Multi-Ethnic Study Of Atherosclerosis Cohort Research Articles

Association of Water Arsenic With Incident Diabetes in U.S. Adults: The Multi-Ethnic Study of Atherosclerosis and the Strong Heart Study.

We examined the association of arsenic in federally regulated community water systems (CWSs) and unregulated private wells with type 2 diabetes (T2D) incidence in the Strong Heart Family Study (SHFS), a prospective study of American Indian communities, and the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of racially and ethnically diverse urban U.S. communities. We evaluated 1,791 participants from SHFS and 5,777 participants from MESA who had water arsenic estimates available and were free of T2D at baseline (2001-2003 and 2000-2002, respectively). Participants were followed for incident T2D until 2010 (SHFS cohort) or 2019 (MESA cohort). We used Cox proportional hazards mixed-effects models to account for clustering by family and residential zip code, with adjustment for sex, baseline age, BMI, smoking status, and education. T2D incidence was 24.4 cases per 1,000 person-years (mean follow-up, 5.6 years) in SHFS and 11.2 per 1,000 person-years (mean follow-up, 14.0 years) in MESA. In a meta-analysis across the SHFS and MESA cohorts, the hazard ratio (95% CI) per doubling in CWS arsenic was 1.10 (1.02, 1.18). The corresponding hazard ratio was 1.09 (0.95, 1.26) in the SHFS group and 1.10 (1.01, 1.20) in the MESA group. The corresponding hazard ratio (95% CI) for arsenic in private wells and incident T2D in SHFS was 1.05 (0.95, 1.16). We observed statistical interaction and larger magnitude hazard ratios for participants with BMI <25 kg/m2 and female participants. Low to moderate water arsenic levels (<10 µg/L) were associated with T2D incidence in the SHFS and MESA cohorts.

Approaches to estimate bidirectional causal effects using Mendelian randomization with application to body mass index and fasting glucose.

Mendelian randomization (MR) is an epidemiological framework using genetic variants as instrumental variables (IVs) to examine the causal effect of exposures on outcomes. Statistical methods based on unidirectional MR (UMR) are widely used to estimate the causal effects of exposures on outcomes in observational studies. To estimate the bidirectional causal effects between two phenotypes, investigators have naively applied UMR methods separately in each direction. However, bidirectional causal effects between two phenotypes create a feedback loop that biases the estimation when UMR methods are naively applied. To overcome this limitation, we proposed two novel approaches to estimate bidirectional causal effects using MR: BiRatio and BiLIML, which are extensions of the standard ratio, and limited information maximum likelihood (LIML) methods, respectively. We compared the performance of the two proposed methods with the naive application of UMR methods through extensive simulations of several scenarios involving varying numbers of strong and weak IVs. Our simulation results showed that when multiple strong IVs are used, the proposed methods provided accurate bidirectional causal effect estimation in terms of median absolute bias and relative median absolute bias. Furthermore, compared to the BiRatio method, the BiLIML method provided a more accurate estimation of causal effects when weak IVs were used. Therefore, based on our simulations, we concluded that the BiLIML should be used for bidirectional causal effect estimation. We applied the proposed methods to investigate the potential bidirectional relationship between obesity and diabetes using the data from the Multi-Ethnic Study of Atherosclerosis cohort. We used body mass index (BMI) and fasting glucose (FG) as measures of obesity and type 2 diabetes, respectively. Our results from the BiLIML method revealed the bidirectional causal relationship between BMI and FG in across all racial populations. Specifically, in the White/Caucasian population, a 1 kg/m2 increase in BMI increased FG by 0.70 mg/dL (95% confidence interval [CI]: 0.3517-1.0489; p = 8.43×10-5), and 1 mg/dL increase in FG increased BMI by 0.10 kg/m2 (95% CI: 0.0441-0.1640; p = 6.79×10-4). Our study provides novel findings and quantifies the effect sizes of the bidirectional causal relationship between BMI and FG. However, further studies are needed to understand the biological and functional mechanisms underlying the bidirectional pathway.

Association of Lipoprotein(a) Levels With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis.

Lipoprotein(a) (Lp[a]) has been identified as an emerging risk factor for adverse cardiovascular (CV) outcomes, including heart failure. However, the connections among Lp(a), myocardial fibrosis (interstitial and replacement), and cardiac remodeling as pathways to CV diseases remains unclear. This study investigated the relationship between Lp(a) levels and myocardial fibrosis by cardiac magnetic resonance (CMR) T1 mapping and late gadolinium enhancement, as well as cardiac remodeling by cine CMR, in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. The study included 2,040 participants with baseline Lp(a) measurements and T1 mapping for interstitial myocardial fibrosis (IMF) evaluation in 2010. Lp(a) was analyzed as a continuous variable (per log unit) and using clinical cutoff values of 30 and 50mg/dL. Multivariate linear and logistic regression were used to assess the associations of Lp(a) with CMR measures of extracellular volume (ECV fraction [ECV%]), native T1 time, and myocardial scar, as well as parameters of cardiac remodeling, in 2,826 participants. Higher Lp(a) levels were associated with increased ECV% (per log-unit Lp[a]; β=0.2%; P=0.007) and native T1 time (per log-unit Lp[a]; β=4%; P< 0.001). Similar relationships were observed between elevated Lp(a) levels and a higher risk of clinically significant IMF defined by prognostic thresholds per log-unit Lp(a) of ECV% (OR: 1.20; 95%CI: 1.04-1.43) and native T1 (OR: 1.2; 95%CI: 1.1-1.4) equal to 30% and 955ms, respectively. Clinically used Lp(a) cutoffs (30 and 50mg/dL) were associated with greater prevalence of myocardial scar (OR: 1.85; 95%CI: 1.1-3.2 and OR: 1.9; 95%CI: 1.1-3.4, respectively). Finally, higher Lp(a) levels were associated with left atrial enlargement and dysfunction. Elevated Lp(a) levels are linked to greater subclinical IMF, increased myocardial scar prevalence, and left atrial remodeling.

Differences in left anterior descending coronary artery disease in participants without standard modifiable cardiovascular risk factors: the Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract Background/Introduction The development of coronary artery disease (CAD) and myocardial infarction (MI) in the absence of standard modifiable cardiovascular risk factors (SMuRFs) has been highlighted as an unmet clinical need, accounting for between 10-27% of ST elevation MI and associated with higher 30-day mortality. One potential contributor to the early mortality is the higher observed rates of LAD territory culprit lesions in SMuRFless patients compared to those with at least one SMuRF. Purpose To characterise the differential proportion of LAD disease in an asymptomatic population with no prior cardiovascular disease (CVD) history, comparing individuals with CAD despite no SMuRFs to those with at least one SMuRF in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods A MESA sub-cohort with a baseline coronary artery calcium score (CACS) &amp;gt;0 Agatston units (AU) was prepared. SMuRF status was assigned by self-report, treatment, or biomarkers for hypertension, hypercholesterolaemia, diabetes, and smoking. Proportion of disease in the left main, LAD, circumflex, and right coronary arteries were calculated by the vessel CACS divided by the total CACS. Standard descriptive statistics were used to characterise baseline differences. Group comparisons were completed with Wilcoxon rank sum for continuous measures and Chi-square for categorical. Results A CAC positive cohort of 3,417 participants was prepared from participants with SMuRF and CT imaging data, 14.3% of whom were considered SMuRFless. Total CACS was lower in SMuRFless participants compared to those with ≥1 SMuRF (58 AU vs. 102 AU, p&amp;lt;0.0001). However, proportion of calcium burden in the LAD was significantly higher in SMuRFless participants with CAD (74.2% vs. 56.8%, p&amp;lt;0.0001). When considering clinically significant CACS strata, proportion of LAD calcium burden was not significantly different between SMuRFless vs. ≥1 SMuRF participants with a total CACS of 1-99 AU (93.7% vs. 80.0%). However, statistically significant differences in LAD calcium proportion were observed between SMuRFless vs. ≥1 SMuRF participants with a total CACS 100-400 AU (69.5% vs. 57.8%) and CACS&amp;gt;400AU (45.2% vs. 40.5%). This difference remained significant during multivariate modelling, including consideration of absolute CACS. Conclusion Of patients with evidence of CAD (CACS&amp;gt;0) in the MESA cohort, SMuRFless status was associated with a higher proportion of LAD disease compared to participants with ≥1 SMuRF. This adds to previous observations in STEMI cohorts suggesting a heightened susceptibility to atherosclerosis development in the LAD territory against a lower traditional risk burden, and highlights the need for consideration of distinct biology and clinical significance in future studies.Fig. 1Fig. 2

Abstract 11652: The Addition of Social Determinants of Health to Coronary Heart Disease Risk Prediction

Introduction: Coronary heart disease (CHD) remains a leading cause of death worldwide, with an unequal distribution of this burden placed on individuals of lower socioeconomic status. Individual social determinants of health (SDoH) have been shown to be associated with CHD; however, whether the addition of SDoH can improve current CHD risk prediction algorithms has not been delineated. Hypothesis: We hypothesize that the addition of SDoH to the Multi-Ethnic Study of Atherosclerosis (MESA) risk score improves the prediction of 10-year CHD events. Methods: In 6,286 individuals from the MESA cohort, we evaluated the additional predictive value of SDoH beyond the traditional factors included in the existing MESA Risk Score. SDoH considered were employment, family income, house tenure, financial strain, education, marital status, social support, chronic stress, discrimination, neighborhood characteristics, healthcare access, and health insurance, which were organized into five composite domains. A penalized Cox proportional hazards model was used to select SDoH variables with the potential to improve prediction, then an unpenalized Cox regression model was fitted with traditional risk factors plus the selected SDoH variables. Results: Statistically significant differences in the distribution of SDoH were observed between racial and ethnic groups. Notably, unfavorable SDoH were concentrated in Black and Hispanic/Latino persons. Economic stability, education, and community and social context were associated with CHD events. The area under the curve (AUC) for prediction of a 10-year CHD event was 0.816 without SDoH factors and 0.818 with the addition of SDoH. Conclusions: Racial and ethnic differences in social determinants of health were obsserved. Economic stability, education, and community and social context were significantly associated with cardiovascular events, however the addition of SDoH did not significantly improve CHD risk prediction.

Omega-3 Polyunsaturated Fatty Acids are not associated with Peripheral Artery Disease in a Meta-Analysis from the Multi-Ethnic Study of Atherosclerosis and Atherosclerosis Risk in Communities Study Cohorts

BackgroundResearch suggests omega-3 polyunsaturated fatty acids (PUFAs) exert favorable effects on several biological processes involved in the development and progression of atherosclerotic cardiovascular disease (ASCVD). However, studies examining the relationship between omega-3 PUFAs and peripheral artery disease (PAD) are scarce. ObjectivesWe evaluated the associations between omega-3 PUFAs and incident PAD in a meta-analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and Atherosclerosis Risk in Communities (ARIC) study cohorts. MethodsOmega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured at baseline for all MESA (n = 6495) and Minnesota ARIC participants (n = 3612). Incident clinical PAD events (MESA n = 106; ARIC n = 149) identified primarily through ICD discharge codes were assessed through follow-up of each cohort. Associations between omega-3 PUFAs (EPA, DHA, and EPA+DHA) and incident PAD were modeled in MESA and ARIC as quartiles and continuously using Cox proportional hazards regression, respectively. A fixed-effects meta-analysis was conducted to evaluate associations in the 2 cohorts combined. ResultsIn the fully adjusted model, in 10,107 participants, no significant associations were observed between EPA, DHA, or EPA+DHA, and incident PAD modeled as quartiles or continuously for either MESA or ARIC cohorts separately or in the meta-analysis after a follow-up of approximately 15 y. ConclusionThis study is consistent with previous literature indicating that the beneficial effects of omega-3 PUFAs on the markers of ASCVD may not translate to a clinically meaningful decrease in PAD risk.

Novel Size-Based High-Density Lipoprotein Subspecies and Incident Vascular Events.

Background High-density lipoprotein (HDL) particle concentration likely outperforms HDL cholesterol in predicting atherosclerotic cardiovascular events. Whether size-based HDL subspecies explain the atheroprotective associations of HDL particle concentration remains unknown. Our objective was to assess whether levels of specific size-based HDL subspecies associate with atherosclerotic cardiovascular disease in a multiethnic pooled cohort and improve risk prediction beyond traditional atherosclerotic cardiovascular disease risk factors. Methods and Results Seven HDL size-based subspecies were quantified by nuclear magnetic resonance (LP4 algorithm; H1=smallest; H7=largest) among participants without prior atherosclerotic cardiovascular disease in ARIC (Atherosclerosis Risk in Communities), MESA (Multi-Ethnic Study of Atherosclerosis), PREVEND (Prevention of Renal and Vascular Endstage Disease), and DHS (Dallas Heart Study) cohorts (n=15 371 people). Multivariable Cox proportional hazards models were used to evaluate the association between HDL subspecies and incident myocardial infarction (MI) or ischemic stroke at follow-up (average 8-10 years) adjusting for HDL cholesterol and risk factors. Improvement in risk prediction was assessed via discrimination and reclassification analysis. Within the pooled cohort (median age 57 years; female 54%; Black 22%) higher H1 (small) and H4 (medium) concentrations were inversely associated with incident MI (hazard ratio [HR]/SD, H1 0.88 [95% CI, 0.81-0.94]; H4 0.89 [95% CI, 0.82-0.97]). H4 but not H1 improved risk prediction indices for incident MI. Increasing H2 and H4 were inversely associated with improved risk prediction indices for composite end point of stroke, MI, and cardiovascular death (HR/SD, H2 0.94 [95% CI, 0.88-0.99]; H4 0.91 [95% CI, 0.85-0.98]). Levels of the large subspecies (H6 and H7) were not associated with any vascular end point. Conclusions Two of 7 HDL size-based subspecies modestly improved risk prediction for MI and composite vascular end points in a large multiethnic pooled cohort. These findings support assessment of precise HDL subspecies for future studies regarding clinical utility.

Development and Validation of the US Diabetes, Obesity, Cardiovascular Disease Microsimulation (DOC-M) Model: Health Disparity and Economic Impact Model.

Few simulation models have incorporated the interplay of diabetes, obesity, and cardiovascular disease (CVD); their upstream lifestyle and biological risk factors; and their downstream effects on health disparities and economic consequences. We developed and validated a US Diabetes, Obesity, Cardiovascular Disease Microsimulation (DOC-M) model that incorporates demographic, clinical, and lifestyle risk factors to jointly predict overall and racial-ethnic groups-specific obesity, diabetes, CVD, and cause-specific mortality for the US adult population aged 40 to 79 y at baseline. An individualized health care cost prediction model was further developed and integrated. This model incorporates nationally representative data on baseline demographics, lifestyle, health, and cause-specific mortality; dynamic changes in modifiable risk factors over time; and parameter uncertainty using probabilistic distributions. Validation analyses included assessment of 1) population-level risk calibration and 2) individual-level risk discrimination. To illustrate the application of the DOC-M model, we evaluated the long-term cost-effectiveness of a national produce prescription program. Comparing the 15-y model-predicted population risk of primary outcomes among the 2001-2002 National Health and Nutrition Examination Survey (NHANES) cohort with the observed prevalence from age-matched cross-sectional 2003-2016 NHANES cohorts, calibration performance was strong based on observed-to-expected ratio and calibration plot analysis. In most cases, Brier scores fell below 0.0004, indicating a low overall prediction error. Using the Multi-Ethnic Study of Atherosclerosis cohorts, the c-statistics for assessing individual-level risk discrimination were 0.85 to 0.88 for diabetes, 0.93 to 0.95 for obesity, 0.74 to 0.76 for CVD history, and 0.78 to 0.81 for all-cause mortality, both overall and in three racial-ethnic groups. Open-source code for the model was posted at https://github.com/food-price/DOC-M-Model-Development-and-Validation. The validated DOC-M model can be used to examine health, equity, and the economic impact of health policies and interventions on behavioral and clinical risk factors for obesity, diabetes, and CVD. We developed a novel microsimula'tion model for obesity, diabetes, and CVD, which intersect together and - critically for prevention and treatment interventions - share common lifestyle, biologic, and demographic risk factors.Validation analyses, including assessment of (1) population-level risk calibration and (2) individual-level risk discrimination, showed strong performance across the overall population and three major racial-ethnic groups for 6 outcomes (obesity, diabetes, CVD, and all-cause mortality, CVD- and DM-cause mortality)This paper provides a thorough explanation and documentation of the development and validation process of a novel microsimulation model, along with the open-source code (https://github.com/food-price/ DOCM_validation) for public use, to serve as a guide for future simulation model assessments, validation, and implementation.

Association between Left Atrial Late Gadolinium Enhancement and Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA).

To determine the prevalence and correlates of left atrial (LA) late gadolinium enhancement (LGE) at cardiac MRI and its association with atrial fibrillation (AF) in a population-based sample from the Multi-Ethnic Study of Atherosclerosis (MESA). In this secondary post hoc analysis of the MESA cohort (ClinicalTrials.gov no. NCT00005487), participants without AF underwent LGE cardiac MRI at the fifth examination (2010-2012). LA LGE burden was quantified using the image intensity ratio technique on biplane long-axis two-dimensional (2D) LGE images without fat saturation. Survival analysis was performed with log-rank testing and Cox regression. Of 1697 participants (mean age, 67 years ± 9 [SD]; 872 men), 1035 (61%) had LA LGE, and 75 (4.4%) developed AF during follow-up (median, 3.95 years). At univariable analysis, LA LGE was associated with age (β = .010 [95% CI: .005, .015], P < .001), diastolic blood pressure (β = .005 [95% CI: .001, .009], P = .02), HbA1c level (β = .06 [95% CI: .02, .11], P = .009), heart failure (β = .60 [95% CI: .11, 1.08], P = .02), LA volume (β = .008 [95% CI: .004, .012], P < .001), and LA function (emptying fraction, LA global longitudinal strain, LA early diastolic peak longitudinal strain rate, and LA late diastolic peak strain rate; all P < .05). After adjusting for the variables in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AF score, LA LGE independently helped predict incident AF (hazard ratio = 1.46 [95% CI: 1.13, 1.88], P = .003). The highest tertile (LGE > 2%) was twice as likely to develop AF. Although limited by the 2D LGE technique employed, LA LGE was associated with adverse atrial remodeling and helped predict AF in a multiethnic population-based sample.Clinical trial registration no. NCT00005487Keywords: MR Imaging, Cardiac, Epidemiology Supplemental material is available for this article. © RSNA, 2023.

Endogenous Sex Hormone Levels and Myocardial Fibrosis in Men and Postmenopausal Women

BackgroundSex hormone (SH) imbalances have been linked to a higher risk of heart failure in both sexes. However, mechanisms that underlie this relationship remain unclear. We examined the association of baseline SH with interstitial and replacement myocardial fibrosis in the MESA (Multi-Ethnic Study of Atherosclerosis) using cardiac magnetic resonance (CMR) T1 mapping and late gadolinium enhancement (LGE). ObjectivesThe purpose of this study was to assess the link between baseline sex hormone levels and myocardial fibrosis in the MESA cohort using CMR. MethodsA total of 2,324 participants (men and postmenopausal women [PMW]) were included in the MESA with SH measured at baseline and had underwent CMR 10 years later. All analyses were stratified by sex and age. Regression models were constructed to assess the associations of baseline SH with extracellular volume (ECV)% and native T1 time and with LGE. Higher native T1 time and ECV% are interpreted as evidence of increasing interstitial myocardial fibrosis (IMF). Given the limited number of myocardial scars present in PMW, analysis of LGE was limited to men. ResultsAmong older men (age ≥65 years), a 1-SD increment higher free testosterone was significantly associated with 2.45% lower ECV% and 21.5% lower native T1 time, while a 1-SD increment higher bioavailable testosterone was associated with 12.5% lower native T1 time. A 1-SD increment greater sex hormone-binding globulin level was associated with 1% higher ECV%. Among PMW of 55 to 64 years, a 1-SD increment higher total testosterone was associated with 9.5% lower native T1 time. Higher levels of estradiol in older men were independently associated with higher odds of having a myocardial scar (OR: 4.10; 95% CI: 1.35-12.40; P = 0.01). ConclusionsAmong older men, SH imbalances at initial evaluation were independently associated with CMR defined IMF and replacement fibrosis, respectively; while increasing total testosterone in middle-aged PMW was associated with lesser marker of IMF.

Epidermal growth factor receptor inhibition prevents vascular calcifying extracellular vesicle biogenesis.

Chronic kidney disease (CKD) increases the risk of cardiovascular disease, including vascular calcification, leading to higher mortality. The release of calcifying extracellular vesicles (EVs) by vascular smooth muscle cells (VSMCs) promotes ectopic mineralization of vessel walls. Caveolin-1 (CAV1), a structural protein in the plasma membrane, plays a major role in calcifying EV biogenesis in VSMCs. Epidermal growth factor receptor (EGFR) colocalizes with and influences the intracellular trafficking of CAV1. Using a diet-induced mouse model of CKD followed by a high-phosphate diet to promote vascular calcification, we assessed the potential of EGFR inhibition to prevent vascular calcification. Furthermore, we computationally analyzed 7,651 individuals in the Multi-Ethnic Study of Atherosclerosis (MESA) and Framingham cohorts to assess potential correlations between coronary artery calcium and single-nucleotide polymorphisms (SNPs) associated with elevated serum levels of EGFR. Mice with CKD developed widespread vascular calcification, associated with increased serum levels of EGFR. In both the CKD mice and human VSMC culture, EGFR inhibition significantly reduced vascular calcification by mitigating the release of CAV1-positive calcifying EVs. EGFR inhibition also increased bone mineral density in CKD mice. Individuals in the MESA and Framingham cohorts with SNPs associated with increased serum EGFR exhibit elevated coronary artery calcium. Given that EGFR inhibitors exhibit clinical safety and efficacy in other pathologies, the current data suggest that EGFR may represent an ideal target to prevent pathological vascular calcification in CKD.NEW & NOTEWORTHY Here, we investigate the potential of epidermal growth factor receptor (EGFR) inhibition to prevent vascular calcification, a leading indicator of and contributor to cardiovascular morbidity and mortality. EGFR interacts and affects the trafficking of the plasma membrane scaffolding protein caveolin-1. Previous studies reported a key role for caveolin-1 in the development of specialized extracellular vesicles that mediate vascular calcification; however, no role of EGFR has been reported. We demonstrated that EGFR inhibition modulates caveolin-1 trafficking and hinders calcifying extracellular vesicle formation, which prevents vascular calcification. Given that EGFR inhibitors are clinically approved for other indications, this may represent a novel therapeutic strategy for vascular calcification.

Adipokines and incident venous thromboembolism: The Multi-Ethnic Study of Atherosclerosis

BackgroundObesity leads to adipocyte hypertrophy and adipokine dysregulation and is an independent risk factor for venous thromboembolism (VTE). However, the association between adipokines and VTE is not well established. ObjectivesTo examine whether adipokines are associated with increased risk of incident VTE. MethodsWe studied 1888 participants of the Multi-Ethnic Study of Atherosclerosis cohort who were initially free of VTE and had adipokine (adiponectin, leptin, and resistin) levels measured at either examination 2 or 3 (2002-2004 or 2004-2005, respectively). During follow-ups, VTE was ascertained through hospitalization records and death certificates by using ICD-9 and 10 codes. We used multivariable Cox proportional hazards regression to assess the association between 1 standard deviation (SD) log-transformed increments in adipokines and incident VTE. ResultsThe mean ± SD age was 64.7 ± 9.6 years, and 49.8% of participants were women. Medians (interquartile range) of adiponectin, leptin, and resistin were 17.3 (11.8-26.2) mcg/mL, 13.5 (5.6-28.2) ng/mL, and 15.0 (11.9-19.0) ng/mL, respectively. There were 78 incident cases of VTE after a median of 9.7 (5.0-12.4) years of follow-up. After adjusting for sociodemographics, smoking, and physical activity, the hazard ratios (95% CIs) per 1 SD increment of adiponectin, leptin, and resistin were 1.14 (0.90-1.44), 1.29 (1.00-1.66), and 1.38 (1.09-1.74), respectively. The association for resistin persisted after further adjustments for body mass index and computed tomography–derived total visceral adipose tissue area. ConclusionHigher resistin levels were independently associated with greater risk of incident VTE. Larger prospective cohort studies are warranted to confirm this association.

Associations of urinary isoprostanes with measures of subclinical atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA)

BackgroundUrinary isoprostanes are markers of systemic oxidative stress, which is implicated in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Coronary artery calcium (CAC), thoracic aortic calcium (TAC) and carotid plaque are measure subclinical atherosclerosis and prognosticate ASCVD risk. We examined the associations between urinary isoprostane levels and measures of plaque prevalence, burden, incidence and progression across three vascular beds in a cohort from the Multi-Ethnic Study of Atherosclerosis. MethodsUrinary levels of 8-isoprostane and 2,3-dinor-8-F2-isoprostane were measured in 1089 participants (mean ± SD 62 ± 8 years, 48% women) at baseline. Participants underwent computed tomography for CAC and TAC, and duplex ultrasound for carotid plaque. TAC and CAC were reassessed at 2.4 and 10 years, respectively. Regression models were adjusted for CVD risk factors. ResultsIn adjusted models, there were no significant associations between isoprostane levels with CAC prevalence or progression. Highest versus lowest tertile of 8-isoprostane was associated with 28% lower prevalence of descending TAC at baseline [prevalence ratio (PR) 0.72 95% CI (0.56, 0.94)], while 1-SD higher 2,3-dinor-8-F2-isoprostane was associated with 96% higher incident ascending TAC at follow-up [Relative Risk 1.96 (1.24, 3.09)]. Highest versus lowest tertile of isoprostane measures were associated with 22% higher prevalence of carotid plaque [(PR 1.22 (1.04, 1.45)] and 14% difference [3,26] in greater extent of carotid plaque at baseline. ConclusionsHigher urinary isoprostanes were inconsistently associated with some measures of subclinical atherosclerosis by imaging. This suggests a limited role of urinary isoprostane levels as a prognostic marker for the development of ASCVD. Trial registrationThe MESA cohort design is registered at clinicaltrials.gov as follows: https://clinicaltrials.gov/ct2/show/NCT00005487.

Association of immune cell subsets with incident heart failure in two population-based cohorts.

Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)]. Peripheral blood immune cell subsets were measured in adults from the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0±10.4years with 51% women, and in the CHS cohort, it was 79.6±4.4years with 62% women. In the meta-analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95% CI 0.83-0.99), P=0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95% CI 0.62-0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF. We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population-based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.

Longitudinal Associations of Physical Activity Patterns and the Environment: An 18-Year Follow-Up to the MESA Study.

Introduction: Cross-sectional association between the neighborhood-built environment and physical activity (PA) has been demonstrated previously, indicating the importance of neighborhood perception characteristics such as walkability, safety, and the connectivity of streets on PA levels. Our study aimed to assess the longitudinal data from participants of the Multi-Ethnic Study of Atherosclerosis (MESA) to evaluate the potential relationship between perceived environment and PA patterns. Methods: We analyzed data from a subset of participants (n = 3097) with available PA data who participated in a prospective cohort conducted from 2000 to 2018. The exposure variables were the perceived aspects of the neighborhood environment and the perception of safety, and the outcome was patterns of PA. Patterns were defined as categories reflecting meeting versus not meeting PA guidelines over time. We created the following categories: adopters (individuals who did not meet guidelines at baseline but met guidelines at Exam 6), relapsers (individuals who met guidelines at baseline but did not meet guidelines at Exam 6), maintainers (individuals who met guidelines both at baseline and Exam 6), and insufficiently active (individuals who did not meet guidelines at either baseline or Exam 6). The maintainers’ group was considered the reference category. We estimated the relative risk to assess the magnitude effect of the association between environmental perceptions and the outcome. Results: Individuals who reported that lack of parks and playgrounds was “not a problem” in their neighborhood had a 2.3-times higher risk of decreasing their physical activity (i.e., the “relapser” category) compared to maintainers. After full adjustment, perceiving poor sidewalks as “somewhat a serious problem” was associated with a 64% lower risk of becoming an adopter than a maintainer. When compared to those who perceive the neighborhood as “very safe”, perception of the neighborhood as “safe” to “not at all safe” (ratings 3, 4, and 5, respectively, on the perceived safety scale) was significantly associated with being classified in the adopter category. Conclusions: As the first longitudinal study of the association of perceived environment and physical activity within the MESA cohort, we conclude that a few aspects are longitudinally associated with being physically active among adults.

Supranormal Left Ventricular Ejection Fraction, Stroke Volume, and Cardiovascular Risk: Findings From Population-Based Cohort Studies

BackgroundSupranormal ejection fraction by echocardiography in clinically referred patient populations has been associated with an increased risk of cardiovascular disease (CVD). The prognostic implication of supranormal left ventricular ejection fraction (LVEF)—assessed by cardiac magnetic resonance (CMR)—in healthy, community-dwelling individuals is unknown. ObjectivesThe purpose of this study is to investigate the prognostic implication of supranormal LVEF as assessed by CMR and its inter-relationship with stroke volume among community-dwelling adults without CVD. MethodsParticipants from the MESA (Multi-Ethnic Study of Atherosclerosis) and DHS (Dallas Heart Study) cohorts free of CVD who underwent CMR with LVEF above the normal CMR cutoff (≥57%) were included. The association between cohort-specific LVEF categories and risk of clinically adjudicated major adverse cardiovascular events (MACE) was assessed using adjusted Cox models. Subgroup analysis was also performed to evaluate the association of LVEF and risk of MACE among individuals stratified by left ventricular stroke volume index. ResultsThe study included 4,703 participants from MESA and 2,287 from DHS with 727 and 151 MACE events, respectively. In adjusted Cox models, the risk of MACE was highest among individuals in LVEF Q4 (vs Q1) in both cohorts after accounting for potential confounders (MESA: HR = 1.27 [95% CI: 1.01-1.60], P = 0.04; DHS: HR = 1.72 [95% CI: 1.05-2.79], P = 0.03). A significant interaction was found between the continuous measures of LVEF and left ventricular stroke volume index (P interaction = 0.02) such that higher LVEF was significantly associated with an increased risk of MACE among individuals with low but not high stroke volume. ConclusionsAmong community-dwelling adults without CVD, LVEF in the supranormal range is associated with a higher risk of adverse cardiovascular outcomes, particularly in those with lower stroke volume.

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

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. 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. 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. 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.

Abstract 400: Cardiometabolic Profile Of Haptoglobin Genotype In A Multi-Ethnic Diabetes Cohort

Background: Haptoglobin has three common genotypes: Hp 1-1, Hp 2-1, and Hp 2-2. The Hp 2-2 genotype, known to have poorer antioxidizing capacity, is associated with worse cardiovascular outcomes in select patients with diabetes. In this study, we explore the association between various cardiometabolic biomarker profiles and the three Hp genotypes in a multiethnic population. Methods: A cross-sectional analysis was performed for all participants with diabetes in the Dallas Heart Study and Multi-Ethnic Study of Atherosclerosis cohorts. Hp genotype was measured in 1,158 participants (399 from DHS and 759 from MESA) using ELISA technique (Savyon Diagnostics, Ltd). Associations between Hp genotype and 26 cardiometabolic circulating and imaging biomarkers were assessed by ANOVA and stratified by ethnicity. Results: The study included 51% women, 44% Black (513 of 1,158: Hp 1-1=45%, Hp 2-1=35%, Hp 2-2=20%), 26% Hispanic (300 of 1,158: Hp 1-1=25%, Hp 2-1=49%, Hp 2-2=26%), 20% White (237 of 1,158: Hp 1-1=16%, Hp 2-1=56%, Hp 2-2=28%), and 9.2% Asian/Pacific Islander/East Indian (107 of 1,158: Hp 1-1=15%, Hp 2-1=36%, Hp 2-2=49%) participants. Significant differences were seen in lipid metabolism as well as atherosclerosis, inflammatory, structural, and endothelial markers with no significant differences seen in imaging biomarkers. In White participants, Hp 1-1 was associated with elevated total cholesterol (p=0.016), LDL-p (p=0.001), and LDL-C (p=0.004). In Asian/Pacific Islander/East Indian participants, Hp 2-2 was associated with elevated systolic blood pressure (p=0.029), BMI (p=0.029), and inflammatory markers such as IL-6 (p=0.018) and D-dimer (p=0.027). In Black participants, Hp 2-2 was associated with elevated ICAM (p=0.048) and BMI (p=0.007). Lastly, in Hispanic participants, no significant associations were seen. In exploratory analysis, when comparing Hp 1-1 and Hp 2-1 with Hp 2-2, there was greater magnitude effect size of certain biomarkers in Black and Asian participants, suggesting potential differential effects by ethnicity. Conclusion: Associations between Hp genotype and various cardiometabolic biomarkers are varied and ethnicity dependent with further studies needed to investigate the underlying physiologic mechanisms.

The Interplay of Race/Ethnicity and Obesity on the Incidence of Venous Thromboembolism

Factors predisposing asymptomatic individuals within the community to venous thromboembolism are not fully understood. This study characterizes the incidence and determinants of venous thromboembolism among the Multiethnic Study of Atherosclerosis cohort with a focus on race/ethnicity and obesity. This study (analyzed in 2020-2021) used the Multiethnic Study of Atherosclerosis cohort (2000-2017), which included participants with diverse ethnic/racial backgrounds aged 45-84 years without cardiovascular disease at baseline. The primary endpoint was time to diagnosis of venous thromboembolism defined using International Classification of Diseases codes (415, 451, 453, 126, 180, and 182). Multivariable-adjusted hazard ratios of the predictors of venous thromboembolism were calculated with a focus on the interaction between obesity and race/ethnicity categories. Over a median follow-up period of 14 years, 233 individuals developed venous thromboembolism. Incidence rates (per 1,000 person-years) varied across racial/ethnic groups with the highest incidence among Black (4.02) followed by White (2.98), Hispanic (2.08), and Chinese (0.79) participants. There was a stepwise increase in the incidence rate of venous thromboembolism with increasing BMI regardless of race/ethnicity: normal (1.95), overweight (2.52), obese (3.63), and morbidly obese (4.55). The association between BMI and venous thromboembolism was strongest among non-White women with the highest incidence rate for obese (4.8) compared with non-obese (1.6). The interaction among obesity, gender, and race was statistically significant (p=0.01) in non-White obese women. Risk of venous thromboembolism increased with age for all race/ethnicities. This study finds that obesity may confer an increased risk for venous thromboembolism among non-White women compared with other groups-White men, White women, and non-White men.

Deep Learning-based Automated Aortic Area and Distensibility Assessment: the Multi-Ethnic Study of Atherosclerosis (MESA).

This study details application of deep learning for automatic segmentation of the ascending and descending aorta from 2D phase-contrast cine magnetic resonance imaging for automatic aortic analysis on the large MESA cohort with assessment on an external cohort of thoracic aortic aneurysm (TAA) patients. This study includes images and corresponding analysis of the ascending and descending aorta at the pulmonary artery bifurcation from the MESA study. Train, validation, and internal test sets consisted of 1123 studies (24,282 images), 374 studies (8067 images), and 375 studies (8069 images), respectively. The external test set of TAAs consisted of 37 studies (3224 images). CNN performance was evaluated utilizing a dice coefficient and concordance correlation coefficients (CCC) of geometric parameters. Dice coefficients were as high as 97.55% (CI: 97.47-97.62%) and 93.56% (CI: 84.63-96.68%) on the internal and external test of TAAs, respectively. CCC for maximum and minimum and ascending aortic area were 0.969 and 0.950, respectively, on the internal test set and 0.997 and 0.995, respectively, for the external test. The absolute differences between manual and deep learning segmentations for ascending and descending aortic distensibility were 0.0194 × 10-4 ± 9.67 × 10-4 and 0.002 ± 0.001mmHg-1, respectively, on the internal test set and 0.44 × 10-4 ± 20.4 × 10-4 and 0.002 ± 0.001mmHg-1, respectively, on the external test set. We successfully developed a U-Net-based aortic segmentation and analysis algorithm in both MESA and in external cases of TAA.