Relationship of Subendocardial Perfusion to Myocardial Injury, Cardiac Structure, and Clinical Outcomes Among Patients With Hypertension.

BACKGROUND: Coronary microvascular dysfunction has been implicated in the development of hypertensive heart disease and heart failure, with subendocardial ischemia identified as a driver of sustained myocardial injury and fibrosis. We aimed to evaluate the relationships of subendocardial perfusion with cardiac injury, structure, and a composite of major adverse cardiac and cerebrovascular events consisting of death, heart failure hospitalization, myocardial infarction, and stroke. METHODS: Layer-specific blood flow and myocardial flow reserve (MFR; stress/rest myocardial blood flow) were assessed by 13N-ammonia perfusion positron emission tomography in consecutive patients with hypertension without flow-limiting coronary artery disease (summed stress score <3) imaged at Brigham and Women's Hospital (Boston, MA) from 2015 to 2021. In this post hoc observational study, biomarkers, echocardiographic parameters, and longitudinal clinical outcomes were compared by tertiles of subendocardial MFR (MFRsubendo). RESULTS: Among 358 patients, the mean age was 70.6±12.0 years, and 53.4% were male. The median MFRsubendo was 2.57 (interquartile range, 2.08-3.10), and lower MFRsubendo was associated with older age, diabetes, lower renal function, greater coronary calcium burden, and higher systolic blood pressure (P<0.05 for all). In cross-sectional multivariable regression analyses, the lowest tertile of MFRsubendo was associated with myocardial injury and with greater left ventricular wall thickness and volumes compared with the highest tertile. Relative to the highest tertile, low MFRsubendo was independently associated with an increased rate of major adverse cardiac and cerebrovascular events (adjusted hazard ratio, 2.99 [95% CI, 1.39-6.44]; P=0.005) and heart failure hospitalization (adjusted hazard ratio, 2.76 [95% CI, 1.04-7.32; P=0.042) over 1.1 (interquartile range, 0.6-2.8) years median follow-up. CONCLUSIONS: Among patients with hypertension without flow-limiting coronary artery disease, impaired MFRsubendo was associated with cardiovascular risk factors, elevated cardiac biomarkers, cardiac structure, and clinical events.

Quantitative 99mTc-pyrophosphate myocardial uptake: Changes on transthyretin stabilization therapy.

BACKGROUND: Quantitative technetium-99m-pyrophosphate cardiac single-photon emission computed tomography (99mTc-PYP SPECT/CT) is an emerging method for estimating myocardial burden of transthyretin cardiac amyloidosis (ATTR-CA), but its efficacy in monitoring longitudinal changes remains uncertain. We aimed to investigate longitudinal changes in cardiac ATTR amyloid burden following transthyretin stabilization therapy using visual and quantitative 99mTc-PYP SPECT/CT and to relate these with changes in cardiac biomarkers and function. METHODS: This prospective longitudinal cohort study investigated changes in 99mTc-PYP SPECT/CT in 23 participants with ATTR-CA on transthyretin stabilization therapy (median: 2.6 years). Quantitative analysis included left ventricular (LV) standardized uptake values (SUVs) (SUVmax, SUVmean), cardiac amyloid activity (CAA; SUVmean∗LV activity volume), and percent injected dose (%ID) (mean activity concentration∗LV activity volume/injected activity), calculated using a threshold of >1.5 times left atrial blood pool activity concentration on SPECT/CT. Longitudinal changes of paired continuous and ordinal variables were analyzed using Wilcoxon signed-rank test. RESULTS: Following therapy, visual grade decreased significantly (P = 0.003). Several quantitative 99mTc-PYP metrics also decreased significantly: SUVmax (median -0.75, P = 0.011), CAA (median: -406.6, P < 0.001), and %ID (median: -0.45, P < 0.001). Serum transthyretin levels improved (median: +6.5 mg/dL, P = 0.008). Echocardiographic parameters (global longitudinal strain, LV mass index, and LV wall thickness), N-terminal pro-B-type natriuretic peptide, and estimated glomerular filtration rate remained stable. CONCLUSIONS: Favorable changes in 99mTc-PYP myocardial uptake were observed in participants on transthyretin stabilization therapy, whereas echocardiographic parameters and biomarkers remained stable. These results likely signify myocardial ATTR amyloid stabilization rather than amyloid burden regression. Further investigation is needed to understand the implications of these findings.

Reproducibility and Repeatability of Assessment of Myocardial Light Chain Amyloidosis Burden Using 18F-Florbetapir PET/CT.

BACKGROUND: 18F-florbetapir PET is emerging as an excellent quantitative tool to quantify cardiac light chain (AL) amyloidosis burden. The primary aim of this study was to determine interobserver reproducibility and intraobserver repeatability, defined per the recommendations of the Quantitative Imaging Biomarker Alliance technical performance group, of PET 18F-florbetapir retention index (RI) in patients with cardiac AL amyloidosis. METHODS: The study cohort comprised 37 subjects with systemic AL amyloidosis enrolled in the prospective study: Molecular Imaging of Primary Amyloid Cardiomyopathy (clinical trials.gov NCT: 02641145). Using 10 mCi of 18F-florbetapir, a 60-minute dynamic cardiac scan was acquired. Global and segmental left ventricular estimates of retention index (RI) of 18F-florbetapir were calculated (Carimas 2.9 software, Turku, Finland). RI was analyzed twice, at least 24 hours apart, by two independent observers. Intraobserver repeatability and interobserver reproducibility were evaluated using Bland-Altman plots and scatter plots with fitted linear regression curves. RESULTS: All reproducibility (interobserver, r = 0.98) and repeatability (intraobserver, R=0.99 for each observer) measures of 18F-florbetapir RI are excellent. On the Bland-Altman plots, the agreement limits for global 18F-florbetapir RI were high and ranged for reproducibility (interobserver) from - 9.3 to + 9.4% (Fig. 1), and for repeatability (observer 1 from - 10.8 to + 10.7% and from - 9.2 to + 11.4%, for observer 2). CONCLUSIONS: The present study showed excellent interobserver reproducibility and intraobserver repeatability of 18F-florbetapir PET retention index in patients with cardiac AL amyloidosis.

Reversal of heart failure in a chemogenetic model of persistent cardiac redox stress.

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 [18F]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.

Functional Status and Quality of Life in Light-Chain Amyloidosis: Advanced Imaging, Longitudinal Changes, and Outcomes.

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 18F-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.

Quantification of right ventricular amyloid burden with 18F-florbetapir positron emission tomography/computed tomography and its association with right ventricular dysfunction and outcomes in light-chain amyloidosis.

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.

Myocardial Characteristics, Cardiac Structure, and Cardiac Function in Systemic Light-Chain Amyloidosis.

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).

Mechanisms of left ventricular systolic dysfunction in light chain amyloidosis: a multiparametric cardiac MRI study.

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.

Prognostic Value of Left Ventricular 18F-Florbetapir Uptake in Systemic Light-Chain Amyloidosis.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) with 18F-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 18F-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 18F-florbetapir PET/CT imaging. Amyloid burden was quantified using 18F-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 18F-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.

Molecular Imaging of Systemic and Cardiac Amyloidosis: Recent Advances and Focus on the Future.

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.

Cardiac Amyloid Quantification Using 124I-Evuzamitide (124I-P5+14) Versus 18F-Florbetapir: A Pilot PET/CT Study.

BACKGROUND: Cardiac amyloid quantification could advance early diagnosis of amyloid cardiomyopathy (CMP) and treatment monitoring. However, current imaging tools are based on indirect measurements. 124I-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 124I-evuzamitide uptake and to compare its diagnostic value to 18F-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 124I-evuzamitide and 18F-florbetapir. Control subjects underwent 124I-evuzamitide (n = 10) or 18F-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. 124I-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 18F-florbetapir LV %ID. Notably, for ATTRwt-CMP, LV %ID was higher with 124I-evuzamitide than 18F-florbetapir (P = 0.002). 124I-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: 124I-evuzamitide demonstrates uptake by cardiac amyloid and accurately discriminates amyloid CMP from control subjects. In AL-CMP, discrimination performance is similar to 18F-florbetapir. In ATTRwt-CMP, performance may be better with 124I-evuzamitide. Moderate-to-strong correlations of 124I-evuzamitide uptake with cardiac structural and functional metrics suggest valid amyloid quantification. Hence, 124I-evuzamitide is a promising novel radiotracer to detect and quantify cardiac amyloid.

Feasibility of Simultaneous Quantification of Myocardial and Renal Perfusion With Cardiac Positron Emission Tomography.

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 13N-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 13N-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.

Myocardial Characterization for Early Diagnosis, Treatment Response Monitoring, and Risk Assessment in Systemic Light-Chain Amyloidosis.

Aims: In systemic light-chain (AL) amyloidosis, cardiac involvement portends poor prognosis. Using myocardial characteristics on magnetic resonance imaging (MRI), this study aimed to detect early myocardial alterations, to analyze temporal changes with plasma cell therapy, and to predict risk of major adverse cardiac events (MACE) in AL amyloidosis. Methods and Results: Participants with recently diagnosed AL amyloidosis were prospectively enrolled. Presence of AL cardiomyopathy (AL-CMP vs. AL-non-CMP) was determined by abnormal cardiac biomarkers. MRI was performed at baseline and 6 months, with 12-month imaging in AL-CMP cohort. MACE was defined as all-cause death, heart failure hospitalization, or cardiac transplantation. Mayo AL stage was based on troponin T, NT-proBNP, and difference in free light chains. The study cohort included 80 participants (median age 62 years, 58% males). Median left ventricular extracellular volume (ECV) was significantly higher in AL-CMP (53% vs. 30%, p<0.001). ECV was abnormal (>32%) in all AL-CMP and in 47% of AL-non-CMP. ECV tended to increase at 6 months and decreased significantly from 6 to 12 months in AL-CMP (median -3%, p=0.011). ECV was strongly associated with MACE (p<0.001), and improved MACE prediction when added to Mayo AL stage (p=0.002). ECV≤32% identified a cohort without MACE, while ECV>48% identified a cohort with 74% MACE. Conclusions: In AL amyloidosis, ECV detects subclinical cardiomyopathy. ECV tends to increase from baseline to 6 months and decreases significantly from 6 and 12 months of plasma cell therapy in AL-CMP. ECV provides excellent risk stratification and offers additional prognostic performance over Mayo AL stage.

Prognostic Value of Left Ventricular 18 F-Florbetapir Uptake in Systemic Light-Chain Amyloidosis.

Background: Myocardial immunoglobulin light-chain (AL) amyloid deposits trigger heart failure, cardiomyocyte stretch and myocardial injury, leading to adverse cardiac outcomes. Positron emission tomography/computed tomography (PET/CT) with 18 F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden, but its prognostic value is not known. Therefore, we aimed 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: Eighty-one participants with newly-diagnosed systemic AL amyloidosis were prospectively enrolled and underwent 18 F-florbetapir PET/CT. LV amyloid burden was quantified using 18 F-florbetapir LV percent injected dose (%ID). Mayo AL stage was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and difference between involved and uninvolved 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. Incidence of MACE increased across tertiles of LV amyloid burden from 7% to 63% (p<0.001). LV amyloid burden was significantly associated with MACE in univariable analysis (hazard ratio 1.45, 95% confidence interval 1.15-1.82, p=0.002). However, this association became non-significant in multivariable analyses adjusted for Mayo AL stage. Mediation analysis showed that the association between 18 F-florbetapir LV %ID and MACE was primarily mediated by NT-proBNP (p<0.001), a marker of cardiomyocyte stretch and component of Mayo AL stage. Conclusion: In this first study to link cardiac 18 F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by LV %ID predicted MACE in AL amyloidosis. But this effect was not independent of Mayo AL stage. LV amyloid burden was associated with MACE primarily via NT-pro-BNP, a marker of cardiomyocyte stretch and component of Mayo AL stage. These findings provide novel insights into the mechanism through which myocardial AL amyloid leads to MACE. Clinical Perspective: In systemic light-chain (AL) amyloidosis, cardiac involvement is the key determinant of adverse outcomes. Usually, prognosis is based on the Mayo AL stage, determined by troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the difference between involved and uninvolved immunoglobulin free light chain levels (dFLC). Cardiac amyloid burden is not considered in this staging. In the present study, we used the amyloid-specific radiotracer 18 F-florbetapir to quantify left ventricular (LV) amyloid burden in 81 participants with newly-diagnosed AL amyloidosis and evaluated its prognostic value on major adverse outcomes (MACE: all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months). We found that higher LV amyloid burden by 18 F-florbetapir positron emission tomography/computed tomography (PET/CT) was strongly associated with MACE. However, this association became non-significant after adjustment for the Mayo AL stage. Mediation analysis offered novel pathophysiological insights, implying that LV amyloid burden leads to MACE predominantly through cardiomyocyte stretch and light chain toxicity (by NT-proBNP), rather than through myocardial injury (by troponin T), also considering the severity of plasma cell dyscrasia (by dFLC). This mediation by NT-proBNP may explain why the association with outcomes was non-significant with adjustment for Mayo AL stage. Together, these results establish quantitative 18 F-florbetapir PET/CT as a valid method to predict adverse outcomes in AL amyloidosis. These results support the use of 18 F-florbetapir PET/CT to measure the effects of novel fibril-depleting therapies, in addition to plasma cell therapy, to improve outcomes in systemic AL amyloidosis.

Ultrasound-based sensors for respiratory motion assessment in multimodality PET imaging.

Breathing motion can displace internal organs by up to several cm; as such, it is a primary factor limiting image quality in medical imaging. Motion can also complicate matters when trying to fuse images from different modalities, acquired at different locations and/or on different days. Currently available devices for monitoring breathing motion often do so indirectly, by detecting changes in the outline of the torso rather than the internal motion itself, and these devices are often fixed to floors, ceilings or walls, and thus cannot accompany patients from one location to another. We have developed small ultrasound-based sensors, referred to as 'organ configuration motion' (OCM) sensors, that attach to the skin and provide rich motion-sensitive information. In the present work we tested the ability of OCM sensors to enable respiratory gating duringin vivoPET imaging. A motion phantom involving an FDG solution was assembled, and two cancer patients scheduled for a clinical PET/CT exam were recruited for this study. OCM signals were used to help reconstruct phantom andin vivodata into time series of motion-resolved images. As expected, the motion-resolved images captured the underlying motion. In Patient #1, a single large lesion proved to be mostly stationary through the breathing cycle. However, in Patient #2, several small lesions were mobile during breathing, and our proposed new approach captured their breathing-related displacements. In summary, a relatively inexpensive hardware solution was developed here for respiration monitoring. Because the proposed sensors attach to the skin, as opposed to walls or ceilings, they can accompany patients from one procedure to the next, potentially allowing data gathered in different places and at different times to be combined and compared in ways that account for breathing motion.

Myocardial Composition in Light-Chain Cardiac Amyloidosis More Than 1 Year After Successful Therapy.

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 T1 and T2 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 T2 relaxation times (47.7 ± 3.2 ms vs 45.5 ± 3.0 ms; P = 0.008) as well as native T1 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 T1 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).

Improved Quantification of Cardiac Amyloid Burden in Systemic Light Chain Amyloidosis: Redefining Early Disease?

OBJECTIVES: The purpose of this study was to determine phenotypes characterizing cardiac involvement in AL amyloidosis by using direct (fluorine-18-labeled florbetapir {[18F]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 [18F]florbetapir PET/CT to evaluate cardiac amyloid burden. RESULTS: The active-CA group demonstrated the largest myocardial AL amyloid burden, quantified by [18F]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 [18F]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 [18F]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 [18F]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).

Relative Apical Sparing of Myocardial Longitudinal Strain Is Explained by Regional Differences in Total Amyloid Mass Rather Than the Proportion of Amyloid Deposits.

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 (18F-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 18F-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.