with a number of cardiovascular manifestations in this population. Since coronary heart disease events were not mutually exclusive, it is possible that a relatively small number of subjects who were free of a specific manifestation (eg, definite myocardial infarction) may have had another manifestation (eg, coronary surgery); thus, the magnitude of these associations could be slightly underestimated. The lower total cholesterol levels in subjects with each clinical manifestation compared with those without these conditions could reflect risk factorreduction efforts as a result of increased medical attention. This possibility would be consistent with significantly higher triglyceride levels observed in those with peripheral vascular disease, since identification of this disorder was more likely to involve subclinical disease (a sizable proportion of those with disease may not have been identified previously and therefore less intervention may have been instituted). Peripheral vascular disease was the only manifestation in which an adverse profile for all four lipid components was demonstrated. In general, differences were statistically significant more frequently for HDL cholesterol than for other lipids and lipoproteins in this study, consistent with findings from the CHS, in which strong associations of HDL cholesterol and triglyceride concentrations (but not total and LDL cholesterol levels) with prevalent coronary heart disease and stroke were observed.1 Significant protective associations were observed between HDL cholesterol and all cardiovascular manifestations except hemorrhagic stroke in the present study. Although causal inferences cannot be made, these cross-sectional associations are consistent with an atherogenic role for adverse lipid profiles in the elderly.
Potential strengths of this investigation include the population-based assessment of lipids and lipoproteins in one of the largest cohorts of a minority population in the United States, the elderly nature of the cohort, and the availability of multiple cardiovascular risk factors and disease manifestations assessed in a standardized manner. In addition to its cross-sectional design, the study is limited by the fact that the results may not be generalizable to the US population nor to other minority populations. However, previous investigations of lipid correlates and associations of lipids with cardiovascular manifestations in this population6 7 39 62 appear consistent with other studies. A small proportion of the most recent nonfatal cases of stroke may not have been identified through hospital surveillance. To maximize ascertainment of cardiovascular manifestations such as angina that might not require hospitalization, a physician's diagnostic impression at each examination was included in the definition. Potential misclassification of these events, which is likely to be small, could have underestimated these associations of lipids with cardiovascular manifestations.
In conclusion, lipid and lipoprotein concentrations have been characterized for a large population of elderly Japanese-American men. Although adverse lipid levels occurred less frequently in these men than in other Caucasian populations and in men from the same cohort at a younger age, associations of lipids and lipoproteins with other cardiovascular risk factors and disease manifestations were strong and, in general, consistent with previous studies. Whether adverse lipid patterns increase the risk of cardiovascular disease to the same degree in the very old as in younger or middle-aged adults and whether there are ethnic differences in these risks are not fully resolved and will need further assessment in future prospective investigations.
| Acknowledgments |
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| Footnotes |
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Received December 19, 1995;
revision received April 10, 1996;
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