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1.  Association of inflammatory markers with subclinical atherosclerosis in middle-aged white, Japanese-American, and Japanese men: the ERA-JUMP Study 
To examine whether the inflammatory markers, C-reactive protein (CRP) and fibrinogen, are associated with biomarkers of atherosclerosis [carotid intima-media thickness (IMT) and coronary artery calcification (CAC)] in the general male population, including Asians.
Population-based samples of 310 Japanese, 293 Japanese-American and 297 White men aged 40-49 years without clinical cardiovascular disease had IMT, CAC, CRP and fibrinogen levels, and other conventional risk factors measured using standardized methods. Statistical associations between the variables were evaluated using multiple linear or logistic regression models.
The Japanese group had significantly lower levels of inflammatory markers and subclinical atherosclerosis than the Japanese-American and White groups (P-values all <0.001). The mean levels of CRP were 0.66 vs. 1.11 and 1.47 mg/L, and fibrinogen 255.0 vs. 313.0 and 291.5 mg/dl, respectively. Mean carotid IMT was 0.61 vs. 0.73 and 0.68 mm, and the prevalence of CAC 11.6% vs. 32.1% and 26.3%, respectively. Body mass index (BMI) showed significant positive associations with both CRP and fibrinogen levels. Although CRP showed a significant positive association with IMT in Japanese men, this association became non-significant after adjustment for traditional risk factors or BMI. In all three populations, CRP was not associated significantly with the prevalence of CAC. Similarly, fibrinogen did not show a significant association with either IMT or the prevalence of CAC.
The associations of inflammatory markers with subclinical atherosclerosis may merely reflect the strong association of BMI with inflammatory markers and subclinical atherosclerosis in both Eastern and Western populations.
PMCID: PMC4449327  PMID: 25445888
obesity; C-reactive protein; fibrinogen; intima-media thickness; coronary artery calcification
2.  Modeling Regional Vulnerability to Alzheimer Pathology 
Neurobiology of aging  2011;33(8):1556-1563.
Latent growth curve (LGC) models estimate change over time in a cohort's serially obtained measurements. We have applied LGC techniques to a spatial distribution of Alzheimer's disease (AD) pathology using autopsy data from 435 participants in the Honolulu-Asia Aging Study. Neurofibrillary tangle (NFT) and neuritic plaques (NP) were distributed across differently ordered sets of anatomical regions. The gradient of spatial change in NP (dNP), was significantly associated with that of NFT (dNFT), but weakly and inversely (r = -0.12, p <0.001). Both dNFT and dNP correlated significantly and inversely with Braak stage. 61% of the variance in Braak stage was explained by dNFT independent of covariates. Only dNFT was significantly associated with longitudinal change in cognition. Only dNP was associated with apolipoprotein (APOE) e4 burden. This is the first application of LGC models to spatially ordered data. The result is a quantification of the inter-individual variation in the inter-regional vulnerability to AD lesions.
PMCID: PMC4459133  PMID: 21803455
Old Age; Neuropathology; Alzheimer's disease
3.  Combining Quality Improvement and Geriatrics Training: The Nursing Home Polypharmacy Outcomes Project 
To examine sustained effects of an educational intervention, we repeated a successful quality improvement (QI) project on medication safety and cost-effectiveness. In October 2007 and August 2008, facility leadership and geriatrics faculty identified all patients receiving ≥9 medications (polypharmacy cohort) in a 170-bed teaching nursing home and taught Geriatric Medicine fellows (n=12 in 2007, 11 in 2008) to: 1) systematically collect medication data; 2) generate medication recommendations (stop, taper, or continue) based on expert criteria (Beers Criteria) or drug-drug interaction programs; 3) discuss recommendations with patients’ attending physicians; and 4) implement approved recommendations. Over the two projects, the polypharmacy cohorts demonstrated decreased potentially inappropriate medications (odds ratio (OR) 0.78, 95% confidence interval (95%CI)0.69–0.88, p<0.001), contraindicated medications (OR=0.63, 95%CI=0.47–0.85, p=0.002) and medication costs (OR=0.97, 95%CI=0.96–0.99, p<0.001). Our findings suggest that programs planning educational QI projects for trainees may benefit from a multi-year approach to maximize both clinical and educational benefits.
PMCID: PMC4190157  PMID: 24829040
Geriatric Education; Quality improvement; Polypharmacy; Nursing homes; Geriatric Medicine Fellowship
4.  Proteinuria in Mid-Life and 39-Year Total Mortality: The Honolulu Heart Program 
Annals of epidemiology  2014;24(5):407-409.
PMCID: PMC3992477  PMID: 24613198
proteinuria; urinalysis; mortality; cohort studies; Japanese Americans
5.  Late-Life Factors Associated With Healthy Aging in Older Men 
To identify potentially modifiable late-life biological, lifestyle and sociodemographic factors associated with overall and healthy survival to age 85.
Prospective longitudinal cohort study with 21 years of follow-up (1991–2012)
The Hawaii Lifespan Study
1,292 American men of Japanese ancestry (mean age 75.7 years, range 71–82 years) without baseline major clinical morbidity and functional impairments.
Overall survival and healthy survival (free from six major chronic diseases and without physical or cognitive impairment) to age 85. Factors were measured at late-life baseline examinations (1991–1993).
Of 1,292 participants, 1,000 men (77%) survived to age 85 years (34% healthy) and 309 (24%) survived to age 95 years (<1% healthy). Late-life factors associated with survival and/or healthy survival included biological (body mass index, ankle:brachial index, cognitive score, blood pressure, inflammatory markers); lifestyle (smoking, alcohol use, physical activity), and sociodemographic factors (education, marital status). Cumulative late-life baseline risk factor models demonstrated that age-standardized (at 70 years) probability of survival to age 95 years ranged from 27% (no factors) to 7% (≥5 factors); to age 100 years ranged from 4% (no factors) to 0.1% (≥5 factors). Age-standardized (at 70 years) probability of healthy survival to 90 years ranged from 4% (no factors) to 0.01% (≥ 5 factors). There were nine healthy survivors at age 95 years and one healthy survivor at age 100 years.
Several potentially modifiable risk factors in men in late-life (mean age 75.7 years) were associated with markedly increased probability of subsequent healthy survival and longevity.
PMCID: PMC4024082  PMID: 24779449
healthy aging; risk factors; longevity; longitudinal cohort study; late-life
6.  Pre-Stroke Weight Loss is Associated with Post-Stroke Mortality among Men in the Honolulu-Asia Aging Study 
To examine baseline pre-stroke weight loss and post-stroke mortality among men.
Longitudinal study of late-life pre-stroke body mass index (BMI), weight loss and BMI change (midlife to late-life), with up to 8-year incident stroke and mortality follow-up.
Honolulu Heart Program/Honolulu-Asia Aging Study.
3,581 Japanese-American men aged 71–93 years and stroke-free at baseline.
Main Outcome Measure
Post-stroke Mortality: 30-day post-stroke, analyzed with stepwise multivariable logistic regression and long-term post-stroke (up to 8-year), analyzed with stepwise multivariable Cox regression.
Weight loss (10-pound decrements) was associated with increased 30-day post-stroke mortality (aOR=1.48, 95%CI 1.14–1.92), long-term mortality after incident stroke (all types n=225, aHR=1.25, 95%CI=1.09–1.44) and long-term mortality after incident thromboembolic stroke (n=153, aHR 1.19, 95%CI-1.01–1.40). Men with overweight/obese late-life BMI (≥25kg/m2, compared to normal/underweight BMI) had increased long-term mortality after incident hemorrhagic stroke (n=54, aHR=2.27, 95%CI=1.07–4.82). Neither desirable nor excessive BMI reductions (vs. no change/increased BMI) were associated with post-stroke mortality. In the overall sample (n=3,581), nutrition factors associated with increased long-term mortality included 1) weight loss (10-pound decrements, aHR=1.15, 1.09–1.21); 2) underweight BMI (vs. normal BMI, aHR=1.76, 1.40–2.20); and 3) both desirable and excessive BMI reductions (vs. no change or gain, separate model from weight loss and BMI, aHRs=1.36–1.97, p<0.001).
Although obesity is a risk factor for stroke incidence, pre-stroke weight loss was associated with increased post-stroke (all types and thromboembolic) mortality. Overweight/obese late-life BMI was associated with increased post-hemorrhagic stroke mortality. Desirable and excessive BMI reductions were not associated with post-stroke mortality. Weight loss, underweight late-life BMI and any BMI reduction were all associated with increased long-term mortality in the overall sample.
PMCID: PMC3943854  PMID: 24113337
older men; stroke; weight loss; BMI; mortality; aged; longitudinal
7.  Association Analyses of Insulin Signaling Pathway Gene Polymorphisms With Healthy Aging and Longevity in Americans of Japanese Ancestry 
Evidence from model organisms suggests that the insulin/IGF-1 signaling pathway has an important, evolutionarily conserved influence over rate of aging and thus longevity. In humans, the FOXO3 gene is the only widely replicated insulin/IGF-1 signaling pathway gene associated with longevity across multiple populations. Therefore, we conducted a nested case–control study of other insulin/IGF-1 signaling genes and longevity, utilizing a large, homogeneous, long-lived population of American men of Japanese ancestry, well characterized for aging phenotypes. Genotyping was performed of single nucleotide polymorphisms, tagging most of the genetic variation across several genes in the insulin/IGF-1 signaling pathway or related gene networks that may be influenced by FOXO3, namely, ATF4, CBL, CDKN2, EXO1, and JUN. Two initial, marginal associations with longevity did not remain significant after correction for multiple comparisons, nor were they correlated with aging-related phenotypes.
PMCID: PMC3968832  PMID: 23770741
Longevity; Molecular genetics; Insulin signaling genes; Human.
8.  Obesity and Survival to Age 85 Years without Major Disease or Disability in Older Women 
JAMA internal medicine  2014;174(1):98-106.
The impact of obesity on late-age survival without disease or disability in women is unknown.
To investigate if higher baseline body mass index and waist circumference affects women’s survival to age 85 years without major chronic disease (coronary disease, stroke, cancer, diabetes, or hip fracture) and mobility disability.
Design, Setting, Participants
Examination of 36,611 women from the Women’s Health Initiative who could have reached age 85 years or older if they survived to the last outcomes evaluation on September 17, 2012. Recruitment was from 40 US Clinical Centers from October 1993–December 1998. Multinomial logistic regression models were used to estimate odds ratios and 95% confidence intervals for the association of baseline body mass index and waist circumference with the outcomes, adjusting for demographic, behavioral, and health characteristics.
Main Outcome Measures
Mutually-exclusive classifications: 1) survived without major chronic disease and without mobility disability (“healthy”); 2) survived with ≥1 major chronic disease at baseline, but without new disease or disability (“prevalent diseased”); 3) survived and developed ≥1 major chronic disease but not disability during study follow-up (“incident diseased”); 4) survived and developed mobility disability with or without disease (“disabled”); and 5) did not survive (“died”).
Mean (SD) baseline age was 72.4 (3.0) years (range: 66–81). The distribution of women classified as healthy, prevalent diseased, incident diseased, disabled, and died was 19%, 15%, 23%, 18%, and 25%, respectively. Compared to normal-weight women, underweight and obese women were more likely to die before age 85 years. Overweight and obese women had higher risks of incident disease and mobility disability. Disability risks were striking. Relative to normal-weight women, adjusted odds ratios (95% confidence intervals) of mobility disability was 1.6 (1.5–1.8) for overweight women and 3.2 (2.9–3.6), 6.6 (5.4–8.1), and 6.7 (4.8–9.2), for class I, II, and III obesity, respectively. Waist circumference >88 centimeters was also associated with higher risk of earlier death, incident disease, and mobility disability.
Overall and abdominal obesity were important and potentially modifiable factors associated with dying or developing mobility disability and major chronic disease before age 85 years in older women.
PMCID: PMC3963496  PMID: 24217806
9.  Association of Total Marine Fatty Acids, Eicosapentaenoic and Docosahexaenoic Acids, With Aortic Stiffness in Koreans, Whites, and Japanese Americans 
American Journal of Hypertension  2013;26(11):1321-1327.
Few previous studies have reported the association of aortic stiffness with marine n-3 fatty acids (Fas) in the general population. The aim of this study was to determine the combined and independent associations of 2 major marine n-3 FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with aortic stiffness evaluated using carotid–femoral pulse wave velocity (cfPWV) in Korean, white, and Japanese American men.
A population-based sample of 851 middle-aged men (299 Koreans, 266 whites, and 286 Japanese Americans) was examined for cfPWV during 2002–2006. Serum FAs, including EPA and DHA, were measured as a percentage of total FAs using gas chromatography. Multiple regression analysis was used to examine the association of EPA and DHA with cfPWV after adjusting for blood pressure and other confounders.
Mean EPA and DHA levels were 1.9 (SD = 1.0) and 4.8 (SD = 1.4) for Koreans, 0.8 (SD = 0.6) and 2.4 (SD = 1.2) for whites, and 1.0 (SD = 1.0) and 3.2 (SD = 1.4) for Japanese Americans. Both EPA and DHA were significantly higher in Koreans than in the other 2 groups (P < 0.01). Multiple regression analyses in Koreans showed that cfPWV had a significant inverse association with total marine n-3 FAs and with EPA alone after adjusting for blood pressure and other potential confounders. In contrast, there was no significant association of cfPWV with DHA. Whites and Japanese Americans did not show any significant associations of cfPWV with total marine n-3 FAs, EPA, or DHA.
High levels of EPA observed in Koreans have an inverse association with aortic stiffness.
PMCID: PMC3790451  PMID: 23820020
aortic stiffness; blood pressure; carotid femoral pulse wave velocity; docosahexaenoic acid; eicosapentaenoic acid; fish oil; hypertension.
10.  Do Differences in Risk Factors Explain the Lower Rates of Coronary Heart Disease in Japanese Versus U.S. Women? 
Journal of Women's Health  2013;22(11):966-977.
Mortality from coronary heart disease (CHD) in women in Japan is one of the lowest in developed countries. In an attempt to shed some light on possible reasons of lower CHD in women in Japan compared with the United States, we extensively reviewed and analyzed existing national data and recent literature.
We searched recent epidemiological studies that reported incidence of acute myocardial infarction (AMI) and examined risk factors for CHD in women in Japan. Then, we compared trends in risk factors between women currently aged 50–69 years in Japan and the United States, using national statistics and other available resources.
Recent epidemiological studies have clearly shown that AMI incidence in women in Japan is lower than that reported from other countries, and that lipids, blood pressure (BP), diabetes, smoking, and early menopause are independent risk factors. Comparing trends in risk factors between women in Japan and the United States, current levels of serum total cholesterol are higher in women in Japan and levels have been similar at least since 1990. Levels of BP have been higher in in Japan for the past 3 decades. Prevalence of type 2 diabetes has been similar in Japanese and white women currently aged 60–69 for the past 2 decades. In contrast, rates of cigarette smoking, although low in women in both countries, have been lower in women in Japan.
Differences in risk factors and their trends are unlikely to explain the difference in CHD rates in women in Japan and the United States. Determining the currently unknown factors responsible for low CHD mortality in women in Japan may lead to new strategy for CHD prevention.
PMCID: PMC3820126  PMID: 24073782
11.  Antihypertensive medication use and risk of cognitive impairment 
Neurology  2013;81(10):888-895.
To determine the associations between classes of antihypertensive medication use and the risk of cognitive impairment among elderly hypertensive men.
The Honolulu-Asia Aging Study is a prospective, community-based cohort study of Japanese American men conducted in Honolulu, Hawaii. We examined 2,197 participants (mean age 77 years at cohort entry, 1991–1993, followed through September 2010) with hypertension and without dementia or cognitive impairment at baseline, who provided information on medication use. Cognitive function was assessed at 7 standardized examinations using the Cognitive Abilities Screening Instrument (CASI). Cognitive impairment was defined as a CASI score <74.
A total of 854 men developed cognitive impairment (median follow-up, 5.8 years). β-Blocker use as the sole antihypertensive drug at baseline was consistently associated with a lower risk of cognitive impairment (incidence rate ratio [IRR] 0.69; 95% confidence interval [CI] 0.50–0.94), as compared with men not taking any antihypertensive medications, adjusting for multiple potential confounders. The use of diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, or vasodilators alone was not significantly associated with cognitive impairment. Results were similar excluding those with cardiovascular disease or <1 year of follow-up, and additionally adjusting for pulse pressure, heart rate, baseline and midlife systolic blood pressure, and midlife antihypertensive treatment (IRR 0.65; 95% CI 0.45–0.94). The association between β-blocker use and cognitive impairment was stronger among men with diabetes, men aged >75 years, and those with pulse pressure ≥70 mm Hg.
β-blocker use is associated with a lower risk of developing cognitive impairment in elderly Japanese American men.
PMCID: PMC3885214  PMID: 23911753
12.  Total and Differential White Blood Cell Counts Predict Eight-Year Incident Stoke in Elderly Japanese-American Men: The Honolulu Heart Program 
Previous studies have found that a higher white blood cell (WBC) count is associated with incident stroke. There have been few studies examining differential WBC counts in elderly or Asian populations. We studied the association between total and differential WBC counts and incident stroke in an older Asian population.
The Honolulu Heart Program is a prospective population-based study of cardiovascular diseases in Japanese-American men that started in 1965. At exam 4 (1991–93), 3,741 men ages 71–93 years participated, and total and differential WBC counts were measured in 3,569 men using a Coulter counter machine. Data on incident stroke (all strokes [ALL-CVA], thromboembolic [TE-CVA] and hemorrhagic [HEM-CVA]) were available through December 1999 (8 years follow-up) from a comprehensive hospital surveillance system. After excluding 227 subjects with prevalent stroke, 3,342 subjects were divided into quartiles of total WBC, neutrophil (segmented and band), granulocyte (neutrophil, eosinophil and basophil), lymphocyte, and monocyte counts for separate analyses.
Age-adjusted incident ALL-CVA rates increased significantly with total WBC quartiles (7.68, 9.04, 9.26, 14.1, per 1,000 person years follow-up, respectively, P = .0014). Relative risks for ALL-CVA for each quartile of total and differential WBC counts were obtained using Cox proportional hazards, using the lowest quartile as the reference group. After full adjustment including age, cardiovascular risk factors, fibrinogen, prevalent CHD, cancer or COPD, and aspirin/NSAID use, the relative risks in the highest quartiles of total WBC, neutrophil, and granulocyte counts were 1.63 (95%CI = 1.05–2.54, P = .03), 2.19 (95%CI = 1.41–3.39, P < .001) and 1.91 (95%CI = 1.25–2.92, P = .003), respectively. These significant associations were also seen for TE-CVA, but not for HEM-CVA. No significant associations were found between lymphocyte or monocyte counts and incident stroke or subtypes.
In elderly Japanese-American men, higher total WBC, neutrophil, and granulocyte counts were independent predictors of overall stroke, as well as thromboembolic stroke. Further studies are needed to establish cut-points and treatment options.
PMCID: PMC4175930
13.  A cross-sectional association of obesity with coronary calcium among Japanese, Koreans, Japanese Americans, and US Whites 
Conflicting evidence exists regarding whether obesity is independently associated with coronary artery calcium (CAC), a measure of coronary atherosclerosis. We examined an independent association of obesity with prevalent CAC among samples of multi-ethnic groups whose background populations have varying levels of obesity and coronary heart disease (CHD).
Methods and results
We analysed a population-based sample of 1212 men, aged 40–49 years free of clinical cardiovascular disease recruited in 2002–06; 310 Japanese in Japan (JJ), 294 Koreans in South Korea (KN), 300 Japanese Americans (JA), and 308 Whites in the USA (UW). We defined prevalent CAC as an Agatston score of ≥10. Prevalent CAC was calculated by tertile of the body mass index (BMI) in each ethnic group and was plotted against the corresponding median of tertile BMI. Additionally, logistic regression was conducted to examine whether an association of the BMI was independent of conventional risk factors. The median BMI and crude prevalence of CAC for JJ, KN, JA, and UW were 23.4, 24.4, 27.4, and 27.1 (kg/m2); 12, 11, 32, and 26 (%), respectively. Despite the absolute difference in levels of BMI and CAC across groups, higher BMI was generally associated with higher prevalent CAC in each group. After adjusting for age, smoking, alcohol, hypertension, lipids, and diabetes mellitus, the BMI was positively and independently associated with prevalent CAC in JJ, KN, UW, but not in JA.
In this multi-ethnic study, obesity was independently associated with subclinical stage of coronary atherosclerosis among men aged 40–49 years regardless of the BMI level.
PMCID: PMC3738098  PMID: 23764486
Coronary artery calcium; Obesity; Body mass index; Multi-ethnic; Men; Risk factors
14.  Pre-Stroke Factors Associated with Post-Stroke Mortality and Recovery in Older Women in the Women’s Health Initiative 
We sought to examine pre-stroke lifestyle factorsassociated with post-stroke mortalityand recovery in older women.
Longitudinal prospective cohort study.
The Women’s Health Initiative (clinical trials and observational study), 40 clinical centers in the U.S.
WHI participants, women aged 50–79, who were stroke-free at baseline 1993–1998, with incident stroke prior to 2005.
Participants were followed for mortality through 2010. Pre-stroke characteristics were from the most proximal examination before the stroke event. Annual follow-up for clinical events ascertained hospitalization for stroke which was subsequently physician-adjudicated with medical records. Multivariable regression models analyzed factors associated with post-stroke mortality and post-stroke recovery at hospital discharge (post-stroke Glasgow score), adjusting for stroke type.
Of 3,173 women with incident stroke, 1,111 (35%) died. Overweight and obese BMI pre-stroke was associated with reduced post-stroke mortality (vs. normal BMI, obese BMI hazards ratio, HR=0.69, 95% confidence interval (CI)=0.53–0.88; overweight BMI: HR=0.72, 95%CI=0.58–0.90); underweight pre-stroke BMI had borderline increased post-stroke mortality (HR=2.02, 95%CI=0.98–4.16).Other pre-stroke factors associated with post-stroke mortality included diabetes (HR=1.28, 95%CI=1.01–1.64), current smoking (vs. nonsmoker, hazard ratio (HR)=2.13, 95%CI=1.53–3.00), physical inactivity (vs. >150 minutes exercise/week, HR=1.39, 95%CI=1.09–1.78) and lowest physical function quartile (vs. highest, HR=1.54, 95%CI=1.18–2.02). Pre-stroke diabetes was associated with reduced odds of good recovery post-stroke (odds ratio (OR)= 0.60, 95%CI= 0.44–0.82). Current hormone use pre-stroke was associated with increased odds of moderate vs. severe disability post-stroke (OR=1.29, 95%CI=1.00–1.66).
Potentially modifiable factors pre-stroke, including smoking, diabetes and underweight BMI, were associated with increased post-stroke mortality in older women. Pre-stroke overweight or obese BMI and physical activity were associated with reduced post-stroke mortality in older women.
PMCID: PMC3743941  PMID: 23869842
stroke; mortality; women; BMI; recovery; diabetes
15.  Particle Numbers of Lipoprotein Subclasses and Arterial Stiffness among Middle-aged men from the ERA JUMP study 
Journal of human hypertension  2013;28(2):111-117.
We examined the association between serum lipoprotein subclasses and the three measures of arterial stiffness i.e. (i) carotid-femoral pulse wave velocity (cfPWV) which is a gold standard measure of central arterial stiffness, (ii) brachial-ankle PWV (baPWV) which is emerging as a combined measure of central and peripheral arterial stiffness, and (iii) femoral-ankle PWV (faPWV) which is a measure of peripheral arterial stiffness. Among a population-based sample of 701 apparently healthy Caucasian, Japanese American and Korean men aged 40–49 years, concentrations of lipoprotein particles were assessed by nuclear magnetic resonance (NMR) spectroscopy, and PWV was assessed with an automated waveform analyzer (VP2000, Omron, Japan). Multiple linear regressions were performed to analyze the association between each NMR lipoprotein subclasses and PWV measures, after adjusting for cardiovascular risk factors and other confounders. A cut-off of p<0.01 was used for determining significance. All PWV measures had significant correlations with total and small low-density lipoprotein particle number (LDL-P) (all p<0.0001) but not LDL-cholesterol (LDL-C) (all p>0.1), independent of race and age. In multivariate regression analysis, no NMR lipoprotein subclass was significantly associated with cfPWV (all p>0.01). However, most NMR lipoprotein subclasses had significant associations with both baPWV and faPWV (p<0.01). In this study of healthy middle-aged men, as compared to cfPWV, both baPWV and faPWV had stronger associations with particle numbers of lipoprotein subclasses. Our results may suggest that both baPWV and faPWV are related to arterial stiffness and atherosclerosis, whereas cfPWV may represent arterial stiffness alone.
PMCID: PMC3800263  PMID: 23823580
lipoproteins; lipoprotein fractions; pulse wave velocity; atherosclerosis
16.  The Associations of Indices of Obesity with Lipoprotein Subfractions in Japanese American, African American and Korean Men 
Global heart  2013;8(3):273-280.
Both indices of obesity and lipoprotein subfractions contribute to coronary heart disease risk. However, associations between indices of obesity and lipoprotein subfractions remain undetermined across different ethnic groups. This study aims to examine the associations of indices of obesity in Japanese Americans (JA), African Americans (AA) and Koreans with lipoprotein subfractions.
A population-based sample of 230 JA, 91 AA, and 291 Korean men aged 40–49 was examined for indices of obesity, i.e., visceral and subcutaneous adipose tissue (VAT and SAT, respectively), waist circumference (WC), and body-mass index (BMI), and for lipoprotein subfractions by nuclear-magnetic-resonance spectroscopy. Multiple regression analyses were performed in each of the three ethnic groups to examine the associations of each index of obesity with lipoprotein.
VAT had significant positive associations with total and small low-density lipoprotein (LDL) and a significant negative association with large high-density lipoprotein (HDL) in all three ethnicities (p < 0.01). SAT, WC, and BMI had significant positive associations with total and small LDL in only JA and Koreans, while these indices had significant inverse associations with large HDL in all ethnic groups (p < 0.01). Compared to SAT, VAT had larger R2 values in the associations with total and small LDL and large HDL in all three ethnic groups.
VAT is significantly associated with total and small LDL and large HDL in all three ethnic groups. The associations of SAT, WC, and BMI with lipoprotein subfractions are weaker compared to VAT in all three ethnic groups.
PMCID: PMC4110345  PMID: 25068101
visceral adipose tissue; subcutaneous adipose tissue; body-mass index; waist circumference; lipoprotein subfractions
17.  The Prevalence of Aortic Calcification in Japanese Compared to White and Japanese-American Middle-Aged Men is Confounded by the Amount of Cigarette Smoking 
International journal of cardiology  2012;167(1):134-139.
Prevalence of coronary artery calcification (CAC) in Japanese men is lower than in white and Japanese-American men. It is unclear if aortic calcification (AC) strongly linked to smoking is also lower in Japanese men who have many times higher smoking prevalence compared to US men.
We conducted a population-based study of 903 randomly-selected men aged 40–49 years: 310 Japanese men in Kusatsu, Japan, 301 white men in Allegheny County, U.S., and 292 Japanese men in Hawaii, U.S. (2002–2006). The presence of AC was assessed by electron-beam tomography. AC was defined as Agatston aortic calcium scores (AoCaS) >0 and ≥100.
Japanese (35.8%) had significantly less AoCaS>0 compared to both white (68.8%, p<0.001) and Japanese-American (62.3%, p<0.001) but similar AoCaS≥100 (19.4%, 18.3%, 22.6%, respectively, p=0.392). Pack-years of smoking, which was highest in Japanese, was the most important single associate of AC in all populations. Additionally age, low-density-lipoprotein cholesterol (LDL-C), and triglycerides in Japanese; body-mass index (BMI) in white; and BMI, LDL-C, hypertension, diabetes, and lipid medications in Japanese-American were independent associates of AC. The risk of AC using either cut points adjusted for pack-years of smoking and additional risk factors was lower in Japanese compared to both white and Japanese-American. AC and CAC had moderately positive and significant correlations in Japanese (r=0.26), white (r=0.39), and Japanese-American (r=0.45).
Prevalence of AC defined both >0 and ≥100 was significantly lower in Japanese than in white and Japanese-American men after adjusting for cigarette smoking and additional risk factors
PMCID: PMC3328605  PMID: 22240754
Epidemiology; risk factors; atherosclerosis; aorta; calcification; electron-beam tomography; Caucasian; Japanese; Japanese American
18.  Shorter Men Live Longer: Association of Height with Longevity and FOXO3 Genotype in American Men of Japanese Ancestry 
PLoS ONE  2014;9(5):e94385.
To determine the relation between height, FOXO3 genotype and age of death in humans.
Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years. A Cox regression model with age as the time scale, stratified by year of birth, was used to estimate the effect of baseline height on mortality during follow-up. An analysis of height and longevity-associated variants of the key regulatory gene in the insulin/IGF-1 signaling (IIS) pathway, FOXO3, was performed in a HHP-HAAS subpopulation. A study of fasting insulin level and height was conducted in another HHP-HAAS subpopulation.
A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003–1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002–1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. A Cox regression model with time-dependent covariates showed that relative risk for baseline height on mortality increased as the population aged. Comparison of genotypes of a longevity-associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality. Regression analysis of fasting insulin level (mIU/L) on height (cm) adjusting for the age both data were collected yielded a regression coefficient of 0.26 (95% CI 0.10–0.42; P = 0.001).
Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway.
PMCID: PMC4013008  PMID: 24804734
19.  Long-chain n-3 polyunsaturated fatty acids and incidence rate of coronary artery calcification in Japanese in Japan and United States whites – population-based prospective cohort study 
Heart (British Cardiac Society)  2013;100(7):569-573.
To determine whether serum levels of long-chain n-3 polyunsaturated fatty acids (LCn3PUFAs) contribute to the difference in incidence rate of coronary artery calcification (CAC) between Japanese in Japan and U.S. whites.
In a population-based prospective-cohort study, 214 Japanese and 152 white men aged 40–49 years at baseline (2002–2006) with coronary calcium score (CCS) = 0 were reexamined for CAC in 2007–2010. Among these, 175 Japanese and 113 whites participated in the follow-up exam. Incident cases were defined as participants with CCS ≥ 10 at follow-up. A relative risk regression analysis was used to model incidence rate ratio between Japanese and whites. The incidence rate ratio was first adjusted for potential confounders at baseline and then further adjusted for serum LCn3PUFAs at baseline.
Mean (standard deviation) serum percentage of LCn3PUFA was > 100% higher in Japanese than in whites (9.08 (2.49) versus 3.84 (1.79), respectively, p<0.01). Japanese had a significantly lower incidence rate of CAC compared to whites (0.9 versus 2.9/100 person-years, respectively, p < 0.01). Incidence rate ratio of CAC taking follow-up time into account between Japanese and white men was 0.321 (95% confidence interval (CI) 0.150, 0.690: p<0.01). After adjusting for age, systolic-blood pressure, low-density-lipoprotein cholesterol, diabetes, and other potential confounders, the ratio remained significant: 0.262 (95% CI: 0.094, 0.731, p=0.01). After further adjusting for LCn3PUFAs, however, the ratio was attenuated and became non-significant (0.376 (95% CI: 0.090, 1.572, p=0.18).
LCn3PUFAs significantly contributed to the difference in CAC incidence between Japanese and white men.
PMCID: PMC3949146  PMID: 24352736
long-chain n-3 fatty acids; coronary artery calcification; prospective cohort study; incidence; risk factors
20.  Regional pulse wave velocities and their cardiovascular risk factors among healthy middle-aged men: a cross-sectional population-based study 
Both carotid-femoral (cf) pulse wave velocity (PWV) and brachial-ankle (ba) PWV employ arterial sites that are not consistent with the path of blood flow. Few previous studies have reported the differential characteristics between cfPWV and baPWV by simultaneously comparing these with measures of pure central (aorta) and peripheral (leg) arterial stiffness, i.e., heart-femoral (hf) PWV and femoral-ankle (fa) PWV in healthy populations. We aimed to identify the degree to which these commonly used measures of cfPWV and baPWV correlate with hfPWV and faPWV, respectively, and to evaluate whether both cfPWV and baPWV are consistent with either hfPWV or faPWV in their associations with cardiovascular (CV) risk factors.
A population-based sample of healthy 784 men aged 40–49 (202 white Americans, 68 African Americans, 202 Japanese-Americans, and 282 Koreans) was examined in this cross-sectional study. Four regional PWVs were simultaneously measured by an automated tonometry/plethysmography system.
cfPWV correlated strongly with hfPWV (r = .81, P < .001), but weakly with faPWV (r = .12, P = .001). baPWV correlated moderately with both hfPWV (r = .47, P < .001) and faPWV (r = .62, P < .001). After stepwise regression analyses with adjustments for race, cfPWV shared common significant correlates with both hfPWV and faPWV: systolic blood pressure (BP) and body mass index (BMI). However, BMI was positively associated with hfPWV and cfPWV, and negatively associated with faPWV. baPWV shared common significant correlates with hfPWV: age and systolic BP. baPWV also shared the following correlates with faPWV: systolic BP, triglycerides, and current smoking.
Among healthy men aged 40 – 49, cfPWV correlated strongly with central PWV, and baPWV correlated with both central and peripheral PWVs. Of the CV risk factors, systolic BP was uniformly associated with all the regional PWVs. In the associations with factors other than systolic BP, cfPWV was consistent with central PWV, while baPWV was consistent with both central and peripheral PWVs.
PMCID: PMC3893368  PMID: 24410766
Arterial stiffness; Aorta; Carotid arteries; Brachial artery; Femoral artery
21.  Influence of Type 2 Diabetes on Brain Volumes and Changes in Brain Volumes 
Diabetes Care  2012;36(1):90-97.
To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function.
Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72–89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined.
The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits.
Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.
PMCID: PMC3526228  PMID: 22933440
22.  Calcium and Vitamin D Supplementation and Cognitive Impairment in the Women’s Health Initiative 
Calcium and vitamin D are thought to play important roles in neuronal functioning. Studies have found associations between low serum vitamin D levels and reduced cognitive functioning, as well as high serum calcium levels and reduced cognitive functioning.
To examine the effects of vitamin D and calcium on cognitive outcomes in elderly women.
Post-hoc analysis of a randomized double-blinded placebo-controlled trial.
40 Women’s Health Initiative clinical centers across the U.S.
4143 women aged 65 years and older without probable dementia at baseline who participated in the WHI Calcium and Vitamin D trial and the Women’s Health Initiative Memory Study.
2034 women were randomized to 1000 mg of calcium carbonate combined with 400 IU of vitamin D3; 2109 women were randomized to placebo.
Primary: classifications of probable dementia or mild cognitive impairment via a 4-phase protocol that included central adjudication. Secondary: global cognitive function and individual cognitive subtests.
Mean age of participants was 71 years. During mean follow-up of 7.8 years, there were 39 cases of incident dementia among calcium plus vitamin D subjects compared to 37 cases among placebo subjects (hazard ratio=1.11, 95% CI: 0.71–1.74, p=0.64). Likewise, there were 98 cases of incident mild cognitive impairment among calcium plus vitamin D subjects compared to 108 cases among placebo subjects (hazard ratio=0.95, 95% CI: 0.72–1.25, p=0.72). There were no significant differences in incident dementia or mild cognitive impairment, or in global or domain-specific cognitive function between groups.
There was no association between treatment assignment and incident cognitive impairment. Further studies are needed to investigate the effects of vitamin D and calcium separately, on men and in other age and ethnic groups, and with other doses.
PMCID: PMC3521077  PMID: 23176129
Vitamin D; Calcium; Dementia; Cognition; Mild Cognitive Impairment
23.  Relation of Serum Leptin and Adiponectin Level to Serum C-Reactive Protein: The INTERLIPID Study 
Objective. Despite considerable study, the relevance of leptin and adiponectin for atherosclerosis development is still unsettled. We investigated relations of serum leptin and adiponectin to serum C-reactive protein (CRP), using the INTERLIPID dataset on Japanese emigrants living in Hawaii and Japanese in Japan. Design and Methods. Serum leptin, adiponectin, and CRP were measured by standardized methods in men and women of ages 40 to 59 years from two population samples, one Japanese-American in Hawaii (83 men, 89 women) and the other Japanese in central Japan (111 men, 104 women). Participants with CRP >10 mg/L were excluded. Results. Sex-specific multiple linear regression analyses, with log-transformed leptin and adiponectin (log-leptin, log-adipo), site (Hawaii = 1, Japan = 0), SBP, HbA1c, smoking (cigarettes/day), and physical activity index score of the Framingham Offspring Study as covariates, showed that log-leptin directly related and log-adipo inversely related to log-CRP for both sexes (Ps < 0.05 to <0.01). Addition to the model of BMI and interaction terms (BMI × log-leptin, BMI × log-adipo, SITE × log-leptin, SITE × log-adipo) resulted in disappearance of statistical significance except for direct relation of log-leptin to log-CRP in men (P = 0.006). Conclusions. Leptin directly related to CRP independent of BMI and other confounding factors in men but not in women.
PMCID: PMC3859203  PMID: 24371525
24.  Correlation of a Self-Report and Direct Measure of Physical Activity Level in the Electron-Beam Tomography and Risk Assessment Among Japanese and US Men in the Post World War II Birth Cohort (ERA JUMP) Study 
Journal of Epidemiology  2013;23(6):411-417.
Physical activity (PA) is complex and a difficult behavior to assess as there is no ideal assessment tool(s) that can capture all contexts of PA. Therefore, it is important to understand how different assessment tools rank individuals. We examined the extent to which self-report and direct assessment PA tools yielded the same ranking of PA levels.
PA levels were measured by the Modifiable Activity Questionnaire (MAQ) and pedometer at baseline among 855 white (W), African-American (AA), Japanese-American (JA), and Korean (K) men (mean age 45.3 years) in 3 geographic locations in the ERA JUMP study.
Korean men were more active than W, AA, and JA men, according to both the MAQ and pedometer (MAQ total PA [mean ± SD]: 41.6 ± 17.8, 20.9 ± 9.9, 20.0 ± 9.1, and 29.4 ± 10.3 metabolic equivalent [MET] hours/week, respectively; pedometer: 9584.4 ± 449.4, 8363.8 ± 368.6, 8930.3 ± 285.6, 8335.7 ± 368.6 steps/day, respectively). Higher levels of total PA in Korean men, as shown by MAQ, were due to higher occupational PA. Spearman correlations between PA levels reported on the MAQ and pedometer indicated positive associations ranging from rho = 0.29 to 0.42 for total activity, rho = 0.13 to 0.35 for leisure activity, and rho = 0.10 to 0.26 for occupational activity.
The 2 assessment methods correlated and were complementary rather than interchangeable. The MAQ revealed why Korean men were more active. In some subpopulations it may be necessary to assess PA domains other than leisure and to use more than 1 assessment tool to obtain a more representative picture of PA levels.
PMCID: PMC3834277  PMID: 24064592
ethnic groups; exercise; pedometry; self-report; occupational activity
25.  Reducing Cost by Reducing Polypharmacy: The Polypharmacy Outcomes Project 
PMCID: PMC3489959  PMID: 22959733
Polypharmacy; Long-term care; Nursing homes

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