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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Background and purpose

Cerebral atrophy, detected as ventricular enlargement (VE) or sulcal widening (SW) on magnetic resonance imaging (MRI), is recognized as a risk factor for vascular dementia or Alzheimer’s disease. However, its underlying pathophysiology is not known. We examined whether retinal microvascular assessment could provide predictive information on the risk of VE and SW on MRI.

Methods

A prospective, population-based study of 810 middle-aged persons without clinical stroke or MRI infarcts. All participants had a first cranial MRI and retinal photography in 1993-95, and returned for a repeated MRI in 2004-06 (median follow-up of 10.5 years). Retinal photographs were graded for presence of retinopathy and retinal microvascular abnormalities, and MRI images were graded for ventricular size (VS) and sulcal size (SS) according to standardized protocols. VE and SW were defined as an increase in VS or SS of ≥3 of 10 grades between baseline and follow-up.

Results

After adjusting for age, gender and cardiovascular risk factors, retinopathy and arterio-venous nicking at baseline were associated with 10-year VE (odds ratio [OR] and 95% confidence interval [CI]: 2.03, 1.20-4.42 for retinopathy and 2.19, 1.23-3.90 for arterio-venous nicking). Retinal signs were not associated with 10-year SW.

Conclusions

Retinopathy and arteriovenous nicking are predictive of long-term risk of VE, but not of SW, independent of cardiovascular risk factors. These data support a microvascular etiology for subcortical but not cortical cerebral atrophy.

Silent brain infarct and white matter lesions are common radiological findings associated with the risk of clinical stroke and dementia; however, our understanding of their underlying pathophysiology and risk factors remains limited. This study aimed to determine whether assessment of retinal microvascular abnormalities could provide prognostic information regarding the risk of brain infarct and white matter lesions on magnetic resonance imaging. This study is based on a subset of 810 middle-aged persons without clinical stroke or baseline magnetic resonance imaging infarct enrolled in the Atherosclerosis Risk in Communities Brain Magnetic Resonance Imaging Study, a prospective, population-based study. Participants had a baseline magnetic resonance imaging brain examination and retinal photography in 1993–1995, and returned for a repeat magnetic resonance imaging examination in 2004–2006. Magnetic resonance images were graded for presence of any cerebral infarct, infarct with lacunar characteristics and white matter lesions according to standardized protocols. Retinal photographs were graded for presence of retinopathy lesions and retinal arteriolar abnormalities following a standardized protocol. Over a median follow-up of 10.5 years, 164 (20.2%) participants developed cerebral infarct, 131 (16.2%) developed lacunar infarct, 182 (24.2%) developed new white matter lesions and 49 (6.1%) had evidence of white matter lesion progression. After adjusting for age, gender, race, cardiovascular risk factors and carotid intima-media thickness, retinopathy was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval 1.42–5.60) and lacunar infarct (odds ratio 3.19; 95% confidence interval: 1.56–6.50). Retinal arteriovenous nicking was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval: 1.66–4.76), lacunar infarct (odds ratio 2.48; 95% confidence interval: 1.39–4.40) and white matter lesion incidence (odds ratio 2.12; 95% confidence interval: 1.18–3.81) and progression (odds ratio 2.22; 95% confidence interval: 1.00–5.88). In conclusion, retinal microvascular abnormalities are associated with emergence of subclinical magnetic resonance imaging brain infarcts and white matter lesions, independent of shared risk factors. Retinal vascular imaging may offer a non-invasive tool to investigate the pathogenesis and natural history of cerebral small-vessel disease.

Background

Individuals with exaggerated exercise blood pressure (BP) tend to develop future hypertension. It is controversial if they have higher risk of death from cardiovascular disease (CVD).

Methods and Results

6,578 asymptomatic Lipid Research Clinic Prevalence Study participants (45% women, mean age 46 years, 74% untreated baseline BP <140/90mmHg [non-hypertensive]) performing submaximal Bruce treadmill tests were followed for 20 years (385 CVD deaths occurred). Systolic and diastolic BP at rest, Bruce stage 2, and maximal BP during exercise were significantly associated with CVD death. Comparing multivariate hazard ratios (HRs) and 95% confidence intervals per 10/5mmHg BP increments, the association was strongest for rest BP (systolic 1.21 [1.14–1.27]; diastolic 1.20 [1.14–1.26]), then Bruce stage 2 BP (systolic 1.09 [1.04–1.14]; diastolic 1.09 [1.05–1.13]), then maximal exercise BP (systolic 1.06 [1.01–1.10]; diastolic 1.04 [1.01–1.08]). Overall, exercise BP was not significant after adjustment for rest BP. However, hypertension status modified the risk associated with exercise BP (p, interaction=0.03). Among non-hypertensives, whether they had normal BP (<120/80mmHg) or prehypertension, Bruce stage 2 BP >180/90 vs. ≤180/90mmHg carried increased risk independent of rest BP and risk factors (adjusted HR for systolic 1.96 [1.40–2.74], p<0.001; diastolic 1.48 [1.06–2.06], p=0.02), and added predictive value (net reclassification improvement systolic 12.0% [−0.1–24.2%], diastolic 9.9% [−0.3–20.0%]; relative integrated discrimination improvement 14.3% and 12.0%, respectively).

Conclusions

In asymptomatic individuals, elevated exercise BP carried higher risk of CVD death, but became non-significant after accounting for rest BP. However, Bruce stage 2 BP >180/90mmHg identified non-hypertensive individuals at higher risk of CVD death.

Circulating levels of inflammatory markers predict the risk of cardiovascular disease (CVD), mediated perhaps in part by dietary fat intake, through mechanisms only partially understood. To evaluate post-fat load changes in inflammatory markers and genetic influences on these changes, we administered a standardized high-fat meal to 838 related Amish subjects as part of the Heredity and Phenotype Intervention (HAPI) Heart Study and measured a panel of inflammatory markers, including C-reactive protein (CRP), interleukin-1 β (IL-1β), matrix metalloproteinase-1 and -9 (MMP-1 and MMP-9), and white blood cell (WBC) count, before and 4 hours post-fat challenge (CRP pre-challenge only). Heritabilities (h2 ± SD) of basal inflammatory levels ranged from 16 ± 8% for MMP-9 (P = 0.02) to 90 ± 7% for MMP-1 (P < 0.0001). Post-fat load, circulating levels of WBC, MMP-1 and MMP-9 increased by 16%, 32% and 43% (all P < 0.0001), with no significant changes in IL-1β. Postprandial changes over the 4-hour period were modestly heritable for WBC (age- and sex-adjusted h2 = 14 ± 9%, P = 0.04), but the larger MMP-1 and MMP-9 changes appeared to be independent of additive genetic effects. These results reveal that a high fat meal induces a considerable inflammatory response. Genetic factors appear to play a significant role influencing basal inflammatory levels but to have minimal influence on post-fat intake inflammatory changes.

Background. Individuals infected with human immunodeficiency virus (HIV) have increased risk of cardiovascular events. It is unknown whether T cell activation and senescence, 2 immunologic sequelae of HIV infection, are associated with vascular disease among HIV-infected adults.

Methods. T cell phenotyping and carotid ultrasound were assessed among 115 HIV-infected women and 43 age- and race/ethnicity-matched HIV-uninfected controls participating in the Women's Interagency HIV Study. Multivariate analyses were used to assess the association of T cell activation (CD38+HLA-DR+) and senescence (CD28−CD57+) with subclinical carotid artery disease.

Results. Compared with HIV-uninfected women, frequencies of CD4+CD38+HLA-DR+, CD8+CD38+HLA-DR+, and CD8+CD28−CD57+ T cells were higher among HIV-infected women, including those who achieved viral suppression while receiving antiretroviral treatment. Among HIV-infected women, adjusted for age, antiretroviral medications, and viral load, higher frequencies of activated CD4+ and CD8+ T cells and immunosenescent CD8+ T cells were associated with increased prevalence of carotid artery lesions (prevalence ratiolesions associated with activated CD4+ T cells, 1.6 per SD [95% confidence interval {CI}, 1.1–2.2]; P = .02; prevalence ratiolesions associated with activated CD8+ T cells, 2.0 per SD [95% CI, 1.2–3.3]; P < .01; prevalence ratiolesions associated with senescent CD8+ T cells, 1.9 per SD [95% CI, 1.1–3.1]; P = .01).

Conclusions. HIV-associated T cell changes are associated with subclinical carotid artery abnormalities, which may be observed even among those patients achieving viral suppression with effective antiretroviral therapy.

Background and Purpose

Blood pressure (BP) is a predictor of concurrent and subsequently measured white matter hyperintensity (WMH), but longitudinal studies of WMH change and data in black participants are lacking. We hypothesized that WMH progression would be 1) strongly related to BP in blacks and whites, and 2) predicted more strongly by earlier (midlife) or cumulative BP measurements than by measures at older ages.

Methods

Participants were 983 individuals (49% African-American) from the Atherosclerosis Risk in Communities (ARIC) Study, who underwent cerebral MRIs in 1993–5 and 2004–6. Associations between BP (measured at each of five visits, in addition to a time-averaged cumulative BP) and progression of WMH were analyzed and compared.

Results

Cumulative SBP was the strongest BP predictor of WMH progression in adjusted models. Higher cumulative SBP by 20 mm Hg was associated with greater progression of WMH, and was similar in blacks (2.5 cc; p<0.0001) and whites (2.6 cc; p<0.0001). Higher cumulative SBP (per 20 mm Hg) was also associated with being in the top quintile of WMH progression (adjusted OR 2.0; 95% CI 1.6–2.6). Earlier SBP measurements were stronger predictors of WMH progression than later SBP, in blacks only.

Conclusions

In this population-based cohort, cumulative SBP was a stronger predictor of WMH progression than SBP from individual visits, in both blacks and whites. Earlier BPs were stronger predictors than BPs measured at later timepoints, in blacks only.

Background

To examine the association between orthostatic hypotension (OH) and cognitive function in middle-aged adults.

Methods

Participants were 12,702 men and women from the Atherosclerosis Risk in Communities Study. OH was defined as decrease in systolic blood pressure (BP) by ≥20 mm Hg or diastolic BP by ≥10 mm Hg upon standing. At the 2nd and the 4th follow-up examinations, cognitive function was assessed using the Delayed Word Recall Test, Digit Symbol Substitution Test (DSST) and Word Fluency Test (WFT).

Results

After age adjustment, those with OH were more likely to be in the lowest quintile of the DSST (OR = 1.34, 95% CI = 1.12–1.62) and WFT (OR = 1.25, 95% CI = 1.03–1.51) than were those without OH. After adjustment for sociodemographic and cardiovascular risk factors, associations were no longer significant. In age-adjusted models only, OH was associated with increased odds of being in the greatest quintile of decline in DSST score between visits 2 and 4 (OR = 1.28, 95% CI = 1.04–1.58).

Conclusions

OH was associated with less favorable cognitive function, but this association was largely attributable to demographic and cardiovascular risk factors. Episodic asymptomatic hypotension in middle age may not be an independent cause of cognitive decline. Further study, including emphasis on neuroimaging, is needed.

Background and Purpose

Retinal microvasculature reflects cumulative small vessel damage from hypertension and other vascular processes. No study has prospectively examined retinal findings in relation to incidence of clinical lacunar stroke in comparison with other ischemic stroke subtypes.

Methods

In 10,496 adults initially free of stroke, we related retinal findings imaged during 1993-95 with incidence of hospitalized ischemic strokes through 2005.

Results

During a median of 11.2 years 338 incident ischemic strokes occurred (lacunar: 66, nonlacunar thrombotic: 192, cardioembolic: 80). Generalized arteriolar narrowing as measured by central retinal arteriole equivalent (CRAE) was associated with an increased incidence of lacunar stroke (multivariate-adjusted hazard ratio (HR) per 1-standard deviation (SD) decrement of CRAE: 1.67, 95% confidence interval (CI): 1.23-2.26), but was not associated with other ischemic stroke subtypes. Generalized venular widening as measured by central venule equivalent (CRVE) was also positively associated with only lacunar stroke (multivariate-adjusted HR per 1-SD increment: 1.44, 95% CI: 1.09-1.91). Retinal microvascular abnormalities were positively associated with lacunar stroke incidence (HR for focal arteriolar narrowing: 2.22, 95% CI: 1.11-4.48; for arteriovenous nicking: 2.38, 95% CI: 1.20-4.71), whereas retinopathy signs (microaneurysms, retinal hemorrhages, and others) were positively associated with nonlacunar thrombotic (HR: 2.41, 95% CI: 1.47-3.95) and cardioembolic stroke incidence (HR: 2.25, 95% CI: 1.09-4.65).

Conclusions

Narrower CRAE, wider CRVE, focal arteriolar narrowing and arteriovenous nicking were predictive of lacunar stroke. Retinal imaging is useful in understanding the pathophysiology and mechanisms of cerebral small vessel disease.

Objective

To describe the prospective relationship of retinal vessel diameters with risk of hypertension in a multiethnic population-based cohort.

Methods

The Multi-Ethnic Study of Atherosclerosis is a population-based study of subclinical cardiovascular disease among white, African–American, Hispanic, and Chinese American adults aged 45–84 years. Retinal vessel diameters were measured using a standardized imaging software at the second examination (considered baseline in this analysis) and summarized as the central retinal artery/vein equivalent. Presence of retinopathy and retinal focal arteriolar narrowing and arteriovenous nicking was assessed by trained graders. Incidence of hypertension was defined among participants at risk as systolic blood pressure at least 140 mmHg, diastolic blood pressure at least 90 mmHg, or use of an antihypertensive medication.

Results

Of the initial 6237 participants at baseline, 2583 were at risk of hypertension. After 3.2±0.5 years of follow-up, 448 (17.3%) participants developed hypertension. After adjusting for age, sex, race/ethnicity, the average of mean arterial blood pressure in the first and second examination, and other vascular risk factors, persons with narrower retinal arteriolar diameter and wider venular diameter at baseline were more likely to develop hypertension [odds ratio per SD decrease in central retinal artery equivalent 1.20, 95% confidence intervals 1.02, 1.42; and odds ratio per SD increase in central retinal vein equivalent 1.18, 95% confidence interval 1.02, 1.37]. Persons with focal arteriolar narrowing were also more likely to develop hypertension (odds ratio 1.80, 95% confidence interval 1.09, 2.97).

Conclusion

Findings from this multiethnic population confirm that narrower retinal arteriolar diameter and wider venular diameter are associated with the development of hypertension independent of traditional risk factors.

Objectives

To examine the relative contributions of systemic cardiovascular factors to retinal arteriolar and venular caliber in men and women and in whites and African-Americans.

Methods

In the Atherosclerosis Risk in Communities (ARIC) study, retinal arteriolar caliber (central retinal arteriolar equivalent, CRAE) and venular caliber (central retinal venular equivalent, CRVE) were measured from digitized retinal photographs for 8,794 participants.

Results

The main systemic determinants of narrower CRAE were, in order of decreasing relative contribution, higher current mean arterial blood pressure (MABP), lower serum albumin, current alcohol consumption and higher body mass index. The main systemic determinants of wider CRVE were current cigarette smoking and higher current MABP, followed by higher white cell count, body mass index and plasma LDL cholesterol levels. These associations were generally similar in whites and African-Americans and in men and women.

Conclusions

The major systemic determinant of narrower retinal arteriolar caliber is higher blood pressure, while those of wider retinal venular caliber are cigarette smoking, higher blood pressure, systemic inflammation and obesity. These data offer further insights into systemic processes influencing arteriolar and venular characteristics, and may help explain the observed associations of retinal vascular caliber and the risk of clinical cardiovascular disease.

Background

Cardiovascular risk factors are associated with a higher risk of developing dementia. Studies in older populations, however, have often failed to show this relationship. We assessed the association between cardiovascular risk factors measured in midlife and risk of being hospitalized with dementia and determined whether this association was modified by age and ethnicity.

Methods

We studied 11,151 participants in the population-based Atherosclerosis Risk in Communities cohort, aged 46-70 (23% African Americans) in 1990-1992, when participants underwent a physical exam and cognitive testing. Hospitalizations with dementia were ascertained through December 2004.

Results

During follow-up, 203 cases of hospitalization with dementia were identified. Smoking (hazard ratio (HR), 95% confidence interval (CI): 1.7, 1.2-2.5), hypertension (HR, 95% CI: 1.6, 1.2-2.2) and diabetes (HR, 95% CI: 2.2, 1.6-3.0) were strongly associated with dementia, both in whites and African-Americans. These associations were stronger when risk factors were measured at younger age than at older age. In analyses including updated information on risk factors during follow-up, the HR of dementia in hypertensive versus non-hypertensive participants was 1.8 at age <55 years compared to 1.0 at age 70+ years. Parallel results were observed for diabetes (HR 3.4 in <55, 2.0 in ≥70), smoking (4.8 in <55, 0.5 in ≥70), and hypercholesterolemia (HR 1.7 in <55, 0.9 in ≥70)

Conclusion

In this prospective study, smoking, hypertension, and diabetes were strongly associated with subsequent risk of hospitalization with dementia, particularly in middle aged individuals. Our results emphasize the importance of early lifestyle modification and risk factor treatment to prevent dementia.