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1.  Association of blood lactate with carotid atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
Atherosclerosis  2013;228(1):249-255.
Objectives
Cardiovascular risk factors such as aging, smoking, and insulin resistance may lead to atherosclerosis through various mechanisms of which their association with mitochondrial dysfunction may be one of them. In order to examine this hypothesis, we assessed the association between elevated blood lactate, a marker of mitochondrial dysfunction, and carotid atherosclerosis.
Methods
From a total of 2066 participants from the Atherosclerosis Risk In Communities Carotid MRI study, 1496 were included for this analysis. Wall Thickness and Lipid core presence were measured using gadolinium-enhanced MRI. Blood lactate was categorized into quartiles (Q1: < 5.9 mg/dl, Q2: 5.9 to 7.2mg/dl, Q3: 7.3 to 9.2 mg/dl, and Q4: >9.2 mg/dl).
Results
Of the 1496 study participants, 763 (51%) were females, 296 (19.8%) African American, 539 (36%) obese and 308 (20.6%) had diabetes. There was a strong and graded association between lactate and wall thickness [Q1: 1.08 mm (95% CI: 1.01 mm – 1.15 mm), Q2: 1.33 mm (95% CI: 1.19 mm – 1.47 mm), Q3: 1.44 (95% CI: 1.34 mm – 1.54 mm) and Q4: 1.62 (95% CI: 1.53 mm – 1.71 mm); p for trend <0.001] after adjusting for age, gender, ethnicity, stature, body mass index (BMI), waist circumference, LDL, High sensitivity C reactive protein (HsCRP), statin use, thiazolodinedione use, hypertension, and diabetes. This association was attenuated, but still significant, after adjusting for a marker of insulin resistance, the triglyceride/HDL ratio, [Q1: 0.96 mm (95% CI: 0.82 mm – 1.10 mm), Q2: 1.17 mm (95% CI: 1.08 mm – 1.26 mm), Q3: 1.18 mm (95% CI: 1.07 mm – 1.29 mm), Q4: 1.22 mm (95% CI: 1.13 mm – 1.31 mm), p for linear trend 0.039]. There was no association of lactate with lipid core presence after adjustment for wall thickness.
Conclusions
Blood lactate is associated with carotid atherosclerosis. Attenuation of the association with adjustment for triglyceride/HDL ratio, a marker of insulin resistance, suggests that lactate’s association with carotid atherosclerosis may be related to insulin resistance.
doi:10.1016/j.atherosclerosis.2013.02.014
PMCID: PMC3657708  PMID: 23510829
atherosclerosis; carotid arteries; plaque; epidemiology; lactate
2.  Hyperglycemia and Arterial Stiffness: the Atherosclerosis Risk in the Communities Study 
Atherosclerosis  2012;225(1):246-251.
Objectives
Hyperglycemia has been associated with an increased risk of cardiovascular morbidity and mortality. Although numerous studies have demonstrated that hyperglycemia is associated with the atherosis component of atherosclerosis, limited studies have addressed the independent role of hyperglycemia in the pathophysiology of sclerotic vascular disease. We hypothesized that hyperglycemia, as assessed by hemoglobin A1c (HbA1c), would be independently associated two common indices of arterial stiffness (pressure-strain elastic modulus (Ep) and Young’s elastic modulus (YEM)).
Methods
We examined the cross-sectional association between HbA1c and arterial stiffness using B-mode ultrasound examination of the carotid artery in 9,050 participants from the community-based Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable linear and logistic regression models to characterize the association between HbA1c and increased Ep and YEM.
Results
Higher values of HbA1c were associated in a graded fashion with increased arterial stiffness (P-trend <0.001 for both EP and YEM). After adjusting for traditional risk factors, increasing HbA1c deciles were significantly associated with elevated EP (OR for the highest decile of HbA1c compared to the lowest, 2.01, 95% CI 1.30, 3.11) and YEM (OR = 1.71, 95% CI 1.15, 2.55).
Conclusion
Elevated HbA1c is associated with measures of increased arterial stiffness, even after accounting for arterial wall thickness. This is consistent with the hypothesis that hyperglycemia contributes to arterial stiffness beyond its effects on atherosis and suggests that hyperglycemia is associated with altered material within the arterial wall.
doi:10.1016/j.atherosclerosis.2012.09.003
PMCID: PMC3936879  PMID: 23031361
atherosclerosis; distensibility; hyperglycemia; epidemiology
3.  Cognition and Incident Dementia Hospitalization: Results from the Atherosclerosis Risk in Communities (ARIC) Study 
Neuroepidemiology  2012;40(2):117-124.
Background/Aims
Cognitive decline is a defining feature of dementia. We sought to determine if a single baseline cognitive test score or change in test score over time is more strongly associated with risk of dementia hospitalization. We also sought to compare short- and long-term dementia risk.
Methods
Prospective cohort study of 9,399 individuals from the Atherosclerosis Risk in Communities (ARIC) Study (median 10 years follow-up). Cognition was assessed at two time points (6 years apart) using three tests: Delayed Word Recall (DWRT), Digit Symbol Substitution (DSST), and Word Fluency (WFT). Dementia hospitalizations were determined using ICD-9 codes.
Results
Baseline cognitive test scores were associated with both short-term and long-term risk of dementia. The association of 6-year change in cognitive test score with dementia risk was stronger than that of individual test scores at a single visit (change from highest to lowest tertile, DWRT: HR=6.45 (1.80, 23.08), DSST: HR=10.94 (3.07, 38.97)).
Conclusions
In this community-based population, 6-year changes in cognitive scores were more strongly associated with risk of incident dementia hospitalization than baseline scores, although single DWRT and DSST scores at were predictive. Our findings support the contention that cognitive changes may precede clinical dementia by a decade or more.
doi:10.1159/000342308
PMCID: PMC3642775  PMID: 23095770
Cognition; Dementia; Hospitalizations; Cognitive Function; Cognitive Decline
4.  Impact of long-term measures of glucose and blood pressure on the retinal microvasculature 
Atherosclerosis  2012;225(2):412-417.
Objective
Retinopathy and retinal microvascular abnormalities are common in adult populations, yet few long-term predictors have been identified. We therefore examined the association between systolic blood pressure (SBP) and fasting plasma glucose, assessed over 18 years, with retinopathy and retinal vascular caliber in 2,066 Carotid MRI participants, an Atherosclerosis Risk in Communities ancillary study.
Methods
Retinopathy and retinal vascular caliber were assessed by retinal photography. Confounder-adjusted weighted regression models were used to examine exposures defined as cumulative, long-term prospective, concurrent, and 18-year change.
Results
Long-term prospective (prevalence odds ratio (POR) per 10 mmHg: 1.14 (95% CI: 1.01, 1.30)) and cumulative (POR per 10 mmHg: 1.30 (95% CI: 1.09, 1.56) effects spanning approximately 18 years were found for SBP and retinopathy. The strongest long-term prospective association for plasma glucose and retinopathy was identified at the baseline visit (POR per 10 mg/dl: 1.26 (95% CI: 1.16, 1.38)); sustained glucose elevations over 18 years were also associated with prevalent retinopathy (POR per 10 mg/dl: 1.33 (95% CI: 1.24, 1.43)). Results were robust to the exclusion of participants with diabetes.
Conclusions
Modest and sustained long-term elevations in glucose and blood pressure are associated with retinopathy and retinal vascular caliber.
doi:10.1016/j.atherosclerosis.2012.10.034
PMCID: PMC3513355  PMID: 23102597
epidemiology; microvascular disease; retinopathy; glucose; blood pressure
5.  Retinal Microvascular Signs and Risk of Stroke: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background and Purpose
Small vessel disease contributes to the pathophysiology of stroke, and retinal microvascular signs have been linked to risk of stroke. We examined the relationship of retinal signs with incident stroke in a multi-ethnic cohort.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study that enrolled participants without clinical cardiovascular diseases from six United States communities between 2000–02. Of the participants, 4,849 (71.2%) had fundus photography performed in 2002–04. Retinopathy and retinal vessel caliber were assessed from retinal images. Stroke risk factors including high-sensitivity C-reactive protein (hsCRP), carotid artery intima-media thickness (IMT) and coronary artery calcium (CAC) were measured using standardized protocols. Incident stroke was confirmed from medical record review and death certificates.
Results
After 6 years of follow-up, there were 62 incident strokes. Narrower retinal arteriolar caliber was associated with increased risk of stroke after adjusting for conventional cardiovascular risk factors (adjusted incidence rate ratio [IRR] 2.83, 95% confidence interval [CI] 1.34–5.95, p=0.006; adjusted hazard ratio [HR] 3.01, 95% CI 1.29–6.99, p=0.011). Retinopathy in persons without diabetes was associated with increased risk of stroke (adjusted IRR 2.96, 95% CI 1.50–5.84, p=0.002; adjusted HR 3.07, 95%CI 1.17–8.09, p=0.023). These associations remained significant after adjusting for hsCRP, carotid IMT or CAC.
Conclusions
Narrower retinal arteriolar caliber and retinopathy in non-diabetic persons were associated with increased risk of stroke in this relatively healthy multi-ethnic cohort independent of traditional risk factors and measures of atherosclerosis. The association between narrower retinal arteriolar caliber and stroke warrants further investigation.
doi:10.1161/STROKEAHA.112.673335
PMCID: PMC3508325  PMID: 23111439
Stroke; Retinal microvascular signs; Retinopathy; Retinal vessel caliber
6.  Education and Cognitive Change over 15 Years: The Atherosclerosis Risk in Communities Study 
OBJECTIVES
To evaluate whether education level is associated with change in cognitive performance.
DESIGN
Prospective cohort study.
SETTING
The Atherosclerosis Risk in Communities (ARIC) Study, a community-based cohort.
PARTICIPANTS
Nine thousand two hundred sixty-eight ARIC participants who underwent cognitive evaluation at least twice over a 15-year period.
MEASUREMENTS
Education was evaluated as a predictor of change in word recall, the Digit Symbol Substitution Test (DSST), and word fluency. A random-effects linear regression model, and a time by educational level interaction was used.
RESULTS
Educational level was highly associated with cognitive performance. The effect on performance of a less than high school education (vs more than high school) was equivalent to the effect of as much as 22 years of cognitive aging, but educational level was not associated with change in cognitive performance in whites or blacks, with the exception of the DSST for whites, in whom those with lower levels of education had less decline in scores.
CONCLUSION
Educational level was not associated with change in cognitive performance, although the higher baseline cognitive performance of individuals with more education might explain lower rates of dementia in more-educated individuals, because more decline would have to take place between baseline higher performance and time at which dementia was diagnosed in more-educated individuals.
doi:10.1111/j.1532-5415.2012.04164.x
PMCID: PMC3662980  PMID: 23013064
education; cognition; cognitive reserve
7.  Associations Between Lipoprotein(a) Levels and Cardiovascular Outcomes in African Americans and Caucasians: The Atherosclerosis Risk in Communities (ARIC) Study 
Circulation  2011;125(2):241-249.
Background
Based on studies with limited statistical power, lipoprotein(a) [Lp(a)] is not considered a risk factor for cardiovascular disease (CVD) in African Americans. We evaluated associations between Lp(a) and incident CVD events in African Americans and Caucasians in the Atherosclerosis Risk in Communities (ARIC) study.
Methods and Results
Plasma Lp(a) was measured in African Americans (n=3,467) and Caucasians (n=9,851). Hazards ratios (HRs) for incident CVD events (coronary heart disease [CHD] and ischemic strokes) were calculated. Lp(a) levels were higher with wider interindividual variation in African Americans (median [interquartile range]: 12.8 [7.1–21.7] mg/dl) than Caucasians (4.3 [1.7–9.5] mg/dl; p <0.0001). At 20 years of follow-up, 676 CVD events occurred in African Americans and 1,821 events occurred in Caucasians. Adjusted HRs (95% confidence interval [CI]) per race-specific 1-SD–greater log-transformed Lp(a) were 1.13 (1.04–1.23) for incident CVD, 1.11 (1.00–1.22) for incident CHD, and 1.21 (1.06–1.39) for ischemic strokes in African Americans. For Caucasians, the respective HRs (95% CIs) were 1.09 (1.04–1.15), 1.10 (1.05–1.16), and 1.07 (0.97–1.19). Quintile analyses showed that risk for incident CVD was graded but statistically significant only for the highest compared with the lowest quintile (HR [95%CI] 1.35 [1.06–1.74] for African Americans; HR 1.27 [1.10–1.47] for Caucasians). Similar results were obtained using Lp(a) cut-offs of ≤10 mg/dl, >10–≤20 mg/dl, >20–≤30 mg/dl, and >30 mg/dl.
Conclusions
Lp(a) levels were positively associated with CVD events. Associations were at least as strong, with a larger range of Lp(a) concentrations, in African Americans compared with Caucasians.
doi:10.1161/CIRCULATIONAHA.111.045120
PMCID: PMC3760720  PMID: 22128224
lipoproteins; cardiovascular diseases; risk factors; race/ethnicity; cardiovascular disease risk factors
8.  Cytomegalovirus Immunoglobulin G Antibody Is Associated With Subclinical Carotid Artery Disease Among HIV-Infected Women 
The Journal of Infectious Diseases  2012;205(12):1788-1796.
Background. Cytomegalovirus (CMV) infection has been implicated in immune activation and accelerated progression of immunodeficiency from human immunodeficiency virus (HIV) coinfection. We hypothesized that CMV is associated with vascular disease in HIV-infected adults.
Methods. In the Women's Interagency HIV Study, we studied 601 HIV-infected and 90 HIV-uninfected participants. We assessed the association of CMV immunoglobulin G (IgG) level with carotid artery intima-media thickness, carotid artery distensibility, Young's elastic modulus, and blood pressures. Multivariable models adjusted for age, race/ethnicity, smoking, diabetes, and body mass index.
Results. Mean CMV IgG levels were higher in HIV-infected women compared with HIV-uninfected women (P < .01). Among HIV-infected women, higher CMV IgG level was associated with decreased carotid artery distensibility (P < .01) and increased Young's modulus (P = .02). Higher CMV IgG antibody level was associated with increased prevalence of carotid artery lesions among HIV-infected women who achieved HIV suppression on antiretroviral therapy, but not among viremic or untreated HIV-infected women. Adjustment for Epstein–Barr virus antibody levels and C-reactive protein levels had no effect on the associations between CMV IgG levels and vascular parameters.
Conclusions. Cytomegalovirus antibody titers are increased in HIV-infected women and associated with subclinical cardiovascular disease. Host responses to CMV may be abnormal in HIV infection and associated with clinical disease.
doi:10.1093/infdis/jis276
PMCID: PMC3415890  PMID: 22492856
9.  Is Cognitive Aging Predicted by Educational Level? 
American Journal of Epidemiology  2012;175(8):760-761.
A higher educational level has consistently been associated with a lower incidence of dementia. However, in the current issue of the Journal, Glymour et al. (Am J Epidemiol. 2012;175(8):750–759.) present findings that are in agreement with other research in showing a lack of association between educational level and cognitive decline in the elderly. These findings are not inconsistent with the hope, yet unproven, that persons might reduce their risk of dementia by engaging in cognitively stimulating activities.
doi:10.1093/aje/kwr513
PMCID: PMC4047279  PMID: 22472114
bias (epidemiology); cognitive disorders/dementia; cognitive reserve; cohort studies
10.  25(OH)D deficiency is associated with fatal stroke among whites but not blacks: The NHANES-III linked mortality files 
Objective
Deficient 25-hydroxyvitamin D [25(OH)D] levels are associated with cardiovascular disease (CVD) events and mortality. Both 25(OH)D deficiency and stroke are more prevalent among blacks. We examined whether low 25(OH)D contributes to the excess risk of fatal stroke in blacks compared to whites.
Research Methods and Procedures
The Third National Health and Nutrition Examination Survey, a probability sample of US civilians, measured 25(OH)D levels and CVD risk factors between 1988–1994. Vital status through December 2006 was obtained via linkage with the National Death Index. Among white and black adults without CVD reported at baseline (n=7981), Cox regression models were fit to estimate hazard ratios (HR) for fatal stroke by 25(OH)D status and race.
Results
During a median of 14.1 years, there were 116 and 60 fatal strokes among whites and blacks respectively. The risk of fatal stroke was greater in blacks compared to whites in models adjusted for socio-economic status and CVD risk factors, [HR 1.60 (95% CI 1.01–2.53)]. Mean baseline 25(OH)D levels were significantly lower in blacks compared to whites (19.4 vs 30.8 ng/mL, respectively). In multivariable-adjusted models, deficient 25(OH)D levels <15 ng/mL were associated with fatal stroke among whites [HR 2.13 (1.01–4.50)] but not blacks [HR 0.93 (0.49–1.80)].
Conclusions
Vitamin D deficiency was associated with increased risk of stroke death in whites but not blacks. Although blacks had a higher rate of fatal stroke compared to whites, the low 25(OH)D levels in blacks were unrelated to stroke incidence and therefore 25(OH)D levels did not explain this excess risk.
doi:10.1016/j.nut.2011.10.015
PMCID: PMC3304002  PMID: 22261577
vitamin D; stroke; racial differences
11.  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.
doi:10.1016/j.atherosclerosis.2007.12.038
PMCID: PMC3612981  PMID: 18243217
CETP; CVD; HDL; MESA
12.  Effect of Correcting for Long Term Variation in Major Coronary Heart Disease Risk Factors: Relative Hazard Estimation and Risk Prediction in the ARIC Study 
Annals of Epidemiology  2012;22(3):191-197.
Purpose
To examine the effect of correcting coronary heart disease (CHD) risk factors for long-term within-person variation on CHD risk.
Method
Using 5533 men and 7301 women from the Atherosclerosis Risk in Communities (ARIC) Study, we compared models incorporating risk factors measured at a single visit and models incorporating additional measurements for systolic blood pressure, total cholesterol and high-density lipoprotein cholesterol taken 3 years prior to baseline.
Results
The largest change away from null was seen for systolic blood pressure: Hazard ratio (HR) 1.38 to 1.69 (+81%) in women and HR 1.26 to 1.41 (+56%) in men. Hazard ratios also decreased for age (−32% in women, −9% in men), race (−67% in women), diabetes (−13% in men and women), and medication use for hypertension (−27% in women, −26% in men) and cholesterol (−97% in women, HR 1.06 to 0.93 in men). The area under the ROC curve did not improve significantly in men or women, while reclassification was only significant in women (NRI 5.4%, p = 0.016).
Conclusion
Modeling long-term variation in CHD risk factors had a substantial impact on HR estimates, with new effect estimates further from the null for some risk factors and closer for others including age and medication use, but only improved risk classification in women.
doi:10.1016/j.annepidem.2011.12.001
PMCID: PMC3288692  PMID: 22221585
epidemiology; risk factors; statistics; heart diseases; models, cardiovascular; risk assessment
13.  Blood Lipid Levels, Lipid Lowering Medications, and the Incidence of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study 
Background
Several cardiovascular risk factors have been associated with the risk of atrial fibrillation (AF). Limited and inconsistent evidence exists on the association of blood lipid levels and lipid lowering medication use with AF risk.
Methods and Results
We analyzed 13,969 participants (25% African-American, 45% men) free of AF at baseline from the Atherosclerosis Risk in Communities (ARIC) study. Fasting HDL cholesterol (HDLc), LDL cholesterol (LDLc), triglycerides, and total cholesterol were measured at baseline (1987–89) and each of three follow-up visits. Incidence of AF was ascertained through 2007. The association of the use of statins and other lipid lowering medications with AF was estimated in 13,044 ARIC participants attending visit 2 (1990–92), adjusting for covariates from the previous visit. During a median follow-up of 18.7 years there were 1433 incident AF cases. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) of AF associated with a one standard deviation increase in lipid levels were: HDLc: 0.97 (0.91–1.04); LDLc: 0.90 (0.85–0.96); total cholesterol: 0.89 (0.84–0.95); and triglycerides: 1.00 (0.96–1.04). Participants taking lipid lowering medications had an adjusted HR (95% CI) of AF of 0.96 (0.82–1.13) compared to those not on medications, while those taking statins had an adjusted HR of 0.91 (0.66–1.25) compared to those taking other lipid lowering mediations.
Conclusions
Higher levels of LDLc and total cholesterol were associated with a lower incidence of AF. HDLc and triglycerides, however, were not independently associated with AF incidence. No association was found between the use of lipid lowering medications and incident AF.
doi:10.1161/CIRCEP.111.966804
PMCID: PMC3290134  PMID: 22227953
lipids; epidemiology; atrial fibrillation; statins
14.  Carotid arterial wall characteristics are associated with incident ischemic stroke but not coronary heart disease in the ARIC Study 
Background and Purpose
Ultrasound measurements of arterial stiffness are associated with atherosclerosis risk factors, but limited data exist on their association with incident cardiovascular events. We evaluated the association of carotid ultrasound derived arterial stiffness measures with incident coronary heart disease (CHD) and ischemic stroke in the ARIC study.
Methods
Carotid arterial strain (CAS) and compliance (AC), distensibility (AD) and stiffness indices (SI), pressure-strain (Ep) and Young’s elastic moduli (YEM) were measured in 10,407 individuals using ultrasound. Hazard ratios for incident CHD (myocardial infarction [MI], fatal CHD, coronary revascularization) and stroke in minimally adjusted (age, sex, center, race) and fully adjusted models (minimally adjusted model + diabetes, height, weight, total cholesterol, high-density lipoprotein cholesterol, tobacco use, systolic blood pressure, antihypertensive medication use, and carotid intima-media thickness (CIMT) were calculated.
Results
The mean age was 55.3 years. Over a mean follow up of 13.8 years, 1,267 incident CHD and 383 ischemic stroke events occurred. After full adjustment for risk factors and CIMT, all arterial stiffness parameters [CAS HR (95% confidence interval [CI]) =1.14 (1.02, 1.28); AD HR=1.19 (1.02, 1.39); SI HR=1.14 (1.04, 1.25); Ep HR=1.17 (1.06, 1.28); YEM HR=1.13 (1.03, 1.24)], except arterial compliance HR=1.02 (0.90, 1.16), were significantly associated with incident stroke but not with CHD.
Conclusions
After adjusting for cardiovascular risk factors, ultrasound measures of carotid arterial stiffness are associated with incident ischemic stroke but not incident CHD events, despite that the 2 outcomes sharing similar risk factors.
doi:10.1161/STROKEAHA.111.626200
PMCID: PMC3246524  PMID: 22033999
arterial stiffness; carotid ultrasound; coronary heart disease; stroke; ARIC
15.  Relation of Cholesterol and Lipoprotein Parameters with Carotid Artery Plaque Characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
Atherosclerosis  2011;219(2):596-602.
Objective
There is a paucity of data regarding relations of apolipoproteins (apolipoprotein B [ApoB] and apolipoprotein A-1 [Apo A-1]), lipoprotein particle measures (low-density lipoprotein particle concentration [LDLp] and high-density lipoprotein particle concentration [HDLp]), and lipoprotein cholesterol measures (low-density lipoprotein cholesterol [LDL-C], non–high-density lipoprotein cholesterol [non– HDL-C], and high-density lipoprotein cholesterol [HDL-C]) with atherosclerotic plaque burden, plaque eccentricity, and lipid-rich core presence as a marker of high-risk plaques.
Methods
Carotid artery magnetic resonance imaging was performed in 1,670 Atherosclerosis Risk in Communities study participants. Vessel wall and lipid cores were measured; normalized wall index (NWI), standard deviation (SD) of wall thickness (measure of plaque eccentricity) were calculated; and lipid cores were detected in vessels with ≥1.5 mm thickness. Fasting concentrations of cholesterol, ApoB and Apo A-1, and LDLp and HDLp were measured.
Results
Measures of plaque burden (carotid wall volume, wall thickness, and NWI) were positively associated with atherogenic cholesterol and lipoproteins (p<0.05 for total cholesterol, LDL-C, non–HDL-C, ApoB, and LDLp), but not with HDL-C, Apo A-1, or HDLp. SD of wall thickness was associated with total cholesterol (p 0.01) and non-HDL-C (p 0.02). Although measures of atherogenic or anti-atherogenic cholesterol or lipoprotein were not individually associated with detection of a lipid-rich core, their ratios (total cholesterol/HDL-C, non–HDL-C/ HDL-C, and LDLp/HDLp) were associated with lipid-rich core presence (p≤0.05).
Conclusion
Extent of carotid atherosclerosis is associated with atherogenic cholesterol and lipoproteins. Atherogenic/anti-atherogenic cholesterol or particle ratios were associated with presence of a detectable lipid-rich core.
doi:10.1016/j.atherosclerosis.2011.08.001
PMCID: PMC3226845  PMID: 21868017
atherogenic lipoproteins; anti-atherogenic lipoproteins; plaque burden; lipid-rich necrotic core
16.  10-Year Longitudinal Changes in Retinal Microvascular Lesions: The Atherosclerosis Risk in Communities Study 
Ophthalmology  2011;118(8):1612-1618.
Objective
There are limited data on the natural history and longitudinal changes of retinal microvascular lesions. We examined 10-year changes in retinal microvascular lesions, focusing on those related to hypertension and shown to predict development of cardiovascular disease.
Design
Prospective cohort
Participants
1,120 middle-aged participants without diabetes of the Atherosclerosis Risk in Communities (ARIC) Study in 1993–5 and again 10 years later in 2003–5.
Methods
. Retinal microvascular lesions were graded from retinal photographs using the same protocol at both examinations, with changes (incidence or disappearance) adjudicated by a side-by-side comparison of photographs. The study sample was stratified by carotid intima-media thickness (IMT) and ARIC field center; thus all analyses were weighted by these factors. Persons with diabetes were excluded because the frequency and pathophysiology of diabetic retinal lesions is different.
Main Outcome Measures
Incidence and disappearance rates of lesions.
Results
. The 10 year incidence of focal arteriolar narrowing, arteriovenous (AV) nicking, and retinopathy in persons without diabetes was 3.4% (95% confidence intervals 2.3–4.9), 2.5% (1.6–3.9), and 2.2% (1.3–3.5) respectively. Over the 10 year period, of 32, 219, and 24 eyes with focal arteriolar narrowing, AV nicking and retinopathy at baseline, 50.3% (28.6–71.9), 40.7% (32.7–49.4) and 65.9% (42.4–83.5), respectively, disappeared. Higher baseline plasma fibrinogen and white cell count were associated with incident focal arteriolar narrowing; antihypertensive medication use associated with incident AV nicking; and higher diastolic blood pressure, carotid IMT and white cell count associated with incident retinopathy. Higher fasting serum glucose was not significantly associated with incident retinopathy, though this may be related to the small number of lesions.(Odds ratio 5.88, 95% confidence interval 0.74–46.64 per standard deviation difference)
Conclusions
In this sample of middle-aged adults, new retinal microvascular lesions appeared at a rate between 2–4% over 10 years. A high percentage of lesions (40% or more) disappeared over the same period, suggesting considerable remodeling in the retinal microvasculature.
doi:10.1016/j.ophtha.2011.01.003
PMCID: PMC3150229  PMID: 21529953
microvascular signs; hypertension; microcirculation; retina; ARIC
17.  Urine Arsenic and Hypertension in U.S. Adults: the 2003–2008 NHANES 
Epidemiology (Cambridge, Mass.)  2011;22(2):153-161.
Background
High chronic exposure to inorganic arsenic may contribute to the development of hypertension. Limited information is available, however, on the association of low to moderate exposure to inorganic arsenic with blood pressure levels and hypertension. We investigated the association of exposure to inorganic arsenic (as measured in urine) with systolic and diastolic blood pressure levels and the prevalence of hypertension in U.S. adults.
Methods
We studied 4167 adults 20 years of age or older who participated in the National Health and Nutrition Examination Survey (NHANES) from 2003 through 2008 and for whom total arsenic, dimethylarsinate (DMA) and arsenobetaine had been assessed in urine.
Results
The median (inter-quartile range) urine concentrations were 8.3 μg/L (4.2– 17.1) for total arsenic, 3.6 μg/L (2.0– 6.0) for DMA and 1.4 μg/L (0.3– 6.3) for arsenobetaine. The weighted prevalence of hypertension in the study population was 36%. After multivariable adjustment, a 2-fold increase in total arsenic was associated with a hypertension odds ratio of 0.98 (95% confidence interval = 0.86 to 1.11). A doubling of total arsenic minus arsenobetaine was associated with a hypertension OR of 1.03 (0.94 to 1.14) and a doubling of DMA concentrations was associated with a hypertension OR of 1.11 (0.99 to 1.24). Total arsenic, total arsenic minus arsenobetaine, or DMA levels were not associated with systolic or diastolic blood pressure.
Conclusions
At the low to moderate levels typical of the U.S. population, total arsenic, total arsenic minus arsenobetaine, and DMA concentrations in urine were not associated with the prevalence of hypertension or with systolic or diastolic blood pressure levels. A weak association of DMA with hypertension could not be ruled out.
doi:10.1097/EDE.0b013e318207fdf2
PMCID: PMC3388808  PMID: 21206367
18.  T cell activation predicts carotid artery stiffness among HIV-infected women 
Atherosclerosis  2011;217(1):207-213.
Objectives
HIV disease is associated with increased arterial stiffness, which may be related to inflammation provoked by HIV-related immune perturbation. We assessed the association of T cell markers of immune activation and immunosenescence with carotid artery stiffness among HIV-infected women.
Methods
Among 114 HIV-infected and 43 HIV-uninfected women, we measured CD4+ and CD8+ T cell populations expressing activation (CD38+HLA-DR+) and senescence (CD28-CD57+) markers. We then related these measures of immune status with parameters of carotid artery stiffness, including decreased distensibility, and increased Young’s elastic modulus, as assessed by B-mode ultrasound.
Results
HIV infection was associated with increased CD4+ T cell activation, CD8+ T cell activation and CD8+ T cell senescence. Among HIV-infected women, adjusted for age, HIV medications, and vascular risk factors, higher CD4+CD38+HLA-DR+ T cell frequency was associated with decreased carotid artery distensibility (β= −2.00, 95% confidence interval [CI]= −3.86,−0.14, P=0.04) and increased Young’s modulus (β=1.00, 95% CI=0.03,1.97, P=0.04). These associations were affected little by further adjustment for CD4+ T cell count and viral load. Among HIV-infected women, higher frequencies of immunosenescent T cells, including CD4+CD28-CD57+ and CD8+CD28-CD57+ T cells, were also associated with decreased arterial distensibility. Among HIV-uninfected women, frequencies of activated or senescent T cells were not significantly associated with measures of carotid stiffness.
Discussion
T cell activation and senescence are associated with arterial stiffness, suggesting that pro-inflammatory populations of T cells may produce functional or structural vascular changes in HIV-infected women.
doi:10.1016/j.atherosclerosis.2011.03.011
PMCID: PMC3139014  PMID: 21492857
19.  Association of Lung Function with Cognitive Decline and Dementia: The Atherosclerosis Risk in Communities (ARIC) Study 
Background
Previous studies reported a higher risk of cognitive decline and dementia among individuals with impaired lung function. However, many did not adjust for important confounders or did not include women and nonwhites.
Methods
We studied 10,975 men and women aged 47–70 (23% African-Americans), enrolled in the Atherosclerosis Risk in Communities Study. Pulmonary function tests and a cognitive assessment, including the Delayed Word Recall, the Digit Symbol Substitution, and the World Fluency Tests, were done in 1990–92. Repeated cognitive assessments were performed in 1996–98 for the entire cohort, and in 1993–95 and 2004–06 in 904 eligible individuals. Dementia hospitalization was ascertained through 2005.
Results
In analysis adjusted for lifestyles, APOE genotype, and cardiovascular risk factors, impaired lung function was associated with worse cognitive function at baseline. No association was found between lung function and cognitive decline over time. Impaired lung function at baseline was associated with higher risk of dementia hospitalization during follow-up, particularly among younger individuals. The hazard ratios (95% confidence intervals) of dementia hospitalization were 1.6 (0.9, 2.8) and 2.1 (1.2, 3.7) comparing the lowest to the highest quartile of forced expiratory volume in 1 second and forced vital capacity, respectively. Presence of a restrictive ventilatory pattern, but not of an obstructive pattern, was associated with reduced cognitive scores and higher dementia risk.
Conclusion
Reduced lung function was associated with worse performance in cognitive assessments and with an increased risk of dementia hospitalization. Future research should determine whether maintaining optimal pulmonary health might prevent cognitive impairment and dementia.
doi:10.1111/j.1468-1331.2010.03340.x
PMCID: PMC3092022  PMID: 21244584
Lung function; cognitive decline; dementia; prospective studies
20.  Is Diabetic Retinopathy Related to Subclinical Cardiovascular Disease? 
Ophthalmology  2010;118(5):860-865.
OBJECTIVE
Persons with diabetic retinopathy (DR) have an increased risk of clinical cardiovascular events. Our study aimed to determine whether DR is associated with a range of measures of subclinical cardiovascular disease (CVD) in persons without clinical CVD.
DESIGN
Population-based, cross-sectional epidemiologic study
PARTICIPANTS
Nine hundred and twenty seven persons with diabetes without clinical CVD in the Multi-Ethnic Study of Atherosclerosis.
METHODS
DR was ascertained from retinal photographs according to modification of the Airlie House Classification system. Vision threatening DR (VTDR) was defined as severe non-proliferative DR, proliferative DR or clinically significant macular edema. Subclinical CVD measures were assessed and defined as follows: high coronary artery calcium (CAC) score, defined as CAC score≥400; low ankle-brachial index (ABI), defined as ABI<0.9; high ABI, defined as ABI≥1.4; high carotid intima-media thickness (IMT), defined as highest 25% of IMT; and carotid stenosis, defined as >25% stenosis or presence of carotid plaque.
MAIN OUTCOME MEASURES
Associations between DR and subclinical CVD measures.
RESULTS
The prevalence of DR and VTDR in this sample was 30.0% and 7.2%, respectively. VTDR was associated with a high CAC score (odds ratio [OR] 2.33, 95% condifence interval [CI] 1.15–4.73), low ABI (OR 2.54; 95%CI, 1.08–5.99) and high ABI (OR 12.6, 95% CI, 1.14, 140.6), after adjusting for risk factors including hemoglobin A1c level and duration of diabetes. The association between VTDR and high CAC score remained significant after further adjustment for hypoglycemic, anti-hypertensive and cholesterol-lowering medications. DR was not significantly associated with measures of carotid artery disease.
CONCLUSIONS
In persons with diabetes without a history of clinical CVD, the presence of advanced stage of DR is associated with subclinical coronary artery disease. These findings emphasize the need to be careful about the use of anti-vascular endothelial growth factor for the treatment of DR.
doi:10.1016/j.ophtha.2010.08.040
PMCID: PMC3087839  PMID: 21168222
21.  Carotid Artery Wall Thickness and Risk of Stroke Subtypes. The Atherosclerosis Risk in Communities (ARIC) Study 
Background and Purpose
Understanding associations of carotid atherosclerosis with stroke subtypes may contribute to more effective prevention of stroke.
Methods
Between 1987 and 1989, 13,560 men and women aged 45 to 64 years and free of clinical stroke, took part in the first examination of the Atherosclerosis Risk in Communities study. Incident strokes were ascertained by hospital surveillance.
Results
During an average follow up of 15.7-years, 82 incident hemorrhagic and 621 incident ischemic strokes (131 lacunar, 358 nonlacunar, and 132 cardioembolic strokes) occurred. The incidence rates of hemorrhagic and ischemic strokes were greater across higher carotid intima-media thickness (IMT) levels. Although this positive association was observed for all stroke subtypes, the age-, sex-, and race-adjusted risk ratios (RR) were higher for cardioembolic and nonlacunar strokes than for hemorrhagic and lacunar strokes. Compared with participants in the lowest quintile (<0.61mm), the adjusted RRs for those in the highest quintile (≥0.85mm) of IMT were 2.55 (95%CI, 1.09 to 5.94) for hemorrhagic, 2.89 (95%CI, 1.50 to 5.54) for lacunar, 3.61 (95%CI, 2.33 to 5.99) for nonlacunar, and 6.12 (95%CI, 2.71 to 13.9) for cardioembolic stroke. The RRs were attenuated by additional adjustment for covariates, but remained statistically significant for nonlacunar and cardioembolic strokes (p for trend <0.001, respectively). The association between carotid IMT and lacunar stroke was somewhat stronger in African Americans than in whites (P for interaction = 0.07).
Conclusions
Carotid atherosclerosis was associated with increased risk of all stroke subtypes, but the association of carotid atherosclerosis with stroke may vary by subtypes.
doi:10.1161/STROKEAHA.110.592261
PMCID: PMC3026889  PMID: 21164133
Brain Infarction; Carotid artery; Epidemiology; Intima-media thickness; Stroke subtypes
22.  Glycated Hemoglobin and the Risk of Kidney Disease and Retinopathy in Adults With and Without Diabetes 
Diabetes  2010;60(1):298-305.
OBJECTIVE
Glycated hemoglobin was recently recommended for use as a diagnostic test for diabetes. We examined the association between 2010 American Diabetes Association diagnostic cut points for glycated hemoglobin and microvascular outcomes (chronic kidney disease, end-stage renal disease [ESRD], and retinopathy) and formally tested for the presence of risk thresholds in the relationships of glycated hemoglobin with these outcomes.
RESEARCH DESIGN AND METHODS
Prospective cohort and cross-sectional analyses of 11,357 participants (773 with a history of diagnosed diabetes) from the Atherosclerosis Risk in Communities (ARIC) Study.
RESULTS
During a median of 14 years of follow-up of individuals without diagnosed diabetes at baseline, clinical categories of glycated hemoglobin were associated with risk of chronic kidney disease, with adjusted hazard ratios (HRs) of 1.12 (0.94–1.34) and 1.39 (1.04–1.85) for glycated hemoglobin 5.7–6.4% and ≥6.5%, respectively, as compared with <5.7% (P trend = 0.002). The corresponding HRs for ESRD were 1.51 (0.82–2.76) and 1.98 (0.83–4.73), respectively (P trend = 0.047). In the absence of diagnosed diabetes, glycated hemoglobin was cross sectionally associated with the presence of moderate/severe retinopathy, with adjusted odds ratios of 1.42 (0.69–2.92) and 2.91 (1.19–7.11) for glycated hemoglobin 5.7–<6.5% and ≥6.5%, respectively, compared with <5.7% (P trend = 0.011). Risk associations were stronger among individuals with a history of diabetes. We did not observe significant thresholds in the associations of glycated hemoglobin with kidney disease risk or retinopathy.
CONCLUSIONS
These data from a community-based, biracial population support the use of new 2010 American Diabetes Association glycated hemoglobin cut points for the diagnosis of diabetes.
doi:10.2337/db10-1198
PMCID: PMC3012185  PMID: 20978092
23.  Association between human immunodeficiency virus (HIV) infection and stiffness of the common carotid artery 
Background and purpose
Human immunodeficiency virus (HIV)-infected persons taking highly active antiretroviral therapy (HAART) may have an increased risk for cardiovascular-related events, although the underlying mechanism remains unclear. We tested the hypothesis that carotid arterial stiffness was higher among persons taking HAART compared to HAART-naïve and HIV-uninfected persons.
Methods
Between 2004 and 2006, we performed high resolution B-mode ultrasound on 2,789 HIV-infected and HIV-uninfected participants of the Women’s Interagency HIV Study (WIHS; 1865 women) and the Multicenter AIDS Cohort Study (MACS; 924 men) and determined carotid arterial distensibility, a direct measure of carotid arterial stiffness. We used generalized estimating equations to evaluate the association between distensibility and HIV infection, CD4+ cell count, and exposure to HAART adjusted for demographic, behavioral, and clinical characteristics.
Results
In multivariable analysis, distensibility was 4.3% lower (95% confidence interval (CI): -7.4% to -1.1%) among HIV-infected versus uninfected participants. Among HIV-infected participants with fewer than 200 CD4+ cells, distensibility was 10.5% lower (95% CI: -14.5% to -6.2%) than that among HIV-uninfected participants, and this effect did not differ significantly by cohort or race. Concurrent HAART use was independently associated with lower distensibility among MACS participants but not among WIHS participants.
Conclusions
Our finding that advanced HIV-related immunosuppression was associated with increased carotid arterial stiffness independent from the effects of traditional atherosclerosis risk factors suggests that the etiologic mechanism underlying reports of an increased cardiovascular disease risk among HIV-infected individuals might involve HIV-related immunosuppression leading to vascular dysfunction and arterial stiffening.
doi:10.1161/STROKEAHA.110.583856
PMCID: PMC2972735  PMID: 20798374
atherosclerosis; cardiovascular disease; carotid arteries; HIV; epidemiology
24.  Cadmium and Peripheral Arterial Disease: Gender Differences in the 1999–2004 US National Health and Nutrition Examination Survey 
American Journal of Epidemiology  2010;172(6):671-681.
Gender differences in the association of blood and urine cadmium concentrations with peripheral arterial disease (PAD) were evaluated by using data from 6,456 US adults aged ≥40 years who participated in the 1999–2004 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial blood pressure index of <0.9 in at least one leg. For men, the adjusted odds ratios for PAD comparing the highest with the lowest quintiles of blood and urine cadmium concentrations were 1.82 (95% confidence interval (CI): 0.82, 4.05) and 4.90 (95% CI: 1.55, 15.54), respectively, with a progressive dose-response relation and no difference by smoking status. For women, the corresponding odds ratios were 1.19 (95% CI: 0.66, 2.16) and 0.56 (95% CI: 0.18, 1.71), but there was evidence of effect modification by smoking: among women ever smokers, there was a positive, progressive dose-response relation; among women never smokers, there was a U-shaped dose-response relation. Higher blood and urine cadmium levels were associated with increased prevalence of PAD, but women never smokers showed a U-shaped relation with increased prevalence of PAD at very low cadmium levels. These findings add to the concern of increased cadmium exposure as a cardiovascular risk factor in the general population.
doi:10.1093/aje/kwq172
PMCID: PMC2950816  PMID: 20693268
cadmium; health surveys; metals; peripheral vascular diseases; sex characteristics
25.  Paired Comparison of Observed and Expected Coronary Heart Disease Rates over 12 Years from the Atherosclerosis Risk In Communities Study 
Annals of epidemiology  2010;20(9):683-690.
Purpose
To quantify the relationship between coronary heart disease (CHD) risk factor levels and changes over time and population-wide CHD morbidity and mortality.
Methods
We used a paired cohort and community surveillance of hospitalized myocardial infarction and CHD deaths of community members aged 53 to 64 in four geographic areas to compare observed community CHD to expected CHD rates and trends based on cohort risk factors.
Results
Observed CHD rates declined by 1 to 3% per year in all communities except one, while CHD death rates declined 3 to 6% per year in all communities. Risk factor trends predicted a 2 to 3% per year decline in both total events and death. In all communities except one, expected rates of total CHD events were lower than the observed rates while expected and observed CHD death rates were similar. Across all communities women had a higher CHD death rate than expected.
Conclusion
Overall, trends in CHD risk factors provide a useful indicator of changes in community event rates and of CHD death, but caution is warranted in prediction of absolute risk of CHD events.
doi:10.1016/j.annepidem.2010.05.016
PMCID: PMC2928717  PMID: 20696408
Adult; Coronary Disease; Humans; Mortality/trends; Myocardial Infarction/mortality/prevention & control; Myocardial Revascularization/statistics & numerical data; Risk Factors; United States/epidemiology

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