Background Genetic determinants of resilience remain poorly defined beyond family studies. Objectives The purpose of this study was to perform an unbiased study of individuals with discordance between clinical/genetic risk and atherosclerotic burden to discover novel genetic pathways underpinning atherosclerosis. Methods We used 2 genotyped cohorts with well-defined coronary anatomy: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) (discovery cohort: coronary computed tomography angiography) and CATHGEN (CATHeterization GENetics) (validation cohort: invasive angiography). Resilience was defined as high clinical and polygenic risk of coronary artery disease (CAD), yet without coronary plaque. Resilient individuals were compared to patients with obstructive CAD (oCAD) (stenosis ≥70%) using genome-wide association analyses at variant, gene, and pathway levels. Results In PROMISE (n = 605), 46 (8%) were resilient and 88 (15%) had oCAD. In CATHGEN (n = 3,236), 127 (4%) were resilient and 1,852 (57%) had oCAD. Clinical risk factors and polygenic risk scores were similar between resilient and oCAD patients in both cohorts. Variant- and gene-level analyses did not yield genome-wide significant signals. Pathway-level analyses identified 4 resilience-associated pathways in PROMISE that replicated in CATHGEN: adipocytokine signaling, fatty acid metabolism, fatty acid degradation, and vascular smooth muscle contraction. Conclusions Resilience to CAD—defined as the absence of coronary atherosclerosis despite high clinical and polygenic risk—is present in both lower- (PROMISE) and higher-risk (CATHGEN) cohorts and is linked to protective variants in metabolic and vascular pathways. This unbiased, proof-of-concept approach reveals biologically plausible targets for replication and mechanistic studies in larger imaging-based genetics cohorts.

AIMS:To investigate whether computed tomography (CT)-derived pericoronary adipose tissue (PCAT) metrics are associated with coronary artery disease (CAD) characteristics and adverse cardiovascular outcomes in patients with stable chest pain. METHODS AND RESULTS:PCAT attenuation and body surface area-indexed PCAT volume were quantified on non-contrast, electrocardiogram (ECG)-gated CT in the PROMISE CT arm. Associations with CAD characteristics were assessed using mixed-effects logistic regression adjusted for technical parameters, atherosclerotic cardiovascular disease (ASCVD) risk score, and body mass index. Cox proportional hazards models evaluated major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction), with additional adjustment for obstructive CAD. PCAT attenuation and volume were included simultaneously in all models.Among 3,799 individuals (51% female; mean age 61±8 years), PCAT attenuation and volume were -81.4±6.4 Hounsfield units (HU) and 12.9±3.1 cm3/m2, respectively. Higher (less negative) PCAT attenuation and higher PCAT volume were independently associated with stenosis ≥50% and high-risk plaque (adjusted odds ratios; attenuation: 1.02-1.03 (per 1 HU) and volume: 1.42-1.47 (per 1 cm3/m2); all p≤0.04). Both were independently associated with MACE (adjusted hazard ratios [aHR]: 1.09-1.15; all p≤0.02). PCAT improved MACE discrimination beyond ASCVD risk score, body mass index, and obstructive CAD (area under the curve: 0.70-0.72; p=0.03). In an exploratory analysis among participants without coronary plaque, higher PCAT attenuation remained associated with MACE (aHR 1.21, 95% CI 1.05-1.39; p=0.007). CONCLUSION:PCAT metrics, measured on ECG-gated non-contrast CT, are independently associated with adverse CAD features and MACE and provide incremental prognostic value beyond clinical risk factors and obstructive CAD.

Coronary artery calcification (CAC) is a strong predictor of cardiovascular risk but remains underutilized in clinical routine thoracic imaging due to the need for dedicated imaging protocols and manual annotation. We present DeepCAC2, a publicly available dataset containing automated CAC segmentations, coronary artery calcium scores, and derived risk categories generated from low-dose chest CT scans of the National Lung Screening Trial (NLST). Using a fully automated deep learning pipeline trained on expert-annotated cardiac CT data, we processed 127,776 CT scans from 26,228 individuals and generated standardized CAC segmentations and risk estimates for each acquisition. We already provide a public dashboard as a simple tool to visually inspect a random subset of 200 NLST patients of the dataset. The dataset will be released with DICOM-compatible segmentation objects and structured metadata to support reproducible downstream analysis. The deep learning pipeline will be made publicly available as a DICOM-compatible MHub.ai container. DeepCAC2 provides a transparent, large-scale, public, fully reproducible resource for research in cardiovascular risk assessment, opportunistic screening, and imaging biomarker development.

BACKGROUND:Quantitative coronary plaque measures differ in prognostic value between women and men. It remains unclear whether cardiovascular risk increases proportionally with plaque extent in both sexes. We aimed to compare cardiovascular risk trajectories across quantitative coronary plaque measures in women and men with stable chest pain. METHODS:We analyzed data from the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) coronary computed tomography angiography arm, quantifying total coronary plaque volume and burden (plaque burden [PB]; % vessel volume), including calcified, noncalcified, and low-attenuation components. Associations with major adverse cardiovascular events (death, myocardial infarction, or unstable angina hospitalization) were assessed using sex-stratified spline Cox models over a median 26 months (interquartile range, 18-34). RESULTS:Among 4267 patients (mean age, 60.4±8.2; 2199 women), plaque was less frequent in women (55% versus 75%; P<0.001), with lower total plaque volume but similar total PB and incident major adverse cardiovascular events (2.3% versus 3.4%). Major adverse cardiovascular event risk became elevated at lower PB in women than in men: for total PB, hazard ratio crossed 1.0 at 20% in women versus 28% in men, reaching hazard ratio 1.5 at 32% in women versus 42% in men, respectively. Noncalcified PB showed a similar pattern, crossing hazard ratio 1.0 at 7% in women versus 9% in men; hazard ratio 1.5 at 13% in women versus 20% in men. Findings were similar after adjustment for atherosclerotic cardiovascular disease risk score. CONCLUSIONS:In women, major adverse cardiovascular events appeared to emerge at a lower PB, and to rise more sharply. Findings support sex-specific interpretation of coronary computed tomography angiography-derived plaque metrics for timely intervention in women. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01174550.

AIMS:Risk factor-weighted clinical likelihood (RF-CL) estimates the probability of obstructive coronary artery disease (CAD) in patients without known CAD. We examined whether adding lipoprotein(a) [Lp(a)] measurements to the RF-CL model improves predictions of obstructive CAD. METHODS AND RESULTS:In a derivation cohort (N = 4262; 54% male; mean age 58 years), the prevalence of obstructive CAD at invasive angiography with fractional flow reserve was assessed by Lp(a)-strata. On the basis of initial results, an Lp(a)-adjusted model (RF-CLLp(a)) was developed: RF-CL was multiplied by 1.5 in patients with elevated Lp(a) (≥125 nmol/L) and otherwise unchanged. Discrimination, calibration, and reclassification were compared. Findings were validated in an external validation cohort (N = 1595; 49% male; mean age 60 years) using a comparative endpoint; significant stenosis at invasive angiography or coronary computed tomography.In the derivation cohort, 473 patients (11.1%) had obstructive CAD; in the validation cohort, 206 patients (12.9%) had significant stenosis. The relative risk in patients with elevated Lp(a) was 1.51 [95% confidence interval (CI) 1.23-1.86] and 1.19 (95% CI 0.88-1.60) in the derivation and validation cohort, respectively. In the derivation cohort, the RF-CLLp(a) model showed a higher area under the receiver operating curve than the RF-CL model [0.743 (standard error 0.011) vs. 0.740 (0.013)] and better calibration in patients with elevated Lp(a). Reclassification from RF-CL to RF-CLLp(a) improved likelihood stratification in the derivation cohort but not in the validation cohort. CONCLUSION:Adding elevated Lp(a) as a risk factor to the RF-CL model improves accuracy of obstructive CAD in patients with high Lp(a).

Importance:Despite the increasing use of coronary computed tomographic angiography (CCTA) in patients with known or suspected coronary artery disease (CAD), comparatively little is known about its predictive value for adverse events or clinical applicability of volumetric plaque analysis. Objective:To assess the incremental prognostic value of quantitative CAD measures in symptomatic outpatients without known CAD. Design, Setting, and Participants:This post hoc analysis involved a prospective randomized clinical trial conducted across 193 clinical sites in North America. Participants were symptomatic outpatients without known CAD who were randomized to receive CCTA. The trial was conducted from July 27, 2010, to October 31, 2014, and the data analyzed for this report from January 2021 to July 2024. Exposures:Core laboratory-based quantitative plaque measures, including total plaque volume (TPV), calcified (CPV) and noncalcified (NCPV) plaque volume, low-attenuation plaque volume (LAPV), total plaque burden (TPB), and noncalcified plaque burden (NCPB), normalized with vessel volume. Main Outcomes and Measures:The primary outcome was major adverse cardiovascular events MACE (composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina). Optimal predictive cut points for plaque measures were identified using Euclidean distance methods and tested in multivariable Cox regression models. Results:Among 4267 patients, the mean (SD) age was 60.4 (8.2) years; 2199 patients (51.5%) were female and 2068 (48.5%) were male. The median (IQR) TPV was 39.8 mm3 (0-167) mm3. Patients with TPV at the median or higher were older (mean [SD] age, 62.1 [8.4] vs 58.7 [7.5] years for those with lower than median TPV), more likely to be male (1286/2133 [60.3%] vs 782/2134 [36.6%], respectively), and had higher median (IQR) atherosclerotic cardiovascular disease risk scores (14.4 [8.8-24.0] vs 7.9 [4.5-13.4], respectively). TPB showed similar demographic associations. Both TPB and NCPB independently predicted MACE after adjusting for clinical risk factors, statin use, and qualitative CCTA findings (TPB: adjusted HR [aHR], 1.18; 95% CI, 1.05-1.34; P = .006; NCPB: aHR, 1.20; 95% CI, 1.05-1.37; P = .007). Optimal cutoffs of TPV 87 mm3 or greater, TPB 35% or greater, and NCPB 20% or greater were each associated with nearly a 2-fold increase in MACE risk (TPV: aHR, 2.07; 95% CI, 1.24-3.49; TPB: aHR, 1.96; 95% CI, 1.21-3.17; and NCPB: aHR, 1.77; 95% CI, 1.12-2.82). Conclusions and Relevance:In symptomatic patients without known CAD, coronary plaque volumes and burdens are low but are related to CAD risk factors and independently predictive of MACE. The clinical utility of quantitative CCTA-based cardiovascular risk estimation in early CAD requires prospective evaluation. Trial Registration:ClinicalTrials.gov Identifier: NCT01174550.

BACKGROUND:Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL (low-density lipoprotein) cholesterol (LDL-C), and reduces apoB (apolipoprotein B) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. METHODS:We conducted a coronary computed tomography angiography study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen versus placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence of or high risk for cardiovascular disease, and, for this imaging study, noncalcified plaque on baseline coronary computed tomography angiography. The primary end point was percent change from baseline to 12 months in noncalcified plaque volume. RESULTS:Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (interquartile range, 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (interquartile range, 197-331), and remnant cholesterol was 53 mg/dL (interquartile range, 38-76). Median baseline noncalcified plaque volume was 125.3 mm³ (interquartile range, 63.2-213.3). At 6 months, olezarsen reduced triglycerides by 63.9%, remnant cholesterol by 71.9%, and apoB by 16.0% over placebo, with no difference in LDL-C. The percent change in noncalcified plaque volume from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference, 2.98% [95% CI, -3.4 to 9.3]; p=0.36). No significant differences between olezarsen and placebo were observed for changes in low-attenuation, calcified, or total plaque volumes at 12 months. CONCLUSIONS:Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05610280.

BACKGROUND:Coronary artery disease (CAD) polygenic risk scores (PRS) may identify individuals at elevated genetic risk "flying under the radar" in contemporary practice. The aims of the PROACT (Polygenic Risk Based Detection and Treatment of Subclinical Coronary Atherosclerosis) trials are to prospectively identify these individuals, quantify subclinical coronary plaque, and slow its progression with pharmacologic interventions. OBJECTIVES:The aim of this study is to report interim feasibility and implementation findings from PROACT, a genotype-first, biobank-enabled trial, characterizing eligibility yield, callback engagement, and subclinical coronary atherosclerosis on coronary computed tomographic angiography among individuals with high CAD PRS. METHODS:Within a hospital-based biobank, adults 40 to 75 years of age with high CAD PRS, without cardiovascular disease, and not on lipid-lowering therapy were invited. The authors characterize 2,495 eligible individuals with high CAD PRS, report on the feasibility and early operational outcomes of a genotype-first callback strategy for a clinical trial in the first 1,314 invited, and describe plaque prevalence by age and sex in the first 204 participants using coronary computed tomographic angiography. RESULTS:Among 64,092 genotyped participants, 2,495 (3.9%) were eligible and had high CAD PRS despite low clinical risk (median 10-year pooled cohort equations risk for atherosclerotic cardiovascular disease 3%; Q1-Q3: 1%-8%). Recruitment showed high engagement: among 1,314 invited individuals, 283 (21.5%) opted in, and 204 (15.5%) completed baseline imaging. Compared with participants who did not opt in, those who opted in had higher specialty care engagement and lived closer to the study site. Analysis of the first 204 participants enrolled by January 31, 2025 (mean age 56.3 ± 8.5 years, 69% women), showed that despite the low clinical risk and favorable cardiovascular health (mean Life's Essential 8 score 73.3 ± 11.5 vs the U.S. average of ∼65), one-half the participants (102 of 204) had subclinical plaque. Subclinical plaque prevalence was 76.2% in men and 38.3% in women and was high across age groups. CONCLUSIONS:These exploratory findings highlight the feasibility of implementing genotype-first recruitment for prevention trials and reveal a large proportion of "silent" high-genetic risk individuals with subclinical plaque for whom pharmacotherapy could be beneficial but who remain undetected by standard clinical assessments. (Polygenic Risk Based Detection of Subclinical Coronary Atherosclerosis and Change in Cardiovascular Health [PROACT 1], NCT05819814; Polygenic Risk Based Detection of Subclinical Coronary Atherosclerosis and Intervention With Statin and Colchicine [PROACT 2], NCT05850091).

The thymus is essential for establishing T cell diversity early in life, but undergoes profound involution with age and has therefore traditionally been regarded as largely nonfunctional in adults1,2. Here we propose that preserving thymic functionality is integral to adult health and longevity. We developed a deep learning framework to quantify thymic health from routine radiographic images and evaluated its association with longevity and risk of major age-associated diseases in two large prospective cohorts of asymptomatic adults: the National Lung Screening Trial (n = 25,031) and the Framingham Heart Study (n = 2,581). In both cohorts, thymic health varied markedly across the population. In the National Lung Screening Trial, higher thymic health was consistently associated with lower all-cause mortality, reduced lung cancer incidence and lower cardiovascular mortality over 12 years of follow-up after adjustment for age, sex, smoking and comorbidities. In the independent Framingham Heart Study cohort, higher thymic health was significantly associated with reduced cardiovascular mortality, independent of age, sex and smoking. Thymic health was further linked to systemic inflammation and metabolic dysregulation, and associated with modifiable lifestyle factors including smoking, obesity and physical activity. Together, these findings reposition the thymus as a central regulator of immune-mediated ageing and disease susceptibility in adulthood, highlighting its potential as a target for preventive and regenerative strategies to promote healthy ageing and longevity.

Chest radiographs (CXRs) are among the most common tests in medicine; automated interpretation may reduce radiologists' workload and expand access. Deep learning multi-task and foundation models have shown strong CXR interpretation performance but are vulnerable to shortcut learning, where spurious correlations drive decision-making. We introduce RoentMod, a counterfactual image editing framework that generates realistic CXRs with user-specified and synthetic pathology while maintaining the original anatomical features. RoentMod combines an open-source medical image generator (RoentGen) with an image-to-image modification model without retraining. In reader studies of RoentMod-produced images, 93% appeared realistic, 89-99% correctly incorporated the specified finding, and all preserved native anatomy comparable to real follow-up CXRs. Using RoentMod, we demonstrate that state-of-the-art multi-task and foundation models frequently exploit off-target pathology as shortcuts, limiting their specificity. Incorporating RoentMod-generated counterfactual images during training mitigated this vulnerability, improving model discrimination across multiple pathologies by 3-19% AUC in internal validation and by 1-11% for 5 out of 6 tested pathologies in external testing. These findings establish RoentMod as a tool to probe and correct shortcut learning in medical AI. By enabling controlled counterfactual interventions, RoentMod enhances the robustness and interpretability of CXR interpretation models and provides a strategy to improve medical imaging models.

BACKGROUND & AIMS:Hepatic steatosis has been associated with major adverse cardiovascular events independently of other cardiovascular risk factors and the severity of coronary artery disease. Nevertheless, the relationship between hepatic steatosis, coronary plaque composition, and major adverse cardiovascular events remains unclear. METHODS:A central core laboratory analyzed Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) participants randomized to the computed tomography arm. Hepatic steatosis was assessed on noncontrast computed tomography using standard hepatic and splenic attenuation methods. Coronary computed tomography angiography was used to quantify total, calcified, noncalcified, and low-attenuation plaque volume and burden (% vessel volume). Multivariable regression and mediation analyses assessed relationships between hepatic steatosis, plaque components, and major adverse cardiovascular events (death, myocardial infarction, unstable angina hospitalization). The median follow-up was 25 months (interquartile range, 18-33 months). RESULTS:Among 3637 patients (age, 60.6 ± 8.2 years; 51.4% female), 25.5% had hepatic steatosis and were slightly younger, more often male, had more cardiovascular risk factors, and had a higher rate of major adverse cardiovascular events (4.1% vs 2.5%) (all P < .05). After adjustment for clinical risk factors, hepatic steatosis was associated with greater noncalcified plaque burden (β, 0.15%; 95% confidence interval, 0.04-0.27; P = .008). Hepatic steatosis was associated with increased risk of major adverse cardiovascular events independent of atherosclerotic cardiovascular disease risk score, obesity, obstructive stenosis, and noncalcified plaque burden (adjusted hazard ratio, 1.69; 95% confidence interval, 1.12-2.54; P = .012), whereas noncalcified plaque burden mediated 11% of the association between hepatic steatosis and major adverse cardiovascular events. CONCLUSIONS:Hepatic steatosis was associated with greater noncalcified plaque burden and increased risk of major adverse cardiovascular events, with noncalcified plaque burden accounting for a portion of this association, suggesting a link between hepatic steatosis and vulnerable coronary atherosclerosis. These findings support integrated cardiometabolic risk assessment in patients undergoing coronary computed tomography angiography. CLINICALTRIALS:gov number, NCT01174550.

BACKGROUND:Cardiovascular disease prevention relies on accurate risk assessment; however, existing scores are imprecise. Routine imaging may be opportunistically used to predict risk. OBJECTIVES:The authors tested whether computed tomography (CT)-derived cardiac and aortic structure predicts major adverse cardiac events (MACE) beyond standard-of-care scores. METHODS:The authors developed a least absolute shrinkage and selection operator model to predict cardiovascular mortality using "radiomics" features describing cardiac and aortic structure from 13,437 lung cancer screening CTs from the NLST (National Lung Screening Trial). They compared this score to the PREVENT (Predicting Risk of Cardiovascular Disease Events) tool and the coronary artery calcium (CAC) score in patients with routine chest CT and no prior MACE from Mass General Brigham. They calculated discrimination using Harrel's C-index and MACE rates in high-risk groups by the PREVENT score (≥7.5% risk) or the radiomics score (≥3.0% in men, ≥1.5% in women). RESULTS:In external testing (n = 14,577, mean age 61.1 ± 8.6 years, 47.5% male), 6.2% had incident MACE over a median of 5.7 years of follow-up. The radiomics score had higher discrimination for MACE than PREVENT (C-index 0.66 [95% CI: 0.64-0.68] vs 0.61 [95% CI: 0.59-0.63]) and was complementary to CAC (combined C-index 0.69 [95% CI: 0.67-0.71] vs CAC alone 0.66 [95% CI: 0.65-0.68]). High-risk patients by the radiomics score but not PREVENT had 3.6-fold higher MACE incidence than low-risk patients by both scores (23.1 [95% CI: 16.7-30.2] vs 6.5 [95% CI: 5.5-7.5] MACE per 1,000 person-years). Aortic surface-to-volume ratio, left ventricular volume, and left atrial short-axis length were among the most predictive features of MACE. CONCLUSIONS:CT-derived structural cardiac and aortic radiomics identified high-risk patients missed by clinical scores and further stratified risk among CAC risk groups. High-risk patients may benefit from intensified primary prevention.

This secondary analysis of a randomized clinical trial examines plaque measures from coronary computed tomographic angiography to assess the incremental prognostic value of quantitative coronary artery disease measures among symptomatic patients. QuestionDoes quantitative plaque assessment improve prognostication of major adverse cardiovascular events (MACE) in patients with unknown history of coronary artery disease?FindingsIn this substudy of the randomized clinical trial PROMISE, among 4267 symptomatic patients, higher total plaque volume (>= 87 mm), total plaque burden (>= 35%), and noncalcified plaque burden (>= 20%) were associated with an increased risk of MACE, independent of atherosclerotic cardiovascular disease risk, statin use, 50% or more stenosis, coronary artery calcium score, and high-risk plaque.MeaningQuantitative plaque measures on coronary computed tomographic angiography (CCTA) improve risk prediction for MACE and may enhance early cardiovascular risk assessment beyond clinical risk and routinely assessed CCTA metrics. ImportanceDespite the increasing use of coronary computed tomographic angiography (CCTA) in patients with known or suspected coronary artery disease (CAD), comparatively little is known about its predictive value for adverse events or clinical applicability of volumetric plaque analysis.ObjectiveTo assess the incremental prognostic value of quantitative CAD measures in symptomatic outpatients without known CAD.Design, Setting, and ParticipantsThis post hoc analysis involved a prospective randomized clinical trial conducted across 193 clinical sites in North America. Participants were symptomatic outpatients without known CAD who were randomized to receive CCTA. The trial was conducted from July 27, 2010, to October 31, 2014, and the data analyzed for this report from January 2021 to July 2024.ExposuresCore laboratory-based quantitative plaque measures, including total plaque volume (TPV), calcified (CPV) and noncalcified (NCPV) plaque volume, low-attenuation plaque volume (LAPV), total plaque burden (TPB), and noncalcified plaque burden (NCPB), normalized with vessel volume.Main Outcomes and MeasuresThe primary outcome was major adverse cardiovascular events MACE (composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina). Optimal predictive cut points for plaque measures were identified using Euclidean distance methods and tested in multivariable Cox regression models.ResultsAmong 4267 patients, the mean (SD) age was 60.4 (8.2) years; 2199 patients (51.5%) were female and 2068 (48.5%) were male. The median (IQR) TPV was 39.8 mm3 (0-167) mm3. Patients with TPV at the median or higher were older (mean [SD] age, 62.1 [8.4] vs 58.7 [7.5] years for those with lower than median TPV), more likely to be male (1286/2133 [60.3%] vs 782/2134 [36.6%], respectively), and had higher median (IQR) atherosclerotic cardiovascular disease risk scores (14.4 [8.8-24.0] vs 7.9 [4.5-13.4], respectively). TPB showed similar demographic associations. Both TPB and NCPB independently predicted MACE after adjusting for clinical risk factors, statin use, and qualitative CCTA findings (TPB: adjusted HR [aHR], 1.18; 95% CI, 1.05-1.34; P = .006; NCPB: aHR, 1.20; 95% CI, 1.05-1.37; P = .007). Optimal cutoffs of TPV 87 mm3 or greater, TPB 35% or greater, and NCPB 20% or greater were each associated with nearly a 2-fold increase in MACE risk (TPV: aHR, 2.07; 95% CI, 1.24-3.49; TPB: aHR, 1.96; 95% CI, 1.21-3.17; and NCPB: aHR, 1.77; 95% CI, 1.12-2.82).Conclusions and RelevanceIn symptomatic patients without known CAD, coronary plaque volumes and burdens are low but are related to CAD risk factors and independently predictive of MACE. The clinical utility of quantitative CCTA-based cardiovascular risk estimation in early CAD requires prospective evaluation.Trial RegistrationClinicalTrials.gov Identifier: NCT01174550

BACKGROUND:The Tesamorelin as an Adjunct to Exercise for Improving Physical Function in HIV (TRIUMPH) study is a randomised controlled trial with the overall goal of examining the combined effect of exercise and the growth hormone-releasing hormone analogue tesamorelin on physical function. METHODS:TRIUMPH is a two-site, double-blind, randomised trial of 100 sedentary older adults (aged 50-80 years) living with HIV who are frail or at risk for frailty and have excess abdominal adiposity. Enrolled participants will be randomised to receive tesamorelin or placebo as an adjunct to a home-based semisupervised exercise programme for 24 weeks, followed by a 24-week extension phase of independent exercise. We will determine short-term and sustained effects of tesamorelin plus exercise on clinical endpoints, including physical function, muscle content and quality, quality of life, and exercise adherence at Weeks 24 and 48. We also will elucidate effects of tesamorelin plus exercise on biological endpoints, including muscle fat and mitochondrial function at Week 24. ETHICS AND DISSEMINATION:Ethical approval for the TRIUMPH study was obtained from the Institutional Review Boards at participating sites. All participants provide written informed consent prior to enrolment. Study findings will be disseminated through peer-reviewed publications and scientific conferences and may inform future interventions to improve physical function among older adults living with HIV. TRIAL REGISTRATION NUMBER:NCT06554717.

Background Although the relationship between smoking and cardiovascular events is well established, it remains uncertain whether the outcomes of noninvasive testing (NIT) influence this relationship and how systemic biomarkers may aid risk stratification in patients presenting with chest pain. Methods This study included PROMISE participants with stable chest pain and available smoking status (current, ever, or never) and NIT results (Positive NIT: ≥70% coronary stenosis on CT angiography or inducible ischemia on stress testing). Smoking was associated with systemic biomarkers (e.g., hsCRP, IL-6, MMP-9), NIT results, and major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, unstable angina), using regression and mediation models adjusted for traditional cardiovascular risk factors (median follow-up 24.4 months). Results Among 9100 individuals (mean age 61±8 years; 53% female), 51% were ever-smokers, including 18% current smokers. Smoking was independently associated with MACE, with positive NIT mediating this relationship (current: 16%; ever: 12%, p ≤ 0.006). Compared with never-smokers, smoking was associated with MACE despite negative NIT (current: aHR 2.41, 95%CI 1.49–3.89; ever: aHR 1.80, 95%CI 1.25–2.59), with the most pronounced differences seen in men vs. women and CV death/MI (sex interaction p = 0.047). Smoking was associated with high levels of inflammatory biomarkers, particularly MMP-9 (+51%; current vs. never-smokers), which partially mediated the smoking-MACE association (current: 25%; ever: 8%, ≤0.05). Conclusions Negative NIT does not reduce smoking-associated MACE risk in patients with stable chest pain. Particularly, current smoking confers substantial residual cardiovascular risk, potentially mediated by MMP-9-related matrix remodeling not captured by standard testing, supporting aggressive smoking cessation irrespective of NIT results.