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1.  Ethnicity and Sex Modify the Association of Serum C-Reactive Protein with Microalbuminuria 
Ethnicity & disease  2008;18(3):324-329.
Objectives
To study the association between serum C-reactive protein (CRP) and urinary albumin excretion in the Multi-Ethnic Study of Atherosclerosis and to assess whether the association is modified by ethnicity, sex, or systolic blood pressure.
Methods
This was a cross-sectional study of 6675 participants who were free from macro albuminuria and clinical cardiovascular disease (mean age 62.1 years, 53% female; 39% White, 27% African American, 22% Hispanic, and 12% Chinese). Urinary albumin excretion was measured by spot urine albumin-to-creatinine ratio (ACR). Effect modifications were tested after adjusting for age, diabetes, body mass index, smoking, use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, other antihypertensive drugs, estrogens, statins, and high-density lipoprotein cholesterol and triglyceride levels.
Results
The association between CRP and ACR was modified by ethnicity (P=.01) and sex (P<.001), but not by systolic blood pressure. After multivariate adjustment, the association remained in Chinese, African American, and Hispanic men and African American women (P<.02 for African American men, and P<.04 for the other subgroups).
Conclusions
The association between CRP and ACR was modified by ethnicity and sex; it was stronger in non-White men and African American women. These interactions have not been reported before, and future studies should consider them.
PMCID: PMC4089959  PMID: 18785447
Albuminuria; C-Reactive Protein; Ethnicity; Gender
2.  Regulatory Decisions on Endocrine Disrupting Chemicals Should be Based on the Principles of Endocrinology 
For years, scientists from various disciplines have studied the effects of endocrine disrupting chemicals (EDCs) on the health and wellbeing of humans and wildlife. Some studies have specifically focused on the effects of low doses, i.e. those in the range that are thought to be safe for humans and/or animals. Others have focused on the existence of non-monotonic dose-response curves. These concepts challenge the way that chemical risk assessment is performed for EDCs. Continued discussions have clarified exactly what controversies and challenges remain. We address several of these issues, including why the study and regulation of EDCs should incorporate endocrine principles; what level of consensus there is for low dose effects; challenges to our understanding of non-monotonicity; and whether EDCs have been demonstrated to produce adverse effects. This discussion should result in a better understanding of these issues, and allow for additional dialogue on their impact on risk assessment.
doi:10.1016/j.reprotox.2013.02.002
PMCID: PMC3902067  PMID: 23411111
weight of evidence; organizational; adaptive effect; hormesis; human exposure; epidemiology; flare
3.  Arterial Wave Reflections and Incident Cardiovascular Events and Heart Failure: The Multiethnic Study of Atherosclerosis 
Background
Experimental and physiologic data mechanistically implicate wave reflections in the pathogenesis of left ventricular failure and cardiovascular disease, but their association with these outcomes in the general population is unclear.
Objectives
To assess the relationship between central pressure profiles and incident cardiovascular events.
Methods
Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded non-invasively from 5,960 participants in the Multiethnic Study of Atherosclerosis (MESA). The central pressure waveform was separated into forward and reflected waves using a physiologic flow waveform. Reflection magnitude (RM=[reflected/forward wave amplitude] ×100), augmentation index (AIx=[second/first systolic peak] ×100) and pulse pressure amplification (PPA=[radial/aortic pulse pressure] ×100) were assessed as predictors of cardiovascular events (CVE) and congestive heart failure (CHF) during median 7.61 years of follow-up.
Results
After adjustment for established risk factors, aortic AIx independently predicted hard CVE (HR per 10%-increase=1.08; 95%CI=1.01-1.14; P=0.016), whereas PPA independently predicted all CVE (HR per 10%-increase=0.82; 95%CI=0.70-0.96; P=0.012). RM was independently predictive of all CVE (hazard ratio [HR] per 10%-increase=1.34; 95%CI=1.08-1.67; P=0.009), hard CVE (HR per 10%-increase=1.46; 95%CI=1.12-1.90; P=0.006) and strongly predictive of new-onset CHF (HR per 10%-increase=2.69; 95%CI=1.79-4.04; P<0.0001), comparing favorably to other risk factors for CHF as judged by various measures of model performance, reclassification and discrimination. In a fully-adjusted model, compared to non-hypertensive subjects with low RM, the HR for hypertensive subjects with low RM, non-hypertensive subjects with high RM and hypertensive subjects with high RM were 1.81 (95%CI=0.85-3.86), 2.16 (95%CI=1.07-5.01) and 3.98 (95%CI=1.96-8.05), respectively.
Conclusions
Arterial wave reflections represent a novel strong risk factor for CHF in the general population.
doi:10.1016/j.jacc.2012.07.054
PMCID: PMC4065497  PMID: 23103044
wave reflections; cardiovascular risk; heart failure. arterial hemodynamics; left ventricular afterload
4.  Population correlates of circulating mercury levels in Korean adults: the Korea National Health and Nutrition Examination Survey IV 
BMC Public Health  2014;14:527.
Background
Prior studies focused on bioaccumulation of mercury (Hg) and on large, long-lived fish species as the major environmental source of Hg, but little is known about consumption of small-sized fish or about non-dietary determinants of circulating Hg levels. The purpose of this study was to evaluate whole blood mercury concentration (WBHg) and its major dietary and non-dietary correlates in Korean adults.
Methods
We analyzed cross-sectional data from 3,972 (male = 1,994; female = 1,978) participants who completed the Korean National Health and Nutrition Examination Survey IV, 2008 to 2009. Relevant factors included diet, geographic location of residence, demographics, and lifestyle. WBHg concentration was measured using cold-vapor atomic absorption spectrometry. Multivariable linear models assessed independent correlates of dietary and non-dietary factors for WBHg levels.
Results
Median levels of WBHg were 5.1 μg/L in men and 3.7 μg/L in women. Higher levels of fish/shellfish intake were associated with higher levels of WBHg. Higher consumption of small-sized fish was linked to higher levels of WBHg. Non-dietary predictors of higher WBHg were being male, greater alcohol consumption, higher income and education, overweight/obesity, increasing age, and living in the southeast region.
Conclusions
Both dietary and non-dietary factors were associated with WBHg levels in the Korean population. There is significant geographic variation in WBHg levels; residents living in the mid-south have higher WBHg levels. We speculate that uncontrolled geographic characteristics, such as local soil/water content and specific dietary habits are involved.
doi:10.1186/1471-2458-14-527
PMCID: PMC4083352  PMID: 24884916
Blood mercury; Correlates; Fish intake; Korean adults
5.  Reproducibility of Arterial Elasticity Parameters Derived from Radial Artery Diastolic Pulse Contour Analysis: The Multi-Ethnic Study of Atherosclerosis 
Blood pressure monitoring  2010;15(6):312-315.
Objective
The aim of this report was to describe the reproducibility of arterial elasticity parameters derived from radial artery diastolic pulse contour analysis.
Methods
Two measurements were performed on the same day by the same technician with the HDI/Pulsewave CR-2000 (Eagan, MN) on each of a subset of participants selected at random from the Multi-Ethnic Study of Atherosclerosis (MESA). Large and small artery elasticity (C1 and C2), C1 and C2 each multiplied by systemic vascular resistance (C1xR and C2xR, which are functions of the radial artery pulse waveform only), and systolic and diastolic blood pressure (SBP and DBP) were evaluated.
Results
Two measurements were performed on each of 131 participants. The mean difference ± standard deviation of the difference was −0.13 ± 3.5 mmHgx10 for C1, −0.03 ± 1.5 mmHg ×100 for C2, 0.10 ± 4.6 seconds ×10 for C1xR, 0.05 ± 1.8 seconds ×100 for C2xR, 2.8 ± 8.2 mmHg for SBP, and 1.5 ± 5.0 mmHg for DBP. The between-measure correlation was 0.74 for C1, 0.84 for C2, 0.58 for C1xR, 0.74 for C2xR, 0.90 for SBP, and 0.86 for DBP.
Conclusion
The reproducibility of arterial elasticity measurements is less than that of systolic and diastolic blood pressure. Multiple measurements of arterial elasticity from a participant are recommended.
doi:10.1097/MBP.0b013e32833fe2a6
PMCID: PMC4028156  PMID: 20890179
arterial elasticity; arterial compliance; reproducibility; blood pressure measurement
6.  Whole Grains, Type 2 Diabetes, Coronary Heart Disease, and Hypertension: Links to the Aleurone preferred over Indigestible Fiber 
BioFactors (Oxford, England)  2013;39(3):242-258.
Higher whole grain cereal intakes are associated with substantially lower risks of type 2 diabetes, coronary heart disease, and hypertension. These reduced risks have been established in large prospective studies that now include millions of person-years of follow-up. We analyze the results of 11 major prospective studies to provide recommendations about whole grain consumption. The following review establishes the amount of whole grains that should ideally be consumed based on prospective evidence; defines the nature of whole grains; identifies that the whole grain evidence is robust and not due to confounding; and provides a detailed assessment of several potential mechanisms for the effect of whole grains on health. We draw the following conclusions. Firstly, to maintain health, 40 grams or more of whole grains should be consumed daily. This is about a bowl of whole grain breakfast cereal daily, but 80% of the population does not achieve this. Secondly, aleurone in bran is a critical grain component generally overlooked in favor of indigestible fiber. Live aleurone cells constitute 50% of millers’ bran. They store minerals, protein, and the antioxidant ferulic acid, and are clearly more than just indigestible fiber. Finally, we suggest potential roles for magnesium, zinc, and ferulic acid in the development of chronic disease. If the results of prospective studies were applied to the life-style practices of modern societies there exists the potential for enormous personal health and public financial benefits.
doi:10.1002/biof.1077
PMCID: PMC3640698  PMID: 23355358
Whole grains; Type 2 Diabetes; Hypertension; Coronary Heart Disease; Prospective studies; Fiber; Bran; Aleurone; Ferulic Acid; Magnesium; Zinc
7.  Reproductive, lifestyle and anthropometric risk factors for cancer in elderly women 
Background
With an increasing elderly population, the United States will experience an increased cancer burden in the coming years. We evaluated associations between anthropometric, lifestyle and reproductive factors and risk of breast, ovarian, and colorectal cancer in a prospective study of postmenopausal women with a focus on diagnoses occurring among very elderly women (≥75 years).
Methods
For each cancer type, we estimated associations with relevant exposures in two age bands (< vs. ≥75 years of age). During 22 years of follow-up, 322 ovarian, 1,311 colon, 315 rectal, and 2,664 breast cancers occurred among 37,459 postmenopausal women (mean age at baseline 62 years, range 55–71 years).
Results
For ovarian cancer, we identified few significant associations in either age band. Colon cancer cases had a higher body mass index and were less likely to report estrogen or aspirin use than non-cases, yet these associations were consistent in both age bands. Few risk factors were identified for rectal cancer in women ≥75 years of age. For breast cancer, notably different patterns were revealed, with alcohol consumption associated with risk in the younger group and previous hysterectomy associated with risk only in the older group.
Conclusion
These analyses suggest some important differences in risk factors for cancer depending on age at diagnosis.
Impact
This study suggests that etiologic differences may exist in cancers occurring in the very elderly. The ongoing demographic shift in the United States provides a strong rationale for studies evaluating cancer etiology in the elderly.
doi:10.1158/1055-9965.EPI-12-0966
PMCID: PMC3617066  PMID: 23429062
cancer risk; elderly; ovarian; colorectal; breast
8.  Dietary patterns are associated with plasma F2-isoprostanes in an observational cohort study of adults 
Free radical biology & medicine  2012;57:10.1016/j.freeradbiomed.2012.08.574.
Associations between individual foods or nutrients and oxidative markers have been reported. Comprehensive measures of food intake may be uniquely informative, given the complexity of oxidative systems and the possibility for antioxidant synergies. We quantified associations over a 20 y history between 3 food-based dietary patterns, summary measures of whole diet, and a plasma biomarker of lipid peroxidation, F2-isoprostanes in a cohort of Americans, aged 18–30 at year 0 (1985–86). We assessed diet at years 0, 7, and 20 through a detailed history of past-month food consumption and supplement use, and measured plasma F2-isoprostanes at years 15 and 20. We created 3 different dietary patterns: 1) a priori (“a priori diet quality score”) based on hypothesized healthy foods, 2) an empirical pattern reflecting high fruit and vegetable intake (“fruit-veg”), and 3) an empirical pattern reflecting high meat intake (“meat”). We used linear regression to estimate associations between each dietary pattern and plasma F2-isoprostanes cross-sectionally (at year 20, n=2,736) and prospectively (year 0/7 average diet and year 15/20 average F2-isoprostanes, n=2,718), adjusting for age, sex, race, total energy intake, education, smoking, body mass index (BMI), waist circumference, physical activity, and supplement use. In multivariable-adjusted cross-sectional analysis, the a priori diet quality score and the fruit-veg diet pattern were negatively, and the meat pattern positively, associated with F2-isoprostanes (all p-values<0.001). These associations remained statistically significant in prospective analysis. Our findings suggest that a long-term adherence to a diet rich in fruits and vegetables and low in red meat may decrease lipid peroxidation.
doi:10.1016/j.freeradbiomed.2012.08.574
PMCID: PMC3872789  PMID: 22982044
cohort; epidemiology; diet; oxidative stress
9.  The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study 
Respiratory Research  2014;15(1):31.
Background
Clinical studies of the associations of vitamin E with lung function have reported conflicting results. However, these reports primarily examine the α-tocopherol isoform of vitamin E and have not included the isoform γ-tocopherol which we recently demonstrated in vitro opposes the function of α-tocopherol. We previously demonstrated, in vitro and in animal studies, that the vitamin E isoform α-tocopherol protects, but the isoform γ-tocopherol promotes lung inflammation and airway hyperresponsiveness.
Methods
To translate these findings to humans, we conducted analysis of 4526 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center cohort with available spirometry and tocopherol data in blacks and whites. Spirometry was obtained at years 0, 5, 10, and 20 and serum tocopherol was from years 0, 7 and 15 of CARDIA.
Results
In cross-sectional regression analysis at year 0, higher γ-tocopherol associated with lower FEV1 (p = 0.03 in blacks and p = 0.01 in all participants) and FVC (p = 0.01 in blacks, p = 0.05 in whites, and p = 0.005 in all participants), whereas higher α-tocopherol associated with higher FVC (p = 0.04 in blacks and whites and p = 0.01 in all participants). In the lowest quartile of α-tocopherol, higher γ-tocopherol associated with a lower FEV1 (p = 0.05 in blacks and p = 0.02 in all participants). In contrast, in the lowest quartile of γ-tocopherol, higher α-tocopherol associated with a higher FEV1 (p = 0.03) in blacks. Serum γ-tocopherol >10 μM was associated with a 175–545 ml lower FEV1 and FVC at ages 21–55 years.
Conclusion
Increasing serum concentrations of γ-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of α-tocopherol was associated with higher FEV1 or FVC. Based on the prevalence of serum γ-tocopherol >10 μM in adults in CARDIA and the adult U.S. population in the 2011 census, we expect that the lower FEV1 and FVC at these concentrations of serum γ-tocopherol occur in up to 4.5 million adults in the population.
doi:10.1186/1465-9921-15-31
PMCID: PMC4003816  PMID: 24629024
α-tocopherol; γ-tocopherol; FEV1; FVC; Human
10.  Cardiovascular Health through Young Adulthood and Cognitive Functioning in Midlife 
Annals of neurology  2013;73(2):170-179.
Objective
To examine the association between overall cardiovascular health as recently defined by the American Heart Association in young adulthood to middle-age and cognitive function in midlife. Overall ideal cardiovascular health incorporates 7 metrics, including the avoidance of overweight or obesity, a healthful diet, nonsmoking, and physical activity, total cholesterol, blood pressure, and fasting glucose at goal levels.
Methods
This analysis of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a multicenter community-based study with 25 years of follow-up, included 2,932 participants aged 18 to 30 years at baseline (Year 0) who attended follow-up exams at Years 7 and 25. Cardiovascular health metrics were measured at each examination. The Digit Symbol Substitution Test (DSST), modified Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT) were completed at Year 25.
Results
A greater number of ideal cardiovascular metrics in young adulthood and middle-age was independently associated with better cognitive function in midlife (p-trend<0.01, for all). Specifically, each additional ideal metric was associated with 1.32 more symbols on the DSST (95% CI: 0.93 to 1.71), a 0.77-point lower interference score on the Stroop Test (−1.03 to −0.45), and 0.12 more words on the RAVLT (0.04 to 0.20). Participants who had ≥5 ideal metrics at a greater number of the 3 examinations over the 25-year period exhibited better performance on each cognitive test in middle-age (p-trend<0.01, for all).
Interpretation
Ideal cardiovascular health in young adulthood and its maintenance to middle-age is associated with better psychomotor speed, executive function, and verbal memory in midlife.
doi:10.1002/ana.23836
PMCID: PMC3608821  PMID: 23443990
11.  Asthma and lung structure on CT: The MESA Lung Study 
Background
The potential consequences of asthma in childhood and young adulthood on lung structure in older adults have not been studied in a large, population-based cohort.
Objective
The authors hypothesized that a history of asthma onset in childhood (age 18 or before) or young adulthood (age 19 to 45) was associated with altered lung structure on computed tomography (CT) in later life.
Methods
The Multi-Ethnic Study of Atherosclerosis Lung Study recruited 3,965 participants and assessed asthma history using standardized questionnaires, spirometry following guidelines, and segmental airway dimensions and percent low attenuation areas on CT scans.
Results
Asthma with onset in childhood and young adulthood was associated with large decrements in the forced expiratory volume in one second among participants with a mean age of 66 years (−365 ml and −343 ml, respectively; P<0.001). Asthma with onset in childhood and young adulthood was associated with increased mean airway wall thickness standardized to an internal perimeter of 10 mm (Pi10) (0.1 mm, P<0.001 for both), predominantly from narrower segmental airway lumens (−0.39 mm and −0.34 mm, respectively; P<0.001). Asthma with onset in childhood and young adulthood also was associated with a greater percentage of low attenuation areas (1.69% and 4.30%, respectively; P<0.001). Findings were similar among never smokers except that differential percentage of low attenuation areas in child-onset asthma was not seen in them.
Conclusion
Asthma with onset in childhood or young adulthood, was associated with reduced lung function, narrower airways and, among asthmatics who smoked, greater percentage of low attenuation areas in later life.
doi:10.1016/j.jaci.2012.11.036
PMCID: PMC3564253  PMID: 23374265
airway remodeling; airway structure; asthma; emphysema; epidemiology
12.  Associations among Lung Function, Arterial Elasticity and Circulating Endothelial and Inflammation Markers: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2013;61(2):542-548.
A parallel physiologic pathway for elastic changes is hypothesized for declines in arterial elasticity and lung function. Endothelial dysfunction and inflammation could potentially decrease elasticity of both vasculature and lung tissue. We examined biomarkers, large (LAE) and small (SAE) arterial elasticity, and forced vital capacity (FVC) in a period cross-sectional design in the Multi-Ethnic Study of Atherosclerosis, which recruited 1,823 women and 1,803 men, age range 45–84 years, black, white, Hispanic, and Chinese, free of clinically recognized CVD. Radial artery tonometric pulse waveform registration was performed and LAE and SAE were derived from diastole. Spirometric data and markers of endothelial dysfunction and inflammation (soluble intracellular adhesion molecule-1, fibrinogen, hs-C-reactive protein, and interleukin-6) were obtained. Mean LAE was 13.7 ± 5.5 ml/mmHgx10 and SAE was 4.6 ± 2.6 ml/mmHgx100. Mean FVC was 3,192 ± 956.0 mL and FEV1 was 2,386 ± 734.5 mL. FVC was about 40 ± 5 mL higher per SD of SAE, stronger in men than women. The association was slightly weaker with LAE, with no sex interaction. After regression adjustment for demographic, anthropometric, and cardiovascular risk factors, the biomarkers tended to be related to reduced SAE and FVC, particularly in men. These biomarker associations suggest important CVD risk alterations that occur concurrently with lower arterial elasticity and lung function. The observed positive association of SAE with FVC and with FEV1 in middle-aged to older free-living people is consistent with the hypothesis of parallel physiologic pathways for elastic changes in the vasculature and in lung parenchymal tissue.
doi:10.1161/HYPERTENSIONAHA.111.00272
PMCID: PMC3586233  PMID: 23283358
arterial stiffness; endothelial markers; inflammatory markers; large and small artery elasticity; lung function; MESA Study
13.  Passive Smoke Exposure Trends and Workplace Policy in the Coronary Artery Risk Development in Young Adults (CARDIA) study (1985–2001) 
Preventive medicine  2007;44(6):490-495.
Objective
There has been reduced active smoking, decreased societal acceptance for smoking indoors, and changing smoking policy since the mid-1980s. We quantified passive smoke exposure trends and their relationship with workplace policy.
Method
We studied 2,504 CARDIA participants (blacks and whites, 18–30 years old when recruited in 1985–86 from four US cities, reexamination 2, 5, 7, 10, and 15 years later) who never reported smoking and attended exams at 10 or 15 years.
Results
In non-smokers with a college degree (n = 1,581), total passive smoke exposure declined from 16.3 hr/wk in 1985/86 to 2.3 hr/wk in 2000/01. Less education tended to be associated with more exposure at all timepoints for example, in high school or less (n = 349) 22.2 hours/wk in 1985/86 to 8.5 hr/wk in 2000/01. Those who experienced an increase in the restrictiveness of self-reported workplace smoking policy from 1995/96 to 2000/01 were exposed to almost 3 hours per week less passive smoke than those whose workplace policies became less restrictive in this time period.
Conclusions
The increasing presence of restrictive workplace policies seemed to be a component of the substantial decline in self-reported passive smoke exposure since 1985.
doi:10.1016/j.ypmed.2007.02.014
PMCID: PMC3902070  PMID: 17433426
Environmental Tobacco Smoke Pollution; Occupational Health; Passive Smoking; Socioeconomic factors
14.  AHA Scientific Statement Population Approaches to Improve Diet, Physical Activity, and Smoking Habits A Scientific Statement From the American Heart Association 
Circulation  2012;126(12):10.1161/CIR.0b013e318260a20b.
Background
Poor lifestyle, including suboptimal diet, physical inactivity, and tobacco use are leading causes of preventable diseases globally. Although even modest population shifts in risk substantially alter health outcomes, the optimal population-level approaches to improve lifestyle are not well established.
Methods and Results
For this American Heart Association Scientific Statement, the writing group systematically reviewed and graded the current scientific evidence for effective population approaches to improve dietary habits, increase physical activity, and reduce tobacco use. Strategies were considered in 6 broad domains: (1) media and education campaigns; (2) labeling and consumer information; (3) taxation, subsidies, and other economic incentives; (4) school and workplace approaches; (5) local environmental changes; and (6) direct restrictions and mandates. The writing group also reviewed the potential contributions of healthcare systems and surveillance systems to behavior change efforts. Several specific population interventions that achieved a Class I or IIa recommendation with grade A or B evidence were identified, providing a set of specific evidence-based strategies that deserve close attention and prioritization for wider implementation. Effective interventions included specific approaches in all 6 domains evaluated for improving diet, increasing activity, and reducing tobacco use. The writing group also identified several specific interventions in each of these domains for which current evidence was less robust, as well as other inconsistencies and evidence gaps, informing the need for further rigorous and interdisciplinary approaches to evaluate population programs and policies.
Conclusions
This systematic review identified and graded the evidence for a range of population-based strategies to promote lifestyle change. The findings provide a framework for policy makers, advocacy groups, researchers, clinicians, communities, and other stakeholders to understand and implement the most effective approaches. New strategic initiatives and partnerships are needed to translate this evidence into action.
doi:10.1161/CIR.0b013e318260a20b
PMCID: PMC3881293  PMID: 22907934
15.  Prevalence, Prospective Risk Markers, and Prognosis Associated With the Presence of Left Ventricular Diastolic Dysfunction in Young Adults 
American Journal of Epidemiology  2012;177(1):20-32.
The authors sought to determine the prevalence, prospective risk markers, and prognosis associated with diastolic dysfunction in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The CARDIA Study cohort includes approximately equal proportions of white and black men and women. The authors collected data on risk markers at year 0 (1985–1986), and echocardiography was done at year 5 when the participants were 23–35 years of age. Participants were followed for 20 years (through 2010) for a composite endpoint of all-cause mortality, myocardial infarction, heart failure, and stroke. Diastolic function was defined according to a validated hierarchical classification algorithm. In the 2,952 participants included in the primary analysis, severe diastolic dysfunction was present in 1.1% and abnormal relaxation was present in 9.3%. Systolic blood pressure at year 0 was associated with both severe diastolic dysfunction and abnormal relaxation 5 years later, whereas exercise capacity and pulmonary function abnormalities were associated only with abnormal relaxation 5 years later. After multivariate adjustment, the hazard ratios for the composite endpoint in participants with severe diastolic dysfunction and abnormal relaxation were 4.3 (95% confidence interval: 2.0, 9.3) and 1.6 (95% confidence interval: 1.1, 2.5), respectively. Diastolic dysfunction in young adults is associated with increased morbidity and mortality, and the identification of prospective risk markers associated with diastolic dysfunction could allow for targeted primary prevention efforts.
doi:10.1093/aje/kws224
PMCID: PMC3590041  PMID: 23211639
CARDIA study; clinical outcomes; diastolic dysfunction; left ventricle
16.  Relationship of Body Mass Index in Young Adulthood and Health-Related Quality of Life Two Decades Later: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
International journal of obesity (2005)  2010;35(1):10.1038/ijo.2010.120.
Objective
The expanding overweight and obesity epidemic notwithstanding, little is known about their long-term effect on health-related quality of life (HRQoL). The main objective of this study was to investigate whether overweight (body mass index [BMI] 25–<30 kg/m2) and obese (BMI ≥ 30 kg/m2) young adults have poorer HRQoL 20 years later.
Methods
The authors studied 3014 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal, community-dwelling, biracial cohort from four cities. BMI was measured at baseline and 20 years later. HRQoL was assessed via the physical component summary (PCS) and the mental component summary (MCS) scores of the Medical Outcomes Study 12-Item Short Form Health Survey at year 20. Higher PCS or MCS scores indicate better HRQoL.
Results
Mean year 20 PCS score was 52.2 for normal weight participants at baseline, 50.3 for overweight, and 46.4 for obese (P-trend <0.001). This relation persisted after adjustment for baseline demographics, general health, and physical and behavioral risk factors and after further adjustment for 20-year changes in risk factors. No association was observed for MCS scores (P-trend 0.43).
Conclusion
Overweight and obesity in early adulthood are adversely associated with self-reported physical HRQoL, but not mental HRQoL 20 years later.
doi:10.1038/ijo.2010.120
PMCID: PMC3875360  PMID: 20548305
17.  Circulating soluble ICAM-1 and subclinical atherosclerosis: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Clinical chemistry  2011;58(2):10.1373/clinchem.2011.168559.
Background
Soluble intercellular adhesion molecule-1 (sICAM-1) is associated with endothelial dysfunction and clinical cardiovascular disease. We investigated the relationship of subclinical atherosclerosis with sICAM-1 concentration.
Methods
sICAM-1 concentration was assayed at year 15 of the Coronary Artery Risk Development in Young Adults (CARDIA) Study (black and white men and women, average age 40 years). We assessed progression of coronary artery calcification through year 20 (CAC, n=2378), and both carotid artery stenosis (n=2432) and intima media thickness at year 20 (IMT, n = 2240).
Results
Median sICAM-1 was 145.9 ng/ml. Among a subgroup with advanced atherosclerotic plaque (either CAC or stenosis), IMT was 0.010 (95% confidence interval (CI) 0.003–0.017 mm) higher per standard deviation of sICAM-1 (44 ng/ml) in a model adjusted for age, race, sex, clinic, smoking, exercise, body size, education, blood pressure, antihypertensive medication, plasma lipids, and cholesterol lowering medication. With the same adjustment, the odds ratios (OR) for the presence of year 20 carotid artery stenosis per SD of sICAM-1 was 1.12 (CI 1.01–1.25, p<0.04), while for occurrence of CAC progression the OR was 1.16 (CI 1.04–1.31, p<0.01). The associations with CAC and carotid stenosis were strongest in the top 20th of the sICAM-1 distribution.
Conclusion
sICAM-1 concentration may be an early biomarker that indicates changes in the artery wall that accompany atherosclerosis, as well as the presence of advanced plaque in the coronary and carotid arteries. This finding holds in people with low total burden of atherosclerosis, decades prior to the development of clinical CVD.
doi:10.1373/clinchem.2011.168559
PMCID: PMC3867124  PMID: 22179741
18.  Circulating and Dietary Omega‐3 and Omega‐6 Polyunsaturated Fatty Acids and Incidence of CVD in the Multi‐Ethnic Study of Atherosclerosis 
Background
Dietary guidelines support intake of polyunsaturated fatty acids (PUFAs) in fish and vegetable oils. However, some controversy remains about benefits of PUFAs, and most prior studies have relied on self‐reported dietary assessment in relatively homogeneous populations.
Methods and Results
In a multiethnic cohort of 2837 US adults (whites, Hispanics, African Americans, Chinese Americans), plasma phospholipid PUFAs were measured at baseline (2000–2002) using gas chromatography and dietary PUFAs estimated using a food frequency questionnaire. Incident cardiovascular disease (CVD) events (including coronary heart disease and stroke; n=189) were prospectively identified through 2010 during 19 778 person‐years of follow‐up. In multivariable‐adjusted Cox models, circulating n‐3 eicosapentaenoic acid and docosahexaenoic acid were inversely associated with incident CVD, with extreme‐quartile hazard ratios (95% CIs) of 0.49 for eicosapentaenoic acid (0.30 to 0.79; Ptrend=0.01) and 0.39 for docosahexaenoic acid (0.22 to 0.67; Ptrend<0.001). n‐3 Docosapentaenoic acid (DPA) was inversely associated with CVD in whites and Chinese, but not in other race/ethnicities (P‐interaction=0.01). No significant associations with CVD were observed for circulating n‐3 alpha‐linolenic acid or n‐6 PUFA (linoleic acid, arachidonic acid). Associations with CVD of self‐reported dietary PUFA were consistent with those of the PUFA biomarkers. All associations were similar across racial‐ethnic groups, except those of docosapentaenoic acid.
Conclusions
Both dietary and circulating eicosapentaenoic acid and docosahexaenoic acid, but not alpha‐linolenic acid or n‐6 PUFA, were inversely associated with CVD incidence. These findings suggest that increased consumption of n‐3 PUFA from seafood may prevent CVD development in a multiethnic population.
doi:10.1161/JAHA.113.000506
PMCID: PMC3886748  PMID: 24351702
cardiovascular disease prevention; cardiovascular risk factors; diet; fatty acids
19.  Changes in Clinical and Microbiological Periodontal Profiles Relate to Progression of Carotid Intima‐Media Thickness: The Oral Infections and Vascular Disease Epidemiology Study 
Background
No prospective studies exist on the relationship between change in periodontal clinical and microbiological status and progression of carotid atherosclerosis.
Methods and Results
The Oral Infections and Vascular Disease Epidemiology Study examined 420 participants at baseline (68±8 years old) and follow‐up. Over a 3‐year median follow‐up time, clinical probing depth (PD) measurements were made at 75 766 periodontal sites, and 5008 subgingival samples were collected from dentate participants (average of 7 samples/subject per visit over 2 visits) and quantitatively assessed for 11 known periodontal bacterial species by DNA‐DNA checkerboard hybridization. Common carotid artery intima‐medial thickness (CCA‐IMT) was measured using high‐resolution ultrasound. In 2 separate analyses, change in periodontal status (follow‐up to baseline), defined as (1) longitudinal change in the extent of sites with a ≥3‐mm probing depth (Δ%PD≥3) and (2) longitudinal change in the relative predominance of bacteria causative of periodontal disease over other bacteria in the subgingival plaque (Δetiologic dominance), was regressed on longitudinal CCA‐IMT progression adjusting for age, sex, race/ethnicity, diabetes, smoking status, education, body mass index, systolic blood pressure, and low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol. Mean (SE) CCA‐IMT increased during follow‐up by 0.139±0.008 mm. Longitudinal IMT progression attenuated with improvement in clinical or microbial periodontal status. Mean CCA‐IMT progression varied inversely across quartiles of longitudinal improvement in clinical periodontal status (Δ%PD≥3) by 0.18 (0.02), 0.16 (0.01), 0.14 (0.01), and 0.07 (0.01) mm (P for trend<0.0001). Likewise, mean CCA‐IMT increased by 0.20 (0.02), 0.18 (0.02), 0.15 (0.02), and 0.12 (0.02) mm (P<0.0001) across quartiles of longitudinal improvement in periodontal microbial status (Δetiologic dominance).
Conclusion
Longitudinal improvement in clinical and microbial periodontal status is related to a decreased rate of carotid artery IMT progression at 3‐year average follow‐up.
doi:10.1161/JAHA.113.000254
PMCID: PMC3886779  PMID: 24166489
atherosclerosis; infection; inflammation; periodontal; progression
20.  Correlates of heart rate recovery over 20 years in a population sample 
Medicine and science in sports and exercise  2012;44(2):10.1249/MSS.0b013e31822cb190.
Introduction
Slow heart rate recovery (HRR) from a graded exercise treadmill test (GXT) is a marker of impaired parasympathetic reactivation that is associated with elevated mortality. Our objective was to test whether demographic, behavioral or coronary heart disease (CHD) risk factors during young adulthood were associated with the development of slow HRR.
Methods
Participants from the Coronary Artery Risk Development in Young Adults study underwent symptom-limited maximal GXT using a modified Balke protocol at baseline (1985–86) and 20-year follow-up (2005–06) examinations. HRR was calculated as the difference between peak heart rate (HR) and HR two-minutes following cessation of the GXT. Slow HRR was defined as 2-minute HRR < 22 beats·min−1.
Results
In 2,730 participants who did not have slow HRR at baseline, mean HRR was 44 beats*min−1 (SD = 11) at baseline and declined to 40 beats·min−1 (SD=12) in 2005–06; slow HRR developed in 5% (n=135) of the sample by 2005–06. Female sex, black race, fewer years of education, obesity, cigarette smoking, higher depressive symptoms, higher fasting glucose, hypertension, metabolic syndrome and physical inactivity and low fitness were each associated with incident slow HRR. In a multivariable model higher BMI, larger waist, low education, fasting glucose and current smoking remained significantly associated with incident slow HRR. Increasing BMI (per SD higher) over follow-up and incident hypertension, diabetes and metabolic syndrome (in the subsets of participants who were free from those conditions at baseline), were each associated with a significantly elevated odds of incident slow HRR.
Conclusions
On average, HRR declines with aging; however, the odds of having slow HRR in early middle age is significantly associated with traditional CHD risk factors.
doi:10.1249/MSS.0b013e31822cb190
PMCID: PMC3838873  PMID: 21796053
Epidemiology; Cardiovascular Disease; Exercise; Autonomic Nervous System
21.  Kidney stones and subclinical atherosclerosis in young adults: Coronary Artery Risk Development in Young Adults (CARDIA) study 
The Journal of urology  2011;185(3):10.1016/j.juro.2010.10.086.
Purpose
Recent reports suggest that nephrolithiasis and atherosclerosis share a number of risk factors. There has been no previous examination of the relationship between kidney stones and subclinical atherosclerotic disease Here we assessed the relationship between nephrolithiasis and carotid wall thickness and carotid stenosis assessed by B-mode ultrasound in the general community using data from The Coronary Artery Risk Development in Young Adults (CARDIA) study.
Methods
CARDIA is a U.S. population-based, observational study of 5,115 white and African-American men and women between the ages of 18 and 30 years at recruitment in 1985-1986.
Results
By the year 20 exam, 200 (3.9%) of CARDIA participants had reported ever having kidney stones. Symptomatic kidney stones were associated with greater carotid wall thickness measured at the year 20 exam, particularly of the internal carotid/bulb region. Using a composite dichotomous endpoint of carotid stenosis and/or upper quartile of internal carotid/bulb wall thickness, the association of kidney stones with carotid atherosclerosis was significant (odds ratio=1.6; 95% confidence interval 1.1-2.3; p=0.01) even after adjusting for major atherosclerotic risk factors.
Conclusions
The association between a history of kidney stones and subclinical carotid atherosclerosis in young adults adds further support to the notion that nephrolithiasis and atherosclerosis share common systemic risk factors and/or pathophysiology.
doi:10.1016/j.juro.2010.10.086
PMCID: PMC3827917  PMID: 21251678
urolithiasis; atherosclerosis
22.  Periodontal Infection, Systemic Inflammation, and Insulin Resistance 
Diabetes Care  2012;35(11):2235-2242.
OBJECTIVE
Adverse microbial exposures might contribute to diabetogenesis. We hypothesized that clinical periodontal disease (a manifestation of microbial exposures in dysbiotic biofilms) would be related to insulin resistance among diabetes-free participants. The roles of inflammatory mediation and effect modification were also studied.
RESEARCH DESIGN AND METHODS
The continuous National Health and Nutrition Examination Survey 1999–2004 enrolled 3,616 participants (51% women) who received a periodontal examination and fasting blood draw. Participants were mean age (± SD) 43 ± 17 years and 28% Hispanic, 52% Caucasian, 17% African American, and 3% other. Log-transformed values of the homeostasis model assessment of insulin resistance (HOMA-IR) or HOMA-IR ≥3.30 (75th percentile) were regressed across full-mouth periodontal probing depth (PD) levels using linear and logistic models. White blood cell (WBC) count and C-reactive protein (CRP) were considered as either mediators or effect modifiers in separate analyses. Risk ratios (RRs) stem from marginal predictions derived from the logistic model. Results were adjusted for multiple periodontal disease and insulin resistance risk factors.
RESULTS
In linear regression, geometric mean HOMA-IR levels increased by 1.04 for every 1-mm PD increase (P = 0.007). WBC mediated 6% of the association (P < 0.05). Among participants with WBC ≤6.4 × 109, PD was unrelated to HOMA-IR ≥3.30. Fourth-quartile PD was associated with HOMA-IR ≥3.30 among participants with WBC >7.9 × 109; RR 2.60 (1.36–4.97) (P for interaction = 0.05). Findings were similar among participants with CRP >3.0 mg/L (P for interaction = 0.04).
CONCLUSIONS
Periodontal infection was associated with insulin resistance in a nationally representative U.S. sample of diabetes-free adults. These data support the role of inflammation as both mediator and effect modifier of the association.
doi:10.2337/dc12-0072
PMCID: PMC3476901  PMID: 22837370
23.  Association of Osteocalcin With Obesity, Insulin Resistance, and Cardiovascular Risk Factors in Young Adults 
Obesity (Silver Spring, Md.)  2012;20(11):2194-2201.
Low levels of osteocalcin (OCN), an osteoblast-specific hormone, have recently been associated with insulin resistance (homeostasis model assessment-insulin resistance (HOMA-IR)) and obesity, particularly in older adults. The aim of this study was to determine whether low levels of OCN would be associated with insulin resistance, obesity, and greater cardiovascular (CV) risk in young adults just emerging from adolescence. Undercarboxylated OCN and carboxylated OCN levels were measured on stored serum samples (total OCN = undercarboxylated OCN + carboxylated OCN) on 137 participants (67 males) at mean age 18.6 years (range 17–22 years). Insulin resistance was measured by hyperinsulinemic–euglycemic clamp (Mlbm). Multivariable regression analyses with ln(OCN) as the independent variable were adjusted for age, sex, ethnicity, and BMI as indicated. Total OCN was inversely related to BMI, waist circumference, systolic blood pressure (SBP), interleukin (IL)-6, and directly related to Mlbm; only SBP remained significant (with Mlbm P = 0.0560) after further adjustment for BMI. Carboxylated OCN was inversely related to BMI, waist circumference, SBP, low-density lipoprotein cholesterol (LDL-C), and directly related to adiponectin; SBP and adiponectin remained significant after further adjustment for BMI. There were no significant associations with undercarboxylated OCN. In summary, most associations with OCN were mediated via BMI. However, the significant associations of OCN with SBP, obesity, and adiponectin and borderline with Mlbm, suggest a potential role for OCN in the development of insulin resistance and CV risk that becomes more apparent with aging into older adulthood.
doi:10.1038/oby.2012.108
PMCID: PMC3483437  PMID: 22573135
24.  Prospective Study of Particulate Air Pollution Exposures, Subclinical Atherosclerosis, and Clinical Cardiovascular Disease 
American Journal of Epidemiology  2012;176(9):825-837.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45–84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
doi:10.1093/aje/kws169
PMCID: PMC3571256  PMID: 23043127
air pollution; atherosclerosis; cardiovascular diseases; environmental exposure; epidemiologic methods; particulate matter
25.  Trends in blood pressure and hypertension detection, treatment and control 1980–2009: The Minnesota Heart Survey 
Circulation  2012;126(15):1852-1857.
Background
Hypertension is common and treatable but detection and control remain a major health challenge. This study sought to determine population trends in blood pressure and in the control of hypertension in the Minneapolis/St. Paul area (2010 population: 2.85 million) from 1980–2009.
Methods and Results
Surveys of risk factors were carried out every five years among randomly selected adults aged 25–74.
Data on hypertension knowledge and use of medications were collected by interview. Blood pressure was measured using standardized methods with hypertension defined as blood pressure ≥140 and/or 90 mmHg or controlled (<140 and/or 90mmHg) on medications.
Six surveys included 11,192 men and 12,795 women. Mean systolic blood pressure (SBP) fell from 124.9 mmHg in 1980–82 to 121.1 mmHg in 2007–09 for men (p<.0001) and for women from 120.1 mmHg to 114.7 mmHg (p<.0001). Similar trends for diastolic blood pressure wereobserved. Adults with uncontrolled blood pressure (≥140 and/or 90 mmHg) with or without medication fell from 20.3% to 5.8% (p<.001) for men and 13.1% to 2.7% (p<.0001) for women. Anti-hypertensive medication use rose to over 50% among all adults aged 55–74. Men (66%) and women (72%) with hypertension were treated and controlled by 2007–09. A majority of the decline in mean population blood pressure was the result of control with aggressive use of anti-hypertensive drugs. Stroke mortality in this population fell in parallel.
Conclusions
Hypertension detection and control in this community is among the highest observed in a US population and already exceeds Health People 2020 goals.
doi:10.1161/CIRCULATIONAHA.112.098517
PMCID: PMC3482957  PMID: 22962433
Hypertension; Blood Pressure; Stroke; Epidemiology

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