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AIMS: The totality of atherosclerotic plaque derived from coronary computed tomography angiography (CCTA) emerges as a comprehensive measure to assess the intensity of medical treatment that patients need. This study examines the differences in age onset and prognostic significance of atherosclerotic plaque burden between sexes. METHODS AND RESULTS: From a large multi-center CCTA registry the Leiden CCTA score was calculated in 24 950 individuals. A total of 11 678 women (58.5 ± 12.4 years) and 13 272 men (55.6 ± 12.5 years) were followed for 3.7 years for major adverse cardiovascular events (MACE) (death or myocardial infarction). The age where the median risk score was above zero was 12 years higher in women vs. men (64-68 years vs. 52-56 years, respectively, P < 0.001). The Leiden CCTA risk score was independently associated with MACE: score 6-20: HR 2.29 (1.69-3.10); score > 20: HR 6.71 (4.36-10.32) in women, and score 6-20: HR 1.64 (1.29-2.08); score > 20: HR 2.38 (1.73-3.29) in men. The risk was significantly higher for women within the highest score group (adjusted P-interaction = 0.003). In pre-menopausal women, the risk score was equally predictive and comparable with men. In post-menopausal women, the prognostic value was higher for women [score 6-20: HR 2.21 (1.57-3.11); score > 20: HR 6.11 (3.84-9.70) in women; score 6-20: HR 1.57 (1.19-2.09); score > 20: HR 2.25 (1.58-3.22) in men], with a significant interaction for the highest risk group (adjusted P-interaction = 0.004). CONCLUSION: Women developed coronary atherosclerosis approximately 12 years later than men. Post-menopausal women within the highest atherosclerotic burden group were at significantly higher risk for MACE than their male counterparts, which may have implications for the medical treatment intensity.

Coronary computed tomographic angiography (CCTA) is becoming the first-line investigation for establishing the presence of coronary artery disease and, with fractional flow reserve (FFRCT), its haemodynamic significance. In patients without significant epicardial obstruction, its role is either to rule out atherosclerosis or to detect subclinical plaque that should be monitored for plaque progression/regression following prevention therapy and provide risk classification. Ischaemic non-obstructive coronary arteries are also expected to be assessed by non-invasive imaging, including CCTA. In patients with significant epicardial obstruction, CCTA can assist in planning revascularisation by determining the disease complexity, vessel size, lesion length and tissue composition of the atherosclerotic plaque, as well as the best fluoroscopic viewing angle; it may also help in selecting adjunctive percutaneous devices (e.g., rotational atherectomy) and in determining the best landing zone for stents or bypass grafts.

Background and hypothesisThe recently introduced Bayesian quantile regression (BQR) machine-learning method enables comprehensive analyzing the relationship among complex clinical variables. We analyzed the relationship between multiple cardiovascular (CV) risk factors and different stages of coronary artery disease (CAD) using the BQR model in a vessel-specific manner.MethodsFrom the data of 1,463 patients obtained from the PARADIGM (NCT02803411) registry, we analyzed the lumen diameter stenosis (DS) of the three vessels: left anterior descending (LAD), left circumflex (LCx), and right coronary artery (RCA). Two models for predicting DS and DS changes were developed. Baseline CV risk factors, symptoms, and laboratory test results were used as the inputs. The conditional 10%, 25%, 50%, 75%, and 90% quantile functions of the maximum DS and DS change of the three vessels were estimated using the BQR model.ResultsThe 90th percentiles of the DS of the three vessels and their maximum DS change were 41%-50% and 5.6%-7.3%, respectively. Typical anginal symptoms were associated with the highest quantile (90%) of DS in the LAD; diabetes with higher quantiles (75% and 90%) of DS in the LCx; dyslipidemia with the highest quantile (90%) of DS in the RCA; and shortness of breath showed some association with the LCx and RCA. Interestingly, High-density lipoprotein cholesterol showed a dynamic association along DS change in the per-patient analysis.ConclusionsThis study demonstrates the clinical utility of the BQR model for evaluating the comprehensive relationship between risk factors and baseline-grade CAD and its progression.

BACKGROUND: Ischemia with nonobstructive coronary arteries (INOCA) is common clinically, particularly among women, but its prevalence among patients with at least moderate ischemia and the relationship between ischemia severity and non-obstructive atherosclerosis severity are unknown. OBJECTIVES: The authors investigated predictors of INOCA in enrolled, nonrandomized participants in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), sex differences, and the relationship between ischemia and atherosclerosis in patients with INOCA. METHODS: Core laboratories independently reviewed screening noninvasive stress test results (nuclear imaging, echocardiography, magnetic resonance imaging or nonimaging exercise tolerance testing), and coronary computed tomography angiography (CCTA), blinded to results of the screening test. INOCA was defined as all stenoses

AimObstructive coronary artery disease (CAD) in proximal coronary segments is associated with a poor prognosis. However, the relative importance of plaque location regarding the risk for major adverse cardiovascular events (MACE) in patients with non-obstructive CAD has not been well defined.Methods and resultsFrom the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry, 4644 patients without obstructive CAD were included in this study. The degree of stenosis was classified as 0 (no) and 1-49% (non-obstructive). Proximal involvement was defined as any plaque present in the left main or the proximal segment of the left anterior descending artery, left circumflex artery, and right coronary artery. Extensive CAD was defined as segment involvement score of >4. During a median follow-up of 5.2 years (interquartile range 4.1-6.0), 340 (7.3%) MACE occurred. Within the non-obstructive CAD group (n = 2065), proximal involvement was observed in 1767 (85.6%) cases. When compared to non-obstructive CAD patients without proximal involvement, those with proximal involvement had an increased MACE risk (log-rank P = 0.033). Multivariate Cox analysis showed when compared to patients with no CAD, proximal non-obstructive CAD was associated with increased MACE risk [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.47-2.45, P < 0.001] after adjusting for extensive CAD and conventional cardiovascular risk factors; however, non-proximal non-obstructive CAD did not increase MACE risk (HR 1.26, 95% CI 0.79-2.01, P = 0.339).ConclusionsIndependent of plaque extent, proximal coronary involvement was associated with increased MACE risk in patients with non-obstructive CAD. The plaque location information by coronary computed tomography angiography may provide additional risk prediction over CAD extent in patients with non-obstructive CAD.

BackgroundAtherosclerosis-related adverse events are commonly observed even in conditions with low cardiovascular (CV) risk. Longitudinal data regarding the association of normal systolic blood pressure maintenance (SBPmaintain ) with coronary plaque volume changes (PVC) has been limited in adults without traditional CV disease.HypothesisNormal SBPmaintain is important to attenuate coronary atherosclerosis progression in adults without baseline CV disease.MethodsWe analyzed 95 adults (56.7 ± 8.5 years; 40.0% men) without baseline CV disease who underwent serial coronary computed tomographic angiography with mean 3.5 years of follow-up. All participants were divided into two groups of normal SBPmaintain (follow-up SBP

ObjectivesThe aim of this study was to describe the potential of 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) to identify graft vasculopathy and to investigate the influence of coronary artery bypass graft (CABG) surgery on native coronary artery disease activity and progression.BackgroundAs well as developing graft vasculopathy, CABGs have been proposed to accelerate native coronary atherosclerosis.MethodsPatients with established coronary artery disease underwent baseline 18F-NaF PET, coronary artery calcium scoring, coronary computed tomographic angiography, and 1-year repeat coronary artery calcium scoring. Whole-vessel coronary microcalcification activity (CMA) on 18F-NaF PET and change in calcium scores were quantified in patients with and without CABG surgery.ResultsAmong 293 participants (mean age 65 ± 9 years, 84% men), 48 (16%) underwent CABG surgery 2.7 years [IQR: 1.4-10.4 years] previously. Although all arterial and the majority (120 of 128 [94%]) of vein grafts showed no 18F-NaF uptake, 8 saphenous vein grafts in 7 subjects had detectable CMA. Bypassed native coronary arteries had 3 times higher CMA values (2.1 [IQR: 0.4-7.5] vs 0.6 [IQR: 0-2.7]; P < 0.001) and greater progression of 1-year calcium scores (118 Agatston unit [IQR: 48-194 Agatston unit] vs 69 [IQR: 21-142 Agatston unit]; P = 0.01) compared with patients who had not undergone CABG, an effect confined largely to native coronary plaques proximal to the graft anastomosis. In sensitivity analysis, bypassed native coronary arteries had higher CMA (2.0 [IQR: 0.4-7.5] vs 0.8 [IQR: 0.3-3.2]; P < 0.001) and faster disease progression (24% [IQR: 16%-43%] vs 8% [IQR: 0%-24%]; P = 0.002) than matched patients (n = 48) with comparable burdens of coronary artery disease and cardiovascular comorbidities in the absence of bypass grafting.ConclusionsNative coronary arteries that have been bypassed demonstrate increased disease activity and more rapid disease progression than nonbypassed arteries, an observation that appears independent of baseline atherosclerotic plaque burden. Microcalcification activity is not a dominant feature of graft vasculopathy.

AimsThe relationship between dyspnoea, coronary artery disease (CAD), and major cardiovascular events (MACE) is poorly understood. This study evaluated (i) the association of dyspnoea with the severity of anatomical CAD by coronary computed tomography angiography (CCTA) and (ii) to which extent CAD explains MACE in patients with dyspnoea.Methods and resultsFrom the international COronary CT Angiography EvaluatioN for Clinical Outcomes: An InteRnational Multicenter (CONFIRM) registry, 4425 patients (750 with dyspnoea) with suspected but without known CAD were included and prospectively followed for ≥5 years. First, the association of dyspnoea with CAD severity was assessed using logistic regression analysis. Second, the prognostic value of dyspnoea for MACE (myocardial infarction and death), and specifically, the interaction between dyspnoea and CAD severity was investigated using Cox proportional-hazard analysis. Mean patient age was 60.3 ± 11.9 years, 63% of patients were male and 592 MACE events occurred during a median follow-up duration of 5.4 (IQR 5.1-6.0) years. On uni- and multivariable analysis (adjusting for age, sex, body mass index, chest pain typicality, and risk factors), dyspnoea was associated with two- and three-vessel/left main (LM) obstructive CAD. The presence of dyspnoea increased the risk for MACE [hazard ratio (HR) 1.57, 95% confidence interval (CI): 1.29-1.90], which was modified after adjusting for clinical predictors and CAD severity (HR 1.26, 95% CI: 1.02-1.55). Conversely, when stratified by CAD severity, dyspnoea did not provide incremental prognostic value in one-, two-, or three-vessel/LM obstructive CAD, but dyspnoea did provide incremental prognostic value in non-obstructive CAD.ConclusionIn patients with suspected CAD, dyspnoea was independently associated with severe obstructive CAD on CCTA. The severity of obstructive CAD explained the elevated MACE rates in patients presenting with dyspnoea, but in patients with non-obstructive CAD, dyspnoea portended additional risk.

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

ObjectivesThis study sought to identify distinct patient groups and their association with outcome based on the patient similarity network using quantitative coronary plaque characteristics from coronary computed tomography angiography (CTA).BackgroundCoronary CTA can noninvasively assess coronary plaques quantitatively.MethodsPatients who underwent 2 coronary CTAs at a minimum of 24 months' interval were analyzed (n = 1,264). A similarity Mapper network of patients was built by topological data analysis (TDA) based on the whole-heart quantitative coronary plaque analysis on coronary CTA to identify distinct patient groups and their association with outcome.ResultsThree distinct patient groups were identified by TDA, and the patient similarity network by TDA showed a closed loop, demonstrating a continuous trend of coronary plaque progression. Group A had the least coronary plaque amount (median 12.4 mm3 [interquartile range (IQR): 0.0 to 39.6 mm3]) in the entire coronary tree. Group B had a moderate coronary plaque amount (31.7 mm3 [IQR: 0.0 to 127.4 mm3]) with relative enrichment of fibrofatty and necrotic core (32.6% [IQR: 16.7% to 46.2%] and 2.7% [IQR: 0.1% to 6.9%] of the total plaque, respectively) components. Group C had the largest coronary plaque amount (187.0 mm3 [IQR: 96.7 to 306.4 mm3]) and was enriched for dense calcium component (46.8% [IQR: 32.0% to 63.7%] of the total plaque). At follow-up, total plaque volume, fibrous, and dense calcium volumes increased in all groups, but the proportion of fibrofatty component decreased in groups B and C, whereas the necrotic core portion decreased in only group B (all p

ObjectivesThe aim of the current study was to explore the impact of plaque calcification in terms of absolute calcified plaque volume (CPV) and in the context of its percentage of the total plaque volume at a lesion and patient level on the progression of coronary artery disease.BackgroundCoronary artery calcification is an established marker of risk of future cardiovascular events. Despite this, plaque calcification is also considered a marker of plaque stability, and it increases in response to medical therapy.MethodsThis analysis included 925 patients with 2,568 lesions from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry, in which patients underwent clinically indicated serial coronary computed tomography angiography. Plaque calcification was examined by using CPV and percent CPV (PCPV), calculated as (CPV/plaque volume) × 100 at a per-plaque and per-patient level (summation of all individual plaques).ResultsCPV was strongly correlated with plaque volume (r = 0.780; p

AimsAlthough there is increasing evidence supporting coronary atherosclerosis evaluation by coronary computed tomography angiography (CCTA), no data are available on age and sex differences for quantitative plaque features. The aim of this study was to investigate sex and age differences in both qualitative and quantitative atherosclerotic features from CCTA prior to acute coronary syndrome (ACS).Methods and resultsWithin the ICONIC study, in which 234 patients with subsequent ACS were propensity matched 1:1 with 234 non-event controls, our current subanalysis included only the ACS cases. Both qualitative and quantitative advance plaque analysis by CCTA were performed by a core laboratory. In 129 cases, culprit lesions identified by invasive coronary angiography at the time of ACS were co-registered to baseline CCTA precursor lesions. The study population was then divided into subgroups according to sex and age (

Patient-specific phenotyping of coronary atherosclerosis would facilitate personalized risk assessment and preventive treatment. We explored whether unsupervised cluster analysis can categorize patients with coronary atherosclerosis according to their plaque composition, and determined how these differing plaque composition profiles impact plaque progression. Patients with coronary atherosclerotic plaque (n = 947; median age, 62 years; 59% male) were enrolled from a prospective multi-national registry of consecutive patients who underwent serial coronary computed tomography angiography (median inter-scan duration, 3.3 years). K-means clustering applied to the percent volume of each plaque component and identified 4 clusters of patients with distinct plaque composition. Cluster 1 (n = 52), which comprised mainly fibro-fatty plaque with a significant necrotic core (median, 55.7% and 16.0% of the total plaque volume, respectively), showed the least total plaque volume (PV) progression (+ 23.3 mm3), with necrotic core and fibro-fatty PV regression (- 5.7 mm3 and - 5.6 mm3, respectively). Cluster 2 (n = 219), which contained largely fibro-fatty (39.2%) and fibrous plaque (46.8%), showed fibro-fatty PV regression (- 2.4 mm3). Cluster 3 (n = 376), which comprised mostly fibrous (62.7%) and calcified plaque (23.6%), showed increasingly prominent calcified PV progression (+ 21.4 mm3). Cluster 4 (n = 300), which comprised mostly calcified plaque (58.7%), demonstrated the greatest total PV increase (+ 50.7mm3), predominantly increasing in calcified PV (+ 35.9 mm3). Multivariable analysis showed higher risk for plaque progression in Clusters 3 and 4, and higher risk for adverse cardiac events in Clusters 2, 3, and 4 compared to that in Cluster 1. Unsupervised clustering algorithms may uniquely characterize patient phenotypes with varied atherosclerotic plaque profiles, yielding distinct patterns of progressive disease and outcome.

BackgroundThe association between triglyceride glucose (TyG) index and coronary atherosclerotic change remains unclear. We aimed to evaluate the association between TyG index and coronary plaque progression (PP) using serial coronary computed tomography angiography (CCTA).MethodsA total of 1143 subjects (aged 60.7 ± 9.3 years, 54.6% male) who underwent serial CCTA with available data on TyG index and diabetic status were analyzed from The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry. PP was defined as plaque volume (PV) (mm3) at follow-up minus PV at index > 0. Annual change of PV (mm3/year) was defined as PV change divided by inter-scan period. Rapid PP was defined as the progression of percent atheroma volume (PV divided by vessel volume multiplied by 100) ≥ 1.0%/year.ResultsThe median inter-scan period was 3.2 (range 2.6-4.4) years. All participants were stratified into three groups based on TyG index tertiles. The overall incidence of PP was 77.3%. Baseline total PV (group I [lowest]: 30.8 (0.0-117.7), group II: 47.2 (6.2-160.4), and group III [highest]: 57.5 (8.4-154.3); P

ObjectivesThis study sought to identify culprit lesion (CL) precursors among acute coronary syndrome (ACS) patients based on qualitative and quantitative computed tomography-based plaque characteristics.BackgroundCoronary computed tomography angiography (CTA) has been validated for patient-level prediction of ACS. However, the applicability of coronary CTA to CL assessment is not known.MethodsUtilizing the ICONIC (Incident COroNary Syndromes Identified by Computed Tomography) study, a nested case-control study of 468 patients with baseline coronary CTA, the study included ACS patients with invasive coronary angiography-adjudicated CLs that could be aligned to CL precursors on baseline coronary CTA. Separate blinded core laboratories adjudicated CLs and performed atherosclerotic plaque evaluation. Thereafter, the study used a boosted ensemble algorithm (XGBoost) to develop a predictive model of CLs. Data were randomly split into a training set (80%) and a test set (20%). The area under the receiver-operating characteristic curve of this model was compared with that of diameter stenosis (model 1), high-risk plaque features (model 2), and lesion-level features of CL precursors from the ICONIC study (model 3). Thereafter, the machine learning (ML) model was applied to 234 non-ACS patients with 864 lesions to determine model performance for CL exclusion.ResultsCL precursors were identified by both coronary angiography and baseline coronary CTA in 124 of 234 (53.0%) patients, with a total of 582 lesions (containing 124 CLs) included in the analysis. The ML model demonstrated significantly higher area under the receiver-operating characteristic curve for discriminating CL precursors (0.774; 95% confidence interval [CI]: 0.758 to 0.790) compared with model 1 (0.599; 95% CI: 0.599 to 0.599; p

AimsHigh-risk plaque (HRP) and non-obstructive coronary artery disease independently predict adverse events, but their importance to future culprit lesions has not been resolved. We sought to determine in patients prior to confirmed acute coronary syndrome (ACS) the association between lesion percent diameter stenosis (%DS), and the absolute number and prevalence of HRP. The secondary objective was to examine the relative importance of non-obstructive HRP in future culprit lesions.Methods and resultsWithin the ICONIC study, a nested case-control study of patients undergoing coronary computed tomographic angiography (coronary CT), we included ACS cases with culprit lesions confirmed by invasive coronary angiography and coregistered to baseline coronary CT. Quantitative CT was used to evaluate obstructive (≥50%) and non-obstructive (

BACKGROUND AND AIMS:Different methodologies to report whole-heart atherosclerotic plaque on coronary computed tomography angiography (CCTA) have been utilized. We examined which of the three commonly used plaque burden definitions was least affected by differences in body surface area (BSA) and sex. METHODS:The PARADIGM study includes symptomatic patients with suspected coronary atherosclerosis who underwent serial CCTA >2 years apart. Coronary lumen, vessel, and plaque were quantified from the coronary tree on a 0.5 mm cross-sectional basis by a core-lab, and summed to per-patient. Three quantitative methods of plaque burden were employed: (1) total plaque volume (PV) in mm3, (2) percent atheroma volume (PAV) in % [which equaled: PV/vessel volume * 100%], and (3) normalized total atheroma volume (TAVnorm) in mm3 [which equaled: PV/vessel length * mean population vessel length]. Only data from the baseline CCTA were used. PV, PAV, and TAVnorm were compared between patients in the top quartile of BSA vs the remaining, and between sexes. Associations between vessel volume, BSA, and the three plaque burden methodologies were assessed. RESULTS:The study population comprised 1479 patients (age 60.7 ± 9.3 years, 58.4% male) who underwent CCTA. A total of 17,649 coronary artery segments were evaluated with a median of 12 (IQR 11-13) segments per-patient (from a 16-segment coronary tree). Patients with a large BSA (top quartile), compared with the remaining patients, had a larger PV and TAVnorm, but similar PAV. The relation between larger BSA and larger absolute plaque volume (PV and TAVnorm) was mediated by the coronary vessel volume. Independent from the atherosclerotic cardiovascular disease risk (ASCVD) score, vessel volume correlated with PV (P

AimsIn patients without obstructive coronary artery disease (CAD), we examined the prognostic value of risk factors and atherosclerotic extent.Methods and resultsPatients from the long-term CONFIRM registry without prior CAD and without obstructive (≥50%) stenosis were included. Within the groups of normal coronary computed tomography angiography (CCTA) (N = 1849) and non-obstructive CAD (N = 1698), the prognostic value of traditional clinical risk factors and atherosclerotic extent (segment involvement score, SIS) was assessed with Cox models. Major adverse cardiac events (MACE) were defined as all-cause mortality, non-fatal myocardial infarction, or late revascularization. In total, 3547 patients were included (age 57.9 ± 12.1 years, 57.8% male), experiencing 460 MACE during 5.4 years of follow-up. Age, body mass index, hypertension, and diabetes were the clinical variables associated with increased MACE risk, but the magnitude of risk was higher for CCTA defined atherosclerotic extent; adjusted hazard ratio (HR) for SIS >5 was 3.4 (95% confidence interval [CI] 2.3-4.9) while HR for diabetes and hypertension were 1.7 (95% CI 1.3-2.2) and 1.4 (95% CI 1.1-1.7), respectively. Exclusion of revascularization as endpoint did not modify the results. In normal CCTA, presence of ≥1 traditional risk factors did not worsen prognosis (log-rank P = 0.248), while it did in non-obstructive CAD (log-rank P = 0.025). Adjusted for SIS, hypertension and diabetes predicted MACE risk in non-obstructive CAD, while diabetes did not increase risk in absence of CAD (P-interaction = 0.004).ConclusionAmong patients without obstructive CAD, the extent of CAD provides more prognostic information for MACE than traditional cardiovascular risk factors. An interaction was observed between risk factors and CAD burden, suggesting synergistic effects of both.

AimsWe aimed to compare semiquantitative coronary computed tomography angiography (CCTA) risk scores - which score presence, extent, composition, stenosis and/or location of coronary artery disease (CAD) - and their prognostic value between patients with and without diabetes mellitus (DM). Risk scores derived from general chest-pain populations are often challenging to apply in DM patients, because of numerous confounders.MethodsOut of a combined cohort from the Leiden University Medical Center and the CONFIRM registry with 5-year follow-up data, we performed a secondary analysis in diabetic patients with suspected CAD who were clinically referred for CCTA. A total of 732 DM patients was 1:1 propensity-matched with 732 non-DM patients by age, sex and cardiovascular risk factors. A subset of 7 semiquantitative CCTA risk scores was compared between groups: 1) any stenosis ≥50%, 2) any stenosis ≥70%, 3) stenosis-severity component of the coronary artery disease-reporting and data system (CAD-RADS), 4) segment involvement score (SIS), 5) segment stenosis score (SSS), 6) CT-adapted Leaman score (CT-LeSc), and 7) Leiden CCTA risk score. Cox-regression analysis was performed to assess the association between the scores and the primary endpoint of all-cause death and non-fatal myocardial infarction. Also, area under the receiver-operating characteristics curves were compared to evaluate discriminatory ability.ResultsA total of 1,464 DM and non-DM patients (mean age 58 ± 12 years, 40% women) underwent CCTA and 155 (11%) events were documented after median follow-up of 5.1 years. In DM patients, the 7 semiquantitative CCTA risk scores were significantly more prevalent or higher as compared to non-DM patients (p ≤ 0.022). All scores were independently associated with the primary endpoint in both patients with and without DM (p ≤ 0.020), with non-significant interaction between the scores and diabetes (interaction p ≥ 0.109). Discriminatory ability of the Leiden CCTA risk score in DM patients was significantly better than any stenosis ≥50% and ≥70% (p = 0.003 and p = 0.007, respectively), but comparable to the CAD-RADS, SIS, SSS and CT-LeSc that also focus on the extent of CAD (p ≥ 0.265).ConclusionCoronary atherosclerosis scoring with semiquantitative CCTA risk scores incorporating the total extent of CAD discriminate major adverse cardiac events well, and might be useful for risk stratification of patients with DM beyond the binary evaluation of obstructive stenosis alone.

AimsThere are significant sex-specific differences in left ventricular ejection fraction (LVEF), with a higher LVEF being observed in women. We sought to assess the clinical relevance of an increased LVEF in women and men.Methods and resultsA total of 4632 patients from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry (44.8% women; mean age 58.7 ± 13.2 years in men and 59.5 ± 13.3 years in women, P = 0.05), in whom LVEF was measured by cardiac computed tomography, were categorized according to LVEF (low 65%). The prevalence of high LVEF was similar in both sexes (33.5% in women and 32.5% in men, P = 0.46). After 6 years of follow-up, no difference in mortality was observed in patients with high LVEF in the overall cohort (P = 0.41). When data were stratified by sex, women with high LVEF died more often from any cause as compared to women with normal LVEF (8.6% vs. 7.1%, log rank P = 0.032), while an opposite trend was observed in men (5.8% vs. 6.8% in normal LVEF, log rank P = 0.89). Accordingly, a first order interaction term of male sex and high LVEF was significant (hazard ratios 0.63, 95% confidence intervals 0.41-0.98, P = 0.043) in a Cox regression model of all-cause mortality adjusted for age, cardiovascular risk factors, and severity of coronary artery disease (CAD).ConclusionIncreased LVEF is highly prevalent in patients referred for evaluation of CAD and is associated with an increased risk of death in women, but not in men. Differentiating between normal and hyperdynamic left ventricles might improve risk stratification in women with CAD.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT01443637.

Background Rapid coronary plaque progression (RPP) is associated with incident cardiovascular events. To date, no method exists for the identification of individuals at risk of RPP at a single point in time. This study integrated coronary computed tomography angiography-determined qualitative and quantitative plaque features within a machine learning (ML) framework to determine its performance for predicting RPP. Methods and Results Qualitative and quantitative coronary computed tomography angiography plaque characterization was performed in 1083 patients who underwent serial coronary computed tomography angiography from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) registry. RPP was defined as an annual progression of percentage atheroma volume ≥1.0%. We employed the following ML models: model 1, clinical variables; model 2, model 1 plus qualitative plaque features; model 3, model 2 plus quantitative plaque features. ML models were compared with the atherosclerotic cardiovascular disease risk score, Duke coronary artery disease score, and a logistic regression statistical model. 224 patients (21%) were identified as RPP. Feature selection in ML identifies that quantitative computed tomography variables were higher-ranking features, followed by qualitative computed tomography variables and clinical/laboratory variables. ML model 3 exhibited the highest discriminatory performance to identify individuals who would experience RPP when compared with atherosclerotic cardiovascular disease risk score, the other ML models, and the statistical model (area under the receiver operating characteristic curve in ML model 3, 0.83 [95% CI 0.78-0.89], versus atherosclerotic cardiovascular disease risk score, 0.60 [0.52-0.67]; Duke coronary artery disease score, 0.74 [0.68-0.79]; ML model 1, 0.62 [0.55-0.69]; ML model 2, 0.73 [0.67-0.80]; all P

AimsSymptom-based pretest probability scores that estimate the likelihood of obstructive coronary artery disease (CAD) in stable chest pain have moderate accuracy. We sought to develop a machine learning (ML) model, utilizing clinical factors and the coronary artery calcium score (CACS), to predict the presence of obstructive CAD on coronary computed tomography angiography (CCTA).Methods and resultsThe study screened 35 281 participants enrolled in the CONFIRM registry, who underwent ≥64 detector row CCTA evaluation because of either suspected or previously established CAD. A boosted ensemble algorithm (XGBoost) was used, with data split into a training set (80%) on which 10-fold cross-validation was done and a test set (20%). Performance was assessed of the (1) ML model (using 25 clinical and demographic features), (2) ML + CACS, (3) CAD consortium clinical score, (4) CAD consortium clinical score + CACS, and (5) updated Diamond-Forrester (UDF) score. The study population comprised of 13 054 patients, of whom 2380 (18.2%) had obstructive CAD (≥50% stenosis). Machine learning with CACS produced the best performance [area under the curve (AUC) of 0.881] compared with ML alone (AUC of 0.773), CAD consortium clinical score (AUC of 0.734), and with CACS (AUC of 0.866) and UDF (AUC of 0.682), P

OBJECTIVES:To develop, demonstrate and evaluate an automated deep learning method for multiple cardiovascular structure segmentation. BACKGROUND:Segmentation of cardiovascular images is resource-intensive. We design an automated deep learning method for the segmentation of multiple structures from Coronary Computed Tomography Angiography (CCTA) images. METHODS:Images from a multicenter registry of patients that underwent clinically-indicated CCTA were used. The proximal ascending and descending aorta (PAA, DA), superior and inferior vena cavae (SVC, IVC), pulmonary artery (PA), coronary sinus (CS), right ventricular wall (RVW) and left atrial wall (LAW) were annotated as ground truth. The U-net-derived deep learning model was trained, validated and tested in a 70:20:10 split. RESULTS:The dataset comprised 206 patients, with 5.130 billion pixels. Mean age was 59.9 ± 9.4 yrs., and was 42.7% female. An overall median Dice score of 0.820 (0.782, 0.843) was achieved. Median Dice scores for PAA, DA, SVC, IVC, PA, CS, RVW and LAW were 0.969 (0.979, 0.988), 0.953 (0.955, 0.983), 0.937 (0.934, 0.965), 0.903 (0.897, 0.948), 0.775 (0.724, 0.925), 0.720 (0.642, 0.809), 0.685 (0.631, 0.761) and 0.625 (0.596, 0.749) respectively. Apart from the CS, there were no significant differences in performance between sexes or age groups. CONCLUSIONS:An automated deep learning model demonstrated segmentation of multiple cardiovascular structures from CCTA images with reasonable overall accuracy when evaluated on a pixel level.

BackgroundCOPD increases susceptibility to sleep disturbances, which may in turn predispose to increased respiratory symptoms. The objective of this study was to evaluate, in a population-based sample, the relationship between subjective sleep quality and risk of COPD exacerbations.MethodsData were obtained from the Canadian Cohort Obstructive Lung Disease (CanCOLD) study. Participants with COPD who had completed 18 months of follow-up were included. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI) and a three-factor analysis. Symptom-based (dyspnea or sputum change ≥ 48 h) and event-based (symptoms plus medication or unscheduled health services use) exacerbations were assessed. Association of PSQI with exacerbation rate was assessed by using negative binomial regression. Exacerbation-free survival was also assessed.ResultsA total of 480 participants with COPD were studied, including 185 with one or more exacerbations during follow-up and 203 with poor baseline sleep quality (PSQI score > 5). Participants with subsequent symptom-based exacerbations had higher median baseline PSQI scores than those without (6.0 [interquartile range, 3.0-8.0] vs 5.0 [interquartile range, 2.0-7.0]; P = .01), and they were more likely to have baseline PSQI scores > 5 (50.3% vs 37.3%; P = .01). Higher PSQI scores were associated with increased symptom-based exacerbation risk (adjusted rate ratio, 1.09; 95% CI, 1.01-1.18; P = .02) and event-based exacerbation risk (adjusted rate ratio, 1.10; 95% CI, 1.00-1.21; P = .048). The association occurred mainly in those with undiagnosed COPD. Strongest associations were with Factor 3 (sleep disturbances and daytime dysfunction). Time to symptom-based exacerbation was shorter in participants with poor sleep quality (adjusted hazard ratio, 1.49; 95% CI, 1.09-2.03).ConclusionsHigher baseline PSQI scores were associated with increased risk of COPD exacerbation over 18 months' prospective follow-up.

AimsThe long-term prognostic value of coronary computed tomography angiography (CCTA)-identified coronary artery disease (CAD) has not been evaluated in elderly patients (≥70 years). We compared the ability of coronary CCTA to predict 5-year mortality in older vs. younger populations.Methods and resultsFrom the prospective CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry, we analysed CCTA results according to age 50%); (ii) segment involvement score (SIS): number of segments with plaque. Cox-proportional hazard models assessed the relationship between CCTA findings and time to mortality. At a mean 5.6 ± 1.1 year follow-up, CCTA-identified CAD predicted increased mortality compared with patients with a normal CCTA in both

AimsCoronary artery calcium score (CACS) is a strong predictor of major adverse cardiac events (MACE). Conversely, statins, which markedly reduce MACE risk, increase CACS. We explored whether CACS progression represents compositional plaque volume (PV) progression differently according to statin use.Methods and resultsFrom a prospective multinational registry of consecutive patients (n = 2252) who underwent serial coronary computed tomography angiography (CCTA) at a ≥ 2-year interval, 654 patients (61 ± 10 years, 56% men, inter-scan interval 3.9 ± 1.5 years) with information regarding the use of statins and having a serial CACS were included. Patients were divided into non-statin (n = 246) and statin-taking (n = 408) groups. Coronary PVs (total, calcified, and non-calcified; sum of fibrous, fibro-fatty, and lipid-rich) were quantitatively analysed, and CACS was measured from both CCTAs. Multivariate linear regression models were constructed for both statin-taking and non-statin group to assess the association between compositional PV change and change in CACS. In multivariate linear regression analysis, in the non-statin group, CACS increase was positively associated with both non-calcified (β = 0.369, P = 0.004) and calcified PV increase (β = 1.579, P

ObjectivesThis study was designed to assess the prognostic value of a new comprehensive coronary computed tomography angiography (CTA) score compared with the stenosis severity component of the Coronary Artery Disease-Reporting and Data System (CAD-RADS).BackgroundCurrent risk assessment with coronary CTA is mainly focused on maximal stenosis severity. Integration of plaque extent, location, and composition in a comprehensive model may improve risk stratification.MethodsA total of 2,134 patients with suspected but without known CAD were included. The predictive value of the comprehensive CTA score (ranging from 0 to 42 and divided into 3 groups: 0 to 5, 6 to 20, and >20) was compared with the CAD-RADS combined into 3 groups (0% to 30%, 30% to 70% and ≥70% stenosis). Its predictive performance was internally and externally validated (using the 5-year follow-up dataset of the CONFIRM [Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry], n = 1,971).ResultsThe mean age of patients was 55 ± 13 years, mean follow-up 3.6 ± 2.8 years, and 130 events (myocardial infarction or death) occurred. The new, comprehensive CTA score showed strong and independent predictive value using the Cox proportional hazard analysis. A model including clinical variables plus comprehensive CTA score showed better discrimination of events compared with a model consisting of clinical variables plus CAD-RADS (0.768 vs. 0.742, p = 0.001). Also, the comprehensive CTA score correctly reclassified a significant proportion of patients compared with the CAD-RADS (net reclassification improvement 12.4%, p < 0.001). Good predictive accuracy was reproduced in the external validation cohort.ConclusionsThe new comprehensive CTA score provides better discrimination and reclassification of events compared with the CAD-RADS score based on stenosis severity only. The score retained similar prognostic accuracy when externally validated. Anatomic risk scores can be improved with the addition of extent, location, and compositional measures of atherosclerotic plaque. (Comprehensive CTA risk score calculator is available at: http://18.224.14.19/calcApp/).

BackgroundCoronary artery calcification is a marker of underlying atherosclerotic vascular disease. The absence of coronary artery calcification is associated with a low prevalence of obstructive coronary artery disease (CAD), but it cannot be ruled out completely. We sought to develop a clinical tool that can be added to Agatston score of zero to rule out obstructive CAD with high accuracy.MethodsWe developed a clinical score retrospectively from a cohort of 4903 consecutive patients with an Agatston score of zero. Patients with prior diagnosis of CAD, coronary percutaneous coronary intervention, or surgical revascularization were excluded. Obstructive CAD was defined as any epicardial vessel diameter narrowing of ≥50%. The score was validated using an external cohort of 4290 patients with an Agatston score of zero from a multinational registry.ResultsThe score consisted of 7 variables: age, sex, typical chest pain, dyslipidemia, hypertension, family history, and diabetes mellitus. The model was robust with an area under the curve of 0.70 (95% CI, 0.65-0.76) in the derivation cohort and 0.69 (95% CI, 0.65-0.72) in the validation cohort. Patients were divided into 3 risk groups based on the score: low (≤6), intermediate (7-13), and high (≥14). Patients who score ≤6 have a negative likelihood ratio of 0.42 for obstructive CAD, whereas those who score ≥14 have a positive likelihood ratio of >5.5 for obstructive CAD. The outcome was ruled out in >98% of patients with a score ≤6 in the validation cohort.ConclusionsWe developed a score that may be used to identify the likelihood of obstructive CAD in patients with an Agatston score of zero, which may be used to direct the need for additional testing. However, the results of this retrospective analysis are hypothesis generating and before clinical implementation should be validated in a trial with a prospectively collected data.

Invasive coronary plaque imaging such as intravascular ultrasound and optical coherence tomography has been widely used to observe culprit or non-culprit coronary atherosclerosis, as well as optimize stent sizing, apposition and deployment. Coronary computed tomographic angiography (CTA) is non-invasively available to assess coronary artery disease (CAD) and has become an appropriate strategy to evaluate patients with suspected CAD. Given recent technologies, semi-automated plaque software is available to identify coronary plaque stenosis, volume and characteristics and potentially allows to be used for the assessment of more details of plaque information, progression and future risk as a surrogate tool of the invasive imaging modalities. This review article aims to focus on various evidence in coronary plaque imaging by coronary CTA and describes how accurate coronary CTA can classify coronary atherosclerosis.

AimsThis study explored the coronary plaque volume change (PVC) according to the change of percent body mass index (BMI) and categorical BMI group using serial coronary computed tomography angiography (CCTA).Methods and resultsA total of 1568 subjects who underwent serial CCTA with available BMI at baseline (CCTA1) and follow-up (CCTA2) were included. Median inter-scan period was 3.3 (interquartile range: 2.6-4.6) years. Quantitative assessment of coronary plaque was performed at both scans. All participants were categorized into three BMI (kg/m2) groups: normal:

IntroductionNon-statin therapy (NST) is used as second-line treatment when statin monotherapy is inadequate or poorly tolerated.ObjectiveTo determine the association of NST with plaque composition, alone or in combination with statins, in patients undergoing coronary computed tomography angiography (coronary CTA).MethodsFrom the multicenter CONFIRM registry, we analyzed individuals who underwent coronary CTA with known lipid-lowering therapy status and without prior coronary artery disease at baseline. We created a propensity score for being on NST, followed by stepwise multivariate linear regression, adjusting for the propensity score as well as risk factors, to determine the association between NST and the number of coronary artery segments with each plaque type (non-calcified (NCP), partially calcified (PCP) or calcified (CP)) and segment stenosis score (SSS).ResultsOf the 27,125 subjects in CONFIRM, 4,945 met the inclusion criteria; 371 (7.5%) took NST. At baseline, patients on NST had more prevalent risk factors and were more likely to be on concomitant cardiac medications. After multivariate and propensity score adjustment, NST was not associated with plaque composition: NCP (0.07 increase, 95% CI: -0.05, 0.20; p = 0.26), PCP (0.10 increase, 95% CI: -0.10, 0.31; p = 0.33), CP (0.18 increase, 95% CI: -0.10, 0.46; p = 0.21) or SSS (0.45 increase, 95% CI: -0.02,0.93; p = 0.06). The absence of an effect of NST on plaque type was not modified by statin use (p for interaction > 0.05 for all).ConclusionIn this cross-sectional study, non-statin therapy was not associated with differences in plaque composition as assessed by coronary CTA.

Extent of coronary atherosclerotic disease (CAD) burden on coronary computed tomography angiography (CCTA) as measured by segment involvement score (SIS) has a prognostic value. We sought to investigate the incremental prognostic value of 'age adjusted SIS' (aSIS), which may be a marker of premature atherosclerosis and vascular age. Consecutive patients were prospectively enrolled into the CONFIRM (Coronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicentre) multinational observational study. Patients were followed for the outcome of all-cause death. aSIS was calculated on CCTA for each patient, and its incremental prognostic value was evaluated. A total of 22,211 patients [mean age 58.5 ± 12.7 years, 55.8% male) with a median follow-up of 27.3 months (IQR 17.8, 35.4)] were identified. After adjustment for clinical factors and presence of obstructive CAD, higher aSIS was associated with increased death on multivariable analysis, with hazard ratio (HR) 2.40 (1.83-3.16, p

ObjectivesThis study aimed to determine the rate and extent of plaque progression (PP), changes in plaque features, and clinical predictors of PP in patients with diabetes mellitus (DM).BackgroundThe natural history of coronary PP in patients with DM is not well established.MethodsA total of 1,602 patients (age 61.3 ± 9.0 years; 60.3% men; median scan interval 3.8 years) who underwent serial coronary computed tomography angiography over a period of at least 24 months were enrolled and analyzed from the PARADIGM (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging) trial. Study endpoints were changes in plaque features in diabetics with PP and risk factors for PP by serial coronary computed tomography angiography between patients with and without DM. PP was defined if plaque volume at follow-up minus plaque volume at baseline was >0.ResultsDM was an independent risk factor for PP (84.6%; 276 of 326 patients with PP) in multivariate analysis (odds ratio [OR]: 1.526; 95% confidence interval [CI]: 1.100 to 2.118; p = 0.011). Independent risk factors for PP in patients with DM were male sex (OR: 1.485; 95% CI: 1.003 to 2.199; p = 0.048) and mean plaque burden at baseline ≥75% (OR: 3.121; 95% CI: 1.701 to 5.725; p ≤0.001). After propensity matching, percent changes in overall plaque volume (30.3 ± 36.9% in patients without DM and 36.0 ± 29.7% in those with DM; p = 0.032) and necrotic core volume (-7.0 ± 35.8% in patients without DM and 21.5 ± 90.5% in those with DM; p = 0.007) were significantly greater in those with DM. The frequency of spotty calcification, positive remodeling, and burden of low-attenuation plaque were significantly greater in patients with DM.ConclusionsPeople with DM experience greater PP, particularly significantly greater progression in adverse plaque, than those without DM. Male sex and mean plaque burden >75% at baseline were identified as independent risk factors for PP.

ObjectivesThis study sought to describe the impact of statins on individual coronary atherosclerotic plaques.BackgroundAlthough statins reduce the risk of major adverse cardiovascular events, their long-term effects on coronary atherosclerosis remain unclear.MethodsWe performed a prospective, multinational study consisting of a registry of consecutive patients without history of coronary artery disease who underwent serial coronary computed tomography angiography at an interscan interval of ≥2 years. Atherosclerotic plaques were quantitatively analyzed for percent diameter stenosis (%DS), percent atheroma volume (PAV), plaque composition, and presence of high-risk plaque (HRP), defined by the presence of ≥2 features of low-attenuation plaque, positive arterial remodeling, or spotty calcifications.ResultsAmong 1,255 patients (60 ± 9 years of age; 57% men), 1,079 coronary artery lesions were evaluated in statin-naive patients (n = 474), and 2,496 coronary artery lesions were evaluated in statin-taking patients (n = 781). Compared with lesions in statin-naive patients, those in statin-taking patients displayed a slower rate of overall PAV progression (1.76 ± 2.40% per year vs. 2.04 ± 2.37% per year, respectively; p = 0.002) but more rapid progression of calcified PAV (1.27 ± 1.54% per year vs. 0.98 ± 1.27% per year, respectively; p < 0.001). Progression of noncalcified PAV and annual incidence of new HRP features were lower in lesions in statin-taking patients (0.49 ± 2.39% per year vs. 1.06 ± 2.42% per year and 0.9% per year vs. 1.6% per year, respectively; all p < 0.001). The rates of progression to >50% DS were not different (1.0% vs. 1.4%, respectively; p > 0.05). Statins were associated with a 21% reduction in annualized total PAV progression above the median and 35% reduction in HRP development.ConclusionsStatins were associated with slower progression of overall coronary atherosclerosis volume, with increased plaque calcification and reduction of high-risk plaque features. Statins did not affect the progression of percentage of stenosis severity of coronary artery lesions but induced phenotypic plaque transformation. (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging [PARADIGM]; NCT02803411).

BackgroundDiagnosis of coronary artery disease and management strategies have relied solely on the presence of diameter stenosis ≥50%. We assessed whether direct quantification of plaque burden (PB) and plaque characteristics assessed by coronary computed tomography angiography could provide additional value in terms of predicting rapid plaque progression.Methods and resultsFrom a 13-center, 7-country prospective observational registry, 1345 patients (60.4±9.4 years old; 57.1% male) who underwent repeated coronary computed tomography angiography >2 years apart were enrolled. For conventional angiographic analysis, the presence of stenosis ≥50%, number of vessel involved, segment involvement score, and the presence of high-risk plaque feature were determined. For quantitative analyses, PB and annual change in PB (△PB/y) in the entire coronary tree were assessed. Clinical outcomes (cardiac death, nonfatal myocardial infarction, and coronary revascularization) were recorded. Rapid progressors, defined as a patient with ≥median value of △PB/y (0.33%/y), were older, more frequently male, and had more clinical risk factors than nonrapid progressors (all P

AimsCoronary computed tomography angiography (CCTA) and coronary artery calcium score (CACS) have prognostic value for coronary artery disease (CAD) events beyond traditional risk assessment. Age is a risk factor with very high weight and little is known regarding the incremental value of CCTA over CAC for predicting cardiac events in older adults.Methods and resultsOf 27 125 individuals undergoing CCTA, a total of 3145 asymptomatic adults were identified. This study sample was categorized according to tertiles of age (cut-off points: 52 and 62 years). CAD severity was classified as 0, 1-49, and ≥50% maximal stenosis in CCTA, and further categorized according to number of vessels ≥50% stenosis. The Framingham 10-year risk score (FRS) and CACS were employed as major covariates. Major adverse cardiovascular events (MACE) were defined as a composite of all-cause death or non-fatal MI. During a median follow-up of 26 months (interquartile range: 18-41 months), 59 (1.9%) MACE occurred. For patients in the top age tertile, CCTA improved discrimination beyond a model included FRS and CACS (C-statistic: 0.75 vs. 0.70, P-value = 0.015). Likewise, the addition of CCTA improved category-free net reclassification (cNRI) of MACE in patients within the highest age tertile (e.g. cNRI = 0.75; proportion of events/non-events reclassified were 50 and 25%, respectively; P-value

BackgroundThe association of atherosclerotic features with first acute coronary syndromes (ACS) has not accounted for plaque burden.ObjectivesThe purpose of this study was to identify atherosclerotic features associated with precursors of ACS.MethodsWe performed a nested case-control study within a cohort of 25,251 patients undergoing coronary computed tomographic angiography (CTA) with follow-up over 3.4 ± 2.1 years. Patients with ACS and nonevent patients with no prior coronary artery disease (CAD) were propensity matched 1:1 for risk factors and coronary CTA-evaluated obstructive (≥50%) CAD. Separate core laboratories performed blinded adjudication of ACS and culprit lesions and quantification of baseline coronary CTA for percent diameter stenosis (%DS), percent cross-sectional plaque burden (PB), plaque volumes (PVs) by composition (calcified, fibrous, fibrofatty, and necrotic core), and presence of high-risk plaques (HRPs).ResultsWe identified 234 ACS and control pairs (age 62 years, 63% male). More than 65% of patients with ACS had nonobstructive CAD at baseline, and 52% had HRP. The %DS, cross-sectional PB, fibrofatty and necrotic core volume, and HRP increased the adjusted hazard ratio (HR) of ACS (1.010 per %DS, 95% confidence interval [CI]: 1.005 to 1.015; 1.008 per percent cross-sectional PB, 95% CI: 1.003 to 1.013; 1.002 per mm3 fibrofatty plaque, 95% CI: 1.000 to 1.003; 1.593 per mm3 necrotic core, 95% CI: 1.219 to 2.082; all p < 0.05). Of the 129 culprit lesion precursors identified by coronary CTA, three-fourths exhibited

BACKGROUND:The aim of the study is examine the impact of non-obstructive (

Our objective was to assess the prognostic value of symptom typicality in patients without obstructive coronary artery disease (CAD), determined by coronary computed tomographic angiography (CCTA). We identified 4215 patients without prior history of CAD and without obstructive CAD (

IntroductionMachine learning (ML) is a field in computer science that demonstrated to effectively integrate clinical and imaging data for the creation of prognostic scores. The current study investigated whether a ML score, incorporating only the 16 segment coronary tree information derived from coronary computed tomography angiography (CCTA), provides enhanced risk stratification compared with current CCTA based risk scores.MethodsFrom the multi-center CONFIRM registry, patients were included with complete CCTA risk score information and ≥3 year follow-up for myocardial infarction and death (primary endpoint). Patients with prior coronary artery disease were excluded. Conventional CCTA risk scores (conventional CCTA approach, segment involvement score, duke prognostic index, segment stenosis score, and the Leaman risk score) and a score created using ML were compared for the area under the receiver operating characteristic curve (AUC). Only 16 segment based coronary stenosis (0%, 1-24%, 25-49%, 50-69%, 70-99% and 100%) and composition (calcified, mixed and non-calcified plaque) were provided to the ML model. A boosted ensemble algorithm (extreme gradient boosting; XGBoost) was used and the entire data was randomly split into a training set (80%) and testing set (20%). First, tuned hyperparameters were used to generate a trained model from the training data set (80% of data). Second, the performance of this trained model was independently tested on the unseen test set (20% of data).ResultsIn total, 8844 patients (mean age 58.0 ± 11.5 years, 57.7% male) were included. During a mean follow-up time of 4.6 ± 1.5 years, 609 events occurred (6.9%). No CAD was observed in 48.7% (3.5% event), non-obstructive CAD in 31.8% (6.8% event), and obstructive CAD in 19.5% (15.6% event). Discrimination of events as expressed by AUC was significantly better for the ML based approach (0.771) vs the other scores (ranging from 0.685 to 0.701), P

Aim:The long-term prognostic benefit of coronary computed tomographic angiography (CCTA) findings of coronary artery disease (CAD) in asymptomatic populations is unknown. Methods and results:From the prospective multicentre international CONFIRM long-term study, we evaluated asymptomatic subjects without known CAD who underwent both coronary artery calcium scoring (CACS) and CCTA (n = 1226). Coronary computed tomographic angiography findings included the severity of coronary artery stenosis, plaque composition, and coronary segment location. Using the C-statistic and likelihood ratio tests, we evaluated the incremental prognostic utility of CCTA findings over a base model that included a panel of traditional risk factors (RFs) as well as CACS to predict long-term all-cause mortality. During a mean follow-up of 5.9 ± 1.2 years, 78 deaths occurred. Compared with the traditional RF alone (C-statistic 0.64), CCTA findings including coronary stenosis severity, plaque composition, and coronary segment location demonstrated improved incremental prognostic utility beyond traditional RF alone (C-statistics range 0.71-0.73, all P  0.05, for all). Conclusions:Coronary computed tomographic angiography improved prognostication of 6-year all-cause mortality beyond a set of conventional RF alone, although, no further incremental value was offered by CCTA when CCTA findings were added to a model incorporating RF and CACS.

ObjectivesThis study sought to assess clinical outcomes associated with the novel Coronary Artery Disease-Reporting and Data System (CAD-RADS) scores used to standardize coronary computed tomography angiography (CTA) reporting and their potential utility in guiding post-coronary CTA care.BackgroundClinical decision support is a major focus of health care policies aimed at improving guideline-directed care. Recently, CAD-RADS was developed to standardize coronary CTA reporting and includes clinical recommendations to facilitate patient management after coronary CTA.MethodsIn the multinational CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry, 5,039 patients without known coronary artery disease (CAD) underwent coronary CTA and were stratified by CAD-RADS scores, which rank CAD stenosis severity as 0 (0%), 1 (1% to 24%), 2 (25% to 49%), 3 (50% to 69%), 4A (70% to 99% in 1 to 2 vessels), 4B (70% to 99% in 3 vessels or ≥50% left main), or 5 (100%). Kaplan-Meier and multivariable Cox models were used to estimate all-cause mortality or myocardial infarction (MI). Receiver-operating characteristic (ROC) curves were used to compare CAD-RADS to the Duke CAD Index and traditional CAD classification. Referrals to invasive coronary angiography (ICA) after coronary CTA were also assessed.ResultsCumulative 5-year event-free survival ranged from 95.2% to 69.3% for CAD-RADS 0 to 5 (p < 0.0001). Higher scores were associated with elevations in event risk (hazard ratio: 2.46 to 6.09; p < 0.0001). The ROC curve for prediction of death or MI was 0.7052 for CAD-RADS, which was noninferior to the Duke Index (0.7073; p = 0.893) and traditional CAD classification (0.7095; p = 0.783). ICA rates were 13% for CAD-RADS 0 to 2, 66% for CAD-RADS 3, and 84% for CAD-RADS ≥4A. For CAD-RADS 3, 58% of all catheterizations occurred within the first 30 days of follow-up. In a patient subset with available medication data, 57% of CAD-RADS 3 patients who received 30-day ICA were either asymptomatic or not receiving antianginal therapy at baseline, whereas only 32% had angina and were receiving medical therapy.ConclusionsCAD-RADS effectively identified patients at risk for adverse events. Frequent ICA use was observed among patients without severe CAD, many of whom were asymptomatic or not taking antianginal drugs. Incorporating CAD-RADS into coronary CTA reports may provide a novel opportunity to promote evidence-based care post-coronary CTA.

BackgroundThe extent to which the presence and extent of subclinical atherosclerosis by coronary computed tomography angiography influences a potential mortality benefit of statin is unknown. We evaluated the relationship between statin therapy, mortality, and subclinical atherosclerosis.MethodsIn the CONFIRM study, patients with normal or non-obstructive plaque (

BackgroundLeft ventricular (LV) volumetric and functional parameters measured with cardiac computed tomography (cardiac CT) augment risk prediction and discrimination for future mortality. Gender- and age-specific standard values for LV dimensions and systolic function obtained by 64-slice cardiac CT are lacking.Methods and results1155 patients from the Coronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry (54.5% males, mean age 53.1 ± 12.4 years, range: 18-92 years) without known coronary artery disease (CAD), structural heart disease, diabetes, or hypertension who underwent cardiac CT for various indications were categorized according to age and sex. A cardiac CT data acquisition protocol was used that allowed volumetric measuring of LV function. Image interpretation was performed at each site. Patients with significant CAD (>50% stenosis) on cardiac CT were excluded from the analysis. Overall, mean left ventricular ejection fraction (LVEF) was higher in women when compared with men (66.6 ± 7.7% vs. 64.6 ± 8.1%, P < 0.001). This gender-difference in overall LVEF was caused by a significantly higher LVEF in women ≥70 years when compared with men ≥70 years (69.95 ± 8.89% vs. 65.50 ± 9.42%, P = 0.004). Accordingly, a significant increase in LVEF was observed with age (P = 0.005 for males and P < 0.001 for females), which was more pronounced in females (5.21%) than in males (2.6%). LV end-diastolic volume decreased in females from 122.48 ± 27.87 (70 years; P < 0.001) and in males from 155.22 ± 35.07 (70 years; P < 0.001).ConclusionOur findings indicate that the LV undergoes a lifelong remodelling and highlight the need for age and gender adjusted reference values.

AimsTo identify the effect of early revascularization on 5-year survival in patients with CAD diagnosed by coronary-computed tomographic angiography (CCTA).Methods and resultsWe examined 5544 stable patients with suspected CAD undergoing CCTA who were followed a median of 5.5 years in a large international registry. Patients were categorized as having low-, intermediate-, or high-risk CAD based on CCTA findings. Two treatment groups were defined: early revascularization within 90 days of CCTA (n = 1171) and medical therapy (n = 4373). To account for the non-randomized referral to revascularization, we developed a propensity score by logistic regression. This score was incorporated into Cox proportional hazard models to calculate the effect of revascularization on all-cause mortality. Death occurred in 363 (6.6%) patients and was more frequent in medical therapy. In multivariable models, when compared with medical therapy, the mortality benefit of revascularization varied significantly over time and by CAD risk (P for interaction 0.04). In high-risk CAD, revascularization was significantly associated with lower mortality at 1 year (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.11-0.47) and 5 years (HR 0.31, 95% CI 0.18-0.54). For intermediate-risk CAD, revascularization was associated with reduced mortality at 1 year (HR 0.45, 95% CI 0.22-0.93) but not 5 years (HR 0.63, 95% CI 0.33-1.20). For low-risk CAD, there was no survival benefit at either time point.ConclusionsEarly revascularization was associated with reduced 1-year mortality in intermediate- and high-risk CAD detected by CCTA, but this association only persisted for 5-year mortality in high-risk CAD.

Hypertension is an atherosclerosis factor and is associated with cardiovascular risk. We investigated the relationship between hypertension and the presence, extent, and severity of coronary atherosclerosis in coronary computed tomographic angiography and cardiac events risk. Of 17 181 patients enrolled in the CONFIRM registry (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) who underwent ≥64-detector row coronary computed tomographic angiography, we identified 14 803 patients without known coronary artery disease. Of these, 1434 hypertensive patients were matched to 1434 patients without hypertension. Major adverse cardiac events risk of hypertension and non-hypertensive patients was evaluated with Cox proportional hazards models. The prognostic associations between hypertension and no-hypertension with increasing degree of coronary stenosis severity (nonobstructive or obstructive ≥50%) and extent of coronary artery disease (segment involvement score of 1-5, >5) was also assessed. Hypertension patients less commonly had no coronary atherosclerosis and more commonly had nonobstructive and 1-, 2-, and 3-vessel disease than the no-hypertension group. During a mean follow-up of 5.2±1.2 years, 180 patients experienced cardiac events, with 104 (2.0%) occurring in the hypertension group and 76 (1.5%) occurring in the no-hypertension group (hazard ratios, 1.4; 95% confidence intervals, 1.0-1.9). Compared with no-hypertension patients without coronary atherosclerosis, hypertension patients with no coronary atherosclerosis and obstructive coronary disease tended to have higher risk of cardiac events. Similar trends were observed with respect to extent of coronary artery disease. Compared with no-hypertension patients, hypertensive patients have increased presence, extent, and severity of coronary atherosclerosis and tend to have an increase in major adverse cardiac events.

BackgroundPatients with obstructive (≥50% stenosis) left main (LM) coronary artery disease (CAD) are at high risk for adverse events; prior studies have also documented worse outcomes among women than men with severe multivessel/LM CAD. However, the prognostic significance of nonobstructive (1%-49% stenosis) LM CAD, including sex-specific differences, has not been previously examined.Methods and resultsIn the long-term CONFIRM (Coronary CT Angiography Evaluation For Clinical Outcomes: An International Multicenter) registry, patients underwent elective coronary computed tomographic angiography for suspected CAD and were followed for 5 years. After excluding those with obstructive LM CAD, 5166 patients were categorized as having normal LM or nonobstructive LM (18% of cohort). Cumulative 5-year incidence of death, myocardial infarction, or revascularization was higher among patients with nonobstructive LM than normal LM in both women and men: women (34.3% versus 15.4%; P

Background and aimsCoronary artery calcium (CAC) scoring is a predictor of future adverse clinical events, and a surrogate measure of overall coronary artery plaque burden. Coronary computed tomographic angiography (CCTA) is a contrast-enhanced method that allows for visualization of plaque as well as whether that plaque causes luminal narrowing. To date, the prognosis of individuals with CAC but without stenosis has not been reported. We explored the prevalence of CAC>0 and its prognostic utility for future mortality for patients without luminal narrowing by CCTA.MethodsFrom 17 sites in 9 countries, we identified patients without known coronary artery disease, who underwent CAC scoring and CCTA, and were followed for >3 years. CCTA was graded for % stenosis according to a modified American Heart Association 16-segment model. We calculated hazard ratios (HR) with 95% confidence intervals (95% CI) for incident mortality and compared risk of death for patients as a function of presence or absence of CAC and presence or absence of luminal narrowing by CCTA.ResultsAmong 6656 patients who underwent CCTA and CAC scoring, 399 patients (6.0%) had no coronary luminal narrowing but CAC>0. During a median follow-up of 5.1 years (IQR: 3.9-5.9 years), 456 deaths occurred. Compared to individuals without luminal narrowing or CAC, individuals without luminal narrowing but CAC>0 were older, more likely to be male and had higher rates of diabetes, hypertension, and dyslipidemia. Individuals without luminal narrowing but CAC experienced a 2-fold increased risk of mortality, with increasing risk of mortality with higher CAC score. Following adjustment, incident death persisted (HR, 1.8; 95% CI, 1.1-2.9, p = 0.02) among patients without luminal narrowing but with CAC>0 compared with patients whose CACS = 0. Individuals without luminal narrowing but CAC ≥100 had mortality risks similar to individuals with non-obstructive CAD (0

AimsTo investigate the long-term performance of the CONFIRM score for prediction of all-cause mortality in a large patient cohort undergoing coronary computed tomography angiography (CCTA).Methods and resultsPatients with a 5-year follow-up from the international multicentre CONFIRM registry were included. The primary endpoint was all-cause mortality. The predictive value of the CONFIRM score over clinical risk scores (Morise, Framingham, and NCEP ATP III score) was studied in the entire patient population as well as in subgroups. Improvement in risk prediction and patient reclassification were assessed using categorical net reclassification index (NRI) and integrated discrimination improvement (IDI). During a median follow-up period of 5.3 years, 982 (6.5%) of 15 219 patients died. The CONFIRM score outperformed the prognostic value of the studied three clinical risk scores (c-indices: CONFIRM score 0.696, NCEP ATP III score 0.675, Framingham score 0.610, Morise score 0.606; c-index for improvement CONFIRM score vs. NCEP ATP III score 0.650, P < 0.0001). Application of the CONFIRM score allowed reclassification of 34% of patients when compared with the NCEP ATP III score, which was the best clinical risk score. Reclassification was significant as revealed by categorical NRI (0.06 with 95% CI 0.02 and 0.10, P = 0.005) and IDI (0.013 with 95% CI 0.01 and 0.015, P < 0.001). Subgroup analysis revealed a comparable performance in a variety of patient subgroups.ConclusionsThe CONFIRM score permits a significantly improved prediction of mortality over clinical risk scores for >5 years after CCTA. These findings are consistent in a large variety of patient subgroups.

Age-adjusted coronary artery disease (CAD) burden identified on coronary computed tomography angiography predicts major adverse cardiovascular event (MACE) risk; however, it seldom contributes to clinical decision making because of a lack of nomographic data. We aimed to develop clinically pragmatic age- and sex-specific nomograms of CAD burden using coronary computed tomography angiography and to validate their prognostic use. Patients prospectively enrolled in phase I of the CONFIRM registry (Coronary CT Angiography Evaluation for Clinical Outcomes) were included (derivation cohort: n=21,132; 46% female) to develop CAD nomograms based on age-sex percentiles of segment involvement score (SIS) at each year of life (40-79 years). The relationship between SIS age-sex percentiles (SIS%) and MACE (all-cause death, myocardial infarction, unstable angina, and late revascularization) was tested in a nonoverlapping validation cohort (phase II, CONFIRM registry; n=3030, 44% female) by stratifying patients into 3 SIS% groups (≤50th, 51-75th, and >75th) and comparing annualized MACE rates and time to MACE using multivariable Cox proportional hazards models adjusting for Framingham risk and chest pain typicality. Age-sex percentiles were well fitted to second-order polynomial curves (men: R2=0.86±0.12; women: R2=0.86±0.14). Using the nomograms, there were 1576, 965, and 489 patients, respectively, in the ≤50th, 51-75th, and >75th SIS% groups. Annualized event rates were higher among patients with greater CAD burden (2.1% [95% confidence interval: 1.7%-2.7%], 3.9% [95% confidence interval: 3.0%-5.1%], and 7.2% [95% confidence interval: 5.4%-9.6%] in ≤50th, 51-75th, and >75th SIS% groups, respectively; P75th SIS% group; P