Retinal microvascular signs are associated with systemic conditions and cognitive decline. We studied the associations of microvascular changes, measured by retinal signs, with disability in performing activities of daily living (ADL).
Prospective cohort study.
1487 participants in the Cardiovascular Health Study (mean age 78 years) who were free of ADL disability and had available data on retinal signs and carotid intima-media thickness (IMT) at the 1998–99 visit.
Main Outcome Measure
Incident ADL disability, defined as self-reported difficulty in performing any ADLs, by the presence of retinal signs and advanced carotid atherosclerosis, defined by carotid IMT ≥ 80th percentile or ≥ 25% stenosis; and potential mediation by cerebral microvascular disease on brain imaging or by executive dysfunction, slow gait, and depressive mood that are symptoms of frontal subcortical dysfunction.
During the median follow-up of 3.1 years (maximum 7.8 years), participants with ≥ 2 retinal signs had a higher rate of disability than those with < 2 retinal signs (10.1% versus 7.1%; adjusted hazards ratio, 1.45; 95% confidence interval, 1.24–1.69; P < 0.001). There was no evidence of interaction by advanced carotid atherosclerosis (P > 0.10). The association seemed to be partially mediated by executive dysfunction, slow gait, and depressive symptoms, but not by cerebral microvascular disease on brain imaging.
These results provide further support for the pathophysiologic and prognostic significance of microvascular disease in age-related disability. However, it remains to be determined how to best utilize retinal photography in the clinical risk prediction.
We sought to determine whether novel markers not involving ionizing radiation could predict CAC progression in a low-risk population.
Increase in coronary artery calcium (CAC) scores over time (CAC progression) improves prediction of coronary heart disease (CHD) events. Due to radiation exposure, CAC measurement represents an undesirable method for repeated risk assessment, particularly in low predicted risk individuals (Framingham Risk Score [FRS] <10%).
From 6814 MESA participants, 2620 individuals were classified as low risk for CHD events (FRS <10%), and had follow-up CAC measurement. In addition to traditional risk factors [(RFs) - base model], various combinations of novel-marker models were selected based on data-driven, clinical, or backward stepwise selection techniques.
Mean follow-up was 2.5 years. CAC progression occurred in 574 participants (22% overall; 214 of 1830 with baseline CAC =0, and 360 of 790 with baseline CAC >0). Addition of various combinations of novel markers to the base model (c-statistic =0.711), showed improvements in discrimination of approximately only 0.005 each (c-statistics 0.7158, 0.7160 and 0.7164) for the best-fit models. All 3 best-fit novel-marker models calibrated well but were similar to the base model in predicting individual risk probabilities for CAC progression. The highest prevalence of CAC progression occurred in the highest compared to the lowest probability quartile groups (39.2–40.3% versus 6.4–7.1%).
In individuals at low predicted risk by FRS, traditional RFs predicted CAC progression in the short term with good discrimination and calibration. Prediction improved minimally when various novel markers were added to the model.
coronary calcium; Framingham risk score; risk factors; progression
We assessed the association between sleep apnea, snoring, incident cardiovascular (CV) events and all-cause mortality in the Multi Ethnic Study of Atherosclerosis (MESA) cohort.
Out of 5338 respondents to a sleep questionnaire administered during the second MESA exam period, 208 had physician-diagnosed sleep apnea (PDSA), 1452 were habitual snorers (HS) and 3678 were neither a habitual snorer nor had PDSA (normal participants). Cox proportional hazard analysis was used to assess the associations adjusting for age, gender, race/ethnicity, smoking, diabetes mellitus, total cholesterol, HDL, triglycerides, BMI, current alcohol use, benzodiazepine use, BP medications and statin use.
Over a 7.5 year average follow-up period, 310 adjudicated CV events including MI, stroke, angina, resuscitated cardiac arrest, stroke death and CVD death and 189 deaths occurred. Compared to HS, PDSA was associated with higher incident CV rates in both univariate and multivariable models [hazard ratio (95%); 1.89(1.22–2.93), p=0.004 and 1.91(1.20 –3.04), p=0.007 respectively]. PDSA was also associated with a higher death rates compared with HS [hazard ratio (95%); 2.13(1.25 – 3.63), p=0.006 and 2.70(1.52– 4.79), p=0.007 respectively]. Compared with normal participants, PDSA had higher incident CV event rates in both univariate and multivariable models [hazard ratio (95%); 2.23[1.39–3.60], p=0.001 and 2.16[1.30–3.58], p=0.003 respectively]. Similarly, PDSA had a higher death rate compared with normal participants in both the univariate and multivariable models [hazard ratio (95%CI); 2.44(1.36 – 4.37), p=0.003 and 2.71(1.45 – 5.08), p=0.002 respectively]. Habitual snorers had similar incident CV event rates and death rates in both univariate and multivariable models compared with normal participants.
PDSA but not habitual snoring was associated with high incident CV events and all-cause mortality in a multi-ethnic population based study of adults free of clinical CV disease at baseline.
Obstructive sleep apnea; habitual snorers; cardiovascular events; mortality; population
Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.
Methods and Results
Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole.
Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole.
Clinical Trial Registration
URL: www.ClinicalTrials.gov. Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.)
atherosclerosis; blood pressure; carotid arteries; diastole; epidemiology; risk factors; systole; ultrasonics
To assess the cardiovascular risk of impaired fasting glucose (IFG).
The association between IFG, incident type 2 diabetes mellitus (T2DM) and cardiovascular (CV) events remains unclear.
The Multi-Ethnic Study of Atherosclerosis (MESA) included participants aged 45–84 free of clinical CV disease at baseline (2000–2002). T2DM was defined as fasting glucose >125mg/dl or anti-diabetes medication at baseline and follow-up exams, IFG as no T2DM and fasting glucose 100–125.mg/dl. Cox proportional hazard analysis was used to assess the association between IFG and incident DM and also with incident CV events.
Of 6753 participants included in these analyses 840 (12.7%) had T2DM, 940 (13.8%) had IFG at the baseline exam. During 7.5 years of follow-up there were 418 adjudicated CV events. T2DM was associated with an increased CV incidence in the univariate [hazard ratio (HR); 2.83(2.25–3.56), p<0.0001] and multivariable models (adjusted for demographics and traditional risk factors) [HR; 1.87(1.47 – 2.37), p<0.0001] compared with subjects without T2DM (IFG + NFG). IFG was associated with increased incidence of T2DM [HR; 13.2 (95%CI 10.8–16.2), p<0.001] that remained after adjusting for demographics, highest educational level, physical activity and BMI [HR; 10.5(8.4–13.1), p<0.001] compared to NFG. IFG was associated with incident CV events in the univariate [HR; 1.64(1.26 – 2.14), p=<0.001] but not in the full multivariable model [HR; 1.16(95% CI 0.88–1.52), p=0.3] compared with NFG.
Having IFG was not independently associated with an increased short-term risk for incident CV events. These data reiterate the importance of intervention in persons with IFG to reduce their incidence of T2DM.
Impaired fasting glucose; diabetes mellitus; cardiovascular events; population
The prevalence of hypertension is higher among African-Americans than whites. However, inconsistent findings have been reported on the incidence of hypertension among middle-aged and older African-Americans and whites and limited data are available on the incidence of hypertension among Hispanics and Asians in the US. Therefore, this study investigated the age-specific incidence of hypertension by ethnicity for 3,146 participants from the Multi-Ethnic Study of Atherosclerosis. Participants, age 45–84 years at baseline, were followed for a median of 4.8 years for incident hypertension, defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the initiation of antihypertensive medications. The crude incidence rate of hypertension, per 1,000 person-years, was 56.8 for whites, 84.9 for African-Americans, 65.7 for Hispanics, and 52.2 for Chinese. After adjustment for age, gender, and study site, the incidence rate ratio (IRR) for hypertension was increased for African-Americans age 45–54 (IRR=2.05, 95% CI=1.47, 2.85), 55–64 (IRR=1.63, 95% CI=1.20, 2.23), and 65–74 years (IRR=1.67, 95% CI=1.21, 2.30) compared with whites, but not for those 75–84 years of age (IRR=0.97, 95% CI=0.56, 1.66). Additional adjustment for health characteristics attenuated these associations. Hispanic participants also had a higher incidence of hypertension compared with whites; however, hypertension incidence did not differ for Chinese and white participants. In summary, hypertension incidence was higher for African-Americans compared with whites between 45 and 74 years of age but not after age 75 years. Public health prevention programs tailored to middle-age and older adults are needed to eliminate ethnic disparities in incident hypertension.
hypertension; race/ethnicity; epidemiology; incidence
Background and Purpose
We hypothesized that retinal microvascular signs are associated with executive dysfunction, slow gait, and depressive mood that are characteristic features of microvascular disease affecting frontal subcortical regions of the brain.
In the Cardiovascular Health Study, 1744 participants (mean age 78) free of stroke had retinal photographs and carotid ultrasound during the 1997–1998 visit. We examined the cross-sectional association of retinal signs with the digit-symbol substitution test (DSST) score, gait speed, the Center for Epidemiologic Studies – Depression (CES-D) score, and depressive mood, defined as CES-D score > 9 or antidepressant use.
After adjusting for potential confounders, retinal signs were associated with lower DSST score (generalized arteriolar narrowing and arteriovenous nicking), slower gait (retinopathy), and depressive mood (generalized arteriolar narrowing). A higher number of retinal signs was associated with lower DSST score (−0.76 and −2.79 points for 1 sign and ≥ 2 signs versus none; P < 0.001) and slower gait (−0.009 and −0.083 m/sec; P = 0.047), but not with the square root of CES-D score (0.079 and −0.208; P = 0.072). In addition, coexistence of retinal signs (generalized arteriolar narrowing and arteriovenous nicking) and carotid atherosclerosis was associated with lower DSST score compared with either process alone (P for interaction < 0.01). Notably, further adjustment for ventricular size, white matter disease, and infarcts on magnetic resonance imaging did not attenuate the association.
Retinal signs are associated with executive dysfunction and slow gait, and possibly with depressive mood, suggesting a common process involving small vessels.
Retinal Microvascular Signs; Executive Function; Gait Speed; Depression
By examining the distribution of CAC across FRS strata in a large, multi-ethnic, community-based sample of men and women, we sought to determine if lower risk persons could potentially benefit from CAC screening.
The 10-year Framingham risk scores (FRS) and coronary artery calcium (CAC) are predictors of coronary heart disease (CHD). CAC ≥300 is associated with the highest risk for CHD even in low risk (FRS <10%) persons; however expert groups have suggested CAC screening only in intermediate risk (FRS 10–20%) groups.
We included 5660 MESA participants. The number needed to screen [number of people that need to be screened to detect one person with CAC above the specified cut-point (NNS)] was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using chi-square tests.
CAC >0, ≥100 and ≥300 were present in 46.4%, 20.6% and 10.1% of participants, respectively. Prevalence and amount of CAC increased with higher FRS. CAC ≥300 was observed in 1.7% and 4.4% of those with FRS 0–2.5% and 2.6–5%, respectively (NNS =59.7 and 22.7). Likewise, CAC ≥300 was observed in 24% and 30% of those with FRS 15.1–20% and >20%, respectively (NNS =4.2 and 3.3). Trends were similar when stratified by age, gender and race/ethnicity.
Our study suggests that in very low risk individuals (FRS ≤5%), the yield of screening and probability of identifying persons with clinically significant levels of CAC is low, but becomes greater in low and intermediate risk persons (FRS 5.1–20%).
Framingham risk score; coronary calcium; coronary heart disease; number needed to screen; risk factors; population; atherosclerosis; low risk
Increased left ventricular (LV) mass and changes in LV geometry may precede hypertension onset. The authors examined the associations of LV mass and geometry, assessed by cardiac magnetic resonance imaging, with hypertension incidence in 2,567 normotensive participants enrolled in 2000–2002 in the Multi-Ethnic Study of Atherosclerosis, an ethnically diverse, population-based, US study. Over a median follow-up of 4.8 years, 745 (29%) participants developed hypertension. In a fully adjusted model including baseline blood pressure, the relative risks of incident hypertension from the lowest to highest LV mass quartile were 1.00 (referent), 1.13 (95% confidence interval (CI): 0.89, 1.43), 1.28 (95% CI: 1.00, 1.63), and 1.78 (95% CI: 1.38, 2.30) (P < 0.001 for linear trend). Higher levels of LV concentric geometry, defined by higher LV mass to end-diastolic volume quartiles, were associated with higher risk of incident hypertension in a fully adjusted model (P = 0.044 for linear trend). In a final model containing both quartiles of LV mass and LV mass/volume along with all covariates including baseline blood pressure, higher LV mass quartiles were associated with incident hypertension (P < 0.001 for linear trend), whereas higher LV mass/volume quartiles were not (P = 0.643 for linear trend). In this multiethnic cohort, alterations in LV mass preceded hypertension onset among normotensive individuals.
hypertension; hypertrophy, left ventricular; magnetic resonance imaging; risk factors
Alcohol use has been consistently found to have a J-shaped association with coronary heart disease, with moderate drinkers exhibiting a decreased risk compared to both heavy drinkers and non-drinkers. However, studies of the association between alcohol use and subclinical coronary artery disease have conflicted.
To determine whether alcohol is associated with the presence, amount, or progression of coronary calcium over a 2- to 4-year period.
MESA is a prospective community-based cohort study of subclinical cardiovascular disease in a multi-ethnic cohort. In 2000–2002, 6814 participants free of clinical cardiovascular disease were enrolled at 6 participating centers.
There were 3766 (55.5%) current drinkers, 1635 (24.1%) former drinkers, and 1390 (20.5%) never drinkers included in the analysis. Although light to moderate alcohol consumption was associated with lower coronary heart disease risk, we found no evidence of a protective or J-shaped association of alcohol and coronary artery calcium (CAC). In fact there was evidence that heavy consumption of hard liquor was associated with greater CAC accumulation. Other alcoholic beverages were not associated with CAC prevalence, incidence or progression.
This is the first large study to evaluate the association of alcohol and coronary artery calcium in four racial/ethnic groups, and to evaluate progression of calcification. These results suggest that the cardiovascular benefits that may be derived from light to moderate alcohol consumption are not mediated through reduced CAC accumulation.
Excessive non-subcutaneous fat deposition may impair the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids.
We examined the cross-sectional association between non-subcutaneous adiposity and calcified coronary plaque, a non-invasive measure of coronary artery disease burden.
Participants in the Multi-Ethnic Study of Atherosclerosis underwent CT assessment of calcified coronary plaque. We measured multiple fat depots in 398 white and black participants (47% men and 43% black), ages 47–86 years, from Forsyth County, NC during 2002–2005, using cardiac and abdominal CT scans. In addition to examining each depot separately, we also created a non-subcutaneous fat index using the standard scores of non-subcutaneous fat depots.
A total of 219 participants (55%) were found to have calcified coronary plaque. After adjusting for demographics, lifestyle factors and height, calcified coronary plaque was associated with a one standard deviation increment in the non-subcutaneous fat index (OR = 1.41; 95% CI: 1.08, 1.84), pericardial fat (OR = 1.38; 95% CI: 1.04, 1.84), abdominal visceral fat (OR = 1.35; 95% CI: 1.03, 1.76), but not with fat content in the liver, intermuscular fat, or abdominal subcutaneous fat. The relation between non-subcutaneous fat index and calcified coronary plaque remained after further adjustment for abdominal subcutaneous fat (OR = 1.40; 95% CI: 1.00, 1.94). The relation did not differ by gender and ethnicity.
The overall burden of non-subcutaneous fat deposition, but not abdominal subcutaneous fat, may be a correlate of coronary atherosclerosis.
In 2002 the United States Preventive Services Task Force and the American Heart Association recommended aspirin for the primary prevention of Coronary Heart Disease (CHD) in individuals with a Framingham risk score ≥ 6% or ≥ 10%, respectively. The regular use of aspirin (≥ 3 days per week) was examined in a cohort of 6452 White, Black, Hispanic, and Chinese individuals without cardiovascular disease in 2000-2002 and 5181 individuals from the same cohort in 2005-2007. Framingham risk scores were stratified into low (< 6%), increased (6% to 9.9%), and high risk (≥ 10%). In 2000-2002 the prevalence of aspirin use was 18% and 27% for those at increased and high risk, respectively. Whites (25%) used aspirin more than Blacks (14%), Hispanics (12%), or Chinese (14%) (P < 0.001) in the increased risk group. Corresponding prevalences for the high risk group were 38%, 25%, 17%, and 21%, respectively (P < 0.001). In 2005-2007 the prevalence of aspirin use was 31% and 44% for those at increased and high risk, respectively. Whites (41%) used aspirin more than Blacks (27%), Hispanics (24%), or Chinese (15%) in the increased risk group (P < 0.001). Corresponding prevalences for the high risk group were 53%, 43%, 38%, and 28%, respectively (P < 0.001). Racial/ethnic differences persisted after adjustment for age, gender, diabetes, income, and education. In conclusion, regular aspirin use in adults at increased and high risk for CHD remains suboptimal. Important racial/ethnic disparities exist for unclear reasons.
Framingham risk score; aspirin; coronary heart disease; race and ethnicity
Coronary artery calcium (CAC), carotid intima-media thickness, and left ventricular (LV) mass and geometry offer the potential to characterize incident cardiovascular disease (CVD) risk in clinically asymptomatic individuals. The objective of the study was to compare these cardiovascular imaging measures for their overall and sex-specific ability to predict CVD.
Methods and Results
The study sample consisted of 4965 Multi-Ethnic Study of Atherosclerosis participants (48% men; mean age, 62±10 years). They were free of CVD at baseline and were followed for a median of 5.8 years. There were 297 CVD events, including 187 coronary heart disease (CHD) events, 65 strokes, and 91 heart failure (HF) events. CAC was most strongly associated with CHD (hazard ratio [HR], 2.3 per 1 SD; 95% CI, 1.9 to 2.8) and all CVD events (HR, 1.7; 95% CI, 1.5 to 1.9). Most strongly associated with stroke were LV mass (HR, 1.3; 95% CI, 1.1 to 1.7) and LV mass/volume ratio (HR, 1.3; 95% CI, 1.1 to 1.6). LV mass showed the strongest association with HF (HR, 1.8; 95% CI, 1.6 to 2.1). There were no significant interactions for imaging measures with sex and ethnicity for any CVD outcome. Compared with traditional risk factors alone, overall risk prediction (C statistic) for future CHD, HF, and all CVD was significantly improved by adding CAC, LV mass, and CAC, respectively (all P<0.05).
There was no evidence that imaging measures differed in association with incident CVD by sex. CAC was most strongly associated with CHD and CVD; LV mass and LV concentric remodeling best predicted stroke; and LV mass best predicted HF.
imaging; cardiovascular diseases; sex
Pericardial fat has adverse effects on the surrounding vasculature. Previous studies suggest that pericardial fat may contribute to myocardial ischemia in symptomatic individuals. However, it is unknown if pericardial fat has similar effects in asymptomatic individuals.
We determined the association between pericardial fat and myocardial blood flow (MBF) in 214 adults with no prior history of cardiovascular disease from the Minnesota field center of the Multi-Ethnic Study of Atherosclerosis (43% female, 56% Caucasian, 44% Hispanic). Pericardial fat volume was measured by computed tomography. MBF was measured by MRI at rest and during adenosine-induced hyperemia. Myocardial perfusion reserve (PR) was calculated as the ratio of hyperemic to resting MBF.
Gender-stratified analyses revealed significant differences between men and women including less pericardial fat (71.9±31.3 vs. 105.2±57.5 cm3, p<0.0001) and higher resting MBF (1.12±0.23 vs. 0.93±0.19 ml/min/g, p<0.0001), hyperemic MBF (3.49±0.76 vs. 2.65±0.72 ml/min/g, p<0.0001), and PR (3.19±0.78 vs. 2.93±0.89, p = 0.03) in women. Correlations between pericardial fat and clinical and hemodynamic variables were stronger in women. In women only (p = 0.01 for gender interaction) higher pericardial fat was associated with higher resting MBF (p = 0.008). However, this association was attenuated after accounting for body mass index or rate-pressure product. There were no significant associations between pericardial fat and hyperemic MBF or PR after multivariate adjustment in either gender. In logistic regression analyses there was also no association between impaired coronary vasoreactivity, defined as having a PR <2.5, and pericardial fat in men (OR, 1.18; 95% CI, 0.82–1.70) or women (OR, 1.11; 95% CI, 0.68–1.82).
Our data fail to support an independent association between pericardial fat and myocardial perfusion in adults without symptomatic cardiovascular disease. Nevertheless, these findings highlight potentially important differences between asymptomatic and symptomatic individuals with respect to the underlying subclinical disease burden.
In January 2009 the National Heart, Lung, and Blood Institute (NHLBI) convened a 28-member multidisciplinary Working Group to update the recommendations of a 2004 NHLBI Working Group focused on Guidelines to the Return of Genetic Research Results. Changes in the genetic and societal landscape over the intervening five years raise multiple questions and challenges. The group noted the complex issues arising from the fact that the technologic and bioinformatic progress has made it possible to obtain considerable information on individuals which would not have been possible a decade ago. While unable to reach consensus on a number of issues, the Working Group produced five recommendations. The Working Group offers two recommendations addressing the criteria necessary to determine when genetic results should and may be returned to study participants, respectively. In addition, it suggests that a time limit be established to limit the duration of obligation of investigators to return genetic research results. The Group recommends the creation of a central body, or bodies, to provide guidance on when genetic research results are associated with sufficient risk and have established clinical utility to justify their return to study participants. The final Recommendation urges investigators to engage the broader community when dealing with identifiable communities to advise them on the return of aggregate and individual research results. Creation of an entity charged to provide guidance to IRBs, investigators, research institutions and research sponsors would provide rigorous review of available data, promote standardization of study policies regarding return of genetic research results, and enable investigators and study participants to clarify and share expectations for the handling of this increasingly valuable information with appropriate respect for the rights and needs of participants.
consent genetics; ethics; research genetics; risk rediction; single nucleotide polymorphism genetics
We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other race/ethnic groups.
We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n=4764 participants) and two geographically and ethnically diverse cohorts: AGES (Age, Gene/Environment Susceptibility-Reykjavik Study, n=4238), and CHS (Cardiovascular Health Study, n=5410 of whom 874 (16.2%) were African Americans (AA)); aged 45–95 years. The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR-interval, hypertension treatment, and heart failure.
We observed 1359 incident AF events in 100,074 person-years of follow-up. Unadjusted five-year event-rates differed by cohort (AGES 12.8 cases/1000 person-years; CHS whites 22.7 cases/1000 person-years; FHS 4.5 cases/1000 person-years) and race/ethnicity (CHS AA 18.4 cases/1000 person-years).
The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm performed reasonably well in all samples (AGES C-statistic 0.67, 95% confidence interval 0.64–0.71; CHS whites, 0.68, 0.66–0.70; CHS AA 0.66, 0.61–0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population attributable risk.
Risk of incident AF in community-dwelling whites and AA can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% percent of risk.
atrial fibrillation; risk score; epidemiology; cohort study; race/ethnicity
Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis.
A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis.
Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals.
Many studies have documented associations between inflammation and type 2 diabetes incidence. We assessed potential variability in this association in the major U.S. racial/ethnic groups.
RESEARCH DESIGN AND METHODS
Incident type 2 diabetes was assessed among men and women aged 45–84 years without prior clinical cardiovascular disease or diabetes in the prospective Multi-Ethnic Study of Atherosclerosis. Interleukin (IL)-6, fibrinogen, and C-reactive protein (CRP) were measured at baseline (2000–2002); fasting glucose and diabetes medication use was assessed at baseline and three subsequent in-person exams through 2007. Type 2 diabetes was defined as use of diabetes drugs or glucose ≥126 mg/dl. Covariates included baseline demographics, clinic, smoking, alcohol, exercise, hypertension medication, systolic blood pressure, insulin resistance, and BMI. Cox proportional hazards regression was used to calculate hazard ratios (HRs) by quartiles of CRP, IL-6, and fibrinogen.
Among 5,571 participants (mean age 61.6 years, 53% female, 42.1% white, 11.5% Chinese, 25.7% black, and 20.7% Hispanic), 410 developed incident diabetes during a median follow-up time of 4.7 years (incidence 16.8 per 1,000 person-years). CRP, IL-6, and fibrinogen levels were associated with incident diabetes in the entire sample. After adjustment, the associations were attenuated; however, quartile 4 (versus quartile 1) of IL-6 (HR 1.5 [95% CI 1.1–2.2]) and CRP (1.7 [1.3–2.4]) remained associated with incident diabetes. In stratified analyses, similar associations were observed among white, black, and Hispanic participants.
Higher levels of inflammation predict short-term incidence of type 2 diabetes in a multiethnic American sample.
High plasma sphingomyelin level has been associated with subclinical atherosclerosis, coronary artery disease and worse prognosis in subjects with acute coronary syndromes. We assess the predictive value of plasma sphingomyelin levels for incident CHD events in the Multi Ethnic Study of atherosclerosis (MESA).
Method and Results
Plasma sphingomyelin was measured in 6809 out of 6814 subjects with mean age 62.2 ± 10.2 years, participating in the MESA study, a population based cohort study of adults free of clinical CVD at baseline recruited at six clinic sites in USA. The subjects consisted of 52.8% females, 38.5% Caucasian, 11.8% Chinese, 27.8% African Americans and 21.9% Hispanics. Cox proportional hazard analysis was used to examine the association between plasma sphingomyelin and five years of adjudicated incident CHD events including MI, resuscitated cardiac arrest, angina, CHD death and revascularization (CABG or PTCA). Mean (SD) plasma sphingomyelin level was 48 mg/dl (16.0). One hundred and eighty-nine subjects had an adjudicated CHD event during the five years of follow up. In the Kaplan meier analysis, subjects with plasma sphingomyelin level above the sex specific median had similar event free survival rate compared with subjects with plasma sphingomyelin level below or equal to the sex specific median (97.16% vs 97.0%, log rank p= 0.713). In the univariate Cox proportional hazard analysis, plasma sphingomyelin was not a predictor of incident CHD event [hazard ratio 0.992(0.982 – 1.004), p=0.09]. In our multistage multivariable Cox models, higher plasma sphingomyelin had modest negative association with incident CHD events when total cholesterol, HDL and triglycerides were included in the model [hazard ratio 0.985 (0.973 – 0.996), p=0.008] and also in our full model after adjusting for age, gender, total cholesterol, HDL, triglycerides, diabetes, cigarette smoking, systolic BP, diastolic BP, BP medication use, HMG CoA use [hazard ratio 0.984 (0.973 – 0.996), p=0.002]. In other models, plasma sphingomyelin was not associated with incident CHD events.
High plasma sphingomyelin level is not associated with increased risk of incident coronary heart disease in population based adults free of clinical cardiovascular disease at baseline.
Plasma sphingomyelin; prognosis; coronary heart disease events; epidemiology
The purpose of this study was to evaluate the relationship of left ventricular (LV) remodeling assessed by cardiac magnetic resonance to various measures of obesity in a large population-based study.
Obesity is a well-known risk factor for cardiovascular disease, yet its relationship with LV size and function is poorly understood.
A total of 5,098 participants (age 45 to 84 years; 48% men) in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cardiovascular disease underwent cardiac magnetic resonance to assess LV size and function as well as measures of obesity, including body mass index, waist-to-hip ratio and waist circumference, and cardiovascular risk factors. Fat mass (FM) was estimated based on height-weight models derived from bioelectrical impedance studies. The associations of obesity measures with LV size and function were evaluated using linear spline regression models for body mass index and multivariable regression models for other measures of obesity; they were displayed graphically using generalized additive models.
LV mass and end-diastolic volume were positively associated with measures of obesity in both sexes after adjustment for risk factors (e.g., 5.7-g and 6.9-g increase in LV mass per 10-kg increase in FM in women and men, respectively [p < 0.001]). LV mass-to-volume ratio was positively associated with increased body mass index, waist-to-hip ratio, waist circumference, and estimated FM (e.g., 0.02-g/ml and 0.06-g/ml increase in mass-to-volume ratio per 10-kg increase in FM in women and men, respectively [p < 0.001]). The increased mass-to-volume ratio was due to a greater increase in LV mass relative to LV end-diastolic volume. All associations were stronger for men than for women. Ejection fraction showed no significant association with measures of obesity.
Obesity was associated with concentric LV remodeling without change in ejection fraction in a large, multiethnic cohort study.
cardiac magnetic resonance; cardiac morphology; epidemiology; left ventricular function; obesity
The relationship between incident congestive heart failure (CHF) and ethnicity as well as racial/ethnic differences in the mechanisms leading to CHF have not been demonstrated in a multiracial, population-based study. Our objective was to evaluate the relationship between race/ethnicity and incident CHF.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study of 6814 participants of 4 ethnicities: white (38.5%), African American (27.8%), Hispanic (21.9%), and Chinese American (11.8%). Participants with a history of cardiovascular disease at baseline were excluded. Cox proportional hazards models were used for data analysis.
During a median follow-up of 4.0 years, 79 participants developed CHF (incidence rate: 3.1 per 1000 person-years). African Americans had the highest incidence rate of CHF, followed by Hispanic, white, and Chinese American participants (incidence rates: 4.6, 3.5, 2.4, and 1.0 per 1000 person-years, respectively). Although risk of developing CHF was higher among African American compared with white participants (hazard ratio, 1.8; 95% confidence interval, 1.1-3.1), adding hypertension and/or diabetes mellitus to models including ethnicity eliminated statistical ethnic differences in incident CHF. Moreover, African Americans had the highest proportion of incident CHF not preceded by clinical myocardial infarction (75%) compared with other ethnic groups (P = .06).
The higher risk of incident CHF among African Americans was related to differences in the prevalence of hypertension and diabetes mellitus as well as socioeconomic status. The mechanisms of CHF also differed by ethnicity; interim myocardial infarction had the least influence among African Americans, and left ventricular mass increase had the greatest effect among Hispanic and white participants.
Coronary artery calcium score (CACS) has been shown to predict future coronary heart disease (CHD) events. However, the extent to which adding CACS to traditional CHD risk factors improves classification of risk is unclear.
To determine whether adding CACS to a prediction model based on traditional risk factors improves classification of risk.
Design, Setting and Participants
CACS was measured by computed tomography on 6,814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort without known cardiovascular disease. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2008. Participants with diabetes were excluded for the primary analysis. Five-year risk estimates for incident CHD were categorized as 0-<3%, 3-<10%, and ≥10% using Cox proportional hazards models. Model 1 used age, gender, tobacco use, systolic blood pressure, antihypertensive medication use, total and high-density lipoprotein cholesterol, and race/ethnicity. Model 2 used these risk factors plus CACS. We calculated the net reclassification improvement (NRI) and compared the distribution of risk using Model 2 versus Model 1.
Main Outcome Measures
Incident CHD events
Over 5.8 years median follow-up, 209 CHD events occurred, of which 122 were myocardial infarction, death from CHD, or resuscitated cardiac arrest. Model 2 resulted in significant improvements in risk prediction compared to Model 1 (NRI=0.25, 95% confidence interval 0.16-0.34, P<0.001). With Model 1, 69% of the cohort was classified in the highest or lowest risk categories, compared to 77% with Model 2. An additional 23% of those who experienced events were reclassified to high risk, and an additional 13% without events were reclassified to low risk using Model 2.
In the MESA cohort, addition of CACS to a prediction model based on traditional risk factors significantly improved the classification of risk and placed more individuals in the most extreme risk categories.
Though abnormal lipoproteins and lipoprotein ratios are powerful risk factors for clinical cardiovascular (CV) events, these associations are stronger in younger compared to older age. Whether age modifies the relationships of lipoproteins and lipoprotein ratios to the relative risk for subclinical CV disease (CVD), as assessed by coronary artery calcium (CAC) scores, has not been examined in a contemporary, multi-ethnic cohort. We performed multivariate relative risk regression to determine the relative risks (RRs) for associations of lipoproteins and lipoprotein ratios with prevalent CAC in participants in MESA. Participants were community-dwelling adults ages 45–84 years without baseline clinically apparent CVD. We excluded those on lipid lowering therapy (15%), and stratified results by decades of age. 5,092 participants met inclusion criteria. In fully adjusted models, per standard deviation (SD) of low-density lipoprotein (LDL), age-stratified, adjusted relative risks (RRs) for CAC were 1.17 (95% Confidence Interval (CI) 1.07–1.28) for those aged 45–54 but 1.05 (95% CI 1.01–1.10) for those aged 75–84 (p-interaction = 0.12). The RR per SD of Total/HDL cholesterol ratio was 1.20 (95% CI 1.12–1.29) for those aged 45–54 but only 1.04 (1.00–1.09) for those aged 75–84 (p-interaction <0.001). Lipoproteins and lipoprotein ratios were associated with increased RRs for CAC across all age categories. However, these associations were markedly attenuated by age. In conclusion, abnormal lipoproteins in middle age are a powerful risk factor for early atherosclerosis as manifested by prevalent CAC.
lipoproteins; age; coronary artery calcium
Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity.
A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992–1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models.
Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E ϵ4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death.
In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.
Mortality risk; Cause of death; Elderly participants
To assess the relationship between sibling history of myocardial infarction (MI) or stroke with cardiovascular disease (CVD) and risk factors in older adults.
Prospective cohort study of 5,888 older adults participating to the Cardiovascular Health Study (CHS). History of MI and stroke in siblings was obtained by self-report. Participants with positive sibling histories were compared to those with negative histories to determine if prevalent or incident disease (coronary heart disease [CHD], MI, stroke, angina), subclinical CVD (carotid wall thickness, left ventricular mass, hypertension, diabetes, ankle brachial index), CVD risk factors differed between groups.
More than 91 percent (n=5,383) of CHS participants reported at least one sibling. Sibling history of MI was associated with increased disease prevalence (CHD, MI, angina) and incidence (CHD, angina). Sibling history of stroke was associated with increased disease prevalence (CHD, angina). Sibling history of either MI or stroke was associated with increased disease prevalence and incidence for CHD, MI and angina, more subclinical disease, and a higher CVD risk profile.
Sibling history of MI and stroke were markers of higher CVD risk status even in older adults. Of clinical importance, participants with positive sibling history have numerous risk factors amenable to intervention.
Epidemiology; Cardiovascular diseases; Risk Factors; Atherosclerosis; Lifestyle