ESC：心脏淀粉样变的诊断和治疗的立场声明（2021）

Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

Pablo Garcia-Pavia 1 ,2,3 \* , Claudio Rapezzi 4,5 , Yehuda Adler 6 , Michael Arad 7 , Cristina Basso 3,8 , Antonio Brucato 9 , Ivana Burazor 1 0 , Alida L.P. Caforio 3, 11 , Thibaud Damy 1 2 , Urs Eriksson 1 3 , Marianna Fontana 1 4 , Julian D. Gillmore 1 4 , Esther Gonzalez-Lopez 1 ,3 , Martha Grogan 1 5 , Stephane Heymans 1 6, 1 7, 1 8 , Massimo Imazio 1 9 , Ingrid Kindermann 20 , Arnt V. Kristen 2 1 ,22 , Mathew S. Maurer 23 , Giampaolo Merlini 24,25 , Antonis Pantazis 26 , Sabine Pankuweit 27 , Angelos G. Rigopoulos 28 , and Ales Linhart 29

1 Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, CIBERCV, Madrid, Spain; 2 Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcon, Spain; 3 European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart; 4 Cardiologic Centre, University of Ferrara, Ferrara, Italy; 5 Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy; 6 Leviev Heart Centre, Chaim Sheba Medical Centre (affiliated to Tel Aviv University), Ramat Gan, Israel; 7 Heart Failure Institute, Leviev Heart Centre, Sheba Hospital and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 8 Cardiovascular Pathology Unit, University Hospital, and Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padua, Padua, Italy; 9 Department of Biomedical and Clinical Sciences, University of Milan, Fatebenefratelli Hospital, Milan, Italy; 1 0 Belgrade University School of Medicine, Cardiology, Institute for Rehabilitation, Belgrade, Serbia; 11 Cardiology, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padua, Padua, Italy; 1 2 French Referral Centre for Cardiac Amyloidosis, Amyloidosis Mondor Network, GRC Amyloid Research Institute, CHU Henri Mondor, Créteil, France; 1 3 GZO – Zurich Regional Health Centre, Wetzikon & Cardioimmunology, Centre for Molecular Cardiology, University of Zurich, Zurich, Switzerland; 1 4 National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London, UK; 1 5 Cardiac Amyloid Clinic, Division of Circulatory Failure, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA; 1 6 Department of Cardiology, Maastricht University, CARIM School for Cardiovascular Diseases, Maastricht, The Netherlands; 1 7 Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium; 1 8 ICIN-Netherlands Heart Institute, Holland Heart House, Utrecht, The Netherlands; 1 9 University Cardiology, Cardiovascular and Thoracic Department, AOU Città della Salute e della Scienza di Torino, Turin, Italy; 20 Department of Internal Medicine III (Cardiology, Angiology and Intensive Care), Saarland University Medical Centre, Saarland University, Homburg, Germany; 2 1 Department of Cardiology, University of Heidelberg, Heidelberg, Germany; 22 Cardiovascular Centre Darmstadt, Heidelberg, Germany; 23 Cardiac Amyloidosis Program, Centre for Advanced Cardiac Care, Columbia University Irving Medical Centre, New York Presbyterian Hospital, New York, NY, USA; 24 Amyloidosis Research and Treatment Centre, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 25 Department of Molecular Medicine, University of Pavia, Pavia, Italy; 26 Cardiomyopathy Service, Royal Brompton Hospital, London, UK; 27 Department of Cardiology, Philipps-University Marburg, Marburg, Germany; 28 Mid-German Heart Centre, Department of Internal Medicine III, Division of Cardiology, Angiology and Intensive Medical Care, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany; and 29 2nd Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

Received 1 9 February 202 1 ; accepted 1 9 February 202 1

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

\*Corresponding author. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla, 2, Madrid 28222, Spain. Email: pablogpavia@yahoo.es

This article has been co-published with permission in European Heart Journal (published by Oxford University Press on behalf of European Society of Cardiology) and European Journal of Heart Failure (published by John Wiley & Sons Ltd on behalf of European Society of Cardiology) These articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.

Graphical Abstract

![Cardiac amyloidosis ESC Myocardial WG position paper SUSPECT DIAGNOSIS TREATMENT Screenif Diagnostic criteria Cardiac complications and comorbidities Invasive Non-Invasive Leftventriclewall [all types] (only for ATTR) HeartFailure thickness ≥ 12 mm Cardiac Biopsy positive for Grade 2 or 3 cardiac uptake at Thromboembolism amyloid diphosponate Scintigraphy Atrialfibrillation Negative serum free light chains & ≥ 1 Red Flag or ExtracardiaBipsypositve imegativesermanurie Conduction disorderias Clinical Scenario Echocardiographic/CMR criteria Aorticstenosis Diagnosticalgorithm Disease modifying treatment Haematologictests 99mTc-DPD/PYP/HMDP (serum free-light chain Scintigraphywith SPECT quantification & serum and ATTR:geneticsilencers, urine immunofixation) eftVentricu stabilizers andremovers. WallThick ≥1of 212mm AL:chemotherapyandASCT. Diagnosismadeorproceedto AA: anti-inflammatory, CMR and/orbiopsy according toresults anti-infective and immunosuppressive drugs. ](https://venus-trag-1258344701.cos-internal.ap-guangzhou.tencentcos.cn/userUpload/is-62e36cd9/2025-04-14/109c1cea-651b-4840-89da-109f96cd5b21/109c1cea-651b-4840-89da-109f96cd5b21.jpg?q-sign-algorithm=sha1&q-ak=AKID61g5D5fy1TjiRv84nEOHtFJ8gyzjCPL0&q-sign-time=1744641230%3B1744644830&q-key-time=1744641230%3B1744644830&q-header-list=host&q-url-param-list=&q-signature=84bdb22df3e60a2a495072f625206be822c51ab5) Diagnosis and treatment of cardiac amyloidosis.

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Introduction

Cardiac amyloidosis is characterized by the extracellular deposition of misfolded proteins in the heart with the pathognomonic histological property of green birefringence when viewed under cross polarized light after staining with Congo red. 1

Although considered a rare disease, recent data suggest that cardiac amyloidosis is underappreciated as a cause of common cardiac diseases or syndromes. 2 Recent advances in cardiac imaging, diagnostic strategies and therapies have improved the recognition and treatment of cardiac amyloidosis. 1 ,2

The aim of this position paper by the European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases is to help cardiologists and other physicians in recognizing, diagnosing and treating patients with cardiac amyloidosis.

still encountered, is now much less frequent. Accordingly, ${\tt>}98\%$ of currently diagnosed cardiac amyloidosis results from fibrils composed of monoclonal immunoglobulin light chains (AL) or transthyretin (ATTR), either in its hereditary (ATTRv) or acquired (ATTRwt) form. Table 1 describes the main characteristics of each type of cardiac amyloidosis.

Definition of cardiac amyloidosis. Diagnostic criteria

Cardiac amyloidosis is diagnosed when amyloid fibrils are found within cardiac tissue. Both invasive and non-invasive diagnostic criteria have been proposed. Invasive diagnostic criteria apply to all forms of cardiac amyloidosis whereas non-invasive criteria are accepted only for ATTR ( Figure 1 ).

## Definitions and classifications

## Types of cardiac amyloidosis

While more than 30 proteins are known to be capable of aggregating as amyloid in vivo , only nine amyloidogenic proteins accumulate in the myocardium to cause significant cardiac disease. 3

Nevertheless, some forms (AApoAI, AApoAII, AApoAIV, A β 2M, AFib, AGel) are very rare and cardiac amyloidosis secondary to chronic inflammatory and infectious diseases (AA), although

## Invasive diagnostic criteria

Cardiac amyloidosis is confirmed when an endomyocardial biopsy demonstrates amyloid deposits after Congo red staining irrespective of the degree of left ventricular (LV) wall thickness. Identification of amyloid should be followed by classification of the amyloid fibril protein. Although the gold standard for defining the type of amyloid remains mass spectrometry, immunohistochemistry or immunoelectron microscopy are routinely employed for amyloid typing in specialized centres. 4

Table 1 Amyloidosis subtypes that affect the heart

| Amyloidosis type |Protein|Hereditary| Frequency ofheart involvement | Median survival from diagnosis (months) |Usual extracardiac signs| |---|---|---|---|---|---| ||||||| |L| Immunoglobulin light chain |70|70%|24|Nephropathy, proteinuria, autonomic| |||||6 (if HF at diagnosis and |dysfunction, polyneuropathy, macroglossia,| |ATTRwt|Transthyretin|¥70|100%| not treated) S√ | spontaneous bruising, liver involvement| |ATTRv||yes|30-100%|31 (Val142lle)|CTS, LSS, ruptured biceps tendon | ||Transthyretin|||69 (non-Val142lle)| Polyneuropathy, orthostatic hypotension, vitreous opacities, gastrointestinal problems | || Serum amyloid A|¥70| Depending on the mutation ¥5% |133|Renal impairment (95%), proteinuria,| ||||||| |AFib|Fibrinogen α|Yes|Rare|180| hepatomegaly, gastrointestinal problems Renal impairment, proteinuria | |AAPOAI|Apolipoprotein A-l|yes|Rare|No data.|Primarily renal impairment, proteinuria,| |||| Depending on the mutation|Probably >120|hepatosplenomegaly, adrenal insufficiency,| || Apolipoprotein A-ll |Yes|Rare||dysphonia due to laryngeal involvement | |AAPOAlI|||Depending on the mutation|No data| Primarily renal impairment, proteinuria | |AAPOAIV|Apolipoprotein A-IV|¥70|Unknown|| Primarily renal impairment | |AB2M|β2-microglobulin|¥70|80%|No data|Long-term dialysis, CTS, joint problems | |AGel|Gelsolin|yes|5%6|Near-normal life| Corneal lattice dystrophy, cutis laxa, droping| |||| Primarily conduction disease|expectancy|eyelids, paraesthesia, proteinuria (rare)|

AA, serum amyloid A amyloidosis; AApoAI, apolipoprotein A-I amyloidosis; AApoAII, apolipoprotein A-II amyloidosis; AApoAIV, apolipoprotein A-IV amyloidosis; A β 2M, β 2-microglobulin amyloidosis; AFib, fibrinogen amyloidosis; AGel, gelsolin amyloidosis; AL, light-chain amyloidosis; ATTRv, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CTS, carpal tunnel syndrome; HF, heart failure; LSS, lumbar spinal stenosis.

 Figure 1 Invasive and non-invasive diagnosis of cardiac amyloidosis. ATTR, transthyretin amyloidosis; CMR, cardiac magnetic resonance; SPIE, serum protein electrophoresis with immunofixation; UPIE, urine protein electrophoresis with immunofixation.

Diagnosis is also confirmed if amyloid deposits within an extracardiac biopsy are accompanied either by characteristic features of cardiac amyloidosis by echocardiography, in the absence of an alternative cause for increased LV wall thickness, or by characteristic features on cardiac magnetic resonance (CMR) ( Table 2 ).

A recent multicentre study has proposed an echocardiographic score to facilitate echocardiographic diagnosis of AL or ATTR Although not yet externally validated, a score amyloidosis in the presence of increased LV wall thickness. ${\tt\ge}8$ points in the 5 presence of LV wall thickness ${\tt\ge}12\,\mathsf{m m}$ in combination with amyloid deposits in an extra-cardiac biopsy could also be considered diagnostic of cardiac amyloidosis ( Table 2 ).

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Non-invasive diagnostic criteria

Cardiac ATTR amyloidosis can be diagnosed in the absence of histology in the setting of typical echocardiographic/ CMR findings when 99m Tc-pyrophosphate (PYP), 99m Tc-3, 3-diphosphono- 1 ,2-propanodicarboxylic acid (DPD) or 99m Tc-hydroxymethylene diphosphonate (HMDP) scintigraphy shows grade 2 or 3 myocardial uptake of radiotracer ( Figure 2 ) and clonal dyscrasia is excluded by all the following tests: serum free light chain (FLC) assay, serum (SPIE) and urine (UPIE) protein electrophoresis with immunofixation. 6 The combination of SPIE, UPIE and quantification of serum FLC has a sensitivity of $99\%$ for identifying abnormal pro-amyloidotic precursor in AL

Table 2 Echocardiographic and cardiac magnetic resonance criteria for non-invasive and invasive (with extracardiac biopsy-proven amyloidosis) diagnosis of cardiac amyloidosis

Echocardiography

Unexplained LV thickness $(\geq\!12\,\mathsf{m m})$ ) plus 1 or 2:

1 . Characteristic echocardiography findings $(\geq2$ of a, b and c have to be present): a. Grade 2 or worse diastolic dysfunction b. Reduced tissue Doppler $\pmb{\mathscr{s}}^{\prime}$ , ${\bf{e}^{\prime}}$ , and ${\mathsf{a}}^{\prime}$ wave velocities $(<\!5\;{\mathsf{c m}}/{\mathsf{s}})$ c. Decreased LV global longitudinal strain (absolute value $<-15\%$ ). 2. Multiparametric echocardiographic score $\geq\!8$ points: a. Relative LV wall thickness (IVS + PWT)/LVEDD ${\tt>}0.6$ 3 points b. Doppler E wave/e ′ wave velocities ${>}11$ 1 point c. TAPSE ≤ 1 9 mm 2 points d. LV global longitudinal strain absolute value $\leq-13\%$ 1 point e. Systolic longitudinal strain apex to base ratio $>2.9$ 3 points

CMR

Characteristic CMR findings (a and b have to be present):

a. Diffuse subendocardial or transmural LGE b. Abnormal gadolinium kinetics a c. $\mathsf{E C V}\geq0.40\%$ (strongly supportive, but not essential/diagnostic)

CMR, cardiac magnetic resonance; ECV, extracellular cardiac volume; IVS, interventricular septum; LGE, late gadolinium enhancement; LV, left ventricular; LVEDD, left ventricular end-diastolic diameter; PWT, posterior wall thickness; TAPSE, tricuspid annular plane systolic excursion.

a Abnormal gadolinium kinetics: myocardial nulling preceding or coinciding with the blood pool.

normal in patients with CKD. No reference values are available according to the severity of CKD, but in patients with moderate CKD (estimated GFR ${<\!45\,\mathsf{m L}/\mathsf{m i n}}/1.73\,\mathsf{m}^{2}$ by CKD-EPI formula) in the setting of a normal SPIE/UPIE, a FLC ratio up to 2.0 (or 3. 1 if in dialysis) can typically be considered normal ( Table 3 ). Otherwise, consultation with a haematologist is warranted.

amyloidosis. 7 It is important to stress that serum and urine protein electrophoresis should always be performed with immunofixation to increase the sensitivity of the assays for detecting monoclonal proteins ( Table 3 ). Interpretation of low-level monoclonal protein or mild elevations in the kappa:lambda ratio (FLC ratio) could be challenging. These findings can be encountered in patients with chronic kidney disease (CKD) or with monoclonal gammopathy of undetermined significance (MGUS). In patients with CKD, as the glomerular filtration rate (GFR) declines, the renal clearance of polyclonal FLC decreases and serum concentrations rise. 8 The FLC ratio also varies as the GFR declines, but this depends on the FLC assay available [Freelite assay (Binding Site, Birmingham, UK) or N Latex assay (Siemens, Marburg, Germany)]. 8 With the N Latex assay, the FLC ratio decreases as GFR declines but no reference range in CKD has yet been proposed. By contrast, with the most frequently used Freelite assay, FLC ratio increases as GFR declines and a ratio of 0.37 to 3. 1 has been proposed to be

In the absence of a detectable monoclonal protein and/or an abnormal serum FLC ratio, the specificity of grade 2 or 3 bone scintigraphy for cardiac ATTR when the disease is suspected has been proposed to be almost $100\%$ . 6 Please note, however, that scintigraphy should always include single photon emission computed tomography to confirm that cardiac uptake corresponds to myocardium uptake and not from cardiac chambers ( Table 4 ). Nevertheless, recent reports have shown that rare situations can also lead to positive cardiac uptake. 9 These situations should always be considered when interpreting scintigraphy results ( Table 4 ).

Once cardiac ATTR amyloidosis is confirmed, genetic counselling and testing should be performed to assess for the presence of TTR mutations in order to differentiate between ATTRwt and ATTRv. Genetic testing should be performed even in elderly patients, as a significant number can have TTR mutations. 1 0

Essential concepts

- Although nine types of cardiac amyloidosis are known, AL and ATTR currently account for the vast majority of cardiac amyloidosis. - Both invasive and non-invasive diagnostic criteria are accepted to diagnose cardiac amyloidosis. While invasive diagnostic criteria apply to all forms of cardiac amyloidosis, non-invasive criteria are accepted only for ATTR.

Diagnosis of cardiac amyloidosis

Diagnosis of cardiac amyloidosis includes two critical phases: (i) suspicious phase , and (ii) definite diagnosis phase . The latter phase also includes appropriate typing of the amyloid, which is critical to guide specific treatment.

When to suspect cardiac amyloidosis

Red flags

Cardiac amyloidosis typically appears within a constellation of extracardiac signs and symptoms that are extremely useful to suspect the disease in the presence of compatible cardiac imaging findings. These signs and symptoms are termed ‘red flags’ and include proteinuria (even mild), macroglossia, skin bruises and carpal tunnel syndrome, among others ( Table 5 ). There are also various red flags at the cardiac level, such as heart failure [including disproportionately high N-terminal pro B-type natriuretic peptide (NT-proBNP)] that appears to be in disproportion to ‘objective’ findings on echocardiogram, ‘unexplained’ right heart failure in the

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 Figure 2 Cardiac uptake grading in biphosponate scintigraphy. Grade 0: absence of tracer myocardial uptake and normal bone uptake; Grade 1 : myocardial uptake in a lower degree than at bone level; Grade 2: similar myocardial and bone uptake; Grade 3: myocardial uptake greater than bone with reduced/absent bone uptake.

Table 3 Serum and urine tests to rule out AL amyloidosis

|Testsa| What does it detect? | Most sensitive test for: | Normal range| |---|---|---|---| |SPIE| Clonal immunoglobulin and/or clonal |Confirming clonal immunoglobulin || ||| production|No monoclonal protein present | |UPIE| Clonal immunoglobulin and/or clonal | Confirming clonal light chain|No monoclonal protein present | ||light chain| production|| |Serum free light|Ratio of serum kappa:lambda light chains| Detecting low-level clonal light chain production; clonality assumed if |Freelite: 0.26-1.65b| | chain assay||ratio is far from 1:1|N Latex: 0.53-1.51|

eGFR, estimated glomerular filtration rate; SPIE, serum protein electrophoresis with immunofixation; UPIE, urine protein electrophoresis with immunofixation. a If any of these tests are abnormal, bone scintigraphy should not be used to establish the diagnosis of transthyretin amyloidosis. b subjects with eGFR In patients with kidney disease, mild elevations in the kappa:lambda ratio are frequently encountered. In the setting of a normal SPIE/UPIE, a kappa:lambda ratio up to 2.0 in ${\leq}45\,\mathsf{m L/m i n/1.73\,m^{2}}$ (up to 3. 1 if in dialysis) can typically be considered normal. This correction is not applicable to Siemens N Latex assay.

presence of ostensibly ‘normal’ ventricular and valvular function, or ‘idiopathic’ pericardial effusion. Persistent troponin elevation, disproportionally low QRS voltage or early conduction system disease are also signs that could evoke cardiac amyloidosis ( Table 5 ).

Clinical scenarios

In addition to cardiac and extracardiac findings fostering the suspicion, there are several clinical situations in which cardiac amyloidosis should always be considered.

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Cardiac disease in the presence of a typical systemic condition such as plasma cell dyscrasia, nephrotic syndrome, peripheral neuropathy or a chronic systemic inflammatory condition should prompt consideration of amyloidosis, particularly if compatible cardiac imaging findings are present.

Increased wall thickness in a non-dilated left ventricle is a prominent characteristic of cardiac amyloidosis and should trigger further evaluation when found in elderly patients with common cardiac syndromes like heart failure with preserved ejection fraction, hypertrophic cardiomyopathy or severe aortic stenosis,

Table 4 Possible false positives and false negatives of bisphosphonate scintigraphy for detecting transthyretin cardiac amyloidosis

|| Situation| How to suspect and confirm? | |---|---|---| |False positive|AL amyloidosis| Abnormal SPIE, UPIE or serum free light ratio. Requires histologic confirmation. | ||Hydroxychloroquine cardiac toxicity|Interrogation. Requires histologic confirmation.| || AApoAl and AApoAll amyloidosis|Concomitant kidney disease present. Genetic testing.| || ApoAIV amyloidosis|Concomitant kidney disease present. Requires histologic confirmation.| ||Aβ2M amyloidosis|Long-term dialysis (>9 years). Requires histologic confirmation.| ||Blood pool|Cardiac dysfunction could be present. Use SPECT to detect uptake in| |||myocardium. Delay acquisition.| ||Rib fractures,valvular/annular calcifications|Use SPECT to detect uptake in myocardium.| | False negative| Recent myocardial infarction (||

AApoAI, apolipoprotein A-I amyloidosis; AApoAII, apolipoprotein A-II amyloidosis; AApoAIV, apolipoprotein A-IV amyloidosis; A β 2M, β 2-microglobulin amyloidosis; AL, light-chain amyloidosis; ATTRv, hereditary transthyretin amyloidosis; SPIE, serum protein electrophoresis with immunofixation; SPECT, single photon emission computed tomography; UPIE, urine protein electrophoresis with immunofixation.

particularly among those undergoing transcatheter aortic valve replacement. 11 – 1 3

As ATTR has been found in a significant number of patients (up to $7\%$ to $19\%$ ) in the abovementioned clinical scenarios, and with the possibility of non-invasive diagnosis, we recommend ascertainment of cardiac amyloidosis in individuals with increased wall thickness with either heart failure, aortic stenosis or red flag signs/symptoms, particularly if older than 65 years ( Figure 3 ).

Diagnostic algorithm

Once cardiac amyloidosis is suspected, a timely, definitive diagnosis should be obtained as patient outcomes depend largely on early initiation of therapy (particularly in AL).

As the large majority of cases of cardiac amyloidosis are AL and ATTR, we propose a diagnostic algorithm focusing on identifying these subtypes by the initial use of 99m Tc-PYP, DPD or HMDP scintigraphy coupled to assessment for monoclonal proteins by SPIE, UPIE and quantification of serum FLC ( Figure 4 ).

The results of these tests could lead to four scenarios:

1 . Scintigraphy does not show cardiac uptake and assessments for monoclonal proteins are negative . There is a very low probability of cardiac amyloidosis, and ATTR and AL amyloidosis are unlikely. An alternative diagnosis should be considered. Nevertheless, if suspicion persists, consider CMR followed by cardiac or extracardiac biopsy as bone scintigraphy could be negative in some ATTRv mutations (tracer uptake depends on TTR fibril composition) and in rare subtypes of cardiac amyloidosis ( Table 5 ).

2. Scintigraphy shows cardiac uptake and assessments for monoclonal proteins are negative . If cardiac uptake is grade 2 or 3, ATTR cardiac amyloidosis can be diagnosed. Proceed with genetic

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testing to differentiate between ATTRv and ATTRwt forms. In the case that cardiac uptake is grade 1 , non-invasive diagnosis is not possible and histological confirmation of amyloid deposits (could be extracardiac) is required.

3. Scintigraphy does not show cardiac uptake and at least one of the monoclonal protein tests is abnormal . AL amyloidosis has to be ruled out promptly and CMR can be used to confirm cardiac involvement. If CMR findings do not support cardiac amyloidosis, the diagnosis is very unlikely. In the case that CMR findings are supportive or inconclusive, cardiac or extracardiac histological demonstration of amyloid deposits is required to diagnose AL cardiac amyloidosis. Cardiac or other clinically-affected organ biopsy is recommended to avoid time delay to diagnosis and consultation with a haematologist is warranted. 1 4 If CMR cannot be performed promptly, consider performing biopsy directly.

4. Scintigraphy shows cardiac uptake and at least one of the monoclonal protein tests is abnormal . ATTR amyloidosis with concomitant MGUS (or any haematological disorder that produces FLC), AL amyloidosis or coexistence of both AL and ATTR amyloidosis are possible in this scenario. Diagnosis of cardiac amyloidosis in this case requires histology with amyloid typing, usually via endomyocardial biopsy.

Essential concepts

- Cardiac amyloidosis should be considered in patients with increased wall thickness in the presence of cardiac or extracardiac red flags and/or in specific clinical situations.

Table 5 Cardiac and extracardiac amyloidosis red flags

|Extracardiac/cardiac|TyPe|Red flag| Amyloidosis where it is most frequently found | |---|---|---|---| ||||| |Extracardiac|Clinical| Polyneuropathy|ATTRv, AL, AA, AGel| |||Dysautonomia|ATTR, AL| ||| Skin bruising|L| ||| Skin discoloration|AAPOAI| |||Cutis laxa|AGel| |||Macroglossia|L| |||Deafness|ATTRwt| ||| Bilateral carpal tunnel syndrome|ATTRv, ATTRwt| |||Ruptured biceps tendon|ATTRwt| |||Lumbar spinal stenosis|ATTRwt| |||Vitreous deposits|ATTRv| ||| Corneal latice dystrophy|AGel| ||| Family history|ATTRv, AApoAl, AApoAll| ||Laboratory| Renal insufficiency|AL, AA, AApoAl, AApoAll,| |Cardiac|||AApoAIV, Aβ2M, AFib| |Cardiac||Proteinuria|AL, AA, AApoAl, AApoAll, AFib| |Cardiac|Clinical| Hypotension or normotensive if previous |ATTR, AL| |Cardiac|ECG| hypertensive|an| |Cardiac|| Pseudoinfarct pattern Low/decreased QRS voltage to degree of LV thickness |an| |Cardiac||AV conduction disease|ai| |Cardiac|Laboratory| Disproportionally elevated NT-proBNP to degree OfHF |ai| |Cardiac|Laboratory||| |Cardiac|| Persisting elevated troponin levels|ATTR, AL| |Cardiac|Echocardiogram| Granular sparkling of myocardium|ai| |||Increased right ventricular wall thickness |a| |||Increased valve thickness |a| ||| Pericardial effusion|ai| ||| Reduced longitudinal strain with apical sparing |ai| ||CMR| Pattern Subendocardial late gadolinium enhancement |a| ||CMR| Elevated native T1 values |a| ||CMR|Increased extracellular volume|a| ||CMR| Abnormal gadolinium kinetics|a|

AA, serum amyloid A amyloidosis; AApoAI, apolipoprotein A-I amyloidosis; AApoAII, apolipoprotein A-II amyloidosis; AApoAIV, apolipoprotein A-IV amyloidosis; A β 2M, β 2-microglobulin amyloidosis; AFib, fibrinogen amyloidosis; AGel, gelsolin amyloidosis; AL, light-chain amyloidosis; ATTRv, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; AV, atrio-ventricular; CMR, cardiac magnetic resonance; ECG, electrocardiogram; HF, heart failure; LV, left ventricular; NT-proBNP, N-terminal pro B-type natriuretic peptide..

- A diagnostic algorithm based initially on the use of bone scintigraphy coupled to assessment for monoclonal proteins allows appropriate diagnosis in patients with suggestive signs/symptoms.

Outcome and prognosis

Prognosis in cardiac amyloidosis

Although different methods to prognosticate in cardiac amyloidosis have been proposed, the focus has moved to multiparametric biomarker-based prognostic scores, and biomarker-based staging

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systems have been developed for AL and ATTR cardiac amyloidosis ( Table 6 ). 1 5– 1 9

Available scoring systems have been constructed using parameters obtained ‘at presentation’ and provide an initial prognostic stratification. The prognostic impact of any change of the scores during follow-up has not yet been validated, even though recent studies have shown promising results. 20

Progression of cardiac amyloidosis

While there have been multiple studies delineating baseline risk factors associated with adverse outcomes (principally mortality) in AL and ATTR, and data are emerging from the placebo arm of therapeutic trials, 2 1 there is a dearth of published data on longitudinal aspects of disease progression and none that are

 Figure 3 Screening for cardiac amyloidosis. AV, atrio-ventricular; ECG, electrocardiogram; ECV, extracellular volume; LGE, late gadolinium enhancement.

 Figure 4 Diagnostic algorithm for cardiac amyloidosis. ATTR, transthyretin amyloidosis; ATTRv, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; AL, light-chain amyloidosis; CMR, cardiac magnetic resonance; ECG, electrocardiogram; SPECT, single photon emission computed tomography; TTR, transthyretin.

Prognostic staging scores in AL and ATTR amyloidosis Table 6

AL, light-chain amyloidosis; ATTRv, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; BU, Boston University School of Medicine; eGFR, estimated glomerular filtration rate calculated by the Modification of Diet in Renal Disease formula; FLC-diff, difference between involved and uninvolved free light chain; NAC, UK National Amyloidosis Centre; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart

Table 7 Proposed follow-up scheme in cardiac amyloidosis

|| AL | ATTR | |---|---|---| | Patient with cardiac amyloidosis |Every month (during initial haematological treatment):|Every 6 months:| ||· Complete blood count, basic biochemistry,|·ECG| ||NT-proBNP and troponin |● Blood tests including NT-proBNP and troponin| ||· Serum free light chain quantification|●Neurological evaluation (if ATTRv)| ||· Clinical evaluation by Haematology|●6MWD (optional)| ||●Evaluation by Cardiology if clinically indicated|·KCCQ (optional)| ||Every 3-4 months (after completing initial|Every 12 months:| ||haematological treatment):|| ||· Complete blood count, basic biochemistry,|· Echocardiography/CMR| ||NT-proBNP and troponin|●24h Holter ECG| ||· Serum free light chain quantification|· Ophthalmological evaluation (if ATTRv)| ||· Clinical evaluation by Haematology|| ||Every 6 months:|| ||·ECG|| ||● Echocardiography/CMR|| ||● Evaluation by Cardiology|| ||Every 12 months:|| ||·24h Holter ECG|| |ATTRv asymptomatic||Yearly:| |genetic carriersa||·ECG| |||● Blood tests including NT-proBNP and troponin| |||● Echocardiography| |||· Neurological and ophthalmological evaluation| ||| Every 2years: ·Holter ECG | |||Every 3 years or if any of above complementary test| |||is abnormal:| ||| ● Scintigraphy ·CMR |

6MWD, 6-min walking distance; AL, light-chain amyloidosis; ATTR, transthyretin amyloidosis; ATTRv, hereditary transthyretin amyloidosis; CMR, cardiac magnetic resonance; ECG, electrocardiogram; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro B-type natriuretic peptide. a Clinical follow-up to be started 1 0 years before the age of disease onset of affected relatives or predicted usual onset age for the specific ATTRv mutation.

population-based without referral and ascertainment biases. In the era of emerging effective therapies, this is a major unmet need.

Follow-up of patients with cardiac amyloidosis

Although no studies have yet addressed the optimal follow-up scheme in patients with cardiac amyloidosis, a common scheme consists of 6-month visits with electrocardiogram (ECG) and complete blood tests (including NT-proBNP and troponin) and yearly echocardiogram and 24 h Holter ECG. A summary of recommended follow-up tests can be found in Table 7 .

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all hereditary amyloidoses have an adult onset, genetic testing of minors is discouraged. Genetic testing could be offered during young adulthood if genetic information would seem useful to guide professional choices or for reproductive planning.

Follow-up of mutation carriers and genetic counselling

As age of onset, clinical penetrance, and progression depend upon the variant, assessment of penetrance in allele carriers is generally recommended to start $\sim\!10$ years prior to the age of disease onset in affected members of the family (or other individuals with the same mutation), or as soon as symptoms compatible with amyloidosis develop ( Table 7 ). 22

Genetic testing is recommended for relatives of patients with an inheritable form of cardiac amyloidosis. Such testing should occur along with genetic counselling of patients and their families. As

Essential concepts

- While several staging systems are available to facilitate prognosis, there are limited data on how to assess progression. In the era of emerging effective specific therapies, this is a major unmet need.

Treatment of Cardiac Complications and Comorbidities in Cardiac Amyloidosis

Aortic Stenosis

Thromboembolism

Severe AS confers worse prognosis. ConcomitantATTRwt risk factor for periproceduralAVblock. TAVR improves outcome in amyloid-AS.

Conduction disorders

High risk, common. Anticoagulate if AF, considerin selected cases inSR. Anticoagulate independent of CHADS-VASC score.

PPM according to standard indications. Consider CRT if high pacedburdenexpected.

Heart failure

Ventricular arrhythmias

Atrial Fibrillation

Control fluid. Diuretics. Deprescribe B-Blockers. Avoid ACEl/ARB. LVAD not suitable for most patients. Heart transplant for selected cases. Amiodarone, preferred AA. Use digoxin cautiously. Electrical CV has significant riskofcomplicationsandAF recurrence is frequent. Exclude thrombi before electricalCV. AFablationdatascarceand controversial.

ICD for secondary prevention. ICD in primary prevention usuallynotrecommended. Transvenous ICD preferred over subcutaneous ICD.

Figure 5 Treatment of cardiac complications and comorbidities in cardiac amyloidosis. AA, antiarrhythmic; ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; AS, aortic stenosis; ATTRwt, wild-type transthyretin amyloidosis; AV, atrio-ventricular; CRT, cardiac resynchronization therapy; CV, cardioversion; ICD, implantable cardioverter-defibrillator; LVAD, left ventricular assist device; PPM, permanent pacemaker; SR, sinus rhythm; TAVR, transcatheter aortic valve replacement.

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- Follow-up of patients with cardiac amyloidosis and mutation carriers should be conducted following a structured protocol.

Treatment

Treatment of cardiac amyloidosis involves two areas: (i) treatment and prevention of complications; and (ii) stopping or delaying amyloid deposition by specific treatment.

Treatment of complications and comorbidities

Supportive care of patients with cardiac amyloidosis encompasses different clinical aspects including treatment of heart failure, arrhythmias, conduction disturbances, thromboembolism and concomitant presence of severe aortic stenosis ( Figure 5 ). 23–25

Specific (disease-modifying) treatment

Treating the process of amyloid deposition should target the production of amyloid precursor protein or the assembly of amyloid fibrils.

AL amyloidosis

Specific treatment in cardiac AL amyloidosis should be undertaken by multidisciplinary teams involving oncohaematology and cardiology specialists and, whenever possible, patients should be referred to specialised centres. 26

Patients with AL amyloidosis not only have a haematologic malignancy, but also their multiorgan involvement makes them particularly fragile and susceptible to treatment toxicity. Therapeutic approaches depend on risk assessment that are defined in many circumstances by the degree of cardiac involvement (online supplementary Figure S 1 ) and cardiac response depends also on haematological response (online supplementary Table S 1 ). 23,24 The role of the cardiologist in the specific treatment includes: (i) cardiac assessment for initial haematologic strategies, including consideration of autologous stem cell transplantation (online supplementary Table S2 ), (ii) heart transplant evaluation, and (iii) cardiac monitoring during chemotherapy.

ATTR amyloidosis

There is an increasing availability of novel, effective, targeted therapeutic options for ATTRwt and ATTRv. A prompt diagnosis is essential to enable the timely treatment of neurological, cardiac and other systemic manifestations, as therapy is more effective

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in the early stages of the disease. 27–29 Effective therapies reduce the production of mutated (liver transplantation) and overall TTR (genetic silencers) or stabilize circulating TTR molecule (stabilizers), preventing their dissociation or cleavage into amyloidogenic fragments ( Figure 6 ). Several new compounds are under investigation, including agents directed to remove amyloid fibrils (online supplementary material).

Current therapeutic alternatives distinguish between ATTRv and ATTRwt and, in the case of ATTRv, according to the presence of cardiomyopathy, polyneuropathy or both ( Figure 7 ). A detailed description of ATTR therapies that are either available or are being tested in phase III trials can be found in online supplementary material. Tafamidis should be generally considered the agent of choice in ATTR cardiac patients with reasonable expected survival while patisiran could be considered in ATTRv patients with cardiac involvement in whom gene silencers are prescribed due to symptomatic neurological disease.

Essential concepts

- Management of cardiac amyloidosis involves treatment and prevention of complications, and halting or delaying amyloid deposition by specific treatments. - Specific pharmacologic treatments available for ATTR amyloidosis include stabilizing molecules (tafamidis) and genetic silencers (patisiran and inotersen). - Tafamidis is currently the only drug that has shown efficacy in a randomized trial in patients with ATTRwt and ATTRv with cardiomyopathy, and should be considered in patients with reasonable expected survival.

Organization of patient care

Collaboration between centres remains essential because not all centres can perform complex diagnostic techniques (such as endomyocardial biopsy and mass spectrometry) or prescribe disease-modifying therapies, and interaction between cardiologists, haematologists, transplant surgeons, neurologists, and other specialists could be needed. The best strategy for the management of patients with amyloidosis is not the ‘hub-and-spoke’ model, but rather a network where centres can do at least some parts of the diagnostic workup, exchange opinions and information, and refer patients to regional or national referral centres for selected procedures or particularly complex decisions.

Summary and future directions

As knowledge evolves and new therapeutic alternatives to treat cardiac amyloidosis emerge, new areas of research and unsolved questions arise. Some of the grey zones and areas of active research are summarized in Table 8 .

Table 8 Areas of investigation and uncertainty in cardiac amyloidosis

Pathophysiology

Amyloidogenesis

• Mechanism for tissue tropism • Role of enzymatic cleavage • Role of mechanical stress at tissue level

Determinants of phenotypic heterogeneity

• Gender • Modifier genes • Epigenetics • Fibre composition

Diagnosis

Populations to screen for cardiac amyloidosis and optimal screening method Widespread genetic testing Identification of a plasma biomarkers of unfolded TTR Artificial intelligence tools to facilitate diagnosis (imaging, ECG, etc.) Identification of the target of bone tracers within amyloid deposits Validation of PET tracers for diagnosis of cardiac amyloidosis, differential diagnosis of ATTR vs. AL, and evaluation of amyloid burden

Natural history

Disease trajectories among carriers of different mutations Definition and measurement of disease progression

• Ventricular thickness, mass, function • Exercise capacity • Biomarkers including monitoring of prealbumin • TTR stability, kinetics, ligands as monitors of disease progression

Treatment of complications

Initiation of anticoagulation in patients without atrial fibrillation Efficacy of heart failure drugs in patients with different degrees of heart failure Efficacy of beta-blockers. Identification of patients who could benefit Role of invasive heart failure monitoring devices Identification of patients that benefit from prophylactic pacemaker Identification of subgroups that can benefit from ICD and CRT Disease-modifying treatments New antiplasma cell therapy in AL New stabilizers in ATTR New gene silencers in ATTR Early initiation of therapy: • ATTRv mutation carriers without phenotype • ATTR cardiac amyloidosis without heart failure Comparison between diverse disease-modifying drugs in ATTR Definition of disease progression despite therapy in ATTR Criteria for switching from one drug to another Early identification of responders/non-responders to specific therapies Role of combined therapy Antibodies to induce removal of tissue amyloid deposits Genetic editing treatments

AL, light-chain amyloidosis; ATTR, transthyretin amyloidosis; ATTRv, hereditary transthyretin amyloidosis; CRT, cardiac resynchronization therapy; ECG, electrocardiogram; ICD, implantable cardioverter-defibrillator; PET, positron emission tomography; TTR, transthyretin.

 Figure 6 Available and future disease modifying therapies in transthyretin amyloidosis. ATTRv, hereditary transthyretin amyloidosis; TTR, transthyretin.

 Figure 7 Proposed therapeutic alternatives in transthyretin amyloidosis patients. ATTRv, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis.

It is expected that advances in the field will change the way we diagnose, prognosticate and treat cardiac amyloidosis in the next few years. Meanwhile, in this paper the Working Group on Myocardial and Pericardial Diseases proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and

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situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis (graphical abstract). Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

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Supplementary Information

Additional supporting information may be found online in the Supporting Information section at the end of the article.

Conflict of interest: P.G.P. reports grant support from Instituto de Salud Carlos III (PI20/0 1 379); speaking fees from Pfizer, Eidos, Alnylam, and Akcea; consulting fees from Pfizer, Eidos, Neuroinmmune, Alnylam, Prothena and Akcea; research support to his institution from Pfizer, Eidos and Alnylam. C.R. reports speaking fees from Pfizer, Alnylam, and Akcea; consulting fees from Pfizer, Alnylam, Prothena and Akcea; institutional research grants from Pfizer. M.A. reports receiving an advisory board fee and a research grant from Pfizer and from Sanofi Genzyme. U.E. reports consulting fees and grant support from Pfizer and Sanofi; institutional grants from Pfizer. M.F. is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/ 1 8/2 1 /33447) and reports consulting fees from Pfizer, Akcea, Ionis, Alnylam, Alexion, Sanofi and research grant from Pfizer. J.D.G. reports consulting and speaking fees from Pfizer, Akcea, Alnylam, and Eidos. E.G.L. reports grant support from Instituto de Salud Carlos III (PI 1 8/0765); speaking fees from Pfizer and Alnylam; consulting fees from Pfizer and Proclara; research support to her institution from Pfizer, Eidos and Alnylam. M.G. reports grant/clinical trial support from Alnylam, Eidos, Prothena, and Pfizer. I.K. reports speaking fees from Akcea Therapeutics Germany and Pfizer; consulting fees from Akcea Therapeutics Germany. A.V.K. reports consulting fees from Pfizer, Akcea, Alnylam, and Neurimmune and speaking fees from Pfizer, Akcea, and Alnylam. M.S.M. reports grant support from National Institutes of Health [R0 1 HL 1 3967 1 -0 1 ], [R2 1 AG058348] and [K24AG036778], consulting income from Pfizer, GSK, EIdos, Prothena, Akcea and Alnylam, and institution received clinical trial funding from Pfizer, Prothena, Eidos and Alnylam. A.G.R. reports honoraria for presentations from AstraZeneca. A.L. reports speaking fees from Pfizer; consulting fees from Pfizer, Alnylam. All other authors have nothing to disclose.

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