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Background The metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride‐rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease. Methods and Results We studied 1791 MESA (Multi‐Ethnic Study of Atherosclerosis) participants who took part in an ancillary study on body composition with adipokine levels measured (leptin, adiponectin, and resistin) at either visit 2 or visit 3. RC was calculated as non–high‐density lipoprotein cholesterol minus low‐density lipoprotein cholesterol, measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable‐adjusted linear mixed‐effects models were used to assess the cross‐sectional and longitudinal associations between adipokines and log‐transformed levels of RC. Mean±SD age was 64.5±9.6 years; mean±SD body mass index was 29.9±5.0 kg/m2; and 52.0% were women. In fully adjusted cross‐sectional models that included body mass index, diabetes, low‐density lipoprotein cholesterol, and lipid‐lowering therapy, for each 1‐unit increment in adiponectin, there was 14.6% (95% CI, 12.2–16.9) lower RC. With each 1‐unit increment in leptin and resistin, there was 4.8% (95% CI, 2.7–7.0) and 4.0% (95% CI, 0.2–8.1) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow‐up of 5 (interquartile range, 4–8) years. Conclusions Lower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for body mass index and low‐density lipoprotein cholesterol.

Background Immigrants experience changes in cardiovascular risk factors and racial disparities in both cardiovascular health prevention and outcomes upon immigration. We aimed to examine cardiovascular risk factors and outcomes among Chinese American immigrants enrolled in the MESA (Multi‐Ethnic Study of Atherosclerosis) cohort. Methods and Results We analyzed data from 746 Chinese American immigrants in the MESA study with a median follow‐up period of 17.8 years. The mean age of the cohort was 62.3 years, with 52.7% being women. Kaplan–Meier curves and Cox proportional hazards models were used to assess the association of immigration history, geographic location, biomarkers, and cardiac imaging parameters with cardiovascular risk factors and cardiovascular outcomes. The Cox hazards models were adjusted for known family history of heart disease, education level, sex, diabetes, hypertension, age, and body mass index. Although immigration history categorized as earlier (

Background: The relationship between atherogenic lipoproteins and subclinical coronary atherosclerosis has not been thoroughly evaluated in low-risk adults. Objectives: The purpose of this study was to assess the association of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (apoB) with coronary atherosclerosis in adults without traditional risk factors. Methods: We assessed atherosclerosis on coronary computed tomography angiography among asymptomatic adults in the Miami Heart Study not taking lipid-lowering therapy and without hypertension, diabetes, or active tobacco use. Prevalence of atherosclerosis was evaluated based on serum LDL-C, non-HDL-C, and apoB, and multivariable logistic regression with forward selection was used to assess variables associated with coronary plaque. Results: Among 1,033 adults 40 to 65 years of age, 55.0% were women and 86.3% had estimated 10-year atherosclerotic cardiovascular disease risk

Objective: Lipoprotein(a) [Lp(a)] is an atherogenic and prothrombotic lipoprotein associated with atherosclerotic cardiovascular disease (ASCVD). We assessed the association between regular aspirin use and ASCVD mortality among individuals with versus without elevated Lp(a) in a nationally representative US cohort. Methods: Eligible participants were aged 40–70 years without clinical ASCVD, reported on aspirin use, and had Lp(a) measurements from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994), the only cycle of this nationally representative US cohort to measure Lp(a). Regular aspirin use was defined as taking aspirin ≥30 times in the previous month. Using NHANES III linked mortality records and weighted Cox proportional hazards regression, the association between regular aspirin use and ASCVD mortality was observed in those with and without elevated Lp(a) (≥50 versus

BackgroundCirculating immune cells have gained interest as biomarkers of hepatic steatosis. Data on the relationships between immune cell subsets and early-stage steatosis in population-based cohorts are limited.MethodsThis study included 1,944 asymptomatic participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with immune cell phenotyping and computed tomography measures of liver fat. Participants with heavy alcohol use were excluded. A liver-to-spleen ratio Hounsfield units (HU) 30% liver fat content, respectively. Logistic regression estimated cross-sectional associations of immune cell subsets with liver fat parameters adjusted for risk factors. We hypothesized that higher proportions of non-classical monocytes, Th1, Th17, and memory CD4+ T cells, and lower proportions of classical monocytes and naive CD4+ T cells, were associated with liver fat. Exploratory analyses evaluated additional immune cell phenotypes (n = 19).ResultsNone of the hypothesized cells were associated with presence of liver fat. Higher memory CD4+ T cells were associated with >30% liver fat content, but this was not significant after correction for multiple hypothesis testing (odds ratio (OR): 1.31, 95% confidence interval (CI): 1.03, 1.66). In exploratory analyses unadjusted for multiple testing, higher proportions of CD8+CD57+ T cells were associated with liver fat presence (OR: 1.21, 95% CI: 1.02, 1.44) and >30% liver fat content (OR: 1.34, 95% CI: 1.07, 1.69).ConclusionsHigher circulating memory CD4+ T cells may reflect liver fat severity. CD8+CD57+ cells were associated with liver fat presence and severity, but replication of findings is required.

Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study (n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [CDKN2B-AS1] among all COPDGene participants (p = 7.1 × 10−14) and among males (p = 1.0 × 10−9), but the signal was not genome-wide significant among females (p = 6.4 × 10−6). For the sex stratified GWA analyses among females, the chromosome 6p24 region [PHACTR1] had a genome-wide significant association (p = 4.4 × 10−8) with CAC, but this signal was not genome-wide significant among all COPDGene participants (p = 1.7 × 10−7) or males (p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex (p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex (p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers (p = 6.2 × 10−7) than former smokers (p = 7.5 × 10−3) and the SNP by smoking status interaction was marginally significant (p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former (p = 7.7 × 10−8) and current smokers (p = 1.7 × 10−7) and the SNP by smoking status interaction was not significant (p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [PHACTR1] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Objectives: High-density lipoprotein (HDL) removes cholesterol from cells in atherosclerotic lesions, a function known as cholesterol efflux capacity (CEC). ATP-binding-cassette A1 (ABCA1) membrane transporter starts cholesterol transfer from macrophages to HDL particles. In rheumatoid arthritis (RA), methotrexate and biologic disease modifying drugs (bDMARDs) are atheroprotective whereas corticosteroids and C-reactive protein (CRP) are proatherogenic. We evaluated the influence of these factors on the relationship of ABCA1-CEC with atherosclerosis and cardiovascular events. Methods: Atherosclerosis was evaluated with computed tomography angiography in 140 patients with RA and repeated in 99 after 6.9 ± 0.3 years. Events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization, and heart failure were recorded. ABCA1-CEC was quantified in J774A.1 murine macrophages and reported as percentage of effluxed over intracellular cholesterol. Results: Higher ABCA1-CEC associated with (i) more calcified plaques at baseline only in patients with CRP>7 mg/L (median) (p-interaction = 0.001) and methotrexate nonusers (p-interaction = 0.037), and more partially-calcified plaques only in bDMARD nonusers (p-interaction = 0.029); (ii) fewer new calcified plaques in patients with below-median but not higher time-averaged CRP (p-interaction = 0.028); (iii) fewer new total and calcified plaques in prednisone unexposed but not patients exposed to prednisone during follow-up (p-interaction = 0.034 and 0.004) and (iv) more new plaques in baseline bDMARD nonusers and fewer in bDMARD users (p-interaction ≤ 0.001). Also, ABCA1-CEC associated with greater cardiovascular risk only in baseline prednisone users (p-interaction = 0.027). Conclusion: ABCA1-CEC associated with decreased atherosclerosis in patients with below-median baseline and time-averaged CRP and bDMARD use. Conversely, ABCA1-CEC associated with increased plaque in those with higher CRP, corticosteroid users, methotrexate nonusers, and bDMARD nonusers. While in well-treated and controlled disease ABCA1-CEC appears atheroprotective, in uncontrolled RA its action may be masked or fail to counteract the inflammation-driven proatherogenic state.

Objectives: Cholesterol efflux capacity (CEC) is the main antiatherogenic function of high-density lipoprotein (HDL). ATP-binding-cassette A1 (ABCA1) membrane transporter initiates cholesterol export from arterial macrophages to pre-β HDL particles fostering their maturation; in turn, those accept cholesterol through ABCG1-mediated export. Impaired pre-β HDL maturation may disrupt the collaborative function of the two transporters and adversely affect atherosclerosis. Statins exert atheroprotective functions systemically and locally on plaque. We here evaluated associations between ABCA1-CEC, coronary atherosclerosis and cardiovascular risk and the influence of statins on those relationships in rheumatoid arthritis (RA). Methods: Evaluation with computed tomography angiography was undertaken in 140 patients and repeated in 99 after 6.9 ± 0.3 years. Events comprising cardiovascular death, acute coronary syndromes, stroke, claudication, revascularization and heart failure were recorded. ABCA1-CEC and ABCG1-CEC were evaluated in J774A.1 macrophages and Chinese hamster ovary (CHO) cells respectively and expressed as percentage of effluxed over total intracellular cholesterol. Covariates in all cardiovascular event risk and plaque outcome models included atherosclerotic cardiovascular disease (ASCVD) risk score and high-density lipoprotein cholesterol. Results: ABCA1-CEC negatively correlated with ABCG1-CEC (r = −0.167, p = 0.049). ABCA1-CEC associated with cardiovascular risk (adjusted hazard ratio 2.05 [95%CI 1.20–3.48] per standard deviation [SD] increment). There was an interaction of ABCA1-CEC with time-varying statin use (p = 0.038) such that current statin use inversely associated with risk only in patients with ABCA1-CEC below the upper tertile. ABCA1-CEC had no main effect on plaque or plaque progression; instead, ABCA1-CEC (per SD) associated with fewer baseline total plaques (adjusted rate ratio [aRR] 0.81, [95%CI 0.65–1.00]), noncalcified plaques (aRR 0.78 [95%CI 0.61–0.98]), and vulnerable low-attenuation plaques (aRR 0.41 [95%CI 0.23–0.74]) in statin users, and more low-attenuation plaques (aRR 1.91 [95%CI 1.18–3.08]) in nonusers (p-for-interaction = 0.018, 0.011, 0.025 and

Background: Urinary isoprostanes are markers of systemic oxidative stress, which is implicated in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Coronary artery calcium (CAC), thoracic aortic calcium (TAC) and carotid plaque are measure subclinical atherosclerosis and prognosticate ASCVD risk. We examined the associations between urinary isoprostane levels and measures of plaque prevalence, burden, incidence and progression across three vascular beds in a cohort from the Multi-Ethnic Study of Atherosclerosis. Methods: Urinary levels of 8-isoprostane and 2,3-dinor-8-F2-isoprostane were measured in 1089 participants (mean ± SD 62 ± 8 years, 48% women) at baseline. Participants underwent computed tomography for CAC and TAC, and duplex ultrasound for carotid plaque. TAC and CAC were reassessed at 2.4 and 10 years, respectively. Regression models were adjusted for CVD risk factors. Results: In adjusted models, there were no significant associations between isoprostane levels with CAC prevalence or progression. Highest versus lowest tertile of 8-isoprostane was associated with 28% lower prevalence of descending TAC at baseline [prevalence ratio (PR) 0.72 95% CI (0.56, 0.94)], while 1-SD higher 2,3-dinor-8-F2-isoprostane was associated with 96% higher incident ascending TAC at follow-up [Relative Risk 1.96 (1.24, 3.09)]. Highest versus lowest tertile of isoprostane measures were associated with 22% higher prevalence of carotid plaque [(PR 1.22 (1.04, 1.45)] and 14% difference [3,26] in greater extent of carotid plaque at baseline. Conclusions: Higher urinary isoprostanes were inconsistently associated with some measures of subclinical atherosclerosis by imaging. This suggests a limited role of urinary isoprostane levels as a prognostic marker for the development of ASCVD. Trial registration: The MESA cohort design is registered at clinicaltrials.gov as follows: https://clinicaltrials.gov/ct2/show/NCT00005487.

Abstract Background Coronary artery calcium (CAC) density is inversely associated with coronary heart disease (CHD) and cardiovascular disease (CVD) risk. We examined this relation in those with diabetes mellitus (DM) or metabolic syndrome (MetS). Methods We studied 3,818 participants with non-zero CAC scores from the Multiethnic Study of Atherosclerosis and classified them as DM, MetS (without DM) or neither DM/MetS. Risk factor-adjusted CAC density was calculated and examined in relation to incident CHD and CVD events over a median follow-up of 15 years among these three disease groups. Results Adjusted CAC density was 2.54, 2.61 and 2.69 among those with DM, MetS or neither DM/MetS. Hazard ratios (HRs) for CHD per 1 SD increase of CAC density was 0.91 (95% CI: 0.72–1.16), 0.70 (95% CI: 0.56–0.87) and 0.79 (95% CI: 0.66–0.95) for those with DM, MetS or neither DM/MetS groups and were 0.77 (95% CI: 0.64–0.94), 0.83 (95% CI: 0.70–0.99) and 0.82 (95% CI: 0.71–0.95) for CVD, respectively. Adjustment for CAC density increased the HRs of CAC volume for CHD/CVD events. Compared to prediction models with or without single CAC measures, c-statistics of models with CAC volume and density were the highest ranging 0.67–0.72. Conclusion CAC density is lower among patients with DM or MetS than those with neither DM/MetS and is inversely associated with future CHD/CVD risk among them. Including CAC density in risk assessment among those with MetS may improve prediction of CHD and CVD.

Abstract Background The baseline coronary plaque burden is the most important factor for rapid plaque progression (RPP) in the coronary artery. However, data on the independent predictors of RPP in the absence of a baseline coronary plaque burden are limited. Thus, this study aimed to investigate the predictors for RPP in patients without coronary plaques on baseline coronary computed tomography angiography (CCTA) images. Methods A total of 402 patients (mean age: 57.6 ± 10.0 years, 49.3% men) without coronary plaques at baseline who underwent serial coronary CCTA were identified from the Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry and included in this retrospective study. RPP was defined as an annual change of ≥ 1.0%/year in the percentage atheroma volume (PAV). Results During a median inter-scan period of 3.6 years (interquartile range: 2.7–5.0 years), newly developed coronary plaques and RPP were observed in 35.6% and 4.2% of the patients, respectively. The baseline traditional risk factors, i.e., advanced age (≥ 60 years), male sex, hypertension, diabetes mellitus, hyperlipidemia, obesity, and current smoking status, were not significantly associated with the risk of RPP. Multivariate linear regression analysis showed that the serum hemoglobin A1c level (per 1% increase) measured at follow-up CCTA was independently associated with the annual change in the PAV (β: 0.098, 95% confidence interval [CI]: 0.048–0.149; P

AimsResidual cardiovascular risk persists despite statin therapy. In REDUCE-IT, icosapent ethyl (IPE) reduced total events, but the mechanisms of benefit are not fully understood. EVAPORATE evaluated the effects of IPE on plaque characteristics by coronary computed tomography angiography (CCTA). Given the conclusion that the IPE-treated patients demonstrate that plaque burden decreases has already been published in the primary study analysis, we aimed to demonstrate whether the use of an analytic technique defined and validated in histological terms could extend the primary study in terms of whether such changes could be reliably seen in less time on drug, at the individual (rather than only at the cohort) level, or both, as neither of these were established by the primary study result.Methods and ResultsEVAPORATE randomized the patients to IPE 4 g/day or placebo. Plaque morphology, including lipid-rich necrotic core (LRNC), fibrous cap thickness, and intraplaque hemorrhage (IPH), was assessed using the ElucidVivo® (Elucid Bioimaging Inc.) on CCTA. The changes in plaque morphology between the treatment groups were analyzed. A neural network to predict treatment assignment was used to infer patient representation that encodes significant morphological changes. Fifty-five patients completed the 18-month visit in EVAPORATE with interpretable images at each of the three time points. The decrease of LRNC between the patients on IPE vs. placebo at 9 months (reduction of 2 mm3 vs. an increase of 41 mm3, p = 0.008), widening at 18 months (6 mm3 vs. 58 mm3 increase, p = 0.015) were observed. While not statistically significant on a univariable basis, reductions in wall thickness and increases in cap thickness motivated multivariable modeling on an individual patient basis. The per-patient response assessment was possible using a multivariable model of lipid-rich phenotype at the 9-month follow-up, p

Objective: The association of sex-specific hormones with coronary computed tomography angiography(CCTA)-based plaque characteristics in women without cardiovascular disease is not well understood. We investigated the association of sex-specific hormones with coronary artery plaque characteristics in a contemporary multiracial cohort with no clinical coronary artery disease (CAD). Methods: In this cross-sectional analysis, we utilized data from 2,325 individuals with no clinical CAD from the Miami Heart (MiHeart) study. Multivariable logistic regression models were used to investigate the association of sex hormones: sex hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), free and total testosterone, estradiol, with plaque characteristics among women and men. Results: Of the 1,155 women, 34.2% had any plaque and 3.4% had any high-risk plaque features (HRP) while among men (n = 1170), 63.1% had any plaque and 10.4% had HRP. Among women, estradiol and SHBG were associated with lower odds of any plaque after adjusting for age and race-ethnicity (estradiol OR per SD increase: 0.87, 95%CI: 0.76–0.98; SHBG OR per SD increase: 0.82, 95%CI: 0.72–0.93) but the significance did not persist after adjustment of cardiovascular risk factors. High free testosterone was associated with higher odds of HRP (aOR:3.48, 95%CI:1.07–11.26) but null associations for the other sex hormones with HRP, in the context of limited sample size. Among men, there were no significant associations between sex-specific hormones and plaque or HRP. Conclusion: Among young to middle-aged women with no clinical CAD, increasing estradiol and SHBG were associated with lower odds of any plaque and higher free testosterone was associated with HRP. Larger cohorts may be needed to validate this.

Therapeutic Area: ASCVD /CVD Risk Reduction Background: Over half of the US adults use Dietary supplements to improve their general health and prevent cardiovascular disease. We aimed to evaluate the effects of the above mentioned supplements on endothelial function, inflammation and cardiovascular risks over 90 days. Methods: A single-center, prospective, double-blinded, randomized, placebo-controlled (1:1 ratio) clinical trial was performed at the Lundquist institute at harbor-UCLA medical center. 53 asymptomatic volunteers aged ≥18 years, with SBP >120 or DBP >80 mmHg were enrolled. Each participant received 6 capsules daily for 90 days. The primary endpoint was changes from baseline in inflammatory markers including hypersensitive C - reactive protein (hsCRP), interleukin 6 (IL6) and Tumor Necrosis Factor Alpha (TNF-α), urine creatinine and F2-Isoprostane after 90 days. The secondary endpoint was change in endothelial function measured by Flow Mediated Dilatation (FMD) of brachial artery, Cardio-Ankle vascular index (CAVI) and blood pressure. Tertiary endpoint was changes from baseline in cholesterol, lipoprotein fractions (LDL and HDL), Triglycerides, and Omega fatty acids index. The final endpoint was supplement's safety. Results: 53 participants were randomized. 52 completed the trial with 26 in each group. The average age was 44.3±16.4 years and 52% were females. Both groups had similar demographics and risk factors, p>0.20.After taking the supplements for 90 days, the active group showed a significant increase in Omega-3 EPA, Omega-3 DPA and total Omega-3 levels, beside decrease in Omega-6 level, all P

Iodixanol is an iso-osmolar non-ionic dimeric hydrophilic contrast agent with a higher viscosity than the monomeric agents. It is the only Food and Drug Administration (FDA)-approved iso-osmolar agent in the United States, and it is the only contrast agent with an FDA-approved indication for use in cardiac computed tomographic angiography (CCTA), to assist in the diagnostic evaluation of patients with suspected coronary artery disease. In clinical studies, it has been noted to have fewer side effects and similar image quality when compared to low-osmolar contrast media. This can be attributed to the pharmacological properties of iodixanol. These contrast agents are used for coronary computed tomography angiography and cardiac catheterization. In this article, the use, tolerability, and efficacy of iodixanol are reviewed, specifically evaluating the use of CCTA and coronary angiography, including outcome studies, randomized trials, and comparisons to other contrast agents.

Objective: This study aims to evaluate image quality in patients with heart rates above or equal to 70 beats per minute (bpm), performed on a 16 cm scanner (256-slice General Electric Revolution) in comparison to a CT scanner with only 4 cm of coverage (64 slice Volume CT). Background: Recent advancements in image acquisition, such as whole-heart coverage in a single rotation and post-processing methods in coronary computed tomographic angiography (CCTA), include motion-correction algorithms, such as SnapShot Freeze (SSF), which improve temporal resolution and allow for the assessment of coronary artery disease (CAD) with lower motion scores and better image qualities. Studies from the comprehensive evaluation of high temporal- and spatial-resolution cardiac CT using a wide coverage system (CONVERGE) registry (a multicenter registry at four centers) have shown the 16 cm CT scanner having a better image quality in comparison to the 4 cm scanner. However, these studies failed to include patients with undesirable or high heart rates due to well-documented poor image acquisition on prior generations of CCTA scanners. Methods: A prospective, observational, multicenter cohort study comparing image quality, quantitively and qualitatively, on scans performed on a 16 cm CCTA in comparison to a cohort of images captured on a 4 cm CCTA at four centers. Participants were recruited based on broad inclusion criteria, and each patient in the 16 cm CCTA arm of the study received a CCTA scan using a 256-slice, whole-heart, single-beat scanner. These patients were then matched by age, gender, and heart rate to patients who underwent CCTA scans on a 4 cm CT scanner. Image quality was graded based on the signal-to-noise ratio, contrast-to-noise ratio, and on a Likert scale of 0–4: 0, very poor—4, excellent. Results: 104 patients were evaluated for this study. The mean heart rate was 75 ± 7 in the 4 cm scanner and 75 ± 7 in the 16 cm one (p = 0.426). The signal-to-noise and contrast-to-noise ratios were higher in the 16 cm scanner (p = 0.0001). In addition, more scans were evaluated as having an excellent quality on the 16 cm scanner than on the 4 cm scanner (p < 0.0001) based on a 4-point Likert scale. Conclusions: The 16 cm scanner has a superior image quality for fast heart rates compared to the 4 cm scanner. This study shows that there is a significantly higher frequency of excellent and good studies showing better contrast-to-noise and signal-to-noise ratios with the 16 cm scanner compared to the 4 cm scanner.

BackgroundThe value of pooled cohort equations (PCE) as a predictor of major adverse cardiovascular events (MACE) is poorly established among symptomatic patients. Coronary artery calcium (CAC) assessment further improves risk prediction, but non-Western studies are lacking. This study aims to compare PCE and CAC scores within a symptomatic mixed Asian cohort, and to evaluate the incremental value of CAC in predicting MACE, as well as in subgroups based on statin use.MethodsConsecutive patients with stable chest pain who underwent cardiac computed tomography were recruited. Logistic regression was performed to determine the association between risk factors and MACE. Cohort and statin-use subgroup comparisons were done for PCE against Agatston score in predicting MACE.ResultsOf 501 patients included, mean (SD) age was 53.7 (10.8) years, mean follow-up period was 4.64 (0.66) years, 43.5% were female, 48.3% used statins, and 50.0% had no CAC. MI occurred in 8 subjects while 9 subjects underwent revascularization. In the general cohort, age, presence of CAC, and ln(Volume) (OR = 1.05, 7.95, and 1.44, respectively) as well as age and PCE score for the CAC = 0 subgroup (OR = 1.16 and 2.24, respectively), were significantly associated with MACE. None of the risk factors were significantly associated with MACE in the CAC > 0 subgroup. Overall, the PCE, Agatston, and their combination obtained an area under the receiver operating characteristic curve (AUC) of 0.501, 0.662, and 0.661, respectively. Separately, the AUC of PCE, Agatston, and their combination for statin non-users were 0.679, 0.753, and 0.734, while that for statin-users were 0.585, 0.615, and 0.631, respectively. Only the performance of PCE alone was statistically significant (p = 0.025) when compared between statin-users (0.507) and non-users (0.783).ConclusionIn a symptomatic mixed Asian cohort, age, presence of CAC, and ln(Volume) were independently associated with MACE for the overall subgroup, age and PCE score for the CAC = 0 subgroup, and no risk factor for the CAC > 0 subgroup. Whilst the PCE performance deteriorated in statin versus non-statin users, the Agatston score performed consistently in both groups.

Apolipoproteins (apo) C-I and C-II are key regulators of triglyceride and HDL metabolism. Both exist as full-size native and truncated (apoC-I'; apoC-II') posttranslational proteoforms. However, the determinants and the role of these proteoforms in lipid metabolism are unknown. Here, we measured apoC-I and apoC-II proteoforms by mass spectrometry immunoassay in baseline and 10-year follow-up plasma samples from the Multi-Ethnic Study of Atherosclerosis. We found that baseline total apoC-I (mean = 9.2 mg/dl) was lower in African Americans (AA), Chinese Americans (CA), and Hispanics (by 1.8; 1.0; 1.0 mg/dl vs. whites), higher in women (by 1.2 mg/dl), and positively associated with plasma triglycerides and HDL. Furthermore, we observed that the truncated-to-native apoC-I ratio (apoC-I'/C-I) was lower in CA, negatively associated with triglycerides, and positively associated with HDL. We determined that total apoC-II (8.8 mg/dl) was lower in AA (by 0.8 mg/dl) and higher in CA and Hispanics (by 0.5 and 0.4 mg/dl), positively associated with triglycerides, and negatively associated with HDL. In addition, apoC-II'/C-II was higher in AA and women, negatively associated with triglycerides, and positively associated with HDL. We showed that the change in triglycerides was positively associated with changes in total apoC-I and apoC-II and negatively associated with changes in apoC-I'/C-I and apoC-II'/C-II, whereas the change in HDL was positively associated with changes in total apoC-I and apoC-II'/C-II and negatively associated with change in total apoC-II. This study documents racial/ethnic variation in apoC-I and apoC-II plasma levels and highlights apolipoprotein posttranslational modification as a potential regulator of plasma lipids.

Background and Aims: We aimed to determine the utility of coronary artery calcium (CAC) for atherosclerotic cardiovascular disease (ASCVD) risk stratification in women with and without early menopause (EM). Methods: To examine the association between CAC and incident ASCVD, we performed Kaplan-Meier survival analysis and multivariable Cox proportional hazards modeling using data from 2,456 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis (MESA) with or without EM, defined as occurring at 50% of middle-aged postmenopausal women with EM had CAC = 0, similar to those without EM. Among women with CAC = 0, those with EM had a low to borderline 10-year risk of ASCVD, but the 15-year risk was significantly higher for women with EM versus those without EM. When CAC ≥ 1, the incidence of ASCVD was similar for women with and without EM. These findings support the use of CAC to help improve ASCVD risk stratification in women with EM. Condensed abstract: This study investigated the association between coronary artery calcium (CAC) and incident atherosclerotic cardiovascular disease (ASCVD) in postmenopausal women with and without early menopause (EM). We found that >50% of women had CAC = 0 and an associated low-to-borderline 10-year cumulative incidence of ASCVD. However, the risk for ASCVD was significantly higher for women with EM after 15-years follow-up. Additional research is needed to better understand the differences in long-term ASCVD risk between women with and without EM who have CAC = 0.

Risk for atherosclerotic cardiovascular disease (ASCVD) shows considerable heterogeneity both in generally healthy persons and in those with known ASCVD. The foundation of preventive cardiology begins with assessing baseline ASCVD risk using global risk scores based on standard office-based measures. Persons at low risk are generally recommended for lifestyle management only and those at highest risk are recommended for both lifestyle and pharmacologic therapy. Additional “risk enhancing” factors, including both traditional risk factors and novel biomarkers and inflammatory factors can be used to further assess ASCVD risk, especially in those at borderline or intermediate risk. There are also female-specific risk enhancers, social determinants of health, and considerations for high-risk ethnic groups. Screening for subclinical atherosclerosis, especially with the use of coronary calcium screening, can further inform the treatment decision if uncertain based on the above strategies. Persons with pre-existing ASCVD also have variable risk, affected by the number of major ASCVD events, whether recurrent events have occurred recently, and the presence of other major risk factors or high-risk conditions. Current guidelines define high to very high risk ASCVD accordingly. Accurate ASCVD risk assessment is crucial for the appropriate targeting of preventive therapies to reduce ASCVD risk. Finally, the clinician-patient risk discussion focusing on lifestyle management and the risks and benefits of evidence-based pharmacologic therapies to best lower ASCVD risk is central to this process. This clinical practice statement provides the preventive cardiology specialist with guidance and tools for assessment of ASCVD risk with the goal of appropriately targeting treatment approaches for prevention of ASCVD events.

Background Lipoprotein(a) (Lp(a)) is a potent causal risk factor for cardiovascular events and mortality. However, its relationship with subclinical atherosclerosis, as defined by arterial calcification, remains unclear. This study uses the ARIC (Atherosclerosis Risk in Communities Study) to evaluate the relationship between Lp(a) in middle age and measures of vascular and valvular calcification in older age. Methods and Results Lp(a) was measured at ARIC visit 4 (1996–1998), and coronary artery calcium (CAC), together with extracoronary calcification (including aortic valve calcium, aortic valve ring calcium, mitral valve calcification, and thoracic aortic calcification), was measured at visit 7 (2018–2019). Lp(a) was defined as elevated if >50 mg/dL and CAC/extracoronary calcification were defined as elevated if >100. Logistic and linear regression models were used to evaluate the association between Lp(a) and CAC/extracoronary calcification, with further stratification by race. The mean age of participants at visit 4 was 59.2 (SD 4.3) years, with 62.2% women. In multivariable adjusted analyses, elevated Lp(a) was associated with higher odds of elevated aortic valve calcium (adjusted odds ratio [aOR], 1.82; 95% CI, 1.34–2.47), CAC (aOR, 1.40; 95% CI, 1.08–1.81), aortic valve ring calcium (aOR, 1.36; 95% CI, 1.07–1.73), mitral valve calcification (aOR, 1.37; 95% CI, 1.06–1.78), and thoracic aortic calcification (aOR, 1.36; 95% CI, 1.05–1.77). Similar results were obtained when Lp(a) and CAC/extracoronary calcification were examined on continuous logarithmic scales. There was no significant difference in the association between Lp(a) and each measure of calcification by race or sex. Conclusions Elevated Lp(a) at middle age is significantly associated with vascular and valvular calcification in older age, represented by elevated CAC, aortic valve calcium, aortic valve ring calcium, mitral valve calcification, thoracic aortic calcification. Our findings encourage assessing Lp(a) levels in individuals with increased cardiovascular disease risk, with subsequent comprehensive vascular and valvular assessment where elevated.

Background: Adipokines play a role in cardiometabolic pathways. Coronary artery calcium (CAC) progression prognosticates cardiovascular disease (CVD) risk. However, the association of adipokines with CAC progression is not well established. We examined the association of adipokines with CAC progression in a multi-ethnic cohort free of CVD at baseline. Methods: We included 1,904 randomly-selected adults enrolled in the multi-ethnic study of atherosclerosis who had both adipokine levels [leptin, resistin, adiponectin] and CAC measured at either exam 2 (2002–2004) or exam 3 (2004–2005). CAC was previously measured at exam 1 (2000–2002) and a subset (n = 566) had CAC measured at exam 5 (2010–2012). We used logistic regression to examine odds of CAC progression between exam 1 and 2/3 (defined as >0 Agatston units of change/year). We used linear mixed effect models to examine CAC progression from exam 2/3 to 5. Results: At exam 2/3, the mean age was 65(10) yrs; 50% women. In models adjusted for sociodemographic factors and BMI, the highest tertile of leptin, compared to lowest, was associated with an increased odds of CAC progression over the preceding 2.6yrs [OR 1.60 (95% CI: 1.10–2.33)]. In models further adjusted for visceral fat and CVD risk factors, the highest tertile of leptin was statistically significantly associated with a 4% (1–7%) greater CAC progression over an average of 7yrs. No associations were seen for resistin and adiponectin. Conclusions: Higher leptin levels were independently, but modestly, associated with CAC progression. Atherosclerosis progression may be one mechanism through which leptin confers increased CVD risk.

Air pollution might affect atherosclerosis through DNA methylation changes in cells crucial to atherosclerosis, such as monocytes. We conducted an epigenome-wide study of DNA methylation in CD14+ monocytes and long-term ambient air pollution exposure in adults participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We also assessed the association between differentially methylated signals and cis-gene expression. Using spatiotemporal models, one-year average concentrations of outdoor fine particulate matter (PM2.5) and oxides of nitrogen (NOX) were estimated at participants’ homes. We assessed DNA methylation and gene expression using Illumina 450k and HumanHT-12 v4 Expression BeadChips, respectively (n = 1,207). We used bump hunting and site-specific approaches to identify differentially methylated signals (false discovery rate of 0.05) and used linear models to assess associations between differentially methylated signals and cis-gene expression. Four differentially methylated regions (DMRs) located on chromosomes 5, 6, 7, and 16 (within or near SDHAP3, ZFP57, HOXA5, and PRM1, respectively) were associated with PM2.5. The DMRs on chromosomes 5 and 6 also associated with NOX. The DMR on chromosome 5 had the smallest p-value for both PM2.5 (p = 1.4×10−6) and NOX (p = 7.7×10−6). Three differentially methylated CpGs were identified for PM2.5, and cg05926640 (near TOMM20) had the smallest p-value (p = 5.6×10−8). NOX significantly associated with cg11756214 within ZNF347 (p = 5.6×10−8). Several differentially methylated signals were also associated with cis-gene expression. The DMR located on chromosome 7 was associated with the expression of HOXA5, HOXA9, and HOXA10. The DMRs located on chromosomes 5 and 16 were associated with expression of MRPL36 and DEXI, respectively. The CpG cg05926640 was associated with expression of ARID4B, IRF2BP2, and TOMM20. We identified differential DNA methylation in monocytes associated with long-term air pollution exposure. Methylation signals associated with gene expression might help explain how air pollution contributes to cardiovascular disease.

Background Patients who undergo percutaneous coronary intervention (PCI) are at increased risk for recurrent cardiovascular events despite aggressive medical therapy. Methods and Results This post hoc analysis focused on the subset of patients with prior PCI enrolled in REDUCE‐IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, randomized, double‐blind, placebo‐controlled trial of icosapent ethyl versus placebo. Icosapent ethyl was added to statins in patients with low‐density lipoprotein cholesterol

In this clinical practice statement, we represent a summary of the current evidence and clinical applications of cardiac computed tomography (CT) in evaluation of coronary artery disease (CAD), from an expert panel organized by the American Society for Preventive Cardiology (ASPC), and appraises the current use and indications of cardiac CT in clinical practice. Cardiac CT is emerging as a front line non-invasive diagnostic test for CAD, with evidence supporting the clinical utility of cardiac CT in diagnosis and prevention. CCTA offers several advantages beyond other testing modalities, due to its ability to identify and characterize coronary stenosis severity and pathophysiological changes in coronary atherosclerosis and stenosis, aiding in early diagnosis, prognosis and management of CAD. This document further explores the emerging applications of CCTA based on functional assessment using CT derived fractional flow reserve, peri‑coronary inflammation and artificial intelligence (AI) that can provide personalized risk assessment and guide targeted treatment. We sought to provide an expert consensus based on the latest evidence and best available clinical practice guidelines regarding the role of CCTA as an essential tool in cardiovascular prevention – applicable to risk assessment and early diagnosis and management, noting potential areas for future investigation.

Background High triglycerides are associated with atherosclerotic cardiovascular disease (ASCVD) risks. Among patients with advanced chronic kidney disease (CKD), the association of elevated triglycerides with mortality is diminished and, thus, we investigated the relationship of triglycerides with ASCVD and non‐ASCVD hospitalizations across CKD stages. Methods and Results The cohort comprised 2 963 176 veterans who received care in 2004 to 2006 (baseline) and were followed up to 2014. Using Cox models, we evaluated baseline and time‐varying triglycerides with time to ASCVD or non‐ASCVD hospitalizations, stratified by baseline CKD stage, and adjusted for demographics and baseline or time‐updated clinical characteristics. The cohort mean±SD age was 63±14 years, with a baseline median (interquartile range) triglycerides level of 127 (87–189) mg/dL, and a quarter had prevalent CKD. There was a linear association between baseline triglycerides and ASCVD risk; however, the risk with high triglycerides ≥240 mg/dL attenuated with worsening CKD stages (reference: triglycerides 120 to

AimsAnecdotal reports have suggested increased soft tissue calcification in individuals with long-term exposures to high blood glucose. The association of costal cartilage calcification (CCC), a reliably quantifiable marker obtainable from non-contrast cardiac computed tomography (CT) with cumulative fasting blood glucose (FBG) exposure, is unknown. In this study, we aimed to determine the association between quantified CCC and cumulative glucose exposure using non-contrast coronary artery calcium (CAC) scoring computed tomography (CT) images in the Multi-Ethnic Study of Atherosclerosis (MESA).MethodsThe volume of bilateral CCC was quantified in high-density pixels (threshold of Hounsfield Unit>180) using the CAC scoring CT images acquired in the 5th MESA exam. Prior long-term cumulative exposure to FBG was calculated by area under the FBG-time curve over ten years before the time of the CT exam.ResultsA total of 2,305 participants (mean age: 69, female/male: 1.3) were included in this study. The median CCC volume was lower in females than males (1158 mm3 [IQR: 1751] vs. 3054 mm3 [3851], p

Atherosclerotic cardiovascular disease (ASCVD) is a common disease among the general population, and includes four major areas: (1) coronary heart disease (CHD), manifested by stable angina, unstable angina, myocardial infarction (MI), heart failure, and coronary death; (2) cerebrovascular disease, manifested by transient ischemia attack and stroke; (3) peripheral vascular disease, manifested by claudication and critical limb ischemia; and (4) aortic atherosclerosis and aortic aneurysm (thoracic and abdominal). CHD remains the leading cause of death for both men and women in the United States. So, it is imperative to identify people at risk of CHD and provide appropriate medical treatment or intervention to prevent serious complications and outcomes including sudden cardiac death. Coronary artery calcification (CAC) is a marker of subclinical coronary artery disease. Therefore, coronary artery calcium score is an important screening method for Coronary artery disease (CAD). In this article, we performed a comprehensive review of current literatures and studies assessing the prognostic value of CAC for future cardiovascular disease (CVD) events. We searched PubMed, MEDLINE, Google Scholar, and Cochrane library. We also reviewed the 2018 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the assessment of CVD risk. A CAC score of zero corresponds to very low CVD event rates (∼1% per year) and hence a potent negative risk marker. This has been referred to as the ‘power of zero’ and affords the lowest risk of any method of risk calculation. It is now indicated in the 2018 ACC/AHA Cholesterol guidelines to be used to avoid statins for 5–10 years after a score of zero, and then re-assess the patient.