amyloidosis 에 의한 울혈성 심부전 탐구 2020 ...

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다음은 심부전(CHF)의 원인, 근본적인 메커니즘, 예후, 치료 옵션을 다루는 대학원 수준의 종합적인 설명입니다.

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1. 심부전 개요

울혈성 심부전(CHF)은 심장이 혈액을 효율적으로 펌프질할 수 없어 신체의 대사 요구량을 충족할 수 있는 심박출량이 부족해지는 임상 증후군입니다. 이 증후군은 종종 심장 내압 상승을 초래하여 폐와 전신에 울혈을 일으킵니다. CHF는 많은 심장 질환의 최종 공통 경로이지만, 그 병태 생리학은 여러 요인에 의해 발생하며, 혈역학적인 변화뿐만 아니라 신경 호르몬, 세포, 분자 적응도 포함됩니다.

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2. 울혈성 심부전의 원인

울혈성 심부전의 원인은 다양하며, 크게 구조적, 기능적, 전신적 원인으로 분류할 수 있습니다.

A. 허혈성 심장병

• 심근경색(MI): 경색으로 인한 심근 손실은 수축력 감소와 그에 따른 수축기 기능 장애를 초래합니다. 재발성 허혈은 시간이 지남에 따라 누적된 심근 손상을 초래할 수도 있습니다.
• 관상동맥질환(CAD): 만성 심근 허혈은 심실 리모델링과 섬유증의 원인이 됩니다.

B. 고혈압성 심장병

• 만성 압력 과부하: 장기간 지속되는 고혈압은 적응 메커니즘으로 좌심실 비대(LVH)를 유발합니다. 시간이 지남에 따라, 이로 인해 간질성 섬유증과 심근 경직 증가로 인해 이완기 기능 장애와 궁극적으로 수축기 장애가 발생합니다.

C. 판막성 심장병

• 역류성 병변(예: 승모판 또는 대동맥판 역류): 역류로 인한 부피 과부하가 편심성 비대를 유발합니다.
• 협착성 병변(예: 대동맥 협착증): 협착으로 인한 압력 과부하로 인해 동심성 비대 및 이완기 기능 장애가 발생합니다.

D. 심근병증

• 확장성 심근병증(DCM): 일반적으로 특발성 질환이지만, 유전적 돌연변이, 독소(예: 알코올, 화학요법제), 바이러스성 심근염과도 관련이 있습니다.
• 비대성 심근병증(HCM): 근절 단백질에 영향을 미치는 유전적 돌연변이로 인해 비정상적인 심근 비후, 이완기 기능 장애, 부정맥 위험이 발생합니다.
• 제한성 심근병증(RCM): 심실 벽이 경직되어 심실 충진 장애가 발생하는 것이 특징입니다(예: 아밀로이드증 또는 심내막 섬유증으로 인한).

E. 부정맥

• 빈맥 유발 심근병증: 만성적인 빠른 심박수(심실 반응이 빠른 심방세동 등)는 시간이 지남에 따라 수축기 기능을 손상시킬 수 있습니다.
• 서맥성 부정맥: 심박수가 충분하지 않으면 심장 박출량이 감소할 수 있습니다.

F. 고출력 실패

• 전신 상태: 중증 빈혈, 갑상선기능항진증, 동정맥루와 같은 상태는 정상 또는 증가된 심장 박출량에도 불구하고 수요가 공급을 훨씬 초과하는 고출력 상태로 이어질 수 있으며, 궁극적으로 심부전 증상을 초래할 수 있습니다.

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4. 예후

심부전증의 예후는 병인, 중증도, 치료에 대한 반응에 따라 크게 달라집니다. 주요 예후 지표는 다음과 같습니다.

• 박출 비율(EF): 낮은 EF는 나쁜 예후와 관련이 있습니다.
• 기능적 상태: 뉴욕 심장 협회(NYHA) 기준에 따른 분류; 더 높은 등급(III-IV)은 더 심각한 증상을 나타냅니다.
• 바이오마커: BNP, NT-proBNP, 트로포닌 수치가 높으면 예후가 좋지 않습니다.
• 수반되는 질환: 신장 기능 장애, 폐 고혈압, 부정맥은 임상 결과를 악화시킵니다.
• 심실 리모델링: 점진적인 확장 및 역리모델링은 사망률과 입원률 증가와 관련이 있습니다.

대규모 임상 등록 자료에 따르면, 심부전 환자의 5년 사망률은 중증도와 신경호르몬 활성화 정도에 따라 50%에서 75%까지 다양합니다.

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5. 치료

관리 전략은 다면적이며, 증상을 완화하고, 혈역학을 개선하며, 질병의 진행을 수정하는 것을 목표로 합니다. 여기에는 다음이 포함됩니다.

A. 생활 습관 및 비약물적 개입

• 식이 조절: 체액 과부하를 줄이기 위한 저염식.
• 체액 제한: 특히 진행성 심부전증에 중요합니다.
• 운동 재활: 맞춤형 심장 재활은 기능 상태와 삶의 질을 향상시킵니다.

B. 약물 치료

• 안지오텐신 전환 효소 억제제(ACEI) / 안지오텐신 수용체 차단제(ARB): 후부하를 낮추고, 리모델링을 줄이며, 생존율을 향상시킵니다.
• 베타 차단제: 만성 교감 신경 과잉 활성화의 유해한 영향을 완화하고, 심박수를 줄이며, 시간이 지남에 따라 EF를 향상시킵니다.
• 미네랄코르티코이드 수용체 길항제(MRA): 에플레레논 또는 스피로놀락톤은 알도스테론의 효과를 차단함으로써 섬유화를 방지하고 사망률을 감소시킵니다.
• 이뇨제: 루프 이뇨제(예: 푸로세마이드)는 울혈을 완화하고 사전 부하를 감소시켜 증상을 개선합니다.
• 네프릴리신 억제제: ARB(예: 사쿠비트릴/발사르탄)와 함께 사용하면 나트륨 이뇨 펩티드의 효과를 강화합니다.
• 혈관 확장제: 히드랄라진과 질산염은 ACEI/ARB 요법을 견디지 못하는 환자나 특정 인종 집단에게 특히 유용합니다.

D. 새로운 치료법과 미래의 방향

• 유전자 치료: SERCA2a 또는 칼슘 처리의 다른 주요 조절 인자를 표적으로 삼는 것은 새로운 치료 방법을 제공할 수 있습니다.
• 줄기세포 치료: 잃어버린 심근을 재생할 수 있는 가능성에 대한 연구가 진행 중입니다.
• 새로운 신경호르몬 조절제: RAAS, SNS 또는 염증 경로를 보다 정확하게 조절하는 새로운 약제가 연구되고 있습니다.
• 기계적 순환 지원 혁신: 새로운 장치와 최소 침습 전략이 계속 발전하고 있습니다.

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결론

울혈성 심부전은 복잡한 원인과 적응적이지만 궁극적으로 부적응적인 신경호르몬 및 세포 반응을 보이는 증후군입니다. 현대의 치료 전략은 신경호르몬 차단 및 심실 리모델링과 같은 주요 메커니즘을 목표로 삼음으로써 이환율과 사망률을 크게 개선했습니다. 그러나 CHF는 전 세계적으로 이환율과 사망률의 주요 원인으로 남아 있으며, 새로운 약리학적 작용제, 장치 치료법, 재생 접근법에 대한 지속적인 연구가 계속해서 중요합니다.

Review Article

Originally Published 1 June 2020

Free Access

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association

Michelle M. Kittleson, MD, PhD, Chair, Mathew S. Maurer, MD, Vice Chair, Amrut V. Ambardekar, MD, Renee P. Bullock-Palmer, MD, Patricia P. Chang, MD, MHS, Howard J. Eisen, MD, Ajith P. Nair, MD, Jose Nativi-Nicolau, MD, and Frederick L. Ruberg, MD, FAHA On behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical CardiologyAuthor Info & Affiliations

Circulation

Volume 142, Number 1

https://doi.org/10.1161/CIR.0000000000000792

170,065445

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Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.

초록
트랜스티레틴 아밀로이드성 심근병증(ATTR-CM)은 

트랜스티레틴의 세포외 침착에 의해 발생하는 

제한성 심근병증으로, 

일반적으로 티록신과 레티놀 결합 단백질의 수송에 관여하는 

트랜스티레틴이 심근에 침착되어 발생합니다. 

ATTR-CM에 대한 열정은 다음의 세 가지 동시적인 발전의 결과로 인해 커졌습니다: 영상 기술을 통해 확인을 위한 심내막 생검 없이도 ATTR-CM을 정확하게 비침습적으로 진단할 수 있습니다; 관찰 연구에 따르면, 심부전 환자의 상당수에서 ATTR-CM 진단이 제대로 이루어지지 않고 있을 수 있습니다; 

그리고 아밀로이드 형성 메커니즘의 규명을 바탕으로, 

ATTR-CM 치료에 대한 치료법이 승인되었습니다. 

ATTR-CM에 대한 치료는 

심각한 심장 기능 장애가 발생하기 전에 시행하는 것이 가장 효과적이기 때문에, 

쉽게 이용할 수 있는 비침습적 검사를 통해 영향을 받은 개인을 조기에 식별하는 것이 필수적입니다. 

이 과학적 성명은 임상 실습을 안내하고 ATTR-CM의 충족되지 않은 요구 사항과 활발하게 연구 중인 분야뿐만 아니라 현재의 진단 및 치료 전략을 다루어 관리의 일관성을 촉진하기 위한 것입니다.

Cardiac amyloidosis results in a restrictive cardiomyopathy caused by extracellular deposition of proteins in the myocardium. The proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils. More than 30 proteins can form amyloid fibrils in vivo, and the classification is based on the precursor protein. Cardiac amyloidosis is caused mainly by misfolded monoclonal immunoglobulin light chains (ALs) from an abnormal clonal proliferation of plasma cells or transthyretin (TTR) amyloidosis (ATTR), a liver-synthesized protein previously called prealbumin that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein. Given the paramount relevance of transthyretin amyloid cardiomyopathy (ATTR-CM) to the practicing cardiologist, this statement focuses on its diagnosis and management.

ATTR can be inherited as an autosomal dominant trait caused by pathogenic variants in the transthyretin gene TTR (ATTRv) or by the deposition of ATTRwt (wild-type transthyretin protein), previously called senile cardiac amyloidosis. The ATTR amyloid protein can infiltrate other organs, most often the autonomic and peripheral nervous systems, but cardiac involvement, when present, is the principal determinant of survival. Median survival after diagnosis in untreated patients is poor: 2.5 years for ATTRv caused by the TTR Val122Ile (or pV142I) mutation and 3.6 years for ATTRwt.1–3

Over the past few years, enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement. First, imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies. Second, observational studies indicate that ATTR-CM may be underrecognized in a significant proportion of patients with heart failure. Third, on the basis of the understanding of the mechanisms of amyloid formation, therapies are approved for treatment of ATTR-CM.

Because therapy for ATTR-CM is most effective when administered before significant symptoms (New York Heart Association [NYHA] class III–IV) of cardiac dysfunction manifest, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and management by covering current diagnostic and treatment strategies, as well as unmet needs and areas of investigation in ATTR-CM.

심장 아밀로이드증은

심근에 단백질이 세포 외로 침착되어 발생하는

제한성 심근병증을 유발합니다.

이 단백질은 불안정한 구조를 가지고 있어서,

아밀로이드 섬유로 잘못 접히고, 응집되고, 침착됩니다.

30가지 이상의 단백질이 생체 내에서 아밀로이드 섬유를 형성할 수 있으며,

그 분류는 전구체 단백질을 기준으로 합니다.

심장성 아밀로이드증은

주로 혈장 세포의 비정상적인 클론 증식 또는 트랜스티레틴(TTR) 아밀로이드증(ATTR)에서 유래된

잘못 접힌 단일 클론 면역글로불린 경쇄(AL)에 의해 발생합니다.

트랜스티레틴(TTR) 아밀로이드증(ATTR)은 이전에 프리알부민이라고 불렸던 간에서 합성된 단백질로,

일반적으로 호르몬인 티록신과 레티놀 결합 단백질의 수송에 관여합니다.

트랜스티레틴 아밀로이드성 심근병증(ATTR-CM)이

심장 전문의에게 가장 중요한 관련성을 가지고 있다는 점을 감안할 때,

이 글은 그 진단과 관리에 초점을 맞춥니다.

ATTR은

트랜스티레틴 유전자 TTR(ATTRv)의 병원성 변이 또는

이전에 노인성 심장 아밀로이드증으로 불렸던

ATTRwt(야생형 트랜스티레틴 단백질)의 침착에 의해 유발되는 상염색체 우성 형질로 유전될 수 있습니다.

senile cardiac amyloidosis

ATTR 아밀로이드 단백질은 다른 기관,

주로 자율신경계와 말초신경계에 침투할 수 있지만,

심장 침범이 있는 경우 생존의 주요 결정 요인입니다.

치료받지 않은 환자의 진단 후 생존 기간 중앙값은 좋지 않습니다:

TTR Val122Ile(또는 pV142I) 돌연변이로 인한 ATTRv의 경우 2.5년,

ATTRwt의 경우 3.6년입니다.1-3

지난 몇 년 동안, ATTR-CM에 대한 관심은 3가지의 동시적인 발전의 결과로 증가했습니다.

첫째, 영상 기법을 사용하면 심내막 생검을 하지 않고도 ATTR-CM을 정확하게 비침습적으로 진단할 수 있습니다.

둘째, 관찰 연구에 따르면 ATTR-CM은 심부전 환자의 상당수에서 제대로 인식되지 않을 수 있습니다.

셋째, 아밀로이드 형성 메커니즘에 대한 이해를 바탕으로 ATTR-CM 치료법이 승인되었습니다.

ATTR-CM에 대한 치료는 심각한 증상(뉴욕 심장 협회[NYHA] 클래스 III-IV)이 나타나기 전에 시행할 때 가장 효과적이기 때문에, 쉽게 이용할 수 있는 비침습적 검사를 통해 영향을 받은 개인을 조기에 식별하는 것이 필수적입니다. 이 과학적 성명은 ATTR-CM의 현재 진단 및 치료 전략뿐만 아니라 충족되지 않은 요구 사항과 조사 분야를 다루어 임상 실습 및 관리를 안내하기 위한 것입니다.

DiagnosisFacilitating Recognition of ATTR-CM

ATTR-CM has historically been considered rare, but the true preval‎ence is challenging to estimate because it is frequently underrecognized. There are many potential explanations, including the false perception that the diagnosis of ATTR-CM can be made only at expert centers through endomyocardial biopsy; the attribution of the presenting signs and symptoms to aging, hypertension, hypertrophic cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF); and, until recently, the lack of disease-modifying treatments, which rendered accurate diagnosis less relevant.

ATTR-CM can be preval‎ent in certain clinical contexts: ATTR deposition is seen in up to 16% of patients with degenerative aortic stenosis4 and 13% to 17% of patients with HFpEF.5,6 Because ATTR-CM is a multisystemic infiltrative disease associated with noncardiac soft tissue deposition, patients often have carpal tunnel syndrome,7 lumbar spinal stenosis,8 biceps tendon rupture,9 and autonomic or sensory polyneuropathy.

진단 ATTR-CM의 인식 촉진

ATTR-CM은

역사적으로 드문 것으로 여겨져 왔지만,

실제 유병률은 제대로 파악되지 않는 경우가 많기 때문에 추정하기가 어렵습니다.

ATTR-CM 진단은

전문 센터에서만 심내막 생검을 통해 이루어질 수 있다는

잘못된 인식, 노화, 고혈압, 비대성 심근병증,

그리고 박출 분율(HFpEF)이 보존된 심부전으로 인한 증상 및 징후의 귀속,

그리고 최근까지 질병을 조절하는 치료법이 없었기 때문에

정확한 진단이 어려웠다는 점 등 여러 가지 잠재적 설명이 있습니다.

ATTR-CM은 특정 임상 상황에서 널리 퍼져 있을 수 있습니다.

ATTR 침착은

퇴행성 대동맥 협착증 환자의 최대 16%4와

심부전성 심부전 환자의 13%에서 17%에서 관찰됩니다.5,6

ATTR-CM은

비심장 연조직 침착과 관련된 다중 시스템 침윤성 질환이기 때문에,

환자들은 종종

손목 터널 증후군,7

요추 협착증,8

이두박근 힘줄 파열,9

자율신경 또는 감각성 다발신경병증을 앓고 있습니다.

Clinical Clues to the Diagnosis of Cardiac Amyloidosis

Patients with ATTR-CM commonly present with dyspnea, fatigue, and edema, but these findings are nonspecific and often misdiagnosed as nonamyloid HFpEF, a missed opportunity. Assessment of myocardial wall thickness on echocardiogram is helpful; the presence of moderate to severe left ventricular (LV) thickening (wall thickness ≥14 mm) should trigger consideration of ATTR-CM especially if there is discordance between wall thickness on echocardiogram and QRS voltage on ECG.10 Patients with HFpEF and a moderate to severe increase in wall thickness are often mislabeled as having hypertensive cardiomyopathy when this should prompt a broader differential, including cardiac amyloidosis, hypertrophic cardiomyopathy, aortic stenosis, and rarer genetic disorders such as Fabry disease.11

Given the nonspecific presenting findings, the key to diagnosis is a high index of suspicion. Older patients presenting with HFpEF and even milder degrees of increased wall thickness also warrant scrutiny; clinical clues are outlined in Table 1.10,12 Family history is of particular importance because an inherited form of ATTRv, the Val122Ile mutation, is observed almost exclusively in black patients and is associated with a greater burden of autonomic and peripheral neuropathy and worse outcomes than ATTRwt.3,11

심장 아밀로이드증 진단을 위한 임상적 단서

ATTR-CM 환자는

일반적으로 호흡곤란, 피로, 부종을 보이지만,

이러한 증상은 비특이적이며 종종 비아밀로이드성 심부전으로 오진되어 놓칠 수 있는 기회입니다.

심초음파 검사에서

심근벽 두께를 평가하는 것이 도움이 됩니다.

중등도에서 중증의 좌심실(LV) 비후(벽 두께 ≥14mm)가 있는 경우,

특히 심초음파 검사에서 측정한 벽 두께와 ECG에서 측정한 QRS 전압이 일치하지 않는 경우,

ATTR-CM을 고려해야 합니다. 10

심근비대증과 함께 중등도에서 중증의 심벽 두께 증가가 있는 환자는

종종 고혈압성 심근병증으로 잘못 진단되지만,

이 경우 심장 아밀로이드증, 비대성 심근병증, 대동맥 협착증, 그리고 파브리병과 같은

희귀 유전 질환을 포함한 더 광범위한 감별 진단이 필요합니다.11

비특이적 소견이 제시되는 경우,

진단의 핵심은 높은 수준의 의심입니다.

심부전으로 인한 울혈성 심부전증(HFpEF)을 앓고 있거나

심부전증으로 인한 울혈성 심부전증(HFpEF)보다

심부전증으로 인한 울혈성 심부전증(HFpEF)이 더 심한 환자들도

면밀한 검사가 필요합니다.

임상적 단서는 표 1.10,12에 요약되어 있습니다.

가족력은 특히 중요합니다.

왜냐하면

ATTRv의 유전적 형태인 Val122Ile 돌연변이는 흑인 환자들 사이에서 거의 독점적으로 관찰되며,

자율신경 및 말초신경병증의 부담이 더 크고 ATTRwt보다 결과가 더 나쁩니다.3,11

Table 1. Clinical Clues From Routine Cardiac Eval‎uation That Should Prompt Additional Diagnostic Eval‎uation for ATTR-CM

Traditional Cardiac CluesNoncardiac Clues

Intolerance to antihypertensive or heart failure medications because of symptomatic hypotension or orthostasis	Neurological: sensorimotor polyneuropathy (paresthesias and weakness), autonomic dysfunction (orthostatic hypotension, postprandial diarrhea alternating with constipation, gastroparesis, urinary retention, and incontinence)
Persistent low-level elevation in serum troponin	Orthopedic: carpal tunnel syndrome, lumbar spinal stenosis, unprovoked biceps tendon rupture, hip and knee arthroplasty
Discordance between QRS voltage on an ECG and wall thickness on imaging	Black race
Unexplained atrioventricular block or prior pacemaker implantation	Family history of polyneuropathy
Unexplained LV wall thickening, right ventricular thickening, or atrial wall thickening
Family history of cardiomyopathy

Expand Table

ATTR-CM indicates transthyretin amyloid cardiomyopathy; and LV, left ventricular.

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Last, it is important to note that <40% of patients with biopsy-proven ATTR-CM have low voltage on ECG, and these patients often have advanced disease.13 Thus, although helpful if present, the absence of low voltage on ECG should not dissuade clinicians from considering ATTR-CM as a potential cause of HFpEF in the appropriate clinical context.

Rational Approach to Testing in Cardiac Amyloidosis

Although echocardiography offers clues that prompt further testing and cardiac magnetic resonance (CMR) imaging14,15 may indicate an infiltrative process, the use of 99mtechnetium (99mTc) bone-avid compounds represents a paradigm shift because these scans allow the noninvasive diagnosis of ATTR-CM, although the basis for binding to amyloid deposits remains unknown.16–18 99mTc compounds include PYP (pyrophosphate), DPD (3,3-diphosphono-1,2-propanodicarboxylic acid), and hydroxymethylene diphosphonate; PYP is used in the United States. The relative merits of echocardiography, CMR, and 99mTc-PYP scans are outlined in Table 2.

심장 아밀로이드증의 검사에 대한 합리적인 접근법

심장 초음파 검사는

추가 검사를 유도하는 단서를 제공하며,

심장 자기 공명 영상(CMR)은 침윤성 과정을 나타낼 수 있지만14,15

99m 테크네튬(99mTc) 골 흡수성 화합물의 사용은 패러다임의 전환을 의미합니다.

이 스캔을 통해 ATTR-CM의 비침습적 진단이 가능하기 때문입니다. 16-18

99mTc 화합물에는

PYP(피로인산), DPD(3,3-디포스포노-1,2-프로판디카르복실산),

하이드록시메틸렌 디포스포네이트가 포함됩니다.

PYP는 미국에서 사용됩니다.

심초음파, CMR, 99mTc-PYP 스캔의 상대적 장점은 표 2에 요약되어 있습니다.

Table 2. Comparison of Diagnostic Imaging Modalities in ATTR-CM

CostSpecialized Expertise Required for InterpretationExposure to Ionizing RadiationCardiac Devices Affect Image QualityCan Identify Nonamyloid Causes of LV ThickeningClinical Clues Suggesting Cardiac AmyloidosisDistinguish AL-CM and ATTR-CMMarkers of Worse Prognosis

Expand Table

$ indicates lower cost; $$, higher cost; AL-CM, immunoglobulin light chain amyloid cardiomyopathy; apo A1, apolipoprotein A1; ATTR-CM, transthyretin amyloid cardiomyopathy; EF, ejection fraction; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; LV, left ventricular; MRI, magnetic resonance imaging; and SPECT, single-photon emission computed tomography.

*

In the context of normal serum and urine immunofixation electrophoresis and serum kappa/lambda ratio.

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The testing algorithm shown in Figure 1 begins with a high index of suspicion (Table 1). CMR alone is not diagnostic of ATTR-CM. CMR is the appropriate test when an infiltrative cardiomyopathy is suspected but ATTR-CM is less likely, as in younger patients or those with findings suggestive of other infiltrative/inflammatory or restrictive cardiomyopathies, including sarcoidosis, hemochromatosis, or Fabry disease, as well as hypertrophic cardiomyopathy, myocarditis, or constrictive pericarditis.22

그림 1에 나타난 테스트 알고리즘은 높은 의심 지수(표 1)로 시작합니다. CMR만으로는 ATTR-CM을 진단할 수 없습니다. CMR은 침윤성 심근병증이 의심되지만 ATTR-CM은 가능성이 낮은 경우에 적합한 검사입니다. 젊은 환자나 다른 침윤성/염증성 또는 제한성 심근병증(사르코이도증, 혈색소침착증, 파브리병 등)을 시사하는 소견이 있는 환자, 비대성 심근병증, 심근염, 수축성 심낭염 환자 등에서도 ATTR-CM은 가능성이 낮습니다.22

Figure 1. Testing algorithm for transthyretin amyloidosis (ATTR). Cardiac magnetic resonance imaging is not diagnostic for ATTR cardiomyopathy (CM) but can suggest the diagnosis and is useful when infiltrative cardiomyopathy, constrictive pericarditis, or myocarditis is suspected. Although, practically, screening for the presence of a monoclonal light chain and 99mtechnetium-pyrophosphate (99mTc-PYP) scans can be ordered together for convenience, the results of the 99mTc-PYP scan should be interpreted only in the context of a negative monoclonal light chain screen. Single-photon emission computed tomography imaging is required if there is grade 1 or higher 99mTc-PYP to distinguish blood pool from myocardial retention. Note that mild elevations in the serum free light chain kappa/lambda ratio frequently occur in patients with renal disease, and in the setting of normal immunofixation, a kappa/lambda ratio of up to 3.0 can be normal.21 Consultation with a hematologist can be considered in such circumstances. AL indicates immunoglobulin light chain; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CMR, cardiac magnetic resonance; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; and IFE, immunofixation electrophoresis.Open in viewer

Although bone scintigraphy has emerged as a cornerstone of ATTR-CM diagnosis, scans may be positive even in AL amyloidosis,18 and a bone scintigraphy scan alone, without concomitant testing for light chains, is neither appropriate nor valid for distinguishing ATTR-CM from AL amyloid cardiomyopathy (AL-CM).

Serum free light chain concentration and serum and urine immunofixation electrophoresis (IFE) are assessed to rule out AL-CM. Serum plasma electrophoresis testing and urine plasma electrophoresis testing are less sensitive and should be avoided. The sensitivity of serum plasma electrophoresis for AL amyloidosis is ≈70%, whereas the sensitivity of serum IFE is >90%.23 Together, measurement of serum IFE, urine IFE, and serum free light chain is >99% sensitive for AL amyloidosis.24,25

Assessment of ATTR-CM with bone scintigraphy is accomplished by semiquantitative or quantitative approaches (Figure 2). The semiquantitative grading involves comparing heart to rib uptake: grade 0 is no cardiac and normal rib uptake; grade 1 is cardiac less than rib uptake; grade 2 is cardiac equal to rib uptake; and grade 3 is cardiac greater than rib uptake with mild/absent rib uptake. Quantitative analysis involves comparison of mean counts as determined by a region of interest placed over the heart and compared with a similar-sized region of intensity placed over the contralateral chest. In the absence of a light chain abnormality, the 99mTc-PYP scan is diagnostic of ATTR-CM if there is grade 2 to 3 cardiac uptake or a heart/contralateral chest ratio >1.5. Single-photon emission computed tomography is assessed in all positive scans to confirm‎ that uptake represents myocardial retention of the tracer, not blood pool signal.4

Figure 2. 99mTechnetium-pyrophosphate imaging for transthyretin cardiac amyloidosis. Single-photon emission computed tomography (SPECT) imaging to identify myocardial retention of technetium-based isotopes is useful in discriminating blood pool on planar scans that result in a false-positive test from myocardial uptake of the isotope indicative of transthyretin amyloidosis with cardiomyopathy. SQA indicates semiquantitative analysis. Reprinted from Maurer et al.26 Copyright © 2019, American Heart Association, Inc. Source figure adapted from Bokhari et al27 with permission of the American Society of Nuclear Cardiology. Copyright © 2016, American Society of Nuclear Cardiology.Open in viewer

Although the presence of grade 2 or 3 scintigraphic uptake has a high specificity in amyloid centers with a high preval‎ence of ATTR-CM, the test performance in populations with lower disease preval‎ence is unknown. The causes of false-positive 99mTc-PYP scans are shown in Table 2.

In some situations, endomyocardial biopsy may be necessary to establish the diagnosis: (1) a positive 99mTc-PYP scan and evidence of a plasma cell dyscrasia by serum/urine IFE or serum free light chain analysis to exclude AL-CM (because AL-CM and ATTR-CM may very rarely occur together in the same patient, such that patients with biopsy-proven AL-CM, especially if older, may also have superimposed ATTRwt-CM deposits); (2) a negative or equivocal 99mTc-PYP scan despite a high clinical suspicion to confirm‎ ATTR-CM; and (3) unavailability of 99mTc-PYP scanning. Given its low sensitivity, a fat-pad biopsy is not sufficient to exclude ATTR-CM.28

If ATTR-CM is identified, then genetic sequencing of the TTR gene is required to define ATTRv versus ATTRwt disease (Table 3). Differentiating ATTRv from ATTRwt is critical because confirmation of ATTRv should trigger genetic counseling and potential screening of family members; the identification of the Val122Ile mutation suggests aggressive progression meriting closer follow-up; and certain therapies are currently approved only for ATTRv. Neurological consultation should be pursued if neurological involvement is present or suspected or if the identified mutation is associated with neurological involvement. Note that age alone is not a valid discriminator of ATTRwt versus ATTRv disease. Two staging schemes offer prognostic insight into ATTR-CM (Table 4).

Table 3. Common Genotypes in ATTR-CM

Age at Onset, ySex DistributionNational/Ethnic PredominanceCardiac InvolvementOther Organ Involvement

Expand Table

ATTR-CM indicates transthyretin amyloid cardiomyopathy; and TTRwt, wild-type transthyretin.

Data derived from Lane et al,3 Maurer et al,11 Connors et al,29 Lopes et al,30 and Sattianayagam et al.31

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Table 4. Prognostic Staging Systems for ATTR-CM

Mayo Staging System1UK Staging System2

Expand Table

ATTR-CM indicates transthyretin amyloid cardiomyopathy; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; eGFR, estimated glomerular filtration rate; and NT-proBNP, N-terminal pro-B-type natriuretic peptide.

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Overview of Disease-Modifying Therapies for ATTR-CM

Targets for disease-modifying therapies in cardiac amyloidosis include TTR silencing, TTR stabilization, and TTR disruption (Figure 3 and Table 5). TTR stabilizers bind to the TTR tetramer and prevent misfolding and thus deposition of amyloid fibrils. TTR silencers target TTR hepatic synthesis. TTR disruptors target the clearance of amyloid fibrils from tissues.

Table 5. Summary of Disease-Modifying Agents Currently Available for ATTR

DrugIndication/ApprovalDose/DeliveryClinical Trial Key Inclusion/ExclusionPotential Side EffectsMonitoringAverage Wholesale Price

TTR stabilizers
Tafamidis	FDA approved for ATTRwt-CM and ATTRv-CM	20*, 61, or 80 mg once daily	ATTR-ACT trial33 Inclusion:  End-diastolic septal thickness >12 mm  History of heart failure  NT-proBNP ≥600 pg/mL Exclusion:  6MWT <100 m  NYHA class IV symptoms  Liver or heart transplantation  eGFR <25 mL·min−1·1.73 m−2	None	None	$225 000/y
Diflunisal	FDA approved as NSAID Off-label use in ATTRwt or ATTRv with neuropathy/cardiomyopathy	250 mg orally twice daily Administer with proton pump inhibitor	Diflunisal Trial Consortium34 Inclusion:  ATTRv with sensorimotor polyneuropathy (familial amyloid polyneuropathy)  Biopsy-proven amyloid deposits  Confirmed TTR mutation Exclusion:  NYHA class IV symptoms  Estimated creatinine clearance  <30 mL/min†  Anticoagulation	Fluid retention Renal dysfunction Bleeding	Renal function Platelet count Hemoglobin	≈$60/mo
TTR silencers
Patisiran	FDA approved for ATTRv with neuropathy	0.3 mg/kg intravenously every 3 wk Premedication with intravenous corticosteroids, intravenous H1 blocker, H2 blocker Daily vitamin A supplement	APOLLO Trial35 Inclusion:  Documented TTR mutation  Confirmed ATTRv with polyneuropathy (familial amyloid polyneuropathy)  NIS score 5–130  PND score ≤3b Exclusion:  NYHA class III–IV symptoms  Liver transplantation	Infusion-related reactions Vitamin A deficiency	None	$414 162/y‡
Inotersen	FDA approved for ATTRv with neuropathy	284 mg/wk subcutaneously Daily vitamin A supplement	NEURO-TTR Trial36 Inclusion:  ATTRv with polyneuropathy (familial amyloid polyneuropathy) stage 1 and 2 familial amyloid polyneuropathy  NIS ≥10 and ≤130  Documented TTR mutation  Documented amyloid deposit on biopsy Exclusion:  Platelets <125×109/L  Creatinine clearance <60 mL·min−1·1.73 m−2  NYHA class III symptoms  Liver transplantation	Thrombocytopenia Glomerulonephritis Infusion-related reactions Vitamin A deficiency	Weekly platelet count Every 2 wk, serum creatinine, eGFR, and UPCR	$359 840/y

Expand Table

6MWT indicates 6-minute walk test; APOLLO, A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; ATTR, transthyretin amyloidosis; ATTRv, cardiac variant transthyretin amyloidosis; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt, wild-type transthyretin amyloidosis; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; ATTR-ACT, Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy; CM, cardiomyopathy; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; NEURO-TTR, Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; NIS, Neuropathy Impairment Score; NSAID, nonsteroidal anti-inflammatory drug; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PND, polyneuropathy disability; TTR, transthyretin; and UPCR, urine protein to creatinine ratio.

*

Although the 20-mg dose is not FDA-approved, it may be considered by clinicians for patients who have issues with affordability, as there is evidence of benefit from the 20-mg dose.36a,36b

†

In clinical practice, diflunisal is not suggested for patients with creatinine clearance <45 mL/min.

‡

Average wholesale price of patisiran based on a patient weight of 70 kg and does not include the price of premedication or infusion-related expenses.

Average wholesale prices taken from Micromedex online database.37

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Figure 3. TTR (transthyretin) production and targets of therapy. Inherited mutations in cardiac variant transthyretin amyloidosis (ATTRv) or the aging process in wild-type disease (ATTRwt) cause destabilization of the TTR protein into monomers or oligomers, which aggregate into amyloid fibrils. These insoluble fibrils accumulate in the myocardium and result in diastolic dysfunction, restrictive cardiomyopathy, and eventual congestive heart failure. Targets of therapy include TTR production (silencers), TTR dissociation (TTR stabilizers), and TTR clearance from tissues (TTR disruption). TUDCA indicates tauroursodeoxycholic acid. Adapted from Nativi-Nicolau and Maurer32 with permission. Copyright © 2018, Wolters Kluwer Health, Inc.Open in viewer

TTR Silencing

TTR protein silencers target the hepatic synthesis of TTR. Patisiran is an intravenously administered siRNA that degrades TTR mRNA, and inotersen is a subcutaneously administered single-stranded antisense oligonucleotide that binds TTR mRNA, leading to degradation. Both therapies result in >85% reduction in circulating TTR protein concentration.

Two randomized trials of TTR silencers in patients with ATTRv amyloidosis and polyneuropathy have been reported: the APOLLO trial (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; patisiran)35 and NEURO-TTR (Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; inotersen).36 Both demonstrated slower progression of amyloidosis-related polyneuropathy.

Although not explicitly tested, there is evidence that TTR silencers may have beneficial cardiac effects. Prespecified subgroup analyses of APOLLO trial participants with increased LV wall thickening unrelated to hypertension or aortic stenosis (assumed to be from amyloidosis) demonstrated that patisiran attenuated the deterioration of LV global longitudinal strain,38 LV wall thickness, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration.39 Similarly, inotersen demonstrated stabilization of LV wall thickness, 6-minute walk test, and global systolic strain.40 Trials to assess the efficacy of TTR silencers in ATTR-CM are ongoing: APOLLO-B (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy [ATTR Amyloidosis With Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03997383; patisiran), 24 Month Open Label Study of the Tolerability and Efficacy of Inotersen in TTR Amyloid Cardiomyopathy Patients (URL: ClinicalTrials.gov. Unique identifier: NCT03702829; inotersen), HELIOS-B (A Study to Eval‎uate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; URL: ClinicalTrials.gov. Unique identifier: NCT04153149; vutrisiran), and CARDIO-TTRansform (A Study to Eval‎uate the Efficacy and Safety of AKCEA-TTR-LRx in Participants With TransthyretinMediated Amyloid Cardiomyopathy [ATTR CM]; URL: ClinicalTrials.gov. Unique identifier: NCT04136171; AKCEA-TTR-LRx).

TTR Stabilization

Diflunisal is a nonsteroidal anti-inflammatory that stabilizes TTR in vitro. In a randomized trial of patients with ATTRv and polyneuropathy, diflunisal was associated with reduced progression of polyneuropathy.34 There are no controlled trials of diflunisal in patients with ATTR-CM, although single-center retrospective analyses demonstrate safety and tolerability and suggest efficacy.41,42

Tafamidis is a TTR stabilizer that binds the thyroxine-binding site of TTR. In the ATTR-ACT randomized trial (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) of patients with ATTRwt-CM or ATTRv-CM, tafamidis was associated with a significantly lower all-cause mortality (29.5% versus 42.9%) and lower cardiovascular-related hospitalization (0.48 versus 0.70 per year) after 30 months. There was a higher rate of cardiovascular-related hospitalizations in the prespecified subgroup of patients with NYHA class III heart failure, which may have been attributable to longer survival during a more severe period of disease, underscoring the importance of early diagnosis and treatment. Tafamidis was also associated with a lower rate of decline in 6-minute walk distance (P<0.001) and a lower rate of decline in Kansas City Cardiomyopathy Questionnaire-Overall Summary score (P<0.001).33 Tafamidis was approved by the US Food and Drug Administration for use in ATTR-CM in May 2019.

AG10 is a TTR stabilizer that binds to the tetramer and mimics coinheritance of the TTR T119M mutation, providing natural stabilization of TTR to prevent amyloid fibril formation and deposition. A phase 2 trial of AG10 demonstrated an acceptable safety profile,43 and data from the open-label extension indicate that mortality and cardiovascular hospitalization were lower in AG10 open-label extension participants than in placebo-treated ATTR-ACT participants at 15 months.44 A phase 3 trial of AG-10 is in progress (ATTRIBUTE-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03860935).

TTR Disruption/Resorption

TTR disruption targets the clearance of amyloidosis fibrils from tissues. Preclinical studies demonstrated that doxycycline plus TUDCA (tauroursodeoxycholic acid) removed amyloid deposits. However, small open-label studies demonstrated a high incidence of side effects with conflicting results on efficacy.45,46 EGCG (epigallocatechin-3-gallate), a catechin in green tea, inhibits amyloid fibril formation in vitro, but there is little evidence of benefit47 from it or turmeric. With the advent of US Food and Drug Administration–approved therapies, the therapeutic roles of these agents are uncertain. Other agents, including monoclonal antibodies such as PRX004, are under investigation.48

Approach to Treatment in Cardiac Amyloidosis

As outlined in Figure 4, treatment of cardiac amyloidosis focuses on 3 areas: management of heart failure, management of arrhythmias, and initiation of disease-modifying agents.

Figure 4. Treatment algorithm for transthyretin amyloidosis (ATTR). ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor blocker-–neprilysin inhibitor; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; BB, β-blocker; CM, cardiomyopathy; CRT, cardiac resynchronization therapy; DOAC, direct oral anticoagulant; HF, heart failure; ICD, implantable cardioverter-defibrillator; PPM, permanent pacemaker; SCD, sudden cardiac death; VKA, vitamin K antagonist; and VT, ventricular tachycardia.Open in viewer

Management of Heart Failure

The physiology of restrictive LV filling and reduced stroke volume/cardiac output in cardiac amyloidosis renders volume maintenance difficult. Bioavailable loop diuretics are used for decongestion, although they may compromise renal function or systemic perfusion in patients with advanced restrictive disease because diminishing preload may compromise an already fixed stroke volume, leading to low cardiac output. Aldosterone antagonists may be used alone or in conjunction with loop diuretics in patients with adequate blood pressure and renal function.

There are no data supporting the use of standard guideline-directed medical therapy for heart failure with reduced ejection fraction or HFpEF in ATTR-CM, including angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, or angiotensin receptors blockers–neprilysin inhibitors. Furthermore, these therapies may exacerbate hypotension when amyloid-associated autonomic dysfunction is present.

β-Blockers and nondihydropyridine calcium channel blockers are often poorly tolerated, even at low doses, because patients with ATTR-CM rely on heart rate response to maintain cardiac output given a fixed stroke volume. In AL amyloidosis, nondihydropyridine calcium channel blockers also bind amyloid fibrils and can result in heart block or shock.

심부전 관리
심장 아밀로이드증에서 좌심실 수축 기능의 제한과 감소된 박출량/심박출량은 체액 유지에 어려움을 줍니다. 생체이용률이 높은 루프 이뇨제는 울혈을 완화하는 데 사용되지만, 사전 부하가 감소하면 이미 고정된 박출량이 손상되어 심박출량이 낮아질 수 있기 때문에, 진행성 제한성 질환 환자의 신장 기능이나 전신 관류에 악영향을 미칠 수 있습니다. 알도스테론 길항제는 혈압과 신장 기능이 적절한 환자들에게 단독으로 사용하거나 루프 이뇨제와 함께 사용할 수 있습니다.

ATTR-CM의 경우, 배출 분율이 감소된 심부전이나 HFpEF에 대한 표준 지침에 따른 의학적 치료의 사용을 뒷받침하는 데이터는 없습니다. 여기에는 안지오텐신 전환 효소 억제제, 안지오텐신 수용체 길항제, 또는 안지오텐신 수용체 차단제인 네프릴리신 억제제가 포함됩니다. 또한, 이러한 치료법은 아밀로이드 관련 자율신경 기능 장애가 있는 경우 저혈압을 악화시킬 수 있습니다.

β-차단제와 비디하이드로피리딘 칼슘 채널 차단제는 ATTR-CM 환자가 고정된 뇌졸중 부피를 감안할 때 심장 박동수 반응에 의존하여 심장 출력을 유지하기 때문에 저용량으로도 내약성이 좋지 않은 경우가 많습니다. AL 아밀로이드증의 경우, 비디하이드로피리딘 칼슘 채널 차단제도 아밀로이드 섬유에 결합하여 심장 차단이나 쇼크를 유발할 수 있습니다.

Management of Arrhythmias

Amyloid cardiomyopathy is associated with atrial dysfunction and both atrial and ventricular arrhythmias. Atrial dysfunction may be reflected by decreased A-wave amplitude and left atrial appendage velocities on echocardiography, and in such cases, empirical anticoagulation may be warranted even in sinus rhythm.49 There is no definitive reported comparison of warfarin and direct oral anticoagulants to prevent thromboembolism in this setting.

As a result of atrial dysfunction in ATTR-CM, anticoagulation is indicated for atrial fibrillation/flutter regardless of CHA2DS2-VASc score. Left atrial appendage closure devices have not been studied in ATTR-CM but may be considered in patients with prohibitive bleeding risk. Digoxin may be used cautiously for rate control, although there is concern about potential digoxin toxicity caused by binding of digoxin to amyloid fibrils. Amiodarone is the agent of choice for both rhythm and rate control, particularly in cases in which β-blockade is not tolerated; cardioversion and ablation should also be considered in selected cases.

Because of the high incidence of conduction system disease from amyloid infiltration, ambulatory electrocardiographic monitoring is part of the syncope eval‎uation, and pacemakers are indicated per Heart Rhythm Society consensus guidelines.50 Implantable cardioverter-defibrillators (ICDs) are recommended in cases of aborted sudden cardiac death with expected survival >1 year or significant ventricular arrhythmias. However, the benefit of ICDs, particularly for primary prevention of sudden cardiac death, is questionable. In a study of 45 patients with amyloid cardiomyopathy (32 with ATTR-CM), an ICD was placed for primary prevention in 38 of the patients. Over follow-up, 12% of patients had at least 1 appropriate ICD therapy; no clinical characteristics predicted who would receive ICD therapy.51 On the basis of limited experience, although Heart Rhythm Society guidelines assign a Class IIb indication to ICD placement in AL-CM and nonsustained ventricular tachycardia with expected survival >1 year, the use of ICDs for primary prevention of sudden cardiac death in patients with ATTR-CM is not well established.52 Cardiac resynchronization therapy may be useful in pacemaker-dependent patients because the already depressed stroke volume may worsen with long-term right ventricular pacing.53

Implementation of Disease-Modifying Therapies in ATTR-CM

The use of US Food and Drug Administration–approved disease-modifying therapy is based on the presence of cardiomyopathy and polyneuropathy and the distinction between ATTRv and ATTRwt amyloidosis (Figure 5). In patients with predominantly cardiac disease resulting from ATTRv or ATTRwt, tafamidis is indicated in those with NYHA class I to III symptoms,33 and early initiation appears to slow disease progression. The benefit of tafamidis has not been observed in patients with class IV symptoms, severe aortic stenosis, or impaired renal function (glomerular filtration rate <25 mL·min−1·1.73 m−2 body surface area).

Figure 5. Projected Medicare Part D beneficiary monthly out-of-pocket costs for tafamidis. Projected annual out-of-pocket expenses were calculated using the standard 2019 Medicare Part D plan including: (1) an initial $415 deductible; (2) an initial coverage period until drug costs reach $3810; (3) a coverage gap (“donut hole”) with 25% cost sharing until out-of-pocket costs reach $5100; and (4) catastrophic coverage with 5% cost sharing without an upper limit. Monthly insurance premiums and the costs of other medications were not included in this projection.Open in viewer

Patients with ATTRv and polyneuropathy should be considered for TTR silencing therapy with patisiran35 or inotersen36; currently, neither is indicated for ATTRv-CM without polyneuropathy or in ATTRwt-CM. In patients with ATTRv-CM with polyneuropathy, the choice between therapeutic agents is based on accessibility and side-effect profile.

The use of combination therapies is appealing to synergistically target both TTR silencing and stabilization of the remaining synthesized protein, but this approach lacks data and may be cost-prohibitive.

Diflusinal (250 mg orally twice daily) may be considered with caution for off-label therapy for asymptomatic ATTR carriers, for patients with ATTR-CM who are not eligible for TTR silencers, or for patients with ATTR-CM who are intolerant of or cannot afford tafamidis. Because of the nonsteroidal anti-inflammatory properties, close monitoring is needed, and diflunisal is contraindicated in patients with significant thrombocytopenia and renal dysfunction (glomerular filtration rate <40 mL·min−1·1.73 m−2) and should be used cautiously in patients on anticoagulation or with a history of gastrointestinal bleeding.

Advanced Heart Failure Therapies in ATTR-CM

For patients with ATTR-CM with stage D heart failure, use of an LV assist device is challenging because of the small LV cavity size and concomitant right ventricular dysfunction.54 There are limited data to support considering the total artificial heart as a bridge to transplantation in patients without significant extracardiac disease.55

Heart transplantation may be considered in patients with stage D heart failure,56 and the current adult donor allocation system provides priority as status 4 to amyloid cardiomyopathy given the lack of durable mechanical circulatory support options. Generally, heart-liver transplantation is performed in patients with ATTRv-CM at risk for neuropathy because neuropathy may progress with heart transplantation alone, although the criteria for heart alone versus heart-liver transplantation are not well defined,57 especially with the advent of silencer therapy, which may have a role after heart transplantation. Liver transplantation alone in ATTRv would offer prohibitive risk in the presence of severe cardiac dysfunction, and preexisting cardiac dysfunction can progress despite subsequent synthesis of wild-type TTR by the donor liver.

Areas of Uncertainty and Future Investigation

Despite advances in the management of ATTR-CM, areas of uncertainty remain in screening, disease progression, role of TTR silencers in patients with ATTR-CM, timing of therapy initiation, and financial burden of new therapies (Table 6).

Table 6. Areas of Active Investigation and Uncertainty in Diagnosis, Prognosis, Progression, and Treatment

Diagnosis

 Should we screen for ATTR-CM? If so, in which populations?

 Which diagnostic tests should be used for screening?

 Are there biomarkers that can raise suspicion of ATTR-CM with sufficient diagnostic certainty to be used for screening?

 Which noninvasive test has the best sensitivity for diagnosis of ATTR-CM?

 How does bone scintigraphy perform as a screening test (eg, in populations with a lower preval‎ence of disease than specialized amyloid centers)?

 What is the cost-effectiveness of screening or active ascertainment?

 How should asymptomatic allele carriers of TTR mutations be followed up for disease penetrance?

Prognosis

 What is the best combination of prognostic variables in ATTR-CM?

 Which biomarkers are most effective for following up patients with ATTR-CM?

 What is the role of imaging in ATTR-CM for prognostication?

 How does one determine whether a patient with ATTR-CM is progressing on therapy?

 What is the role of defibrillators and pacemakers in patients with ATTR-CM?

Progression of disease

 How should one measure disease progression?

 Do the various domains (eg, QOL, functional measures, biomarkers, imaging) progress at the same rate?

 Is there an early marker of disease progression?

 Are there biological processes (TTR stability, TTR kinetics or levels, or TTR ligands) that can be used to monitor progression?

 Can disease progression inform the choice of therapies and when to change therapies?

 Can TTR amyloidosis be reversed? If so, what factors predict regression?

Treatment

 How do the efficacies of stabilizers and silencers compare? Do TTR stabilizers differ in efficacy and side-effect profile?

 Is combination therapy with TTR stabilizers or silencers additive, synergistic, or not beneficial?

 In what order should TTR therapies be administered?

 How does the cost of therapy influence adherence, treatment, and outcomes?

 Does the cost of therapy affect the development of novel therapies?

 When should ATTR-specific therapy be initiated in patients with ATTR-CM?

 When should patients with ATTR-CM be considered for advanced surgical heart failure therapies such as LVAD and cardiac transplantation?

Expand Table

ATTR indicates transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; LVAD, left ventricular assist device; QOL, quality of life; and TTR, transthyretin.

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Identifying Populations for Screening

Given that the preval‎ence of cardiac amyloidosis is increased in specific populations (patients with HFpEF, individuals of West African descent, those with small-fiber polyneuropathy), more active ascertainment or screening may be indicated10 because early identification can maximize the benefit of therapy and delayed diagnosis results in worse outcomes. However, much is not known: the natural history of subclinical TTR cardiac amyloidosis, how testing will perform in groups with lower pretest probability, and the cost-effectiveness of screening.

Biomarkers such as NT-proBNP and troponin, electrocardiography, and echocardiography have low sensitivity/specificity for ATTR-CM. More specific testing may involve measurement of circulating RBP4 (retinol binding protein 4) or misfolded TTR oligomers; both discriminate patients with ATTRv from those with nonamyloid HF and healthy control subjects.58,59

Because HFpEF disproportionately affects older blacks and Hispanics compared with whites, there is currently a recruiting National Institutes of Health–funded prospective cohort study using 99mTc-PYP imaging and measurement of RBP4 and misfolded TTR oligomers to detect ATTR-CM in minority subjects with heart failure (SCAN-MP [Screening for Cardiac Amyloidosis Using Nuclear Imaging for Minority Populations]; URL: ClinicalTrials.gov. Unique identifier: NCT03812172). Other screening studies are ongoing in Afro-Caribbean individuals with increased wall thickness (Frequency of Cardiac Amyloidosis in the Caribbean's [TEAM Amylose]; URL: ClinicalTrials.gov. Unique identifier: NCT03322319), HFpEF patients with increased wall thickness (Transthyretin Cardiac Amyloidosis in HFpEF; URL: ClinicalTrials.gov. Unique identifier: NCT03414632), and those with small-fiber polyneuropathy using TTR gene sequencing (Screening for the Transthyretin-Related Familial Amyloidotic Polyneuropathy [TTR FAP]; URL: ClinicalTrials.gov. Unique identifier: NCT01705626). Last, large-scale biobank genotype studies hold promise for determining the preval‎ence of TTR mutations among target populations.

Another area of significant uncertainty is monitoring in asymptomatic carriers of TTR mutations.60 Given the age-dependent penetrance, the general consensus is to begin assessment 10 years before the affected proband’s age at disease onset, although this approach is limited by the unclear natural history of disease. Assessment can include physical examination, electrocardiography, echocardiography, bone scintigraphy, or CMR imaging.61

Assessing the Progression of Disease

There is no accepted definition of progression or response to therapy of ATTR-CM, but several measures have been proposed: survival, hospitalizations, functional capacity (NYHA class, 6-minute walk test, gait speed, cardiopulmonary exercise stress testing), quality of life, and cardiac biomarkers and imaging (echocardiography, magnetic resonance imaging, or positron emission tomography).

Currently, the role of imaging modalities in eval‎uating response to therapy is not established. Each imaging modality has a different sensitivity for detecting the burden of amyloid fibril deposition, varying capacity to quantify deposition, and therefore different ability to identify progression or improvement. Decreasing levels of misfolded TTR may reflect response to therapy,59 but the role of surveillance imaging and laboratories in assessing response to or guiding changes in therapy requires further study.

Role of TTR Silencers in ATTR-CM Without Neuropathy

Although it is biologically plausible that TTR silencers such as inotersen and patisiran could improve outcomes in ATTR-CM, such conclusions must await the results of adequately powered clinical trials. As a cautionary example, a subcutaneous RNA interference agent similar to patisiran, revusiran, was associated with increased mortality compared with placebo in ATTRv-CM in the ENDEAVOUR clinical trial (Phase 3 Multicenter Study of Revusiran [ALN-TTRSC] in Patients With Transthyretin [TTR] Mediated Familial Amyloidotic Cardiomyopathy [FAC]; URL: ClinicalTrials.gov. Unique identifier: NCT02319005).

Timing of Initiation of Disease-Modifying Agents

Given the lack of consensus on defining disease onset in carriers of TTR mutations and what methods (imaging or biomarkers) should be used to monitor disease progression, the timing of initiation of therapy in ATTRv carriers remains an area of uncertainty.

In contrast, in patients with advanced disease, treatment aimed at TTR stabilization is unlikely to be of significant benefit. Although the package label for tafamidis does not provide restrictions on administration, patients with NYHA class IV symptoms, minimally ambulatory patients (walk <100 m on a 6-minute walk test), and those with advanced renal dysfunction (estimated glomerular filtration rate <25 mL·min−1·m−2) were ineligible for inclusion in ATTR-ACT. Thus, tafamidis is not suggested for patients with advanced heart failure.

Financial Impact of Disease-Modifying Agents

Significantly affecting equitable prescription of these therapies is their considerable cost, especially because lifelong treatment is required, and the financial implication of potentially treating asymptomatic TTR mutation carriers is tremendous.

As noted in Table 6, costs are similar to those of new biologics or chemotherapeutic agents. A significant proportion of patients with ATTR-CM in the United States are older adults with Medicare as their primary insurance. Because Medicare does not allow direct-to-consumer drug maker copay assistance programs, these patients can have significant out-of-pocket expenses.62

Even with Medicare Part D prescription drug coverage, the average cost of tafamidis could approach $18 000 per year, more than half of which occurs after the catastrophic coverage threshold, and would reset annually for every year of treatment (Figure 5). Despite independent charity assistance foundations, the most common income limit was 500% of the federal poverty level (annual income of $62 450 for an individual and $84 550 for a married couple in 2019).63 There are a significant number of patients who may fall above such thresholds but for whom this annual out-of-pocket expense would not be feasible on fixed incomes.

Manufacturers have committed to work with insurers and patients to ensure that no one who merits drug is deprived because of cost, but the practice and impact of such commitments have yet to be fully demonstrated, and a cost-effectiveness analysis of tafamidis indicated that the list price would need to be reduced by >90% for it to be cost-effective.64 Thus, a growing area of concern, for which ATTR-CM is not unique but perhaps emblematic, is the gap between ideal medical therapies and the ability of patients to afford them.

Conclusions

The landscape for the diagnosis of and therapy for ATTR-CM is rapidly evolving. Readily accessible, accurate, noninvasive diagnostic tests and therapies to improve symptoms and survival are now available. ATTR-CM is no longer accurately regarded as a “zebra” diagnosis. Given the now-recognized clinical relevance of ATTR-CM, clinicians must have a high index of suspicion for cardiac amyloidosis when patients present with clinical clues and should invoke a rational diagnostic algorithm to eval‎uate for both AL-CM and ATTR-CM. Once the diagnosis is made, differentiating between ATTRv-CM, ATTRwt-CM, and the presence or absence of neuropathy will allow clinicians to implement an appropriate strategy of heart failure and arrhythmia management along with disease-modifying agents.

Uncertainties exist in screening, the assessment of progression, the management of asymptomatic carriers of ATTRv, the use of TTR silencing agents in ATTR-CM, and the financial impact of disease-modifying therapies. Current and future studies will assess these unanswered knowledge gaps, and advocacy from clinicians at every level may aid in closing the gap between the best medical therapies for ATTR-CM and the ability of patients to afford them.

References

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Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A. Natural history of wild-type transthyretin cardiac amyloidosis andrisk stratification using a novel staging system. J Am Coll Cardiol. 2016;68:1014–1020. doi: 10.1016/j.jacc.2016.06.033

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Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, Quarta CC, Rezk T, Whelan CJ, Gonzalez-Lopez E, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39:2799–2806. doi: 10.1093/eurheartj/ehx589

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Review Article

Originally Published 1 June 2020

Free Access

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association

Michelle M. Kittleson, MD, PhD, Chair, Mathew S. Maurer, MD, Vice Chair, Amrut V. Ambardekar, MD, Renee P. Bullock-Palmer, MD, Patricia P. Chang, MD, MHS, Howard J. Eisen, MD, Ajith P. Nair, MD, Jose Nativi-Nicolau, MD, and Frederick L. Ruberg, MD, FAHA On behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical CardiologyAuthor Info & Affiliations

Circulation

Volume 142, Number 1

https://doi.org/10.1161/CIR.0000000000000792

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Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.

Cardiac amyloidosis results in a restrictive cardiomyopathy caused by extracellular deposition of proteins in the myocardium. The proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils. More than 30 proteins can form amyloid fibrils in vivo, and the classification is based on the precursor protein. Cardiac amyloidosis is caused mainly by misfolded monoclonal immunoglobulin light chains (ALs) from an abnormal clonal proliferation of plasma cells or transthyretin (TTR) amyloidosis (ATTR), a liver-synthesized protein previously called prealbumin that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein. Given the paramount relevance of transthyretin amyloid cardiomyopathy (ATTR-CM) to the practicing cardiologist, this statement focuses on its diagnosis and management.

ATTR can be inherited as an autosomal dominant trait caused by pathogenic variants in the transthyretin gene TTR (ATTRv) or by the deposition of ATTRwt (wild-type transthyretin protein), previously called senile cardiac amyloidosis. The ATTR amyloid protein can infiltrate other organs, most often the autonomic and peripheral nervous systems, but cardiac involvement, when present, is the principal determinant of survival. Median survival after diagnosis in untreated patients is poor: 2.5 years for ATTRv caused by the TTR Val122Ile (or pV142I) mutation and 3.6 years for ATTRwt.1–3

Over the past few years, enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement. First, imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies. Second, observational studies indicate that ATTR-CM may be underrecognized in a significant proportion of patients with heart failure. Third, on the basis of the understanding of the mechanisms of amyloid formation, therapies are approved for treatment of ATTR-CM.

Because therapy for ATTR-CM is most effective when administered before significant symptoms (New York Heart Association [NYHA] class III–IV) of cardiac dysfunction manifest, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and management by covering current diagnostic and treatment strategies, as well as unmet needs and areas of investigation in ATTR-CM.

DiagnosisFacilitating Recognition of ATTR-CM

ATTR-CM has historically been considered rare, but the true preval‎ence is challenging to estimate because it is frequently underrecognized. There are many potential explanations, including the false perception that the diagnosis of ATTR-CM can be made only at expert centers through endomyocardial biopsy; the attribution of the presenting signs and symptoms to aging, hypertension, hypertrophic cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF); and, until recently, the lack of disease-modifying treatments, which rendered accurate diagnosis less relevant.

ATTR-CM can be preval‎ent in certain clinical contexts: ATTR deposition is seen in up to 16% of patients with degenerative aortic stenosis4 and 13% to 17% of patients with HFpEF.5,6 Because ATTR-CM is a multisystemic infiltrative disease associated with noncardiac soft tissue deposition, patients often have carpal tunnel syndrome,7 lumbar spinal stenosis,8 biceps tendon rupture,9 and autonomic or sensory polyneuropathy.

Clinical Clues to the Diagnosis of Cardiac Amyloidosis

Patients with ATTR-CM commonly present with dyspnea, fatigue, and edema, but these findings are nonspecific and often misdiagnosed as nonamyloid HFpEF, a missed opportunity. Assessment of myocardial wall thickness on echocardiogram is helpful; the presence of moderate to severe left ventricular (LV) thickening (wall thickness ≥14 mm) should trigger consideration of ATTR-CM especially if there is discordance between wall thickness on echocardiogram and QRS voltage on ECG.10 Patients with HFpEF and a moderate to severe increase in wall thickness are often mislabeled as having hypertensive cardiomyopathy when this should prompt a broader differential, including cardiac amyloidosis, hypertrophic cardiomyopathy, aortic stenosis, and rarer genetic disorders such as Fabry disease.11

Given the nonspecific presenting findings, the key to diagnosis is a high index of suspicion. Older patients presenting with HFpEF and even milder degrees of increased wall thickness also warrant scrutiny; clinical clues are outlined in Table 1.10,12 Family history is of particular importance because an inherited form of ATTRv, the Val122Ile mutation, is observed almost exclusively in black patients and is associated with a greater burden of autonomic and peripheral neuropathy and worse outcomes than ATTRwt.3,11

Table 1. Clinical Clues From Routine Cardiac Eval‎uation That Should Prompt Additional Diagnostic Eval‎uation for ATTR-CM

Traditional Cardiac CluesNoncardiac Clues

Intolerance to antihypertensive or heart failure medications because of symptomatic hypotension or orthostasis	Neurological: sensorimotor polyneuropathy (paresthesias and weakness), autonomic dysfunction (orthostatic hypotension, postprandial diarrhea alternating with constipation, gastroparesis, urinary retention, and incontinence)
Persistent low-level elevation in serum troponin	Orthopedic: carpal tunnel syndrome, lumbar spinal stenosis, unprovoked biceps tendon rupture, hip and knee arthroplasty
Discordance between QRS voltage on an ECG and wall thickness on imaging	Black race
Unexplained atrioventricular block or prior pacemaker implantation	Family history of polyneuropathy
Unexplained LV wall thickening, right ventricular thickening, or atrial wall thickening
Family history of cardiomyopathy

Expand Table

ATTR-CM indicates transthyretin amyloid cardiomyopathy; and LV, left ventricular.

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Last, it is important to note that <40% of patients with biopsy-proven ATTR-CM have low voltage on ECG, and these patients often have advanced disease.13 Thus, although helpful if present, the absence of low voltage on ECG should not dissuade clinicians from considering ATTR-CM as a potential cause of HFpEF in the appropriate clinical context.

Rational Approach to Testing in Cardiac Amyloidosis

Although echocardiography offers clues that prompt further testing and cardiac magnetic resonance (CMR) imaging14,15 may indicate an infiltrative process, the use of 99mtechnetium (99mTc) bone-avid compounds represents a paradigm shift because these scans allow the noninvasive diagnosis of ATTR-CM, although the basis for binding to amyloid deposits remains unknown.16–18 99mTc compounds include PYP (pyrophosphate), DPD (3,3-diphosphono-1,2-propanodicarboxylic acid), and hydroxymethylene diphosphonate; PYP is used in the United States. The relative merits of echocardiography, CMR, and 99mTc-PYP scans are outlined in Table 2.

Table 2. Comparison of Diagnostic Imaging Modalities in ATTR-CM

CostSpecialized Expertise Required for InterpretationExposure to Ionizing RadiationCardiac Devices Affect Image QualityCan Identify Nonamyloid Causes of LV ThickeningClinical Clues Suggesting Cardiac AmyloidosisDistinguish AL-CM and ATTR-CMMarkers of Worse Prognosis

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$ indicates lower cost; $$, higher cost; AL-CM, immunoglobulin light chain amyloid cardiomyopathy; apo A1, apolipoprotein A1; ATTR-CM, transthyretin amyloid cardiomyopathy; EF, ejection fraction; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; LV, left ventricular; MRI, magnetic resonance imaging; and SPECT, single-photon emission computed tomography.

*

In the context of normal serum and urine immunofixation electrophoresis and serum kappa/lambda ratio.

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The testing algorithm shown in Figure 1 begins with a high index of suspicion (Table 1). CMR alone is not diagnostic of ATTR-CM. CMR is the appropriate test when an infiltrative cardiomyopathy is suspected but ATTR-CM is less likely, as in younger patients or those with findings suggestive of other infiltrative/inflammatory or restrictive cardiomyopathies, including sarcoidosis, hemochromatosis, or Fabry disease, as well as hypertrophic cardiomyopathy, myocarditis, or constrictive pericarditis.22

Figure 1. Testing algorithm for transthyretin amyloidosis (ATTR). Cardiac magnetic resonance imaging is not diagnostic for ATTR cardiomyopathy (CM) but can suggest the diagnosis and is useful when infiltrative cardiomyopathy, constrictive pericarditis, or myocarditis is suspected. Although, practically, screening for the presence of a monoclonal light chain and 99mtechnetium-pyrophosphate (99mTc-PYP) scans can be ordered together for convenience, the results of the 99mTc-PYP scan should be interpreted only in the context of a negative monoclonal light chain screen. Single-photon emission computed tomography imaging is required if there is grade 1 or higher 99mTc-PYP to distinguish blood pool from myocardial retention. Note that mild elevations in the serum free light chain kappa/lambda ratio frequently occur in patients with renal disease, and in the setting of normal immunofixation, a kappa/lambda ratio of up to 3.0 can be normal.21 Consultation with a hematologist can be considered in such circumstances. AL indicates immunoglobulin light chain; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CMR, cardiac magnetic resonance; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; and IFE, immunofixation electrophoresis.Open in viewer

Although bone scintigraphy has emerged as a cornerstone of ATTR-CM diagnosis, scans may be positive even in AL amyloidosis,18 and a bone scintigraphy scan alone, without concomitant testing for light chains, is neither appropriate nor valid for distinguishing ATTR-CM from AL amyloid cardiomyopathy (AL-CM).

Serum free light chain concentration and serum and urine immunofixation electrophoresis (IFE) are assessed to rule out AL-CM. Serum plasma electrophoresis testing and urine plasma electrophoresis testing are less sensitive and should be avoided. The sensitivity of serum plasma electrophoresis for AL amyloidosis is ≈70%, whereas the sensitivity of serum IFE is >90%.23 Together, measurement of serum IFE, urine IFE, and serum free light chain is >99% sensitive for AL amyloidosis.24,25

Assessment of ATTR-CM with bone scintigraphy is accomplished by semiquantitative or quantitative approaches (Figure 2). The semiquantitative grading involves comparing heart to rib uptake: grade 0 is no cardiac and normal rib uptake; grade 1 is cardiac less than rib uptake; grade 2 is cardiac equal to rib uptake; and grade 3 is cardiac greater than rib uptake with mild/absent rib uptake. Quantitative analysis involves comparison of mean counts as determined by a region of interest placed over the heart and compared with a similar-sized region of intensity placed over the contralateral chest. In the absence of a light chain abnormality, the 99mTc-PYP scan is diagnostic of ATTR-CM if there is grade 2 to 3 cardiac uptake or a heart/contralateral chest ratio >1.5. Single-photon emission computed tomography is assessed in all positive scans to confirm‎ that uptake represents myocardial retention of the tracer, not blood pool signal.4

Figure 2. 99mTechnetium-pyrophosphate imaging for transthyretin cardiac amyloidosis. Single-photon emission computed tomography (SPECT) imaging to identify myocardial retention of technetium-based isotopes is useful in discriminating blood pool on planar scans that result in a false-positive test from myocardial uptake of the isotope indicative of transthyretin amyloidosis with cardiomyopathy. SQA indicates semiquantitative analysis. Reprinted from Maurer et al.26 Copyright © 2019, American Heart Association, Inc. Source figure adapted from Bokhari et al27 with permission of the American Society of Nuclear Cardiology. Copyright © 2016, American Society of Nuclear Cardiology.Open in viewer

Although the presence of grade 2 or 3 scintigraphic uptake has a high specificity in amyloid centers with a high preval‎ence of ATTR-CM, the test performance in populations with lower disease preval‎ence is unknown. The causes of false-positive 99mTc-PYP scans are shown in Table 2.

In some situations, endomyocardial biopsy may be necessary to establish the diagnosis: (1) a positive 99mTc-PYP scan and evidence of a plasma cell dyscrasia by serum/urine IFE or serum free light chain analysis to exclude AL-CM (because AL-CM and ATTR-CM may very rarely occur together in the same patient, such that patients with biopsy-proven AL-CM, especially if older, may also have superimposed ATTRwt-CM deposits); (2) a negative or equivocal 99mTc-PYP scan despite a high clinical suspicion to confirm‎ ATTR-CM; and (3) unavailability of 99mTc-PYP scanning. Given its low sensitivity, a fat-pad biopsy is not sufficient to exclude ATTR-CM.28

If ATTR-CM is identified, then genetic sequencing of the TTR gene is required to define ATTRv versus ATTRwt disease (Table 3). Differentiating ATTRv from ATTRwt is critical because confirmation of ATTRv should trigger genetic counseling and potential screening of family members; the identification of the Val122Ile mutation suggests aggressive progression meriting closer follow-up; and certain therapies are currently approved only for ATTRv. Neurological consultation should be pursued if neurological involvement is present or suspected or if the identified mutation is associated with neurological involvement. Note that age alone is not a valid discriminator of ATTRwt versus ATTRv disease. Two staging schemes offer prognostic insight into ATTR-CM (Table 4).

Table 3. Common Genotypes in ATTR-CM

Age at Onset, ySex DistributionNational/Ethnic PredominanceCardiac InvolvementOther Organ Involvement

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ATTR-CM indicates transthyretin amyloid cardiomyopathy; and TTRwt, wild-type transthyretin.

Data derived from Lane et al,3 Maurer et al,11 Connors et al,29 Lopes et al,30 and Sattianayagam et al.31

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Table 4. Prognostic Staging Systems for ATTR-CM

Mayo Staging System1UK Staging System2

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ATTR-CM indicates transthyretin amyloid cardiomyopathy; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; eGFR, estimated glomerular filtration rate; and NT-proBNP, N-terminal pro-B-type natriuretic peptide.

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Overview of Disease-Modifying Therapies for ATTR-CM

Targets for disease-modifying therapies in cardiac amyloidosis include TTR silencing, TTR stabilization, and TTR disruption (Figure 3 and Table 5). TTR stabilizers bind to the TTR tetramer and prevent misfolding and thus deposition of amyloid fibrils. TTR silencers target TTR hepatic synthesis. TTR disruptors target the clearance of amyloid fibrils from tissues.

Table 5. Summary of Disease-Modifying Agents Currently Available for ATTR

DrugIndication/ApprovalDose/DeliveryClinical Trial Key Inclusion/ExclusionPotential Side EffectsMonitoringAverage Wholesale Price

TTR stabilizers
Tafamidis	FDA approved for ATTRwt-CM and ATTRv-CM	20*, 61, or 80 mg once daily	ATTR-ACT trial33 Inclusion:  End-diastolic septal thickness >12 mm  History of heart failure  NT-proBNP ≥600 pg/mL Exclusion:  6MWT <100 m  NYHA class IV symptoms  Liver or heart transplantation  eGFR <25 mL·min−1·1.73 m−2	None	None	$225 000/y
Diflunisal	FDA approved as NSAID Off-label use in ATTRwt or ATTRv with neuropathy/cardiomyopathy	250 mg orally twice daily Administer with proton pump inhibitor	Diflunisal Trial Consortium34 Inclusion:  ATTRv with sensorimotor polyneuropathy (familial amyloid polyneuropathy)  Biopsy-proven amyloid deposits  Confirmed TTR mutation Exclusion:  NYHA class IV symptoms  Estimated creatinine clearance  <30 mL/min†  Anticoagulation	Fluid retention Renal dysfunction Bleeding	Renal function Platelet count Hemoglobin	≈$60/mo
TTR silencers
Patisiran	FDA approved for ATTRv with neuropathy	0.3 mg/kg intravenously every 3 wk Premedication with intravenous corticosteroids, intravenous H1 blocker, H2 blocker Daily vitamin A supplement	APOLLO Trial35 Inclusion:  Documented TTR mutation  Confirmed ATTRv with polyneuropathy (familial amyloid polyneuropathy)  NIS score 5–130  PND score ≤3b Exclusion:  NYHA class III–IV symptoms  Liver transplantation	Infusion-related reactions Vitamin A deficiency	None	$414 162/y‡
Inotersen	FDA approved for ATTRv with neuropathy	284 mg/wk subcutaneously Daily vitamin A supplement	NEURO-TTR Trial36 Inclusion:  ATTRv with polyneuropathy (familial amyloid polyneuropathy) stage 1 and 2 familial amyloid polyneuropathy  NIS ≥10 and ≤130  Documented TTR mutation  Documented amyloid deposit on biopsy Exclusion:  Platelets <125×109/L  Creatinine clearance <60 mL·min−1·1.73 m−2  NYHA class III symptoms  Liver transplantation	Thrombocytopenia Glomerulonephritis Infusion-related reactions Vitamin A deficiency	Weekly platelet count Every 2 wk, serum creatinine, eGFR, and UPCR	$359 840/y

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6MWT indicates 6-minute walk test; APOLLO, A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; ATTR, transthyretin amyloidosis; ATTRv, cardiac variant transthyretin amyloidosis; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt, wild-type transthyretin amyloidosis; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; ATTR-ACT, Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy; CM, cardiomyopathy; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; NEURO-TTR, Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; NIS, Neuropathy Impairment Score; NSAID, nonsteroidal anti-inflammatory drug; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PND, polyneuropathy disability; TTR, transthyretin; and UPCR, urine protein to creatinine ratio.

*

Although the 20-mg dose is not FDA-approved, it may be considered by clinicians for patients who have issues with affordability, as there is evidence of benefit from the 20-mg dose.36a,36b

†

In clinical practice, diflunisal is not suggested for patients with creatinine clearance <45 mL/min.

‡

Average wholesale price of patisiran based on a patient weight of 70 kg and does not include the price of premedication or infusion-related expenses.

Average wholesale prices taken from Micromedex online database.37

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Figure 3. TTR (transthyretin) production and targets of therapy. Inherited mutations in cardiac variant transthyretin amyloidosis (ATTRv) or the aging process in wild-type disease (ATTRwt) cause destabilization of the TTR protein into monomers or oligomers, which aggregate into amyloid fibrils. These insoluble fibrils accumulate in the myocardium and result in diastolic dysfunction, restrictive cardiomyopathy, and eventual congestive heart failure. Targets of therapy include TTR production (silencers), TTR dissociation (TTR stabilizers), and TTR clearance from tissues (TTR disruption). TUDCA indicates tauroursodeoxycholic acid. Adapted from Nativi-Nicolau and Maurer32 with permission. Copyright © 2018, Wolters Kluwer Health, Inc.Open in viewer

TTR Silencing

TTR protein silencers target the hepatic synthesis of TTR. Patisiran is an intravenously administered siRNA that degrades TTR mRNA, and inotersen is a subcutaneously administered single-stranded antisense oligonucleotide that binds TTR mRNA, leading to degradation. Both therapies result in >85% reduction in circulating TTR protein concentration.

Two randomized trials of TTR silencers in patients with ATTRv amyloidosis and polyneuropathy have been reported: the APOLLO trial (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; patisiran)35 and NEURO-TTR (Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; inotersen).36 Both demonstrated slower progression of amyloidosis-related polyneuropathy.

Although not explicitly tested, there is evidence that TTR silencers may have beneficial cardiac effects. Prespecified subgroup analyses of APOLLO trial participants with increased LV wall thickening unrelated to hypertension or aortic stenosis (assumed to be from amyloidosis) demonstrated that patisiran attenuated the deterioration of LV global longitudinal strain,38 LV wall thickness, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration.39 Similarly, inotersen demonstrated stabilization of LV wall thickness, 6-minute walk test, and global systolic strain.40 Trials to assess the efficacy of TTR silencers in ATTR-CM are ongoing: APOLLO-B (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy [ATTR Amyloidosis With Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03997383; patisiran), 24 Month Open Label Study of the Tolerability and Efficacy of Inotersen in TTR Amyloid Cardiomyopathy Patients (URL: ClinicalTrials.gov. Unique identifier: NCT03702829; inotersen), HELIOS-B (A Study to Eval‎uate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; URL: ClinicalTrials.gov. Unique identifier: NCT04153149; vutrisiran), and CARDIO-TTRansform (A Study to Eval‎uate the Efficacy and Safety of AKCEA-TTR-LRx in Participants With TransthyretinMediated Amyloid Cardiomyopathy [ATTR CM]; URL: ClinicalTrials.gov. Unique identifier: NCT04136171; AKCEA-TTR-LRx).

TTR Stabilization

Diflunisal is a nonsteroidal anti-inflammatory that stabilizes TTR in vitro. In a randomized trial of patients with ATTRv and polyneuropathy, diflunisal was associated with reduced progression of polyneuropathy.34 There are no controlled trials of diflunisal in patients with ATTR-CM, although single-center retrospective analyses demonstrate safety and tolerability and suggest efficacy.41,42

Tafamidis is a TTR stabilizer that binds the thyroxine-binding site of TTR. In the ATTR-ACT randomized trial (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) of patients with ATTRwt-CM or ATTRv-CM, tafamidis was associated with a significantly lower all-cause mortality (29.5% versus 42.9%) and lower cardiovascular-related hospitalization (0.48 versus 0.70 per year) after 30 months. There was a higher rate of cardiovascular-related hospitalizations in the prespecified subgroup of patients with NYHA class III heart failure, which may have been attributable to longer survival during a more severe period of disease, underscoring the importance of early diagnosis and treatment. Tafamidis was also associated with a lower rate of decline in 6-minute walk distance (P<0.001) and a lower rate of decline in Kansas City Cardiomyopathy Questionnaire-Overall Summary score (P<0.001).33 Tafamidis was approved by the US Food and Drug Administration for use in ATTR-CM in May 2019.

AG10 is a TTR stabilizer that binds to the tetramer and mimics coinheritance of the TTR T119M mutation, providing natural stabilization of TTR to prevent amyloid fibril formation and deposition. A phase 2 trial of AG10 demonstrated an acceptable safety profile,43 and data from the open-label extension indicate that mortality and cardiovascular hospitalization were lower in AG10 open-label extension participants than in placebo-treated ATTR-ACT participants at 15 months.44 A phase 3 trial of AG-10 is in progress (ATTRIBUTE-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03860935).

TTR Disruption/Resorption

TTR disruption targets the clearance of amyloidosis fibrils from tissues. Preclinical studies demonstrated that doxycycline plus TUDCA (tauroursodeoxycholic acid) removed amyloid deposits. However, small open-label studies demonstrated a high incidence of side effects with conflicting results on efficacy.45,46 EGCG (epigallocatechin-3-gallate), a catechin in green tea, inhibits amyloid fibril formation in vitro, but there is little evidence of benefit47 from it or turmeric. With the advent of US Food and Drug Administration–approved therapies, the therapeutic roles of these agents are uncertain. Other agents, including monoclonal antibodies such as PRX004, are under investigation.48

Approach to Treatment in Cardiac Amyloidosis

As outlined in Figure 4, treatment of cardiac amyloidosis focuses on 3 areas: management of heart failure, management of arrhythmias, and initiation of disease-modifying agents.

Figure 4. Treatment algorithm for transthyretin amyloidosis (ATTR). ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor blocker-–neprilysin inhibitor; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; BB, β-blocker; CM, cardiomyopathy; CRT, cardiac resynchronization therapy; DOAC, direct oral anticoagulant; HF, heart failure; ICD, implantable cardioverter-defibrillator; PPM, permanent pacemaker; SCD, sudden cardiac death; VKA, vitamin K antagonist; and VT, ventricular tachycardia.Open in viewer

Management of Heart Failure

The physiology of restrictive LV filling and reduced stroke volume/cardiac output in cardiac amyloidosis renders volume maintenance difficult. Bioavailable loop diuretics are used for decongestion, although they may compromise renal function or systemic perfusion in patients with advanced restrictive disease because diminishing preload may compromise an already fixed stroke volume, leading to low cardiac output. Aldosterone antagonists may be used alone or in conjunction with loop diuretics in patients with adequate blood pressure and renal function.

There are no data supporting the use of standard guideline-directed medical therapy for heart failure with reduced ejection fraction or HFpEF in ATTR-CM, including angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, or angiotensin receptors blockers–neprilysin inhibitors. Furthermore, these therapies may exacerbate hypotension when amyloid-associated autonomic dysfunction is present.

β-Blockers and nondihydropyridine calcium channel blockers are often poorly tolerated, even at low doses, because patients with ATTR-CM rely on heart rate response to maintain cardiac output given a fixed stroke volume. In AL amyloidosis, nondihydropyridine calcium channel blockers also bind amyloid fibrils and can result in heart block or shock.

Management of Arrhythmias

Amyloid cardiomyopathy is associated with atrial dysfunction and both atrial and ventricular arrhythmias. Atrial dysfunction may be reflected by decreased A-wave amplitude and left atrial appendage velocities on echocardiography, and in such cases, empirical anticoagulation may be warranted even in sinus rhythm.49 There is no definitive reported comparison of warfarin and direct oral anticoagulants to prevent thromboembolism in this setting.

As a result of atrial dysfunction in ATTR-CM, anticoagulation is indicated for atrial fibrillation/flutter regardless of CHA2DS2-VASc score. Left atrial appendage closure devices have not been studied in ATTR-CM but may be considered in patients with prohibitive bleeding risk. Digoxin may be used cautiously for rate control, although there is concern about potential digoxin toxicity caused by binding of digoxin to amyloid fibrils. Amiodarone is the agent of choice for both rhythm and rate control, particularly in cases in which β-blockade is not tolerated; cardioversion and ablation should also be considered in selected cases.

Because of the high incidence of conduction system disease from amyloid infiltration, ambulatory electrocardiographic monitoring is part of the syncope eval‎uation, and pacemakers are indicated per Heart Rhythm Society consensus guidelines.50 Implantable cardioverter-defibrillators (ICDs) are recommended in cases of aborted sudden cardiac death with expected survival >1 year or significant ventricular arrhythmias. However, the benefit of ICDs, particularly for primary prevention of sudden cardiac death, is questionable. In a study of 45 patients with amyloid cardiomyopathy (32 with ATTR-CM), an ICD was placed for primary prevention in 38 of the patients. Over follow-up, 12% of patients had at least 1 appropriate ICD therapy; no clinical characteristics predicted who would receive ICD therapy.51 On the basis of limited experience, although Heart Rhythm Society guidelines assign a Class IIb indication to ICD placement in AL-CM and nonsustained ventricular tachycardia with expected survival >1 year, the use of ICDs for primary prevention of sudden cardiac death in patients with ATTR-CM is not well established.52 Cardiac resynchronization therapy may be useful in pacemaker-dependent patients because the already depressed stroke volume may worsen with long-term right ventricular pacing.53

Implementation of Disease-Modifying Therapies in ATTR-CM

The use of US Food and Drug Administration–approved disease-modifying therapy is based on the presence of cardiomyopathy and polyneuropathy and the distinction between ATTRv and ATTRwt amyloidosis (Figure 5). In patients with predominantly cardiac disease resulting from ATTRv or ATTRwt, tafamidis is indicated in those with NYHA class I to III symptoms,33 and early initiation appears to slow disease progression. The benefit of tafamidis has not been observed in patients with class IV symptoms, severe aortic stenosis, or impaired renal function (glomerular filtration rate <25 mL·min−1·1.73 m−2 body surface area).

Figure 5. Projected Medicare Part D beneficiary monthly out-of-pocket costs for tafamidis. Projected annual out-of-pocket expenses were calculated using the standard 2019 Medicare Part D plan including: (1) an initial $415 deductible; (2) an initial coverage period until drug costs reach $3810; (3) a coverage gap (“donut hole”) with 25% cost sharing until out-of-pocket costs reach $5100; and (4) catastrophic coverage with 5% cost sharing without an upper limit. Monthly insurance premiums and the costs of other medications were not included in this projection.Open in viewer

Patients with ATTRv and polyneuropathy should be considered for TTR silencing therapy with patisiran35 or inotersen36; currently, neither is indicated for ATTRv-CM without polyneuropathy or in ATTRwt-CM. In patients with ATTRv-CM with polyneuropathy, the choice between therapeutic agents is based on accessibility and side-effect profile.

The use of combination therapies is appealing to synergistically target both TTR silencing and stabilization of the remaining synthesized protein, but this approach lacks data and may be cost-prohibitive.

Diflusinal (250 mg orally twice daily) may be considered with caution for off-label therapy for asymptomatic ATTR carriers, for patients with ATTR-CM who are not eligible for TTR silencers, or for patients with ATTR-CM who are intolerant of or cannot afford tafamidis. Because of the nonsteroidal anti-inflammatory properties, close monitoring is needed, and diflunisal is contraindicated in patients with significant thrombocytopenia and renal dysfunction (glomerular filtration rate <40 mL·min−1·1.73 m−2) and should be used cautiously in patients on anticoagulation or with a history of gastrointestinal bleeding.

Advanced Heart Failure Therapies in ATTR-CM

For patients with ATTR-CM with stage D heart failure, use of an LV assist device is challenging because of the small LV cavity size and concomitant right ventricular dysfunction.54 There are limited data to support considering the total artificial heart as a bridge to transplantation in patients without significant extracardiac disease.55

Heart transplantation may be considered in patients with stage D heart failure,56 and the current adult donor allocation system provides priority as status 4 to amyloid cardiomyopathy given the lack of durable mechanical circulatory support options. Generally, heart-liver transplantation is performed in patients with ATTRv-CM at risk for neuropathy because neuropathy may progress with heart transplantation alone, although the criteria for heart alone versus heart-liver transplantation are not well defined,57 especially with the advent of silencer therapy, which may have a role after heart transplantation. Liver transplantation alone in ATTRv would offer prohibitive risk in the presence of severe cardiac dysfunction, and preexisting cardiac dysfunction can progress despite subsequent synthesis of wild-type TTR by the donor liver.

Areas of Uncertainty and Future Investigation

Despite advances in the management of ATTR-CM, areas of uncertainty remain in screening, disease progression, role of TTR silencers in patients with ATTR-CM, timing of therapy initiation, and financial burden of new therapies (Table 6).

Table 6. Areas of Active Investigation and Uncertainty in Diagnosis, Prognosis, Progression, and Treatment

Diagnosis

 Should we screen for ATTR-CM? If so, in which populations?

 Which diagnostic tests should be used for screening?

 Are there biomarkers that can raise suspicion of ATTR-CM with sufficient diagnostic certainty to be used for screening?

 Which noninvasive test has the best sensitivity for diagnosis of ATTR-CM?

 How does bone scintigraphy perform as a screening test (eg, in populations with a lower preval‎ence of disease than specialized amyloid centers)?

 What is the cost-effectiveness of screening or active ascertainment?

 How should asymptomatic allele carriers of TTR mutations be followed up for disease penetrance?

Prognosis

 What is the best combination of prognostic variables in ATTR-CM?

 Which biomarkers are most effective for following up patients with ATTR-CM?

 What is the role of imaging in ATTR-CM for prognostication?

 How does one determine whether a patient with ATTR-CM is progressing on therapy?

 What is the role of defibrillators and pacemakers in patients with ATTR-CM?

Progression of disease

 How should one measure disease progression?

 Do the various domains (eg, QOL, functional measures, biomarkers, imaging) progress at the same rate?

 Is there an early marker of disease progression?

 Are there biological processes (TTR stability, TTR kinetics or levels, or TTR ligands) that can be used to monitor progression?

 Can disease progression inform the choice of therapies and when to change therapies?

 Can TTR amyloidosis be reversed? If so, what factors predict regression?

Treatment

 How do the efficacies of stabilizers and silencers compare? Do TTR stabilizers differ in efficacy and side-effect profile?

 Is combination therapy with TTR stabilizers or silencers additive, synergistic, or not beneficial?

 In what order should TTR therapies be administered?

 How does the cost of therapy influence adherence, treatment, and outcomes?

 Does the cost of therapy affect the development of novel therapies?

 When should ATTR-specific therapy be initiated in patients with ATTR-CM?

 When should patients with ATTR-CM be considered for advanced surgical heart failure therapies such as LVAD and cardiac transplantation?

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ATTR indicates transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; LVAD, left ventricular assist device; QOL, quality of life; and TTR, transthyretin.

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Identifying Populations for Screening

Given that the preval‎ence of cardiac amyloidosis is increased in specific populations (patients with HFpEF, individuals of West African descent, those with small-fiber polyneuropathy), more active ascertainment or screening may be indicated10 because early identification can maximize the benefit of therapy and delayed diagnosis results in worse outcomes. However, much is not known: the natural history of subclinical TTR cardiac amyloidosis, how testing will perform in groups with lower pretest probability, and the cost-effectiveness of screening.

Biomarkers such as NT-proBNP and troponin, electrocardiography, and echocardiography have low sensitivity/specificity for ATTR-CM. More specific testing may involve measurement of circulating RBP4 (retinol binding protein 4) or misfolded TTR oligomers; both discriminate patients with ATTRv from those with nonamyloid HF and healthy control subjects.58,59

Because HFpEF disproportionately affects older blacks and Hispanics compared with whites, there is currently a recruiting National Institutes of Health–funded prospective cohort study using 99mTc-PYP imaging and measurement of RBP4 and misfolded TTR oligomers to detect ATTR-CM in minority subjects with heart failure (SCAN-MP [Screening for Cardiac Amyloidosis Using Nuclear Imaging for Minority Populations]; URL: ClinicalTrials.gov. Unique identifier: NCT03812172). Other screening studies are ongoing in Afro-Caribbean individuals with increased wall thickness (Frequency of Cardiac Amyloidosis in the Caribbean's [TEAM Amylose]; URL: ClinicalTrials.gov. Unique identifier: NCT03322319), HFpEF patients with increased wall thickness (Transthyretin Cardiac Amyloidosis in HFpEF; URL: ClinicalTrials.gov. Unique identifier: NCT03414632), and those with small-fiber polyneuropathy using TTR gene sequencing (Screening for the Transthyretin-Related Familial Amyloidotic Polyneuropathy [TTR FAP]; URL: ClinicalTrials.gov. Unique identifier: NCT01705626). Last, large-scale biobank genotype studies hold promise for determining the preval‎ence of TTR mutations among target populations.

Another area of significant uncertainty is monitoring in asymptomatic carriers of TTR mutations.60 Given the age-dependent penetrance, the general consensus is to begin assessment 10 years before the affected proband’s age at disease onset, although this approach is limited by the unclear natural history of disease. Assessment can include physical examination, electrocardiography, echocardiography, bone scintigraphy, or CMR imaging.61

Assessing the Progression of Disease

There is no accepted definition of progression or response to therapy of ATTR-CM, but several measures have been proposed: survival, hospitalizations, functional capacity (NYHA class, 6-minute walk test, gait speed, cardiopulmonary exercise stress testing), quality of life, and cardiac biomarkers and imaging (echocardiography, magnetic resonance imaging, or positron emission tomography).

Currently, the role of imaging modalities in eval‎uating response to therapy is not established. Each imaging modality has a different sensitivity for detecting the burden of amyloid fibril deposition, varying capacity to quantify deposition, and therefore different ability to identify progression or improvement. Decreasing levels of misfolded TTR may reflect response to therapy,59 but the role of surveillance imaging and laboratories in assessing response to or guiding changes in therapy requires further study.

Role of TTR Silencers in ATTR-CM Without Neuropathy

Although it is biologically plausible that TTR silencers such as inotersen and patisiran could improve outcomes in ATTR-CM, such conclusions must await the results of adequately powered clinical trials. As a cautionary example, a subcutaneous RNA interference agent similar to patisiran, revusiran, was associated with increased mortality compared with placebo in ATTRv-CM in the ENDEAVOUR clinical trial (Phase 3 Multicenter Study of Revusiran [ALN-TTRSC] in Patients With Transthyretin [TTR] Mediated Familial Amyloidotic Cardiomyopathy [FAC]; URL: ClinicalTrials.gov. Unique identifier: NCT02319005).

Timing of Initiation of Disease-Modifying Agents

Given the lack of consensus on defining disease onset in carriers of TTR mutations and what methods (imaging or biomarkers) should be used to monitor disease progression, the timing of initiation of therapy in ATTRv carriers remains an area of uncertainty.

In contrast, in patients with advanced disease, treatment aimed at TTR stabilization is unlikely to be of significant benefit. Although the package label for tafamidis does not provide restrictions on administration, patients with NYHA class IV symptoms, minimally ambulatory patients (walk <100 m on a 6-minute walk test), and those with advanced renal dysfunction (estimated glomerular filtration rate <25 mL·min−1·m−2) were ineligible for inclusion in ATTR-ACT. Thus, tafamidis is not suggested for patients with advanced heart failure.

Financial Impact of Disease-Modifying Agents

Significantly affecting equitable prescription of these therapies is their considerable cost, especially because lifelong treatment is required, and the financial implication of potentially treating asymptomatic TTR mutation carriers is tremendous.

As noted in Table 6, costs are similar to those of new biologics or chemotherapeutic agents. A significant proportion of patients with ATTR-CM in the United States are older adults with Medicare as their primary insurance. Because Medicare does not allow direct-to-consumer drug maker copay assistance programs, these patients can have significant out-of-pocket expenses.62

Even with Medicare Part D prescription drug coverage, the average cost of tafamidis could approach $18 000 per year, more than half of which occurs after the catastrophic coverage threshold, and would reset annually for every year of treatment (Figure 5). Despite independent charity assistance foundations, the most common income limit was 500% of the federal poverty level (annual income of $62 450 for an individual and $84 550 for a married couple in 2019).63 There are a significant number of patients who may fall above such thresholds but for whom this annual out-of-pocket expense would not be feasible on fixed incomes.

Manufacturers have committed to work with insurers and patients to ensure that no one who merits drug is deprived because of cost, but the practice and impact of such commitments have yet to be fully demonstrated, and a cost-effectiveness analysis of tafamidis indicated that the list price would need to be reduced by >90% for it to be cost-effective.64 Thus, a growing area of concern, for which ATTR-CM is not unique but perhaps emblematic, is the gap between ideal medical therapies and the ability of patients to afford them.

Conclusions

The landscape for the diagnosis of and therapy for ATTR-CM is rapidly evolving. Readily accessible, accurate, noninvasive diagnostic tests and therapies to improve symptoms and survival are now available. ATTR-CM is no longer accurately regarded as a “zebra” diagnosis. Given the now-recognized clinical relevance of ATTR-CM, clinicians must have a high index of suspicion for cardiac amyloidosis when patients present with clinical clues and should invoke a rational diagnostic algorithm to eval‎uate for both AL-CM and ATTR-CM. Once the diagnosis is made, differentiating between ATTRv-CM, ATTRwt-CM, and the presence or absence of neuropathy will allow clinicians to implement an appropriate strategy of heart failure and arrhythmia management along with disease-modifying agents.

Uncertainties exist in screening, the assessment of progression, the management of asymptomatic carriers of ATTRv, the use of TTR silencing agents in ATTR-CM, and the financial impact of disease-modifying therapies. Current and future studies will assess these unanswered knowledge gaps, and advocacy from clinicians at every level may aid in closing the gap between the best medical therapies for ATTR-CM and the ability of patients to afford them.

References

1.

Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A. Natural history of wild-type transthyretin cardiac amyloidosis andrisk stratification using a novel staging system. J Am Coll Cardiol. 2016;68:1014–1020. doi: 10.1016/j.jacc.2016.06.033

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Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, Quarta CC, Rezk T, Whelan CJ, Gonzalez-Lopez E, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39:2799–2806. doi: 10.1093/eurheartj/ehx589

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Lane T, Fontana M, Martinez-Naharro A, Quarta CC, Whelan CJ, Petrie A, Rowczenio DM, Gilbertson JA, Hutt DF, Rezk T, et al. Natural history, quality of life, and outcome in cardiac

Review Article

Originally Published 1 June 2020

Free Access

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association

Michelle M. Kittleson, MD, PhD, Chair, Mathew S. Maurer, MD, Vice Chair, Amrut V. Ambardekar, MD, Renee P. Bullock-Palmer, MD, Patricia P. Chang, MD, MHS, Howard J. Eisen, MD, Ajith P. Nair, MD, Jose Nativi-Nicolau, MD, and Frederick L. Ruberg, MD, FAHA On behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical CardiologyAuthor Info & Affiliations

Circulation

Volume 142, Number 1

https://doi.org/10.1161/CIR.0000000000000792

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Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.

Cardiac amyloidosis results in a restrictive cardiomyopathy caused by extracellular deposition of proteins in the myocardium. The proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils. More than 30 proteins can form amyloid fibrils in vivo, and the classification is based on the precursor protein. Cardiac amyloidosis is caused mainly by misfolded monoclonal immunoglobulin light chains (ALs) from an abnormal clonal proliferation of plasma cells or transthyretin (TTR) amyloidosis (ATTR), a liver-synthesized protein previously called prealbumin that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein. Given the paramount relevance of transthyretin amyloid cardiomyopathy (ATTR-CM) to the practicing cardiologist, this statement focuses on its diagnosis and management.

ATTR can be inherited as an autosomal dominant trait caused by pathogenic variants in the transthyretin gene TTR (ATTRv) or by the deposition of ATTRwt (wild-type transthyretin protein), previously called senile cardiac amyloidosis. The ATTR amyloid protein can infiltrate other organs, most often the autonomic and peripheral nervous systems, but cardiac involvement, when present, is the principal determinant of survival. Median survival after diagnosis in untreated patients is poor: 2.5 years for ATTRv caused by the TTR Val122Ile (or pV142I) mutation and 3.6 years for ATTRwt.1–3

Over the past few years, enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement. First, imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies. Second, observational studies indicate that ATTR-CM may be underrecognized in a significant proportion of patients with heart failure. Third, on the basis of the understanding of the mechanisms of amyloid formation, therapies are approved for treatment of ATTR-CM.

Because therapy for ATTR-CM is most effective when administered before significant symptoms (New York Heart Association [NYHA] class III–IV) of cardiac dysfunction manifest, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and management by covering current diagnostic and treatment strategies, as well as unmet needs and areas of investigation in ATTR-CM.

DiagnosisFacilitating Recognition of ATTR-CM

ATTR-CM has historically been considered rare, but the true preval‎ence is challenging to estimate because it is frequently underrecognized. There are many potential explanations, including the false perception that the diagnosis of ATTR-CM can be made only at expert centers through endomyocardial biopsy; the attribution of the presenting signs and symptoms to aging, hypertension, hypertrophic cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF); and, until recently, the lack of disease-modifying treatments, which rendered accurate diagnosis less relevant.

ATTR-CM can be preval‎ent in certain clinical contexts: ATTR deposition is seen in up to 16% of patients with degenerative aortic stenosis4 and 13% to 17% of patients with HFpEF.5,6 Because ATTR-CM is a multisystemic infiltrative disease associated with noncardiac soft tissue deposition, patients often have carpal tunnel syndrome,7 lumbar spinal stenosis,8 biceps tendon rupture,9 and autonomic or sensory polyneuropathy.

Clinical Clues to the Diagnosis of Cardiac Amyloidosis

Patients with ATTR-CM commonly present with dyspnea, fatigue, and edema, but these findings are nonspecific and often misdiagnosed as nonamyloid HFpEF, a missed opportunity. Assessment of myocardial wall thickness on echocardiogram is helpful; the presence of moderate to severe left ventricular (LV) thickening (wall thickness ≥14 mm) should trigger consideration of ATTR-CM especially if there is discordance between wall thickness on echocardiogram and QRS voltage on ECG.10 Patients with HFpEF and a moderate to severe increase in wall thickness are often mislabeled as having hypertensive cardiomyopathy when this should prompt a broader differential, including cardiac amyloidosis, hypertrophic cardiomyopathy, aortic stenosis, and rarer genetic disorders such as Fabry disease.11

Given the nonspecific presenting findings, the key to diagnosis is a high index of suspicion. Older patients presenting with HFpEF and even milder degrees of increased wall thickness also warrant scrutiny; clinical clues are outlined in Table 1.10,12 Family history is of particular importance because an inherited form of ATTRv, the Val122Ile mutation, is observed almost exclusively in black patients and is associated with a greater burden of autonomic and peripheral neuropathy and worse outcomes than ATTRwt.3,11

Table 1. Clinical Clues From Routine Cardiac Eval‎uation That Should Prompt Additional Diagnostic Eval‎uation for ATTR-CM

Traditional Cardiac CluesNoncardiac Clues

Intolerance to antihypertensive or heart failure medications because of symptomatic hypotension or orthostasis	Neurological: sensorimotor polyneuropathy (paresthesias and weakness), autonomic dysfunction (orthostatic hypotension, postprandial diarrhea alternating with constipation, gastroparesis, urinary retention, and incontinence)
Persistent low-level elevation in serum troponin	Orthopedic: carpal tunnel syndrome, lumbar spinal stenosis, unprovoked biceps tendon rupture, hip and knee arthroplasty
Discordance between QRS voltage on an ECG and wall thickness on imaging	Black race
Unexplained atrioventricular block or prior pacemaker implantation	Family history of polyneuropathy
Unexplained LV wall thickening, right ventricular thickening, or atrial wall thickening
Family history of cardiomyopathy

Expand Table

ATTR-CM indicates transthyretin amyloid cardiomyopathy; and LV, left ventricular.

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Last, it is important to note that <40% of patients with biopsy-proven ATTR-CM have low voltage on ECG, and these patients often have advanced disease.13 Thus, although helpful if present, the absence of low voltage on ECG should not dissuade clinicians from considering ATTR-CM as a potential cause of HFpEF in the appropriate clinical context.

Rational Approach to Testing in Cardiac Amyloidosis

Although echocardiography offers clues that prompt further testing and cardiac magnetic resonance (CMR) imaging14,15 may indicate an infiltrative process, the use of 99mtechnetium (99mTc) bone-avid compounds represents a paradigm shift because these scans allow the noninvasive diagnosis of ATTR-CM, although the basis for binding to amyloid deposits remains unknown.16–18 99mTc compounds include PYP (pyrophosphate), DPD (3,3-diphosphono-1,2-propanodicarboxylic acid), and hydroxymethylene diphosphonate; PYP is used in the United States. The relative merits of echocardiography, CMR, and 99mTc-PYP scans are outlined in Table 2.

Table 2. Comparison of Diagnostic Imaging Modalities in ATTR-CM

CostSpecialized Expertise Required for InterpretationExposure to Ionizing RadiationCardiac Devices Affect Image QualityCan Identify Nonamyloid Causes of LV ThickeningClinical Clues Suggesting Cardiac AmyloidosisDistinguish AL-CM and ATTR-CMMarkers of Worse Prognosis

Expand Table

$ indicates lower cost; $$, higher cost; AL-CM, immunoglobulin light chain amyloid cardiomyopathy; apo A1, apolipoprotein A1; ATTR-CM, transthyretin amyloid cardiomyopathy; EF, ejection fraction; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; LV, left ventricular; MRI, magnetic resonance imaging; and SPECT, single-photon emission computed tomography.

*

In the context of normal serum and urine immunofixation electrophoresis and serum kappa/lambda ratio.

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The testing algorithm shown in Figure 1 begins with a high index of suspicion (Table 1). CMR alone is not diagnostic of ATTR-CM. CMR is the appropriate test when an infiltrative cardiomyopathy is suspected but ATTR-CM is less likely, as in younger patients or those with findings suggestive of other infiltrative/inflammatory or restrictive cardiomyopathies, including sarcoidosis, hemochromatosis, or Fabry disease, as well as hypertrophic cardiomyopathy, myocarditis, or constrictive pericarditis.22

Figure 1. Testing algorithm for transthyretin amyloidosis (ATTR). Cardiac magnetic resonance imaging is not diagnostic for ATTR cardiomyopathy (CM) but can suggest the diagnosis and is useful when infiltrative cardiomyopathy, constrictive pericarditis, or myocarditis is suspected. Although, practically, screening for the presence of a monoclonal light chain and 99mtechnetium-pyrophosphate (99mTc-PYP) scans can be ordered together for convenience, the results of the 99mTc-PYP scan should be interpreted only in the context of a negative monoclonal light chain screen. Single-photon emission computed tomography imaging is required if there is grade 1 or higher 99mTc-PYP to distinguish blood pool from myocardial retention. Note that mild elevations in the serum free light chain kappa/lambda ratio frequently occur in patients with renal disease, and in the setting of normal immunofixation, a kappa/lambda ratio of up to 3.0 can be normal.21 Consultation with a hematologist can be considered in such circumstances. AL indicates immunoglobulin light chain; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CMR, cardiac magnetic resonance; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; and IFE, immunofixation electrophoresis.Open in viewer

Although bone scintigraphy has emerged as a cornerstone of ATTR-CM diagnosis, scans may be positive even in AL amyloidosis,18 and a bone scintigraphy scan alone, without concomitant testing for light chains, is neither appropriate nor valid for distinguishing ATTR-CM from AL amyloid cardiomyopathy (AL-CM).

Serum free light chain concentration and serum and urine immunofixation electrophoresis (IFE) are assessed to rule out AL-CM. Serum plasma electrophoresis testing and urine plasma electrophoresis testing are less sensitive and should be avoided. The sensitivity of serum plasma electrophoresis for AL amyloidosis is ≈70%, whereas the sensitivity of serum IFE is >90%.23 Together, measurement of serum IFE, urine IFE, and serum free light chain is >99% sensitive for AL amyloidosis.24,25

Assessment of ATTR-CM with bone scintigraphy is accomplished by semiquantitative or quantitative approaches (Figure 2). The semiquantitative grading involves comparing heart to rib uptake: grade 0 is no cardiac and normal rib uptake; grade 1 is cardiac less than rib uptake; grade 2 is cardiac equal to rib uptake; and grade 3 is cardiac greater than rib uptake with mild/absent rib uptake. Quantitative analysis involves comparison of mean counts as determined by a region of interest placed over the heart and compared with a similar-sized region of intensity placed over the contralateral chest. In the absence of a light chain abnormality, the 99mTc-PYP scan is diagnostic of ATTR-CM if there is grade 2 to 3 cardiac uptake or a heart/contralateral chest ratio >1.5. Single-photon emission computed tomography is assessed in all positive scans to confirm‎ that uptake represents myocardial retention of the tracer, not blood pool signal.4

Figure 2. 99mTechnetium-pyrophosphate imaging for transthyretin cardiac amyloidosis. Single-photon emission computed tomography (SPECT) imaging to identify myocardial retention of technetium-based isotopes is useful in discriminating blood pool on planar scans that result in a false-positive test from myocardial uptake of the isotope indicative of transthyretin amyloidosis with cardiomyopathy. SQA indicates semiquantitative analysis. Reprinted from Maurer et al.26 Copyright © 2019, American Heart Association, Inc. Source figure adapted from Bokhari et al27 with permission of the American Society of Nuclear Cardiology. Copyright © 2016, American Society of Nuclear Cardiology.Open in viewer

Although the presence of grade 2 or 3 scintigraphic uptake has a high specificity in amyloid centers with a high preval‎ence of ATTR-CM, the test performance in populations with lower disease preval‎ence is unknown. The causes of false-positive 99mTc-PYP scans are shown in Table 2.

In some situations, endomyocardial biopsy may be necessary to establish the diagnosis: (1) a positive 99mTc-PYP scan and evidence of a plasma cell dyscrasia by serum/urine IFE or serum free light chain analysis to exclude AL-CM (because AL-CM and ATTR-CM may very rarely occur together in the same patient, such that patients with biopsy-proven AL-CM, especially if older, may also have superimposed ATTRwt-CM deposits); (2) a negative or equivocal 99mTc-PYP scan despite a high clinical suspicion to confirm‎ ATTR-CM; and (3) unavailability of 99mTc-PYP scanning. Given its low sensitivity, a fat-pad biopsy is not sufficient to exclude ATTR-CM.28

If ATTR-CM is identified, then genetic sequencing of the TTR gene is required to define ATTRv versus ATTRwt disease (Table 3). Differentiating ATTRv from ATTRwt is critical because confirmation of ATTRv should trigger genetic counseling and potential screening of family members; the identification of the Val122Ile mutation suggests aggressive progression meriting closer follow-up; and certain therapies are currently approved only for ATTRv. Neurological consultation should be pursued if neurological involvement is present or suspected or if the identified mutation is associated with neurological involvement. Note that age alone is not a valid discriminator of ATTRwt versus ATTRv disease. Two staging schemes offer prognostic insight into ATTR-CM (Table 4).

Table 3. Common Genotypes in ATTR-CM

Age at Onset, ySex DistributionNational/Ethnic PredominanceCardiac InvolvementOther Organ Involvement

Expand Table

ATTR-CM indicates transthyretin amyloid cardiomyopathy; and TTRwt, wild-type transthyretin.

Data derived from Lane et al,3 Maurer et al,11 Connors et al,29 Lopes et al,30 and Sattianayagam et al.31

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Table 4. Prognostic Staging Systems for ATTR-CM

Mayo Staging System1UK Staging System2

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ATTR-CM indicates transthyretin amyloid cardiomyopathy; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; eGFR, estimated glomerular filtration rate; and NT-proBNP, N-terminal pro-B-type natriuretic peptide.

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Overview of Disease-Modifying Therapies for ATTR-CM

Targets for disease-modifying therapies in cardiac amyloidosis include TTR silencing, TTR stabilization, and TTR disruption (Figure 3 and Table 5). TTR stabilizers bind to the TTR tetramer and prevent misfolding and thus deposition of amyloid fibrils. TTR silencers target TTR hepatic synthesis. TTR disruptors target the clearance of amyloid fibrils from tissues.

Table 5. Summary of Disease-Modifying Agents Currently Available for ATTR

DrugIndication/ApprovalDose/DeliveryClinical Trial Key Inclusion/ExclusionPotential Side EffectsMonitoringAverage Wholesale Price

TTR stabilizers
Tafamidis	FDA approved for ATTRwt-CM and ATTRv-CM	20*, 61, or 80 mg once daily	ATTR-ACT trial33 Inclusion:  End-diastolic septal thickness >12 mm  History of heart failure  NT-proBNP ≥600 pg/mL Exclusion:  6MWT <100 m  NYHA class IV symptoms  Liver or heart transplantation  eGFR <25 mL·min−1·1.73 m−2	None	None	$225 000/y
Diflunisal	FDA approved as NSAID Off-label use in ATTRwt or ATTRv with neuropathy/cardiomyopathy	250 mg orally twice daily Administer with proton pump inhibitor	Diflunisal Trial Consortium34 Inclusion:  ATTRv with sensorimotor polyneuropathy (familial amyloid polyneuropathy)  Biopsy-proven amyloid deposits  Confirmed TTR mutation Exclusion:  NYHA class IV symptoms  Estimated creatinine clearance  <30 mL/min†  Anticoagulation	Fluid retention Renal dysfunction Bleeding	Renal function Platelet count Hemoglobin	≈$60/mo
TTR silencers
Patisiran	FDA approved for ATTRv with neuropathy	0.3 mg/kg intravenously every 3 wk Premedication with intravenous corticosteroids, intravenous H1 blocker, H2 blocker Daily vitamin A supplement	APOLLO Trial35 Inclusion:  Documented TTR mutation  Confirmed ATTRv with polyneuropathy (familial amyloid polyneuropathy)  NIS score 5–130  PND score ≤3b Exclusion:  NYHA class III–IV symptoms  Liver transplantation	Infusion-related reactions Vitamin A deficiency	None	$414 162/y‡
Inotersen	FDA approved for ATTRv with neuropathy	284 mg/wk subcutaneously Daily vitamin A supplement	NEURO-TTR Trial36 Inclusion:  ATTRv with polyneuropathy (familial amyloid polyneuropathy) stage 1 and 2 familial amyloid polyneuropathy  NIS ≥10 and ≤130  Documented TTR mutation  Documented amyloid deposit on biopsy Exclusion:  Platelets <125×109/L  Creatinine clearance <60 mL·min−1·1.73 m−2  NYHA class III symptoms  Liver transplantation	Thrombocytopenia Glomerulonephritis Infusion-related reactions Vitamin A deficiency	Weekly platelet count Every 2 wk, serum creatinine, eGFR, and UPCR	$359 840/y

Expand Table

6MWT indicates 6-minute walk test; APOLLO, A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; ATTR, transthyretin amyloidosis; ATTRv, cardiac variant transthyretin amyloidosis; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt, wild-type transthyretin amyloidosis; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; ATTR-ACT, Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy; CM, cardiomyopathy; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; NEURO-TTR, Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; NIS, Neuropathy Impairment Score; NSAID, nonsteroidal anti-inflammatory drug; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PND, polyneuropathy disability; TTR, transthyretin; and UPCR, urine protein to creatinine ratio.

*

Although the 20-mg dose is not FDA-approved, it may be considered by clinicians for patients who have issues with affordability, as there is evidence of benefit from the 20-mg dose.36a,36b

†

In clinical practice, diflunisal is not suggested for patients with creatinine clearance <45 mL/min.

‡

Average wholesale price of patisiran based on a patient weight of 70 kg and does not include the price of premedication or infusion-related expenses.

Average wholesale prices taken from Micromedex online database.37

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Figure 3. TTR (transthyretin) production and targets of therapy. Inherited mutations in cardiac variant transthyretin amyloidosis (ATTRv) or the aging process in wild-type disease (ATTRwt) cause destabilization of the TTR protein into monomers or oligomers, which aggregate into amyloid fibrils. These insoluble fibrils accumulate in the myocardium and result in diastolic dysfunction, restrictive cardiomyopathy, and eventual congestive heart failure. Targets of therapy include TTR production (silencers), TTR dissociation (TTR stabilizers), and TTR clearance from tissues (TTR disruption). TUDCA indicates tauroursodeoxycholic acid. Adapted from Nativi-Nicolau and Maurer32 with permission. Copyright © 2018, Wolters Kluwer Health, Inc.Open in viewer

TTR Silencing

TTR protein silencers target the hepatic synthesis of TTR. Patisiran is an intravenously administered siRNA that degrades TTR mRNA, and inotersen is a subcutaneously administered single-stranded antisense oligonucleotide that binds TTR mRNA, leading to degradation. Both therapies result in >85% reduction in circulating TTR protein concentration.

Two randomized trials of TTR silencers in patients with ATTRv amyloidosis and polyneuropathy have been reported: the APOLLO trial (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; patisiran)35 and NEURO-TTR (Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; inotersen).36 Both demonstrated slower progression of amyloidosis-related polyneuropathy.

Although not explicitly tested, there is evidence that TTR silencers may have beneficial cardiac effects. Prespecified subgroup analyses of APOLLO trial participants with increased LV wall thickening unrelated to hypertension or aortic stenosis (assumed to be from amyloidosis) demonstrated that patisiran attenuated the deterioration of LV global longitudinal strain,38 LV wall thickness, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration.39 Similarly, inotersen demonstrated stabilization of LV wall thickness, 6-minute walk test, and global systolic strain.40 Trials to assess the efficacy of TTR silencers in ATTR-CM are ongoing: APOLLO-B (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy [ATTR Amyloidosis With Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03997383; patisiran), 24 Month Open Label Study of the Tolerability and Efficacy of Inotersen in TTR Amyloid Cardiomyopathy Patients (URL: ClinicalTrials.gov. Unique identifier: NCT03702829; inotersen), HELIOS-B (A Study to Eval‎uate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; URL: ClinicalTrials.gov. Unique identifier: NCT04153149; vutrisiran), and CARDIO-TTRansform (A Study to Eval‎uate the Efficacy and Safety of AKCEA-TTR-LRx in Participants With TransthyretinMediated Amyloid Cardiomyopathy [ATTR CM]; URL: ClinicalTrials.gov. Unique identifier: NCT04136171; AKCEA-TTR-LRx).

TTR Stabilization

Diflunisal is a nonsteroidal anti-inflammatory that stabilizes TTR in vitro. In a randomized trial of patients with ATTRv and polyneuropathy, diflunisal was associated with reduced progression of polyneuropathy.34 There are no controlled trials of diflunisal in patients with ATTR-CM, although single-center retrospective analyses demonstrate safety and tolerability and suggest efficacy.41,42

Tafamidis is a TTR stabilizer that binds the thyroxine-binding site of TTR. In the ATTR-ACT randomized trial (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) of patients with ATTRwt-CM or ATTRv-CM, tafamidis was associated with a significantly lower all-cause mortality (29.5% versus 42.9%) and lower cardiovascular-related hospitalization (0.48 versus 0.70 per year) after 30 months. There was a higher rate of cardiovascular-related hospitalizations in the prespecified subgroup of patients with NYHA class III heart failure, which may have been attributable to longer survival during a more severe period of disease, underscoring the importance of early diagnosis and treatment. Tafamidis was also associated with a lower rate of decline in 6-minute walk distance (P<0.001) and a lower rate of decline in Kansas City Cardiomyopathy Questionnaire-Overall Summary score (P<0.001).33 Tafamidis was approved by the US Food and Drug Administration for use in ATTR-CM in May 2019.

AG10 is a TTR stabilizer that binds to the tetramer and mimics coinheritance of the TTR T119M mutation, providing natural stabilization of TTR to prevent amyloid fibril formation and deposition. A phase 2 trial of AG10 demonstrated an acceptable safety profile,43 and data from the open-label extension indicate that mortality and cardiovascular hospitalization were lower in AG10 open-label extension participants than in placebo-treated ATTR-ACT participants at 15 months.44 A phase 3 trial of AG-10 is in progress (ATTRIBUTE-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03860935).

TTR Disruption/Resorption

TTR disruption targets the clearance of amyloidosis fibrils from tissues. Preclinical studies demonstrated that doxycycline plus TUDCA (tauroursodeoxycholic acid) removed amyloid deposits. However, small open-label studies demonstrated a high incidence of side effects with conflicting results on efficacy.45,46 EGCG (epigallocatechin-3-gallate), a catechin in green tea, inhibits amyloid fibril formation in vitro, but there is little evidence of benefit47 from it or turmeric. With the advent of US Food and Drug Administration–approved therapies, the therapeutic roles of these agents are uncertain. Other agents, including monoclonal antibodies such as PRX004, are under investigation.48

Approach to Treatment in Cardiac Amyloidosis

As outlined in Figure 4, treatment of cardiac amyloidosis focuses on 3 areas: management of heart failure, management of arrhythmias, and initiation of disease-modifying agents.

Figure 4. Treatment algorithm for transthyretin amyloidosis (ATTR). ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor blocker-–neprilysin inhibitor; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; BB, β-blocker; CM, cardiomyopathy; CRT, cardiac resynchronization therapy; DOAC, direct oral anticoagulant; HF, heart failure; ICD, implantable cardioverter-defibrillator; PPM, permanent pacemaker; SCD, sudden cardiac death; VKA, vitamin K antagonist; and VT, ventricular tachycardia.Open in viewer

Management of Heart Failure

The physiology of restrictive LV filling and reduced stroke volume/cardiac output in cardiac amyloidosis renders volume maintenance difficult. Bioavailable loop diuretics are used for decongestion, although they may compromise renal function or systemic perfusion in patients with advanced restrictive disease because diminishing preload may compromise an already fixed stroke volume, leading to low cardiac output. Aldosterone antagonists may be used alone or in conjunction with loop diuretics in patients with adequate blood pressure and renal function.

There are no data supporting the use of standard guideline-directed medical therapy for heart failure with reduced ejection fraction or HFpEF in ATTR-CM, including angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, or angiotensin receptors blockers–neprilysin inhibitors. Furthermore, these therapies may exacerbate hypotension when amyloid-associated autonomic dysfunction is present.

β-Blockers and nondihydropyridine calcium channel blockers are often poorly tolerated, even at low doses, because patients with ATTR-CM rely on heart rate response to maintain cardiac output given a fixed stroke volume. In AL amyloidosis, nondihydropyridine calcium channel blockers also bind amyloid fibrils and can result in heart block or shock.

Management of Arrhythmias

Amyloid cardiomyopathy is associated with atrial dysfunction and both atrial and ventricular arrhythmias. Atrial dysfunction may be reflected by decreased A-wave amplitude and left atrial appendage velocities on echocardiography, and in such cases, empirical anticoagulation may be warranted even in sinus rhythm.49 There is no definitive reported comparison of warfarin and direct oral anticoagulants to prevent thromboembolism in this setting.

As a result of atrial dysfunction in ATTR-CM, anticoagulation is indicated for atrial fibrillation/flutter regardless of CHA2DS2-VASc score. Left atrial appendage closure devices have not been studied in ATTR-CM but may be considered in patients with prohibitive bleeding risk. Digoxin may be used cautiously for rate control, although there is concern about potential digoxin toxicity caused by binding of digoxin to amyloid fibrils. Amiodarone is the agent of choice for both rhythm and rate control, particularly in cases in which β-blockade is not tolerated; cardioversion and ablation should also be considered in selected cases.

Because of the high incidence of conduction system disease from amyloid infiltration, ambulatory electrocardiographic monitoring is part of the syncope eval‎uation, and pacemakers are indicated per Heart Rhythm Society consensus guidelines.50 Implantable cardioverter-defibrillators (ICDs) are recommended in cases of aborted sudden cardiac death with expected survival >1 year or significant ventricular arrhythmias. However, the benefit of ICDs, particularly for primary prevention of sudden cardiac death, is questionable. In a study of 45 patients with amyloid cardiomyopathy (32 with ATTR-CM), an ICD was placed for primary prevention in 38 of the patients. Over follow-up, 12% of patients had at least 1 appropriate ICD therapy; no clinical characteristics predicted who would receive ICD therapy.51 On the basis of limited experience, although Heart Rhythm Society guidelines assign a Class IIb indication to ICD placement in AL-CM and nonsustained ventricular tachycardia with expected survival >1 year, the use of ICDs for primary prevention of sudden cardiac death in patients with ATTR-CM is not well established.52 Cardiac resynchronization therapy may be useful in pacemaker-dependent patients because the already depressed stroke volume may worsen with long-term right ventricular pacing.53

Implementation of Disease-Modifying Therapies in ATTR-CM

The use of US Food and Drug Administration–approved disease-modifying therapy is based on the presence of cardiomyopathy and polyneuropathy and the distinction between ATTRv and ATTRwt amyloidosis (Figure 5). In patients with predominantly cardiac disease resulting from ATTRv or ATTRwt, tafamidis is indicated in those with NYHA class I to III symptoms,33 and early initiation appears to slow disease progression. The benefit of tafamidis has not been observed in patients with class IV symptoms, severe aortic stenosis, or impaired renal function (glomerular filtration rate <25 mL·min−1·1.73 m−2 body surface area).

Figure 5. Projected Medicare Part D beneficiary monthly out-of-pocket costs for tafamidis. Projected annual out-of-pocket expenses were calculated using the standard 2019 Medicare Part D plan including: (1) an initial $415 deductible; (2) an initial coverage period until drug costs reach $3810; (3) a coverage gap (“donut hole”) with 25% cost sharing until out-of-pocket costs reach $5100; and (4) catastrophic coverage with 5% cost sharing without an upper limit. Monthly insurance premiums and the costs of other medications were not included in this projection.Open in viewer

Patients with ATTRv and polyneuropathy should be considered for TTR silencing therapy with patisiran35 or inotersen36; currently, neither is indicated for ATTRv-CM without polyneuropathy or in ATTRwt-CM. In patients with ATTRv-CM with polyneuropathy, the choice between therapeutic agents is based on accessibility and side-effect profile.

The use of combination therapies is appealing to synergistically target both TTR silencing and stabilization of the remaining synthesized protein, but this approach lacks data and may be cost-prohibitive.

Diflusinal (250 mg orally twice daily) may be considered with caution for off-label therapy for asymptomatic ATTR carriers, for patients with ATTR-CM who are not eligible for TTR silencers, or for patients with ATTR-CM who are intolerant of or cannot afford tafamidis. Because of the nonsteroidal anti-inflammatory properties, close monitoring is needed, and diflunisal is contraindicated in patients with significant thrombocytopenia and renal dysfunction (glomerular filtration rate <40 mL·min−1·1.73 m−2) and should be used cautiously in patients on anticoagulation or with a history of gastrointestinal bleeding.

Advanced Heart Failure Therapies in ATTR-CM

For patients with ATTR-CM with stage D heart failure, use of an LV assist device is challenging because of the small LV cavity size and concomitant right ventricular dysfunction.54 There are limited data to support considering the total artificial heart as a bridge to transplantation in patients without significant extracardiac disease.55

Heart transplantation may be considered in patients with stage D heart failure,56 and the current adult donor allocation system provides priority as status 4 to amyloid cardiomyopathy given the lack of durable mechanical circulatory support options. Generally, heart-liver transplantation is performed in patients with ATTRv-CM at risk for neuropathy because neuropathy may progress with heart transplantation alone, although the criteria for heart alone versus heart-liver transplantation are not well defined,57 especially with the advent of silencer therapy, which may have a role after heart transplantation. Liver transplantation alone in ATTRv would offer prohibitive risk in the presence of severe cardiac dysfunction, and preexisting cardiac dysfunction can progress despite subsequent synthesis of wild-type TTR by the donor liver.

Areas of Uncertainty and Future Investigation

Despite advances in the management of ATTR-CM, areas of uncertainty remain in screening, disease progression, role of TTR silencers in patients with ATTR-CM, timing of therapy initiation, and financial burden of new therapies (Table 6).

Table 6. Areas of Active Investigation and Uncertainty in Diagnosis, Prognosis, Progression, and Treatment

Diagnosis

 Should we screen for ATTR-CM? If so, in which populations?

 Which diagnostic tests should be used for screening?

 Are there biomarkers that can raise suspicion of ATTR-CM with sufficient diagnostic certainty to be used for screening?

 Which noninvasive test has the best sensitivity for diagnosis of ATTR-CM?

 How does bone scintigraphy perform as a screening test (eg, in populations with a lower preval‎ence of disease than specialized amyloid centers)?

 What is the cost-effectiveness of screening or active ascertainment?

 How should asymptomatic allele carriers of TTR mutations be followed up for disease penetrance?

Prognosis

 What is the best combination of prognostic variables in ATTR-CM?

 Which biomarkers are most effective for following up patients with ATTR-CM?

 What is the role of imaging in ATTR-CM for prognostication?

 How does one determine whether a patient with ATTR-CM is progressing on therapy?

 What is the role of defibrillators and pacemakers in patients with ATTR-CM?

Progression of disease

 How should one measure disease progression?

 Do the various domains (eg, QOL, functional measures, biomarkers, imaging) progress at the same rate?

 Is there an early marker of disease progression?

 Are there biological processes (TTR stability, TTR kinetics or levels, or TTR ligands) that can be used to monitor progression?

 Can disease progression inform the choice of therapies and when to change therapies?

 Can TTR amyloidosis be reversed? If so, what factors predict regression?

Treatment

 How do the efficacies of stabilizers and silencers compare? Do TTR stabilizers differ in efficacy and side-effect profile?

 Is combination therapy with TTR stabilizers or silencers additive, synergistic, or not beneficial?

 In what order should TTR therapies be administered?

 How does the cost of therapy influence adherence, treatment, and outcomes?

 Does the cost of therapy affect the development of novel therapies?

 When should ATTR-specific therapy be initiated in patients with ATTR-CM?

 When should patients with ATTR-CM be considered for advanced surgical heart failure therapies such as LVAD and cardiac transplantation?

Expand Table

ATTR indicates transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; LVAD, left ventricular assist device; QOL, quality of life; and TTR, transthyretin.

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Identifying Populations for Screening

Given that the preval‎ence of cardiac amyloidosis is increased in specific populations (patients with HFpEF, individuals of West African descent, those with small-fiber polyneuropathy), more active ascertainment or screening may be indicated10 because early identification can maximize the benefit of therapy and delayed diagnosis results in worse outcomes. However, much is not known: the natural history of subclinical TTR cardiac amyloidosis, how testing will perform in groups with lower pretest probability, and the cost-effectiveness of screening.

Biomarkers such as NT-proBNP and troponin, electrocardiography, and echocardiography have low sensitivity/specificity for ATTR-CM. More specific testing may involve measurement of circulating RBP4 (retinol binding protein 4) or misfolded TTR oligomers; both discriminate patients with ATTRv from those with nonamyloid HF and healthy control subjects.58,59

Because HFpEF disproportionately affects older blacks and Hispanics compared with whites, there is currently a recruiting National Institutes of Health–funded prospective cohort study using 99mTc-PYP imaging and measurement of RBP4 and misfolded TTR oligomers to detect ATTR-CM in minority subjects with heart failure (SCAN-MP [Screening for Cardiac Amyloidosis Using Nuclear Imaging for Minority Populations]; URL: ClinicalTrials.gov. Unique identifier: NCT03812172). Other screening studies are ongoing in Afro-Caribbean individuals with increased wall thickness (Frequency of Cardiac Amyloidosis in the Caribbean's [TEAM Amylose]; URL: ClinicalTrials.gov. Unique identifier: NCT03322319), HFpEF patients with increased wall thickness (Transthyretin Cardiac Amyloidosis in HFpEF; URL: ClinicalTrials.gov. Unique identifier: NCT03414632), and those with small-fiber polyneuropathy using TTR gene sequencing (Screening for the Transthyretin-Related Familial Amyloidotic Polyneuropathy [TTR FAP]; URL: ClinicalTrials.gov. Unique identifier: NCT01705626). Last, large-scale biobank genotype studies hold promise for determining the preval‎ence of TTR mutations among target populations.

Another area of significant uncertainty is monitoring in asymptomatic carriers of TTR mutations.60 Given the age-dependent penetrance, the general consensus is to begin assessment 10 years before the affected proband’s age at disease onset, although this approach is limited by the unclear natural history of disease. Assessment can include physical examination, electrocardiography, echocardiography, bone scintigraphy, or CMR imaging.61

Assessing the Progression of Disease

There is no accepted definition of progression or response to therapy of ATTR-CM, but several measures have been proposed: survival, hospitalizations, functional capacity (NYHA class, 6-minute walk test, gait speed, cardiopulmonary exercise stress testing), quality of life, and cardiac biomarkers and imaging (echocardiography, magnetic resonance imaging, or positron emission tomography).

Currently, the role of imaging modalities in eval‎uating response to therapy is not established. Each imaging modality has a different sensitivity for detecting the burden of amyloid fibril deposition, varying capacity to quantify deposition, and therefore different ability to identify progression or improvement. Decreasing levels of misfolded TTR may reflect response to therapy,59 but the role of surveillance imaging and laboratories in assessing response to or guiding changes in therapy requires further study.

Role of TTR Silencers in ATTR-CM Without Neuropathy

Although it is biologically plausible that TTR silencers such as inotersen and patisiran could improve outcomes in ATTR-CM, such conclusions must await the results of adequately powered clinical trials. As a cautionary example, a subcutaneous RNA interference agent similar to patisiran, revusiran, was associated with increased mortality compared with placebo in ATTRv-CM in the ENDEAVOUR clinical trial (Phase 3 Multicenter Study of Revusiran [ALN-TTRSC] in Patients With Transthyretin [TTR] Mediated Familial Amyloidotic Cardiomyopathy [FAC]; URL: ClinicalTrials.gov. Unique identifier: NCT02319005).

Timing of Initiation of Disease-Modifying Agents

Given the lack of consensus on defining disease onset in carriers of TTR mutations and what methods (imaging or biomarkers) should be used to monitor disease progression, the timing of initiation of therapy in ATTRv carriers remains an area of uncertainty.

In contrast, in patients with advanced disease, treatment aimed at TTR stabilization is unlikely to be of significant benefit. Although the package label for tafamidis does not provide restrictions on administration, patients with NYHA class IV symptoms, minimally ambulatory patients (walk <100 m on a 6-minute walk test), and those with advanced renal dysfunction (estimated glomerular filtration rate <25 mL·min−1·m−2) were ineligible for inclusion in ATTR-ACT. Thus, tafamidis is not suggested for patients with advanced heart failure.

Financial Impact of Disease-Modifying Agents

Significantly affecting equitable prescription of these therapies is their considerable cost, especially because lifelong treatment is required, and the financial implication of potentially treating asymptomatic TTR mutation carriers is tremendous.

As noted in Table 6, costs are similar to those of new biologics or chemotherapeutic agents. A significant proportion of patients with ATTR-CM in the United States are older adults with Medicare as their primary insurance. Because Medicare does not allow direct-to-consumer drug maker copay assistance programs, these patients can have significant out-of-pocket expenses.62

Even with Medicare Part D prescription drug coverage, the average cost of tafamidis could approach $18 000 per year, more than half of which occurs after the catastrophic coverage threshold, and would reset annually for every year of treatment (Figure 5). Despite independent charity assistance foundations, the most common income limit was 500% of the federal poverty level (annual income of $62 450 for an individual and $84 550 for a married couple in 2019).63 There are a significant number of patients who may fall above such thresholds but for whom this annual out-of-pocket expense would not be feasible on fixed incomes.

Manufacturers have committed to work with insurers and patients to ensure that no one who merits drug is deprived because of cost, but the practice and impact of such commitments have yet to be fully demonstrated, and a cost-effectiveness analysis of tafamidis indicated that the list price would need to be reduced by >90% for it to be cost-effective.64 Thus, a growing area of concern, for which ATTR-CM is not unique but perhaps emblematic, is the gap between ideal medical therapies and the ability of patients to afford them.

Conclusions

The landscape for the diagnosis of and therapy for ATTR-CM is rapidly evolving. Readily accessible, accurate, noninvasive diagnostic tests and therapies to improve symptoms and survival are now available. ATTR-CM is no longer accurately regarded as a “zebra” diagnosis. Given the now-recognized clinical relevance of ATTR-CM, clinicians must have a high index of suspicion for cardiac amyloidosis when patients present with clinical clues and should invoke a rational diagnostic algorithm to eval‎uate for both AL-CM and ATTR-CM. Once the diagnosis is made, differentiating between ATTRv-CM, ATTRwt-CM, and the presence or absence of neuropathy will allow clinicians to implement an appropriate strategy of heart failure and arrhythmia management along with disease-modifying agents.

Uncertainties exist in screening, the assessment of progression, the management of asymptomatic carriers of ATTRv, the use of TTR silencing agents in ATTR-CM, and the financial impact of disease-modifying therapies. Current and future studies will assess these unanswered knowledge gaps, and advocacy from clinicians at every level may aid in closing the gap between the best medical therapies for ATTR-CM and the ability of patients to afford them.

References

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Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A. Natural history of wild-type transthyretin cardiac amyloidosis andrisk stratification using a novel staging system. J Am Coll Cardiol. 2016;68:1014–1020. doi: 10.1016/j.jacc.2016.06.033

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Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez-Naharro A, Quarta CC, Rezk T, Whelan CJ, Gonzalez-Lopez E, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J. 2018;39:2799–2806. doi: 10.1093/eurheartj/ehx589

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Lane T, Fontana M, Martinez-Naharro A, Quarta CC, Whelan CJ, Petrie A, Rowczenio DM, Gilbertson JA, Hutt DF, Rezk T, et al. Natural history, quality of life, and outcome in cardiac

Review Article

Originally Published 1 June 2020

Free Access

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association

Michelle M. Kittleson, MD, PhD, Chair, Mathew S. Maurer, MD, Vice Chair, Amrut V. Ambardekar, MD, Renee P. Bullock-Palmer, MD, Patricia P. Chang, MD, MHS, Howard J. Eisen, MD, Ajith P. Nair, MD, Jose Nativi-Nicolau, MD, and Frederick L. Ruberg, MD, FAHA On behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical CardiologyAuthor Info & Affiliations

Circulation

Volume 142, Number 1

https://doi.org/10.1161/CIR.0000000000000792

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Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.

Cardiac amyloidosis results in a restrictive cardiomyopathy caused by extracellular deposition of proteins in the myocardium. The proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils. More than 30 proteins can form amyloid fibrils in vivo, and the classification is based on the precursor protein. Cardiac amyloidosis is caused mainly by misfolded monoclonal immunoglobulin light chains (ALs) from an abnormal clonal proliferation of plasma cells or transthyretin (TTR) amyloidosis (ATTR), a liver-synthesized protein previously called prealbumin that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein. Given the paramount relevance of transthyretin amyloid cardiomyopathy (ATTR-CM) to the practicing cardiologist, this statement focuses on its diagnosis and management.

ATTR can be inherited as an autosomal dominant trait caused by pathogenic variants in the transthyretin gene TTR (ATTRv) or by the deposition of ATTRwt (wild-type transthyretin protein), previously called senile cardiac amyloidosis. The ATTR amyloid protein can infiltrate other organs, most often the autonomic and peripheral nervous systems, but cardiac involvement, when present, is the principal determinant of survival. Median survival after diagnosis in untreated patients is poor: 2.5 years for ATTRv caused by the TTR Val122Ile (or pV142I) mutation and 3.6 years for ATTRwt.1–3

Over the past few years, enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement. First, imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies. Second, observational studies indicate that ATTR-CM may be underrecognized in a significant proportion of patients with heart failure. Third, on the basis of the understanding of the mechanisms of amyloid formation, therapies are approved for treatment of ATTR-CM.

Because therapy for ATTR-CM is most effective when administered before significant symptoms (New York Heart Association [NYHA] class III–IV) of cardiac dysfunction manifest, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and management by covering current diagnostic and treatment strategies, as well as unmet needs and areas of investigation in ATTR-CM.

DiagnosisFacilitating Recognition of ATTR-CM

ATTR-CM has historically been considered rare, but the true preval‎ence is challenging to estimate because it is frequently underrecognized. There are many potential explanations, including the false perception that the diagnosis of ATTR-CM can be made only at expert centers through endomyocardial biopsy; the attribution of the presenting signs and symptoms to aging, hypertension, hypertrophic cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF); and, until recently, the lack of disease-modifying treatments, which rendered accurate diagnosis less relevant.

ATTR-CM can be preval‎ent in certain clinical contexts: ATTR deposition is seen in up to 16% of patients with degenerative aortic stenosis4 and 13% to 17% of patients with HFpEF.5,6 Because ATTR-CM is a multisystemic infiltrative disease associated with noncardiac soft tissue deposition, patients often have carpal tunnel syndrome,7 lumbar spinal stenosis,8 biceps tendon rupture,9 and autonomic or sensory polyneuropathy.

Clinical Clues to the Diagnosis of Cardiac Amyloidosis

Patients with ATTR-CM commonly present with dyspnea, fatigue, and edema, but these findings are nonspecific and often misdiagnosed as nonamyloid HFpEF, a missed opportunity. Assessment of myocardial wall thickness on echocardiogram is helpful; the presence of moderate to severe left ventricular (LV) thickening (wall thickness ≥14 mm) should trigger consideration of ATTR-CM especially if there is discordance between wall thickness on echocardiogram and QRS voltage on ECG.10 Patients with HFpEF and a moderate to severe increase in wall thickness are often mislabeled as having hypertensive cardiomyopathy when this should prompt a broader differential, including cardiac amyloidosis, hypertrophic cardiomyopathy, aortic stenosis, and rarer genetic disorders such as Fabry disease.11

Given the nonspecific presenting findings, the key to diagnosis is a high index of suspicion. Older patients presenting with HFpEF and even milder degrees of increased wall thickness also warrant scrutiny; clinical clues are outlined in Table 1.10,12 Family history is of particular importance because an inherited form of ATTRv, the Val122Ile mutation, is observed almost exclusively in black patients and is associated with a greater burden of autonomic and peripheral neuropathy and worse outcomes than ATTRwt.3,11

Table 1. Clinical Clues From Routine Cardiac Eval‎uation That Should Prompt Additional Diagnostic Eval‎uation for ATTR-CM

Traditional Cardiac CluesNoncardiac Clues

Intolerance to antihypertensive or heart failure medications because of symptomatic hypotension or orthostasis	Neurological: sensorimotor polyneuropathy (paresthesias and weakness), autonomic dysfunction (orthostatic hypotension, postprandial diarrhea alternating with constipation, gastroparesis, urinary retention, and incontinence)
Persistent low-level elevation in serum troponin	Orthopedic: carpal tunnel syndrome, lumbar spinal stenosis, unprovoked biceps tendon rupture, hip and knee arthroplasty
Discordance between QRS voltage on an ECG and wall thickness on imaging	Black race
Unexplained atrioventricular block or prior pacemaker implantation	Family history of polyneuropathy
Unexplained LV wall thickening, right ventricular thickening, or atrial wall thickening
Family history of cardiomyopathy

Expand Table

ATTR-CM indicates transthyretin amyloid cardiomyopathy; and LV, left ventricular.

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Last, it is important to note that <40% of patients with biopsy-proven ATTR-CM have low voltage on ECG, and these patients often have advanced disease.13 Thus, although helpful if present, the absence of low voltage on ECG should not dissuade clinicians from considering ATTR-CM as a potential cause of HFpEF in the appropriate clinical context.

Rational Approach to Testing in Cardiac Amyloidosis

Although echocardiography offers clues that prompt further testing and cardiac magnetic resonance (CMR) imaging14,15 may indicate an infiltrative process, the use of 99mtechnetium (99mTc) bone-avid compounds represents a paradigm shift because these scans allow the noninvasive diagnosis of ATTR-CM, although the basis for binding to amyloid deposits remains unknown.16–18 99mTc compounds include PYP (pyrophosphate), DPD (3,3-diphosphono-1,2-propanodicarboxylic acid), and hydroxymethylene diphosphonate; PYP is used in the United States. The relative merits of echocardiography, CMR, and 99mTc-PYP scans are outlined in Table 2.

Table 2. Comparison of Diagnostic Imaging Modalities in ATTR-CM

CostSpecialized Expertise Required for InterpretationExposure to Ionizing RadiationCardiac Devices Affect Image QualityCan Identify Nonamyloid Causes of LV ThickeningClinical Clues Suggesting Cardiac AmyloidosisDistinguish AL-CM and ATTR-CMMarkers of Worse Prognosis

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$ indicates lower cost; $$, higher cost; AL-CM, immunoglobulin light chain amyloid cardiomyopathy; apo A1, apolipoprotein A1; ATTR-CM, transthyretin amyloid cardiomyopathy; EF, ejection fraction; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; LV, left ventricular; MRI, magnetic resonance imaging; and SPECT, single-photon emission computed tomography.

*

In the context of normal serum and urine immunofixation electrophoresis and serum kappa/lambda ratio.

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The testing algorithm shown in Figure 1 begins with a high index of suspicion (Table 1). CMR alone is not diagnostic of ATTR-CM. CMR is the appropriate test when an infiltrative cardiomyopathy is suspected but ATTR-CM is less likely, as in younger patients or those with findings suggestive of other infiltrative/inflammatory or restrictive cardiomyopathies, including sarcoidosis, hemochromatosis, or Fabry disease, as well as hypertrophic cardiomyopathy, myocarditis, or constrictive pericarditis.22

Figure 1. Testing algorithm for transthyretin amyloidosis (ATTR). Cardiac magnetic resonance imaging is not diagnostic for ATTR cardiomyopathy (CM) but can suggest the diagnosis and is useful when infiltrative cardiomyopathy, constrictive pericarditis, or myocarditis is suspected. Although, practically, screening for the presence of a monoclonal light chain and 99mtechnetium-pyrophosphate (99mTc-PYP) scans can be ordered together for convenience, the results of the 99mTc-PYP scan should be interpreted only in the context of a negative monoclonal light chain screen. Single-photon emission computed tomography imaging is required if there is grade 1 or higher 99mTc-PYP to distinguish blood pool from myocardial retention. Note that mild elevations in the serum free light chain kappa/lambda ratio frequently occur in patients with renal disease, and in the setting of normal immunofixation, a kappa/lambda ratio of up to 3.0 can be normal.21 Consultation with a hematologist can be considered in such circumstances. AL indicates immunoglobulin light chain; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CMR, cardiac magnetic resonance; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; and IFE, immunofixation electrophoresis.Open in viewer

Although bone scintigraphy has emerged as a cornerstone of ATTR-CM diagnosis, scans may be positive even in AL amyloidosis,18 and a bone scintigraphy scan alone, without concomitant testing for light chains, is neither appropriate nor valid for distinguishing ATTR-CM from AL amyloid cardiomyopathy (AL-CM).

Serum free light chain concentration and serum and urine immunofixation electrophoresis (IFE) are assessed to rule out AL-CM. Serum plasma electrophoresis testing and urine plasma electrophoresis testing are less sensitive and should be avoided. The sensitivity of serum plasma electrophoresis for AL amyloidosis is ≈70%, whereas the sensitivity of serum IFE is >90%.23 Together, measurement of serum IFE, urine IFE, and serum free light chain is >99% sensitive for AL amyloidosis.24,25

Assessment of ATTR-CM with bone scintigraphy is accomplished by semiquantitative or quantitative approaches (Figure 2). The semiquantitative grading involves comparing heart to rib uptake: grade 0 is no cardiac and normal rib uptake; grade 1 is cardiac less than rib uptake; grade 2 is cardiac equal to rib uptake; and grade 3 is cardiac greater than rib uptake with mild/absent rib uptake. Quantitative analysis involves comparison of mean counts as determined by a region of interest placed over the heart and compared with a similar-sized region of intensity placed over the contralateral chest. In the absence of a light chain abnormality, the 99mTc-PYP scan is diagnostic of ATTR-CM if there is grade 2 to 3 cardiac uptake or a heart/contralateral chest ratio >1.5. Single-photon emission computed tomography is assessed in all positive scans to confirm‎ that uptake represents myocardial retention of the tracer, not blood pool signal.4

Figure 2. 99mTechnetium-pyrophosphate imaging for transthyretin cardiac amyloidosis. Single-photon emission computed tomography (SPECT) imaging to identify myocardial retention of technetium-based isotopes is useful in discriminating blood pool on planar scans that result in a false-positive test from myocardial uptake of the isotope indicative of transthyretin amyloidosis with cardiomyopathy. SQA indicates semiquantitative analysis. Reprinted from Maurer et al.26 Copyright © 2019, American Heart Association, Inc. Source figure adapted from Bokhari et al27 with permission of the American Society of Nuclear Cardiology. Copyright © 2016, American Society of Nuclear Cardiology.Open in viewer

Although the presence of grade 2 or 3 scintigraphic uptake has a high specificity in amyloid centers with a high preval‎ence of ATTR-CM, the test performance in populations with lower disease preval‎ence is unknown. The causes of false-positive 99mTc-PYP scans are shown in Table 2.

In some situations, endomyocardial biopsy may be necessary to establish the diagnosis: (1) a positive 99mTc-PYP scan and evidence of a plasma cell dyscrasia by serum/urine IFE or serum free light chain analysis to exclude AL-CM (because AL-CM and ATTR-CM may very rarely occur together in the same patient, such that patients with biopsy-proven AL-CM, especially if older, may also have superimposed ATTRwt-CM deposits); (2) a negative or equivocal 99mTc-PYP scan despite a high clinical suspicion to confirm‎ ATTR-CM; and (3) unavailability of 99mTc-PYP scanning. Given its low sensitivity, a fat-pad biopsy is not sufficient to exclude ATTR-CM.28

If ATTR-CM is identified, then genetic sequencing of the TTR gene is required to define ATTRv versus ATTRwt disease (Table 3). Differentiating ATTRv from ATTRwt is critical because confirmation of ATTRv should trigger genetic counseling and potential screening of family members; the identification of the Val122Ile mutation suggests aggressive progression meriting closer follow-up; and certain therapies are currently approved only for ATTRv. Neurological consultation should be pursued if neurological involvement is present or suspected or if the identified mutation is associated with neurological involvement. Note that age alone is not a valid discriminator of ATTRwt versus ATTRv disease. Two staging schemes offer prognostic insight into ATTR-CM (Table 4).

Table 3. Common Genotypes in ATTR-CM

Age at Onset, ySex DistributionNational/Ethnic PredominanceCardiac InvolvementOther Organ Involvement

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ATTR-CM indicates transthyretin amyloid cardiomyopathy; and TTRwt, wild-type transthyretin.

Data derived from Lane et al,3 Maurer et al,11 Connors et al,29 Lopes et al,30 and Sattianayagam et al.31

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Table 4. Prognostic Staging Systems for ATTR-CM

Mayo Staging System1UK Staging System2

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ATTR-CM indicates transthyretin amyloid cardiomyopathy; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; eGFR, estimated glomerular filtration rate; and NT-proBNP, N-terminal pro-B-type natriuretic peptide.

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Overview of Disease-Modifying Therapies for ATTR-CM

Targets for disease-modifying therapies in cardiac amyloidosis include TTR silencing, TTR stabilization, and TTR disruption (Figure 3 and Table 5). TTR stabilizers bind to the TTR tetramer and prevent misfolding and thus deposition of amyloid fibrils. TTR silencers target TTR hepatic synthesis. TTR disruptors target the clearance of amyloid fibrils from tissues.

Table 5. Summary of Disease-Modifying Agents Currently Available for ATTR

DrugIndication/ApprovalDose/DeliveryClinical Trial Key Inclusion/ExclusionPotential Side EffectsMonitoringAverage Wholesale Price

TTR stabilizers
Tafamidis	FDA approved for ATTRwt-CM and ATTRv-CM	20*, 61, or 80 mg once daily	ATTR-ACT trial33 Inclusion:  End-diastolic septal thickness >12 mm  History of heart failure  NT-proBNP ≥600 pg/mL Exclusion:  6MWT <100 m  NYHA class IV symptoms  Liver or heart transplantation  eGFR <25 mL·min−1·1.73 m−2	None	None	$225 000/y
Diflunisal	FDA approved as NSAID Off-label use in ATTRwt or ATTRv with neuropathy/cardiomyopathy	250 mg orally twice daily Administer with proton pump inhibitor	Diflunisal Trial Consortium34 Inclusion:  ATTRv with sensorimotor polyneuropathy (familial amyloid polyneuropathy)  Biopsy-proven amyloid deposits  Confirmed TTR mutation Exclusion:  NYHA class IV symptoms  Estimated creatinine clearance  <30 mL/min†  Anticoagulation	Fluid retention Renal dysfunction Bleeding	Renal function Platelet count Hemoglobin	≈$60/mo
TTR silencers
Patisiran	FDA approved for ATTRv with neuropathy	0.3 mg/kg intravenously every 3 wk Premedication with intravenous corticosteroids, intravenous H1 blocker, H2 blocker Daily vitamin A supplement	APOLLO Trial35 Inclusion:  Documented TTR mutation  Confirmed ATTRv with polyneuropathy (familial amyloid polyneuropathy)  NIS score 5–130  PND score ≤3b Exclusion:  NYHA class III–IV symptoms  Liver transplantation	Infusion-related reactions Vitamin A deficiency	None	$414 162/y‡
Inotersen	FDA approved for ATTRv with neuropathy	284 mg/wk subcutaneously Daily vitamin A supplement	NEURO-TTR Trial36 Inclusion:  ATTRv with polyneuropathy (familial amyloid polyneuropathy) stage 1 and 2 familial amyloid polyneuropathy  NIS ≥10 and ≤130  Documented TTR mutation  Documented amyloid deposit on biopsy Exclusion:  Platelets <125×109/L  Creatinine clearance <60 mL·min−1·1.73 m−2  NYHA class III symptoms  Liver transplantation	Thrombocytopenia Glomerulonephritis Infusion-related reactions Vitamin A deficiency	Weekly platelet count Every 2 wk, serum creatinine, eGFR, and UPCR	$359 840/y

Expand Table

6MWT indicates 6-minute walk test; APOLLO, A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; ATTR, transthyretin amyloidosis; ATTRv, cardiac variant transthyretin amyloidosis; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt, wild-type transthyretin amyloidosis; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; ATTR-ACT, Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy; CM, cardiomyopathy; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; NEURO-TTR, Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; NIS, Neuropathy Impairment Score; NSAID, nonsteroidal anti-inflammatory drug; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PND, polyneuropathy disability; TTR, transthyretin; and UPCR, urine protein to creatinine ratio.

*

Although the 20-mg dose is not FDA-approved, it may be considered by clinicians for patients who have issues with affordability, as there is evidence of benefit from the 20-mg dose.36a,36b

†

In clinical practice, diflunisal is not suggested for patients with creatinine clearance <45 mL/min.

‡

Average wholesale price of patisiran based on a patient weight of 70 kg and does not include the price of premedication or infusion-related expenses.

Average wholesale prices taken from Micromedex online database.37

Open in viewer

Figure 3. TTR (transthyretin) production and targets of therapy. Inherited mutations in cardiac variant transthyretin amyloidosis (ATTRv) or the aging process in wild-type disease (ATTRwt) cause destabilization of the TTR protein into monomers or oligomers, which aggregate into amyloid fibrils. These insoluble fibrils accumulate in the myocardium and result in diastolic dysfunction, restrictive cardiomyopathy, and eventual congestive heart failure. Targets of therapy include TTR production (silencers), TTR dissociation (TTR stabilizers), and TTR clearance from tissues (TTR disruption). TUDCA indicates tauroursodeoxycholic acid. Adapted from Nativi-Nicolau and Maurer32 with permission. Copyright © 2018, Wolters Kluwer Health, Inc.Open in viewer

TTR Silencing

TTR protein silencers target the hepatic synthesis of TTR. Patisiran is an intravenously administered siRNA that degrades TTR mRNA, and inotersen is a subcutaneously administered single-stranded antisense oligonucleotide that binds TTR mRNA, leading to degradation. Both therapies result in >85% reduction in circulating TTR protein concentration.

Two randomized trials of TTR silencers in patients with ATTRv amyloidosis and polyneuropathy have been reported: the APOLLO trial (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; patisiran)35 and NEURO-TTR (Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; inotersen).36 Both demonstrated slower progression of amyloidosis-related polyneuropathy.

Although not explicitly tested, there is evidence that TTR silencers may have beneficial cardiac effects. Prespecified subgroup analyses of APOLLO trial participants with increased LV wall thickening unrelated to hypertension or aortic stenosis (assumed to be from amyloidosis) demonstrated that patisiran attenuated the deterioration of LV global longitudinal strain,38 LV wall thickness, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration.39 Similarly, inotersen demonstrated stabilization of LV wall thickness, 6-minute walk test, and global systolic strain.40 Trials to assess the efficacy of TTR silencers in ATTR-CM are ongoing: APOLLO-B (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy [ATTR Amyloidosis With Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03997383; patisiran), 24 Month Open Label Study of the Tolerability and Efficacy of Inotersen in TTR Amyloid Cardiomyopathy Patients (URL: ClinicalTrials.gov. Unique identifier: NCT03702829; inotersen), HELIOS-B (A Study to Eval‎uate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; URL: ClinicalTrials.gov. Unique identifier: NCT04153149; vutrisiran), and CARDIO-TTRansform (A Study to Eval‎uate the Efficacy and Safety of AKCEA-TTR-LRx in Participants With TransthyretinMediated Amyloid Cardiomyopathy [ATTR CM]; URL: ClinicalTrials.gov. Unique identifier: NCT04136171; AKCEA-TTR-LRx).

TTR Stabilization

Diflunisal is a nonsteroidal anti-inflammatory that stabilizes TTR in vitro. In a randomized trial of patients with ATTRv and polyneuropathy, diflunisal was associated with reduced progression of polyneuropathy.34 There are no controlled trials of diflunisal in patients with ATTR-CM, although single-center retrospective analyses demonstrate safety and tolerability and suggest efficacy.41,42

Tafamidis is a TTR stabilizer that binds the thyroxine-binding site of TTR. In the ATTR-ACT randomized trial (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) of patients with ATTRwt-CM or ATTRv-CM, tafamidis was associated with a significantly lower all-cause mortality (29.5% versus 42.9%) and lower cardiovascular-related hospitalization (0.48 versus 0.70 per year) after 30 months. There was a higher rate of cardiovascular-related hospitalizations in the prespecified subgroup of patients with NYHA class III heart failure, which may have been attributable to longer survival during a more severe period of disease, underscoring the importance of early diagnosis and treatment. Tafamidis was also associated with a lower rate of decline in 6-minute walk distance (P<0.001) and a lower rate of decline in Kansas City Cardiomyopathy Questionnaire-Overall Summary score (P<0.001).33 Tafamidis was approved by the US Food and Drug Administration for use in ATTR-CM in May 2019.

AG10 is a TTR stabilizer that binds to the tetramer and mimics coinheritance of the TTR T119M mutation, providing natural stabilization of TTR to prevent amyloid fibril formation and deposition. A phase 2 trial of AG10 demonstrated an acceptable safety profile,43 and data from the open-label extension indicate that mortality and cardiovascular hospitalization were lower in AG10 open-label extension participants than in placebo-treated ATTR-ACT participants at 15 months.44 A phase 3 trial of AG-10 is in progress (ATTRIBUTE-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03860935).

TTR Disruption/Resorption

TTR disruption targets the clearance of amyloidosis fibrils from tissues. Preclinical studies demonstrated that doxycycline plus TUDCA (tauroursodeoxycholic acid) removed amyloid deposits. However, small open-label studies demonstrated a high incidence of side effects with conflicting results on efficacy.45,46 EGCG (epigallocatechin-3-gallate), a catechin in green tea, inhibits amyloid fibril formation in vitro, but there is little evidence of benefit47 from it or turmeric. With the advent of US Food and Drug Administration–approved therapies, the therapeutic roles of these agents are uncertain. Other agents, including monoclonal antibodies such as PRX004, are under investigation.48

Approach to Treatment in Cardiac Amyloidosis

As outlined in Figure 4, treatment of cardiac amyloidosis focuses on 3 areas: management of heart failure, management of arrhythmias, and initiation of disease-modifying agents.

Figure 4. Treatment algorithm for transthyretin amyloidosis (ATTR). ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor blocker-–neprilysin inhibitor; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; BB, β-blocker; CM, cardiomyopathy; CRT, cardiac resynchronization therapy; DOAC, direct oral anticoagulant; HF, heart failure; ICD, implantable cardioverter-defibrillator; PPM, permanent pacemaker; SCD, sudden cardiac death; VKA, vitamin K antagonist; and VT, ventricular tachycardia.Open in viewer

Management of Heart Failure

The physiology of restrictive LV filling and reduced stroke volume/cardiac output in cardiac amyloidosis renders volume maintenance difficult. Bioavailable loop diuretics are used for decongestion, although they may compromise renal function or systemic perfusion in patients with advanced restrictive disease because diminishing preload may compromise an already fixed stroke volume, leading to low cardiac output. Aldosterone antagonists may be used alone or in conjunction with loop diuretics in patients with adequate blood pressure and renal function.

There are no data supporting the use of standard guideline-directed medical therapy for heart failure with reduced ejection fraction or HFpEF in ATTR-CM, including angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, or angiotensin receptors blockers–neprilysin inhibitors. Furthermore, these therapies may exacerbate hypotension when amyloid-associated autonomic dysfunction is present.

β-Blockers and nondihydropyridine calcium channel blockers are often poorly tolerated, even at low doses, because patients with ATTR-CM rely on heart rate response to maintain cardiac output given a fixed stroke volume. In AL amyloidosis, nondihydropyridine calcium channel blockers also bind amyloid fibrils and can result in heart block or shock.

Management of Arrhythmias

Amyloid cardiomyopathy is associated with atrial dysfunction and both atrial and ventricular arrhythmias. Atrial dysfunction may be reflected by decreased A-wave amplitude and left atrial appendage velocities on echocardiography, and in such cases, empirical anticoagulation may be warranted even in sinus rhythm.49 There is no definitive reported comparison of warfarin and direct oral anticoagulants to prevent thromboembolism in this setting.

As a result of atrial dysfunction in ATTR-CM, anticoagulation is indicated for atrial fibrillation/flutter regardless of CHA2DS2-VASc score. Left atrial appendage closure devices have not been studied in ATTR-CM but may be considered in patients with prohibitive bleeding risk. Digoxin may be used cautiously for rate control, although there is concern about potential digoxin toxicity caused by binding of digoxin to amyloid fibrils. Amiodarone is the agent of choice for both rhythm and rate control, particularly in cases in which β-blockade is not tolerated; cardioversion and ablation should also be considered in selected cases.

Because of the high incidence of conduction system disease from amyloid infiltration, ambulatory electrocardiographic monitoring is part of the syncope eval‎uation, and pacemakers are indicated per Heart Rhythm Society consensus guidelines.50 Implantable cardioverter-defibrillators (ICDs) are recommended in cases of aborted sudden cardiac death with expected survival >1 year or significant ventricular arrhythmias. However, the benefit of ICDs, particularly for primary prevention of sudden cardiac death, is questionable. In a study of 45 patients with amyloid cardiomyopathy (32 with ATTR-CM), an ICD was placed for primary prevention in 38 of the patients. Over follow-up, 12% of patients had at least 1 appropriate ICD therapy; no clinical characteristics predicted who would receive ICD therapy.51 On the basis of limited experience, although Heart Rhythm Society guidelines assign a Class IIb indication to ICD placement in AL-CM and nonsustained ventricular tachycardia with expected survival >1 year, the use of ICDs for primary prevention of sudden cardiac death in patients with ATTR-CM is not well established.52 Cardiac resynchronization therapy may be useful in pacemaker-dependent patients because the already depressed stroke volume may worsen with long-term right ventricular pacing.53

Implementation of Disease-Modifying Therapies in ATTR-CM

The use of US Food and Drug Administration–approved disease-modifying therapy is based on the presence of cardiomyopathy and polyneuropathy and the distinction between ATTRv and ATTRwt amyloidosis (Figure 5). In patients with predominantly cardiac disease resulting from ATTRv or ATTRwt, tafamidis is indicated in those with NYHA class I to III symptoms,33 and early initiation appears to slow disease progression. The benefit of tafamidis has not been observed in patients with class IV symptoms, severe aortic stenosis, or impaired renal function (glomerular filtration rate <25 mL·min−1·1.73 m−2 body surface area).

Figure 5. Projected Medicare Part D beneficiary monthly out-of-pocket costs for tafamidis. Projected annual out-of-pocket expenses were calculated using the standard 2019 Medicare Part D plan including: (1) an initial $415 deductible; (2) an initial coverage period until drug costs reach $3810; (3) a coverage gap (“donut hole”) with 25% cost sharing until out-of-pocket costs reach $5100; and (4) catastrophic coverage with 5% cost sharing without an upper limit. Monthly insurance premiums and the costs of other medications were not included in this projection.Open in viewer

Patients with ATTRv and polyneuropathy should be considered for TTR silencing therapy with patisiran35 or inotersen36; currently, neither is indicated for ATTRv-CM without polyneuropathy or in ATTRwt-CM. In patients with ATTRv-CM with polyneuropathy, the choice between therapeutic agents is based on accessibility and side-effect profile.

The use of combination therapies is appealing to synergistically target both TTR silencing and stabilization of the remaining synthesized protein, but this approach lacks data and may be cost-prohibitive.

Diflusinal (250 mg orally twice daily) may be considered with caution for off-label therapy for asymptomatic ATTR carriers, for patients with ATTR-CM who are not eligible for TTR silencers, or for patients with ATTR-CM who are intolerant of or cannot afford tafamidis. Because of the nonsteroidal anti-inflammatory properties, close monitoring is needed, and diflunisal is contraindicated in patients with significant thrombocytopenia and renal dysfunction (glomerular filtration rate <40 mL·min−1·1.73 m−2) and should be used cautiously in patients on anticoagulation or with a history of gastrointestinal bleeding.

Advanced Heart Failure Therapies in ATTR-CM

For patients with ATTR-CM with stage D heart failure, use of an LV assist device is challenging because of the small LV cavity size and concomitant right ventricular dysfunction.54 There are limited data to support considering the total artificial heart as a bridge to transplantation in patients without significant extracardiac disease.55

Heart transplantation may be considered in patients with stage D heart failure,56 and the current adult donor allocation system provides priority as status 4 to amyloid cardiomyopathy given the lack of durable mechanical circulatory support options. Generally, heart-liver transplantation is performed in patients with ATTRv-CM at risk for neuropathy because neuropathy may progress with heart transplantation alone, although the criteria for heart alone versus heart-liver transplantation are not well defined,57 especially with the advent of silencer therapy, which may have a role after heart transplantation. Liver transplantation alone in ATTRv would offer prohibitive risk in the presence of severe cardiac dysfunction, and preexisting cardiac dysfunction can progress despite subsequent synthesis of wild-type TTR by the donor liver.

Areas of Uncertainty and Future Investigation

Despite advances in the management of ATTR-CM, areas of uncertainty remain in screening, disease progression, role of TTR silencers in patients with ATTR-CM, timing of therapy initiation, and financial burden of new therapies (Table 6).

Table 6. Areas of Active Investigation and Uncertainty in Diagnosis, Prognosis, Progression, and Treatment

Diagnosis

 Should we screen for ATTR-CM? If so, in which populations?

 Which diagnostic tests should be used for screening?

 Are there biomarkers that can raise suspicion of ATTR-CM with sufficient diagnostic certainty to be used for screening?

 Which noninvasive test has the best sensitivity for diagnosis of ATTR-CM?

 How does bone scintigraphy perform as a screening test (eg, in populations with a lower preval‎ence of disease than specialized amyloid centers)?

 What is the cost-effectiveness of screening or active ascertainment?

 How should asymptomatic allele carriers of TTR mutations be followed up for disease penetrance?

Prognosis

 What is the best combination of prognostic variables in ATTR-CM?

 Which biomarkers are most effective for following up patients with ATTR-CM?

 What is the role of imaging in ATTR-CM for prognostication?

 How does one determine whether a patient with ATTR-CM is progressing on therapy?

 What is the role of defibrillators and pacemakers in patients with ATTR-CM?

Progression of disease

 How should one measure disease progression?

 Do the various domains (eg, QOL, functional measures, biomarkers, imaging) progress at the same rate?

 Is there an early marker of disease progression?

 Are there biological processes (TTR stability, TTR kinetics or levels, or TTR ligands) that can be used to monitor progression?

 Can disease progression inform the choice of therapies and when to change therapies?

 Can TTR amyloidosis be reversed? If so, what factors predict regression?

Treatment

 How do the efficacies of stabilizers and silencers compare? Do TTR stabilizers differ in efficacy and side-effect profile?

 Is combination therapy with TTR stabilizers or silencers additive, synergistic, or not beneficial?

 In what order should TTR therapies be administered?

 How does the cost of therapy influence adherence, treatment, and outcomes?

 Does the cost of therapy affect the development of novel therapies?

 When should ATTR-specific therapy be initiated in patients with ATTR-CM?

 When should patients with ATTR-CM be considered for advanced surgical heart failure therapies such as LVAD and cardiac transplantation?

Expand Table

ATTR indicates transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; LVAD, left ventricular assist device; QOL, quality of life; and TTR, transthyretin.

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Identifying Populations for Screening

Given that the preval‎ence of cardiac amyloidosis is increased in specific populations (patients with HFpEF, individuals of West African descent, those with small-fiber polyneuropathy), more active ascertainment or screening may be indicated10 because early identification can maximize the benefit of therapy and delayed diagnosis results in worse outcomes. However, much is not known: the natural history of subclinical TTR cardiac amyloidosis, how testing will perform in groups with lower pretest probability, and the cost-effectiveness of screening.

Biomarkers such as NT-proBNP and troponin, electrocardiography, and echocardiography have low sensitivity/specificity for ATTR-CM. More specific testing may involve measurement of circulating RBP4 (retinol binding protein 4) or misfolded TTR oligomers; both discriminate patients with ATTRv from those with nonamyloid HF and healthy control subjects.58,59

Because HFpEF disproportionately affects older blacks and Hispanics compared with whites, there is currently a recruiting National Institutes of Health–funded prospective cohort study using 99mTc-PYP imaging and measurement of RBP4 and misfolded TTR oligomers to detect ATTR-CM in minority subjects with heart failure (SCAN-MP [Screening for Cardiac Amyloidosis Using Nuclear Imaging for Minority Populations]; URL: ClinicalTrials.gov. Unique identifier: NCT03812172). Other screening studies are ongoing in Afro-Caribbean individuals with increased wall thickness (Frequency of Cardiac Amyloidosis in the Caribbean's [TEAM Amylose]; URL: ClinicalTrials.gov. Unique identifier: NCT03322319), HFpEF patients with increased wall thickness (Transthyretin Cardiac Amyloidosis in HFpEF; URL: ClinicalTrials.gov. Unique identifier: NCT03414632), and those with small-fiber polyneuropathy using TTR gene sequencing (Screening for the Transthyretin-Related Familial Amyloidotic Polyneuropathy [TTR FAP]; URL: ClinicalTrials.gov. Unique identifier: NCT01705626). Last, large-scale biobank genotype studies hold promise for determining the preval‎ence of TTR mutations among target populations.

Another area of significant uncertainty is monitoring in asymptomatic carriers of TTR mutations.60 Given the age-dependent penetrance, the general consensus is to begin assessment 10 years before the affected proband’s age at disease onset, although this approach is limited by the unclear natural history of disease. Assessment can include physical examination, electrocardiography, echocardiography, bone scintigraphy, or CMR imaging.61

Assessing the Progression of Disease

There is no accepted definition of progression or response to therapy of ATTR-CM, but several measures have been proposed: survival, hospitalizations, functional capacity (NYHA class, 6-minute walk test, gait speed, cardiopulmonary exercise stress testing), quality of life, and cardiac biomarkers and imaging (echocardiography, magnetic resonance imaging, or positron emission tomography).

Currently, the role of imaging modalities in eval‎uating response to therapy is not established. Each imaging modality has a different sensitivity for detecting the burden of amyloid fibril deposition, varying capacity to quantify deposition, and therefore different ability to identify progression or improvement. Decreasing levels of misfolded TTR may reflect response to therapy,59 but the role of surveillance imaging and laboratories in assessing response to or guiding changes in therapy requires further study.

Role of TTR Silencers in ATTR-CM Without Neuropathy

Although it is biologically plausible that TTR silencers such as inotersen and patisiran could improve outcomes in ATTR-CM, such conclusions must await the results of adequately powered clinical trials. As a cautionary example, a subcutaneous RNA interference agent similar to patisiran, revusiran, was associated with increased mortality compared with placebo in ATTRv-CM in the ENDEAVOUR clinical trial (Phase 3 Multicenter Study of Revusiran [ALN-TTRSC] in Patients With Transthyretin [TTR] Mediated Familial Amyloidotic Cardiomyopathy [FAC]; URL: ClinicalTrials.gov. Unique identifier: NCT02319005).

Timing of Initiation of Disease-Modifying Agents

Given the lack of consensus on defining disease onset in carriers of TTR mutations and what methods (imaging or biomarkers) should be used to monitor disease progression, the timing of initiation of therapy in ATTRv carriers remains an area of uncertainty.

In contrast, in patients with advanced disease, treatment aimed at TTR stabilization is unlikely to be of significant benefit. Although the package label for tafamidis does not provide restrictions on administration, patients with NYHA class IV symptoms, minimally ambulatory patients (walk <100 m on a 6-minute walk test), and those with advanced renal dysfunction (estimated glomerular filtration rate <25 mL·min−1·m−2) were ineligible for inclusion in ATTR-ACT. Thus, tafamidis is not suggested for patients with advanced heart failure.

Financial Impact of Disease-Modifying Agents

Significantly affecting equitable prescription of these therapies is their considerable cost, especially because lifelong treatment is required, and the financial implication of potentially treating asymptomatic TTR mutation carriers is tremendous.

As noted in Table 6, costs are similar to those of new biologics or chemotherapeutic agents. A significant proportion of patients with ATTR-CM in the United States are older adults with Medicare as their primary insurance. Because Medicare does not allow direct-to-consumer drug maker copay assistance programs, these patients can have significant out-of-pocket expenses.62

Even with Medicare Part D prescription drug coverage, the average cost of tafamidis could approach $18 000 per year, more than half of which occurs after the catastrophic coverage threshold, and would reset annually for every year of treatment (Figure 5). Despite independent charity assistance foundations, the most common income limit was 500% of the federal poverty level (annual income of $62 450 for an individual and $84 550 for a married couple in 2019).63 There are a significant number of patients who may fall above such thresholds but for whom this annual out-of-pocket expense would not be feasible on fixed incomes.

Manufacturers have committed to work with insurers and patients to ensure that no one who merits drug is deprived because of cost, but the practice and impact of such commitments have yet to be fully demonstrated, and a cost-effectiveness analysis of tafamidis indicated that the list price would need to be reduced by >90% for it to be cost-effective.64 Thus, a growing area of concern, for which ATTR-CM is not unique but perhaps emblematic, is the gap between ideal medical therapies and the ability of patients to afford them.

Conclusions

The landscape for the diagnosis of and therapy for ATTR-CM is rapidly evolving. Readily accessible, accurate, noninvasive diagnostic tests and therapies to improve symptoms and survival are now available. ATTR-CM is no longer accurately regarded as a “zebra” diagnosis. Given the now-recognized clinical relevance of ATTR-CM, clinicians must have a high index of suspicion for cardiac amyloidosis when patients present with clinical clues and should invoke a rational diagnostic algorithm to eval‎uate for both AL-CM and ATTR-CM. Once the diagnosis is made, differentiating between ATTRv-CM, ATTRwt-CM, and the presence or absence of neuropathy will allow clinicians to implement an appropriate strategy of heart failure and arrhythmia management along with disease-modifying agents.

Uncertainties exist in screening, the assessment of progression, the management of asymptomatic carriers of ATTRv, the use of TTR silencing agents in ATTR-CM, and the financial impact of disease-modifying therapies. Current and future studies will assess these unanswered knowledge gaps, and advocacy from clinicians at every level may aid in closing the gap between the best medical therapies for ATTR-CM and the ability of patients to afford them.

References

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Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, Klarich KW, Miller WL, Maleszewski JJ, Dispenzieri A. Natural history of wild-type transthyretin cardiac amyloidosis andrisk stratification using a novel staging system. J Am Coll Cardiol. 2016;68:1014–1020. doi: 10.1016/j.jacc.2016.06.033

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Review Article

Originally Published 1 June 2020

Free Access

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association

Michelle M. Kittleson, MD, PhD, Chair, Mathew S. Maurer, MD, Vice Chair, Amrut V. Ambardekar, MD, Renee P. Bullock-Palmer, MD, Patricia P. Chang, MD, MHS, Howard J. Eisen, MD, Ajith P. Nair, MD, Jose Nativi-Nicolau, MD, and Frederick L. Ruberg, MD, FAHA On behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical CardiologyAuthor Info & Affiliations

Circulation

Volume 142, Number 1

https://doi.org/10.1161/CIR.0000000000000792

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Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.

Cardiac amyloidosis results in a restrictive cardiomyopathy caused by extracellular deposition of proteins in the myocardium. The proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils. More than 30 proteins can form amyloid fibrils in vivo, and the classification is based on the precursor protein. Cardiac amyloidosis is caused mainly by misfolded monoclonal immunoglobulin light chains (ALs) from an abnormal clonal proliferation of plasma cells or transthyretin (TTR) amyloidosis (ATTR), a liver-synthesized protein previously called prealbumin that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein. Given the paramount relevance of transthyretin amyloid cardiomyopathy (ATTR-CM) to the practicing cardiologist, this statement focuses on its diagnosis and management.

ATTR can be inherited as an autosomal dominant trait caused by pathogenic variants in the transthyretin gene TTR (ATTRv) or by the deposition of ATTRwt (wild-type transthyretin protein), previously called senile cardiac amyloidosis. The ATTR amyloid protein can infiltrate other organs, most often the autonomic and peripheral nervous systems, but cardiac involvement, when present, is the principal determinant of survival. Median survival after diagnosis in untreated patients is poor: 2.5 years for ATTRv caused by the TTR Val122Ile (or pV142I) mutation and 3.6 years for ATTRwt.1–3

Over the past few years, enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement. First, imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirm‎atory endomyocardial biopsies. Second, observational studies indicate that ATTR-CM may be underrecognized in a significant proportion of patients with heart failure. Third, on the basis of the understanding of the mechanisms of amyloid formation, therapies are approved for treatment of ATTR-CM.

Because therapy for ATTR-CM is most effective when administered before significant symptoms (New York Heart Association [NYHA] class III–IV) of cardiac dysfunction manifest, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and management by covering current diagnostic and treatment strategies, as well as unmet needs and areas of investigation in ATTR-CM.

DiagnosisFacilitating Recognition of ATTR-CM

ATTR-CM has historically been considered rare, but the true preval‎ence is challenging to estimate because it is frequently underrecognized. There are many potential explanations, including the false perception that the diagnosis of ATTR-CM can be made only at expert centers through endomyocardial biopsy; the attribution of the presenting signs and symptoms to aging, hypertension, hypertrophic cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF); and, until recently, the lack of disease-modifying treatments, which rendered accurate diagnosis less relevant.

ATTR-CM can be preval‎ent in certain clinical contexts: ATTR deposition is seen in up to 16% of patients with degenerative aortic stenosis4 and 13% to 17% of patients with HFpEF.5,6 Because ATTR-CM is a multisystemic infiltrative disease associated with noncardiac soft tissue deposition, patients often have carpal tunnel syndrome,7 lumbar spinal stenosis,8 biceps tendon rupture,9 and autonomic or sensory polyneuropathy.

Clinical Clues to the Diagnosis of Cardiac Amyloidosis

Patients with ATTR-CM commonly present with dyspnea, fatigue, and edema, but these findings are nonspecific and often misdiagnosed as nonamyloid HFpEF, a missed opportunity. Assessment of myocardial wall thickness on echocardiogram is helpful; the presence of moderate to severe left ventricular (LV) thickening (wall thickness ≥14 mm) should trigger consideration of ATTR-CM especially if there is discordance between wall thickness on echocardiogram and QRS voltage on ECG.10 Patients with HFpEF and a moderate to severe increase in wall thickness are often mislabeled as having hypertensive cardiomyopathy when this should prompt a broader differential, including cardiac amyloidosis, hypertrophic cardiomyopathy, aortic stenosis, and rarer genetic disorders such as Fabry disease.11

Given the nonspecific presenting findings, the key to diagnosis is a high index of suspicion. Older patients presenting with HFpEF and even milder degrees of increased wall thickness also warrant scrutiny; clinical clues are outlined in Table 1.10,12 Family history is of particular importance because an inherited form of ATTRv, the Val122Ile mutation, is observed almost exclusively in black patients and is associated with a greater burden of autonomic and peripheral neuropathy and worse outcomes than ATTRwt.3,11

Table 1. Clinical Clues From Routine Cardiac Eval‎uation That Should Prompt Additional Diagnostic Eval‎uation for ATTR-CM

Traditional Cardiac CluesNoncardiac Clues

Intolerance to antihypertensive or heart failure medications because of symptomatic hypotension or orthostasis	Neurological: sensorimotor polyneuropathy (paresthesias and weakness), autonomic dysfunction (orthostatic hypotension, postprandial diarrhea alternating with constipation, gastroparesis, urinary retention, and incontinence)
Persistent low-level elevation in serum troponin	Orthopedic: carpal tunnel syndrome, lumbar spinal stenosis, unprovoked biceps tendon rupture, hip and knee arthroplasty
Discordance between QRS voltage on an ECG and wall thickness on imaging	Black race
Unexplained atrioventricular block or prior pacemaker implantation	Family history of polyneuropathy
Unexplained LV wall thickening, right ventricular thickening, or atrial wall thickening
Family history of cardiomyopathy

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ATTR-CM indicates transthyretin amyloid cardiomyopathy; and LV, left ventricular.

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Last, it is important to note that <40% of patients with biopsy-proven ATTR-CM have low voltage on ECG, and these patients often have advanced disease.13 Thus, although helpful if present, the absence of low voltage on ECG should not dissuade clinicians from considering ATTR-CM as a potential cause of HFpEF in the appropriate clinical context.

Rational Approach to Testing in Cardiac Amyloidosis

Although echocardiography offers clues that prompt further testing and cardiac magnetic resonance (CMR) imaging14,15 may indicate an infiltrative process, the use of 99mtechnetium (99mTc) bone-avid compounds represents a paradigm shift because these scans allow the noninvasive diagnosis of ATTR-CM, although the basis for binding to amyloid deposits remains unknown.16–18 99mTc compounds include PYP (pyrophosphate), DPD (3,3-diphosphono-1,2-propanodicarboxylic acid), and hydroxymethylene diphosphonate; PYP is used in the United States. The relative merits of echocardiography, CMR, and 99mTc-PYP scans are outlined in Table 2.

Table 2. Comparison of Diagnostic Imaging Modalities in ATTR-CM

CostSpecialized Expertise Required for InterpretationExposure to Ionizing RadiationCardiac Devices Affect Image QualityCan Identify Nonamyloid Causes of LV ThickeningClinical Clues Suggesting Cardiac AmyloidosisDistinguish AL-CM and ATTR-CMMarkers of Worse Prognosis

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$ indicates lower cost; $$, higher cost; AL-CM, immunoglobulin light chain amyloid cardiomyopathy; apo A1, apolipoprotein A1; ATTR-CM, transthyretin amyloid cardiomyopathy; EF, ejection fraction; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; LV, left ventricular; MRI, magnetic resonance imaging; and SPECT, single-photon emission computed tomography.

*

In the context of normal serum and urine immunofixation electrophoresis and serum kappa/lambda ratio.

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The testing algorithm shown in Figure 1 begins with a high index of suspicion (Table 1). CMR alone is not diagnostic of ATTR-CM. CMR is the appropriate test when an infiltrative cardiomyopathy is suspected but ATTR-CM is less likely, as in younger patients or those with findings suggestive of other infiltrative/inflammatory or restrictive cardiomyopathies, including sarcoidosis, hemochromatosis, or Fabry disease, as well as hypertrophic cardiomyopathy, myocarditis, or constrictive pericarditis.22

Figure 1. Testing algorithm for transthyretin amyloidosis (ATTR). Cardiac magnetic resonance imaging is not diagnostic for ATTR cardiomyopathy (CM) but can suggest the diagnosis and is useful when infiltrative cardiomyopathy, constrictive pericarditis, or myocarditis is suspected. Although, practically, screening for the presence of a monoclonal light chain and 99mtechnetium-pyrophosphate (99mTc-PYP) scans can be ordered together for convenience, the results of the 99mTc-PYP scan should be interpreted only in the context of a negative monoclonal light chain screen. Single-photon emission computed tomography imaging is required if there is grade 1 or higher 99mTc-PYP to distinguish blood pool from myocardial retention. Note that mild elevations in the serum free light chain kappa/lambda ratio frequently occur in patients with renal disease, and in the setting of normal immunofixation, a kappa/lambda ratio of up to 3.0 can be normal.21 Consultation with a hematologist can be considered in such circumstances. AL indicates immunoglobulin light chain; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CMR, cardiac magnetic resonance; H/CL, heart/contralateral chest ratio; HCM, hypertrophic cardiomyopathy; and IFE, immunofixation electrophoresis.Open in viewer

Although bone scintigraphy has emerged as a cornerstone of ATTR-CM diagnosis, scans may be positive even in AL amyloidosis,18 and a bone scintigraphy scan alone, without concomitant testing for light chains, is neither appropriate nor valid for distinguishing ATTR-CM from AL amyloid cardiomyopathy (AL-CM).

Serum free light chain concentration and serum and urine immunofixation electrophoresis (IFE) are assessed to rule out AL-CM. Serum plasma electrophoresis testing and urine plasma electrophoresis testing are less sensitive and should be avoided. The sensitivity of serum plasma electrophoresis for AL amyloidosis is ≈70%, whereas the sensitivity of serum IFE is >90%.23 Together, measurement of serum IFE, urine IFE, and serum free light chain is >99% sensitive for AL amyloidosis.24,25

Assessment of ATTR-CM with bone scintigraphy is accomplished by semiquantitative or quantitative approaches (Figure 2). The semiquantitative grading involves comparing heart to rib uptake: grade 0 is no cardiac and normal rib uptake; grade 1 is cardiac less than rib uptake; grade 2 is cardiac equal to rib uptake; and grade 3 is cardiac greater than rib uptake with mild/absent rib uptake. Quantitative analysis involves comparison of mean counts as determined by a region of interest placed over the heart and compared with a similar-sized region of intensity placed over the contralateral chest. In the absence of a light chain abnormality, the 99mTc-PYP scan is diagnostic of ATTR-CM if there is grade 2 to 3 cardiac uptake or a heart/contralateral chest ratio >1.5. Single-photon emission computed tomography is assessed in all positive scans to confirm‎ that uptake represents myocardial retention of the tracer, not blood pool signal.4

Figure 2. 99mTechnetium-pyrophosphate imaging for transthyretin cardiac amyloidosis. Single-photon emission computed tomography (SPECT) imaging to identify myocardial retention of technetium-based isotopes is useful in discriminating blood pool on planar scans that result in a false-positive test from myocardial uptake of the isotope indicative of transthyretin amyloidosis with cardiomyopathy. SQA indicates semiquantitative analysis. Reprinted from Maurer et al.26 Copyright © 2019, American Heart Association, Inc. Source figure adapted from Bokhari et al27 with permission of the American Society of Nuclear Cardiology. Copyright © 2016, American Society of Nuclear Cardiology.Open in viewer

Although the presence of grade 2 or 3 scintigraphic uptake has a high specificity in amyloid centers with a high preval‎ence of ATTR-CM, the test performance in populations with lower disease preval‎ence is unknown. The causes of false-positive 99mTc-PYP scans are shown in Table 2.

In some situations, endomyocardial biopsy may be necessary to establish the diagnosis: (1) a positive 99mTc-PYP scan and evidence of a plasma cell dyscrasia by serum/urine IFE or serum free light chain analysis to exclude AL-CM (because AL-CM and ATTR-CM may very rarely occur together in the same patient, such that patients with biopsy-proven AL-CM, especially if older, may also have superimposed ATTRwt-CM deposits); (2) a negative or equivocal 99mTc-PYP scan despite a high clinical suspicion to confirm‎ ATTR-CM; and (3) unavailability of 99mTc-PYP scanning. Given its low sensitivity, a fat-pad biopsy is not sufficient to exclude ATTR-CM.28

If ATTR-CM is identified, then genetic sequencing of the TTR gene is required to define ATTRv versus ATTRwt disease (Table 3). Differentiating ATTRv from ATTRwt is critical because confirmation of ATTRv should trigger genetic counseling and potential screening of family members; the identification of the Val122Ile mutation suggests aggressive progression meriting closer follow-up; and certain therapies are currently approved only for ATTRv. Neurological consultation should be pursued if neurological involvement is present or suspected or if the identified mutation is associated with neurological involvement. Note that age alone is not a valid discriminator of ATTRwt versus ATTRv disease. Two staging schemes offer prognostic insight into ATTR-CM (Table 4).

Table 3. Common Genotypes in ATTR-CM

Age at Onset, ySex DistributionNational/Ethnic PredominanceCardiac InvolvementOther Organ Involvement

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ATTR-CM indicates transthyretin amyloid cardiomyopathy; and TTRwt, wild-type transthyretin.

Data derived from Lane et al,3 Maurer et al,11 Connors et al,29 Lopes et al,30 and Sattianayagam et al.31

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Table 4. Prognostic Staging Systems for ATTR-CM

Mayo Staging System1UK Staging System2

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ATTR-CM indicates transthyretin amyloid cardiomyopathy; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; eGFR, estimated glomerular filtration rate; and NT-proBNP, N-terminal pro-B-type natriuretic peptide.

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Overview of Disease-Modifying Therapies for ATTR-CM

Targets for disease-modifying therapies in cardiac amyloidosis include TTR silencing, TTR stabilization, and TTR disruption (Figure 3 and Table 5). TTR stabilizers bind to the TTR tetramer and prevent misfolding and thus deposition of amyloid fibrils. TTR silencers target TTR hepatic synthesis. TTR disruptors target the clearance of amyloid fibrils from tissues.

Table 5. Summary of Disease-Modifying Agents Currently Available for ATTR

DrugIndication/ApprovalDose/DeliveryClinical Trial Key Inclusion/ExclusionPotential Side EffectsMonitoringAverage Wholesale Price

TTR stabilizers
Tafamidis	FDA approved for ATTRwt-CM and ATTRv-CM	20*, 61, or 80 mg once daily	ATTR-ACT trial33 Inclusion:  End-diastolic septal thickness >12 mm  History of heart failure  NT-proBNP ≥600 pg/mL Exclusion:  6MWT <100 m  NYHA class IV symptoms  Liver or heart transplantation  eGFR <25 mL·min−1·1.73 m−2	None	None	$225 000/y
Diflunisal	FDA approved as NSAID Off-label use in ATTRwt or ATTRv with neuropathy/cardiomyopathy	250 mg orally twice daily Administer with proton pump inhibitor	Diflunisal Trial Consortium34 Inclusion:  ATTRv with sensorimotor polyneuropathy (familial amyloid polyneuropathy)  Biopsy-proven amyloid deposits  Confirmed TTR mutation Exclusion:  NYHA class IV symptoms  Estimated creatinine clearance  <30 mL/min†  Anticoagulation	Fluid retention Renal dysfunction Bleeding	Renal function Platelet count Hemoglobin	≈$60/mo
TTR silencers
Patisiran	FDA approved for ATTRv with neuropathy	0.3 mg/kg intravenously every 3 wk Premedication with intravenous corticosteroids, intravenous H1 blocker, H2 blocker Daily vitamin A supplement	APOLLO Trial35 Inclusion:  Documented TTR mutation  Confirmed ATTRv with polyneuropathy (familial amyloid polyneuropathy)  NIS score 5–130  PND score ≤3b Exclusion:  NYHA class III–IV symptoms  Liver transplantation	Infusion-related reactions Vitamin A deficiency	None	$414 162/y‡
Inotersen	FDA approved for ATTRv with neuropathy	284 mg/wk subcutaneously Daily vitamin A supplement	NEURO-TTR Trial36 Inclusion:  ATTRv with polyneuropathy (familial amyloid polyneuropathy) stage 1 and 2 familial amyloid polyneuropathy  NIS ≥10 and ≤130  Documented TTR mutation  Documented amyloid deposit on biopsy Exclusion:  Platelets <125×109/L  Creatinine clearance <60 mL·min−1·1.73 m−2  NYHA class III symptoms  Liver transplantation	Thrombocytopenia Glomerulonephritis Infusion-related reactions Vitamin A deficiency	Weekly platelet count Every 2 wk, serum creatinine, eGFR, and UPCR	$359 840/y

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6MWT indicates 6-minute walk test; APOLLO, A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; ATTR, transthyretin amyloidosis; ATTRv, cardiac variant transthyretin amyloidosis; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt, wild-type transthyretin amyloidosis; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; ATTR-ACT, Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy; CM, cardiomyopathy; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; NEURO-TTR, Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; NIS, Neuropathy Impairment Score; NSAID, nonsteroidal anti-inflammatory drug; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PND, polyneuropathy disability; TTR, transthyretin; and UPCR, urine protein to creatinine ratio.

*

Although the 20-mg dose is not FDA-approved, it may be considered by clinicians for patients who have issues with affordability, as there is evidence of benefit from the 20-mg dose.36a,36b

†

In clinical practice, diflunisal is not suggested for patients with creatinine clearance <45 mL/min.

‡

Average wholesale price of patisiran based on a patient weight of 70 kg and does not include the price of premedication or infusion-related expenses.

Average wholesale prices taken from Micromedex online database.37

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Figure 3. TTR (transthyretin) production and targets of therapy. Inherited mutations in cardiac variant transthyretin amyloidosis (ATTRv) or the aging process in wild-type disease (ATTRwt) cause destabilization of the TTR protein into monomers or oligomers, which aggregate into amyloid fibrils. These insoluble fibrils accumulate in the myocardium and result in diastolic dysfunction, restrictive cardiomyopathy, and eventual congestive heart failure. Targets of therapy include TTR production (silencers), TTR dissociation (TTR stabilizers), and TTR clearance from tissues (TTR disruption). TUDCA indicates tauroursodeoxycholic acid. Adapted from Nativi-Nicolau and Maurer32 with permission. Copyright © 2018, Wolters Kluwer Health, Inc.Open in viewer

TTR Silencing

TTR protein silencers target the hepatic synthesis of TTR. Patisiran is an intravenously administered siRNA that degrades TTR mRNA, and inotersen is a subcutaneously administered single-stranded antisense oligonucleotide that binds TTR mRNA, leading to degradation. Both therapies result in >85% reduction in circulating TTR protein concentration.

Two randomized trials of TTR silencers in patients with ATTRv amyloidosis and polyneuropathy have been reported: the APOLLO trial (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy; patisiran)35 and NEURO-TTR (Efficacy and Safety of Inotersen in Familial Amyloid Polyneuropathy; inotersen).36 Both demonstrated slower progression of amyloidosis-related polyneuropathy.

Although not explicitly tested, there is evidence that TTR silencers may have beneficial cardiac effects. Prespecified subgroup analyses of APOLLO trial participants with increased LV wall thickening unrelated to hypertension or aortic stenosis (assumed to be from amyloidosis) demonstrated that patisiran attenuated the deterioration of LV global longitudinal strain,38 LV wall thickness, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration.39 Similarly, inotersen demonstrated stabilization of LV wall thickness, 6-minute walk test, and global systolic strain.40 Trials to assess the efficacy of TTR silencers in ATTR-CM are ongoing: APOLLO-B (A Study to Eval‎uate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy [ATTR Amyloidosis With Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03997383; patisiran), 24 Month Open Label Study of the Tolerability and Efficacy of Inotersen in TTR Amyloid Cardiomyopathy Patients (URL: ClinicalTrials.gov. Unique identifier: NCT03702829; inotersen), HELIOS-B (A Study to Eval‎uate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; URL: ClinicalTrials.gov. Unique identifier: NCT04153149; vutrisiran), and CARDIO-TTRansform (A Study to Eval‎uate the Efficacy and Safety of AKCEA-TTR-LRx in Participants With TransthyretinMediated Amyloid Cardiomyopathy [ATTR CM]; URL: ClinicalTrials.gov. Unique identifier: NCT04136171; AKCEA-TTR-LRx).

TTR Stabilization

Diflunisal is a nonsteroidal anti-inflammatory that stabilizes TTR in vitro. In a randomized trial of patients with ATTRv and polyneuropathy, diflunisal was associated with reduced progression of polyneuropathy.34 There are no controlled trials of diflunisal in patients with ATTR-CM, although single-center retrospective analyses demonstrate safety and tolerability and suggest efficacy.41,42

Tafamidis is a TTR stabilizer that binds the thyroxine-binding site of TTR. In the ATTR-ACT randomized trial (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) of patients with ATTRwt-CM or ATTRv-CM, tafamidis was associated with a significantly lower all-cause mortality (29.5% versus 42.9%) and lower cardiovascular-related hospitalization (0.48 versus 0.70 per year) after 30 months. There was a higher rate of cardiovascular-related hospitalizations in the prespecified subgroup of patients with NYHA class III heart failure, which may have been attributable to longer survival during a more severe period of disease, underscoring the importance of early diagnosis and treatment. Tafamidis was also associated with a lower rate of decline in 6-minute walk distance (P<0.001) and a lower rate of decline in Kansas City Cardiomyopathy Questionnaire-Overall Summary score (P<0.001).33 Tafamidis was approved by the US Food and Drug Administration for use in ATTR-CM in May 2019.

AG10 is a TTR stabilizer that binds to the tetramer and mimics coinheritance of the TTR T119M mutation, providing natural stabilization of TTR to prevent amyloid fibril formation and deposition. A phase 2 trial of AG10 demonstrated an acceptable safety profile,43 and data from the open-label extension indicate that mortality and cardiovascular hospitalization were lower in AG10 open-label extension participants than in placebo-treated ATTR-ACT participants at 15 months.44 A phase 3 trial of AG-10 is in progress (ATTRIBUTE-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]; URL: ClinicalTrials.gov. Unique identifier: NCT03860935).

TTR Disruption/Resorption

TTR disruption targets the clearance of amyloidosis fibrils from tissues. Preclinical studies demonstrated that doxycycline plus TUDCA (tauroursodeoxycholic acid) removed amyloid deposits. However, small open-label studies demonstrated a high incidence of side effects with conflicting results on efficacy.45,46 EGCG (epigallocatechin-3-gallate), a catechin in green tea, inhibits amyloid fibril formation in vitro, but there is little evidence of benefit47 from it or turmeric. With the advent of US Food and Drug Administration–approved therapies, the therapeutic roles of these agents are uncertain. Other agents, including monoclonal antibodies such as PRX004, are under investigation.48

Approach to Treatment in Cardiac Amyloidosis

As outlined in Figure 4, treatment of cardiac amyloidosis focuses on 3 areas: management of heart failure, management of arrhythmias, and initiation of disease-modifying agents.

Figure 4. Treatment algorithm for transthyretin amyloidosis (ATTR). ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor blocker-–neprilysin inhibitor; ATTRv, cardiac variant transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; BB, β-blocker; CM, cardiomyopathy; CRT, cardiac resynchronization therapy; DOAC, direct oral anticoagulant; HF, heart failure; ICD, implantable cardioverter-defibrillator; PPM, permanent pacemaker; SCD, sudden cardiac death; VKA, vitamin K antagonist; and VT, ventricular tachycardia.Open in viewer

Management of Heart Failure

The physiology of restrictive LV filling and reduced stroke volume/cardiac output in cardiac amyloidosis renders volume maintenance difficult. Bioavailable loop diuretics are used for decongestion, although they may compromise renal function or systemic perfusion in patients with advanced restrictive disease because diminishing preload may compromise an already fixed stroke volume, leading to low cardiac output. Aldosterone antagonists may be used alone or in conjunction with loop diuretics in patients with adequate blood pressure and renal function.

There are no data supporting the use of standard guideline-directed medical therapy for heart failure with reduced ejection fraction or HFpEF in ATTR-CM, including angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, or angiotensin receptors blockers–neprilysin inhibitors. Furthermore, these therapies may exacerbate hypotension when amyloid-associated autonomic dysfunction is present.

β-Blockers and nondihydropyridine calcium channel blockers are often poorly tolerated, even at low doses, because patients with ATTR-CM rely on heart rate response to maintain cardiac output given a fixed stroke volume. In AL amyloidosis, nondihydropyridine calcium channel blockers also bind amyloid fibrils and can result in heart block or shock.

Management of Arrhythmias

Amyloid cardiomyopathy is associated with atrial dysfunction and both atrial and ventricular arrhythmias. Atrial dysfunction may be reflected by decreased A-wave amplitude and left atrial appendage velocities on echocardiography, and in such cases, empirical anticoagulation may be warranted even in sinus rhythm.49 There is no definitive reported comparison of warfarin and direct oral anticoagulants to prevent thromboembolism in this setting.

As a result of atrial dysfunction in ATTR-CM, anticoagulation is indicated for atrial fibrillation/flutter regardless of CHA2DS2-VASc score. Left atrial appendage closure devices have not been studied in ATTR-CM but may be considered in patients with prohibitive bleeding risk. Digoxin may be used cautiously for rate control, although there is concern about potential digoxin toxicity caused by binding of digoxin to amyloid fibrils. Amiodarone is the agent of choice for both rhythm and rate control, particularly in cases in which β-blockade is not tolerated; cardioversion and ablation should also be considered in selected cases.

Because of the high incidence of conduction system disease from amyloid infiltration, ambulatory electrocardiographic monitoring is part of the syncope eval‎uation, and pacemakers are indicated per Heart Rhythm Society consensus guidelines.50 Implantable cardioverter-defibrillators (ICDs) are recommended in cases of aborted sudden cardiac death with expected survival >1 year or significant ventricular arrhythmias. However, the benefit of ICDs, particularly for primary prevention of sudden cardiac death, is questionable. In a study of 45 patients with amyloid cardiomyopathy (32 with ATTR-CM), an ICD was placed for primary prevention in 38 of the patients. Over follow-up, 12% of patients had at least 1 appropriate ICD therapy; no clinical characteristics predicted who would receive ICD therapy.51 On the basis of limited experience, although Heart Rhythm Society guidelines assign a Class IIb indication to ICD placement in AL-CM and nonsustained ventricular tachycardia with expected survival >1 year, the use of ICDs for primary prevention of sudden cardiac death in patients with ATTR-CM is not well established.52 Cardiac resynchronization therapy may be useful in pacemaker-dependent patients because the already depressed stroke volume may worsen with long-term right ventricular pacing.53

Implementation of Disease-Modifying Therapies in ATTR-CM

The use of US Food and Drug Administration–approved disease-modifying therapy is based on the presence of cardiomyopathy and polyneuropathy and the distinction between ATTRv and ATTRwt amyloidosis (Figure 5). In patients with predominantly cardiac disease resulting from ATTRv or ATTRwt, tafamidis is indicated in those with NYHA class I to III symptoms,33 and early initiation appears to slow disease progression. The benefit of tafamidis has not been observed in patients with class IV symptoms, severe aortic stenosis, or impaired renal function (glomerular filtration rate <25 mL·min−1·1.73 m−2 body surface area).

Figure 5. Projected Medicare Part D beneficiary monthly out-of-pocket costs for tafamidis. Projected annual out-of-pocket expenses were calculated using the standard 2019 Medicare Part D plan including: (1) an initial $415 deductible; (2) an initial coverage period until drug costs reach $3810; (3) a coverage gap (“donut hole”) with 25% cost sharing until out-of-pocket costs reach $5100; and (4) catastrophic coverage with 5% cost sharing without an upper limit. Monthly insurance premiums and the costs of other medications were not included in this projection.Open in viewer

Patients with ATTRv and polyneuropathy should be considered for TTR silencing therapy with patisiran35 or inotersen36; currently, neither is indicated for ATTRv-CM without polyneuropathy or in ATTRwt-CM. In patients with ATTRv-CM with polyneuropathy, the choice between therapeutic agents is based on accessibility and side-effect profile.

The use of combination therapies is appealing to synergistically target both TTR silencing and stabilization of the remaining synthesized protein, but this approach lacks data and may be cost-prohibitive.

Diflusinal (250 mg orally twice daily) may be considered with caution for off-label therapy for asymptomatic ATTR carriers, for patients with ATTR-CM who are not eligible for TTR silencers, or for patients with ATTR-CM who are intolerant of or cannot afford tafamidis. Because of the nonsteroidal anti-inflammatory properties, close monitoring is needed, and diflunisal is contraindicated in patients with significant thrombocytopenia and renal dysfunction (glomerular filtration rate <40 mL·min−1·1.73 m−2) and should be used cautiously in patients on anticoagulation or with a history of gastrointestinal bleeding.

Advanced Heart Failure Therapies in ATTR-CM

For patients with ATTR-CM with stage D heart failure, use of an LV assist device is challenging because of the small LV cavity size and concomitant right ventricular dysfunction.54 There are limited data to support considering the total artificial heart as a bridge to transplantation in patients without significant extracardiac disease.55

Heart transplantation may be considered in patients with stage D heart failure,56 and the current adult donor allocation system provides priority as status 4 to amyloid cardiomyopathy given the lack of durable mechanical circulatory support options. Generally, heart-liver transplantation is performed in patients with ATTRv-CM at risk for neuropathy because neuropathy may progress with heart transplantation alone, although the criteria for heart alone versus heart-liver transplantation are not well defined,57 especially with the advent of silencer therapy, which may have a role after heart transplantation. Liver transplantation alone in ATTRv would offer prohibitive risk in the presence of severe cardiac dysfunction, and preexisting cardiac dysfunction can progress despite subsequent synthesis of wild-type TTR by the donor liver.

Areas of Uncertainty and Future Investigation

Despite advances in the management of ATTR-CM, areas of uncertainty remain in screening, disease progression, role of TTR silencers in patients with ATTR-CM, timing of therapy initiation, and financial burden of new therapies (Table 6).

Table 6. Areas of Active Investigation and Uncertainty in Diagnosis, Prognosis, Progression, and Treatment

Diagnosis

 Should we screen for ATTR-CM? If so, in which populations?

 Which diagnostic tests should be used for screening?

 Are there biomarkers that can raise suspicion of ATTR-CM with sufficient diagnostic certainty to be used for screening?

 Which noninvasive test has the best sensitivity for diagnosis of ATTR-CM?

 How does bone scintigraphy perform as a screening test (eg, in populations with a lower preval‎ence of disease than specialized amyloid centers)?

 What is the cost-effectiveness of screening or active ascertainment?

 How should asymptomatic allele carriers of TTR mutations be followed up for disease penetrance?

Prognosis

 What is the best combination of prognostic variables in ATTR-CM?

 Which biomarkers are most effective for following up patients with ATTR-CM?

 What is the role of imaging in ATTR-CM for prognostication?

 How does one determine whether a patient with ATTR-CM is progressing on therapy?

 What is the role of defibrillators and pacemakers in patients with ATTR-CM?

Progression of disease

 How should one measure disease progression?

 Do the various domains (eg, QOL, functional measures, biomarkers, imaging) progress at the same rate?

 Is there an early marker of disease progression?

 Are there biological processes (TTR stability, TTR kinetics or levels, or TTR ligands) that can be used to monitor progression?

 Can disease progression inform the choice of therapies and when to change therapies?

 Can TTR amyloidosis be reversed? If so, what factors predict regression?

Treatment

 How do the efficacies of stabilizers and silencers compare? Do TTR stabilizers differ in efficacy and side-effect profile?

 Is combination therapy with TTR stabilizers or silencers additive, synergistic, or not beneficial?

 In what order should TTR therapies be administered?

 How does the cost of therapy influence adherence, treatment, and outcomes?

 Does the cost of therapy affect the development of novel therapies?

 When should ATTR-specific therapy be initiated in patients with ATTR-CM?

 When should patients with ATTR-CM be considered for advanced surgical heart failure therapies such as LVAD and cardiac transplantation?

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ATTR indicates transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; LVAD, left ventricular assist device; QOL, quality of life; and TTR, transthyretin.

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Identifying Populations for Screening

Given that the preval‎ence of cardiac amyloidosis is increased in specific populations (patients with HFpEF, individuals of West African descent, those with small-fiber polyneuropathy), more active ascertainment or screening may be indicated10 because early identification can maximize the benefit of therapy and delayed diagnosis results in worse outcomes. However, much is not known: the natural history of subclinical TTR cardiac amyloidosis, how testing will perform in groups with lower pretest probability, and the cost-effectiveness of screening.

Biomarkers such as NT-proBNP and troponin, electrocardiography, and echocardiography have low sensitivity/specificity for ATTR-CM. More specific testing may involve measurement of circulating RBP4 (retinol binding protein 4) or misfolded TTR oligomers; both discriminate patients with ATTRv from those with nonamyloid HF and healthy control subjects.58,59

Because HFpEF disproportionately affects older blacks and Hispanics compared with whites, there is currently a recruiting National Institutes of Health–funded prospective cohort study using 99mTc-PYP imaging and measurement of RBP4 and misfolded TTR oligomers to detect ATTR-CM in minority subjects with heart failure (SCAN-MP [Screening for Cardiac Amyloidosis Using Nuclear Imaging for Minority Populations]; URL: ClinicalTrials.gov. Unique identifier: NCT03812172). Other screening studies are ongoing in Afro-Caribbean individuals with increased wall thickness (Frequency of Cardiac Amyloidosis in the Caribbean's [TEAM Amylose]; URL: ClinicalTrials.gov. Unique identifier: NCT03322319), HFpEF patients with increased wall thickness (Transthyretin Cardiac Amyloidosis in HFpEF; URL: ClinicalTrials.gov. Unique identifier: NCT03414632), and those with small-fiber polyneuropathy using TTR gene sequencing (Screening for the Transthyretin-Related Familial Amyloidotic Polyneuropathy [TTR FAP]; URL: ClinicalTrials.gov. Unique identifier: NCT01705626). Last, large-scale biobank genotype studies hold promise for determining the preval‎ence of TTR mutations among target populations.

Another area of significant uncertainty is monitoring in asymptomatic carriers of TTR mutations.60 Given the age-dependent penetrance, the general consensus is to begin assessment 10 years before the affected proband’s age at disease onset, although this approach is limited by the unclear natural history of disease. Assessment can include physical examination, electrocardiography, echocardiography, bone scintigraphy, or CMR imaging.61

Assessing the Progression of Disease

There is no accepted definition of progression or response to therapy of ATTR-CM, but several measures have been proposed: survival, hospitalizations, functional capacity (NYHA class, 6-minute walk test, gait speed, cardiopulmonary exercise stress testing), quality of life, and cardiac biomarkers and imaging (echocardiography, magnetic resonance imaging, or positron emission tomography).

Currently, the role of imaging modalities in eval‎uating response to therapy is not established. Each imaging modality has a different sensitivity for detecting the burden of amyloid fibril deposition, varying capacity to quantify deposition, and therefore different ability to identify progression or improvement. Decreasing levels of misfolded TTR may reflect response to therapy,59 but the role of surveillance imaging and laboratories in assessing response to or guiding changes in therapy requires further study.

Role of TTR Silencers in ATTR-CM Without Neuropathy

Although it is biologically plausible that TTR silencers such as inotersen and patisiran could improve outcomes in ATTR-CM, such conclusions must await the results of adequately powered clinical trials. As a cautionary example, a subcutaneous RNA interference agent similar to patisiran, revusiran, was associated with increased mortality compared with placebo in ATTRv-CM in the ENDEAVOUR clinical trial (Phase 3 Multicenter Study of Revusiran [ALN-TTRSC] in Patients With Transthyretin [TTR] Mediated Familial Amyloidotic Cardiomyopathy [FAC]; URL: ClinicalTrials.gov. Unique identifier: NCT02319005).

Timing of Initiation of Disease-Modifying Agents

Given the lack of consensus on defining disease onset in carriers of TTR mutations and what methods (imaging or biomarkers) should be used to monitor disease progression, the timing of initiation of therapy in ATTRv carriers remains an area of uncertainty.

In contrast, in patients with advanced disease, treatment aimed at TTR stabilization is unlikely to be of significant benefit. Although the package label for tafamidis does not provide restrictions on administration, patients with NYHA class IV symptoms, minimally ambulatory patients (walk <100 m on a 6-minute walk test), and those with advanced renal dysfunction (estimated glomerular filtration rate <25 mL·min−1·m−2) were ineligible for inclusion in ATTR-ACT. Thus, tafamidis is not suggested for patients with advanced heart failure.

Financial Impact of Disease-Modifying Agents

Significantly affecting equitable prescription of these therapies is their considerable cost, especially because lifelong treatment is required, and the financial implication of potentially treating asymptomatic TTR mutation carriers is tremendous.

As noted in Table 6, costs are similar to those of new biologics or chemotherapeutic agents. A significant proportion of patients with ATTR-CM in the United States are older adults with Medicare as their primary insurance. Because Medicare does not allow direct-to-consumer drug maker copay assistance programs, these patients can have significant out-of-pocket expenses.62

Even with Medicare Part D prescription drug coverage, the average cost of tafamidis could approach $18 000 per year, more than half of which occurs after the catastrophic coverage threshold, and would reset annually for every year of treatment (Figure 5). Despite independent charity assistance foundations, the most common income limit was 500% of the federal poverty level (annual income of $62 450 for an individual and $84 550 for a married couple in 2019).63 There are a significant number of patients who may fall above such thresholds but for whom this annual out-of-pocket expense would not be feasible on fixed incomes.

Manufacturers have committed to work with insurers and patients to ensure that no one who merits drug is deprived because of cost, but the practice and impact of such commitments have yet to be fully demonstrated, and a cost-effectiveness analysis of tafamidis indicated that the list price would need to be reduced by >90% for it to be cost-effective.64 Thus, a growing area of concern, for which ATTR-CM is not unique but perhaps emblematic, is the gap between ideal medical therapies and the ability of patients to afford them.

Conclusions

The landscape for the diagnosis of and therapy for ATTR-CM is rapidly evolving. Readily accessible, accurate, noninvasive diagnostic tests and therapies to improve symptoms and survival are now available. ATTR-CM is no longer accurately regarded as a “zebra” diagnosis. Given the now-recognized clinical relevance of ATTR-CM, clinicians must have a high index of suspicion for cardiac amyloidosis when patients present with clinical clues and should invoke a rational diagnostic algorithm to eval‎uate for both AL-CM and ATTR-CM. Once the diagnosis is made, differentiating between ATTRv-CM, ATTRwt-CM, and the presence or absence of neuropathy will allow clinicians to implement an appropriate strategy of heart failure and arrhythmia management along with disease-modifying agents.

Uncertainties exist in screening, the assessment of progression, the management of asymptomatic carriers of ATTRv, the use of TTR silencing agents in ATTR-CM, and the financial impact of disease-modifying therapies. Current and future studies will assess these unanswered knowledge gaps, and advocacy from clinicians at every level may aid in closing the gap between the best medical therapies for ATTR-CM and the ability of patients to afford them.

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