2025+ACC简明临床指南：转甲状腺素蛋白心脏淀粉样变的评估与管理

指南内分泌与代谢· 甲状腺疾病 · 2025

2025 ACC Concise Clinical Guidance

A Report of the American College of Cardiology Solution Set Oversight Committee

Writing Committee

Michelle M. Kittleson,MD,PHD,FACC,Chair

Amrut V. Ambardekar, MD, FACC

Richard K. Cheng, MD, MSc, FACC

Jan M. Griffin, MD, FACC

Mathew S. Maurer, MD, FACC

Jose Nativi-Nicolau, MD, FACC

Frederick L. Ruberg, MD, FACC

Solution Set Oversight

Committee

Gurusher S. Panjrath, MBBS,FACC,Chair

Katie Bates,ARNP,DNP,FACC

Eugene H. Chung, MD, MPH, FACC

David M. Dudzinski, MD, JD, FACC

Martha Gulati,MD,MS,FACC

Robert Hendel, MD, MACC

Chayakrit Krittanowong, MD, FACC

Barbara Wiggins, PharmD, FACC

Viet T. Le, PA, FACC, Ex Officio

ABSTRACT

Transthyret amyloid cardiomyopathy has emerged as an increasingly recognized cause of heart failure, particularly in older individuals.There is now greater awareness of transthyretin amyloid cardiomyopathy as an underlying etiology of heart failure, particularly in individuals with musculoskeletal manifestations such as bilateral carpal tunnel syndrome or spinal stenosis. There have also been substantial advances in diagnosis, including the ability to perform accurate noninvasive diagnosis using radionuclide scintigraphy in individuals with a negative monoclonal protein screen. Finally, individuals with transthyretin amyloid cardiomyopathy have benefitted from advances in broadly effective heart failure therapies, namely mineralocorticoid receptor antagonists and sodium glucose-cotransporter 2 inhibitors, as well as specific disease-modifying therapies with transthyretin stabilizers, tafamidis and acoramidis, and the transthyretin silencer vutrisiran. The purpose of this Concise Clinical Guidance is to offer updated strategies to clinicians, reflecting the expanding therapeutic landscape, and reinforcing best practices for the diagnosis and management of transthyretin amyloid cardiomyopathy with a focus on choice of disease-modifying therapies,heart failure therapies, and future directions.

This document was approved by the American College of Cardiology Clinical Policy Approval Committee in October 2025.

The American College of Cardiology requests that this document be cited as follows: Kittleson MM, Ambardekar AV, Cheng RK, Griffin JM, Maurer MS,Nativi-Nicolau J, Ruberg FL. Transthyretin cardiac amyloidosis evaluation and management: 2025 ACC concise clinical guidance. J Am Coll Cardiol.2025;XX:XXX-XX.

Copies: This document is available on the website of the American College of Cardiology(www.acc.org).For copies of this document, please contact Elsevier Inc. Reprint Department via fax(212-633-3820) or e-mail (reprints@elsevier.com).

Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American College of Cardiology. Requests may be completed online via the Elsevier site(https://www.elsevier.com/about/policies/copyright/permissions).

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ABSTRACT 1

PREFACE 2

1. INTRODUCTION 3

2.ASSUMPTIONS, DEFINITIONS, AND ABBREVIATIONS $\ldots$

2.1. General Clinical Assumptions $\ldots$ 3

2.2. Definitions $\ldots$ 3

2.3. Abbreviations $\ldots$

3. SUMMARY GRAPHIC $\ldots$

Figure 1. Challenges in the Evaluation and Management of ATTR-CM 4

4.DESCRIPTION, RATIONALE, AND IMPLICATIONS. 5

4.1. Diagnosis $\ldots$ 5

4.1.1. Clinical Clues $\ldots$ 5

4.1.2. Diagnostic Algorithm 6

Figure 2. Diagnostic Algorithm for Cardiac Amyloidosis 6

4.1.3. Diagnostic Pitfalls 6

4.2. Management $\ldots$ 7

4.2.1. Overview of Disease-Modifying Therapies

4.2.2. Choosing Among Disease-Modifying Therapies $\ldots$ 8

Figure 3. Individual Selection and Choice of ATTR-CM Disease-Modifying Therapies $\ldots$

4.2.3.HF Management $\ldots$ 10

4.3. Future Therapies $\ldots$ 12

4.3.1. Transthyretin Silencing With Gene Editing 12

4.3.2. Transthyretin Depleters With Monoclonal Antibodies $\ldots$ 12

4.4. Conclusions $\ldots$ 12

REFERENCES $\quad$ $\quad$ $\quad$ $\quad$ $\quad$ $\quad$ $\quad$ $\quad$ $\quad$ $\quad$ $\quad$ $\quad$ $\quad$ $\quad$

APPENDIX 1

Author Relationships With Industry and Other Entities(Relevant) $\ldots$ 16

APPENDIX 2

Peer Reviewer Relationships With Industry and Other Entities(Comprehensive) $\ldots$ 17

PREFACE

The American College of Cardiology (ACC) has a long history of developing documents (eg, decision path-ways, appropriate use criteria) to provide clinicians with guidance on both clinical and nonclinical topics relevant to cardiovascular care. In most circumstances,these documents have been created to complement clinical practice guidelines and to inform clinicians about areas where evidence is new and evolving or where sufficient data are more limited. Despite this,numerous gaps persist, highlighting the need for more streamlined and efficient processes to implement best practices in patient care.

Central to the ACC's strategic plan is the generation of actionable knownable knowledge-a concept that places emphasis on making clinical information easier to consume, share,integrate, and update. To this end, the ACC has shifted from developing isolated documents to creating inte-grated“solution sets.” These are groups of closely related activities, policy, mobile applications, decision-support tools, and other resources necessary to transform care,improve heart health, or both. Solution sets address key questions facing care teams and offer practical guidance to be applied at the point of care. They use both estab-lished and emerging methods to disseminate information for cardiovascular conditions and their related manage-ment. The success of solution sets rests firmly on their ability to have a measurable impact on the delivery of care. Because solution sets reflect current evidence and ongoing gaps in care, the associated tools will be refined over time to match changing evidence and member needs.

Concise Clinical Guidance (CCG) documents are a key component of solution sets. Highly focused and limited in scope, CCGs provide recommendations where none currently exist, and outline actions required for evi-dence to be implemented in practice for specific patient populations. CCGs aim to illustrate clinical decision-making processes using tools (ie, figures, tables,checklists) and are limited in scope, focusing on patient populations that share certain characteristics, such as conditions, subtypes, or lines of therapy. In some cases,covered topics will be addressed in subsequent expert consensus decision pathways, appropriate use criteria,clinical practice guidelines, and other related ACC clinical policy as the evidence base evolves. In other cases, these will serve as stand-alone policy and represent best standards.

Gurusher S. Panjrath, MBBS,FACC Chair,ACC Solution Set Oversight Committee

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1. INTRODUCTION

Transthyretin amyloid cardiomyopathy(ATTR-CM) has emerged as an increasingly recognized cause of heart failure(HF) particularly in older individuals. There is now greater awareness of ATTR-CM as an underlying cause of HF1 and a concomitant diagnosis in aortic stenosis,2 particularly in individuals with musculoskeletal mani-festations such as bilateral carpal tunnel syndrome3 or spinal stenosis.4 Substantial advances in diagnosis have been developed, including the ability to perform accurate noninvasive diagnosis using radionuclide scintigraphy in individuals with a negative monoclonal protein screen.5 Finally, individuals with ATTR-CM have benefitted from advances in effective HF therapies, namely mineralo-corticoid receptor antagonists6-8 and sodium glucose-cotransporter 2 inhibitors, 7-9 as well as disease-modifying therapies with the transtyretin stabilizers tafamidis10 and acoramidis,1 and the transthyretin silencer vutrisiran.12

The purpose of this CCG is to offer updated strategies to clinicians, reflecting the expanding therapeutic land-scape, and reinforcing best practices for the diagnosis and management of ATTR-CM with a focus on choice of disease-modifying therapies, future directions, and unanswered questions.

In accordance with ACC's Relationships With Industry policy, relevant disclosures for the writing committee and comprehensive disclosures for external peer re-viewers can be found in Appendices 1 and 2. To ensure complete transparency, a comprehensive listing of re-lationships with industry and other entities for the writing committee, including relationships not pertinent to this document, is available in an online Supplemental Appendix.

2. ASSUMPTIONS, DEFINITIONS, AND ABBREVIATIONS

2.1. General Clinical Assumptions

1. The principal focus of this effort, including CCG con-siderations, applies to individuals with or at risk for cardiac amyloidosis.

2. The writing committee endorses the evidence-based approach to HF management recommended in the“2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.”13

3. These algorithms assume the managing clinician will seek input as needed from a pharmacist, a cardiologist,a HF specialist, hematologist, an amyloidosis referral center, or a combination of these to guide clinical management.

4. Optimal patient care decisions should properly reflect the individual's preferences and priorities, as well as

those of the managing clinician. A shared-decision model regarding care decisions is appropriate partic-ularly when clinical equipoise exists in areas of treat-ment uncertainty.

5. This CCG is not intended to supersede good clinical judgment. The managing clinician should seek input as needed from relevant experts(eg, pharmacists,cardiologists, endocrinologists).

6. This CCG is based on the best data currently available.New information is being generated rapidly(eg, trials of additional agents and including other patient pop-ulations) and, as these data become available, they will impact the considerations made here. Clinicians should be careful to incorporate relevant information published after this CCG is published.

7. Although implementing relevant portions of these recommendations in the acute inpatient setting may be reasonable, this CCG is primarily focused on man-agement in the outpatient ambulatory setting.

2.2. Definitions

Cardiac amyloidosis: a restrictive cardiomyopathy resulting from the deposition of amyloid fibrils in the myocardial interstitium. The 2 most common types are AL amyloidosis, where the amyloid fibrils are composed of monoclonal immunoglobulin light chains, resulting in AL amyloid cardiomyopathy, and ATTR amyloidosis,where the amyloid fibrils are composed of the misfolded transthyretin protein that can occur in the context of variant or wild-type TTR genetics, resulting in variant transthyretin amyloidopathy(ATTRv-CM) or wild-type transthyretin amyloid cardiomyopathy(ATTRv-CM), respectively.

■GDMT: Guideline-directed medical therapy, repre-senting treatment options supported for use by clinical practice guidelines with specific considerations for use in individuals with ATTR-CM.

■ HF: Defined per criteria outlined in the“2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure."13 An HF event, including hospitalization, is defined by the criteria outlined in the“2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials."14

■ HF with reduced ejection fraction(HFrEF): Clinical diagnosis of HF and left ventricular ejection fraction≤40%.13

■ HF with mildly reduced ejection fraction(HFmrEF):Clinical diagnosis of HF and left ventricular ejection fraction 41% to 49%.13

■ HF with preserved ejection fraction(HFpEF): Clinical diagnosis of HF and left ventricular ejection fraction $\geq 50\%^{13}$

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■Monoclonal protein screen: Abnormal serum kappa and lambda free light chain ratio or monoclonal band on serum immunofixation electrophoresis or urine immunofixation electrophoresis which, when taken together, have a>99% sensitivity for the identification of AL amyloidosis.15

New York Heart Association(NYHA) functional classification:

- Class I: No limitation of physical activity.Ordinary physical activity does not cause symptoms of HF.

\Box \Box Class II: Slight limitation of physical activity.Comfortable at rest, but ordinary physical activity re-sults in symptoms of HF.

■ Class III: Marked limitation of physical activity.Comfortable at rest, but less-than-ordinary activity causes symptoms of HF.

- Class IV: Unable to perform any physical activity without symptoms of HF, or symptoms of HF at rest.

2.3. Abbreviations

ATTR-CM= transthyretin cardiomyopathy ATTRv-CM= variant transthyretin amyloid cardiomyopathy IATRwt-CM wild-type transthyretin amyloid cardiomyopathy eGFR= estimated glomerular filtration rate HF= heart failure HFmrEF= heart failure with mildly reduced ejection fraction HFpEF= heart failure with preserved ejection fraction HFSA= Heart Failure Society of America MRA= mineralocorticoid antagonist NYHA= New York Heart Association SGLT2= sodium-glucose cotransporter-2

3. SUMMARY GRAPHIC

Figure 1 summarizes the key challenges encountered in the diagnosis, evaluation, and management of ATTR-CM.

FIGURE 1 Challenges in the Evaluation and Management of ATTR-CM

Appropriate diagnostic evaluation

Individualized management strategy

Unanswered questions

●Cardiac clues

●Start with monoclonal

●HF

● Relative superiority of available disease-modifying therapies

- Aortic stenosis

protein screen

◆ Avoid over-diuresis

● Benefit of combination TTR stabilizer and TTR silencer therapy

$ HfEFE$

◆ Serum IFE

●MRA and SGLT2

●How to assess response to therapy

on ECG

●Radionuclide scintigraphy interpreted in the context of a negative

●Disease-modifying therapies will improve outcomes

● Whether switching therapies will improve outcomes

●Extracardic clues

● Bilateral carpal tunnel syndrome

●Tafamidis, acoramidis, and vutrisan

● Benefit of TTR gene editing over currently available TTR silencers

$\cdot$ Trigger finger

●Biopsy

◆ Insufficient evidence of superiority of any agent

● Benefit of TTR depleters to improve outcomes

Biceps tendon

◆ Spinal stenosis

Joint replacement

● Sensory peripheral or autonomic neuropathy

● Radionucleotide

◆ Insufficient evidence of benefit of combination therapy

A high index of suspicion is required to diagnose ATTR-CM. Multiple challenges exist in the evaluation and management of ATTR-CM including appropriate diagnostic evaluation, individualized management strategy, and awareness of unanswered questions based on evolving evidence. ECG= electrocardiogram;HFPE=heart failure with preserved ejection fraction; IFE= immunofixation electrophoresis; GLS= global longitudinal strain; LV= left ventricular; MRA=mineralocorticoid receptor antagonist; SGLT2= sodium-glucose cotransporter-2; TTR= transthyretin.

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4. DESCRIPTION, RATIONALE, AND IMPLICATIONS

4.1. Diagnosis

4.1.1. Clinical Clues

Cardiac amyloidosis is an underrecognized condition and thus requires a high index of suspicion for diagnosis(Table 1). Presentation is heterogenous and nonspecific,often mimicking other more common age-related cardiac conditions. ATTR deposition is observed in about 15% of patients with degenerative aortic valve stenosis2 or pa-tients with HFpEF.1,16,17 Extracardiac transthyretin amy-loid deposition, typically in soft tissues, often precedes cardiac involvement; about 80% of individuals with ATTR-CM have preceding orthopedic interventions of the shoulder, hip, or knee; carpal tunnel syndrome; spinal stenosis; trigger finger; or biceps tendon rupture.18 Transthyretin deposition in the ligamentum flavum has been reported in up to one-third of older individuals undergoing surgery for lumbar spinal stenosis.19,20 Spontaneous biceps tendon rupture may occur a median of 5 years prior to the HF diagnosis,21 while carpal tunnel syndrome can manifest 5 to 10 years prior to the cardiac diagnosis.22,23 However, the proportion of individuals with musculoskeletal evidence of transthyretin amyloid deposits that will ultimately develop cardiac manifesta-tions remains incompletely characterized.

Polynuropathy, particularly peripheral sensory or autonomic dysfunction, may also occur in ATTR. In ATTRv, the presence of peripheral neuropathy varies with the variant. For individuals in the endemic regions of Portugal with the p.Val50Met variant,>80% develop peripheral neuropathy by age 50 years. By contrast,for patients with the p.Val1421e variant, which is predominantly associated with cardiomyopathy, the prevalence of polynuropathy is about 10%. ATTRw, in turn, predominantly causes cardiomyopathy, while approximately 30% of patients may have a poly-neuropathy that may(or may not) be attributable to amyloidosis.24-26

Electrocardiography, echocardiography, and cardiac magnetic resonance(CMR) imaging(MRI) may suggest the diagnosis(Table 1). Of note, in contrast to AL amyloidosis, low QRS voltage on electrocardiogram(ECG)is not sensitive and only observed in 25% to 40% of cases of ATTR-CM. A more accurate electrocardiographic parameter is voltage-to-mass ratio. ${}^{27,28}$ Echocardiogra-phy demonstrates increased left ventricular wall thick-ness and abnormal global longitudinal strain, often with an apical sparing pattern.29-31 CMR late gadolinium enhancement imaging and extracellular volume deter-mination provides complementary information,32 but neither echocardiography nor CMR can definitively

TABLE 1 Suggestive Findings for ATTR-CM

Modality

Modality Suggestive Findings

|History and physical examination|Cardiac manifestations| |---|---| |$$\begin{array}{l}\text{ examination}\end{array}$$|Fatigue HF symptoms $\begin{array}{l}\text{ Fatigue}\\\text{ HF symptoms}\\\text{ Aortosis}\end{array}$ history of HF $\begin{array}{l}\text{ Function system disease/pacemaker}\\\text{ Bilateral carpal tunnel syndrome}\end{array}$ $\begin{array}{l}\text{ Bilateral carpal tunnel syndrome}\\\text{ Bilateral/cervical spinal stenosis}\\\text{ Spontaneous biceps tendon rupture}\\ \end{array}$ $\begin{array}{l}\text{ Hip or knee replacement}\\\text{ Sensor peripheral neuropathy}\\\text{ Family history of neuropathy}\\\text{ Autonomic dysfunction}\end{array}$ $\begin{array}{l}\text{ Stability: knee replacement}\\\text{ Sensor: peripheral neuropathy}\\\text{ Family history of neuropathy}\\\text{ Autonomic dysfunction}\end{array}$ $\begin{array}{l}\text{ Laboratory test results}\\\end{array}$ $\begin{array}{l}\text{ Persistent low-level troponin elevation}\\\text{ Elevated natriuretic peptides}\\\end{array}$ $\begin{array}{l}\text{. Low voltage to LV mass ratio}\\\text{ Atrial fbrillation/flutter especially with}\\\text{ controlled ventricular response}\\\text{ Conduction delay}(\text{ atrioventricular block}\pm\\ \text{ intraventricular conduction delay})\\\text{ Pseudoinfact} pattern\end{array}$ $\begin{array}{l}\text{ Echocardiogram}\\\end{array}$ $\begin{array}{l}\text{ Dimensional imaging}\\\text{ Increased LV and RV wall thickness}\\\text{ Interatrial septal and diffuse valve thickening}\\\text{ Pericarial effusion}\\\text{ Biatrial enlargement and dysfunction}\\\text{ Doppler}$ $\begin{array}{l}\text{ Reduced tissue Doppler s', e', and a'velocities}\\\text{ Restrictive transmitral Doppler filling pattern}\\\text{ Diastolic dysfunction}\geq 2\text{ grade} 2\text{ with high E/A}\\\text{ratio(> 1.5) and reduced E deceleration time}\\\text{ Reduced TAPSE}\\\text{ Other}\end{array}$ $\begin{array}{l}\text{ Reduced global longitudinal strain; ratio}\\\text{ Between EF and global longitudinal strain}\\\text{ Apical sparing on 2-dimensional speckle}\\\text{ tracking images}(\text{ classically referred to as}\\\text{ "cherry on top")}\end{array}$ $\begin{array}{l}\text{. Low flow, low-gradient severe aortic stenosis}\\\text{ Impaired left atrial strain}\end{array}$ $\begin{array}{l}\text{. Diffuse subendocardial or transmural late}\\\text{ gadolinium enhancement}\\\text{ ECV increased myocardial native T1}\\\text{ ECV expansion(>40%)}\end{array}$ $\begin{array}{l}\text{. Reversal of nulling (nulling of the myocardium before or at the same inversion time as blood}\\\text{ pool)}\end{array}$| |$$\text{ACDriogram}$$|2-Dimensional imaging ■ Increased LV and RV wall thickness ■ Interatrial septal and diffuse valve thickening| ||RV hypertrophy ■ Pericarial effusion Biatrial enlargement and dysfunction ■ ■ Presented EF with low stroke volume index| |Doppler|Doppler| ||Reduced tissue Doppler s',e', and a'velocities ■ Restrictive transmitral Doppler filling pattern| ||Diastolic dysfunction $\geq$ grade 2 with high E/A ratio(> 1.5) and reduced E deceleration time| ||(<150 ms)| ||Reduced TAPSE Other| ||Reduced global longitudinal strain; ratio ■ Reduced TAPSE Other| ||between EF and global longitudinal strain $\bullet$ Apical sparing on 2-dimensional speckle tracking images(classically referred to as "cherry on top")| ||Low flow, low-gradient severe aortic stenosis ■ Impaired left atrial strain| |Cardiac MRI|Diffuse subendocardial or transmural late gadolinium enhancement| ||Increased myocardial native T1 ECV expansion(>40%)| ||■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■■ ■ ■■■|

ATTR-CM= transthyretin cardiac amyloidosis; ECV= extracellular volume; EF=jection fraction; E/A= early(E) to atrial(A) diastolic flow velocity ratio; LV= left ventricular; MRI= magnetic resonance imaging; RV= right ventricular; TAPSE=tricuspid annular plane systolic excursion.

diagnose ATTR-CM without tissue biopsy or reliably distinguish ATTR-CM from AL amyloidosis.

Cardiac biomarkers may serve as adjunctive tools to exclude ATTR-CM in individuals with a low clinical sus-picion; thresholds of N-terminal pro-B-type natriuretic peptide<180ng/L and high-sensitivity troponin T(hs-TnT)<14 ng/L can exclude ATTR-CM.33,34

Although no established evidence-based algorithm exists for translating cardiac and noncardiac clinical clues into a pretest probability of ATTR-CM, a 6-variable score

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incorporating age, sex, hypertension diagnosis, relative wall thickness, posterior wall thickness, and ejection fraction has been reported and offers insight as a screening tool.35 Artificial intelligence and machine learning screening algorithms for ECG,36 echocardiogra-phy,37 and cardiac MRI38 are emerging tools for the diagnosis of ATTR-CM. Additionally, a summary of high-yield clinical and imaging clues, which should prompt initiation of the diagnostic algorithm, is shown in Table 1.

4.1.2. Diagnostic Algorithm

The first and most critical step in the diagnostic evalua-tion of ATTR-CM is the exclusion of light chain amyloidosis(Figure 2). This is achieved by performing serum free light chain analysis, and serum and urine electrophoresis with immunofixation; a combination of these 3 tests has a 99% sensitivity for the detection of AL amyloidosis.39

The ratio of kappa and lambda free light chains, rather than the absolute levels, should be used for diagnostic purposes. Of note, the ratio is affected by kidney dysfunction with subsequent reduced renal clearance of kappa light chains resulting in a higher kappa-to-lambda

ratio than expected. In such cases, serum and urine immunofixation electrophoresis results are typically normal, and AL amyloidosis is uncommon(Figure 2).40 However,elevated lambda free light chains resulting in a lower kappa-to-lambda ratio should be further investi-gated. If there is uncertainty regarding interpretation of an abnormal monoclonal protein screen, consultation with a hematologist may be useful to confirm the need for further investigation to confirm the presence of a plasma cell dyscrasia.41

Once AL amyloid has been ruled out with a negative monoclonal protein screen, radionuclide scintigraphy can be used for noninvasive diagnosis. Perugini grade 2 or 3 myocardial radiotracer uptake has a 100% positive pre-dictive value for ATTR-CM in the absence of a mono-clonal protein.5 However, any individual with an abnormal monoclonal protein screen result must undergo tissue biopsy and amyloid typing by mass spectrometry for definitive diagnosis.

4.1.3. Diagnostic Pitfalls

Care must be taken to avoid the common diagnostic pit-falls. In individuals with suspected cardiac amyloidosis

FIGURE 2 Diagnostic Algorithm for Cardiac Amyloidosis

![Clues from history, ECG, imaging\n●SPEP/UPEP not as sensitive as IFE\n●Reference K/L ratio is higher in chronic kidney disease\n(see text and Table 1)\n●SNOP/PEF\nAcceptable Free Light Chain Ratio Range\n0.46-2.62\n0.48-3.38\nMonoclonal protein?\n0.54-3.30\n0.48-3.38\nMonoclonal protein on serum/urine IFE\n●Abnormal serum kappa/lambda free light chain(depends on eGFR)\n●Monoclonal protein on serum/urine IFE\n●Cardiac scintigraphy could be ordered\nATTRv\n459\n419\n47%\n30%\n84%\n99%\n99%\n99\nNo\n●Adcalac scintigraphy could be ordered\nconsultation with hematologist\n●Grade 2/3 uptake\ncanylid\nBiopsy(affected organ/surrogate site)\n●Positive Congo Red\n●Tissue typing by mass spectrometry\nNo\nYes\n●Yes\n●ATTR-CM\n●Corne\nATTR-CM\nATCR\nATTR-CM with MGUS\nATTR-CM\nGenetic testing\nATTRv-CM\nATTRv-CM\n](2/aj0YEe4oUhYkBdfpda0fYP/figure112cb9b591ce493b8659bace183a109a_0_12.png) AL-CM=amyloid monoclonal immunoglobulin light chain cardiomyopathy; ATTRV-Cm= transthyretin amyloid cardiomyopathy; ATTRV-Cm= variant transthyretin amyloid cardiomyopathy; ATTRV-cM = wild-type transthyretin amyloid cardiomyopathy; CMR= cardiac magnetic resonance; CT= computed tomography;ECG=electrocardiogram; egFGR=estimated glomérular filtration rate;IFE=immunofixation electrophoresis;K/L=kappa/lambda;MGUS=monoclonal gammopathy of undetermined significance; SPECT= single-photon emission computed tomography; SPEP/UPEP= serum/urine protein electrophoresis. Range of sensitivity of surrogate site biopsies adapted from Cohen et al ${}^{42}$ ; Quarta et al ${}^{43}$ ; Fine et al ${}^{44}$ ; Gertz et al ${}^{45}$ ; Kyle et al ${}^{46}$ ; Hansen et al ${}^{47}$ ; and van Gameren et al. ${}^{48}$ Range of normal K/L ratio by eGFR from Long et al ${}^{40}$ and Hutchison et al. ${}^{49}$

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and an abnormal monoclonal protein screen, biopsy of a surrogate site(eg, the abdominal fat pad or bone marrow)offers low sensitivity(Figure 2).42-44 Thus, although helpful if positive, a negative fat pad biopsy result excludes neither AL amyloid cardiomyopathy nor ATTR-CM, and biopsy of an affected organ may be required to adjudicate the diagnosis.

For the nonbiopsy diagnosis of ATTR-CM, strict adherence to standardized radionuclide imaging pro-tocols is essential.2999mTechnetium(99mTc) bone-avid compounds(including pyrophosphate), DPD(3,3-diphospho-no-1,2-propanodicarboxylic acid), and HDP(hydroxymethylene diphosphonate) are used. Pyro-phosphate is historically used in the United States,although HDP can be used in the case of pyrophosphate shortages to avoid diagnostic delays or as an alternative imaging agent.50 Diffuse myocardial uptake on planar imaging must be differentiated from blood pool activity using single-photon emission computed tomography or single-photon emission computed tomography/computed tomographic imaging techniques, at 2 to 3 hours after radiotracer injection to avoid misclassifica-tion.51 Other causes of a false-positive scintigraphy scan include prior myocardial infarction, rib fractures over-lying the heart, hydroxychloroquine toxicity, and AL amyloidosis. Conversely, false-negative scans can occur in individuals with certain ATTR variants(p.Phe84Leu and p.Val5oMet) or in the early stages of disease.

4.2. Management

4.2.1. Overview of Disease-Modifying Therapies

4.2.1.1. Transthyretin Stabilizers

Transthyretin stabilizers preserve the normal tetrameric structure of transthyretin to prevent dissociation, mis-folding, and aggregation into amyloid fibrils that deposit into tissues. In 2019, tafamidis became the first U.S. Food and Drug Administration(FDA)-approved transthyretin stabilizer for ATTR-CM based on the results of ATTR-ACT(Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), which randomized 441 individuals with ATTR-CM to tafamidis versus placebo.10 After 30 months, tafami-dis demonstrated a lower all-cause death and frequency of cardiovascular-related hospitalizations(Table 2). A long-term extension study with a median follow-up of 51 months showed a 30% relative reduction in the risk of death with 80 mg compared with 20 mg.52 Tafamidis of 61 mg free acid is bioequivalent to tafamidis meglumine 80 mg(4 x 20 mg),53 both of which are FDA-approved for ATTR-CM. Although well-tolerated, caution should be used when administering tafamidis with rosuvatin

|TABLE 2|Overview of FDA-Approved Disease-Modifying Therapies for ATTR-CM| |---|---| |Mechanism of action|Tafamidis| |Mechanism of action|Transthyretin stabilizer at T4 stabilizer binding site binding site (mimicking the stabilizing transthyretin p. Thr139Met variant)| |Trial|ATTR-ACT-10| |Years conducted (published)|2013-2018 (2018)| |Study type|Randomized, double-blind, placebo-compatible-03 phase 3| |Duration, mo|30| |Study dose|20 mg or 80 mg orally once a day;| |results poolled in primary analysis|| |FDA-approved dose|Tafamidis 61 mg or taamifidis meglumine 80 mg| |FDA-approved dose|| |No. of participants|441| |Mean age, y|74| |Male sex, No.(\%)|398(90)| |Race, No.(\%)|| |White|357(81)| |Black|63 (14)| |Asian|18(4)| |TTR genotype,No.(\%)|| |ATTRW|335(76)| |ATTRv|106 (24)| |NYHA class, No.(\%)|| |Class I|37(8)| |Class II|263 (60)| |Class III|141(32)| |NT-proBNP, pg/mL, median|3078278272| |6MWD,m,mean|351.9354.8| |KCCQ-OSS,mean|66.6| |NAC stage, No.(\%)|| |1|190(42)| |2|167(38)| |3|84 (20)| |Tafamidis use, No.(\%)|| |Treatment group|264 of 264 (100)| |Placebo group|0 of 177(0)|

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TABLE 2 Continued

||Tafamidis|Tafamidis|Acoramidis|Vutrisiran| |---|---|---|---|---| ||Primary outcome|Death,CV hospitalizations win ratio:1.7(95% CI,1.3-2.3)|Death,CV hospitalizations,NTROproBNP change, 6MWT change win ratio 1.8 (95% CI,1.4-2.2)|Death,recurrent CV events:HR: 0.72(95% CI: 0.56-0.93)| |All-cause death,HR (95% CI)|0.70(0.51-0.96)|0.77(0.54-1.1)|0.69(0.49- 0.98)|| |All-cause death,%, treatment vs placebo|29.5 vs 42.9|19.3 vs 25.7|16 vs 215|| |CV Hospitalizations, RRR(95% CI)|0.68(0.56-0.81)|0.496(0.36-0.70)|0.73(0.61-0.88)|| |6MWD,LS mean change(95% CI)|75.7(57.6-93.8)|39.6(21.1-58.2)|26.5(13-4.39-6)|| |KCCQ-OSS,LS mean change(95% CI)|13.65(9.5-17.8)|9.94(6.0-13.9)|5.8(2.4-9.2)|| |Side effects|Similar to placebo|DiarthehaA%|12(15%) Arthralgia(11%) Dyspnea(7%) Vitamin A (7%) Vitamin A reaction(4%)|| |Vitamin A supplementation|Not required|Not required|Supplement containing the locally RDA of vitamin A|| |Annual cost#|$267,987$|$244,539$|$477,404$||

*Tafamidis only depleted after 12 mo.

Tafamidis use at baseline.

Tafamidis use initiated after randomization.

S During double-blind placebo-controlled period: 30 mo for afamidis and acoramidis and 36 mo for vutrisan.

$\mid$ Recurrent cardiovascular events that included urgent visits for heart failure(adjusted by a Clinical Events Committee in ATTRibute-CM and nonadjudicated in HELIOS-B).

Reported in the FDA labels.

Average wholesale price per year from Micromedex Red Book as of July 11,2025.58

6MWD=6-minute walk distance; ATTR-BACT=Tafamidis in Transthyretin Cardiomyopathy Clinical Trial; ATTRBute-CM=Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy; ATTRC-MC=transthyretin amyloid cardiomyopathy; ATTRV=variant trans-thyrretiny acid cardiomyosis; ATTRW=wild-type transthyretin amyloidosis; CV=cardiovascular; FDA=U.S. Food and Drug Administration; HELIOS-B= A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis with Cardiomyopathy; HR= hazard ratio; KCCQ-OSS= Kansas City Cardiomyopathy Questionnaire- Overall Summary Score; LS= least squares; NAC= National Amyloidosis Centre; NT-proBNP= N-terminal pro-B-type natriuretic peptide; NYHA= New York Heart Association; RDA=recommended dietary allowance; RRR= relative risk reduction; siRNA=small interfering ribonucleic acid;TTR= transthyretin.

\>20 mg or atorvastatin\>40 mg due to the risk of rhabdomyolysis.

Acoramidis is another transthyretin stabilizer54 and was FDA-approved in 2024 after the results of the ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy) clinical trial that compared acoramidis hydrochloride 800 mg twice a day to placebo in 632 individuals.11 After 30 months, acoramidis was associated with a favorable effect on all-cause death and cardiovascular

hospitalizations ${}^{11,55,56}$ (Table 2). The FDA-approved dose is 712 mg(equivalent to acoramidis hydrochloride 800 mg) orally twice a day.

4.2.1.2. Transthyretin Silencers

Transthyretin silencers cause degradation of trans-thyrretin messenger ribonucleic acid in hepatocytes,reducing transthyretin production.57 The 2 types of gene silencer approaches studied for amyloidosis include small-interfering ribonucleic acids and antisense oligo-nucleotides.

Vutrisiran is approved by the FDA in 2022 for ATTRvR with polyneuropathy; approval for ATTR-CM occurred in 2025. The HELIOS-B(A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardio-myopathy) trial compared vutrisiran 25 mg subcutaneous every 12 weeks versus placebo in 655 individuals.12 Vutrisiran is associated with a lower risk of death from any cause and recurrent cardiovascular events(Table 2).Because transthyretin is the major transporter of retinol,vitamin A supplementation is advised for any therapy that reduces production of circulating transthyretin. The FDA-approved dose of vutrisiran is 25 mg subcutaneous every 3 months with vitamin A supplementation.

4.2.2. Choosing Among Disease-Modifying Therapies

4.2.2.1. Selecting Appropriate Individuals for ATTR-CM Disease-Modifying Therapies

By their mechanisms of action, the transthyretin stabi-lizers tafamidis and acoramidis and the transthyretin silencer vutrisran all slow progression, but do not reverse end-organ damage, and thus should be expected to preserve, but not improve, functional status and quality of life. The optimal time to start ATTR-CM dis-ease-modifying therapy is at the earliest onset of symp-tomatic disease before significant end-organ dysfunction has ensued(Figure 3).

See Kittleson et al ${}^{41}$ for details on screening recom-mendations for asymptomatic carriers of pathogenic TTR variants or those with noncardiac transthyretin amyloidosis with no evidence of cardiac involvement, as well as for details on management of arrhythmias in ATTR-CM.

Generally, appropriate individuals for ATTR-CM dis-ease-modifying therapy reflect landmark clinical trial criteria: confirmed diagnosis of ATTR-CM and symptom-atic HF with NYHA class I-III symptoms, including those with hospitalization for HF or use of loop diuretic, and a left ventricular wall thickness of≥12 mm. ${}^{10-12}$ However,these criteria should be applied with nuance, because:1) earlier diagnosis may obviate hospitalization; and 2)

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FIGURE 3 Individual Selection and Choice of ATTR-C Disease-Modifying Therapies

Patient Selection and Choice of ATTR-CM Disease-Modifying Therapies

Too Early for Disease-Modifying Therapy

● Asymptomatic carriers of pathogenic TTR variants

●Noncardiiac biopsy evidence of

TTR amyloid deposition(eg, carpal

tunnel or vertebral ligament tissue)

without cardiac disease

Appropriate for Disease-Modifying Therapy

•Confirmed ATTR-CM based on radionuclide

scintigraphy in the absence of a monoclonal protein or biopsy with transthyretin amyloid

●Clinical history of HF

●NYHA Class I-III symptoms

•Patients with milder symptoms(earlier diagnosis) have best outcomes

HF Therapies

•Biomarkers

●Potential subsequent

radionuclide imaging

●Diuretics titrated to symptoms; avoid over-diuresis

●Caution with vasodilators and beta-blockers

●MRA and SGLT2 inhibitors assist in relief of congestion

Atrial Fibrillation

●Anticoagulation regardless of CHA2DS2-VASc score

ATTRv-CM With Cardiomyopathy and Polyneuropathy

● Vutrisan

● Neurology consultation

ATTRv-CM or ATTRv-CM Without Polyneuropathy

●Tafamidis,oracamidis,or vutilisan based on

● Cost/payer coverage

$\blacktriangleright$ Access

● Patient preference including route of administration

●Insufficient evidence to recommend combination therapy

with TTR stabilizer and TTR silencer

●Insufficient evidence to change therapies if disease

progression

6MWD=6-minute walk distance;ATTR-CM=transthyretin cardiac amyloidosis;ATTRv-Cm=variant transthyretin amyloid cardiomyopathy;ATTRwt-CM=wild-type transthyretin cardiac amyloidosis;eGFR=estimated glomerular filtration rate;HF=heart failure MRA=mineralcorticoid antagonist;NT-proBNP=N-terminal pro-B-type natriuretic peptide;NYHA=New York Heart Association;SGLT2=sodium-glucose cotransporter-2;TTR=transthyretin.

improvements in HF management with sodium-glucose cotransporter-2(SGLT2) inhibitors and mineralocorti-coid receptor antagonists(MRAs) may control volume status without need for a loop diuretic. Thus, the lack of HF hospitalizations or need for loop diuretics should not preclude prescription of ATTR-CM disease-modifying therapy. Furthermore, because some individuals with ATTR-CM(particularly women)59 may not have a wall thickness of≥12 mm, absence of this specific criterion should not preclude initiation of therapy.

Notably, the cohorts for which data do not exist regarding potential benefit from disease-modifying therapy, include the following scenarios: 1) cascade screening of family members of individuals with ATTRv-CM will identify asymptomatic carriers of pathogenic TTR variants; and 2) individuals with paral tunnel syndrome and spinal stenosis may have transthyretin amyloid involvement of ligamentous structures but no evidence of cardiac disease. Although these individuals have a greater chance of subsequent ATTR-CM develop-ment,3,4,19,22 current evidence does not support therapy initiation. However, ACT-EARLY(Acoramidis Trans-thyrretin Amyloidis Prevention Trial in the Young Study

in Asymptomatic Carriers of a Pathogenic TTR Variant;NCT06563895) will assess the role of the transthyretin stabilizer acoramidis on the development of cardiomy-opathy and polyneuropathy. Also, the nonsteroidal anti-inflammatory drug diflunisal can stabilize the transthyretin tetramer and slow progression of ATTRv polyneuropathy,60,61 and prophylactic use warrants further investigation.

Some individuals with disease may be too advanced to derive benefit from disease-modifying therapy. All 3 trials that resulted in drug approval excluded in-dividuals with advanced symptoms. Specifically, exclu-sion criteria were: 1) significant functional impairment(6-minute walk distance<100 m for ATTR-ACT and<150 m for ATTRibute-CM and HELIOS-B); 2) high natriuretic peptide levels(N-terminal pro-B-type natri-uretic peptide>8,500 pg/mL for ATTRibute-CM and HELIOS-B); and 3) severe kidney impairment(estimated glomerular filtration rate[egGFR]<15 mL/min/1.73 m2 in ATTRibute-CM; eGFR<25 mL/min/1.73 m2 in ATTR-ACT;and eGFR<30 mL/min/1.73 m2 in HELIOS-B).10-12 Although therapy may offer no harm in individuals with advanced ATTR-CM, benefits have not been

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demonstrated. For such individuals, referral for heart transplantation evaluation if otherwise eligible based on comorbidities, or palliative care consultation if not,would be appropriate.62

4.2.2.2. Choosing Between Stabilizer Versus Silencer Disease-Modifying Therapy

Because all 3 landmark trials of tafamidis, acoramidis,and vutrisiran were placebo-controlled, no direct ran-domized clinical trial or comparative effectiveness evi-dence is available to offer insight into the relative superiority of any agent relative to another. Because all have minimal side effects, this consideration would also not affect choice of therapy. In addition, comparisons of individual clinical trials are limited by differences in trial populations; more contemporary trials enrolled in-dividuals at earlier disease stages as evidenced by lower N-terminal pro-B-type natriuretic peptide, higher 6-minute walk distance, better quality of life, and succes-vively lower event rates even in the placebo arms of each trial(Table 2). Additionally, no evidence is available to date that differential changes in serum transthyretin levels after stabilizer therapy are indicative of clinical superiority. Thus, without active controlled clinical tri-als, it remains unknown whether tafamidis, acoramidis,or vutrisiran is the superior initial therapy for individuals with ATTR-CM.

Consequently, based on current data, the choice of therapy should be based on factors including: 1) cost; 2)access based on payoff preferences; and 3) individual preference regarding route and frequency of administra-tion(oral once per day versus oral twice per day versus subcutaneous injection every 3 months with vitamin A supplementation).

The notable exception is an individual with ATTRv-CM and amyloid polyneuropathy. In such individuals, trans-thyrethin silencer therapy with vutrisan may be preferred because clinical trials show benefit of trans-thyrethin silencers in ATTRv-polyneuropathy.63-65 Of note, the polyneuropathy observed in individuals with ATTRv-CM is less common than the more common musculoskeletal manifestations(eg, carpal tunnel syn-drome, spinal stenosis).25,26 Although transthyretin silencer therapy is effective in ATTRv-polyneuropathy,no data suggest that transthyretin silencer therapy miti-gates the musculoskeletal manifestations. Therefore,transthyretin silencer therapy is not indicated specifically to address these conditions.

4.2.2.3. The Role of Combination Stabilizer and Silencer Therapy

In ATTR-CM, the rationale for combination therapy is based on the potential to enhance efficacy and reduce the risk of disease progression, however at the expense of

increased cost (with a lower financial impact when generic options become available). To date, an additive effect is unknown of stabilizing remaining circulating transthyretin after significant transthyretin knockdown.

Current clinical trial data do not justify the use of combination therapy with either 2 stabilizers or a com-bination of a stabilizer and silencer. In HELIOS-B, 40% of enrolled individuals were on tafamidis at baseline. The remaining 60% of patients comprised the monotherapy group, in whom another 20% initiated tafamidis after randomization at a median of about 17 months. Although the HELIOS-B study was not specifically powered to address the question of combination therapy of vutrisiran and tafamidis, addition of vutrisiran to baseline tafamidis therapy did not result in statistically significant im-provements in clinical endpoints in this subgroup.66-68 Thus, routine combination transthyretin silencer and stabilizer therapy is not recommended based on current available evidence.

The ongoing CARDIO-TTRansform(Study to Evaluate the Efficacy and Safety of Eplontersen in Participants with Transthyretin-Mediated Amyloid Cardiomyopathy;NCTO413617) trial may clarify this issue. CARDIO-TTRansform has enrolled 1,432 participants, 70% of whom were receiving concomitant tafamidis,69 with results expected in 2026. Given the high number of participants on concurrent stabilizer therapy, the trial may provide critical information about combination therapy in this population, although the power to detect a benefit of combination versus single therapy is still limited.

4.2.2.4. Progression of Disease and Role of Adjustments to Therapy

Currently, no widely accepted definition is available of what constitutes response to or failure of disease-modifying therapy. Although many individuals with ATTR-CM develop worsening HF symptoms, new ar-rhythmias, or both, it is unclear if this represents sequela from baseline or ongoing ATTR fibril deposition. ${}^{70}$ The advanced age of the affected population(median age, 75-77 years in the ATTR-CM clinical trials) ${}^{10-12}$ and comorbid conditions(eg, kidney dysfunction, frailty) may account for disease progression more than mechanisms linked to transthyretin misfolding and aggregation. At this time,evidence is insufficient to guide adjustment in disease-modifying therapy for worsening symptoms.

4.2.3. HF Management

4.2.3.1. Effects of Restrictive Physiology

Individuals with restrictive physiology exhibit physio-logic alterations in the pressure-volume relationships with impaired ventricular compliance leading to elevated

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left- and right-sided filling pressures, dependence on heart rate to maintain cardiac output due to a decreased and relatively fixed stroke volume, and impaired vascular-ventricular coupling due to increased ventricu-lar stiffness and abnormal arterial elastance.41,71 These hemodynamic changes result in preload dependence and afterload intolerance, requiring a tailored approach to HF management(Figure 3, Table 3).

4.2.3.2. Diuretics

Loop diuretics alleviate pulmonary and systemic congestion but should be titrated cautiously because of preload dependence and risk for hypotension, reduced stroke volume, and acute kidney injury from over-diuretics. In individuals with diuretic resistance, switch-ing from furosemide to the more bioavailable torsemi or bumatide, or using sequential nephron blockade by adding thiazides(eg, metolazone), can be considered with careful monitoring of electrolytes. Higher baseline diuretic requirements72 and the need for diuretic inten-sification67,73 are associated with a worse prognosis.

4.2.3.3. Indications and Pitfalls of Traditional Guideline-Directed Medical Therapy

Historically, the use of beta-blockers in individuals with ATTR-CM raised concern because of dependence on heart rate to maintain cardiac output, chronotropic incompe-tence from amyloid infiltration of the conduction system,and autonomic dysfunction. Observational data remain mixed, and beta-blocker discontinuation among studies was high, ranging from 22% to 43%.7,74,75 One study reporting no benefit included individuals with more advanced disease and used higher doses of nonselective beta-blockers. ${}^{74}$ By contrast, the largest cohort suggested that low-dose beta-blockers(bisoprolol $\leq 2.5 mg$ /d) may be beneficial in individuals with an ejection fraction$\leq 40\%.^{7}$ Thus, beta-blockers may be cautiously consid-ered at low doses in those with an ejection fraction$\leq 40\%$ , especially if needed for rate control of atrial fibrillation, with a low threshold for reduction or discontinuation for intolerance.

Retrospective observational studies suggest no clinical benefit with vasodilating angiotensin-converting enzyme inhibitors or angiotensin receptor blockers regardless of stratification by reduced ejection fraction and with high discontinuation rates of 33% to 59% due to side effects.7 However, a post-hoc analysis of PARADIGM-HF(Prospective Comparison of ARNI[Angiotensin Receptor-Neprilysin Inhibitor] with ACEI[Angiotensin Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), demon-strated benefit of sacubitril and valstarian in a subpopula-tion of individuals with HFmrEF and HFpEF who may have had amyloidosis identified with an ATTR-CM clinical

|TABLE 3|$$\begin{array}{l}\text{ Potential Indications in}\\ \text{ ATTR-CM}\end{array}$$|$$\begin{array}{l}\text{ Concerns for Use in}\\ \text{ ATTR-CM}\end{array}$$|$$\begin{array}{l}\text{ Specific}\\ \text{ Considerations for HF}\\ \text{ ATTR-CM}\end{array}$$|| |---|---|---|---|---| |HF GDMT Class|$$\begin{array}{l}\text{ Potential Indications in}\\ \text{ ATTR-CM}\end{array}$$|$$\begin{array}{l}\text{ Concerns for Use in}\\ \text{ ATTR-CM}\end{array}$$|$$\begin{array}{l}\text{ Specific}\\\text{ Considerations for HF}\\ \text{ ATTR-CM}\end{array}$$|| |Beta-blockers|$$\begin{array}{l}\text{ LV}\\ \text{ dysfunction}\\ \text{ atrial fibril-}\\ \text{ lation with}\\ \text{ rapid ven-}\\ \text{ tricular}\\ \text{ response}\\ \text{ Coexisting}\\ \text{ coronary ar-}\\ \text{ tery disease}\\ \text{ Ventricular}\\ \text{ arrhythmias}\end{array}$$|$$\begin{array}{l}\text{ Low stroke volume}\\ \text{ and dependence}\\ \text{ on HR to augment}\\ \text{ cardiac output}\\ \text{ rapid ven-}\\ \text{ intricular}\\ \text{ response}\\ \text{ Coexisting}\\ \text{ coronary ar-}\\ \text{ tery disease}\\ \text{ Ventricular}\\ \text{ arrhythmias}\end{array}$$|$$\begin{array}{l}\text{ No randomized clin-}\\\text{ ical trials to date}\\ \text{ Observational data}\\ \text{ with mixed results}\\ \text{ regarding benefit,}\\ \text{ likely due to differ}\\ \text{ ences in baseline}\\ \text{ characteristics}^{7,74,75}\\ \text{ tion rates of 22%-}\\ \text{ 43% in retrospec-}\\ \text{ tive studies}^{7,74,75}\\ \text{ Consider low-dose}\\ \text{ beta-blocker in}\\ \text{ individuals with}\\ \text{ EF}<40\%\text{ or other}\\ \text{ indications, such as}\\ \text{ AF rate control}\end{array}$$|| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| |||||| ||||||

ACEI= angiotensin-converting enzyme inhibitor, AF= atrial fibrillation; ARB= angiotensin re-ceptor blocker; ARNI= angiotensin receptor-nerprilyin inhibitor; ATTR-CM= transthyretin cardiac amyloidosis; EF= ejection fraction; GDMT= guideline-directed medical therapy; HF= heart failure; HR= heart rate; LV= left ventricular; SGLT2= sodium-glucose cotransporter-2.

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score.35 Although vasodilators may not be tolerated due to presence of symptomatic orthostasis or acute kidney injury, angiotensin receptor neprilyin inhibitor may be cautiously attempted based on these data.

Similarly, a subgroup analysis of TOPCAT-Americas(Treatment of Preserved Cardiac Function Heart Failure With Aldosterone Antagonist in the Americas) of in-dividuals with HFmRF and HFpEF randomized to spi-ronolactone versus placebo and similarly enriched for amyloidosis35 demonstrated comparable treatment benefit to the overall population.8 Comparable findings have been observed in other retrospective analyses6 with acceptable tolerance with a discontinuation rate of only 8%.7 No evidence to date has been observed with epler-enone or finerenone in ATTR-CM, although the benefit of MRAs could be considered likely a class effect. MRAs are an option to relieve congestion in individuals with ATTR-CM requiring diuretics.

SGLT2 inhibitors may also provide clinical benefit in individuals with ATTR-CM.9,76. In a retrospective analysis of the DELIVER trial(Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure),be to dapagliflozin was observed in individuals with HFmrEF and HFpEF with a phenotype consistent with ATTR-CM.8 In a multicenter cohort study,SGLT2 inhibitors had a discontinuation rate of only 4.5%and associated with improvements in functional status,reductions in cardiac biomarkers, stabilization of kidney function, and a reduction in all-cause death and HF hospitalization.9 Supporting these findings, a single-center cohort showed that SGLT2 inhibitors use was associated with greater weight reductions and lower loop diuretic dosage.76 Taken together, this suggests that both MRA and SGLT2 inhibitors are options to effectively relieve congestion in individuals with ATTR-CM requiring diuretic therapy. However, the routine use of MRA and SGLT2 inhibitors in all individuals with ATTR-CM is not yet supported by evidence.

4.3. Future Therapies

4.3.1. Transthyretin Silencing With Gene Editing

The demonstrated efficacy of transthyretin messenger ribonucleic acid silencers suggests that permanent modification of genomic TTR would be similarly effec-tive. Preliminary data regarding the CRISPR(Clustered Regularly Interspaced Short Palindromic Repeats) trial-Cas9 agent nexurigan ziclumeran(nex-z) demonstrate durable reduction in transthyretin levels and stabiliza-tion of cardiac biomarkers and functional capacity at 12 months.69 The primary advantage of nex-z is single-dose administration, as well as the potential advan-tage of a greater degree of transthyretin knockdown(89%) than has been reported with vetrisiran(81%)” or

eplontersen(82%).12 A phase 3 study of nex-z is ongoing(MAGNITUDE[A Phase 3 Study of NTLA-2001 in Participants With Transthyretin Amyloidosis With Cardiomyopathy(ATTR-CM)] NCT06128629),78 with an estimated completion date of 2028. Nonetheless, the relative clinical benefit, safety, and cost of permanent modification of genomic TTR versus currently available transthyretin messenger ribonucleic acid silencers remain unclear.

4.3.2. Transthyretin Depleters With Monoclonal Antibodies

Current disease-modifying therapies slow or arrest the deposition of transthyretin amyloid fibrils and slow the progression of ATTR-CM but cannot reverse disease. The ability to remove transthyretin amyloid deposits, how-ever, could restore myocardial compliance, reverse injury, and improve outcomes.79 The development of targeted monoclonal antibodies that recognize misfolded transthyretin and facilitate degradation through activa-tion of macrophage clearance mechanisms represents the therapeutic potential of ATTR fibril depletion agents.80,81 One agent has completed enrollment for a phase 3 clinical trial(ALXN2220 formerly known as NIOo6; DepleTTR-CM[Study of ALXN2220 Versus Placebo in Adults With ATTR-CM] trial; NCTO618393182; estimated completion date 2027), while another is in phase 2(coramitug, formerly known as PRX-0004; NCT0544204783; enrollment completed May 2025) with a phase 3 trial expected. These agents, if confirmed effective with no safety concerns,could offer a therapeutic advance for individuals later in their disease course with significant symptom burden and organ involvement, leading to“reverse remodeling”of their ATTR-CM.

4.4. Conclusions

The profound consequence of parallel advances in early recognition, accurate diagnosis, and effective manage-ment of ATTR-CM over the past decade is highlighted by the increasingly healthier trial populations in the land-mark trials of amyloid therapies. Notably, in the treat-ment arm of the most contemporary trial, HELIOS-B, all-cause death approached the population-expected age-adjusted 3-year mortality rate.84 Nonetheless, despite this substantial progress, many important unanswered questions remain(Table 4).

With transthyretin-disease-modifying therapies currently approved-2 transthyretin stabilizers(acor-amidis and tafamidis) and a transthyretin silencer(vutrisan)-clinians now have multiple options to preserve the quality of life and improve the survival of individuals living with ATTR-CM. Although no studies presently demonstrate superiority of 1 agent over another, and although data are currently insufficient to recommend routine combination therapy and a change in

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TABLE 4 Important Unanswered Questions in the Management of ATTR-CM

|Therapeutic Area|Question(s)|Potential Approaches to Address Emerging Questions| |---|---|---| |Initial therapy|■ Stabilizer or silencer? Which agent?|Comparative effectiveness research using national data repositories or registries Single- or multicenter collaborative research studies Endpoints including progression of disease and costs in addition to mortality and cardiovascular events| |Combination therapy and HF management|Which combination? Initially or in series? Choice of HF therapies|Randomized trials with active controls to determine efficacy of combination therapy compared with monotherapy Comparison of combination therapy at diagnosis versus sequential initiation based on indicators of disease progression Crossover studies comparing single and combination therapy Randomized trials or prospective observational analyses to identify optimal combi- nation of HF-focused therapies(including MRA and SGLT2 inhibitor)| |Monitoring disease progression|What is the optimal combination of metrics? When to reassess?|Determine contributions of potential indicators of therapeutic efficacy or disease progression in multiple complementary domains including circulating biomarkers (transthyretin/prealbumin, ${}^{63}$ troponin, ${}^{68}$ natriuretic peptides, ${}^{87}$ eGFR ${}^{87,88}$ ), imaging biomarkers (echocardiogram GLS, ${}^{89}$ CMR ECV, ${}^{90}$ radionuclide scintigraphy ${}^{91,92}$ ),functional markers (6MWD, ${}^{93}$ CPET-derived parameters ${}^{94}$ ), quality of life (KCCQ) ${}^{95}$ Post-hoc analysis of clinical trials, multisite registries| |Prevention of disease|Can the development of ATTR-CM be prevented in at-risk individuals?|Screening in at-risk populations (SCAN-MP; NCT0381217296) Randomized trials of stabilizers in carriers of pathogenic TTR variants approaching predicted age of disease onset (ACT-EARLY; NCT0656389597) Randomized trials of disease-modifying therapies in older adults with orthopedic transthyretin amyloid identification (carpal tunnel, spinal ligament)| |Cost-effectiveness|■ Costs to individuals as well as health- care system|Cost-effectiveness analysis regarding efficacy vs pricing ${}^{98}$ Analysis of access, administrative burden of the prescription process, regional vari-ations in management|

6MWD=6-minute walk distance; ACT-EARLY= Acoramidis Transthyr Amyloidosis Prevention Trial in the Young; ATTRx-thnyretin cardiac amyloidosis;CM ECV=cardiac magnetic resonance extracellular volume; PETC=cardiopulmonary exercise stress test; ECV= extracellular volume; eGFR= estimated glomerular filtration rate;GLS=global longitudinal strain; HF= heart failure; KCCQ= Kansas City Cardiomyopathy Questionnaire; MRA= mineralocorticoid antagonist; SCAN-MP= Screening for Cardiac Amyloidosis with Nuclear Imaging Inarity Minority Populations; SGLT= 20.5-oglustratine cotransporter-2; TTR= transthyretin.

therapy to mitigate disease progression, ongoing studies may help to clarify some of the unanswered questions to promote optimal care for individuals with ATTR-CM.

PRESIDENT AND STAFF

Christopher M. Kramer, MD, FACC, President Cathleen C. Gates, Chief Executive Officer

Richard J. Kovacs, MD, MACC, Chief Medical Officer Brendan Mullen, Senior Executive Vice President Joseph M. Allen, MA, Team Leader, Science& Quality Amy Dearborn, Team Lead, Decision Science Ashley M. Covington, MA, Team Lead, Decision Science Delivery Grace D. Ronan, Senior Production and Operations Manager, Clinical Policy Publication

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KEY WORDS ACC Concise Clinical Guidance,amyloidosis,amyloid neuropathy,atrial fibrillation, cardiomyopathies, genetic testing,heart failure, heart transplantation

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APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES(RELEVANT)-TRANSTHYRETIN CARDIAC AMYLOIDOSIS EVALUATION AND MANAGEMENT:

2025 ACC CONCISE CLINICAL GUIDANCE

|Committee Member|Employment|Consultant|Speakers Bureau|Ownership/ Partnership/ Principal|Personal Research|Institutional, Organizational, or Other Financial Benefit|Expert Witness| |---|---|---|---|---|---|---|---| |Michelle M. Kittleson, Chair|Smidt Heart Institute, Cedars-Sinai Medical Center-Professor of Medicine|None|None|None|None|None|None| |Amrut V. Ambardekar|University of Colorado- Professor of Medicine- Cardiology|None|None|None|None|None|None| |Richard K. Cheng|University of Washington- Professor of Cardiology|None|None|None|None|None|None| |Jan M. Griffin|Medical University of South Carolina-Associate Professor of Medicine|■ AstraZeneca Pharmaceuticals ■ BridgeBio Pfizer Inc|■ BridgeBio|None|Pfzer*|■ BridgeBio* Scripps*|None| |Mathew S. Maurer|Columbia University Irving of Medicine|■ AstraZeneca Pharmaceuticals* Attralus ■ BridgeBio Eidos, Inc Ionis Novo Nordisk Inc+|None|None|Alnylam Inc Intellia(DSMB)*|None|None| |Jose Nati-vicolau|Mayo Clinic Florida- Transplant Cardiologist|None|None|None|None|None|None| |Frederick L. Ruberg|Boston University- Professor of Medicine|■ AstraZeneca|None|None|Accea Therapeutics* Anumylam Pharmacnutics* Health* Pfizer, Inc* TriethX|None|None|

This table represents all relationships with industry and other entities that were reported by authors, including those not deemed to be relevant to this document, at the time this document was under development. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of≥5% of the voting stock or share of the business entity, or ownership of≥3,000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Please refer to https://www.acc.org/guidelines/about-guidelines-and-clinical-documents/relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC Disclosure Policy for Writing Committees.

ACC=American College of Cardiology; DSMB= data and safety monitoring board.

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APPENDIX 2. PEER REVIEWER RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES(COMPREHENSIVE)-TRANSTHYRETIN CARDIAC AMYLOIDOSIS EVALUATION AND MANAGEMENT:2025 ACC CONCISE CLINICAL GUIDANCE

|Peer Reviewer Representation Employment Employment Consultant Ownership/ Ownership/ Personal Research or Other|||||||| |---|---|---|---|---|---|---|---| |Nadia Fida|Official Reviewer-ACC Heart Failure& Transplant Council|Houston Methodist Baytown-Advanced Heart Failure and Transplant Cardiologist; Medical Director of Cardiology|None|None|None|■ CVRx|None| |Robert C Hendel|Official Reviewer- Solution Set Oversight Committee|Tulane School of Medicine- Professor of Medicine and Radiology|None|None|None|None|None| |Chayakrit Krittawanog|Official Reviewer- Solution Set Oversight Committee|New York University Langone Health-Cardiologist|None|None|None|None|None| |Senthil Selvaraj|Content Reviewer-ACC Expert|Duke University-Assistant Professor of Medicine|■ AstraZeneca Pharmaceuticals BridgeBio PeerView|None|None|None|Heart Failure Society of America| |Brett Wesley Sperry|Content Reviewer-ACC Expert|Saint Luke's Mid America Heart Institute-Cardiologist|Alnylam AstraZeneca Pharmaceuticals BrastrigBio AstraZeneca Pharmaceuticals|Alnylam Pfizer Inc*|None|None|ATTRibute-CM,Eidos CARDIO- TTRansform, Ionist DepleTTR, Alexiont|

This table represents all relationships with industry and other entities that were reported by peer reviewers, including those not deemed to be relevant to this document, at the time this document was under development. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of≥5% of the voting stock or share of the business entity, or ownership of≥5,000 of the fair market value of the business entity;or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Please refer to https://www.acc.org/guidelines/about-guidelines-and-clinical-documents/relationships-with-industry-policy for definitions of disclosure categories or additional information about the ACC Disclosure Policy for Writing Committees.*Significant relationship.

tRelationship with this company is limited to enrolling patients in clinical trials. This disclosure was entered under the Clinical Trial Enroller category in the ACC's disclosure system.To appear in this category, the peer reviewer acknowledges that there is no direct or institutional relationship with the trial sponsor as defined in the ACC Disclosure Policy for Writing Committees.

ACC=American College of Cardiology;ATTribute-CM=Acoramidis in Transthyretin Cardiomyopathy Clinical Trial; CARDIO-TTransform=Evaluate the Efficacy and Safety of Elpontersen in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy Clinical Trial; DepleTTR-CM=Study of ALXN2220 Versus Placebo in Adults With ATTR-CM Clinical Trial.

表 1
History and physical examination	Cardiac manifestations
$$\begin{array}{l}\text{ examination}\end{array}$$	Fatigue HF symptoms $\begin{array}{l}\text{ Fatigue}\\\text{ HF symptoms}\\\text{ Aortosis}\end{array}$ history of HF $\begin{array}{l}\text{ Function system disease/pacemaker}\\\text{ Bilateral carpal tunnel syndrome}\end{array}$ $\begin{array}{l}\text{ Bilateral carpal tunnel syndrome}\\\text{ Bilateral/cervical spinal stenosis}\\\text{ Spontaneous biceps tendon rupture}\\ \end{array}$ $\begin{array}{l}\text{ Hip or knee replacement}\\\text{ Sensor peripheral neuropathy}\\\text{ Family history of neuropathy}\\\text{ Autonomic dysfunction}\end{array}$ $\begin{array}{l}\text{ Stability: knee replacement}\\\text{ Sensor: peripheral neuropathy}\\\text{ Family history of neuropathy}\\\text{ Autonomic dysfunction}\end{array}$ $\begin{array}{l}\text{ Laboratory test results}\\\end{array}$ $\begin{array}{l}\text{ Persistent low-level troponin elevation}\\\text{ Elevated natriuretic peptides}\\\end{array}$ $\begin{array}{l}\text{. Low voltage to LV mass ratio}\\\text{ Atrial fbrillation/flutter especially with}\\\text{ controlled ventricular response}\\\text{ Conduction delay}(\text{ atrioventricular block}\pm\\ \text{ intraventricular conduction delay})\\\text{ Pseudoinfact} pattern\end{array}$ $\begin{array}{l}\text{ Echocardiogram}\\\end{array}$ $\begin{array}{l}\text{ Dimensional imaging}\\\text{ Increased LV and RV wall thickness}\\\text{ Interatrial septal and diffuse valve thickening}\\\text{ Pericarial effusion}\\\text{ Biatrial enlargement and dysfunction}\\\text{ Doppler}$ $\begin{array}{l}\text{ Reduced tissue Doppler s', e', and a'velocities}\\\text{ Restrictive transmitral Doppler filling pattern}\\\text{ Diastolic dysfunction}\geq 2\text{ grade} 2\text{ with high E/A}\\\text{ratio(> 1.5) and reduced E deceleration time}\\\text{ Reduced TAPSE}\\\text{ Other}\end{array}$ $\begin{array}{l}\text{ Reduced global longitudinal strain; ratio}\\\text{ Between EF and global longitudinal strain}\\\text{ Apical sparing on 2-dimensional speckle}\\\text{ tracking images}(\text{ classically referred to as}\\\text{ "cherry on top")}\end{array}$ $\begin{array}{l}\text{. Low flow, low-gradient severe aortic stenosis}\\\text{ Impaired left atrial strain}\end{array}$ $\begin{array}{l}\text{. Diffuse subendocardial or transmural late}\\\text{ gadolinium enhancement}\\\text{ ECV increased myocardial native T1}\\\text{ ECV expansion(>40%)}\end{array}$ $\begin{array}{l}\text{. Reversal of nulling (nulling of the myocardium before or at the same inversion time as blood}\\\text{ pool)}\end{array}$
$$\text{ACDriogram}$$	2-Dimensional imaging ■ Increased LV and RV wall thickness ■ Interatrial septal and diffuse valve thickening
	RV hypertrophy ■ Pericarial effusion Biatrial enlargement and dysfunction ■ ■ Presented EF with low stroke volume index
Doppler	Doppler
	Reduced tissue Doppler s',e', and a'velocities ■ Restrictive transmitral Doppler filling pattern
	Diastolic dysfunction $\geq$ grade 2 with high E/A ratio(> 1.5) and reduced E deceleration time
	(<150 ms)
	Reduced TAPSE Other
	Reduced global longitudinal strain; ratio ■ Reduced TAPSE Other
	between EF and global longitudinal strain $\bullet$ Apical sparing on 2-dimensional speckle tracking images(classically referred to as "cherry on top")
	Low flow, low-gradient severe aortic stenosis ■ Impaired left atrial strain
Cardiac MRI	Diffuse subendocardial or transmural late gadolinium enhancement
	Increased myocardial native T1 ECV expansion(>40%)
	■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■■ ■ ■■■

表 2
TABLE 2	Overview of FDA-Approved Disease-Modifying Therapies for ATTR-CM
Mechanism of action	Tafamidis
Mechanism of action	Transthyretin stabilizer at T4 stabilizer binding site binding site (mimicking the stabilizing transthyretin p. Thr139Met variant)
Trial	ATTR-ACT-10
Years conducted (published)	2013-2018 (2018)
Study type	Randomized, double-blind, placebo-compatible-03 phase 3
Duration, mo	30
Study dose	20 mg or 80 mg orally once a day;
results poolled in primary analysis
FDA-approved dose	Tafamidis 61 mg or taamifidis meglumine 80 mg
FDA-approved dose
No. of participants	441
Mean age, y	74
Male sex, No.(\%)	398(90)
Race, No.(\%)
White	357(81)
Black	63 (14)
Asian	18(4)
TTR genotype,No.(\%)
ATTRW	335(76)
ATTRv	106 (24)
NYHA class, No.(\%)
Class I	37(8)
Class II	263 (60)
Class III	141(32)
NT-proBNP, pg/mL, median	3078278272
6MWD,m,mean	351.9354.8
KCCQ-OSS,mean	66.6
NAC stage, No.(\%)
1	190(42)
2	167(38)
3	84 (20)
Tafamidis use, No.(\%)
Treatment group	264 of 264 (100)
Placebo group	0 of 177(0)

表 3
	Tafamidis	Tafamidis	Acoramidis	Vutrisiran
	Primary outcome	Death,CV hospitalizations win ratio:1.7(95% CI,1.3-2.3)	Death,CV hospitalizations,NTROproBNP change, 6MWT change win ratio 1.8 (95% CI,1.4-2.2)	Death,recurrent CV events:HR: 0.72(95% CI: 0.56-0.93)
All-cause death,HR (95% CI)	0.70(0.51-0.96)	0.77(0.54-1.1)	0.69(0.49- 0.98)
All-cause death,%, treatment vs placebo	29.5 vs 42.9	19.3 vs 25.7	16 vs 215
CV Hospitalizations, RRR(95% CI)	0.68(0.56-0.81)	0.496(0.36-0.70)	0.73(0.61-0.88)
6MWD,LS mean change(95% CI)	75.7(57.6-93.8)	39.6(21.1-58.2)	26.5(13-4.39-6)
KCCQ-OSS,LS mean change(95% CI)	13.65(9.5-17.8)	9.94(6.0-13.9)	5.8(2.4-9.2)
Side effects	Similar to placebo	DiarthehaA%	12(15%) Arthralgia(11%) Dyspnea(7%) Vitamin A (7%) Vitamin A reaction(4%)
Vitamin A supplementation	Not required	Not required	Supplement containing the locally RDA of vitamin A
Annual cost#	$267,987$	$244,539$	$477,404$

表 4
TABLE 3	$$\begin{array}{l}\text{ Potential Indications in}\\ \text{ ATTR-CM}\end{array}$$	$$\begin{array}{l}\text{ Concerns for Use in}\\ \text{ ATTR-CM}\end{array}$$	$$\begin{array}{l}\text{ Specific}\\ \text{ Considerations for HF}\\ \text{ ATTR-CM}\end{array}$$
HF GDMT Class	$$\begin{array}{l}\text{ Potential Indications in}\\ \text{ ATTR-CM}\end{array}$$	$$\begin{array}{l}\text{ Concerns for Use in}\\ \text{ ATTR-CM}\end{array}$$	$$\begin{array}{l}\text{ Specific}\\\text{ Considerations for HF}\\ \text{ ATTR-CM}\end{array}$$
Beta-blockers	$$\begin{array}{l}\text{ LV}\\ \text{ dysfunction}\\ \text{ atrial fibril-}\\ \text{ lation with}\\ \text{ rapid ven-}\\ \text{ tricular}\\ \text{ response}\\ \text{ Coexisting}\\ \text{ coronary ar-}\\ \text{ tery disease}\\ \text{ Ventricular}\\ \text{ arrhythmias}\end{array}$$	$$\begin{array}{l}\text{ Low stroke volume}\\ \text{ and dependence}\\ \text{ on HR to augment}\\ \text{ cardiac output}\\ \text{ rapid ven-}\\ \text{ intricular}\\ \text{ response}\\ \text{ Coexisting}\\ \text{ coronary ar-}\\ \text{ tery disease}\\ \text{ Ventricular}\\ \text{ arrhythmias}\end{array}$$	$$\begin{array}{l}\text{ No randomized clin-}\\\text{ ical trials to date}\\ \text{ Observational data}\\ \text{ with mixed results}\\ \text{ regarding benefit,}\\ \text{ likely due to differ}\\ \text{ ences in baseline}\\ \text{ characteristics}^{7,74,75}\\ \text{ tion rates of 22%-}\\ \text{ 43% in retrospec-}\\ \text{ tive studies}^{7,74,75}\\ \text{ Consider low-dose}\\ \text{ beta-blocker in}\\ \text{ individuals with}\\ \text{ EF}<40\%\text{ or other}\\ \text{ indications, such as}\\ \text{ AF rate control}\end{array}$$

表 5
Therapeutic Area	Question(s)	Potential Approaches to Address Emerging Questions
Initial therapy	■ Stabilizer or silencer? Which agent?	Comparative effectiveness research using national data repositories or registries Single- or multicenter collaborative research studies Endpoints including progression of disease and costs in addition to mortality and cardiovascular events
Combination therapy and HF management	Which combination? Initially or in series? Choice of HF therapies	Randomized trials with active controls to determine efficacy of combination therapy compared with monotherapy Comparison of combination therapy at diagnosis versus sequential initiation based on indicators of disease progression Crossover studies comparing single and combination therapy Randomized trials or prospective observational analyses to identify optimal combi- nation of HF-focused therapies(including MRA and SGLT2 inhibitor)
Monitoring disease progression	What is the optimal combination of metrics? When to reassess?	Determine contributions of potential indicators of therapeutic efficacy or disease progression in multiple complementary domains including circulating biomarkers (transthyretin/prealbumin, ${}^{63}$ troponin, ${}^{68}$ natriuretic peptides, ${}^{87}$ eGFR ${}^{87,88}$ ), imaging biomarkers (echocardiogram GLS, ${}^{89}$ CMR ECV, ${}^{90}$ radionuclide scintigraphy ${}^{91,92}$ ),functional markers (6MWD, ${}^{93}$ CPET-derived parameters ${}^{94}$ ), quality of life (KCCQ) ${}^{95}$ Post-hoc analysis of clinical trials, multisite registries
Prevention of disease	Can the development of ATTR-CM be prevented in at-risk individuals?	Screening in at-risk populations (SCAN-MP; NCT0381217296) Randomized trials of stabilizers in carriers of pathogenic TTR variants approaching predicted age of disease onset (ACT-EARLY; NCT0656389597) Randomized trials of disease-modifying therapies in older adults with orthopedic transthyretin amyloid identification (carpal tunnel, spinal ligament)
Cost-effectiveness	■ Costs to individuals as well as health- care system	Cost-effectiveness analysis regarding efficacy vs pricing ${}^{98}$ Analysis of access, administrative burden of the prescription process, regional vari-ations in management

表 6
Committee Member	Employment	Consultant	Speakers Bureau	Ownership/ Partnership/ Principal	Personal Research	Institutional, Organizational, or Other Financial Benefit	Expert Witness
Michelle M. Kittleson, Chair	Smidt Heart Institute, Cedars-Sinai Medical Center-Professor of Medicine	None	None	None	None	None	None
Amrut V. Ambardekar	University of Colorado- Professor of Medicine- Cardiology	None	None	None	None	None	None
Richard K. Cheng	University of Washington- Professor of Cardiology	None	None	None	None	None	None
Jan M. Griffin	Medical University of South Carolina-Associate Professor of Medicine	■ AstraZeneca Pharmaceuticals ■ BridgeBio Pfizer Inc	■ BridgeBio	None	Pfzer*	■ BridgeBio* Scripps*	None
Mathew S. Maurer	Columbia University Irving of Medicine	■ AstraZeneca Pharmaceuticals* Attralus ■ BridgeBio Eidos, Inc Ionis Novo Nordisk Inc+	None	None	Alnylam Inc Intellia(DSMB)*	None	None
Jose Nati-vicolau	Mayo Clinic Florida- Transplant Cardiologist	None	None	None	None	None	None
Frederick L. Ruberg	Boston University- Professor of Medicine	■ AstraZeneca	None	None	Accea Therapeutics* Anumylam Pharmacnutics* Health* Pfizer, Inc* TriethX	None	None

表 7
Peer Reviewer Representation Employment Employment Consultant Ownership/ Ownership/ Personal Research or Other
Nadia Fida	Official Reviewer-ACC Heart Failure& Transplant Council	Houston Methodist Baytown-Advanced Heart Failure and Transplant Cardiologist; Medical Director of Cardiology	None	None	None	■ CVRx	None
Robert C Hendel	Official Reviewer- Solution Set Oversight Committee	Tulane School of Medicine- Professor of Medicine and Radiology	None	None	None	None	None
Chayakrit Krittawanog	Official Reviewer- Solution Set Oversight Committee	New York University Langone Health-Cardiologist	None	None	None	None	None
Senthil Selvaraj	Content Reviewer-ACC Expert	Duke University-Assistant Professor of Medicine	■ AstraZeneca Pharmaceuticals BridgeBio PeerView	None	None	None	Heart Failure Society of America
Brett Wesley Sperry	Content Reviewer-ACC Expert	Saint Luke's Mid America Heart Institute-Cardiologist	Alnylam AstraZeneca Pharmaceuticals BrastrigBio AstraZeneca Pharmaceuticals	Alnylam Pfizer Inc*	None	None	ATTRibute-CM,Eidos CARDIO- TTRansform, Ionist DepleTTR, Alexiont

图示：Clues from history, ECG, imaging ●SPEP/UPEP not as sensitive as IFE ●Reference K/L ratio is higher in chronic kidney disease (see text and Table 1) ●SNOP/PEF Acceptable Free Light Chain Ratio Range 0.46-2.62 0.48-3.38 Monoclonal protein? 0.54-3.30 0.48-3.38 Monoclonal protein on serum/urine IFE ●Abnormal serum kappa/lambda free light chain(depends on eGFR) ●Monoclonal protein on serum/urine IFE ●Cardiac scintigraphy could be ordered ATTRv 459 419 47% 30% 84% 99% 99% 99 No ●Adcalac scintigraphy could be ordered consultation with hematologist ●Grade 2/3 uptake canylid Biopsy(affected organ/surrogate site) ●Positive Congo Red ●Tissue typing by mass spectrometry No Yes ●Yes ●ATTR-CM ●Corne ATTR-CM ATCR ATTR-CM with MGUS ATTR-CM Genetic testing ATTRv-CM ATTRv-CM

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2025+ACC简明临床指南：转甲状腺素蛋白心脏淀粉样变的评估与管理. 2025.

2025+ACC简明临床指南：转甲状腺素蛋白心脏淀粉样变的评估与管理

2025 ACC Concise Clinical Guidance

ABSTRACT

TABLE OF CONTENTS

APPENDIX 1

APPENDIX 2

PREFACE

1. INTRODUCTION

2. ASSUMPTIONS, DEFINITIONS, AND ABBREVIATIONS

2.1. General Clinical Assumptions

2.2. Definitions

2.3. Abbreviations

3. SUMMARY GRAPHIC

4. DESCRIPTION, RATIONALE, AND IMPLICATIONS

4.1. Diagnosis

4.1.1. Clinical Clues

Modality

Modality Suggestive Findings

4.1.2. Diagnostic Algorithm

4.1.3. Diagnostic Pitfalls

4.2. Management

4.2.1. Overview of Disease-Modifying Therapies

4.2.1.1. Transthyretin Stabilizers

4.2.1.2. Transthyretin Silencers

4.2.2. Choosing Among Disease-Modifying Therapies

4.2.2.1. Selecting Appropriate Individuals for ATTR-CM Disease-Modifying Therapies

Patient Selection and Choice of ATTR-CM Disease-Modifying Therapies

Too Early for Disease-Modifying Therapy

Appropriate for Disease-Modifying Therapy

HF Therapies

Atrial Fibrillation

ATTRv-CM With Cardiomyopathy and Polyneuropathy

ATTRv-CM or ATTRv-CM Without Polyneuropathy

4.2.2.2. Choosing Between Stabilizer Versus Silencer Disease-Modifying Therapy

4.2.2.3. The Role of Combination Stabilizer and Silencer Therapy

4.2.2.4. Progression of Disease and Role of Adjustments to Therapy

4.2.3. HF Management

4.2.3.1. Effects of Restrictive Physiology

4.2.3.2. Diuretics

4.2.3.3. Indications and Pitfalls of Traditional Guideline-Directed Medical Therapy

4.3. Future Therapies

4.3.1. Transthyretin Silencing With Gene Editing

4.3.2. Transthyretin Depleters With Monoclonal Antibodies

4.4. Conclusions

PRESIDENT AND STAFF

REFERENCES

APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES(RELEVANT)-TRANSTHYRETIN CARDIAC AMYLOIDOSIS EVALUATION AND MANAGEMENT:

APPENDIX 2. PEER REVIEWER RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES(COMPREHENSIVE)-TRANSTHYRETIN CARDIAC AMYLOIDOSIS EVALUATION AND MANAGEMENT:2025 ACC CONCISE CLINICAL GUIDANCE

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