Association of silent myocardial infarction on electrocardiogram and coronary artery calcium: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Silent myocardial infarction (SMI) on electrocardiogram (ECG) is associated with atherosclerotic cardiovascular disease, but the relationship between SMI on ECG and coronary artery calcium (CAC) remains poorly understood. OBJECTIVE: Characterize the relationship between SMI on ECG and CAC. METHODS: Eligible participants from the Multi-Ethnic Study of Atherosclerosis study had ECG and CAC scoring at study enrollment (2000-2002). SMI was defined as ECG evidence of myocardial infarction in the absence of a history of clinical cardiovascular disease. CAC was modeled both continuously and categorically. The cross-sectional relationships between SMI on ECG and CAC were assessed using logistic regression and linear regression. RESULTS: Among 6705 eligible participants, 178 (2.7%) had baseline SMI. Compared to participants without SMI, those with SMI had higher CAC (median [IQR]: 61.2 [0-261.7] vs. 0 [0-81.5]; p < .0001). Participants with SMI were more likely to have non-zero CAC (74% vs. 49%) and were more likely to have CAC ≥ 100 (40% vs. 23%). In a multivariable-adjusted logistic model, SMI was associated with higher odds of non-zero CAC (odds ratio 2.17, 95% CI 1.48-3.20, p < .0001) and 51% higher odds of CAC ≥ 100 (odds ratio 1.51, 95% CI 1.06-2.16, p = .02). CONCLUSION: An incidental finding of SMI on ECG may serve to identify patients who have a higher odds of significant CAC and may benefit from additional risk stratification to further refine their cardiovascular risk. Further exploration of the utility of CAC assessment in this patient population is needed.

Focus group study of factors relevant to treatment decisions and experiences among patients with symptomatic peripheral artery disease.

BACKGROUND: Clinical guidelines recommend shared decision-making for treatment of peripheral artery disease (PAD), which requires understanding of patient perspectives and preferences. We conducted a focus group study of patients with symptomatic PAD to identify factors important and relevant to treatment choices, and to characterize aspects of the health care process that contribute to positive vs negative experiences apart from the specific treatment(s) received. METHODS: Participants were recruited from an academic medical center over 2 years using a purposeful sampling approach based on a clinical diagnosis of symptomatic PAD (either claudication or chronic limb-threatening ischemia [CLTI]) confirmed by the abnormal ankle or toe brachial index. Focus groups were led by a nonphysician moderator, consisted of 5 to 12 participants, and were conducted separately for patients with CLTI and claudication. Audio recordings converted to verbatim transcripts were used for qualitative analysis. RESULTS: A total of 51 patients (26 with CLTI and 25 with claudication) were enrolled and participated in focus groups. Major themes identified related to treatment preferences and decisions included specific interventions under consideration, the chance of technical success versus failure, anticipated degree of symptom improvement, outcome durability, and risk. Major themes related to the process of care included decision-making input, provider communication and trust, the timeline from diagnosis to definitive treatment, and compartmentalized care (including different venues of care). CONCLUSIONS: The results provide insights into patient preferences, perspectives, and experiences related to PAD treatment. These observations can be used to inform patient-centered approaches to shared decision-making, communication, and assessment of PAD treatment outcomes.

ASSOCIATION OF PLASMA ω-3 FATTY ACIDS WITH EARLY AGE-RELATED MACULAR DEGENERATION IN THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS.

PURPOSE: To examine the association between omega-3 polyunsaturated fatty acids, docosahexaenoic acid, and eicosapentaenoic acid and age-related macular degeneration (AMD) in the Multi-Ethnic Study of Atherosclerosis cohort. METHODS: Multi-Ethnic Study of Atherosclerosis is a multicenter, prospective cohort study designed to identify risk factors for cardiovascular disease in four ethnic groups. Six thousand eight hundred and fourteen participants of White, African American, Hispanic/Latino, and Chinese descent, aged 45-84 years, were recruited, with those found to have cardiovascular disease excluded. Our study population included all Multi-Ethnic Study of Atherosclerosis participants with baseline polyunsaturated fatty acid measurements and retinal photography at Examination 5 (n = 3,772). Fundus photographs were assessed for AMD using a standard grading protocol. Relative risk regression (log link) determined associations between polyunsaturated fatty acid levels and AMD. RESULTS: There was a significant association between increasing docosahexaenoic acid levels and increasing docosahexaenoic acid + eicosapentaenoic acid levels with reduced risk for early AMD (n = 214 participants with early AMD, of which n = 99 (46.3%) are non-White). Eicosapentaenoic acid levels alone were not significantly associated with AMD. CONCLUSION: Our analysis suggests increasing levels of docosahexaenoic acid are associated with reduced risk for early AMD in a multiethnic cohort. This represents the first racially diverse study demonstrating an association between omega-3 polyunsaturated fatty acids and AMD risk.

Associations among vascular risk factors, neuroimaging biomarkers, and cognition: Preliminary analyses from the Multi-Ethnic Study of Atherosclerosis (MESA).

INTRODUCTION: Little is known about how antecedent vascular risk factor (VRF) profiles impact late-life brain health. METHODS: We examined baseline VRFs, and cognitive testing and neuroimaging measures (ß-amyloid [Aß] PET, MRI) in a diverse longitudinal cohort (N = 159; 50% African-American, 50% White) from Wake Forest's Multi-Ethnic Study of Atherosclerosis Core. RESULTS: African-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aß positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aß. Aß was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline. DISCUSSION: Results suggest the convergence of multiple vascular and Alzheimer's processes underlying neurodegeneration and cognitive decline.

The utility of silent myocardial infarction on electrocardiogram as an ASCVD risk enhancer for primary prevention: The multi-ethnic study of atherosclerosis.

BACKGROUND: The 2018 AHA/ACC cholesterol guidelines introduced a new list of markers called "risk enhancers" that, if present, confer an increased risk of atherosclerotic cardiovascular disease (ASCVD). Silent myocardial infarction (SMI) on electrocardiogram (ECG) is notably absent, even though it associated with future ASCVD. METHODS: We assessed the utility of SMI on ECG as a risk-enhancer in intermediate-risk participants in MESA (Multi-Ethnic Study of Atherosclerosis) - those with 10-year ASCVD risk of 5-20% by the pooled cohort equation (PCE). SMI was defined as major Q-wave abnormality or minor Q/QS waves in the setting of major ST-T abnormalities without prevalent clinical cardiovascular disease. RESULTS: Among 2946 participants (mean age 63.1 ± 7.6, 53.9% women, 36% white, 11% Chinese-American, 33% African-American, 19% Hispanic), 66 (2.2%) had SMI at baseline. After a median 15.8 years of follow-up, incident ASCVD events occurred in 431/2876 (15.0%) of those without SMI and 16/66 (24.2%) of those with SMI. In a multivariable-adjusted Cox proportional hazards model, baseline SMI was associated with an increased risk of incident ASCVD events (HR 1.68, 95% CI 1.02-2.77, p = 0.04). However, adding SMI to the PCE did not improve discrimination and reclassification was modest-net reclassification improvement was 0.0161 (95% CI 0.002-0.034, p = 0.08). CONCLUSION: Our findings suggest that the prevalence of SMI is 2.2% among those without known clinical cardiovascular disease considered intermediate-risk by the PCE. In our analysis, SMI only modestly improved classification of risk, suggesting that it may not be very useful as an ASCVD risk enhancer.

Safely Identifying Emergency Department Patients With Acute Chest Pain for Early Discharge.

BACKGROUND: The HEART Pathway (history, ECG, age, risk factors, and initial troponin) is an accelerated diagnostic protocol designed to identify low-risk emergency department patients with chest pain for early discharge without stress testing or angiography. The objective of this study was to determine whether implementation of the HEART Pathway is safe (30-day death and myocardial infarction rate <1% in low-risk patients) and effective (reduces 30-day hospitalizations) in emergency department patients with possible acute coronary syndrome. METHODS: A prospective pre-post study was conducted at 3 US sites among 8474 adult emergency department patients with possible acute coronary syndrome. Patients included were ≥21 years old, investigated for possible acute coronary syndrome, and had no evidence of ST-segment-elevation myocardial infarction on ECG. Accrual occurred for 12 months before and after HEART Pathway implementation from November 2013 to January 2016. The HEART Pathway accelerated diagnostic protocol was integrated into the electronic health record at each site as an interactive clinical decision support tool. After accelerated diagnostic protocol integration, ED providers prospectively used the HEART Pathway to identify patients with possible acute coronary syndrome as low risk (appropriate for early discharge without stress testing or angiography) or non-low risk (appropriate for further in-hospital evaluation). The primary safety and effectiveness outcomes, death, and myocardial infarction (MI) and hospitalization rates at 30 days were determined from health records, insurance claims, and death index data. RESULTS: Preimplementation and postimplementation cohorts included 3713 and 4761 patients, respectively. The HEART Pathway identified 30.7% as low risk; 0.4% of these patients experienced death or MI within 30 days. Hospitalization at 30 days was reduced by 6% in the postimplementation versus preimplementation cohort (55.6% versus 61.6%; adjusted odds ratio, 0.79; 95% CI, 0.71-0.87). During the index visit, more MIs were detected in the postimplementation cohort (6.6% versus 5.7%; adjusted odds ratio, 1.36; 95% CI, 1.12-1.65). Rates of death or MI during follow-up were similar (1.1% versus 1.3%; adjusted odds ratio, 0.88; 95% CI, 0.58-1.33). CONCLUSIONS: HEART Pathway implementation was associated with decreased hospitalizations, increased identification of index visit MIs, and a very low death and MI rate among low-risk patients. These findings support use of the HEART Pathway to identify low-risk patients who can be safely discharged without stress testing or angiography. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02056964.

New statin use and left ventricular structure: Estimating long-term associations in the Multi-Ethnic Study of Atherosclerosis (MESA).

PURPOSE: Only small and short-term studies have evaluated statins in relation to changes in heart structure. We estimated the association between new statin use and 10-year remodeling of the left ventricle. METHODS: The Multi-Ethnic Study of Atherosclerosis collected data on statin use over approximately 10 years, conducting cardiac magnetic resonance (CMR) imaging at baseline and the 10-year exam. Participants were free of baseline cardiovascular disease, and we excluded users of statins at baseline. Statin initiation was defined as a report of current use at any of the 4 subsequent exams. Primary outcomes were the change in left ventricular mass index (LVMI; % predicted by height, weight, and sex) and mass-to-volume ratio. Associations were estimated in a propensity score-matched analysis. RESULTS: A total of 3113 participants (53% female; 40% European-American, 25% African-American, 22% Hispanic-American, and 13% Chinese-American) were eligible; 2431 returned for follow-up CMR imaging after a median of 9.4 years. Statin therapy (moderate dose, 76%) was started by 36% of participants (N = 872). We excluded 42 participants with incident myocardial infarction. Compared with nonuse, statin use was associated with less 10-year progression in LVMI (-2.35 percentage points; 95% CI, -4.24 to -0.47; P = .01) and mass-to-volume ratio (-0.03 absolute difference; 95% CI, -0.07 to -0.00; P = .02); effects were small in magnitude. A dose response was observed: Higher statin dose was associated with less LVMI progression. CONCLUSIONS: In contrast to previous small studies, we found very modest associations between statin use and indices of left ventricular remodeling over 10 years in this prospective study of a diverse cohort.

Role of Coronary Artery Calcium Score of Zero and Other Negative Risk Markers for Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Limited attention has been paid to negative cardiovascular disease (CVD) risk markers despite their potential to improve medical decision making. We compared 13 negative risk markers using diagnostic likelihood ratios (DLRs), which model the change in risk for an individual after the result of an additional test. METHODS AND RESULTS: We examined 6814 participants from the Multi-Ethnic Study of Atherosclerosis. Coronary artery calcium score of 0, carotid intima-media thickness <25th percentile, absence of carotid plaque, brachial flow-mediated dilation >5% change, ankle-brachial index >0.9 and <1.3, high-sensitivity C-reactive protein <2 mg/L, homocysteine <10 µmol/L, N-terminal pro-brain natriuretic peptide <100 pg/mL, no microalbuminuria, no family history of coronary heart disease (any/premature), absence of metabolic syndrome, and healthy lifestyle were compared for all and hard coronary heart disease and all CVD events over the 10-year follow-up. Models were adjusted for traditional CVD risk factors. Among all negative risk markers, coronary artery calcium score of 0 was the strongest, with an adjusted mean DLR of 0.41 (SD, 0.12) for all coronary heart disease and 0.54 (SD, 0.12) for CVD, followed by carotid intima-media thickness <25th percentile (DLR, 0.65 [SD, 0.04] and 0.75 [SD, 0.04], respectively). High-sensitivity C-reactive protein <2 mg/L and normal ankle-brachial index had DLRs >0.80. Among clinical features, absence of any family history of coronary heart disease was the strongest (DLRs, 0.76 [SD, 0.07] and 0.81 [SD, 0.06], respectively). Net reclassification improvement analyses yielded similar findings, with coronary artery calcium score of 0 resulting in the largest, most accurate downward risk reclassification. CONCLUSIONS: Negative results of atherosclerosis-imaging tests, particularly coronary artery calcium score of 0, resulted in the greatest downward shift in estimated CVD risk. These results may help guide discussions on the identification of individuals less likely to receive net benefit from lifelong preventive pharmacotherapy.

Concordance With Prevention Guidelines and Subsequent Cancer, Cardiovascular Disease, and Mortality: A Longitudinal Study of Older Adults.

Reports on the associations between multiple clinical and behavioral health indicators and major health outcomes among older adults are scarce. We prospectively examined concordance with guidelines from the American Cancer Society and American Heart Association for disease prevention in relation to cancer, cardiovascular disease (CVD), and mortality among Cardiovascular Health Study enrollees aged 65-98 years who, at baseline assessment in 1989-1996 (n = 3,491), were free of CVD and cancer. Total and cause-specific mortality, as well as incidence of cancer and CVD, were lower with higher guideline concordance. Independent of body mass index, blood pressure, total cholesterol, and fasting plasma glucose, better health behaviors (diet, physical activity, and alcohol consumption) were associated with lower mortality (2-sided P < 0.0001). Among individuals with ideal levels for 3-4 of these 4 cardiometabolic biomarkers, those with poor concordance with health behavior recommendations had higher mortality compared with those who had the highest concordance with these behavioral recommendations (adjusted mortality hazard ratio = 1.82, 95% confidence interval: 1.25, 2.67). Older adults who are concordant with recommendations for cancer and CVD prevention have reduced rates of chronic disease and mortality. Interventions to achieve and maintain healthy lifestyle behaviors may offer benefits both in the presence and absence of adverse traditional clinical risk factors.

Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study.

BACKGROUND: Long-term exposure to fine particulate matter less than 2.5 µm in diameter (PM2.5) and traffic-related air pollutant concentrations are associated with cardiovascular risk. The disease process underlying these associations remains uncertain. We aim to assess association between long-term exposure to ambient air pollution and progression of coronary artery calcium and common carotid artery intima-media thickness. METHODS: In this prospective 10-year cohort study, we repeatedly measured coronary artery calcium by CT in 6795 participants aged 45-84 years enrolled in the Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) in six metropolitan areas in the USA. Repeated scans were done for nearly all participants between 2002 and 2005, for a subset of participants between 2005 and 2007, and for half of all participants between 2010 and 2012. Common carotid artery intima-media thickness was measured by ultrasound in all participants at baseline and in 2010-12 for 3459 participants. Residence-specific spatio-temporal pollution concentration models, incorporating community-specific measurements, agency monitoring data, and geographical predictors, estimated concentrations of PM2.5 and nitrogen oxides (NOX) between 1999 and 2012. The primary aim was to examine the association between both progression of coronary artery calcium and mean carotid artery intima-media thickness and long-term exposure to ambient air pollutant concentrations (PM2.5, NOX, and black carbon) between examinations and within the six metropolitan areas, adjusting for baseline age, sex, ethnicity, socioeconomic characteristics, cardiovascular risk factors, site, and CT scanner technology. FINDINGS: In this population, coronary calcium increased on average by 24 Agatston units per year (SD 58), and intima-media thickness by 12 µm per year (10), before adjusting for risk factors or air pollutant exposures. Participant-specific pollutant concentrations averaged over the years 2000-10 ranged from 9.2-22.6 µg PM2.5/m(3) and 7.2-139.2 parts per billion (ppb) NOX. For each 5 µg PM2.5/m(3) increase, coronary calcium progressed by 4.1 Agatston units per year (95% CI 1.4-6.8) and for each 40 ppb NOX coronary calcium progressed by 4.8 Agatston units per year (0.9-8.7). Pollutant exposures were not associated with intima-media thickness change. The estimate for the effect of a 5 µg/m(3) higher long-term exposure to PM2.5 in intima-media thickness was -0.9 µm per year (95% CI -3.0 to 1.3). For 40 ppb higher NOX, the estimate was 0.2 µm per year (-1.9 to 2.4). INTERPRETATION: Increased concentrations of PM2.5 and traffic-related air pollution within metropolitan areas, in ranges commonly encountered worldwide, are associated with progression in coronary calcification, consistent with acceleration of atherosclerosis. This study supports the case for global efforts of pollution reduction in prevention of cardiovascular diseases. FUNDING: US Environmental Protection Agency and US National Institutes of Health.

Cumulative Number of Treatment Interventions Predicts Health-Related Quality of Life in Patients with Critical Limb Ischemia.

BACKGROUND: Health-related quality of life (QOL) is usually assessed after a defined interval following a single intervention, but critical limb ischemia (CLI) is a chronic condition where multiple interventions are often required over a patient's lifetime. We hypothesized that the impact of CLI treatment interventions on QOL is diminished in the setting of multiple previous interventions. To test this hypothesis, we performed a cross-sectional study evaluating associations between cumulative number of previous peripheral artery disease (PAD) treatment interventions and QOL adjusting for both comorbidity and disease severity. METHODS: Participants with CLI (abnormal ankle brachial index [ABI] plus rest pain and/or tissue loss) were enrolled in a cross-sectional study and completed a disease-specific QOL assessment, (the Vascular Quality of Life Questionnaire-6 [VascuQol-6]). Minimum ABI was used to assess disease severity, and comorbidity was evaluated based on Charlson Comorbidity Index. Cumulative number of PAD treatment interventions was defined based on the lifelong total for both legs. QOL associations were evaluated using a multivariable linear regression model adjusted for age and gender. RESULTS: Thirty-two patients with CLI participated. Mean age was 63 ± 10 years, 72% were men, and 63% were white; mean ABI was 0.6 ± 0.2. Mean VQ-6 score was 11.6 ± 4.2, and QOL was lower in patients with more previous interventions. Multivariable models demonstrated that an increasing number of previous treatment interventions negatively impacted QOL (P = 0.047), whereas positive associations were identified for female gender (P = 0.006) and ABI (P = 0.006). No association between comorbidity and QOL was identified. CONCLUSIONS: Vascular-specific factors appear to be key determinants of QOL among patients with CLI, whereas comorbidity appears less important. Strategies focused on definitive and durable revascularization may reduce cumulative interventions and potentially maximize QOL for patients with CLI.

Utility of Nontraditional Risk Markers in Individuals Ineligible for Statin Therapy According to the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines.

BACKGROUND: In the general population, the majority of cardiovascular events occur in people at the low to moderate end of population risk distribution. The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol recommends consideration of statin therapy for adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5% based on traditional risk factors. Whether use of nontraditional risk markers can improve risk assessment in those below this threshold for statin therapy is unclear. METHODS AND RESULTS: Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population sample free of clinical CVD at baseline, we calibrated the Pooled Cohort Equations (cPCE). ASCVD was defined as myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke. Adults with an initial cPCE <7.5% and elevated levels of additional risk markers (abnormal test) whose new calculated risk was ≥7.5% were considered statin eligible: low-density lipoprotein cholesterol ≥160 mg/dL; family history of ASCVD; high-sensitivity C-reactive protein ≥2 mg/dL; coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity; and ankle-brachial index <0.9. We compared the absolute and relative ASCVD risks among those with versus without elevated posttest estimated risk. We calculated the number needed to screen to identify 1 person with abnormal test for each risk marker, defined as the number of participants with baseline cPCE risk <7.5% divided by the number with an abnormal test reclassified as statin eligible. Of 5185 participants not taking statins with complete data (age, 45-84 years), 4185 had a cPCE risk <7.5%. During 10 years of follow-up, 57% of the ASCVD events (183 of 320) occurred among adults with a cPCE risk <7.5%. When people with diabetes mellitus were excluded, the coronary artery calcium criterion reclassified 6.8% upward, with an event rate of 13.3%, absolute risk of 10%, relative risk of 4.0 (95% confidence interval [CI], 2.8-5.7), and number needed to screen of 14.7. The corresponding numbers for family history of ASCVD were 4.6%, 15.1%, 12%, 4.3 (95% CI, 3.0-6.4), and 21.8; for high-sensitivity C-reactive protein criteria, 2.6%, 10%, 6%, 2.6 (95% CI, 1.4-4.8), and 39.2; for ankle-brachial index criteria, 0.6%, 9%, 5%, 2.3 (95% CI, 0.6-8.6), and 176.5; and for low-density lipoprotein cholesterol criteria, 0.5%, 5%, 1%, 1.2 (95% CI, 0.2-8.4), and 193.3, respectively. Of the 3882 with <7.5% cPCE risk, 431 (11.1%) were reclassified to ≥7.5% (statin eligible) by at least 1 of the additional risk marker criteria. CONCLUSIONS: In this generally low-risk population sample, a large proportion of ASCVD events occurred among adults with a 10-year cPCE risk <7.5%. We found that the coronary artery calcium score, high-sensitivity C-reactive protein, family history of ASCVD, and ankle-brachial index recommendations by the American College of Cardiology/American Heart Association cholesterol guidelines (Class IIB) identify small subgroups of asymptomatic population with a 10-year cPCE risk <7.5% but with observed ASCVD event rates >7.5% who may warrant statin therapy considerations.

Long-term Coarse Particulate Matter Exposure and Heart Rate Variability in the Multi-ethnic Study of Atherosclerosis.

BACKGROUND: Reduced heart rate variability, a marker of impaired cardiac autonomic function, has been linked to short-term exposure to airborne particles. This research adds to the literature by examining associations with long-term exposures to coarse particles (PM10-2.5). METHODS: Using electrocardiogram recordings from 2,780 participants (45-84 years) from three Multi-ethnic Study of Atherosclerosis sites, we assessed the standard deviation of normal to normal intervals and root-mean square differences of successive normal to normal intervals at a baseline (2000-2002) and follow-up (2010-2012) examination (mean visits/person = 1.5). Annual average concentrations of PM10-2.5 mass, copper, zinc, phosphorus, silicon, and endotoxin were estimated using site-specific spatial prediction models. We assessed associations for baseline heart rate variability and rate of change in heart rate variability over time using multivariable mixed models adjusted for time, sociodemographic, lifestyle, health, and neighborhood confounders, including copollutants. RESULTS: In our primary models adjusted for demographic and lifestyle factors and site, PM10-2.5 mass was associated with 1.0% (95% confidence interval [CI]: -4.1, 2.1%) lower standard deviation of normal to normal interval levels per interquartile range of 2 µg/m. Stronger associations, however, were observed before site adjustment and with increasing residential stability. Similar patterns were found for root-mean square differences of successive normal to normal intervals. We found little evidence for associations with other chemical species and with the rate of change in heart rate variability, though endotoxin was associated with increasing heart rate variability over time. CONCLUSION: We found only weak evidence that long-term PM10-2.5 exposures are associated with lowered heart rate variability. Stronger associations among residentially stable individuals suggest that confirmatory studies are needed.

Incidence of Age-Related Macular Degeneration in a Multi-Ethnic United States Population: The Multi-Ethnic Study of Atherosclerosis.

PURPOSE: To describe the incidence of age-related macular degeneration (AMD) and associated risk factors in 4 racial/ethnic groups (white, black, Hispanic, and Chinese) residing in the United States. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 3811 participants, aged 46 to 86 years, from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, with retinal data collected twice, on average, 8 years apart. METHODS: Fundus images, taken using a digital camera through dark-adapted pupils using a standard protocol and the same equipment at both study visits, were graded centrally for early and late AMD on the basis of drusen size, type and area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions, and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Demographic, clinical, and laboratory measures were included in multivariable regression models to determine their impact on the variation in AMD incidence among racial/ethnic groups. MAIN OUTCOME MEASURES: Incident early and late AMD. RESULTS: The overall 8-year age- and sex-standardized incidence of early and late AMD were 4.1% and 2.3%, respectively, with incidence of early and late AMD highest in whites (5.3% and 4.1%, respectively), intermediate in Chinese (4.5% and 2.2%, respectively) and Hispanics (3.3% and 0.8%, respectively), and lowest in blacks (1.6% and 0.4%, respectively). By adjusting for age and sex, blacks had a 70% lower risk of developing early AMD than whites, and this decreased only slightly to a 67% lower risk after multivariable adjustment. By adjusting for age, sex, and race/ethnicity, hyperopia was associated with early AMD (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.04-2.20), as was astigmatism (OR, 1.47; 95% CI, 1.00-2.16), but not myopia (P = 0.29). Age, race/ethnicity, current smoking, hyperopia, and AMD-susceptibility genotypes Complement Factor H (CFH) RS1061170 and Age Related Maculopathy Susceptibility 2 (ARMS2) RS3793917 were independently associated with incident early AMD in multivariable models for the combined sample. However, the only statistically significant factor consistently associated with incident early AMD across the 4 racial/ethnic groups was increasing age. Risk factors for late AMD were not assessed because of its low incidence, particularly across racial/ethnic groups. CONCLUSIONS: Variation in the incidence of early AMD exists among racial/ethnic groups in the United States and is not explained by the clinical, genetic, and environmental factors included in this study.

Methylomics of gene expression in human monocytes.

DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3' UTR, gene bodies, CpG shores or 'offshore' sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10(-308)) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.

Implications of the new American College of Cardiology/American Heart Association cholesterol guidelines for primary atherosclerotic cardiovascular disease event prevention in a multi ethnic cohort: Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: The impact of replacing the National Cholesterol Education Program (NCEP)/Adult Treatment Program (ATP) III cholesterol guidelines with the new 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for primary prevention of cardiovascular disease is unclear. METHODS: We used risk factor and 10-year clinical event rate data from MESA, combined with estimates of efficacy of moderate and high-intensity statin therapy from meta-analyses of statin primary prevention trials to estimate (a) the change in number of subjects eligible for drug therapy and (2) the anticipated reduction in atherosclerotic cardiovascular disease (ASCVD) events and increment in type 2 diabetes mellitus (T2DM) associated with the change in cholesterol guidelines. RESULTS: Of the 6,814 MESA participants, 5,437 were not on statins at baseline and had complete data for analysis (mean age 61.4±10.3). Using the NCEP/ATP III guidelines, 1,334 (24.5%) would have been eligible for statin therapy compared with 3,015 (55.5%) under the new ACC/AHA guidelines. Among the subset of newly eligible, 127/1,742 (7.3%) had an ASCVD event during 10years of follow-up. Assuming 10years of moderate-intensity statin therapy, the estimated absolute reduction in ASCVD events for the newly eligible group was 2.06% (number needed to treat [NNT] 48.6) and the estimated absolute increase in T2DM was 0.90% (number needed to harm [NNH] 110.7). Assuming 10years of high-intensity statin therapy, the corresponding estimates for reductions in ASCVD and increases in T2DM were as follows: ASCVD 2.70% (NNT 37.5) and T2DM 2.60% (NNH 38.6). The estimated effects of moderate-intensity statins on 10-year risk for ASCVD and T2DM in participants eligible for statins under the NCEP/ATP III were as follows: 3.20% (NNT 31.5) and 1.06% (NNH 94.2), respectively. CONCLUSION: Substituting the NCEP/ATP III cholesterol guidelines with the 2013 ACC/AHA cholesterol guidelines in MESA more than doubled the number of participants eligible for statin therapy. If the new ACC/AHA cholesterol guidelines are adopted and extend the primary prevention population eligible for treatment, the risk-benefit profile is much better for moderate-intensity than high-intensity statin treatment.

Exploring patient involvement in decision making for vascular procedures.

BACKGROUND: Developing patient-centered approaches to health care requires increased engagement of patients in their own care, including treatment decisions. Current levels of patient involvement in treatment choices have not been quantified, however, and whether patients desire greater decision-making responsibility is unknown. We conducted a prospective study to explore patients' desired vs experienced roles in treatment decisions, characterize perceptions of treatment outcomes, and identify important sources of information. METHODS: Patients undergoing elective vascular procedures completed a survey consisting of multiple choice, Likert scale, and open-ended questions. Statistics are displayed as mean ± standard deviation or count (%). Differences among procedure categories were evaluated using χ(2) or the Fisher exact test at P < .05 based on responses scored 1 to 2, indicating importance, agreement, or satisfaction based on a 1 to 5 Likert scale where 1 = "very important," "strongly agree" or "very satisfied". RESULTS: Of 101 patients who were contacted, 81 participated. Procedure categories included abdominal aortic aneurysm (AAA) repair in 20, arteriovenous (AV) hemodialysis access in 21, carotid endarterectomy (CEA) in 20, and intervention for lower extremity peripheral arterial disease (PAD) in 20. Participants preferred discussion of all treatments being considered vs only the provider's recommended treatment (90% vs 56%) and choosing together with the provider vs having the provider choose for them (93% vs 62%). Although participants indicated adequate information to ask questions without feeling overwhelmed, only 77% agreed that they had the opportunity to ask questions and only 54% indicated that they were offered a choice. Thirty-seven participants (46%) considered their first treatment was successful, 38% considered a subsequent treatment was successful, and 16% considered none of their treatments were successful. Participants undergoing PAD and AV access procedures most often felt confused or overwhelmed (25% and 24%, respectively, vs 0% for AAA and CEA; P < .01). Patients with PAD had adequate information least often (70% vs 85% for AAA, 100% for AV access, and 95% for CEA; P = .01), had the lowest satisfaction with understanding of their diagnosis (65% vs 95% for AAA, 100% for AV access, and 95% for CEA; P < .01), and most often considered none of their treatments successful (35% vs 0% for AAA, 15% for AV access, and 15% for CEA; P = .02). Providers were identified as the most important information source. CONCLUSIONS: Patients have variable levels of participation in decision making related to vascular procedures and often consider their treatments unsuccessful. Although providers are important sources of information, patients still prefer to discuss all options being considered and contribute to shared decision making.

Mediation of cardiovascular risk factor effects through subclinical vascular disease: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and brachial flow-mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT, and FMD. APPROACH AND RESULTS: Six thousand three hundred fifty-five of 6814 Multi-Ethnic Study of Atherosclerosis participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) was used to assess whether CAC, CIMT, or FMD are mediators of the association between traditional risk factors and incident CVD event. Mean age was 62 years, with 47% men, 12% diabetics, and 13% current smokers. After a mean follow-up of 7.5 years, there were 539 CVD adjudicated events. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes, whereas current cigarette smoking had the least percent of total effect mediated via CAC (percent [95% confidence interval]: 80.2 [58.8-126.7] versus 10.6 [6.1-38.5], respectively). Body mass index showed the highest percent of total effect mediated via CIMT (17.7 [11.6-38.9]); only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD. CONCLUSIONS: Many of the risk factors for incident CVD (other than age, sex, and body mass index) showed a modest level of mediation via CAC, CIMT, and FMD, suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification.

APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema.

Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2100 genes selected for cardiovascular diseases among 20 077 European-Americans and 6900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with per cent emphysema and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and per cent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10(-6)) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10(-7)). Both single-nucleotide polymorphisms (SNPs) flank the gene for apolipoprotein M (APOM), a component of high-density lipoprotein (HDL) cholesterol. Both were replicated in an independent cohort. SNPs in a second gene related to apolipoprotein M and HDL, PCSK9, were associated with FEV1/FVC ratio among African-Americans. rs707974 was associated with per cent emphysema among European-Americans and African-Americans and APOM expression was related to FEV1/FVC ratio and per cent emphysema. Higher HDL levels were associated with lower FEV1/FVC ratio and greater per cent emphysema. These findings suggest a novel role for the apolipoprotein M/HDL pathway in the pathogenesis of COPD and emphysema.