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ObjectiveThe study evaluates the relationship of coronary stenosis, atherosclerotic plaque characteristics (APCs) and age using artificial intelligence enabled quantitative coronary computed tomographic angiography (AI-QCT).MethodsThis is a post-hoc analysis of data from 303 subjects enrolled in the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic Determinants of Myocardial IsChEmia) trial who were referred for invasive coronary angiography and subsequently underwent coronary computed tomographic angiography (CCTA). In this study, a blinded core laboratory analysing quantitative coronary angiography images classified lesions as obstructive (≥50%) or non-obstructive (<50%) while AI software quantified APCs including plaque volume (PV), low-density non-calcified plaque (LD-NCP), non-calcified plaque (NCP), calcified plaque (CP), lesion length on a per-patient and per-lesion basis based on CCTA imaging. Plaque measurements were normalised for vessel volume and reported as % percent atheroma volume (%PAV) for all relevant plaque components. Data were subsequently stratified by age <65 and ≥65 years.ResultsThe cohort was 64.4±10.2 years and 29% women. Overall, patients >65 had more PV and CP than patients <65. On a lesion level, patients >65 had more CP than younger patients in both obstructive (29.2 mm3 vs 48.2 mm3; p<0.04) and non-obstructive lesions (22.1 mm3 vs 49.4 mm3; p<0.004) while younger patients had more %PAV (LD-NCP) (1.5% vs 0.7%; p<0.038). Younger patients had more PV, LD-NCP, NCP and lesion lengths in obstructive compared with non-obstructive lesions. There were no differences observed between lesion types in older patients.ConclusionAI-QCT identifies a unique APC signature that differs by age and degree of stenosis and provides a foundation for AI-guided age-based approaches to atherosclerosis identification, prevention and treatment.

Nanotechnology could improve our understanding of the pathophysiology of atherosclerosis and contribute to the development of novel diagnostic and therapeutic strategies to further reduce the risk of cardiovascular disease. Macrophages have key roles in atherosclerosis progression and, therefore, macrophage-associated pathological processes are important targets for both diagnostic imaging and novel therapies for atherosclerosis. In this Review, we highlight efforts in the past two decades to develop imaging techniques and to therapeutically manipulate macrophages in atherosclerotic plaques with the use of rationally designed nanoparticles. We review the latest progress in nanoparticle-based imaging modalities that can specifically target macrophages. Using novel molecular imaging technology, these modalities enable the identification of advanced atherosclerotic plaques and the assessment of the therapeutic efficacy of medical interventions. Additionally, we provide novel perspectives on how macrophage-targeting nanoparticles can deliver a broad range of therapeutic payloads to atherosclerotic lesions. These nanoparticles can suppress pro-atherogenic macrophage processes, leading to improved resolution of inflammation and stabilization of plaques. Finally, we propose future opportunities for novel diagnostic and therapeutic strategies and provide solutions to challenges in this area for the purpose of accelerating the clinical translation of nanomedicine for the treatment of atherosclerotic vascular disease.In this Review, Tao and colleagues discuss the latest advances in nanoparticle-based imaging and therapeutic approaches targeting macrophages in atherosclerotic plaques, highlight opportunities for novel macrophage-targeting nanomedicines for atherosclerosis diagnosis and treatment, and provide solutions to challenges in this area to accelerate clinical translation.

The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG). In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent 18F-NaF and 18F-FDG PET-CT, and invasive coronary angiography. 18F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of 18F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction. In 37 (93%) patients with myocardial infarction, the highest coronary 18F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40–2·25] vs highest non-culprit 1·24 [1·06–1·38], p<0·0001). By contrast, coronary 18F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 [1·40–2·13] vs 1·58 [1·28–2·01], p=0·34). Marked 18F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal 18F-NaF uptake (maximum tissue-to-background ratio 1·90 [IQR 1·61–2·17]) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 [1·09–1·19] vs 1·01 [0·94–1·06]; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% [21–29] vs 18% [14–22], p=0·001). 18F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease. Chief Scientist Office Scotland and British Heart Foundation.

ObjectivesWe sought to investigate the diagnostic performance of coronary CT angiography (cCTA)–derived plaque markers combined with deep machine learning–based fractional flow reserve (CT-FFR) to identify lesion-specific ischemia using invasive FFR as the reference standard.MethodsEighty-four patients (61 ± 10 years, 65% male) who had undergone cCTA followed by invasive FFR were included in this single-center retrospective, IRB-approved, HIPAA-compliant study. Various plaque markers were derived from cCTA using a semi-automatic software prototype and deep machine learning–based CT-FFR. The discriminatory value of plaque markers and CT-FFR to identify lesion-specific ischemia on a per-vessel basis was evaluated using invasive FFR as the reference standard.ResultsOne hundred three lesion-containing vessels were investigated. 32/103 lesions were hemodynamically significant by invasive FFR. In a multivariate analysis (adjusted for Framingham risk score), the following markers showed predictive value for lesion-specific ischemia (odds ratio [OR]): lesion length (OR 1.15, p = 0.037), non-calcified plaque volume (OR 1.02, p = 0.007), napkin-ring sign (OR 5.97, p = 0.014), and CT-FFR (OR 0.81, p < 0.0001). A receiver operating characteristics analysis showed the benefit of identifying plaque markers over cCTA stenosis grading alone, with AUCs increasing from 0.61 with ≥ 50% stenosis to 0.83 with addition of plaque markers to detect lesion-specific ischemia. Further incremental benefit was realized with the addition of CT-FFR (AUC 0.93).ConclusionCoronary CTA–derived plaque markers portend predictive value to identify lesion-specific ischemia when compared to cCTA stenosis grading alone. The addition of CT-FFR to plaque markers shows incremental discriminatory power.Key Points• Coronary CT angiography (cCTA)–derived quantitative plaque markers of atherosclerosis portend high discriminatory power to identify lesion-specific ischemia.• Coronary CT angiography–derived fractional flow reserve (CT-FFR) shows superior diagnostic performance over cCTA alone in detecting lesion-specific ischemia.• A combination of plaque markers with CT-FFR provides incremental discriminatory value for detecting flow-limiting stenosis.

Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients.

Question Which of the following is the next best step in management? calcium channel blocker therapy for coronary spasm coronary stenting for revascularisation of plaque rupture cardiac surgery for myocardial bridging (MB) systemic anticoagulation for coronary embolism For the answer see page 656 From the question on page 636 Answer: C Intravascular ultrasound (IVUS) showed an extravascular 'half-moon' structure (arrow), representing an overlying muscle band with corresponding atherosclerotic plaque (figure 1C).

The natural history of coronary artery disease (CAD) in patients with low-to-intermediate risk is not well characterized. Although earlier invasive serial studies have documented the progression of atherosclerotic burden, most were focused on high-risk patients only. The PARADIGM registry is a large, prospective, multinational dynamic observational registry of patients undergoing serial coronary computed tomographic angiography (CCTA). The primary aim of PARADIGM is to characterize the natural history of CAD in relation to clinical and laboratory data. The PARADIGM registry (ClinicalTrials.govNCT02803411) comprises ≥2,000 consecutive patients across 9 cluster sites in 7 countries. PARADIGM sites were chosen on the basis of adequate CCTA volume, site CCTA proficiency, local demographic characteristics, and medical facilities to ensure a broad-based sample of patients. Patients referred for clinically indicated CCTA will be followed up and enrolled if they had a second CCTA scan. Patients will also be followed up beyond serial CCTA performance to identify adverse CAD events that include cardiac and noncardiac death, myocardial infarction, unstable angina, target vessel revascularization, and CAD-related hospitalization. The results derived from the PARADIGM registry are anticipated to add incremental insight into the changes in CCTA findings in accordance with the progression or regression of CAD that confer prognostic value beyond demographic and clinical characteristics.

ObjectivesWe sought to evaluate the accuracy of standardized total plaque volume (TPV) measurement and low-density non-calcified plaque (LDNCP) assessment from coronary CT angiography (CTA) in comparison with intravascular ultrasound (IVUS).MethodsWe analyzed 118 plaques without extensive calcifications from 77 consecutive patients who underwent CTA prior to IVUS. CTA TPV was measured with semi-automated software comparing both scan-specific (automatically derived from scan) and fixed attenuation thresholds. From CTA, %LDNCP was calculated voxels below multiple LDNCP thresholds (30, 45, 60, 75, and 90 Hounsfield units [HU]) within the plaque. On IVUS, the lipid-rich component was identified by echo attenuation, and its size was measured using attenuation score (summed score ∕ analysis length) based on attenuation arc (1 = < 90°; 2 = 90–180°; 3 = 180–270°; 4 = 270–360°) every 1 mm.ResultsTPV was highly correlated between CTA using scan-specific thresholds and IVUS (r = 0.943, p < 0.001), with no significant difference (2.6 mm3, p = 0.270). These relationships persisted for calcification patterns (maximal IVUS calcium arc of 0°, < 90°, or ≥ 90°). The fixed thresholds underestimated TPV (− 22.0 mm3, p < 0.001) and had an inferior correlation with IVUS (p < 0.001) compared with scan-specific thresholds. A 45-HU cutoff yielded the best diagnostic performance for identification of lipid-rich component, with an area under the curve of 0.878 vs. 0.840 for < 30 HU (p = 0.023), and corresponding %LDNCP resulted in the strongest correlation with the lipid-rich component size (r = 0.691, p < 0.001).ConclusionsStandardized noninvasive plaque quantification from CTA using scan-specific thresholds correlates highly with IVUS. Use of a < 45-HU threshold for LDNCP quantification improves lipid-rich plaque assessment from CTA.Key Points• Standardized scan-specific threshold-based plaque quantification from coronary CT angiography provides an accurate total plaque volume measurement compared with intravascular ultrasound.• Attenuation histogram-based low-density non-calcified plaque quantification can improve lipid-rich plaque assessment from coronary CT angiography.

ObjectiveIntraplaque hemorrhage (IPH) and ulceration of carotid atherosclerotic plaques have been associated with vulnerability while calcification has been conventionally thought protective. However, studies suggested calcification size and location may increase plaque vulnerability. This study explored the association between calcium configurations and ulceration with IPH.MethodsOne hundred thirty-seven consecutive symptomatic patients scheduled for carotid endarterectomy were recruited. CTA and CTP were performed prior to surgery. Plaque samples were collected for histology. According to the location, calcifications were categorized into superficial, deep and mixed types; according to the size and number, calcifications were classified as thick and thin, multiple and single.ResultsSeventy-one plaques had IPH (51.8%) and 83 had ulceration (60.6%). The appearance of IPH and ulceration was correlated (r = 0.49; p < 0.001). The incidence of multiple, superficial and thin calcifications was significantly higher in lesions with IPH and ulceration compared with those without. After adjusting factors including age, stenosis and ulceration, the presence of calcification [OR (95% CI), 3.0 (1.1-8.2), p = 0.035], multiple calcification [3.9 (1.4-10.9), p = 0.009] and superficial calcification [3.4 (1.1-10.8), p = 0.001] were all associated with IPH. ROC analysis showed that the AUC of superficial and multiple calcifications in detecting IPH was 0.63 and 0.66, respectively (p < 0.05). When the ulceration was combined, AUC increased significantly to 0.82 and 0.83, respectively. Results also showed that patients with lesions of both ulceration and IPH have significantly reduced brain perfusion in the area ipsilateral to the infarction.ConclusionsSuperficial and multiple calcifications and ulceration were associated with carotid IPH, and they may be a surrogate for higher risk lesions.Key Points• CTA-defined superficial and multiple calcifications in carotid atherosclerotic plaques are independently associated with the presence of intraplaque hemorrhage.• The combination of superficial and multiple calcifications and ulceration is highly predictive of carotid intraplaque hemorrhage.• Patients with lesions of both ulceration and intraplaque hemorrhage have significantly reduced brain perfusion in the area ipsilateral to the infarction.

It is indicated that lipids profiles are associated with carotid plaque and Atherosclerosis. However, studies about the relationship between serum lipid profiles and carotid plaque composition in Chinese Population is limited. We conducted a cross-sectional study among 3,214 participants between January 2015 and December 2017 in China, to investigate the association between various lipid profiles and the prevalence of carotid plaque. Logistic regression model was used to investigate the association between plasma lipid profiles and odds of carotid plaque. Analysis of covariance (ANCOVA) was used to compare the mean plasma lipid profiles among different number and composition of carotid artery plaques. HDL-C, Non-HDL-C levels, TC/HDL-C, LDL-C/HDL-C were significantly associated with the presence of carotid plaque; HDL-C, LDL-C, Non-HDL-C levels, TC/HDL-C, LDL-C/HDL-C were significantly associated with the presence of common carotid artery (CCA) plaque. Compare with participants without carotid plaque, increased level of LDL-C/HDL-C was found in those with echolucent/polytype plaque. Similarly, compared with participants without CCA plaque, increased level of LDL-C/HDL-C was found in those with echolucent plaque. In conclusion, we found that serum HDL-C, Non-HDLc level, TC/HDLc, and LDLc/HDLc were all associated with the prevalence of carotid plaque, and LDL-C/HDL-C differed among different group of carotid plaque composition.