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1.  Longitudinal association between serum urate and subclinical atherosclerosis: the Coronary Artery Risk Development in Young Adults (CARDIA) study 
Journal of internal medicine  2013;274(6):10.1111/joim.12120.
Objective
The aim of the present study was to determine whether serum urate (sUA) concentration is positively associated with subclinical atherosclerosis, independent of body mass index (BMI), among generally healthy adults.
Design and setting
The CARDIA study followed 5115 black and white individuals aged 18–30 years in 1985–1986 (year 0). Subclinical atherosclerosis comprised coronary artery calcified plaque (CAC; years 15, 20 and 25) and maximum common carotid intima–media thickness (IMT; year 20). sUA (years 0, 10, 15 and 20) was modelled as gender-specific quartiles that were pooled. Discrete-time hazard regressions and generalized linear regressions were used for analyses.
Results
Mean sUA concentration was lower in women than in men, and increased with age. Adjusting for demographic and lifestyle factors, the highest versus lowest quartile of sUA at year 0 was associated with a 44% [95% confidence interval (CI) 20%, 73%] greater risk of CAC progression from year 15 to 25 (Ptrend < 0.001), which was attenuated by adjustment for BMI at year 0 (Ptrend = 0.45). A stronger association was found between sUA at year 15 and CAC progression at year 20 or 25 (hazard ratio 2.07, 95% CI 1.66, 2.58 for the highest versus lowest sUA quartile Ptrend < 0.001), which was attenuated but remained significant with additional adjustment for BMI at year 15 (Ptrend = 0.01). A greater increment in sUA concentration from year 0 to year 15, independent of change in BMI, was related to a higher risk of CAC progression (Ptrend < 0.001). Similar associations were found between sUA and IMT, but only in men.
Conclusion
sUA may be an early biomarker for subclinical atherosclerosis in young adults; starting in early middle age, sUA predicts subclinical atherosclerosis independently of BMI.
doi:10.1111/joim.12120
PMCID: PMC3825786  PMID: 23952533
calcified plaque; intima–media thickness; subclinical atherosclerosis; urate; uric acid
2.  Left atrial dimension and traditional cardiovascular risk factors predict 20-year clinical cardiovascular events in young healthy adults: the CARDIA study 
Aims
We investigated whether the addition of left atrial (LA) size determined by echocardiography improves cardiovascular risk prediction in young adults over and above the clinically established Framingham 10-year global CV risk score (FRS).
Methods and results
We included white and black CARDIA participants who had echocardiograms in Year-5 examination (1990–91). The combined endpoint after 20 years was incident fatal or non-fatal cardiovascular disease: myocardial infarction, heart failure, cerebrovascular disease, peripheral artery disease, and atrial fibrillation/flutter. Echocardiography-derived M-mode LA diameter (LAD; n = 4082; 149 events) and 2D four-chamber LA area (LAA; n = 2412; 77 events) were then indexed by height or body surface area (BSA). We used Cox regression, areas under the receiver operating characteristic curves (AUC), and net reclassification improvement (NRI) to assess the prediction power of LA size when added to calculated FRS or FRS covariates. The LAD and LAA cohorts had similar characteristics; mean LAD/height was 2.1 ± 0.3 mm/m and LAA/height 9.3 ± 2.0 mm2/m. After indexing by height and adjusting for FRS covariates, hazard ratios were 1.31 (95% CI 1.12, 1.60) and 1.43 (95% CI 1.13, 1.80) for LAD and LAA, respectively; AUC was 0.77 for LAD and 0.78 for LAA. When LAD and LAA were indexed to BSA, the results were similar but slightly inferior. Both LAD and LAA showed modest reclassification ability, with non-significant NRIs.
Conclusion
LA size measurements independently predict clinical outcomes. However, it only improves discrimination over clinical parameters modestly without altering risk classification. Indexing LA size by height is at least as robust as by BSA. Further research is needed to assess subgroups of young adults who may benefit from LA size information in risk stratification.
doi:10.1093/ehjci/jeu018
PMCID: PMC4215562  PMID: 24534011
Left atrial size; Cardiovascular events; Echocardiography; Young adults
3.  Associations between Nonalcoholic Fatty Liver Disease and Subclinical Atherosclerosis in Middle-Aged Adults: The Coronary Artery Risk Development in Young Adults Study 
Atherosclerosis  2014;235(2):599-605.
Objective
Non-alcoholic fatty liver disease (NAFLD) is an obesity-related condition associated with cardiovascular mortality. Yet, whether or not NAFLD is independently related to atherosclerosis is unclear. In a population-based cross-sectional sample of middle-aged adults free from liver or heart disease, we tested the hypothesis that NAFLD is associated with subclinical atherosclerosis (coronary artery (CAC) and abdominal aortic calcification (AAC)) independent of obesity.
Methods
Participants from the Coronary Artery Risk Development in Young Adults study with CT quantification of liver fat, CAC and AAC were included (n=2,424). NAFLD was defined as liver attenuation ≤ 40 Hounsfield Units after exclusion of other causes of liver fat. CAC and AAC presence was defined as Agatston score > 0.
Results
Mean participant age was 50.1±3.6 years, (42.7% men, 50.0% black) and BMI was 30.6±7.2 kg/m2. The prevalence of NAFLD, CAC, and AAC was 9.6%, 27.1%, and 51.4%. NAFLD participants had increased prevalence of CAC (37.9% vs. 26.0%, p<0.001) and AAC (65.1% vs. 49.9%, p<0.001). NAFLD remained associated with CAC (OR, 1.33; 95% CI, 1.001–1.82) and AAC (OR, 1.74; 95% CI, 1.29–2.35) after adjustment for demographics and health behaviors. However, these associations were attenuated after additional adjustment for visceral adipose tissue (CAC OR, 1.05; 95% CI, 0.74–1.48, AAC OR=1.20; 95% CI, 0.86–1.67). There was no interaction by race or sex.
Conclusion
In contrast to prior research, these findings suggest that obesity attenuates the relationship between NAFLD and subclinical atherosclerosis. Further studies evaluating the role of NAFLD duration on atherosclerotic progression and cardiovascular events are needed.
doi:10.1016/j.atherosclerosis.2014.05.962
PMCID: PMC4124046  PMID: 24956534
calcium; cardiovascular diseases; epidemiology; imaging; liver; obesity; risk factors
4.  Periodontal Infection, Impaired Fasting Glucose and Impaired Glucose Tolerance: Results from The Continuous National Health and Nutrition Examination Survey 2009–2010 
Aim
We investigated the relationship between periodontal disease, a clinical manifestation of periodontal infection, and prediabetes.
Methods
The National Health and Nutrition Examination Survey, 2009–2010 enrolled 1,165 diabetes-free adults (51% female) aged 30–80 years (mean ± SD=50±14) who received a full-mouth periodontal examination and an oral glucose tolerance test. Participants were classified as having none/mild, moderate or severe periodontitis and also according to mean probing depth≥2.19 mm or attachment loss≥1.78 mm, (respective 75th percentiles). Pre-diabetes was defined according to ADA criteria as either: i) impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). In multivariable logistic regression models, the odds of IFG and IGT were regressed on levels of periodontitis category.
Results
The odds ratios and 95% confidence intervals for having IGT among participants with moderate or severe periodontitis, relative to participants with none/mild periodontitis were 1.07[0.50,2.25] and 1.93[1.18,3.17], P=0.02. The ORs for having IFG were 1.14[0.74, 1.77] and 1.12[0.58, 2.18], P =0.84. PD≥75th percentile was related to a 105% increase in the odds of IGT: OR[95%CI] =2.05[1.24, 3.39], P=0.005.
Conclusions
Periodontal infection was positively associated with prevalent impaired glucose tolerance in a cross-sectional study among a nationally representative sample.
doi:10.1111/jcpe.12258
PMCID: PMC4072528  PMID: 24708451
5.  Greater Cognitive Decline with Aging among Elders with High Serum Concentrations of Organochlorine Pesticides 
PLoS ONE  2015;10(6):e0130623.
Although cognitive decline is very common in elders, age-related cognitive decline substantially differs among elders and the determinants of the differences in age-related cognitive decline are unclear. We investigated our hypothesis that the association between age and cognition was stronger in those with higher serum concentrations of organochlorine (OC) pesticides, common persistent and strongly lipophilic neurotoxic chemicals. Participants were 644 elders aged 60-85, participating in the National Health and Nutrition Examination Survey 1999-2002. Six OC pesticides (p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodipenyldichloroethylene (DDE), β-hexachlorocyclohexane, trans-nonachlor, oxychlordane, and heptachlor epoxide) were evaluated. “Lower cognitive function” was defined as having a low Digit-Symbol Substitution Test (DSST) score (<25th percentile of DSST score, cutpoint 28 symbols substituted). Higher levels of β-hexachlorocyclohexane, trans-nonachlor, oxychlordane, and heptachlor epoxide modified the associations between age and lower cognitive function (Pinteraction<0.01, 0.03, <0.01, and 0.02, respectively). Elders in the 3rd tertile of these chemicals demonstrated a greater risk of lower cognitive function with aging, compared to those in the combined 1st and 2nd tertiles. Among those with highest OC pesticides (3rd tertile), the odds ratio for the risk of lower cognitive function was about 6 to 11 for the highest quintile of age (80-85 years) vs. the first quintile of age (60-63 years), while the association between age and lower cognitive function became flatter in those with lower OC pesticides (combined 1st and 2nd tertiles). Both DDT and DDE showed no interaction, with lower DSST scores for higher age irrespective of serum concentrations of DDT or DDE. Even though DSST score measures only one aspect of cognition, several OC pesticides modified aging-related prevalence of low cognitive score, a finding which should be evaluated in prospective studies.
doi:10.1371/journal.pone.0130623
PMCID: PMC4480979  PMID: 26107947
6.  A Test of Biological and Behavioral Explanations for Gender Differences in Telomere Length: The Multi-Ethnic Study of Atherosclerosis 
Biodemography and social biology  2014;60(2):156-173.
The purpose of this study was to examine biological and behavioral explanations for gender differences in leukocyte telomere length (LTL), a biomarker of cell aging that has been hypothesized to contribute to women’s greater longevity. Data are from a subsample (n = 851) of the Multi-Ethnic Study of Atherosclerosis, a population-based study of women and men aged 45 to 84. Mediation models were used to examine study hypotheses. We found that women had longer LTL than men, but the gender difference was smaller at older ages. Gender differences in smoking and processed meat consumption partially mediated gender differences in telomere length, whereas gender differences in estradiol, total testosterone, oxidative stress, and body mass index did not. Neither behavioral nor biological factors explained why the gender difference in LTL was smaller at older ages. Longitudinal studies are needed to assess gender differences in the rate of change in LTL over time; to identify the biological, behavioral, and psychosocial factors that contribute to these differences throughout the life course; and to determine whether gender differences in LTL explain the gender gap in longevity.
doi:10.1080/19485565.2014.947471
PMCID: PMC4460606  PMID: 25343364
7.  Diet quality and markers of endothelial function: the CARDIA study 
Background:
Dietary patterns are associated cross-sectionally with cellular adhesion molecules (CAMs).
Objective:
We studied prospective associations of three dietary patterns with CAMs.
Design:
In the Coronary Artery Risk Development in Young Adults (CARDIA) study, diet was assessed at years 0 (1985-86) and 7 (1992-93) examinations. Four circulating CAMs (E-selectin, P-selectin, soluble intercellular adhesion molecule 1 (sICAM-1), and vascular cellular adhesion molecule (VCAM)) were assayed at years 7 and 15 (2000-01). We created one index score “A Priori Diet Quality Score” and derived dietary patterns using principal components analysis (PCA). Multivariable linear regression models predicted year 15 CAMs from averaged (year 0/7) dietary patterns.
Results:
The A Priori Diet Quality Score rated 46 food groups beneficial, neutral or adverse based on hypothesized health effects. We derived two PCA dietary patterns: “fruit and vegetables (FV)” (high intakes of fruit, vegetables, and whole grains) and “meat” (high intakes of red meat, refined grain, and butter). All dietary patterns were related to E-selectin and sICAM-1. P-selectin was not related to the FV dietary pattern. VCAM was only related to the A Priori Diet Quality Score. Strongest associations were for the meat dietary pattern with E-selectin (effect size 28% of an SD (+3.9/13.7 ng/mL) and P-selectin (effect size 37% of an SD (+4.1/11.2 ng/mL) and the A Priori Diet Quality Score with sICAM-1 (effect size 34% of an SD (−15.1/44.7 ng/mL) and VCAM (effect size of 26% of an SD (−45.1/170.3 ng/mL).
Conclusion:
This prospective analysis suggests that dietary patterns are associated with CAMs.
doi:10.1016/j.numecd.2013.12.010
PMCID: PMC4037360  PMID: 24534074
Cohort; Epidemiology; Diet; Endothelial function; Cellular Adhesion Molecules (CAMs)
8.  Clinical Characteristics and Outcomes Associated with the Natural History of Early Repolarization in a Young, Biracial Cohort Followed to Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Background
Early repolarization (ER), a common electrocardiographic phenotype, has been associated with increased mortality risk in middle-aged adults. Data are sparse on long-term follow-up and outcomes associated with ER in younger adults.
Methods and Results
We prospectively examined 5,039 participants (mean age 25 years at baseline, 40% black) from the CARDIA cohort over 23 years. Twelve-lead electrocardiograms were recorded and analyzed at Years 0, 7 and 20 and coded as definite or probable ER using a standardized algorithm. Cox regression was used, and models were adjusted for important baseline and clinical covariates. Kaplan-Meier curves were created for presence of ER and total mortality and cardiovascular (CV) mortality. Participants with ER were more likely to be black, male, smoke, have higher systolic blood pressure, lower heart rate, and BMI, and also higher exercise duration, and longer PR, QRS and QT intervals. ER was associated with total mortality (HR1.77, 1.38–2.28, p<0.01), and CV mortality (HR 1.59, 1.01–2.50, p=0.04) in unadjusted analyses, but adjustment for age, sex, and race attenuated associations almost completely. Sex-race stratified analyses showed no significant associations between ER and outcome for any of the subgroups except blacks.
Conclusions
The presence of ER at any time point over 23 years of follow-up was not associated with adverse outcomes. Black race and male sex confound the unadjusted association of ER and outcomes, with no race-sex interactions noted. Further studies are necessary to understand the factors associated with heightened risk of death in those who maintain ER into and beyond middle age.
doi:10.1161/CIRCEP.113.000874
PMCID: PMC4136505  PMID: 24759868
ECG; ECG criteria; outcome; mortality; early repolarization
9.  Markers of Inflammation and Coagulation after Long-Term Exposure to Coarse Particulate Matter: A Cross-Sectional Analysis from the Multi-Ethnic Study of Atherosclerosis 
Environmental Health Perspectives  2015;123(6):541-548.
Background
Toxicological research suggests that coarse particles (PM10–2.5) are inflammatory, but responses are complex and may be best summarized by multiple inflammatory markers. Few human studies have investigated associations with PM10–2.5 and, of those, none have explored long-term exposures. Here we examine long-term associations with inflammation and coagulation in the Multi-Ethnic Study of Atherosclerosis.
Methods
Participants included 3,295 adults (45–84 years of age) from three metropolitan areas. Site-specific spatial models were used to estimate 5-year concentrations of PM10–2.5 mass and copper, zinc, phosphorus, silicon, and endotoxin found in PM10–2.5. Outcomes included interleukin-6, C-reactive protein, fibrinogen, total homocysteine, D-dimer, factor VIII, plasmin–antiplasmin complex, and inflammation and coagulation scores. We used multivariable regression with multiply imputed data to estimate associations while controlling for potential confounders, including co-pollutants such as fine particulate matter.
Results
Some limited evidence was found of relationships between inflammation and coagulation and PM10–2.5. Endotoxin was the PM10–2.5 component most strongly associated with inflammation, with an interquartile range (IQR) increase (0.08 EU/m3) associated with 0.15 (95% CI: 0.01, 0.28; p = 0.03) and 0.08 (95% CI: –0.07, 0.23; p = 0.28) higher inflammation scores before and after control for city, respectively. Copper was the component with the strongest association with coagulation, with a 4-ng/m3 increase associated with 0.19 (95% CI: 0.08, 0.30; p = 0.0008) and 0.12 (95% CI: –0.05, 0.30; p = 0.16) unit higher coagulation scores before and after city adjustment, respectively.
Conclusions
Our cross-sectional analysis provided some evidence that long-term PM10–2.5 exposure was associated with inflammation and coagulation, but associations were modest and depended on particle composition.
Citation
Adar SD, D’Souza J, Mendelsohn-Victor K, Jacobs DR Jr, Cushman M, Sheppard L, Thorne PS, Burke GL, Daviglus ML, Szpiro AA, Diez Roux AV, Kaufman JD, Larson TV. 2015. Markers of inflammation and coagulation after long-term exposure to coarse particulate matter: a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 123:541–548; http://dx.doi.org/10.1289/ehp.1308069
doi:10.1289/ehp.1308069
PMCID: PMC4455582  PMID: 25616153
10.  Association of Sickle Cell Trait With Chronic Kidney Disease and Albuminuria in African Americans 
JAMA  2014;312(20):2115-2125.
IMPORTANCE
The association between sickle cell trait (SCT) and chronic kidney disease (CKD) is uncertain.
OBJECTIVE
To describe the relationship between SCT and CKD and albuminuria in self-identified African Americans.
DESIGN, SETTING, AND PARTICIPANTS
Using 5 large, prospective, US population-based studies (the Atherosclerosis Risk in Communities Study [ARIC, 1987–2013; n = 3402], Jackson Heart Study [JHS, 2000–2012; n = 2105], Coronary Artery Risk Development in Young Adults [CARDIA, 1985–2006; n = 848], Multi-Ethnic Study of Atherosclerosis [MESA, 2000–2012; n = 1620], and Women’s Health Initiative [WHI, 1993–2012; n = 8000]), we evaluated 15 975 self-identified African Americans (1248 participants with SCT [SCT carriers] and 14 727 participants without SCT [noncarriers]).
MAIN OUTCOMES AND MEASURES
Primary outcomes were CKD (defined as an estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m2 at baseline or follow-up), incident CKD, albuminuria (defined as a spot urine albumin:creatinine ratio of >30 mg/g or albumin excretion rate >30 mg/24 hours), and decline in eGFR (defined as a decrease of >3 mL/min/1.73 m2 per year). Effect sizes were calculated separately for each cohort and were subsequently meta-analyzed using a random-effects model.
RESULTS
A total of 2233 individuals (239 of 1247 SCT carriers [19.2%] vs 1994 of 14 722 noncarriers [13.5%]) had CKD, 1298 (140 of 675 SCT carriers [20.7%] vs 1158 of 8481 noncarriers [13.7%]) experienced incident CKD, 1719 (150 of 665 SCT carriers [22.6%] vs 1569 of 8249 noncarriers [19.0%]) experienced decline in eGFR, and 1322 (154 of 485 SCT carriers [31.8%] vs 1168 of 5947 noncarriers [19.6%]) had albuminuria during the study period. Individuals with SCT had an increased risk of CKD (odds ratio [OR], 1.57 [95% CI, 1.34–1.84]; absolute risk difference [ARD], 7.6% [95% CI, 4.7%–10.8%]), incident CKD (OR, 1.79 [95% CI, 1.45–2.20]; ARD, 8.5% [95% CI, 5.1%–12.3%]), and decline in eGFR (OR, 1.32 [95% CI, 1.07–1.61]; ARD, 6.1% [95% CI, 1.4%–13.0%]) compared with noncarriers. Sickle cell trait was also associated with albuminuria (OR, 1.86 [95% CI, 1.49–2.31]; ARD, 12.6% [95% CI, 7.7%–17.7%]).
CONCLUSIONS AND RELEVANCE
Among African Americans in these cohorts, the presence of SCT was associated with an increased risk of CKD, decline in eGFR, and albuminuria, compared with noncarriers. These findings suggest that SCT may be associated with the higher risk of kidney disease in African Americans.
doi:10.1001/jama.2014.15063
PMCID: PMC4356116  PMID: 25393378
11.  Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry 
Human Molecular Genetics  2015;24(16):4728-4738.
Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist–hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjusted WHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006–0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjusted WHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.
doi:10.1093/hmg/ddv186
PMCID: PMC4512626  PMID: 25994509
12.  Age-related variations in the methylome associated with gene expression in human monocytes and T cells 
Nature communications  2014;5:5366.
Age-related variations in DNA methylation have been reported; however, the functional relevance of these differentially methylated sites (age-dMS) are unclear. Here we report potentially functional age-dMS, defined as age- and cis-gene expression-associated methylation sites (age-eMS), identified by integrating genome-wide CpG methylation and gene expression profiles collected ex vivo from circulating T cells (227 CD4+ samples) and monocytes (1,264 CD14+ samples, age range: 55–94 years). None of the age-eMS detected in 227 T cell samples are detectable in 1,264 monocyte samples, in contrast to the majority of age-dMS detected in T cells that replicated in monocytes. Age-eMS tend to be hypomethylated with older age, located in predicted enhancers, and preferentially linked to expression of antigen processing and presentation genes. These results identify and characterize potentially functional age-related methylation in human T cells and monocytes, and provide novel insights into the role age-dMS may play in the aging process.
doi:10.1038/ncomms6366
PMCID: PMC4280798  PMID: 25404168
13.  Serum Urate Association with Hypertension in Young Adults: Analysis from the Coronary Artery Risk Development in Young Adults Cohort 
Annals of the rheumatic diseases  2012;72(8):1321-1327.
Objective
To determine if serum urate concentration is associated with development of hypertension in young adults.
Methods
Retrospective cohort analysis from 4752 participants with available serum urate and without hypertension at baseline from the Coronary Artery Risk Development in Young Adults (CARDIA) Study; a mixed race (African-American and White) cohort established in 1985 with 20 years of follow-up data for this analysis. Associations between baseline serum urate concentration and incident hypertension (defined as a blood pressure greater or equal to 140/90 or being on antihypertensive drugs) were investigated in sex-stratified bivariate and multivariable Cox-proportional analyses.
Results
Mean age (standard deviation) at baseline was 24.8 (3.6) years for men and 24.9 (3.7) years for women. Compared with the referent category, we found a greater hazard of developing hypertension starting at 345 μmol/L (5.8 mg/ dL) of serum urate for men and 214 μmol/L (3.6 mg/dL) for women. There was a 25% increase in the hazard of developing hypertension in men (HR1.25 [95% CI 1.15-1.36]) per each mg/dL increase in serum urate but no significant increase in women (HR 1.06 [95%CI 0.97-1.16]).
Conclusions
We found a significant independent association between higher serum urate concentrations and the subsequent hazard of incident hypertension, even at concentrations below the conventional hyperuricemia threshold of 404 μmol/L (6.8 mg/dL).
doi:10.1136/annrheumdis-2012-201916
PMCID: PMC4428756  PMID: 22984170
health services research; hypertension; epidemiology
14.  Depression and Risk of Incident Asthma in Adults. The CARDIA Study 
Rationale: Asthma is associated with depression, but the temporality of the association has not been established.
Objectives: To examine the association between prevalent elevated depressive symptoms and incident asthma, and between prevalent asthma and incident elevated depressive symptoms in a cohort of young and middle-aged adults.
Methods: We examined the longitudinal association between asthma and depressive symptoms bidirectionally in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. First, 3,614 participants, free of asthma, were classified by elevated depressive symptoms at the CARDIA Year-5 exam (n = 856 elevated vs. 2,758 not elevated; ages 23–35 yr) and followed for 20 years to incident asthma. Then, 3,016 participants, free of elevated depressive symptoms, were classified by self-reported current asthma status (n = 188 prevalent vs. 2,828 not prevalent) at the CARDIA Year-5 exam and followed for 20 years until onset of elevated depressive symptoms.
Measurements and Main Results: The relative hazard of incident asthma among those with elevated depressive symptoms was 1.26 (95% confidence interval [CI] = 1.02–1.56) after adjustment for covariates. When depressive status was modeled as the total number of reports of elevated depressive symptoms before the onset of asthma, the adjusted hazard ratio was 1.15 (95% CI = 1.02–1.29). The hazard of incident elevated depressive symptoms for those with asthma was no different than the hazard in those without asthma (adjusted hazard ratio = 0.92; 95% CI = 0.70–1.20).
Conclusions: This longitudinal observational study points to depression as a marker of risk for incident adult-onset asthma. On the other hand, prevalent asthma is not associated with incident adult-onset depression.
doi:10.1164/rccm.201307-1349OC
PMCID: PMC4098106  PMID: 24456492
adult; asthma; depression
15.  Transcriptomic profiles of aging in purified human immune cells 
BMC Genomics  2015;16(1):333.
Background
Transcriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret.
Results
Using transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55–94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age.
Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types.
Conclusions
An overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1522-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1522-4
PMCID: PMC4417516  PMID: 25898983
Aging; Monocyte; T cell; Transcriptome; Mitochondrial ribosome; Translation; Protein synthesis; Ribonucleoprotein complex; Oxidative phosphorylation; Autophagy; Methylation
16.  Cardiorespiratory fitness and cognitive function in middle age 
Neurology  2014;82(15):1339-1346.
Objective:
To investigate whether greater cardiorespiratory fitness (CRF) is associated with better cognitive function 25 years later.
Methods:
We studied 2,747 participants in the community-based Coronary Artery Risk Development in Young Adults Study of black and white men and women aged 18 to 30 years at recruitment in 1985–1986 (baseline year 0). Symptom-limited maximal treadmill test durations at years 0 and 20 provided measures of CRF. Cognitive tests at year 25 measured verbal memory (Rey Auditory Verbal Learning Test [RAVLT]), psychomotor speed (Digit Symbol Substitution Test [DSST]), and executive function (Stroop Test).
Results:
Per minute of baseline CRF, the RAVLT was 0.12 words recalled higher (standard error [SE] = 0.03, p < 0.0001), the DSST was 0.92 digits higher (SE = 0.13, p < 0.0001), and the Stroop Test score was 0.52 lower (better performance, SE = 0.11, p < 0.0001), after accounting for race, sex, age, education, and clinical center. Compared with the lowest quartile of CRF, each cognitive test was 21% to 34% of an SD better in the highest CRF quartile. Further adjustment for lifestyle and clinical measures attenuated coefficients for RAVLT and DSST slightly, while the coefficient predicting the Stroop Test lost more than half its value (p = 0.07). Analysis in the subset of 1,957 participants who also completed the year-20 treadmill test showed that 20-year change in CRF was positively associated only with DSST (p < 0.001).
Conclusions:
Better verbal memory and faster psychomotor speed at ages 43 to 55 years were clearly associated with better CRF 25 years earlier.
doi:10.1212/WNL.0000000000000310
PMCID: PMC4001190  PMID: 24696506
17.  The associations between metabolic variables and NT-proBNP are blunted at pathological ranges: the Multi-Ethnic Study of Atherosclerosis 
Objective
Under physiological conditions brain natriuretic peptide (BNP) is inversely associated with metabolic risk factors, but under pathological conditions these associations may tend to plateau.
Material end methods
5597 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA), 45–84 years of age, free of overt cardiovascular disease in 2000–02 and then again in 2003–05 participated in this study. Associations between NT-proBNP and BMI, blood lipids, homeostasis model of insulin resistance (HOMA-IR) using linear regression models were adjusted for age, race, sex, BMI, % of energy from saturated fats, intentional exercise, statin use, antihypertensive medication use, diabetes and glomerular filtration rate. The inflection points (IP) at which these associations became nonlinear were determined using linear splines with knots at different levels of NT-proBNP.
Results
Participants with NT-proBNP ≥100 pg/mL (29%) tended to be older, on statins and anti-hypertensive medications vs. those with NT-proBNP <100 pg/mL. The IP point varies among variables and ranged from 50–120 pg/mL. NT-proBNP
Conclusions
In a large cardiovascular disease-free cohort, NT-proBNP within the lower (physiological) range was inversely associated with TC, LDL-C, TG and insulin resistance with different inflection points, but at higher (pathological) levels these associations were blunted.
doi:10.1016/j.metabol.2013.11.017
PMCID: PMC3965618  PMID: 24388001
NT-proBNP; lipids; inflammatory markers; HOMA; BMI
Background
Identifying potentially modifiable risk factors is critically important for reducing the burden of chronic kidney disease. We sought to examine the association of body mass index (BMI) with kidney function decline in a cohort of young adults with preserved glomerular filtration at baseline.
Study Design
Longitudinal cohort.
Setting & Participants
2,891 black and white young adults with cystatin C-based estimated glomerular filtration rate (eGFRcys) >90 ml/min/1.73 m2 taking part in the year-10 examination (in 1995–1996) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Predictor
BMI, categorized as 18.5–24.9 (reference), 25.0–29.9. 30.0–39.9, and ≥40.0 kg/m2.
Outcomes
Trajectory of kidney function decline, rapid decline (>3% per year), and incident eGFRcys <60 ml/min/1.73 m2 over 10 years of follow-up.
Measurements
GFRcys estimated from the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation for calibrated cystatin C at CARDIA years 10, 15, and 20.
Results
At year 10, participants had a mean age of 35.1 years, median eGFRcys of 114 ml/min/1.73 m2, and 24.5% had BMI ≥30.0 kg/m2. After age 30 years, average eGFRcys was progressively lower with each increment of BMI after adjustment for baseline age, race, sex, hyperlipidemia, smoking status, and physical activity. Higher BMI category was associated with successively higher odds of rapid decline (for 25.0–29.9, 30.0–39.9, and ≥40.0 kg/m2, the adjusted ORs were 1.50 [95% CI, 1.21–1.87], 2.01 [95% CI, 1.57–2.87], and 2.57 [95% CI, 1.67–3.94], respectively). Eighteen participants (0.6%) had incident eGFRcys <60 ml/min/1.73 m2. In unadjusted analysis, higher BMI category was associated with incident eGFRcys <60 ml/min/1.73 m2 (for 25.0–29.9, 30.0–39.9, and ≥40.0 kg/m2, the ORs were 5.17 [95% CI, 1.10–25.38], 7.44 [95% CI, 1.54–35.95], and 5.55 [95% CI, 0.50–61.81], respectively); adjusted associations were no longer significant.
Limitations
Inability to describe kidney function before differences by BMI category were already evident. Absence of data on measured GFR or GFR estimated from serum creatinine.
Conclusions
Higher BMI categories are associated with greater declines in kidney function among a cohort of young adults with preserved GFR at baseline. Clinicians should vigilantly monitor overweight and obese patients for evidence of early kidney function decline.
doi:10.1053/j.ajkd.2013.10.055
PMCID: PMC3969447  PMID: 24295611
Atherosclerosis  2014;233(2):387-393.
OBJECTIVE
To evaluate associations between total serum γ-glutamyltransferase activity (GGT) and biomarkers of arteriosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA), including 6,783 participants from four ethnic subgroups, i.e., White, Chinese, Black and Hispanic.
METHODS
Associations between fasting total serum GGT activity and oxidized low-density lipoproteins (oxLDL), interleukin-6 (IL-6), C-reactive protein (CRP), and soluble intercellular adhesion molecule-1 (sICAM-1) were assessed. Following evaluation of linear trends between GGT and biomarkers of interest, multivariable linear regression models were serially adjusted for age, gender, site, ethnicity (M1); M1+lifestyle variables (M2); M2+traditional cardiovascular risk factors plus medications (M3); and M3+metabolic status (M4). Interactions were evaluated between GGT and age and ethnicity in all models.
RESULTS
Linear trends were positive and significant between GGT and oxLDL, IL-6, CRP and sICAM-1 in crude models, and trends remained significant in all ethnic subgroups for CRP (p<0.0001) and sICAM-1 (p<0.001), and for IL-6 except in the Chinese. Trends between GGT and oxLDL were significant in the entire cohort and the White subgroup (p<0.0001), but not in other ethnic subgroups. Multivariable models demonstrated continuous strong, positive associations between GGT and CRP, IL-6 and sICAM-1. Associations between GGT and oxLDL were attenuated upon adjustment for LDL-C and other traditional risk factors. All models were attenuated with adjustment for metabolic status. No age interactions were evident.
CONCLUSIONS
Our findings support the hypothesis that total serum GGT activity represents the impact of metabolic disease on vascular injury and atherosclerosis.
doi:10.1016/j.atherosclerosis.2014.01.010
PMCID: PMC4000064  PMID: 24530768
GGT; oxidative stress; oxidized LDL; sICAM; CRP; endothelial dysfunction
PLoS ONE  2015;10(3):e0122138.
Objective
To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF).
Design
Cross-sectional brain Magnetic Resonance I (MRI) study.
Setting
Community based cohort in three U.S. sites.
Participants
A Caucasian and African-American sub-sample (n= 680; mean age 50.3 yrs) attending the 25 year follow-up exam of the Coronary Artery Risk Development in Young Adults Study.
Primary and Secondary Outcomes
3T brain MR images processed for quantitative estimates of: total brain (TBV) and abnormal white matter (AWM) volume; white matter fractional anisotropy (WM-FA); and gray matter cerebral blood flow (GM-CBF). Total intracranial volume is TBV plus cerebral spinal fluid (TICV). A Global Cognitive Function (GCF) score was derived from tests of speed, memory and executive function.
Results
Adjusting for TICV and demographic factors, current smoking was significantly associated with lower GM-CBF and TBV, and more AWM (all <0.05); SA with lower GM-CBF, WM-FA and TBV (p=0.01); increasing BMI with decreasing GM-CBF (p<0003); hypertension with lower GM-CBF, WM-FA, and TBV and higher AWM (all <0.05); and diabetes with lower TBV (p=0.007). The GCS was lower as TBV decreased, AWM increased, and WM-FA (all p<0.01).
Conclusion
In middle age adults, CVRF are associated with brain health, reflected in MRI measures of structure and perfusion, and cognitive functioning. These findings suggest markers of mid-life cardiovascular and brain health should be considered as indication for early intervention and future risk of late-life cerebrovascular disease and dementia.
doi:10.1371/journal.pone.0122138
PMCID: PMC4374951  PMID: 25812012
International journal of cardiology  2014;172(2):350-355.
Background
Framingham risk score (FRS) underestimates risk in young adults. LV mass (LVM) relates to cardiovascular disease (CVD), with unclear value in youth. In a young biracial cohort, we investigate how FRS predicts CVD over 20 years and the incremental value of LVM. We also explore the predictive ability of different cut-points for hypertrophy.
Methods
We assessed FRS and echocardiography-derived LVM (indexed by BSA or height2.7) from 3980 African-American and white CARDIA participants (1990-1991); and followed over 20 years for a combined endpoint: cardiovascular death; nonfatal myocardial infarction, heart failure, cerebrovascular disease, and peripheral artery disease. We assessed the predictive ability of FRS for CVD and also calibration, discrimination, and net reclassification improvement for adding LVM to FRS.
Results
Mean age was 30±4 years, 46% males, and 52% white. Event incidence (n = 118) across FRS groups was, respectively, 1.3%, 5.4%, and 23.1% (p<0.001); and was 1.4%, 1.3%, 3.7%, and 5.4% (p<0.001) across quartiles of LVM (cut-points 117g, 144g, and 176g). LVM predicted CVD independently of FRS, with the best performance in normal weight participants. Adding LVM to FRS modestly increased discrimination and had a statistically significant reclassification. The 85th percentile (≥116 g/m2 for men; ≥96 g/m2 for women) showed event prediction more robust than currently recommended cut-points for hypertrophy.
Conclusion
In a biracial cohort of young adults, FRS and LVM are helpful independent predictors of CVD. LVM can modestly improve discrimination and reclassify participants beyond FRS. Currently recommended cut-points for hypertrophy may be too high for young adults.
doi:10.1016/j.ijcard.2014.01.003
PMCID: PMC4068332  PMID: 24507735
young adults; cardiovascular risk; left ventricular hypertrophy; echocardiography
Background
We investigated race–ethnic and sex‐specific relationships of left ventricular (LV) structure and LV function in African American and white men and women at 43 to 55 years of age.
Methods and Results
The Coronary Artery Risk Development in Young Adults (CARDIA) Study enrolled African American and white adults, age 18 to 30 years, from 4 US field centers in 1985–1986 (Year‐0) who have been followed prospectively. We included participants with echocardiographic assessment at the Year‐25 examination (n=3320; 44% men, 46% African American). The end points of LV structure and function were assessed using conventional echocardiography and speckle‐tracking echocardiography. In the multivariable models, we used, in addition to race–ethnic and gender terms, demographic (age, physical activity, and educational level) and cardiovascular risk variables (body mass index, systolic blood pressure, diastolic blood pressure, heart rate, presence of diabetes, use of antihypertensive medications, number of cigarettes/day) at Year‐0 and ‐25 examinations as independent predictors of echocardiographic outcomes at the Year‐25 examination (LV end‐diastolic volume [LVEDV]/height, LV end‐systolic volume [LVESV]/height, LV mass [LVM]/height, and LVM/LVEDV ratio for LV structural indices; LV ejection fraction [LVEF], Ell, and Ecc for systolic indices; and early diastolic and atrial ratio, mitral annulus early peak velocity, ratio of mitral early peak velocity/mitral annulus early peak velocity; ratio, left atrial volume/height, longitudinal peak early diastolic strain rate, and circumferential peak early diastolic strain rate for diastolic indices). Compared with women, African American and white men had greater LV volume and LV mass (P<0.05). For LV systolic function, African American men had the lowest LVEF as well as longitudinal (Ell) and circumferential (Ecc) strain indices among the 4 sex/race–ethnic groups (P<0.05). For LV diastolic function, African American men and women had larger left atrial volumes; African American men had the lowest values of Ell and Ecc for diastolic strain rate (P<0.05). These race/sex differences in LV structure and LV function persisted after adjustment.
Conclusions
African American men have greater LV size and lower LV systolic and diastolic function compared to African American women and to white men and women. The reasons for these racial‐ethnic differences are partially but not completely explained by established cardiovascular risk factors.
doi:10.1161/JAHA.114.001264
PMCID: PMC4392424  PMID: 25770024
echocardiography; left ventricular function; left ventricular mass; speckle‐tracking echocardiography
Background
Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure.
Methods and Results
We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure–time integrals (PTI) of the aortic pressure waveform, independently predicts incident heart failure (HF) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults. The late/early systolic PTI ratio (L/ESPTI) was assessed as a predictor of incident HF during median 8.5 years of follow‐up. The L/ESPTI was predictive of incident HF (hazard ratio per 1% increase=1.22; 95% CI=1.15 to 1.29; P<0.0001) even after adjustment for established risk factors for HF (HR=1.23; 95% CI=1.14 to 1.32: P<0.0001). In a multivariate model that included brachial systolic and diastolic blood pressure and other standard risk factors of HF, L/ESPTI was the modifiable factor associated with the greatest improvements in model performance. A high L/ESPTI (>58.38%) was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF, the HR associated with hypertension was 1.39 (95% CI=0.86 to 2.23; P=0.18), whereas the HR associated with a high L/E was 2.31 (95% CI=1.52 to 3.49; P<0.0001).
Conclusions
Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population.
doi:10.1161/JAHA.114.001335
PMCID: PMC4392425  PMID: 25736440
arterial hemodynamics; heart failure; late systolic load; left ventricular afterload
Background
Blood pressure (BP) trajectories derived from measurements repeated over years have low measurement error and may improve cardiovascular disease prediction compared to single, average, and usual BP (single BP adjusted for regression dilution). We characterized 10‐year BP trajectories and examined their association with cardiovascular mortality, all‐cause mortality, and life years lost.
Methods and Results
Data from 2 prospective and nearly extinct cohorts of middle‐aged men—the Minnesota Business and Professional Men Study (n=261) and the Zutphen Study (n=632)—were used. BP was measured annually during 1947–1957 in Minnesota and 1960–1970 in Zutphen. BP trajectories were identified by latent mixture modeling. Cox proportional hazards and linear regression models examined BP trajectories with cardiovascular mortality, all‐cause mortality, and life years lost. Associations were adjusted for age, serum cholesterol, smoking, and diabetes mellitus. Mean initial age was about 50 years in both cohorts. After 10 years of BP measurements, men were followed until death on average 20 years later. All Minnesota men and 98% of Zutphen men died. Four BP trajectories were identified, in which mean systolic BP increased by 5 to 49 mm Hg in Minnesota and 5 to 20 mm Hg in Zutphen between age 50 and 60. The third systolic BP trajectories were associated with 2 to 4 times higher cardiovascular mortality risk, 2 times higher all‐cause mortality risk, and 4 to 8 life years lost, compared to the first trajectory.
Conclusions
Ten‐year BP trajectories were the strongest predictors, among different BP measures, of cardiovascular mortality, all‐cause mortality, and life years lost in Minnesota. However, average BP was the strongest predictor in Zutphen.
doi:10.1161/JAHA.114.001378
PMCID: PMC4392427  PMID: 25753924
blood pressure; cardiovascular disease; epidemiology; prospective cohort study
Journal of biosocial science  2012;45(2):267-278.
Prior studies examining the association between self-reported experiences of racial/ethnic discrimination and obesity have had mixed results and primarily been cross-sectional. This study tests the hypothesis that an increase in self-reported experiences of racial/ethnic discrimination predicts gains in waist circumference and body mass index in Black and White women and men over eight years. In race/ethnicity- and gender-stratified models, this study examined whether change in self-reported experiences of racial/ethnic discrimination predicts changes in waist circumference and body mass index over time using a fixed-effect regression approach in SAS statistical software, providing control for both measured and unmeasured time-invariant covariates. Between 1992–93 and 2000–01, self-reported experiences of racial/ethnic discrimination decreased among 843 Black women (75% to 73%), 601 Black men (80% to 77%), 893 White women (30% to 23%), and 856 White men (28% to 23%). In fixed-effect regression models, controlling for all time-invariant covariates, social desirability bias, and changes in education and parity (women only) over time, an increase in self-reported experiences of racial/ethnic discrimination over time was significantly associated with an increase in waist circumference (b=1.09, 95% CI: 0.00–2.19, p=0.05) and an increase in body mass index (b=0.67, 95% CI: 0.19–1.16, p=0.007) among Black women. No associations were observed among Black men and White women and men. These findings suggest that an increase in self-reported experiences of racial/ethnic discrimination may be associated with increases in waist circumference and body mass index among Black women over time.
doi:10.1017/S0021932012000429
PMCID: PMC4310212  PMID: 22856616

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