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Purpose of Review: Recent evidence suggests that transthyretin cardiac amyloidosis (ATTR-CM) is significantly more common than once believed, yet it remains frequently under- and mis-diagnosed. With effective treatments now available, early and accurate diagnosis has become critical for better patient outcomes. Understanding the interplay between genetics, race, and social determinants of health (SDOH) in influencing both ATTR-CM diagnosis and management is essential for bridging the current gaps., Recent Findings: Our analysis reveals multiple barriers affecting ATTR-CM care. Specifically, we discuss how clinician awareness, regional differences in clinical practice, and limited access to health care and specialty centers contribute to diagnostic delays. Additionally, we identify several management obstacles, such as inadequate diversity in clinical trials, high cost of available treatments, and limited ancillary resources. We examine these challenges in detail and provide practical solutions to address them. While disparities in heart failure outcomes have been well-documented, those specific to ATTR-CM remain underrepresented in the literature. This review establishes a structured approach to understanding how biological, structural and SDOH-related disparities impact ATTR-CM diagnosis and management while offering concrete strategies to overcome these challenges. We emphasize the need for enhanced SDOH identification and advocate for coordinated, multidisciplinary efforts to improve ATTR-CM patient outcomes., Competing Interests: Declarations. Human and Animal Rights and Informed Consent: All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines). Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE., Methods: Participants who previously received acoramidis through month 30 in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through month 30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through month 42 included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, serum transthyretin, and Kansas City Cardiomyopathy Questionnaire Overall Summary score. Safety outcomes were analyzed through month 42., Results: Overall, 438 of 632 participants in ATTRibute-CM completed treatment, and 389 enrolled in the ongoing OLE (263 continuous acoramidis and 126 placebo to acoramidis). The hazard ratio for ACM or first CVH was 0.57 (95% CI, 0.46-0.72) at month 42 based on a stratified Cox proportional hazards model ( P <0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with hazard ratios of 0.64 (95% CI, 0.47-0.88) and 0.53 (95% CI, 0.41-0.69), respectively, at month 42. Treatment effects for NT-proBNP and 6-minute walk distance also favored continuous acoramidis. On initiation of open-label acoramidis in the placebo-to-acoramidis arm, there was a prompt increase in serum transthyretin. Quality of life assessed by Kansas City Cardiomyopathy Questionnaire Overall Summary score was well preserved in continuous-acoramidis participants compared with the placebo-to-acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation., Conclusions: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through month 42 of the ongoing OLE study were associated with sustained clinical benefits in a contemporary transthyretin amyloid cardiomyopathy cohort, with no clinically important safety issues newly identified., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04988386., Competing Interests: Dr Judge has received consultancy fees from Alexion Pharmaceuticals, Alleviant Medical, Alnylam Pharmaceuticals, Attralus, BridgeBio Pharma, Cytokinetics, Lexeo Therapeutics, Novo Nordisk, Pfizer, Rocket Pharmaceuticals, Renovacor, and Tenaya Therapeutics; his institution received clinical trial funding from Array Biopharma, BridgeBio Pharma (formerly Eidos Therapeutics), MyoKardia, and Pfizer. Dr Gillmore has acted as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio Pharma, Intellia Therapeutics, Ionis Pharmaceuticals, Lycia Therapeutics, and Pfizer. Dr Alexander has acted as a consultant, advisor, or speaker for Arbor Biotechnologies, Attralus, Intellia Therapeutics, and Prothena Biosciences. Dr Ambardekar reports no conflicts. Dr Cappelli has acted as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, Amicus Therapeutics, AstraZeneca, BridgeBio Pharma (formerly Eidos Therapeutics), Novo Nordisk, Bayer, and Pfizer. Dr Fontana has acted as a consultant, advisor, or speaker for Alnylam, Alexion, AstraZeneca, Attralus, Bayer, BridgeBio Pharma (formerly Eidos Therapeutics), Caelum Biosciences, Cardior, Intellia Therapeutics, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Lexeo Therapeutics, Novo Nordisk, Pfizer, and Prothena Biosciences; owns stock or stock options of Lexeo Therapeutics and Myocardium; has received research grants from Alnylam, AstraZeneca, BridgeBio Pharma, and Pfizer; and has received a salary from British Heart Foundation intermediate fellowship. Dr García-Pavía has acted as a consultant, advisor, or speaker for Alexion Pharmaceuticals, Alnylam Pharmaceuticals, AstraZeneca, Attralus, Bayer, BridgeBio Pharma (formerly Eidos Therapeutics), Intellia Therapeutics, Ionis Pharmaceuticals, Neuroimmune, Novo Nordisk, and Pfizer; his institution received research or educational funding from Alnylam Pharmaceuticals, AstraZeneca, BridgeBio Pharma (formerly Eidos Therapeutics), Intellia Therapeutics, Novo Nordisk, and Pfizer. Dr Grodin has acted as a researcher for the Texas Health Resources clinical scholarship, BridgeBio Pharma (formerly Eidos Therapeutics), Pfizer, and National Heart, Lung, and Blood Institute (R01HL160892) and as a consultant, advisor, or speaker for Alexion, Alnylam, AstraZeneca, BridgeBio Pharma, Intellia, Lumanity, Novo Nordisk, Pfizer, Tenax Therapeutics, and Ultromics. Dr Grogan has acted as a researcher for Alnylam Pharmaceuticals, BridgeBio Pharma (formerly Eidos Therapeutics), Intellia Therapeutics, Janssen Pharmaceuticals, Novo Nordisk, and Pfizer and as a consultant, advisor, or speaker for Alnylam, BridgeBio Pharma, Janssen Pharmaceuticals, Novo Nordisk, and Pfizer. Dr Hanna has acted as a consultant, advisor, or speaker for Alexion Pharmaceuticals, Alnylam Pharmaceuticals, Attralus, BridgeBio Pharma (formerly Eidos Therapeutics), Ionis Pharmaceuticals, and Pfizer. Dr Masri has acted as a researcher for Attralus, Cytokinetics, Ionis Pharmaceuticals, and Pfizer and as a consultant, advisor, or speaker for Akros Pharma, Alexion Pharmaceuticals, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BioMarin Pharmaceutical, BridgeBio Pharma (formerly Eidos Therapeutics), Bristol Myers Squibb, Cytokinetics, Haya Therapeutics, Ionis Pharmaceuticals, Lexicon Pharmaceuticals, Pfizer, Prothena Biosciences, and Tenaya Therapeutics. Dr Nativi-Nicolau has acted as a researcher for Alnylam Pharmaceuticals, AstraZeneca, BridgeBio Pharma (formerly Eidos Therapeutics), and Pfizer. Dr Obici has acted as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, AstraZeneca, BridgeBio Pharma (formerly Eidos Therapeutics), Ionis Pharmaceuticals, Novo Nordisk, Pfizer, and Sobi–Swedish Orphan Biovitrum. Dr Hvitfeldt Poulsen has received consulting fees from Bayer A/S, BridgeBio Pharma (formerly Eidos Therapeutics), and Pfizer A/S and research support from Novo Nordisk A/S. Dr Sarswat has acted as a researcher for Pfizer and as a consultant, advisor, or speaker for Alnylam, AstraZeneca, BridgeBio Pharma (formerly Eidos Therapeutics), Novo Nordisk, and Pfizer. Dr Shah has acted as a consultant, advisor, or speaker for Pfizer. Dr Soman has acted as a researcher for Pfizer and as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, BridgeBio Pharma (formerly Eidos Therapeutics), and Pfizer. Drs Lystig, Cao, Wang, Pecoraro, Tamby, Katz, Sinha, and Fox are employees and stockholders of BridgeBio Pharma. Dr Maurer has acted as a researcher for the National Institutes of Health (R01HL139671 and R01AG081582-01), Alnylam Pharmaceuticals, Attralus, BridgeBio Pharma (formerly Eidos Therapeutics), Intellia Therapeutics, Ionis Pharmaceuticals, and Pfizer and as a consultant or advisor for Akcea Therapeutics, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio Pharma (formerly Eidos Therapeutics), Intellia Therapeutics, Ionis Pharmaceuticals, Novo Nordisk, and Pfizer.

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., Competing Interests: Funding Support and Author Disclosures The Amyloidosis Forum is funded by the Amyloidosis Research Consortium (ARC). ARC is funded through private/philanthropic donations and grants from for-profit pharmaceutical and biotechnology companies. ARC retains all influence, control, and autonomy over projects for which it has received external support. ARC has received grants from Alexion, Alnylam, Attralus, joint funding from AstraZeneca and Ionis, BridgeBio, GlaxoSmithKline, Intellia Therapeutics, Janssen, Life Molecular Imaging, Pfizer, Protego, and Prothena in support of the Amyloidosis Forum Pathways for the Development of Imaging Endpoints meeting. ARC was responsible for designing the meeting, co-developing the meeting agenda, recruitment of speakers, moderators, and panelists, production of meeting materials, hosting the hybrid meeting, and publications. U.S. Government Employee Disclaimer: This paper reflects the views of the authors and should not be construed to represent official views or policies of the U.S. Food and Drug Administration, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), or the U.S. Department of Health and Human Services. Medicines and Healthcare Products Regulatory Agency (MHRA) Disclosure: The positions expressed in this document are individual opinions and should not be interpreted as agreed positions or policy of MHRA or the UK government. European Medicines Agency (EMA) Disclosure: This paper reflects the views of the authors and should not be interpreted as official positions of EMA, or member agencies, specifically the Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM), or Agence Nationale de Securite du Medicament et des Produtis de Sante (ANSM). Dr Dorbala has received research grants from Pfizer, Attralus, GE Healthcare, Siemens, and Phillips; and consulting fees from Pfizer, BridgeBio, Novo Nordisk, and MedScape. Dr Alexander has received consulting fees from Alnylam, Arbor Biotechnologies, Bristol Myers Squibb, Intellia, and Novo Nordisk. Dr Brambatti is a shareholder at Ionis pharmaceuticals and employee and shareholder at Merck and Co. Dr Cuddy has received grant support from NIH 1K23HL166686-01 and American Heart Association 23CDA857664; and personal fees from Pfizer, Eidos/BridgeBio, Ionis, AstraZeneca, and Novo Nordisk. Dr Dispenzieri is on the advisory board and independent review committee of Janssen, Oncopeptides, and Sorrento; is on the data monitoring safety committee of Alnylam, Pfizer, and Takeda; and has received research dollars from BMS. Dr Ezzeddine has received research grants from Pfizer Inc; consulting fees from Alnylam Pharmaceuticals and Medscape from WebMD; and intellectual property on AI-enabled amyloid detection from ECG/Anumana, Inc. Dr Falk has received consulting fees from Alnylam and AstraZeneca. Dr Fontana is on the advisory board and/or a consultant for Alexion, Alnylam, Caelum, Intellia, Janssen, Novo Nordisk, Pfizer, Attralus, Lexeo, and Prothena. Dr Grodin has received sources of funding from Texas Health Resources Clinical Scholarship, Pfizer, Eidos/BridgeBio, and NHLBI (R01HL160892); and consultancy fees from Alnylam, AstraZeneca, Intellia Pfizer, Eidos/BridgeBio, and Sarepta. Dr Guthrie is an employee and shareholder of Attralus. Dr Hofling is a U.S. government employee. Dr Lin is an advisory board member for Ionis (Cardio TTransform Trial); and has received research funding for an investigator-initiated trial on TTR amyloid from Pfizer and Biotronik. Dr Masri has received research grants from Pfizer, Ionis, Attralus, and Cytokinetics; and fees from Cytokinetics, BMS, Eidos, Pfizer, Ionis, Lexicon, Alnylam, Attralus, Haya, BioMarin, and Tenaya. Dr Maurer has received grant support from NIH R01HL139671 and R01AG081582-01; grants and personal fees from Alnylam, Pfizer, Eidos, Prothena, and Ionis; and personal fees from AstraZeneca, Akcea, Intellia, and Novo Nordisk. Dr Mittmann is an employee of EMA/BrArM. Dr Quarta is an Alexion/AstraZeneca employee. Dr Race is an employee of EMA/ANSM. Dr Rajendran is a U.S. government employee. Dr Ruberg has received research grants from NIH/NHLBI (HL139671), Alnylam, Akcea/Ionis, and Pfizer; and consulting fees from AstraZeneca. Dr Sanchorawala has received research support from Celgene, Millennium-Takeda, Janssen, Prothena, Sorrento, Karyopharm, Oncopeptide, Caelum, and Alexion; consultant fees from Pfizer, Jansen, and Attralus; and is on the scientific advisory board for Proclara, Caelum, Abbvie, Janssen, Regeneron, Protego, Pharmatrace, Telix, Prothena, and AstraZeneca. Dr Signorovitch is an employee of Analysis Group, Inc, which has received consulting fees from ARC. Dr Sirac has received a research grant from Attralus, Inc. Dr Soman has received institutional grants from Pfizer; and consultancy fees from Pfizer, Anylam, BridgeBio, and Spectrum Dynamics. Dr Sperry has received personal fees from Pfizer, AstraZeneca, Alnylam, and BridgeBio. Dr Stephens is a full-time employee of Life Molecular Imaging, GmbH. Dr Stockbridge is a U.S. government employee. Dr Vest is an employee and shareholder of Alnylam Pharmaceuticals. Dr Wall is an inventor of IP related to iodine (124)I evuzamitide; and is co-founder, shareholder, and chief scientific officer of Attralus, Inc. Dr Wechalekar is on the advisory board/received honorarium from Janssen, GlaxoSmithKline, Prothena, Alexion/AstraZeneca, and Attralus. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosures MGK reports institutional research support from Pfizer, BridgeBio Pharma, Alnylam Pharmaceuticals, and Ionis Pharmaceuticals, consulting/advisory board support from BridgeBio Pharma and Alnylam Pharmaceuticals, and is a member of Alnylam Pharmaceuticals Speaker's Bureau. OAO receives research support from National Institute on Minority Health and Health Disparities (5R01-MD016401) KMA has received an investigator-initiated research grant from Alnylam and consulting fees from Arbor Biotechnologies, Attralus, Intellia, and Prothena. SHS reports research funding through sponsored research agreements to Duke University from Astra Zeneca, Lilly, and Verily and is a coinventor of unlicensed patents held by Duke University. SS receives research support from the National Heart, Lung, and Blood Institute (K23HL161348), Doris Duke Charitable Foundation (#2020061), American Heart Association (#935275), the Mandel Foundation, Duke Heart Center Leadership Council, the Institute for Translational Medicine and Therapeutics, and Foundation for Sarcoidosis Research and has participated in advisory boards for AstraZeneca. All other authors report no relevant disclosures.