Review Article

Transthyretin Amyloid Cardiomyopathy: The Plot Thickens as Novel Therapies Emerge

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Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) has transitioned from an underdiagnosed condition to a rapidly evolving therapeutic frontier. This review highlights the expanding treatment landscape, beginning with evidence from key clinical trials for transthyretin tetramer stabilizers and RNA silencers, and extending to novel therapies including gene-editing agents and monoclonal antibody-based fibril depleters. We summarize pivotal trial data – including the ATTR-ACT, HELIOS-B, and APOLLO-B trials – and describe ongoing investigations aimed at broadening therapeutic options. Practical considerations such as route and frequency of administration, tolerability, and regulatory status are outlined to support clinical decision-making. A dedicated section on limitations and special populations addresses the generalizability of trial findings to the diverse patients encountered in practice. Finally, we explore key unresolved questions, including the need for head-to-head comparative trials, the potential role of combination therapy, and the optimal timing for initiating treatment as earlier recognition becomes more common. As novel therapies gain approval this review serves as a timely, focused resource to support clinicians managing ATTR-CM.

Keywords

Amyloidosis, transthyretin, tafamidis, acoramidis, vutrisiran, cardiomyopathy, novel therapies,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/usc.2025.11

Disclosure: JLG has received consulting fees from Pfizer, Novo Nordisk, Tenax Therapeutics, Lumanity, Ultromics, AstraZeneca, Alexion, Alnylam, and Eidos/BridgeBio and research funding from Pfizer, Eidos/BridgeBio, Texas Health Resources Clinical Scholars Program, and NHLBI R01HL160892, and has served on a data safety monitoring board for Tenax Therapeutics and a steering committee for BridgeBio. All other authors have no conflicts of interest to declare.

Correspondence: Justin L Grodin, MD, MPH, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9045, US. E: Justin.Grodin@utsouthwestern.edu

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease characterized by the deposition of misfolded transthyretin (TTR) fibrils in the myocardium (Figure 1). It occurs in both hereditary variant (ATTRv) and wild-type (ATTRwt) forms and is increasingly recognized as a key cause of heart failure in older adults. Although conventional heart failure therapies have demonstrated considerable morbidity and mortality benefit in other cardiomyopathies, their efficacy in ATTR-CM has not been established as they are often poorly tolerated due to hypotension and, in some cases, may even be harmful.1,2

Figure 1: Mechanisms of Action for Transthyretin Amyloid Cardiomyopathy Therapies

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For years, there were no reliable treatments for ATTR-CM. In 2019, tafamidis became the first Food and Drug Administration (FDA)-approved treatment for and remained the only available therapy option for ATTR-CM until 2024.3 However, since that time, several novel therapies – including TTR stabilizers, TTR gene silencers, and amyloid fibril depleters – have emerged. Recently, acoramidis and vutrisiran have gained FDA approval for the treatment of ATTR-CM. There are also several clinical trials underway that are testing the efficacy of highly anticipated novel therapies.

This review summarizes current and emerging therapies, their clinical applications, and key considerations regarding treatment selection and timing as the therapeutic landscape continues to expand.

Current and Emerging Therapies for ATTR-CM

There are two broad strategies aimed at treating ATTR-CM: agents that halt amyloid progression, which include TTR tetramer stabilizers and TTR gene silencers and agents that deplete deposited amyloid fibrils, such as monoclonal antibodies and peptides which activate macrophage clearance of amyloid deposits (Supplementary Table 1).

Tetramer Stabilizers

Tetramer stabilizers bind to TTR to prevent tetramer dissociation, which is the rate-limiting step in TTR amyloidogenesis. Two TTR stabilizers, tafamidis and acoramidis, are currently approved by the FDA for the treatment of ATTR-CM.

Tafamidis is a small molecule that selectively binds to the thyroxine binding site of the TTR tetramer and has been evaluated for the treatment of transthyretin amyloid polyneuropathy (ATTR-PN) and ATTR-CM. Tafamidis was initially studied at a low dose (tafamidis meglumine 20 mg/day) and approved in the EU for the treatment of patients with familial amyloidotic polyneuropathy or ATTR-PN.4 The ATTR-ACT trial was a large multicenter randomized controlled trial that included 441 patients with both ATTRv-CM and ATTRwt-CM.5 The primary hierarchical endpoint, assessed at 30 months post-randomization, included all-cause mortality followed by the frequency of cardiovascular hospitalizations. Tafamidis was found to be clinically superior to placebo, as demonstrated by a win ratio of 1.695 (95% CI [1.255–2.289]).5 Secondary outcomes also favored tafamidis because it was associated with a lower all-cause mortality (HR 0.70; 95% CI [0.51–0.96]) and lower rate of cardiovascular-related hospitalization compared with placebo (0.48 versus 0.70/year; 95% CI [0.56–0.81]).5

Acoramidis, while also a TTR stabilizer similar to tafamidis, was specifically designed to mimic the TTR structural stabilization conferred by the p.T139M variant.6 This variant has a protective effect on amyloidogenesis by promoting a more stabilized TTR structure due to the arrangement of hydrogen bonds. As a result, acoramidis binds to the TTR tetramer with high affinity and selectivity.6 Unlike tafamidis, acoramidis has only been evaluated in ATTR-CM. The ATTRibute-CM trial included 632 patients with symptomatic heart failure and either ATTRv-CM or ATTRwt-CM.7 The primary outcome was a hierarchical composite endpoint that incorporated all-cause mortality, cardiovascular hospitalizations, change in N-terminal pro-B-type natriuretic peptide (NT-proBNP), and 6-minute walk distance, which was analyzed using a win ratio. At 30 months, acoramidis was favored over placebo with a win ratio of 1.8 (95% CI [1.4–2.2]).7 All-cause mortality and cardiovascular hospitalizations accounted for 58% of the pairwise comparisons.7 Secondary and post hoc analyses by Judge et al. demonstrated that acoramidis was associated with a 36% RR reduction in the first incidence of all-cause mortality or cardiovascular hospitalization, primarily driven by fewer cardiovascular hospitalizations, and a 50% reduction in the frequency of cardiovascular hospitalizations.8 Long-term follow up of ATTRibute-CM to 42 months showed HR 0.57 (95% CI [0.46–0.72]; p<0.0001) for acoramidis use in comparison with placebo for all-cause mortality or first cardiovascular hospitalization.9

Transthyretin Silencers

Another disease-modifying strategy for ATTR is to inhibit the hepatic synthesis of amyloidogenic TTR. Previously, prophylactic liver transplantation was the long-standing treatment for ATTRv amyloidosis in patients with variant disease and significant polyneuropathy.10 However, due to the emergence of several new promising therapeutics, liver transplantation for ATTRv is uncommon. Inhibiting hepatic synthesis of TTR is accomplished by small RNA-interfering (siRNA) molecules and antisense oligonucleotides (ASO), which act as TTR mRNA silencers by inhibiting TTR mRNA translation.

Revusiran, an early-stage siRNA, was studied in the ENDEAVOUR trial.11 The trial was prematurely stopped at a median 6.7 months due to higher mortality in the revusiran group (12.9%) compared with placebo (3.0%). Post hoc analysis suggested that the patients who died were significantly older (>75 years) and had more advanced heart failure.11 No clear causative mechanism or deleterious effect on cardiovascular parameters was found for the therapy; however, due to this signal of harm, further development of revusiran was halted.11

Patisiran (siRNA molecule) and inotersen (an ASO) are early generation agents that were approved for patients with ATTRv polyneuropathy with or without cardiac involvement. Patisiran has more recently been studied in patients with ATTR-CM in the APOLLO-B trial which included 360 patients with both wild-type and variant ATTR-CM.12 Patisiran met the primary endpoint of a better 6-minute walk test at 12 months showing a smaller decline compared with placebo (−8 m versus −25 m) and the secondary endpoint of an improved Kansas City Cardiomyopathy Questionnaire (KCCQ) score.12 However, data from the APOLLO-B trial were not sufficient to support an FDA label for the treatment of ATTR-CM.

Unlike patisiran, which is administered intravenously every 3 weeks, vutrisiran, which is also an siRNA, can be given subcutaneously every 3 months. This is achieved by the N-acetylgalactosamine platform, which provides greater stability and can target hepatic asialoglycoprotein receptors. The clinical impact of vutrisiran for ATTR-CM was evaluated in the HELIOS-B trial which included 655 patients with either wild-type or variant ATTR-CM.13 The primary composite endpoint was rate of death from any cause and recurrent cardiovascular events, with vutrisiran demonstrating a significant reduction compared with placebo (HR 0.72; 95% CI [0.56–0.93]; p=0.01). At 42 months, vutrisiran also showed a lower risk of death from any cause (HR 0.65; 95% CI [0.46–0.90]; p=0.01). Key secondary endpoints, including 6-minute walk test distance and KCCQ scores also favored vutrisiran.13 Consequently, vutrisiran was approved by the FDA for patients with ATTR-CM.

Another emerging TTR-silencing agent, eplontersen (a second-generation ASO), is being studied in the phase III CARDIO-TTRansform study (NCT04136171) for patients with ATTR-CM with a primary endpoint of cardiovascular mortality or a recurrent cardiovascular event up to 140 weeks. The estimated completion date for this study is in 2026.

The phase 1 study results for the novel siRNA nucresiran (ALN-TTRsc04) (NCT05661916) showed that a single subcutaneous dose led to rapid reduction of serum TTR levels from baseline, exceeding 90% at 15 days and reaching 96% by 29 days. This effect was sustained for 6 months. Phase 3 development plans are ongoing.

A highly novel TTR silencing strategy under investigation involves gene editing, seeking to permanently knock out TTR protein synthesis. This therapy uses clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-CAS-9)-targeted gene editing. CRISPR-CAS-9 technology was developed from the Nobel Prize-winning work to employ a bacterial enzyme guided by RNA to direct the precise editing of a specific DNA sequence.14 Diseases, such as sickle cell anemia and transthyretin amyloidosis, are appealing targets due to their monogenic pathophysiological mechanism and gene target properties.

Nexiguran ziclumeran (NTLA-2001) is a CRISPR-cas9-based therapy, administered as a single IV infusion designed to be endocytosed by hepatocytes and introduce a double-strand DNA break to a specific exon in the TTR gene. This therapy has shown promising results for the treatment of ATTR amyloidosis in early in vitro and in vivo studies. The phase I trial of six participants supported the safety and plausibility of this therapy, demonstrating a mean 52% reduction in serum TTR over 28 days (range 47–56%).15 MAGNITUDE (NCT04601051) is an ongoing Phase III study investigating the safety and efficacy of NTLA-2001 in patients with ATTR-CM. The expected completion date of this study is 2028.

Transthyretin Amyloid Fibril Depletion

In contrast to TTR stabilizers and silencers, which aim to halt disease progression, ATTR fibril depleting agents are designed to target the clearance of amyloid deposits and offer potential for disease regression. In recent years, monoclonal antibodies (mAbs) have shown increasing promise to promote amyloid fibril clearance. Preclinical studies identified TTR epitopes that become exposed only on misfolded TTR protein, allowing ATTR protein to be distinguished from normal TTR.16,17 This led to the generation of monoclonal antibodies specific for misfolded TTR through immunization of mice with antigenic peptides.18 Four antibodies were identified that resulted in suppression of fibril formation and targeted amyloid fibril deposits for phagocytosis without binding to other forms of amyloid in normal tissue.18 Coramitug (PRX004) is one mAb that has shown safety and tolerability in a phase I trial (NCT03336580) and has an ongoing phase II trial in ATTR-CM.19

Since this discovery, intriguing evidence has suggested the possibility of human-derived immunity as a therapeutic strategy for amyloidosis. Analysis of memory B-cell repertoires in healthy elderly individuals led to the discovery of another ATTR mAb which is being studied as ALXN2220 (N1006).20 A phase 1 trial involving 40 patients with ATTR-CM has assessed the safety and pharmacokinetics of ALXN220.21 Additionally, a notable reduction in extracellular volume (ECV) on MRI (a reduction in ECV of up to 17.8 % at 12 months) and reduction in cardiac tracer uptake on scintigraphy suggests the possibility of profound phenotypic regression in amyloid deposition.21 A Phase III study – DepleTTR-CM (NCT06183931) – is testing the efficacy and safety of ALXN2220 for patients with ATTR-CM with a primary composite endpoint of all-cause mortality and cardiovascular events. The estimated completion date for this study is 2028. Further support for the hypothesis of amyloid immunity comes from the observation of rare cases of spontaneous recovery in ATTR-CM.22 Fontana et al. described three patients with ATTR-CM who experienced clinical, biomarker and imaging evidence of near complete disease regression. These patients were found to have a high titer of circulating polyclonal IgG antibodies to TTR amyloid fibrils.22

Evuzamitide is a synthetic peptide that has been found to bind to both light-chain amyloid and transthyretin amyloid fibrils via electrostatic lysine side chain interactions.23 This discovery prompted diagnostic and therapeutic investigations. Positron emission tomography (PET)/CT imaging using iodine-tagged evuzamitide as a pan-amyloid diagnostic tool is currently the subject of a phase 3 clinical trial (NCT06788535). AT-02 (Attralus) is an immunoglobulin G1 peptide engineered to mimic evuzamitide to bind to amyloid fibrils, resulting in macrophage activation and clearance. Early preclinical data of AT-02 demonstrated promising results with high potency affinity to reduce cardiac, hepatic, and renal amyloid.24

Although tafamidis, acoramidis, and vutrisiran are the only agents with FDA approval for the management of ATTR-CM, these and other therapeutic strategies currently under investigation will continue to change the landscape of ATTR management in the coming years. The recent FDA approvals of acoramidis and vutrisiran have expanded the range of available options and may influence treatment selection and insurance coverage. The current evidence and future prospects have generated a growing sense of optimism in the field for a debilitating disease. With these emerging therapies, more nuanced questions will arise as we increase use in clincial practice, prompting further investigation.

Limitations and Special Populations

It is important to consider the generalizability of the results from these clinical trials with contemporary ATTR-CM patient populations (Table 1). Although ATTRwt-CM is a more common cause of heart failure in older individuals compared with ATTRv-CM, ATTRv-CM is more common than previously appreciated and up to 20.7% of individuals with ATTR-CM over the age of 70 have an identifiable mutation.25 This raises the question of whether targeted therapies for ATTR-CM are equally effective in both subgroups. In 2012, Bulawa et al. demonstrated the molecular plausibility of the effectiveness of tafamidis in preventing amyloid fibril formation in both ATTRv and ATTRwt.26 Furthermore, clinical trial results of ATTR-CM therapies do not suggest heterogeneity in outcomes between wild-type and variant ATTR-CM. For example, in the ATTR-ACT trial, tafamidis demonstrated a similar benefit on mortality and functional decline across both ATTRv and ATTRwt subgroups.27 Similarly, in the HELIOS-B trial, vutrisiran showed consistent effects on all-cause mortality and recurrent hospitalizations across these subgroups.13

Table 1: Baseline Demographics and Clinical Characteristics of Participants in Key ATTR-CM Clinical Trials

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Treatment selection may be influenced by phenotypic presentation, particularly in patients with ATTRv who exhibit both cardiac and neuropathic involvement. Prior to the FDA approval of vutrisiran for ATTR-CM, silencer therapy was only approved for ATTRv-PN while stabilizer therapy was approved for ATTR-CM. This has therefore informed ATTR treatment strategy. However, whether one treatment strategy is preferred over the other and ATTR pathology can inform that decision are areas of uncertainty. Further investigation is needed to clarify the optimal approach to therapy in patients with mixed cardiac and neurologic phenotypes.

Finally, a special population that has not been included in any of the trials are individuals with ATTR-CM who have undergone heart transplantation. It was initially found after liver transplantation that amyloid can still progress due to amyloid fibril ‘seeds’ that continue to promote amyloid deposition.28 Therefore, it is generally accepted that treatment should be continued after organ transplantation. A current clinical trial (NCT05489523) is evaluating the safety, efficacy, and pharmacokinetics of tafamidis in patients with ATTR-CM who have undergone orthotopic heart transplantation. As novel therapies emerge and are approved for ATTR-CM, considerations that are specific to transplant recipients may have an impact on drug selection.

Comparing ATTR-CM Therapies

The choice between TTR stabilizers, silencers, and possibly depleters, in the future, is a growing area of interest. Indeed, this decision is a complex one that leverages a number of factors that include different contextualization of clinical trial outcomes, FDA approval status, timing of diagnosis, and practical considerations, including dose frequency and administration routes (Table 2).

Table 2: Comparison of Current and Investigational Therapies for Transthyretin Amyloidosis: Dosing, Route of Administration, and Regulatory Status

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Although there is biological plausibility that acoramidis may be a superior stabilizer to tafamidis this has not been confirmed in clinical trials. In preclinical studies using equimolar concentrations (10 μM), acoramidis stabilized 97.6% ± 9.4% of wild-type TTR tetramers in serum, compared with 49.4% ± 4.3% for tafamidis.29 The clinical significance of this comparison remains uncertain. Additionally, selecting a TTR stabilizer versus a silencer is often empirical and driven primarily by payer coverage given current lack of head-to-head trials.

A direct comparison of the trial outcomes for the three FDA-approved ATTR-CM therapies is not possible due to differences in study population, study design, endpoint selection, statistical analyses, and randomization schemes. When compared with ATTRibute-CM (acoramidis) and HELIOS-B (vutrisiran), ATTR-ACT (tafamidis) included a higher risk population with a more severe phenotype of heart failure, as evidenced by greater risk of death in the placebo group (ATTR-ACT: 42.9%; ATTRibute: 25.7%; HELIOS-B: 21%) and higher median NTproBNP (ATTR-ACT: 2,995; ATTRibute: 2,326; HELIOS-B: 2,021).5,7,13 ATTR-ACT also had a much higher proportion of participants with ATTRv (ATTR-ACT: 24%; ATTRibute: 9.7%; HELIOS-B: 11%), which has implications for the onset of diagnosis and disease progression.5,7,13

As the landscape shifts towards earlier diagnosis and treatment of ATTR-CM, it is possible that the population of patients being treated may more accurately reflect the severity of illness of participants in ATTRibute and HELIOS-B rather than ATTR-ACT.30

The safety profiles of TTR stabilizers and silencers are generally well tolerated, with few-to-no treatment-related adverse events.5,7,13 The tolerability of mAbs for the treatment of ATTR-CM is a critical consideration that can affect their implementation. For example, in the phase I trial of ALXN2220, increased rates of arthralgia were observed with ascending doses and following crossover from placebo to active treatment.21 Additionally, two out of 40 patients developed asymptomatic thrombocytopenia, one of whom needed to be withdrawn from the study.21 Larger phase 3 clinical trials of ALXN2220 and coramitug will provide better insight into the tolerability and safety of mAbs for ATTR-CM and may inform patient risk-profiles where these treatments may be more appropriate.

Ultimately, the selection of therapy is likely to depend on factors such as cost, availability, frequency of administration, and route of delivery. Additionally, payer coverage and patient access will play crucial roles in determining widespread adoption of newer therapies. Head-to-head studies designed to test the comparative efficacy of these treatments would clarify optimal treatment strategies for ATTR-CM and would benefit patients and caregivers, and help to inform payer preferences.

Combination Therapy: Theoretical Rationale and Practical Considerations

There are many justifications for the use of combination therapies in medicine. For example, there is a clear additive benefit of combination therapy for the management of heart failure with reduced ejection fraction, and there is likely to be a similar rationale for combination-based strategies for the treatment of ATTR-CM. Specifically, TTR stabilizers prevent formation of new amyloid fibrils by stabilizing the TTR tetramer, TTR silencers reduce overall amyloidogenic TTR protein synthesis, and TTR depleters actively clear existing amyloid deposits. Together, these treatments could theoretically offer maximal protection against disease progression. However, this approach lacks robust evidence and given the high cost of these drugs, may lack economic feasibility.

Some limited data on combination therapy with stabilizers and silencers may be gathered from trials that include tafamidis background therapy. In the HELIOS-B trial, a sub-analysis of 40% of participants was performed for patients receiving tafamidis at baseline and those on monotherapy.13 There was no significant difference observed in outcomes in the overall population who had been using tafamidis and the monotherapy group when comparing death from any cause and recurrent cardiovascular events in the overall population (HR 0.72; 95% CI [0.56–0.93]; p=0.01; HR in the monotherapy population 0.67; 95% CI [0.49–0.93]; p=0.02).13 However, there are several limitations to this analysis and the assumption that background therapy did not affect outcomes. For instance, there is significant heterogeneity in the timing and duration of tafamidis use with a median duration of 9.2 months and a range of 1.1–65.3 months.13 Additionally, the same level of rigor in ensuring accurate documentation of adherence to the study therapy was not used for background therapies. Therefore, although the use of combination therapy with silencers and stabilizers cannot be ruled out, data from these studies does not adequately address whether there is any incremental benefit of combination therapy over monotherapy.

As amyloid fibril-depleting therapies emerge, future studies will need to address strategies of combination and sequential use. For example, should mAb therapies be reserved for more advanced amyloid deposition and organ involvement? Should mAb be continued indefinitely or, instead, administered in a treatment cycle to a point of phenotypic ATTR-CM regression at which point a TTR stabilizer or silencer could be used indefinitely? These and other critical questions must be addressed in the context of any potential side effects and the substantial cost burden.

When Should Therapy Be Initiated?

The majority of ATTR-CM patients are diagnosed at advanced stages when they are symptomatic, which has been highlighted in previous studies.31 Despite the progressive nature of disease development, therapeutic efficacy appears to diminish as the disease advances, emphasizing the need for earlier intervention. A cross-trial comparison of ATTR-ACT, ATTRibute-CM, and HELIOS-B suggested that treating patients with lower severity of illness by age, levels of NTproBNP, and New York Heart Association class resulted in improved outcomes with an all-cause mortality that approached the expected 3-year rate for the population.32 Current consensus suggests that ATTR therapy should be initiated at the first sign of clinical symptoms to prevent irreversible myocardial dysfunction.33

There are now several emerging strategies for earlier detection of preclinical ATTR-CM including traditional biomarkers such as NT-proBNP, cardiac MRI with extracellular volume mapping, novel circulating biomarkers such as transthyretin aggregate detector (TAD1) and peptide-based nuclear tracers.34–36 Currently, there is no FDA-approved therapy for asymptomatic ATTR amyloidosis and it is not clear whether some findings may indicate the potential for clinical progression or whether they may be incidental which could lead to overdiagnosis and potentially unnecessary treatment.

ACT-EARLY (NCT06563895) is the first Phase III randomized controlled study to evaluate prophylactic treatment of asymptomatic carriers of pathogenic TTR alleles. Participants who are within 10 years of the predicted age of disease onset will be randomized to placebo or acoramidis and followed for the development of disease penetrance. This study is estimated to complete in 2032.

Conclusion

The therapeutic landscape of ATTR-CM treatment is rapidly evolving, shifting from supportive care in the recent past to targeted, disease-modifying therapies that improve survival and quality of life. The continued emergence of novel agents will not only provide long-awaited therapeutic answers, but will also raise more questions. Given this current landscape, we must continue to think critically about the generalizability of the findings of current trials to various subpopulations. It will be vital to design trials that help determine which agents should be used in certain subpopulations and outline the role of combination therapy. Defining the optimal time to initiate therapy for both ATTRv-CM and ATTRwt-CM could drastically change the disease progression and prognosis for countless individuals. In navigating these complexities, it will be crucial to refine our approach to treatment, ensuring that the benefits of novel therapies are maximized to ultimately transform patient outcomes, and reshape the future care for this population.

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References

  1. Ioannou A, Massa P, Patel RK, et al. Conventional heart failure therapy in cardiac ATTR amyloidosis. Eur Heart J 2023;44:2893–907. 
    Crossref | PubMed
  2. Aus dem Siepen F, Hein S, Bauer R, et al. Standard heart failure medication in cardiac transthyretin amyloidosis: useful or harmful? Amyloid 2017;24(Suppl 1):132–3. 
    Crossref | PubMed
  3. Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation 2020;142:e7–22. 
    Crossref | PubMed
  4. Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 2012;79:785–92. 
    Crossref | PubMed
  5. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379:1007–16. 
    Crossref | PubMed
  6. Zhou S, Ge S, Zhang W, et al. Conventional molecular dynamics and metadynamics simulation studies of the binding and unbinding mechanism of TTR stabilizers AG10 and tafamidis. ACS Chem Neurosci 2020;11:3025–35. 
    Crossref | PubMed
  7. Gillmore JD, Judge DP, Cappelli F, et al. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. N Engl J Med 2024;390:132–42. 
    Crossref | PubMed
  8. Judge DP, Alexander KM, Cappelli F, et al. Efficacy of acoramidis on all-cause mortality and cardiovascular hospitalization in transthyretin amyloid cardiomyopathy. J Am Coll Cardiol 2025;85:1003–14. 
    Crossref | PubMed
  9. Judge DP, Gillmore JD, Alexander KM, et al. Long-term efficacy and safety of acoramidis in ATTR-CM: initial report from the open-label extension of the ATTRibute-CM trial. Circulation 2025;151:601–11.
    Crossref | PubMed
  10. Martin P, DiMartini A, Feng S, et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology 2014;59:1144–65. 
    Crossref | PubMed
  11. Judge DP, Kristen AV, Grogan M, et al. Phase 3 multicenter study of revusiran in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with cardiomyopathy (ENDEAVOUR). Cardiovasc Drugs Ther 2020;34:357–70. 
    Crossref | PubMed
  12. Maurer MS, Kale P, Fontana M, et al. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med 2023;389:1553–65. 
    Crossref | PubMed
  13. Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med 2025;392:33–44. 
    Crossref | PubMed
  14. Jinek M, Chylinski K, Fonfara I, et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 2012;337:816–21. 
    Crossref | PubMed
  15. Gillmore JD, Gane E, Taubel J, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med 2021;385:493–502. 
    Crossref | PubMed
  16. Gustavsson A, Engström U, Westermark P. Mechanisms of transthyretin amyloidogenesis. Antigenic mapping of transthyretin purified from plasma and amyloid fibrils and within in situ tissue localizations. Am J Pathol 1994;144:1301–11.
    PubMed
  17. Goldsteins G, Persson H, Andersson K, et al. Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants. Proc Natl Acad Sci U S A 1999;96:3108–13. 
    Crossref | PubMed
  18. Higaki JN, Chakrabartty A, Galant NJ, et al. Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin. Amyloid 2016;23:86–97. 
    Crossref | PubMed
  19. Suhr OB, Grogan M, Silva AMD, et al. PRX004 in variant amyloid transthyretin (ATTRv) amyloidosis: results of a phase 1, open-label, dose-escalation study. Amyloid 2025;32:14–21. 
    Crossref | PubMed
  20. Michalon A, Hagenbuch A, Huy C, et al. A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells. Nat Commun 2021;12:3142. 
    Crossref | PubMed
  21. Garcia-Pavia P, Aus dem Siepen F, Donal E, et al. Phase 1 trial of antibody NI006 for depletion of cardiac transthyretin amyloid. N Engl J Med 2023;389:239–50. 
    Crossref | PubMed
  22. Fontana M, Gilbertson J, Verona G, et al. Antibody-associated reversal of ATTR amyloidosis-related cardiomyopathy. N Engl J Med 2023;388:2199–201. 
    Crossref | PubMed
  23. Wall JS, Martin EB, Lands R, et al. Cardiac amyloid detection by PET/CT imaging of iodine (124I) evuzamitide (124I-p5+14): a phase 1/2 study. JACC Cardiovasc Imaging 2023;16:1433–48. 
    Crossref | PubMed
  24. Fontana MGJD, Selvanayagam J, Korczyk D, et al. Phase 2 clinical trial design of AT-02 Phase 2 open-label extension study in systemic amyloidosis. Presented at: XIX International Symposium on Amyloidosis, Rochester, MN, May 26–30, 2024.
  25. Porcari A, Razvi Y, Masi A, et al. Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy. Eur J Heart Fail 2023;25:515–24. 
    Crossref | PubMed
  26. Bulawa CE, Connelly S, Devit M, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A 2012;109:9629–34. 
    Crossref | PubMed
  27. Rapezzi C, Elliott P, Damy T, et al. Efficacy of tafamidis in patients with hereditary and wild-type transthyretin amyloid cardiomyopathy: further analyses from ATTR-ACT. JACC Heart Fail 2021;9:115–23. 
    Crossref | PubMed
  28. Morfino P, Aimo A, Panichella G, et al. Amyloid seeding as a disease mechanism and treatment target in transthyretin cardiac amyloidosis. Heart Fail Rev 2022;27:2187–200. 
    Crossref | PubMed
  29. Penchala SC, Connelly S, Wang Y, et al. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A 2013;110:9992–7. 
    Crossref | PubMed
  30. Grodin JL. Transthyretin amyloid cardiomyopathy: wherever protein stabilization leads, disease stabilization follows. J Am Coll Cardiol 2025;85:1015–7. 
    Crossref | PubMed
  31. Grodin JL, Maurer MS. The truth is unfolding about transthyretin cardiac amyloidosis. Circulation 2019;140:27–30. 
    Crossref | PubMed
  32. Girard AA, Sperry BW. Contextualizing the results of HELIOS-B in the broader landscape of clinical trials for the treatment of transthyretin cardiac amyloidosis. Heart Fail Rev 2025;30:69–73. 
    Crossref | PubMed
  33. ACC Expert Consensus Writing Committee. 2023 ACC expert consensus decision pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis: a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol 2023;81:1076–126. 
    Crossref | PubMed
  34. Pan JA, Kerwin MJ, Salerno M. Native T1 mapping, extracellular volume mapping, and late gadolinium enhancement in cardiac amyloidosis: a meta-analysis. JACC Cardiovasc Imaging 2020;13:1299–310. 
    Crossref | PubMed
  35. Pedretti R, Wang L, Hanna M, et al. Detection of circulating transthyretin amyloid aggregates in plasma: a novel biomarker for transthyretin amyloidosis. Circulation 2024;149:1696–9. 
    Crossref | PubMed
  36. Martin EB, Stuckey A, Powell D, et al. Clinical confirmation of pan-amyloid reactivity of radioiodinated peptide 124I-p5+14 (AT-01) in patients with diverse types of systemic amyloidosis demonstrated by PET/CT imaging. Pharmaceuticals (Basel) 2023;16:629. 
    Crossref | PubMed
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