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Myocardial bridging (MB) is a common anatomic variant in coronary arteries with unclear functional significance. We evaluated regional myocardial strain by speckle tracking during dobutamine stress echocardiography (DSE) in patients with MB in the left anterior descending coronary artery (LAD). We studied 11 patients with MB in the LAD and no obstructive coronary artery disease (CAD), 7 patients without MB, but obstructive CAD in the LAD, and 12 controls without MB or obstructive CAD. MB was defined as either > 1 mm (superficial) or > 2 mm (deep) intramyocardial course of the LAD in coronary CT angiography. Regional longitudinal, radial and circumferential strains and strain rates as well as post-systolic strain index (PSI) were measured at rest, peak stress, and early recovery (1 min after stress). Strain parameters during DSE were similar in the myocardium distal to MB and other myocardial regions of the same patients as well as the LAD territory in controls. However, patients with obstructive CAD showed impaired LS and strain rate as well as increased PSI at peak stress. None of the MB was associated with systolic compression in invasive coronary angiography and strain parameters were similar between superficial and deep MB. Stress myocardial blood flow by positron emission tomography correlated with LS and RS at peak stress in the myocardium distal to MB (r = - 0.73, p = 0.03, and r = 0.64, p = 0.04, respectively). Myocardial strain is not reduced during DSE in patients with MB in the LAD and no significant systolic compression., Competing Interests: Declarations Conflict of interest The authors declare no competing interests. Consent to participate Informed consent was obtained from all individual participants included in the study. The authors affirm that human research participants provided informed consent for publication of the images as in Fig. 1. Ethical approval The study was performed according to the Declaration of Helsinki, it was approved by the local ethics committee., (© 2024. The Author(s).)

Aim: To determine the effectiveness of functional stress testing and computed tomography angiography (CTA) for diagnosis of obstructive coronary artery disease (CAD)., Methods and Results: Two-thousand nine-hundred twenty symptomatic stable chest pain patients were included in the international Collaborative Meta-Analysis of Cardiac CT consortium to compare CTA with exercise electrocardiography (exercise-ECG) and single-photon emission computed tomography (SPECT) for diagnosis of CAD defined as ≥ 50% diameter stenosis by invasive coronary angiography (ICA) as reference standard. Generalised linear mixed models were used for calculating the diagnostic accuracy of each diagnostic test including non-diagnostic results as dependent variables in a logistic regression model with random intercepts and slopes. Covariates were the reference standard ICA, the type of diagnostic method, and their interactions. CTA showed significantly better diagnostic performance (p < 0.0001) with a sensitivity of 94.6% (95% CI 92.7-96) and a specificity of 76.3% (72.2-80) compared to exercise-ECG with 54.9% (47.9-61.7) and 60.9% (53.4-66.3), SPECT with 72.9% (65-79.6) and 44.9% (36.8-53.4), respectively. The positive predictive value of CTA was ≥ 50% in patients with a clinical pretest probability of 10% or more while this was the case for ECG and SPECT at pretest probabilities of ≥ 40 and 28%. CTA reliably excluded obstructive CAD with a post-test probability of below 15% in patients with a pretest probability of up to 74%., Conclusion: In patients with stable chest pain, CTA is more effective than functional testing for the diagnosis as well as for reliable exclusion of obstructive CAD. CTA should become widely adopted in patients with intermediate pretest probability., Systematic Review Registration: PROSPERO Database for Systematic Reviews-CRD42012002780., Critical Relevance Statement: In symptomatic stable chest pain patients, coronary CTA is more effective than functional testing for diagnosis and reliable exclusion of obstructive CAD in intermediate pretest probability of CAD., Key Points: Coronary computed tomography angiography showed significantly better diagnostic performance (p < 0.0001) for diagnosis of coronary artery disease compared to exercise-ECG and SPECT. The positive predictive value of coronary computed tomography angiography was ≥ 50% in patients with a clinical pretest probability of at least 10%, for ECG ≥ 40%, and for SPECT 28%. Coronary computed tomography angiography reliably excluded obstructive coronary artery disease with a post-test probability of below 15% in patients with a pretest probability of up to 74%., (© 2024. The Author(s).)

Background: We developed an explainable deep-learning (DL)-based classifier to identify flow-limiting coronary artery disease (CAD) by O-15 H 2 O perfusion positron emission tomography computed tomography (PET/CT) and coronary CT angiography (CTA) imaging. The classifier uses polar map images with numerical data and visualizes data findings., Methods: A DLmodel was implemented and evaluated on 138 individuals, consisting of a combined image-and data-based classifier considering 35 clinical, CTA, and PET variables. Data from invasive coronary angiography were used as reference. Performance was evaluated with clinical classification using accuracy (ACC), area under the receiver operating characteristic curve (AUC), F1 score (F1S), sensitivity (SEN), specificity (SPE), precision (PRE), net benefit, and Cohen's Kappa. Statistical testing was conducted using McNemar's test., Results: The DL model had a median ACC = 0.8478, AUC = 0.8481, F1S = 0.8293, SEN = 0.8500, SPE = 0.8846, and PRE = 0.8500. Improved detection of true-positive and false-negative cases, increased net benefit in thresholds up to 34%, and comparable Cohen's kappa was seen, reaching similar performance to clinical reading. Statistical testing revealed no significant differences between DL model and clinical reading., Conclusions: The combined DL model is a feasible and an effective method in detection of CAD, allowing to highlight important data findings individually in interpretable manner., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Vascular adhesion protein-1 (VAP-1) is an adhesion molecule and primary amine oxidase, and Gallium-68-labeled 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetra-acetic acid conjugated sialic acid-binding immunoglobulin-like lectin 9 motif containing peptide ([ 68 Ga]Ga-DOTA-Siglec-9) is a positron emission tomography (PET) tracer targeting VAP-1. We evaluated the feasibility of PET imaging with [ 68 Ga]Ga-DOTA-Siglec-9 for the detection of myocardial lesions in rats with autoimmune myocarditis., Methods: Rats (n = 9) were immunized twice with porcine cardiac myosin in complete Freund's adjuvant. Control rats (n = 6) were injected with Freund's adjuvant alone. On day 21, in vivo PET/computed tomography (CT) imaging with [ 68 Ga]Ga-DOTA-Siglec-9 was performed, followed by ex vivo autoradiography, histology, and immunohistochemistry of tissue sections. In addition, myocardial samples from three patients with cardiac sarcoidosis were studied., Results: [ 68 Ga]Ga-DOTA-Siglec-9 PET/CT images of immunized rats showed higher uptake in myocardial lesions than in myocardium outside lesions (SUV mean , 0.5 ± 0.1 vs 0.3 ± 0.1; P = .003) or control rats (SUV mean , 0.2 ± 0.03; P < .0001), which was confirmed by ex vivo autoradiography of tissue sections. Immunohistochemistry showed VAP-1-positive staining in lesions of rats with myocarditis and in patients with cardiac sarcoidosis., Conclusion: VAP-1-targeted [ 68 Ga]Ga-DOTA-Siglec-9 PET is a potential novel technique for the detection of myocardial lesions., (© 2023. The Author(s).)

Background: Machine Learning (ML) allows integration of the numerous variables delivered by cardiac PET/CT, while traditional survival analysis can provide explainable prognostic estimates from a restricted number of input variables. We implemented a hybrid ML-and-survival analysis of multimodal PET/CT data to identify patients who developed myocardial infarction (MI) or death in long-term follow up., Methods: Data from 739 intermediate risk patients who underwent coronary CT and selectively stress 15 O-water-PET perfusion were analyzed for the occurrence of MI and all-cause mortality. Images were evaluated segmentally for atherosclerosis and absolute myocardial perfusion through 75 variables that were integrated through ML into an ML-CCTA and an ML-PET score. These scores were then modeled along with clinical variables through Cox regression. This hybridized model was compared against an expert interpretation-based and a calcium score-based model., Results: Compared with expert- and calcium score-based models, the hybridized ML-survival model showed the highest performance (CI .81 vs .71 and .64). The strongest predictor for outcomes was the ML-CCTA score., Conclusion: Prognostic modeling of PET/CT data for the long-term occurrence of adverse events may be improved through ML imaging score integration and subsequent traditional survival analysis with clinical variables. This hybridization of methods offers an alternative to traditional survival modeling of conventional expert image scoring and interpretation., (© 2023. The Author(s).)

Risk stratification of patients with ischemic heart disease (IHD) still depends mainly on the left ventricular ejection fraction (LVEF). LV inward displacement (InD) is a novel parameter of LV systolic function, derived from feature tracking cardiac magnetic resonance (CMR) imaging. We aimed to investigate the prognostic impact of InD in patients with IHD and prior myocardial infarction. A total of 111 patients (mean age 57 ± 10, 86% male) with a history of myocardial infarction who underwent CMR were included. LV InD was quantified by measuring the displacement of endocardially tracked points towards the centreline of the LV during systole with feature tracking CMR. The endpoint was a composite of all-cause mortality, heart failure hospitalization and arrhythmic events. During a median follow-up of 142 (IQR 107-159) months, 31 (27.9%) combined events occurred. Kaplan-Meier analysis demonstrated that patients with LV InD below the study population median value (23.0%) had a significantly lower event-free survival (P < 0.001). LV InD remained independently associated with outcomes (HR 0.90, 95% CI 0.84-0.98, P = 0.010) on multivariate Cox regression analysis. InD also provided incremental prognostic value to LVEF, LV global radial strain and CMR scar burden. LV InD, measured with feature tracking CMR, was independently associated with outcomes in patients with IHD and prior myocardial infarction. LV InD also provided incremental prognostic value, in addition to LVEF and LV global radial strain. LV InD holds promise as a pragmatic imaging biomarker for post-infarct risk stratification., (© 2023. The Author(s).)

Carimas is a multi-purpose medical imaging data processing tool, which can be used to visualize, analyze, and model different medical images in research. Originally, it was developed only for positron emission tomography data in 2009, but the use of this software has extended to many other tomography imaging modalities, such as computed tomography and magnetic resonance imaging. Carimas is especially well-suited for analysis of three- and four-dimensional image data and creating polar maps in modeling of cardiac perfusion. This article explores various parts of Carimas, including its key features, program structure, and application possibilities., (© 2023. The Author(s).)

Background: New Block-Sequential-Regularized-Expectation-Maximization (BSREM) image reconstruction technique has been introduced for clinical use mainly for oncologic use. Accurate and quantitative image reconstruction is essential in myocardial perfusion imaging with positron emission tomography (PET) as it utilizes absolute quantitation of myocardial blood flow (MBF). The aim of the study was to evaluate BSREM reconstruction for quantitation in patients with suspected coronary artery disease (CAD)., Methods and Results: We analyzed cardiac [ 15 O]H 2 O PET studies of 177 patients evaluated for CAD. Differences between BSREM and Ordered-Subset-Expectation-Maximization with Time-Of-Flight (TOF) and Point-Spread-Function (PSF) modeling (OSEM-TOF-PSF) in terms of MBF, perfusable tissue fraction, and vascular volume fraction were measured. Classification of ischemia was assessed between the algorithms. OSEM-TOF-PSF and BSREM provided similar global stress MBF in patients with ischemia (1.84 ± 0.21 g⋅ml -1 ⋅min -1 vs 1.86 ± 0.21 g⋅ml -1 ⋅min -1 ) and no ischemia (3.26 ± 0.34 g⋅ml -1 ⋅min -1 vs 3.28 ± 0.34 g⋅ml -1 ⋅min -1 ). Global resting MBF was also similar (0.97 ± 0.12 g⋅ml -1 ⋅min -1 and 1.12 ± 0.06 g⋅ml -1 ⋅min -1 ). The largest mean relative difference in MBF values was 7%. Presence of myocardial ischemia was classified concordantly in 99% of patients using OSEM-TOF-PSF and BSREM reconstructions CONCLUSION: OSEM-TOF-PSF and BSREM image reconstructions produce similar MBF values and diagnosis of myocardial ischemia in patients undergoing [ 15 O]H 2 O PET due to suspected obstructive coronary artery disease., (© 2023. The Author(s).)

Some studies have indicated that the use of 2D-Speckle tracking echocardiography (2DSTE) aids in predicting recovery of myocardial contractile function after revascularization in patients with chronic ischemic left ventricular (LV) dysfunction or acute myocardial infarction (MI). The purpose of this meta-analysis was to evaluate the diagnostic accuracy of 2DSTE strain in the detection of myocardial viability at rest and during low-dose dobutamine (LDD) stress. A systematic review for all prospective trials using 2DSTE to assess myocardial viability until January 2019 was done. Using a standard approach of meta-analysis for diagnostic tests. Overall, nine studies including 525 patients with either chronic ischemic heart disease or acute MI fulfilled the inclusion criteria. Seven studies used longitudinal strain (LS) at rest, nine studies used circumferential strain (CS) at rest, four studies used LS during LDD stress, and four studies used CS during LDD stress. LS and CS during LDD stress showed equally high sensitivity (81.5% and 81.5% respectively) and specificity (81.3% and 81.4% respectively) for detecting reversible dysfunction. At rest, LS and CS showed equally lower sensitivity (67.1%, p < 0.0001 vs. LDD stress and 68.7%, p < 0.0001, vs. LDD stress, respectively) and specificity (64%, p < 0.0001 vs. LDD stress and 65.7%, p = 0.0008 vs. LDD stress, respectively) as compared with LDD stress. LS and CS by 2DSTE during LDD stress accurately identify reversible ischemic myocardial dysfunction in patients with chronic ischemic LV dysfunction or after MI. The use of LDD stress can be recommended over resting strain measures in this setting., (© 2022. The Author(s).)

Endothelial wall shear stress (ESS) is a biomechanical force which plays a role in the formation and evolution of atherosclerotic lesions. The purpose of this study is to evaluate coronary computed tomography angiography (CCTA)-based ESS in coronary arteries without atherosclerosis, and to assess factors affecting ESS values. CCTA images from patients with suspected coronary artery disease were analyzed to identify coronary arteries without atherosclerosis. Minimal and maximal ESS values were calculated for 3-mm segments. Factors potentially affecting ESS values were examined, including sex, lumen diameter and distance from the ostium. Segments were categorized according to lumen diameter tertiles into small (< 2.6 mm), intermediate (2.6-3.2 mm) or large (≥ 3.2 mm) segments. A total of 349 normal vessels from 168 patients (mean age 59 ± 9 years, 39% men) were included. ESS was highest in the left anterior descending artery compared to the left circumflex artery and right coronary artery (minimal ESS 2.3 Pa vs. 1.9 Pa vs. 1.6 Pa, p < 0.001 and maximal ESS 3.7 Pa vs. 3.0 Pa vs. 2.5 Pa, p < 0.001). Men had lower ESS values than women, also after adjusting for lumen diameter (p < 0.001). ESS values were highest in small segments compared to intermediate or large segments (minimal ESS 3.8 Pa vs. 1.7 Pa vs. 1.2 Pa, p < 0.001 and maximal ESS 6.0 Pa vs. 2.6 Pa vs. 2.0 Pa, p < 0.001). A weak to strong correlation was found between ESS and distance from the ostium (ρ = 0.22-0.62, p < 0.001). CCTA-based ESS values increase rapidly and become widely scattered with decreasing lumen diameter. This needs to be taken into account when assessing the added value of ESS beyond lumen diameter in highly stenotic lesions., (© 2022. The Author(s).)

Background: Additional strategies are needed to refine the referral for diagnostic testing of symptomatic patients with suspected coronary artery disease (CAD). We aimed to compare various models to predict hemodynamically obstructive CAD., Methods and Results: Symptomatic patients with suspected CAD who underwent coronary artery calcium scoring (CACS) and sequential coronary computed tomography angiography (CCTA) and [ 15 O]H 2 O positron emission tomography (PET) myocardial perfusion imaging were analyzed. Obstructive CAD was defined as a suspected coronary artery stenosis on CCTA with myocardial ischemia on PET (absolute stress myocardial perfusion ≤ 2.4 mL/g/min in ≥ 1 segment). Three models were developed to predict obstructive CAD-induced myocardial ischemia using logistic regression analysis: (1) basic model: including age, sex and cardiac symptoms, (2) risk factor model: adding number of risk factors to the basic model, and (3) CACS model: adding CACS to the risk factor model. Model performance was evaluated using discriminatory ability with area under the receiver-operating characteristic curves (AUC). A total of 647 patients (mean age 62 ± 9 years, 45% men) underwent CACS and sequential CCTA and PET myocardial perfusion imaging. Obstructive CAD with myocardial ischemia on PET was present in 151 (23%) patients. CACS was independently associated with myocardial ischemia (P < .001). AUC for the discrimination of ischemia for the CACS model was superior over the basic model and risk factor model (P < .001)., Conclusions: Adding CACS to the model including age, sex, cardiac symptoms and number of risk factors increases the accuracy to predict obstructive CAD with myocardial ischemia on PET in symptomatic patients with suspected CAD., (© 2022. The Author(s).)

Pericoronary adipose tissue (PCAT) attenuation, derived from coronary computed tomography angiography (CCTA), is associated with coronary artery inflammation. Values for PCAT attenuation in men and women without atherosclerosis on CCTA are lacking. The aim of the current study was to assess the mean PCAT attenuation in individuals without coronary artery atherosclerosis on CCTA. Data on PCAT attenuation in men and women without coronary artery atherosclerosis on CCTA were included in this retrospective analysis. The PCAT attenuation was analyzed from the proximal part of the right coronary artery (RCA), the left anterior descending artery (LAD), and the left circumflex artery (LCx). For patient level analyses the mean PCAT attenuation was defined as the mean of the three coronary arteries. In 109 individuals (mean age 45 ± 13 years; 44% men), 320 coronary arteries were analyzed. The mean PCAT attenuation of the overall population was - 64.4 ± 8.0 HU. The mean PCAT attenuation was significantly lower in the LAD compared with the LCx and RCA (- 67.8 ± 7.8 HU vs - 62.6 ± 6.8 HU vs - 63.6 ± 7.9 HU, respectively, p < 0.001). In addition, the mean PCAT attenuation was significantly higher in men vs. women in all three coronary arteries (LAD: - 65.7 ± 7.6 HU vs - 69.4 ± 7.6 HU, p = 0.014; LCx: - 60.6 ± 7.4 HU vs - 64.3 ± 5.9 HU, p = 0.008; RCA: -61.7 ± 7.9 HU vs - 65.0 ± 7.7 HU, p = 0.029, respectively). The current study provides mean PCAT attenuation values, derived from individuals without CAD. Moreover, the mean PCAT attenuation is lower in women vs. men. Furthermore, the mean PCAT attenuation is significantly lower in the LAD vs LCx and RCA., (© 2022. The Author(s).)

Women with severe aortic stenosis (AS) have better long-term prognosis after transcatheter aortic valve implantation (TAVI) compared to men. Whether this is caused by sex-related differences in left ventricular (LV) reverse remodeling after TAVI is unknown. Patients with severe AS who underwent transfemoral TAVI between 2007 and 2018 were selected. LV dimensions, volumes, and ejection fraction (LVEF) were assessed by transthoracic echocardiography before TAVI and at 6 and 12 months follow-up after TAVI. LV reverse remodeling was defined as the percentual LV mass index (LVMi) reduction compared to baseline. The primary outcome was all-cause mortality. A total of 459 patients (80 ± 8 years; 52% male) were included. At 6 and 12 months follow-up, both sexes showed significant reductions in LV volumes and LVMi accompanied by improvement in LVEF, without significant differences between the sexes over time. During a median follow-up of 2.8 [IQR 1.9-4.3] years, 181 (39%) patients died. Women showed better outcomes compared to men (log-rank p = 0.024). In addition, male sex was independently associated with all-cause mortality in multivariable Cox regression (HR 1.423, 95% CI 1.039-1.951, p = 0.028). No association was observed between the interaction of percentual LVMi reduction and sex with outcomes (p = 0.64). Men and women with severe AS had similar improvement in LVEF, and similar reductions in LV volumes and LVMi at 6 and 12 months after TAVI. Women showed better survival after TAVI as compared to men. The superior outcomes noted in women after TAVI are not associated with sex differences in LV reverse remodeling., (© 2022. The Author(s).)

Patients with diabetes mellitus (DM) may show diffuse coronary artery atherosclerosis on coronary computed tomography angiography (CTA). The present study aimed at quantification of atherosclerotic plaque with CTA and its association with myocardial ischemia on positron emission tomography (PET) in DM patients. Of 922 symptomatic outpatients without previously known coronary artery disease who underwent CTA, 115 with DM (mean age 65 ± 8 years, 58% male) who had coronary atherosclerosis and underwent both quantified CTA (QCTA) and PET were included in the study. QCTA analysis was performed on a per-vessel basis and the most stenotic lesion of each vessel was considered. Myocardial ischemia on PET was based on absolute myocardial blood flow at stress ≤ 2.4 ml/g/min. Of the 345 vessels included in the analysis, 135 (39%) had flow-limiting stenosis and were characterized by having longer lesions, higher plaque volume, more extensive plaque burden and higher percentage of dense calcium (37 ± 22% vs 28 ± 22%, p = 0.001). On univariable analysis, QCTA parameters indicating the degree of stenosis, the plaque extent and composition were associated with presence of ischemia. The addition of the QCTA degree of stenosis parameters (x 2 36.45 vs 88.18, p < 0.001) and the QCTA plaque extent parameters (x 2 88.18 vs 97.44, p = 0.01) to a baseline model increased the association with ischemia. In DM patients, QCTA variables of vessel stenosis, plaque extent and composition are associated with ischemia on PET and characterize the hemodynamic significant atherosclerotic lesion., (© 2022. The Author(s).)

Hypo-attenuated leaflet thickening (HALT) of transcatheter aortic valves is detected on multidetector computed tomography (MDCT) and reflects leaflet thrombosis. Whether HALT affects left ventricular (LV) reverse remodeling, a favorable effect of LV afterload reduction after transcatheter aortic valve implantation (TAVI) is unknown. The aim of this study was to examine the association of HALT after TAVI with LV reverse remodeling. In this multicenter case-control study, patients with HALT on MDCT were identified, and patients without HALT were propensity matched for valve type and size, LV ejection fraction (LVEF), sex, age and time of scan. LV dimensions and function were assessed by transthoracic echocardiography before and 12 months after TAVI. Clinical outcomes (stroke or transient ischemic attack, heart failure hospitalization, new-onset atrial fibrillation, all-cause mortality) were recorded. 106 patients (age 81 ± 7 years, 55% male) with MDCT performed 37 days [IQR 32-52] after TAVI were analyzed (53 patients with HALT and 53 matched controls). Before TAVI, all echocardiographic parameters were similar between the groups. At 12 months follow-up, patients with and without HALT showed a significant reduction in LV end-diastolic volume, LV end-systolic volume and LV mass index (from 125 ± 37 to 105 ± 46 g/m 2 , p = 0.001 and from 127 ± 35 to 101 ± 27 g/m 2 , p < 0.001, respectively, p for interaction = 0.48). Moreover, LVEF improved significantly in both groups. In addition, clinical outcomes were not statistically different. Improvement in LVEF and LV reverse remodeling at 12 months after TAVI were not limited by HALT., (© 2021. The Author(s).)

Introduction: The purpose of this study was to evaluate subjects with high-risk alcohol cardiotoxicity and patients with alcoholic cardiomyopathy (ACM) via dynamic 11 C-Acetate positron emission tomography (PET) imaging as a myocardial oxidative metabolic probe., Methods and Results: We recruited 37 subjects with chronic alcohol consumption [18 with moderate consumption (MC), 19 with heavy consumption (HC)], 5 ACM patients, and 12 healthy controls to receive dynamic 11 C-Acetate PET scans. PET imaging data were analyzed to calculate kinetic parameters (e.g., K mono , K 1 and k 2 ) based on the mono-exponential and one-tissue compartmental models. Myocardial oxygen consumption (MVO 2 ) and myocardial external efficiency (MEE) were then derived from these kinetic parameters. MVO 2 was significantly lowered in the HC group and in ACM patients (0.121± 0.018 and 0.111 ± 0.017 mL·g -1 ·min -1 , respectively) compared with those in healthy controls and MC subjects (0.144 ± 0.023 and 0.146 ± 0.027 mL·g -1 ·min -1 , respectively; P < .01). MEE was significantly reduced in ACM patients (13.0% ± 4.3%) compared with those of healthy controls (22.4% ± 4.6%, P < .01), MC subjects (20.1% ± 4.5%, P < .05), and HC subjects (22.3% ± 4.5%, P < .001)., Conclusion: Functional assessment via dynamic 11 C-Acetate PET imaging may represent a clinically feasible probe for identifying cohorts with high-risk cardiotoxicity due to addictive alcohol consumption and ACM., (© 2020. American Society of Nuclear Cardiology.)

Background: The aim of the present study was to compare the quantitative flow responses of regadenoson against adenosine using cardiac 15 O-water PET imaging in patients with suspected or known coronary artery disease (CAD)., Methods: Hyperemic myocardial blood flow (MBF) after adenosine and regadenoson was compared using correlation and Bland-Altman analysis in 21 patients who underwent rest and adenosine 15 O-water PET scans followed by rest and regadenoson 15 O-water PET scans., Results: Global mean (± SD) MBF values at rest and stress were 0.92 ± 0.27 and 2.68 ± 0.80 mL·g·min for the adenosine study and 0.95 ± 0.29 and 2.76 ± 0.79 mL·g·min for the regadenoson study (P = 0.55 and P = 0.49). The correlations between global and regional adenosine- and regadenoson-based stress MBF were strong (r = 0.80 and r = 0.77). The biases were small for both global and regional MBF comparisons (0.08 and 0.09 mL·min·g), but the limits of agreement were wide for stress MBF., Conclusion: The correlation between regadenoson- and adenosine-induced hyperemic MBF was strong but the agreement was only moderate indicating that established cut-off values for 15 0-water PET should be used cautiously if using regadenoson as vasodilator., (© 2021. The Author(s).)

Background: The diagnosis of cardiac implantable electronic device (CIED) infection is challenging because of its variable presentations. We studied the value of 2-[ 18 F]fluoro-2-deoxy-D-glucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) in the detection of CIED infection., Methods and Results: Thirty patients with suspected CIED infection underwent 18 F-FDG-PET/CT. The control group was ten patients with asymptomatic CIED who underwent cancer-related 18 F-FDG-PET/CT. 18 F-FDG-PET/CT was evaluated visually, semiquantitatively as maximum standardized uptake value (SUV max ) and target-to-background ratio (TBR). Final diagnosis of CIED infection was based on clinical and bacteriological data. 18 F-FDG-PET/CT was visually positive in all 9 patients with recent (≤ 8 weeks) implantation of CIED, but only 4 had confirmed CIED infection. 18 F-FDG-PET/CT was true positive in 9 out of 21 cases with remote implantation of CIED and false positive in 3 (14.3%) cases. 18 F-FDG-PET/CT was also false positive in 3 (30%) cases of control group. The SUV max of the pocket area was significantly higher in patients with CIED infection than in the control group (4.8 ± 2.4 vs 2.0 ± .8, P < .001). By using the cut-off value of TBR ≥ 1.8, sensitivity of 18 F-FDG-PET/CT for the diagnosis of CIED infection in patients with remote implantation was 90% and specificity 73%, PPV 75%, and NPV 89%., Conclusions: 18 F-FDG-PET/CT is a sensitive but nonspecific method in the diagnosis of CIED infection., (© 2020. The Author(s).)

Background: Assessment of myocardial viability is often needed in patients with chest pain and reduced ejection fraction. We evaluated the performance of reduced resting MBF, perfusable tissue fraction (PTF), and perfusable tissue index (PTI) in the assessment of myocardial viability in a pig model of myocardial infarction (MI)., Methods and Results: Pigs underwent resting [ 15 O]water PET perfusion study 12 weeks after surgical (n = 16) or 2 weeks after catheter-based (n = 4) occlusion of the proximal left anterior descending coronary artery. MBF, PTF, and PTI were compared with volume fraction of MI in matched segments as assessed by triphenyl tetrazolium chloride staining of LV slices. MBF and PTF were lower in infarcted than non-infarcted segments. Segmental analysis of MBF showed similar area under the curve (AUC) of 0.85, 0.86, and 0.90 with relative MBF, PTF, and PTI for the detection of viable myocardium defined as infarct volume fraction of < 75%. Cut-off values of relative MBF of ≥ 67% and PTF of ≥ 66% resulted in accuracies of 90% and 81%, respectively., Conclusions: Our results indicate that resting MBF, PTF, and PTI based on [ 15 O]water PET perfusion imaging are useful for the assessment of myocardial viability., (© 2019. The Author(s).)

Long-term data on sex-differences in coronary plaque changes over time is lacking in a low-to-intermediate risk population of stable coronary artery disease (CAD). The aim of this study was to evaluate the role of sex on long-term plaque progression and evolution of plaque composition. Furthermore, the influence of menopause on plaque progression and composition was also evaluated. Patients that underwent a coronary computed tomography angiography (CTA) were prospectively included to undergo a follow-up coronary CTA. Total and compositional plaque volumes were normalized using the vessel volume to calculate a percentage atheroma volume (PAV). To investigate the influence of menopause on plaque progression, patients were divided into two groups, under and over 55 years of age. In total, 211 patients were included in this analysis, 146 (69%) men. The mean interscan period between baseline and follow-up coronary CTA was 6.2 ± 1.4 years. Women were older, had higher HDL levels and presented more often with atypical chest pain. Men had 434 plaque sites and women 156. On a per-lesion analysis, women had less fibro-fatty PAV compared to men (β -1.3 ± 0.4%; p < 0.001), with no other significant differences. When stratifying patients by 55 years age threshold, fibro-fatty PAV remained higher in men in both age groups (p < 0.05) whilst women younger than 55 years demonstrated more regression of fibrous (β -0.8 ± 0.3% per year; p = 0.002) and non-calcified PAV (β -0.7 ± 0.3% per year; p = 0.027). In a low-to-intermediate risk population of stable CAD patients, no significant sex differences in total PAV increase over time were observed. Fibro-fatty PAV was lower in women at any age and women under 55 years demonstrated significantly greater reduction in fibrous and non-calcified PAV over time compared to age-matched men. (ClinicalTrials.gov number, NCT04448691.)., (© 2021. The Author(s).)

Background: Positron emission tomography (PET) myocardial perfusion imaging (MPI) with the novel radiopharmaceutical Fluorine-18 Flurpiridaz has been shown in Phase 1, 2, and first Phase 3 clinical studies to be safe and effective in diagnosing coronary artery disease (CAD). We describe the methodology of the second FDA-mandated phase 3 prospective, open-label, international, multi-center trial of F-18 Flurpiridaz PET MPI., Methods: The primary study end point is to assess the diagnostic efficacy of F-18 Flurpiridaz PET MPI in the detection of significant CAD [≥ 50% by quantitative invasive coronary angiography (ICA)] in patients with suspected CAD. The secondary endpoints are to evaluate the diagnostic efficacy of F-18 Flurpiridaz PET MPI compared to Tc-99 m-labeled SPECT MPI in the detection of CAD in all patients and in the following subgroups: (1) females; (2) patients with body mass index ≥ 30 kg/m 2 ; and (3) diabetic patients. This trial's design differs from the first phase 3 trial in that (1) comparison to SPECT is now a secondary end point; (2) patients with known CAD are excluded; and (3) both SPECT and PET MPI are performed before ICA., Conclusions: This second phase 3 study will provide additional evidence on the diagnostic efficacy of F-18 Flurpiridaz PET MPI in the detection of significant CAD., Trial Registration Number: NCT03354273.

Background: Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling protects against cardiac dysfunction and remodeling after myocardial infarction (MI). The aim of the study was to evaluate 68 Ga-NODAGA-exendin-4 positron emission tomography (PET) for assessment of GLP-1R expression after MI in rats., Methods and Results: Rats were studied at 3 days, 1 and 12 weeks after permanent coronary ligation or a sham-operation. Rats were injected with 68 Ga-NODAGA-exendin-4 and scanned with PET and contrast-enhanced computed tomography (CT) followed by digital autoradiography and histology of left ventricle tissue sections. 68 Ga-NODAGA-exendin-4 PET/CT showed focally increased tracer uptake in the infarcted regions peaking at 3 days and continuing at 1 week after MI. Pre-treatment with an unlabeled exendin-4 peptide significantly reduced 68 Ga-NODAGA-exendin-4 uptake. By autoradiography, 68 Ga-NODAGA-exendin-4 uptake was 8.6-fold higher in the infarcted region and slightly increased also in the remote, non-infarcted myocardium at 1 week and 12 weeks post-MI compared with sham. Uptake of 68 Ga-NODAGA-exendin-4 correlated with the amount of CD68-positive macrophages in the infarcted area and alpha-smooth muscle actin staining in the remote myocardium., Conclusions: 68 Ga-NODAGA-exendin-4 PET detects up-regulation of cardiac GLP-1R expression during healing of MI in rats and may provide information on the activated repair mechanisms after ischemic myocardial injury.

Background: We explored agreement in the quantification of myocardial perfusion by cross-comparison of implemented software packages (SPs) in three distinguishable patient profile populations., Methods: We studied 91 scans of patients divided into 3 subgroups based on their semi-quantitative perfusion findings: patients with normal perfusion, with reversible perfusion defects, and with fixed perfusion defects. Rest myocardial blood flow (MBF), stress MBF, and myocardial flow reserve (MFR) were obtained with QPET, SyngoMBF, and Carimas. Agreement between SPs was considered adequate when a pairwise standardized difference was found to be < 0.20 and its corresponding intraclass correlation coefficient was ≥ 0.75., Results: In patients with normal perfusion, two out of three comparisons of global stress MBF quantifications were outside the limits of agreement. In ischemic patients, all comparisons of global stress MBF and MFR were outside the limits of established agreement. In patients with fixed perfusion defects, all SP comparisons of perfusion quantifications were within the limit of agreement. Regionally, agreement of these perfusion estimates was mostly found for the left anterior descending artery vascular territory., Conclusion: Reversible defects demonstrated the worst agreement in global stress MBF and MFR and discrepancies showed to be regional dependent. Reproducibility between SPs should not be assumed.

Background: Magnetic resonance imaging (MRI) with Gadolinium 1,4,7,10-tetraazacyclododecane-N',N″,N''',N″″-tetraacetic acid (Gd-DOTA) enables assessment of myocardial perfusion during first-pass of the contrast agent, while increased retention can signify areas of myocardial infarction (MI). We studied whether Gallium-68-labeled analog, 68 Ga-DOTA, can be used to assess myocardial perfusion on positron emission tomography/computed tomography (PET/CT) in rats, comparing it with 11 C-acetate., Methods: Rats were studied with 11 C-acetate and 68 Ga-DOTA at 24 hours after permanent ligation of the left coronary artery or sham operation. One-tissue compartmental models were used to estimate myocardial perfusion in normal and infarcted myocardium. After the PET scan, hearts were sectioned for autoradiographic detection of 68 Ga-DOTA distribution., Results: 11 C-acetate PET showed perfusion defects and histology showed myocardial necrosis in all animals after coronary ligation. Kinetic modeling of 68 Ga-DOTA showed significantly higher k 1 values in normal myocardium than in infarcted areas. There was a significant correlation (r = 0.82, P = 0.001) between k 1 values obtained with 68 Ga-DOTA and 11 C-acetate. After 10 minutes of tracer distribution, the 68 Ga-DOTA concentration was significantly higher in the infarcted than normal myocardium on PET imaging and autoradiography., Conclusions: Our results indicate that acute MI can be detected as reduced perfusion, as well as increased late retention of 68 Ga-DOTA.

Background: A significant number of variables are obtained when characterizing patients suspected with myocardial ischemia or at risk of MACE. Guidelines typically use a handful of them to support further workup or therapeutic decisions. However, it is likely that the numerous available predictors maintain intrinsic complex interrelations. Machine learning (ML) offers the possibility to elucidate complex patterns within data to optimize individual patient classification. We evaluated the feasibility and performance of ML in utilizing simple accessible clinical and functional variables for the identification of patients with ischemia or an elevated risk of MACE as determined through quantitative PET myocardial perfusion reserve (MPR)., Methods: 1,234 patients referred to Nitrogen-13 ammonia PET were analyzed. Demographic (4), clinical (8), and functional variables (9) were retrieved and input into a cross-validated ML workflow consisting of feature selection and modeling. Two PET-defined outcome variables were operationalized: (1) any myocardial ischemia (regional MPR < 2.0) and (2) an elevated risk of MACE (global MPR < 2.0). ROC curves were used to evaluate ML performance., Results: 16 features were included for boosted ensemble ML. ML achieved an AUC of 0.72 and 0.71 in identifying patients with myocardial ischemia and with an elevated risk of MACE, respectively. ML performance was superior to logistic regression when the latter used the ESC guidelines risk models variables for both PET-defined labels (P < .001 and P = .01, respectively)., Conclusions: ML is feasible and applicable in the evaluation and utilization of simple and accessible predictors for the identification of patients who will present myocardial ischemia and an elevated risk of MACE in quantitative PET imaging.

Noninvasive imaging modalities offer the possibility to dynamically evaluate cardiac motion during the cardiac cycle by means of ECG-gated acquisitions. Such motion characterization along with orientation, segmentation preprocessing, and ultimately, phase analysis, can provide quantitative estimates of ventricular mechanical synchrony. Current evidence on the role of mechanical synchrony evaluation is mainly available for echocardiography and gated single-photon emission computed tomography, but less is known about the utilization of gated positron emission tomography (PET). Although data available are sparse, there is indication that mechanical synchrony evaluation can be of diagnostic and prognostic values in patients with known or suspected coronary artery disease-related myocardial ischemia, prediction of response to cardiac resynchronization therapy, and estimation of risk for adverse cardiac events in patients' heart failure. As such, the evaluation of mechanical ventricular synchrony through phase analysis of gated acquisitions represents a value addition to modern cardiac PET imaging modality, which warrants further research and development in the evaluation of patients with cardiovascular disease.

Combined myocardial flow reserve (MFR) by PET and CT coronary angiography (CTA) is a promising tool for assessment of coronary artery disease. Prior analyses of MFR/CTA has been performed as side-by-side interpretation, not as volume rendered, full hybrid analysis, with fused MFR/CTA. We aimed to: (i) establish a method for full hybrid analysis of MFR/CTA, (ii) validate the inter- and intra-observer reproducibility of MFR values, and (iii) determine the diagnostic value of side-by-side versus full hybrid MFR/CTA with 15-O-water PET. Forty-four outpatients scheduled for invasive coronary angiography (ICA) were enrolled prospectively. All underwent rest/stress 15-O-water PET/CTA with ICA as reference. Within two observers of different experience, the Pearson r at global and territorial level exceeded 0.953 for rest, stress, and MFR values, as determined by Carimas software. Within and between observers, the mean differences between rest, stress, and MFR values were close to zero and the confidence intervals for 95% limits of agreement were narrow. The diagnostic performance of full hybrid PET/CTA did not outperform the side-by-side approach, but performed better than MFR without CTA at vessel level: specificity 93% (95% confidence limits: 89-97%) versus 76% (64-88%), p = 0.0004; positive predictive value 71% (55-86%) versus 51% (37-65%), p = 0.0001; accuracy 90% (84-95%) versus 77% (69-84%), p = 0.0009. MFR showed high reproducibility within and between observers of different experience. The full hybrid model was not superior to side-by-side interpretation of MFR/CTA, but proved better than MFR alone at vessel level with regard to specificity, positive predictive value, and accuracy.

Background: Matrix metalloproteinases 2 and 9 (MMP-2/9) play a role in extracellular matrix remodeling after an ischemic myocardial injury. We evaluated 68 Ga-DOTA-peptide targeting MMP-2/9 for the detection of gelatinase expression after myocardial infarction (MI) in rat., Methods: Rats were injected with 43 ± 7.7 MBq of 68 Ga-DOTA-peptide targeting MMP-2/9 at 7 days (n = 7) or 4 weeks (n = 8) after permanent coronary ligation or sham operation (n = 5 at both time points) followed by positron emission tomography (PET). The left ventricle was cut in frozen sections for autoradiography and immunohistochemistry 30 minutes after tracer injection., Results: Immunohistochemical staining showed MMP-2 and MMP-9 expressing cells, CD31-positive endothelial cells, and CD68-positive macrophages in the infarcted myocardium. Autoradiography showed increased tracer uptake in the infarcted area both at 7 days and 4 weeks after MI (MI-to-remote area ratio 2.5 ± 0.46 and 3.1 ± 1.0, respectively). Tracer uptake in damaged tissue correlated with the amount of CD68-positive macrophages at 7 days after MI, and CD31-positive endothelial cells at 7 days and 4 weeks after MI. The tracer was rapidly metabolized, radioactivity in the blood exceeded that of the myocardium, and tracer accumulation in the heart was not detectable by in vivo PET., Conclusions: 68 Ga-DOTA-peptide targeting MMP-2/9 accumulates in the damaged rat myocardium after an ischemic injury, but tracer instability and slow clearance in vivo make it unsuitable for further evaluation.

Background: Radioligands of 18-kDa translocator protein (TSPO) expressed on activated macrophages are a potential approach for imaging of inflammation in atherosclerosis. We evaluated a novel TSPO-targeted tracer 18 F-FEMPA for the detection of atherosclerotic plaque inflammation in mice., Methods and Results: The distribution kinetics of 18 F-FEMPA was evaluated by in vivo PET/CT imaging. 18 F-FEMPA uptake was compared in atherosclerotic (LDLR -/- ApoB 100/100 , n = 10) and healthy mice (C57BL/6 N, n = 7) ex vivo at twenty minutes post-injection. Biodistribution was analyzed from harvested tissue samples, and aortas were sectioned for autoradiography. Aortas of LDLR -/- ApoB 100/100 mice showed large, macrophage-rich atherosclerotic plaques. In vivo, 18 F-FEMPA showed rapid blood clearance but no difference in aortic uptake between atherosclerotic and healthy mice. In the mice studied ex vivo at 20 minutes post-injection, quantification of radioactivity in the whole aorta showed 1.3-fold higher 18 F-FEMPA accumulation in atherosclerotic than healthy mice (P = .028). Autoradiography showed higher tracer uptake in plaque areas with high macrophage content as compared with areas of no macrophages (count densities 190 ± 54 vs 40 ± 13 PSL/mm 2 , P < .001), but the uptake in the plaques was not higher than in the normal vessel wall (230 ± 78 PSL/mm 2 ). In vitro blocking showed specific accumulation in mouse and human atherosclerotic plaques. Immunohistochemistry confirmed co-localization of TSPO and macrophages., Conclusions: 18 F-FEMPA shows rapid blood clearance and uptake in the mouse aorta. Uptake in atherosclerotic plaques correlated with the amount of macrophages, but did not exceed that in the normal vessel wall.

Background: The diagnosis of infective endocarditis (IE), especially the diagnosis of prosthetic valve endocarditis (PVE) is challenging since echocardiographic findings are often scarce in the early phase of the disease. We studied the use of 2-[ 18 F]fluoro-2-deoxy-D-glucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) in IE., Methods: Sixteen patients with suspected PVE and 7 patients with NVE underwent visual evaluation of 18 F-FDG-PET/CT. 18 F-FDG uptake was measured also semiquantitatively as maximum standardized uptake value (SUV max ) and target-to-background ratio (TBR). The modified Duke criteria were used as a reference., Results: There was strong, focal 18 F-FDG uptake in the area of the affected valve in all 6 cases of definite PVE, in 3 of 5 possible PVE cases, and in 2 of 5 rejected cases. In all patients with definite PVE, SUV max of the affected valve was higher than 4 and TBR higher than 1.8. In contrast to PVE, only 1 of 7 patients with NVE had uptake of 18 F-FDG by PET/CT in the valve area. Embolic infectious foci were detected in 58% of the patients with definite IE., Conclusions: 18 F-FDG-PET/CT appears to be a sensitive method for the detection of paravalvular infection associated with PVE. Instead, the sensitivity of PET/CT is limited in NVE.

Sudden cardiac death (SCD) represents a significant portion of all cardiac deaths. Current guidelines focus mainly on left ventricular ejection fraction (LVEF) as the main criterion for SCD risk stratification and management. However, LVEF alone lacks both sensitivity and specificity in stratifying patients. Recent research has provided interesting data which supports a greater role for advanced cardiac imaging in risk stratification and patient management. In this article, we will focus on nuclear cardiac imaging, including left ventricular function assessment, myocardial perfusion imaging, myocardial blood flow quantification, metabolic imaging, and neurohormonal imaging. We will discuss how these can be used to better understand SCD and better stratify patient with both ischemic and non-ischemic cardiomyopathy.