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Abstract Metabolic comorbidities, such as obesity and diabetes, are associated with subclinical alterations in both cardiac structure/function and natriuretic peptides prior to the onset of heart failure (HF). Despite this, the exact metabolic pathways of cardiac dysfunction which precede HF are not well-defined. Among older individuals without HF in the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of 47 circulating metabolites measured by 1H-NMR with echocardiographic measures of cardiac structure and function. We then evaluated associations of significant metabolites with circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a separate cohort, we evaluated differences between top metabolites in patients with HF with preserved ejection fraction (HFpEF) and comorbidity-matched controls. Genetic variants associated with top metabolites (mQTLs) were then related to echocardiographic measures and NT-proBNP. Among 3440 individuals with metabolic and echocardiographic data in MESA (62 ± 10 years, 52% female, 38% White), 10 metabolites broadly reflective of glucose and amino acid metabolism were associated with at least 1 measure of cardiac structure or function. Of these 10 metabolites, 4 (myo-inositol, glucose, dimethylsulfone, carnitine) were associated with higher NT-proBNP and 2 (d-mannose, acetone) were associated with lower NT-proBNP. In a separate cohort, patients with HFpEF had higher circulating myo-inositol levels compared with comorbidity-matched controls. Genetic analyses revealed that 1 of 6 known myo-inositol mQTLs conferred risk of higher NT-proBNP. In conclusion, metabolomic profiling identifies several novel metabolites associated with cardiac dysfunction in a cohort at high risk for HF, revealing pathways potentially relevant to future HF risk.

Abstract People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. −10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed. Clinical Trials.gov registration: NCT03743636.

Abstract Objective To examine maternal, psychosocial, and pregnancy factors associated with breastfeeding for at least 6 months in those giving birth for the first time. Methods We performed a planned secondary analysis of an observational cohort study of 5249 women giving birth for the first time. Women were contacted at least 6 months after delivery and provided information regarding breastfeeding initiation, duration, and exclusivity. Maternal demographics, psychosocial measures, and delivery methods were compared by breastfeeding groups. Results 4712 (89.8%) of the women breastfed at some point, with 2739 (58.2%) breastfeeding for at least 6 months. Of those who breastfed, 1161 (24.7% of the entire cohort), breastfed exclusively for at least 6 months. In the multivariable model among those who ever breastfed, not smoking in the month prior to delivery (adjusted odds ratio [aOR] 2.04, 95%CI 1.19–3.45), having a Master’s degree of higher (aOR 1.89, 95%CI 1.51–2.36), having a planned pregnancy (aOR 1.48, 95%CI 1.27–1.73), older age (aOR 1.02, 95% CI, 1.01–1.04), lower BMI (aOR 0.96 95% CI 0.95–0.97), and having less anxiety measured during pregnancy (aOR 0.990, 95%CI 0.983–0.998) were associated with breastfeeding for at least 6 months. Compared to non-Hispanic White women, Hispanic women, while being more likely to breastfeed initially (aOR 1.40, 95%CI 1.02–1.92), were less likely to breastfeed for 6 months (aOR 0.72, 95%CI 0.59–0.88). While non-Hispanic Black women were less likely than non-Hispanic White women to initiate breastfeeding (aOR 0.68, 95%CI 0.51–0.90), the odds of non-Hispanic Black women of continuing to breastfeed for at least 6 months was similar to non-Hispanic White women (aOR 0.92, 95%CI 0.71–1.19). Conclusions In this cohort of women giving birth for the first time, duration of breastfeeding was associated with several characteristics which highlight groups at greater risk of not breastfeeding as long as currently recommended. Trial registration NCT01322529 (nuMoM2b) and NCT02231398 (nuMoM2b-Heart Health)

Background: Elevated highly-sensitive cardiac troponin-T (hs-cTnT≥14 ng/L) and low ankle-brachial index (ABI

Abstract 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 500 METS min/week) across four visits (≈ 5 years) were summed to create an optimal lifestyle score. Carotid arterial stiffness was measured using distensibility coefficient (DC) and Young's elastic modulus (YEM) at visit 1 and after a mean of 9.5 years (visit 5). The association of optimal lifestyle with 10‐year percent change in DC and YEM was assessed using multiple linear regression. DC decreased by 5.3% and YEM increased by 24.4% over 10 years. Mean optimal lifestyle score was 9.4 ± 3.1 (range: 0–16). Individuals in quintiles 2–5 of optimal lifestyle score compared to quintile 1 (with the least optimal lifestyle score) did not show slower deceleration of DC [Q2, −0.3% (95% CI: −6.0, 5.4); Q3, −0.01% (−4.5, 4.5); Q4, −0.6% (−5.2, 3.9); Q5, −0.4% (−5.3, 4.4)], trend p‐value = .82] or slower progression of YEM [Q2, 0.1% (−7.1, 7.3); Q3, −0.8% (−8.0, 6.5); Q4, 4.5% (−2.3, 11.3); Q5, −0.2% (−8.3, 7.9)], trend p‐value = .49] after adjusting for risk factors. The association remained non‐significant when stratified by categories of age, sex, race, BP control, and diabetes. Our findings indicate that optimal score on multiple health behaviors may not independently slow arterial stiffness progression.

Introduction Previous studies have shown disruption of glycometabolic control and new diabetes mellitus (DM) diagnosis among patients with COVID-19. It is still unclear how the association of COVID-19 and new-onset DM may be modified by disease severity or vary over time, during acute and post-acute phases.Research design and methods In this retrospective matched cohort study, 157 936 patients with COVID-19 (aged ≥25 years, diagnosis date between March 01, 2020 and August 31, 2021) were compared with individuals without COVID-19, separately for non-hospitalized, hospitalized, and severe hospitalized patients. Stratified Cox proportional hazards models, with changing baseline time (starting at the date of COVID-19 diagnosis, and at 1, 2, 3, and 4 months afterwards), were used to evaluate the occurrence of new DM in relation to COVID-19 infection in different time frames—from each landmark date until end of study.Results During mean follow-up time of 10.9 months, there were 1145 (0.72%) new diagnoses of DM compared with 1013 (0.64%) in the individuals without COVID-19 (p=0.004). Non-hospitalized patients with COVID-19 were not at higher risk of new DM neither during the acute phase nor afterward. Hospitalized patients with COVID-19 had a higher risk of developing DM, with the highest risk among severe hospitalized patients. This risk among hospitalized patients was highest in the acute phase (HR 2.47 (95% CI 1.86 to 3.29)), attenuated over time, but remained significant at 4-month landmark analysis (HR 1.60 (95% CI 1.12 to 2.29)).Conclusions Acute and post-acute COVID-19 were associated with new DM only among hospitalized patients, with the highest risk among those hospitalized with severe disease. Those patients should be followed and monitored post-discharge for new DM. Patients who were not hospitalized did not have higher risk of new-onset DM.

Serum urate concentration can be studied in large datasets to find genetic and epigenetic loci that may be related to cardiometabolic traits. Here the authors identify and replicate 100 urate-associated CpGs, which provide insights into urate GWAS loci and shared CpGs of urate and cardiometabolic traits.

Many genetic loci have been identified to be associated with kidney disease, but the molecular mechanisms are not well understood. Here, the authors perform epigenome-wide association studies on kidney function measures to identify epigenetic marks and pathways involved in kidney function.

Objective: Inflammatory markers are associated with cardiovascular disease (CVD); however, the ability to specifically predict myocardial infarction (MI) as well as ischemic stroke remains unknown. There has not been a direct comparison of the associations between GlycA and hsCRP and MI and ischemic stroke in a multi-ethnic pooled cohort. Methods: Multi-center, multi-ethnic, population-based community prospective pooled cohort of the Dallas Heart Study (DHS) and Multi-Ethnic Study of Atherosclerosis (MESA). 9,785 participants without baseline CVD enrolled with median follow-up of 13.4 years. Fatal/nonfatal MI and fatal/nonfatal ischemic stroke were assessed separately and then combined. Results: GlycA was moderately associated with hsCRP (R=0.58 in DHS and R=0.55 in MESA). In adjusted Cox proportional hazards models with competing risk adjusted for both inflammatory markers, GlycA was directly associated with MI (HR Q4 vs. Q1 1.90, 95% CI 1.39 to 2.58), whereas hsCRP was not (HR Q4 vs. Q1 0.92, 95% CI 0.70 to 1.21). Conversely, hsCRP was directly associated with ischemic stroke (HR Q4 vs. Q1 1.73, 95% CI 1.15 to 2.59), but GlycA was not (HR Q4 vs. Q1 1.21, 95% CI 0.77 to 1.90). GlycA improved net reclassification for MI and hsCRP did so for ischemic stroke. Conclusions: Although both GlycA and hsCRP were associated with incident CVD, GlycA more strongly predicted incident MI, and hsCRP more strongly predicted ischemic stroke.

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

Background The value of coronary artery calcium (CAC) in the allocation of PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors) among individuals without clinically evident atherosclerotic cardiovascular disease (ASCVD) is unknown for indications that do not require confirmed familial hypercholesterolemia. We aimed to assess the ability of CAC to stratify ASCVD risk under 3 non–familial hypercholesterolemia PCSK9i allocation paradigms. Methods and Results We included participants without clinically evident ASCVD from MESA (Multi‐Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults) study, DHS (Dallas Heart Study), and HNR (Heinz Nixdorf Recall) study. Three PCSK9i eligibility scenarios were defined: a broad scenario informed only by high low‐density lipoprotein cholesterol levels (N=567), a restrictive one combining higher low‐density lipoprotein cholesterol levels and presence of ≥2 additional risk factors (N=127), and a high‐risk scenario where individuals with subclinical organ damage or high estimated risk would be treated to achieve low‐density lipoprotein cholesterol

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.

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.

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.

IntroductionThe NIH All of Us Research Program will have the scale and scope to enable research for a wide range of diseases, including cancer. The program's focus on diversity and inclusion promises a better understanding of the unequal burden of cancer. Preliminary cancer ascertainment in the All of Us cohort from two data sources (self-reported versus electronic health records (EHR)) is considered.Materials and methodsThis work was performed on data collected from the All of Us Research Program's 315,297 enrolled participants to date using the Researcher Workbench, where approved researchers can access and analyze All of Us data on cancer and other diseases. Cancer case ascertainment was performed using data from EHR and self-reported surveys across key factors. Distribution of cancer types and concordance of data sources by cancer site and demographics is analyzed.Results and discussionData collected from 315,297 participants resulted in 13,298 cancer cases detected in the survey (in 89,261 participants), 23,520 cancer cases detected in the EHR (in 203,813 participants), and 7,123 cancer cases detected across both sources (in 62,497 participants). Key differences in survey completion by race/ethnicity impacted the makeup of cohorts when compared to cancer in the EHR and national NCI SEER data.ConclusionsThis study provides key insight into cancer detection in the All of Us Research Program and points to the existing strengths and limitations of All of Us as a platform for cancer research now and in the future.

Objective: To evaluate contemporary patterns in prepregnancy cardiovascular health (CVH) in the United States (US). Methods: We conducted a serial, cross-sectional study of National Center for Health Statistics Natality Data representing all live births in the US from 2011 to 2019. We assigned 1 point for each of four ideal prepregnancy metrics (nonsmoking and ideal body mass index [18.5–24.9 kg/m2] provided by maternal self-report, and absence of hypertension and diabetes ascertained by the healthcare professional at delivery) to construct a prepregnancy clinical CVH score ranging from 0 to 4. We described the distribution of prepregnancy CVH, overall and stratified by self-reported race/ethnicity, age, insurance status, and receipt of the Women, Infants, and Children program (WIC) for supplemental nutrition. We examined trends by calculating average annual percent changes (AAPCs) in optimal prepregnancy CVH (score of 4). Results: Of 31,643,982 live births analyzed between 2011 and 2019, 53.6% were to non-Hispanic White, 14.5% non-Hispanic Black, 23.3% Hispanic, and 6.6% non-Hispanic Asian women. The mean age (SD) was 28.5 (5.8) years. The prevalence (per 100 live births) of optimal prepregnancy CVH score of 4 declined from 42.1 to 37.7 from 2011 to 2019, with an AAPC (95% CI) of -1.4% per year (-1.3,-1.5). While the relative decline was observed across all race/ethnicity, insurance, and WIC subgroups, significant disparities persisted by race, insurance status, and receipt of WIC. In 2019, non-Hispanic Black women (28.7 per 100 live births), those on Medicaid (30.4), and those receiving WIC (29.1) had the lowest prevalence of optimal CVH. Conclusions: Overall, less than half of pregnant women had optimal prepregnancy CVH, and optimal prepregnancy CVH declined in each race/ethnicity, age, insurance, and WIC subgroup between 2011-2019 in the US. However, there were persistent disparities by race/ethnicity and socioeconomic status.

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/m2; body mass index ≥27.5 kg/m2 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/m2; 18.5–22.9 kg/m2 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

Skeletal muscle quantity and quality decrease with older age, which is partly attributed to ectopic fat infiltration and has negative metabolic consequences. To inform efforts to preserve skeletal muscle with aging, a better understanding of biologic correlates of quantity and quality of muscle and intermuscular adipose tissue (IMAT) is needed. We used targeted lipidomics of lipoprotein subfractions among 947 Multi-Ethnic Study of Atherosclerosis participants to provide a detailed metabolic characterization of area and density of abdominal muscle and IMAT. Serum lipoprotein subfractions were measured at the first visit using 1H-Nuclear Magnetic Resonance spectroscopy. Muscle and IMAT area (cm2) and density (Hounsfield units) were estimated at visit 2 or 3 using computed tomography of the total abdominal, locomotion (psoas), and stabilization (paraspinal, oblique, rectus abdominis) muscles. We identified lipoprotein subfractions associated with body composition using linear regression adjusting for demographics, lifestyle, and multiple comparisons. Among 105 lipoprotein subfractions, 24 were associated with total muscle area (absolute standardized regression coefficient range: 0.07–0.10, p-values ≤ 0.002), whereas none were associated with total muscle density. When examining muscle subgroups, 25 lipoprotein subfractions were associated with stabilization muscle area, with associations strongest among the obliques. For total IMAT area, there were 27 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.09–0.13, p-values ≤ 0.002). Specifically, 27 lipoprotein subfractions were associated with stabilization IMAT area, with associations strongest among the oblique and rectus abdominis muscles. For total IMAT density, there were 39 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.10–0.19, p-values ≤ 0.003). Specifically, 28 and 33 lipoprotein subfractions were associated with IMAT density of locomotion and stabilization (statistically driven by obliques) muscles, respectively. Higher VLDL (cholesterol, unesterified cholesterol, phospholipids, triglycerides, and apolipoprotein B) and lower HDL (cholesterol and unesterified cholesterol) were associated with higher muscle area, higher IMAT area, and lower IMAT density. Several associations between lipoprotein subfractions and abdominal muscle area and IMAT area and density were strongest among the stabilization muscles, particularly the obliques, illustrating the importance of examining muscle groups separately. Future work is needed to determine whether the observed associations indicate a lipoprotein profile contributing to worse skeletal muscle with fat infiltration.

Background: Reduced uterine artery compliance is associated with adverse pregnancy outcomes (APOs) and may indicate underlying maternal cardiovascular pathology. We investigated associations between second trimester uterine artery Doppler (UAD) parameters and incident maternal hypertension 2–7 years after delivery. Methods: A cohort of 10,038 nulliparous US participants was recruited early in pregnancy. A subgroup of 3739, without baseline hypertension and with complete follow-up visits 2–7 years after delivery, were included in this analysis. We investigated UAD indicators of compliance including: 1) early diastolic notch; 2) resistance index (RI); and 3) pulsatility index (PI). We defined hypertension as systolic blood pressure ≥130 mmHg, diastolic ≥80 mmHg, or antihypertensive medication use. We calculated odds ratios (OR) and 95 % confidence intervals (95%CI) for associations between UAD parameters and hypertension, adjusting for age, obesity, race/ethnicity, insurance, smoking, and APOs. Results: A total of 187 (5 %) participants developed hypertension after the index pregnancy. Presence of early diastolic notch on UAD was not associated with incident hypertension. Increased RI and PI correlated with higher odds of hypertension (RI: adjusted OR 1.15 [95 % CI 1.03–1.30]; PI: adjusted OR 1.03 [95%CI 1.01–1.05] for each 0.1 unit increase). Maximum RI above 0.84 or maximum PI above 2.3 more than doubled the odds of incident hypertension (RI: adjusted OR 2.49, 95%CI 1.45–4.26; PI: adjusted OR 2.36, 95%CI 1.45–3.86). Conclusion: Higher resistance and pulsatility indices measured on second trimester UAD were associated with increased odds of incident hypertension 2–7 years later, and may be biomarkers of higher maternal cardiovascular risk.

Background Prevalence of atrial fibrillation (AF) continues to increase and is associated with significant cardiovascular morbidity and mortality. To inform prevention strategies aimed at reducing the burden of AF, we sought to quantify trends in cardiovascular mortality related to AF in the United States. Methods and Results We performed serial cross‐sectional analyses of national death certificate data for cardiovascular mortality related to AF, whereby cardiovascular disease was listed as underlying cause of death and AF as multiple cause of death among adults aged 35 to 84 years using the Centers for Disease Control and Prevention's Wide‐Ranging Online Data for Epidemiologic Research. We calculated age‐adjusted mortality rates per 100 000 population and examined trends over time, estimating average annual percentage change using the Joinpoint Regression Program. Subgroup analyses were performed by race‐sex and across 2 age groups (younger: 35–64 years; older: 65–84 years). A total of 276 373 cardiovascular deaths related to AF were identified in the United States between 2011 and 2018 in decedents aged 35 to 84 years. Age‐adjusted mortality rate increased from 18.0 (95% CI, 17.8–18.2) to 22.3 (95% CI, 22.0–22.4) per 100 000 population between 2011 and 2018. The increase in age‐adjusted mortality rate (average annual percentage change) between 2011 and 2018 was greater among younger decedents (7.4% per year [95% CI, 6.8%–8.0%]) compared with older decedents (3.0% per year [95% CI, 2.6%–3.4%]). Conclusions Cardiovascular deaths related to AF are increasing, especially among younger adults, and warrant greater attention to prevention earlier in the life course.

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

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

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, pConclusions 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.

Background Current strategies for cardiovascular disease (CVD) risk assessment focus on 10‐year or longer timeframes. Shorter‐term CVD risk is also clinically relevant, particularly for high‐risk occupations, but is under‐investigated. Methods and Results We pooled data from participants in the ARIC (Atherosclerosis Risk in Communities study), MESA (Multi‐Ethnic Study of Atherosclerosis), and DHS (Dallas Heart Study), free from CVD at baseline (N=16 581). Measurements included N‐terminal pro‐B‐type natriuretic peptide (>100 pg/mL prospectively defined as abnormal); high‐sensitivity cardiac troponin T (abnormal >5 ng/L); high‐sensitivity C‐reactive protein (abnormal >3 mg/L); left ventricular hypertrophy by ECG (abnormal if present); carotid intima‐media thickness, and plaque (abnormal >75th percentile for age and sex or presence of plaque); and coronary artery calcium (abnormal >10 Agatston U). Each abnormal test result except left ventricular hypertrophy by ECG was independently associated with increased 3‐year risk of global CVD (myocardial infarction, stroke, coronary revascularization, incident heart failure, or atrial fibrillation), even after adjustment for traditional CVD risk factors and the other test results. When a simple integer score counting the number of abnormal tests was used, 3‐year multivariable‐adjusted global CVD risk was increased among participants with integer scores of 1, 2, 3, and 4, by ≈2‐, 3‐, 4.5‐ and 8‐fold, respectively, when compared with those with a score of 0. Qualitatively similar results were obtained for atherosclerotic CVD (fatal or non‐fatal myocardial infarction or stroke). Conclusions A strategy incorporating multiple biomarkers and atherosclerosis imaging improved assessment of 3‐year global and atherosclerotic CVD risk compared with a standard approach using traditional risk factors.

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

Abstract 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 Identifying pregnancy‐associated risk factors before the development of major cardiovascular disease events could provide opportunities for prevention. The objective of this study was to determine the association between outcomes in first pregnancies and subsequent cardiovascular health. Methods and Results The Nulliparous Pregnancy Outcomes Study Monitoring Mothers‐to‐be Heart Health Study is a prospective observational cohort that followed 4484 women 2 to 7 years (mean 3.2 years) after their first pregnancy. Adverse pregnancy outcomes (defined as hypertensive disorders of pregnancy, small‐for‐gestational‐age birth, preterm birth, and stillbirth) were identified prospectively in 1017 of the women (22.7%) during this pregnancy. The primary outcome was incident hypertension (HTN). Women without adverse pregnancy outcomes served as controls. Risk ratios (RR) and 95% CIs were adjusted for age, smoking, body mass index, insurance type, and race/ethnicity at enrollment during pregnancy. The overall incidence of HTN was 5.4% (95% CI 4.7% to 6.1%). Women with adverse pregnancy outcomes had higher adjusted risk of HTN at follow‐up compared with controls (RR 2.4, 95% CI 1.8‐3.1). The association held for individual adverse pregnancy outcomes: any hypertensive disorders of pregnancy (RR 2.7, 95% CI 2.0‐3.6), preeclampsia (RR 2.8, 95% CI 2.0‐4.0), and preterm birth (RR 2.7, 95% CI 1.9‐3.8). Women who had an indicated preterm birth and hypertensive disorders of pregnancy had the highest risk of HTN (RR 4.3, 95% CI 2.7‐6.7). Conclusions Several pregnancy complications in the first pregnancy are associated with development of HTN 2 to 7 years later. Preventive care for women should include a detailed pregnancy history to aid in counseling about HTN risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov Unique identifier: NCT02231398.

Background Identifying associations between serum metabolites and visceral adipose tissue (VAT) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity‐related diseases. We aimed to discover and replicate metabolites reflecting pathways related to VAT. Methods and Results Associations between fasting serum metabolites and VAT area (by computed tomography or magnetic resonance imaging) were assessed with cross‐sectional linear regression of individual‐level data from participants in MESA (Multi‐Ethnic Study of Atherosclerosis; discovery, N=1103) and the NEO (Netherlands Epidemiology of Obesity) study (replication, N=2537). Untargeted 1H nuclear magnetic resonance metabolomics profiling of serum was performed in MESA, and metabolites were replicated in the NEO study using targeted 1H nuclear magnetic resonance spectroscopy. A total of 30 590 metabolomic spectral variables were evaluated. After adjustment for age, sex, race/ethnicity, socioeconomic status, smoking, physical activity, glucose/lipid‐lowering medication, and body mass index, 2104 variables representing 24 nonlipid and 49 lipid/lipoprotein subclass metabolites remained significantly associated with VAT (P=4.88×10−20–1.16×10−3). These included conventional metabolites, amino acids, acetylglycoproteins, intermediates of glucose and hepatic metabolism, organic acids, and subclasses of apolipoproteins, cholesterol, phospholipids, and triglycerides. Metabolites mapped to 31 biochemical pathways, including amino acid substrate use/metabolism and glycolysis/gluconeogenesis. In the replication cohort, acetylglycoproteins, branched‐chain amino acids, lactate, glutamine (inversely), and atherogenic lipids remained associated with VAT (P=1.90×10−35–8.46×10−7), with most associations remaining after additional adjustment for surrogates of VAT (glucose level, waist circumference, and serum triglycerides), reflecting novel independent associations. Conclusions We identified and replicated a metabolite panel associated with VAT in 2 community‐based cohorts. These findings persisted after adjustment for body mass index and appear to define a metabolic signature of visceral adiposity.

Background To understand how blood pressure (BP) from midlife and beyond is related to cognition in older age, a lifespan approach is needed. We assessed the associations of BP levels and variability from midlife on with subsequent cognitive change. Methods and Results The ARIC (Atherosclerosis Risk in Communities) Study participants underwent 4 clinic BP measurements (visit 1, 2, 3, and 4 BPs) between 1987 and 1998, and their mean levels and average real variability (ARV) were assessed as exposures. A global cognitive z score, estimated from the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test scores, was calculated at 1996 to 1998 (visit 4) and 2011 to 2013 (visit 5). Among 11 408 participants (mean age, 54 years; 56% women; 21% black race), mean systolic BP (SBP)/diastolic BP (DBP) level was 123/72 mm Hg, and ARVSBP/ARVDBP was 11/7 mm Hg. With linear mixed models, 1‐SD increases of ARVSBP (standardized regression coefficient [95% confidence interval], −0.03 [−0.04 to −0.01] points) and ARVDBP (standardized regression coefficient [95% confidence interval], −0.02 [−0.03 to −0.002] points; both P

BackgroundExisting equations for prediction of atrial fibrillation (AF) have been developed and validated in white and African‐American populations. Whether these models adequately predict AF in more racially and ethnically diverse populations is unknown. Methods and ResultsWe studied 6663 men and women 45 to 84 years of age without AF at baseline (2000–2002) enrolled in the Multi‐Ethnic Study of Atherosclerosis (MESA). Of these, 38% were non‐Hispanic whites, 28% non‐Hispanic African Americans, 22% Hispanics, and 12% Chinese Americans. AF during follow‐up was ascertained from hospitalization discharge codes through 2012. Information collected at baseline was used to calculate predicted 5‐year risk of AF using the previously published simple CHARGE‐AF model, which only includes clinical variables, and a biomarker‐enriched CHARGE‐AF model, which also considers levels of circulating N‐terminal of the prohormone B‐type natriuretic peptide and C‐reactive protein. For comparison purposes, we also assessed performance of the 10‐year Framingham AF model. During a mean follow‐up of 10.2 years, 351 cases of AF were identified. The C‐statistic of the CHARGE‐AF models were 0.779 (95% CI, 0.744–0.814) for the simple model and 0.825 (95% CI, 0.791–0.860) for the biomarker‐enriched model. Calibration was adequate in the biomarker‐enriched model (χ2=7.9; P=0.55), but suboptimal in the simple model (χ2=25.6; P=0.002). In contrast, the 10‐year Framingham score had a C‐statistic (95% CI) of 0.746 (0.720–0.771) and showed poor calibration (χ2=57.4; P

BACKGROUND:New technologies are diffusing into medical practice swiftly. Hand-held devices such as smartphones can record short-duration (e.g., 1-minute) ECGs, but their effectiveness in identifying patients with paroxysmal atrial fibrillation (AF) is unknown. METHODS:We used data from the TRENDS study, which included 370 patients (mean age 71 years, 71% men, CHADS2 score≥1 point: mean 2.3 points) who had no documentation of atrial tachycardia (AT)/AF or antiarrhythmic or anticoagulant drug use at baseline. All were subsequently newly diagnosed with AT/AF by a cardiac implantable electronic device (CIED) over one year of follow-up. Using a computer simulation approach (5,000 repetitions), we estimated the detection rate for paroxysmal AT/AF via daily snapshot ECG monitoring over various periods, with the probability of detection equal to the percent AT/AF burden on each day. RESULTS:The estimated AT/AF detection rates with snapshot monitoring periods of 14, 28, 56, 112, and 365 days were 10%, 15%, 21%, 28%, and 50% respectively. The detection rate over 365 days of monitoring was higher in those with CHADS2 scores ≥2 than in those with CHADS2 scores of 1 (53% vs. 38%), and was higher in those with AT/AF burden ≥0.044 hours/day compared to those with AT/AF burden

BackgroundThe classic view of blood pressure (BP) reactivity to psychological stress in relation to cardiovascular risks assumes that excess reactivity is worse and lower reactivity is better. Evidence addressing how stress‐induced BP reactivity in young adults is associated with midlife cognitive function is sparse. Methods and ResultsWe assessed BP reactivity during a star tracing task and a video game in adults aged 20 to 32 years. Twenty‐three years later, cognitive function was assessed with use of the Digit Symbol Substitution Test (a psychomotor speed test), the Rey Auditory Verbal Learning Test (a verbal memory test), and the modified Stroop test (an executive function test). At the time of follow‐up, participants (n=3021) had a mean age of 50.2 years; 56% were women, and 44% were black. In linear regression models adjusted for demographic and clinical characteristics including baseline and follow‐up resting BP, lower systolic BP (SBP) reactivity during the star tracing and video game was associated with worse Digit Symbol Substitution Test scores (β [SE]: 0.11 [0.02] and 0.05 [0.02], respectively) and worse performance on the Stroop test (β [SE]: −0.06 [0.02] and −0.05 [0.02]; all P

Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans.Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1 × 10(-8)), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium.Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.