Lipoprotein subclasses are associated with Hepatic steatosis: insights from the prospective multicenter imaging study for the evaluation of chest pain (PROMISE) clinical trial.

Objectives: To determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis. Methods: Individuals with available CT data and blood samples enrolled in the PROMISE trial were studied. HS was defined based on CT attenuation. Lipoprotein particle size/number were measured by nuclear magnetic resonance spectroscopy. Principal components analysis (PCA) was used for dimensionality reduction. The association of PCA factors and individual lipoprotein particle size/number with HS were assessed in multivariable regression models. Associations were validated in an independent cohort of 59 individuals with histopathology defined HS. Results: Individuals with HS (n=410/1,509) vs those without (n=1,099/1,509), were younger (59±8 vs 61±8 years) and less often females (47.6 % vs 55.9 %). All PCA factors were associated with HS: factor 1 (OR:1.36, 95 %CI:1.21-1.53), factor 3 (OR:1.75, 95 %CI:1.53-2.02) and factor 4 (OR:1.49; 95 %CI:1.32-1.68) were weighted heavily with small low density lipoprotein (LDL) and triglyceride-rich (TRL) particles, while factor 2 (OR:0.86, 95 %CI:0.77-0.97) and factor 5 (OR:0.74, 95 %CI:0.65-0.84) were heavily loaded with high density lipoprotein (HDL) and larger LDL particles. These observations were confirmed with the analysis of individual lipoprotein particles in PROMISE. In the validation cohort, association between HS and large TRL (OR: 8.16, 95 %CI:1.82-61.98), and mean sizes of TRL- (OR: 2.82, 95 %CI:1.14-9.29) and HDL (OR:0.35, 95 %CI:0.13-0.72) were confirmed. Conclusions: Large TRL, mean sizes of TRL-, and HDL were associated with radiographic and histopathologic HS. The use of lipoprotein particle size/number could improve cardiovascular risk assessment in HS.

Selective Use of CT Fractional Flow at a Large Academic Medical Center: Insights from Clinical Implementation after 1 Year of Practice.

Purpose This special report outlines a retrospective observational study of CT fractional flow reserve (CT-FFR) analysis using dual-source coronary CT angiography (CTA) scans performed without heart rate control and its impact on clinical outcomes. Materials and Methods All patients who underwent clinically indicated coronary CTA between August 2020 and August 2021 were included in this retrospective observational study. Scans were performed in the late systolic to early diastolic period without heart rate control and analyzed at the interpreting physician's discretion. Demographics, coronary CTA features, and rates of invasive coronary angiography (ICA), percutaneous coronary intervention (PCI), myocardial infarction, and all-cause death at 3 months were assessed by chart review. Results During the study period, 3098 patients underwent coronary CTA, of whom 113 with coronary bypass grafting were excluded. Of the remaining 2985 patients, 292 (9.7%) were referred for CT-FFR analysis. Two studies (0.7%) were rejected from CT-FFR analysis, and six (2.1%) analyses did not evaluate the lesion of concern. A total of 160 patients (56.3%) had CT-FFR greater than 0.80. Among patients with significant stenosis at coronary CTA, patients who underwent CT-FFR analysis presented with lower rates of ICA (74.5% vs 25.5%, P = .04) and PCI (78.9% vs 21.1%, P = .05). Conclusion CT-FFR was implemented in patients not requiring heart rate control by using dual-source coronary CTA acquisition and showed the potential to decrease rates of ICA and PCI without compromising safety in patients with significant stenosis and an average heart rate of 65 beats per minute. Keywords: Angiography, CT, CT-Angiography, Fractional Flow Reserve, Cardiac, Heart, Arteriosclerosis Supplemental material is available for this article. © RSNA, 2024.

Deep learning analysis of epicardial adipose tissue to predict cardiovascular risk in heavy smokers.

BACKGROUND: Heavy smokers are at increased risk for cardiovascular disease and may benefit from individualized risk quantification using routine lung cancer screening chest computed tomography. We investigated the prognostic value of deep learning-based automated epicardial adipose tissue quantification and compared it to established cardiovascular risk factors and coronary artery calcium. METHODS: We investigated the prognostic value of automated epicardial adipose tissue quantification in heavy smokers enrolled in the National Lung Screening Trial and followed for 12.3 (11.9-12.8) years. The epicardial adipose tissue was segmented and quantified on non-ECG-synchronized, non-contrast low-dose chest computed tomography scans using a validated deep-learning algorithm. Multivariable survival regression analyses were then utilized to determine the associations of epicardial adipose tissue volume and density with all-cause and cardiovascular mortality (myocardial infarction and stroke). RESULTS: Here we show in 24,090 adult heavy smokers (59% men; 61 ± 5 years) that epicardial adipose tissue volume and density are independently associated with all-cause (adjusted hazard ratios: 1.10 and 1.38; P < 0.001) and cardiovascular mortality (adjusted hazard ratios: 1.14 and 1.78; P < 0.001) beyond demographics, clinical risk factors, body habitus, level of education, and coronary artery calcium score. CONCLUSIONS: Our findings suggest that automated assessment of epicardial adipose tissue from low-dose lung cancer screening images offers prognostic value in heavy smokers, with potential implications for cardiovascular risk stratification in this high-risk population.

Heavy smokers are at increased risk of poor health outcomes, particularly outcomes related to cardiovascular disease. We explore how fat surrounding the heart, known as epicardial adipose tissue, may be an indicator of the health of heavy smokers. We use an artificial intelligence system to measure the heart fat on chest scans of heavy smokers taken during a lung cancer screening trial and following their health for 12 years. We find that higher amounts and denser epicardial adipose tissue are linked to an increased risk of death from any cause, specifically from heart-related issues, even when considering other health factors. This suggests that measuring epicardial adipose tissue during lung cancer screenings could be a valuable tool for identifying heavy smokers at greater risk of heart problems and death, possibly helping to guide their medical management and improve their cardiovascular health.

Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers in HIV: Mechanistic Substudy of the REPRIEVE Randomized Clinical Trial.

Importance: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years. Objective: To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites. PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023. Intervention: Oral pitavastatin calcium, 4 mg per day. Main Outcomes and Measures: Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque. Results: Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, -1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, -4.3 mm3; 95% CI, -8.6 to -0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (-8.8 mm3 [95% CI, -17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, -28.5 mg/dL; 95% CI, -31.9 to -25.1; placebo, -0.8; 95% CI, -3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (-29% [95% CI, -32 to -26] vs -13% [95% CI, -17 to -9]; P < .001) and lipoprotein-associated phospholipase A2 (-7% [95% CI, -11 to -4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months. Conclusions and Relevance: In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE. Trial Registration: ClinicalTrials.gov Identifier: NCT02344290.

Incidence of brain injuries in a large cohort of very preterm and extremely preterm infants at term-equivalent age: results of a single tertiary neonatal care center over 10 years.

OBJECTIVES: Cerebral magnetic resonance imaging (cMRI) at term-equivalent age (TEA) can detect brain injury (BI) associated with adverse neurological outcomes in preterm infants. This study aimed to assess BI incidences in a large, consecutive cohort of preterm infants born < 32 weeks of gestation, the comparison between very (VPT, ≥ 28 + 0 to < 32 + 0 weeks of gestation) and extremely preterm infants (EPT, < 28 + 0 weeks of gestation) and across weeks of gestation. METHODS: We retrospectively analyzed cMRIs at TEA of VPT and EPT infants born at a large tertiary center (2009-2018). We recorded and compared the incidences of BI, severe BI, intraventricular hemorrhage (IVH), periventricular hemorrhagic infarction (PVHI), cerebellar hemorrhage (CBH), cystic periventricular leukomalacia (cPVL), and punctate white matter lesions (PWML) between VPTs, EPTs, and across weeks of gestation. RESULTS: We included 507 preterm infants (VPT, 335/507 (66.1%); EPT, 172/507 (33.9%); mean gestational age (GA), 28 + 2 weeks (SD 2 + 2 weeks); male, 52.1%). BIs were found in 48.3% of the preterm infants (severe BI, 12.0%) and increased with decreasing GA. IVH, PVHI, CBH, cPVL, and PWML were seen in 16.8%, 0.8%, 10.5%, 3.4%, and 18.1%, respectively. EPT vs. VPT infants suffered more frequently from BI (59.3% vs. 42.7%, p < 0.001), severe BI (18.6% vs. 8.7%, p = 0.001), IVH (31.9% vs. 9.0%, p < 0.001), and CBH (18.0% vs. 6.6%, p < 0.001). CONCLUSION: Brain injuries are common cMRI findings among preterm infants with a higher incidence of EPT compared to VPT infants. These results may serve as reference values for clinical management and research. CLINICAL RELEVANCE STATEMENT: Our results with regard to gestational age might provide valuable clinical insights, serving as a key reference for parental advice, structured follow-up planning, and enhancing research and management within the Neonatal Intensive Care Unit. KEY POINTS: • Brain injury is a common cMRI finding in preterm infants seen in 48.3% individuals. • Extremely preterm compared to very preterm infants have higher brain injury incidences driven by brain injuries such as intraventricular and cerebellar hemorrhage. • Reference incidence values are crucial for parental advice and structured follow-up planning.

Calcium Scoring Improves Clinical Management in Patients With Low Clinical Likelihood of Coronary Artery Disease.

BACKGROUND: Coronary artery calcium scoring (CACS) improves management of chest pain patients. However, it is unknown whether the benefit of CACS is dependent on the clinical likelihood (CL). OBJECTIVES: This study aims to investigate for which patients CACS has the greatest benefit when added to a CL model. METHODS: Based on data from a clinical database, the CL of obstructive coronary artery disease (CAD) was calculated for 39,837 patients referred for cardiac imaging due to symptoms suggestive of obstructive CAD. Patients were categorized according to the risk factor-weighted (RF-CL) model (very low, ≤5%; low, >5 to ≤15%; moderate >15 to ≤50%; high, >50%). CL was then recalculated incorporating the CACS result (CACS-CL). Reclassification rates and the number needed to test with CACS to reclassify patients were calculated and validated in 3 independent cohorts (n = 9,635). RESULTS: In total, 15,358 (39%) patients were down- or upclassified after including CACS. Reclassification rates were 8%, 75%, 53%, and 30% in the very low, low, moderate, and high RF-CL categories, respectively. Reclassification to very low CACS-CL occurred in 48% of reclassified patients. The number needed to test to reclassify 1 patient from low RF-CL to very low CACS-CL was 2.1 with consistency across age, sex, and cohorts. CACS-CL correlated better to obstructive CAD prevalence than RF-CL. CONCLUSIONS: Added to an RF-CL model for obstructive CAD, CACS identifies more patients unlikely to benefit from further testing. The number needed to test with CACS to reclassify patients depends on the pretest RF-CL and is lowest in patients with low (>5% to ≤15%) likelihood of CAD.

Advanced CT measures of coronary artery disease with intermediate stenosis in patients with severe aortic valve stenosis.

BACKGROUND: Coronary artery disease (CAD) and severe aortic valve stenosis (AS) frequently coexist. While pre-transcatheter aortic valve replacement (TAVR) computed tomography angiography (CTA) allows to rule out obstructive CAD, interpreting hemodynamic significance of intermediate stenoses is challenging. This study investigates the incremental value of CT-derived fractional flow reserve (CT-FFR), quantitative coronary plaque characteristics (e.g., stenosis degree, plaque volume, and composition), and peri-coronary adipose tissue (PCAT) density to detect hemodynamically significant lesions among those with AS and CAD. MATERIALS AND METHODS: We included patients with severe AS and intermediate coronary lesions (20-80% diameter stenosis) who underwent pre-TAVR CTA and invasive coronary angiogram (ICA) with resting full-cycle ratio (RFR) assessment between 08/16 and 04/22. CTA image analysis included assessment of CT-FFR, quantitative coronary plaque analysis, and PCAT density. Coronary lesions with RFR ≤ 0.89 indicated hemodynamic significance as reference standard. RESULTS: Overall, 87 patients (age 77.9 ± 7.4 years, 38% female) with 95 intermediate coronary artery lesions were included. CT-FFR showed good discriminatory capacity (area under receiver operator curve (AUC) = 0.89, 95% confidence interval (CI) 0.81-0.96, p < 0.001) to identify hemodynamically significant lesions, superior to anatomical assessment, plaque morphology, and PCAT density. Plaque composition and PCAT density did not differ between lesions with and without hemodynamic significance. Univariable and multivariable analyses revealed CT-FFR as the only predictor for functionally significant lesions (odds ratio 1.28 (95% CI 1.17-1.43), p < 0.001). Overall, CT-FFR ≤ 0.80 showed diagnostic accuracy, sensitivity, and specificity of 88.4% (95%CI 80.2-94.1), 78.5% (95%CI 63.2-89.7), and 96.2% (95%CI 87.0-99.5), respectively. CONCLUSION: CT-FFR was superior to CT anatomical, plaque morphology, and PCAT assessment to detect functionally significant stenoses in patients with severe AS. CLINICAL RELEVANCE STATEMENT: CT-derived fractional flow reserve in patients with severe aortic valve stenosis may be a useful tool for non-invasive hemodynamic assessment of intermediate coronary lesions, while CT anatomical, plaque morphology, and peri-coronary adipose tissue assessment have no incremental or additional benefit. These findings might help to reduce pre-transcatheter aortic valve replacement invasive coronary angiogram. KEY POINTS: • Interpreting the hemodynamic significance of intermediate coronary stenoses is challenging in pre-transcatheter aortic valve replacement CT. • CT-derived fractional flow reserve (CT-FFR) has a good discriminatory capacity in the identification of hemodynamically significant coronary lesions. • CT-derived anatomical, plaque morphology, and peri-coronary adipose tissue assessment did not improve the diagnostic capability of CT-FFR in the hemodynamic assessment of intermediate coronary stenoses.

Reduction of contrast medium for transcatheter aortic valve replacement planning using a spectral detector CT: a prospective clinical trial.

INTRODUCTION: This study investigated the use of dual-energy spectral detector computed tomography (CT) and virtual monoenergetic imaging (VMI) reconstructions in pre-interventional transcatheter aortic valve replacement (TAVR) planning. We aimed to determine the minimum required contrast medium (CM) amount to maintain diagnostic CT imaging quality for TAVR planning. METHODS: In this prospective clinical trial, TAVR candidates received a standardized dual-layer spectral detector CT protocol. The CM amount (Iohexol 350 mg iodine/mL, standardized flow rate 3 mL/s) was reduced systematically after 15 patients by 10 mL, starting at 60 mL (institutional standard). We evaluated standard, and 40- and 60-keV VMI reconstructions. For image quality, we measured signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and diameters in multiple vessel sections (i.e., aortic annulus: diameter, perimeter, area; aorta/arteries: minimal diameter). Mixed regression models (MRM), including interaction terms and clinical characteristics, were used for comparison. RESULTS: Sixty consecutive patients (mean age, 79.4 ± 7.5 years; 28 females, 46.7%) were included. In pre-TAVR CT, the CM reduction to 40 mL is possible without affecting the image quality (MRM: SNR: -1.1, p = 0.726; CNR: 0.0, p = 0.999). VMI 40-keV reconstructions showed better results than standard reconstructions with significantly higher SNR (+ 6.04, p < 0.001). Reduction to 30 mL CM resulted in a significant loss of quality (MRM: SNR: -12.9, p < 0.001; CNR: -13.9, p < 0.001), regardless of the reconstruction. Across the reconstructions, we observed no differences in the metric evaluation (p > 0.914). CONCLUSION: Among TAVR candidates undergoing pre-interventional CT at a dual-layer spectral detector system, applying 40 mL CM is sufficient to maintain diagnostic image quality. VMI 40-keV reconstructions improve the vessel attenuation and are recommended for evaluation. CLINICAL RELEVANCE STATEMENT: Contrast medium reduction to 40 mL in pre-interventional transcatheter aortic valve replacement CT using dual-energy CT maintains image quality, while 40-keV virtual monoenergetic imaging reconstructions enhance vessel attenuation. These results offer valuable recommendations for interventional transcatheter aortic valve replacement evaluation and potentially improve nephroprotection in patients with compromised renal function. KEY POINTS: • Patients undergoing transcatheter aortic valve replacement (TAVR), requiring pre-interventional CT, are often multimorbid with impaired renal function. • Using a spectral detector dual-layer CT, contrast medium reduction to 40 mL is feasible, maintaining diagnostic image quality. • The additional application of virtual monoenergetic image reconstructions with 40 keV improves vessel attenuation significantly in clinical practice.

CT-derived coronary artery calcium density is affected by regional lesion distribution and image reconstruction parameters.

PURPOSE: The prognostic relevance of coronary artery calcium (CAC) density, assessed from cardiac CT scans, is established. However, the influence of CAC distribution, volume, image reconstruction, and clinical factors on CAC density warrants further examination. METHODS: In this study, 120 patients underwent non-contrast ECG-gated cardiac CT scans using a prospectively defined CAC scoring protocol with 1-, 3-, and 5-mm thick image reconstructions, both with and without a 20% image overlap. We segmented CAC in all reconstructions and assessed the relationship between CAC density, volume, and number of detected calcifications/patient. RESULTS: Overall, 75/120 (63%) patients (66% men, mean age 63 ± 11 years) presented CAC across 342 segments. CAC density, CAC volume, and the number of detected calcifications decreased with increasing slice thickness (p < 0.001 for all); these effects were slightly reduced by image overlap (p < 0.001 for all). Higher CAC density correlated with greater CAC volume (ρ = 0.62; p < 0.001) and more calcified segments per person (ρ = 0.32; p = 0.006). Higher CAC density was also associated with lower patient weight (beta: -0.6, 95%CI: -1.1--0.1, p = 0.022) and increased high-density lipoprotein (HDL) levels (beta: 0.7, 95%CI: 0.0-1.4, p = 0.046). In a multivariable analysis adjusted for clinical covariates, lower CAC density was associated with broader CAC distribution (i.e., a higher number of calcified segments at a given CAC volume; beta-coefficient: -58.9; 95%CI: -84.7 to -33.1; p < 0.001). CONCLUSION: CAC density is significantly impacted by regional CAC distribution and image reconstruction, potentially confounding its prognostic value. Accounting for these factors may improve patient risk assessment, management, and cardiovascular health outcomes.

Pitavastatin to Prevent Cardiovascular Disease in HIV Infection.

BACKGROUND: The risk of cardiovascular disease is increased among persons with human immunodeficiency virus (HIV) infection, so data regarding primary prevention strategies in this population are needed. METHODS: In this phase 3 trial, we randomly assigned 7769 participants with HIV infection with a low-to-moderate risk of cardiovascular disease who were receiving antiretroviral therapy to receive daily pitavastatin calcium (at a dose of 4 mg) or placebo. The primary outcome was the occurrence of a major adverse cardiovascular event, which was defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause. RESULTS: The median age of the participants was 50 years (interquartile range, 45 to 55); the median CD4 count was 621 cells per cubic millimeter (interquartile range, 448 to 827), and the HIV RNA value was below quantification in 5250 of 5997 participants (87.5%) with available data. The trial was stopped early for efficacy after a median follow-up of 5.1 years (interquartile range, 4.3 to 5.9). The incidence of a major adverse cardiovascular event was 4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002). Muscle-related symptoms occurred in 91 participants (2.3%) in the pitavastatin group and in 53 (1.4%) in the placebo group; diabetes mellitus occurred in 206 participants (5.3%) and in 155 (4.0%), respectively. CONCLUSIONS: Participants with HIV infection who received pitavastatin had a lower risk of a major adverse cardiovascular event than those who received placebo over a median follow-up of 5.1 years. (Funded by the National Institutes of Health and others; REPRIEVE ClinicalTrials.gov number, NCT02344290.).

Impact of immune checkpoint inhibitors on atherosclerosis progression in patients with lung cancer.

BACKGROUND: Patients with lung cancer face a heightened risk of atherosclerosis-related cardiovascular events. Despite the strong scientific rationale, there is currently a lack of clinical evidence examining the impact of immune checkpoint inhibitors (ICIs) on the advancement of atherosclerosis in patients with lung cancer. The objective of our study was to investigate whether there is a correlation between ICIs and the accelerated progression of atherosclerosis among individuals with lung cancer. METHODS: In this case-control (2:1 matched by age and gender) study, total, non-calcified, and calcified plaque volumes were measured in the thoracic aorta using sequential contrast-enhanced chest CT scans. Univariate and multivariate rank-based estimation regression models were developed to estimate the effect of ICI therapy on plaque progression in 40 cases (ICI) and 20 controls (non-ICI). RESULTS: The patients had a median age of 66 years (IQR: 58-69), with 50% of them being women. At baseline, there were no significant differences in plaque volumes between the groups, and their cardiovascular risk profiles were similar. However, the annual progression rate for non-calcified plaque volume was 7 times higher in the ICI group compared with the controls (11.2% vs 1.6% per year, p=0.001). Conversely, the controls showed a greater progression in calcified plaque volume compared with the ICI group (25% vs 2% per year, p=0.017). In a multivariate model that considered cardiovascular risk factors, the use of an ICI was associated with a more substantial progression of non-calcified plaque volume. Additionally, individuals treated with combination ICI therapy exhibited greater plaque progression. CONCLUSIONS: ICI therapy was associated with more non-calcified plaque progression. These findings underscore the importance of conducting studies aimed at identifying the underlying mechanisms responsible for plaque advancement in patients undergoing ICI treatment. TRIAL REGISTRATION NUMBER: NCT04430712.

Pericoronary Adipose Tissue Density, Inflammation, and Subclinical Coronary Artery Disease Among People With HIV in the REPRIEVE Cohort.

BACKGROUND: Pericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population. METHODS: In this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates. RESULTS: Among 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001). CONCLUSIONS: Among PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH.

Branched-Chain Amino Acids in Computed Tomography-Defined Adipose Depots and Coronary Artery Disease: A PROMISE Trial Biomarker Substudy.

Background The interplay between branched-chain amino acid (BCAA) metabolism, an important pathway in adiposity and cardiometabolic disease, and visceral adipose depots such as hepatic steatosis (HS) and epicardial adipose tissue is unknown. We leveraged the PROMISE clinical trial with centrally adjudicated coronary computed tomography angiography imaging to determine relationships between adipose depots, BCAA dysregulation, and coronary artery disease (CAD). Methods and Results The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial randomized 10 003 outpatients with stable chest pain to computed tomography angiography versus standard-of-care diagnostics. For this study, we included 1798 participants with available computed tomography angiography data and biospecimens. Linear and logistic regression were used to determine associations between a molar sum of BCAAs measured by nuclear magnetic resonance spectroscopy with body mass index, adipose traits, and obstructive CAD. Mendelian randomization was then used to determine if BCAAs are in the causal pathway for adipose depots or CAD. The study sample had a mean age of 60 years (SD, 8.0), body mass index of 30.6 (SD, 5.9), and epicardial adipose tissue volume of 57.3 (SD, 21.3) cm3/m2; 27% had HS, and 14% had obstructive CAD. BCAAs were associated with body mass index (multivariable beta 0.12 per SD increase in BCAA [95% CI, 0.08-0.17]; P=4×10-8). BCAAs were also associated with HS (multivariable odds ratio [OR], 1.46 per SD increase in BCAAs [95% CI, 1.28-1.67]; P=2×10-8), but BCAAs were associated only with epicardial adipose tissue volume (odds ratio, 1.18 [95% CI, 1.07-1.32]; P=0.002) and obstructive CAD (OR, 1.18 [95% CI, 1.04-1.34]; P=0.009) in univariable models. Two-sample Mendelian randomization did not support the role of BCAAs as within the causal pathways for HS or CAD. Conclusions BCAAs have been implicated in the pathogenesis of cardiometabolic diseases, and adipose depots have been associated with the risk of CAD. Leveraging a large clinical trial, we further establish the role of dysregulated BCAA catabolism in HS and CAD, although BCAAs did not appear to be in the causal pathway of either disease. This suggests that BCAAs may serve as an independent circulating biomarker of HS and CAD but that their association with these cardiometabolic diseases is mediated through other pathways.

Pulmonary perfusion defect volume on dual-energy CT: prognostic marker of adverse events in patients with suspected pulmonary embolism.

To assess whether quantification of pulmonary perfusion defects on dual-energy computed tomography (DECT) relates to adverse events beyond clinical parameters and traditional embolus detection in patients with suspected pulmonary embolism (PE). We included consecutive patients who underwent DECT to rule out acute PE in 2018-2020 and recorded incident adverse events, defined as a composite of short-term (< 30 days) in-hospital all-cause mortality or admission to intensive care unit. Relative perfusion defect volume (PDV) was measured on DECT and indexed by total lung volume. PDV was then related to adverse events using logistic regressions adjusting for clinical parameters, clinical PE pre-test probability (Wells score), and visual PE burden on pulmonary angiography (Qanadli score). Among 136 included patients (63 [46%] females; age: 70 ± 14 years), 19/136 (14%) experienced adverse events during a median hospitalization of 7.5 (4-14) days. Overall, 7/19 (37%) events occurred in those without visible emboli but with measurable perfusion defects. An increase of PDV by one standard deviation was associated with over two times higher odds of adverse events (OR = 2.24; 95%CI:1.37-3.65; p = 0.001). This association remained significant after adjusting for the Wells and Qanadli scores (OR = 2.34; 95%CI:1.20-4.60; p = 0.013). PDV significantly increased the combined discriminatory capacity of Wells and Qanadli scores (AUC 0.76 vs. 0.80; p = 0.011 for difference). DECT-derived PDV may represent a prognostic imaging marker with incremental value beyond clinical and traditional imaging findings, improving risk stratification and aiding clinical management in patients with suspected PE.

Prognostic value of CT-derived coronary artery disease characteristics varies by ASCVD risk: insights from the PROMISE trial.

OBJECTIVES: To compare the prognostic value of individual CT-derived coronary artery disease (CAD) characteristics across categories of clinical cardiovascular risk. METHODS: The central core laboratory assessed coronary artery calcium (CAC), obstructive CAD (stenosis ≥ 50%), and high-risk plaque (HRP) in stable outpatients with suspected CAD enrolled in the PROMISE trial. Multivariable Cox regression models (endpoint: unstable angina, nonfatal myocardial infarction, or all-cause mortality; median follow-up: 2 years) were used to compare hazard ratios (HR) of the CT measures between low-borderline (< 7.5%) and moderate-high (≥ 7.5%) atherosclerotic cardiovascular disease (ASCVD) risk based on the pooled cohort equation. RESULTS: Among 4356 included patients (aged 61 ± 8 years, 52% women), 67% had ASCVD risk ≥ 7.5%. Stratified by ASCVD risk, CAD ≥ 50% had nearly threefold greater HR in individuals with ASCVD < 7.5% (aHR, 6.85; 95% CI, 2.33-20.15; p < 0.001) vs. ASCVD ≥ 7.5% (aHR: 2.66, 95% CI: 1.67-4.25, p < 0.001; interaction p = 0.041). CAC predicted events solely in ASCVD ≥ 7.5% patients (aHR: 1.92, 95% CI: 1.01-3.63, p = 0.045; interaction p = 0.571), while HRP predicted events only in ASCVD < 7.5% (aHR: 3.11, 95% CI: 1.09-8.85, p = 0.034; interaction p = 0.034). CONCLUSIONS: Prognostic values of CT-derived CAD characteristics differ by ASCVD risk categories. While CAD ≥ 50% has the highest prognostic value regardless of ASCVD risk, CAC is prognostic in high and HRP in low ASCVD risk. These findings suggest that CAD ≥ 50% and HRP detection rather than CAC scoring may better risk-stratify symptomatic low-risk patients and thus potentially improve downstream care. KEY POINTS: • Prognostic value of individual CT-derived CAD characteristics differs by categories of cardiovascular risk. • Presence of obstructive coronary artery stenosis ≥ 50% has the highest prognostic value regardless of cardiovascular risk. • Coronary artery calcium is independently prognostic in high and high-risk plaque features in low cardiovascular risk.

Ideal cardiovascular health, biomarkers, and coronary artery disease in persons with HIV.

OBJECTIVE: To investigate relationships between Life's Simple 7 (LS7), an assessment of cardiovascular health (CVH), and coronary plaque among people with HIV (PWH). DESIGN: Cross-sectional. METHODS: Coronary computed tomography angiography, immune/inflammatory biomarkers, and characterization of LS7 were collected among a subset of ART-treated PWH enrolled in REPRIEVE, a primary prevention trial. Analyses adjusted for cardiovascular disease risk (ASCVD score). RESULTS: Median age of the 735 participants was 51(±6) years, 16% female, and median (Q1-Q3) CVD risk was 4.5% (2.6-6.9). Forty percent had poor (≤2 ideal components), 51% had intermediate (three or four ideal components), and only 9% had ideal CVH (≥5). Coronary plaque was present in 357 (49%); 167 (23%) had one or more vulnerable plaque features, 293 (40%) had noncalcified plaque, and 242 (35%) had a coronary artery calcium score >0. All three phenotypes were increasingly more prevalent with poorer CVH and these relationships remained after adjusting for ASCVD risk. Poor CVH was associated with higher high-sensitivity C-reactive protein, oxidized low-density cholesterol, and interleukin-6. The relationship of LS7 to plaque remained after adjusting for these biomarkers. CONCLUSIONS: Among PWH, poor CVH as measured by LS7 was associated with coronary plaque presence, vulnerable features, and calcification. LS7 was also associated with selected biomarkers; adjustment for these and ASCVD score reduced but did not eliminate LS7's association with plaque, suggesting the possibility of additional protective mechanisms against atherogenesis and plaque remodeling. Clinical use of LS7 and further exploration of its relationships with coronary artery disease may enhance efforts to reduce cardiovascular morbidity and mortality in PWH. CLINICAL TRIALS REGISTRATION: NCT02344290.

Lipoprotein Subclasses Associated With High-Risk Coronary Atherosclerotic Plaque: Insights From the PROMISE Clinical Trial.

BACKGROUND More than half of major adverse cardiovascular events (MACE) occur in the absence of obstructive coronary artery disease and are often attributed to the rupture of high-risk coronary atherosclerotic plaque (HRP). Blood-based biomarkers that associate with imaging-defined HRP and predict MACE are lacking. METHODS AND RESULTS Nuclear magnetic resonance-based lipoprotein particle profiling was performed in the biomarker substudy of the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial (N=4019) in participants who had stable symptoms suspicious for coronary artery disease. Principal components analysis was used to reduce the number of correlated lipoproteins into uncorrelated lipoprotein factors. The association of lipoprotein factors and individual lipoproteins of significantly associated factors with core laboratory determined coronary computed tomographic angiography features of HRP was determined using logistic regression models. The association of HRP-associated lipoproteins with MACE was assessed in the PROMISE trial and validated in an independent coronary angiography biorepository (CATHGEN [Catheterization Genetics]) using Cox proportional hazards models. Lipoprotein factors composed of high-density lipoprotein (HDL) subclasses were associated with HRP. In these factors, large HDL (odds ratio [OR], 0.70 [95% CI, 0.56-0.85]; P<0.001) and medium HDL (OR, 0.84 [95% CI, 0.72-0.98]; P=0.028) and HDL size (OR, 0.82 [95% CI, 0.69-0.96]; P=0.018) were associated with HRP in multivariable models. Medium HDL was associated with MACE in PROMISE (hazard ratio [HR], 0.76 [95% CI, 0.63-0.92]; P=0.004), which was validated in the CATHGEN biorepository (HR, 0.91 [95% CI, 0.88-0.94]; P<0.001). CONCLUSIONS Large and medium HDL subclasses and HDL size inversely associate with HRP features, and medium HDL subclasses inversely associate with MACE in PROMISE trial participants. These findings may aid in the risk stratification of individuals with chest pain and provide insight into the pathobiology of HRP. REGISTRATION URL: https://clinicaltrials.gov; Unique identifier: NCT01174550.

Cytomegalovirus Immunoglobulin G (IgG) Titer and Coronary Artery Disease in People With Human Immunodeficiency Virus (HIV).

BACKGROUND: Cytomegalovirus (CMV) infection is thought to result in increased immune activation in people with human immunodeficiency virus (HIV, PWH). Although some data have linked asymptomatic CMV infection to cardiovascular disease among PWH, it remains unknown whether CMV is associated with increased or high-risk coronary plaque. METHODS: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) enrolled PWH aged 40-75 years on stable antiretroviral therapy (ART) with low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk. Among a subset of US REPRIEVE participants, coronary plaque was assessed by coronary computed tomography angiography. Here, we assessed the relationship between CMV immunoglobulin G (IgG) titer and (1) levels of immune activation, (2) inflammatory biomarkers, and (3) coronary plaque phenotypes at study entry. RESULTS: Of 672 participants, mean age was 51 years, 83% were men, median ASCVD risk score was 4.5%, and 66% had current CD4+ T-cell count ≥500 cells/mm3. Higher CMV IgG quartile group was associated with older age and lower current and nadir CD4+ T-cell counts. CMV IgG titer was associated with specific inflammatory biomarkers (sCD163, MCP-1, interleukin [IL]-6, hsCRP) in univariate analysis, but not after controlling for HIV-specific factors. In contrast, CMV IgG titer was not associated with coronary artery disease indexes, including presence of plaque, coronary artery calcium (CAC) score >0, vulnerable plaque presence, or Leaman score >5. CONCLUSIONS: No meaningful association was seen between CMV IgG titer and coronary artery disease indexes among ART-treated PWH at study enrollment. Longitudinal assessments in REPRIEVE will determine the relationship of CMV IgG titer to plaque progression and cardiovascular events. CLINICAL TRIALS REGISTRATION: NCT02344290.

Sex Differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation Among People With Human Immunodeficiency Virus in the United States.

BACKGROUND: Among people with HIV (PWH), sex differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by differences in coronary plaque parameters, immune/inflammatory biomarkers, or relationships therein. METHODS: REPRIEVE, a primary ASCVD prevention trial, enrolled antiretroviral therapy (ART)-treated PWH. At entry, a subset of US participants underwent coronary computed tomography angiography (CTA) and immune phenotyping (n = 755 CTA; n = 725 CTA + immune). We characterized sex differences in coronary plaque and immune/inflammatory biomarkers and compared immune-plaque relationships by sex. Unless noted otherwise, analyses adjust for ASCVD risk score. RESULTS: The primary analysis cohort included 631 males and 124 females. ASCVD risk was higher among males (median: 4.9% vs 2.1%), while obesity rates were higher among females (48% vs 21%). Prevalence of any plaque and of plaque with either ≥1 visible noncalcified portion or vulnerable features (NC/V-P) was lower among females overall and controlling for relevant risk factors (RR [95% CI] for any plaque: .67 [.50, .92]; RR for NC/V-P: .71 [.51, 1.00] [adjusted for ASCVD risk score and body mass index]). Females showed higher levels of IL-6, hs-CRP, and D-dimer and lower levels of Lp-PLA2 (P < .001 for all). Higher levels of Lp-PLA2, MCP-1, and oxLDL were associated with higher plaque (P < .02) and NC/V-P prevalence, with no differences by sex. Among females but not males, D-dimer was associated with higher prevalence of NC/V-P (interaction P = .055). CONCLUSIONS: Among US PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer but not other tested parameters. Clinical Trial Registration. ClinicalTrials.gov; identifier: NCT0234429 (date of initial registration: 22 January 2015).

Coronary Calcium Scoring Improves Risk Prediction in Patients With Suspected Obstructive Coronary Artery Disease.

BACKGROUND: In patients with suspected obstructive coronary artery disease (CAD), the risk factor-weighted clinical likelihood (RF-CL) model and the coronary artery calcium score-weighted clinical likelihood (CACS-CL) model improves the identification of obstructive CAD compared with basic pretest probability (PTP) models. OBJECTIVES: The aim of this study was to assess the prognostic value of the new models. METHODS: The incidences of myocardial infarction and death were stratified according to categories by the RF-CL and CACS-CL and compared with categories by the PTP model. We used cohorts from a Danish register (n = 41,177) and a North American randomized study (n = 3,952). All patients were symptomatic and were referred for diagnostic testing because of clinical indications. RESULTS: Despite substantial down-reclassification of patients to a likelihood ≤5% of CAD with either the RF-CL (45%) or CACS-CL (60%) models compared with the PTP (18%), the annualized event rates of myocardial infarction and death were low using all 3 models; RF-CL 0.51% (95% CI: 0.46-0.56), CACS-CL 0.48% (95% CI: 0.44-0.56), and PTP 0.37% (95% CI: 0.31-0.44), respectively. Overall, comparison of the predictive power of the 3 models using Harrell's C-statistics demonstrated superiority of the RF-CL (0.64 [95% CI: 0.63-0.65]) and CACS-CL (0.69 [95% CI: 0.67-0.70]) compared with the PTP model (0.61 [95% CI: 0.60-0.62]). CONCLUSIONS: The simple clinical likelihood models that include classical risk factors or risk factors combined with CACS provide improved risk stratification for myocardial infarction and death compared with the standard PTP model. Hence, the optimized RF-CL and CACS-CL models identify 2.5 and 3.3 times more patients, respectively, who may not benefit from further diagnostic testing.