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The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.

ObjectiveThe aim of this study was to assess the association of cardiovascular disease (CVD) risk scores and coronary artery plaque (CAP) progression in HIV-infected participants.MethodsWe studied men with and without HIV-infection enrolled in the Multicenter AIDS Cohort Study (MACS) CVD study. CAP at baseline and follow-up was assessed with cardiac computed tomography angiography (CCTA). We examined the association between baseline risk scores including pooled cohort equation (PCE), Framingham risk score (FRS), and Data collect of Adverse effects of anti-HIV drugs equation (D:A:D) and CAP progression.ResultsWe studied 495 men (211 HIV-uninfected, 284 HIV-infected). The adjusted odds ratio (aOR) of total plaque volume (TPV) and noncalcified plaque volume (NCPV) progression in the highest relative to lowest tertile was 9.4 [95% confidence interval (95% CI) 2.4-12.1, P

Both left atrial and left ventricular functional parameters influence the prognosis of patients with cardiovascular diseases. This study aimed to investigate the prognostic value of a novel left atrioventricular coupling index (LACI) in a population without history of cardiovascular diseases at baseline. Participants of the Multi-Ethnic Study of Atherosclerosis who underwent a baseline cardiovascular magnetic resonance study were analyzed. LACI was defined by the ratio of the left atrial end-diastolic volume divided by the left ventricular end-diastolic volume. Cox proportional hazard models were used to evaluate the association between LACI and atrial fibrillation, heart failure, coronary heart disease death, and hard cardiovascular disease defined by myocardial infarction, resuscitated cardiac arrest, fatal and nonfatal stroke, or coronary heart disease death. Among the 4124 participants (61.5±10.1 years, 47.4% men), 1074 cardiovascular events were observed (mean follow-up, 13.0±3.2 years). Greater LACI was independently associated with atrial fibrillation (hazard ratio, 1.86 [95% CI, 1.69–2.04]), heart failure (hazard ratio, 1.50 [95% CI, 1.38–1.62]), hard cardiovascular disease (1.23 [95% CI, 1.13–1.34]), and coronary heart disease death (hazard ratio, 1.29 [95% CI, 1.15–1.45]; all P

Objectives This study assessed the association of diabetes duration with incident heart failure (HF). Background Diabetes increases HF risk. However, the independent effect of diabetes duration on incident HF is unknown. Methods We included 9,734 participants (mean age 63 years, 58% women, 22% Black) at ARIC (Atherosclerosis Risk In Communities) Visit 4 (1996-1998) without HF or coronary heart disease. We calculated diabetes duration at Visit 4 (baseline), utilizing diabetes status at the first 4 ARIC visits spaced 3 years apart, and self-reported diagnosis date for those with diabetes diagnosed before Visit 1. We used Cox regression to estimate associations of diabetes duration with incident HF, accounting for intercurrent coronary heart disease and other risk factors. We performed analyses stratified by age ( Results Over 22.5 years of follow-up, there were 1,968 HF events. Compared to those without diabetes, HF risk rose with longer diabetes duration, with the highest risk among those with ≥15 y diabetes duration (HR: 2.82; 95% CI: 2.25-3.63). Each 5-year increase in diabetes duration was associated with a 17% (95% CI: 11-22) relative increase in HF risk. Similar results were observed across HF subtypes. The HF and diabetes duration associations were stronger among those aged Conclusions Delaying diabetes onset may augment HF prevention efforts, and therapies to improve HF outcomes might target those with long diabetes duration.

Background Vascular risk scores are associated with incident dementia. Information regarding their association with cognitive performance and decline in racially/ethnically diverse cohorts is lacking. Method In 4 392 Multi-Ethnic Study of Atherosclerosis participants (aged 60.1 ± 9.4 years; 53% women; 41% White, 11% Chinese American, 26% African American, 21% Hispanic), we compared associations of Exam 1 (2000–2002) Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham Stroke Risk Profile (FSRP), and atherosclerotic cardiovascular disease pooled cohort equation (ASCVD-PCE) risk scores with Exam 5 (2010–2012) Cognitive Abilities Screening Instrument (CASI), Digit Symbol Coding (DSC), and Digit Span (DS) cognitive test performance using multivariable linear regression, and examined racial/ethnic interactions. In 1 838 participants with repeat CASI data at Exam 6 (2016–2018), we related risk scores to odds of a 1-SD decline in CASI performance using multivariable logistic regression. Results SD increments in each risk score were associated with worse cognitive performance. CAIDE had stronger associations with CASI performance than the FSRP and ASCVD-PCE, but associations of ASCVD-PCE with the DSC and DS were similar to CAIDE (difference in β [95% CI] = −0.57 [−1.48, 0.34] and −0.21 [−0.43, 0.01], respectively). Race/ethnicity modified associations. For example, associations between CAIDE and CASI were greater in African Americans and Hispanics than in Whites (difference in β = 0.69 [0.02, 1.36] and 1.67 [0.95, 2.39], respectively). Risk scores were comparably associated with decline in CASI performance. Conclusions Antecedent vascular risk scores are associated with cognitive performance and decline in the 4 most common U.S. racial/ethnic groups, but associations differ among risk scores and by race/ethnicity.

Background Lower exercise capacity, as measured by 6-minute walk distance (6MWD), is associated with incident heart failure (HF). Among those without HF, the associations of measures of cardiac function with 6MWD are unclear, and may provide insight regarding the risk of incident HF. Objectives The purpose of this study was to understand the relationships between cardiac function and exercise capacity. Methods This study evaluated the associations of cardiac mechanics with 6MWD in the sixth examination of the Multi-Ethnic Study of Atherosclerosis. Echocardiography (2-dimensional, Doppler, and speckle-tracking) was performed at rest and after passive leg raise to evaluate functional reserve after intravascular volume challenge. Results Of 2,096 participants without HF (mean age 73 years, 48% men, 58% non-White), individuals with lower (worse) left atrial (LA) reservoir strain were older and had higher blood pressure. Lower resting LA reservoir strain (β coefficient per SD decrease: −5.0; 95% confidence interval [CI]: −8.8 to −1.3 m; p = 0.009), inability to augment LA reservoir strain after passive leg raise (β coefficient per SD decrease: −5.8; 95% CI: −9.1 to −2.5 m; p Conclusions Among individuals without HF, worse biatrial function, lack of LA functional reserve, and worse LV diastolic function were associated with reduced submaximal exercise capacity. Therapies aimed to improve these functional domains may increase exercise capacity and prevent HF.

Heart failure with preserved ejection fraction (HFpEF) affects more women than men. Menopause may influence HFpEF development in women. We assessed cross-sectional and longitudinal associations between menopause and echocardiographic measures of left ventricular (LV) function and cardiac remodeling.We studied 1,723 women with available echo data from at least two of: year 5 (Y5) (1990-1991), Y25 (2010-2011), or Y30 (2015-2016) in the Coronary Artery Risk Development in Young Adults study. Cardiac structure and function were measured using 2D and Doppler echocardiography. Cross-sectional associations between menopausal status and repeated echo measures at Y25 and Y30 were analyzed using linear mixed models. Two-segmented models were used to compare longitudinal changes in echocardiographic measures in the premenopausal period to changes in the postmenopausal period.Mean ± SD age (years) at enrollment was 27 ± 3 in those with menopause by Y25, 25 ± 3 in those with menopause between Y25 and Y30, and 21 ± 3 in those premenopausal at Y30. There were no significant differences in race, body mass index, systolic blood pressure, or diabetes between the groups. Postmenopausal women had higher early diastolic mitral inflow (E) to annular (e') velocity ratio than premenopausal after adjusting for demographics and risk factors (P 0.05). Menopause was associated with relative increases in the rates of change in LV mass and left atrial volume, even after adjustment. Change in E/e' ratio was similar before and after menopause.Menopause is associated cross-sectionally with worse diastolic function and longitudinally with adverse LV and left atrial remodeling. This may contribute to the increased HFpEF risk in postmenopausal women.Video Summary:http://links.lww.com/MENO/A787.

Cardiac involvement among hospitalized patients with severe coronavirus disease 2019 (COVID-19) is common and associated with adverse outcomes. This study aimed to determine the prevalence and clinical implications of COVID-19 cardiac involvement in young competitive athletes.In this prospective, multicenter, observational cohort study with data from 42 colleges and universities, we assessed the prevalence, clinical characteristics, and outcomes of COVID-19 cardiac involvement among collegiate athletes in the United States. Data were collected from September 1, 2020, to December 31, 2020. The primary outcome was the prevalence of definite, probable, or possible COVID-19 cardiac involvement based on imaging definitions adapted from the Updated Lake Louise Imaging Criteria. Secondary outcomes included the diagnostic yield of cardiac testing, predictors for cardiac involvement, and adverse cardiovascular events or hospitalizations.Among 19 378 athletes tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 3018 (mean age, 20 years [SD, 1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least 1 element of cardiac triad testing (12-lead ECG, troponin, transthoracic echocardiography) followed by cardiac magnetic resonance imaging (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21 of 2999 [0.7%]), cardiac troponin (24 of 2719 [0.9%]), and transthoracic echocardiography (24 of 2556 [0.9%]). Definite, probable, or possible SARS-CoV-2 cardiac involvement was identified in 21 of 3018 (0.7%) athletes, including 15 of 2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6 of 198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-CoV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15 of 119 [12.6%]) versus a primary screening CMR (6 of 198 [3.0%]). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (odds ratio, 3.1 [95% CI, 1.2, 7.7]) or at least 1 abnormal triad test result (odds ratio, 37.4 [95% CI, 13.3, 105.3]). Five (0.2%) athletes required hospitalization for noncardiac complications of COVID-19. During clinical surveillance (median follow-up, 113 days [interquartile range=90 146]), there was 1 (0.03%) adverse cardiac event, likely unrelated to SARS-CoV-2 infection.SARS-CoV-2 infection among young competitive athletes is associated with a low prevalence of cardiac involvement and a low risk of clinical events in short-term follow-up.

Aims The extent to which human immunodeficiency viral (HIV) infection is independently associated with myocardial disease in the era of combination antiretroviral therapy (cART) remains understudied. We assessed differences in cardiovascular magnetic resonance imaging (CMR) metrics among people living with HIV (PLWH) and without HIV (PWOH). Methods and results Among 436 participants (aged 54.7 ± 6.0 years, 29% women) from three cohorts, we acquired CMR cines, late gadolinium enhancement (LGE), and T1 mapping. Multivariable linear regressions were used to evaluate associations between HIV serostatus and CMR metrics. Baseline characteristics were similar by HIV serostatus; 63% were PLWH of whom 88% received cART and 73% were virally suppressed. Median left ventricular ejection fraction was normal and similar by HIV serostatus (73%, PWOH vs. 72%, PLWH, P = 0.43) as were right ventricular function, biventricular volumes, and masses. LGE prevalence was similar (32%, PWOH vs. 36%, PLWH, P = 0.46) with low scar extents (4.1, PWOH vs. 4.9 g, PLWH, P = 0.51) and few ischaemic scars (3%, PWOH vs. 4%, PLWH, P = 0.70). Extracellular volume fraction (ECV) was higher among PLWH (29.2 ± 4.1% vs. 28.3 ± 3.7%, P = 0.04) as was indexed maximum left atrial (LA) volume (LAVI, 29.7 ± 10.3 vs. 27.8 ± 8.7 mL/m2, P = 0.05). After multivariate adjustment, ECV was 0.84% higher among PLWH (P = 0.05) and LAVI was 2.45 mL/m2 larger (P = 0.01). HIV seropositivity and higher ECV contributed to higher LAVI (P Conclusion HIV seropositivity was independently associated with greater diffuse non-ischaemic fibrosis and larger LA volume but no other differences in CMR metrics.

Background: Recent clinical guidelines support intensive blood pressure treatment targets. However, observational data suggest that excessive diastolic blood pressure (DBP) lowering might increase the risk of myocardial infarction (MI), reflecting a J- or U-shaped relationship. Methods: We analyzed 47 407 participants from 5 cohorts (median age, 60 years). First, to corroborate previous observational analyses, we used traditional statistical methods to test the shape of association between DBP and cardiovascular disease (CVD). Second, we created polygenic risk scores of DBP and systolic blood pressure and generated linear Mendelian randomization (MR) estimates for the effect of DBP on CVD. Third, using novel nonlinear MR approaches, we evaluated for nonlinearity in the genetic relationship between DBP and CVD events. Comprehensive MR interrogation of DBP required us to also model systolic blood pressure, given that the 2 are strongly correlated. Results: Traditional observational analysis of our cohorts suggested a J-shaped association between DBP and MI. By contrast, linear MR analyses demonstrated an adverse effect of increasing DBP increments on CVD outcomes, including MI (MI hazard ratio, 1.07 per unit mm Hg increase in DBP; P Conclusions: In this analysis of the genetic effect of DBP, we found no evidence for a nonlinear J- or U-shaped relationship between DBP and adverse CVD outcomes; including MI.

Supplemental Digital Content is available in the text., Background: Knowledge gaps remain in the epidemiology and clinical implications of myocardial injury in coronavirus disease 2019 (COVID-19). We aimed to determine the prevalence and outcomes of myocardial injury in severe COVID-19 compared with acute respiratory distress syndrome (ARDS) unrelated to COVID-19. Methods: We included intubated patients with COVID-19 from 5 hospitals between March 15 and June 11, 2020, with troponin levels assessed. We compared them with patients from a cohort study of myocardial injury in ARDS and performed survival analysis with primary outcome of in-hospital death associated with myocardial injury. In addition, we performed linear regression to identify clinical factors associated with myocardial injury in COVID-19. Results: Of 243 intubated patients with COVID-19, 51% had troponin levels above the upper limit of normal. Chronic kidney disease, lactate, ferritin, and fibrinogen were associated with myocardial injury. Mortality was 22.7% among patients with COVID-19 with troponin under the upper limit of normal and 61.5% for those with troponin levels >10 times the upper limit of normal (P

Context Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes. Objective To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). Design Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years. Setting General community. Participants 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation [SD] 5.7) and 62.8 (5.5) years, respectively. Exposure Plasma sex hormone levels were measured at visit 4 (1996-1998). Main Outcome Measures Incident HF events were identified through hospital discharge codes and death certificates. Results The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant. Conclusion In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex.

The 2017 American blood pressure (BP) guidelines recommended a personalized risk-based approach to treatment in stage 1 hypertension. We sought to establish the utility of coronary artery or thoracic aortic calcium (CAC or TAC) as additional risk modifiers in this setting. We included 1859 Multiethnic Study of Atherosclerosis participants with stage 1 hypertension. We compared adjusted HR for the composite outcome of incident atherosclerotic cardiovascular disease or heart failure across predefined categories of either CAC or TAC (0, 1 to 100, or >100) in: (1) the full sample; (2) 4 high-risk subgroups recommended for pharmacotherapy to a BP goal 100. CAC >100 was independently associated with a higher relative risk of events compared with CAC = 0 (e.g., adjusted HR [9.5 (1.8 to 18.7)] in the low-risk subgroup). NNT10 for CAC = 0 were 3 to 5 times higher than those for CAC >100 in all analyses. TAC was not a reliable risk modifier in our study. In conclusion, CAC, but not TAC, can further guide risk-based allocation of treatment in stage 1 hypertension and should be considered as a risk modifier in future guidelines.

Background The purpose of this study is to determine if a new score calculated with coronary artery calcium (CAC) density and volume is associated with total coronary artery plaque burden and composition on coronary CT angiography (CCTA) compared to the Agatston score (AS). Methods We identified 347 men enrolled in the Multicenter AIDS cohort study who underwent contrast and non-contrast CCTs, and had CAC>0. CAC densities (mean Hounsfield Units [HU]) per plaque) and volumes on non-contrast CCT were measured. A Density-Volume Calcium score was calculated by multiplying the plaque volume by a factor based on the mean HU of the plaque (4, 3, 2 and 1 for 130–199, 200–299, 300–399, and ≥400HU). Total Density-Volume Calcium score was determined by the sum of these individual scores. The semi-quantitative partially calcified and total plaque scores (PCPS and TPS) on CCTA were calculated. The associations between Density-Volume Calcium score, PCPS and TPS were examined. Results Overall, 2879 CAC plaques were assessed. Multivariable linear regression models demonstrated a stronger association between the log Density-Volume Calcium score and both the PCPS (β 0.99, 95%CI 0.80–1.19) and TPS (β 2.15, 95%CI 1.88–2.42) compared to the log of AS (PCPS: β 0.77, 95%CI 0.61–0.94; TPS: β 1.70, 95%CI 1.48–1.94). Similar results were observed for numbers of PC or TP segments. Conclusion The new CAC score weighted towards lower density demonstrated improved correlation with semi-quantitative PC and TP burden on CCTA compared to the traditional AS, which suggests it has utility as an alternative measure of atherosclerotic burden.

Objectives Elite controllers (ECs), viraemic controllers (VCs), and long-term nonprogressors (LTNPs) control HIV viral replication or maintain CD4 T-cell counts without antiretroviral therapy, but may have increased cardiovascular disease (CVD) risk compared to HIV-uninfected persons. We evaluated subclinical carotid and coronary atherosclerosis and inflammatory biomarker levels among HIV controllers, LTNPs and noncontrollers and HIV-uninfected individuals in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). Methods We measured carotid plaque presence and common carotid artery intima-media thickness (IMT) in 1729 women and 1308 men, and the presence of coronary artery calcium and plaque in a subgroup of men. Associations between HIV control category and carotid and coronary plaque prevalences were assessed by multivariable regression analyses adjusting for demographics and CVD risk factors. Serum inflammatory biomarker concentrations [soluble CD163 (sCD163), soluble CD14 (sCD14), galectin-3 (Gal-3), galectin-3 binding protein (Gal-3BP) and interleukin (IL)-6] were measured and associations with HIV control category assessed. Results We included 135 HIV controllers (30 ECs) and 135 LTNPs in the study. Carotid plaque prevalence and carotid IMT were similar in HIV controllers, LTNPs and HIV-uninfected individuals. HIV controllers and LTNPs had lower prevalences of carotid plaque compared to viraemic HIV-infected individuals. The prevalence of coronary atherosclerosis was similar in HIV controllers/LTNPs compared to HIV-uninfected and viraemic HIV-infected men. Controllers and LTNPs had higher concentrations of sCD163 and sCD14 compared to HIV-uninfected persons. Conclusions Subclinical CVD was similar in HIV controllers, LTNPs and HIV-uninfected individuals despite elevated levels of some inflammatory biomarkers. Future studies of HIV controllers and LTNPs are needed to characterize the risk of CVD among HIV-infected persons.

Funding Acknowledgements Type of funding sources: None. BACKGROUND Left atrial (LA) and left ventricular (LV) structural and functional parameters have independent prognostic values as predictors of atrial fibrillation (AF). PURPOSE To investigate the prognostic value of a left atrioventricular coupling index (LACI) and average annualized change in LACI measured by cardiac MRI to predict incident AF in a population-based sample from the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS In a secondary analysis of the prospective Multi-Ethnic Study of Atherosclerosis (MESA) study, 1,911 study participants, free of clinically recognized AF and cardiovascular disease at baseline, had LACI assessed with cardiac MRI at baseline (Exam 1, 2000-2002), and ten years later (Exam 5, 2010-2012). LACI was defined as the ratio of LA to LV end-diastolic volumes. Univariable and multivariable Cox proportional hazard models were used to evaluate the associations of LACI and average annualized change in LACI (ΔLACI) with incident AF. RESULTS Among the 1,911 participants (mean age 59 ± 9 years and 907 men), 87 incident AF events occurred over 3.9 ± 0.9 years following the second imaging (Exam 5). After adjustment for traditional risk factors, greater LACI and ΔLACI were independently associated with AF (HR 1.69, 95% CI[1.46-1.96] and HR 1.71, 95% CI[1.50-1.94], respectively; both p CONCLUSIONS Atrioventricular coupling (LACI) and coupling change (ΔLACI) were strong predictors for AF in a multi-ethnic population. Both had incremental prognostic value for predicting AF over traditional risk factors, and superior discrimination compared to the CHARGE-AF score and to individual LA or LV parameters. ClinicalTrials.gov Identifier: NCT00005487 Abstract Figure. Kaplan-Meier curves by change in LACI Abstract Figure. Kaplan-Meier curves by ΔLACI and LACI

Rationale and Objective: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. beta 2-Microglobulin (B2M) and beta-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.Study Design: Study of diagnostic test accuracy.Setting and Participants: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. Tests Compared: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. Outcomes: GFRmeasured as the urinary clearance of iothalamate, plasmaclearanceof iohexol, orplasma clearance of [Cr-51]EDTA.Results: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m(2), and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1-P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1-P-30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.Limitations: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.Conclusions: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.

Background The complexity of physical activity (PA) and DNA methylation interaction in the development of cardiovascular disease (CVD) is rarely simultaneously investigated in one study. We examined the role of DNA methylation on the association between PA and CVD. Results The Multi-Ethnic Study of Atherosclerosis (MESA) cohort Exam 5 data with 1065 participants free of CVD were used for final analysis. The quartile categorical total PA variable was created by activity intensity (METs/week). During a median follow-up of 4.0 years, 69 participants developed CVD. Illumina HumanMethylation450 BeadChip was used to provide genome-wide DNA methylation profiles in purified human monocytes (CD14+). We identified 23 candidate DNA methylation loci to be associated with both PA and CVD. We used the structural equation modeling (SEM) approach to test the complex relationships among multiple variables and the roles of mediators. Three of the 23 identified loci (corresponding to genes VPS13D, PIK3CD and VPS45) remained as significant mediators in the final SEM model along with other covariates. Bridged by the three genes, the 2nd PA quartile (β = − 0.959; 95%CI: − 1.554 to − 0.449) and the 3rd PA quartile (β = − 0.944; 95%CI: − 1.628 to − 0.413) showed the greatest inverse associations with CVD development, while the 4th PA quartile had a relatively weaker inverse association (β = − 0.355; 95%CI: − 0.713 to − 0.124). Conclusions The current study is among the first to simultaneously examine the relationships among PA, DNA methylation, and CVD in a large cohort with long-term exposure. We identified three DNA methylation loci bridged the association between PA and CVD. The function of the identified genes warrants further investigation in the pathogenesis of CVD.

Chronic inflammation, including among people with HIV (PWH), elevates immune cell expression of lymphocyte activation gene 3 (LAG3); however, low plasma LAG3 predicts cardiovascular disease (CVD) events in the general population. The associations among LAG3 plasma levels, subclinical atherosclerosis, inflammation, and HIV infection have not been well described. We measured plasma LAG3 in 704 men with and without HIV from the multicenter AIDS cohort study, who underwent coronary computed tomography angiography. HIV serostatus was not independently associated with LAG3 after adjustment for sociodemographic and CVD risk factors. Current smoking status and African American race were associated with lower LAG3, and age and sTNFαRI concentration were associated with greater LAG3. LAG3 was not associated with coronary artery stenosis. Thus, no difference was found in plasma LAG3 concentration by HIV serostatus, and no association between LAG3 and subclinical coronary atherosclerosis in men with and without HIV was observed.

Background: Although left atrial (LA) and left ventricular (LV) structural and functional parameters have independent prognostic value as predictors of heart failure (HF), the close physiological relationship between the LA and LV suggest that the assessment of LA/LV coupling could better reflect left atrioventricular dysfunction and be a better predictor of HF.Aim: We investigated the prognostic value of a left atrioventricular coupling index (LACI), measured by cardiovascular magnetic resonance (CMR), as well as change in LACI to predict incident HF in the Multi-Ethnic Study of Atherosclerosis (MESA).Materials and Methods: In the MESA, 2,250 study participants, free of clinically recognized HF and cardiovascular disease (CVD) at baseline, had LACI assessed by CMR imaging at baseline (Exam 1, 2000–2002), and 10 years later (Exam 5, 2010–2012). Left atrioventricular coupling index was defined as the ratio of LA to LV end-diastolic volumes. Univariable and multivariable Cox proportional hazard models were used to evaluate the associations of LACI and average annualized change in LACI (ΔLACI) with incident HF after adjustment for traditional MESA-HF risk factors. The incremental risk prediction was calculated using C-statistic, categorical net reclassification index (NRI) and integrative discrimination index (IDI).Results: Among the 2,250 participants (mean age 59.3 ± 9.3 years and 47.6% male participants), 50 incident HF events occurred over 6.8 ± 1.3 years after the second CMR exam. After adjustment, greater LACI and ΔLACI were independently associated with HF (adjusted HR 1.44, 95% CI [1.25–1.66] and adjusted HR 1.55, 95% CI [1.30–1.85], respectively; both p < 0.0001). Adjusted models for LACI showed significant improvement in model discrimination and reclassification compared to currently used HF risk score model for predicting HF incidence (C-statistic: 0.81 vs. 0.77; NRI = 0.411; IDI = 0.043). After adjustment, ΔLACI showed also significant improvement in model discrimination compared to the multivariable model with traditional MESA-HF risk factors for predicting incident HF (C-statistic: 0.82 vs. 0.77; NRI = 0.491; IDI = 0.058).Conclusions: In a multi-ethnic population, atrioventricular coupling (LACI), and coupling change (ΔLACI) are independently associated with incident HF. Both have incremental prognostic value for predicting HF events over traditional HF risk factors.

Cross-sectionally measured NT-proBNP (N-terminal pro-B-type natriuretic peptide) is related to incident dementia. However, data linking changes in NT-proBNP to risk of future dementia are lacking. We aimed to examine the association of change in NT-proBNP over 3.2 years with incident dementia. We included 4563 participants in MESA (Multi-Ethnic Study of Atherosclerosis) prospective cohort who were free of cardiovascular disease at enrollment, had NT-proBNP level measured at MESA exams 1 (baseline, 2000–2002) and 3 (2004–2005), and had no diagnosis of dementia before exam 3. The association of change in NT-proBNP level between MESA exams 1 through 3 and all-cause hospitalized dementia (by International Classification of Diseases, Ninth Revision , codes) after MESA exam 3 (2004–2005) through 2015 was assessed using competing-risks Cox proportional hazard regression analysis. During 45 522 person-years of follow-up, 223 dementia cases were documented. Increase in log-NT-proBNP from MESA exams 1 through 3 was positively associated with incidence of dementia (multivariable hazard ratio, 1.28 [95% CI, 1.001–1.64]; P =0.049). An increase of at least 25% in NT-proBNP level from MESA exam 1 through 3 was associated with a 55% ( P =0.02) increase in the risk of dementia in multivariable analysis. Addition of temporal NT-proBNP change to a model including risk factors and baseline NT-proBNP improved the prediction of dementia (Harrell C statistic from 0.85 to 0.87, P =0.049). Increase in NT-proBNP is independently associated with future all-cause hospitalized dementia and offers a moderately better predictive performance for risk of dementia compared with risk factors and baseline NT-proBNP. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00005487.

Heart failure is a major public health problem affecting over 23 million people worldwide. In this study, we present the results of a large scale meta-analysis of heart failure GWAS and replication in a comparable sized cohort to identify one known and two novel loci associated with heart failure. Heart failure sub-phenotyping shows that a new locus in chromosome 1 is associated with left ventricular adverse remodeling and clinical heart failure, in response to different initial cardiac muscle insults. Functional characterization and fine-mapping of that locus reveal a putative causal variant in a cardiac muscle specific regulatory region activated during cardiomyocyte differentiation that binds to the ACTN2 gene, a crucial structural protein inside the cardiac sarcolemma (Hi-C interaction p-value = 0.00002). Genome-editing in human embryonic stem cell-derived cardiomyocytes confirms the influence of the identified regulatory region in the expression of ACTN2. Our findings extend our understanding of biological mechanisms underlying heart failure., Heart failure has a heterogeneous etiology and the genetic underpinnings are not well understood. Here, Arvanitis et al. perform GWAS meta-analysis including 10,976 heart failure cases and 437,573 controls, identify new loci near ABO and ACTN2 and show that deletion of a ACTN2 enhancer leads to reduced ACTN2 expression in differentiating cardiomyocytes.

Background:People living with human immunodeficiency virus (HIV+) have greater risk for sudden arrhythmic death than HIV-uninfected (HIV–) individuals. HIV-associated abnormal cardiac repolarization may contribute to this risk. We investigated whether HIV serostatus is associated with ventricular repolarization lability by using the QT variability index (QTVI), defined as a log measure of QT-interval variance indexed to heart rate variance.Methods:We studied 1123 men (589 HIV+ and 534 HIV–) from MACS (Multicenter AIDS Cohort Study), using the ZioXT ambulatory electrocardiography patch. Beat-to-beat analysis of up to 4 full days of electrocardiographic data per participant was performed using an automated algorithm (median analyzed duration [quartile 1–quartile 3]: 78.3 [66.3–83.0] hours/person). QTVI was modeled using linear mixed-effects models adjusted for demographics, cardiac risk factors, and HIV-related and inflammatory biomarkers.Results:Mean (SD) age was 60.1 (11.9) years among HIV– and 54.2 (11.2) years among HIV+ participants (PConclusions:HIV+ men have greater beat-to-beat variability in QT interval (QTVI) than HIV– men, especially in the setting of HIV viremia and heightened inflammation. Among HIV+ men, higher QTVI suggests ventricular repolarization lability, which can increase susceptibility to arrhythmias, whereas lower heart rate variability signals a component of autonomic dysfunction.

Objectives Adipose tissue (AT) density measurement may provide information about AT quality among people living with HIV. We assessed AT density and evaluated relationships between AT density and immunometabolic biomarker concentrations in men with HIV. Design Cross-sectional analysis of men enrolled in the Multicenter AIDS Cohort Study. Methods Abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density (Hounsfield units, HU; less negative = more dense) were quantified from computed tomography (CT) scans. Multivariate linear regression models described relationships between abdominal AT density and circulating biomarker concentrations. Results HIV+ men had denser SAT (−95 vs −98 HU HIV−, P s.d. greater SAT or VAT density was associated with higher levels of adiponectin, leptin, HOMA-IR and triglyceride:HDL cholesterol ratio and lower hs-CRP concentrations in HIV− men. Conversely, in HIV+ men, each s.d. greater SAT density was not associated with metabolic parameter improvements and was significantly (P s.d. greater VAT density were also observed among HIV+ men. Conclusions Among men living with HIV, greater SAT density was associated with greater systemic inflammation independent of SAT area. AT density measurement provides additional insight into AT density beyond measurement of AT quantity alone, and may have implications for metabolic disease risk.

ObjectiveWhether HIV modifies the relationship of serum lipids with coronary atherosclerosis and coronary plaque subtypes is uncertain. We examined the associations between traditional lipids and coronary atherosclerosis among HIV-infected (HIV+) and HIV-uninfected (HIV-) men.DesignThe Multicenter AIDS Cohort Study is an observational cohort with a total of 429 HIV+ and 303 HIV- men who had non-contrast cardiac computed tomography performed to measure coronary artery calcium and coronary computed tomography angiography to measure coronary stenosis, coronary plaque presence, and composition.MethodsWe used multivariable adjusted prevalence ratios to examine the relationship between the SD difference in each lipid parameter and coronary atherosclerosis.ResultsTotal cholesterol (TC)/HDL-cholesterol had the strongest associations with coronary atherosclerosis regardless of HIV status. Overall, lipid parameters were most strongly associated with the presence of mixed plaque, stenosis more than 50%, and coronary artery calcium for both HIV+ and HIV- men. HIV+ men had similar, but weaker associations, between lipid parameters and coronary atherosclerosis compared with HIV- men. The strongest association was between the TC/HDL-cholesterol and stenosis more than 50% for both HIV+ [prevalence ratios 1.25 per SD (95% confidence interval 1.07-1.43)] and HIV- men [prevalence ratios 1.46 per SD (95% confidence interval 1.08-1.85)].ConclusionThe associations between lipids and coronary atherosclerosis tended to be weaker for HIV+ compared with HIV- men, although TC/HDL had the strongest association for both HIV+ and HIV- men. A weaker association between lipid levels and coronary atherosclerosis for HIV+ men may contribute to the decreased discrimination of cardiovascular disease risk observed in HIV+ individuals.

Background High-sensitivity cardiac troponin (hs-cTn) elevations are associated with incident cardiovascular disease events in primary prevention samples. However, the mechanisms underlying this association remain unclear. Methods We studied 458 men without known cardiovascular disease who participated in the cardiovascular disease substudy of the Multicenter AIDS Cohort Study and had cardiac CT angiography. We used multivariable linear and logistic regression models to examine the cross-sectional associations between coronary artery stenosis, coronary artery plaque, indexed left ventricular mass (LVMi), and the outcome of hs-cTnI. We also evaluated the associations between HIV serostatus or use of highly active antiretroviral therapy (HAART) and hs-cTnI. Results The mean age was 54 years, 54% were white, and 61% were HIV infected. In multivariable-adjusted logistic models, comparing the highest quartile of LVMi with the lowest quartile, the odds ratio (OR) of hs-cTnI ≥75th percentile was 2.59 (95% CI, 1.20-5.75). There was no significant association between coronary stenosis severity or plaque type and hs-cTnI in linear models; however, in logistic regression models, coronary artery stenosis ≥70% (8% of sample) was marginally associated with a higher likelihood (OR, 2.75 [95% CI, 1.03, 7.27]) of having hs-cTnI ≥75th percentile. There were no associations between HIV serostatus or HAART use and hs-cTnI in either linear or logistic models. Conclusion Among primary prevention men with or at risk for HIV, hs-cTnI concentrations were strongly associated with LVMi but were not associated with HIV infection or treatment status or with coronary plaque type or stenosis until the extremes of severity (≥70% stenosis).

Background: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual. Methods: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age ≤55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations. Results: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7%) and was associated with a 3.8-fold (95% CI, 2.1-6.8; P3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00597922. ©2019, National Institutes of Health (no. TR001100), American Heart Association (no. 17SDG33680041), National Human Genome Research Institute (no. 5UM1HG008895)

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) are proxies for variant pathogenicity. Effect sizes were associated with pathogenic ClinVar assertions (P

The early stages of aortic valve calcification (AVC) and coronary artery calcification (CAC) include shared ASCVD risk factors, yet there is considerable heterogeneity between the burden of AVC, and CAC. We sought to identify the markers associated with limited CAC among persons with significant AVC. There were 325 participants from the Multi-Ethnic Study of Atherosclerosis without clinical ASCVD and with AVC ≥100 Agatston units (AU) at Visit 1. Multivariable-adjusted prevalence ratios for limited CAC (0 to 99 AU) were calculated using modified Poisson regression. Participants had a mean age of 72.1 years, median AVC score of 209, and 34% were women. A total of 133 (41%) participants had CAC100, of whom 46/133 had CAC = 0. Younger age (PR = 1.40, 95% CI: 1.22 to 1.62, per 10-years), female gender (PR = 1.68, 95% CI: 1.28 to 2.20), and low 10-year ASCVD risk (PR = 2.30, 95% CI: 1.85 to 2.85) were most strongly associated with limited CAC. Neither a normal lipoprotein(a) nor normal measures of inflammation were significantly associated with limited CAC. Lower serum phosphate (PR = 1.15, 95% CI: 1.01 to 1.31; per 0.5 mg/dl lower) and calcium-phosphate product (PR = 1.16, 95% CI: 1.02 to 1.34; per SD lower) were associated with an approximately 15% higher prevalence of limited CAC. In conclusion, more than 40% of persons with significant AVC had CAC. Beyond traditional risk factors, lower serum phosphate, and lower calcium-phosphate product were associated with a higher prevalence of limited CAC.

Background Racial and ethnic inequities exist in surgical aortic valve replacement for aortic stenosis (AS), and early studies have suggested similar inequities in transcatheter aortic valve replacement. Methods and Results We performed a retrospective analysis of the Maryland Health Services Cost Review Commission inpatient data set from 2016 to 2018. Black patients had half the incidence of any inpatient AS diagnosis compared with White patients (incidence rate ratio [IRR], 0.50; 95% CI, 0.48–0.52; P P P =0.97) but was significantly lower in Hispanic compared with White patients (IRR, 0.36; 95% CI, 0.33–0.40; P P P =0.002) among those with any inpatient diagnosis of AS. Hispanic patients had a similar rate of surgical aortic valve replacement and transcatheter aortic valve replacement compared with White patients. Conclusions Hospitalization with any diagnosis of AS is less common in Black and Hispanic patients than in White patients. In hospitalized patients with AS, Black race is associated with a lower incidence of both surgical aortic valve replacement and transcatheter aortic valve replacement compared with White patients, whereas Hispanic patients have a similar incidence of both. The reasons for these inequities are likely multifactorial.

Background C-reactive protein (CRP) is an inflammatory biomarker associated with all-cause mortality and morbidities such as cardiovascular disease. CRP is increased with HIV infection and thought to increase with age, though trajectories of CRP with aging have not been well characterized. We investigated trajectories of CRP in men from the Multicenter AIDS Cohort Study, according to HIV infection and HIV viral load status. Methods CRP measurements from 12 250 serum samples, provided by 2132 men over a span of 30 years, were categorized by HIV status at sample collection: HIV uninfected (HIV−, n = 1717), HIV infected with undetectable RNA (HIV+ suppressed, n = 4075), and detectable HIV RNA (HIV+ detectable, n = 6458). Age-related trajectories of CRP were fit to multivariable linear mixed models; we tested for differences in trajectories by HIV status. Results CRP increased with age in all sample groups. HIV+ detectable and HIV+ suppressed samples had higher CRP than HIV− samples throughout the observed age range of 20–70 years (p < .05). CRP concentrations at age 45 years were 38% (95% CI: 26%–50%) and 26% (15%–38%) higher in HIV+ detectable and HIV+ suppressed samples, respectively, relative to HIV− samples. HIV+ detectable samples showed more rapid linear increases with age (8% higher/decade, 0.3%–16%) than HIV− samples. Conclusions We observed higher concentrations of CRP across 5 decades of age in men living with HIV, and steeper increases with age in men with detectable HIV RNA, relative to HIV− men. These results are consistent with a contribution of inflammation to the higher risk of age-related comorbidities with HIV infection.

Background Given the central role of skeletal muscles in glucose homeostasis, deposition of adipose depots beneath the fascia of muscles (versus subcutaneous adipose tissue [SAT]) may precede insulin resistance and type 2 diabetes (T2D) incidence. This study was aimed to investigate the associations between computed tomography (CT)–derived biomarkers for adipose tissue and T2D incidence in normoglycemic adults. Methods and findings This study was a population-based multiethnic retrospective cohort of 1,744 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with normoglycemia (baseline fasting plasma glucose [FPG] less than 100 mg/dL) from 6 United States of America communities. Participants were followed from April 2010 and January 2012 to December 2017, for a median of 7 years. The intermuscular adipose tissue (IMAT) and SAT areas were measured in baseline chest CT exams and were corrected by height squared (SAT and IMAT indices) using a predefined measurement protocol. T2D incidence, as the main outcome, was based on follow-up FPG, review of hospital records, or self-reported physician diagnoses. Participants’ mean age was 69 ± 9 years at baseline, and 977 (56.0%) were women. Over a median of 7 years, 103 (5.9%) participants were diagnosed with T2D, and 147 (8.4%) participants died. The IMAT index (hazard ratio [HR]: 1.27 [95% confidence interval [CI]: 1.15–1.41] per 1-standard deviation [SD] increment) and the SAT index (HR: 1.43 [95% CI: 1.16–1.77] per 1-SD increment) at baseline were associated with T2D incidence over the follow-up. The associations of the IMAT and SAT indices with T2D incidence were attenuated after adjustment for body mass index (BMI) and waist circumference, with HRs of 1.23 (95% CI: 1.09–1.38) and 1.29 (95% CI: 0.96–1.74) per 1-SD increment, respectively. The limitations of this study include unmeasured residual confounders and one-time measurement of adipose tissue biomarkers. Conclusions In this study, we observed an association between IMAT at baseline and T2D incidence over the follow-up. This study suggests the potential role of intermuscular adipose depots in the pathophysiology of T2D. Trial registration ClinicalTrials.gov NCT00005487, In a cohort study, Shadpour Demehri and colleagues investigate the association between adipose tissue biomarkers and type 2 diabetes incidence in normoglycemic participants in US., Author summary Why was this study done? This study was designed to investigate the associations between computed tomography (CT)–derived biomarkers for adipose tissue at baseline and type 2 diabetes (T2D) incidence in normoglycemic adults. What did the researchers do and find? We assessed 1,744 normoglycemic participants with chest CT exams between 2010 and 2012. The intermuscular adipose tissue (IMAT) and subcutaneous adipose tissue (SAT) areas were measured in these chest CT exams using a predefined measurement protocol. Participants were followed from April 2010 and January 2012 to December 2017, for a median of 7 years, for T2D incidence. T2D incidence was based on follow-up fasting plasma glucose (FPG), review of hospital records, or self-reported physician diagnoses. This study found that a higher CT-derived IMAT at baseline was associated with T2D incidence over the follow-up. What do these findings mean? In normoglycemic participants, the IMAT deposition was associated with T2D incidence. This study suggests the potential role of intermuscular adipose depots in the pathophysiology of T2D. The CT-derived adipose tissue biomarkers are obtainable from CT exams performed for other initial indications and can extend the value of the routinely performed chest CT exams. Such biomarkers may be associated with T2D incidence.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias., Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.