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About ATTR-CMAbout

Learn about ATTR-CM and uncover the differences between hereditary and wild-type ATTR-CM

Types of ATTR-CM



Suspect ATTR-CMDetect ATTR-CMSupporting ResourcesTreatment Option

Click here for Vyndaqel®▼ (tafamidis) Prescribing Information.

Suspect ATTR-CM with cardiac and noncardiac clues The diagnostic flowchart takes you through the first signs of ATTR-CM to diagnosis1

An approach for patients with suspected cardiac amyloidosis that includes testing for monoclonal protein followed by scintigraphy and/or biopsy1

VYNDAQEL® 61 mg (tafamidis) is indicated for the treatment of wild‑type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM).

Amyloid light chain (AL) amyloidosis must be excluded before starting treament with VYNDAQEL.

When cardiac amyloidosis is suspected, grade 2 or 3 myocardial uptake, with concurrent testing to rule out AL amyloidosis, can be reliably considered to diagnose ATTR-CM.

DPD and other tracers are not licensed for ATTR-CM diagnostic nuclear scintigraphy in the UK.


Rule out AL: testing for presence of monoclonal protein via serum and urine immunofixation (IFE) and serum free light chain (SFLC) assay.2


  • Serum protein electrophoresis with immunofixation (Normal range: No monoclonal protein present)
  • Urine protein electrophoresis with immunofixation (Normal range: No monoclonal protein present)
  • Serum kappa/lambda free light chain ratio (Normal range: Freelite assay: 0.26-1.65, N Latex assay: 0.53-1.51)

This combination of tests has a 99% sensitivity for identifying AL amyloidosis.3 Serum and urine protein electrophoresis should always be performed with immunofixation to increase the sensitivity of the assays for detecting low-level monoclonal proteins.3

Importance of early diagnosis of ATTR-CM


Early diagnosis and treatment of ATTR-CM are critical

In the UK there is a delay to diagnosis (>4 years in 42% of cases of wild-type ATTR-CM). Barriers to diagnosis are thought to be a major reason for shortened survival, with patients using hospital services a median (interquartile range) of 17 (9–27) times during the 3 years before diagnosis; by which time physical function and quality of life is greatly depleted.4 The median survival of patients depends on the mutation and once diagnosed is 2.0–5.0 years.5

As prognosis for patients with ATTR-CM worsens with continued amyloid deposition, early diagnosis is key to improving patient outcomes3,5

Look for the red flags: Consider these clinical clues, especially in combination, to help raise suspicion and the need for further testing.

What are the ATTR-CM signs I should be looking for?

Heart failure with preserved ejection fraction (HFpEF) or other cardiac conditions

For example, severe aortic stenosis (AS)*, arrhythmias, in patients typically over the age of 606,7,8

  • In ATTR-CM, diastolic function is impaired due to amyloid fibril deposition in the myocardium, resulting in thicker and inelastic ventricles, thereby decreasing stroke volume. It is not until the later stages of ATTR-CM disease that ejection fraction drops9,10
  • Imaging clues, such as echo showing reduction in longitudinal strain with relative apical sparing (Figure A & B) can help to differentiate cardiac amyloidosis from other causes of left ventricular hypertrophy.3

Examples of strain imaging showing relative apical sparing:

(A): Apical sparing of longitudinal strain (commonly referred to as apical sparing)11
(B): Bull’s-eye plot of longitudinal strain showing apical sparing. This is often referred to as a “cherry on top” pattern11


Intolerance to standard heart failure therapies

For example, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers12

  • Patients can develop a decrease in stroke volume, which can lead to low blood pressure. As a result, they can develop an intolerance to blood pressure–lowering therapies.
Dicordance between QRS voltage on electrocardiograhy and left ventricular wall thickness
  • The classic ECG feature of ATTR-CM is a discordance between QRS voltage and LV mass ratio3
  • The amplitude of the QRS voltage is not reflective of the increased LV wall thickness, because the increase is due to extracellular amyloid protein deposition rather than myocyte hypertrophy11
  • Absence of a low QRS voltage does not, however, rule out ATTR-CM, as low voltage can vary among cardiac amyloidosis aetiologies.
ECG and echocardiography images showing discordance of limb lead QRS voltages and the degree of LV wall thickness in a patient with cardiac amyloidosis13
Illustrative representation
Diagnosis of orthopaedic conditions

Including carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, and/or hip and knee arthroplasty14

  • Carpal tunnel syndrome and lumbar stenosis are often seen in ATTR-CM due to amyloid deposition in these areas.
  • ATTR-CM frequently presents with a history of bilateral carpal tunnel syndrome and lumbar spinal stenosis. Bilateral carpal tunnel syndrome may manifest up to 10 years prior to diagnosis.14
Echo showing increased left venticular wall thickness, not attributed to another cause (e.g. hypertension)

Using echocardiography to suspect ATTR-CM3,15

Echocardiography (echo), including tissue Doppler imaging (TDI) and strain analysis, can play a role in the noninvasive diagnosis of ATTR-CM due to its:16

  • Widespread availability and portability
  • Capacity to assess structure and diastolic function. 

Echo can help identify characteristics related to amyloid infiltration but cannot distinguish between ATTR-CM and other types of cardiac amyloidosis.16

Parasternal long-axis view16

Illustrative representation

Characteristic appearance of cardiac amyloidosis on echo16

Transthoracic echocardiography, parasternal long-axis view, left ventricular hypertrophy with preserved ejection fraction. Image courtesy of Filiale d'Imagerie Cardiovasculaire.
Echo findings that are strongly suggestive of cardiac amyloidosis and should be reported include:16

  • Increased LV wall thickness
  • Increased LV mass
  • Typical LV longitudinal strain pattern
  • Mitral annular TDI <5 cm/s
  • Biatrial enlargement
  • Small A wave in sinus rhythm
  • Small pericardial and/or pleural effusions
Nervous system dysfunction

Including gastrointestinal complaints (e.g., diarrhoea or constipation)3,17

  • Gastrointestinal complaints due to autonomic dysfunction include diarrhoea and constipation.
  • Orthostatic hypotension due to autonomic dysfunction is another symptom that may occur with ATTR-CM17,18
Using cardiovascular magnetic resonance (CMR) to suspect ATTR-CM

Using CMR to suspect ATTR-CM

CMR may raise suspicion of disease in two scenarios:16

  • Differentiation between cardiac amyloidosis and other cardiomyopathic conditions with increased wall thickening
  • Detection of early cardiac involvement in patients presenting with symptoms of systemic amyloidosis

CMR may be advantageous in the following scenarios if echocardiographic acoustic windows are poor:16

  • To characterise the right ventricle 
  • To characterise tissue based on the contrast-enhanced patterns of myocardial infiltration.
  • To precisely quantify cardiac chamber volumes and ventricular mass

Patient A: Normal heart 

Patient B: Heart shows a significantly high amyloid burden (elevated native T1, transmural late gadolinium enhancement, and increased extracellular volume)

Adapted from Dorbala et al. Expert consensus recommendations for multimodality imaging in cardiac amyloidosis. J Nucl Cardiol. 2019

Additional key considerations

There are several additional signs/symptoms that could be clues for cardiac amyloidosis and ATTR-CM, which include:

  • Strain imaging showing apical sparing or apical preservation.
    • Longitudinal strain seen on echocardiography is reduced in the basal and midwall area; however, the apical strain is spared or preserved3
  • A history of bicep tendon rupture in wild type patients19
  • A diagnosis of hypertrophic cardiomyopathy after the sixth decade20
  • Arrhythmias such as atrial fibrillation or other conduction abnormalities, which may require a pacemaker21
  • Aortic stenosis (AS) and transthyretin cardiac amyloidosis may occur in elderly patients, notably those with a low-flow, low-gradient AS pattern21
  • Hip and knee arthroplasty22

Common signs and symptoms in wild-type ATTR-CM and hereditary ATTR-CM3,8,17,23-28

European Society of Cardiology (ESC) recommendations1

The ESC Working Group recommends screening for ATTR-CM if LV wall thickness is ≥12 mm + the presence of ≥1 red flag or clinical scenario.

*Notably those with a low-flow, low-gradient aortic stenosis (AS) pattern.21,29

ATTR=transthyretin amyloidosis; AL=lightchain amyloidosis; AS=aortic stenosis; CMR=cardiac magnetic resonance; CTS=carpal tunnel syndrome; DPD=99mtechnetium-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid; Echo=echocardiography; ECG= electrocardiography; HFpEF= Heart failure with preserved ejection fraction; HMDP=99mtechnetium-labelled hydroxymethylene diphosphonate; LV=left ventricle; PYP=99mtechnetium-labelled pyrophosphate; SFLC=serum-free light chain assay; SPECT= single photon emission computed tomography; TDI=tissue Doppler imaging; TTR= transthyretin.

References:Garcia- Pavia P, Rapezzi C, Adler Y, et al. Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur J Heart Fail. 2021;23:512–526;Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404 –2412. doi:10.1161/CIRCULATIONAHA.116.021612; Witteles RM, Bokhari S, Damy T, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail. 2019;7(8):709–716.doi:10.1016/j.jchf.2019.04.010;
Lane T, Fontana M, Martinez-Naharro A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation 2019;140:16–26;
Lane T, Fontana M, Martinez-Naharro A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation 2019;140:16–26;Maurer MS, Elliott P, Comenzo R, et al. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation 2017;135:1357–1377;Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2:113–122;González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015; 36:2585 –2594;Maurer MS, Hanna M, Grogan M, et al. Genotype and Phenotype of Transthyretin Cardiac Amyloidosis. J Am Coll Cardiol. 2016;68:161–172;Siddiqi OK, Ruberg FL. Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med. 2018;28:10–21;Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;2:670–679;Narotsky DL, Castaño A, Weinsaft JW, Bokhari S, Maurer MS. Wild-type transthyretin cardiac amyloidosis: novel insights from advanced imaging. Can J Cardiol. 2016;32: 1166.e1–1166.e10;Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail 2016;22:996 –1003;Grogan M, Dispenzieri A, Gertz MA. Light-chain cardiac amyloidosis: strategies to promote early diagnosis and cardiac response. Heart. 2017;103:1065–1072;Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and Cardiac Amyloidosis in Patients Undergoing Carpal Tunnel Release. J Am Coll Cardiol. 2018;72:2040–2050;Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart 2012;98:1442–1448;Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2—evidence base and standardized methods of imaging. J Nucl Cardiol. 2019;26:2065 –2123;Nativi-Nicolau J, Maurer MS. Amyloidosis cardiomyopathy: update in the diagnosis and treatment of the most common types. Curr Opin Cardiol 2018;33:571–579; Rapezzi C, Merlini G, Quarta CC et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120:1203–1212;Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29:63–76;Hahn VS, Yanek LR, Vaishnav J, et al. Endomyocardial biopsy characterization of heart failure with preserved ejection fraction and prevalence of cardiac amyloidosis. JACC Heart Fail. 2020;8(9):712-724;Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73:2872 -2891;Aldinc E, Campbell C, Gustafsson F, Beveridge A, Macey R, Marr L, Summers C, Zhang D. Musculoskeletal manifestations associated with transthyretin-mediated (ATTR) amyloidosis: a systematic review. BMC Musculoskelet Disord. 2023;24:751;Geller HI, Singh A, Alexander KM, et al. Association between ruptured distal biceps tendon and wild-type transthyretin cardiac amyloidosis. JAMA 2017;318:962–963;Connors LH, Sam F, Skinner M, et al. Heart failure due to age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study. Circulation 2016;133:282–290;Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc 2013;2:e000098;Yanagisawa A, Ueda M, Sueyoshi T, et al. Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis. Mod Pathol 2015;28:201–207;Westermark P, Westermark GT, Suhr O, et al. Transthyretin-derived amyloidosis: Probably a common cause of lumbar spinal stenosis. Upsala J Med Sci 2014;119:223–228; Galat A, Guellich A, Bodez D, et al. Aortic stenosis and transthyretincardiac amyloidosis: the chicken or the egg? Eur Heart J 2016;37:3525 –3531;Bokhari S, Gupta R. Aging, Aortic Stenosis, and Transthyretin Cardiac Amyloidosis: A Perfect Cardiac Storm? JACC CardioOncol. 2021;3:577-579;Explore more Explore available Supporting Resources Supporting ResourcesLoading
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