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OBJECTIVES: To evaluate the association between aspirin use during first pregnancy and later maternal cardiovascular risk. STUDY DESIGN: In this secondary analysis of a prospective cohort, we included participants who carried their first pregnancy to 20+ weeks, had data regarding aspirin use, and attended a study visit 2-7 years following delivery. The exposure was aspirin use during the first pregnancy. We calculated aspirin use propensity scores from logistic regression models including baseline variables associated with aspirin use in pregnancy and cardiovascular risk. Outcomes of interest were incident cardiovascular-related diagnoses 2-7 years following delivery. Robust Poisson regression calculated the risk of outcomes by aspirin exposure, adjusting for the aspirin use propensity score. MAIN OUTCOME MEASURES: The primary outcome was a composite of incident cardiovascular diagnoses at the time of the study visit: cardiovascular events, chronic hypertension, metabolic syndrome, prediabetes or type 2 diabetes, dyslipidemia, and chronic kidney disease. RESULTS: Of 4,480 women included, 84 (1.9%) reported taking aspirin during their first pregnancy. 52.6% of participants in the aspirin-exposed group and 43.0% in the unexposed group had the primary outcome. After adjusting for the aspirin use propensity scores, aspirin use during the first pregnancy was not associated with any of the outcomes. CONCLUSION: We did not detect an association between aspirin use during the first pregnancy and cardiovascular-related diagnoses 2-7 years later. Our study was only powered to detect a large difference in relative risk, so we cannot rule out a smaller difference that may be clinically meaningful.

Heart failure prevalence is increasing worldwide and is associated with significant morbidity and mortality. Guidelines emphasize prevention in those at risk, but HF-specific risk prediction equations developed in US population-based cohorts lack external validation in large, real-world datasets outside of the US. The purpose of this study was to assess the model performance of the Pooled Cohort Equations to Prevent Heart Failure (PCP-HF) within a contemporary electronic health record for 5-year and 10-year risk. Utilizing a retrospective cohort study design of Israeli residents between 2008 and 2018 with continuous membership until end of follow-up, HF or death, we quantified 5-year and 10-year estimated risk of HF using the PCP-HF equations, which integrate demographics (age, sex, race) and risk factors (body mass index, systolic blood pressure, glucose, medication use for hypertension or diabetes, and smoking status). Of 1,394,411 patients included, 56% were women with mean age of 49.6 (standard deviation 13.2) years. Incident HF occurred in 1.2% and 4.5% of participants over 5- and 10-years of follow-up. The PCP-HF model had excellent discrimination for 5-year and 10-year prediction of incident HF (C statistic 0.82 [0.82, 0.82] and 0.84 [0.84, 0.84]), respectively. In conclusion, HF-specific risk equations (PCP-HF) accurately predict the risk of incident HF in ambulatory and hospitalized patients using routinely available clinical data.

Background: Elastic arteries stiffen via 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to changes in the vessel wall. It is unknown how these different mechanisms contribute to incident cardiovascular disease (CVD) events. Methods: The MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study of 6814 men and women without CVD at enrollment, from 6 communities in the United States. MESA participants with B-mode carotid ultrasound and brachial blood pressure at baseline Exam in (2000–2002) and CVD surveillance (mean follow-up 14.3 years through 2018) were included (n=5873). Peterson’s elastic modulus was calculated to represent total arterial stiffness. Structural stiffness was calculated by adjusting Peterson’s elastic modulus to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. Results: In Cox models adjusted for traditional risk factors, load-dependent stiffness was significantly associated with higher incidence of CVD events (hazard ratio/100 mm Hg, 1.21 [95% CI, 1.09–1.34] P P =0.10). Analysis of participants who were normotensive (blood pressure P P =0.16). Conclusions: These results provide valuable new insights into mechanisms underlying the association between arterial stiffness and CVD. Load-dependent stiffness was significantly associated with CVD events but structural stiffness was not.

IMPORTANCE: Hypertensive disorders of pregnancy are associated with future cardiovascular disease, perhaps because of subclinical cardiac dysfunction before pregnancy leading to impaired adaptation to pregnancy. Natriuretic peptides are promising biomarkers for detecting subclinical cardiac dysfunction outside of pregnancy. OBJECTIVE: To investigate whether higher concentrations of N-terminal pro–brain natriuretic peptide (NT-proBNP) in early pregnancy would be associated with hypertensive disorders of pregnancy and hypertension 2 to 7 years post partum. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the The Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study, a prospective multicenter observational study. A total of 4103 nulliparous women with complete data and no prepregnancy hypertension or diabetes who were treated at 8 clinical sites were included. Women were followed up with for 2 to 7 years after pregnancy. Data were collected from October 2010 to October 2017, and data were analyzed from August 2020 to November 2021. EXPOSURES: NT-proBNP concentration, measured using an electrochemiluminescence immunoassay from a first-trimester blood sample. MAIN OUTCOMES AND MEASURES: Hypertensive disorders of pregnancy and incident hypertension (systolic blood pressure of 130 mm Hg or diastolic blood pressure of 80 mm Hg or use of antihypertensive agents) at follow-up visit. RESULTS: A total of 4103 women met inclusion criteria; the mean (SD) age was 27.0 (5.6) years. Among these women, 909 (22.2%) had an adverse pregnancy outcome, and 817 (19.9%) had hypertension at the follow-up visit. Higher NT-proBNP concentrations were associated with a lower risk of hypertensive disorders of pregnancy (adjusted odds ratio per doubling, 0.81; 95% CI, 0.73-0.91), which persisted after adjustment for age, self-reported race and ethnicity, early-pregnancy body mass index, smoking, and aspirin use. Similarly, higher NT-proBNP concentration in early pregnancy was also associated with a lower risk of incident hypertension 2 to 7 years after delivery (adjusted odds ratio per doubling, 0.84; 95% CI, 0.77-0.93), an association that persisted after controlling for confounders, including hypertensive disorders of pregnancy. CONCLUSIONS AND RELEVANCE: In this cohort study, higher NT-proBNP concentrations in early pregnancy were associated with a lower risk of hypertensive disorders of pregnancy and hypertension 2 to 7 years post partum. These findings suggest that normal early-pregnancy cardiovascular physiology, as assessed by NT-proBNP concentration, may provide biologic insights into both pregnancy outcome and cardiovascular disease risk.

Rationale: Epigenetic aging is a novel measure of biological age, reflecting exposures and disease risks independent of chronological age. It may serve as a useful biomarker of cardiovascular health (CVH) or cardiovascular disease risk for early detection or prevention. Objective: To examine associations between GrimAge acceleration (GrimAA), a measure of epigenetic aging calculated from the residuals of GrimAge regressed on chronological age, and 2 repeated CVH measures: a full score for the AHA Life’s Simple 7 (diet, smoking, physical activity, body mass index, blood pressure, total cholesterol, and glucose) and a clinical CVH score (body mass index, blood pressure, cholesterol, and glucose). Methods and Results: We used Illumina array DNA methylation data from 2 prospective cohort studies, the CARDIA study (Coronary Artery Risk Development in Young Adults) and FHS (Framingham Heart Study), to calculate GrimAA and model associations with CVH. CARDIA randomly selected 1118 participants for assays at Y15 (2000–2001; mean age, 40 years) and Y20 (2005–2006); in FHS, 2106 Offspring participants had DNA methylation measured at exam 8 (2005–2008; mean age, 66 years). We examined multiple cross-sectional and longitudinal models of GrimAA and each CVH score measured at CARDIA Y0 to Y20 and FHS exams 7 to 8. In CARDIA, clinical CVH score from Y0 to Y20 was associated with Y15 and Y20 GrimAA (β range, −0.41 to −0.21 years per 1-point increase in CVH; P range, P P Conclusions: Our data demonstrate that faster GrimAA is associated with the loss of CVH from young age. Epigenetic age may be a useful biomarker of cardiovascular disease risk and provides biological insight into the role of epigenetic mechanisms linking age-related CVH loss and cardiovascular disease.

Background Both parental and neighbourhood socio-economic status (SES) are linked to poorer health independently of personal SES measures, but the biological mechanisms are unclear. Our objective was to examine these influences via epigenetic age acceleration (EAA)—the discrepancy between chronological and epigenetic ages. Methods We examined three USA-based [Coronary Artery Risk Disease in Adults (CARDIA) study, Fragile Families and Child Wellbeing Study (FFCWS) and Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS)] and one Mexico-based (Project Viva) cohort. DNA methylation was measured using Illumina arrays, personal/parental SES by questionnaire and neighbourhood disadvantage from geocoded address. In CARDIA, we examined the most strongly associated personal, parental and neighbourhood SES measures with EAA (Hannum’s method) at study years 15 and 20 separately and combined using a generalized estimating equation (GEE) and compared with other EAA measures (Horvath’s EAA, PhenoAge and GrimAge calculators, and DunedinPoAm). Results EAA was associated with paternal education in CARDIA [GEEs: βsome college = −1.01 years (−1.91, −0.11) and β Conclusions These findings suggest that EAA captures epigenetic impacts of paternal education independently of personal SES later in life. Longitudinal studies should explore these associations at different life stages and link them to health outcomes. EAA could be a useful biomarker of SES-associated health and provide important insight into the pathogenesis and prevention of chronic disease.

Background Atrial fibrillation (AF) is associated with increased stroke risk and accelerated cognitive decline, but the association of early manifestations of left atrial (LA) impairment with subclinical changes in brain structure is unclear. We investigated whether abnormal LA structure and function, greater supraventricular ectopy, and intermittent AF are associated with small vessel disease on magnetic resonance imaging of the brain. Methods and Results In the Multi‐Ethnic Study of Atherosclerosis, 967 participants completed 14‐day ambulatory electrocardiographic monitoring, speckle tracking echocardiography and, a median 17 months later, magnetic resonance imaging of the brain. We assessed associations of LA volume index and reservoir strain, supraventricular ectopy, and prevalent AF with brain magnetic resonance imaging measures of small vessel disease and atrophy. The mean age of participants was 72 years; 53% were women. In multivariable models, LA enlargement was associated with lower white matter fractional anisotropy and greater prevalence of microbleeds; reduced LA strain, indicating worse LA function, was associated with more microbleeds. More premature atrial contractions were associated with lower total gray matter volume. Compared with no AF, intermittent AF (prevalent AF with Conclusions In individuals without a history of stroke or transient ischemic attack, alterations of LA structure and function, including enlargement, reduced strain, frequent premature atrial contractions, and intermittent AF, were associated with increased markers of small vessel disease. Detailed assessment of LA structure and function and extended ECG monitoring may enable early identification of individuals at greater risk of small vessel disease.

Although there is a significant reduction in atherosclerotic cardiovascular disease risk with statins, a higher risk of diabetes mellitus has been demonstrated in randomized clinical trials. The risk of incident diabetes with statins may be heterogeneous by presence of coronary artery calcium (CAC). We evaluated participants without prevalent diabetes at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of subjects free of clinical cardiovascular disease at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between statin use and incident diabetes, adjusting for sociodemographic and cardiovascular risk factors, including time-varying statin use and stratifying by baseline CAC (0, 1 to 100, ≥100). The study population included 5,943 participants with a mean (SD) age of 62 (10) years, 54% women, 41% White, 26% Black, 12% Chinese-American, and 21% Hispanic. In the unadjusted analyses, statin use was associated with a higher risk of incident diabetes (hazard ratio [HR] 1.62, 95% confidence interval [CI] 1.27 to 2.06). After adjustment, this risk was no longer significant (HR 1.13, 95% CI 0.83 to 1.54). Although imprecise, the HR expressing the association of statins with diabetes was lower for those with CAC = 0 (HR 0.80, 95% CI 0.45 to 1.40) than for those with a higher CAC burden (HR 1.30, 95% CI 0.71 to 2.39 for CAC 1 to 100 and HR 1.39, 95% CI 0.85 to 2.28 for CAC ≥100), but this heterogeneity was not statistically significant. In conclusion, statin therapy was not significantly associated with incident diabetes mellitus in this observational study. The risk of incident diabetes did not significantly differ by baseline CAC.

Background DNA methylation-based GrimAge acceleration (GrimAA) is associated with a wide range of age-related health outcomes including cardiovascular disease. Since DNA methylation is modifiable by external and behavioral exposures, it is important to identify which of these exposures may have the strongest contributions to differences in GrimAA, to help guide potential intervention strategies. Here, we assessed the relative contributions of lifestyle- and health-related components, as well as their collective association, to GrimAA. Results We included 744 participants (391 men and 353 women) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with blood DNA methylation information at CARDIA Exam Year (Y) 20 (2005–2006, mean age 45.9 years). Six cumulative exposures by Y20 were included in the analysis: total packs of cigarettes, total alcohol consumption, education years, healthy diet score, sleep hours, and physical activity. We used quantile-based g-computation (QGC) and Bayesian kernel machine regression (BKMR) methods to assess the relative contribution of each exposure to a single overall association with GrimAA. We also assessed the collective association of the six components combined with GrimAA. Smoking showed the greatest positive contribution to GrimAA, accounting for 83.5% of overall positive associations of the six exposures with GrimAA (QGC weight = 0.835). The posterior inclusion probability (PIP) of smoking also achieved the highest score of 1.0 from BKMR analysis. Healthy diet and education years showed inverse contributions to GrimAA. We observed a U-shaped pattern in the contribution of alcohol consumption to GrimAA. While smoking was the greatest contributor across sex and race subgroups, the relative contributions of other components varied by subgroups. Conclusions Smoking, alcohol consumption, and education showed the highest contributions to GrimAA in our study. Higher amounts of smoking and alcohol consumption were likely to contribute to greater GrimAA, whereas achieved education was likely to contribute to lower GrimAA. Identifying pertinent lifestyle- and health-related exposures in a context of collective components can provide direction for intervention strategies and suggests which components should be the primary focus for promoting younger GrimAA.

Background Adverse pregnancy outcomes (APOs) (hypertensive disorders of pregnancy [HDP], preterm delivery [PTD], or low birth weight [LBW]) are associated adverse maternal and offspring cardiovascular outcomes. Therefore, we sought to describe nationwide temporal trends in the burden of each APO (HDP, PTD, LBW) from 2007 to 2019 to inform strategies to optimize maternal and offspring health outcomes. Methods and Results We performed a serial cross‐sectional analysis of APO subtypes (HDP, PTD, LBW) from 2007 to 2019. We included maternal data from all live births that occurred in the United States using the National Center for Health Statistics Natality Files. We quantified age‐standardized and age‐specific rates of APOs per 1000 live births and their respective mean annual percentage change. All analyses were stratified by self‐report of maternal race and ethnicity. Among 51 685 525 live births included, 15% were to non‐Hispanic Black individuals, 24% Hispanic individuals, and 6% Asian individuals. Between 2007 and 2019, age standardized HDP rates approximately doubled, from 38.4 (38.2–38.6) to 77.8 (77.5–78.1) per 1000 live births. A significant inflection point was observed in 2014, with an acceleration in the rate of increase of HDP from 2007 to 2014 (+4.1% per year [3.6–4.7]) to 2014 to 2019 (+9.1% per year [8.1–10.1]). Rates of PTD and LBW increased significantly when co‐occurring in the same pregnancy with HDP. Absolute rates of APOs were higher in non‐Hispanic Black individuals and in older age groups. However, similar relative increases were seen across all age,racial and ethnic groups. Conclusions In aggregate, APOs now complicate nearly 1 in 5 live births. Incidence of HDP has increased significantly between 2007 and 2019 and contributed to the reversal of favorable trends in PTD and LBW. Similar patterns were observed in all age groups, suggesting that increasing maternal age at pregnancy does not account for these trends. Black–White disparities persisted throughout the study period.

Some previous studies demonstrated that first-degree atrioventricular block (f-AVB) was associated with incident atrial fibrillation (AF), while evidence is scarce regarding the association between f-AVB and incident AF in older populations. Therefore, we sought to investigate the association of f-AVB with incident AF in the population predominantly including participants aged ≥ 60 years. Eligible participants were residents in Kanazawa City, Japan aged ≥ 40 years who underwent 12-lead ECG at the National Japanese Health Check-up in 2013. Participants with AF detected at the baseline exam and those without adequate follow-up were excluded. f-AVB was defined as PR interval ≥ 220 ms based on the Minnesota code (6–3). The cumulative incidence of AF was estimated by the Kaplan–Meier curve analysis, and statistical significance was evaluated by the Log-rank test. Unadjusted and adjusted hazard ratios (HRs) were computed by Cox proportional hazard models. HRs were adjusted for conventional risk factors for AF. 37,730 participants (mean age, 72.3 ± 9.6 years; male, 37%) were included. Baseline f-AVB was observed in 667 (1.8%) participants. During the median follow-up period of 5 years (interquartile range, 4.0–5.0 years), 691 cases of incident AF were observed. A 5-year cumulative incidence of AF was significantly higher in f-AVB (+) group compared with f-AVB (−) group (6.8% vs 2.1%, p < 0.01). In the fully adjusted model, f-AVB was significantly associated with incident AF (HR, 1.75; 95% confidence interval 1.25–2.45; p value < 0.01). f-AVB was independently associated with incident AF in the population predominantly including participants aged ≥ 60 years.

BACKGROUND: Although proteinuria has been associated with incident atrial fibrillation (AF) in Western countries, the association has not been investigated in the general Japanese population. METHODS: Participants aged ≥ 40 years who underwent the Japanese specific health checkup in Kanazawa City in 2013 and who completed a urine dipstick test were included in this study. Exposure was considered as presence or absence of proteinuria (≥ 1+). The outcome was incident AF confirmed by 12-lead ECG. The Cox proportional hazard model was used to compute hazard ratio (HR) of proteinuria (≥ 1+) for incident AF after adjustment for traditional risk factors. We also completed stratified analyses by baseline characteristics. RESULTS: A total of 37,910 participants aged ≥ 40 years were included (mean age: 72.3 years, male sex: 37%). Proteinuria ≥ 1+ was observed in 2,765 (7.3%) participants. During a median follow-up period of 5 years, 708 incident AF cases were observed. Proteinuria ≥ 1+ was associated with incident AF (HR, 1.47: 95% confidence interval, 1.18 - 1.84) after covariate adjustment. Stratified analysis demonstrated that the association of proteinuria with AF was stronger in participants

Rates of maternal mortality are increasing in the United States with significant rural-urban disparities. Pre-pregnancy hypertension is a well-established risk factor for adverse maternal and offspring outcomes.The purpose of this study was to describe trends in maternal pre-pregnancy hypertension among women in rural and urban areas in 2007 to 2018 in order to inform community-engaged prevention and policy strategies.We performed a nationwide, serial cross-sectional study using maternal data from all live births in women age 15 to 44 years between 2007 and 2018 (CDC Natality Database). Rates of pre-pregnancy hypertension were calculated per 1,000 live births overall and by urbanization status. Subgroup analysis in standard 5-year age categories was performed. We quantified average annual percentage change using Joinpoint Regression and rate ratios (95% confidence intervals [CIs]) to compare yearly rates between rural and urban areas.Among 47,949,381 live births to women between 2007 and 2018, rates of pre-pregnancy hypertension per 1,000 live births increased among both rural (13.7 to 23.7) and urban women (10.5 to 20.0). Two significant inflection points were identified in 2010 and 2016, with highest annual percentage changes between 2016 and 2018 in rural and urban areas. Although absolute rates were lower in younger compared with older women in both rural and urban areas, all age groups experienced similar increases. The rate ratios of pre-pregnancy hypertension in rural compared with urban women ranged from 1.18 (95% CI: 1.04 to 1.35) for ages 15 to 19 years to 1.51 (95% CI: 1.39 to 1.64) for ages 40 to 44 years in 2018.Maternal burden of pre-pregnancy hypertension has nearly doubled in the past decade and the rural-urban gap has persisted.

Objective To illustrate the problem of subpopulation miscalibration, to adapt an algorithm for recalibration of the predictions, and to validate its performance. Materials and Methods In this retrospective cohort study, we evaluated the calibration of predictions based on the Pooled Cohort Equations (PCE) and the fracture risk assessment tool (FRAX) in the overall population and in subpopulations defined by the intersection of age, sex, ethnicity, socioeconomic status, and immigration history. We next applied the recalibration algorithm and assessed the change in calibration metrics, including calibration-in-the-large. Results 1 021 041 patients were included in the PCE population, and 1 116 324 patients were included in the FRAX population. Baseline overall model calibration of the 2 tested models was good, but calibration in a substantial portion of the subpopulations was poor. After applying the algorithm, subpopulation calibration statistics were greatly improved, with the variance of the calibration-in-the-large values across all subpopulations reduced by 98.8% and 94.3% in the PCE and FRAX models, respectively. Discussion Prediction models in medicine are increasingly common. Calibration, the agreement between predicted and observed risks, is commonly poor for subpopulations that were underrepresented in the development set of the models, resulting in bias and reduced performance for these subpopulations. In this work, we empirically evaluated an adapted version of the fairness algorithm designed by Hebert-Johnson et al. (2017) and demonstrated its use in improving subpopulation miscalibration. Conclusion A postprocessing and model-independent fairness algorithm for recalibration of predictive models greatly decreases the bias of subpopulation miscalibration and thus increases fairness and equality.

Background Cardiovascular risk factors are associated with cognitive decline and dementia. Magnetic resonance imaging provides sensitive measurement of brain morphology and vascular brain injury. However, associations of risk factors with brain magnetic resonance imaging findings have largely been studied in White participants. We investigated associations of race, ethnicity, and cardiovascular risk factors with brain morphology and white matter (WM) injury in a diverse population. Methods and Results In the Multi‐Ethnic Study of Atherosclerosis, measures were made in 2018 to 2019 of total brain volume, gray matter and WM volume, and WM injury, including WM hyperintensity volume and WM fractional anisotropy. We assessed cross‐sectional associations of race and ethnicity and of cardiovascular risk factors with magnetic resonance imaging measures. Magnetic resonance imaging data were complete in 1036 participants; 25% Black, 15% Chinese‐American, 19% Hispanic, and 41% White. Mean (SD) age was 72 (8) years and 53% were women. Although WM injury was greater in Black than in White participants in a minimally adjusted model, additional adjustment for cardiovascular risk factors and socioeconomic status each attenuated this association, rendering it nonsignificant. Overall, greater average WM hyperintensity volume was associated with older age and current smoking (69% greater vs never smoking); lower fractional anisotropy was additionally associated with higher diastolic blood pressure, use of antihypertensive medication, and diabetes. Conclusions We found no statistically significant difference in measures of WM injury by race and ethnicity after adjustment for cardiovascular risk factors and socioeconomic status. In all racial and ethnic groups, older age, current smoking, hypertension, and diabetes were strongly associated with WM injury.

The prognostic utility of coronary artery calcium (CAC) for individuals taking statins is unclear. We hypothesized that CAC remains associated with atherosclerotic cardiovascular disease (ASCVD) events in individuals using statins at baseline or among those started on statin at follow-up. The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of 6,814 participants who were enrolled between 2000 and 2002 and were free of clinical ASCVD at baseline. Four follow-up visits were conducted in 2002 to 2004, 2004 to 2006, 2005 to 2007, and 2010 to 2012. CAC was assessed at baseline and follow-up using either an electron-beam CT scanner or a multidetector CT system. Statin use at baseline and follow up was self-reported. Among 6,811 participants with complete information on statin use, mean age was 62 (SD = 10) years, 53% were women, 38% white, 12% Chinese-American, 28% African American, and 22% Hispanic. In multivariable analyses, CAC >0 was associated with a significantly higher risk of ASCVD events regardless of baseline or incident statin use. For example, hazard ratios (95% confidence interval) for the association between CAC >0 and ASCVD were 2.46 (1.41, 4.28) for baseline statin users, 2.08 (1.68, 2.57) for baseline-statin nonusers, and 2.21 (1.56, 3.15) for those started on a statin at follow-up. In conclusion, current statin use does not weaken the prognostic utility of CAC. CAC is associated with incident ASCVD regardless of baseline or incident statin use.

Atrial fibrillation (AF) is prevalent and strongly associated with higher cardiovascular disease (CVD) risk. Machine learning is increasingly used to identify novel predictors of CVD risk, but prediction improvements beyond established risk scores are uncertain. We evaluated improvements in predicting 5-year AF risk when adding novel candidate variables identified by machine learning to the CHARGE-AF Enriched score, which includes age, race/ethnicity, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and NT-proBNP. We included 3534 participants (mean age, 61.3 years; 52.0% female) with complete data from the prospective Multi-Ethnic Study of Atherosclerosis (MESA). Incident AF was defined based on study electrocardiograms and hospital discharge diagnosis ICD-9 codes, supplemented by Medicare claims. Prediction performance was evaluated using Cox regression and a parsimonious. model was selected using LASSO. Within 5 years of baseline, 124 participants had incident AF. Compared with the CHARGE-AF Enriched model (c-statistic, 0.804), variables identified by machine learning, including biomarkers, cardiac magnetic resonance imaging variables, electrocardiogram variables, and subclinical CVD variables, did not significantly improve prediction. A 23-item score derived by machine learning achieved a c-statistic of 0.806, while a parsimonious model including the clinical risk factors age, weight, current smoking, NT-proBNP, coronary artery calcium score, and cardiac troponin-T achieved a c-statistic of 0.802. This analysis confirms that the CHARGE-AF Enriched model and a parsimonious 6-item model performed similarly to a more extensive model derived by machine learning. In conclusion, these simple models remain the gold standard for risk prediction of AF, although addition of the coronary artery calcium score should be considered.

BACKGROUND: Polygenic risk scores (PRS) are associated with atherosclerotic cardiovascular disease (ASCVD) events. We studied incident ASCVD among individuals with absent coronary artery calcium (CAC = 0), to investigate the association of PRS with incident ASCVD among such individuals. METHODS: Data was used from Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study of participants free of clinical CVD at baseline. PRS were developed based on a literature-derived list of single-nucleotide polymorphisms (SNPs) weighted by effect size. The coronary heart disease (CHD) PRS contained 180 SNPs, and the stroke PRS had 32 SNPs. These SNPs were combined to compute an ASCVD PRS. The PRS were calculated among 3132 participants with CAC = 0. Multivariable-adjusted Cox proportional hazards models evaluated the association between each PRS (top 20% vs bottom 50%) and ASCVD. RESULTS: The study population included 3132 individuals with CAC = 0 [mean (SD) age 58 (9) years; 63% female, 33% White, 31% Black, 12% Chinese-American, 24% Hispanic]. Over a median follow-up of 16 years, there were 108 incident CHD events and 93 stroke events. ASCVD event rates were generally

Evidence suggests an association between autonomical nervous system (ANS) function and atrial fibrillation (AF) development. We sought to examine the association of baseline resting heart rate (RHR) and short-term heart rate variability (HRV) as surrogates of (ANS) with incident AF in individuals without previous cardiovascular disease. A total of 6,261 participants of the Multi-Ethnic Study of Atherosclerosis who were free of AF and diagnosed cardiovascular disease were enrolled. Three standard 10-second, 12-lead electrocardiograms (ECG) were used to measure RHR, the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences in RR intervals (RMSSD). Cox proportional hazards models adjusted for demographics, atrioventricular nodal agents, and known cardiovascular risk factors were used to examine the association of baseline RHR, and log transformed SDNN and RMSDD with incident AF. Over a mean follow-up of 11.3 ± 3.7 years, 754 (12%) participants developed AF. Spline curve analysis revealed a nonlinear association between RHR, HRV, and incident AF. In fully adjusted models higher (but not lower) baseline RHR (RHR >76 beats/min) was associated with incident AF (hazard ratio 1.48 95% confidence interval 1.18 to 1.86). Additionally, lower values of RMSDD and SDNN and higher values of RMSDD were independently associated with incident AF. In conclusion, cardiac ANS dysregulation indicated as higher RHR and lower HRV is associated with incident AF independent of known cardiovascular risk factors.

Background: The 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline states that statin therapy may be withheld or delayed among intermediate-risk individuals in the absence of coronary artery calcium (CAC=0). We evaluated whether traditional cardiovascular risk factors are associated with incident atherosclerotic cardiovascular disease (ASCVD) events among individuals with CAC=0 over long-term follow-up. Methods: We included participants with CAC=0 at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of clinical ASCVD at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between cardiovascular risk factors (cigarette smoking, diabetes, hypertension, preventive medication use [aspirin and statin], family history of premature ASCVD, chronic kidney disease, waist circumference, lipid and inflammatory markers) and adjudicated incident ASCVD outcomes. Results: We studied 3416 individuals (mean [SD] age 58 [9] years; 63% were female, 33% White, 31% Black, 12% Chinese American, and 24% Hispanic). Over a median follow-up of 16 years, there were 189 ASCVD events (composite of coronary heart disease and stroke) of which 91 were coronary heart disease, 88 were stroke, and 10 were both coronary heart disease and stroke events. The unadjusted event rates of ASCVD were ≤5 per 1000 person-years among individuals with CAC=0 for most risk factors with the exception of current cigarette smoking (7.3), diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8). After multivariable adjustment, risk factors that were significantly associated with ASCVD included current cigarette smoking: hazard ratio, 2.12 (95% CI, 1.32–3.42); diabetes: hazard ratio, 1.68 (95% CI, 1.01–2.80); and hypertension: hazard ratio, 1.57 (95% CI, 1.06–2.33). Conclusions: Current cigarette smoking, diabetes, and hypertension are independently associated with incident ASCVD over a 16-year follow-up among those with CAC=0.

Background The prevalence, incidence and risk factors of atrial fibrillation (AF) in a large, geographically and ethnically diverse cohort in the United States have not been fully described. Methods We analyzed data from 173,099 participants of the All of Us Research Program recruited in the period 2017–2019, with 92,318 of them having electronic health records (EHR) data available, and 35,483 having completed a medical history survey. Presence of AF at baseline was identified from self-report and EHR records. Incident AF was obtained from EHR. Demographic, anthropometric and clinical risk factors were obtained from questionnaires, baseline physical measurements and EHR. Results At enrollment, mean age was 52 years old (range 18–89). Females and males accounted for 61% and 39% respectively. Non-Hispanic Whites accounted for 67% of participants, with non-Hispanic Blacks, non-Hispanic Asians and Hispanics accounting for 26%, 4% and 3% of participants, respectively. Among 92,318 participants with available EHR data, 3,885 (4.2%) had AF at the time of study enrollment, while the corresponding figure among 35,483 with medical history data was 2,084 (5.9%). During a median follow-up of 16 months, 354 new cases of AF were identified among 88,433 eligible participants. Individuals who were older, male, non-Hispanic white, had higher body mass index, or a prior history of heart failure or coronary heart disease had higher prevalence and incidence of AF. Conclusion The epidemiology of AF in the All of Us Research Program is similar to that reported in smaller studies with careful phenotyping, highlighting the value of this new resource for the study of AF and, potentially, other cardiovascular diseases.

Majority of previous studies showed no association between a single health behavior and arterial stiffness, but the benefit of simultaneously having multiple healthy behaviors (optimal lifestyle) on the progression of arterial stiffness is unknown. Among 2810 individuals (age 60.0 ± 9.4, 46.5% male), optimal lifestyle marker (yes/no) on four health behaviors (ie, BMI 25 kg/m

The prevalence of ideal cardiovascular health (CVH) among adults in the United States is low and decreases with age. Our objective was to identify specific age windows when the loss of CVH accelerates, to ascertain preventive opportunities for intervention. Data were pooled from 5 longitudinal cohorts (Project Heartbeat!, Cardiovascular Risk in Young Finns Study, The Bogalusa Heart Study, Coronary Artery Risk Development in Young Adults, Special Turku Coronary Risk Factor Intervention Project) from the United States and Finland from 1973 to 2012. Individuals with clinical CVH factors (i.e., body mass index, blood pressure, cholesterol, blood glucose) measured from ages 8 to 55 years were included. These factors were categorized and summed into a clinical CVH score ranging from 0 (worst) to 8 (best). Adjusted, segmented, linear mixed models were used to estimate the change in CVH over time. Among the 18,343 participants, 9,461 (52%) were female and 12,346 (67%) were White. The baseline mean (standard deviation) clinical CVH score was 6.9 (1.2) at an average age of 17.6 (8.1) years. Two inflection points were estimated: at 16.9 years (95% confidence interval: 16.4, 17.4) and at 37.2 years (95% confidence interval: 32.4, 41.9). Late adolescence and early middle age appear to be influential periods during which the loss of CVH accelerates.

Background GrimAge acceleration (GAA), an epigenetic marker that represents physiologic aging, is associated with atherosclerotic cardiovascular disease. However, the associations between early adulthood lipid levels and GAA in midlife are unknown. Also, it is unknown whether GAA mediates the associations between lipid levels in young adults and subclinical atherosclerosis in midlife. Results We estimated measures of epigenetic age acceleration in 1118 White and Black participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Study at examination years (Y) 15 and 20. We used multivariable regression models to examine associations of Y15 and Y20 GAA estimates with plasma lipid levels measured at prior examination years (Y0, Y5, and Y10) and concurrently: triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels. Mediation analysis was used to assess the extent to which GAA may mediate associations between plasma lipids and coronary artery calcification (CAC). In our study each 1-SD higher cumulative TG level was associated with an average 0.73 ± 0.12 years older GAA. Each 1-SD higher cumulative HDL-C level was associated with an average 0.57 ± 0.17 years younger GAA. Stratified analyses showed that the associations between TG and GAA were stronger among female and Black participants and the associations between HDL-C and GAA were stronger among female and White participants. GAA statistically mediated 17.4% of the association of cumulative TG with CAC. Conclusions High TG and low HDL-C in early adulthood are associated with accelerated epigenetic aging by midlife. Increased epigenetic age acceleration may partially mediate the associations between high TG levels and the presence of subclinical atherosclerosis.

Background: Polygenic risk scores (PRS) may enhance risk stratification for coronary heart disease among young adults. Whether a coronary heart disease PRS improves prediction beyond modifiable risk factors in this population is not known. Methods: Genotyped adults aged 18 to 35 years were selected from the CARDIA study (Coronary Artery Risk Development in Young Adults; n=1132) and FOS (Framingham Offspring Study; n=663). Systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, triglycerides, smoking, and waist circumference or body mass index were measured at the visit 1 exam of each study, and coronary artery calcium, a measure of coronary atherosclerosis, was assessed at year 15 (CARDIA) or year 30 (FOS). A previously validated PRS for coronary heart disease was computed for each subject. The C statistic and integrated discrimination improvement were used to compare improvements in prediction of elevated coronary artery calcium between models containing the PRS, risk factors, or both. Results: There were 62 (5%) and 93 (14%) participants with a coronary artery calcium score >20 (CARDIA) and >300 (FOS), respectively. At these thresholds, the C statistic changes of adding the PRS to a risk factor–based model were 0.015 (0.004–0.028) and 0.020 (0.001–0.039) in CARDIA and FOS, respectively. When adding risk factors to a PRS-based model, the respective changes were 0.070 (0.033–0.109) and 0.051 (0.017–0.079). The integrated discrimination improvement, when adding the PRS to a risk factor model, was 0.027 (−0.006 to 0.054) in CARDIA and 0.039 (0.0005–0.072) in FOS. Conclusions: Among young adults, a PRS improved model discrimination for coronary atherosclerosis, but improvements were smaller than those associated with modifiable risk factors.

Background The prevalence of obesity in the population has increased in parallel with increasing rates of adverse pregnancy outcomes (APOs). Quantifying contemporary trends in prepregnancy obesity and associations with interrelated APOs (preterm birth, low birth weight, and pregnancy‐associated hypertension) together and individually can inform prevention strategies to optimize cardiometabolic health in women and offspring. Methods and Results We performed a serial, cross‐sectional study using National Center for Health Statistics birth certificate data including women aged 15 to 44 years with live singleton births between 2013 and 2018, stratified by race/ethnicity (non‐Hispanic White, non‐Hispanic Black, Hispanic, and non‐Hispanic Asian). We quantified the annual prevalence of prepregnancy obesity (body mass index ≥30.0 kg/m 2 ; body mass index ≥27.5 kg/m 2 if non‐Hispanic Asian). We then estimated adjusted associations using multivariable logistic regression (odds ratios and population attributable fractions) for obesity‐related APOs compared with normal body mass index (18.5–24.9 kg/m 2 ; 18.5–22.9 kg/m 2 if non‐Hispanic Asian). Among 20 139 891 women, the prevalence of prepregnancy obesity increased between 2013 and 2018: non‐Hispanic White (21.6%–24.8%), non‐Hispanic Black (32.5%–36.2%), Hispanic (26.0%–30.5%), and non‐Hispanic Asian (15.3%–18.6%) women ( P ‐trend P ‐trend Conclusions The prevalence of prepregnancy obesity and burden of obesity‐related APOs have increased, driven primarily by pregnancy‐associated hypertension, and vary across racial/ethnic subgroups.

Background: Atrial fibrillation (AF) is associated with substantial morbidity and mortality. Short-term exposures to air pollution have been associated with AF triggering; less is known regarding associations between long-term air pollution exposures and AF incidence. Objectives: Our objective was to assess the association between long-term exposures to air pollution and distance to road on incidence of AF in a cohort of U.S. women. Methods: We assessed the association of high resolution spatiotemporal model predictions of long-term exposures to particulate matter (PM10 and PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and distance to major roads with incidence of AF diagnosis, identified through Medicare linkage, among 83,117 women in the prospective Women’s Health Initiative cohort, followed from enrollment in Medicare through December 2012, incidence of AF, or death. Using time-varying Cox proportional hazards models adjusted for age, race/ethnicity, study component, body mass index, physical activity, menopausal hormone therapy, smoking, diet quality, alcohol consumption, educational attainment, and neighborhood socioeconomic status, we estimated the relative risk of incident AF in association with each pollutant. Results: A total of 16,348 incident AF cases were observed over 660,236 person-years of follow-up. Most exposure–response associations were nonlinear. NO2 was associated with risk of AF in multivariable adjusted models [Hazard Ratio (HR)=1.18; 95% confidence interval (CI): 1.13, 1.24, comparing the top to bottom quartile, p-for-trend=

Hypertensive disorders of pregnancy are leading causes of morbidity and mortality among pregnant individuals as well as newborns, with increasing incidence during the past decade. Understanding the individual associations of advancing age of pregnant individuals at delivery, more recent delivery year (period), and more recent birth year of pregnant individuals (cohort) with adverse trends in hypertensive disorders of pregnancy could help guide public health efforts to improve the health of pregnant individuals.To clarify the independent associations of delivery year and birth year of pregnant individuals, independent of age of pregnant individuals, with incident rates of hypertensive disorders of pregnancy.This serial cross-sectional study of 38 141 561 nulliparous individuals aged 15 to 44 years with a singleton, live birth used 1995-2019 natality data from the National Vital Statistics System.Year of delivery (period) and birth year (cohort) of pregnant individuals.Rates of incident hypertensive disorders of pregnancy, defined as gestational hypertension, preeclampsia, or eclampsia, recorded on birth certificates. Generalized linear mixed models were used to calculate adjusted rate ratios (aRRs) comparing the incidence of hypertensive disorders of pregnancy in each delivery period (adjusted for age and cohort) and birth cohort (adjusted for age and period) with the baseline group as the reference for each. Analyses were additionally stratified by the self-reported racial and ethnic group of pregnant individuals.Of 38 141 561 individuals, 20.2% were Hispanic, 0.8% were non-Hispanic American Indian or Alaska Native, 6.5% were non-Hispanic Asian or Pacific Islander, 13.9% were non-Hispanic Black, and 57.8% were non-Hispanic White. Among pregnant individuals who delivered in 2015 to 2019 compared with 1995 to 1999, the aRR for the incidence of hypertensive disorders of pregnancy was 1.59 (95% CI, 1.57-1.62), adjusted for age and cohort. Among pregnant individuals born in 1996 to 2004 compared with 1951 to 1959, the aRR for the incidence of hypertensive disorders of pregnancy was 2.61 (95% CI, 2.41-2.84), adjusted for age and period. The incidence was higher among self-identified non-Hispanic Black individuals in each birth cohort, with similar relative changes for period (aRR, 1.76 [95% CI, 1.70-1.81]) and cohort (aRR, 3.26 [95% CI, 2.72-3.91]) compared with non-Hispanic White individuals (period: aRR, 1.60 [95% CI, 1.57-1.63]; cohort: aRR, 2.53 [95% CI, 2.26-2.83]).This cross-sectional study suggests that more recent birth cohorts of pregnant individuals have experienced a doubling of rates of hypertensive disorders of pregnancy, even after adjustment for age and delivery period. Substantial racial and ethnic disparities persisted across generations.

The long-term prognostic significance of a coronary artery calcium (CAC) score of 0 is poorly defined in younger adults. We evaluated this among participants aged 45 to 55 years from the Multi-Ethnic Study of Atherosclerosis, and assessed whether additional biomarkers can identify subgroups at increased absolute risk. We included 1,407 participants (61% women) without diabetes or severe hypercholesterolemia, with estimated 10-year risk20% and CAC = 0. We evaluated all and hard cardiovascular disease (CVD) events, overall and among subjects with each of the following: high-sensitivity C-reactive protein levels ≥2 mg/L, homocysteine ≥10 µmol/L, high-sensitivity cardiac troponin T ≥95th percentile, lipoprotein (a)50 mg/dl, triglycerides ≥175 mg/dl, apolipoprotein B ≥130 mg/dl, albuminuria, thoracic aortic calcium, aortic valve calcium (AVC), mitral annular calcium, ankle-brachial index0.9, any carotid plaque, and maximum internal carotid artery intima-media thickness (ICA-IMT) ≥1.5 mm. Median follow-up was 16 years, and overall CVD event rates were low (4% at 15 years). For most exposures evaluated, rates of all CVD events were6 per 1,000 person-years, except for ICA-IMT ≥1.5 mm (6.43) and AVC (13.8). The number needed to screen to detect ICA-IMT ≥1.5 mm was 8, and 84 for AVC. Among participants with borderline/intermediate risk or premature family history, hard CVD event rates were7 per 1,000 for most exposures, except for ICA-IMT ≥1.5 mm (8.25), albuminuria (8.30), and AVC (13.47). Nonsmokers and those with ICA-IMT1.5 mm had very low rates. In conclusion, our results demonstrate a favorable long-term prognosis of CAC = 0 among adults aged ≤55 years, particularly among nonsmokers. ICA-IMT testing could be considered for further risk assessment in adults ≤55 years with CAC = 0 and uncertain management.

Background In people with lower‐extremity peripheral artery disease, the effects of exercise on patient‐reported outcomes remain unclear. Methods and Results Four hundred four people with peripheral artery disease in 3 clinical trials were randomized to exercise (N=205) or a control group (N=199) and completed the 6‐minute walk and the Walking Impairment Questionnaire distance score (score 0–100, 100=best) at baseline and 6‐month follow‐up. Compared with the control group, exercise improved 6‐minute walk distance by +39.8 m (95% CI, 26.8–52.8, P P =0.003). In all, 2828 individual Walking Impairment Questionnaire distance score questions were completed at baseline and follow‐up. Among participants who perceived no change in ability to walk 1 or more distances between baseline and follow‐up, 6‐minute walk improved in the exercise group and declined in the control group (+26.8 versus −6.5 m, P P P Conclusions In 3 randomized trials, exercise significantly improved the 6‐minute walk distance in people with peripheral artery disease, but many participants randomized to exercise reported no change or decline in walking ability. These findings suggest a significant discrepancy in objectively measured walking improvement relative to perceived walking improvement in people with peripheral artery disease. Registration Information clinicaltrials.gov. Identifiers: NCT 00106327, NCT 01408901.

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D). We aimed to identify the peripheral blood DNA methylation signature of hepatic fat. We conducted epigenome-wide association studies of hepatic fat in 3,400 European ancestry (EA) participants and in 401 Hispanic ancestry and 724 African ancestry participants from four population-based cohort studies. Hepatic fat was measured using computed tomography or ultrasound imaging and DNA methylation was assessed at >400,000 cytosine-guanine dinucleotides (CpGs) in whole blood or CD14+ monocytes using a commercial array. We identified 22 CpGs associated with hepatic fat in EA participants at a false discovery rate

Background Cardiovascular risk in young adulthood is an important determinant of lifetime cardiovascular disease risk. Women with adverse pregnancy outcomes (APOs) have increased cardiovascular risk, but the relationship of other factors is unknown. Methods and Results Among 4471 primiparous women, we related first‐trimester atherogenic markers to risk of APO (hypertensive disorders of pregnancy, preterm birth, small for gestational age), gestational diabetes mellitus (GDM) and hypertension (130/80 mm Hg or antihypertensive use) 2 to 7 years after delivery. Women with an APO/GDM (n=1102) had more atherogenic characteristics (obesity [34.2 versus 19.5%], higher blood pressure [systolic blood pressure 112.2 versus 108.4, diastolic blood pressure 69.2 versus 66.6 mm Hg], glucose [5.0 versus 4.8 mmol/L], insulin [77.6 versus 60.1 pmol/L], triglycerides [1.4 versus 1.3 mmol/L], and high‐sensitivity C‐reactive protein [5.6 versus 4.0 nmol/L], and lower high‐density lipoprotein cholesterol [1.8 versus 1.9 mmol/L]; P P Conclusions Individual and combined first‐trimester atherogenic characteristics are associated with APO/GDM occurrence and hypertension 2 to 7 years later. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02231398.

Targeted prevention of heart failure (HF) remains a critical need given the high prevalence of HF morbidity and mortality. Similar to risk-based prevention of atherosclerotic cardiovascular disease, optimal HF prevention strategies should include quantification of risk in the individual patient. In this review, we discuss incorporation of a quantitative risk-based approach into the existing HF staging landscape and the clinical opportunity that exists to translate available data on risk estimation to help guide personalized decision making. We first summarize the recent development of key HF risk prediction tools that can be applied broadly at a population level to estimate risk of incident HF. Next, we provide an in-depth description of the clinical utility of biomarkers to personalize risk estimation in select patients at the highest risk of developing HF. We also discuss integration of genomics-enhanced approaches (eg, Titin [TTN] ) and other risk-enhancing features to reclassify risk with a precision medicine approach to HF prevention. Although sequential testing is very likely to identify low and high-risk individuals with excellent accuracy, whether or not interventions based on these risk models prevent HF in clinical practice requires prompt attention including randomized placebo-controlled trials of candidate therapies in risk-enriched populations. We conclude with a summary of unanswered questions and gaps in evidence that must be addressed to move the field of HF risk assessment forward.

Background Cardiovascular health (CVH) has been defined by the American Heart Association (AHA) as the presence of the “Life’s Simple 7” ideal lifestyle and clinical factors. CVH is known to predict longevity and freedom from cardiovascular disease, the leading cause of death for women in the United States. DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age. Methods and results We performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women’s Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score. We examined the association between CVH score and EAA using linear regression modeling adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, 50% were white and mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (~ 6 months younger age per 1 point higher CVH score, p p Conclusions These cross-sectional observations suggest a possible mechanism by which ideal CVH is associated with greater longevity.

Background Studies of outpatients with mild or moderate COVID-19 are uncommon. We studied: 1) association of symptoms with reverse transcriptase polymerase chain reaction (RT-PCR) test results; and 2) association of initial RT-PCR cycle threshold (Ct) in relation to duration of RT-PCR positivity in outpatients with mild or moderate COVID-19. Methods This was a cohort study of outpatients with confirmed COVID-19 and at least one symptom. Participants had repeat nasopharyngeal swabs and symptom checklists every 3–5 days until two consecutive RT-PCR tests were negative. RT-PCR tests were used to assess viral load. Antibody tests for COVID-19 were performed at 2 weeks, 4 weeks, and 8 weeks after symptom onset. Results Twenty-five patients (nine females) were enrolled, ranging in age from 19–58 (median age 28 years). All patients reported at least one symptom, with a median of six symptoms per patient. Symptoms persisted for 6–67 days (median duration 18 days). In all 25 patients, blood samples collected a median of 13 days after symptom onset were positive for SARS-CoV-2 antibodies in 15 (60%). After a median of 28 days following symptom onset, 23/23 patients with available samples tested positive for antibodies. The longest duration of positive RT-PCR test was 49 days from first positive PCR test (Mean = 27.4, SD = 12.5, Median = 24). Initial Ct was significantly associated with longer duration (β = -1.3, SE = 0.3, p Conclusions In mildly or moderately ill COVID-19 outpatients, RT-PCT tests remained positive for as long as 49 days and test positivity and symptom duration correlated with initial viral load.

DNA methylation (DNAm)-based biological age (epigenetic age) has been suggested as a useful biomarker of age-related conditions including type 2 diabetes (T2D), and its newest iterations (GrimAge measurements) have shown early promise. In this study, we explored the association between epigenetic age and incident T2D in the context of their relationships with obesity. A total of 1,057 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were included in the current analyses. We stratified the participants into three groups: normal weight, overweight, and obese. A 1-year increase of GrimAge was associated with higher 10-year (study years 15–25) incidence of T2D (odds ratio [OR] 1.06, 95% CI 1.01–1.11). GrimAge acceleration, which represents the deviation of GrimAge from chronological age, was derived from the residuals of a model of GrimAge and chronological age, and any GrimAge acceleration (positive GrimAA: having GrimAge older than chronological age) was associated with significantly higher odds of 10-year incidence of T2D in obese participants (OR 2.57, 95% CI 1.61–4.11). Cumulative obesity was estimated by years since obesity onset, and GrimAge partially mediated the statistical association between cumulative obesity and incident diabetes or prediabetes (proportion mediated = 8.0%). In conclusion, both older and accelerated GrimAge were associated with higher risk of T2D, particularly among obese participants. GrimAge also statistically mediated the associations between cumulative obesity and T2D. Our findings suggest that epigenetic age measurements with DNAm can potentially be used as a risk factor or biomarker associated with T2D development.

This cohort study evaluates the performance of the pooled cohort equations in estimating the risk of atherosclerotic cardiovascular disease risk by body mass index range., Key Points Question What is the performance of the pooled cohort equations (PCE) for estimation of atherosclerotic cardiovascular disease (ASCVD) risk by body mass index? Findings In this pooled analysis of 8 longitudinal cohort studies that included 37 311 adults, the PCE demonstrated acceptable model discrimination but significantly overestimated risk of atherosclerotic cardiovascular disease in individuals with higher body mass index, with better calibration near clinical decision thresholds and less optimal calibration for the groups at highest risk. Incorporation of usual clinical measures of obesity did not result in more accurate risk estimation compared with standard PCE. Meaning These findings suggest that the PCE could be used as a risk-estimation tool to guide prevention and treatment strategies in adults across clinical BMI categories, but may overestimate risk of ASCVD for individuals in overweight and obese categories., Importance Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown. Objective To assess performance of the PCE across clinical BMI categories. Design, Setting, and Participants This cohort study used pooled individual-level data from 8 community-based, prospective, longitudinal cohort studies with 10-year ASCVD event follow-up from 1996 to 2016. We included all adults ages 40 to 79 years without baseline ASCVD or statin use, resulting in a sample size of 37 311 participants. Data were analyzed from August 2017 to July 2020. Exposures Participant BMI category: underweight (

PURPOSE This study used a 5D flow framework to explore the influence of arrhythmia on thrombogenic hemodynamic parameters in patients with atrial fibrillation (AF). METHODS A fully self-gated, 3D radial, highly accelerated free-running 5D flow sequence with interleaved four-point velocity-encoding was acquired using an in vitro arrhythmic flow phantom and in 25 patients with a history of AF (68 ± 8 y, 6 female). Self-gating signals were used to calculate AF burden, bin data, and tag each k-space line with its RRLength . Data were binned as an RR-resolved dataset with four RR-interval bins (RR1-RR4, short-to-long) for compressed sensing reconstruction. AF burden was calculated as interquartile range of all intrascan RR-intervals divided by median RR-interval, and left atrial (LA) stasis as the percent of the cardiac cycle where the velocity was

Maternal stress is a risk factor for adverse pregnancy outcomes (APOs). This study evaluates the associations of prenatal stress and APOs with maternal stress years after pregnancy. The 10-item Perceived Stress Scale (PSS) (0–40 range) was completed in the first and third trimesters, and 2–7 years after delivery among a subsample (n = 4161) of nulliparous women enrolled at eight US medical centers between 2010 and 2013 in a prospective, observational cohort study. Demographics, medical history, and presence of APOs (gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), preeclampsia (PE), and medically indicated or spontaneous preterm birth (miPTB, sPTB)) were obtained. The associations of prenatal PSS and the presence of APOs with PSS scores years after delivery were estimated using multivariable linear regression. Mean PSS scores were 12.5 (95% CI 12.3, 12.7) and 11.3 (95% CI 11.1, 11.5) in the first and third trimesters respectively and 14.9 (95% CI 14.7, 15.1) 2–7 years later, an average increase of 2.4 points (95% CI 2.2, 2.6) from the start of pregnancy. Regressing PSS scores after delivery on first-trimester PSS and PSS increase through pregnancy showed positive associations, with coefficients (95% CI) of 2.8 (2.7, 3.0) and 1.5 (1.3, 1.7) per 5-point change, respectively. Adding APO indicator variables separately showed higher PSS scores for women with HDP (0.7 [0.1, 1.3]), PE (1.3 [0.6, 2.1]), and miPTB (1.3 [0.2, 2.4]), but not those with GDM or sPTB. In this geographically and demographically diverse sample, prenatal stress and some APOs were positively associated with stress levels 2–7 years after pregnancy. ClinicalTrials.gov Registration number NCT02231398.

Background Reproductive events, that is, a preterm birth ( PTB ), small‐for‐gestational‐age infant ( SGA ), and vasomotor symptoms of menopause, are associated with subclinical atherosclerotic cardiovascular disease ( ASCVD ). We evaluated whether women with a past PTB and/or SGA (henceforth PTB / SGA ) were more likely to have severe vasomotor symptoms of menopause and whether the estimated 10‐year ASCVD risk was higher in women with PTB / SGA and vasomotor exposures. Methods and Results We assigned 1866 women (mean age=55±1 years) in the CARDIA (Coronary Artery Risk Development in Young Adults) study to the following categories of reproductive exposures: none, PTB / SGA only, vasomotor symptoms only, or both PTB / SGA and vasomotor symptoms. We used Kruskal‐Wallis tests to evaluate the differences in pooled cohort equation ASCVD risk scores by category and linear regression to evaluate the associations of categories with ASCVD risk scores adjusted for study center, body mass index , education, current hormone replacement therapy use, parity, and hysterectomy. Women with PTB / SGA were more likely to have severe vasomotor symptoms, 36% versus 30%, P ASCVD risk score was higher in women with both PTB / SGA and vasomotor symptoms (4.6%; 95% CI, 4.1%–5.1%) versus women with no exposures (3.3%; 95% CI , 2.9%–3.7%) or vasomotor symptoms only (3.8%; 95% CI , 3.5%–4.0%). ASCVD risk score was higher in women PTB / SGA (4.8%; 95% CI , 3.6%–5.9%) versus no exposures. PTB / SGA and vasomotor symptoms was associated with ASCVD risk score in white women versus no exposures (β=0.40; 95% CI, 0.02–0.78). Conclusions Women with prior PTB / SGA were more likely to have severe vasomotor symptoms of menopause. Reproductive exposures were associated with an estimated 10‐year ASCVD risk in white women.

Background: Recent American College of Cardiology/American Heart Association Primary Prevention Guidelines recommended considering low-dose aspirin therapy only among adults 40 to 70 years of age who are at higher atherosclerotic cardiovascular disease (ASCVD) risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified. The present study aimed to assess the value of coronary artery calcium (CAC) for guiding aspirin allocation for primary prevention by using 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk. Methods: The study included 6470 participants from the MESA Study (Multi-Ethnic Study of Atherosclerosis). ASCVD risk was estimated using the pooled cohort equations, and 3 strata were defined: 20%. All participants underwent CAC scoring at baseline, and CAC scores were stratified as =0, 1 to 99, ≥100, and ≥400. A 12% relative risk reduction in cardiovascular disease events was used for the 5-year number needed to treat (NNT 5 ) calculations, and a 42% relative risk increase in major bleeding events was used for the 5-year number needed to harm (NNH 5 ) estimations. Results: Only 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the American College of Cardiology/American Heart Association guidelines and using >20% estimated ASCVD risk to define higher risk. Benefit/harm calculations were restricted to aspirin-naive participants 5 with aspirin to prevent 1 cardiovascular disease event was 476 and the NNH 5 was 355. The NNT 5 was also greater than or similar to the NNH 5 among estimated ASCVD risk strata. Conversely, CAC≥100 and CAC≥400 identified subgroups in which NNT 5 was lower than NNH 5 . This was true both overall (for CAC≥100, NNT 5 =140 versus NNH 5 =518) and within ASCVD risk strata. Also, CAC=0 identified subgroups in which the NNT 5 was much higher than the NNH 5 (overall, NNT 5 =1190 versus NNH 5 =567). Conclusions: CAC may be superior to the pooled cohort equations to inform the allocation of aspirin in primary prevention. Implementation of current 2019 American College of Cardiology/American Heart Association guideline recommendations together with the use of CAC for further risk assessment may result in a more personalized, safer allocation of aspirin in primary prevention. Confirmation of these findings in experimental settings is needed.

Importance Although the associations between processed meat intake and cardiovascular disease (CVD) and all-cause mortality have been established, the associations of unprocessed red meat, poultry, or fish consumption with CVD and all-cause mortality are still uncertain. Objective To identify the associations of processed meat, unprocessed red meat, poultry, or fish intake with incident CVD and all-cause mortality. Design, Setting, and Participants This cohort study analyzed individual-level data of adult participants in 6 prospective cohort studies in the United States. Baseline diet data from 1985 to 2002 were collected. Participants were followed up until August 31, 2016. Data analyses were performed from March 25, 2019, to November 17, 2019. Exposures Processed meat, unprocessed red meat, poultry, or fish intake as continuous variables. Main Outcomes and Measures Hazard ratio (HR) and 30-year absolute risk difference (ARD) for incident CVD (composite end point of coronary heart disease, stroke, heart failure, and CVD deaths) and all-cause mortality, based on each additional intake of 2 servings per week for monotonic associations or 2 vs 0 servings per week for nonmonotonic associations. Results Among the 29 682 participants (mean [SD] age at baseline, 53.7 [15.7] years; 13 168 [44.4%] men; and 9101 [30.7%] self-identified as non-white), 6963 incident CVD events and 8875 all-cause deaths were adjudicated during a median (interquartile range) follow-up of 19.0 (14.1-23.7) years. The associations of processed meat, unprocessed red meat, poultry, or fish intake with incident CVD and all-cause mortality were monotonic (Pfor nonlinearity ≥ .25), except for the nonmonotonic association between processed meat intake and incident CVD (Pfor nonlinearity = .006). Intake of processed meat (adjusted HR, 1.07 [95% CI, 1.04-1.11]; adjusted ARD, 1.74% [95% CI, 0.85%-2.63%]), unprocessed red meat (adjusted HR, 1.03 [95% CI, 1.01-1.06]; adjusted ARD, 0.62% [95% CI, 0.07%-1.16%]), or poultry (adjusted HR, 1.04 [95% CI, 1.01-1.06]; adjusted ARD, 1.03% [95% CI, 0.36%-1.70%]) was significantly associated with incident CVD. Fish intake was not significantly associated with incident CVD (adjusted HR, 1.00 [95% CI, 0.98-1.02]; adjusted ARD, 0.12% [95% CI, −0.40% to 0.65%]). Intake of processed meat (adjusted HR, 1.03 [95% CI, 1.02-1.05]; adjusted ARD, 0.90% [95% CI, 0.43%-1.38%]) or unprocessed red meat (adjusted HR, 1.03 [95% CI, 1.01-1.05]; adjusted ARD, 0.76% [95% CI, 0.19%-1.33%]) was significantly associated with all-cause mortality. Intake of poultry (adjusted HR, 0.99 [95% CI, 0.97-1.02]; adjusted ARD, −0.28% [95% CI, −1.00% to 0.44%]) or fish (adjusted HR, 0.99 [95% CI, 0.97-1.01]; adjusted ARD, −0.34% [95% CI, −0.88% to 0.20%]) was not significantly associated with all-cause mortality. Conclusions and Relevance These findings suggest that, among US adults, higher intake of processed meat, unprocessed red meat, or poultry, but not fish, was significantly associated with a small increased risk of incident CVD, whereas higher intake of processed meat or unprocessed red meat, but not poultry or fish, was significantly associated with a small increased risk of all-cause mortality. These findings have important public health implications and should warrant further investigations.

Background: Oral anticoagulant (OAC) therapy is proven to be effective at reducing risk of stroke in patients with atrial fibrillation (AF). However, racial minorities with AF are less likely to be prescribed vitamin K anticoagulants (VKA). There is little information on the racial disparity in the prescription of the non-vitamin K oral anticoagulants (NOACs) and the associated risks of stroke and bleeding. Methods: We used data from the Northwestern Medicine Enterprise Data Warehouse – a joint initiative across 11 Northwestern Medicine affiliated healthcare centers within metropolitan Chicago, Illinois. Newly diagnosed AF patients between Jan, 2011 and Dec, 2017 with CHA2DS2VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, female sex) score of 2 or more and no prior history of stroke or major bleeding were eligible. Logistic regression was used to examine differences in the prescription of any OAC and NOACs by race. Racial differences in the associations of NOACs prescription with incident stroke (a composite of ischemic and hemorrhagic stroke and cerebral embolism) and major bleeding were evaluated using Cox regression. Results: Among 11,575 newly diagnosed AF patients with CHA2DS2VASc score of 2 or more, 48.7% (47.8-49.6) were on any OAC and among those 40.1% (38.8.3-41.4) received any NOACs. After adjusting for age, gender, income, insurance status, and stroke risk factors, the odds of receiving any OAC was .69 (95% CI: .58-.83) in blacks, .74 (.53-1.903) in Hispanics, and .75 (.58-.95) in Asians compared to whites. Among anticoagulated patients, blacks and Hispanics had significantly lower odds of receiving NOACs: .72 (.53-.97) and .53 (.29-.99), respectively. Use of NOACs, as compared to VKAs, was associated with significantly lower risk of stroke [.52(.31-.85)] and bleeding [.72(.54-.95)] in whites but not in non-whites [stroke: .71 (.22-2.31); bleeding .83(.43-1.57)] independent of other risk factors. Conclusions: Racial minorities with AF who are at risk of stroke were less likely to receive any OAC and NOACs specifically compared to whites even after accounting for insurance status, income, and stroke risk factors. Independent of other risk factors, use of NOACs as compared to VKA was associated with significantly lower risk of stroke and bleeding only in whites but not in non-whites.

Background: The prognostic value of hsCRP in contemporary multi-ethnic populations is unclear, particularly in statin users. The aim of this study was to characterize the prognostic utility of hsCRP for atherosclerotic CVD (ASCVD) risk prediction in a multi-ethnic population including non-users and users of statins followed for >13 years. Associations with heart failure (HF), atrial fibrillation (AF), venous thromboembolism (VTE), cancer, and all-cause death were also examined. Methods and results: We evaluated 6757 participants from the Multi-Ethnic Study of Atherosclerosis (MESA; 1002 using statins at baseline), median follow-up 13.2 years. Higher levels of hsCRP were associated with a higher risk of all study endpoints in the unadjusted Cox Proportional Hazards regression analyses, except AF. Among non-users of statins, hsCRP only remained associated with VTE after adjusting for ASCVD risk factors, and did not improve risk prediction. Among users of statins, hsCRP did not improve ASCVD risk prediction either, although it was strongly associated with incident HF (HR for hsCRP ≥ 2 vs

ObjectiveThe 6-minute walk test is a common outcome measure in clinical trials of people with lower extremity peripheral artery disease (PAD). However, what constitutes a meaningful change in the 6-minute walk distance has not been well defined for people with PAD. The present study related the change in the 6-minute walk distance to the degree of participant-reported improvement or decline in the 6-minute walk distance to define a meaningful change in the 6-minute walk distance for those with PAD.MethodsParticipants with PAD from three observational longitudinal studies completed the walking impairment questionnaire (WIQ) distance score and 6-minute walk at baseline and 1year later. The WIQ distance score measures participants' perceived difficulty walking seven different distances without stopping (ranging from walking around the home to walking 5 blocks) on a 0 to 4 Likert scale, with 0 representing an inability to walk the distance and 4 representing no difficulty. The mean changes in the 6-minute walk distance corresponding to the participants' report of no change, 1-unit change, or 2-unit change, respectively, in the Likert scale score between the baseline and 1-year follow-up measures were calculated for each WIQ distance.ResultsA total of 777 participants with PAD (mean age, 71.2± 8.8years; mean baseline 6-minute walk distance, 350.1±118.1meters) completed 5439 questions about their difficulty walking each WIQ distance at baseline and follow-up. Participants with PAD who reported no change in their difficulty in walking each WIQ distance between baseline and follow-up had a decline of 7.2meters (95% confidence interval [CI],-11.6 to-2.8meters) in the 6-minute walk test. Relative to those reporting no change in difficulty walking, the participants reporting 1- and 2-point improvements in walking ability showed 6-minute walk distance improvements of 7.8meters (95% CI,-0.3 to 15.9meters) and 20.1meters (95% CI, 1.1-39.2meters), respectively. Relative to those reporting no change in walking difficulty, those reporting 1- and 2-point declines in perceived walking difficulty showed declines of-11.2meters (95% CI,-19.0 to-3.4meters) and-23.8meters (95% CI,-37.4 to-10.3meters) in the 6-minute walk distance.ConclusionsAmong people with PAD, ∼8- and ∼20-meter improvements in the 6-minute walk distance represent small and large improvements in walking ability, respectively. People with PAD who reported no change in their ability to walk distances over 1year simultaneously declined by a mean of 7meters in the 6-minute walk test. These findings will be useful for interpreting the results from randomized trials of interventions to improve the walking performance of people with PAD.

Background The metabolic syndrome (MetS) is a collection of metabolic disturbances that can lead to various cardiovascular diseases. Previous studies have shown a more adverse metabolic risk profile is associated with more advanced biological aging. The associations between epigenetic biomarkers of age with MetS, however, are not well understood. We therefore investigated the associations between epigenetic age acceleration and MetS severity score and incident MetS. Results A subset of study participants with available whole blood at examination years 15 and 20 from the Coronary Artery Risk Development in Young Adults Study underwent epigenomic profiling using the Illumina MethylationEPIC Beadchip (~ 850,000 sites). Intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA) were calculated from DNA methylation levels. The MetS severity score was positively associated with IEAA at years 15 (P = 0.016) and 20 (P = 0.016) and EEAA at year 20 (P = 0.040) in cross-sectional analysis. IEAA at year 20 was significantly associated with incident MetS at year 30 (OR = 1.05 [95% CI 1.01, 1.10], P = 0.028). Conclusions To our knowledge, this is the first report of the longitudinal association between epigenetic age acceleration and MetS. These findings suggest that a higher MetS severity score is associated with accelerated epigenetic aging and such aging may play a role in the development of metabolic disorders, potentially serving as a useful biomarker of and early detection tool for future MetS.

Background Although leisure-time physical activity (PA) contributes to overall health, including pregnancy health, patterns across pregnancy have not been related to birth outcomes. We hypothesized that women with sustained low leisure-time PA would have excess risk of adverse pregnancy outcomes, and that changing patterns across pregnancy (high to low and low to high) may also be related to risk of adverse pregnancy outcomes. Methods Nulliparous women (n = 10,038) were enrolled at 8 centers early in pregnancy (mean gestational age in weeks [SD] = 12.05 [1.51]. Frequency, duration, and intensity (metabolic equivalents) of up to three leisure activities reported in the first, second and third trimesters were analyzed. Growth mixture modeling was used to identify leisure-time PA patterns across pregnancy. Adverse pregnancy outcomes (preterm birth, [PTB, overall and spontaneous], hypertensive disorders of pregnancy [HDP], gestational diabetes [GDM] and small-for-gestational-age births [SGA]) were assessed via chart abstraction. Results Five patterns of leisure-time PA across pregnancy were identified: High (35%), low (18%), late decreasing (24%), early decreasing (10%), and early increasing (13%). Women with sustained low leisure-time PA were younger and more likely to be black or Hispanic, obese, or to have smoked prior to pregnancy. Women with low vs. high leisure-time PA patterns had higher rates of PTB (10.4 vs. 7.5), HDP (13.9 vs. 11.4), and GDM (5.7 vs. 3.1, all p

Background The purpose of this study was to determine how American College of Cardiology/American Heart Association (ACC/AHA) 2013 and European Society of Cardiology 2016 guidelines for the primary prevention of atherosclerotic cardiovascular disease (CVD) compare in reflecting the totality of accrued randomised clinical trial evidence for statin treatment at population level. Methods From 1997–2008, 7279 participants aged 45–75 years, free of atherosclerotic cardiovascular disease, from the population-based Rotterdam Study were included. For each participant, we compared eligibility for each one of 11 randomised clinical trials on statin use in primary prevention of CVD, with recommendations on lipid-lowering therapy from the ACC/AHA and European Society of Cardiology (ESC) guidelines. Atherosclerotic cardiovascular disease incidence and cardiovascular disease mortality rates were calculated. Results The proportion of participants eligible for each trial ranged from 0.4% for ALLHAT-LLT to 30.8% for MEGA. The likelihood of being recommended for lipid-lowering treatment was lowest for those eligible for low-to-intermediate risk RCTs (HOPE-3, MEGA, and JUPITER), and highest for high-risk individuals with diabetes (MRC/BHF HPS, CARDS, and ASPEN) or elderly PROSPER. Eligibility for an increasing number of randomised clinical trials correlated with a greater likelihood of being recommended lipid-lowering treatment by either guideline ( p Conclusion Compared to RCTs done in high risk populations, randomised clinical trials targeting low-to-intermediate risk populations are less well-reflected in the ACC/AHA, and even less so in the ESC guideline recommendations. Importantly, the low-to-intermediate risk population targeted by HOPE-3, the most recent randomised clinical trial in this field, is not well-captured by the current European prevention guidelines and should be specifically considered in future iterations of the guidelines.

ObjectivesRecently, the density score of coronary artery calcium (CAC) has been shown to be associated with a lower risk of cardiovascular disease (CVD) events at any level of CAC volume. Whether risk factors for CAC volume and CAC density are similar or distinct is unknown. We sought to evaluate the associations of CVD risk factors with CAC volume and CAC density scores.MethodsBaseline measurements from 6814 participants free of clinical CVD were collected for the Multi-Ethnic Study of Atherosclerosis. Participants with detectable CAC (n=3398) were evaluated for this study. Multivariable linear regression models were used to evaluate independent associations of CVD risk factors with CAC volume and CAC density scores.ResultsWhereas most CVD risk factors were associated with higher CAC volume scores, many risk factors were associated with lower CAC density scores. For example, diabetes was associated with a higher natural logarithm (ln) transformed CAC volume score (standardised β=0.44 (95% CI 0.31 to 0.58) ln-units) but a lower CAC density score (β=−0.07 (−0.12 to −0.02) density units). Chinese, African-American and Hispanic race/ethnicity were each associated with lower ln CAC volume scores (β=−0.62 (−0.83to −0.41), −0.52 (−0.64 to −0.39) and −0.40 (−0.55 to −0.26) ln-units, respectively) and higher CAC density scores (β= 0.41 (0.34 to 0.47), 0.18 (0.12 to 0.23) and 0.21 (0.15 to 0.26) density units, respectively) relative to non-Hispanic White.ConclusionsIn a cohort free of clinical CVD, CVD risk factors are differentially associated with CAC volume and density scores, with many CVD risk factors inversely associated with the CAC density score after controlling for the CAC volume score. These findings suggest complex associations between CVD risk factors and these components of CAC.