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Background: Cardiac systolic dysfunction is a poor prognostic marker in light-chain (AL) cardiomyopathy, a primary interstitial disorder; however, its pathogenesis is poorly understood., Purpose: This study aims to analyze the effects of extracellular volume (ECV) expansion, a surrogate marker of amyloid burden on myocardial blood flow (MBF), myocardial work efficiency (MWE), and left ventricular (LV) systolic dysfunction in AL amyloidosis., Methods: Subjects with biopsy-proven AL amyloidosis were prospectively enrolled (April 2016-June 2021; Clinicaltrials.gov ID NCT02641145) and underwent cardiac magnetic resonance imaging (MRI) to quantify rest MBF by perfusion imaging, LV ejection fraction (LVEF) by cine MRI, and ECV by pre- and post-contrast T1 mapping. The MWE was estimated as external cardiac work from the stroke volume and mean arterial pressure normalized to the LV myocardial mass., Results: Rest MBF in 92 subjects (62 ± 8 years, 52 men) with AL amyloidosis averaged 0.87 ± 0.21 ml/min/g and correlated with MWE ( r  = 0.42; p  < 0.001). Rest MBF was similarly low in subjects with sustained hematologic remission after successful AL amyloidosis therapy ( n  = 21), as in those with recently diagnosed AL amyloidosis. Both MBF and MWE decreased by ECV tertile ( p  < 0.01 for linear trends). The association of ECV with MWE comprised a direct effect (84% of the total effect; p  < 0.001) on MWE from adverse interstitial remodeling assessed by ECV and an indirect effect (16% of the total effect; p  < 0.001) mediated by MBF. There was a significant base-to-apex gradient of rest MBF in subjects with higher amyloid burden., Conclusions: In AL amyloidosis, both MBF and MWE decrease as cardiac amyloid burden and ECV expansion increase. Both structural and vascular changes from ECV expansion and myocardial amyloid burden appear to contribute to lower MWE., Competing Interests: SC: investigator—initiated a research grant from Pfizer. FR: consulting fees—Pfizer, AstraZeneca, Attralus; research support—Pfizer, Alnylam Pharmaceuticals, Akcea Therapeutics. MDC: research grant—Spectrum Dynamics and Gilead; consulting fees—Sanofi and GE HealthCare. RF: consulting fees—Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences; research funding—GlaxoSmithKline and Akcea. SD: consulting fees—Pfizer, GE HealthCare, and AstraZeneca; investigator—initiated a grant from Pfizer, Attralus, Phillips, and Siemens. OC: research fellowship from the International Society of Amyloidosis and Pfizer. AY: consulting fees—AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK Janssen, Karyopharm, Oncopeptides, Regeneron, Sanofi, and Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Katznelson, Jerosch-Herold, Cuddy, Clerc, Benz, Taylor, Rao, Kijewski, Liao, Landau, Yee, Ruberg, Di Carli, Falk, Kwong and Dorbala.)

Aims: In systemic light-chain (AL) amyloidosis, quantification of right ventricular (RV) amyloid burden has been limited and the pathogenesis of RV dysfunction is poorly understood. Using 18F-florbetapir positron emission tomography/computed tomography (PET/CT), we aimed to quantify RV amyloid; correlate RV amyloid with RV structure and function; determine the independent contributions of RV, left ventricular (LV), and lung amyloid to RV function; and associate RV amyloid with major adverse cardiac events (MACE: death, heart failure hospitalization, cardiac transplantation)., Methods and Results: We prospectively enrolled 106 participants with AL amyloidosis (median age 62 years, 55% males) who underwent 18F-florbetapir PET/CT, magnetic resonance imaging, and echocardiography. 18F-florbetapir PET/CT identified RV amyloid in 63% of those with and 40% of those without cardiac involvement by conventional criteria. RV amyloid burden correlated with RV ejection fraction (EF), RV free wall longitudinal strain (FWLS), RV wall thickness, RV mass index, N-terminal pro-brain natriuretic peptide, troponin T, LV amyloid, and lung amyloid (each P < 0.001). In multivariable analysis, RV amyloid burden, but not LV or lung amyloid burden, predicted RV dysfunction (EF P = 0.014; FWLS P < 0.001). During a median follow-up of 28 months, RV amyloid burden predicted MACE (P < 0.001)., Conclusion: This study shows for the first time that 18F-florbetapir PET/CT identifies early RV amyloid in systemic AL amyloidosis prior to alterations in RV structure and function. Increasing RV amyloid on 18F-florbetapir PET/CT is associated with worse RV structure and function, predicts RV dysfunction, and predicts MACE. These results imply a central role for RV amyloid in the pathogenesis of RV dysfunction., Competing Interests: Conflict of interest: O.F.C.: Research fellowship from the International Society of Amyloidosis and Pfizer. S.A.M.C.: Investigator-initiated research grant from Pfizer. A.J.Y.: Consulting fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Regeneron, Sanofi, and Takeda. V.S.: Research support from Takeda, Celgene, Janssen, and Prothena and scientific advisory board for Caelum Biosciences. F.L.R.: Consulting fees from AstraZeneca and research support from Pfizer, Alnylam, and Ionis/Akcea. H.L.: Consulting fees from Celgene, Takeda, Janssen, Prothena, Pfizer, and Juno and research support from Amgen, Spectrum, and Takeda. R.Y.K.: Grant funding from Alnylam Pharmaceuticals. M.F.D.C.: Research grant from Spectrum Dynamics and Gilead and consulting fees from Sanofi and General Electric. R.H.F.: Consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences and research funding from GlaxoSmithKline and Akcea. S.D.: Consulting fees from Pfizer and GE HealthCare and investigator-initiated grant from Pfizer, Attralus, GE HealthCare, Phillips, and Siemens. The other authors do not have any conflicts of interest related to this study to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cardiac amyloid quantification could advance early diagnosis of amyloid cardiomyopathy (CMP) and treatment monitoring. However, current imaging tools are based on indirect measurements. 124 I-evuzamitide is a novel pan-amyloid radiotracer binding to amyloid deposits from multiple amyloidogenic proteins. Its ability to quantify cardiac amyloid has not yet been investigated., Objectives: The objectives of this pilot study were to quantify myocardial 124 I-evuzamitide uptake and to compare its diagnostic value to 18 F-florbetapir in participants with amyloid CMP and control subjects., Methods: This study included 46 participants: 12 with light-chain (AL) CMP, 12 with wild-type transthyretin (ATTRwt) CMP, 2 with hereditary amyloidosis, and 20 control subjects. All amyloidosis participants underwent positron emission tomography/computed tomography with 124 I-evuzamitide and 18 F-florbetapir. Control subjects underwent 124 I-evuzamitide (n = 10) or 18 F-florbetapir (n = 8) positron emission tomography/computed tomography. Left ventricular percent injected dose (LV% ID) was measured as mean activity concentration × myocardial volume/injected activity. High LV %ID was defined using Youden's index., Results: In CMP participants, median age was 74 years and 92% were men. 124 I-evuzamitide LV %ID differed across groups: median AL-CMP 1.48 (IQR: 1.12-1.89), ATTRwt-CMP 2.12 (IQR: 1.66-2.47), and control subjects 0.00 (IQR: 0.00-0.01; overall P < 0.001). High LV %ID perfectly discriminated CMP from control subjects. Discrimination performance was similar for 18 F-florbetapir LV %ID. Notably, for ATTRwt-CMP, LV %ID was higher with 124 I-evuzamitide than 18 F-florbetapir (P = 0.002). 124 I-evuzamitide LV %ID was correlated with interventricular septum thickness (Spearman's ρ = 0.78) and LV global longitudinal strain (ρ = 0.54) from echocardiography, and with LV mass index (ρ = 0.82) and extracellular volume (ρ = 0.51) from cardiac magnetic resonance., Conclusions: 124 I-evuzamitide demonstrates uptake by cardiac amyloid and accurately discriminates amyloid CMP from control subjects. In AL-CMP, discrimination performance is similar to 18 F-florbetapir. In ATTRwt-CMP, performance may be better with 124 I-evuzamitide. Moderate-to-strong correlations of 124 I-evuzamitide uptake with cardiac structural and functional metrics suggest valid amyloid quantification. Hence, 124 I-evuzamitide is a promising novel radiotracer to detect and quantify cardiac amyloid., Competing Interests: Funding Support and Author Disclosures This work was supported by Attralus. Dr Clerc has received a research fellowship from the International Society of Amyloidosis and Pfizer. Dr Cuddy has received an investigator-initiated research grant from Pfizer; and has received consulting fees from Ionis Pharmaceuticals, AstraZeneca, BridgeBio, Novo Nordisk, and Pfizer. Dr Di Carli has received research grants from Spectrum Dynamics and Gilead; and has received consulting fees from Sanofi and General Electric. Dr Falk has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences; and has received research funding from GlaxoSmithKline and Akcea. Dr Dorbala is supported by National Institutes of Health K24HL157648; has received consulting fees from Pfizer, GE Healthcare, Novo Nordisk, and AstraZeneca; and has received investigator-initiated grants from Pfizer, Attralus, GE Healthcare, Philips, and Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Myocardial infiltration by amyloid fibrils causes a severe and progressive form of heart failure. Until recently, this was not treatable. Several novel therapies have recently become available, increasing the urgency to make an accurate diagnosis, evaluate risk, and determine treatment response. Molecular imaging with positron-emitting amyloid tracers has a key emerging role in the evaluation and management of cardiac amyloidosis. In this review, we discuss molecular imaging of cardiac amyloidosis using amyloid PET tracers, including recent advances with a focus on the future., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Given the central importance of cardiorenal interactions, mechanistic tools for evaluating cardiorenal physiology are needed. In the heart and kidneys, shared pathways of neurohormonal activation, hypertension, and vascular and interstitial fibrosis implicate the relevance of systemic vascular health. The availability of a long axial field of view positron emission tomography (PET)/computed tomography (CT) system enables simultaneous evaluation of cardiac and renal blood flow., Methods: This study evaluated the feasibility of quantification of renal blood flow using data acquired during routine, clinically indicated 13 N-ammonia myocardial perfusion PET/CT. Dynamic PET image data were used to calculate renal blood flow. Reproducibility was assessed by the intraclass correlation coefficient among 3 independent readers. PET-derived renal blood flow was correlated with imaging and clinical parameters in the overall cohort and with histopathology in a small companion study of patients with a native kidney biopsy., Results: Among 386 consecutive patients with myocardial perfusion PET/CT, 296 (76.7%) had evaluable images to quantify renal perfusion. PET quantification of renal blood flow was highly reproducible (intraclass correlation coefficient 0.98 [95% CI, 0.93-0.99]) and was correlated with the estimated glomerular filtration rate ( r =0.64; P <0.001). Compared across vascular beds, resting renal blood flow was correlated with maximal stress myocardial blood flow and myocardial flow reserve (stress/rest myocardial blood flow), an integrated marker of endothelial health. In patients with kidney biopsy (n=12), resting PET renal blood flow was strongly negatively correlated with histological interstitial fibrosis ( r =-0.85; P <0.001)., Conclusions: Renal blood flow can be reliably measured from cardiac 13 N-ammonia PET/CT and allows for simultaneous assessment of myocardial and renal perfusion, opening a potential novel avenue to interrogate the mechanisms of emerging therapies with overlapping cardiac and renal benefits., Competing Interests: Disclosures Dr Brown reports consulting fees from Bayer. Dr Weber reports consulting fees from Horizon Therapeutics and Kiniksa Pharmaceuticals. Dr Dorbala reports unrelated grant support from Attralus, Pfizer, GE healthcare, and Phillips. Dr Blankstein reports research support from Amgen and Novartis and has consulted for Caristo Inc and Elucid Inc. Dr Di Carli reports grant support from Gilead Sciences, in-kind research support from Amgen, and consulting fees from MedTrace. The other authors report no conflicts.

Objectives: The goals of this study were to characterize myocardial composition during the active and remission phases of light-chain (AL) cardiac amyloidosis., Background: Cardiac dysfunction in AL amyloidosis is characterized by dual insults to the myocardium from infiltration and toxicity from light chains during the active phase and by infiltration alone in the remission phase., Methods: Prospectively enrolled subjects with cardiac AL amyloidosis (21 remission AL amyloidosis; age: 63.4 ± 7.3 years; 47.6% male; and 48 active AL amyloidosis; age: 62.5 ± 7.4 years; 60.4% male) underwent contrast-enhanced cardiac magnetic resonance with T 1 and T 2 mapping and measurement of extracellular volume (ECV). By definition, serum free light-chain levels were normal for at least 1 year following successful AL therapy in the remission group and abnormal in the active group., Results: Myocardial ECV was similarly expanded in the remission and active AL amyloidosis groups (0.488 ± 0.082 vs 0.519 ± 0.083, respectively; P = 0.15). However, myocardial T 2 relaxation times (47.7 ± 3.2 ms vs 45.5 ± 3.0 ms; P = 0.008) as well as native T 1 times (1,368 ms [IQR: 1,290-1,422 ms] vs 1,264 ms [IQR: 1,203-1,380 ms]; P = 0.024) were significantly higher in the remission compared to the active AL amyloidosis group., Conclusions: Myocardial ECV is substantially expanded in the active AL and remission AL cardiac amyloidosis groups, but native T 1 values were higher, suggesting a different myocardial composition. There is no evidence of myocardial edema in active AL cardiac amyloidosis. Future phenotyping studies of AL cardiac amyloidosis need to consider complementary myocardial markers that define the interstitial milieu in addition to changes in extracellular volume. (Molecular Imaging of Primary Amyloid Cardiomyopathy; NCT02641145)., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health (to Dr Dorbala: R01 HL 130563, R01 HL 150342, AHA16 CSA 2888 0004, and K24 HL157648 AHA19SRG34950011; to Dr Falk: HL 130563; to Dr Liao: AHA16 CSA 2888 0004 and AHA19SRG34950011; to Dr Ruberg: HL 130563 and R01 HL 093148) (NCT02641145). Dr Cuddy has received an investigator-initiated research grant from Pfizer. Dr Singh has received a research grant from American Society of Nuclear Cardiology/Pfizer. Dr Ruberg has received consulting fees from Pfizer, GlaxoSmithKline, and Caleum Biosciences and research support from Eidos Therapeutics. Dr Sanchorawala has received research support from Takeda, Celgene, Janssen, and Prothena and has served on the Scientific Advisory Board for Caleum Biosciences. Dr Landau has received consulting fees from Celgene, Takeda, Janssen, Prothena, Pfizer, and Juno and research support from Amgen, Spectrum, and Takeda. Dr Maurer has received consulting income and his institution has received clinical trial funding from Pfizer, Eidos, Prothena, Akcea, and Alnylam. Dr Yee has received consulting fees from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Sanofi, and Takeda. Dr Di Carli has received research grants from Spectrum Dynamics and Gilead and consulting fees from Sanofi and GE. Dr Falk has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences and research funding from GlaxoSmithKline and Akcea. Dr Dorbala has received consulting fees from Pfizer and GE Health Care; and her institution has received investigator-initiated grants from Pfizer, GE Healthcare, and Attralus. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The primary aims of this study were to determine the correlation between absolute quantitative 99m Tc-pyrophosphate metrics and traditional measures of cardiac amyloid burden and to measure the intraobserver repeatability of the quantitative metrics. Methods: We studied 72 patients who underwent 99m Tc-pyrophosphate SPECT/CT using a novel general-purpose cadmium-zinc-telluride-based SPECT/CT system. The clinical standard for these studies is visual grading (with grades of 0, 1, 2, and 3 indicating myocardial uptake absent, less than rib uptake, equal to rib uptake, or more than rib uptake, respectively). A visual grade of 2 or more was considered positive. For 72 patients, SUV max , SUV mean , cardiac amyloid activity (CAA; i.e., SUV mean × left ventricular [LV] volume), and percentage injected dose (%ID) were calculated, and visual grading was performed. The correlation was determined between the 4 quantitative metrics or visual grades and the LV mass index (LVMI) (indexed to body surface area on echocardiography, 67 patients). For a subset of 11 patients, the correlation was determined between the visual or quantitative metrics and the extracellular volume (ECV) on cardiac MRI. Normal linear regression was used to compare the standardized association of each of the 4 quantitative metrics with LVMI, as a surrogate for amyloid burden. Receiver-operating-characteristic curve analysis was used to determine the diagnostic accuracy of quantitative metrics, using visual grading as the reference standard. The intraobserver repeatability of generating quantitative metrics was also determined. Results: All 4 quantitative metrics were highly accurate, with an area under the receiver-operating-characteristic curve of more than 0.96 for diagnosis of transthyretin cardiac amyloidosis. SUV max , SUV mean , CAA, %ID, and visual grade were moderately positively correlated with LVMI ( r = 0.485 for %ID) and strongly positively correlated, albeit in a small cohort, with ECV ( r = 0.873, SUV max ). Intraobserver repeatability was excellent, with less than a 2% coefficient of variation for SUV max , %ID, and CAA and 3.8% for SUV mean All 4 quantitative metrics had a standardized effect of more than 0.324 on LVMI; the largest standardized effect was 0.485, for %ID. Conclusion: In this first (to our knowledge) study of 99m Tc-pyrophosphate cardiac imaging using a novel cadmium-zinc-telluride SPECT/CT scanner, SUV max , SUV mean , CAA, and %ID measured by absolute quantitation of 99m Tc-pyrophosphate were moderately correlated with LVMI and strongly correlated, albeit in a small cohort, with ECV. The intraobserver repeatability of generating the quantitative metrics was excellent., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: The purpose of this study was to determine phenotypes characterizing cardiac involvement in AL amyloidosis by using direct (fluorine-18-labeled florbetapir {[ 18 F]florbetapir} positron emission tomography [PET]/computed tomography) and indirect (echocardiography and cardiac magnetic resonance [CMR]) imaging biomarkers of AL amyloidosis., Background: Cardiac involvement in systemic light chain amyloidosis (AL) is the main determinant of prognosis and, therefore, guides management. The hypothesis of this study was that myocardial AL deposits and expansion of extracellular volume (ECV) could be identified before increases in N-terminal pro-B-type natriuretic peptide or wall thickness., Methods: A total of 45 subjects were prospectively enrolled in 3 groups: 25 with active AL amyloidosis with cardiac involvement (active-CA), 10 with active AL amyloidosis without cardiac involvement by conventional criteria (active-non-CA), and 10 with AL amyloidosis with cardiac involvement in remission for at least 1 year (remission-CA). All subjects underwent echocardiography, CMR, and [ 18 F]florbetapir PET/CT to evaluate cardiac amyloid burden., Results: The active-CA group demonstrated the largest myocardial AL amyloid burden, quantified by [ 18 F]florbetapir retention index (RI) 0.110 (interquartile range [IQR]: 0.078 to 0.139) min -1 , and the lowest cardiac function by global longitudinal strain (GLS), median GLS -11% (IQR: -8% to -13%). The remission-CA group had expanded extracellular volume (ECV) and [ 18 F]florbetapir RI of 0.097 (IQR: 0.070 to 0.124 min -1 ), and abnormal GLS despite hematologic remission for >1 year. The active-non-CA cohort had evidence of cardiac amyloid deposition by advanced imaging metrics in 50% of the subjects; cardiac involvement was identified by late gadolinium enhancement in 20%, elevated ECV in 20%, and elevated [ 18 F]florbetapir RI in 50%., Conclusions: Evidence of cardiac amyloid infiltration was found based on direct and indirect imaging biomarkers in subjects without CA by conventional criteria. The findings from [ 18 F]florbetapir PET imaging provided insight into the preclinical disease process and on the basis of interpretation of expanded ECV on CMR and have important implications for future research and clinical management of AL amyloidosis. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin light-chain (AL) amyloidosis affects multiple systemic organs. However, determination of the precise extent of organ involvement remains challenging. Targeted amyloid imaging with 18 F-florbetapir PET/CT offers the potential to detect AL deposits in multiple organs. The primary aim of this study was to determine the distribution and frequency of AL deposits in the various organs of subjects with systemic AL amyloidosis using 18 F-florbetapir PET/CT. Methods: This prospective study included 40 subjects with biopsy-proven AL amyloidosis including active AL amyloidosis ( n = 30) or AL amyloidosis in hematologic remission for more than 1 y ( n = 10). All subjects underwent 18 F-florbetapir PET/CT, skull base to below the kidney scan field, from 60 to 90 min after injection of radiotracer. Volume-of-interest measurements of SUV max were obtained using Hermes software for the parotid gland, tongue, thyroid, lung, gastric wall, pancreas, spleen, kidney, muscle, abdominal fat, lower thoracic spine, vertebral body, and humeral head. Uptake in each organ was visually compared with that in spine bone marrow. An SUV max of at least 2.5 was considered abnormal in all organs other than the liver. Results: Compared with the international consensus definition of organ involvement, 18 F-florbetapir PET/CT identified amyloid deposits in substantially higher percentages of subjects for several organ systems, including parotid gland (50% vs. 3%), tongue (53% vs. 10%), and lung (35% vs. 10%). In several organ systems, including kidney (13% vs. 28%) and abdominal wall fat (10% vs. 13%), PET identified involvement in fewer subjects than did international consensus. Quantitative analysis of 18 F-florbetapir PET/CT revealed more frequent organ involvement than did visual analysis in the tongue, thyroid, lung, pancreas, kidney, muscle, and humeral head. Extensive organ amyloid deposits were observed in active AL as well as in AL remission cohorts, and in both cardiac and noncardiac AL cohorts. Conclusion: 18 F-florbetapir PET/CT detected widespread organ amyloid deposition in subjects with both active AL and AL hematologic remission. In most instances, amyloid deposits in the various organs were not associated with clinical symptoms and, thus, were unrecognized. Early recognition of systemic organ involvement may help tailor treatment, and noninvasive monitoring of organ-level disease may guide management with novel fibril-resorbing therapies., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

We previously described a novel "chemogenetic" animal model of heart failure that recapitulates a characteristic feature commonly found in human heart failure: chronic oxidative stress. This heart failure model uses a chemogenetic approach to activate a recombinant yeast d-amino acid oxidase in rat hearts in vivo to generate oxidative stress, which then rapidly leads to the development of a dilated cardiomyopathy. Here we apply this new model to drug testing by studying its response to treatment with the angiotensin II (ANG II) receptor blocker valsartan, administered either alone or with the neprilysin inhibitor sacubitril. Echocardiographic and [ 18 F]fluorodeoxyglucose positron emission tomographic imaging revealed that valsartan in the presence or absence of sacubitril reverses the anatomical and metabolic remodeling induced by chronic oxidative stress. Markers of oxidative stress, mitochondrial function, and apoptosis, as well as classical heart failure biomarkers, also normalized following drug treatments despite the persistence of cardiac fibrosis. These findings provide evidence that chemogenetic heart failure is rapidly reversible by drug treatment, setting the stage for the study of novel heart failure therapeutics in this model. The ability of ANG II blockade and neprilysin inhibition to reverse heart failure induced by chronic oxidative stress identifies a central role for cardiac myocyte angiotensin receptors in the pathobiology of cardiac dysfunction caused by oxidative stress. NEW & NOTEWORTHY The chemogenetic approach allows us to distinguish cardiac myocyte-specific pathology from the pleiotropic changes that are characteristic of other "interventional" animal models of heart failure. These features of the chemogenetic heart failure model facilitate the analysis of drug effects on the progression and regression of ventricular remodeling, fibrosis, and dysfunctional signal transduction. Chemogenetic approaches will be highly informative in the study of the roles of redox stress in heart failure providing an opportunity for the identification of novel therapeutic targets.

Objectives: This study sought to test whether relative apical sparing (RELAPS) of left ventricular (LV) longitudinal strain (LS) in cardiac amyloidosis (CA) is explained by regional differences in markers of amyloid burden ( 18 F-florbetapir uptake by positron emission tomography [PET] and/or extracellular volume fraction [ECV] by cardiac magnetic resonance (CMR)]., Background: Further knowledge of the pathophysiological basis for RELAPS can help understand the adverse outcomes associated with apical LS impairment., Methods: This was a prospective study of 32 subjects (age 62 ± 7 years; 50% males) with light chain CA. All subjects underwent two-dimensional echocardiography for LS estimation and 18 F-florbetapir PET for quantification of LV florbetapir retention index (RI). A subset also underwent CMR (n = 22) for ECV quantification. Extracellular LV mass (LV mass*ECV) and total florbetapir binding (extracellular LV mass*florbetapir RI) were also calculated. All parameters were measured globally and regionally (base, mid, and apex)., Results: There was a significant base-to-apex gradient in LS (-7.4 ± 3.2% vs. -8.6 ± 4.0% vs. -20.8 ± 6.6%; p < 0.0001), maximal LV wall thickness (15.7 ± 1.9 cm vs. 15.4 ± 2.9 cm vs. 10.1 ± 2.4 cm; p < 0.0001), and LV mass (74.8 ± 21.2 g vs. 60.8 ± 17.3 g vs. 23.4 ± 6.2 g; p < 0.0001). In contrast, florbetapir RI (0.089 ± 0.03 μmol/min/g vs. 0.097 ± 0.03 μmol/min/g vs. 0.085 ± 0.03 μmol/min/g; p = 0.45) and ECV (0.53 ± 0.08 vs. 0.49 ± 0.08 vs. 0.49 ± 0.07; p = 0.15) showed no significant base-to-apex gradient in the tissue concentration or proportion of amyloid infiltration, whereas markers of total amyloid load, such as total florbetapir binding (3.4 ± 1.7 μmol/min vs. 2.8 ± 1.5 μmol/min vs. 0.93 ± 0.49 μmol/min; p < 0.0001) and extracellular LV mass (40.0 ± 15.6 g vs. 30.2 ± 10.9 g vs. 11.6 ± 3.9 g; p < 0.0001), did show a marked base-to-apex gradient., Conclusions: Segmental differences in the distribution of the total amyloid mass, rather than the proportion of amyloid deposits, appear to explain the marked regional differences in LS in CA. Although these 2 matrices are clearly related concepts, they should not be used interchangeably., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Microcalcifications in atherosclerotic plaques are destabilizing, predict adverse cardiovascular events, and are associated with increased morbidity and mortality. 18 F-fluoride positron emission tomography (PET)/computed tomography (CT) imaging has demonstrated promise as a useful clinical diagnostic tool in identifying high-risk plaques; however, there is confusion as to the underlying mechanism of signal amplification seen in PET-positive, CT-negative image regions. This study tested the hypothesis that 18 F-fluoride PET/CT can identify early microcalcifications., Methods: 18 F-fluoride signal amplification derived from microcalcifications was validated against near-infrared fluorescence molecular imaging and histology using an in vitro 3-dimensional hydrogel collagen platform, ex vivo human specimens, and a mouse model of atherosclerosis., Results: Microcalcification size correlated inversely with collagen concentration. The 18 F-fluoride ligand bound to microcalcifications formed by calcifying vascular smooth muscle cell derived extracellular vesicles in the in vitro 3-dimensional collagen system and exhibited an increasing signal with an increase in collagen concentration (0.25 mg/mL collagen -33.8×10 2 ±12.4×10 2 counts per minute; 0.5 mg/mL collagen -67.7×10 2 ±37.4×10 2 counts per minute; P=0.0014), suggesting amplification of the PET signal by smaller microcalcifications. We further incubated human atherosclerotic endarterectomy specimens with clinically relevant concentrations of 18 F-fluoride. The 18 F-fluoride ligand labeled microcalcifications in PET-positive, CT-negative regions of explanted human specimens as evidenced by 18 F-fluoride PET/CT imaging, near-infrared fluorescence, and histological analysis. Additionally, the 18 F-fluoride ligand identified micro and macrocalcifications in atherosclerotic aortas obtained from low-density lipoprotein receptor-deficient mice., Conclusions: Our results suggest that 18 F-fluoride PET signal in PET-positive, CT-negative regions of human atherosclerotic plaques is the result of developing microcalcifications, and high surface area in regions of small microcalcifications may amplify PET signal.

Purpose: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations of the TSC1 or TSC2 gene, characterized by neurocognitive impairment and benign tumors of the brain, skin, heart, and kidneys. Lymphangioleiomyomatosis (LAM) is a diffuse proliferation of α-smooth muscle actin-positive cells associated with cystic destruction of the lung. LAM occurs almost exclusively in women, as a TSC manifestation or a sporadic disorder ( TSC1/TSC2 somatic mutations). Biomarkers of whole-body tumor burden/activity and response to rapalogs or other therapies remain needed in TSC/LAM., Experimental Design: These preclinical studies aimed to assess feasibility of [ 18 F]fluorocholine (FCH) and [ 18 F]fluoroacetate (FACE) as TSC/LAM metabolic imaging biomarkers., Results: We previously reported that TSC2-deficient cells enhance phosphatidylcholine synthesis via the Kennedy pathway. Here, we show that TSC2-deficient cells exhibit rapid uptake of [ 18 F]FCH in vivo and can be visualized by PET imaging in preclinical models of TSC/LAM, including subcutaneous tumors and pulmonary nodules. Treatment with rapamycin (72 hours) suppressed [ 18 F]FCH standardized uptake value (SUV) by >50% in tumors. Interestingly, [ 18 F]FCH-PET imaging of TSC2-deficient xenografts in ovariectomized mice also showed a significant decrease in tumor SUV. Finally, we found rapamycin-insensitive uptake of FACE by TSC2-deficient cells in vitro and in vivo , reflecting its mitochondrial accumulation via inhibition of aconitase, a TCA cycle enzyme., Conclusions: Preclinical models of TSC2 deficiency represent informative platforms to identify tracers of potential clinical interest. Our findings provide mechanistic evidence for testing the potential of [ 18 F]FCH and [ 18 F]FACE as metabolic imaging biomarkers for TSC and LAM proliferative lesions, and novel insights into the metabolic reprogramming of TSC tumors., (©2018 American Association for Cancer Research.)

We have developed a new method of compensating for effects of partial volume and spillover in dual-modality imaging. The approach requires segmentation of just a few tissue types within a small volume-of-interest (VOI) surrounding a lesion; the algorithm estimates simultaneously, from projection data, the activity concentration within each segmented tissue inside the VOI. Measured emission projections were fitted to the sum of resolution-blurred projections of each such tissue, scaled by its unknown activity concentration, plus a global background contribution obtained by reprojection through the reconstructed image volume outside the VOI. The method was evaluated using multiple-pinhole μSPECT data simulated for the MOBY mouse phantom containing two spherical lung tumors and one liver tumor, as well as using multiple-bead phantom data acquired on μSPECT and μCT scanners. Each VOI in the simulation study was 4.8 mm (12 voxels) cubed and, depending on location, contained up to four tissues (tumor, liver, heart, lung) with different values of relative (99m)Tc concentration. All tumor activity estimates achieved bias after ∼ 15 ordered-subsets expectation maximization (OSEM) iterations (×10 subsets) , with better than 8% precision ( ≤ 25% greater than the Cramer-Rao lower bound). The projection-based fitting approach also outperformed three standardized uptake value (SUV)-like metrics, one of which was corrected for count spillover. In the bead phantom experiment, the mean ± standard deviation of the bias of VOI estimates of bead concentration were 0.9±9.5%, comparable to those of a perturbation geometric transfer matrix (pGTM) approach (-5.4±8.6%); however, VOI estimates were more stable with increasing iteration number than pGTM estimates, even in the presence of substantial axial misalignment between μCT and μSPECT image volumes.

Unlabelled: The aim of this work was to develop a rigorous evaluation methodology to assess performance of different acquisition and processing methods for variable patient sizes in the context of lesion detection in whole-body (18)F-FDG PET., Methods: Fifty-nine bed positions were acquired in 32 patients in 2-dimensional (2D) and 3-dimensional (3D) modes 1-4 h after (18)F-FDG injection (740 MBq) using a BGO PET scanner. Three spheres (1.0-, 1.3-, and 1.6-cm diameter) containing (68)Ge were also imaged separately in air, at locations corresponding to possible lesion sites in 2D and 3D (590 targets per condition). Each bed position was acquired for 7 min in 2D and 6 min in 3D and corrected for randoms using delayed window randoms subtraction (DWS) or randoms variance reduction (RVR). Sphere sinograms were attenuated using the 2D or 3D attenuation map derived from the transmission scan of the patient, after scaling 2D and 3D sinograms with identical factors to ensure marginal detectability. Resulting 2D sinograms were reconstructed with filtered backprojection (FBP) and ordered-subsets expectation maximization (OSEM) without any scatter or attenuation correction (FBP-NATS and OSEM-NATS) or corrected for scatter and attenuation and reconstructed using FBP (FBP-ATT) or attenuation-weighted OSEM (AWOSEM). 3D sinograms were processed identically after Fourier rebinning. Next, reconstructed volumes were compared on the basis of performance of a 3-channel Hotelling observer (CHO-SNR [SNR is signal-to-noise ratio]) in detecting the presence of a sphere of unknown size on an anatomic background while modeling observer noise. The noise equivalent count (NEC) rate was computed in 2D and 3D for 3 different phantoms sizes (40, 60, and 95 kg) and compared with lesion detection SNR., Results: 3D imaging yielded better lesion detectability than 2D (P < 0.025, 2-tailed paired t test) in patients of normal size (body mass index [BMI] < or = 31). However, 2D imaging yielded better lesion detectability than 3D in large patients (BMI > 31), as 3D performance deteriorated in large patients (P < 0.05). 2D and 3D yielded similar results for different lesion sizes. CHO-SNR were 40% greater for AWOSEM, FBP-ATT, and FBPNAT than for OSEM (P < 0.05), and AWOSEM yielded significantly better lesion detectability than did FBP. In all patients, RVR yielded a systematic improvement in CHO-SNR over DWS in both 2D and 3D. radicalNEC was characterized by a behavior similar to that of SNR(CHO) for the 3 different phantom sizes considered in this study.

Unlabelled: We have addressed 2 major challenges of (82)Rb cardiac PET, noninvasive estimation of an accurate input function and absolute quantitation of myocardial perfusion, using a generalized form of least-squares factor analysis of dynamic sequences (GFADS) and a novel compartment analysis approach., Methods: Left and right ventricular (LV + RV) time-activity curves (TACs) were generated from 10 rest/stress studies, and 30 myocardial TACs were modeled to cover a range of clinical values. Two-dimensional PET Monte Carlo simulations of the LV, RV, myocardium, and other organs were generated separately and combined using the above TACs to form 30 realistic dynamic (82)Rb studies. LV and RV TACs were estimated by GFADS and used as input to a 2-compartment kinetic analysis that estimates parametric maps of myocardial tissue extraction (k(1)) and egress (k(2)), as well as LV + RV contributions (f(v), r(v)), by orthogonal voxel grouping. In addition, 13 patients were injected with 2.22 +/- 0.19 GBq (60 +/- 5 mCi) of (82)Rb and imaged dynamically for 6 min at rest and during dipyridamole stress., Results: In Monte Carlo simulations, GFADS yielded estimates of the 3 factors and corresponding factor images, with average errors of -4.2% +/- 6.3%, 3.5% +/- 4.3%, and 2.0% +/- 5.5% in the LV, RV, and myocardial factor estimates, respectively. The estimates were significantly more accurate and robust to noise than those obtained using TACs based on manually drawn volumes of interest (P < 0.01). The 2-compartment approach yielded accurate k(1), k(2), f(v), and r(v) parametric maps; the average error of estimates of k(1) was 6.8% +/- 3.6%. In all patient studies, our approach yielded robust estimates of k(1), k(2), f(v), and r(v), which correlated very well with the status of the subject and the catheterization results., Conclusion: Quantitative dynamic (82)Rb PET using generalized factor analysis of dynamic sequences and compartmental modeling yields estimates of parameters of absolute myocardial perfusion and kinetics with errors of <9%.

Unlabelled: We investigated the impact of the quantitation and reconstruction protocol on clinical tasks. The performance of standard clinical reconstruction procedures in discrimination tasks related to the diagnosis of prodromal Alzheimer's disease (AD) was compared with the performance of a quantitative approach incorporating improved corrections for scatter, attenuation, intrinsic spatial resolution, and distance-dependent spatial resolution., Methods: Seventeen normal controls (normal group), 56 subjects who did not have dementia, who did have memory problems, but who did not develop AD within 5 y of follow-up (questionable group), and 27 subjects who did not have dementia, who did have memory problems, and who did develop AD over the follow-up period (converter group) were considered in this study. (99m)Tc-hexamethylpropyleneamine oxime SPECT and MRI studies were performed for each subject at baseline. The standard quantitation protocol (STD), routinely used in our clinic, consisted of Compton window scatter correction followed by filtered backprojection with attenuation correction using a uniform attenuation map. In the improved quantitative approach (QUAN), projections were corrected for scatter by use of a general spectral method and reconstructed by use of ordered-subset(s) expectation maximization, incorporating corrections for collimator response and attenuation using both a uniform attenuation map (QUANunif) and a nonuniform attenuation map (QUANnonunif). Mean SPECT activity concentration and MRI volume were estimated for 7 structures: rostral anterior cingulate gyrus, caudal anterior cingulate gyrus, posterior cingulate gyrus, hippocampus, basal forebrain, amygdala, and the banks of the superior temporal sulcus. Data were analyzed by pairwise discriminant analysis, and performance in binary group discrimination was measured by correlated receiver-operating-characteristic analysis., Results: The use of QUANnonunif yielded a small but systematic improvement in discrimination accuracy for normal versus converter groups (accuracy or area under the receiver-operating-characteristic curve [Az], 0.965), normal versus questionable groups (Az, 0.973), and questionable versus converter groups (Az, 0.881) compared with the results obtained with QUANunif (Az, 0.955, 0.962, and 0.866, respectively). Discrimination performance was significantly lower (P < 0.05) with STD than with QUAN in all 3 tasks (Az with STD, 0.906, 0.878, and 0.768, respectively). MRI volume estimation led to a lower overall performance in all 3 tasks than did QUANnonunif (Az with MRI, 0.947, 0.917, and 0.872, respectively)., Conclusion: Improved quantitative image reconstruction with accurate compensation for scatter, attenuation, and variable collimator response led to significantly better performance in discrimination tasks related to the diagnosis of prodromal AD than did standard clinical reconstruction procedures. The use of a nonuniform brain attenuation map yields a small improvement in discrimination accuracy.

Unlabelled: Dual-isotope imaging can allow simultaneous assessment of brain perfusion using a 99mTc-labeled tracer and neurotransmission using an 123I-labeled tracer. However, the images are affected by scatter, cross talk, attenuation, distance-dependent collimator response (DCR), and partial-volume effect. We determined the accuracy and precision of activity quantitation in simulated normal and pathologic studies of simultaneous 123I/99mTc brain SPECT when compensating for all degrading phenomena., Methods: Monte Carlo simulations were performed using the Zubal brain phantom. Contamination caused by high-energy 123I decay photons was incorporated. Twenty-four 99mTc and 123I activity distributions were simulated on the basis of normal and pathologic patient activity distributions. Cross talk and scatter were corrected using a new method based on a multilayer perceptron artificial neural network (ANN), as well as by the asymmetric window (AW) approach; for comparison, unscattered (U) photons of 99mTc and 123I were recorded. Nonuniform attenuation and DCR were modeled in an iterative ordered-subset expectation maximization (OSEM) algorithm. Mean percentage biases and SDs over the 12 normal and 12 pathologic simulated studies were computed for each structure with respect to the known activity distributions., Results: For 123I, AW + OSEM yielded a bias of 7% in the cerebellum, 21% in the frontal cortex, and 36% in the corpus callosum in the simulated normal population. The bias was increased significantly in the striata of simulated pathologic studies (P < 0.05). The bias associated with ANN was significantly lower (<9% in these brain structures, P < 0.05). For 99mTc with AW + OSEM, the bias was 60% in the corpus callosum, 36% in the striata, and 18%-22% in the cortical lobes in the simulated normal population. This bias was <11% in all brain structures with ANN. In the simulated pathologic population, the bias associated with AW increased significantly in the cortical lobes to 55% (P < 0.05), although it did not change significantly with ANN., Conclusion: The accuracy and variability over simulated normal and pathologic studies of both 99mTc and 123I activity estimates were very close with ANN to those obtained with U + OSEM. ANN + OSEM is a promising approach for absolute activity quantitation in simultaneous 99mTc/123I SPECT.

Unlabelled: A method for performing scatter corrections that would directly use the photopeak information and would be straightforward for use in clinical practice would be attractive in SPECT imaging. The dual-photopeak window method may be such a method. It relates the scatter fraction to the ratio of the lower to the total parts of a split-photopeak window. We investigated the use of this scatter correction method on a dedicated brain camera., Methods: Calibration curves for the Ceraspect, a dedicated brain imaging camera, were obtained for four split-window combinations using point sources in air and water. Simulations of the Ceraspect calibration curves at several energy resolution values were obtained using a Monte Carlo simulation of the instrument., Results: The calibration curves, experimental and simulated, revealed an ambiguous and unstable relationship between lower-to-total ratio and scatter fraction., Conclusion: The unsatisfactory calibration curves can be attributed to the limited scatter produced in a brain-sized phantom during the calibration process and inherent stability problems in the calibration process. The dual-photopeak window method is not usable for small-field imaging systems and may even be unstable for larger-field systems.

Unlabelled: Attenuation of photons degrades both the accuracy and the precision of SPECT images; attenuation correction algorithms correct the bias but cannot improve precision. Increased noise due to photon attenuation is most pronounced in regions deep in solid body sections, such as the brain and abdomen. We have quantified the degradation in performance in several estimation tasks that can be attributed to photon attenuation and determined the degree to which performance might be improved by a collimator with a nonuniform sensitivity profile., Methods: The analysis used ideal-observer models of performance in tasks involving estimation of the activity and size of a focal lesion. The models were based on the Cramer-Rao lower bound on the variance with which lesion activity and size can be estimated by an unbiased procedure. To quantify the effects of attenuation, values of the Cramer-Rao bound were calculated for each estimation task as a function of location of the lesion in circularly-shaped attenuators of 10- and 20-cm radii, with and without attenuation. Values of the bound were also determined for two nonuniform sensitivity profiles, one of which was designed to equalize (or nearly equalize) task performance throughout the image., Results: For 99mTc, photon attenuation increased the variance of the estimates by factors of up to 4.5 for the 10-cm radius attenuator and up to 20.0 for the 20-cm radius attenuator. A collimator with a nonuniform sensitivity function reduced variance by factors of up to 1.8 for the 10-cm radius attenuator and up to 2.8 for the 20-cm radius attenuator. These gains in estimation performance were insensitive to the imaging task and to deviations from the assumed attenuator size and shape., Conclusion: Performance in estimation tasks using images from SPECT systems with uniform sensitivity collimators is considerably lower than the theoretical optimum. We have derived a sensitivity function, realizable using existing technology, that improves performance substantially.

To improve the diagnostic utility of brain single-photon emission computed tomography (SPECT) in Alzheimer's disease (AD), we have developed and evaluated an objective method of differentiating patients and healthy elderly controls using a quantitative image analysis protocol. HMPAO-SPECT image datasets from 29 patients with probable AD and 78 age-matched controls were registered to a common anatomic frame of reference. Activity levels within 120 standardized cortical volumes were determined by an automated procedure. Subjects were classified into normal and AD groups by quadratic discriminant analysis using two features: global average activity level and average normalized activity levels within the two clusters of standardized volumes identified as most significantly different in AD by analysis of covariance. The classification used split-half replication to ensure valid results. Classification performance quantified by the area under a binormal ROC curve fitted to the data was 0.923 +/- 0.036; at a threshold likelihood ratio of 1, the sample sensitivity was 91% and specificity was 86%. We conclude that quantitative SPECT accurately distinguishes AD patients from elderly controls.

In a stimulation study, we investigated the limitations of quantitation in nuclear medicine using a maximum-likelihood (ML) estimation model. We estimated activity, size, and position of a disk-shaped object on a circular, uniform background of unknown activity. The parameter estimates were unbiased, and their standard error was proportional to the square root of the total image counts. The estimates of object activity and size were strongly (negatively) correlated; the position estimates, however, were not correlated with estimates of any other parameters. This implies that a priori knowledge of object location does not improve precision. The minimal model of quantitation tasks should incorporate unknown object activity and size as well as unknown background activity. The ML estimation procedure was used to investigate the trade-off between resolution and sensitivity in gamma camera collimator design. The results implied that for complex tasks such as the multiparameter estimation task investigated here, optimum performance is achieved at a better resolution than that previously found optimal for detection of a well-specified object in a known background.

The effects of nonstationary projection noise and attenuation compensation are included in a theoretic calculation of the radial noise power spectrum (NPS) of single photon emission computed tomographic (SPECT) images. The nonstationary projection noise is shown to cause a relatively large d.c. component in the NPS, especially for small objects; whereas, attenuation compensation increases the total noise variance while only changing the d.c. component slightly. The theoretic calculation agrees well with a radial NPS estimated from 1,250 SPECT images simulated from projections of random Gaussian noise, even though the effects of discrete data collection and reconstruction were not included in the theoretical model.

We compared a prototype long-bore (LB) high-resolution collimator with a low-energy, general-purpose collimator (LEGP) using 99mTc and 123I. The LB collimator provided a 56% improvement in tomographic resolution (autocorrelation width) over the LEGP for 99mTc; for 123I, the gain was 79%, providing substantially improved contrast for small structures. The sensitivity of the LB collimator, however, is only 32% of that of the LEGP. The imaging tasks to be performed on [123I]IMP brain scans involve localization and discrimination of small, high-contrast brain structures and detection of abnormalities in shape, size, or uptake, rather than simple detection of lesions. Observer performance in such higher-order imaging tasks is known to depend on high spatial resolution, even at the cost of sensitivity. Patient studies confirmed that, for resolution-limited tasks, the increase in resolution outweighs the increased noise due to a loss in sensitivity. When the tomographic resolution of the LB collimator was degraded by smoothing to that of the LEGP, the noise in the LB images was lower than that of the LEGP by a factor of 2.9 for the same imaging time, demonstrating the advantage of high-resolution detectors and a smooth reconstruction filter over low-resolution detectors without smoothing. Therefore, collimators designed for high resolution, even at substantial cost in sensitivity, are expected to yield significant improvements for brain SPECT. Geometric calculations show that commercially available low-energy, high-resolution cast collimators promise to meet these requirements.