Long-term exposure to fine particulate matter, residential proximity to major roads and measures of brain structure.

BACKGROUND AND PURPOSE: Long-term exposure to ambient air pollution is associated with cerebrovascular disease and cognitive impairment, but whether it is related to structural changes in the brain is not clear. We examined the associations between residential long-term exposure to ambient air pollution and markers of brain aging using magnetic resonance imaging. METHODS: Framingham Offspring Study participants who attended the seventh examination were at least 60 years old and free of dementia and stroke were included. We evaluated associations between exposures (fine particulate matter [PM2.5] and residential proximity to major roadways) and measures of total cerebral brain volume, hippocampal volume, white matter hyperintensity volume (log-transformed and extensive white matter hyperintensity volume for age), and covert brain infarcts. Models were adjusted for age, clinical covariates, indicators of socioeconomic position, and temporal trends. RESULTS: A 2-µg/m(3) increase in PM2.5 was associated with -0.32% (95% confidence interval, -0.59 to -0.05) smaller total cerebral brain volume and 1.46 (95% confidence interval, 1.10 to 1.94) higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 (95% confidence interval, 0.01 to 0.19) greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter. CONCLUSIONS: Exposure to elevated levels of PM2.5 was associated with smaller total cerebral brain volume, a marker of age-associated brain atrophy, and with higher odds of covert brain infarcts. These findings suggest that air pollution is associated with insidious effects on structural brain aging even in dementia- and stroke-free persons.

Variations in common carotid artery intima-media thickness during the cardiac cycle: implications for cardiovascular risk assessment.

BACKGROUND: Common carotid artery intima-media thickness (IMT), a measure of atherosclerosis, varies between peak systole and end-diastole. This difference might affect cardiovascular risk assessment. METHODS: IMT measurements of the right and left common carotid arteries were synchronized with an electrocardiogram, using the R wave for end-diastole and the T wave for peak systole. IMT was measured in 2,930 members of the Framingham Offspring Study. Multivariate regression models were generated with end-diastolic IMT, peak systolic IMT, and change in IMT as dependent variables and Framingham risk factors as independent variables. End-diastolic IMT estimates were compared with the upper quartile of IMT on the basis of normative data obtained at peak systole. RESULTS: The average age of the study population was 57.9 years. The average difference in IMT during the cardiac cycle was 0.037 mm (95% confidence interval, 0.035-0.038 mm). End-diastolic IMT and peak systolic IMT had similar associations with Framingham risk factors (total R(2) = 0.292 vs 0.275) and were significantly associated with all risk factors. In a fully adjusted multivariate model, thinner IMT at peak systole was associated with pulse pressure (P < .0001), low-density lipoprotein cholesterol (P = .0064), age (P = .046), and no other risk factors. Performing end-diastolic IMT measurements while using upper quartile peak systolic IMT normative data led to inappropriately increasing by 42.1% the number of individuals in the fourth IMT quartile (high cardiovascular risk category). CONCLUSION: The difference in IMT between peak systole and end diastole is associated with pulse pressure, low-density lipoprotein cholesterol, and age. In this study, the mean IMT difference during the cardiac cycle led to an overestimation by 42.1% of individuals at high risk for cardiovascular disease.

Cardiac index is associated with brain aging: the Framingham Heart Study.

BACKGROUND: Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. METHODS AND RESULTS: Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61+/-9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92). CONCLUSIONS: Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.

Burden and prognostic importance of subclinical cardiovascular disease in overweight and obese individuals.

BACKGROUND: The burden and prognostic importance of subclinical cardiovascular disease (CVD) in obesity has not been investigated systematically. METHODS AND RESULTS: We examined prevalence of subclinical disease in 1938 Framingham Study participants (mean age, 57 years; 59% women) by use of 5 tests (electrocardiography, echocardiography, carotid ultrasound, ankle-brachial pressure, and urinary albumin excretion) and stratified by body mass index (BMI) (normal, < 25; overweight, 25 to < 30.0; obese, > or = 30 kg/m2) and waist circumference (WC) (increased, > or = 88 cm for women or > or = 102 cm for men). We investigated risk of overt CVD associated with adiposity according to presence versus absence of subclinical disease on any of the 5 tests. Prevalence of subclinical disease was higher in overweight (40.0%; adjusted odds ratio, 1.68) and obese individuals (49.7%; odds ratio, 2.82) compared with individuals with normal BMI (29.3%) and in individuals with increased WC (44.9%; odds ratio, 1.67) compared with normal WC (31.9%). On follow-up (mean 7.2 years), 139 participants had developed overt CVD. Presence of subclinical disease was associated with > 2-fold risk of overt CVD in all BMI and WC strata, with no evidence of an interaction between BMI and subclinical disease. CVD risk was attenuated in participants with obesity or increased WC but without subclinical disease (adjusted hazard ratio for obesity, 1.57; 95% confidence interval, 0.74 to 3.33; adjusted hazard ratio for increased WC, 1.22; 95% confidence interval, 0.69 to 2.15), compared with individuals with normal BMI or WC and no subclinical disease, respectively. CONCLUSIONS: In our community-based sample, overweight and obesity were associated with high prevalence of subclinical disease, which partly contributed to the increased risk of overt CVD in these strata.

The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination.

For nearly 60 years, the Framingham Heart Study has examined the natural history, risk factors, and prognosis of cardiovascular, lung, and other diseases. Recruitment of the Original Cohort began in 1948. Twenty-three years later, 3,548 children of the Original Cohort, along with 1,576 of their spouses, enrolled in the Offspring Cohort. Beginning in 2002, 4,095 adults having at least one parent in the Offspring Cohort enrolled in the Third Generation Cohort, along with 103 parents of Third Generation Cohort participants who were not previously enrolled in the Offspring Cohort. The objective of new recruitment was to complement phenotypic and genotypic information obtained from prior generations, with priority assigned to larger families. From a pool of 6,553 eligible individuals, 1,912 men and 2,183 women consented and attended the first examination (mean age: 40 (standard deviation: 9) years; range: 19-72 years). The examination included clinical and laboratory assessments of vascular risk factors and imaging for subclinical atherosclerosis, as well as assessment of cardiac structure and function. The comparison of Third Generation Cohort data with measures previously collected from the first two generations will facilitate investigations of genetic and environmental risk factors for subclinical and overt diseases, with a focus on cardiovascular and lung disorders.

Assessment by cardiovascular magnetic resonance, electron beam computed tomography, and carotid ultrasonography of the distribution of subclinical atherosclerosis across Framingham risk strata.

Screening for subclinical atherosclerosis has been advocated for individuals at intermediate global risk for coronary heart disease (CHD). However, the distribution of subclinical atherosclerosis test values across CHD risk strata is unknown. We studied a stratified random sample of 292 participants (mean age 59.5 years, 50% women) from the offspring cohort of the Framingham Heart Study who were free of clinically apparent cardiovascular disease. We assessed abdominal and thoracic aortic plaque burden by cardiovascular magnetic resonance (CMR), coronary artery calcification (CAC) and thoracic aortic calcification (TAC) by electron beam computed tomography, and common carotid intima-media thickness (C-IMT) by ultrasonography. We categorized the upper 20% of each measurement as a high level of atherosclerosis and evaluated these variables across clinically relevant Framingham CHD risk score strata (low, intermediate, and high risk). In age-adjusted analyses in men and women, correlations across CMR aortic plaque, CAC, TAC, and C-IMT were low (maximum r = 0.30 for CAC:TAC in women, p <0.005). In men and women, the proportion of subjects with high atherosclerosis test results for any of these measurements increased significantly across Framingham CHD risk score strata (Kruskal-Wallis test, p <0.0001). In the intermediate Framingham CHD risk score category, 14% of men and 25% of women had a high atherosclerosis result on >or=2 measurements. However, different participants were identified as having high atherosclerosis by each modality. For example, in a comparison of the overlap across CMR aortic plaque, CAC, and C-IMT, only 4% of men and 16% of women were classified as having high atherosclerosis on all 3 measurements. In conclusion, in a community-based sample, correlations among subclinical atherosclerosis test results are low, and a substantial proportion has high levels of subclinical atherosclerosis detected on >or=2 imaging tests.

Peripheral and cerebral atherothrombosis and cardiovascular events in different vascular territories: insights from the Framingham Study.

Major risk factors for clinical atherosclerosis include dyslipidemia, hypertension, glucose intolerance, adiposity, cigarette smoking, hemostatic factors, inflammatory markers, and sedentary lifestyle. Sets of some of these and evidence of vascular damage such as left ventricular hypertrophy and atrial fibrillation are used to formulate multivariable risk profiles for peripheral artery disease and stroke. These global risk formulations facilitate office estimation of the risk of these disabling diseases, which often indicate diffuse systemic atherosclerosis. Because predisposing risk factors usually cluster, and the risk each imposes varies widely, global risk assessment is a necessity, especially now that average risk factor levels are recommended for treatment. Novel risk factors deserve attention, but the standard cardiovascular risk factors account for as much as 85% of the cardiovascular disease arising within the population. Further improvement in detection, evaluation, and control of the major risk factors by implementation of guidelines for primary and secondary prevention of stroke and peripheral artery disease is needed, particularly in the high-risk segment of the population.