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Background: In light-chain (AL) amyloidosis, whether functional status and heart failure-related quality of life (HF-QOL) correlate with cardiomyopathy severity, improve with therapy, and are associated with major adverse cardiac events (MACE) beyond validated scores is not well-known., Objectives: The authors aimed to: 1) correlate functional status and HF-QOL with cardiomyopathy severity; 2) analyze their longitudinal changes; and 3) assess their independent associations with MACE., Methods: This study included 106 participants with AL amyloidosis, with 81% having AL cardiomyopathy. Functional status was evaluated using the NYHA functional class, the Karnofsky scale, and the 6-minute walk distance (6MWD), and HF-QOL using the MLWHFQ (Minnesota Living with Heart Failure Questionnaire). Cardiomyopathy severity was assessed by cardiac 18 F-florbetapir positron emission tomography/computed tomography, cardiac magnetic resonance, echocardiography, and serum cardiac biomarkers. MACE were defined as all-cause death, heart failure hospitalization, or cardiac transplantation., Results: NYHA functional class, Karnofsky scale, 6MWD, and MLWHFQ were impaired substantially in participants with recently diagnosed AL cardiomyopathy (P < 0.001), and correlated with all markers of cardiomyopathy severity (P ≤ 0.010). NYHA functional class, 6MWD, and MLWHFQ improved at 12 months in participants with cardiomyopathy (P ≤ 0.013). All measures of functional status and HF-QOL were associated with MACE (P ≤ 0.017), independent of Mayo stage for 6MWD and MLWHFQ (P ≤ 0.006)., Conclusions: Functional status and HF-QOL were associated with AL cardiomyopathy severity, improved on therapy within 12 months, and were associated with MACE, independently of Mayo stage for 6MWD and MLWHFQ. They may be validated further in addition to prognostic scores and as surrogate outcomes for future studies., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health (NIH) (NCT02641145). Dr Clerc has received a research fellowship from the International Society of Amyloidosis and Pfizer. Dr Vijayakumar has received a research fellowship from the Amyloidosis Foundation. Dr Cuddy is supported by NIH 1K23HL166686-01 and AHA 23CDA857664; has received an investigator-initiated research grant from Pfizer; and has received consulting fees from Ionis Pharmaceuticals, AstraZeneca, BridgeBio, and Novo Nordisk. Dr Bianchi was partially supported by a grant K08 CA245100; and has received consulting fees from Prothena. Dr Benz has received investigator-initiated funding from AstraZeneca; and has received consulting fees from Pfizer and travel support from Philips Research and Pfizer. Dr Yee has received consulting fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Oncopeptides, Regeneron, Sanofi, and Takeda. Dr Ruberg is supported by NIH R01 HL 130563; has received consulting fees from Pfizer, AstraZeneca, and Attralus; and has received research support to his institution from Pfizer, Alnylam, Anumana, and Ionis/Akcea. Dr Liao is supported by NIH AHA16 CSA 2888 0004 and AHA19SRG34950011. Dr Falk is supported by NIH R01 HL 130563; has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, and Caelum Biosciences; and has received research funding from GlaxoSmithKline and Akcea. Dr Sanchorawala has received research support from Takeda, Celgene, Janssen, and Prothena; and is a scientific advisory board member for Caleum Biosciences. Dr Dorbala is supported by NIH R01 HL 130563, K24 HL 157648, AHA16 CSA 2888 0004, and AHA19SRG34950011; has received consulting fees from Pfizer, GE Health Care, AstraZeneca, and Novo Nordisk; and has received investigator-initiated grant from Pfizer, GE Healthcare, Attralus, Siemens, and Philips. 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: In systemic light-chain (AL) amyloidosis, cardiac involvement portends poor outcomes., Objectives: The authors' objectives were to detect early myocardial alterations, to analyze longitudinal changes with therapy, and to predict major adverse cardiac events (MACE) in participants with AL amyloidosis using cardiac magnetic resonance imaging (MRI)., Methods: Recently diagnosed participants were prospectively enrolled. AL amyloidosis with and without cardiomyopathy (AL-CMP, AL-non-CMP) were defined based on abnormal cardiac biomarkers and wall thickness. MRI was performed at baseline, 6 months in all participants, and 12 months in participants with AL-CMP. MACE were defined as all-cause death, heart failure hospitalization, and cardiac transplantation. Mayo stage was based on troponin T, N-terminal pro-B-type natriuretic peptide, and difference in free light chains., Results: This study included 80 participants (median age 62 years, 58% men). Extracellular volume (ECV) was abnormal (>32%) in all participants with AL-CMP and in 47% of those with AL-non-CMP. ECV tended to increase at 6 months (median +2%; AL-CMP P = 0.120; AL-non-CMP P = 0.018) and returned to baseline values at 12 months in participants with AL-CMP. Global longitudinal strain (GLS) improved at 6 months (median -0.6%; P = 0.048) and 12 months (median -1.2%; P < 0.001) in participants with AL-CMP. ECV and GLS were strongly associated with MACE (P < 0.001) and improved the prognostic value when added to Mayo stage (P ≤ 0.002). No participant with ECV ≤32% had MACE, while 74% of those with ECV >48% had MACE., Conclusions: In patients with systemic AL amyloidosis, ECV detects subclinical myocardial alterations. With therapy, ECV tends to increase at 6 months and returns to values unchanged from baseline at 12 months, whereas GLS improves at 6 and 12 months in participants with AL-CMP. ECV and GLS offer additional prognostic performance over Mayo stage. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145)., Competing Interests: Funding Support and Author Disclosures This work was supported by National Institutes of Health. Dr Dorbala was supported by grants R01 HL 130563, K24 HL 157648, AHA16 CSA 2888 0004, and AHA19SRG34950011. Dr Falk was supported by grant R01 HL 130563. Dr Liao was supported by grants AHA16 CSA 2888 0004 and AHA19SRG34950011. Dr Ruberg was supported by grants R01 HL 130563 and R01 HL 093148. Dr Cuddy was supported by grants NIH 1K23HL166686-01 and AHA 23CDA857664NIH. Dr Bianchi was partially supported by a grant K08 CA245100. 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, as well as consulting fees from BridgeBio, Ionis, Astra Zeneca and Novo Nordisk. Dr Bianchi has received consulting fees from Prothena. Dr Ruberg has received consulting fees from AstraZeneca and Attralus; and has received research support from Pfizer, Alnylam, Anumana, and Ionis/Akcea. Dr DiCarli has received a research grant from Spectrum Dynamics and Gilead; and has received consulting fees from Sanofi and General Electric. Dr Kwong has received grant funding from Alynlam Pharmaceuticals. 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 has received consulting fees from Pfizer, GE Healthcare, and Novo Nordisk; and has received investigator-initiated grants from Pfizer, GE Healthcare, Attralus, Siemens, and Phillips. 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: Positron emission tomography/computed tomography (PET/CT) with 18 F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden in systemic light-chain (AL) amyloidosis. However, its prognostic value is not known., Objectives: The authors' aim was to evaluate the prognostic value of LV amyloid burden quantified by 18 F-florbetapir PET/CT, and to identify mechanistic pathways mediating its association with outcomes., Methods: A total of 81 participants with newly diagnosed AL amyloidosis underwent 18 F-florbetapir PET/CT imaging. Amyloid burden was quantified using 18 F-florbetapir LV uptake as percent injected dose. The Mayo stage for AL amyloidosis was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and free light chain levels. Major adverse cardiac events (MACE) were defined as all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months., Results: Among participants (median age, 61 years; 57% males), 36% experienced MACE, increasing from 7% to 63% across tertiles of LV amyloid burden (P < 0.001). LV amyloid burden was associated with MACE (HR: 1.46; 95% CI: 1.16-1.83; P = 0.001). However, this association became nonsignificant when adjusted for Mayo stage. In mediation analysis, the association between LV amyloid burden and MACE was mediated by NT-proBNP (P < 0.001), a marker of cardiomyocyte stretch and heart failure, and a component of Mayo stage., Conclusions: In this first study to link cardiac 18 F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by percent injected dose predicted MACE in AL amyloidosis. This effect was not independent of Mayo stage and was mediated primarily through NT-proBNP. These findings provide novel insights into the mechanism linking myocardial amyloid deposits to MACE., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Institutes of Health. Dr Dorbala was supported by grants R01 HL 130563; K24 HL 157648; AHA16 CSA 2888 0004; AHA19SRG34950011. Dr Falk was supported by a grant R01 HL 130563. Dr Liao was supported by grants AHA16 CSA 2888 0004; AHA19SRG34950011. Dr Ruberg was supported by grants R01 HL 130563; R01 HL 093148. Dr Bianchi was partially supported by a grant K08 CA245100; and has received consulting fees from Prothena. Dr Clerc has received a research fellowship from the International Society of Amyloidosis and Pfizer. Dr Cuddy was supported by grants NIH 1K23HL166686-01 and AHA 23CDA857664NIH; and has received an investigator-initiated research grant from Pfizer; and has received consulting fees from BridgeBio, Ionis, AstraZeneca, and Novo Nordisk. Dr DiCarli has received a research grant from Gilead and Alnylam Pharmaceuticals; in-kind research support from Amgen; and consulting fees from Sanofi, MedTrace Pharma, and Valo Health. Dr Kwong has received grant funding from Alynlam Pharmaceuticals. Dr Falk has received consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, Caelum Biosciences; and research funding from GlaxoSmithKline and Akcea. Dr Ruberg has received consulting fees from AstraZeneca, and Attralus; and has received research support from Pfizer, Alnylam, Anumana, and Ionis/Akcea. Dr Dorbala has received consulting fees from Pfizer, GE Health Care, and Novo Nordisk; and investigator-initiated grants from Pfizer, GE Healthcare, Attralus, Siemens, and Philips. 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: 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.)

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.)

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.)

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.)