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Objective: Coronary artery, aortic valve, and descending aorta calcification (CAC, AVC, DAC) are manifestations of atherosclerosis, and cardiac epicardial adipose tissue (EAT) indicates heart adiposity. This study explored the association between cardiac adipose tissue and cardiovascular calcification in participants with long-standing T1D. Methods: EAT and intra-thoracic adipose tissue (IAT) were measured in 100 T1D subjects with cardiac computed tomography (CT) scans in the EDIC study. Volume analysis software was used to measure fat volumes. Spearman correlations were calculated between CAC, AVC, DAC with EAT, and IAT. Associations were evaluated using multiple linear and logistic regression models. Results: Participants ranged in age from 32 to 57. Mean EAT, and IAT were 38.5 and 50.8 mm3, respectively, and the prevalence of CAC, AVC, and DAC was 43.6 %, 4.7 %, and 26.8 %, respectively. CAC was positively correlated with age (p-value = 0.0001) and EAT (p-value = 0.0149) but not with AVC and DAC; IAT was not associated with calcified lesions. In models adjusted for age and sex, higher levels of EAT and IAT were associated with higher CAC (p-value < 0.0001 for both) and higher AVC (p-values of 0.0111 and 0.0053, respectively), but not with DAC. The associations with CAC remained significant (p-value < 0.0001) after further adjustment for smoking, systolic blood pressure, BMI, and LDL, while the associations with AVC did not remain significant. Conclusion: In participants with T1D, higher EAT and IAT levels are correlated with higher CAC scores. EAT and IAT were not independently correlated with DAC or AVC.

Therapeutic Area: ASCVD/CVD Risk Assessment Background: Low socioeconomic status (SES) is associated with atherosclerotic cardiovascular disease (ASCVD) and possible underestimation of risk by pooled cohort equations (PCE). Whether coronary artery calcium (CAC) scores can improve risk discrimination in low SES populations is unknown. Methods: Multi-Ethnic Study of Atherosclerosis (MESA) and Dallas Heart Study (DHS) participants free of ASCVD and with CAC scans were evaluated. Low SES was defined as annual household income $30,000) or educational attainment HS). The relationships between SES, CAC scores (0, 1-99, ≥100), and ASCVD events (fatal/non-fatal MI or stroke) were assessed before/after ASCVD risk factor adjustment (Table). The incremental predictive value of CAC across SES groups was assessed using c-statistics and categorical net reclassification improvement (NRI) ($30K comprised 19.1%, 18.4%, and 62.5%, and 18.2%, 22.4%, and 59.4% of the study populations, respectively. Individuals with low SES by income ($30K) [HRadj 1.38 (95% CI 1.14-1.54) MESA; HRadj 2.52 (1.65-3.85) DHS]. Higher CAC scores were associated with greater 10-year ASCVD risk in each SES category, but the low SES group had the greatest ASCVD risk with CAC=0 (4.9% MESA; 4.3% DHS). CAC scores were independently associated with ASCVD risk among low SES individuals in MESA but not in DHS [CAC>0 vs. 0 HRadj 2.38 (1.64-3.45) MESA; HRadj 1.09 (0.43-2.76) DHS]. Overall, the discriminative ability of CAC for ASCVD was smallest in low SES individuals (c-statistics 0.643 vs. 0.685, 0.711 MESA; 0.680 vs. 0.790, 0.806 DHS) (Table). The addition of CAC to PCE for low SES individuals yielded the smallest incremental improvement in c-statistic and NRI. Defining SES by education yielded similar results. Conclusions: Individuals with low SES have significantly higher ASCVD risk. CAC scores may predict this risk, but have lower ASCVD risk discrimination in this group, and CAC=0 provides less reassurance compared to those at higher SES. These results can assist in determining applications of CAC scanning in those with low SES.

South Asian (SA) individuals, particularly those that reside in the United States and other Westernized countries, are at an elevated risk for ASCVD and mortality related to ASCVD. The 2018 ACC/AHA/Multi-society Cholesterol guideline listed SA as a high-risk ethnicity, underscoring the importance of treating modifiable risk factors to reduce ASCVD burden. Coronary artery calcium (CAC), a highly specific marker of subclinical atherosclerosis, may be a useful test to improve risk stratification among SA individuals. CAC testing is a cost-effective, highly reproducible, and specific marker of subclinical atherosclerosis, shown to improve ASCVD risk assessment across all racial/ethnic groups, thereby serving as a guide for initiating or deferring preventive therapies. In this White Paper we will discuss the use of CAC scoring to optimize risk stratification and delivery of preventive therapies to individuals of SA ethnicity.

Rationale and objectives: We previously reported a novel manual method for measuring bone mineral density (BMD) in coronary artery calcium (CAC) scans and validated our method against Dual X-Ray Absorptiometry (DEXA). Furthermore, we have developed and validated an artificial intelligence (AI) based automated BMD (AutoBMD) measurement as an opportunistic add-on to CAC scans that recently received FDA approval. In this report, we present evidence of equivalency between AutoBMD measurements in cardiac vs lung CT scans. Materials and methods: AI models were trained using 132 cases with 7649 (3 mm) slices for CAC, and 37 cases with 21918 (0.5 mm) slices for lung scans. To validate AutoBMD against manual measurements, we used 6776 cases of BMD measured manually on CAC scans in the Multi-Ethnic Study of Atherosclerosis (MESA). We then used 165 additional cases from Harbor UCLA Lundquist Institute to compare AutoBMD in patients who underwent both cardiac and lung scans on the same day. Results: Mean±SD for age was 69 ± 9.4 years with 52.4% male. AutoBMD in lung and cardiac scans, and manual BMD in cardiac scans were 153.7 ± 43.9, 155.1 ± 44.4, and 163.6 ± 45.3 g/cm3, respectively (p = 0.09). Bland-Altman agreement analysis between AutoBMD lung and cardiac scans resulted in 1.37 g/cm3 mean differences. Pearson correlation coefficient between lung and cardiac AutoBMD was R2 = 0.95 (p

Objectives Cholesterol loading capacity (CLC) describes the ability of serum to deliver cholesterol to cells. It is linked to foam cell formation, a pivotal step in atherosclerotic plaque development. We evaluate the associations of CLC with coronary atherosclerosis presence, burden and cardiovascular risk in patients with rheumatoid arthritis (RA).Methods Coronary atherosclerosis (any, high-risk low-attenuation plaque and obstructive plaque) was evaluated with CT angiography in 141 patients. Participants were prospectively followed for 6.0±2.4 years and cardiovascular events including cardiac death, myocardial infarction, unstable angina, stroke, claudication, revascularisation and hospitalised heart failure were recorded. CLC was quantified as intracellular cholesterol in human macrophages after incubation with patient serum.Results CLC was not linked to overall plaque presence or burden after adjustments for atherosclerotic cardiovascular disease (ASCVD) score, statin use and low-density lipoprotein cholesterol. However, CLC associated with presence and numbers of any, low-attenuation and obstructive plaques exclusively in biologic disease-modifying antirheumatic drugs (bDMARD) non-users (p for interaction ≤0.018). CLC associated with cardiovascular event risk overall after adjustments for ASCVD and number of segments with plaque (HR=1.76 (95% CI 1.16 to 2.67) per 1 SD increase in CLC, p=0.008). Additionally, bDMARD use modified the impact of CLC on event risk; CLC associated with events in bDMARD non-users (HR=2.52 (95% CI 1.36 to 4.65) per 1SD increase in CLC, p=0.003) but not users.Conclusion CLC was linked to long-term cardiovascular event risk in RA and associated with high-risk low attenuation and obstructive coronary plaque presence and burden in bDMARD non-users. Its prospective validation as a predictive biomarker may be, therefore, warranted.

Background: The coronavirus disease-2019 (COVID-19) pandemic significantly affected management of cardiovascular disease around the world. The effect of the pandemic on volume of cardiovascular diagnostic procedures is not known. Objectives: This study sought to evaluate the effects of the early phase of the COVID-19 pandemic on cardiovascular diagnostic procedures and safety practices in Asia. Methods: The International Atomic Energy Agency conducted a worldwide survey to assess changes in cardiovascular procedure volume and safety practices caused by COVID-19. Testing volumes were reported for March 2020 and April 2020 and were compared to those from March 2019. Data from 180 centers across 33 Asian countries were grouped into 4 subregions for comparison. Results: Procedure volumes decreased by 47% from March 2019 to March 2020, showing recovery from March 2020 to April 2020 in Eastern Asia, particularly in China. The majority of centers cancelled outpatient activities and increased time per study. Practice changes included implementing physical distancing and restricting visitors. Although COVID testing was not commonly performed, it was conducted in one-third of facilities in Eastern Asia. The most severe reductions in procedure volumes were observed in lower-income countries, where volumes decreased 81% from March 2019 to April 2020. Conclusions: The COVID-19 pandemic in Asia caused significant reductions in cardiovascular diagnostic procedures, particularly in low-income countries. Further studies on effects of COVID-19 on cardiovascular outcomes and changes in care delivery are warranted.

Abstract Coronary artery disease (CAD), the most common manifestation of cardiovascular disease, remains the most common cause of mortality in the United States. Risk assessment is key for primary prevention of coronary events and coronary artery calcium (CAC) scoring using computed tomography (CT) is one such non-invasive tool. Despite the proven clinical value of CAC, the current clinical practice implementation for CAC has limitations such as the lack of insurance coverage for the test, need for capital-intensive CT machines, specialized imaging protocols, and accredited 3D imaging labs for analysis (including personnel and software). Perhaps the greatest gap is the millions of patients who undergo routine chest CT exams and demonstrate coronary artery calcification, but their presence is not often reported or quantitation is not feasible. We present two deep learning models that automate CAC scoring demonstrating advantages in automated scoring for both dedicated gated coronary CT exams and routine non-gated chest CTs performed for other reasons to allow opportunistic screening. First, we trained a gated coronary CT model for CAC scoring that showed near perfect agreement (mean difference in scores = −2.86; Cohen’s Kappa = 0.89, P

Emerging evidence suggests that “leanness” and good metabolic health markers may predict larger increases in LDL cholesterol (LDL-C) in response to carbohydrate restriction. Specifically, a recent cohort study demonstrated an inverse association between BMI and LDL-C change among individuals on carbohydrate-restricted diets and identified a subgroup of “Lean Mass Hyper-Responders” (LMHR) who exhibit exceptional increases in LDL-C, in the context of low triglycerides and high HDL-C. We present the case of one subject, LM, who adopted a ketogenic diet for management of ulcerative colitis. He subsequently experienced an increase in LDL-C from 95 to 545 mg/dl, at peak, in association with HDL-C >100 mg/dl and triglycerides ~40 mg/dl, typical of the emergent LMHR phenotype. Assessments of LM’s dietary intake, lipid panels, and BMI are consistent with prior data and suggest that the LMHR phenomenon is not dependent on saturated fat intake but inversely associates with BMI changes. Finally, computed tomography angiography conducted on LM after over 2 years of hypercholesterolemia revealed no evidence of calcified or non-calcified plaque.

Background The prevalence and extent of subclinical large vessel vasculopathy is not well defined among people living with HIV. We aimed to evaluate associations between aortic root and ascending aortic sizes measured by 2‐dimensional transthoracic echocardiography and HIV serostatus, and to identify risk factors for larger aortic sizes among men with HIV, including levels of circulating inflammatory markers. Methods and Results Using clinical and echocardiographic data from the MACS (Multicenter AIDS Cohort Study), adjusted multivariable linear and logistic regression was performed. Four segments of the proximal aorta were measured: aortic annulus, aortic root at the sinuses of Valsalva, sinotubular junction, and ascending aorta. HIV infection was associated with significantly larger aortic root (0.03 cm [95% CI, 0.002–0.06 cm]) and ascending aorta (0.04 cm [95% CI, 0.01–0.06 cm]) diameters. Higher standardized nadir CD4 (cluster of differentiation 4) T‐cell count was significantly associated with smaller aortic root (−0.03 cm [95% CI, −0.05 to −0.01 cm]), sinotubular junction (−0.03 cm [95% CI, −0.05 to −0.01 cm]), and ascending aorta (−0.03 cm [95% CI, −0.05 to −0.004 cm]) diameters. Higher levels of standardized TNF‐α (tumor necrosis factor‐α) were associated with larger diameters of the aortic annulus (0.02 cm [95% CI, 0.003–0.04 cm]) and sinotubular junction (0.02 cm [95% CI, 0.002–0.04 cm]). There were no other cardiovascular or HIV disease severity–related risk factors associated with the aortic dimensions. Conclusions HIV infection is an independent risk factor for greater ascending aortic sizes. Lower nadir CD4 T‐cell count and higher TNF‐α levels are associated with larger aortic sizes in men with HIV. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00046280.

BackgroundThere is limited knowledge about the risk of non-alcoholic fatty liver disease (NAFLD) associated with cardiometabolic disorders in lean persons. This study examines the contribution of cardiometabolic disorders to NAFLD risk among lean individuals and compares to non-lean individuals.MethodsWe analyzed longitudinal data from 6,513 participants of a yearly voluntary routine health testing conducted at the Hospital Israelita Albert Einstein, Brazil. NAFLD was defined as hepatic ultrasound diagnosed fatty liver in individuals scoring below 8 on the alcohol use disorders identification test. Our main exposure variables were elevated blood glucose, elevated blood pressure (BP), presence of atherogenic dyslipidemia (AD, defined as the combination of elevated triglycerides and low HDL cholesterol) and physical inactivity (ResultsOver 15,580 person-years (PY) of follow-up, the incidence rate of NAFLD was 7.7 per 100 PY. In multivariate analysis adjusting for likely confounders, AD was associated with a 72% greater risk of NAFLD (IRR: 1.72 [95% CI:1.32-2.23]). Elevated blood glucose (IRR: 1.71 [95%CI: 1.29-2.28]) and physical inactivity (IRR: 1.46 [95%CI: 1.28-1.66]) were also independently associated with increased risk of NAFLD. In lean individuals, AD, elevated blood glucose and elevated BP were significantly associated with NAFLD although for elevated blood glucose, statistical significance was lost after adjusting for possible confounders. Physical inactivity and elevations in HsCRP were not associated with the risk of NAFLD in lean individuals only. Among lean (and non-lean) individuals, there was an independent association between progressively increasing waist circumference and NAFLD.ConclusionCardiometabolic risk factors are independently associated with NAFLD. However, there are significant differences in the metabolic risk predictors of NAFLD between lean and non-lean individuals. Personalized cardiovascular disease risk stratification and appropriate preventive measures should be considered in both lean and non-lean individuals to prevent the development of NAFLD.

Summary: Excess liver fat, called hepatic steatosis, is a leading risk factor for end-stage liver disease and cardiometabolic diseases but often remains undiagnosed in clinical practice because of the need for direct imaging assessments. We developed an abdominal MRI-based machine-learning algorithm to accurately estimate liver fat (correlation coefficients, 0.97–0.99) from a truth dataset of 4,511 middle-aged UK Biobank participants, enabling quantification in 32,192 additional individuals. 17% of participants had predicted liver fat levels indicative of steatosis, and liver fat could not have been reliably estimated based on clinical factors such as BMI. A genome-wide association study of common genetic variants and liver fat replicated three known associations and identified five newly associated variants in or near the MTARC1, ADH1B, TRIB1, GPAM, and MAST3 genes (p < 3 × 10−8). A polygenic score integrating these eight genetic variants was strongly associated with future risk of chronic liver disease (hazard ratio > 1.32 per SD score, p < 9 × 10−17). Rare inactivating variants in the APOB or MTTP genes were identified in 0.8% of individuals with steatosis and conferred more than 6-fold risk (p < 2 × 10−5), highlighting a molecular subtype of hepatic steatosis characterized by defective secretion of apolipoprotein B-containing lipoproteins. We demonstrate that our imaging-based machine-learning model accurately estimates liver fat and may be useful in epidemiological and genetic studies of hepatic steatosis.

Background Trimethylamine N‐oxide (TMAO) is a gut microbiota‐dependent metabolite of dietary choline, L‐carnitine, and phosphatidylcholine‐rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community‐based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community‐based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography–tandem mass spectrometry (laboratory coefficient of variation,

BackgroundGiven 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 findingsThis 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.ConclusionsIn 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 registrationClinicalTrials.gov NCT00005487.

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

When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases in both LDL-C and HDL-C. The inverse association between BMI and LDL-C and HDL-C change on CRD contributed to the discovery of a subset of individuals—termed Lean Mass Hyper-Responders (LMHR)—who, despite normal pre-diet LDL-C, as compared to non-LMHR (mean levels of 148 and 145 mg/dL, respectively), exhibited a pronounced hyperlipidemic response to a CRD, with mean LDL-C and HDL-C levels increasing to 320 and 99 mg/dL, respectively, in the context of mean TG of 47 mg/dL. In some LMHR, LDL-C levels may be in excess of 500 mg/dL, again, with relatively normal pre-diet LDL-C and absent of genetic findings indicative of familial hypercholesterolemia in those who have been tested. The Lipid Energy Model (LEM) attempts to explain this metabolic phenomenon by positing that, with carbohydrate restriction in lean persons, the increased dependence on fat as a metabolic substrate drives increased hepatic secretion and peripheral uptake of TG contained within very low-density lipoproteins (VLDL) by lipoprotein lipase, resulting in marked elevations of LDL-C and HDL-C, and low TG. Herein, we review the core features of the LEM. We review several existing lines of evidence supporting the model and suggest ways to test the model’s predictions.

Background Positive remodelling index and presence of low-attenuation non-calcified plaque (LANCP) are characteristic vessel changes in unstable coronary plaques. We sought to characterise these high-risk plaque features in patients with systemic lupus erythematosus (SLE) and to compare them with controls.Methods A total of 72 patients who satisfied the SLICC classification criteria for SLE had coronary CT angiography (CCTA) studies, 30 of which had follow-up CCTA, as screening for occult coronary atherosclerotic disease in asymptomatic individuals. A total of 100 consecutive controls with no known history of lupus, heart disease or revascularisation who had two coronary CT angiograms at least 1 year apart were included in the study. These were asymptomatic patients referred by their primary physicians for screening of coronary artery disease and the screening interval was decided by the primary physicians. The methodology for image acquisition was identical.Results LANCP burden at baseline was significantly greater in patients with SLE compared with controls. LANCP volume was significantly greater in patients over 60 years of age (p10 mg/day. LANCP burden remained stable over follow-up. There were no significant differences in remodelling index compared with controls.Conclusion This is the first study describing high-risk CCTA features of coronary plaque in patients with SLE. Both LANCP and positive remodelling are common in SLE. These characteristic vessel changes may identify patients with SLE at increased risk of cardiovascular events and those in need for more frequent cardiac monitoring.

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

Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article.

Background Studies have demonstrated that the current US guidelines based on American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equations Risk Calculator may underestimate risk of atherosclerotic cardiovascular disease (CVD) in certain high‐risk individuals, therefore missing opportunities for intensive therapy and preventing CVD events. Similarly, the guidelines may overestimate risk in low risk populations resulting in unnecessary statin therapy. We used Machine Learning (ML) to tackle this problem. Methods and Results We developed a ML Risk Calculator based on Support Vector Machines (SVMs) using a 13‐year follow up data set from MESA (the Multi‐Ethnic Study of Atherosclerosis) of 6459 participants who were atherosclerotic CVD‐free at baseline. We provided identical input to both risk calculators and compared their performance. We then used the FLEMENGHO study (the Flemish Study of Environment, Genes and Health Outcomes) to validate the model in an external cohort. ACC/AHA Risk Calculator, based on 7.5% 10‐year risk threshold, recommended statin to 46.0%. Despite this high proportion, 23.8% of the 480 “Hard CVD” events occurred in those not recommended statin, resulting in sensitivity 0.76, specificity 0.56, and AUC 0.71. In contrast, ML Risk Calculator recommended only 11.4% to take statin, and only 14.4% of “Hard CVD” events occurred in those not recommended statin, resulting in sensitivity 0.86, specificity 0.95, and AUC 0.92. Similar results were found for prediction of “All CVD” events. Conclusions The ML Risk Calculator outperformed the ACC/AHA Risk Calculator by recommending less drug therapy, yet missing fewer events. Additional studies are underway to validate the ML model in other cohorts and to explore its ability in short‐term CVD risk prediction.

Previously, we reported that inverse associations of high-density lipoprotein (HDL) with cardiovascular disease and diabetes were only observed for HDL that lacked the pro-inflammatory protein apolipoprotein C3 (apoC3). To provide further insight into the cardiometabolic properties of HDL subspecies defined by the presence or absence of apoC3, we aimed to examine these subspecies with liver fat content and non-alcoholic fatty liver disease (NAFLD). We investigated cross-sectional associations between ELISA-measured plasma levels of apoA1 in HDL that contained or lacked apoC3 and computed tomography-determined liver fat content and NAFLD (14 drinks/week in men and >7 drinks/week in women). In multivariable-adjusted regression models, apoA1 in HDL that contained or lacked apoC3 was differentially associated with liver fat content (Pheterogeneity = 0.048). While apoA1 in HDL that lacked apoC3 was inversely associated with liver fat content (Ptrend < 0.0001), apoA1 in HDL that contained apoC3 was not statistically significantly associated with liver fat content (Ptrend = 0.57). Higher apoA1 in HDL that lacked apoC3 was related to a lower prevalence of NAFLD (OR per SD: 0.80; 95% CI: 0.72, 0.89), whereas no association was found for apoA1 in HDL that contained apoC3 (OR per SD: 0.95; 95% CI: 0.85, 1.05; Pheterogeneity = 0.09). Higher apoA1 in HDL that lacked apoC3 was associated with less liver fat content and a lower prevalence of NAFLD. This finding extends the inverse association of HDL lacking apoC3 from cardiovascular disease to NAFLD. Lack of biopsy-proven hepatic steatosis and fibrosis data requires the replication of our study in further studies.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: Detecting coronary artery disease (CAD) is pivotal in etiologic assessment and management of left ventricular (LV) systolic dysfunction. Only a limited number of studies have specifically addressed the accuracy of coronary computed tomographic angiography (CCTA) in detection/exclusion of CAD in patients with LV systolic dysfunction. Methods: We included patients who were referred for CCTA and invasive coronary angiography within 6 months of each other because of chest pain, either as part of clinical work-up in two Los Angeles medical centers from September 2006 to May 2010 or as part of the multicenter ACCURACY trial. Sensitivity, specificity, positive and negative predictive value, and likelihood ratios of 64 slice multidetector CCTA against coronary angiography were calculated. Results: Five hundred and thirty-seven patients were included: 228 (42.5%) were women, mean age was 62 ± 12 years, 82 (15.3%) had LV systolic dysfunction (defined by LVEF

Coronary artery calcium (CAC) has been advocated as one of the strongest cardiovascular risk prediction markers. It performs better across a wide range of Framingham risk categories (6%–10% and 10%–20% 10-year risk categories) and also helps in reclassifying the risk of these subjects into either higher or lower risk categories based on CAC scores. It also performs better among population subgroups where Framingham risk score does not perform well, especially young subjects, women, family history of premature coronary artery disease and ethnic differences in coronary risk. The absence of CAC is also associated with excellent prognosis, with 10-year event rate of 1%. Studies have also compared with other commonly used markers of cardiovascular disease risk such as Carotid intima-media thickness and highly sensitive C-reactive protein. CAC also performs better compared with carotid intima-media thickness and highly sensitive C-reactive protein in prediction of coronary heart disease and cardiovascular disease events. CAC scans are associated with relatively low radiation exposure (0.9–1.1 mSv) and provide information that can be used not only for risk stratification but also can be used to track the progression of atherosclerosis and the effects of statins.

BackgroundAlthough the association between coronary artery calcium (CAC) and future heart failure (HF) has been shown previously, the value of CAC progression in the prediction of HF has not been investigated. In this study, we investigated the association of CAC progression with subclinical left ventricular (LV) dysfunction and incident HF in the Multi‐Ethnic Study of Atherosclerosis. Methods and ResultsThe Multi‐Ethnic Study of Atherosclerosis is a population‐based study consisting of 6814 men and women aged 45 to 84, free of overt cardiovascular disease at enrollment, who were recruited from 4 ethnicities. We included 5644 Multi‐Ethnic Study of Atherosclerosis participants who had baseline and follow‐up cardiac computed tomography and were free of HF and coronary heart disease before the second cardiac computed tomography. Mean (±SD) age was 61.7±10.2 years and 47.2% were male. The Cox proportional hazard models and multivariable linear regression models were deployed to determine the association of CAC progression with incident HF and subclinical LV dysfunction, respectively. Over a median follow‐up of 9.6 (interquartile range: 8.8–10.6) years, 182 participants developed incident HF. CAC progression of 10 units per year was associated with 3% of increased risk of HF independent of overt coronary heart disease (P=0.008). In 2818 participants with available cardiac magnetic resonance images, CAC progression was associated with increased LV end diastolic volume (β=0.16; P=0.03) and LV end systolic volume (β=0.12; P=0.006) after excluding participants with any coronary heart disease. ConclusionsCAC progression was associated with incident HF and modestly increased LV end diastolic volume and LV end systolic volume at follow‐up exam independent of overt coronary heart disease.

BackgroundEvaluation of impaired left ventricular (LV) filling has focused on intrinsic causes of LV dysfunction; however, pulmonary vascular changes may contribute to reduced LV filling and dyspnea. We hypothesized that lower total pulmonary vascular volume (TPVV) on computed tomography (CT) would be associated with dyspnea and decrements in LV end-diastolic volume, particularly among ever-smokers.MethodsThe Multi-Ethnic Study of Atherosclerosis recruited adults without clinical cardiovascular disease in 2000-02. In 2010-12, TPVV was ascertained as the volume of arteries and veins in the lungs detectable on non-contrast chest CT (vessels ≥1 mm diameter). Cardiac measures were assessed by magnetic resonance imaging (MRI). Dyspnea was self-reported.ResultsOf 2303 participants, 53% had ever smoked cigarettes. Among ever-smokers, a lower TPVV was associated with a lower LV end-diastolic volume (6.9 mL per SD TPVV), stroke volume, and cardiac output and with dyspnea (all P-values ConclusionReductions in pulmonary vascular volume were associated with lower LV filling and dyspnea among ever-smokers, including those without lung disease, suggesting that smoking-related pulmonary vascular changes may contribute to symptoms and impair cardiac filling and function without evidence of impaired LV relaxation.

BackgroundDiagnostic testing in the care of patients newly presenting with symptoms suggestive of coronary artery disease may influence risk factor management, independent of test type or test results. However, little is known about changes in medications and lifestyle after anatomical or functional testing. Methods and ResultsWe examined what factors influenced preventive medical therapy and lifestyle practices at 60 days among 10 003 symptomatic patients (53% women; mean age 61 years) randomly assigned to anatomical testing with coronary computed tomographic angiography or functional testing (NCT01174550). We also assessed the association of preventive changes with major cardiovascular events. There were no differences in medications/lifestyle at baseline. At 60 days, relative to baseline, the computed tomographic angiography strategy was associated with a higher proportion of patients newly initiating aspirin (11.8% versus 7.8%), statins (12.7% versus 6.2%), and β‐blockers (8.1% versus 5.3%), compared to functional testing (P

BackgroundRecent randomized data suggest that calcium supplements may be associated with increased risk of cardiovascular disease (CVD) events. Using a longitudinal cohort study, we assessed the association between calcium intake, from both foods and supplements, and atherosclerosis, as measured by coronary artery calcification (CAC). Methods and ResultsWe studied 5448 adults free of clinically diagnosed CVD (52% female; aged 45–84 years) from the Multi‐Ethnic Study of Atherosclerosis. Baseline total calcium intake was assessed from diet (using a food frequency questionnaire) and calcium supplements (by a medication inventory) and categorized into quintiles. Baseline CAC was measured by computed tomography, and CAC measurements were repeated in 2742 participants ≈10 years later. At baseline, mean calcium intakes across quintiles were 313.3, 540.3, 783.0, 1168.9, and 2157.4 mg/day. Women had higher calcium intakes than men. After adjustment for potential confounders, among 1567 participants without baseline CAC, the relative risk (RR) of developing incident CAC over 10 years, by quintile 1 to 5 of calcium intake, were 1 (reference), 0.95 (0.79–1.14), 1.02 (0.85–1.23), 0.86 (0.69–1.05), and 0.73 (0.57–0.93). After accounting for total calcium intake, calcium supplement use was associated with increased risk for incident CAC (RR=1.22 [1.07–1.39]). No relation was found between baseline calcium intake and 10‐year changes in log‐transformed CAC among those participants with baseline CAC >0. ConclusionsHigh total calcium intake was associated with a decreased risk of incident atherosclerosis over long‐term follow‐up, particularly if achieved without supplement use. However, calcium supplement use may increase the risk for incident CAC.

BackgroundDespite evidence for higher risk of coronary artery disease among HIV+ individuals, the underlying mechanisms are not well understood. We investigated associations of inflammatory markers with subclinical coronary artery disease in 923 participants of the Multicenter AIDS Cohort Study (575 HIV+ and 348 HIV− men) who underwent noncontrast computed tomography scans for coronary artery calcification, the majority (n=692) also undergoing coronary computed tomography angiography. Methods and ResultsOutcomes included presence and extent of coronary artery calcification, plus computed tomography angiography analysis of presence, composition, and extent of coronary plaques and severity of coronary stenosis. HIV+ men had significantly higher levels of interleukin‐6 (IL‐6), intercellular adhesion molecule‐1, C‐reactive protein, and soluble‐tumor necrosis factor‐α receptor (sTNFαR) I and II (all P

BackgroundThe clinical implications of ankle‐brachial index (ABI) cutpoints are not well defined in patients with chronic kidney disease (CKD) despite increased prevalence of high ABI attributed to arterial stiffness. We examined the relationship of ABI with cardiovascular disease (CVD) and all‐cause mortality among CKD patients. Methods and ResultsThree thousand six hundred twenty‐seven participants without clinical peripheral artery disease (PAD) at baseline from the Chronic Renal Insufficiency Cohort Study were included. ABI was obtained per standard protocol and CVD events were confirmed by medical record adjudication. A U‐shaped association of ABI with PAD, myocardial infarction (MI), composite CVD, and all‐cause mortality was observed. Individuals with an ABI between 1.0 and

BACKGROUND:Persistent inflammation and immune activation has been hypothesized to contribute to increased prevalence of subclinical atherosclerosis and cardiovascular disease (CVD) risk in patients with chronic HIV infection. In this study, we examined the correlation of peripheral monocyte subsets and soluble biomarkers of inflammation to coronary artery calcium (CAC) progression, as measured by cardiac computed tomography scan. METHODS:We conducted a longitudinal analysis utilizing baseline data of 78 participants with HIV infection on stable antiretroviral therapy (ART) in the Hawaii Aging with HIV-Cardiovascular study who had available baseline monocyte subset analysis as well as CAC measurement at baseline and at 2-year follow up. Monocyte phenotypes were assessed from cryopreserved blood by flow cytometry and plasma was assayed for soluble biomarkers using antibody-coated beads in a high sensitivity Milliplex Luminex platform. Change in CAC over 2 years was analyzed as the primary outcome variable. RESULTS:Of all monocyte subsets and biomarkers tested, higher non-classical monocyte percentage (ρ = 0.259, p = 0.022), interleukin (IL)-6 (ρ = 0.311, p = 0.012), and monocyte chemoattractant protein (MCP)-1 (ρ = 0.524, p =

BACKGROUND:We characterized associations between smoking, alcohol, and recreational drug use and coronary plaque by HIV serostatus within the Multicenter AIDS Cohort Study (MACS). METHODS:MACS participants (N = 1005, 621 HIV+ and 384 HIV-) underwent non-contrast CT scanning to measure coronary artery calcium; 764 underwent coronary CT angiograms to evaluate plaque type and extent. Self-reported use of alcohol, tobacco, smoked/inhaled cocaine, methamphetamine, ecstasy, marijuana, inhaled nitrites, and erectile dysfunction drugs was obtained at semi-annual visits beginning 10 years prior to CT scanning. Multivariable logistic and linear regression models were performed, stratified by HIV serostatus. RESULTS:Among HIV+ men, current smoking, former smoking, and cumulative pack years of smoking were positively associated with multiple coronary plaque measures (coronary artery calcium presence and extent, total plaque presence and extent, calcified plaque presence, and stenosis >50%). Smoking was significantly associated with fewer plaque measures of comparable effect size among HIV- men; current smoking and calcified plaque extent was the only such association. Heavy alcohol use (>14 drinks/week) was associated with stenosis >50% among HIV+ men. Among HIV- men, low/moderate (1-14 drinks/week) and heavy alcohol use were inversely associated with coronary artery calcium and calcified plaque extent. Few significant associations between other recreational drug use and plaque measures were observed. CONCLUSION:Smoking is strongly associated with coronary plaque among HIV+ men, underscoring the value of smoking cessation for HIV+ persons. Alcohol use may protect against coronary artery calcium and calcified plaque progression in HIV- (but not HIV+) men. Few positive associations were observed between recreational drug use and coronary plaque measures.

Although metabolic syndrome is associated with increased risk of cardiovascular disease and events, its added prognostic value beyond its components remains unknown. This study compared the prevalence, severity of coronary artery disease (CAD), and prognosis of patients with metabolic syndrome to those with individual metabolic syndrome components. The study cohort consisted of 27125 consecutive individuals who underwent ≥ 64-detector row coronary CT angiography (CCTA) at 12 centers from 2003 to 2009. Metabolic syndrome was defined as per NCEP/ATP III criteria. Metabolic syndrome patients (n = 690) were matched 1:1:1 to those with 1 component (n = 690) and 2 components (n = 690) of metabolic syndrome for age, sex, smoking status, and family history of premature CAD using propensity scoring. Major adverse cardiac events (MACE) were defined by a composite of myocardial infarction (MI), acute coronary syndrome, mortality and late target vessel revascularization. Patients with 1 component of metabolic syndrome manifested lower rates of obstructive 1-, 2-, and 3-vessel/left main disease compared to metabolic syndrome patients (9.4% vs 13.8%, 2.6% vs 4.5%, and 1.0% vs 2.3%, respectively; p < 0.05), while those with 2 components did not (10.5% vs 13.8%, 2.8% vs 4.5% and 1.3% vs 2.3%, respectively; p > 0.05). At 2.5 years, metabolic syndrome patients experienced a higher rate of MACE compared to patients with 1 component (4.4% vs 1.6%; p = 0.002), while no difference observed compared to individuals with 2 components (4.4% vs 3.2% p = 0.25) of metabolic syndrome. In conclusion, Metabolic syndrome patients have significantly greater prevalence, severity, and prognosis of CAD compared to patients with 1 but not 2 components of metabolic syndrome.

Coronary artery calcification (CAC) is as an independent risk predictor of cardiovascular disease and can classify an individual's risk of atherosclerotic cardiovascular disease, particularly in intermediate-risk individuals. Also, CAC progression is associated with greater rates of cardiovascular events. This article provides available data and expert recommendations for CAC based on current publications. We focus on the utility of CAC for stratification of individuals and describe its diagnostic value in identifying patients at risk. We also describe the important ability of CAC to derisk a patient with a score of zero.

BackgroundFine particulate matter (PM2.5) has been linked to cardiovascular disease, possibly via accelerated atherosclerosis. We examined associations between the progression of the intima-medial thickness (IMT) of the common carotid artery, as an indicator of atherosclerosis, and long-term PM2.5 concentrations in participants from the Multi-Ethnic Study of Atherosclerosis (MESA).Methods and resultsMESA, a prospective cohort study, enrolled 6,814 participants at the baseline exam (2000-2002), with 5,660 (83%) of those participants completing two ultrasound examinations between 2000 and 2005 (mean follow-up: 2.5 years). PM2.5 was estimated over the year preceding baseline and between ultrasounds using a spatio-temporal model. Cross-sectional and longitudinal associations were examined using mixed models adjusted for confounders including age, sex, race/ethnicity, smoking, and socio-economic indicators. Among 5,362 participants (5% of participants had missing data) with a mean annual progression of 14 µm/y, 2.5 µg/m(3) higher levels of residential PM2.5 during the follow-up period were associated with 5.0 µm/y (95% CI 2.6 to 7.4 µm/y) greater IMT progressions among persons in the same metropolitan area. Although significant associations were not found with IMT progression without adjustment for metropolitan area (0.4 µm/y [95% CI -0.4 to 1.2 µm/y] per 2.5 µg/m(3)), all of the six areas showed positive associations. Greater reductions in PM2.5 over follow-up for a fixed baseline PM2.5 were also associated with slowed IMT progression (-2.8 µm/y [95% CI -1.6 to -3.9 µm/y] per 1 µg/m(3) reduction). Study limitations include the use of a surrogate measure of atherosclerosis, some loss to follow-up, and the lack of estimates for air pollution concentrations prior to 1999.ConclusionsThis early analysis from MESA suggests that higher long-term PM2.5 concentrations are associated with increased IMT progression and that greater reductions in PM2.5 are related to slower IMT progression. These findings, even over a relatively short follow-up period, add to the limited literature on air pollution and the progression of atherosclerotic processes in humans. If confirmed by future analyses of the full 10 years of follow-up in this cohort, these findings will help to explain associations between long-term PM2.5 concentrations and clinical cardiovascular events.

Purpose. To compare radiation dose and image quality using predefined narrow phase window versus complete phase window with dose modulation during R-R using 320-row MDCTA. Methods. 114 patients underwent coronary CTA study using 320-row MDCT scanner. 87 patients with mean age (61 + 13 years), mean BMI (29 + 6), and mean heart rate (HR) (58 + 7 bpm) were imaged at predefined 66–80% R-R interval and then reconstructed at 75% while 27 patients with mean age (63 + 16 years), mean BMI (28 + 5), and mean HR (57 + 7 bpm) were scanned throughout the complete R-R interval with tube current modulation. The effective dose (ED) was calculated from dose length product (DLP) and conversion k (0.014 mSv/mGy/cm). Image quality was assessed using a three-point ordinal scale (1 = excellent, 2 = good, and 3 = nondiagnostic). Results. Both groups were statistically similar to each other with reference of HR (P=0.59), BMI (P=0.17), and tube current mAs (P=0.68). The median radiation dose was significantly higher in those scanned with complete R-R phase window versus narrow phase window (P

Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7 × 10(-08)). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.