BACKGROUND:The objective of this study is to describe the rationale and design of the multicenter phase 3 Research with EVuzamitide to Evaluate for cardiac AmyLoidosis (REVEAL) trial evaluating the diagnostic performance of 124I-evuzamitide positron emission tomography/computed tomography (PET/CT) for detection of cardiac amyloidosis (CA) in patients undergoing evaluation for suspected disease. 124I-evuzamitide is a novel fibril-targeting positron-emitting radiotracer that binds hypersulfated heparan sulfate glycans in amyloid fibrils across multiple amyloid subtypes. METHODS:This open-label, single-arm study, enrolled adults with suspected CA at 18 USA centers. Participants with previously diagnosed CA or systemic amyloidosis with known organ involvement, precursor protein targeted therapy use, estimated glomerular filtration rate less than 15 mL/min/1.73 m2, recent myocardial infarction, or recent heparin exposure were excluded. Cardiac and partial-body static PET/CT imaging was performed 4 ± 1 hour after intravenous administration of 124I-evuzamitide (1.0 ± 0.1 mCi). Potassium iodide was administered to reduce thyroid uptake of free radioiodine. Three blinded expert physicians independently assessed myocardial tracer uptake visually on PET/CT scans. Separately, three blinded amyloidosis experts adjudicated the presence or absence of CA using standard-of-care clinical, laboratory, biopsy, genetic, electrocardiographic, echocardiographic, cardiac magnetic resonance, and bone-avid tracer cardiac scintigraphy data. The primary endpoints were the sensitivity and specificity of visually interpreted 124I-evuzamitide PET/CT for the diagnosis of CA compared with the adjudicated standard-of-care diagnosis. CONCLUSIONS:REVEAL is the first multicenter phase 3 study evaluating a fibril-targeted PET radiotracer for the diagnosis of CA and may establish a noninvasive molecular imaging approach for detecting cardiac and systemic amyloid deposition across multiple amyloid subtypes.

Importance:Diagnosing cardiac amyloidosis remains challenging because current imaging approaches are limited to transthyretin amyloidosis. A noninvasive test capable of directly imaging cardiac amyloidosis from various amyloid types and in multiple organs could address an important unmet diagnostic need. Objective:To evaluate the sensitivity and specificity of 124I-evuzamitide positron emission tomography (PET)/computed tomography (CT) for diagnosing cardiac amyloidosis. Design, Setting, and Participants:Prospective, multicenter (18 US centers), single-group study evaluating the efficacy of 124I-evuzamitide to diagnose cardiac amyloidosis. This study was conducted from January 14, 2025, to March 12, 2026, including a 60-day follow-up period. Three physicians with cardiac PET/CT experience independently reviewed PET/CT images for visual cardiac 124I-evuzamitide uptake while blinded to clinical data. Three expert clinical amyloidosis physicians, blinded to PET/CT data, independently adjudicated the diagnosis based on the standard-of-care diagnostic algorithm. A total of 195 adults suspected of having cardiac amyloidosis were enrolled when they presented for diagnostic evaluation at participating institutions, excluding patients with an established diagnosis of cardiac or systemic amyloidosis. Interventions:PET/CT scans were obtained 3 to 5 hours after intravenous administration of 1 mCi of 124I-evuzamitide. Potassium iodide (130 mg) was given orally for 3 days starting at least 30 minutes prior to 124I-evuzamitide injection. Main Outcomes and Measures:Coprimary end points of this study were to assess the sensitivity and specificity of 124I-evuzamitide for the diagnosis of cardiac amyloidosis. Results:Overall, 170 patients were included (median [IQR] age, 72 [64-79] years; 75.3% male, 19.2% Black, 79.0% White). Median N-terminal pro-brain natriuretic peptide was 471 pg/mL and 61.7% had New York Heart Association class II or III heart failure symptoms. The overall sensitivity was 94% (95% CI, 85%-98%; P < .001); specificity, 86% (95% CI, 77%-92%; P < .001); positive predictive value, 85% (95% CI, 75%-92%); and negative predictive value, 94% (95% CI, 87%-98%). Conclusions and Relevance:124I-evuzamitide PET/CT is highly sensitive and specific for diagnosing cardiac amyloidosis with an acceptable safety profile. These results support 124I-evuzamitide PET/CT as a diagnostic test to evaluate patients with suspected cardiac amyloidosis. Trial Registration:ClinicalTrials.gov Identifier: NCT06788535.

BACKGROUND:Myocardial hypertrophy and interstitial fibrosis are the structural hallmarks evaluated on histopathology in heart failure (HF). Direct study of myocardial tissue has re-emerged as a strategy to dissect the biology of HF with preserved ejection fraction (HFpEF), but whether these features, assessed together, define distinct subgroups within HF phenotypes remains unknown. OBJECTIVES:We assessed whether phenogroups defined by fibrosis and hypertrophy (histogroups) display distinct clinical profiles and outcomes in HFpEF versus HF with reduced ejection fraction (HFrEF). METHODS:We identified patients with HF who underwent right ventricular endomyocardial biopsy (EMB) from 1999 to 2023, after excluding transplant, infiltrative, inflammatory, and hypertrophic cardiomyopathy cases. Patients with HFpEF (LVEF ≥50%; n=124) and HFrEF (LVEF <50%; n=170) were studied. A single cardiac pathologist, blinded to clinical data, graded fibrosis semiquantitatively and measured cardiomyocyte diameter to assess hypertrophy. Prespecified histogroups integrated the severity of fibrosis and hypertrophy. Associations with clinical characteristics and 10-year all-cause mortality were assessed separately in HFpEF and HFrEF. RESULTS:In HFpEF, more advanced histogroups showed a higher proportion of men, diabetes, higher NT-proBNP, lower LVEF, and greater left ventricular mass index (P<0.05 for all), whereas most other clinical and hemodynamic characteristics were similar. The severe histogroup was associated with higher mortality overall and after adjustment for age and sex (severe vs mild: HR, 2.3 [95% CI, 1.05-4.9]; P=0.037), whereas histogroup was not associated with mortality in HFrEF. The prognostic association differed significantly by HF phenotype (adjusted interaction P=0.034). CONCLUSIONS:Integrated assessment of fibrosis and hypertrophy identifies clinically and prognostically distinct histogroups in HFpEF, but not in HFrEF. These findings should be interpreted within the context of a tertiary-referral cohort undergoing diagnostic EMB.

Isolated cardiac sarcoidosis (iCS), defined by granulomatous inflammation limited to the myocardium, represents the most diagnostically challenging and prognostically adverse form of sarcoidosis. As it is fundamentally a diagnosis of exclusion, iCS diagnosis relies on the absence of extracardiac sarcoid and the integration of multimodality imaging, endomyocardial biopsy, and molecular testing, each with inherent limitations. Cardiac magnetic resonance and positron emission tomography provide complementary assessment of inflammation, fibrosis, and ventricular function, enhancing diagnostic confidence. Electroanatomic mapping-guided biopsy may improve histologic yield, whereas genetic testing helps exclude phenocopies such as arrhythmogenic, hypertrophic, or dilated cardiomyopathies. Circulating biomarkers remain non-specific but may complement imaging-based algorithms. Future research should focus on harmonized imaging protocols, non-FDG radiotracers, and molecular tissue profiling to refine activity assessment and guide therapy. Multimodal, probability-based frameworks represent the most promising approach for earlier, more accurate diagnosis and risk stratification in iCS.

AL amyloidosis often presents with nonspecific symptoms, leading to delayed diagnosis and increased early mortality, even in patients with known multiple myeloma or other monoclonal gammopathies. This study assessed the cardiac amyloid artificial intelligence electrocardiogram (CA-AI-ECG) tool’s utility in predicting treatment outcomes and detecting CA in a cohort of multiple myeloma patients undergoing autologous stem cell transplantation (ASCT). Among 2934 multiple myeloma patients studied, 81% received early ASCT (< 12 months from diagnosis) and therefore had an early ECG performed (early ASCT/ECG cohort), with 5% having a positive pre-ASCT CA-AI-ECG score. In the early ASCT/ECG group, a positive CA-AI-ECG score did not correlate with decreased overall survival. However, in the delayed ASCT/ECG group, a positive CA-AI-ECG score was associated with significantly lower overall survival (HR: 1.73, 95% CI: 1.07–2.78), remaining an independent risk factor on multivariate analysis. The observed overall survival difference between cohorts may be attributable to the longer time interval from diagnosis to ECG in the delayed ASCT group, leading to prolonged light chain exposure. During follow-up, 25 patients developed AL amyloidosis, of which, 12 patients had systemic involvement. Those with a positive pre-ASCT CA-AI-ECG were five times as likely to progress to systemic amyloidosis compared to those with a negative score (LR 5.0 p=0.025). These findings suggest that the CA-AI-ECG tool may enhance subclinical CA detection, especially as an early screening tool.

BACKGROUND:To improve screening for cardiac amyloidosis (CA), several models using artificial intelligence (AI) and conventional statistics have been developed. However, few data are available to compare the relative utility of these tools. In this study, models were compared to determine their potential roles in optimizing diagnostic algorithms. METHODS:In this retrospective cohort study at a tertiary medical center, patients referred for cardiac scintigraphy for the detection of transthyretin amyloid CA (ATTR-CA) who underwent electrocardiography (ECG) and transthoracic echocardiography within 6 months and had clinical characteristics for risk score calculation were included. The performance of previously developed and validated clinical and AI risk models for ATTR-CA, including the transthyretin amyloid cardiomyopathy (ATTR-CM) clinical score and AI models applied to ECG (AI-ECG) and echocardiography (AI-Echo), was compared in a population referred for cardiac scintigraphy. Previously defined thresholds were used for each model. As the ATTR-CM score was validated following the exclusion of monoclonal immunoglobulin light chain (AL) amyloidosis, 28 patients with AL amyloidosis were excluded. AL amyloidosis and ATTR-CA were defined per guideline criteria. RESULTS:Among 598 patients (median age, 76 years; interquartile range, 67-82 years; 72.6% men), 181 (30%) had ATTR-CA. AI-Echo identified ATTR-CA with 86% sensitivity and 85% specificity, compared with 80% and 64% for AI-ECG and 86% and 69% for the ATTR-CM score. The area under the receiver operating characteristic curve was 0.93 (95% CI, 0.91-0.95) for AI-Echo, 0.79 (95% CI, 0.76-0.83) for AI-ECG, and 0.87 (95% CI, 0.84-0.90) for ATTR-CM score (P < .001). In this cohort, the use of AI-Echo could have avoided more unnecessary scintigraphy than AI-ECG or ATTR-CM score (45 vs 24 vs 37 per 100, respectively) at a threshold probability of 0.25 (1 case of ATTR-CA per 4 referrals for scintigraphy). CONCLUSIONS:Within a population at high risk for CA, the AI-Echo model demonstrated superior diagnostic discrimination and clinical utility for the identification of ATTR-CA compared with the AI-ECG model and the ATTR-CM clinical score.

Infiltrative and inflammatory cardiomyopathies carry substantial morbidity and mortality. Nonspecific clinical presentations can delay recognition; prognostic tools are limited. Artificial intelligence (AI) can mine clinical, imaging, biomarker, and histologic data to reveal multidimensional patterns beyond conventional interpretation. In infiltrative cardiomyopathies, early applications have concentrated on cardiac amyloidosis, with emerging work in Fabry disease and myocardial iron overload. For inflammatory cardiomyopathies, early studies suggest roles for AI-enhanced electrocardiography and imaging in detection, prognosis, and guidance for therapy. Evidence remains largely single-center, retrospective, and small, with heterogeneous comparators and risks of circularity, limiting generalizability. Ethical, regulatory, and implementation barriers also impede adoption. AI’s likely value is in complementing clinical judgment by flagging subtle signals that deserve attention and in nudging clinicians toward earlier or more focused testing. In this review, we outline recent progress, reflect on the barriers that remain, and consider how these tools might eventually be woven into everyday care.

Cardiac amyloidosis (CA) has transitioned from a rare, frequently fatal disease to an increasingly recognized cause of heart failure, driven by heightened awareness, noninvasive diagnostic strategies, and the advent of disease-modifying therapies. As a result, molecular imaging has become central to contemporary management by providing signals that reflect underlying disease biology. Transthyretin CA predominantly involves progressive extracellular fibril accumulation causing myocardial stiffening, whereas light-chain CA is characterized by early myocardial dysfunction mediated by direct proteotoxic effects of circulating light chains in addition to extracellular fibril accumulation. These divergent mechanisms may underlie different behaviors of diagnostic imaging such as bone-avid scintigraphy and β-sheet-binding positron emission tomography tracers. In this compendium review, we integrate pathophysiological insights across major and rarer amyloid subtypes with nuclear imaging and contextualize these mechanisms through clinical phenotypes, red flags, and risk stratification tools.

BACKGROUND:Technetium-based cardiac amyloid radionuclide imaging enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM), but conventional planar and visual semiquantitative approaches have important limitations. We developed the quantitative 3-dimensional Mayo 3D Score, defined as the ratio of mean left ventricular myocardial radiotracer uptake to right atrial blood-pool uptake using computed tomography (CT)-fused single-photon emission CT (SPECT) volumes of interest, and sought to validate its diagnostic performance against myocardial pathology. METHODS:Consecutive patients who underwent 99mTc-pyrophosphate SPECT/CT at Mayo Clinic for suspected ATTR-CM between June 2017 and January 2025 with archived myocardial tissue were included. Baseline characteristics, including demographics, echocardiogram, biomarkers, visual semiquantitative, and Mayo 3D Score metrics, were collected. Myocardial specimens underwent histopathologic confirmation of amyloid, with amyloid subtype determination and further semiquantitative grading of amyloid burden and deposition patterns. RESULTS:Among 230 patients (median age, 72 years; 78% male), 107 (47%) had ATTR-CM, of whom 9 had hereditary ATTR-CM. The Mayo 3D Score showed excellent discrimination against pathology (area under the receiver operating characteristic curve, 0.92 [0.88-0.96]), exceeding planar Perugini (0.87 [0.83-0.92]; P=0.006), and heart-to-contralateral lung ratio (0.86 [0.81-0.91]; P=0.004) and comparable to SPECT Perugini (0.90 [0.86-0.94]; P=0.12). A cutoff ≥1.0 yielded 86.0% sensitivity, 92.7% specificity, 91.1% positive predictive value, and 88.4% negative predictive value. Among ATTR-positive cases, the Mayo 3D Score correlated strongly with semiquantitative amyloid burden (Spearman ρ=0.69), was higher in pericellular than nodular deposition patterns (P<0.001), and was not associated with vascular involvement (P=0.42). CONCLUSIONS:In patients with suspected ATTR-CM undergoing 99mTc-pyrophosphate SPECT/CT, the Mayo 3D Score demonstrated superior diagnostic performance compared with planar metrics and comparable to SPECT Perugini, while correlating with myocardial ATTR burden and deposition patterns on pathology. These findings support its integration as a quantitative adjunct within clinical diagnostic ATTR-CM workflows.

Importance Diagnosing cardiac amyloidosis remains challenging because current imaging approaches are limited to transthyretin amyloidosis. A noninvasive test capable of directly imaging cardiac amyloidosis from various amyloid types and in multiple organs could address an important unmet diagnostic need. Objective To evaluate the sensitivity and specificity of 124 I-evuzamitide positron emission tomography (PET)/computed tomography (CT) for diagnosing cardiac amyloidosis. Design, Setting, and Participants Prospective, multicenter (18 US centers), single-group study evaluating the efficacy of 124 I-evuzamitide to diagnose cardiac amyloidosis. This study was conducted from January 14, 2025, to March 12, 2026, including a 60-day follow-up period. Three physicians with cardiac PET/CT experience independently reviewed PET/CT images for visual cardiac 124 I-evuzamitide uptake while blinded to clinical data. Three expert clinical amyloidosis physicians, blinded to PET/CT data, independently adjudicated the diagnosis based on the standard-of-care diagnostic algorithm. A total of 195 adults suspected of having cardiac amyloidosis were enrolled when they presented for diagnostic evaluation at participating institutions, excluding patients with an established diagnosis of cardiac or systemic amyloidosis. Interventions PET/CT scans were obtained 3 to 5 hours after intravenous administration of 1 mCi of 124 I-evuzamitide. Potassium iodide (130 mg) was given orally for 3 days starting at least 30 minutes prior to 124 I-evuzamitide injection. Main Outcomes and Measures Coprimary end points of this study were to assess the sensitivity and specificity of 124 I-evuzamitide for the diagnosis of cardiac amyloidosis. Results Overall, 170 patients were included (median [IQR] age, 72 [64-79] years; 75.3% male, 19.2% Black, 79.0% White). Median N-terminal pro–brain natriuretic peptide was 471 pg/mL and 61.7% had New York Heart Association class II or III heart failure symptoms. The overall sensitivity was 94% (95% CI, 85%-98%; P < .001); specificity, 86% (95% CI, 77%-92%; P < .001); positive predictive value, 85% (95% CI, 75%-92%); and negative predictive value, 94% (95% CI, 87%-98%). Conclusions and Relevance 124 I-evuzamitide PET/CT is highly sensitive and specific for diagnosing cardiac amyloidosis with an acceptable safety profile. These results support 124 I-evuzamitide PET/CT as a diagnostic test to evaluate patients with suspected cardiac amyloidosis. Trial Registration ClinicalTrials.gov Identifier: NCT06788535

BACKGROUND:The Mayo transthyretin amyloid cardiomyopathy (ATTR-CM) and AMY scores were developed to identify patients at risk for ATTR-CM. However, both were derived largely from White male cohorts with preserved ejection fraction (EF ≥40%) and their performance in more diverse populations is uncertain. OBJECTIVES:The objective of the study was to validate and compare performance of the Mayo ATTR-CM and AMY scores across racially, ethnically, and sex-diverse populations, and across the EF spectrum. METHODS:Two complementary cohorts were evaluated: a Mayo Clinic cardiac amyloid radionuclide imaging referral cohort (n = 1,553; 449 [29%] ATTR-CM) and Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations (SCAN-MP), a prospective community-based study of Black or Caribbean Hispanic individuals (n = 646; 43 [6.6%] ATTR-CM). Scores were calculated as published. Discrimination was assessed using receiver operating characteristic-area under the curve (AUC), with comparisons performed using DeLong's nonparametric method. RESULTS:The Mayo ATTR-CM score demonstrated superior discrimination in both cohorts (AUC: 0.86; 95% CI: 0.84-0.88 Mayo; AUC: 0.81; 95% CI: 0.75-0.87 SCAN-MP) compared with AMY (AUC: 0.67; 95% CI: 0.64-0.70 Mayo; AUC: 0.70; 95% CI: 0.62-0.78 SCAN-MP; DeLong P < 0.001 for both). Performance remained robust among individuals with EF <40% and among women. The AMY score showed lower sensitivity across cohorts. Among individuals exceeding score cutoffs, the probability of ATTR-CM ranged from ∼1 in 2 in the Mayo cohort to ∼1 in 6 in SCAN-MP. CONCLUSIONS:The Mayo ATTR-CM score demonstrates strong, consistent performance across diverse populations, including women, Black, and Hispanic individuals, and those with reduced EF, and outperforms the AMY score. Its reliance on routinely available clinical and echocardiographic data supports automated implementation and may facilitate earlier detection of ATTR-CM.

BACKGROUND:Guidelines recommend 3-hour cardiac amyloid radionuclide imaging (CARI) for transthyretin amyloid cardiomyopathy. Citing rapid blood clearance of 99mTc-hydroxymethylene-diphosphonate (HMDP) and efficient laboratory throughput, 1-hour imaging is increasingly practiced despite limited supporting evidence. We sought to compare diagnostic performance and interpreter experience of 1-hour versus 3-hour HMDP-CARI. METHODS:Consecutive patients with suspected transthyretin amyloid cardiomyopathy (n=114) underwent both 1-hour and 3-hour HMDP single photon emission computed tomography (CT)/CT. Two cardiologist-radiologist reader teams, blinded to imaging timepoint (1 versus 3 hours), assessed overall interpretation, single photon emission CT-based Perugini grade, interpretation difficulty, interpreter confidence, and need for CT-fused images for anatomic localization. Discordant, equivocal, and difficult cases were arbitrated by a third tie-breaking team. The myocardial-to-blood-pool radiotracer uptake ratio (3-dimensional Score) was measured as a surrogate of contrast resolution. RESULTS:Interinterpreter agreement was high at both time points (κ≥0.81), with more cases requiring arbitration at 3 hours versus 1 hour (22% versus 13%; P=0.049). Overall interpretation and Perugini grades were concordant between time points in 111/114 (97%) and 106/114 (93%) patients, respectively. Three patients (3%) were negative at 1 hour but equivocal at 3 hours, all of which were clinically ruled out for transthyretin amyloid cardiomyopathy. Interpreter confidence was comparable at both timepoints (97% versus 95%; P=0.317). Compared with 3-hour imaging, contrast resolution was inferior (lower 3-dimensional score, P<0.001) and CT fusion was more frequently needed (57% versus 31%, P<0.001) at 1-hour imaging. CONCLUSIONS:In a prospective, blinded comparison of 1-hour versus 3-hour HMDP-CARI, diagnostic performance and interpreter experience were similar, with readers requesting CT fusion more frequently at 1 hour to optimize myocardial-to-blood pool discrimination.

BACKGROUND Technetium Tc 99m pyrophosphate scintigraphy (99mTc PYP imaging) is a diagnostic tool for transthyretin amyloid cardiomyopathy (ATTR-CM). Cardiac biomarkers, particularly high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), may help identify patients at low or high risk for ATTR-CM. OBJECTIVES The authors sought to evaluate the predictive value of hs-cTnT and NT-proBNP in patients undergoing 99m Tc PYP imaging for suspected ATTR-CM in a large U.S. cohort. METHODS This was a retrospective study of patients who underwent 99m Tc PYP imaging between May 2013 and September 2022, including those with at least 1 hs-cTnT measurement within 6 months of the scan. RESULTS ATTR-CM was diagnosed in 427 of 1,442 patients (29.6%). A hs-cTnT level <6 ng/L (n = 50, 3.5%) showed a negative predictive value of 100% (95% CI: 93%-100%) and sensitivity of 100% (95% CI: 99%-100%) for ruling out ATTR-CM. As the hs-cTnT threshold increased, the number of patients who could be ruled out also increased, but false negatives emerged. The positive predictive value for ruling in ATTR-CM remained low. NT-proBNP showed similar results (n = 1,378). The combination of hs-cTnT <14 ng/L and NT-proBNP <60 ng/L identified 45 patients (3.3%) without ATTR-CM. CONCLUSIONS In patients undergoing 99m Tc PYP imaging for suspected ATTR-CM, very low hs-cTnT levels can effectively rule out the diagnosis, although in a small subset of patients. Higher thresholds increase the risk of false negatives. NT-proBNP and combined biomarker strategies showed similar trends, the utility of hs-cTnT and NT-proBNP for ruling in the disease is limited. (JACC CardioOncol. 2025;7:70-78) (c) 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND:The prognosis in patients with advanced cardiac amyloidosis (CA) remains poor. OBJECTIVES:We sought to describe survival post heart transplantation (HT) in amyloid compared with non-amyloid recipients, highlight waitlist times within the new allocation system across three Organ Procurement and Transplantation Network (OPTN) regions, and describe multiorgan transplantation (MOT) in hereditary amyloidosis. METHODS:This is a retrospective review of end-stage CA patients who underwent HT at Mayo Clinic from January 2007 to December 2020. Wait time was compared in the new versus old OPTN allocation era starting December 18, 2018 by Wilcoxon rank sum test. All-cause mortality for those with and without CA was compared using Kaplan-Meier estimates with log rank analysis, censoring December 16, 2022. RESULTS:Fifty-five patients with CA underwent HT between 2007 and 2020, 8 light chain amyloidosis (AL) (14.5%), 28 hereditary transthyretin (ATTRv) (50.9%), 17 wildtype transthyretin (ATTRwt) (30.9%), and 2 hereditary apolipoprotein A1 (AApoA1) amyloidosis patients (3.6%). No significant difference in overall survival post-transplant was seen in amyloid compared with non-amyloid (p = 0.816). Median time to HT was shorter in the new system, 45 days (IQR 24, 78) versus 174 days (IQR 76.5, 483.5), p = 0.006. There was a decline in MOT in hereditary amyloidosis over time with the concomitant rise in disease-targeted therapies. CONCLUSIONS:HT survival in CA patients was similar to non-amyloid patients. The new allocation system benefits this cohort with shorter wait times. There is less MOT in hereditary amyloidosis with increased utilization of disease-targeted therapy.

AIMS:The safety and efficacy of heart failure (HF)-directed medical therapy among patients who might be considered for further diagnostic evaluation to rule out transthyretin amyloid cardiomyopathy (ATTR-CM) is largely unknown. METHODS AND RESULTS:We applied a previously validated ATTR-CM screening score in patients with HF and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and assessed treatment effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i), angiotensin receptor-neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRAs) based on their score-based ATTR-CM risk, from the DELIVER, PARAGON-HF and TOPCAT Americas trials. We applied a re-derived five-variable modified ATTR-CM score (range -1 to 9) which included age, male sex, hypertension, left ventricular ejection fraction <60%, posterior wall thickness ≥12 mm. We calculated the modified ATTR-CM risk score from DELIVER (available in 4085 patients; 65%), PARAGON-HF (4067; 85%) and TOPCAT Americas (645; 37%). Median scores were 5 (interquartile range [IQR] 4-6) in DELIVER and 4 (IQR 3-6) in both PARAGON-HF and TOPCAT Americas. Higher modified ATTR-CM score was associated with greater risk of the primary endpoint for each trial. However, ATTR-CM risk score did not significantly modify the treatment effect of dapagliflozin (pinteraction = 0.85), sacubitril/valsartan (pinteraction = 0.10), or spironolactone (pinteraction = 0.57). The safety profile of each drug was consistent irrespective of modified ATTR-CM score. CONCLUSIONS:Among three large contemporary HFmrEF/HFpEF trials, the safety and efficacy of SGLT2i, ARNI, and MRA were not modified in patients at risk for ATTR-CM, suggesting that the diagnostic process to rule out amyloidosis should not necessarily delay the introduction of conventional HF medical therapies. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifiers: DELIVER, NCT03619213; PARAGON-HF, NCT01920711; TOPCAT, NCT00094302.

Light chain amyloidosis and transthyretin amyloidosis are rare protein misfolding disorders characterized by amyloid deposition in organs, varied clinical manifestations, and poor outcomes. Amyloid fibrils trigger various signaling pathways that initiate cellular, metabolic, structural, and functional changes in the heart and other organs. Imaging modalities have advanced to enable detection of amyloid deposits in involved organs and to assess organ dysfunction, disease stage, prognosis, and treatment response. The Amyloidosis Forum hosted a hybrid meeting to focus on the use of imaging endpoints in clinical trials for systemic immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Stakeholders from academia and industry, together with representatives from multiple regulatory agencies reviewed the use of imaging biomarkers with a focus on cardiac amyloidosis, described applications and limitations of imaging in clinical trials, and discussed qualification of imaging as a surrogate clinical outcome. Survey results provided important patient perspectives. This review summarizes the proceedings of the Amyloidosis Forum.

BACKGROUND:Cardiac amyloid radionuclide imaging (CARI) with 99mTc-pyrophosphate (PYP) enables the noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Recent PYP shortages have necessitated substitution with 99mTc-hydroxymethylene diphosphonate (HMDP), yet direct comparative data are limited. We aimed to compare scan interpretation, ATTR-CM prevalence, and myocardial-to-blood pool discrimination between PYP and HMDP in real-world clinical practice. METHODS:We retrospectively analyzed 992 consecutive patients who underwent SPECT/CT for suspected ATTR-CM at a single referral center between October 2022 and January 2025. PYP was used except during two shortage periods (December 2023 to February 2024 and October 2024 to January 2025), when HMDP was substituted. Scan interpretation and final ATTR-CM diagnoses were recorded. The myocardial-to-blood-pool radiotracer uptake ratio (3D Score) was measured as a surrogate for contrast resolution. RESULTS:Of 992 unique patients (median age 76, 27% female), 816 received PYP and 176 (18%) received HMDP. Baseline clinical, echocardiographic, and biomarker characteristics were similar between groups. Rates of positive scans (PYP: 26%, HMDP: 25%; P = 0.95) and final ATTR-CM diagnoses (28% vs 26%; P = 0.59) were comparable. Among patients with positive scans (n = 256), HMDP yielded significantly higher 3D Scores (2.0 [1.7-2.5] vs 1.4 [1.2-1.7], P < 0.001), suggesting enhanced myocardial-to-blood pool contrast resolution. CONCLUSIONS:In a large cohort with similar clinical profiles, HMDP provided equivalent diagnostic yield and superior myocardial-to-blood-pool discrimination compared to PYP. These findings support HMDP as a good alternative during PYP shortages, with potential advantages in contrast resolution.