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Background/objectives: Numerous studies reported beneficial effects of marine n-3 fatty acids (n-3 FAs) on cardiovascular disease (CVD) and its risk factors. However, the association of marine n-3 FAs with plasma fibrinogen, a risk factor for CVD, remains uncertain., Subjects/methods: In a population-based, cross-sectional study of 795 men aged 40-49 without CVD (262 whites in Allegheny County, Pennsylvania, USA, 302 Japanese in Kusatsu, Japan and 229 Japanese Americans in Honolulu, Hawaii, USA), we examined the association of marine n-3 FAs with plasma fibrinogen. Serum FAs were measured by capillary gas-liquid chromatography. Marine n-3 FAs were defined as the sum of docosahexaenoic, eicosapentaenoic and docosapentaenoic acids. Plasma fibrinogen was measured by an automated clot-rate assay. Multiple linear regression analyses were performed to assess the association., Results: White, Japanese and Japanese-American men had mean marine n-3 FAs levels of 3.47%, 8.78% and 4.46%, respectively. Japanese men had a significant inverse association of marine n-3 FAs with fibrinogen (standardized regression coefficient of -0.11, P=0.049), after adjusting for age, body-mass index and current smoking. The significant inverse association remained after further adjusting for diabetes, C-reactive protein, triglycerides and other variables. White or Japanese-American men did not show a significant association., Conclusions: We observed the significant inverse association of marine n-3 FAs with fibrinogen in Japanese, but not in whites or Japanese Americans. The observation suggests that marine n-3 FAs at very high levels, as seen in the Japanese, may decrease plasma fibrinogen levels.

Context: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction., Objective: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction., Data Sources: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies., Study Selection: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality., Data Extraction: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease., Results: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women., Conclusion: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Background: A generally held belief is that cholesterol concentrations should be kept low to lessen the risk of cardiovascular disease. However, studies of the relation between serum cholesterol and all-cause mortality in elderly people have shown contrasting results. To investigate these discrepancies, we did a longitudinal assessment of changes in both lipid and serum cholesterol concentrations over 20 years, and compared them with mortality., Methods: Lipid and serum cholesterol concentrations were measured in 3572 Japanese/American men (aged 71-93 years) as part of the Honolulu Heart Program. We compared changes in these concentrations over 20 years with all-cause mortality using three different Cox proportional hazards models., Findings: Mean cholesterol fell significantly with increasing age. Age-adjusted mortality rates were 68.3, 48.9, 41.1, and 43.3 for the first to fourth quartiles of cholesterol concentrations, respectively. Relative risks for mortality were 0.72 (95% CI 0.60-0.87), 0.60 (0.49-0.74), and 0.65 (0.53-0.80), in the second, third, and fourth quartiles, respectively, with quartile 1 as reference. A Cox proportional hazard model assessed changes in cholesterol concentrations between examinations three and four. Only the group with low cholesterol concentration at both examinations had a significant association with mortality (risk ratio 1.64, 95% CI 1.13-2.36)., Interpretation: We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4.65 mmol/L) in elderly people.

Cardiovascular risk factors often cluster into a metabolic syndrome that may increase the risk of dementia. The objective of the present study was to assess the long-term association between clustered metabolic cardiovascular risk factors measured at middle age and the risk of dementia in old age. This prospective cohort study of cardiovascular disease was started in 1965 and was extended to a study of dementia in 1991. The subjects were Japanese-American men with an average age of 52.7+/-4.7 (mean+/-SD) years at baseline. Dementia was diagnosed in 215 men, according to international criteria, and was based on a clinical examination, neuropsychological testing, and an informant interview. The z scores were calculated for 7 risk factors (random postload glucose, diastolic and systolic blood pressures, body mass index, subscapular skinfold thickness, random triglycerides, and total cholesterol). The relative risk (RR [95% CI]) of dementia (subtypes) per 1 SD increase in the sum of the z scores was assessed after adjustment for age, education, occupation, alcohol consumption, cigarette smoking, and years of childhood lived in Japan. The z-score sum was higher in demented subjects than in nondemented subjects, indicating a higher risk factor burden (0.74 versus -0.06, respectively; P=0. 008). Per SD increase in the z-score sum, the risk of dementia was increased by 5% (RR 1.05, 95% CI 1.02 to 1.09). The z-score sum was specifically associated with vascular dementia (RR 1.11, 95% CI 1.05 to 1.18) but not with Alzheimer's disease (RR 1.00, 95% CI 0.94 to 1.05). Clustering of metabolic cardiovascular risk factors increases the risk of dementia (mainly, dementia of vascular origin).

Hyperinsulinemia has been associated with cardiovascular disease (CVD), but whether this relation is independent of other CVD risk factors is uncertain. Most studies have focused on coronary heart disease (CHD), but few have included peripheral vascular disease (PVD) and stroke. Moreover, evidence in elderly and minority populations is limited. Between 1991 and 1993, 3562 elderly (71 to 93 years) Japanese-American men from the Honolulu Heart Program were examined and had fasting insulin levels measured. Hyperinsulinemia, defined as a fasting insulin > or =95th percentile among nonobese men with normal glucose tolerance and no diabetic history or medication use, was observed in 22% of the population. Subjects with hyperinsulinemia had a more adverse CVD risk factor profile and had higher age-adjusted prevalences of CHD, angina, PVD, thromboembolic stroke, and hemorrhagic stroke compared with those without hyperinsulinemia. Age-adjusted fasting insulin levels but not 2-hour levels were also significantly elevated (P<.01) in those with prevalent CVD compared with those without. In logistic regression analyses, adjustment for multiple CVD risk factors attenuated the relations of hyperinsulinemia with CHD, angina, and PVD to nonsignificant levels, whereas those involving thromboembolic and hemorrhagic stroke were strengthened and remained significant (odds ratios=2.27 and 7.53, 95% confidence intervals=1.25 to 4.13 and 1.65 to 34.25, respectively). When multivariate analyses were restricted to nondiabetic subjects, associations were slightly weaker and in general nonsignificant. Nondiabetic men with thromboembolic stroke were twice as likely to have hyperinsulinemia as those who were stroke-free, although this association was of borderline significance (odds ratio= 1.99, 95% confidence interval=0.95 to 4.17, P=.069). In subjects with elevated total cholesterol levels, somewhat stronger associations were observed for PVD and stroke but not for CHD. Although further prospective studies are indicated, particularly for PVD and stroke, these cross-sectional results are consistent with an indirect role for insulin in CVD, wherein hyperinsulinemia or an underlying insulin-resistant state may adversely affect other CVD risk factors or serve as a marker for an atherogenic or thrombogenic state.

Objective: To investigate whether fasting hyperinsulinemia is associated with a clustering of cardiovascular disease (CVD) risk factors, manifesting as the insulin resistance syndrome (IRS), in a population of native Hawaiians., Research Design and Methods: A total of 574 native Hawaiians > or = 30 years of age were examined for blood pressure, waist-to-hip ratio (WHR), BMI, oral glucose tolerance, and fasting lipid, insulin, and C-peptide concentrations. All statistical analyses (n = 384) excluded 190 individuals who had NIDDM or who were taking hypertension medication. Using logistic regression analysis, fasting insulin and C-peptide levels were compared with CVD risk factors (glucose intolerance, hypertension, central adiposity, elevated triglyceride levels, and low HDL cholesterol levels) after adjusting for age and obesity., Results: Sixty-six percent of native Hawaiians were overweight or obese, and 70% were found to have central adiposity. Fasting insulin concentrations were correlated with BMI, WHR, blood pressure, and triglyceride, HDL cholesterol, and glucose concentrations. Fasting insulin was also significantly associated with an increasing number of CVD risk factors in each participant (P < 0.001). Fasting insulin and C-peptide concentrations were independently associated with glucose intolerance, high triglyceride levels, and low HDL cholesterol levels. However, only fasting C-peptide concentrations were independently associated with hypertension and central adiposity. Apparent differences in the correlates of fasting insulin and C-peptide may be related to multiple factors and warrant further evaluation., Conclusions: This study provides cross-sectional data confirming the existence of the IRS in native Hawaiians. However, further longitudinal studies are needed to examine the relationship of insulin resistance and/or surrogate markers to increased rates of NIDDM and CVD mortality in native Hawaiians.

Objective: To identify lifestyle, anthropometric, biochemical, and clinical characteristics associated with pulmonary function in elderly men., Design: Cross-sectional population-based study., Participants: Japanese-American men (n=3,111) aged 71 to 93 years, who completed spirometry at the fourth examination of the Honolulu Heart Program (1991 to 1993)., Methods: Pulmonary function measurements (FEV1 and FVC) were obtained using American Thoracic Society guidelines. Potential factors associated with pulmonary function were examined using Pearson correlation coefficients and general linear models. Age- and height-adjusted mean levels of FEV1 and FVC were compared across quintiles of continuous variables and by status of prevalent disease and medication or vitamin use. Stepwise multiple linear regression was used to identify factors independently associated with pulmonary function overall and among never smokers., Results: A number of correlates of pulmonary function were initially identified. In multivariate analyses, age, current smoking, pack-years of smoking, emphysema, asthma, wheezing without colds, subscapular skinfold thickness, ECG abnormality, heart rate, WBC count, and eosinophil count were all negatively and independently associated with FEV1, while height, grip strength, physical activity, and mean corpuscular hemoglobin concentration were positively associated. With a few exceptions, similar relations were observed with FVC and among never-smokers., Conclusion: Cigarette smoking, respiratory symptoms and disease, and several cardiovascular risk factors were independently associated with pulmonary function in elderly Japanese-American men. In most cases, inadequate control for smoking does not appear to account for these associations. Results suggest that a number of factors that are correlates of FEV1 and FVC in younger age groups are also associated with pulmonary function beyond the age of 70 years.

Objective: To assess the effect of low-dose, diuretic-based antihypertensive treatment on major cardiovascular disease (CVD) event rates in older, non-insulin-treated diabetic patients with isolated systolic hypertension (ISH), compared with nondiabetic patients., Design: Double-blind, randomized, placebo-controlled trial: the Systolic Hypertension in the Elderly Program (SHEP)., Setting: Multiple clinical and support centers in the United States., Participants: A total of 4736 men and women aged 60 years and older at baseline with ISH (systolic blood pressure [BP], > or = 160 mm Hg; diastolic BP, <90 mm Hg) at baseline, 583 non-insulin-dependent diabetic patients and 4149 nondiabetic patients (4 additional patients not so classifiable were randomized but not included in these analyses). Diabetes mellitus defined as physician diagnosis, taking oral hypoglycemic drugs, fasting glucose level of 7.8 mmol/L or more (> or = 140 mg/dL), or any combination of these characteristics., Intervention: The active treatment group received a low dose of chlorthalidone (12.5-25.0 mg/d) with a step-up to atenolol (25.0-50.0 mg/d) or reserpine (0.05-0.10 mg/d) if needed. The placebo group received placebo and any active antihypertensive drugs prescribed by patient's private physician for persistently high BP., Main Outcome Measures: The 5-year rates of major CVD events, nonfatal plus fatal stroke, nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD), major CHD events, and all-cause mortality., Results: The SHEP antihypertensive drug regimen lowered BP of both diabetic and nondiabetic patients, with few adverse effects. For both diabetic and nondiabetic patients, all outcome rates were lower for participants randomized to the active treatment group than for those randomized to the placebo group. Thus, 5-year major CVD rate was lower by 34% for active treatment compared with placebo, both for diabetic patients (95% confidence interval [CI], 6%-54%) and nondiabetic patients (95% CI, 21%-45%). Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic vs nondiabetic patients (101/1000 vs 51/1000 randomized participants at the 5-year follow-up), reflecting the higher risk of diabetic patients., Conclusion: Low-dose diuretic-based (chlorthalidone) treatment is effective in preventing major CVD events, cerebral and cardiac, in both non-insulin-treated diabetic and nondiabetic older patients with ISH.

Associations of cardiovascular risk factors, including several measures of adiposity, with hyperinsulinemia were assessed in 3562 elderly (71 to 93 years of age) Japanese American men from the Honolulu Heart Program who were examined between 1991 and 1993. In addition, cardiovascular risk factors measured 25 years earlier were also examined in relation to hyperinsulinemia. Hyperinsulinemia was defined as fasting insulin > or = 95th percentile (20 microU/mL) among the subset of subjects (n = 504) who were nonobese and free of clinical diabetes and glucose intolerance. When this definition was applied to the entire population, the prevalence of hyperinsulinemia declined cross-sectionally with age (P < 0.001) from 24.2% in men aged 71 to 74 years to 16.4% in men aged 85 to 93 years. Factors having a positive and independent association with hyperinsulinemia included body mass index (BMI), triglycerides, glucose, hematocrit, use of diabetic medication, heart rate, and hypertension. The association with physical activity was negative. Triglycerides, BMI, diabetic medication, hypertension, and smoking levels measured 25 years earlier were also associated independently with hyperinsulinemia. Associations were similar in nondiabetic subjects. Three measures of adiposity (BMI, waist circumference, and subscapular skinfold thickness) were independently related to hyperinsulinemia cross-sectionally. However, associations involving a difference between the 80th and 20th percentiles in each adiposity measure appeared strongest for BMI (odds ratio (OR) = 4.5, 95% confidence interval (CI) = 3.7 to 5.6) and waist circumference (OR = 4.1, 95% CI = 3.3-5.1) and slightly weaker for subscapular skinfold thickness (OR = 2.1, 95% CI = 1.8-2.5). These findings suggest that features of an insulin resistance syndrome including dyslipidemia, glucose intolerance, hypertension, and obesity, assessed both cross-sectionally and 25 years previously, are associated independently with hyperinsulinemia in elderly Japanese American men.

Objective: The relationship between glucose tolerance status and other cardiovascular disease (CVD) risk factors was evaluated in a cohort of Japanese-American men (n = 3,741) ages 71-93 years who participated in the fourth examination of the Honolulu Heart Program in 1991-1993., Research Design and Methods: In this cross-sectional study, subjects were classified by reported diabetes and glucose tolerance status using questionnaires and the World Health Organization (WHO) criteria, respectively., Results: The prevalence of reported diabetes was 17%. Among the men who completed an oral glucose tolerance test and had no history of diabetes (n = 1,900), 23% were diagnosed as diabetic and 39% had impaired glucose tolerance (IGT) by WHO criteria. The CVD risk factor profiles of men with IGT and diabetes were significantly more adverse compared with men with normal glucose tolerance after adjustment for age. The rates of hypertension, mean levels of BMI, waist-to-hip ratio, triglycerides, and fasting insulin were higher in men with IGT and diabetes compared with normal subjects. Opposite trends were observed for HDL cholesterol. Two-hour insulin was significantly higher among men with IGT and previously undiagnosed diabetes. Men with known diabetes had a lower physical activity index and higher fibrinogen levels than normal subjects. No significant differences were observed for current smoking and alcohol intake. Differences in risk factor levels by glucose tolerance status remained after adjustment for age, physical activity, BMI, and waist-to-hip ratio., Conclusions: These findings show that among elderly men of Japanese ancestry, impaired glucose tolerance and undiagnosed and known diabetes are highly prevalent, and these conditions are associated with adverse CVD factor profiles.

In a Honolulu Heart Program cohort of 1,604 elderly men aged 70-90 years who were sampled from the most recent follow-up examination (1991-1992), current risk factor values were compared with those obtained 25 years earlier when the same men were between ages 45-64 and free of clinically diagnosed cardiovascular disease. Cardiovascular disease risk factors studied included systolic blood pressure, diastolic blood pressure, serum cholesterol, cigarette smoking, body mass index, and alcohol intake. For systolic pressure, 65% of the men had moved into a different quartile by old age, with 25% changing by more than one quartile. For diastolic pressure, 68% had moved into another quartile, with 28% moving more than one quartile, and for body mass index, 53% had moved into another quartile, with 14% moving more than a quartile. Less than 1% started to smoke, while 27% were reclassified from smokers to nonsmokers. Only 4% started to drink alcohol, while 30% were reclassified from drinkers to nondrinkers. When the men were stratified into cardiovascular disease, noncardiovascular disease, and healthy follow-up groups, modest deviations from the overall pattern were observed, with morbidity groups showing a greater tendency to reduction in risk factor levels. The results show that there is a substantial redistribution of major cardiovascular disease risk factor values between midlife and old age. Since midlife values are more likely to represent lifelong exposure values that, in turn, make the main contribution to the development of atherosclerosis, investigators and clinicians may need to be cautious in using risk factor values measured late in life as the only means of assessing risk for subsequent disease.

Objective: To determine whether there is a relationship of low to moderate alcohol consumption with cardiovascular mortality in the elderly., Design: Prospective cohort studies with 5-year mortality follow-up., Setting: Three populations of community-dwelling elders., Participants: Population-based cohorts of men and women, aged 65 or older, in three populations. Subjects with prior myocardial infarction, stroke, or cancer, as well as those lacking alcohol consumption data, were excluded from statistical analyses leaving 2,694 subjects in East Boston, Massachusetts, 2,293 subjects in Iowa, and 1,904 subjects in New Haven, Connecticut., Main Outcome Measurements: Alcohol consumption, total mortality, cardiovascular mortality, and cancer mortality., Results: Low to moderate alcohol consumption was associated with statistically significant lowered total as well as cardiovascular mortality in East Boston and New Haven. The relative risks of total mortality for low to moderate consumers of alcohol compared to those consuming no alcohol in the previous year were 0.7 (95% CI 0.6-0.8) in East Boston and 0.6 (95% CI 0.5-0.8) in New Haven. For cardiovascular mortality, the RRs were 0.6 in East Boston and 0.5 in New Haven (95% CI's exclude null). These results persisted after control for potential confounding variables. In Iowa, there were no significant differences in total or cardiovascular mortality according to alcohol consumption patterns. For cancer mortality, there were no significant associations with alcohol consumption in any of the three populations., Conclusions: These data suggest that the relationship of low to moderate alcohol consumption with reduced total and cardiovascular mortality, which are well documented in middle age, also occur in older populations.

We report a cardiovascular risk factor survey of "native" Hawaiians 20-59 years old (70 percent, or 257), living on the Hawaiian Homestead lands on the island of Molokai, Hawaii. More than 60 percent of both sexes were overweight. Among males, 42 percent were smokers. The percent of the population with systolic blood pressure greater than 140 mm Hg or a diastolic pressure greater than 90 mm Hg or taking hypertensive medications was 14 percent of those ages 20-39 and 36 percent of those ages 40-59. The percent with serum cholesterol greater than or equal to 6.2 mmol/L ranged from 8 percent of those 20-29 years old to 46 percent in those 50-59 years old. Two percent of those ages 20-29 had a history of diabetes, or 2 + or greater glycosuria by dipstick, as did 23 percent of those ages 50-59. The majority of the known diabetics exhibited glycosuria and elevated glycohemoglobin levels, indicating poor control. Hypertension, although usually known to the participant, was frequently uncontrolled. From these data, it appears that among this group of Hawaiians major risk factors for cardiovascular disease were frequent, while at the same time the levels of awareness and/or control for most of these factors were low.

The relationship between coffee consumption and serum cholesterol was investigated in a cohort of 5,858 Japanese males born in 1900-1919 and living in Hawaii in 1965 who are currently followed by the Honolulu Heart Program. Data on coffee consumption, other dietary variables from a 24-hour dietary recall, and other potentially confounding variables collected in 1965 were correlated with serum cholesterol at that examination and at examination six years later. The mean coffee and tea consumption was 3.4 and 1.8 cups/day, respectively. Those consuming no coffee had a mean serum cholesterol of 210 mg/dl, while that of those drinking 9+ cups/day was 220 mg/dl (no such relationship was apparent with tea or cola). The relationship of coffee consumption and serum cholesterol with potentially confounding variables including body mass index, cigarette smoking, diastolic blood pressure, alcohol consumption, physical activity index, serum glucose, serum uric acid, education, age, and fat consumption was examined. When these variables were entered into a multiple regression equation with coffee consumption, a significant relationship between coffee consumption and serum cholesterol (p less than 0.001) persisted, as did that between baseline coffee consumption and serum cholesterol six years later (p less than 0.001). There was no significant relationship between tea or cola, the other major caffeine contributors to the diet, and baseline serum cholesterol. Thus, this analysis indicates a significant positive relationship between coffee consumption and serum cholesterol which is not present with other sources of caffeine.

Death certificates representing 766 decedents who had participated in the Hypertension Detection and Follow-up Program (1973-1979) at one of 14 US centers were given to three nosologists for purposes of coding underlying cause of death. Analyses examined interobserver variability among the three nosologists as well as intraobserver variability for each of the three nosologists. All three nosologists agreed on a three-digit International Classification of Diseases, Adapted (ICDA) code in 90.2% of the cases and at least two out of three agreed in 99.7% of the death certificates examined. Agreement rates improved when disease codes were collapsed into broader categories utilized in the Hypertension Detection and Follow-up Program. When particular disease classifications (e.g., cerebrovascular, ischemic heart disease, myocardial infarction, and neoplasms) were examined, three out of three agreement rates were highest for neoplasms (97.8%) and lowest for myocardial infarction (86.5%). Similarly, two out of three agreement was highest for neoplasms (98.5%) and lowest for myocardial infarction (88.0%). Intranosologist agreement rates were based on a recoded 20% sample of death certificates. Agreement rates for three-digit ICDA codes ranged from 94.8% to 96.1% for the three nosologists. The agreement rates for the general disease categories ranged from 96.7% to 97.4%.