Heterogeneity in the Association Between the Presence of Coronary Artery Calcium and Cardiovascular Events: A Machine-Learning Approach in the MESA Study.

BACKGROUND: Coronary artery calcium (CAC) has been widely recognized as an important predictor of cardiovascular disease (CVD). Given the finite resources, it is important to identify individuals who would receive the most benefit from detecting positive CAC by screening. However, the evidence is limited as to whether the burden of positive CAC on CVD differs by multidimensional individual characteristics. We sought to investigate the heterogeneity in the association between positive CAC and incident CVD. METHODS: This cohort study included adults from MESA (Multi-Ethnic Study of Atherosclerosis) ages ≥45 years and free of cardiovascular disease. After propensity score matching in a 1:1 ratio, we applied a machine learning causal forest model to (1) evaluate the heterogeneity in the association between positive CAC and incident CVD, and (2) predict the increase in CVD risk at 10-years when CAC>0 (versus CAC=0) at the individual level. We then compared the estimated increase in CVD risk when CAC>0 to the absolute 10-year atherosclerotic CVD (ASCVD) risk calculated by the 2013 American College of Cardiology/American Heart Association pooled cohort equations. RESULTS: Across 3328 adults in our propensity score-matched analysis, our causal forest model showed the heterogeneity in the association between CAC>0 and incident CVD. We found a dose-response relationship of the estimated increase in CVD risk when CAC>0 with higher 10-year ASCVD risk. Almost all individuals (2293 of 2428 [94.4%]) with borderline risk of ASCVD or higher showed ≥2.5% increase in CVD risk when CAC>0. Even among 900 adults with low ASCVD risk, 689 (69.2%) showed ≥2.5% increase in CVD risk when CAC>0; these individuals were more likely to be male, Hispanic, and have unfavorable CVD risk factors than others. CONCLUSIONS: The expected increases in CVD risk when CAC>0 were heterogeneous across individuals. Moreover, nearly 70% of people with low ASCVD risk showed a large increase in CVD risk when CAC>0, highlighting the need for CAC screening among such low-risk individuals. Future studies are needed to assess whether targeting individuals for CAC measurements based on not only the absolute ASCVD risk but also the expected increase in CVD risk when CAC>0 improves cardiovascular outcomes.

Coronary artery calcium and cardiovascular outcomes in patients with lymphoma undergoing autologous hematopoietic cell transplantation.

BACKGROUND: Patients undergoing autologous hematopoietic cell transplantation (HCT) have a >2-fold risk of developing cardiovascular disease (CVD; heart failure, myocardial infarction, and stroke), compared to the general population. Coronary artery calcium (CAC) is predictive of CVD in nononcology patients but is not as well studied in patients who underwent HCT and survivors of HCT.The objective of this study was to examine the association between CAC and CVD risk and outcomes after HCT in patients with lymphoma. METHODS: This was a retrospective cohort study of 243 consecutive patients who underwent a first autologous HCT for lymphoma between 2009 and 2014. CAC (Agatston score) was determined from chest computed tomography obtained <60 days from HCT. Multivariable Cox regression analysis was used to calculate hazard ratio (HR) estimates and 95% confidence intervals (CIs), adjusted for covariates (age, conventional risk factors [e.g., hypertension and dyslipidemia], and cancer treatment). RESULTS: The median age at HCT was 55.7 years (range, 18.5-75.1 years), 59% were male, and 60% were non-Hispanic White. The prevalence of CAC was 37%. The 5-year CVD incidence for the cohort was 12%, and there was an incremental increase in the incidence according to CAC score: 0 (6%), 1-100 (20%), and >100 (32%) (p = .001). CAC was significantly associated with CVD risk (HR, 3.0; 95% CI, 1.2-7.5) and worse 5-year survival (77% vs. 50%; p < .001; HR, 2.0; 95% CI, 1.1-3.4), compared to those without CAC. CONCLUSIONS: CAC is independently associated with CVD and survival after HCT. This highlights the importance of integrating readily available imaging information in risk stratification and decision-making in patients undergoing HCT, which sets the stage for strategies to optimize outcomes after HCT.

High Incidence Rate of Computed Tomography-Measured Steatotic Liver Disease in Men With and Without HIV Infection.

INTRODUCTION: We determined steatotic liver disease (SLD) incidence in a prospective cohort of men with HIV (MWH) and men without HIV (MWOH). METHODS: Incident SLD was defined using paired noncontrast computed tomography scans performed during 2010-2013 and repeated during 2015-2017. RESULTS: Of 268 men, 173 MWH and 95 MWOH, 33 had incident SLD (11.1%, incidence rate 2.4 and 2.7/100 person-years for MWH and MWOH, respectively). Overall, higher abdominal visceral adipose tissue was independently associated with increased SLD risk. In MWH, increased visceral adipose tissue, insulin resistance, chronic hepatitis B, and cumulative etravirine use were associated with SLD. DISCUSSION: Metabolic factors, but not HIV, were associated with incident SLD. The high incidence rate suggests that SLD will continue to increase in PWH.

Trabecular bone mineral density as measured by thoracic vertebrae predicts incident hip and vertebral fractures: the multi-ethnic study of atherosclerosis.

We evaluated the relationship of bone mineral density (BMD) by computed tomography (CT), to predict fractures in a multi-ethnic population. We demonstrated that vertebral and hip fractures were more likely in those patients with low BMD. This is one of the first studies to demonstrate that CT BMD derived from thoracic vertebrae can predict future hip and vertebral fractures. PURPOSE/INTRODUCTION: Osteoporosis affects an enormous number of patients, of all races and both sexes, and its prevalence increases as the population ages. Few studies have evaluated the association between the vertebral trabecular bone mineral density(vBMD) and osteoporosis-related hip fracture in a multiethnic population, and no studies have demonstrated the predictive value of vBMD for fractures. METHOD: We sought to determine the predictive value of QCT-based trabecular vBMD of thoracic vertebrae derived from coronary artery calcium scan for hip fractures in the Multi-Ethnic Study of Atherosclerosis(MESA), a nationwide multicenter cohort included 6814 people from six medical centers across the USA and assess if low bone density by QCT can predict future fractures. Measures were done using trabecular bone measures, adjusted for individual patients, from three consecutive thoracic vertebrae (BDI Inc, Manhattan Beach CA, USA) from non-contrast cardiac CT scans. RESULTS: Six thousand eight hundred fourteen MESA baseline participants were included with a mean age of 62.2 ± 10.2 years, and 52.8% were women. The mean thoracic BMD is 162.6 ± 46.8 mg/cm3 (95% CI 161.5, 163.7), and 27.6% of participants (n = 1883) had osteoporosis (T-score 2.5 or lower). Over a median follow-up of 17.4 years, Caucasians have a higher rate of vertebral fractures (6.9%), followed by Blacks (4.4%), Hispanics (3.7%), and Chinese (3.0%). Hip fracture patients had a lower baseline vBMD as measured by QCT than the non-hip fracture group by 13.6 mg/cm3 [P < 0.001]. The same pattern was seen in the vertebral fracture population, where the mean BMD was substantially lower 18.3 mg/cm3 [P < 0.001] than in the non-vertebral fracture population. Notably, the above substantial relationship was unaffected by age, gender, race, BMI, hypertension, current smoking, medication use, or activity. Patients with low trabecular BMD of thoracic vertebrae showed a 1.57-fold greater risk of first hip fracture (HR 1.57, 95% CI 1.38-1.95) and a nearly threefold increased risk of first vertebral fracture (HR 2.93, 95% CI 1.87-4.59) compared to normal BMD patients. CONCLUSION: There is significant correlation between thoracic trabecular BMD and the incidence of future hip and vertebral fracture. This study demonstrates that thoracic vertebrae BMD, as measured on cardiac CT (QCT), can predict both hip and vertebral fractures without additional radiation, scanning, or patient burden. Osteopenia and osteoporosis are markedly underdiagnosed. Finding occult disease affords the opportunity to treat the millions of people undergoing CT scans every year for other indications.

The association of microvascular disease and endothelial dysfunction with vertebral trabecular bone mineral density : The MESA study.

Retinopathy and albuminuria are associated with hip fracture risk. We investigated whether these disorders and endothelial dysfunction (which underlies microvascular diseases) were associated with low trabecular bone density. No significant associations were found, suggesting that microvascular diseases are not related to fracture risk through low trabecular bone density. PURPOSE: Microvascular diseases of the eye, kidney, and brain are associated with endothelial dysfunction and increased hip fracture risk. To explore the basis for higher hip fracture risk, we comprehensively examined whether markers of microvascular disease and/or endothelial dysfunction are related to trabecular bone mineral density (BMD), a proximate risk factor for osteoporotic fractures. METHODS: Among 6814 participants in the Multi-Ethnic Study of Atherosclerosis study (MESA), we derived thoracic vertebral trabecular BMD from computed tomography of the chest and measured urine albumin to creatinine ratios (UACR), retinal arteriolar and venular widths, flow mediated dilation (FMD) of the brachial artery after 5 min of ischemia; and levels of five soluble endothelial adhesion markers (ICAM-1, VCAM-1, L-selectin, P-selectin, and E-selectin). Linear regression models were used to examine the association of trabecular BMD with markers of microvascular disease and with markers of endothelial dysfunction. RESULTS: We observed no significant associations of UACR, retinal arteriolar or venular widths, or FMD with BMD. We also observed no statistically significant association of spine trabecular BMD with levels of endothelial adhesion markers. Men and women had largely similar results. CONCLUSION: We conclude that there is little evidence to connect thoracic spine trabecular BMD to microvascular disorders or to endothelial dysfunction among multi-ethnic middle-aged and older adults. Other factors beyond trabecular BMD (e.g., bone quality or predisposition to falling) may be responsible for the associations of microvascular disease with osteoporotic fractures.

Combination of computed tomography angiography with coronary artery calcium score for improved diagnosis of coronary artery disease: a collaborative meta-analysis of stable chest pain patients referred for invasive coronary angiography.

OBJECTIVES: Coronary computed tomography angiography (CCTA) has higher diagnostic accuracy than coronary artery calcium (CAC) score for detecting obstructive coronary artery disease (CAD) in patients with stable chest pain, while the added diagnostic value of combining CCTA with CAC is unknown. We investigated whether combining coronary CCTA with CAC score can improve the diagnosis of obstructive CAD compared with CCTA alone. METHODS: A total of 2315 patients (858 women, 37%) aged 61.1 ± 10.2 from 29 original studies were included to build two CAD prediction models based on either CCTA alone or CCTA combined with the CAC score. CAD was defined as at least 50% coronary diameter stenosis on invasive coronary angiography. Models were built by using generalized linear mixed-effects models with a random intercept set for the original study. The two CAD prediction models were compared by the likelihood ratio test, while their diagnostic performance was compared using the area under the receiver-operating-characteristic curve (AUC). Net benefit (benefit of true positive versus harm of false positive) was assessed by decision curve analysis. RESULTS: CAD prevalence was 43.5% (1007/2315). Combining CCTA with CAC improved CAD diagnosis compared with CCTA alone (AUC: 87% [95% CI: 86 to 89%] vs. 80% [95% CI: 78 to 82%]; p < 0.001), likelihood ratio test 236.3, df: 1, p < 0.001, showing a higher net benefit across almost all threshold probabilities. CONCLUSION: Adding the CAC score to CCTA findings in patients with stable chest pain improves the diagnostic performance in detecting CAD and the net benefit compared with CCTA alone. CLINICAL RELEVANCE STATEMENT: CAC scoring CT performed before coronary CTA and included in the diagnostic model can improve obstructive CAD diagnosis, especially when CCTA is non-diagnostic. KEY POINTS: • The combination of coronary artery calcium with coronary computed tomography angiography showed significantly higher AUC (87%, 95% confidence interval [CI]: 86 to 89%) for diagnosis of coronary artery disease compared to coronary computed tomography angiography alone (80%, 95% CI: 78 to 82%, p < 0.001). • Diagnostic improvement was mostly seen in patients with non-diagnostic C. • The improvement in diagnostic performance and the net benefit was consistent across age groups, chest pain types, and genders.

Progression of non-obstructive coronary plaque: a practical CCTA-based risk score from the PARADIGM registry.

OBJECTIVES: No clear recommendations are endorsed by the different scientific societies on the clinical use of repeat coronary computed tomography angiography (CCTA) in patients with non-obstructive coronary artery disease (CAD). This study aimed to develop and validate a practical CCTA risk score to predict medium-term disease progression in patients at a low-to-intermediate probability of CAD. METHODS: Patients were part of the Progression of AtheRosclerotic PlAque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry. Specifically, 370 (derivation cohort) and 219 (validation cohort) patients with two repeat, clinically indicated CCTA scans, non-obstructive CAD, and absence of high-risk plaque (≥ 2 high-risk features) at baseline CCTA were included. Disease progression was defined as the new occurrence of ≥ 50% stenosis and/or high-risk plaque at follow-up CCTA. RESULTS: In the derivation cohort, 104 (28%) patients experienced disease progression. The median time interval between the two CCTAs was 3.3 years (2.7-4.8). Odds ratios for disease progression derived from multivariable logistic regression were as follows: 4.59 (95% confidence interval: 1.69-12.48) for the number of plaques with spotty calcification, 3.73 (1.46-9.52) for the number of plaques with low attenuation component, 2.71 (1.62-4.50) for 25-49% stenosis severity, 1.47 (1.17-1.84) for the number of bifurcation plaques, and 1.21 (1.02-1.42) for the time between the two CCTAs. The C-statistics of the model were 0.732 (0.676-0.788) and 0.668 (0.583-0.752) in the derivation and validation cohorts, respectively. CONCLUSIONS: The new CCTA-based risk score is a simple and practical tool that can predict mid-term CAD progression in patients with known non-obstructive CAD. CLINICAL RELEVANCE STATEMENT: The clinical implementation of this new CCTA-based risk score can help promote the management of patients with non-obstructive coronary disease in terms of timing of imaging follow-up and therapeutic strategies. KEY POINTS: • No recommendations are available on the use of repeat CCTA in patients with non-obstructive CAD. • This new CCTA score predicts mid-term CAD progression in patients with non-obstructive stenosis at baseline. • This new CCTA score can help guide the clinical management of patients with non-obstructive CAD.

Apo CIII Proteoforms, Plasma Lipids, and Cardiovascular Risk in MESA.

BACKGROUND: Apo CIII (apolipoprotein CIII) is an important regulator of triglyceride metabolism and was associated with cardiovascular risk in several cohorts. It is present in 4 major proteoforms, a native peptide (CIII0a), and glycosylated proteoforms with zero (CIII0b), 1 (CIII1, most abundant), or 2 (CIII2) sialic acids, which may differentially modify lipoprotein metabolism. We studied the relationships of these proteoforms with plasma lipids and cardiovascular risk. METHODS: Apo CIII proteoforms were measured by mass spectrometry immunoassay in baseline plasma samples of 5791 participants of Multi-Ethnic Study of Atherosclerosis, an observational community-based cohort. Standard plasma lipids were collected for up to 16 years and cardiovascular events (myocardial infarction, resuscitated cardiac arrest, or stroke) were adjudicated for up to 17 years. RESULTS: Apo CIII proteoform composition differed by age, sex, race and ethnicity, body mass index, and fasting glucose. Notably, CIII1 was lower in older participants, men and Black and Chinese (versus White) participants, and higher in obesity and diabetes. In contrast, CIII2 was higher in older participants, men, Black, and Chinese persons, and lower in Hispanic individuals and obesity. Higher CIII2 to CIII1 ratio (CIII2/III1) was associated with lower triglycerides and higher HDL (high-density lipoprotein) in cross-sectional and longitudinal models, independently of clinical and demographic risk factors and total apo CIII. The associations of CIII0a/III1 and CIII0b/III1 with plasma lipids were weaker and varied through cross-sectional and longitudinal analyses. Total apo CIII and CIII2/III1 were positively associated with cardiovascular disease risk (n=669 events, hazard ratios, 1.14 [95% CI, 1.04-1.25] and 1.21 [1.11-1.31], respectively); however, the associations were attenuated after adjustment for clinical and demographic characteristics (1.07 [0.98-1.16]; 1.07 [0.97-1.17]). In contrast, CIII0b/III1 was inversely associated with cardiovascular disease risk even after full adjustment including plasma lipids (0.86 [0.79-0.93]). CONCLUSIONS: Our data indicate differences in clinical and demographic relationships of apo CIII proteoforms, and highlight the importance of apo CIII proteoform composition in predicting future lipid patterns and cardiovascular disease risk.

Methods and Reproducibility of Liver Fat Measurement Using 3-Dimensional Liver Segmentation From Noncontrast Computed Tomography in EVAPORATE Cohort.

OBJECTIVE: Nonalcoholic fatty liver disease not only shares multiple risk factors with cardiovascular disease but also independently predicts its increased risk and related outcomes. Here, we evaluate reproducibility of 3-dimensional (3D) liver volume segmentation method to identify fatty liver on noncontrast cardiac computed tomography (CT) and compare measures with previously validated 2-dimensional (2D) segmentation CT criteria for the measurement of liver fat. METHODS: The study included 68 participants enrolled in the EVAPORATE trial and underwent serial noncontrast cardiac CT. Liver attenuation < 40 Hounsfield units (HU) was used for diagnosing fatty liver, as done in the MESA study. Two-dimensional and 3D segmentation of the liver were performed by Philips software. Bland-Altman plot analysis was used to assess reproducibility. RESULTS: Interreader reproducibility of 3D liver mean HU measurements was 96% in a sample of 111 scans. Reproducibility of 2D and 3D liver mean HU measurements was 93% in a sample of 111 scans. Reproducibility of change in 2D and 3D liver mean HU was 94% in 68 scans. Kappa, a measure of agreement in which the 2D and 3D measures both identified fatty liver, was excellent at 96.4% in 111 scans. CONCLUSIONS: Fatty liver can be reliably diagnosed and measured serially in a stable and reproducible way by 3D liver segmentation of noncontrast cardiac CT scans. Future studies need to explore the sensitivity and stability of measures for low liver fat content by 3D segmentation, over the current 2D methodology. This measure can serve as an imaging biomarker to understand mechanistic correlations between atherosclerosis, fatty liver, and cardiovascular disease risk.

Trimethylamine N-oxide is associated with long-term mortality risk: the multi-ethnic study of atherosclerosis.

AIMS: Little is known about associations of trimethylamine N-oxide (TMAO), a novel gut microbiota-generated metabolite of dietary phosphatidylcholine and carnitine, and its changes over time with all-cause and cause-specific mortality in the general population or in different race/ethnicity groups. The study aimed to investigate associations of serially measured plasma TMAO levels and changes in TMAO over time with all-cause and cause-specific mortality in a multi-ethnic community-based cohort. METHODS AND RESULTS: The study included 6,785 adults from the Multi-Ethnic Study of Atherosclerosis. TMAO was measured at baseline and year 5 using mass spectrometry. Primary outcomes were adjudicated all-cause mortality and cardiovascular disease (CVD) mortality. Secondary outcomes were deaths due to kidney failure, cancer, or dementia obtained from death certificates. Cox proportional hazards models with time-varying TMAO and covariates assessed the associations with adjustment for sociodemographics, lifestyles, diet, metabolic factors, and comorbidities. During a median follow-up of 16.9 years, 1704 participants died and 411 from CVD. Higher TMAO levels associated with higher risk of all-cause mortality [hazard ratio (HR): 1.12, 95% confidence interval (CI): 1.08-1.17], CVD mortality (HR: 1.09, 95% CI: 1.00-1.09), and death due to kidney failure (HR: 1.44, 95% CI: 1.25-1.66) per inter-quintile range, but not deaths due to cancer or dementia. Annualized changes in TMAO levels associated with higher risk of all-cause mortality (HR: 1.10, 95% CI: 1.05-1.14) and death due to kidney failure (HR: 1.54, 95% CI: 1.26-1.89) but not other deaths. CONCLUSION: Plasma TMAO levels were positively associated with mortality, especially deaths due to cardiovascular and renal disease, in a multi-ethnic US cohort.

Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study.

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study.

BACKGROUND: Lifestyle intervention and metformin have been shown to prevent diabetes; however, their efficacy in preventing cardiovascular disease associated with the development of diabetes is unclear. We examined whether these interventions reduced the incidence of major cardiovascular events over a 21-year median follow-up of participants in the DPP trial (Diabetes Prevention Program) and DPPOS (Diabetes Prevention Program Outcomes Study). METHODS: During DPP, 3234 participants with impaired glucose tolerance were randomly assigned to metformin 850 mg twice daily, intensive lifestyle or placebo, and followed for 3 years. During the next 18-year average follow-up in DPPOS, all participants were offered a less intensive group lifestyle intervention, and unmasked metformin was continued in the metformin group. The primary outcome was the first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. An extended cardiovascular outcome included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction by ECG. ECGs and cardiovascular risk factors were measured annually. RESULTS: Neither metformin nor lifestyle intervention reduced the primary outcome: metformin versus placebo hazard ratio 1.03 (95% CI, 0.78-1.37; P = 0.81) and lifestyle versus placebo hazard ratio 1.14 (95% CI, 0.87-1.50; P = 0.34). Risk factor adjustment did not change these results. No effect of either intervention was seen on the extended cardiovascular outcome. CONCLUSIONS: Neither metformin nor lifestyle reduced major cardiovascular events in DPPOS over 21 years despite long-term prevention of diabetes. Provision of group lifestyle intervention to all, extensive out-of-study use of statin and antihypertensive agents, and reduction in the use of study metformin together with out-of-study metformin use over time may have diluted the effects of the interventions. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: DPP (NCT00004992) and DPPOS (NCT00038727).

Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.

Prognostic value of coronary artery calcium score for the prediction of atherosclerotic cardiovascular disease in participants with suspected nonalcoholic hepatic steatosis: Results from the multi-ethnic study of atherosclerosis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) events; thus, a diagnostic approach to help identify NAFLD patients at high risk is needed. In this study, we hypothesized that coronary artery calcium (CAC) screening could help stratify the risk of ASCVD events in participants with suspected nonalcoholic hepatic steatosis. METHODS: A total of 713 participants with suspected nonalcoholic hepatic steatosis without previous cardiovascular events from the Multi-Ethnic Study of Atherosclerosis (MESA) were followed for the occurrence of incident ASCVD. Nonalcoholic hepatic steatosis was defined using nonenhanced computed tomography and liver/spleen attenuation ratio <1. Cox proportional hazards regression models were used to estimate hazard ratios (HR). C-statistics and areas under the time-dependent receiver operating characteristic curves (tAUC) were used to compare incremental contributions of CAC score when added to the clinical risk factors. RESULTS: In multivariable analyses, CAC score was found to be independently associated with incident ASCVD (HR = 1.33, 95% CI = 1.22-1.44, P < .001). The addition of CAC score to clinical risk factors increased the C-statistic from 0.677 to 0.739 (P < .001) and tAUC at 10 years from 0.668 to 0.771, respectively. In subgroup analyses, the incremental prognostic value of CAC score was more significant in participants with low/borderline- (<7.5%) and intermediate- (7.5%-20%) 10-year ASCVD risk scores. CONCLUSIONS: The inclusion of CAC score in global risk assessment was found to significantly improve the classification of incident ASCVD events in participants with suspected nonalcoholic hepatic steatosis, indicating a potential role for CAC screening in risk assessment.

Associations between alcohol and cigarette use and type 1 and 2 myocardial infarction among people with HIV.

OBJECTIVES: People with HIV have a higher risk of myocardial infarction (MI) than the general population, with a greater proportion of type 2 MI (T2MI) due to oxygen demand-supply mismatch compared with type 1 (T1MI) resulting from atherothrombotic plaque disruption. People living with HIV report a greater prevalence of cigarette and alcohol use than do the general population. Alcohol use and smoking as risk factors for MI by type are not well studied among people living with HIV. We examined longitudinal associations between smoking and alcohol use patterns and MI by type among people living with HIV. DESIGN AND METHODS: Using longitudinal data from the Centers for AIDS Research Network of Integrated Clinical Systems cohort, we conducted time-updated Cox proportional hazards models to determine the impact of smoking and alcohol consumption on adjudicated T1MI and T2MI. RESULTS: Among 13 506 people living with HIV, with a median 4 years of follow-up, we observed 177 T1MI and 141 T2MI. Current smoking was associated with a 60% increase in risk of both T1MI and T2MI. In addition, every cigarette smoked per day was associated with a 4% increase in risk of T1MI, with a suggestive, but not significant, 2% increase for T2MI. Cigarette use had a greater impact on T1MI for men than for women and on T2MI for women than for men. Increasing alcohol use was associated with a lower risk of T1MI but not T2MI. Frequency of heavy episodic alcohol use was not associated with MI. CONCLUSIONS: Our findings reinforce the prioritization of smoking reduction, even without cessation, and cessation among people living with HIV for MI prevention and highlight the different impacts on MI type by gender.

ATP-binding cassette G1 membrane transporter-mediated cholesterol efflux capacity influences coronary atherosclerosis and cardiovascular risk in Rheumatoid Arthritis.

OBJECTIVES: Cholesterol efflux capacity (CEC) measures the ability of high-density lipoprotein (HDL) to remove cholesterol from macrophages and reduce the lipid content of atherosclerotic plaques. CEC inversely associated with cardiovascular risk beyond HDL-cholesterol levels. CEC through the ATP-binding-cassette G1 (ABCG1) membrane transporter is impaired in rheumatoid arthritis (RA). We evaluated associations of ABCG1-CEC with coronary atherosclerosis, plaque progression and cardiovascular risk in RA. METHODS: Coronary atherosclerosis (noncalcified, partially, fully-calcified, low-attenuation plaque) was assessed with computed tomography angiography in 140 patients and reevaluated in 99 after 6.9 ± 0.3 years. Cardiovascular events including acute coronary syndromes, stroke, cardiovascular death, claudication, revascularization and hospitalized heart failure were recorded. ABCG1-CEC was measured in Chinese hamster ovary cells as percentage of effluxed over total intracellular cholesterol. RESULTS: ABCG1-CEC inversely associated with extensive atherosclerosis (≥5 plaques) (adjusted odds ratio 0.50 [95% CI 0.28-0.88]), numbers of partially-calcified (rate ratio [RR] 0.71 [0.53-0.94]) and low-attenuation plaques (RR 0.63 [0.43-0.91] per standard deviation increment). Higher ABCG1-CEC predicted fewer new partially-calcified plaques in patients with lower baseline and time-averaged CRP and fewer new noncalcified and calcified plaques in those receiving higher mean prednisone dose. ABCG1-CEC inversely associated with events in patients with but not without noncalcified plaques, with

Serum cholesterol loading capacity of macrophages is regulated by seropositivity and C-reactive protein in rheumatoid arthritis patients.

OBJECTIVE: Excessive cholesterol accumulation in macrophages is the pivotal step underlying atherosclerotic plaque formation. We here explore factors in the serum of patients with RA, and mechanisms through which they interact with and influence cholesterol loading capacity (CLC) of macrophages. METHODS: In a cross-sectional observational cohort of 104 patients with RA, CLC was measured as intracellular cholesterol content in human THP-1-derived macrophages after incubation with patient serum. Low-density lipoprotein (LDL) oxidation was measured in terms of oxidized phospholipids on apoB100-containing particles (oxPL-apoB100). Antibodies against oxidized LDL (anti-oxLDL), proprotein convertase subtilisin/Kexin type-9 (PCSK9) and high-sensitivity CRP were also quantified. All analyses adjusted for atherosclerotic cardiovascular disease (ASCVD) risk score, obesity, total LDL, statin use, age at diagnosis, and anti-oxLDL IgM. RESULTS: OxPL-apoB100, anti-oxLDL IgG and PCSK9 were positively associated with CLC (all P < 0.020). OxPL-apoB100 directly influenced CLC only in dual RF- and ACPA-positive patients [unstandardized b (95% bootstrap CI)=2.08 (0.38, 3.79)]. An indirect effect of oxPL-apoB100 on CLC through anti-oxLDL IgG increased, along with level of CRP [index of moderated mediation = 0.55 (0.05-1.17)]. CRP also moderated yet another indirect effect of oxPL-apoB100 on CLC through upregulation of PCSK9, but only among dual-seropositive patients [conditional indirect effect = 0.64 (0.13-1.30)]. CONCLUSION: Oxidized LDL can directly influence CLC in dual-seropositive RA patients. Two additional and independent pathways-via anti-oxLDL IgG and PCSK9-may mediate the effects of oxPL-apoB100 on CLC, depending on CRP and seropositivity status. If externally validated, these findings may have clinical implications for cardiovascular risk prevention.

Role of Omega-3 Fatty Acids in Cardiovascular Disease: the Debate Continues.

PURPOSE OF REVIEW: The omega-3 fatty acids (n3-FAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have recently undergone testing for their ability to reduce residual cardiovascular (CV) risk among statin-treated subjects. The outcome trials have yielded highly inconsistent results, perhaps attributable to variations in dosage, formulation, and composition. In particular, CV trials using icosapent ethyl (IPE), a highly purified ethyl ester of EPA, reproducibly reduced CV events and progression of atherosclerosis compared with mixed EPA/DHA treatments. This review summarizes the mechanistic evidence for differences among n3-FAs on the development and manifestations of atherothrombotic disease. RECENT FINDINGS: Large randomized clinical trials with n3-FAs have produced discordant outcomes despite similar patient profiles, doses, and triglyceride (TG)-lowering effects. A large, randomized trial with IPE, a prescription EPA only formulation, showed robust reduction in CV events in statin treated patients in a manner proportional to achieved blood EPA concentrations. Multiple trials using mixed EPA/DHA formulations have not shown such benefits, despite similar TG lowering. These inconsistencies have inspired investigations into mechanistic differences among n3-FAs, as EPA and DHA have distinct membrane interactions, metabolic products, effects on cholesterol efflux, antioxidant properties, and tissue distribution. EPA maintains normal membrane cholesterol distribution, enhances endothelial function, and in combination with statins improves features implicated in plaque stability and reduces lipid content of plaques. Insights into reductions in residual CV risk have emerged from clinical trials using different formulations of n3-FAs. Among high-risk patients on contemporary care, mixed n3-FA formulations showed no reduction in CV events. The distinct benefits of IPE in multiple trials may arise from pleiotropic actions that correlate with on-treatment EPA levels beyond TG-lowering. These effects include altered platelet function, inflammation, cholesterol distribution, and endothelial dysfunction. Elucidating such mechanisms of vascular protection for EPA may lead to new interventions for atherosclerosis, a disease that continues to expand worldwide.

Does Coronary Plaque Morphology Matter Beyond Plaque Burden?

PURPOSE OF REVIEW: Imaging of adverse coronary plaque features by coronary computed tomography angiography (CCTA) has advanced greatly and at a fast pace. We aim to describe the evolution, present and future in plaque analysis, and its value in comparison to plaque burden. RECENT FINDINGS: Recently, it has been demonstrated that in addition to plaque burden, quantitative and qualitative assessment of coronary plaque by CCTA can improve the prediction of future major adverse cardiovascular events in diverse coronary artery disease scenarios. The detection of high-risk non-obstructive coronary plaque can lead to higher use of preventive medical therapies such as statins and aspirin, help identify culprit plaque, and differentiate between myocardial infarction types. Even more, over traditional plaque burden, plaque analysis including pericoronary inflammation can potentially be useful tools for tracking disease progression and response to medical therapy. The identification of the higher risk phenotypes with plaque burden, plaque characteristics, or ideally both can allow the allocation of targeted therapies and potentially monitor response. Further observational data are now required to investigate these key issues in diverse populations, followed by rigorous randomized controlled trials.