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Intima-media thickness of the carotid artery and the distribution of lipoprotein subclasses in men aged 40 to 49 years between whites in the United States and the Japanese in Japan for the ERA JUMP study
Abstract
In men in the post-World War II birth cohort, that is, men aged 40 to 49 years, whites in the United States had significantly higher levels of intima-media thickness of the carotid arteries (IMT) than the Japanese in Japan (Electron-Beam Tomography and Risk Assessment Among Japanese and US Men in the Post World War II Birth Cohort [ERA JUMP] study). The difference remained after adjusting for traditional risk factors. Primary genetic effects are unlikely, given the degree to which IMT is increased in the Japanese who migrated to the United States. We investigated whether the differences in the distributions of lipoprotein subclasses explain the difference in IMT between the 2 populations. We examined population-based samples of 466 randomly selected men aged 40 to 49 years (215 whites from Allegheny County, Pennsylvania, and 241 Japanese from Kusatsu, Shiga, Japan). Lipoprotein subclasses were determined by nuclear magnetic resonance (NMR) spectroscopy. The whites had significantly higher levels of large very low-density lipoprotein particles and significantly lower levels of large high-density lipoprotein particles than the Japanese, whereas the 2 populations had similar levels of small low-density lipoprotein particles. The 2 populations had similar associations of IMT with NMR lipoproteins. Adjusting for NMR lipoproteins did not attenuate the significant difference in IMT between the 2 populations (0.671 +/- 0.006 mm for the whites and 0.618 +/- 0.006 mm for the Japanese, P = .01, mean +/- SE). Differences in the distributions of NMR lipoproteins between the 2 populations did not explain the higher IMT in the whites.
... Details of the study methods were described elsewhere. [15][16][17][18] A total of 623 Japanese and US Caucasian men aged 40-49 years without past history of cardiovascular disease (310 US Caucasian men from Allegheny County, Pennsylvania, US and 313 Japanese men from Kusatsu City, Shiga, Japan) were randomly selected from each community. Informed consent was obtained from all participants. ...
... Serum total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), triglycerides (TG) and glucose were measured. [15][16][17][18] LDL-C was estimated by the Friedewald formula. [19] Creactive protein (CRP) was measured by an immunosorbent assay and total LDL particles were measured by nuclear magnetic resonance (NMR) spectroscopy. ...
... [19] Creactive protein (CRP) was measured by an immunosorbent assay and total LDL particles were measured by nuclear magnetic resonance (NMR) spectroscopy. [16] Diabetes was defined as a fasting serum glucose ≥ 7.0 mmol/L (126 mg/dl), the use of anti-diabetic agents, or both. Hypertension was defined as either systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg or the use of antihypertensive agents. ...
Objective:
The serum level of LOX-1 ligand containing ApoB (LAB) may reflect atherogenicity better than LDL cholesterol (LDLC), total LDL particles and usual measurement of oxidized LDL. The association between LAB and intima-media thickness (IMT) of carotid artery was investigated by ultrasound in US and Japan men.
Methods:
Participants were 297 US Caucasian and 310 Japanese men, aged 40-49 years without past history of cardiovascular disease. Serum LAB levels were measured by ELISAs with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody.
Results:
Serum LAB levels [median (interquartile range), μg/L] were 1321 (936, 1730) in US Caucasians and 940 (688, 1259) in Japanese. For Caucasian men, average IMT was higher in higher LAB quartile, which was 0.653, 0.667, 0.688, and 0.702 mm, respectively (p for trend = 0.02). Linear regression analysis showed serum LAB was significantly associated with IMT after adjustment for LDLC or total LDL particles in addition to other traditional or novel risk factors for atherosclerosis such as C-reactive protein. However, there was no significant relationship between LAB and IMT in Japanese men.
Conclusion:
Serum LAB, a new candidate biomarker for residual risk, was associated with an increased carotid IMT in US Caucasian men independently of various risk factors; however, ethnic difference should be clarified in the future.
... Despite the evidence linking vitamin D deficiency to CHD, the findings on the association between vitamin D deficiency and CAC, remain inconclusive. [5,22,23] Michos et al. [22] and Pilz et al. [23] reported no significant association of vitamin D deficiency with CAC, whereas Lim et al. showed significant trends between CAC and vitamin D (<15, [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]30 ng/ml). [5] Moreover, previous studies between vitamin D deficiency and CAC were conducted in diseased individuals such as diabetes, [24,25] or elderly individuals. ...
... Detailed descriptions of the ERA-JUMP study population and measurements have been previously published. [26] Briefly, between 2002 and 2006, 613 men aged 40 to 49 years, were randomly selected from two study centers (310 white men from Pennsylvania, U.S. were randomly enrolled from the voter registration list of Allegheny County; 303 Japanese-Americans men from Honolulu, Hawaii, U.S. were randomly selected among the offspring of the participants of the Honolulu Heart Program. These Japanese Americans were third or fourth generations of Japanese without ethnic admixture. ...
Objective:
Although a significant positive association of vitamin D deficiency with coronary heart disease has been demonstrated in cross-sectional as well as prospective studies, only a few studies have examined the association of vitamin D deficiency with subclinical atherosclerosis. We examined whether vitamin D deficiency is associated with subclinical atherosclerosis, as measured by coronary artery calcification (CAC) in asymptomatic adults.
Methods:
In a population-based cross-sectional study, 195 men aged 40 to 49 years without cardiovascular disease were randomly selected (98 Caucasian and 97 Japanese American men). Liquid chromatography-tandem mass spectrometry was utilized to measure serum vitamin D. CAC was examined by electron beam computed tomography using standardized protocols and read centrally at the University of Pittsburgh using Agatston's methods. To investigate an association between vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] < 20 ng/mL) and CAC (defined as Agatston score ≥ 10), we utilized multivariable logistic regression models.
Results:
Prevalence of CAC and vitamin D deficiency was 27.2% and 10.3%, respectively. Participants with CAC were significantly older, had significantly higher body mass index (BMI), and had higher rates of smoking. Those with CAC were 3.31 times likely to be vitamin D deficient, after adjusting for traditional cardiovascular risk factors (odds ratio [OR] = 3.31, 95% confidence interval [CI], 1.12-9.77).
Conclusions:
In this population-based study of healthy middle-aged men, vitamin D deficiency had a significant positive association with the presence of CAC.
... [12][13][14][15] We have previously reported differential distributions of NMR-measured lipoproteins between US-White and Japanese. 16 To the best of our knowledge, however, no previous study has examined whether these results (differences in the distributions of NMR-measured lipoproteins) account for the difference in the CAC-prevalence between US-White and Japanese. Therefore, we aimed first, to evaluate the association between NMR-measured lipoproteins and CAC in asymptomatic US-White and Japanese men aged 40-49 years, and second, to assess the role of NMR-measured lipoproteins in determining the difference in CAC-prevalence between the two populations using the ERA-JUMP study data (the electron beam computed tomography (EBCT), risk factor assessment among Japanese and US men in the post-World War II birth cohort). ...
Objective
This cross-sectional study examined whether contrasting distributions of nuclear magnetic resonance (NMR)-measured lipoproteins contribute to differences in the prevalence of subclinical atherosclerosis measured using coronary artery calcium (CAC) between the two groups of middle-aged males: the US-residing Caucasian (US-White) and Japan-residing Japanese (Japanese).
Methods
In a population-based study of 570 randomly selected asymptomatic men aged 40–49 years (270 US-White and 300 Japanese), we examined the relationship between race/ethnicity, NMR-measured lipoproteins and CAC (measured by Electron Beam CT and quantified using the Agatston method) using multivariable robust Poisson regression adjusting for traditional and novel risk factors for coronary heart disease (CHD).
Results
The US-White compared with the Japanese had significantly different NMR-measured lipoprotein particle distributions. The US-White had a significantly higher prevalence of CAC≥10 (CAC-prevalence) compared with the Japanese adjusting for CHD risk factors (prevalence ratio (PR)=2.10; 95% CI=1.24 to 3.48), and this difference was partially attenuated (~18%) with further adjustment for lipoprotein levels (PR=1.73; 95% CI=1.02 to 3.08). There was no reclassification improvement with further addition of lipoproteins particle concentrations/size to a model that already included traditionally measured lipids (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), cardiovascular risk factors, and inflammatory markers (net reclassification improvement index=−2% to 3%).
Conclusions
Variations in the distribution of NMR-measured lipoprotein particles partially accounted for the difference in the CAC-prevalence between middle-aged US-White and Japanese men.
... 42 The scanning and reading protocols have been used in numerous studies. 43,44 Covariates Self-reported history of preeclampsia (high BP and proteinuria), gestational hypertension, and gestational diabetes mellitus (no diabetes mellitus prepregnancy) were also assessed at visit 13 using the detailed pregnancy history questionnaire. Previous studies have shown that maternal recall of hypertensive disorders of pregnancy has low sensitivity (yet high specificity, >90%) for all hypertensive disorders. ...
Background:
Adverse pregnancy outcomes, such as preterm birth (PTB), have been associated with elevated risk of maternal cardiovascular disease, but their effect on late midlife blood pressure (BP) and subclinical vascular measures remains understudied.
Methods and results:
We conducted a cross-sectional analysis with 1220 multiethnic parous women enrolled in SWAN (Study of Women's Health Across the Nation) to evaluate the impact of self-reported history of adverse pregnancy outcomes (PTB, small-for-gestational-age, stillbirth), on maternal BP, mean arterial pressure, and subclinical vascular measures (carotid intima-media thickness, plaque, and pulse wave velocity) in late midlife. We also examined whether these associations were modified by race/ethnicity. Associations were tested in linear and logistic regression models adjusting for sociodemographics, reproductive factors, cardiovascular risk factors, and medications. Women were on average aged 60 years and 255 women reported a history of an adverse pregnancy outcome. In fully adjusted models, history of PTB was associated with higher BP (systolic: β=6.40; SE, 1.62 [P<0.0001] and diastolic: β=3.18; SE, 0.98 [P=0.001]) and mean arterial pressure (β=4.55; SE 1.13 [P<0.0001]). PTB was associated with lower intima-media thickness, but not after excluding women with prevalent hypertension. There were no significant associations with other subclinical vascular measures.
Conclusions:
Findings suggest that history of PTB is associated with higher BP and mean arterial pressure in late midlife. Adverse pregnancy outcomes were not significantly related to subclinical cardiovascular disease when excluding women with prevalent hypertension. Future studies across the menopause transition may be important to assess the impact of adverse pregnancy outcomes on midlife progression of BP.
... There is a possibility that similar CAC score among various regions is associated wi th significantly different absolute risk of ASCVD 87) and, thus, a universal cut-off value of CAC score for increased risk may not be possible. Similarly, in Japanese populations, cIMT is generally lower than that of Caucasians in the US 88) , and so, cut-off values of cIMT for risk prediction obtained from western studies may not be appropriate for the Japanese population or other Asian populations 81) . Abnormal values of cIMT also depend on the methodology used for IMT measurements 21) . ...
Atherosclerosis begins in early life and has a long latent period prior to onset of clinical disease. Measures of subclinical atherosclerosis, therefore, may have important implications for research and clinical practice of atherosclerotic cardiovascular disease (ASCVD). In this review, we focus on coronary artery calcium (CAC) and carotid artery intima-media thickness (cIMT) and plaque as many population-based studies have investigated these measures due to their non-invasive features and ease of administration. To date, a vast majority of studies have been conducted in the US and European countries, in which both CAC and cIMT/plaque have been shown to be associated with future risk of ASCVD, independent of conventional risk factors. Furthermore, these measures improve risk prediction when added to a global risk prediction model, such as the Framingham risk score. However, no clinical trial has assessed whether screening with CAC or cIMT/plaque will lead to improved clinical outcomes and healthcare costs. Interestingly, similar levels of CAC or cIMT/plaque among various regions and ethnic groups may in fact be associated with significantly different levels of absolute risk of ASCVD. Therefore, it remains to be determined whether measures of subclinical atherosclerosis improve risk prediction in non-US/European populations. Although CAC and cIMT/plaque are promising surrogates of ASCVD in research, we conclude that their use in clinical practice, especially as screening tools for primary prevention in asymptomatic adults, is premature due to many vagaries that remain to be clarified.
... NMR spectroscopy using LipoProfile-3 algorithm was performed to quantify the particle numbers of very low-density lipoprotein (VLDL-P), LDL-P, and high-density lipoprotein (HDL-P). 13 ...
We examined the association between serum lipoprotein subclasses and the three measures of arterial stiffness, that is, (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 the PWV was assessed with an automated waveform analyzer (VP2000, Omron, Japan). Multiple linear regressions were performed to analyse the association between each NMR lipoprotein subclasses and PWV measures, after adjusting for cardiovascular risk factors and other confounders. A cutoff 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 with 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.Journal of Human Hypertension advance online publication, 4 July 2013; doi:10.1038/jhh.2013.60.
Objective:
The purpose of this study was to determine if mid-life social role quality, defined by the stress and rewards associated with four social roles, is related to later-life subclinical cardiovascular disease (SCVD) in a cohort of women transitioning through menopause.
Methods:
The Study of Women's Health Across the Nation (SWAN) is a longitudinal cohort study of mid-life women. Stress and reward from four social roles (spouse, parent, employee, caregiver) were assessed at seven early visits. Later-life SCVD was assessed via carotid ultrasound and brachial-ankle pulse wave velocity at two later visits. We tested whether ever reporting an "extremely" or "quite a bit" stressful role was related to SCVD. We also tested whether cumulative stress and reward, as well as baseline and change in stress and reward were related to SCVD, adjusting for demographics and cardiovascular risk factors.
Results:
Among 1,602 women, reporting a stressful role during mid-life (between ages 47-52) was associated with later-life (age 61) carotid intima-media thickness that was 21 μm thicker than never reporting a stressful role. No significant relationships between stressful roles and other SCVD measures were identified. Cumulative and baseline-change models of stress and reward were not related to SCVD.
Conclusion:
A stressful social role in mid-life was associated with greater atherosclerotic burden in later-life in a cohort of women transitioning through menopause. Social role rewards were unrelated to better later-life SCVD. These findings extend the knowledge of stress and cardiovascular disease in women by using measures of stress and reward for multiple social roles over the years of mid-life.
The main risk factors in ischemic heart diseases, including myocardial infarction, are hypertension, dyslipidemia, diabetes, obesity and smoking. The incidence of ischemic heart disease in Japan has been lower than that in Western countries because of differences in lifestyle and the anatomy of the coronary arteries, but the situation has been changing recently because of the westernization of lifestyle. Cardiovascular diseases have become the second most common cause of death in Japan, and 40% of those deaths are attributed to ischemic heart disease. Patients with a history of myocardial infarction, especially, have an increased risk of re-infarction, so strict management of coronary risk factors is important for the prevention of secondary ischemic heart disease. Although there are many guidelines about how to manage the risk factors, there are still many problems. Although lipid management has been demonstrated to have a protective effect against coronary artery disease and arteriosclerotic guidelines have been developed, it is reported that only about one third of patients achieved the low-density lipoprotein (LDL) target value under secondary prevention. Moreover, it is unclear whether the lower target value is required for high-risk patients. Recent research on diabetes has reported increased mortality in patients with intensive glycemic control. We should discuss when to start treatment, which medicine to use, and to what extent we should manage glycemic control. Strict management based on current therapeutic guidelines is effective for secondary prevention of ischemic heart disease, with target values of less than 135/85 mmHg for home blood pressure, less than 100 mg/dl for LDL-C, more than 40 mg/dl for HDL-C, less than 150 mg/dl for TG, and, for diabetic patients, less than 7.0% for HbA1c (NGSP).
Background and aims:
Atherogenic dyslipidemia is common in type 2 diabetes (T2DM) and predicts cardiovascular disease, but information on the association of its components with atherosclerosis is scarce. We aimed to assess differences in the lipoprotein profile in newly-diagnosed T2DM and matched control individuals and their associations with preclinical carotid atherosclerosis.
Methods:
In a case-control study, we evaluated lipoprotein profiles by nuclear magnetic resonance (NMR) spectroscopy and determined carotid intima-media thickness (IMT) and plaque presence (IMT ≥1.5 mm) by B-mode ultrasonography.
Results:
We assessed 96 T2DM patients (median age 63 years, 44% women, 19% smokers, 54% hypertension, 38% dyslipidemia) and 90 non-diabetic controls matched for age, sex, and cardiovascular risk factors. In T2DM VLDL-particles (mainly large and enriched in cholesterol and triglycerides) were increased, and large HDL-particles (enriched in triglycerides and depleted in cholesterol) were reduced (p < 0.05; all comparisons). Regarding associations with preclinical atherosclerosis, VLDL triglyceride content (odds ratio [OR], 8.975; 95% confidence interval [CI], 2.330-34.576), total number of VLDL particles (OR, 2.713; CI, 1.601-4.598) and VLDL size (OR, 2.044; CI, 1.320-3.166), and the ratio cholesterol/triglycerides in HDL (OR, 0.638; CI, 0.477-0.852) were associated with plaque burden (≥3 plaques) independently of confounders, including conventional lipid levels.
Conclusion:
NMR-assessed advanced lipoprotein profile identifies lipid abnormalities associated with newly-diagnosed T2DM and preclinical atherosclerosis that are not captured by the traditional lipid profile. At this early stage of diabetes, NMR lipoproteins could be useful to identify candidates for a more comprehensive cardiovascular risk prevention strategy.
Background:
Low-density lipoprotein particle (LDL-P) has recently been found to be a stronger predictor of cardiovascular disease (CVD) than LDL-cholesterol (LDL-C).
Objectives:
Whether LDL-P is associated with subclinical atherosclerosis, independent of LDL-C, as well as other lipid measures has not been fully examined. We aimed to analyze LDL-P associations with measures of subclinical atherosclerosis.
Methods:
We examined 870 Japanese men randomly selected from Kusatsu City, Shiga, Japan, aged 40-79 years from 2006-2008, free of clinical CVD and not using lipid-lowering medication. Cross-sectional associations of lipid measures with carotid intima-media thickness (cIMT) and coronary artery calcification (CAC; >0 Agatston score) were examined.
Results:
LDL-P was significantly positively associated with cIMT and maintained this association after adjustments for LDL-C and other lipid measures. Although these lipid measures were positively associated with cIMT, model adjustment for LDL-P removed any significant relationships. Higher LDL-P was associated with a significantly higher odds ratio of CAC and further adjustment for LDL-C did not affect this relationship. In contrast, the LDL-C association with CAC was no longer significant after adjustment for LDL-P. Other lipid measures attenuated associations of LDL-P with CAC. Likewise, associations of these measures with CAC were attenuated when model adjustments for LDL-P were made.
Conclusions:
In a community-based sample of Japanese men, free of clinical CVD, LDL-P was a robust marker for subclinical atherosclerosis, independent of LDL-C and other lipid measures. Associations of LDL-C and other lipid measures with either cIMT or CAC were generally not independent of LDL-P.
Objective:
To reveal any association between rheumatoid arthritis (RA) and cardiovascular comorbidities using a Japanese health insurance database.
Method:
This population-based cross-sectional study was conducted using health insurance data provided by the Japan Medical Data Center Co., Ltd. We identified 2762 RA subjects having RA diagnostic codes (ICD10 codes; M05, M060, M062-63, M068-069) with at least two physician visits more than two months apart between June 2011 and May 2012 (RA group, n = 2762). We selected age- (±5 years), sex-, and study period-matched non-RA subjects (non-RA group, n = 27,620). We compared the prevalence of cardiovascular and related comorbidities (ischemic heart diseases [IHD], cerebral infarction, hypertension [HT], dyslipidemia [DL], and diabetes mellitus [DM]) between these groups and investigated the association between RA and cardiovascular comorbidities using a conditional logistic regression analysis.
Results:
The prevalence of all the investigated comorbidities in the RA group was significantly higher compared to the non-RA group. Odds ratios [95% confidence interval] of RA for IHD and cerebral infarction were 2.0 [1.5-2.5] and 3.1 [2.2-4.2] respectively, after adjusting for HT, DL, and DM.
Conclusions:
This study revealed for the first time in the Japanese population that RA was significantly associated with cardiovascular comorbidities.
The association of high-density lipoprotein particle (HDL-P) with atherosclerosis may be stronger than that of HDL-cholesterol (HDL-C) and independent of conventional cardiovascular risk factors. Whether associations persist in populations at low risk of coronary heart disease (CHD) remains unclear. This study examines the associations of HDL-P and HDL-C with carotid intima-media thickness (cIMT) and plaque counts among Japanese men, who characteristically have higher HDL-C levels and a lower CHD burden than those in men of Western populations.
We cross-sectionally examined a community-based sample of 870 Japanese men aged 40-79 years, free of known clinical cardiovascular disease (CVD) and not on lipid-lowering medication. Participants were randomly selected among Japanese living in Kusatsu City in Shiga, Japan.
Both HDL-P and HDL-C were inversely and independently associated with cIMT in models adjusted for conventional CHD risk factors, including low-density lipoprotein cholesterol (LDL-C) and diabetes. HDL-P maintained an association with cIMT after further adjustment for HDL-C (P < 0.01), whereas the association of HDL-C with cIMT was noticeably absent after inclusion of HDL-P in the model. In plaque counts of the carotid arteries, HDL-P was significantly associated with a reduction in plaque count, whereas HDL-C was not.
HDL-P, in comparison to HDL-C, is more strongly associated with measures of carotid atherosclerosis in a cross-sectional study of Japanese men. Findings demonstrate that, HDL-P is a strong correlate of subclinical atherosclerosis even in a population at low risk for CHD.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Objective
The utility of lipoprotein particle profiles measured by nuclear magnetic resonance (NMR) spectroscopy beyond standard serum lipids remains inconclusive. Furthermore, few studies have compared NMR measurements with standard lipids in association with coronary artery calcification (CAC) in Japanese, where the coronary atherosclerotic burden is low. We examined whether NMR-based lipoprotein particle profiles are associated with CAC, and compared them with standard lipid and lipid ratios in the Japanese general population.
Methods and Results
We conducted a cross-sectional study in 851 men aged 40–79 years without cardiovascular diseases and lipid-lowering therapies. Adjusted odds ratios (ORs) (95% confidence intervals) for the top versus the bottom quartile of NMR-measured particle concentrations were 2.01 (1.24–3.23) for low-density lipoprotein (LDL-P), 1.04 (0.62–1.75) for high-density lipoprotein (HDL-P), 1.82 (1.13–2.95) for very-low-density lipoprotein (VLDL-P), and 1.92 (1.18–3.17) for LDL-P/HDL-P ratio. Similarly adjusted ORs of NMR-measured particle sizes were 0.59 (0.36–0.97) for LDL-P, 0.66 (0.40–1.10) for HDL-P, and 0.67 (0.40–1.12) for VLDL-P. The corresponding ORs were 1.82 (1.14–2.90) for total cholesterol (TC), 2.06 (1.28–3.30) for low-density lipoprotein cholesterol (LDL-C), 0.56 (0.34–0.91) for high-density lipoprotein cholesterol (HDL-C), 2.02 (1.24–3.29) for triglycerides, 2.08 (1.29–3.36) for non-high-density lipoprotein cholesterol (non-HDL-C), 2.27 (1.37–3.78) for TC/HDL-C ratio, and 1.73 (1.06–2.85) for LDL-C/HDL-C ratio. After mutual adjustment for total LDL-P concentration and TC/HDL-C ratio or non-HDL-C, LDL-P was no longer associated, whereas TC/HDL-C ratio remained significantly associated with CAC.
Conclusions
In community-based Japanese men, the overall association of CAC with NMR-measured lipoprotein indices is comparable, but not superior, to that with standard lipids.
Both American and European guidelines recommend coronary artery calcification (CAC) as a tool for screening asymptomatic individuals at intermediate risk for coronary heart disease (CHD). These recommendations are based on epidemiologic studies mostly in the United States. We review (1) the use of CAC in primary prevention of CHD in the United States, (2) epidemiologic studies of CAC in asymptomatic adults outside of the United States, and (3) international epidemiologic studies of CAC. This review will not consider clinical studies of CAC among patients or symptomatic individuals. US studies have shown that CAC is a strong independent predictor of CHD in both sexes among middle-aged and old age groups, various ethnic groups, and individuals with and without diabetes and that CAC plays an important role in reclassifying individuals from intermediate to high risk. Studies in Europe support these conclusions. The Electron-Beam Tomography, Risk Factor Assessment Among Japanese and US Men in the Post-World-War-II birth cohort (ERA JUMP) Study is the first international study to compare subclinical atherosclerosis, including CAC among Japanese, Japanese Americans, Koreans, and whites. It showed that as compared with whites, Japanese had lower levels of atherosclerosis, whereas Japanese Americans had similar or higher levels. CAC is being increasingly used as a screening tool for asymptomatic individuals in Europe and the United States. CAC is a powerful research tool, because it enables us to describe differences in atherosclerotic burden across populations. Such research could identify factors responsible for differences among populations, which may improve CHD prevention.
With increasing interest in the role of non-traditional lipid risk factors in coronary artery disease, we undertook this study to relate LDL subclass size and carotid intima-media thickness of the common carotid artery in coronary artery disease patients.
The study was conducted in 106 patients during their first visit (study group I) and after 12 months (study group II). Intima-media thickness of the common carotid artery was determined using B-mode ultrasound. Separation of LDL subclasses was preformed by 3-31 % polyacrylamide gradient gel electrophoresis.
LDL3 was the dominant subclass in both study groups, but there was statistically significant difference in the distribution of dominant LDL subclasses (p<0.01). The mean carotid intima- media thickness was significantly increased (p<0.001) in coronary artery disease patients after 12 months period. There was significant negative correlation between intima-media thickness and LDL size in both study groups (p<0.05). Intima-media thickness was not significantly correlated with plasma lipid concentrations. Multiple regression analyses show that strongest independent predictor of the intima-media thickness variation was diastolic blood pressure, followed by LDL size and age, and accounted for 29 % of the observed variability in intima-media thickness.
LDL particle size is independently associated with carotid intima-media thickness in coronary artery disease patients with normal levels of traditional lipid risk. These results imply that small, dense LDL subclasses are an important indicator for assessing atherosclerosis and its progression (Tab. 4, Ref. 39).
Clinicians require more discriminating measures of cardiovascular risk than those currently used in most clinical settings. A promising avenue of research concerns the relationship of low-density lipoprotein (LDL) subfractions to subclinical atherosclerosis.
To assess cross-sectional associations between subfractions of LDL cholesterol and coronary artery calcification (CAC).
The study sample comprised 284 asymptomatic clinic patients who were at intermediate risk of cardiovascular disease, aged 40-69 years, who were not taking a statin or niacin. Lipoprotein subclass measures were obtained by the use of proton nuclear magnetic resonance spectroscopy. CAC was assessed with computed tomography angiography (CTA). The analyses modeled the presence or absence of CAC.
Total LDL particle number (LDL-P) had a stronger association with CAC than the traditional lipoprotein measures. Patients in the highest tercile of total LDL-P (1935-3560 nmol/L) were 3.7 times more likely to exhibit coronary artery calcification as those in the lowest tercile (620-1530 nmol/L). The independent effects of small LDL-P remained significant after adjustment for LDL-cholesterol, high-density lipoprotein (HDL), triglycerides, non-HDL, and large LDL-P. HDL and non-HDL were not significant, independent predictors of CAC.
Small LDL-P was a strong, independent predictor of the presence of CAC. Large prospective studies are needed to examine the effect of LDL particle number and size on coronary artery calcification.
D-dimer and von Willebrand factor (vWF) are associated with atherosclerosis. We recently reported that in a post-World War II birth cohort, Japanese men in Japan had lower levels of atherosclerosis than white men in the United States (U.S.). We examined whether the differences in D-dimer and vWF levels are associated with differences in atherosclerosis between the two populations.
Population-based samples of 99 Japanese and 100 white American men aged 40-49 years were examined for coronary artery calcification (CAC), carotid intima-media thickness (IMT), D-dimer, vWF, and other factors using a standardized protocol. When compared to white American men,Japanese had similar levels of D-dimer (0.22 +/- 0.28 vs. 0.19 +/- 0.24 microg/L, respectively, P = 0.39) but significantly higher levels of vWF (124.1 +/- 36.6 vs. 91.3 +/- 48.8%, respectively, P < 0.01). Japanese as compared to white American men had significantly lower prevalence of CAC (13.1 vs. 28.0%, P < 0.01, respectively) and significantly lower IMT (0.61 +/- 0.07 vs. 0.66 +/- 0.08 mm, P < 0.01, respectively). Japanese men had a significant positive association of D-dimer with the prevalence of CAC and a negative association of vWF with IMT, whereas white American men did not have any significant associations.
In men aged 40-49 years, Japanese as compared to white Americans had similar levels of D-dimer and higher levels of vWF although Japanese had a significantly lower prevalence of CAC and IMT. These haemostatic factors are unlikely to explain the difference in atherosclerosis in these populations.
The associations of serum omega-6 (n-6) fatty acids with lipoprotein subclasses at the population level are uncertain.
We aimed to examine associations between major n-6 fatty acids [ie, linoleic acid (LA, 18:2n-6) and arachidonic acid (AA, 20:4n-6)] and the lipoprotein subclasses VLDL, LDL, and HDL.
We conducted a cross-sectional study in 1098 participants using population-based data from US white, Japanese American, Japanese, and Korean men aged 40-49 y. Serum fatty acids were analyzed by capillary gas-liquid chromatography. Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy. Multiple linear regression models as a function of each fatty acid were used after adjustment for age, population, body mass index, pack-years of smoking, alcohol consumption, diabetes, hypertension, and omega-3 (n-3) and trans fatty acids.
Serum LA was inversely associated with large VLDL (beta = -0.62, P < 0.001), total LDL (beta = -22.08, P < 0.001), and small LDL (beta = -31.89, P < 0.001) particle concentrations and VLDL size (beta = -0.72, P < 0.001). Serum LA was positively associated with large HDL particle concentration (beta = 0.21, P < 0.001) and HDL size (beta = 0.03, P < 0.001). The patterns of association of AA with large VLDL and large HDL particle concentrations were comparable with those of LA.
At the population level, higher serum concentrations of LA were significantly associated with lower concentrations of total LDL particles. Higher serum concentrations of LA and AA were significantly associated with a lower concentration of large VLDL particles and a higher concentration of large HDL particles. These associations were consistent across the population groups. This trial was registered at clinicaltrials.gov as NCT00069797.
Since World War II, people in Japan, South Korea, and Taiwan have been exposed to a westernized lifestyle. It is most likely that the post World War II cohorts (1950+) have been more exposed. We hypothesize that there would be an increase in mortality from coronary heart disease (CHD) in men aged 35-44 in these countries.
Mortality from CHD in men aged 35-44 in South Korea and Taiwan has recently increased, and in Japan it has decreased. Mortality from CHD in men aged 35-44 is lower in Japan than in either South Korea or Taiwan, and much lower than in the US. National sample data and several epidemiological studies have shown that risk factors for CHD including hypercholesterolaemia and hypertension in the past decade were not much different between young adult men in Japan and the US. Based upon these risk factors, CHD death rates among post World War II cohorts should be similar in Japan and the US. However, the rates are five times higher in the US for men aged 35-44. The majority of deaths in the category of diseases of the heart were from heart failure in men in this age group in Japan; the mortality from heart failure was about three times higher than the mortality from CHD. Heart failure was rarely used in men aged 35-44 in the US.
The continued low mortality rates from CHD in young men in Japan may be an artifact. It is possible that CHD death rates in post World War II birth cohort in Japan are similar to US rates.
Few studies have determined whether carotid artery intima-media thickness (IMT) is associated prospectively with risk of first ischemic stroke. In the Atherosclerosis Risk in Communities Study, carotid IMT, an index of generalized atherosclerosis, was defined as the mean of IMT measured by B-mode ultrasonography at six sites of the carotid arteries. The authors assessed the relation of mean IMT to stroke incidence over 6-9 years' follow-up (1987-1995) among 7,865 women and 6,349 men aged 45-64 years without prior stroke at baseline in four US communities. There were 90 incident ischemic stroke events for women and 109 for men. In sex-specific Cox proportional hazards models adjusting only for age, race, and community, the hazard rate ratios comparing extreme mean IMT values (> or =1 mm) to values less than 0.6 mm were 8.5 for women (95% confidence interval: 3.5, 20.7) and 3.6 for men (95% confidence interval: 1.5, 9.2). The relation was graded, and models with cubic splines indicated significant nonlinearity, with hazards increasing more rapidly at lower IMTs than at higher IMTs. Thus, models using linear IMT values substantially underestimate the strength of the association at lower IMTs. The strength of the association was reduced by the inclusion of putative stroke risk factors, but it remained elevated at higher IMTs. Hence, mean carotid IMT is a noninvasive predictor of future ischemic stroke incidence.
Despite similar traditional risk factors, morbidity and mortality rates from coronary heart disease in western and non-western cohorts remain substantially different. Careful study of such cohorts may help identify novel risk factors for CHD, and contribute to the formulation of new preventive strategies
The sex differential in coronary heart disease (CHD) risk, which is not explained by male/female differences in lipid and lipoprotein concentrations, narrows with age. We examined whether this differential CHD risk might, in part, be attributable to the sizes of lipoprotein particles or concentrations of lipoprotein subclasses.
We analyzed frozen plasma samples from 1574 men and 1692 women from exam cycle 4 (1988-1990) of the Framingham Offspring Study. Nuclear magnetic resonance (NMR) spectroscopy was used to determine the subclass concentrations and mean sizes of VLDL, LDL, and HDL particles. Concentrations of lipids and apolipoproteins were measured by standard chemical methods.
In addition to the expected sex differences in concentrations of triglycerides, LDL-cholesterol, and HDL-cholesterol, women also had a lower-risk subclass profile consisting of larger LDL (0.4 nm) and HDL (0.5 nm) particles. The sex difference was most pronounced for HDL, with women having a twofold higher (8 vs 4 micromol/L) concentration of large HDL particles than men. Furthermore, similar to the narrowing of the sex difference in CHD risk with age, the observed male/female difference in HDL particle size also decreased with age. Although lipoprotein particle sizes were highly correlated with lipid and lipoprotein concentrations, the sex differences in the mean sizes of lipoprotein particles persisted (P <0.001) even after adjustment for lipid and lipoprotein concentrations.
Women have a less atherogenic subclass profile than men, even after accounting for differences in lipid concentrations.
Coronary heart disease incidence and mortality remain very low in Japan despite major dietary changes and increases in risk
factors that should have resulted in a substantial increase in coronary heart disease rates (Japanese paradox). Primary genetic
effects are unlikely, given the substantial increase in coronary heart disease in Japanese migrating to the United States.
For men aged 40–49 years, levels of total cholesterol and blood pressure have been similar in Japan and the United States
throughout their lifetimes. The authors tested the hypothesis that levels of subclinical atherosclerosis, coronary artery
calcification, and intima-media thickness of the carotid artery in men aged 40–49 years are similar in Japan and the United
States. They conducted a population-based study of 493 randomly selected men: 250 in Kusatsu City, Shiga, Japan, and 243 White
men in Allegheny County, Pennsylvania, in 2002–2005. Compared with the Whites, the Japanese had a less favorable profile regarding
many risk factors. The prevalence ratio for the presence of a coronary calcium score of ≥10 for the Japanese compared with
the Whites was 0.52 (95% confidence interval: 0.35, 0.76). Mean intima-media thickness was significantly lower in the Japanese
(0.616 mm (standard error, 0.005) vs. 0.672 (standard error, 0.005) mm, p < 0.01). Both associations remained significant after adjusting for risk factors. The findings warrant further investigations.
Although risk factors for coronary artery disease are also associated with increased carotid artery intima-media thickness (IMT) as measured by B-mode ultrasonography in middle-aged and older persons, information on the impact of multiple risk factors on the IMT of different segments of the carotid artery in young adults is limited. This relation was examined in a sample of 518 black and white subjects (mean age 32 years; 71% white, 39% male) enrolled in the Bogalusa Heart Study. IMT was thicker and more skewed in the bulb compared with other carotid segments. Race differences (blacks more than whites) were noted for the common carotid (p <0.001) and carotid bulb (bifurcation) IMT (women only, p <0.001). Men had a greater IMT in the common carotid (p <0.05), internal carotid (p <0.05), and carotid bulb (whites only, p <0.001). In a multivariate analysis, systolic blood pressure, race, age, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol weree entered into a model in that order and accounted for the 16.7% variance in the common carotid IMT; age, systolic blood pressure, HDL cholesterol, LDL cholesterol, race, and insulin levels explained the 19.4% variance in the carotid bulb IMT. Gender and body mass index (BMI) accounted for the 4.7% variance in the internal carotid IMT. Increases in IMT with increasing number of risk factors (cigarette smoking, higher total cholesterol to HDL cholesterol ratio, higher systolic blood pressure, greater waist circumference, and higher insulin level) were noted for the common carotid and carotid bulb segments (p for trend <0.001 for both). The observed deleterious trend of increasing IMT at different carotid segments with increasing number of risk factors in free-living, asymptomatic young subjects underscores the importance of profiling multiple risk factors early in life. Ultrasonography of carotid arteries, especially at the bifurcation, may be helpful along with measurements of risk factors for evaluation of asymptomatic atherosclerotic disease.
Despite similar traditional risk factors, morbidity and mortality rates from coronary heart disease in western and non-western cohorts remain substantially different. Careful study of such cohorts may help identify novel risk factors for CHD, and contribute to the formulation of new preventive strategies
Background Reduced insulin sensitivity has been proposed as an important risk factor in the development of atherosclerosis. However, insulin sensitivity is related to many other cardiovascular risk factors, including plasma insulin levels, and it is unclear whether an independent role of insulin sensitivity exists. Large epidemiological studies that measure insulin sensitivity directly have not been conducted.
Methods and Results The Insulin Resistance Atherosclerosis Study (IRAS) evaluated insulin sensitivity (S I ) by the frequently sampled intravenous glucose tolerance test with analysis by the minimal model of Bergman. IRAS measured intimal-medial thickness (IMT) of the carotid artery as an index of atherosclerosis by use of noninvasive B-mode ultrasonography. These measures, as well as factors that may potentially confound or mediate the relationship between insulin sensitivity and atherosclerosis, were available in relation to 398 black, 457 Hispanic, and 542 non-Hispanic white IRAS participants. There was a significant negative association between S I and the IMT of the carotid artery both in Hispanics and in non-Hispanic whites. This effect was reduced but not totally explained by adjustment for traditional cardiovascular disease risk factors, glucose tolerance, measures of adiposity, and fasting insulin levels. There was no association between S I and the IMT of the carotid artery in blacks. The association between S I and the IMT was stronger for the internal carotid artery than for the common carotid artery in all ethnic groups.
Conclusions Higher levels of insulin sensitivity are associated with less atherosclerosis in Hispanics and non-Hispanic whites but not in blacks. This effect is partially mediated by traditional cardiovascular risk factors.
The levels of risk factors for coronary heart disease (CHD) in men in the post World War II (WWII) birth cohort are almost similar between Japan and the USA, except for the considerably higher prevalence of cigarette smoking in Japan and the much higher prevalence of obesity in the USA. The present study evaluated the CHD mortality among men in the post WWII birth cohort by prefecture in Japan in 1995-1999 and then compared the data with those for white men in different states in the USA. There was a greater than 2-fold difference in CHD mortality among men aged 35-44 by prefecture in Japan: 5.3/100,000 in Kumamoto vs 12.6/100,000 in Tochigi. CHD mortality among men aged 35-44 in the top 3 prefectures in Japan is about half that of white men in the USA and is similar to that of white men in the lowest 3 states. The much lower CHD mortality in Japan does not appear to be caused by differences in the classification of causes of death and the results suggest that there may be strong and important protective factors that reduce the risk of CHD in Japan.
A continuous quality improvement (CQI) system can result in higher quality carotid duplex exams and may eventually be a prerequisite for vascular laboratory accreditation. Reproducibility studies are frequently used in research, and this methodology can be adapted for use in clinical laboratories. This paper describes the development and results of a CQI program that can be adapted for use in either a research or clinical facility. The program included equipment standardization, calibration, and function, sonographer and reader training, and quantification of scan variability. A reproducibility study conducted in 15 subjects was used to evaluate variability in measures of carotid wall thickness (IMT),extent of focal plaque, and blood flow velocity. Reproducibility was high, with between-scan correlations above .94 for both readers and sonographers. The absolute difference of mean IMT measures was 0.031 mm between readers and 0.042 mm between sonographers. The absolute difference between replicate measures of systolic blood flow velocity ranged from 4.86 to 13.60 cm/s. As specific and ongoing feedback was given to the laboratory staff, performance improved and commitment to the program rose. CQI programs such as the one outlined here are effective and are recommended in preparation for lab accreditation.
Associations of age, sex, and race with the distribution of fasting plasma cholesterol and triglyceride were studied in 6775 school children (4946 white and 1829 black students, ages 6–17 yr) in a biethnic school district. The target population included 8906 students with 84% of eligible white and 78% of eligible black children participating. In children ages 6–10, mean cholesterol and triglyceride levels varied only minimally. Females 6–10 yr old generally had higher mean plasma cholesterol and triglyceride than males, and blacks had higher mean cholesterol and lower mean triglyceride than whites, p < 0.001. In comparison to the cross-sectional stability of cholesterol and triglyceride over ages 6–10, plasma cholesterol began to fall at ages 11 and 12, continued to fall through ages 15–16, and rose at age 17. An inverse pattern was observed for mean triglycerides. The major increment in triglyceride levels occurred between the ages of 11 and 12, temporally concordant with decrements in cholesterol. Subsequently, in males mean triglycerides continued to rise through age 17, while in females mean triglycerides dipped sharply at ages 16 and 17. Withinrace comparisons of changes in triglyceride over age show the males first having lower triglyceride than females at ages 11–13, and the female levels falling below the male levels at ages 15–17. The decrements of cholesterol and increments in triglyceride during adolescence were also generally observed for the extremes of the distribution, the 5th and 95th percentiles. As was the case for 6–11-yr olds, in the 12–17-yr-old children, blacks had higher mean cholesterols and lower mean triglycerides than whites. Within the limitations of the cross-sectional nature of this study, the inverse changes of cholesterol and triglyceride suggest that hormonal and growth changes during adolescence may have a notable effect on plasma lipids. The availability of age-, sex-, and race-specific cholesterol and triglyceride distributions may allow more meaningful assessment of plasma cholesterol and triglyceride levels of any individual child.
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Serum lipid profiles of 3,446 (91% of population) children, ages 5-14 years, were determined in a biracial community (Bogalusa, Louisiana) as part of a program investigating the early natural history of atherosclerosis. Black children had significantly higher mean levels of serum cholesterol than white children (170 mg/dl vs 162 mg/dl, P less than 0.0001). On the other hand, significantly lower levels of triglycerides were found in blacks than in whites (61 mg/dl vs 73 mg/dl, P less than 0.0001). Girls had higher levels of triglycerides than boys in both races (blacks, 64 mg/dl vs 59 mg/dl, P less than 0.001; whites, 77 mg/dl vs 69 mg/dl, P less than 0.001). The racial differences in serum cholesterol and triglyceride levels were even more apparent at the 95th percentile. The serum cholesterol level remained relatively constant in all children until ages 11 and 12 years, after which a slight reduction occurred. This reduction was more pronounced in boys than in girls. In contrast, a significant increase in the level of triglycerides with age was observed in all children except black girls, the increasing slope being most pronounced in white girls.
We investigated the progression of carotid atherosclerosis in a population-based sample of 100 Eastern Finnish men aged 42, 48, 54 or 60 years. A high-resolution B-mode ultrasonographic examination was repeated after a follow-up of 24 months for each subject. The intimal-medial thickness (IMT) in the common carotid artery increased by -0.06 mm to 0.90 mm (mean 0.12 mm, SD 0.20 mm). Age (standardised partial coefficient, beta = 0.325, P = 0.0003), serum LDL cholesterol concentration (beta = 0.229, P = 0.0011), pack-years of smoking (beta = 0.274, P = 0.0023), blood leukocyte count (beta = 0.201, P = 0.0239), and platelet aggregability (beta = 0.165, P = 0.0646), measured at baseline, were the strongest predictors of atherosclerosis progression. Neither hypertension, current blood pressure level, serum HDL cholesterol nor serum HDL2 cholesterol concentration at the baseline examination had any association with the change of IMT over 2 yrs.
The authors surveyed serum cholesterol and triglyceride levels in 238 male and 217 female students aged 15 years in Osaka, Japan, in 1977, as well as dietary intake, using a 24-hour record in 81 male and 61 female students. Serum cholesterol and triglyceride levels of Japanese students were 163.6 mg/dl and 81.7 mg/dl, respectively, for males, and 182.2 mg/dl and 78.9 mg/dl for females. For female students, those who participated in a school sports club regularly during the previous three years had cholesterol levels 10 mg/dl lower than the subjects who had not participated in a sports club; these active students also had smaller skinfold thickness, although there was no difference in other anthropometric measurements. Although the dietary intake of Japanese students was found to be westernized, compared with that of Japanese adults, Japanese students reported low fat intake (25-30% of energy), high polyunsaturated/saturated fatty acid ratio (1.1-1.2), and high carbohydrate intake (55-61% of energy), differing considerably from US students.
B-mode ultrasound is a widely used technique for the clinical and epidemiological assessment of carotid atherosclerosis. This article provides a description of the distribution of carotid atherosclerosis in the general population.
Intimal-medial arterial wall thickness was measured by B-mode real-time ultrasound as an index of atherosclerotic involvement in the extracranial carotid arteries as part of the population-based Atherosclerosis Risk in Communities (ARIC) study. The distribution was described by race-sex strata, in which 759 to 4952 individuals were imaged depending on strata and location in the carotid system.
Median wall thickness ranged between 0.5 and 1 mm at all ages; fewer than 5% of ARIC participants had values exceeding 2 mm. Individuals tended to have a larger wall thickness in the carotid bifurcation than in the common carotid artery. Internal carotid artery values were more variable, with higher proportions of both large and small wall thicknesses than in the common carotid. The proportion of individuals with a large wall thickness was greatest at the bifurcation and smallest at the common carotid artery. Men had uniformly larger wall thickness than women. Cross-sectional analysis suggests that age-related increases in wall thickness average approximately 0.015 mm/y in women and 0.018 mm/y in men in the carotid bifurcation, 0.010 mm/y for women and 0.014 mm/y for men in the internal carotid artery, and 0.010 mm/y in both sexes in the common carotid artery.
Estimates provided for wall thickness percentiles can serve as "nomograms" by age, race, and sex.
Reduced insulin sensitivity has been proposed as an important risk factor in the development of atherosclerosis. However, insulin sensitivity is related to many other cardiovascular risk factors, including plasma insulin levels, and it is unclear whether an independent role of insulin sensitivity exists. Large epidemiological studies that measure insulin sensitivity directly have not been conducted.
The Insulin Resistance Atherosclerosis Study (IRAS) evaluated insulin sensitivity (SI) by the frequently sampled intravenous glucose tolerance test with analysis by the minimal model of Bergman. IRAS measured intimal-medial thickness (IMT) of the carotid artery as an index of atherosclerosis by use of noninvasive B-mode ultrasonography. These measures, as well as factors that may potentially confound or mediate the relationship between insulin sensitivity and atherosclerosis, were available in relation to 398 black, 457 Hispanic, and 542 non-Hispanic white IRAS participants. There was a significant negative association between SI and the IMT of the carotid artery both in Hispanics and in non-Hispanic whites. This effect was reduced but not totally explained by adjustment for traditional cardiovascular disease risk factors, glucose tolerance, measures of adiposity, and fasting insulin levels. There was no association between SI and the IMT of the carotid artery in blacks. The association between SI and the IMT was stronger for the internal carotid artery than for the common carotid artery in all ethnic groups.
Higher levels of insulin sensitivity are associated with less atherosclerosis in Hispanics and non-Hispanic whites but not in blacks. This effect is partially mediated by traditional cardiovascular risk factors.
Ethnic differences in cardiovascular disease (CVD) morbidity and mortality have been observed in US adults. However, little data exist on differences in indices of preclinical atherosclerosis such as carotid wall intima-media thickness (IMT) for US non-Hispanic whites, Hispanics, and blacks. This study was undertaken to determine whether there were ethnic differences in carotid wall IMT.
Internal carotid artery (ICA) IMT and common carotid artery (CCA) IMT, indices of atherosclerosis, were assessed with the use of B-mode ultrasound in 1020 nondiabetic participants in the Insulin Resistance Atherosclerosis Study, a multicenter study designed to examine the association between insulin resistance and carotid atherosclerosis. The study included 281 blacks, 329 Hispanics, and 410 non-Hispanic whites aged 40 to 69 years.
Blacks had significantly greater CCA IMT than non-Hispanic whites (865 versus 808 microns); this remained significant after adjustment for major CVD risk factors and insulin sensitivity (864 versus 823 microns). There were no significant differences in ICA IMT between blacks and non-Hispanic whites. Hispanics had significantly lesser CCA IMT than non-Hispanic whites (749 versus 776 microns), and these differences remained significant after adjustment for traditional cardiovascular risk factors and insulin sensitivity (750 versus 778 microns). There were no significant differences in ICA IMT between non-Hispanic whites and Hispanics.
We conclude that ethnic differences exist in CCA but not in ICA IMT in nondiabetic subjects. These differences in IMT, which are indicators of atherosclerosis, are a non-invasive measure that is consistent with some of the data on clinical end points. These differences may be associated with the observed differences in CVD morbidity and mortality among major ethnic groups in the United States.
It has been reported that insulin resistance is associated with essential hypertension and that an aggregation of risk factors-hypertension, dyslipidemia, and glucose intolerance-together with insulin resistance leads to the more frequent appearance of coronary artery disease. We examined the relation between early asymptomatic atherosclerosis and these risk factors in 72 nondiabetic subjects with essential hypertension (41 men, 31 women) aged 50 to 59 years. Intima-media thickness and plaque formation of the carotid artery were assessed by B-mode ultrasonography, and insulin sensitivity was measured by the steady-state plasma glucose method. Lipoprotein profile was analyzed by ultracentrifugation. The intima-media thickness of the common carotid artery significantly correlated with systolic pressure; mean blood pressure; steady-state plasma glucose, indicating insulin resistance; fasting insulin; area under the curve of plasma insulin and glucose; body mass index; apolipoprotein B; apolipoprotein B in low-density lipoprotein; lower ratio of cholesterol to apolipoprotein B of low-density lipoprotein; and decreased high-density lipoprotein cholesterol. By multiple regression analysis, steady-state plasma glucose was the strongest risk, followed by lower high-density lipoprotein and systolic pressure. These three factors accounted for 54.9% of all the risk for increased intima-media thickness of the common carotid artery. In conclusion, insulin resistance was the strongest risk factor for carotid intima-media thickness, followed by lower high-density lipoprotein cholesterol and hypertension. An effort to maintain normal insulin sensitivity is essential for the prevention of early atheromatous lesions in essential hypertension.
Because extracranial carotid atherosclerotic lesions have been considered rare, no reports have been published on the prevalence and distribution of these lesions in a general Japanese population. However, recent changes in lifestyle are thought to have caused an increase in these lesions. The aim of this study was to use high-resolution ultrasonography to examine the prevalence of asymptomatic extracranial carotid artery lesions and its relation to cardiovascular risk factors in an urban Japanese population.
The subjects were 814 men and 880 women aged 50 to 79 years randomly sampled from the residents of Suita, a city located in the second largest urban area of Japan. Asymptomatic carotid lesions were detected and evaluated by a single physician with high-resolution B-mode ultrasonography.
We found significant sex differences in the prevalence of atherosclerotic lesions in the extracranial carotid artery; 4.4% of all the subjects, 7.9% of the men, and 1.3% of the women had atherosclerosis accompanied by stenosis of >50%. A strong association between these lesions and the results of a 75-g oral glucose tolerance test was found in both sexes. Multiple regression analysis of carotid atherosclerosis showed significant relationships with age, systolic blood pressure, fasting blood glucose, pack-years of smoking, total serum cholesterol, and HDL cholesterol in men (P<.05) and significant relationships with age, systolic blood pressure, pack-years of smoking, and total serum cholesterol in women (P<.05).
Our data showed that cardiovascular risk factors were strongly related to carotid atherosclerosis and that the proportion of severe carotid atherosclerosis with >50% stenosis was not low and was almost equal to that reported in developed western countries.
Results of cross-sectional and prospective studies have suggested that small, dense low-density lipoprotein (LDL) particles predispose to coronary heart disease. We investigated the relationships between plasma concentrations of LDL subfractions and intima-media thickness (IMT) of the common carotid artery (CCA), quantified by B-mode ultrasound, in 94 healthy, 50-year-old men, all of whom were homozygous for the apolipoprotein E3 allele. A novel 3% to 7.5% polyacrylamide gradient gel was developed to provide separation of LDL subfractions with high resolution, as was a procedure to quantify plasma concentrations of these LDL subspecies. The LDL particle size distribution pattern obtained by the gradient gel electrophoresis procedure was in good agreement with the one obtained by a well-established, single-spin density gradient ultracentrifugation technique. LDL-II (particle size, 23.5 to 25.0 nm) was the most abundant subfraction, and its plasma concentration correlated closely with the total LDL cholesterol concentration (r=0. 61, P<0.001) but not with CCA IMT (r=-0.13, NS). In contrast, the plasma concentration of the predominant small, dense LDL particle subfraction (LDL-III; particle size, 22.5 to 23.5 nm) correlated strongly with CCA IMT (r=0.42, P<0.001). In multivariate analysis, the plasma concentration of the LDL-III subfraction contributed significantly to the variation in CCA IMT (R(2)=0.19). When plasma triglycerides and LDL cholesterol were forced into the multivariate model, 10% of the variation in CCA IMT was still accounted for by the LDL-III subfraction. In summary, use of a novel and sensitive gradient gel electrophoresis method for evaluation of LDL heterogeneity provided the basis for demonstrating an independent relation between the plasma concentration of small LDL and IMT of the CCA in healthy, middle-aged men.
A multicenter exploratory study at three university hospitals was performed to evaluate the effect of oral cilostazol on intima media thickness (IMT) in diabetic patients. A total of 141 patients was recruited in this study and randomized into a cilostazol group and a placebo (control) group. One hundred and twenty patients completed the study (i.e. 60 on cilostazol and 60 on placebo). Biochemical profiles and the IMT of the common carotid artery (CCA) determined by high-resolution B-mode ultrasonography were measured at 0, 6, and 12 months after the oral administration of 100--200 mg of cilostazol or placebo (i.e. two or four times daily for 12 months). Clinical and biochemical characteristics, the treatment modality, and microvascular diabetic complications after randomization were not significantly different between the two groups after the study. In the cilostazol treatment group, left CCA average IMT significantly decreased from 0.94+/-0.03 to 0.91+/-0.02 mm at 6 months (P<0.05), and thereafter increased to 0.92+/-0.01 mm (P>0.05) at 12 months, whereas in the control group, it increased from 0.92+/-0.03 to 0.93+/-0.01 mm at 6 months (P>0.05), and to 0.94+/-0.01 mm at 12 months (P>0.05). As for the right CCA average IMT, it decreased from 0.83+/-0.03 to 0.82+/-0.01 mm at 6 months (P<0.05), and to 0.81+/-0.01 mm at 12 months (P<0.05) in the cilostazol group, whereas it increased from 0.87+/-0.03 to 0.89+/-0.01 mm at 6 months (P<0.05), and to 0.90+/-0.01 mm at 12 months (P<0.05) in the control group (P<0.05). After correction for risk factors such as blood pressure, smoking, and lipid profiles, there were significant changes in left and right CCA average IMT for both groups (P<0.05). Left and right CCA average IMT was significantly different between the two groups (P<0.05). After making statistical corrections for blood pressure, smoking, and lipid profiles, the differences between these two groups remained significant (P<0.05). Meanwhile, there were no differences between the groups in the change of risk factors such as BMI, blood pressure, blood sugar, HbA(1c), and lipid profiles. Generally, cilostazol was well tolerated and the most common side effect in the cilostazol group was headache (12/60), mostly early in the treatment regimen. The results suggest that oral cilostazol may be helpful in the treatment of atherosclerosis in type 2 diabetic patients, although conventional cardiovascular risk factors remained unmodified.
The levels of risk factors for coronary heart disease (CHD) in men in the post World War II (WWII) birth cohort are almost similar between Japan and the USA, except for the considerably higher prevalence of cigarette smoking in Japan and the much higher prevalence of obesity in the USA. The present study evaluated the CHD mortality among men in the post WWII birth cohort by prefecture in Japan in 1995-1999 and then compared the data with those for white men in different states in the USA. There was a greater than 2-fold difference in CHD mortality among men aged 35-44 by prefecture in Japan: 5.3/100,000 in Kumamoto vs 12.6/100,000 in Tochigi. CHD mortality among men aged 35-44 in the top 3 prefectures in Japan is about half that of white men in the USA and is similar to that of white men in the lowest 3 states. The much lower CHD mortality in Japan does not appear to be caused by differences in the classification of causes of death and the results suggest that there may be strong and important protective factors that reduce the risk of CHD in Japan.
In addition to low-density lipoprotein (LDL) cholesterol, small, dense LDL particles and oxidative modification of LDL have been linked to the pathogenesis of atherosclerosis. The present study was aimed at investigating the association between carotid artery intima-media thickness (IMT) and LDL particle size and susceptibility of LDL to oxidation in vitro in asymptomatic members of familial combined hyperlipidemia (FCHL) families.
LDL particle size, susceptibility of LDL to oxidation in vitro, and carotid IMT were measured in 148 asymptomatic FCHL family members.
LDL particle size and lag time for LDL oxidation were reduced in hyperlipidemic compared with normolipidemic family members. LDL particle size, serum total cholesterol, and alpha-tocopherol in LDL were independently associated with lag time for LDL oxidation in multivariate analysis. LDL particle size was associated with carotid mean IMT independently of clinical, lipid, and antioxidant variables in multivariate analysis. Although the susceptibility of LDL to oxidation in vitro was correlated with mean IMT, it did not have a significant independent contribution to variation in mean IMT in the multivariate model.
We conclude that LDL particle size but not susceptibility of LDL to oxidation in vitro is independently associated with carotid IMT in asymptomatic FCHL family members. These results imply that small, dense LDL as an inherent feature of FCHL is an important diagnostic indicator for coronary artery disease risk in FCHL.
To illustrate the impact of westernization of lifestyle on the development of pre-clinical atherosclerosis in Japanese people, we compared risk factors for atherosclerosis such as serum lipids, blood pressure, BMI, insulin resistance, and smoking habits between non-diabetic native Japanese and non-diabetic Japanese Americans. Two hundred and twenty two non-diabetic Japanese Americans living in Hawaii and 271 non-diabetic Japanese living in Hiroshima, Japan were studied. Carotid intima-media wall thickness (IMT) was measured in all subjects by one physician. For all measurements the same ultrasound instrumentation was used. Although no significant differences were seen in serum total cholesterol (TC), triglycerides, or LDL-cholesterol (LDL-C) levels between the two groups in the 1998 study, previous to 1998 these three parameters were significantly higher in Japanese Americans than native Japanese in our study which has spanned the past 20 years. IMT was significantly greater in Japanese Americans than native Japanese (1.20+/-0.03 mm vs. 0.98+/-0.03 mm, (mean+/-S.E.) respectively; P<0.0001). Moreover Japanese Americans reach an IMT of 1.1 mm at age 50, whereas the native Japanese reach this value at age 70. These observations indicate more rapid atherosclerosis progression in Japanese Americans. Based on our IMT measurements, the status and the estimated progression of atherosclerosis in Japanese Americans is increased. Since IMT is a validated endpoint for assessment of atherosclerotic disease risk, it can be concluded that Japanese Americans are at increased risk for cardiovascular disease.
To evaluate the role of adiposity in the relationship between specific and surrogate estimates of insulin-mediated glucose uptake (IMGU) in a large nondiabetic population.
Healthy volunteers were classified by BMI into normal weight (<25.0 kg/m(2), n = 208), overweight (25.0-29.9 kg/m(2), n = 168), and obese (>or=30.0 kg/m(2), n = 109) groups. We then assessed how differences in BMI affect the correlation between steady-state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide, glucose, and insulin (a specific measure of IMGU) and five surrogate estimates: fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and area under the curve for insulin in response to oral glucose (I-AUC).
Correlation coefficients (r values) between SSPG and surrogate measures of IMGU were all significant (P < 0.05), but the magnitude varied between BMI groups: normal weight: fasting plasma glucose 0.20, fasting plasma insulin 0.33, HOMA-IR 0.36, QUICKI -0.33, and I-AUC 0.69; overweight: fasting plasma glucose 0.19, fasting plasma insulin 0.55, HOMA-IR 0.55, QUICKI -0.54, and I-AUC 0.72; and obese: fasting plasma glucose 0.40, fasting plasma insulin 0.56, HOMA-IR 0.60, QUICKI -0.61, and I-AUC 0.69.
The relationship between direct and surrogate estimates of IMGU varies with BMI, with the weakest correlations seen in the normal-weight group and the strongest in the obese group. In general, I-AUC is the most useful surrogate estimate of IMGU in all weight groups. Fasting plasma insulin, HOMA-IR, and QUICKI provide comparable information about IMGU. Surrogate estimates of IMGU based on fasting insulin and glucose account for no more than 13% of the variability in insulin action in the normal-weight group, 30% in the overweight group, and 37% in the obese group.
Epidemiological studies have shown an inverse relationship between intake of N-3 fatty acids and incidence of stroke. And, there is a high incidence of stroke in patients with carotid atherosclerosis. We investigated the relationship between intake of N-3 fatty acids and carotid atherosclerosis in the cross-sectional study. A total of 1920 Japanese, aged over 40 years, received a population-based health examination in 1999. They underwent B-mode carotid ultrasonography to evaluate the carotid intimal-medial thickness (IMT). Eating patterns were evaluated by a 105 items food frequency questionnaire. A complete data set was available for 1902 subjects (785 men and 1117 women). The mean eicosapentaenoic acid (EPA) intake in men was 0.32+/-0.23 g/day and in women was 0.31+/-0.20 g/day. The mean docosahexaenoic acid (DHA) intake in men was 0.52+/-0.34 g/day and in women was 0.49+/-0.29 g/day. With multiple linear regression analysis, after adjustments for age, sex, and total energy intake, intakes of EPA (P < 0.05), DHA (P < 0.05), and docosapentaenoic acid (P < 0.05) were significantly and inversely related to IMT. These data indicate that dietary N-3 fatty acid, especially very long chain N-3 fatty acids, may protect against carotid atherosclerosis.
Few cohort studies have examined the association of carotid intima-media thickness (IMT) and plaque characteristics with the risk of stroke in apparently healthy persons. We examined the relationship of carotid IMT and the surface, morphology, and calcification of carotid plaques with the incidence of stroke among Japanese men.
Carotid IMT and plaque were evaluated bilaterally with ultrasonography in 1289 men aged 60 to 74 years without a previous stroke or coronary heart disease. In this cohort, the subsequent incidence of stroke was investigated.
During the 4.5-year follow-up, 34 strokes occurred. The multivariate-adjusted relative risk (95% CI) for the highest versus lowest quartiles of maximum IMT of the common carotid artery (CCA; > or =1.07 versus < or =0.77 mm) was 3.0 (1.1 to 8.3) for stroke. The combination of CCA and internal carotid artery (ICA) wall thickness was a better predictor of the risk of stroke than was CCA wall thickness alone. Men with a plaque, defined as a focal wall thickness of > or =1.5 mm, in the ICA had a 3-fold higher risk of stroke than those without a plaque, and the plaque surface irregularity further increased the stroke risk. A significant excess risk of stroke was confined to men with an uncalcified plaque.
Increased IMT of the CCA and an uncalcified plaque in the ICA, as assessed by ultrasonography, are risk factors for stroke in elderly Japanese men.
Insulin resistance and obesity are associated with a dyslipidemia composed of high levels of triglycerides (TG), low levels of high-density lipoprotein cholesterol (HDL-C), and no change in level of low-density lipoprotein cholesterol (LDL-C). We examined the association of insulin resistance and adiposity with lipoprotein particle size, concentration, and subclass concentrations.
The Insulin Resistance Atherosclerosis Study is a multicenter cohort study of middle-aged men and women. Lipoprotein lipid concentrations were determined using standard methods. Lipoprotein size, particle concentration, and subclass concentrations were determined using nuclear magnetic resonance technology. Insulin resistance (SI) was determined based on the frequently sampled intravenous glucose tolerance test and the MINMOD program. A higher SI represents less insulin resistance. Fasting insulin, body mass index, waist circumference, and waist/hip ratio were assessed.
Among the 1371 participants were 754 women and 617 men; 459 Hispanics, 383 African Americans, and 529 non-Hispanic whites; 437 with type 2 diabetes, 301 with impaired glucose tolerance, and 633 with normal glucose tolerance. The mean (SD) age was 55.5 (8.5) years, body mass index was 29.3 (5.8) kg/m2 , and SI was 1.6 (1.8) units. Adjusted for age, sex, and ethnicity, SI was not associated with LDL-C (r = 0.01); however, S I was associated with LDL size (r = 0.34, P < .001), LDL particle concentration (r = -0.28, P < .001), small LDL (r = -0.34, P < .001), intermediate LDL (r = -0.37, P < .001), and large LDL (r = 0.21, P < .001). In addition, S I was associated with TG (r = -0.36, P < .001), VLDL particles (r = -0.08, P < .01), large VLDL (r = -0.32, P < .001), VLDL size (r = -0.38, P < .001), HDL-C (r = 0.37, P < .001), HDL particles (r = 0.09, P < .001), large HDL (r = 0.31, P < .001), and HDL size (r = 0.33, P < .001). A factor analysis revealed a factor that accounted for 41.4% of the variance across the lipoprotein measures and that was correlated with SI (r = -0.33, P < .001). Similar results of opposing direction were observed for analyses of lipoprotein measures with fasting insulin and adiposity.
The dyslipidemia associated with insulin resistance and obesity includes effects on lipoprotein metabolism that are missed when traditional lipoprotein cholesterol and total TG are examined. Lipoprotein size and subclasses should be examined in studies investigating the roles of insulin resistance and obesity in the pathogenesis and prevention of atherosclerosis.
To examine the association of socioeconomic factors with progression of carotid intimal-medial thickness (IMT) in middle-aged adults. Cross-sectional associations of IMT with socioeconomic status (SES) have been demonstrated in middle-aged cohorts. It is unclear whether these factors are associated with progression of IMT.
We examined IMT progression over 9 years among a middle-aged cohort of 12,085 black and white subjects free of cardiovascular disease recruited from 4 US sites participating in the Atherosclerosis Risk in Communities (ARIC) study. Baseline IMT was inversely related to SES among whites and blacks. Repeated measures regression models of IMT progression showed moderate inverse relationships of IMT progression with income in whites so that the difference in 5-year IMT progression rates between the highest and lowest categories was -11.5 microm (CI, -17.4 to -5.6). In contrast, among blacks, this gradient is reversed, with an 11.1 microm (CI, -0.1 to 22.3) difference in 5-year progression between highest and lowest income category. Generally, similar patterns were observed for other socioeconomic indicators. Patterns were not accounted for by baseline cardiovascular risk factors.
SES is inversely related to IMT progression in middle-aged whites but positively related to IMT progression among middle-aged blacks. These differences do not appear to be attributable to selective attrition or higher IMT among blacks at baseline.
Previous studies showing that smaller low-density lipoprotein (LDL) size is associated with greater atherosclerotic risk did not adequately control for small and large LDL particle correlation.
We studied the association of lipoproteins measured by proton nuclear magnetic resonance spectroscopy with carotid intima-media thickness (IMT) in apparently healthy individuals (N = 5538, 38% White, 28% African American, 22% Hispanic, 12% Chinese). Small and large LDL particle concentrations (LDL-p) were inversely correlated (r = /-0.63, P < 0.0001). Controlling for risk factors but not for LDL subclass correlation, LDL size and small LDL-p separately were associated with IMT (-20.9 and 31.7 microm change in IMT per 1-S.D., respectively, both P < 0.001), but large LDL-p was not (4.9 microm, P = 0.27). When LDL subclasses were included in the same model, large and small LDL-p were both associated with IMT (36.6 and 52.2 microm higher IMT per 1-S.D., respectively, both P < 0.001; 17.7 and 11.6 microm per 100 nmol/L, respectively). LDL size was not significant after accounting for LDL subclasses and risk factors (P = 0.10).
Both LDL subclasses were significantly associated with subclinical atherosclerosis, with small LDL confounding the association of large LDL with atherosclerosis. Future studies of LDL size should account for the strong inverse correlation of LDL subclasses.
We determined intima-media thickness (IMT) and diameter of carotid artery and estimated their correlations with cardiovascular risk factors in 1129 men aged 60-74 years, who participated in a cardiovascular risk survey in three Japanese communities. The multivariate odds ratios (95% confidence interval) for the maximum IMT > or = 1.1 mm in the common carotid artery (CCA) were 1.3 (1.1-1.5) per 4 years of age, 1.8 (1.4-2.5) for hypertension, 1.4 (1.2-1.7) for a 34.4 mg/dl increase in serum total cholesterol, 0.7 (0.6-0.8) for a 14.7 mg/dl increase in serum HDL-cholesterol, and 2.4 (1.1-5.0) for history of stroke, while the maximum IMT > or = 1.5mm in the internal carotid artery (ICA) were 1.6 (1.4-1.8) per 4 years of age, 1.9 (1.5-2.4) for hypertension, 1.6 (1.2-2.1) for current smoking, and 3.5 (1.6-7.6) for history of stroke. Age, height, hypertension, current smoking, ethanol intake and history of coronary heart disease were independent determinants of both the outer and inner CCA diameter. Maximum IMT correlated positively with the outer diameter and inversely with the inner diameter in the CCA. Carotid atherosclerosis suggests to be a risk factor for stroke among Japanese elderly men, although future prospective studies are required to confirm this finding.
Intima-media thickness of the carotid artery and associated risk factors in Japanese men in Japan and Hawaii
- T Kadowaki
- Dj Curb
- Rd Abbott
- A Sekikawa
- C Shin
- T Okamura
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- A Yano
- H Ueshima
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Yano, A.; Ueshima, H.; Iida, K.; Yamazaki, S.; Kohima, S.; Tanaka, H., et al. Primary prevention of
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LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA) Atherosclerosis
- S Mora
- M Szklo
- Jd Otvos
- P Greenland
- Bm Psaty
- Dc Goff
- Jr
Mora S, Szklo M, Otvos JD, Greenland P, Psaty BM, Goff DC Jr, et al. LDL particle subclasses, LDL
particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA).
Atherosclerosis. in press. (e-release date June 9, 2006)
Comparison of multivariate-adjusted carotid intima-media thickness (mm) among men aged 40–49 between whites in Allegheny County
Comparison of multivariate-adjusted carotid intima-media thickness (mm) among men aged 40–49 between
whites in Allegheny County, Pennsylvania, U.S. and the Japanese in Kusatsu, Shiga, Japan in 2002–2005
Whites (n = 215)
Japanese (n = 241)
P
Author manuscript; available in PMC
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Intima-media thickness of the carotid artery and associated risk factors in Japanese men in Japan and Hawaii
- Kadowaki
Primary prevention of cardiovascular disease in youth
- Yano