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

Learn about the red flags that may raise suspicion of and techniques used to diagnose ATTR-CM

Explore a range of educational resources to support the diagnosis of ATTR-CM

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Formal diagnosis of Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

When cardiac amyloidosis is suspected, a diagnosis can be made non-invasively using echocardiograms in conjunction with electrocardiograms (ECG) and cardiac MRI. Using nuclear scintigraphy alongside laboratory testing (serum free light chain ratio, serum, and urine immunofixation testing) a differentiation can be made between AL amyloidosis and ATTR-CM.​​​​​​​1

Initial tools used in diagnosing ATTR-CM ​​​​​​​

Routine blood and urine tests, routine heart failure assessments - such as echocardiography and electrocardiogram - and advanced imaging techniques, can help identify signs of ATTR-CM.​​​​​​​2

A standard 12 lead ECG can detect an ATTR-CM feature of a discordance between QRS voltage and left ventricular (LV) mass ratio.2

Electrocardiogram (ECG)

Echocardiography shows reduced longitudinal strain on the basal and midwall area with relative apical sparing3

Echocardiography (Echo)

Cardiac magnetic resonance (CMR)

Cardiac magnetic resonance is a non-invasive imaging method that is used to help with the diagnosis of cardiac amyloid:1

  • Pericardial effusion, atrioventricular block, interatrial septal and valvular thickening, and apical sparing of longitudinal strain are all suggestive of ATTR-CM.​​​​​​​2
  • Myocardial deposition of amyloid fibrils increases the extracellular volume and results in the accumulation of exogenous gadolinium contrast.2
  • Marked extracellular volume expansion, abnormal nulling time for the myocardium and diffuse late gadolinium enhancement (LGE) on CMR, especially in combination, are highly suspicious of ATTR-CM.2
  • A pattern of transmural and patchy LGE in the right ventricle and atrial walls can be seen in ATTR-CM.​​​​​​​1

Diagnostic reliability

A recent key study suggests that a reliable diagnosis of ATTR-CM can be made with nuclear scintigraphy when the following criteria are met:4

  • The patient has heart failure consistent with or suggestive of cardiac amyloidosis based on findings from echocardiography or CMR4
  • ​​​​​​​AL cardiac amyloidosis has been ruled out via blood and urine tests4
  • Nuclear scintigraphy results demonstrate grade 2 or 3 cardiac uptake on a radionuclide scan4

Histological confirmation and typing of amyloid should be sought in all cases of suspected cardiac amyloidosis in which these criteria from the diagnostic algorithm are not met.

If a patient is positive for ATTR-CM with nuclear scintigraphy, genotyping is recommended to determine the type: wild-type ATTR or hereditary ATTR.4

Nuclear scintigraphy​​​​​​​

Scintigraphy in combination with testing* to rule out AL amyloidosis can diagnose ATTR-CM4

  • Scintigraphy is a non-invasive, readily available diagnostic tool with high sensitivity and specificity for ATTR-CM4
  • Scintigraphy uses a radioactive bone tracer4
  • A multicentre international study demonstrated 99% sensitivity for ATTR-CM (visual grade 1-3). A separate analysis within the study demonstrated 100% specificity for visual grade 2 or 3 with concurrent testing to rule out AL.4*+

​​​​​​​+All patients with suspected or proven cardiac ATTR amyloidosis underwent diagnostic investigations including bone scintigraphy, immunofixation electrophoresis of serum and urine, and serum free light-chain assay. All patients underwent echocardiography, previous CMRs were reviewed, and new CMRs were performed according to local clinical practice. Final diagnosis was made based on the results of these tests accompanied by histological and genetic findings. Number of evaluable patients n=1217, of which 374 underwent endomyocardial biopsy and 843 had extracardiac histology.​​​​​​​4

*Rule out AL amyloidosis: testing for presence of monoclonal protein via serum and urine immunofixation, and serum-free light chain assay.4

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

Histological confirmation and typing of amyloid should be sought in all cases of suspected cardiac amyloidosis in which the diagnostic criteria of the algorithm not met.4

  • Diagnosis of cardiac amyloidosis by biopsy requires histology to show Congo red staining with apple-green birefringence4
  • Additional tests to determine amyloid type are recommended following diagnosis of cardiac amyloidosis.4
  • The need for specialised centres and expertise may contribute to a diagnostic delay4

Histological confirmation

  • Genetic testing is used to determine if the disease is hereditary due to a mutation in the TTR gene5
  • Genetic counselling and gene sequencing are recommended following confirmation of ATTR-CM5

Genetic testing

Requires quantifying myocardial uptake of the radioactive tracer:
​​​​​​​
  • Semiquantitative approach: visual comparison to bone (rib) uptake at 3 hours4 
  • Cardiac uptake is evaluated using a visual scoring method in relation to bone uptake4
  • Images are graded as 0 to 3:4
    • Grade 0 no cardiac uptake and normal bone uptake
    • Grade 1 cardiac uptake less than bone uptake 
    • Grade 2 cardiac uptake equal to bone uptake
    • Grade 3 high cardiac uptake greater than bone uptake 
  • Grade 2–3 uptake is strongly suggestive of TTR amyloidosis4

Diagnosing ATTR-CM with nuclear scintigraphy

IIllustrative representation developed in collaboration with Torbjörn Sundström - MD, PhD, Radiology/Nuclear Medicine, Umeå University Hospital Sweden. 
​​​​​​​

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

    The proposed algorithm is based on using the visual grading system with nuclear scintigraphy:6

    A diagnostic algorithm for patients with suspected ATTR-CM

    Diagnostic algorithm for patients with suspected amyloid cardiomyopathy.​​​​​​​
    ​​​​​​​
    Echocardiographic features suggesting/indicating cardiac amyloid include (but are not limited to) increased left ventricular wall thickness, restrictive filling pattern, abnormal left and right ventricular longitudinal strain, and atrial septal thickening. Features suggesting/indicating cardiac amyloid on cardiac magnetic resonance imaging (CMR) include (but are not limited to) restrictive morphology, abnormal gadolinium kinetics, and extracellular volume expansion based on T1 mapping. AApoA1 indicates apolipoprotein A-I; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; HDMP, hydroxymethylene diphosphonate; and PYP, pyrophosphate.

    Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases, Garcia Pavia P, Rapezzi C, Adler Y, et al. © European Society of Cardiology 2021. Reproduced with permission of John Wiley & Sons Ltd.

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

    Building the knowledge: Appropriately diagnosing ATTR-CM

    This is a series of animated, educational modules that outline key background information on ATTR amyloidosis. This video reviews non-invasive and invasive approaches for the diagnosis of ATTR-CM.

    Current standards of care and emerging treatment strategies

    Learn more

    See other educational resources available

     Explore more

    References​​​​​​​:
    1. Donnelly JP, Hanna M. Cardiac amyloidosis: An update on diagnosis and treatment. Cleve Clin J Med. 2017; 84(12 Suppl 3): 12–26.
    2. Witteles RM, Bokhari S, Damy T et al. Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice. JACC Heart Fail. 2019; 7(8): 709–716
    3. 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(9): 1166.e1–1166.e10.
    4. Gillmore JD, Maurer MS, Falk RH et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016; 133: 2404–2412
    5. Maurer MS, Hanna M, Grogan M, et al. Genotype and Phenotype of Transthyretin Cardiac Amyloidosis. J Am Coll Cardiol. 2016; 68(2): 161–172. 
    6. Garcia-Pavia et al., (2021) Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases, European Journal of Heart Failure, 24(4) 512-526​​​​​​​.
      ​​​​​​​
    PP-VYN-GBR-0944. March 2022

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