The prognostic role of high-risk plaque (HRP) features, including high coronary calcium scores detected by CT, beyond traditional cardiovascular risk factors and obstructive coronary artery disease (CAD), remains uncertain. This study evaluated the prognostic value of a combined HRP definition in stable chest pain patients with low-to-intermediate pretest probability of CAD. This prespecified analysis included participants randomized to the CT arm of the pragmatic, prospective 26-center European DISCHARGE trial (NCT02400229). The primary endpoint was major adverse cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, or stroke); the secondary endpoint was expanded MACE (transient ischemic attack and major procedure-related complications). Our combined HRP definition was any coronary plaque with positive remodeling, napkin-ring sign, low attenuation, or total calcium score ≥ 400 Agatston units. Among 1745 participants (age: 60 ± 10 years, 990 female), 35 MACE and 47 expanded MACE occurred at a median follow-up of 3.5 years (IQR: 2.9–4.2). After risk factor adjustment, the combined HRP definition was associated with a higher risk of MACE (HR: 3.81; 95

BACKGROUND:Increased epicardial adipose tissue volume (EATV) is a potentially important risk marker for coronary artery disease (CAD) available from cardiac computed tomography (CT) images. Sex differences and effects of age and body size on EATV have been insufficiently explored, and no reliable reference values exist. Consequently, EATV has yet to find its deserved use in clinical practice. OBJECTIVES:To define normal values by sex and age, the best normalization procedure for EATV to neutralize effects of body size, explore the relationship between normalized EATV and cardiac risk, and propose a clinically meaningful cut-off. METHODS:AI-based automated EATV data from the general population (n = 25,155) and a clinical cohort (n = 2,482) with suspected CAD was normalized to height, BSA and heart volumes. Correlation between EATV and EAT attenuation (EATA) was tested with Spearman's rank correlation and linear regression to find the optimal normalization. Normalized EATV was compared to high-risk by SCORE2 and obstructive CAD in the population cohort. A cut-off including 95% of cases with obstructive CAD was defined in the general population and tested in the clinical cohort. RESULTS:EATV varied with sex and age across cohorts. Normalization of EATV to total heart volume (EATVh) improved correlation with EATA and successfully neutralized sex differences. High-risk by SCORE2 and the prevalence of obstructive CAD increased over quartiles of EATVh in the population cohort, and significantly higher EATVh was seen with obstructive CAD in both cohorts. A cut-off of 0.1 in EATVh had a negative predictive value for obstructive CAD of 97.1% in the general population and 88.9% in the clinical cohort. CONCLUSIONS:EATV varies considerably with sex, age and body size. EATVh is largely sex-neutral and likely reflects true EAT expansion better than absolute EATV. EATVh is a potentially useful marker of obstructive CAD in both the general population and symptomatic patients.

AIMS:Conflicting results have been reported on the prognostic value of coronary stenosis grade and plaque burden. We aimed to investigate the time-varying risk for cardiovascular events associated with diameter stenosis (DS%) and plaque burden. METHODS AND RESULTS:Patients without a documented cardiac history who underwent coronary computed tomography angiography for suspected coronary artery disease were included. The most severe DS% and plaque burden, defined as percentage atheroma volume (PAV), were used for analysis. The primary endpoint was a composite of all-cause mortality and non-fatal myocardial infarction. For analysis, the maximal follow-up time was 8 years. Among 2819 patients [mean age 62 ± 10; 1245 (45%) male], 235 events occurred during a median follow-up of 6.9 years. Cox models including cardiovascular risk factors, DS%, and PAV demonstrated that DS% but not PAV was predictive for short-term events at 1-year follow-up [adjusted hazard ratio (aHR) 1.028, 95% confidence interval (CI) 1.013-1.044 vs. 1.015, 95% CI 0.978-1.053]. In contrast, PAV but not DS% was predictive for long-term events at 8-year follow-up (aHR 1.035, 95% CI 1.021-1.050 vs. 1.005, 95% CI 0.999-1.012). The predictive value of DS% was stronger before than after 1 year of follow-up (aHR <1 year 1.027, 95% CI 1.012-1.042 vs. aHR 1-8 years 1.001, 95% CI 0.994-1.008; P < 0.01 for difference), while the predictive value of PAV did not significantly change (P = 0.12). CONCLUSION:Coronary diameter stenosis holds the highest prognostic significance for short-term cardiovascular events, while plaque burden predicts events in the long term.

BACKGROUND:In patients with obstructive coronary artery disease, early revascularization does not improve outcomes but may reduce angina symptoms. The objective of this study was to examine whether changes in health status outcomes following revascularization are explained by the extent of myocardial perfusion defects and improvement in myocardial perfusion. METHODS:Two trials enrolling stable patients with new-onset chest pain suggestive of obstructive coronary artery disease, the ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) and the Dan-NICAD (Danish Study of Noninvasive Testing in Coronary Artery Disease) trials, were analyzed. Patients with single-vessel coronary artery disease who underwent nuclear myocardial perfusion imaging (nMPI) were included. In the ISCHEMIA trial, patients with moderate/severe ischemia were randomized to either optimal medical therapy alone or optimal medical therapy and invasive angiography. The Dan-NICAD trial enrolled patients with suspected stenosis on coronary computed tomographic angiography undergoing nMPI. Test-guided revascularization blinded to nMPI was performed, and patients with initially abnormal nMPI were reassessed after 12 months. The primary outcome was the change in the Seattle Angina Questionnaire angina frequency score. RESULTS:In total, 584 patients were eligible. In patients with a summed difference score of 5≤10 (n=149 [25%]) and ≥10 (n=152 [26%]), revascularization was associated with an improved angina frequency score (mean change ±SD: 16.4±20.9 and 19.0±24.1). No improvement was demonstrated in patients with a summed difference score <5. In multivariable logistic regression analysis (n=91), an increase in hyperemic myocardial blood flow at follow-up was associated with freedom from angina (odds ratio, 2.89 [95% CI, 1.04-8.70]). CONCLUSIONS:In patients with single-vessel coronary artery disease, nMPI may identify patients more likely to experience improved symptoms from revascularization, potentially reflecting enhanced myocardial perfusion.

BACKGROUND:Folate receptor β (FR-β) is expressed on activated macrophages in inflammatory conditions. In order to study FR-β in inflammatory response following myocardial infarction (MI), we evaluated FR-β-targeted PET imaging using aluminum fluoride-18-labeled NOTA-folate ([18F]FOL) in a rat model of MI. METHODS:Rats underwent [18F]FOL PET imaging on 3, 7, 15, and 90 days after induction of MI by permanent coronary artery ligation or sham operation. [18F]FDG PET was performed a day before [18F]FOL scans to localize the infarct area. A subset of rats underwent [18F]FOL PET on day 7 and serial echocardiography until 90 days post-surgery. RESULTS:The [18F]FOL uptake was significantly higher in the infarct area than in the myocardium of sham-operated rats on day 3 (SUV 1.97 ± 0.17 vs 0.74 ± 0.13), and remained higher on day 7 (SUV 1.35 ± 0.33 vs 0.70 ± 0.16), day 15 (SUV 1.24 ± 0.20 vs 0.59 ± 0.07), and day 90 (SUV 1.39 ± 0.25 vs 0.69 ± 0.11). Autoradiography of tissue sections confirmed tracer uptake in the infarct area, where immunofluorescence showed FR-β in CD68-positive macrophages. Uptake of [18F]FOL correlated with CD68-positive macrophage density (r = 0.669, P < 0.001) and was associated with decline in left ventricular ejection fraction between days 7 and 90 post-MI (r = -0.665, P = 0.007). CONCLUSION:[18F]FOL PET detects expression of FR-β, a marker of activated macrophages after MI. FR-β expression peaks early and remains elevated up to 3 months post-MI. Early FR-β expression is associated with worsening of left ventricular systolic function.

AIMS:We aimed to investigate whether plaque burden from coronary computed tomography angiography (CCTA) could be used to identify patients potentially benefitting from revascularization. METHODS AND RESULTS:We assessed consecutive patients undergoing CCTA and selective 15O-water perfusion positron emission tomography for evaluation of coronary artery disease (CAD) at two tertiary care centres in Finland and The Netherlands. Per-patient percent atheroma volume (PAV) and maximum per-vessel PAV in each patient was quantified by artificial intelligence-guided quantitative computed tomography (AI-QCT). We constructed a Cox regression for death, myocardial infarction (MI), or unstable angina pectoris (uAP) including continuous PAV, revascularization, and their interaction, adjusted for calcium score, ischaemia, cardiovascular risk factors, symptoms, and medication in a subcohort of 2233 patients (206 events; median follow-up 6.8 years). There was significant interaction between revascularization and continuous PAV on patient-level (p-interaction = 0.042) and vessel-level (p-interaction = 0.026). Revascularization was associated with a significantly lower event rate at per-patient PAV 22% (HR 0.70, 95% CI 0.43-0.98) and per-vessel PAV 22% (HR 0.64, 95% CI 0.29-0.99) or higher. In subgroup analyses, after adjustment for age, sex, cardiovascular risk factors, ischaemia, anti-platelet, and lipid-lowering drugs, revascularization in patients with per-vessel PAV ≥22% was associated with a significantly reduced event rate (HR 0.50, 95% CI 0.27-0.91, P = 0.024) (p-interaction = 0.016), whereas patient-level results remained non-significant (HR 0.62, 95% CI 0.35-1.10, P = 0.104) (p-interaction < 0.001). CONCLUSIONS:In this cohort study of patients referred for CCTA, revascularization on top of medical therapy was associated with a lower rate of long-term death, MI, or uAP from per-vessel PAV of 22% upwards.

Folate receptor β (FR-β) expression may serve as a marker of activated macrophages involved in autoimmune myocarditis. The positron emission tomography (PET) tracer N-succinimidyl 4-[18F]-fluorobenzoate-conjugated folate ([18F]-SFB-FOL) effectively targets FR-β-positive macrophages in rheumatoid arthritis. Here, we examined [18F]-SFB-FOL for detecting myocardial inflammation via FR-β in a rat model of experimental autoimmune myocarditis (EAM), in comparison with the established FR-β-targeted PET tracer aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate ([18F]-FOL). EAM was induced in 22 Lewis rats through cardiac myosin immunization. Rats underwent 2-deoxy-2-[18F]-fluoro-d-glucose ([18F]-FDG) PET to visualize myocardium, followed by dynamic PET with [18F]-SFB-FOL or [18F]-FOL at Days 14, 21, or 28 postimmunization. Postimaging, myocardial tissues were assessed by γ-counting, autoradiography, and CD68 immunohistochemistry to quantify macrophage presence. Both tracers showed high radiochemical purity and in vivo stability. Inflammation-rich myocardial lesions were confirmed, with macrophages occupying 9.9% ± 1.1 of the tissue area. PET imaging revealed significantly higher uptake of both tracers in inflamed myocardium versus remote areas, confirmed by histology and autoradiography. Lesion-to-remote uptake ratios were 5.7 ± 1.8 for [18F]-SFB-FOL and 3.8 ± 0.5 for [18F]-FOL. Blood clearance and renal excretion were rapid for both tracers. No significant differences were observed in tracer uptake or macrophage density between Days 21 and 28. [18F]-SFB-FOL is a suitable tracer for detecting active myocardial inflammation via FR-β in EAM and performs comparably to [18F]-FOL.

The impact of myocardial scar on coronary microcirculation is not well understood. This study aims to evaluate the association between microvascular resistance reserve (MRR) and scar tissue. In this post-hoc analysis of the PACIFIC 2 trial, symptomatic patients with prior myocardial infarction (MI) and/or percutaneous coronary intervention (PCI) underwent [15O]H2O positron emission tomography (PET), cardiac magnetic resonance (CMR) imaging, and fractional flow reserve (FFR). MRR was assessed utilizing PET-derived coronary flow reserve and FFR measurements. Scar quantification was assessed by CMR late gadolinium enhancement (LGE). Vessel LGE burden was defined as the scar tissue proportion in each myocardial territory. Total LGE burden was defined as the proportion of overall scar. The study included 154 patients with 397 vessels with a mean MRR of 3.56 ± 1.24. Patients with any scar tissues (LGE > 0

Segmentation is a routine step in PET image analysis, and few automatic tools have been developed for it. However, excluding supervised methods with their own limitations, they are typically designed for older, small images and the implementations are no longer publicly available. Here, we test if different commonly used building blocks of the automatic methods work with large modern total-body PET images. Dynamic total-body images from five different datasets are used for evaluation purposes, and the tested algorithms cover wide range of different preprocessing approaches and unsupervised segmentation methods. The validation is done by comparing the obtained segments to manually drawn ones using Jaccard index, Dice score, precision, and recall as measures of match. Out of the 17 considered segmentation methods, only 6 were computationally usable and provided enough segments for the needs of this study. Among these six feasible methods, hierarchical clustering and HDBSCAN had systematically the lowest Jaccard indices with the manual segmentations, whereas both GMM and k -means had median Jaccards of 0.58 over different organ segments and data sets. GMM outperformed k -means in human data, but with rat images, the two methods had equally good performance k -means having slightly stronger precision and GMM recall. We conclude that most of the commonly used unsupervised segmentation methods are computationally infeasible with the modern PET images, classical clustering algorithms k -means and especially Gaussian mixture model being the most promising candidates for further method development. Even though preprocessing, particularly denoising, improved the results, small organs remained difficult to segment.

KEJA: Speaker: Bayer, Pfizer and Boehringer-Ingelheim. Research grants from the Finnish Foundation for Cardiovascular Research and Clinical Research Fund of Turku University Hospital; VL: Speaker: Boehringer-Ingelheim. Research grant from the State Research Funding of the Turku University Hospital expert responsibility area; KT: none. GYHL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos. No fees are received personally. He is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-PI of the AFFIRMO project on multimorbidity in AF (grant agreement No 899871), TARGET project on digital twins for personalized management of atrial fibrillation and stroke (grant agreement No 101136244) and ARISTOTELES project on artificial intelligence for management of chronic long-term conditions (grant agreement No 101080189), which are all funded by the EU's Horizon Europe Research & Innovation programme. Perspective article is based on interpretation of the articles in the reference list. Data used to support the findings of this study are available from the corresponding author upon request.

A first-in-human phase I clinical study aimed to assess the safety profile, radiation dosimetry, and biodistribution of a potential cardiac PET myocardial perfusion imaging tracer, [18F]SYN2 (18F-labeled acridine derivative), in healthy subjects. Methods: [18F]SYN2 intravenous administration with PET imaging was performed on healthy volunteers, and sequential whole-body imaging was performed over 4 h. Blood and urine samples were collected for up to 240 min. Safety follow-up visits took place at 2, 5, and 14 d after the administration. Results: Ten subjects (8 women and 2 men) completed all study procedures. The mean age was 38.1 ± 8.8 y, and the mean body mass index was 22.7 ± 3.0 kg/m2 The mean administered dose of radioactivity was 258 MBq (range, 246-272 MBq). There were no drug-related adverse events, and the tracer was well tolerated in all subjects. The mean whole-body effective radiation dose for [18F]SYN2 was 0.0195 mSv/MBq. The tracer was rapidly taken up by the myocardial wall and cleared from plasma, leading to good image quality within minutes of tracer injection. Conclusion: On the basis of the safety profile, radiation dosimetry, and biodistribution of [18F]SYN2, it appears to be a promising agent for clinical PET myocardial perfusion imaging and to warrant further clinical studies.

Background: Interventional studies on sedentary behaviour (SB) and cardiac health are missing. Therefore, this study investigates the effects of reducing SB on cardiac structure and function in inactive and sedentary adults with metabolic syndrome. Methods: In this randomized controlled trial, the intervention group (n = 33) aimed at reducing SB by 1 h/d for 6 months. The control group (n = 31) continued their SB and physical activity (PA) as usual. All participants wore accelerometers throughout the study. Echocardiography was performed at rest and during incremental exercise tests before and after the intervention. Results: No intervention effects were observed in any echocardiographic variables between the randomized groups. However, when participants were regrouped into a less sedentary (mean SB reduction 60 min/d) or a continuously sedentary group, based on their actual measured behaviour change, left ventricular (LV) mass index and end-diastolic diameter decreased more in the less sedentary than in the continuously sedentary group (group x time P = 0.045 and 0.020, respectively). Moreover, LV global longitudinal strain during exercise improved in the less sedentary group compared to the continuously sedentary group. Among all participants, the change in light PA was correlated inversely with the change in LV mass index (r = -0.32, P = 0.026), and the change in standing time was correlated with the change in the early diastolic flow velocity / lateral mitral annular velocity (E/e') ratio (r = 0.28, P = 0.048). Conclusions: A 6-month intervention aimed at reducing SB did not affect cardiac structure or function. However, in participants with successful SB reduction and increased light PA regardless of original randomization, LV mass index may have decreased, and LV function during exercise may have improved. Clinical Trial Registration: NCT03101228.

AIMS:Obesity is an independent risk factor for chronic kidney disease, and weight loss interventions lead to better kidney outcomes. We aimed to assess whether reducing sedentary behaviour in patients with metabolic syndrome impacts renal glucose uptake rate (GU) during insulin stimulation. MATERIALS AND METHODS:Forty-four participants with metabolic syndrome were randomized to receive either guidance to reduce sedentary behaviour (INT) by 1 h/day during a 6-month intervention or to maintain usual sedentary behaviour (CONT). For this post-hoc analysis, we included all participants with available renal data: 34 participants at baseline and 30 at the end of the intervention. Participants underwent 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) during a hyperinsulinemic clamp at baseline and at 6 months. Renal [18F]FDG-PET data were analysed using fractional uptake rate (FUR). A correction for the estimated residual amount of [18F]FDG inside the tubuli was applied. Corrected GU was calculated as the product of FUR and glycemia. RESULTS:At the study end, light and moderate-to-vigorous physical activity (PA) were increased and BMI was slightly decreased, with no significant intervention effect. Cortical and medullary GU increased vs baseline, similarly in both groups. At baseline, cortical GU was directly related to the degree of insulin sensitivity and inversely to BMI and circulating FFA levels. Change in renal GU was directly related to change in liver GU, but not to the change in whole-body insulin sensitivity. CONCLUSIONS:In patients with metabolic syndrome, insulin-stimulated renal GU increases concomitantly with a small decrease in body adiposity, independently of changes in whole-body glucose disposal.

Metabolic syndrome increases the risk of developing noncommunicable diseases such as metabolic dysfunction-associated steatotic liver disease. The aim was to investigate the effects of sedentary behavior (SB) reduction on liver glucose uptake (LGU), endogenous glucose production (EGP), liver fat content (LFC), and liver enzyme levels [alanine aminotransferase (ALT), aspartate aminotransferase, and γ-glutamyltransferase]. Forty-four sedentary (daily SB time ≥ 10 h), physically inactive middle-aged adults with metabolic syndrome were randomized into intervention (INT; n = 23, 21 completed) and control (CON; n = 21, 19 completed) groups. For 6 mo, INT aimed to limit SB by 1 h/day, whereas CON aimed to maintain usual habits. SB and physical activity (PA) were measured continuously with hip-worn accelerometers. Before and at the end of the intervention, LGU was measured using positron emission tomography during the hyperinsulinemic-euglycemic clamp. EGP was calculated, and LFC was measured by magnetic resonance spectroscopy. INT reduced SB by 51 [95% confidence interval (CI): 22, 78] min/day and increased moderate-to-vigorous physical activity (MVPA) by 22 (95% CI: 12, 33) min/day, with no significant change in CON. Differences in liver health markers between the groups were not significant. However, according to the exploratory analyses among participants who successfully reduced SB, ALT decreased (-1.1 [95% CI: 0.93, 1.36] U/L) compared with the continuously sedentary participants (+0.8 [95% CI: 0.65, 1.05] U/L) (group × time, P = 0.006). To enhance liver health, reducing SB for longer durations and/or increasing the intensity of PA may be necessary. However, successfully reducing SB may lead to better levels of circulating ALT liver enzymes.NEW & NOTEWORTHY Aiming to reduce sedentary behavior (SB) by 1 h/day did not significantly influence liver health markers, suggesting that more substantial reductions or a different approach might be necessary to see improvements. However, achieving the desired behavioral change could lead to improvements in ALT levels. This study is the first to analyze how reducing SB and replacing it with nonguided physical activity impacts liver health in adults with metabolic syndrome, offering insights for future intervention strategies.

Aims:AI-QCTischaemia is an FDA-cleared novel artificial intelligence-guided method that utilizes features from coronary computed tomography angiography (CCTA) to predict myocardial ischaemia. Objective:To identify factors associated with discrepancy between AI-QCTischaemia and positron emission tomography (PET) perfusion. Methods and results:Six hundred and sixty-two patients with suspected obstructive coronary artery disease (CAD) on CCTA and undergoing [15O]H2O PET were analysed using AI-QCTischaemia. Multivariable logistic regression identified factors associated with discrepancy. Perfusion homogeneity was measured by relative flow reserve. A total of 209 (32%) patients showed discrepancies: 62 (9%) exhibited normal AI-QCTischaemia but abnormal perfusion (false negative AI-QCTischaemia), whereas 147 (22%) had abnormal AI-QCTischaemia despite normal perfusion (false positive AI-QCTischaemia). False positive AI-QCTischaemia patients (vs. true positive) were more often females, older, with less typical angina, and less advanced CAD. In multivariable analysis, typical angina [OR 95% CI: 1.796 (1.015-3.179), P = 0.044], diameter stenosis per 1% increase [1.058 (1.036-1.080), P < 0.001], and percent atheroma volume per 1% increase [1.103 (1.051-1.158), P < 0.001] significantly predicted true positive, while age was inversely associated [0.955 (0.923-0.989), P = 0.010]. False-negative AI-QCTischaemia patients (vs. true negative) were more often males, smokers, with less good CCTA image quality, and more advanced CAD. However, none was significant in multivariable analysis. Furthermore, false-negative AI-QCTischaemia showed more homogenously reduced perfusion by relative flow reserve compared to true positive (median ± IQR: 0.68 ± 0.15 vs. 0.56 ± 0.23, P < 0.001) and 21 (34%) of false negative showed globally reduced perfusion. Conclusion:For abnormal AI-QCTischaemia, younger age, typical angina, more severe stenosis, and more extensive atherosclerosis predicted abnormal PET perfusion. With false negative AI-QCTischaemia, perfusion abnormalities were partly explained by microvascular disease.