Risk factor effects and total mortality in older Japanese men in Japan and Hawaii.

PURPOSE: We sought to identify factors related to total mortality in older Japanese men in Japan and Hawaii. METHODS: Baseline data were collected from 1980 to 1982 in 1379 men in Hawaii and 954 men in Japan. Ages ranged from 61 to 81 years, with mortality follow-up during a 19-year period. RESULTS: Compared with Japan, men in Hawaii had a 2-fold excess of diabetes and a 4-fold excess of prevalent coronary heart disease (P < .001). Total cholesterol and body mass index were also greater in Hawaiian men (P < .001). In contrast, men in Japan had greater systolic blood pressure and were nearly 3 times more likely to smoke cigarettes (P < .001). Although each cohort had elements of a poor risk factor profile, there was a 1.4-fold excess in the risk of death in Japan (49.4 vs. 36.2/1,000 person-years, P < .001). Although mortality was similar after risk factor adjustment, only blood pressure and cigarette smoking accounted for the higher risk of death in Japan. CONCLUSIONS: Cigarette smoking and hypertension explain much of the excess mortality in Japan versus Hawaii. In this comparison of genetically similar cohorts, evidence further suggests that Japanese in Japan are equally susceptible to develop the same adverse risk factor conditions that exist in Hawaii.

FOXO3A genotype is strongly associated with human longevity.

Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.

Coronary artery calcification and total mortality in elderly men.

OBJECTIVES: To examine the relationship between coronary artery calcification (CAC) and mortality in a sample of elderly men. DESIGN: Prospective cohort study. SETTING: The Honolulu Heart Program. PARTICIPANTS: A population-based sample of 224 men aged 84 to 96 with good cognitive function. METHODS: From 2004 to 2005, subjects received physical examinations including CAC determinations. Participants were followed for up to 3 years for all-cause mortality. RESULTS: In the course of follow-up, there were 17 deaths (28.0/1,000 person-years). Risk of death rose consistently and significantly as CAC scores increased (P=.001). For CAC scores less than 10, no deaths were observed. For scores of 10 or higher, risk of death rose from 13.2 per 1,000 person-years for CAC scores of 10 to 100 to 48.6 per 1,000 person-years for CAC scores greater than 1,000. Findings persisted after adjusting for age and traditional risk factors. In this sample of elderly men, CAC was the only factor with a significant relationship with total mortality. CONCLUSION: Higher CAC scores in elderly men are associated with greater risk of death. Screening for CAC could be important for developing strategies to improve longevity in elderly people, particularly at an age when associations between mortality and traditional risk factors are weak.

Midlife risk factors and healthy survival in men.

CONTEXT: Healthy survival has no clear phenotypic definition, and little is known about its attributes, particularly in men. OBJECTIVE: To test whether midlife biological, lifestyle, and sociodemographic risk factors are associated with overall survival and exceptional survival (free of a set of major diseases and impairments). DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study within the Honolulu Heart Program/Honolulu Asia Aging Study. A total of 5820 Japanese American middle-aged men (mean age, 54 [range, 45-68] years) free of morbidity and functional impairments were followed for up to 40 years (1965-2005) to assess overall and exceptional survival. Exceptional survival was defined as survival to a specified age (75, 80, 85, or 90 years) without incidence of 6 major chronic diseases and without physical and cognitive impairment. MAIN OUTCOME MEASURE: Overall survival and exceptional survival. RESULTS: Of 5820 original participants, 2451 participants (42%) survived to age 85 years and 655 participants (11%) met the criteria for exceptional survival to age 85 years. High grip strength and avoidance of overweight, hyperglycemia, hypertension, smoking, and excessive alcohol consumption were associated with both overall and exceptional survival. In addition, high education and avoidance of hypertriglyceridemia were associated with exceptional survival, and lack of a marital partner was associated with mortality before age 85 years. Risk factor models based on cumulative risk factors (survival risk score) suggest that the probability of survival to oldest age is as high as 69% with no risk factors and as low as 22% with 6 or more risk factors. The probability of exceptional survival to age 85 years was 55% with no risk factors but decreased to 9% with 6 or more risk factors. CONCLUSION: These data suggest that avoidance of certain risk factors in midlife is associated with the probability of a long and healthy life among men.

Proteinuria and risk for stroke and coronary heart disease during 27 years of follow-up: the Honolulu Heart Program.

BACKGROUND: Urinary protein excretion has been linked to coronary heart disease (CHD); the relationship to stroke is less clear. We assessed whether urine dipstick screening for protein predicted stroke and CHD in the Honolulu Heart Program cohort. METHODS: Prospective, observational study of 6252 Japanese American men in Honolulu aged 45 to 68 years. Proteinuria was detected by means of urine dipstick screening during the first and third examinations. Subjects were classified as having no proteinuria if results were negative at both examinations, transient proteinuria if results were positive at 1 examination, and persistent proteinuria if results were positive at both examinations. Relative risk was derived using those subjects with no proteinuria as the reference. Outcomes were assessed through 27 years. RESULTS: No proteinuria was found in 92.8% of subjects, transient proteinuria in 6.1%, and persistent proteinuria in 1.1%. The age-adjusted incident stroke rates were 3.7, 7.3, and 11.8 per 1000 person-years in subjects with no, transient, or persistent proteinuria, respectively (P<.001). Age-adjusted rates of incident CHD were 9.4, 15.8, and 35.2 events per 1000 person-years, respectively (P<.001). Using Cox proportional hazards models, adjusting for age, body mass index, physical activity, smoking status, cholesterol level, presence of hypertension or diabetes mellitus, and alcohol consumption, the relative risk for 27-year incident stroke was 1.66 (95% confidence interval, 1.21-2.30; P = .002) with transient proteinuria and 2.84 (95% confidence interval, 1.51-5.34; P = .001) with persistent proteinuria, and relative risk for 27-year incident CHD was 1.48 (95% confidence interval, 1.19-1.83; P<.001) with transient proteinuria and 3.72 (95% confidence interval, 2.62-5.27; P<.001) with persistent proteinuria. CONCLUSION: Proteinuria detected at urine dipstick screening independently predicted increased risk for incident stroke and incident CHD over 27 years in this cohort.

Low-fat dietary pattern and risk of invasive breast cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial.

CONTEXT: The hypothesis that a low-fat dietary pattern can reduce breast cancer risk has existed for decades but has never been tested in a controlled intervention trial. OBJECTIVE: To assess the effects of undertaking a low-fat dietary pattern on breast cancer incidence. DESIGN AND SETTING: A randomized, controlled, primary prevention trial conducted at 40 US clinical centers from 1993 to 2005. PARTICIPANTS: A total of 48,835 postmenopausal women, aged 50 to 79 years, without prior breast cancer, including 18.6% of minority race/ethnicity, were enrolled. INTERVENTIONS: Women were randomly assigned to the dietary modification intervention group (40% [n = 19,541]) or the comparison group (60% [n = 29,294]). The intervention was designed to promote dietary change with the goals of reducing intake of total fat to 20% of energy and increasing consumption of vegetables and fruit to at least 5 servings daily and grains to at least 6 servings daily. Comparison group participants were not asked to make dietary changes. MAIN OUTCOME MEASURE: Invasive breast cancer incidence. RESULTS: Dietary fat intake was significantly lower in the dietary modification intervention group compared with the comparison group. The difference between groups in change from baseline for percentage of energy from fat varied from 10.7% at year 1 to 8.1% at year 6. Vegetable and fruit consumption was higher in the intervention group by at least 1 serving per day and a smaller, more transient difference was found for grain consumption. The number of women who developed invasive breast cancer (annualized incidence rate) over the 8.1-year average follow-up period was 655 (0.42%) in the intervention group and 1072 (0.45%) in the comparison group (hazard ratio, 0.91; 95% confidence interval, 0.83-1.01 for the comparison between the 2 groups). Secondary analyses suggest a lower hazard ratio among adherent women, provide greater evidence of risk reduction among women having a high-fat diet at baseline, and suggest a dietary effect that varies by hormone receptor characteristics of the tumor. CONCLUSIONS: Among postmenopausal women, a low-fat dietary pattern did not result in a statistically significant reduction in invasive breast cancer risk over an 8.1-year average follow-up period. However, the nonsignificant trends observed suggesting reduced risk associated with a low-fat dietary pattern indicate that longer, planned, nonintervention follow-up may yield a more definitive comparison. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT00000611.

High density lipoprotein cholesterol and the risk of stroke in elderly men: the Honolulu heart program.

High density lipoprotein (HDL) cholesterol has been inversely associated with coronary heart disease. Associations with stroke are less clear, particularly among the elderly. In this study, the authors examined the relation between HDL cholesterol levels and the risk of stroke in elderly men. Levels of HDL cholesterol were measured in 2,444 Honolulu Heart Program men aged 71-93 years at the 1991-1993 examinations. The participants, who were free of prevalent stroke, coronary heart disease, and cancer at baseline, were followed to the end of 1998 for thromboembolic and hemorrhagic stroke. While HDL cholesterol was unrelated to hemorrhagic events, incidence of thromboembolic stroke declined consistently with increasing HDL cholesterol level (p = 0.003). There was a nearly threefold excess of thromboembolic stroke in men with low HDL cholesterol levels (<1.0 mmol/liter (<40 mg/dl)) compared with men with high levels (> or =1.6 mmol/liter (> or =60 mg/dl)) (10.6/1,000 person-years vs. 3.6/1,000 person-years; p = 0.001). Adjustment for other risk factors had little effect on these findings, although associations appeared strongest in elderly men with "desirable" total cholesterol levels, hypertension, or diabetes mellitus. These findings suggest that HDL cholesterol level is inversely related to the risk of thromboembolic stroke in elderly men. Whether HDL cholesterol alters the effect of other factors on stroke risk in elderly men warrants further study.

C-reactive protein and myocardial infarction.

C-reactive protein (CRP) has been shown to predict cardiovascular disease. Whether predictions differ across risk factor strata and for short and long-term follow-up has not been clearly examined. The purpose of this report is to assess the relation between CRP and the development of myocardial infarction (MI) over a 20-year period in men in the Honolulu Heart Program. Subjects were aged 48 to 70 years and free of prevalent disease at the time when CRP levels were measured and follow-up began. Using a case-control design, 369 cases of MI were compared with 1,348 control subjects. After risk factor adjustment, the odds of an MI rose with increasing levels of CRP as early as 5 years into follow-up (P = 0.009). Associations appeared to persist beyond this time, but after 15 years, effects became modest. Adverse effects of an elevated CRP level were observed in middle-aged men (< or =55 years), in men without hypertension or diabetes, and in those who were nonsmokers (P < 0.05). Although positive effects were also observed in those who were hypertensive and smoking at the time of CRP measurement, findings suggest that in clinically healthy men, atherosclerosis could have origins more closely linked with inflammation than with other processes.

Age-related changes in risk factor effects on the incidence of coronary heart disease.

PURPOSE: The purpose of this report is to examine the potential for risk factor effects on the incidence of CHD to change over a broad range of ages from middle adulthood to late-life. METHODS: Findings are based on repeated risk factor measurements at four examinations over a 26-year period in men enrolled in the Honolulu Heart Program. After each examination, six years of follow-up were available to assess risk factor effects as the cohort aged from 45 to 93 years. RESULTS: Based on 18,456 person intervals of follow-up, 677 men developed CHD (3.7%). After risk factor adjustment, a positive relation between hypertension and CHD declined significantly with age (p = 0.013), primarily due to a large increase in the risk of CHD in elderly men (75 to 93) without hypertension. Effects of total cholesterol on CHD also seemed to decline with advancing age, although changes were not statistically significant. In contrast, men with diabetes had a consistent 2-fold excess risk of CHD across all age groups, while a positive association with body mass index in younger men (45 to 54) became negative in those who were the oldest (75 to 93). Due to infrequent smoking in the elderly, associations between smoking and CHD weakened with age. In the oldest men (75 to 93), alcohol intake was unrelated to CHD, while effects of sedentary life-styles on promoting CHD appeared stronger than in those who were younger. CONCLUSION: Findings suggest that changes in risk factor effects on the incidence of CHD with advancing age may require updated strategies for CHD prevention as aging occurs.

Risk of hospitalized stroke in men enrolled in the Honolulu Heart Program and the Framingham Study: A comparison of incidence and risk factor effects.

BACKGROUND AND PURPOSE: Risk of death due to stroke in Japan is more than double the risk in the United States. It remains unknown why some ethnic groups are more prone to stroke than others. Our purpose was to compare the 20-year incidence of hospitalized stroke between Japanese-American men in the Honolulu Heart Program and white men in the Framingham Study. METHODS: This was a 20-year follow-up study beginning around 1965, a population-based study on the island of Oahu, Hawaii, and in Framingham, Mass. Participants were 7589 men in Honolulu and 1216 men in Framingham without prevalent coronary heart disease and stroke. Subjects were 45 to 68 years old when follow-up began. Main outcome measures were incident thromboembolic and hemorrhagic stroke. RESULTS: Framingham men had a 40% excess of thromboembolic stroke compared with Honolulu men after adjustment for age and other risk factors (62/1000 versus 45/1000, respectively, P<0.001), whereas incidence of hemorrhagic stroke was nearly identical (14.8/1000). In both cohorts, each stroke type was consistently elevated in the presence of hypertension and cigarette smoking. Diabetes and body mass index increased the risk of thromboembolic stroke in both samples, and diabetes increased the risk of hemorrhagic events in Framingham. Alcohol intake and low total cholesterol were associated with hemorrhagic events in Honolulu but not in Framingham. Despite occasional differences in risk factor effects, none were significantly different between cohorts. CONCLUSIONS: The incidence of thromboembolic stroke requiring hospitalization is markedly less in Honolulu than in Framingham. The difference in stroke incidence rates observed cannot be explained by the traditional risk factors. Further studies are needed to identify factors that protect Japanese-American men in Honolulu from stroke.