Racial and Ethnic Differences in All-Cause and Cardiovascular Disease Mortality: The MESA Study.

BACKGROUND: Despite improvements in population health, marked racial and ethnic disparities in longevity and cardiovascular disease (CVD) mortality persist. This study aimed to describe risks for all-cause and CVD mortality by race and ethnicity, before and after accounting for socioeconomic status (SES) and other factors, in the MESA study (Multi-Ethnic Study of Atherosclerosis). METHODS: MESA recruited 6814 US adults, 45 to 84 years of age, free of clinical CVD at baseline, including Black, White, Hispanic, and Chinese individuals (2000-2002). Using Cox proportional hazards modeling with time-updated covariates, we evaluated the association of self-reported race and ethnicity with all-cause and adjudicated CVD mortality, with progressive adjustments for age and sex, SES (neighborhood SES, income, education, and health insurance), lifestyle and psychosocial risk factors, clinical risk factors, and immigration history. RESULTS: During a median of 15.8 years of follow-up, 22.8% of participants (n=1552) died, of which 5.3% (n=364) died of CVD. After adjusting for age and sex, Black participants had a 34% higher mortality hazard (hazard ratio [HR], 1.34 [95% CI, 1.19-1.51]), Chinese participants had a 21% lower mortality hazard (HR, 0.79 [95% CI, 0.66-0.95]), and there was no mortality difference in Hispanic participants (HR, 0.99 [95% CI, 0.86-1.14]) compared with White participants. After adjusting for SES, the mortality HR for Black participants compared with White participants was reduced (HR, 1.16 [95% CI, 1.01-1.34]) but still statistically significant. With adjustment for SES, the mortality hazards for Chinese and Hispanic participants also decreased in comparison with White participants. After further adjustment for additional risk factors and immigration history, Hispanic participants (HR, 0.77 [95% CI, 0.63-0.94]) had a lower mortality risk than White participants, and hazard ratios for Black participants (HR, 1.08 [95% CI, 0.92-1.26]) and Chinese participants (HR, 0.81 [95% CI, 0.60-1.08]) were not significantly different from those of White participants. Similar trends were seen for CVD mortality, although the age- and sex-adjusted HR for CVD mortality for Black participants compared with White participants was greater than all-cause mortality (HR, 1.72 [95% CI, 1.34-2.21] compared with HR, 1.34 [95% CI, 1.19-1.51]). CONCLUSIONS: These results highlight persistent racial and ethnic differences in overall and CVD mortality, largely attributable to social determinants of health, and support the need to identify and act on systemic factors that shape differences in health across racial and ethnic groups.

Health insurance status and type associated with varying levels of glycemic control in the US: The multi-ethnic study of atherosclerosis (MESA).

AIMS: To investigate associations of health insurance with measures of glucose metabolism, and whether associations vary by diabetes status or insurance type. METHODS: Cross-sectional analysis of baseline data from the Multi-Ethnic Study of Atherosclerosis. Cohort a priori stratified by age <65 (N = 3,665) and ≥65 years (N = 2,924). Multivariable linear and logistic regression assessed associations between insurance and fasting glucose, HOMA-IR, and prevalent diabetes, controlling for relevant confounders, including age, sex, race/ethnicity, income, and education. RESULTS: In participants <65, compared to uninsured, having any insurance was associated with lower fasting glucose in participants with diabetes (Mean Difference = -20.4 mg/dL, P = 0.01), but not in participants without diabetes. Compared to Private insurance, uninsured participants had higher fasting glucose (Mean Difference = 3.8 mg/dL, P = 0.03), while participants with Medicaid had higher HOMA-IR (Mean Difference = 3.5 mg/dL, P < 0.01). In participants ≥65, compared to Private insurance, uninsured participants (Mean Difference = 7.5 mg/dL, P = 0.02), and participants with Medicaid only (Mean Difference = 19.9 mg/dL, P < 0.01) or Medicare + Medicaid (Mean Difference = 5.2 mg/dL, P = 0.03) had higher fasting glucose. CONCLUSIONS: In this large multiethnic cohort, having any insurance was associated with significantly lower fasting glucose for individuals with diabetes. Levels of fasting glucose and insulin resistance varied across different insurance types.

Sex and ethnicity modify the associations between individual and contextual socioeconomic indicators and ideal cardiovascular health: MESA study.

BACKGROUND: Low socioeconomic status (SES) is associated with cardiovascular disease (CVD) risk, but its association with different markers of SES may be heterogeneous by sex and race/ethnicity. METHODS: We have examined the relationships of four SES markers (education, family income, occupation and neighborhood SES) to ideal cardiovascular health (ICH), an index formed by seven variables. A total of 6792 cohort participants from six regions in the USA: Baltimore City and Baltimore County, MD; Chicago, IL; Forsyth County, NC; Los Angeles County, CA; New York, NY; and St. Paul, MN of the Multi-Ethnic Study of Atherosclerosis (MESA) (52.8% women) were recruited at baseline (2000-2) and included in the present analysis. RESULTS: ICH was classified as poor, intermediate or ideal. Level of education was significantly and inversely associated with ICH in non-Hispanic White men and women, in Chinese-American and Hispanic American men and African-American women. Family income was inversely and significantly associated with poor ICH in African-American men only. CONCLUSIONS: We conclude that the strength of the associations between some SES markers and ICH differ between sexes and race/ethnic groups.

Life's Simple 7 and Peripheral Artery Disease: The Multi-Ethnic Study of Atherosclerosis.

INTRODUCTION: In 2010, the American Heart Association initiated Life's Simple 7 with the goal of significantly improving cardiovascular health by the year 2020. The association of Life's Simple 7 with risk of peripheral artery disease has not been thoroughly explored. METHODS: Racially diverse individuals from the Multi-Ethnic Study of Atherosclerosis (2000-2012) were followed for incident peripheral artery disease (ankle brachial index ≤0.90) and decline in ankle brachial index (≥0.15) over approximately 10 years of follow-up. Cox and logistic regression were used to assess associations of individual Life's Simple 7 components (score 0-2) and overall Life's Simple 7 score (score 0-14) with incident peripheral artery disease and ankle brachial index decline, respectively, adjusted for age, sex, race/ethnicity, education, and income. Analyses were performed in 2016-2018. RESULTS: Of 5,529 participants, 251 (4.5%) developed incident peripheral artery disease; 419 (9.8%) of 4,267 participants experienced a decline in ankle brachial index. Each point higher for the overall Life's Simple 7 score was associated with a 17% lower rate of incident peripheral artery disease (hazard ratio=0.83, 95% CI=0.78, 0.88, p<0.001). Additionally, each point higher in overall Life's Simple 7 was associated with a 0.94-fold lower odds of decline in ankle brachial index (OR=0.94, 95% CI=0.87, 0.97, p=0.003). Four components (smoking, physical activity, glucose, and blood pressure) were associated with incident peripheral artery disease and two (smoking and glucose) with decline in ankle brachial index. CONCLUSIONS: Better cardiovascular health as measured by Life's Simple 7 is associated with lower incidence of peripheral artery disease and less decline in ankle brachial index. Use of the Life's Simple 7 to target modifiable health behaviors may aid in decreasing the population burden of peripheral artery disease-related morbidity and mortality.

Use of coronary artery calcium testing to improve coronary heart disease risk assessment in a lung cancer screening population: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Assessment of coronary artery calcium (CAC) during lung cancer screening chest computed tomography (CT) represents an opportunity to identify asymptomatic individuals at increased coronary heart disease (CHD) risk. We determined the improvement in CHD risk prediction associated with the addition of CAC testing in a population recommended for lung cancer screening. METHODS: We included 484 out of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants without baseline cardiovascular disease who met U.S. Preventive Service Task Force CT lung cancer screening criteria and underwent gated CAC testing. 10 year-predicted CHD risks with and without CAC were calculated using a validated MESA-based risk model and categorized into low (<5%), intermediate (5%-10%), and high (≥10%). The net reclassification improvement (NRI) and change in Harrell's C-statistic by adding CAC to the risk model were subsequently determined. RESULTS: Of 484 included participants (mean age = 65; 39% women; 32% black), 72 (15%) experienced CHD events over the course of follow-up (median = 12.5 years). Adding CAC to the MESA CHD risk model resulted in 17% more participants classified into the highest or lowest risk categories and a NRI of 0.26 (p = 0.001). The C-statistic improved from 0.538 to 0.611 (p = 0.01). CONCLUSIONS: CHD event rates were high in this lung cancer screening eligible population. These individuals represent a high-risk population who merit consideration for CHD prevention measures regardless of CAC score. Although overall discrimination remained poor with inclusion of CAC scores, determining whether those reclassified to an even higher risk would benefit from more aggressive preventive measures may be important.

A method to account for covariate-specific treatment effects when estimating biomarker associations in the presence of endogenous medication use.

In the modern era, cardiovascular biomarkers are often measured in the presence of medication use, such that the observed biomarker value for the treated participants is different than their underlying natural history value. However, for certain predictors (e.g. age, gender, and genetic exposures) the observed biomarker value is not of primary interest. Rather, we are interested in estimating the association between these predictors and the natural history of the biomarker that would have occurred in the absence of treatment. Nonrandom medication use obscures our ability to estimate this association in cross-sectional observational data. Structural equation methodology (e.g. the treatment effects model), while historically used to estimate treatment effects, has been previously shown to be a reasonable way to correct endogeneity bias when estimating natural biomarker associations. However, the assumption that the effects of medication use on the biomarker are uniform across participants on medication is generally not thought to be reasonable. We derive an extension of the treatment effects model to accommodate effect modification. Based on several simulation studies and an application to data from the Multi-Ethnic Study of Atherosclerosis, we show that our extension substantially improves bias in estimating associations of interest, particularly when effect modifiers are associated with the biomarker or with medication use, without a meaningful cost of efficiency.

Associations of cardiovascular disease risk factors with abdominal aortic calcium volume and density: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Abdominal aortic calcium (AAC) predicts future cardiovascular disease (CVD) events and all-cause mortality independent of CVD risk factors. The standard AAC score, the Agatston, up-weights for greater calcium density, and thus models higher calcium density as associated with increased CVD risk. We determined associations of CVD risk factors with AAC volume and density (separately). METHODS: In a multi-ethnic cohort of community living adults, we used abdominal computed tomography scans to measure AAC volume and density. Multivariable linear regression was used to determine the period cross-sectional independent associations of CVD risk factors with AAC volume and AAC density in participants with prevalent AAC. RESULTS: Among 1413 participants with non-zero AAC scores, the mean age was 65 ± 9 years, 52% were men, 44% were European-, 24% were Hispanic-, 18% were African-, and 14% were Chinese Americans (EA, HA, AA, and CA respectively). Median (interquartile range, IQR) for AAC volume was 628 mm3 (157-1939 mm3), and mean AAC density was 3.0 ± 0.6. Compared to EA, each of HA, AA, and CA had lower natural log (ln) AAC volume, but higher AAC density. After adjustments for AAC density, older age, ever smoking history, higher systolic blood pressure, elevated total cholesterol, reduced HDL cholesterol, statin and anti-hypertensive medication use, family history of myocardial infarction, and alcohol consumption were significantly associated with higher ln(AAC volume). In contrast, after adjustments for ln(AAC volume), older age, ever smoking history, higher BMI, and lower HDL cholesterol were significantly associated with lower AAC density. CONCLUSIONS: Several CVD risk factors were associated with higher AAC volume, but lower AAC density. Future studies should investigate the impact of calcium density of aortic plaques in CVD.

Utility of Nontraditional Risk Markers in Atherosclerotic Cardiovascular Disease Risk Assessment.

BACKGROUND: The improvement in discrimination gained by adding nontraditional cardiovascular risk markers cited in the 2013 American College of Cardiology/American Heart Association cholesterol guidelines to the atherosclerotic cardiovascular disease (ASCVD) risk estimator (pooled cohort equation [PCE]) is untested. OBJECTIVES: This study assessed the predictive accuracy and improvement in reclassification gained by the addition of the coronary artery calcium (CAC) score, the ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP) levels, and family history (FH) of ASCVD to the PCE in participants of MESA (Multi-Ethnic Study of Atherosclerosis). METHODS: The PCE was calibrated (cPCE) and used for this analysis. The Cox proportional hazards survival model, Harrell's C statistics, and net reclassification improvement analyses were used. ASCVD was defined as myocardial infarction, coronary heart disease-related death, or fatal or nonfatal stroke. RESULTS: Of 6,814 MESA participants not prescribed statins at baseline, 5,185 had complete data and were included in this analysis. Their mean age was 61 years; 53.1% were women, 9.8% had diabetes, and 13.6% were current smokers. After 10 years of follow-up, 320 (6.2%) ASCVD events occurred. CAC score, ABI, and FH were independent predictors of ASCVD events in the multivariable Cox models. CAC score modestly improved the Harrell's C statistic (0.74 vs. 0.76; p = 0.04); ABI, hsCRP levels, and FH produced no improvement in Harrell's C statistic when added to the cPCE. CONCLUSIONS: CAC score, ABI, and FH were independent predictors of ASCVD events. CAC score modestly improved the discriminative ability of the cPCE compared with other nontraditional risk markers.

Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals.

CONTEXT: Risk markers including coronary artery calcium, carotid intima-media thickness, ankle-brachial index, brachial flow-mediated dilation, high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score (FRS) for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort. OBJECTIVE: We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate-risk participants (FRS >5%-<20%) in the Multi-Ethnic Study of Atherosclerosis (MESA). DESIGN, SETTING, AND PARTICIPANTS: Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Probability-weighted Cox proportional hazard models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement were used to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity. MAIN OUTCOME MEASURES: Incident CHD defined as myocardial infarction, angina followed by revascularization, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death. RESULTS: After 7.6-year median follow-up (IQR, 7.3-7.8), 94 CHD and 123 CVD events occurred. Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independently associated with incident CHD in multivariable analyses (HR, 2.60 [95% CI, 1.94-3.50]; HR, 0.79 [95% CI, 0.66-0.95]; HR, 1.28 [95% CI, 1.00-1.64]; and HR, 2.18 [95% CI, 1.38-3.42], respectively). Carotid intima-media thickness and brachial flow-mediated dilation were not associated with incident CHD in multivariable analyses (HR, 1.17 [95% CI, 0.95-1.45] and HR, 0.95 [95% CI, 0.78-1.14]). Although addition of the markers individually to the FRS plus race/ethnicity improved AUC, coronary artery calcium afforded the highest increment (0.623 vs 0.784), while brachial flow-mediated dilation had the least (0.623 vs 0.639). For incident CHD, the net reclassification improvement with coronary artery calcium was 0.659, brachial flow-mediated dilation was 0.024, ankle-brachial index was 0.036, carotid intima-media thickness was 0.102, family history was 0.160 and high-sensitivity CRP was 0.079. Similar results were obtained for incident CVD. CONCLUSIONS: Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independent predictors of incident CHD/CVD in intermediate-risk individuals. Coronary artery calcium provided superior discrimination and risk reclassification compared with other risk markers.

Evaluating the incremental value of new biomarkers with integrated discrimination improvement.

The integrated discrimination improvement (IDI) index is a popular tool for evaluating the capacity of a marker to predict a binary outcome of interest. Recent reports have proposed that the IDI is more sensitive than other metrics for identifying useful predictive markers. In this article, the authors use simulated data sets and theoretical analysis to investigate the statistical properties of the IDI. The authors consider the common situation in which a risk model is fitted to a data set with and without the new, candidate predictor(s). Results demonstrate that the published method of estimating the standard error of an IDI estimate tends to underestimate the error. The z test proposed in the literature for IDI-based testing of a new biomarker is not valid, because the null distribution of the test statistic is not standard normal, even in large samples. If a test for the incremental value of a marker is desired, the authors recommend the test based on the model. For investigators who find the IDI to be a useful measure, bootstrap methods may offer a reasonable option for inference when evaluating new predictors, as long as the added predictive capacity is large.

Coronary artery calcium in relation to initiation and continuation of cardiovascular preventive medications: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Whether measuring and reporting of coronary artery calcium scores (CACS) might lead to changes in cardiovascular risk management is not established. In this observational study, we examined whether high baseline CACS were associated with the initiation as well continuation of new lipid-lowering medication (LLM), blood pressure-lowering medication (BPLM), and regular aspirin (ASA) use in a multi-ethnic population-based cohort. METHODS AND RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study of 6814 participants free of clinical cardiovascular disease at entry who underwent CAC testing at baseline examination (examination 1). Information on LLM, BPLM, and regular ASA usage was also obtained at baseline and at exams 2 and 3 (average of 1.6 and 3.2 years after baseline, respectively). In this study, we examined (1) initiation of these medications at examination 2 among participants not taking these medications at baseline; and (2) continuation of medication use to examination 3 among participants already on medication at baseline. Among MESA participants, initiation of LLM, BPLM, and ASA was greater in those with higher CACS. After taking into account age, sex, race, MESA site, LDL cholesterol, diabetes mellitus, body mass index, smoking status, hypertension, systolic blood pressure, and socioeconomic status (income, education, and health insurance), the risk ratios for medication initiation comparing those with CACS >400 versus CACS=0 were 1.53 (95% confidence interval [CI], 1.08, 2.15) for LLM, 1.55 (95% CI, 1.10 to 2.17) for BPLM, and 1.32 (95% CI, 1.03 to 1.69) for ASA initiation, respectively. The risk ratios for medication continuation among those with CAC >400 versus CACS=0 were 1.10 (95% CI, 1.01 to 1.20) for LLM, 1.05 (95% CI, 1.02 to 1.08) for BPLM, and 1.14 (95% CI, 1.04 to 1.25) for ASA initiation, respectively. CONCLUSIONS: CACS >400 was associated with a higher likelihood of initiation and continuation of LLM, BPLM, and ASA. The association was weaker for continuation than for initiation of these preventive therapies.

Multiple imputation for missing with cardiac magnetic resonance imaging data: results from the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Cardiac magnetic resonance imaging (MRI) is a noninvasive technique used to accurately and reproducibly measure biological parameters such as left ventricular mass. However, some subjects either refuse or are unable to complete testing, and the impact of excluding these missing data from predictive models is unknown. METHODS: Multiple imputation was applied to cardiac MRI data that were previously analyzed using a complete case approach. The model variables - 10 traditional cardiovascular risk factors and five sociodemographic variables - were used as a basis for imputation. Men and women were imputed separately. The primary focus was assessing the change in the cardiovascular predictors of left ventricular geometry and systolic function. RESULTS: Although 27% of participants were missing cardiac MRI data, multiple imputation returned results similar to those of a complete case analysis. These results were robust to the point of including additional variables in the imputation analysis above and beyond the model variables. The degree of variance explained by the models increased marginally but the statistical inference was altered for only two predictors out of 53 cardiovascular risk factors using multiple imputation. DISCUSSION: The results suggest that the cardiac MRI data in the Multi-Ethnic Study of Atherosclerosis (MESA) do not substantively change when missing data are handled using multiple imputation. Future analyses of cardiac MRI data may consider the complete case approach to be adequate despite the high rate of missing data in this population.

A nationwide survey of the extent of autopsy in sudden unexplained death in epilepsy.

Sudden unexplained death in epilepsy is a catastrophic event that requires autopsy for definitive diagnosis. Lack of awareness of sudden unexplained death in epilepsy as an important cause of death in epilepsy has been observed among coroners and pathologists. This survey study of US coroners and medical examiners (MEs) assesses their postmortem examinations of persons with epilepsy who had died suddenly without obvious cause. Analysis of the 510 survey responses shows that pathologists are significantly more likely than nonpathologists to inquire routinely about a history of cardiac disease, remove the brain for examination, or collect blood samples for determinations of anticonvulsant and psychotropic drugs. Urban coroners and MEs are significantly more likely than their nonurban colleagues to remove the brain for examination or collect blood samples for these determinations. Lack of family consent and the cost of autopsy are major reasons for not performing an autopsy of persons with epilepsy. Our study underscores the importance of promoting to all coroners and MEs and to the public the need for thorough autopsy of persons with epilepsy when the cause of death is not obvious.

Clinical elements that predict outcome after traumatic brain injury: a prospective multicenter recursive partitioning (decision-tree) analysis.

Traumatic brain injury (TBI) often presents clinicians with a complex combination of clinical elements that can confound treatment and make outcome prediction challenging. Predictive models have commonly used acute physiological variables and gross clinical measures to predict mortality and basic outcome endpoints. The primary goal of this study was to consider all clinical elements available concerning a survivor of TBI admitted for inpatient rehabilitation, and identify those factors that predict disability, need for supervision, and productive activity one year after injury. The Traumatic Brain Injury Model Systems (TBIMS) database was used for decision tree analysis using recursive partitioning (n = 3463). Outcome measures included the Functional Independence Measure(), the Disability Rating Scale, the Supervision Rating Scale, and a measure of productive activity. Predictor variables included all physical examination elements, measures of injury severity (initial Glasgow Coma Scale score, duration of post-traumatic amnesia [PTA], length of coma, CT scan pathology), gender, age, and years of education. The duration of PTA, age, and most elements of the physical examination were predictive of early disability. The duration of PTA alone was selected to predict late disability and independent living. The duration of PTA, age, sitting balance, and limb strength were selected to predict productive activity at 1 year. The duration of PTA was the best predictor of outcome selected in this model for all endpoints and elements of the physical examination provided additional predictive value. Valid and reliable measures of PTA and physical impairment after TBI are important for accurate outcome prediction.

Cost of treating high-risk symptomatic carotid artery stenosis: stent insertion and angioplasty compared with endarterectomy.

OBJECT: Definitive data characterizing the safety and efficacy of carotid angioplasty with stent placement (CAS) for symptomatic, occlusive carotid artery (CA) disease require further refinements and standardization of techniques as well as large prospective studies on a par with the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Despite the absence of such data, many surgeons have performed angioplasty and stent placement in patients with clinical or anatomical features known to add significant perioperative risk and capable of disqualifying the patients from participation in NASCET: There exists no cost analysis comparing high-risk endarterectomy with percutaneous angioplasty and stent insertion. METHODS: Forty-five patients (29 men and 16 women) with high-risk, symptomatic CA stenosis have been treated with CAS at the authors' institution since 1996. Indications for this procedure included symptomatic recurrent stenosis following CA endarterectomy (CEA), active coronary disease, high CA bifurcation, and severe medical comorbidities. A longstanding CEA computer database was screened for control patients with similar risk factors; 391 patients (276 men and 115 women) were identified. Actual cost data, duration of hospital stay, and relevant clinical data from the time of treatment until hospital discharge were collected in each patient. The median total cost of CAS was dollar 10,628, whereas that for CEA was dollar 10,148 (p = 0.495). CONCLUSIONS: In patients with high-risk, NASCET-ineligible CA stenosis there was no overall statistically significant cost difference between CEA and CAS. Given that there may not be a cost advantage for either procedure, procedural risk, efficacy, and durability should be key factors in determining the optimal treatment strategy.