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1.  Associations of Pentraxin 3 with Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Pentraxin 3 (PTX3) is likely a specific marker of vascular inflammation. However, associations of PTX3 with cardiovascular disease (CVD) risk have not been well studied in healthy adults or multi-ethnic populations. We examined associations of PTX3 with CVD risk factors, measures of subclinical CVD, coronary artery calcification (CAC) and CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA).
Approach and Results
2838 participants free of prevalent CVD with measurements of PTX3 were included in the present study. Adjusting for age, sex and ethnicity, PTX3 was positively associated with age, obesity, insulin, systolic blood pressure, C-reactive protein (CRP) and carotid intima media thickness (all p<0.045). A one standard deviation increase in PTX3 (1.62 ng/ml) was associated with the presence of CAC in fully adjusted models including multiple CVD risk factors (relative risk; 95% confidence interval 1.05; 1-01-1.08). In fully adjusted models, a standard deviation higher level of PTX3 was associated with an increased risk of myocardial infarction (hazard ratio; 95% confidence interval 1.51; 1.16-1.97), combined CVD events (1.23; 1.05-1.45) and combined CHD events (1.33; 1.10-1.60) but not stroke, CVD-related mortality or all cause death.
In these apparently healthy adults, PTX3 was associated with CVD risk factors, subclinical CVD, CAC and incident coronary heart disease events independent of CRP and CVD risk factors. These results support the hypothesis that PTX3 reflects different aspects of inflammation than CRP and may provide additional insight into the development and progression of atherosclerosis.
PMCID: PMC4055511  PMID: 24628740
Atherosclerosis; Cardiovascular Diseases; Epidemiology; Inflammation; Pentraxin 3
2.  Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) and Risk of Cardiovascular Disease in Older Adults: Results from the Cardiovascular Health Study 
Atherosclerosis  2009;209(2):528-532.
To examine associations between lipoprotein-associated phospholipase A2 (Lp-PLA2) antigen level (mass) and enzymatic activity (activity) and cardiovascular disease (CVD) in older adults.
We examined associations of Lp-PLA2 mass and activity with incident myocardial infarction (MI; n=508), stroke (n= 565) and CVD death (n=665) using Cox regressions adjusted for age, sex, ethnicity and CVD risk factors in 3,949 older adults, aged ≥ 65 years at baseline, from the Cardiovascular Health Study (CHS).
Lp-PLA2 was associated with incident CVD events in these older adults. Hazard ratios (95% confidence intervals) for highest versus lowest tertiles of Lp-PLA2 mass were 1.49 (1.19–1.85) for MI, 1.21 (0.98–1.49) for stroke and 1.11 (0.92–1.33) for CVD death. The highest tertile of Lp-PLA2 activity was associated with MI (1.36; 1.09–1.70) and CVD death (1.23; 1.02–1.50). Combined Lp-PLA2 tertile 3 and CRP >3mg/l, compared to Lp-PLA2 tertile 1 and CRP <1 mg/l, was associated with MI (2.29; 1.49–3.52) for Lp-PLA2 mass and MI (1.66; 1.10–2.51) and CVD death (1.57; 1.08–2.26) for activity. For MI, both mass and activity added excess risk to elevated CRP alone (~20% excess risk) and activity added excess risk for CVD death (~12%).
Lp-PLA2 mass and activity were associated with incident CVD events in older adults in CHS. Lp-PLA2 and CRP were independent and additive in prediction of events. While associations were modest, these results support further exploration of Lp-PLA2 to identify older individuals at risk for CVD.
PMCID: PMC2846186  PMID: 19804884
Epidemiology; Inflammation; Cardiovascular diseases; Lipoprotein-associated phospholipase A2
3.  Associations of Inflammatory Markers with Coronary Artery Calcification: Results from the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;209(1):226-229.
Inflammatory markers predict coronary heart disease (CHD). However, associations with coronary artery calcium (CAC), a marker of subclinical CHD, are not established.
We examined cross-sectional associations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with CAC presence (Agatston score > 0 by computed tomography) in 6,783 Multi-Ethnic Study of Atherosclerosis (MESA) participants.
In all participants, those in the highest, compared to lowest, quartile of CRP had a relative risk (RR, 95% confidence interval) of 1.13 (1.06-1.19; p<0.01) for CAC in age, sex and ethnicity adjusted models. For highest versus lowest quartiles, relative risks were 1.22 (1.15-1.30; p<0.01) for IL-6 and 1.18 (1.11-1.24; p<0.01) for fibrinogen. Adjusting for CHD risk factors (smoking, diabetes, blood pressure, obesity and dyslipidemia) attenuated RRs. RRs for CAC were 1.05 (0.99-1.12; p=0.63) for CRP, 1.12 (1.06-1.20; p<0.01) for IL-6 and 1.09 (1.02-1.16; p=0.01) for fibrinogen in multivariable adjusted models. Results were similar for men and women and across ethnic groups.
Inflammatory markers were weakly associated with CAC presence and burden in MESA. Our data support the hypothesis that inflammatory biomarkers and CAC reflect distinct pathophysiology.
PMCID: PMC2830357  PMID: 19766217
Atherosclerosis; Calcium; Inflammation; Population
4.  Associations of Pentraxin 3 with Cardiovascular Disease and All Cause Death: The Cardiovascular Health Study 
We examined associations of pentraxin 3 (PTX3), a vascular inflammation marker, with incident cardiovascular disease (CVD) and all cause death.
Methods and Results
1,583 Cardiovascular Health Study participants free of prevalent CVD were included. Non-exclusive case groups were angina (n=476), myocardial infarction (MI; n=237), stroke (n=310), CVD death (n=282) and all cause death (n=772). 535 participants had no events. PTX3 levels were higher in those with subclinical CVD (1.90 ± 1.89 ng/ml) than those without (1.71 ± 1.88 ng/ml; p=0.001). Using Cox regression adjusted for age, sex and ethnicity, a standard deviation increase in PTX3 (1.89 ng/ml) was associated with CVD death (hazard ratio 1.11; 95% confidence interval 1.02–1.21) and all cause death (1.08; 1.02–1.15). PTX3 was not associated with angina (1.09; 0.98–1.20), MI (0.96; 0.81–1.12) or stroke (1.06; 0.95–1.18). Adding C-reactive protein (CRP) or CVD risk factors to the models had no significant effects on associations.
In these older adults, PTX3 was associated with CVD and all cause death independent of CRP and CVD risk factors. PTX3 likely reflects different aspects of inflammation than CRP and may provide insight into vascular health in aging and chronic diseases of aging that lead to death.
PMCID: PMC2661204  PMID: 19164811
Cardiovascular Diseases; Epidemiology; Inflammation; Mortality; Pentraxin 3
Journal of human hypertension  2014;29(2):127-133.
Among obese individuals, increased sympathetic nervous system activity results in increased renin and aldosterone production, as well as renal tubular sodium reabsorption. This study determined the associations between adipokines and selected measures of the reninangiotensinogen-aldosterone system (RAAS). The sample was 1,970 men and women from the Multi-Ethnic Study of Atherosclerosis who were free of clinical cardiovascular disease at baseline and had blood assayed for adiponectin, leptin, plasma renin activity (PRA) and aldosterone. The mean age was 64.7 years and 50% were female. The mean (SD) PRA and aldosterone were 1.45 (0.56) ng/ml and 150.1 (130.5) pg/ml, respectively. After multivariable adjustment, a 1-SD increment of leptin was associated with a 0.55 ng/ml higher PRA and 8.4 pg/ml higher aldosterone (p < 0.01 for both). Although adiponectin was not significantly associated with PRA levels, the same increment in this adipokine was associated with lower aldosterone levels (−5.5 pg/ml, p = 0.01). Notably, the associations between aldosterone and both leptin and adiponectin were not materially changed with additional adjustment for PRA. Exclusion of those taking anti-hypertensive medications modestly attenuated the associations. The associations between leptin and both PRA and aldosterone were not different by gender but were significantly stronger among non-Hispanic Whites and Chinese Americans than African and Hispanic Americans (p < 0.01). The findings suggest that both adiponectin and leptin may relevant to blood pressure regulation via the RAAS, that the associations appear to be robust to anti-hypertension medication use and that the associations are likely different by ethnicity.
PMCID: PMC4265023  PMID: 24919752
Adipokines; Renin; Aldosterone; Ethnicity
6.  Metabolic Syndrome, C-Reactive Protein, and Mortality in U.S. Blacks and Whites: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Diabetes Care  2014;37(8):2284-2290.
We evaluate associations of metabolic syndrome (MetS), C-reactive protein (CRP), and a CRP-incorporated definition of MetS (CRPMetS) with risk of all-cause mortality in a biracial population.
We studied 23,998 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, an observational study of black and white adults ≥45 years old across the U.S. Elevated CRP was defined as ≥3 mg/L and MetS by the revised Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III; ATP III) criteria (three of five components). CRPMetS was defined as presence of three out of six components, with elevated CRP added to ATP III criteria as a sixth component. Cox models were used to calculate hazard ratios (HRs) for all-cause mortality, and population attributable risk (PAR) was calculated. Stratified analyses based on race and diabetes status were performed.
There were 9,741 participants (41%) with MetS and 12,179 (51%) with CRPMetS at baseline. Over 4.8 years of follow-up, 2,050 participants died. After adjustment for multiple confounders, MetS, elevated CRP, and CRPMetS were each significantly associated with increased mortality risk (HRs 1.26 [95% CI 1.15–1.38], 1.55 [1.41–1.70], and 1.34 [1.22–1.48], respectively). The PAR was 9.5% for MetS, 18.1% for CRP, and 14.7% for CRPMetS. Associations of elevated CRP and of CRPMetS with mortality were significantly greater in whites than blacks, while no differences in associations were observed based on diabetes status.
By definition, CRPMetS identifies more people at risk than MetS but still maintains a similar mortality risk. Incorporating CRP into the definition for MetS may be useful in identifying additional high-risk populations to target for prevention.
PMCID: PMC4113170  PMID: 24879838
7.  Incident Physical Disability in People with Lower Extremity Peripheral Arterial Disease: The Role of Cardiovascular Disease 
To evaluate the risk of incident physical disability and the decline in gait speed over a six year follow-up associated with a low ankle-arm index (AAI) in older adults.
Observational cohort study.
Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; or Allegheny County, Pennsylvania.
4705 older adults, 58% women and 17.6% black, participating in the Cardiovascular Health Study were included.
The AAI was measured in 1992–93 (baseline). Self-reported mobility disability, activities of daily living (ADL) and instrumental activities of daily living (IADL) disability and gait speed were recorded at baseline and at 1 year intervals over 6 years of follow-up. Mobility disability was defined as any difficulty walking ½ mile and ADL/IADL disability was defined as any difficulty with 11 specific ADL/IADL tasks. Individuals with mobility and/or ADL/IADL disability at baseline were excluded from the respective incident disability analyses.
Lower baseline AAI values were associated with increased risk of mobility disability and ADL/IADL disability. These associations were partially explained by clinical cardiovascular disease (CVD), diabetes and interim CVD events for mobility disability and by clinical CVD and diabetes for ADL/IADL disability. Individuals with AAI < 0.90 had on average a mean decrease in gait speed of 0.02 m/s/year or a decline of 0.12 m/s over the 6 year follow-up. This decrease was partly explained by prevalent CVD but not further attenuated by interim CVD events.
Low AAI serves as marker of future disability risk. Reduction of disability risk in patients with a low AAI should consider cardiovascular comorbidity and the prevention of additional disabling CVD events.
PMCID: PMC4509641  PMID: 18384579
Peripheral arterial disease; disability; cardiovascular disease
8.  Associations between γ-glutamyltransferase (GGT) and Biomarkers of Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2014;233(2):387-393.
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.
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.
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.
Our findings support the hypothesis that total serum GGT activity represents the impact of metabolic disease on vascular injury and atherosclerosis.
PMCID: PMC4000064  PMID: 24530768
GGT; oxidative stress; oxidized LDL; sICAM; CRP; endothelial dysfunction
9.  A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease 
Sabater-Lleal, Maria | Huang, Jie | Chasman, Daniel | Naitza, Silvia | Dehghan, Abbas | Johnson, Andrew D | Teumer, Alexander | Reiner, Alex P | Folkersen, Lasse | Basu, Saonli | Rudnicka, Alicja R | Trompet, Stella | Mälarstig, Anders | Baumert, Jens | Bis, Joshua C. | Guo, Xiuqing | Hottenga, Jouke J | Shin, So-Youn | Lopez, Lorna M | Lahti, Jari | Tanaka, Toshiko | Yanek, Lisa R | Oudot-Mellakh, Tiphaine | Wilson, James F | Navarro, Pau | Huffman, Jennifer E | Zemunik, Tatijana | Redline, Susan | Mehra, Reena | Pulanic, Drazen | Rudan, Igor | Wright, Alan F | Kolcic, Ivana | Polasek, Ozren | Wild, Sarah H | Campbell, Harry | Curb, J David | Wallace, Robert | Liu, Simin | Eaton, Charles B. | Becker, Diane M. | Becker, Lewis C. | Bandinelli, Stefania | Räikkönen, Katri | Widen, Elisabeth | Palotie, Aarno | Fornage, Myriam | Green, David | Gross, Myron | Davies, Gail | Harris, Sarah E | Liewald, David C | Starr, John M | Williams, Frances M.K. | Grant, P.J. | Spector, Timothy D. | Strawbridge, Rona J | Silveira, Angela | Sennblad, Bengt | Rivadeneira, Fernando | Uitterlinden, Andre G | Franco, Oscar H | Hofman, Albert | van Dongen, Jenny | Willemsen, G | Boomsma, Dorret I | Yao, Jie | Jenny, Nancy Swords | Haritunians, Talin | McKnight, Barbara | Lumley, Thomas | Taylor, Kent D | Rotter, Jerome I | Psaty, Bruce M | Peters, Annette | Gieger, Christian | Illig, Thomas | Grotevendt, Anne | Homuth, Georg | Völzke, Henry | Kocher, Thomas | Goel, Anuj | Franzosi, Maria Grazia | Seedorf, Udo | Clarke, Robert | Steri, Maristella | Tarasov, Kirill V | Sanna, Serena | Schlessinger, David | Stott, David J | Sattar, Naveed | Buckley, Brendan M | Rumley, Ann | Lowe, Gordon D | McArdle, Wendy L | Chen, Ming-Huei | Tofler, Geoffrey H | Song, Jaejoon | Boerwinkle, Eric | Folsom, Aaron R. | Rose, Lynda M. | Franco-Cereceda, Anders | Teichert, Martina | Ikram, M Arfan | Mosley, Thomas H | Bevan, Steve | Dichgans, Martin | Rothwell, Peter M. | Sudlow, Cathie L M | Hopewell, Jemma C. | Chambers, John C. | Saleheen, Danish | Kooner, Jaspal S. | Danesh, John | Nelson, Christopher P | Erdmann, Jeanette | Reilly, Muredach P. | Kathiresan, Sekar | Schunkert, Heribert | Morange, Pierre-Emmanuel | Ferrucci, Luigi | Eriksson, Johan G | Jacobs, David | Deary, Ian J | Soranzo, Nicole | Witteman, Jacqueline CM | de Geus, Eco JC | Tracy, Russell P. | Hayward, Caroline | Koenig, Wolfgang | Cucca, Francesco | Jukema, J Wouter | Eriksson, Per | Seshadri, Sudha | Markus, Hugh S. | Watkins, Hugh | Samani, Nilesh J | Wallaschofski, Henri | Smith, Nicholas L. | Tregouet, David | Ridker, Paul M. | Tang, Weihong | Strachan, David P. | Hamsten, Anders | O’Donnell, Christopher J.
Circulation  2013;128(12):10.1161/CIRCULATIONAHA.113.002251.
Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease (CVD), range from 34 to 50%. Genetic variants so far identified by genome-wide association (GWA) studies only explain a small proportion (< 2%) of its variation.
Methods and Results
We conducted a meta-analysis of 28 GWA studies, including more than 90,000 subjects of European ancestry, the first GWA meta-analysis of fibrinogen levels in 7 African Americans studies totaling 8,289 samples, and a GWA study in Hispanic-Americans totaling 1,366 samples. Evaluation for association of SNPs with clinical outcomes included a total of 40,695 cases and 85,582 controls for coronary artery disease (CAD), 4,752 cases and 24,030 controls for stroke, and 3,208 cases and 46,167 controls for venous thromboembolism (VTE). Overall, we identified 24 genome-wide significant (P<5×10−8) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the three structural fibrinogen genes and pathways related to inflammation, adipocytokines and thyrotrophin-releasing hormone signaling. Whereas lead SNPs in a few loci were significantly associated with CAD, the combined effect of all 24 fibrinogen-associated lead SNPs was not significant for CAD, stroke or VTE.
We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and CAD, stroke or VTE.
PMCID: PMC3842025  PMID: 23969696
Fibrinogen; cardiovascular disease; genome-wide association study
10.  Intakes of long-chain n-3 polyunsaturated fatty acids and fish in relation to measurements of subclinical atherosclerosis 
Data on the relations of different types of fish meals and long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) with measures of atherosclerosis are sparse.
We examined intakes of long-chain n-3 PUFAs and fish in relation to clinical measures of subclinical atherosclerosis.
A cross-sectional study was conducted in 5,488 multiethnic adults aged 45–84 years and free of clinical cardiovascular disease. Diet was assessed using self-administered food frequency questionnaires. Subclinical atherosclerosis was determined by common carotid intima-media thickness (cCIMT, >80th percentile), internal CIMT (iCIMT, >80th percentile), coronary artery calcium score (CAC, >0) or ankle-brachial index (ABI, <0.90), respectively.
After adjustment for potential confounders, intakes of long-chain n-3 PUFAs and non-fried (broiled, steamed, baked or raw) fish were inversely related to subclinical atherosclerosis determined by cCIMT but not iCIMT, CAC or ABI. The multivariable odds ratio comparing the highest to the lowest quartile of dietary exposures in relation to subclinical atherosclerosis determined by cCIMT was 0.69 (95% CI: 0.55, 0.86; p for trend<0.01) for n-3 PUFA intake, 0.80 (95% CI: 0.64, 1.01; p=0.054) for non-fried fish and 0.90 (95% CI: 0.73, 1.10; p=0.33) for fried fish consumption.
This study indicates that dietary intake of long-chain n-3 PUFAs or non-fried fish is associated with lower prevalence of subclinical atherosclerosis classified by cCIMT although significant changes in iCIMT, CAC and ABI were not observed. Our findings also suggest that the association of fish and atherosclerosis may vary depending on the type of fish meal consumed and the measures of atherosclerosis.
PMCID: PMC4151325  PMID: 18842801
long-chain n-3 polyunsaturated fatty acids; fish; fish oil; biomarker; subclinical atherosclerosis; multi-ethnicities
11.  Current employment status, occupational category, occupational hazard exposure, and job stress in relation to telomere length: The Multiethnic Study of Atherosclerosis (MESA) 
Telomere length has been proposed as a biomarker of cell senescence, which is associated with a wide array of adverse health outcomes. While work is a major determinant of health, few studies have investigated the association of telomere length with various dimensions of occupation. Accelerated cellular aging could be a common pathway linking occupational exposure to several health outcomes.
Leukocyte telomere length was assessed using quantitative polymerase chain reaction (Q-PCR) in a community-based sample of 981 individuals (age: 45–84 years old). Questionnaires were used to collect information on current employment status, current or main occupation before retirement, and job strain. The O*NET (Occupational Resource Network) database was linked to the questionnaire data to create 5 exposure measures: physical activity on the job, physical hazard exposure, interpersonal stressors, job control, and job demands. Linear regression was used to estimate associations of occupational characteristics with telomere lengths after adjustment for age, sex, race, socioeconomic position, and several behavioral risk factors.
There were no mean differences in telomere lengths across current employment status, occupational category, job strain categories or levels of most O*NET exposure measures. There was also no evidence that being in lower status occupational categories or being exposed to higher levels of adverse physical or psychosocial exposures accelerated the association between age and telomere shortening.
Cellular aging as reflected by shorter telomeres does not appear to be an important pathway linking occupation to various health outcomes.
PMCID: PMC4068015  PMID: 23686115
12.  n-3 and n-6 Fatty acids are independently associated with lipoprotein-associated phospholipase A2 in the Multi-Ethnic Study of Atherosclerosis 
The British journal of nutrition  2013;110(9):1664-1671.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an independent risk factor for CVD and has been proposed as a marker of vascular inflammation. Polyunsaturated n-3 fatty acids (FA) and several n-6 FA are known to suppress inflammation and may influence Lp-PLA2 mass and activity. The associations of n-3 and n-6 plasma FA with Lp-PLA2 mass and activity were analysed using linear regression analysis in 2246 participants of the Multi-Ethnic Study of Atherosclerosis; statistical adjustments were made to control for body mass, inflammation, lipids, diabetes, and additional clinical and demographic factors. Lp-PLA2 mass and activity were significantly lower in participants with the higher n-3 FA EPA (β = −4·72, P<0·001; β = −1·53; P=0·023) and DHA levels (β = −4·47, β = −1·87; both P<0·001). Those in the highest quintiles of plasma EPA and DHA showed 12·71 and 19·15 ng/ml lower Lp-PLA2 mass and 5·7 and 8·90 nmol/min per ml lower Lp-PLA2 activity than those in the first quintiles, respectively. In addition, lower Lp-PLA2 mass and activity were associated with higher levels of n-6 arachidonic acid (β = −1·63, β = −1·30; both P<0·001), while γ-linolenic acid was negatively associated with activity (β = −27·7, P=0·027). Lp-PLA2 mass was significantly higher in participants with greater plasma levels of n-6 linoleic (β = 0·828, P=0·011) and dihomo-γ-linolenic acids (β = 4·17, P=0·002). Based on their independent associations with Lp-PLA2 mass and activity, certain n-3 and n-6 FA may have additional influences on CVD risk. Intervention studies are warranted to assess whether these macronutrients may directly influence Lp-PLA2 expression or activity.
PMCID: PMC4060439  PMID: 23551952
Fatty acids; n-3; Atherosclerosis; Lipoprotein-associated phospholipase; Lipoprotein-associated phospholipase A2
13.  13-Year Long-Term Associations between Changes in Traditional Cardiovascular Risk Factors and Changes in Fibrinogen Levels: The Coronary Artery Risk Development in Young Adults (CARDIA) Study 
Atherosclerosis  2012;226(1):214-219.
Cross-sectional and prospective studies have linked cardiovascular events and traditional risk factors (TRFs) with higher plasma fibrinogen levels. In a young cohort, we sought to determine longitudinal associations between changes in/development of TRFs and fibrinogen levels over 13 years.
We included 2525 adults from the CARDIA study, aged 25-37 with fibrinogen and TRFs measured at year 7 (study baseline; 1992-1993); and year 20 (follow-up). Multiple linear regressions were used to compare mean changes in fibrinogen to TRFs.
Mean fibrinogen increased by 71mg/dL vs. 70mg/dL (p=NS) in black vs. white men, and 78mg/dL vs. 68mg/dL (p<0.05) in black vs. white women, respectively over 13 years. After multivariable adjustments, fibrinogen generally rose with increasing BMI (p<0.001; all sex/race groups), LDL-cholesterol, log triglycerides and diastolic blood pressure; and fell with increasing HDL-cholesterol and physical activity. 13-year increase in fibrinogen for persons who quit smoking or became non-obese were comparable (p=NS) to that of never-smokers and never-obese persons.
Among young black and white men and women with few baseline cardiovascular risk factors, fibrinogen tracked longitudinally with changes in TRFs over 13 years through middle-age. There was a strong inverse longitudinal relationship between modifiable risk factors (weight loss/smoking cessation) and 13-year change in fibrinogen. Our study helps provide some insight into the role of fibrinogen as a disease marker in the associations between fibrinogen and CVD.
PMCID: PMC3529787  PMID: 23177973
Fibrinogen; risk factors; cardiovascular disease prevention; obesity; smoking; sex; race
14.  Decreased Naive and Increased Memory CD4+ T Cells Are Associated with Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2013;8(8):e71498.
Adaptive immunity has been implicated in atherosclerosis in animal models and small clinical studies. Whether chronic immune activation is associated with atherosclerosis in otherwise healthy individuals remains underexplored. We hypothesized that activation of adaptive immune responses, as reflected by higher proportions of circulating CD4+ memory cells and lower proportions of naive cells, would be associated with subclinical atherosclerosis.
Methods and Findings
We examined cross-sectional relationships of circulating CD4+ naive and memory T cells with biomarkers of inflammation, serologies, and subclinical atherosclerosis in 912 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Circulating CD4+ naive cells were higher in women than men and decreased with age (all p-values <0.0001). European-Americans had higher levels of naive cells and lower levels of memory cells compared with African-Americans and Hispanic-Americans (all p-values ≤0.0005). Lower naive/higher memory cells were associated with interleukin-6 levels. In multivariate models, cytomegalovirus (CMV) and H. Pylori titers were strongly associated with higher memory and lower naive cells (all p-values <0.05). Higher memory cells were associated with coronary artery calcification (CAC) level in the overall population [β-Coefficient (95% confidence interval (CI))  = 0.20 (0.03, 0.37)]. Memory and naive (inversely) cells were associated with common carotid artery intimal media thickness (CC IMT) in European-Americans [memory: β =  0.02 (0.006, 0.04); naive: β = −0.02 (−0.004, −0.03)].
These results demonstrate that the degree of chronic adaptive immune activation is associated with both CAC and CC IMT in otherwise healthy individuals, consistent with the known role of CD4+ T cells, and with innate immunity (inflammation), in atherosclerosis. These data are also consistent with the hypothesis that immunosenescence accelerates chronic diseases by putting a greater burden on the innate immune system, and suggest the importance of prospective studies and research into strategies to modulate adaptive immune activation in chronic disease states such as atherosclerosis.
PMCID: PMC3751895  PMID: 24009662
15.  Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;200(2):359-367.
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
PMCID: PMC3612981  PMID: 18243217
16.  Association of Endothelial and Oxidative Stress with Metabolic Syndrome and Subclinical Atherosclerosis: Multi-Ethnic Study of Atherosclerosis 
A cluster of metabolic abnormalities termed metabolic syndrome (MetS) is associated with vascular endothelial dysfunction and oxidative internal milieu. We examined whether the association of MetS with subclinical atherosclerosis is explained by biomarkers of endothelial damage and oxidative stress.
MESA is a population based study of 45-84 year old individuals of four US ethnicities without clinical cardiovascular disease. A random sample of 997 MESA participants had data on the following biomarkers: von Willebrand Factor, soluble intercellular adhesion molecule-1 (sICAM1), CD40 ligand, soluble thrombomodulin, E-selectin, and oxidized LDL (oxLDL). We examined whether the associations of MetS with B-mode ultrasound-defined common and internal carotid intimal medial thickness (IMT) and coronary artery calcium (CAC) measured using computerized tomography were explained by the biomarkers using multiple regression methods.
MetS was associated with higher levels of each of the biomarkers (p<0.001, CD40L suggestive association p=0.004), with greater IMT (p<0.001), and with greater extent of CAC in those in whom CAC was detectable (p=0.01). The association of MetS with measures of subclinical atherosclerosis remained unchanged after adjustment for the biomarkers. After adjusting for MetS, oxLDL was suggestively associated with greater prevalence of detectable CAC (p=0.005) and thicker internal carotid IMT (p=0.002), while sICAM-1was significantly associated with greater prevalence of detectable CAC (p=0.001).
The association of MetS with subclinical atherosclerosis was independent of its association with biomarkers of endothelial damage and oxidative stress, suggesting that metabolic abnormalities and oxidative endothelial damage may lead to atherosclerotic disease through distinct mechanisms.
PMCID: PMC3130805  PMID: 21505504
Metabolic syndrome; biomarkers; coronary artery atherosclerosis; carotid arteries
17.  Association between Baseline Kidney Function and Change in CRP: An Analysis of the Cardiovascular Health Study 
Nephron. Clinical Practice  2010;115(2):c114-c121.
In cross-sectional analyses, C-reactive protein (CRP) levels are inversely related to levels of kidney function. The relationship between kidney function and subsequent changes in CRP is unknown.
We studied 4,364 individuals from the Cardiovascular Health Study, a longitudinal cohort of community-dwelling older adults. Baseline eGFRcys was estimated using cystatin C. CRP was measured at baseline and after 3 and 7 years of follow-up; slopes of change in CRP were calculated.
The mean (SD) age of the cohort was 72 (5.2) years; mean (SD) eGFRcys was 78.9 (18.4) ml/min/1.73 m2. The median (interquartile range IQR) baseline CRP was 2.39 (1.22, 4.33) mg/l; the median (IQR) yearly change in CRP was −0.0051 (−0.020 to 0.27) mg/l/year. After adjustment for demographic characteristics and the initial level of CRP, each standard deviation lower baseline eGFR was associated with a small and non-significant yearly increase in CRP (0.032 mg/l/year; 95% CI: −0.005 to 0.070, p = 0.094).
We did not find a relationship between eGFR and subsequent changes in CRP. The association between kidney function and CRP in cross-sectional analyses may reflect unmeasured confounding by atherosclerosis; alternatively, the burden of comorbidity and interval mortality in this population may have masked a stronger longitudinal association between kidney function and change in CRP. Further study in younger populations may clarify whether impaired kidney function leads to change in inflammation over time.
PMCID: PMC2892648  PMID: 20413990
Inflammation; Cystatin C; Kidney function; Epidemiology
18.  Comparative Validity of 3 Diabetes Mellitus Risk Prediction Scoring Models in a Multiethnic US Cohort 
American Journal of Epidemiology  2010;171(9):980-988.
Several models for estimating risk of incident diabetes in US adults are available. The authors aimed to determine the discriminative ability and calibration of published diabetes risk prediction models in a contemporary multiethnic cohort. Participants in the Multi-Ethnic Study of Atherosclerosis without diabetes at baseline (2000–2002; n = 5,329) were followed for a median of 4.75 years. The predicted risk of diabetes was calculated using published models from the Framingham Offspring Study, the Atherosclerosis Risk in Communities (ARIC) Study, and the San Antonio Heart Study. The mean age of participants was 61.6 years (standard deviation, 10.2); 29.3% were obese, 53.1% had hypertension, 34.9% had a family history of diabetes, 27.5% had high triglyceride levels, 33.8% had low high density lipoprotein cholesterol levels, and 15.3% had impaired fasting glucose. There were 446 incident cases of diabetes (fasting glucose level ≥126 mg/dL or initiation of antidiabetes medication use) diagnosed during follow-up. C statistics were 0.78, 0.84, and 0.83 for the Framingham, ARIC, and San Antonio risk prediction models, respectively. There were significant differences between observed and predicted diabetes risks (Hosmer-Lemeshow goodness-of-fit chi-squared test for each model: P < 0.001). The recalibrated and best-fit models achieved sufficient goodness of fit (each P > 0.10). The Framingham, ARIC, and San Antonio models maintained high discriminative ability but required recalibration in a modern, multiethnic US cohort.
PMCID: PMC2877477  PMID: 20375194
cohort studies; diabetes mellitus; models, statistical; risk; validation studies as topic
19.  The Association of Statin Use and Statin Type on Cognitive Performance: Analysis of The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Clinical cardiology  2010;33(5):280-288.
Statin use and type has been variably associated with impaired or improved cognitive performance.
To assess the association of statin use and type (lipophilic vs hydrophilic) and cognitive impairment
Cross-sectional analysis of 24595 (7191 statin users and 17404 non-users) participants (age >45), from a population-based national cohort study (REasons for Geographic And Racial Differences in Stroke) enrolled from January 2003-October 2008 with over-sampling from the southeastern Stroke Belt, and African Americans.
Main Outcomes
Statin use and type were documented in participants’ homes by a trained health professional. Cognitive performance was assessed with a prior validated instrument of global cognitive status (Six-Item Screener). Cognitive impairment was defined as a score of < 4. .
Overall, an association of cognitive impairment and statin use was observed (8.6% of users vs 7.7% or non-users had cognitive impairment p=.014) but, after adjusting for variables known to be associated with cognition (age, gender, race, income, levels of education, and cardiovascular disease) the association was attenuated (OR 0.98, CI; 0.87;1.10). No association was observed between statin type (lipophilic vs hydrophilic) and cognition (OR 1.03, CI; 0.86;1.24), and there were no regional differences in cognitive impairment in statin users (8% in the stroke belt and 7.9% other regions p=0.63).
Statin use and type was marginally associated with cognitive impairment. After adjusting for known variables that affect cognition, no association was observed. No regional differences were observed. This large study found no evidence to support an association between statins and cognitive performance.
PMCID: PMC2925406  PMID: 20513066
Statins; Cognition
20.  Differential White Blood Cell Count and Type 2 Diabetes: Systematic Review and Meta-Analysis of Cross-Sectional and Prospective Studies 
PLoS ONE  2010;5(10):e13405.
Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.
Research Design and Methods
Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.
The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10−18). Substantial heterogeneity was present (I2 = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10−4), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10−13), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10−5). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.
A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.
PMCID: PMC2956635  PMID: 20976133
21.  Lipoprotein-Associated Phospholipase A2 and Risk of Congestive Heart Failure in Older Adults: the Cardiovascular Health Study 
Circulation. Heart failure  2009;2(5):429-436.
Inflammation may be an etiologic factor in congestive heart failure (CHF). Lipoprotein associated phospholipase A2 (Lp-PLA2) is an inflammation marker associated with vascular risk. One previous study showed an association of Lp-PLA2 activity with CHF risk, but there were only 94 CHF cases and Lp-PLA2 antigen, which is available clinically in the US, was not measured.
Methods and Results
We measured baseline Lp-PLA2 antigen and activity in 3991 men and women without baseline CHF or cardiovascular disease, participating in the Cardiovascular Health Study, a prospective observational study of adults ≥65 years old. Cox proportional hazards models adjusted for age, sex, clinic site, race, LDL and HDL cholesterol, body-mass index, systolic and diastolic blood pressure, hypertension, smoking status, pack-years and diabetes were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHF. Further models adjusted for coronary disease events during follow up and C-reactive protein (CRP). 829 participants developed CHF over 12.1 years. Adjusted HRs for CHF with Lp-PLA2 in the fourth compared to first quartile, were 1.44 (CI 1.16–1.79) for Lp-PLA2 antigen and 1.06 (CI 0.84–1.32) for activity. Adjustment for incident coronary disease attenuated the HR for Lp-PLA2 antigen to 1.26 (CI 1.02–1.57), adjustment for CRP had minimal impact.
Lp-PLA2 antigen was associated with risk of future CHF in older people, independent of CHF and coronary risk factors, and partly mediated by coronary disease events. Further clinical and basic research is needed to better understand the role of Lp-PLA2 in CHF.
PMCID: PMC2756764  PMID: 19808373
22.  Associations of Dietary Long-Chain n-3 Polyunsaturated Fatty Acids and Fish with Biomarkers of Inflammation and Endothelial Activation (From the Multi-Ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2009;103(9):1238-1243.
Cardioprotective effects of long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) and fish consumption have been observed. However, data on the specific associations of these dietary factors with inflammation and endothelial activation are sparse. We conducted a cross-sectional study of 5,677 men and women from the MESA cohort including African Americans, Caucasians, Chinese and Hispanics, aged 45-84 years, and free of clinical cardiovascular disease. Dietary information was collected by self-administered food frequency questionnaire. Multivariable linear regression analyses were used to examine relations between intake of LC n-3 PUFAs, non-fried fish and fried fish and biomarkers of inflammation and endothelial activation. LC n-3 PUFA intakes were inversely associated with plasma concentrations of interleukin-6 (IL-6, P=0.01) and matrix metalloproteinase-3 (MMP-3, P=0.03) independent of age, body mass index, physical activity, smoking, alcohol consumption and dietary variables. Non-fried fish consumption was found inversely related to C-reactive protein (CRP, P=0.045) and IL-6 (P<0.01); and fried fish was observed being inversely related to soluble intercellular adhesion molecules-1 (sICAM-1) (P<0.01) but not associated with other biomarkers after adjustment for potential confounders. In conclusion, this study suggests that dietary intakes of LC n-3 PUFAs and fish are inversely associated with concentrations of some biomarkers reflecting lower levels of inflammation and endothelial activation. These results may partially explain the cardioprotective effects of fish consumption.
PMCID: PMC2697819  PMID: 19406265
long-chain n-3 polyunsaturated fatty acids; fish oil; biomarker; inflammation; endothelial function
23.  ICAM1 and VCAM1 polymorphisms, coronary artery calcium, and circulating levels of soluble ICAM-1: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2008;201(2):339-344.
Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) may be important contributors to the development and progression of atherosclerosis. Using a stratified random sample of 2,880 participants of the Multi-Ethnic Study of Atherosclerosis we investigated the relationship of 12 ICAM1 and 17 VCAM1 SNPs and coronary artery calcium (CAC) and ICAM1 SNPs and circulating levels of soluble ICAM-1 (sICAM-1). There were no ICAM1 or VCAM1 SNPs significantly associated with CAC in any of the four race/ethnic groups. In a subset of 1,451 subjects with sICAM-1 measurements, we observed a significant association with rs5491 in all four race/ethnic groups corroborating previous research that has shown that the T-allele of rs5491 interferes with the monoclonal antibody used to measure sICAM-1 in this study. After excluding all rs5491 T-allele carriers, several ICAM1 SNPs were significantly associated with sICAM-1 levels; rs5496 in African Americans, rs5498 and rs3093030 in European Americans, and rs1799969 in Hispanics. Our results identified ICAM1 polymorphisms that were significantly associated with sICAM-1 level but not CAC, a subclinical marker of atherosclerosis.
PMCID: PMC2615541  PMID: 18420209
coronary artery calcium; intercellular adhesion molecule-1 (ICAM-1); vascular adhesion molecule-1 (VCAM-1); soluble intercellular adhesion molecule-1 (sICAM-1); gene; single nucleotide polymorphism (SNP); haplotypes
24.  Metabolic Syndrome, Inflammation, and the Incident Heart Failure in the Elderly: the Cardiovascular Health Study 
Circulation. Heart failure  2008;1(4):242-248.
Inflammation markers and MetS are associated with risk of CHF. We evaluated whether combining inflammation markers and metabolic syndrome (MetS) provided additive information for incident congestive heart failure (CHF), and if incorporating inflammation markers to the MetS definition added prognostic information.
Methods and Results
We studied 4017 men and women ≥ 65 years old, without baseline CHF or diabetes, participating in the Cardiovascular Health Study, an observational study with 12.2 years follow-up and 966 cases of incident CHF. Baseline “C-reactive protein (CRP)-MetS” or “interleukin-6 (IL-6)-MetS” were defined as presence of 3 out of 6 components, with elevated CRP (≥3 mg/L) or IL-6 (≥2.21 pg/mL) as a 6th component added to ATPIII criteria. Cox models adjusted for CHF risk factors and incident coronary disease, were used to calculate HRs for CHF. MetS and elevated inflammation markers were independently associated with CHF risk (HRs, 95 % CI: 1.32, 1.16–1.51 for MetS; 1.53, 1.34–1.75 for CRP; 1.37, 1.19–1.55 for IL-6). There was a 20% relative excess risk attributed to the combination of MetS and CRP (95% CI −44% to 88%). CRP-MetS and IL-6-MetS definitions reclassified 18% and 13%, respectively of participants as MetS. Both CRP-MetS and IL-6-MetS increased risk of CHF by 60% compared to those without MetS.
MetS and inflammation markers provided additive information on CHF risk in this elderly cohort. Inflammation-incorporated MetS definitions identified more participants with the same risk level as ATPIII MetS. Considering inflammation markers and MetS together may be useful in clinical and research settings.
PMCID: PMC2762642  PMID: 19808298
heart failure; metabolism; inflammation
25.  Race/ethnicity and telomere length in the Multi-Ethnic Study of Atherosclerosis 
Aging cell  2009;8(3):251-257.
Telomere length has emerged as a marker of exposure to oxidative stress and aging. Race/ethnic differences in telomere length have been infrequently investigated. Leucocyte telomere length (LTL) was assessed 981 white, black and Hispanic men and women aged 45-84 years participating in the Multi-Ethnic Study of Atherosclerosis. Direct measurement and questionnaire were used to assess covariates. Linear regression was used to estimate associations of LTL with race/ethnicity and age after adjustment for sex, income, education, smoking, physical activity, diet, and body mass index. On average blacks and Hispanics had shorter telomeres than whites (adjusted mean differences (standard error) in T/S ratio compared to whites: -0.041 (0.018) for blacks and -0.044 (0.018) for Hispanics). Blacks and Hispanics showed greater differences in telomere length associated with age than whites (adjusted mean differences in T/S ratio per one year increase in age -0.0018, -0.0047, and -0.0055 in whites, blacks, and Hispanics respectively). Differences in age associations were more pronounced and only statistically significant in women. Race/ethnic differences in LTL may reflect the cumulative burden of differential exposure to oxidative stress (and its predictors) over the lifecourse.
PMCID: PMC2713110  PMID: 19302371
Telomeres; race/ethnicity; aging

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