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1.  Comparison of Racial Differences in Plaque Composition and Stenosis among HIV Positive and Negative Men from the Multicenter Aids Cohort Study (MACS) 
The American journal of cardiology  2014;114(3):369-375.
Previous studies demonstrated that blacks have less coronary artery calcification (CAC) than whites. We evaluated racial differences in plaque composition and stenosis in the Multicenter AIDS Cohort Study (MACS). HIV positive and negative men completed non-contrast cardiac CT if they were 40–70 years, weighed <300 pounds, and had no prior history of cardiac surgery or revascularization, and if eligible, coronary CT angiography (CTA). There were 1001 men who underwent CT scans and 759 men had CTA. We measured CAC on non-contrast CT, and total plaque, non-calcified, calcified, and mixed plaque, and identified coronary stenosis >50% on CTA. The association of presence and extent of plaque with race was determined after adjustment for HIV serostatus, cardiovascular risk factors and measures of socioeconomic status. The prevalences of any plaque on CTA and non-calcified plaque were not different between black and white men; however, black men had lower prevalences of CAC (Prevalence ratio (PR)=0.79, p=0.01), calcified plaque (PR=0.69, p=0.002), and stenosis >50% (PR=0.59, p=0.009). There were no associations between black race and extent of plaque in fully adjusted models. Using log-linear regression, black race was associated with a lower extent of any plaque on CTA in HIV positive men (estimate=−0.24, p=0.051) but not in HIV negative men (0.12, p=0.50, HIV interaction p=0.005). In conclusion, a lower prevalence of CAC in black compared to white men appears to reflect less calcification of plaque and stenosis rather than a lower overall prevalence of plaque.
PMCID: PMC4143765  PMID: 24929623
Epidemiology; plaque; coronary angiography; coronary artery disease; HIV
2.  High-sensitivity cardiac troponin T and cognitive function and dementia risk: the atherosclerosis risk in communities study 
European Heart Journal  2014;35(27):1817-1824.
Clinical cardiovascular disease is a major risk factor for cognitive impairment and dementia. However, less is known about the association of subclinical myocardial damage with cognition and dementia. We sought to examine the associations of high-sensitivity cardiac troponin T (hs-cTnT) with cognition and dementia.
Methods and results
Cross-sectional analysis of cognition (baseline 1996–98) and prospective analysis of dementia (follow-up through 2010) in 9472 participants in the Atherosclerosis Risk in Communities study. High-sensitivity cardiac troponin T was measured using a novel highly sensitive assay with a lower limit of the blank of 3 ng/L. Cognitive function was assessed by three tests: the delayed word recall test (DWRT), the digit symbol substitution test (DSST), and the word fluency test (WFT). Dementia was defined using ICD-9 codes. Linear regression and Cox models were adjusted for traditional cardiovascular risk factors. The mean age of participants was 63 years, 59% were female, 21% were black, and 66% had hs-cTnT ≥3 ng/L. In cross-sectional analyses, higher hs-cTnT was associated with lower scores on the DSST (P-trend < 0.001) and the WFT (P-trend = 0.002), but not on the DWRT (P-trend = 0.089). Over a median of 13 years, there were 455 incident dementia hospitalizations. In prospective analyses, higher baseline concentrations of hs-cTnT were associated with an increased risk for dementia hospitalizations overall (P-trend < 0.001) and for vascular dementia (P-trend = 0.029), but not for Alzheimer's dementia (P-trend = 0.212).
Elevations in baseline concentrations of hs-cTnT were associated with lower cognitive test scores at baseline and increased dementia hospitalization risk during the follow-up. Our results suggest that subclinical myocardial injury is associated with cognition and dementia.
PMCID: PMC4097965  PMID: 24685712
High-sensitivity Troponin T; Cognition; Dementia
3.  Diabetes in midlife and cognitive change over 20 years: the Atherosclerosis Risk in Communities Neurocognitive Study 
Annals of internal medicine  2014;161(11):785-793.
Type 2 diabetes mellitus is associated with dementia risk, however evidence is limited for possible associations of diabetes and pre-diabetes with cognitive decline.
To determine if diabetes in mid-life is associated with 20-year cognitive decline, and to characterize long-term cognitive decline across clinical categories of hemoglobin A1c (HbA1c).
Prospective cohort.
The community-based Atherosclerosis Risk in Communities (ARIC) Study.
13351 black and white adults aged 48-67 years at baseline (1990-1992).
Diabetes was defined by self-report of physician diagnosis or medication use or HbA1c≥6.5%. Undiagnosed diabetes, pre-diabetes, and glucose control in persons with diagnosed diabetes were defined using clinical categories of HbA1c. Delayed Word Recall, Digit Symbol Substitution, and Word Fluency tests were used to assess cognitive performance, and were summarized using a global Z-score.
Diabetes in midlife was associated with significantly greater cognitive decline over 20 years (adjusted global Z-score difference=-0.15, 95% CI:-0.22,-0.08), representing a 19% greater decline than those without diabetes. Cognitive decline was significantly greater among persons with pre-diabetes (HbA1c 5.7-6.4%) than those without diabetes and HbA1c<5.7%. Participants with poorly controlled diabetes (HbA1c≥7.0%) had a larger decline compared to persons whose diabetes was controlled (adjusted global Z-score difference=-0.16,p-value=0.071). Longer duration of diabetes was also associated with greater late-life cognitive decline (p-value-for-trend=<0.001). No significant differences in the rates of declines were seen in whites compared to blacks (p-value-for-interaction=0.4357).
Single measurement of HbA1c at baseline, only one test to per cognitive domain, potential geographic confounding of race comparisons.
These findings suggest that diabetes prevention and glucose control in midlife may protect against late-life cognitive decline.
PMCID: PMC4432464  PMID: 25437406
4.  Impact of Differential Attrition on the Association of Education With Cognitive Change Over 20 Years of Follow-up 
American Journal of Epidemiology  2014;179(8):956-966.
Studies of long-term cognitive change should account for the potential effects of education on the outcome, since some studies have demonstrated an association of education with dementia risk. Evaluating cognitive change is more ideal than evaluating cognitive performance at a single time point, because it should be less susceptible to confounding. In this analysis of 14,020 persons from a US cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, we measured change in performance on 3 cognitive tests over a 20-year period, from ages 48–67 years (1990–1992) through ages 70–89 years (2011–2013). Generalized estimating equations were used to evaluate the association between education and cognitive change in unweighted adjusted models, in models incorporating inverse probability of attrition weighting, and in models using cognitive scores imputed from the Telephone Interview for Cognitive Status for participants not examined in person. Education did not have a strong relationship with change in cognitive test performance, although the rate of decline was somewhat slower among persons with lower levels of education. Methods used to account for selective dropout only marginally changed these observed associations. Future studies of risk factors for cognitive impairment should focus on cognitive change, when possible, to allow for reduction of confounding by social or cultural factors.
PMCID: PMC3966720  PMID: 24627572
aging; cognition; cognitive decline; cognitive reserve; education
5.  Retinal Microvascular Abnormalities Predict Progression of Brain Microvascular Disease: An ARIC MRI Study 
Background and Purpose
Brain microvascular disease leads to leukoaraiosis and lacunar infarcts, and contributes to risk of stroke and cognitive decline. Given a shared pathophysiology, retinal microvascular signs are expected to predict brain microvascular disease progression. We investigated if either leukoaraiosis volume progression measured continuously or combined with incident lacunar infarcts would better demonstrate expected associations with retinal disease than has previously been shown.
830 participants in the Atherosclerosis Risk in Communities study ages 55 and older and without previous stroke received an initial brain MRI, retinal photography, and 10 years later, a follow up MRI. We evaluated retinal vascular sign phenotypes as predictors of 1) leukoaraiosis volume increase and 2) a new score combining leukoaraiosis volume change and incident lacunar infarcts. Hypertension and diabetes were evaluated as confounders and effect modifiers.
Individuals with any retinopathy (3.34 cm3; 95% CI 0.74–5.96) or with AV nicking (2.61cm3; 95% CI 0.80–4.42) each had greater progression of leukoaraiosis than those without these conditions. Any retinopathy (OR 3.18; 95% CI 1.71–5.89) or its components—microaneurysms (OR 3.06; 95% CI 1.33–7.07) and retinal hemorrhage (OR 3.02; 95% CI 1.27–7.20)—as well as AV nicking (OR 1.93; 95% CI 1.24–3.02) and focal arteriolar narrowing (OR 1.76; 95% CI 1.19–2.59), were associated with a higher quartile of a novel brain microvascular disease score combining leukoaraiosis progression with incident subclinical lacunes.
A novel scoring method revealed associations of retinal signs with leukoaraiosis progression and brain microvascular disease which have not been shown before.
PMCID: PMC4191897  PMID: 24549866
retina; leukoaraiosis; lacune
6.  Prognostic utility of fructosamine and glycated albumin for incident diabetes and microvascular complications 
Hemoglobin A1c (HbA1c) is the standard measure to monitor long-term glucose control in diabetes management and is now used for diagnosis. Fructosamine and glycated albumin are markers of short-term glycemic control that may add complementary information to HbA1c. However, the performance of fructosamine and glycated albumin to identify people at risk of complications is unclear.
We measured glycated albumin and fructosamine in 11348 adults without diabetes and 958 adults with diagnosed diabetes who attended the second examination of the Atherosclerosis Risk in Communities (ARIC) Study in 1990–1992 (baseline). We evaluated the associations of fructosamine and glycated albumin with retinopathy and risk of incident chronic kidney disease and incident diabetes during two decades of follow-up. We compared these associations to those for HbA1c.
Fructosamine and glycated albumin were strongly associated with retinopathy and these associations were very similar to that observed for HbA1c. Fructosamine and glycated albumin were also significantly associated with risk of incident chronic kidney disease and incident diabetes. Compared to persons with no diabetes and fructosamine or glycated albumin levels <75th percentile, the multivariable-adjusted hazard ratios (95%CIs) for chronic kidney disease for persons with fructosamine and glycated albumin levels >95th percentile were 1.50 (1.22, 1.85) and 1.48 (1.20, 1.83), respectively. The HRs for incident diabetes were 4.96 (4.36, 5.64) for fructosamine >95th percentile and 6.17 (5.45, 6.99) for glycated albumin >95th percentile. Associations were attenuated but persisted after adjustment for HbA1c. Prediction of incident chronic kidney disease by fructosamine (C-statistic, 0.717) and glycated albumin (C-statistic, 0.717) were nearly as strong as by HbA1c (C-statistic, 0.726) but HbA1c outperformed fructosamine and glycated albumin for prediction of incident diabetes with C-statistics of 0.760, 0.706, and 0.703, respectively.
Fructosamine and glycated albumin were strongly associated with diabetes and its microvascular complications and complemented the prognostic utility of HbA1c.
PMCID: PMC4212648  PMID: 24703046
7.  Retinal vascular caliber and the development of hypertension: a meta-analysis of individual participant data 
Journal of hypertension  2014;32(2):207-215.
Microvascular dysfunction has been suggested to be a major pathogenic factor for the development of hypertension. We examined the association between retinal vascular caliber, a marker of systemic microvascular dysfunction, and incident hypertension on a meta-analysis of individual participant data.
We performed a systematic review with relevant studies identified through a search of electronic databases, a review of reference lists, and correspondence with experts. Studies were included if participants were selected from a general population, retinal vascular caliber was measured from photographs using computer-assisted methods at baseline, and individuals were followed up to ascertain the incidence of hypertension. Prespecified individual recorded data from six population-based prospective cohort studies were included. Discrete time proportional odds models were constructed for each study with adjustment for hypertension risk factors. Log odds ratios (ORs) per 20-μm difference were pooled using random-effects meta-analysis.
Among 10 229 participants without prevalent hypertension, diabetes, or cardiovascular disease, 2599 developed new-onset hypertension during median follow-up periods ranging from 2.9 to 10 years. Both narrower retinal arterioles [pooled multivariate-adjusted OR per 20-μm difference 1.29, 95% confidence interval (CI) 1.20–1.39] and wider venules (OR per 20-μm difference 1.14, 95% CI 1.06–1.23) were associated with an increased risk of hypertension. Each 20 μm narrower arterioles at baseline were associated with a 1.12 mmHg (95% CI 0.25–1.99) greater increase in SBP over 5 years.
Retinal arteriolar narrowing and venular widening were independently associated with an increased risk of hypertension. These findings underscore the importance of microvascular remodeling in the pathogenesis of hypertension.
PMCID: PMC4120649  PMID: 24322199
hypertension; meta-analysis; microvascular dysfunction
8.  Vitamin D and Subclinical Cerebrovascular Disease 
JAMA neurology  2014;71(7):863-871.
Vitamin D deficiency has been associated with hypertension, diabetes mellitus, and incident stroke. Little is known about the association between vitamin D and subclinical cerebrovascular disease.
To examine the relationship of 25-hydroxyvitamin D (25[OH]D) levels with cerebrovascular abnormalities as assessed on brain magnetic resonance imaging (MRI) among participants of the Atherosclerosis Risk in Communities (ARIC) Brain MRI study.
Participants were white and black adults aged 55 to 72 years with no history of clinical stroke who underwent a cerebral MRI at ARIC visit 3 (n = 1622) and a second cerebral MRI approximately 10 years later (n = 888).
The 25(OH)D level was measured by mass spectrometry at visit 3, with levels adjusted for calendar month and categorized using race-specific quartiles.
The cross-sectional and prospective associations of 25(OH)D levels with white matter hyperintensities (WMHs) and MRI-defined infarcts were investigated using multivariable regression models.
The mean age of the participants was 62 years, 59.6% were women, and 48.6% were black. Lower 25(OH)D levels were not significantly associated with WMH score of severity, prevalent high-grade WMH score (≥3), or prevalent infarcts in cross-sectional, multivariable-adjusted models (all P > .05). Similarly, no significant prospective associations were found for lower 25(OH)D levels with change in WMH volume, incident high WMH score (≥3), or incident infarcts on the follow-up MRI, which occurred approximately 10 years later.
A single measure of 25(OH)D was not cross-sectionally associated with WMH grade or prevalent subclinical infarcts and was not prospectively associated with WMH progression or subclinical brain infarcts seen on serial cerebral MRIs obtained approximately 10 years apart. These findings do not support optimizing vitamin D levels for brain health.
PMCID: PMC4218739  PMID: 24861877
9.  Hypertensive Retinopathy and Risk of Stroke 
Hypertension  2013;62(4):706-711.
Although assessment of hypertensive retinopathy signs has been recommended for determining end-organ damage and stratifying vascular risk in hypertensive persons, its value remains unclear. In this study, we examine whether hypertensive retinopathy predicts the long-term risk of stroke in hypertensives.
A total of 2907 hypertensive participants aged 50–73 at the 1993–1995 examination, who had gradable retinal photographs, no history of diabetes, stroke and coronary heart disease at baseline and data on incident stroke were included from the Atherosclerosis Risk in Communities (ARIC) Study. Retinal photographs were assessed for hypertensive retinopathy signs and classified as none, mild, and moderate/severe. Incident events of any stroke, cerebral infarction and hemorrhagic stroke were identified and validated.
After a mean follow-up period of 13.0 years, 165 persons developed incident stroke (146 cerebral infarctions and 15 hemorrhagic strokes). After adjusting for age, sex, blood pressure, and other risk factors, persons with moderate hypertensive retinopathy were more likely to have stroke (multivariable hazard ratios (HR), moderate versus no retinopathy: 2.37, 95%CI 1.39-4.02). In hypertensives on medication with good control of blood pressure, hypertensive retinopathy was related to an increased risk of cerebral infarction (HR, mild retinopathy: 1.96, 95%CI 1.09-3.55; moderate retinopathy: 2.98, 95%CI 1.01-8.83).
Hypertensive retinopathy predicts the long-term risk of stroke, independent of blood pressure, even in treated hypertensives with good hypertension control. Retinal photographic assessment of hypertensive retinopathy signs may be useful for assessment of stroke risk.
PMCID: PMC4085393  PMID: 23940194
Hypertension; Hypertensive retinopathy; Stroke; Cerebral infarction
10.  Differential Influence of Distinct Components of Increased Blood Pressure on Cardiovascular OutcomesR3 
Hypertension  2013;62(3):10.1161/HYPERTENSIONAHA.113.01561.
Elevation in blood pressure (BP) increases risk for all cardiovascular events. Nevertheless, the extent to which different indices of BP elevation may be associated to varying degrees with different cardiovascular outcomes remains unclear. We studied 13,340 participants (aged 54±6 years, 56% women, 27% black) of the Atherosclerosis Risk in Communities Study who were free of baseline cardiovascular disease. We used Cox proportional hazards models to compare the relative contributions of systolic (SBP), diastolic (DBP), pulse pressure (PP), and mean arterial pressure (MAP) to risk for coronary heart disease (CHD), heart failure (HF), stroke, and all-cause mortality. For each multivariable-adjusted model, the largest area under the receiver-operating curve (AUC) and smallest -2 log likelihood values were used to identify BP measures with the greatest contribution to risk prediction for each outcome. A total of 2095 CHD events, 1669 HF events, 771 stroke events, and 3016 deaths occurred during up to 18±5 years of follow up. In multivariable analyses adjusting for traditional cardiovascular risk factors, the BP measures with the greatest risk contributions were: SBP for CHD (AUC=0.74); PP for HF (AUC=0.79), SBP for stroke (AUC=0.74), and PP for all-cause mortality (AUC=0.74). With few exceptions, results were similar in analyses stratified by age, sex, and race. Our data indicate that distinct BP components contribute variably to risk for different cardiovascular outcomes.
PMCID: PMC3828292  PMID: 23876475
hypertension; blood pressure; cardiovascular disease; outcomes; epidemiology
11.  Association of blood lactate with carotid atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study 
Atherosclerosis  2013;228(1):249-255.
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.
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).
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.
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.
PMCID: PMC3657708  PMID: 23510829
atherosclerosis; carotid arteries; plaque; epidemiology; lactate
12.  Hyperglycemia and Arterial Stiffness: the Atherosclerosis Risk in the Communities Study 
Atherosclerosis  2012;225(1):246-251.
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)).
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.
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).
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.
PMCID: PMC3936879  PMID: 23031361
atherosclerosis; distensibility; hyperglycemia; epidemiology
13.  Cognition and Incident Dementia Hospitalization: Results from the Atherosclerosis Risk in Communities (ARIC) Study 
Neuroepidemiology  2012;40(2):117-124.
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.
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.
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)).
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.
PMCID: PMC3642775  PMID: 23095770
Cognition; Dementia; Hospitalizations; Cognitive Function; Cognitive Decline
14.  Impact of long-term measures of glucose and blood pressure on the retinal microvasculature 
Atherosclerosis  2012;225(2):412-417.
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.
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.
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.
Modest and sustained long-term elevations in glucose and blood pressure are associated with retinopathy and retinal vascular caliber.
PMCID: PMC3513355  PMID: 23102597
epidemiology; microvascular disease; retinopathy; glucose; blood pressure
15.  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.
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.
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.
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.
PMCID: PMC3508325  PMID: 23111439
Stroke; Retinal microvascular signs; Retinopathy; Retinal vessel caliber
16.  Education and Cognitive Change over 15 Years: The Atherosclerosis Risk in Communities Study 
To evaluate whether education level is associated with change in cognitive performance.
Prospective cohort study.
The Atherosclerosis Risk in Communities (ARIC) Study, a community-based cohort.
Nine thousand two hundred sixty-eight ARIC participants who underwent cognitive evaluation at least twice over a 15-year period.
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.
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.
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.
PMCID: PMC3662980  PMID: 23013064
education; cognition; cognitive reserve
17.  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.
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.
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.
PMCID: PMC3760720  PMID: 22128224
lipoproteins; cardiovascular diseases; risk factors; race/ethnicity; cardiovascular disease risk factors
18.  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.
PMCID: PMC3415890  PMID: 22492856
19.  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.
PMCID: PMC4047279  PMID: 22472114
bias (epidemiology); cognitive disorders/dementia; cognitive reserve; cohort studies
20.  25(OH)D deficiency is associated with fatal stroke among whites but not blacks: The NHANES-III linked mortality files 
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.
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)].
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.
PMCID: PMC3304002  PMID: 22261577
vitamin D; stroke; racial differences
21.  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
22.  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.
To examine the effect of correcting coronary heart disease (CHD) risk factors for long-term within-person variation on CHD risk.
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.
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).
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.
PMCID: PMC3288692  PMID: 22221585
epidemiology; risk factors; statistics; heart diseases; models, cardiovascular; risk assessment
23.  Blood Lipid Levels, Lipid Lowering Medications, and the Incidence of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study 
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.
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.
PMCID: PMC3290134  PMID: 22227953
lipids; epidemiology; atrial fibrillation; statins
24.  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.
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.
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.
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.
PMCID: PMC3246524  PMID: 22033999
arterial stiffness; carotid ultrasound; coronary heart disease; stroke; ARIC
25.  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.
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.
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.
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).
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.
PMCID: PMC3226845  PMID: 21868017
atherogenic lipoproteins; anti-atherogenic lipoproteins; plaque burden; lipid-rich necrotic core

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