Heart Failure Reviews (2022) 27:785–793

[Link]

Screening for ATTR amyloidosis in the clinic: overlapping disorders,

misdiagnosis, and multiorgan awareness
Jose N. Nativi‑Nicolau1 · Chafic Karam2 · Sami Khella3 · Mathew S. Maurer4

Accepted: 26 January 2021 / Published online: 20 February 2021

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2021

Abstract
Amyloid transthyretin (ATTR) amyloidosis is a clinically heterogeneous and fatal disease that results from deposition of
insoluble amyloid fibrils in various organs and tissues, causing progressive loss of function. The objective of this review is to
increase awareness and diagnosis of ATTR amyloidosis by improving recognition of its overlapping conditions, misdiagnosis,
and multiorgan presentation. Cardiac manifestations include heart failure, atrial fibrillation, intolerance to previously
prescribed antihypertensives, sinus node dysfunction, and atrioventricular block, resulting in the need for permanent pacing.
Neurologic manifestations include progressive sensorimotor neuropathy (e.g., pain, weakness) and autonomic dysfunction
(e.g., erectile dysfunction, chronic diarrhea, orthostatic hypotension). Non-cardiac red flags often precede the diagnosis
of ATTR amyloidosis and include musculoskeletal manifestations (e.g., carpal tunnel syndrome, lumbar spinal stenosis,
spontaneous rupture of the distal tendon biceps, shoulder and knee surgery). Awareness and recognition of the constellation
of symptoms, including cardiac, neurologic, and musculoskeletal manifestations, will help with early diagnosis of ATTR
amyloidosis and faster access to therapies, thereby slowing the progression of this debilitating disease.

Keywords Amyloidosis · ATTRv · hATTR​· Cardiomyopathy · Transthyretin amyloidosis

Introduction any or all of which can precede by several years the cardiac
or neurologic manifestations [3–8]. Disease progression in
Amyloid transthyretin (ATTR) amyloidosis is a patients with ATTR amyloidosis is remarkably fast, resulting
progressively debilitating, clinically heterogeneous, and in significant impairment of function and irretrievable loss
fatal disease caused by the buildup of transthyretin (TTR) of quality of life [9–13]. With therapies available to slow
amyloid fibrils in various organs and tissues, resulting in disease progression, early recognition and diagnosis of
multisystem dysfunction particularly in the heart, along with patients with ATTR amyloidosis are important to facilitate
the peripheral and autonomic nervous systems [1–3]. The early treatment. The aim of this review is to increase
diagnosis of ATTR amyloidosis has been increasing over awareness of the constellation of symptoms in patients with
the last decade, and many patients have had musculoskeletal ATTR amyloidosis—especially the non-cardiac symptoms
manifestations, such as carpal tunnel syndrome, distal biceps that cardiologists and others may not traditionally associate
tendon rupture, idiopathic trigger finger, or spinal stenosis, with ATTR amyloidosis but that are key for identifying
patients with this progressive, fatal disease.
* Jose N. Nativi‑Nicolau
[Link]@[Link]
1
Wild‑type vs hereditary ATTR amyloidosis
Department of Internal Medicine, University of Utah Health, symptoms
Salt Lake City, UT, USA
2
Department of Neurology, Oregon Health & Science There are two forms of ATTR amyloidosis: wild type
University, Portland, OR, USA
(ATTRwt) and hereditary (ATTRv [variant]). In ATTRwt
3
Department of Neurology, University of Pennsylvania, amyloidosis, which was previously termed senile cardiac
Philadelphia, PA, USA
amyloidosis, a native non-mutated TTR protein misfolds
4
Department of Medicine, Columbia University, New York, into amyloid fibrils, primarily resulting in dysfunction of the
NY, USA

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heart that is characterized by restrictive cardiomyopathy; The signs and symptoms that should raise suspicion
this is predominantly seen in males aged > 60 years of ATTR amyloidosis with cardiomyopathy (ATTR-CM)
[14–16]. Although ATTRwt amyloidosis typically manifests often overlap with other more commonly recognized
as cardiac symptoms, patients may also have signs and cardiovascular diseases, such as heart failure with preserved
symptoms of sensorimotor neuropathy and autonomic ejection fraction, hypertensive cardiomyopathy, aortic
neuropathy [14, 15], along with a clinical history of carpal stenosis, hypertrophic cardiomyopathy, and light chain
tunnel syndrome, spinal stenosis, and other musculoskeletal amyloidosis (Table 1) [25, 27–29]. Given that the life
manifestations [7]. ATTRv amyloidosis, originally called expectancy of a patient with ATTR-CM is 2 to 5 years
familial amyloidotic polyneuropathy, is caused by a single after diagnosis, early and accurate diagnosis is key to
amino acid substitution produced by a point mutation in the forestalling disease progression. Recognizing the disease’s
TTR​gene. More than 130 mutations have been identified to signs and symptoms, which affect multiple systems, may aid
date, with some mutations more often associated with either cardiologists in avoiding misdiagnosis.
predominant polyneuropathy or cardiomyopathy; however,
most patients experience a mixed phenotype with both
neuropathic and cardiac symptoms [14, 15, 17–19]. The Recognizing a constellation of ATTR
mechanisms by which mutations influence TTR aggregation amyloidosis symptoms
or fibril morphology leading to organ dysfunction with
such variable clinical presentations are poorly understood Early suspicion and recognition of ATTR amyloidosis can lead
[20, 21]. In addition, phenotypic expression can be highly to an earlier diagnosis and treatment; there is evidence to suggest
variable among individuals with a specific mutation, even that a delay in treatment leads to irretrievable loss of quality
within the same family [14]. of life and progression of the polyneuropathic and cardiac
manifestations for most patients [3, 9–13]. Recognition of a
constellation of symptoms may raise suspicion of amyloidosis
Overlapping conditions and misdiagnosis early in its course (Fig. 1). Although patients may present with
of ATTR amyloidosis predominant symptoms of cardiomyopathy or progressive
polyneuropathy, there can be substantial overlap, with many
ATTR amyloidosis is often overlooked or misdiagnosed in individuals presenting with a combination of both, as well
patients, at least early in its course, due to the non-specific, as other abnormalities, such as musculoskeletal symptoms,
heterogeneous, multisystem presentation of the disease orthostatic hypotension, erectile dysfunction, gastrointestinal
[3]. As the disease progresses, the symptoms and clinical abnormalities, and unexplained weight loss (Fig. 2) [14,
manifestations of ATTR amyloidosis often mimic those 15]. Patients may also present with ocular manifestations
of other more common diseases, further complicating and and symptoms of nephropathy, which are discussed in other
delaying diagnosis [22–24]. Thus, patients with ATTR reviews [3, 30]. This phenotypic variability poses a considerable
amyloidosis could receive inappropriate treatments, such as diagnostic challenge. ATTR amyloidosis should be considered
chemotherapy for light-chain amyloidosis and intravenous in patients with signs and symptoms associated with cardiac,
immunoglobulins or steroids for immune polyneuropathies neurologic, or musculoskeletal manifestations, particularly
[3, 25, 26]. when the constellation of those symptoms suggests that multiple
organs are affected [3, 31].

Table 1  Overlapping conditions and misdiagnosis of ATTR amyloidosis

Cardiac [27–29] Neurologic [3, 24, 25]

• Heart failure with preserved ejection fraction • Chronic inflammatory demyelinating polyneuropathy
• Hypertensive cardiomyopathy • Paraproteinemic peripheral neuropathy (e.g., monoclonal gammopathy-associated)
• Aortic stenosis • Toxic peripheral neuropathy
• Hypertrophic cardiomyopathy • Vasculitic peripheral neuropathy
• Light chain amyloidosis with cardiac involvement • Idiopathic axonal polyneuropathy
• Idiopathic restrictive cardiomyopathy • Paraneoplastic neuropathy
• Iron overload • Diabetic neuropathy
• Other infiltrative cardiomyopathies (e.g., Fabry disease) • Alcoholic neuropathy
• Motor neuron disease (e.g., amyotrophic lateral sclerosis)
• Fibromyalgia
• Light chain amyloidosis

ATTR​amyloid transthyretin

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Fig. 1  A constellation of

multisystem clinical signs and
symptoms increases aware-
ness of amyloid transthyretin
(ATTR) amyloidosis. Recogni-
tion of non-cardiac symptoms
clustered with cardiac and/or
neurologic symptoms should
prompt diagnostic testing and
patient referral to a multidisci-
plinary team at an amyloidosis
expert center

Cardiovascular symptoms of ATTR and decline in functional capacity (~26 m decrease in 6-min
amyloidosis walk distance every 6 months) [15, 27, 33, 37–39]. In patients
with ATTRwt and ATTRv amyloidosis, troponin levels or
ATTR-CM is characterized by increased ventricular wall N-terminal pro–B-type natriuretic peptide (NT-proBNP)
thickness, increased valve thickness, and interatrial and levels are elevated and increase over time; this is an indicator
interventricular septum thickness that present as restrictive of clinical progression of heart failure [33, 36].
cardiomyopathy and progress to heart failure—initially
in the setting of preserved ejection fraction, conduction
system disturbances, and arrhythmias—with resulting Neurologic symptoms of ATTR amyloidosis
impaired functional capacity, syncope, or palpitations [14,
15, 17, 32–34]. The signs and symptoms that should raise Patients with amyloid polyneuropathy, such as ATTR
suspicion of ATTR-CM include a history of right-sided amyloidosis, are frequently misdiagnosed with chronic
heart failure; heart failure with preserved ejection fraction inflammatory demyelinating polyradiculoneuropathy (CIDP)
(especially in men); intolerance to angiotensin-converting [24, 25, 40]. Other neuropathies confused with ATTR
enzyme inhibitors, angiotensin receptor blockers, angiotensin amyloidosis include paraproteinemic peripheral neuropathy,
receptor neprilysin inhibitors (ARNi), or beta-blockers; or toxic peripheral neuropathy, vasculitic peripheral neuropathy,
atrial arrhythmias, conduction system disease, or need for idiopathic axonal polyneuropathy, diabetic polyneuropathy,
a pacemaker (Table 2) [28, 29, 35, 36]. Additionally, heart alcoholic neuropathy, paraneoplastic neuropathy, monoclonal
failure in patients with ATTR amyloidosis progressively gammopathy–associated neuropathy, and, more rarely, motor
worsens over time, with patients experiencing decline in neuropathy and amyotrophic lateral sclerosis (Table 1) [24,
diastolic dysfunction, decrease in left ventricular ejection 25, 40]. Recently published guidelines review in greater
fraction (~3% every 6 months), increased restrictive filling, detail the misleading features that often lead to these

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Fig. 2  Symptoms of ATTR amyloidosis. Patients with ATTR amyloi- considered for patients with cardiac, neurologic, or musculoskeletal
dosis may present with clinical signs or symptoms of cardiomyopathy manifestations, particularly when those symptoms suggest multiple
or progressive polyneuropathy along with musculoskeletal symptoms organs are affected. ATTR​amyloid transthyretin
and signs of autonomic dysfunction. ATTR amyloidosis should be

misdiagnoses [24]. Two key features of ATTR amyloidosis clinical manifestations experienced by the patient with ATTR-PN
with polyneuropathy (ATTR-PN) distinguish it from the more [19, 41–43]. Early symptoms of ATTR-PN include burning
common diabetic polyneuropathy: its progressive nature and, pain, especially in younger patients; older patients experience
frequently, distal limb weakness. Diabetic polyneuropathy is burning pain, numbness, and loss of pain and temperature
typically a slow, progressive, and distal sensory neuropathy sensation, whereas the ability to perceive touch pressure and
without much limb weakness (Table 3). joint position is relatively preserved [3, 41]. Examination of
ATTR-PN is characterized by symmetrical length-dependent nerve fiber involvement at this stage demonstrates degeneration
peripheral neuropathy; depending on the TTR​mutation in the of unmyelinated and small myelinated nerve fibers more than
case of ATTRv amyloidosis, distal and occasionally proximal large myelinated fibers [41]. As ATTR-PN progresses, muscle
limb weakness may be prominent [3, 19]. As the disease weakness increases, especially in the lower limbs; patients
progresses through each stage, the pattern of progression and with ATTR-PN suffer from progressive lower limb numbness,
class of nerve fiber impacted is reflected through heterogeneous weakness, and gait imbalance [15, 43–45].

Table 2  Signs and symptoms Signs/symptoms

that should raise suspicion
of ATTR amyloidosis with Heart failure with predominant right-sided symptoms (e.g., distended jugular veins, anorexia, gastrointesti-
cardiomyopathy nal upset, dependent edema, weight gain)
HFpEF, especially in men
Intolerance to ACE inhibitors, angiotensin receptor blockers, ARNi, or beta-blockers
Unexplained atrial arrhythmias, conduction system disease, or need for a pacemaker
History of musculoskeletal syndromes or procedures: CTS; lumbar spinal stenosis; spontaneous distal
bicep tendon rupture; or shoulder, knee, or hip surgery

ACE angiotensin-converting enzyme, ARNi angiotensin receptor-neprilysin inhibitors, ATTR​ amyloid tran-
sthyretin, CTS carpal tunnel syndrome, HFpEF heart failure with preserved ejection fraction

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Table 3  Comparison of Feature ATTR polyneuropathy Diabetic References

neuropathies related to ATTR polyneuropathy
amyloidosis and diabetes
Pain Mild, moderate, or severe Mild [61–64]
Motor weakness Common Uncommon [14, 15, 43, 44, 63, 64]
Muscle loss Common Uncommon [15, 43, 44, 63, 64]
Progression Months Years [44, 62]
Distribution Distal and occasionally proximal Distal [61–64]

ATTR​amyloid transthyretin

In addition to signs and symptoms of sensorimotor diarrhea (possibly alternating with constipation), or fecal
neuropathy, autonomic dysfunction is observed early in incontinence and unintentional weight loss [3, 14, 15, 49].
the course of ATTR amyloidosis and can precede motor
impairment, but it often goes unrecognized [41, 46, 47].
Furthermore, in cases of severe autonomic dysfunction with Musculoskeletal manifestations of ATTR
reduced sympathetic function, the signs and symptoms of heart amyloidosis
failure can be masked [48]. Autonomic neuropathy can manifest
as orthostatic hypotension, recurrent urinary tract infection, Patients with ATTR amyloidosis may develop musculoskeletal
erectile dysfunction, and/or gastrointestinal disturbances [3, 14, manifestations 5 to 15 years prior to other symptoms (Fig. 3)
15, 49]. Orthostatic hypotension, which is commonly reported [4, 7, 50, 51]. Numerous studies have reported the presence
as a symptom of ATTR amyloidosis, may manifest as dizziness of ATTR amyloid in tissue removed during orthopedic
or fainting when standing up, blurred vision, confusion, or surgeries, including the flexor tenosynovium, rotator cuff
light-headedness [15, 17, 46]. Meanwhile, gastrointestinal tendons, and ligamentum flavum [52, 53]. Rotator cuff surgery
disturbances may include nausea, vomiting, constipation, has been predominately reported in patients with ATTRwt

Fig. 3  Musculoskeletal manifestations associated with ATTR orthopedic surgery, or idiopathic trigger finger. Patients with
amyloidosis. Buildup of TTR amyloid fibrils has been detected ATTR amyloidosis may experience musculoskeletal signs and
in tissue-resulting musculoskeletal manifestations, such as carpal symptoms years prior to cardiac or neurologic manifestations.
tunnel syndrome, spinal stenosis, distal biceps tendon rupture, ATTR​ amyloid transthyretin; TTR​ transthyretin

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amyloidosis [53]. Carpal tunnel syndrome, the most common Orthopedic surgery is significantly more common
non-cardiac manifestation in patients with ATTR-CM, often in patients with ATTR-CM compared with the general
presents years before a diagnosis of ATTRwt or ATTRv population [57]. Arthroplasty typically occurs over 6
amyloidosis [4, 15, 37, 51, 54]. Carpal tunnel syndrome is to 8 years before diagnosis of ATTR amyloidosis [57].
caused by median nerve compression resulting in numbness, One study found that 25.9% (28/108) and 18.8% (12/64)
tingling sensations, or hand weakness. A recent study found of patients with ATTRwt and ATTRv amyloidosis with
that 10.2% of patients with bilateral carpal tunnel syndrome cardiomyopathy, respectively, underwent hip or knee
tested positive for amyloid deposits [6]. Of the 10 patients arthroplasty [57]. In addition, rotator cuff repair occurred
identified in the study, five were diagnosed with ATTRwt in 9.9% of patients with ATTR amyloidosis [53, 57].
amyloidosis and two with ATTRv amyloidosis, and several A history of a constellation of these musculoskeletal
also had a clinical history of trigger finger, lumbar spinal syndromes and surgeries in a patient along with cardiac or
stenosis, or biceps tendon rupture [6]. Trigger finger due to neurologic symptoms should raise clinical suspicion and
amyloidosis is thought to occur when amyloid fibrils deposit prompt physicians to screen for ATTR amyloidosis [7].
in connective tissue, causing restricted movement of the flexor
tendon, which then results in the finger being stuck in a bent
position. The coexistence of trigger finger and carpal tunnel Implementation of screening for ATTR
syndrome was also reported in members of a Japanese family amyloidosis in clinical practice
with ATTRv amyloidosis [8]. In addition, a clinical history of
lumbar spinal stenosis has been reported by several studies in Cardiologists should screen for ATTR amyloidosis in patients
patients with ATTRwt and ATTRv amyloidosis [5, 6, 53, 55]. with clinical signs and symptoms suggestive of multisystem
Similarly, rupture of the distal biceps tendon (also known as involvement, particularly those with the constellation of
Popeye sign) can be an early sign of amyloidosis; in patients cardiac, neurologic, and musculoskeletal manifestations
aged >50 years, Popeye sign should raise suspicion of ATTR described in this review. Given the multisystemic nature
amyloidosis [56]. of ATTR amyloidosis, a multidisciplinary approach to

Fig. 4  Constellation of symptoms checklist for cardiac ATTR amy- neuropathy or autonomic dysfunction. Clustering of these clinical
loidosis. Healthcare practitioners should evaluate patients with heart signs and symptoms should prompt screening for cardiac amyloido-
failure with preserved ejection fraction for a clinical history of car- sis and trigger referral to a multidisciplinary team at an amyloidosis
pal tunnel syndrome or lumbar spinal stenosis, along with progressive expert center. ATTR​amyloid transthyretin

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Heart Failure Reviews (2022) 27:785–793 791

assessment, diagnosis, and management of patients is included in the article’s Creative Commons licence and your intended
recommended by the guidelines [24, 28]. The assessment of use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
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invasive procedures, as described elsewhere [28, 30, 58, 59]. org/licen​ses/by/4.0/.
It can be challenging to identify ATTR amyloidosis given
the diversity of diagnostic clues that can manifest in a patient
over time (across many years). As cardiac amyloidosis is
present in 10% to 15% of patients with heart failure with References
preserved ejection fraction [27, 33, 58, 60], the addition of
screening questions and a check of multiple symptoms could 1. Costa PP, Figueira AS, Bravo FR (1978) Amyloid fibril protein
help to identify patients with ATTR amyloidosis (Fig. 4). related to prealbumin in familial amyloidotic polyneuropathy. Proc
Natl Acad Sci USA 75:4499–4503
2. Saraiva MJ, Birken S, Costa PP, Goodman DS (1984) Amyloid
fibril protein in familial amyloidotic polyneuropathy, Portuguese
type. Definition of molecular abnormality in transthyretin
Conclusion (prealbumin). J Clin Invest 74:104–119
3. Conceicao I, Gonzalez-Duarte A, Obici L, Schmidt HH, Simoneau
Awareness of the non-cardiac symptoms that cluster with D, Ong ML, Amass L (2016) “Red-flag” symptom clusters in
cardiac and neurologic symptoms can unmask a diagnosis transthyretin familial amyloid polyneuropathy. J Peripher Nerv
Syst 21:5–9
of ATTR amyloidosis and prompt referral to a center with 4. Nakagawa M, Sekijima Y, Yazaki M, Tojo K, Yoshinaga T,
expertise in this disease (Fig. 4) [3, 24, 28]. Because ATTR Doden T, Koyama J, Yanagisawa S, Ikeda S (2016) Carpal tunnel
amyloidosis is now a treatable disease, recognizing the syndrome: a common initial symptom of systemic wild-type
constellation of associated signs and symptoms, including those ATTR (ATTRwt) amyloidosis. Amyloid 23:58–63
5. Ikram A, Donnelly JP, Sperry BW, Samaras C, Valent J, Hanna M
that are neurologic and musculoskeletal, is important because (2018) Diflunisal tolerability in transthyretin cardiac amyloidosis:
early treatment will make a meaningful impact on a patient’s a single center’s experience. Amyloid 25:197–202
quality of life, autonomy, and physical function [9–13]. 6. Sperry BW, Reyes BA, Ikram A, Donnelly JP, Phelan D, Jaber
WA, Shapiro D, Evans PJ, Maschke S, Kilpatrick SE, Tan CD,
Acknowledgements Medical writing support was provided by Rodriguez ER, Monteiro C, Tang WHW, Kelly JW, Seitz WH
Monique N. O’Leary, PhD, of ApotheCom (San Francisco, CA, USA). Jr, Hanna M (2018) Tenosynovial and cardiac amyloidosis in
patients undergoing carpal tunnel release. J Am Coll Cardiol
72:2040–2050
Author contribution All the authors met the International Committee
7. Donnelly JP, Hanna M, Sperry BW, Seitz WH Jr (2019) Carpal
of Medical Journal Editors (ICMJE) criteria for authorship for this
tunnel syndrome: a potential early, red-flag sign of amyloidosis. J
manuscript and take responsibility for the integrity of the work as
Hand Surg Am 44:868–876
a whole. All the authors contributed substantial intellectual content
8. Uotani K, Kawata A, Nagao M, Mizutani T, Hayashi H (2007)
to drafts of the manuscript and have read and approved the final
Trigger finger as an initial manifestation of familial amyloid
manuscript.
polyneuropathy in a patient with Ile107Val TTR. Intern Med
46:501–504
Funding Medical writing support was funded by Akcea Therapeutics. 9. Coelho T, Yarlas A, Waddington-Cruz M, White MK, Sikora
Kessler A, Lovley A, Pollock M, Guthrie S, Ackermann EJ, Hughes
Declarations SG, Karam C, Khella S, Gertz M, Merlini G, Obici L, Schmidt HH,
Polydefkis M, Dyck PJB, Brannagan Iii TH, Conceicao I, Benson
MD, Berk JL (2019) Inotersen preserves or improves quality of life
Conflict of interest Jose N. Nativi-Nicolau reports funding for clinical
in hereditary transthyretin amyloidosis. J Neurol 267:1070–1079
trials from Pfizer, Akcea Therapeutics, and Eidos; educational grants
10. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda
from Pfizer; and consulting fees from Pfizer, Eidos, Akcea Therapeutics,
M, Kristen AV, Tournev I, Schmidt HH, Coelho T, Berk JL,
and Alnylam. Chafic Karam reports consulting/educational activities for
Lin KP, Vita G, Attarian S, Plante-Bordeneuve V, Mezei MM,
Akcea Therapeutics, Alexion, Alnylam, Argenx, Biogen, CSL Behring,
Campistol JM, Buades J, Brannagan TH 3rd, Kim BJ, Oh J,
Medscape, and Sanofi Genzyme; and has received research grants
Parman Y, Sekijima Y, Hawkins PN, Solomon SD, Polydefkis
from Sanofi Genzyme and Akcea Therapeutics. Sami Khella reports
M, Dyck PJ, Gandhi PJ, Goyal S, Chen J, Strahs AL, Nochur
honoraria from Akcea Therapeutics and Alnylam. Mathew S. Maurer
SV, Sweetser MT, Garg PP, Vaishnaw AK, Gollob JA, Suhr OB
reports grants from Pfizer and Alnylam; and personal fees from Pfizer,
(2018) Patisiran, an RNAi therapeutic, for hereditary transthyretin
Eidos, GlaxoSmithKline, Prothena, Akcea Therapeutics, and Ionis.
amyloidosis. N Engl J Med 379:11–21
11. Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck
Open Access This article is licensed under a Creative Commons PJ, Wang AK, Plante-Bordeneuve V, Barroso FA, Merlini G,
Attribution 4.0 International License, which permits use, sharing, Obici L, Scheinberg M, Brannagan TH 3rd, Litchy WJ, Whelan C,
adaptation, distribution and reproduction in any medium or format, Drachman BM, Adams D, Heitner SB, Conceicao I, Schmidt HH,
as long as you give appropriate credit to the original author(s) and the Vita G, Campistol JM, Gamez J, Gorevic PD, Gane E, Shah AM,
source, provide a link to the Creative Commons licence, and indicate Solomon SD, Monia BP, Hughes SG, Kwoh TJ, McEvoy BW,
if changes were made. The images or other third party material in this Jung SW, Baker BF, Ackermann EJ, Gertz MA, Coelho T (2018)
article are included in the article’s Creative Commons licence, unless Inotersen treatment for patients with hereditary transthyretin
indicated otherwise in a credit line to the material. If material is not amyloidosis. N Engl J Med 379:22–31

13
792 Heart Failure Reviews (2022) 27:785–793

12. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, 26. Karam C, Dimitrova D, Heitner SB (2019) Misdiagnosis of
Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, hATTR amyloidosis: a single US site experience. Amyloid
Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber 27:69–70
P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, 27. Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G, de
Rapezzi C (2018) Tafamidis treatment for patients with transthyretin Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B,
amyloid cardiomyopathy. N Engl J Med 379:1007–1016 Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P (2015)
13. Obici L, Berk JL, Gonzalez-Duarte A, Coelho T, Gillmore J, Schmidt Wild-type transthyretin amyloidosis as a cause of heart failure
HH, Schilling M, Yamashita T, Labeyrie C, Brannagan TH 3rd, with preserved ejection fraction. Eur Heart J 36:2585–2594
Ajroud-Driss S, Gorevic P, Kristen AV, Franklin J, Chen J, Sweetser 28. Maurer MS, Bokhari S, Damy T, Dorbala S, Drachman BM,
MT, Wang JJ, Adams D (2020) Quality of life outcomes in APOLLO, Fontana M, Grogan M, Kristen AV, Lousada I, Nativi-Nicolau
the phase 3 trial of the RNAi therapeutic patisiran in patients with J, Cristina Quarta C, Rapezzi C, Ruberg FL, Witteles R, Merlini
hereditary transthyretin-mediated amyloidosis. Amyloid 27:1–10 G (2019) Expert consensus recommendations for the suspicion
14. Coelho T, Maurer MS, Suhr OB (2013) THAOS - The and diagnosis of transthyretin cardiac amyloidosis. Circ Heart
Transthyretin Amyloidosis Outcomes Survey: initial report on Fail 12:e006075
clinical manifestations in patients with hereditary and wild-type 29. Narotsky DL, Castano A, Weinsaft JW, Bokhari S, Maurer
transthyretin amyloidosis. Curr Med Res Opin 29:63–76 MS (2016) Wild-type transthyretin cardiac amyloidosis: novel
15. Maurer MS, Hanna M, Grogan M, Dispenzieri A, Witteles R, insights from advanced imaging. Can J Cardiol 32:1166.
Drachman B, Judge DP, Lenihan DJ, Gottlieb SS, Shah SJ, e1-1166.e10
Steidley DE, Ventura H, Murali S, Silver MA, Jacoby D, Fedson S, 30. Gertz M, Adams D, Ando Y, Beirão JM, Bokhari S, Coelho T,
Hummel SL, Kristen AV, Damy T, Plante-Bordeneuve V, Coelho Comenzo RL, Damy T, Dorbala S, Drachman BM, Fontana M,
T, Mundayat R, Suhr OB, Waddington CM, Rapezzi C (2016) Gillmore JD, Grogan M, Hawkins PN, Lousada I, Kristen AV,
Genotype and phenotype of transthyretin cardiac amyloidosis: Ruberg FL, Suhr OB, Maurer MS, Nativi-Nicolau J, Quarta CC,
THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Rapezzi C, Witteles R, Merlini G (2020) Avoiding misdiagnosis:
Cardiol 68:161–172 expert consensus recommendations for the suspicion and
16. Ruberg FL, Berk JL (2012) Transthyretin (TTR) cardiac diagnosis of transthyretin amyloidosis for the general practitioner.
amyloidosis. Circulation 126:1286–1300 BMC Fam Pract 21:198
17. Rapezzi C, Quarta CC, Obici L, Perfetto F, Longhi S, Salvi F, 31. Lousada I, Maurer M, Warner M, Guthrie S, Hsu K, M. G, (2017)
Biagini E, Lorenzini M, Grigioni F, Leone O, Cappelli F, Palladini Amyloidosis research consortium cardiac amyloidosis survey:
G, Rimessi P, Ferlini A, Arpesella G, Pinna AD, Merlini G, Perlini results from patients with ATTR amyloidosis and their caregivers.
S (2013) Disease profile and differential diagnosis of hereditary Orphanet J Rare Dis 12(Suppl 1):165
transthyretin-related amyloidosis with exclusively cardiac 32. Damy T, Costes B, Hagege AA, Donal E, Eicher JC, Slama
phenotype: an Italian perspective. Eur Heart J 34:520–528 M, Guellich A, Rappeneau S, Gueffet JP, Logeart D, Plante-
18. Rowczenio DM, Noor I, Gillmore JD, Lachmann HJ, Whelan C, Bordeneuve V, Bouvaist H, Huttin O, Mulak G, Dubois-Rande JL,
Hawkins PN, Obici L, Westermark P, Grateau G, Wechalekar AD Goossens M, Canoui-Poitrine F, Buxbaum JN (2016) Prevalence
(2014) Online registry for mutations in hereditary amyloidosis and clinical phenotype of hereditary transthyretin amyloid
including nomenclature recommendations. Hum Mutat cardiomyopathy in patients with increased left ventricular wall
35:E2403–E2412 thickness. Eur Heart J 37:1826–1834
19. Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, 33. Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M,
Lewis WD, Obici L, Plante-Bordeneuve V, Rapezzi C, Said Kim AY, Falk RH, Cheung KN, Patel AR, Pano A, Packman J,
G, Salvi F (2013) Guideline of transthyretin-related hereditary Grogan DR (2012) Prospective evaluation of the morbidity and
amyloidosis for clinicians. Orphanet J Rare Dis 8:31 mortality of wild-type and V122I mutant transthyretin amyloid
20. Schmidt M, Wiese S, Adak V, Engler J, Agarwal S, Fritz G, cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study
Westermark P, Zacharias M, Fandrich M (2019) Cryo-EM (TRACS). Am Heart J 164:222-228.e221
structure of a transthyretin-derived amyloid fibril from a patient 34. Benson MD, Teague SD, Kovacs R, Feigenbaum H, Jung
with hereditary ATTR amyloidosis. Nat Commun 10:5008 J, Kincaid JC (2011) Rate of progression of transthyretin
21. Schonhoft JD, Monteiro C, Plate L, Eisele YS, Kelly JM, Boland amyloidosis. Am J Cardiol 108:285–289
D, Parker CG, Cravatt BF, Teruya S, Helmke S, Maurer M, Berk 35. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS (2016)
J, Sekijima Y, Novais M, Coelho T, Powers ET, Kelly JW (2017) Transthyretin cardiac amyloidosis in older Americans. J Card Fail
Peptide probes detect misfolded transthyretin oligomers in plasma 22:996–1003
of hereditary amyloidosis patients. Sci Transl Med 9:eaam7621 36. Castano A, Drachman BM, Judge D, Maurer MS (2015) Natural
22. Lane T, Bangova A, Fontana M, Hutt DF, Strehina SG, Whelan history and therapy of TTR-cardiac amyloidosis: emerging
CJ, Hawkins PN (2015) Quality of life in ATTR amyloidosis. disease-modifying therapies from organ transplantation to
Orphanet J Rare Dis 10(Suppl 1):026 stabilizer and silencer drugs. Heart Fail Rev 20:163–178
23. Lousada I, Comenzo RL, Landau H, Guthrie S, Merlini G 37. Connors LH, Sam F, Skinner M, Salinaro F, Sun F, Ruberg FL,
(2015) Patient experience with hereditary and senile systemic Berk JL, Seldin DC (2016) Heart failure resulting from age-related
amyloidoses: a survey from the Amyloidosis Research cardiac amyloid disease associated with wild-type transthyretin: a
Consortium. Orphanet J Rare Dis 10(Suppl 1):P22 prospective, observational cohort study. Circulation 133:282–290
24. Adams D, Ando Y, Beirao JM, Coelho T, Gertz MA, Gillmore 38. Mohammed SF, Mirzoyev SA, Edwards WD, Dogan A, Grogan
JD, Hawkins PN, Lousada I, Suhr OB, Merlini G (2020) Expert DR, Dunlay SM, Roger VL, Gertz MA, Dispenzieri A, Zeldenrust
consensus recommendations to improve diagnosis of ATTR SR, Redfield MM (2014) Left ventricular amyloid deposition in
amyloidosis with polyneuropathy. J Neurol. Online ahead of print patients with heart failure and preserved ejection fraction. JACC
25. Cortese A, Vegezzi E, Lozza A, Alfonsi E, Montini A, Moglia Heart Fail 2:113–122
A, Merlini G, Obici L (2017) Diagnostic challenges in hereditary 39. Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine
transthyretin amyloidosis with polyneuropathy: avoiding NM, Gospodinova M, Obici L, Rapezzi C, Garcia-Pavia P (2019)
misdiagnosis of a treatable hereditary neuropathy. J Neurol Screening for transthyretin amyloid cardiomyopathy in everyday
Neurosurg Psychiatry 88:457–458 practice. JACC Heart Fail 7:709–716

13
Heart Failure Reviews (2022) 27:785–793 793

40. Lozeron P, Mariani LL, Dodet P, Beaudonnet G, Theaudin M, 54. Pinney JH, Whelan CJ, Petrie A, Dungu J, Banypersad SM,
Adam C, Arnulf B, Adams D (2018) Transthyretin amyloid Sattianayagam P, Wechalekar A, Gibbs SD, Venner CP, Wassef N,
polyneuropathies mimicking a demyelinating polyneuropathy. McCarthy CA, Gilbertson JA, Rowczenio D, Hawkins PN, Gillmore
Neurology 91:e143–e152 JD, Lachmann HJ (2013) Senile systemic amyloidosis: clinical
41. Dyck PJ, Lambert EH (1969) Dissociated sensation in amylidosis. features at presentation and outcome. J Am Heart Assoc 2:e000098
Compound action potential, quantitative histologic and teased- 55. Yanagisawa A, Ueda M, Sueyoshi T, Okada T, Fujimoto T, Ogi Y,
fiber, and electron microscopic studies of sural nerve biopsies. Kitagawa K, Tasaki M, Misumi Y, Oshima T, Jono H, Obayashi K,
Arch Neurol 20:490–507 Hirakawa K, Uchida H, Westermark P, Ando Y, Mizuta H (2015)
42. Kim DH, Zeldenrust SR, Low PA, Dyck PJ (2009) Quantitative Amyloid deposits derived from transthyretin in the ligamentum
sensation and autonomic test abnormalities in transthyretin flavum as related to lumbar spinal canal stenosis. Mod Pathol
amyloidosis polyneuropathy. Muscle Nerve 40:363–370 28:201–207
43. Coelho T, Vinik A, Vinik EJ, Tripp T, Packman J, Grogan DR 56. Geller HI, Singh A, Alexander KM, Mirto TM, Falk RH (2017)
(2017) Clinical measures in transthyretin familial amyloid Association between ruptured distal biceps tendon and wild-type
polyneuropathy. Muscle Nerve 55:323–332 transthyretin cardiac amyloidosis. JAMA 318:962–963
44. Carr AS, Pelayo-Negro AL, Evans MR, Laura M, Blake J, 57. Rubin J, Alvarez J, Teruya S, Castano A, Lehman RA,
Stancanelli C, Iodice V, Wechalekar AD, Whelan CJ, Gillmore Weidenbaum M, Geller JA, Helmke S, Maurer MS (2017) Hip and
JD, Hawkins PN, Reilly MM (2016) A study of the neuropathy knee arthroplasty are common among patients with transthyretin
associated with transthyretin amyloidosis (ATTR) in the UK. J cardiac amyloidosis, occurring years before cardiac amyloid
Neurol Neurosurg Psychiatry 87:620–627 diagnosis: can we identify affected patients earlier? Amyloid
45. Adams D (2013) Recent advances in the treatment of familial 24:226–230
amyloid polyneuropathy. Ther Adv Neurol Disord 6:129–139 58. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS (2019)
46. Gonzalez-Duarte A (2019) Autonomic involvement in hereditary Transthyretin amyloid cardiomyopathy: JACC state-of-the-art
transthyretin amyloidosis (hATTR amyloidosis). Clin Auton Res review. J Am Coll Cardiol 73:2872–2891
29:245–251 59. Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer
47. Benson MD, Kincaid JC (2007) The molecular biology and RP, Chang PP, Eisen HJ, Nair AP, Nativi-Nicolau J, Ruberg FL
clinical features of amyloid neuropathy. Muscle Nerve 36:411–423 (2020) Cardiac amyloidosis: evolving diagnosis and management:
48. Abramov D, Weimer LH, Marboe CC, Shimbo D, King DL, a scientific statement from the American Heart Association.
Maurer MS (2009) Absence of heart failure in severe cardiac Circulation 142:e7–e22
and autonomic amyloidosis: the essential role of sympathetic 60. Senapati A, Sper r y BW, Grodin JL, Kusunose K,
activation and venous tone in the development of the congestive Thavendiranathan P, Jaber W, Collier P, Hanna M, Popovic ZB,
heart failure syndrome. Congest Heart Fail 15:288–290 Phelan D (2016) Prognostic implication of relative regional strain
49. Wixner J, Mundayat R, Karayal ON, Anan I, Karling P, Suhr OB, ratio in cardiac amyloidosis. Heart 102:748–754
investigators T, (2014) THAOS: gastrointestinal manifestations 61. Koike H, Tanaka F, Hashimoto R, Tomita M, Kawagashira Y,
of transthyretin amyloidosis - common complications of a rare Iijima M, Fujitake J, Kawanami T, Kato T, Yamamoto M, Sobue G
disease. Orphanet J Rare Dis 9:61 (2012) Natural history of transthyretin Val30Met familial amyloid
50. Mazzeo A, Russo M, Di Bella G, Minutoli F, Stancanelli C, polyneuropathy: analysis of late-onset cases from non-endemic
Gentile L, Baldari S, Carerj S, Toscano A, Vita G (2015) areas. J Neurol Neurosurg Psychiatry 83:152–158
Transthyretin-related familial amyloid polyneuropathy (TTR- 62. Yarlas A, Gertz MA, Dasgupta NR, Obici L, Pollock M,
FAP): a single-center experience in Sicily, an Italian endemic Ackermann EJ, Lovley A, Kessler AS, Patel PA, White MK,
area. J Neuromuscul Dis 2:S39–S48 Guthrie SD (2019) Burden of hereditary transthyretin amyloidosis
51. Papoutsidakis N, Miller EJ, Rodonski A, Jacoby D (2018) on quality of life. Muscle Nerve 60:169–175
Time course of common clinical manifestations in patients with 63. Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL
transthyretin cardiac amyloidosis: delay from symptom onset to (2012) Diabetic neuropathy: clinical manifestations and current
diagnosis. J Card Fail 24:131–133 treatments. Lancet Neurol 11:521–534
52. Sekijima Y, Uchiyama S, Tojo K, Sano K, Shimizu Y, Imaeda 64. Yang H, Sloan G, Ye Y, Wang S, Duan B, Tesfaye S, Gao L (2020)
T, Hoshii Y, Kato H, Ikeda S (2011) High prevalence of wild- New perspective in diabetic neuropathy: from the periphery to
type transthyretin deposition in patients with idiopathic carpal the brain, a call for early detection, and precision medicine. Front
tunnel syndrome: a common cause of carpal tunnel syndrome in Endocrinol (Lausanne) 10:929
the elderly. Hum Pathol 42:1785–1791
53. Sueyoshi T, Ueda M, Jono H, Irie H, Sei A, Ide J, Ando Y, Mizuta Publisher’s Note Springer Nature remains neutral with regard to
H (2011) Wild-type transthyretin-derived amyloidosis in various jurisdictional claims in published maps and institutional affiliations.
ligaments and tendons. Hum Pathol 42:1259–1264

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