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BackgroundRare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA).ObjectivesTo identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR.MethodsMESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes (n = 82). Coding variants with a frequency of in-silico scoring tools were assessed by ClinVar database and ACMG curation guidelines for evidence of pathogenicity. Cases were participants with high myocardial fibrosis defined as highest quartile of extracellular volume (ECV) or native T1 time in T1-mapping CMR and controls were the remainder of participants.ResultsA total of 1,135 MESA participants had available genetic data and phenotypic measures and were free of clinical CVD at the time of CMR. We identified 6,349 rare variants in CM-associated genes in the overall MESA population, of which six pathogenic/likely pathogenic (P/LP) variants were present in the phenotyped subpopulation. The genes harboring P/LP variants in the case group were MYH7, CRYAB, and SCN5A. The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], p = 0.03). We identified two MYBPC3 Variants of Unknown Significance (VUS)s with borderline pathogenicity in the case group. The left ventricle (LV) volume, mass, ejection fraction (EF), and longitudinal and circumferential strain in participants with the variants were not different compared to the overall cohort.ConclusionsWe observed a higher prevalence of rare potentially pathogenic CM associated genetic variants in participants with significant myocardial fibrosis quantified in CMR as compared to controls without significant fibrosis. No cardiac structural or functional differences were found between participants with or without P/LP variants.

Key Points Question What is the accuracy of low-density lipoprotein cholesterol (LDL-C) estimation when comparing the Friedewald, extended Martin/Hopkins, and Sampson equations with LDL-C measured through ultracentrifugation at triglyceride levels of 400 to 799 mg/dL? Findings In this cross-sectional study of 111 939 patients, across all individual guideline LDL-C classes from, Importance Low-density lipoprotein cholesterol (LDL-C) is typically estimated with the Friedewald or Martin/Hopkins equation; however, if triglyceride levels are 400 mg/dL or greater, laboratories reflexively perform direct LDL-C (dLDL-C) measurement. The use of direct chemical LDL-C assays and estimation of LDL-C via the National Institutes of Health Sampson equation are not well validated, and data on the accuracy of LDL-C estimation at higher triglyceride levels are limited. Objective To compare an extended Martin/Hopkins equation for triglyceride values of 400 to 799 mg/dL with the Friedewald and Sampson equations. Design, Setting, and Participants This cross-sectional study evaluated consecutive patients at clinical sites across the US with patient lipid distributions representative of the US population in the Very Large Database of Lipids from January 1, 2006, to December 31, 2015, with triglyceride levels of 400 to 799 mg/dL. Data analysis was performed from November 9, 2020, to March 23, 2021. Main Outcomes and Measures Accuracy in LDL-C classification according to guideline-based categories and absolute errors between estimated LDL-C and dLDL-C levels. Patients were randomly assigned 2:1 to derivation and validation data sets. Levels of dLDL-C were measured by vertical spin-density gradient ultracentrifugation. The LDL-C levels were estimated using the Friedewald method, with a fixed ratio of triglycerides to very low-density lipoprotein cholesterol (VLDL-C ratio of 5:1), extended Martin/Hopkins equation with a flexible ratio, and Sampson equation with VLDL-C estimation by multiple least-squares regression. Results A total of 111 939 patients (mean [SD] age, 52 [13] years; 65.0% male) with triglyceride levels of 400 to 799 mg/dL were included, representing 2.2% of 5 081 680 patients in the database. Across all individual guideline LDL-C classes (, This cross-sectional study of patients with lipid distributions representative of the US population compares the accuracy of 3 low-density lipoprotein level estimation methods with triglyceride levels of 400 to 799 mg/dL.

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.

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.

SummaryAs health studies increasingly monitor free-living heart performance via ECG patches with accelerometers, researchers will seek to investigate cardio-electrical responses to physical activity and sedentary behavior, increasing demand for fast, scalable methods to process accelerometer data. We provide the first published analysis of tri-axial accelerometry data from Zio XT patch and introduce an extension of posture classification algorithms for use with ECG patches worn in the free-living environment. Our novel extensions to posture classification include (1) estimation of an upright posture for each individual without the reference measurements used by existing posture classification algorithms; (2) correction for device removal and re-positioning using novel spherical change-point detection; and (3) classification of upright and recumbent periods using a clustering and voting process rather than a simple inclination threshold used in other algorithms. Methods were built using data from 14 participants from the Multicenter AIDS Cohort Study (MACS), and applied to 1, 250 MACS participants. As no posture labels exist in the free-living environment, we evaluate the algorithm against labelled data from the Towson Accelerometer Study and against data labelled by hand from the MACS study.

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.

Aims Whether isolated diastolic hypertension (IDH), as defined by the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline, is associated with cardiovascular disease (CVD) has been disputed. We aimed to further study the associations of IDH with (i) subclinical CVD in the form of coronary artery calcium (CAC), (ii) incident systolic hypertension, and (iii) CVD events. Methods and results We used multivariable-adjusted logistic and Cox regression to test whether IDH by 2017 ACC/AHA criteria (i.e. systolic blood pressure 0 of 0.88 (95% CI 0.66, 1.17)]. Similarly, while IDH was associated with incident systolic hypertension, there was no statistically significant associations with incident CVD [hazard ratio 1.19 (95% CI 0.77, 1.84)] or death [hazard ratio 0.94 (95% CI 0.65, 1.36)] over 13 years in MESA. In a stratified meta-analysis of eight cohort studies (10 037 843 participants), the 2017 IDH definition was also not consistently associated with CVD and the relative magnitude of any potential association was noted to be numerically small [e.g. depending on inclusion criteria applied in the stratification, the adjusted hazard ratios ranged from 1.04 (95% CI 0.98, 1.10) to 1.09 (95% 1.03, 1.15)]. Conclusion The lack of consistent excess in CAC or CVD suggests that emphasis on healthy lifestyle rather than drug therapy is sufficient among the millions of middle-aged or older adults who now meet the 2017 ACC/AHA criteria for IDH, though they require follow-up for incident systolic hypertension. These findings may not extrapolate to adults younger than 40 years, motivating further study in this age group.

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)

Background Sex differences in the incidence and manifestation of cardiovascular disease (CVD) suggest the involvement of sex hormones in disease pathogenesis. Coronary artery calcium (CAC) and its progression, measured by non-contrast cardiac computed tomography, are markers of subclinical atherosclerosis and predict CVD, even among low-risk women. We hypothesized that sex hormone levels were associated with CAC progression among women in the Multi-Ethnic Study of Atherosclerosis. Methods We studied 2759 post-menopausal women (age 65 ± 9 years), free of baseline CVD, with baseline serum sex hormones and CAC measured at Exam 1 (2000–2002). Of this sample, 2427 had ≥1 follow-up CAC measurement through Exam 5 (2010–2012). Using mixed effects linear regression methods, we tested change in log[CAC+1] score by log[sex hormone] levels (continuous, comparing the 90th versus 10th percentiles). Models adjusted for demographics, lifestyle factors, cardiovascular risk factors, hormone therapy, and years since menopause. Results At baseline, we found no associations between sex hormones and prevalent CAC. Over a median of 4.7 years, in fully-adjusted models, women with higher free testosterone levels had relatively greater CAC progression [Ratio 1.26 (95% CI 1.01–1.56)], whereas higher sex hormone binding globulin (SHBG) was associated with lower progression risk [0.80 (0.64–0.99). No associations were seen for total testosterone, estradiol, or dehydroepiandrosterone. Conclusion A more androgenic hormone profile of higher free testosterone and lower SHBG is associated with a greater CAC progression up to 10-years in post-menopausal women. Sex hormone levels may help identify women at increased risk for CVD who may benefit from additional risk-reducing strategies.

Introduction: Cardiovascular risk factors are associated with cognitive decline and dementia. Brain magnetic resonance imaging (MRI) provides sensitive measurement of cerebral atrophy and small vessel disease, reflecting multiple pathologies leading to dementia. However, large brain MRI studies include primarily white participants. We investigated associations in the diverse Multi-Ethnic Study of Atherosclerosis (MESA). Hypothesis: Cardiovascular and sociodemographic risk factors are associated with brain morphology and white matter injury in a racially and ethnically diverse population. Methods: In MESA, brain MRI was performed in 2018-2019 with automated measurement of total brain volume, gray and white matter (GM, WM) volume, and measures of WM injury including WM lesion volume, WM fractional anisotropy, and WM apparent diffusion coefficient. In cross-sectional analyses, we assessed the association of race/ethnicity with MRI measures, with and without adjustment for cardiovascular risk factors, education, and socioeconomic status. In a multivariable model, we assessed the association of cardiovascular risk factors with brain MRI measures. All analyses of volumes, including WM lesion volume, were adjusted for total intracranial volume. Results: MRI data were complete in 1,051 participants; 40% were white, 15% Chinese-American, 25% African-American, and 20% Hispanic. Mean (standard deviation, SD) age was 73 (8) years and 53% of participants were women. Adjusted for age and sex, African-American participants had slightly greater total brain and WM volume than white participants. Adjusted for age and sex, African-American participants had on average more WM injury than whites as measured by higher WM lesion volume (46.7% higher, 95% CI: 19.9, 79.4%) and lower fractional anisotropy (-0.20 SD, 95% CI: -0.34, -0.05); these associations were attenuated after additional adjustment for cardiovascular risk factors and socioeconomic status (24.3% higher WM lesion volume, 95% CI: 0.0, 54.3; -0.06 SD fractional anisotropy, 95% CI: -0.22, 0.09). Conversely, all non-white race/ethnic groups had slightly less WM injury than white participants as estimated by apparent diffusion coefficient. Overall, greater age, diabetes, current smoking, high systolic blood pressure, and treated hypertension were strongly associated with more WM injury; in addition, age and diabetes were strongly associated with lower brain volumes. Conclusions: We found little evidence of differences in measures of brain atrophy and WM injury by race/ethnicity after adjustment for cardiovascular risk factors and socioeconomic status. Findings of differences by race/ethnicity in apparent diffusion coefficient are intriguing and need further investigation. Consistent with previous studies, age, diabetes, current smoking and hypertension were strongly and consistently associated with WM injury.

Introduction: Diabetes and metabolic syndrome (MetS) confer an increased risk of heart failure (HF) through poorly understood mechanisms. Galectin-3 (Gal-3) is a marker of fibrosis linked to greater HF risk. The inter-relationships among diabetes, MetS and Gal-3, and related implications for HF risk, are not well understood. Hypothesis: Diabetes and MetS are associated with elevated Gal-3, and high Gal-3 indicates greater HF risk among those with diabetes or MetS. Methods: We included 8,445 participants (mean age 63, 59% male, 21% Black) at ARIC Visit 4 (1996-1999) without baseline HF. We categorized participants by metabolic risk (no diabetes/no MetS; MetS only; diabetes with or without MetS), and Gal-3 levels (gender-specific quartiles). We assessed the associations of metabolic risk categories with high Gal-3 (≥75 th percentile) using logistic regression. We used Cox regression to evaluate associations of cross-categories of metabolic risk group and Gal-3 quartiles with incident HF. Results: In cross-sectional analyses, those with MetS were more likely to have elevated Gal-3 levels than those with no diabetes or MetS (OR 1.29, 95%CI 1.13-1.47). The additional presence of diabetes did not change the likelihood of elevated Gal-3 (OR 1.29, 95%CI 1.08-1.55). Over 20.5 years of follow-up, there were 1,611 HF events. Higher Gal-3 was associated with higher HF risk in each metabolic risk group, and higher metabolic risk group was associated with greater HF risk in each Gal-3 quartile. There was no interaction between Gal-3 and metabolic risk group on HF risk ( P =0.15). The combination of diabetes &MetS and high Gal-3 was associated with an almost 5-fold higher risk of incident HF (HR 4.93; 95% CI: 3.77 - 6.44) than the combination of no diabetes/MetS and low Gal-3 (first quartile) ( Table ). Conclusions: MetS was associated with higher levels of Gal-3. Metabolic risk group and Gal-3 provided powerful complementary prognostic information regarding HF risk. Fibrosis likely plays a role in the development of HF linked to metabolic risk.

Background: The metabolites associated with a Mediterranean-style (AMED) diet may give insight into why AMED is robustly associated with protection against CVD. Previous investigations seeking to identify these have been limited by the use of modest sample sizes and targeted assays. Methods: Using samples from the Multi-Ethnic Study of Atherosclerosis (MESA), we conducted untargeted 1 H NMR spectroscopy (600 MHz) with internal and external annotation on the sera of ~3,698 participants, ages 45-84, who were free from overt CVD. We included data on baseline dietary intake (self-reported), and all incident CVD events (excluding stroke) over a 10-year period. From >100,000 spectral features, 845 significant associations (P-6 ) were identified via linear regression, and reduced to a putative list of 46 via elastic net regularized models. Hierarchical clustering identified 11 feature groups, from which cluster scores were constructed. The ‘mediate’ package in R used bootstrapping (1000 simulations) to partition the association between AMED and incident CVD into the effects of dietary intake on CVD which are mediated by the metabolomic cluster scores (the “indirect” / mediated effects) and those effects which are not (“direct effects”). All association analyses controlled for age, sex, ethnicity, data collection site and daily caloric intake. Results: AMED score was associated with reductions in the incidence of CVD (HR=0.95; 95% CI: 0.91 - 0.99; P=0.02). All metabolomic cluster scores were associated with AMED (all P-06 ; Table 1 ), with 6 significantly associated with incident CVD (all P-4 ) in the expected direction given their associations with AMED score. Four of these six significantly mediated the association of AMED score with incident CVD (PTable 1 ). Conclusions: These preliminary data suggest that specific molecules, if replicated in other studies, hold promise to identify the underlying pathways by which an AMED diet offers protection against CVD.

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 structure and function with 6MWD are unclear, and may provide insight regarding the risk of incident HF. OBJECTIVES: To understand the relationships between cardiac function and exercise capacity. METHODS: We evaluated the associations of cardiac mechanics with 6MWD in the 6(th) exam of the Multi-Ethnic Study of Atherosclerosis. Two-dimensional, Doppler and speckle-tracking echocardiography 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, 48% male, 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% CI: −8.8, −1.3 meters; P=0.009), inability to augment LA reservoir strain after passive leg raise (β coefficient per SD decrease: −5.8, 95% CI: −9.1, −2.5 meters; P

Aims Traditional atherosclerotic cardiovascular disease (ASCVD) risk factors fail to address the full spectrum of the complex interplay of atherosclerotic and atherothrombotic factors integral to ASCVD events. This study sought to examine the association between atherothrombotic biomarkers and ASCVD events. Methods and results The association between atherothrombotic biomarkers and 877 ASCVD events with and without adjustment for traditional risk factors was evaluated via Cox proportional hazards models and factor analysis in 5789 Multi-Ethnic Study of Atherosclerosis participants over a median follow-up of 14.7 years. Factor analysis accounted for multidimensional relationship and shared variance among study biomarkers, which identified two new variables: a thrombotic factor (Factor 1), principally defined by shared variance in fibrinogen, plasmin–antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a), and a fibrinolytic factor (Factor 2), principally defined by shared variance of plasminogen and oxidized phospholipids on plasminogen. In a model including both factors, the thrombotic factor was associated with the higher risk of ASCVD events [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.45, 1.70], while the fibrinolytic factor was associated with the lower risk of ASCVD events (HR 0.76, 95% CI 0.70, 0.82), with estimated ASCVD free survival highest for low atherothrombotic Factor 1 and high atherothrombotic Factor 2. Conclusion Two atherothrombotic factors, one representative of thrombotic propensity and the other representative of fibrinolytic propensity, were significantly and complementarily associated with incident ASCVD events, remained significantly associated with incident ASCVD after controlling for traditional risk factors, and have promise for identifying patients at high ASCVD event risk specifically due to their atherothrombotic profile.

ObjectivesTestosterone usage (T-use) may alter risk factors for sudden cardiac death in men living with HIV (MLWH). Electrocardiographic QT interval prolongation, which could potentiate ventricular arrhythmias, has previously been associated with HIV infection and, separately, with low testosterone levels. We investigated whether T-use shortens the QT interval duration in MLWH and HIV-uninfected men.MethodsWe utilized data from the Multicenter AIDS Cohort Study, a prospective, longitudinal study of HIV infection among men who have sex with men. Multivariable linear regression analyses were used to evaluate associations between T-use and corrected QT interval (QTc) duration.ResultsTestosterone usage was more common in MLWH compared with HIV-uninfected men (19% vs. 9%). In a multivariable regression analysis, T-use was associated with a 5.7ms shorter QT interval [95% confidence interval (CI): -9.5 to -1.9; P=0.003). Furthermore, stronger associations were observed for prolonged duration of T-use and recent timing of T-use.ConclusionsThis study is the first known analysis of T-use and QTc interval in MLWH. Overall, our data demonstrate that recent T-use is associated with a shorter QTc interval. Increased T-use duration above a threshold of ≥50% of visits in the preceding 5years was associated with a shorter QTc interval while lesser T-use duration was not.

PURPOSE OF REVIEW: This review focuses on lipoprotein abnormalities in South Asians (SA) and addresses risk stratification and management strategies to lower atherosclerotic cardiovascular disease (ASCVD) in this high-risk population. RECENT FINDINGS: South Asians (SAs) are the fastest growing ethnic group in the United States (U.S) and have an increased risk of premature coronary artery disease (CAD). While the etiology may be multifactorial, lipoprotein abnormalities play a key role. SAs have lower low-density lipoprotein cholesterol (LDL-C) compared with Whites and at any given LDL-C level, SA ethnicity poses a higher risk of myocardial infarction (MI) and coronary artery disease (CAD) compared with other non-Asian groups. SAs have lower high-density lipoprotein cholesterol (HDL-C) with smaller particle sizes of HDL-C compared with Whites. SAs also have higher triglycerides than Whites which is strongly related to the high prevalence of metabolic syndrome in SAs. Lipoprotein a (Lp(a)) levels are also higher in SAs compared with many other ethnic groups. This unique lipoprotein profile plays a vital role in the elevated ASCVD risk in SAs. Studies evaluating dietary patterns of SAs in the U.S show high consumption of carbohydrates and saturated fats. SUMMARY: SAs have a high-risk lipoprotein profile compared with other ethnicities. Lipid abnormalities play a central role in the pathogenesis of CAD in SAs. More studies are needed to understand the true impact of the various lipoproteins and their contribution to increasing ASCVD in SAs. Aggressive lowering of LDL-C in high-risk groups using medications, such as statins, and lifestyle modification including dietary changes is essential in overall CAD risk reduction.

Background Obesity and sarcopenia are associated with mortality in chronic obstructive pulmonary disease (COPD). Routine chest CT examinations may allow assessment of obesity and sarcopenia by soft-tissue markers for predicting risks of mortality. Purpose To investigate associations between soft-tissue markers subcutaneous adipose tissue (SAT), intermuscular adipose tissue (IMAT), and pectoralis muscle (PM) index from chest CT with mortality in participants with COPD. Materials and Methods In this secondary analysis of a prospectively enrolled cohort from the Multi-Ethnic Study of Atherosclerosis, participants with available chest CT in 2010-2012 were included. CT examinations were analyzed to determine SAT, IMAT (within PM), and PM areas. The spirometry evaluations were used to establish COPD diagnosis. Mortality data were extracted from the National Death Index (April 2010 to December 2017). The correlations of the soft-tissue markers with fat mass index were studied. The associations of these markers and risks of mortality in participants with COPD were assessed by using Cox proportional-hazard models adjusted for confounders. Results Among 2994 participants who were included (mean age, 69 years ± 9 [standard deviation]; 1551 women), 265 had COPD (9%; mean age, 72 years ± 9; 162 men) and 49 participants with COPD (18%) died during follow-up. The SAT, IMAT, and PM areas had moderate-to-excellent reliabilities (intraclass correlation coefficient, 0.88-0.99). In the 2994 participants, the SAT (ρ = 0.80; 95% CI: 0.78, 0.81; P < .001) and IMAT indexes (ρ = 0.37; 95% CI: 0.34, 0.41; P < .001) were correlated with fat mass index. Those with COPD and higher SAT index had lower risks of mortality (hazard ratio, 0.2; 95% CI: 0.1, 0.4; P < .001, per doubling), whereas a higher IMAT index was associated with a higher risk of mortality (hazard ratio, 1.4; 95% CI: 1.0, 1.9; P = .04, per doubling). Conclusion Soft-tissue markers were reliably obtained by using chest CT performed for lung assessment. In participants with chronic obstructive pulmonary disease, a high intermuscular adipose tissue index was associated with a higher risk of mortality than was a high subcutaneous adipose tissue index. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Sverzellati and Cademartiri in this issue.

OBJECTIVE: The 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, 58% female, 22% Black) at ARIC Visit 4 (1996-1998) without HF or coronary heart disease (CHD). We calculated diabetes duration at Visit 4 (baseline), utilizing diabetes status at the first four 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 CHD and other risk factors. We performed analyses stratified by age (

Background We aimed to investigate whether there are differences in cardiac structure and systolic and diastolic function evaluated by 2‐dimensional echocardiography among men living with versus without HIV in the era of combination antiretroviral therapy. Methods and Results We performed a cross‐sectional analysis of 1195 men from MACS (Multicenter AIDS Cohort Study) who completed a transthoracic echocardiogram examination between 2017 and 2019. Associations between HIV serostatus and echocardiographic indices were assessed by multivariable regression analyses, adjusting for demographics and cardiovascular risk factors. Among men who are HIV+, associations between HIV disease severity markers and echocardiographic parameters were also investigated. Average age was 57.1±11.9 years; 29% of the participants were Black, and 55% were HIV+. Most men who were HIV+ (77%) were virally suppressed; 92% received combination antiretroviral therapy. Prevalent left ventricular (LV) systolic dysfunction (ejection fraction 3 versus Conclusions HIV seropositivity was independently associated with greater LV mass index, left atrial and RV sizes, lower RV function and diastolic abnormalities, but not left ventricular ejection fraction, which may herald a future predisposition to heart failure with preserved ejection fraction among men living with HIV.

Purpose: Cyclic guanosine monophosphate (cGMP) is a second messenger for natriuretic peptide (NP) and nitric oxide pathways; its enhancement a target for heart failure and cardiovascular disease (CVD). We evaluated whether plasma cGMP was associated with change in left ventricular mass (LVM) among individuals free of CVD and if this differed by sex. Methods and Results: In 611 men and 612 women aged 45–84 years with plasma cGMP measured at baseline and cardiac MRI performed at baseline and 10 years later, we tested associations of cGMP [log-transformed, per 1 SD increment] with LVM, adjusting for CVD risk factors and N-terminal pro-B-type-NP (NT-proBNP). Participants had mean (SD) age of 63.1(8.5) years and cGMP 4.8(2.6) pmol/mL. Cross-sectionally, higher cGMP was associated with lesser LVM, non-lin- early. In contrast, longitudinally, higher cGMP was associated with increase in LVM [1.70g (0.61, 2.78)] over 10 years. Higher cGMP was associated with greater LVM change in men [2.68g (1.57, 3.79)] but not women [0.24g ((−0.92, 1.39); p-interaction < 0.001]. Conclusion: In conclusion, in a community-based cohort, higher cGMP levels were associated with increase in LVM over 10 years independent of CVD risk factors and NT-proBNP in men, perhaps reflecting compensatory changes. Further studies are needed to understand mechanistic roles of cGMP in LV remodelling and associated sex differences.

The Go Red for Women movement was initiated by the American Heart Association (AHA) in the early 2000s to raise awareness concerning cardiovascular disease (CVD) risk in women. In 2016, the AHA funded 5 research centers across the United States to advance our knowledge of the risks and presentation of CVD that are specific to women. This report highlights the findings of the centers, showing how insufficient sleep, sedentariness, and pregnancy‐related complications may increase CVD risk in women, as well as presentation and factors associated with myocardial infarction with nonobstructive coronary arteries and heart failure with preserved ejection fraction in women. These projects were augmented by collaborative ancillary studies assessing the relationships between various lifestyle behaviors, including nightly fasting duration, mindfulness, and behavioral and anthropometric risk factors and CVD risk, as well as metabolomic profiling of heart failure with preserved ejection fraction in women. The Go Red for Women Strategically Focused Research Network enhanced the evidence base related to heart disease in women, promoting awareness of the female‐specific factors that influence CVD.

Background High levels of supraventricular ectopy are associated with greater risk of atrial fibrillation, stroke, and death. Little information is available about differences by race/ethnicity in the extent of supraventricular ectopy, or about whether high levels of supraventricular ectopy are associated with impaired left atrial (LA) function and LA enlargement. Methods and Results In the MESA (Multi‐Ethnic Study of Atherosclerosis), 1148 participants (47% men; mean age, 67 years) had cardiovascular magnetic resonance imaging in 2010 to 2012, followed by 14‐day ambulatory electrocardiographic monitoring in 2016 to 2018. We analyzed participant characteristics and cardiovascular magnetic resonance measures of LA function and structure in relation to average count of premature atrial contractions (PACs) per hour and average number of runs per day of supraventricular tachycardia. In adjusted regression analyses, older age, male sex, White race, elevated NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), and a history of clinically detected atrial fibrillation were associated with more PACs/hour. Chinese and Hispanic participants had on average fewer PACs/hour than White participants (Chinese participants, 31% less [95% CI, 8%–49%]; Hispanic participants, 38% less [95% CI, 19%–52%]). Greater LA total emptying fraction was associated with fewer PACs/hour (per SD, 16% fewer PACs/hour [95% CI, 7%–25% fewer PACs/hour]). Larger LA minimum volume was associated with more PACs/hour (per SD, 7% more PACs/hour [95% CI, 2%–13% more PACs/hour]). Associations of LA volumes with runs of supraventricular tachycardia/day were similar in direction but were weaker. Conclusions Impaired LA function and LA enlargement were associated with more PACs/hour on extended ambulatory electrocardiographic monitoring. Measurement of supraventricular ectopy may provide information about the extent of atrial myopathy.

“At MESA Exam 6, the age-adjusted prevalence of AS is lower in Black (1.8%) and Chinese (0.3%) compared to Hispanic (3.7%) and White participants (3.5%).”

Objective Most previous studies have examined associations between metabolic disorders measured at a single point in time and risk of heart failure (HF). However, there are many situations where the values of exposures vary over time before HF occurs. We aimed to examine the associations of time-varying obesity and metabolic syndrome (MetSyn) measured at multiple points in time with HF. Methods A total of 6750 participants in the Multi-Ethnic Study of Atherosclerosis from 2000 were included in the study. Follow-up was completed through December 2015. MetSyn was defined using the American Heart Association criteria. Incident HF was diagnosed by clinical criteria. Subtypes HF (reduced ejection fraction (HFrEF) and preserved (HFpEF) were classified by left ventricular EF. Results A total of 331 HF cases were identified during 82,609 person-years of observation. The incidence (95%CI) of total HF was 4.0 (3.4–4.4) per 1000 person-years. Of the total HF cases, 45.6% were HFrEF (n = 151), 40.8% HFpEF (n = 135), and 13.6% were unclassified HF subtypes (n = 45). After adjusting for key covariates, time-varying obesity (BMI ≥ 30 kg/m2) and MetSyn were significantly associated with HF, with a stronger association for HFpEF than for HFrEF. The corresponding hazards ratios (HR, 95%CI) were 1.97 (1.43–2.72) and 1.86 (1.43–2.42) for HFpEF, and 1.46 (1.07–1.98), and 1.39 (1.06–1.82) for HFrEF respectively. Time-varying large waist circumference was significantly associated with for HFpEF, but not with HFrEF. Conclusion Time-varying obesity and MetSyn were significantly associated with HF risk, with a stronger association with HFpEF than with HFrEF. Continued effort to control these risk factors is recommended.

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

Introduction: Calcific aortic valve disease is the most common valve disorder affecting >5 million US adults. The underlying pathobiology for the early stages of aortic valve calcification (AVC) and coronary artery calcium (CAC) includes many shared ASCVD risk factors, but a considerable proportion of individuals with significant AVC have little to no CAC. Hypothesis: Among persons with significant AVC (>100 AU), those with a low CAC burden (CAC Methods: After excluding 2 persons with bicuspid aortic valve, 325 participants from the Multi-Ethnic Study of Atherosclerosis without clinical ASCVD and with AVC >100 at Visit 1 (2000-02) were included (34% women, 23% African American). We used Poisson regression to calculate adjusted prevalence ratios for CAC 100, using traditional and novel ASCVD risk markers. Results: Participants had a mean age of 72.1 years and 133 (41%) had CAC Conclusions: More than 40% of persons with significant AVC had a low burden of CAC, which is incompletely explained through traditional and novel ASCVD risk markers. These results suggest that unmeasured risk markers, genetics, and/or the non-ASCVD pathways of later stage AVC may be more important in understanding the observed discordance between AVC and CAC.

Introduction: The left atrium (LA) and left ventricle (LV) parameters have both prognostic value for cardiovascular (CV) events. We hypothesize the left atrioventricular coupling to be a strong predictor of CV events. Hypothesis: This study aimed to investigate the prognostic value of a novel left atrioventricular coupling index (LACI) and to assess its predictive value for CV events in a population without a history of CV diseases at baseline. Methods: A total of 4,124 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) underwent a cardiac MRI study. The LACI was defined by the ratio of the LA end-diastolic volume divided by the LV end-diastolic volume by MRI. Cox proportional hazard models were built to predict the endpoints of atrial fibrillation (AF), heart failure (HF), CV death and hard CV disease (CVD) defined by myocardial infarction, resuscitated cardiac arrest, fatal and non-fatal stroke or CV death. In univariable and multivariable Cox analyses, the association between LACI and time-to-event was analysed, adjusting for 14 covariables including traditional CV risk factors and biomarkers. Results: A total of 1151 CV events were observed during a median (IQR) follow-up period of 15.9 (12.9-16.6) years. LACI was associated with AF (HR 2.14, 95%CI [1.97-2.32]), HF (HR 1.70, 95%CI [1.56-1.86]), hard CVD (HR 1.34, 95%CI [1.22-1.48]), and CV death (HR 1.53, 95%CI [1.38-1.70]; for all p Conclusions: The LACI is a predictor of incident HF, AF, hard CV disease, and CV death in MESA.

Introduction: Tracheobronchial calcification (TBC), is a readily available potential biomarker in non-contrast chest CT scans, including cardiac calcium scan CTs. However, there is a paucity in literature investigating how this measure contributes to CVD risk prediction. Hypothesis: TBC is associated with CVD and mortality events independent from CAC score. Methods: Available non-contrast chest CT images from Johns Hopkins Hospital field center within the fifth exam of the MESA cohort (2010-2012) were re-analyzed as part of the MESArthritis ancillary study. The calcifications observed in the wall of tracheobronchial tree were measured from aortic arch to carina, by calcium scoring package (VScore, Vitrea 7.11, Vital Images). Outlier values were excluded using the Interquartile range-based outlier fence estimates. Association of TBC with cardiovascular risk factors was investigated by linear regression models. Cox proportional hazard models were applied for CVD and mortality event prediction by TBC with and without adjustment for age, gender, race, CAC, and Framingham global CVD risk score (FRS). Results: After exclusion of 39 outliers, a total of 382 participants (51.2% female) with a mean age of 69.9 (±8.82) were included. TBC was associated with age (β=3.26, p:.002), gender (β=96.30, p Conclusions: Quantification of calcifications in tracheobronchial area can be used to predict CHD, CVD and all-cause mortality and augment the predictive power of the highly validated CAC and FRS for CHD events.

Background: The development of metabolic syndrome (MetS) and diabetes among those with obesity varies by age, sex, race and socioeconomic status (SES) and is associated with increased heart failure (HF) risk. There are limited data about whether the HF burden related to these metabolic risk factors differs across demographic groups. Hypothesis: There is significant variation in the proportion of HF events attributable to obesity-associated metabolic risk factors across demographic groups. Methods: We studied 10,133 white and black participants at ARIC Visit 4 (1996-98) without baseline HF. Age was categorized as < or ≥65 yrs and SES categorized as low, medium or high based on education, income, and area deprivation index. MetS was defined by AHA/NHLBI criteria. HF follow-up was through 2018. Individuals with obesity (BMI ≥30kg/m 2 ) were grouped as: no MetS or diabetes, MetS alone, or both MetS and diabetes (highest metabolic risk). Across demographic strata, we assessed: metabolic risk group prevalences; hazard ratios (HRs) for HF associated with each metabolic risk group (Cox regression); and the population attributable risk (PAR) for HF associated with metabolic risk factors in those with obesity. Results: Those with age ≥65, male sex, black race and low SES were more likely to be in the highest metabolic risk group ( Table ). Over 20 years (N= 2,194 events), compared to normal weight without MetS or diabetes, the highest metabolic risk was associated with 3-5 fold higher HF risk in all subgroups. Stronger HF associations were seen for those < vs ≥65 years (p interaction Conclusion: There are important demographic differences in the burden of HF related to metabolic risk factors. Addressing disparities in the HF impact of metabolic risk factors is critical to efforts to improve health equity.

Introduction: Costal cartilage calcification (CCC) is an evident yet usually neglected finding in calcium scoring CT scans. Although CAC score is a well-known predictive marker for CVD, little is known about the potential association between CCC and CVD risk factors (RFs) and events. Hypothesis: CCC is associated with CVD RFs and is predictive of CVD events independent from CAC score. Methods: Cardiac CAC score images from Johns Hopkins Hospital field center acquired within the fifth exam of the MESA cohort (2010-2012) were re-analyzed as part of the MESArthritis ancillary study. The CCC was measured bilaterally for the first pair of cartilages at the superior end of image FOVs using calcium scoring package (VScore, Vitrea 7.11, Vital Images) with a 180 HU cut-off. Outlier values were excluded using the IQR-based outlier fence estimates. Association of CCC with CVD RFs, and CVD and mortality time-to-event was investigated by multivariable linear regression and Cox proportional hazard models, respectively. Results: After exclusion of 3 outliers, 329 participants (53% female) with a mean age of 70.1 (±8.75) were included. In cross-sectional analysis, in addition to age (β=8.86, p:.003) and gender (376.0, p Conclusions: CCC is associated with diabetes and can be used to predict CHD and CVD events and augment the predictive power of the highly validated CAC and FRS for CHD events. However, this scoring should be validated in other larger cohorts.

ObjectivesAntiretroviral therapy (ART) use is associated with disrupted lipid and glucose metabolism in people with HIV-infection. We aimed to identify plasma lipid species associated with risk of diabetes in the context of HIV infection.Research Design and MethodsWe profiled 211 plasma lipid species in 491 HIV-infected and 203 HIV-uninfected participants aged 35-55 years from the Women’s Interagency HIV study and the Multicenter AIDS Cohort Study. Cox proportional hazards model was used to examine associations between baseline lipid species and incident diabetes (166 diabetes cases were identified during a median follow-up of 12.6 years).ResultsWe identified 11 lipid species, representing independent signals for 8 lipid classes/subclasses, associated with risk of diabetes (PConclusionsThis study identified multiple plasma lipid species associated with incident diabetes. Regardless of the directions of their associations with diabetes, most diabetes-associated lipid species were elevated in ART-treated people with HIV-infection. This suggests a complex role of lipids in the link between ART and diabetes in HIV infection.

Background and aimsSouth Asians are at increased risk for cardiovascular disease (CVD). Aortic valve calcium (AVC) is associated with CVD risk and aortic stenosis. Elevated Lp(a) is a heritable risk factor for CVD and AVC. AVC prevalence and its association with Lp(a) have not been studied in South Asians.MethodsAmong participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study (n=695), AVC prevalence and extent were compared to four race/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (MESA) (n=4671). Multivariable regression was performed to evaluate associations between Lp(a) and AVC stratified by race/ethnic groups, adjusting for cardiovascular risk factors.ResultsAfter age and sex adjustment, South Asians had higher median Lp(a) (17.0mg/dL) compared to Whites (12.9mg/dL), Hispanics (13.1mg/dL) and Chinese Americans (12.9mg/dL), and Blacks had highest Lp(a) levels (35.1mg/dL). There were no differences in the odds of AVC in South Asians compared with Whites or Hispanics, after age and sex adjustment (p=0.64 and 0.63, respectively). Odds of AVC was lower in Chinese (OR 0.35; 95%CI 0.23-0.54) and somewhat lower in Blacks compared with South Asians (OR 0.76; 0.56-1.04). There were no associations between Lp(a) and AVC presence or extent in South Asians. Lp(a) was associated with AVC only among Blacks and Whites.ConclusionsAlthough present in Whites and Blacks, there were no associations between Lp(a) and AVC in South Asians. These differences may be due to statistic power or race specific modifying factors that influences the effect of Lp(a) particles on AVC pathogenesis.

Objective:Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at theLPAlocus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels.Approach and Results:We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance(P≤5×10-8). In addition to validating previous associations atLPA,APOE, andCETP, we identified a novel variant at theAPOHlocus, encoding β2GPI (beta2-glycoprotein I). TheAPOHvariant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047–0.081];P=2.8×10-13) and demonstrated a stronger effect after adjustment for variation at theLPAlocus (β [95% CI] [ln nmol/L], 0.089 [0.076–0.10];P=3.8×10-42). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044–0.28];P=0.0071).Conclusions:In a large-scale genome-wide association study of Lp(a) levels, we identifiedAPOHas a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop 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 applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.