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Arbutamine, a synthetic catecholamine, coupled with a closed-loop, computerized delivery system was evaluated in conjunction with technetium-99m sestamibi scintigraphy and echocardiography for the detection of coronary artery disease. Concordance between the imaging methods was 68%, with a similar sensitivity for coronary disease using echocardiography (78%) and technetium-99m sestamibi (76%), although more arbutamine-induced ischemia was noted with perfusion imaging. [ABSTRACT FROM AUTHOR]

Background: Although positron emission tomography (PET) imaging is well established for its diagnostic role in cardiac sarcoidosis, less is known about the prognostic value of PET and its use in risk stratification for major adverse cardiac events (MACE)., Objectives: The goal of this study was to perform a systematic review and meta-analysis looking at the prognostic value of PET imaging in patients with cardiac sarcoidosis., Methods: Study investigators systematically searched EMBASE (Excerpta Medica dataBASE), MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ClinicalTrials.gov, and the European Union Clinical Trial Registry for cardiac sarcoidosis and PET imaging. The primary outcome of interest was MACE., Results: The search revealed 3,010 records, of which 55 studies were included. This represented 5,250 patients. Factors associated with MACE included the following: the combination of abnormal fluorodeoxyglucose (FDG) uptake and perfusion defect, which had an OR of 2.86 (95% CI: 1.74-4.71; P < 0.0001); abnormal perfusion or FDG uptake, which had an OR of 2.69 (95% CI: 1.67-4.33); abnormal FDG uptake, which had an OR of 2.61 (95% CI: 1.51-4.50); focal abnormal right ventricular uptake, which had an OR of 6.27 (95% CI: 3.19-12.32; P < 0.00001); and a lack of response to immunosuppression on serial PET, which had an OR of 8.43 (95% CI: 3.25-21.85; P < 0.0001). A QUIPS (Quality in Prognostic Studies) tool analysis found a low to moderate risk of bias, particularly given the small sample sizes in the individual studies., Conclusions: Multiple cardiac PET parameters provide risk stratification value in cardiac sarcoidosis. Focal right ventricular uptake and a lack of response to immunosuppressive therapy on serial PET imaging were particularly predictive of MACE., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to develop a framework for generating three-dimensional (3D) myocardial blood flow (MBF) images, computing their accuracy against clinically validated two-dimensional (2D) polar MBF maps of the left ventricle, and evaluating their improvements in image quality over relative myocardial perfusion imaging (MPI)., Methods: N = 40 patients with a wide range of defect severities and uptake dynamics were retrospectively studied. The FlowQuant™ software was used to generate reference MPI and polar MBF maps and was adapted for voxel-wise MBF mapping. We evaluated agreement between parametric vs polar values for MBF at rest and stress and for reserve (stress/rest MBF). We also assessed improvements in image quality, assessed by signal-to-noise ratio, contrast-to-noise ratio, tissue-to-blood ratio, and defect severity, from relative MPI to MBF., Results: There was excellent agreement between 3D parametric and 2D polar maps for all flow parameters (interclass correlation coefficient >0.96), albeit with minimal bias (<8%) for rest and stress MBF at the patient level. Image quality substantially improved from MPI to MBF in every patient for all image-quality metrics (P < 0.0001) CONCLUSIONS: We developed a robust methodology for producing highly accurate 3D MBF images exhibiting considerably improved image quality compared to relative MPI commonly used in clinical practice., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Positron emission tomography (PET) has demonstrated utility for diagnostic and prognostic assessment of cardiac allograft vasculopathy (CAV) but has not been evaluated in the first year after transplant., Objectives: The authors sought to evaluate CAV at 1 year by PET myocardial blood flow (MBF) quantification., Methods: Adults at 2 institutions enrolled between January 2018 and March 2021 underwent prospective 3-month (baseline) and 12-month (follow-up) post-transplant PET, endomyocardial biopsy, and intravascular ultrasound examination. Epicardial CAV was assessed by intravascular ultrasound percent intimal volume (PIV) and microvascular CAV by endomyocardial biopsy., Results: A total of 136 PET studies from 74 patients were analyzed. At 12 months, median PIV increased 5.6% (95% CI: 3.6%-7.1%) with no change in microvascular CAV incidence (baseline: 31% vs follow-up: 38%; P = 0.406) and persistent microvascular disease in 13% of patients. Median capillary density increased 30 capillaries/mm 2 (95% CI: -6 to 79 capillaries/mm 2 ). PET myocardial flow reserve (2.5 ± 0.7 vs 2.9 ± 0.8; P = 0.001) and stress MBF (2.7 ± 0.6 vs 2.9 ± 0.6; P = 0.008) increased, and coronary vascular resistance (CVR) (49 ± 13 vs 47 ± 11; P = 0.214) was unchanged. At 12 months, PET and PIV had modest correlation (stress MBF: r = -0.35; CVR: r = 0.33), with lower stress MBF and higher CVR across increasing PIV tertiles (all P < 0.05). Receiver-operating characteristic curves for CAV defined by upper-tertile PIV showed areas under the curve of 0.74 for stress MBF and 0.73 for CVR., Conclusions: The 1-year post-transplant PET MBF is associated with epicardial CAV, supporting potential use for early noninvasive CAV assessment. (Early Post Transplant Cardiac Allograft Vasculopahty [ECAV]; NCT03217786)., Competing Interests: Funding Support and Author Disclosures This study was funded by a Heart and Stroke Foundation of Canada Grant in Aid (G-17-00018310) and University of Ottawa Heart Institute ORACLE Innovation Cluster Team Grant. Dr Chih is supported by a Tier 2 University of Ottawa Clinical Research Chair in Cardiac Transplantation. Dr Chong has received honoraria from Abbott and is an Abbott Advisory Board member for optical coherence tomography. Dr deKemp has received royalties from rubidium-82 PET technologies licensed to Jubilant Radiopharma and to INVIA Medical Solutions and has also received research funding and honoraria from Jubilant-DraxImage Radiopharma and IONETIX. Dr Beanlands is a University of Ottawa Distinguished Research Chair in Cardiovascular Imaging; and is a consultant for and has received research grant funding from Jubilant-DraxImage, Lantheus Medical Imaging, and General Electric Health Care. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: 82 Rb PET is commonly performed using the same injected activity in all patients, resulting in lower image quality in larger patients. This study compared 82 Rb dosing with exponential vs proportional functions of body weight on the standardization of myocardial perfusion image (MPI) quality., Methods: Two sequential cohorts of N = 60 patients were matched by patient weight. Rest and dipyridamole stress 82 Rb PET was performed using 0.1 MBq·kg -2 exponential and 9 MBq·kg -1 proportional dosing. MPI scans were compared qualitatively with visual image quality scoring (IQS) and quantitatively using the myocardium-to-blood contrast-to-noise ratio (CNR) and blood background signal-to-noise ratio (SNR) as a function of body weight., Results: Average (min-max) patient body weight was 81 ± 18 kg (46-137 kg). Proportional dosing resulted in decreasing CNR, SNR, and visual IQS with increasing body weight (P < 0.05). Exponential dosing eliminated the weight-dependent decreases in these image quality metrics that were observed in the proportional dosing group., Conclusion: 82 Rb PET dosing as an exponential (squared) function of body weight produced consistent stress perfusion image quality over a wide range of patient weights. Dramatically lower doses can be used in lighter patients, with the equivalent population dose shifted toward the heavier patients to standardize diagnostic image quality., (© 2023. The Author(s).)

Background: Flurpiridaz F-18 (flurpiridaz) is a novel positron emission tomography (PET) myocardial perfusion imaging tracer., Objectives: The purpose of this study was to further assess the diagnostic efficacy and safety of flurpiridaz for the detection and evaluation of coronary artery disease (CAD) defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA)., Methods: In this second phase 3 prospective multicenter clinical study, 730 patients with suspected CAD from 48 clinical sites in the United States, Canada, and Europe were enrolled. Patients underwent 1-day rest/stress flurpiridaz PET and 1- or 2-day rest-stress Tc-99m-labeled single photon emission computed tomography (SPECT) before ICA. PET and SPECT images were read by 3 experts blinded to clinical and ICA data., Results: A total of 578 patients (age 63.7 ± 9.5 years) were evaluable; 32.5% were women, 52.3% had body mass index ≥30 kg/m 2 , and 33.6% had diabetes. Flurpiridaz PET met the efficacy endpoints of the study; its sensitivity and specificity were significantly higher than the prespecified threshold value by 2 of the 3 readers. The sensitivity of flurpiridaz PET was higher than SPECT (80.3% vs 68.7%; P = 0.0003) and its specificity was noninferior to SPECT (63.8% vs 61.7%; P = 0.0004). PET area under the receiver-operating characteristic curves were higher than SPECT in the overall population (0.80 vs 0.68; P < 0.001), women, and obese patients (P < 0.001 for both). Flurpiridaz PET was superior to SPECT (P < 0.001) for perfusion defect size/severity evaluation, image quality, diagnostic certainty, and radiation exposure. Flurpiridaz PET was safe and well tolerated., Conclusions: This second flurpiridaz PET myocardial perfusion imaging trial shows that flurpiridaz has utility as a new tracer for CAD detection, specifically in women and obese patients. (An International Study to Evaluate Diagnostic Efficacy of Flurpiridaz [18F] Injection PET MPI in the Detection of Coronary Artery Disease [CAD]; NCT03354273)., Competing Interests: Funding Support and Author Disclosures This study was funded by GE Healthcare Ltd and its Affiliates, Chalfont St Giles, United Kingdom. Drs Bax, Dorbala, Garcia, Heller, Tamaki, and Udelson have served as a consultant to GE Healthcare Ltd and its Affiliates. Drs Maddahi, Agostini, Bateman, Beanlands, Berman, and Knuuti have served as a consultant to and received a research grant from GE Healthcare Ltd and its Affiliates. Dr Beanlands has served as a consultant for and received research grants from Lantheus Medical Imaging and Jubilant DraxImage. Drs Feldman, Martinez-Clark, Pelletier-Galarneau, and Shepple have received a research grant from GE Healthcare Ltd and its Affiliates. Dr Tranquart is an employee and Global Head of Development of GE Healthcare Ltd and its Affiliates., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Early cardiac allograft vasculopathy (CAV) prognostication is needed to improve long-term outcomes after heart transplantation. We characterized first year posttransplant coronary anatomic-physiologic alterations to determine predictors of early CAV progression., Methods: Heart transplant recipients at 2 institutions (enrolled January 2018 to March 2021) underwent prospective evaluation 3 and 12-month posttransplant with angiography and left anterior descending artery intravascular ultrasound, optical coherence tomography, fractional flow reserve, coronary flow reserve, and index of microcirculatory resistance measurements. CAV progression was assessed by intravascular ultrasound change in percentage intimal volume from baseline to 12-month follow-up., Results: Eighty-two patients (mean age, 51 years; 60% men) completed evaluation at mean 13.8 and 56.3 weeks posttransplant. Donor atherosclerosis (baseline intravascular ultrasound maximal intimal thickness, ≥0.5 mm) was evident in 50%. De novo (follow-up maximal intimal thickness, ≥0.5 mm) and rapidly progressive CAV (maximal intimal thickness, ≥0.5-mm increase from baseline) developed in 24% and 13%, respectively. On optical coherence tomography, baseline to follow-up median intimal volume increased 42% (0.58 mm 3 /mm), percentage intimal volume increased 44% (4.6%), vessel volume decreased 4% (-0.50 mm 3 /mm) and lumen volume decreased 9% (-1.02 mm 3 /mm); P <0.05 for all. Fibrotic plaque was the predominant morphology: baseline, 29% and follow-up, 50%. Coronary physiology was abnormal in 41% at baseline and 45% at follow-up, with 1 in 5 patients having microvascular dysfunction (index of microcirculatory resistance, ≥25). On multivariable linear regression analysis, recipient male sex, fibrotic plaque, and index of microcirculatory resistance were independent predictors of coronary disease progression., Conclusions: Fibrotic plaque on optical coherence tomography and index of microcirculatory resistance early posttransplant predict CAV progression in the first year of transplantation., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03217786., Competing Interests: Disclosures Dr Chih is supported by a Heart and Stroke Foundation of Ontario Clinician Scientist Phase I Award and a Tier 2 University of Ottawa Clinical Research Chair in Cardiac Transplantation. Dr Chong has received honorarium from Abbott and is an Abbot advisory board member for optical coherence tomography. Dr Beanlands is a University of Ottawa Distinguished Research Chair in Cardiovascular Imaging. Dr Beanlands is a consultant for and receives research grant funding from Jubilant-DraxImage, Lantheus Medical Imaging, and General Electric Health Care. The other authors report no conflicts.

Background: Patient motion reduces the accuracy of PET myocardial blood flow (MBF) measurements. This study evaluated the effect of automatic motion correction on test-retest repeatability and inter-observer variability in a clinically relevant population., Methods: Patients with known or suspected CAD underwent repeat rest 82 Rb PET scans within minutes as part of their scheduled rest-stress perfusion study. Two trained observers evaluated the presence of heart motion in each scan. Global LV and per-vessel MBF were computed from the dynamic rest images before and after automatic motion correction. Test-retest and inter-observer variability were assessed using intra-class correlation and Bland-Altman analysis., Results: 140 pairs of test-retest scans were included, with visual motion noted in 18%. Motion correction decreased the global MBF values by 3.5% (0.80 ± 0.24 vs 0.82 ± 0.25 mL⋅min -1 ⋅g -1 ; P < 0.001) suggesting that the blood input function was underestimated in cases with patient motion. Test-retest repeatability of global MBF improved by 9.7% (0.25 vs 0.28 mL⋅min -1 ⋅g -1 ; P < 0.001) and inter-observer repeatability was improved by 7.1% (0.073 vs 0.079 mL⋅min -1 ⋅g -1 ; P = 0.012). There was a marked impact on both test-retest repeatability as well as inter-observer repeatability in the LCX territory, with improvements of 16.5% (0.30 vs 0.36 mL⋅min -1 ⋅g -1 ; P < 0.0000) and 18.4% (0.13 vs 0.16 mL⋅min -1 ⋅g -1 ; P < 0.001), respectively., Conclusion: Automatic motion correction improved test-retest repeatability and reduced differences between observers., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Vasospastic angina (VSA), or variant angina, is an under-recognized cause of chest pain and myocardial infarction, especially in Western countries. VSA leads to a declined quality of life and is associated with increased morbidity and mortality. Currently, the diagnosis of VSA relies on invasive testing that requires the direct intracoronary administration of ergonovine or acetylcholine. However, invasive vasoreactivity testing is underutilized. Several non-invasive imaging alternatives have been proposed to screen for VSA. This review aims to discuss the strengths and limitations of available non-invasive imaging tests for vasospastic angina., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Background: Alterations in atrial metabolism may play a role in the perpetuation of atrial fibrillation (AF). This study sought to compare 18 F-fluorodeoxyglucose (FDG) uptake on PET, in patients with LV dysfunction versus those without AF., Methods: Seventy-two patients who underwent myocardial viability assessment were evaluated. AF patients (36) had persistent or permanent AF based on history and ECG. Patients without AF (36) were matched to AF patients based on sex, diabetes, age, and LVEF. Maximum and mean FDG Standard Uptake Values (SUV) in the left atrial (LA) wall and right atrial (RA) wall were measured. Tissue-to-blood ratios (TBR) were calculated as atrial wall to blood-pool activity. Atrial volumes were measured by echocardiography., Results: Maximum and mean FDG SUV and TBRs were significantly increased in the RA (but not the LA) of patients with AF compared to those without (P < 0.01). When accounting for changes in atrial volume, the presence of AF remained a significant predictor of higher RA MAX , but not RA MEAN FDG uptake., Conclusion: In patients with LV dysfunction from ischemic cardiomyopathy, LA and RA glucose metabolism are differentially altered in those with persistent atrial fibrillation. Further investigations should elucidate the temporal relationship between AF and glucose metabolic changes, as a potential target for therapy., (© 2022. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Aims: This study aimed to evaluate markers of systemic as well as imaging markers of inflammation in the ascending aorta, bone marrow, and spleen measured by 18F-FDG PET/CT, in HIV+ patients at baseline and following therapy with rosuvastatin., Methods and Results: Of the 35 HIV+ patients enrolled, 17 were randomized to treatment with 10 mg/day rosuvastatin and 18 to usual care for 6 months. An HIV- control cohort was selected for baseline comparison of serum inflammatory markers and monocyte markers of inflammation. 18F-FDG-PET/CT imaging of bone marrow, spleen, and thoracic aorta was performed in the HIV+ cohort at baseline and 6 months. While CD14++CD16- and CCR2 expressions were reduced, serum levels of IL-7, IL-8, and MCP-1 were elevated in the HIV+ population compared to the controls. There was a significant drop in FDG uptake in the bone marrow (TBR max ), spleen (SUV max ) and thoracic aortic (TBR max ) in the statin-treated group compared to the control group (bone marrow: - 10.3 ± 16.9% versus 5.0 ± 18.9%, p = .0262; spleen: - 9.8 ± 20.3% versus 11.3 ± 28.8%, p = .0497; thoracic aorta: - 19.1 ± 24.2% versus 4.3 ± 15.4%, p = .003)., Conclusions: HIV+ patients had significantly markers of systemic inflammation including monocyte activation. Treatment with low-dose rosuvastatin in the HIV+ cohort significantly reduced bone marrow, spleen and thoracic aortic FDG uptake., (© 2021. American Society of Nuclear Cardiology.)

Competing Interests: The other author declares no conflicts of interest.

Background: In ischemic cardiomyopathy patients, cardiac sympathetic nervous system dysfunction is a predictor of sudden cardiac arrest (SCA). This study compared abnormal innervation and perfusion measured by [ 11 C]meta-hydroxyephedrine (HED) vs [ 13 N]ammonia (NH 3 ), conventional uptake vs parametric tracer analysis, and their SCA risk discrimination., Methods: This is a sub-study analysis of the prospective PAREPET trial, which followed ischemic cardiomyopathy patients with reduced left ventricular ejection fraction (LVEF ≤ 35%) for events of SCA. Using n = 174 paired dynamic HED and NH 3 positron emission tomography (PET) scans, regional defect scores (%LV extent × severity) were calculated using HED and NH 3 uptake, as well as HED distribution volume and NH 3 myocardial blood flow by kinetic modeling., Results: During 4.1 years follow-up, there were 27 SCA events. HED defects were larger than NH 3 , especially in the lowest tertile of perfusion abnormality (P < .001). Parametric defects were larger than their respective tracer uptake defects (P < .001). SCA risk discrimination was not significantly improved with parametric or uptake mismatch (AUC = 0.73 or 0.70) compared to HED uptake defect scores (AUC = 0.67)., Conclusion: Quantification of HED distribution volume and NH 3 myocardial blood flow produced larger defects than their respective measures of tracer uptake, but did not lead to improved SCA risk stratification vs HED uptake alone., (© 2021. American Society of Nuclear Cardiology.)

Dysfunction of the cardiac sympathetic nervous system contributes to the development of cardiovascular diseases including ischemia, heart failure, and arrhythmias. Molecular imaging probes such as meta -[ 123 I]iodobenzylguanidine have demonstrated the utility of assessing neuronal integrity by targeting norepinephrine transporter (NET, uptake-1). However, current radiotracers can report only on innervation due to suboptimal kinetics and lack sensitivity to NET in rodents, precluding mechanistic studies in these species. The objective of this work was to characterize myocardial sympathetic neuronal uptake mechanisms and kinetics of the positron emission tomography (PET) radiotracer meta -[ 18 F]fluorobenzylguanidine ([ 18 F]mFBG) in rats. Automated synthesis using spirocyclic iodonium(III) ylide radiofluorination produces [ 18 F]mFBG in 24 ± 1% isolated radiochemical yield and 30-95 GBq/μmol molar activity. PET imaging in healthy rats delineated the left ventricle, with monoexponential washout kinetics ( k mono = 0.027 ± 0.0026 min -1 , A mono = 3.08 ± 0.33 SUV). Ex vivo biodistribution studies revealed tracer retention in the myocardium, while pharmacological treatment with selective NET inhibitor desipramine, nonselective neuronal and extraneuronal uptake-2 inhibitor phenoxybenzamine, and neuronal ablation with neurotoxin 6-hydroxydopamine reduced myocardial retention by 33, 76, and 36%, respectively. Clearance of [ 18 F]mFBG from the myocardium was unaffected by treatment with uptake-1 and uptake-2 inhibitors following peak myocardial activity. These results suggest that myocardial distribution of [ 18 F]mFBG in rats is dependent on both NET and extraneuronal transporters and that limited reuptake to the myocardium occurs. [ 18 F]mFBG may therefore prove useful for imaging intraneuronal dysfunction in small animals.

Background: We previously demonstrated high diagnostic accuracy of Rubidium-82 positron emission tomography (PET) myocardial blood flow (MBF) quantification for CAV. The purpose of this study was to validate multiparametric PET detection of CAV by combined rate-pressure-product-corrected myocardial flow reserve (cMFR), stress MBF, and coronary vascular resistance (CVR) assessment., Methods and Results: Diagnostic CAV cut-offs of cMFR < 2.9, stress MBF < 2.3, CVR > 55 determined in a previous study (derivation) were assessed in heart transplant recipients referred for coronary angiography and intravascular ultrasound (IVUS) (validation). CAV was defined as International Society of Heart and Lung Transplantation CAV 1-3 on angiography; and maximal intimal thickness ≥ 0.5 mm on IVUS. Eighty patients (derivation n = 40, validation n = 40) were included: 80% male, mean age 54±14 years, 4.5±5.6 years post transplant. The prevalence of CAV was 44% on angiography and 78% on IVUS. Combined PET cMFR < 2.9, stress MBF < 2.3, CVR > 55 CAV assessment yielded high 88% (specificity 75%) and 83% (specificity 40%) sensitivity for ≥ 1 abnormal parameter and high 88% (sensitivity 59%) and 90% (sensitivity 43%) specificity for 3 abnormal parameters, in the derivation and validation cohorts, respectively., Conclusion: We validate the diagnostic accuracy of multiparametric PET flow quantification by cMFR, stress MBF, and CVR for CAV., (© 2020. American Society of Nuclear Cardiology.)

Background: Survivors of community-acquired pneumonia (CAP) are at increased risk of cardiovascular disease, cognitive and functional decline, and death, but the mechanisms remain unknown., Research Question: Do CAP survivors have evidence of increased inflammatory activity in their lung parenchyma on 2-deoxy-2-[ 18 F]fluoro-d-glucose ( 18 FDG)-PET/CT imaging after clinical resolution of infection?, Study Design and Methods: We obtained 18 FDG-PET/CT scans from 22 CAP survivors during their hospitalization with pneumonia (acute CAP) and 30 to 45 days after hospital discharge (post-CAP). In each set of scans, we assessed the lungs for foci of increased 18 FDG uptake by visual interpretation and by total pulmonary glycolytic activity (tPGA), a background-corrected measure of total metabolic activity (as measured by 18 FDG uptake). We also measured, post-CAP, the glycolytic activity of CAP survivor lung areas with volumes similar to the areas in 28 matched historical control subjects without pneumonia., Results: Overall, 68% of CAP survivors (95% CI, 45%-85%) had distinct residual areas of increased 18 FDG uptake in their post-CAP studies. tPGA decreased from 821.5 (SD, 1,140.2) in the acute CAP period to 80.0 (SD, 81.4) in the post-CAP period (P = .006). The tPGA post-CAP was significantly higher than that in lung areas of similar volume in control subjects (80.0 [SD, 81.4] vs -19.4 [SD, 5.9]; P < .001)., Interpretation: An important proportion of CAP survivors have persistent pulmonary foci of increased inflammatory activity beyond resolution of their infection. As inflammation contributes to cardiovascular disease, cognitive decline, functional waning, and mortality risk in the general population, this finding provides a plausible mechanism for the increased morbidity and mortality that have been observed post-CAP., (Copyright © 2021 American College of Chest Physicians. All rights reserved.)

Heart transplantation is an effective and life-saving therapy for patients with end-stage heart disease. Cardiac allograft vasculopathy (CAV) is a frequent complication after heart transplantation and a leading cause of graft failure and death. The diffuse involvement of the coronary macro- and microvasculature in CAV poses significant challenges for noninvasive imaging surveillance techniques that depend on regional differences in myocardial perfusion or contractility to detect abnormalities. Recent imaging and transplantation guidelines recommend cardiac PET for CAV evaluation. Current evidence demonstrates high diagnostic accuracy of PET myocardial blood flow and myocardial flow reserve quantification for CAV as well as utility for post-transplant patient risk stratification. Multicenter prospective studies are needed to determine optimal PET measures and to define thresholds for diagnostic and prognostic assessment of CAV., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Current risk assessment approaches fail to identify the majority of patients at risk of sudden cardiac arrest (SCA). Noninvasive imaging of the cardiac sympathetic nervous system using single-photon emission computed tomography and positron emission tomography offers the potential for refining SCA risk assessment. While various [ 11 C]meta-hydroxyephedrine quantification parameters have been proposed, it is currently unknown whether regional denervation or global innervation yields greater SCA risk discrimination. The aim of the study was to determine whether the global innervation parameters yield any independent and additive prognostic value over the regional denervation alone., Methods: In a post hoc competing-risks analysis of the PAREPET trial (Prediction of Arrhythmic Events With Positron Emission Tomography), we compared global innervation and regional denervation parameters using the norepinephrine analog [ 11 C]meta-hydroxyephedrine for SCA risk discrimination. Patients with ischemic cardiomyopathy (n=174) eligible for an implantable cardioverter-defibrillator for the primary prevention of SCA were recruited into the trial. [ 11 C]meta-hydroxyephedrine uptake and clearance rates were measured to assess global (left ventricle mean) retention index and volume of distribution. Regional defects were quantified as the percentage of the left ventricle having values <75% of the maximum., Results: During a median follow-up of 4.2 years, there were 56 cardiac-related deaths, of which 26 were SCAs. For any given regional denervation volume, there was substantial heterogeneity in global innervation scores. Global retention index and distribution volume did not decrease until regional defects exceeded 40% left ventricle. Global scale parameters, retention index, and distribution volume (area under the curve=0.61, P =0.034, P =0.046, respectively), yielded inferior SCA risk discrimination compared to regional heterogeneity (area under the curve=0.74)., Conclusions: Regional denervation volume has superior cause-specific mortality prediction for SCA versus global parameters of sympathetic innervation. These results have widespread implications for future cardiac sympathetic imaging, which will greatly simplify innervation analysis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01400334.

Background: Myocardial flow reserve (MFR) measurement provides incremental diagnostic and prognostic information. The objective of the current study was to investigate the application of a simplified model for the estimation of MFR using only the stress/rest myocardial activity ratio (MAR) in patients undergoing rest-stress cardiac PET MPI., Methods and Results: Rest and dipyridamole stress dynamic PET imaging was performed in consecutive patients using 82 Rb or 13 NH 3 (n = 250 each). Reference standard MFR was quantified using a standard one-tissue compartment model. Stress/rest myocardial activity ratio (MAR) was calculated using the LV-mean activity from 2 to 6 minutes post-injection. Simplified estimates of MFR (MFR EST ) were then calculated using an inverse power function. For 13 NH 3 , there was good correlation between MFR and MFR EST values (R = 0.63), with similar results for 82 Rb (R = 0.73). There was no bias in the MFR EST values with either tracer. The overall diagnostic performance of MFR EST for detection of MFR < 2 was good with ROC area under the curve (AUC) = 83.2 ± 1.2% for 13 NH 3 and AUC = 90.4 ± 0.7% for 82 Rb., Conclusion: MFR was estimated with good accuracy using 82 Rb and 13 NH 3 with a simplified method that relies only on stress/rest activity ratios. This novel approach does not require dynamic imaging or tracer kinetic modeling. It may be useful for routine quality assurance of PET MFR measurements, or in scanners where full dynamic imaging and tracer kinetic modeling is not feasible for technical or logistical reasons.

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.

Cardiac sarcoidosis (CS) is an increasingly recognized condition, but cardiac magnetic resonance (CMR) image interpretation in these patients may be challenging as findings are often non-specific. The main objective of this study was to investigate the inter-reader agreement for the overall interpretation of CMR for the diagnosis of CS in an experienced reference center and investigate factors that may lead to discrepancies between readers. Consecutive patients undergoing CMR imaging to investigate for CS were included. CMR images were independently reviewed by two readers, blinded to all clinical, imaging and demographic information. The readers classified each scan as "consistent with cardiac sarcoidosis", "not consistent with cardiac sarcoidosis" or "indeterminate". Inter-reader agreement was assessed using κ-statistics. When there was disagreement on the overall interpretation, a third reader reviewed the images. Also, two readers independently commented on the presence of edema, presence of LGE (both ventricles) and quantified the extent of left ventricular LGE. 87 patients (43 women, mean age 54.3 ± 12.2 years) were included in the study. There was agreement regarding the overall interpretation in 72 of 87 (83%) CMR scans. The κ value was 0.64, indicating moderate agreement. There was similar moderate agreement in the interpretation of LGE parameters. In an experienced referral center, we found moderate agreement between readers in the interpretation of CMR in patients with suspected CS. Physicians should be aware of this inter-observer variability in interpretation of CMR studies in patients with suspected CS.

Introduction: Strontium-82/Rubidium-82 ( 82 Sr/ 82 Rb) generators are used widely for positron emission tomography (PET) imaging of myocardial perfusion. In this study, the 82 Rb isotope yield and production efficiency of two FDA-approved 82 Sr/ 82 Rb generators were compared., Methods: N = 515 sequential daily quality assurance (QA) reports from 9 CardioGen-82 ® and 9 RUBY-FILL ® generators were reviewed over a period of 2 years. A series of test elutions was performed at different flow-rates on the RUBY-FILL ® system to determine an empirical correction-factor used to convert CardioGen-82 ® daily QA values of 82 Rb activity (dose-calibrator 'maximum' of 50 mL elution at 50 mL·min -1 ) to RUBY-FILL ® equivalent values (integrated 'total' of 35 mL elution at 20 mL·min -1 ). The generator yield ( 82 Rb) and production efficiency ( 82 Rb yield/ 82 Sr parent activity) were measured and compared after this conversion to a common scale., Results: At the start of clinical use, the system reported 82 Rb activity from daily QA was lower for CardioGen-82 ® vs RUBY-FILL ® (2.3 ± 0.2 vs 3.0 ± 0.2 GBq, P < 0.001) despite having similar 82 Sr activity. Dose-calibrator 'maximum' (CardioGen-82 ® ) values were found to under-estimate the integrated 'total' (RUBY-FILL ® ) activity by ~ 24% at 50 mL·min -1 . When these data were used to convert the CardioGen-82 values to a common measurement scale (integrated total activity) the CardioGen-82 ® efficiency remained slightly lower than the RUBY-FILL ® system on average (88 ± 4% vs 95 ± 4%, P < 0.001). The efficiency of 82 Rb production improved for both systems over the respective periods of clinical use., Conclusions: 82 Rb generator yield was significantly under-estimated using the CardioGen-82 ® vs RUBY-FILL ® daily QA procedure. When generator yield was expressed as the integrated total activity for both systems, the estimated 82 Rb production efficiency of the CardioGen-82 ® system was ~ 7% lower than RUBY-FILL ® over the full period of clinical use.

Background: Fluorine-18 flurpiridaz is a novel positron emission tomography (PET) myocardial perfusion imaging tracer., Objectives: This study sought to assess the diagnostic efficacy of flurpiridaz PET versus technetium-99m-labeled single photon emission computed tomography SPECT for the detection and evaluation of coronary artery disease (CAD), defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA). Flurpiridaz safety was also evaluated., Methods: In this phase III prospective multicenter clinical study, 795 patients with known or suspected CAD from 72 clinical sites in the United States, Canada, and Finland were enrolled. A total of 755 patients were evaluable, and the mean age was 62.3 ± 9.5 years, 31% were women, 55% had body mass index ≥30 kg/m 2 , and 71% had pharmacological stress. Patients underwent 1-day rest-stress (pharmacological or exercise) flurpiridaz PET and 1- or 2-day rest-stress Tc-99m-labeled SPECT and ICA. Images were read by 3 experts blinded to clinical and ICA data., Results: Sensitivity of flurpiridaz PET (for detection of ≥50% stenosis by ICA) was 71.9% (95% confidence interval [CI]: 67.0% to 76.3%), significantly (p < 0.001) higher than SPECT (53.7% [95% CI: 48.5% to 58.8%]), while specificity did not meet the prespecified noninferiority criterion (76.2% [95% CI: 71.8% to 80.1%] vs. 86.6% [95% CI: 83.2% to 89.8%]; p = NS). Receiver-operating characteristic curve analysis demonstrated superior discrimination of CAD by flurpiridaz PET versus SPECT in the overall population, in women, obese patients, and patients undergoing pharmacological stress testing (p < 0.001 for all). Flurpiridaz PET was superior to SPECT for defect size (p < 0.001), image quality (p < 0.001), diagnostic certainty (p < 0.001), and radiation exposure (6.1 ± 0.4 mSv vs. 13.4 ± 3.2 mSv; p < 0.001). Flurpiridaz PET was safe and well tolerated., Conclusions: Flurpiridaz PET myocardial perfusion imaging shows promise as a new tracer for CAD detection and assessment of women, obese patients, and patients undergoing pharmacological stress testing. A second phase III Food and Drug Administration trial is ongoing. (A Phase 3 Multi-center Study to Assess PET Imaging of Flurpiridaz F 18 Injection in Patients with CAD; NCT01347710)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [ 11 C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF)., Methods: Dynamic HED PET-CT scans were performed 47 ± 22 days apart in 20 patients with stable heart failure and reduced ejection fraction. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (V T ), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC)., Results: Intra- and inter-observer correlations of both V T and RI were excellent (ICC = 0.93-0.99). Observer reproducibility (NPC = 3-13%) was lower than test-retest repeatability (NPC = 12-61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to V T (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or V T . Regional partial-volume correction degraded repeatability of both the global and regional V T measures by 2-12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30-61%) compared with the RI., Conclusions: Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex V T . Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

Aims: Diabetes mellitus (DM) affects the macro- and microvasculature, leading to impairment in coronary vascular reactivity. Microvascular dysfunction is more prevalent in females compared to males, leading to increased cardiovascular risk in women. The purpose of this study was to quantify the association between diabetes and female sex on myocardial flow reserve (MFR) across the spectrum of epicardial coronary artery disease (CAD)., Methods and Results: In 222 patients with known or suspected CAD (63.7 ± 10.7 years, 66 females, 85 with diabetes) who had rubidium-82 positron emission tomography (PET) and invasive coronary angiography within 6 months, a multiple linear regression model was developed to predict MFR based on clinical risk factors and imaging results across a spectrum of regional epicardial disease. A significant interaction effect suggested that impairment of MFR is accelerated in diabetics with increasing severity of epicardial disease. Furthermore, female sex (-13%), decade of age (-6%), ischaemia on electrocardiogram (-10%), resting rate-pressure product (-3%), and rest end-diastolic volume (-0.2%) were associated with reductions in MFR independent of the combined extent and severity of epicardial disease., Conclusion: In the presence of significant obstructive epicardial disease, MFR decreases more rapidly in patients with DM compared to those without. Additional patient demographics and risk factors such as female sex and older age, and stress PET functional parameters should also be considered in the clinical interpretation of MFR. This has implications for the diagnosis and management of CAD patients with these and other risk factors for microvascular disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

At time of initial publication, the USAN Council had assigned the generic name for LMI1195 as Flurobenguan. However, the Council has since changed and finalized this compound name as Flubrobenguane which is recommended as the generic name to be used in the future.

Approximately 5% of patients with sarcoidosis have clinically manifest cardiac involvement. Clinical features of Cardiac Sarcoidosis are dependent on the location, extent, and activity of the disease. First line therapy is usually with prednisone and this is recommended based on clinician experience, expert opinion and small observational cohorts. There are no published clinical trials in cardiac sarcoidosis and multiple experts in the field have called for randomized clinical trials to answer important patient care questions. Corticosteroid are associated with multiple adverse effects including hypertension, diabetes, weight gain, osteoporosis, and increased risk of infections. In contrast Methotrexate is generally well tolerated and is increasingly used in other forms of sarcoidosis., Objectives: The Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial (CHASM CS-RCT; NCT03593759) is a multicenter randomized controlled trial designed to evaluate the optimal initial treatment strategy for patients with active cardiac sarcoidosis. We hypothesize that (1) a low dose prednisone/methotrexate combination will have non-inferior efficacy to standard dose prednisone and that (2) the low dose prednisone/ methotrexate combination will result in significantly better quality of life than standard dose prednisone, as a result of reduced burden of side effects., Methods/design: Eligible study subjects will have active clinically manifest cardiac sarcoidosis presenting with one or more of the following clinical findings: advanced conduction system disease, significant sinus node dysfunction, non-sustained or sustained ventricular arrhythmia, left ventricular dysfunction or right ventricular dysfunction. Subjects will be randomized in a 1:1 ratio to prednisone 0.5 mg/kg/day for 6 months (maximum dose 30 mg daily) OR to prednisone 20 mg daily for 1 month, then 10 mg daily for 1 month, then 5 mg daily for one month then stop AND methotrexate 15-20 mg once weekly for 6 months. The primary endpoint is summed perfusion rest score on 6-month PET (blinded core-lab review). The summed perfusion rest score is measure of myocardial fibrosis/scar. The design is non-inferiority with a sample size of 97 per group., Discussion: Given the multiorgan system potential adverse side effects of prednisone, proving noninferiority of an alternate regimen would be sufficient to make the alternative compare favorably to standard dose steroids. This is the first ever clinical trial in cardiac sarcoidosis and thus in addition to the listed goals of the trial, we will also establish a multi-center, multinational cardiac sarcoidosis clinical trials network. Such a collaborative infrastructure will enable a new era of high quality data to guide physicians when treating cardiac sarcoidosis patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Rubidium-82 ( 82 Rb) PET is used widely for myocardial perfusion imaging. The purpose of this study was to investigate if an additional saline-push following the 82 Rb elution improves PET image quality., Methods: 82 Rb PET scans were acquired with and without 26 mL saline-push in six patients as part of a clinical quality improvement program. Dynamic images were analyzed to measure the total activity delivered to the superior vena cava (SVC) and retained in the left ventricle (LV) myocardium. Tracer uptake images were used to measure blood background coefficient-of-variation (COV), myocardium-to-blood signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) to assess image quality., Results: Similar eluted activity was measured with/without the saline-push (830 vs 795 MBq; P = 0.24). The activity delivered to the heart and retained in the myocardium was consistently increased more than twofold (SVC: + 114% and LV: + 104%; P < 0.001) with the saline-push. Image quality was improved in all patients, with lower background noise (COV: - 19%), higher SNR (+ 24%) and CNR (+ 27%) (all P ≤ 0.01)., Conclusions: The saline-push used to flush 82 Rb activity out of the infuser tubing, patient injection and intravenous access lines consistently increased the activity delivered to the heart by twofold. This technique is recommended to maximize image quality with 82 Rb PET.

Background: Cardiac magnetic resonance perfusion studies with adenosine stress have shown that splenic response can identify patients with inadequate pharmacologic stress. We investigate the incremental prognostic impact of splenic response ratio (SRR) in patients with normal Rubidium (Rb)-82 PET myocardial perfusion imaging (MPI)., Methods: Consecutive patients undergoing dipyridamole Rb-82 PET MPI for the evaluation of coronary artery disease were screened. Spleen and liver Rb-82 activity was measured and the SRR was calculated: SRR = (Spleen stress/Liver stress)/(Spleen rest/Liver rest). Major adverse cardiac events (MACE) were determined at 1 year of follow-up in patients with normal summed stress score and normal summed difference score., Results: Of the 839 patients screened, the spleen was visualized in 703 (84%) of scans. There was significantly higher MACE observed in splenic non-responders vs splenic responders in both the normal SSS (7.8% vs 2.9%, P = .027) and the normal SDS groups (7.4% vs 2.2%, P = .014). In multivariate analysis in patients with normal SDS, splenic response was a significant, independent predictor of MACE (HR 2.97, 95% CI 1.10 to 8.04, P = .033)., Conclusions: SRR is a novel imaging metric to identify patients with sub-maximal vasodilator stress and an incremental prognostic marker in patients with normal SDS and SSS (Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01128023).

Aims: Electrical cardioversion is commonly performed to restore sinus rhythm in patients with atrial fibrillation (AF), but it is unsuccessful in 10-12% of attempts. We sought to evaluate the effectiveness and safety of a novel cardioversion protocol for this arrhythmia., Methods and Results: Consecutive elective cardioversion attempts for AF between October 2012 and July 2017 at a tertiary cardiovascular centre before (Phase I) and after (Phase II) implementing the Ottawa AF cardioversion protocol (OAFCP) as an institutional initiative in July 2015 were evaluated. The primary outcome was cardioversion success, defined as ≥2 consecutive sinus beats or atrial-paced beats in patients with implanted cardiac devices. Secondary outcomes were first shock success, sustained success (sinus or atrial-paced rhythm on 12-lead electrocardiogram prior to discharge from hospital), and procedural complications. Cardioversion was successful in 459/500 (91.8%) in Phase I compared with 386/389 (99.2%) in Phase II (P < 0.001). This improvement persisted after adjusting for age, body mass index, amiodarone use, and transthoracic impedance using modified Poisson regression [adjusted relative risk 1.08, 95% confidence interval (CI) 1.05-1.11; P < 0.001] and when analysed as an interrupted time series (change in level +9.5%, 95% CI 6.8-12.1%; P < 0.001). The OAFCP was also associated with greater first shock success (88.4% vs. 79.2%; P < 0.001) and sustained success (91.6% vs 84.7%; P=0.002). No serious complications occurred., Conclusion: Implementing the OAFCP was associated with a 7.4% absolute increase in cardioversion success and increases in first shock and sustained success without serious procedural complications. Its use could safely improve cardioversion success in patients with AF., Clinical Trial Number: www.clinicaltrials.gov ID: NCT02192957., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)