Heart with magnifying glass revealing a maze in a ventricle, alongside text reading 'ATTR-CM suspect & detect, uncover the clues for diagnosis'

Home > Diagnosis of ATTR-CM > Formal diagnosis of ATTR-CM

 

Formal diagnosis of Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

 

| Initial tools used in diagnosing ATTR-CM

Routine blood and urine tests, routine heart failure assessments - such as echo and ECG - and advanced imaging techniques, can help identify signs on the diagnostic pathway.1


| Electrocardiogram (ECG)

ECG can detect an ATTR-CM feature of a discordance between QRS voltage and LV mass ratio.1-3


| Echocardiography

Echo detects reduced longitudinal strain on the basal and midwall area.1,4–7


| Cardiac magnetic resonance (CMR)

  • A non-invasive imaging method that is useful for the diagnosis of ATTR-CM8
  • Pericardial effusion, atrioventricular block, interatrial septal and valvular thickening, and apical sparing of longitudinal strain are all suggestive of ATTR-CM9
  • Myocardial deposition of the amyloid fibrils increases the extracellular volume and results in the accumulation of exogenous gadolinium contrast9
  • Marked extracellular volume expansion, abnormal nulling time for the myocardium and diffuse late gadolinium (LGE), especially in combination, are highly suspicious of ATTR-CM9
  • A pattern of transmural and patchy LGE in the right ventricle and atrial walls is highly sensitive and specific to ATTR-CM8

Nuclear scintigraphy, endomyocardial biopsy (EMB) and genetic testing can be used to diagnose ATTR-CM:

Diagram showing non-invasive nuclear scintigraphy or invasive endomyocardial biopsy both nested under genetic testing

* In combination with blood and urine testing to rule out AL.10,11


| 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:11

  • The patient has heart failure with evidence of cardiac amyloidosis via echocardiography or CMR
  • AL cardiac amyloidosis has been ruled out via blood and urine tests
  • Nuclear scintigraphy results fall within the parameters of the grading system (i.e. grade 2 or 3, see below)

Histological confirmation and typing should be pursued in cases of suspected cardiac amyloidosis when the above criteria are not satisfied.11

If a patient is positive for ATTR-CM with nuclear scintigraphy, genotyping is recommended to determine the type: wild-type ATTR or hereditary ATTR.11


| Nuclear scintigraphy

Scintigraphy in combination with testing* to rule out AL amyloidosis can diagnose ATTR-CM11

  • A non-invasive, readily available diagnostic tool with high sensitivity and specificity for ATTR-CM11
  • Uses a radioactive bone tracer11
  • 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 AL11

| Endomyocardial biopsy (EMB)

  • EMB can be used to confirm diagnosis in the presence of:7-14
    • a positive result on one of the triple screening tests9
    • a grade 1 scintigraphy scan8,11
    • tests are negative but there is still a strong clinical suspicion of ATTR-CM
  • Histology with positive Congo red staining with apple-green birefringence1,11
  • Additional tests to determine amyloid type are recommended following diagnosis of cardiac amyloidosis11
  • Invasive, plus risk of complications and the need for specialised centres and expertise may contribute to a diagnostic delay1,11

| Genetic testing

  • Used to determine if the disease is hereditary due to a mutation in the TTR gene13
  • Genetic counselling and gene sequencing are recommended following confirmation of ATTR-CM13

| Diagnosing ATTR-CM with nuclear scintigraphy

  • Requires myocardial uptake of the radioactive tracer:
  • Semiquantitative approach: visual comparison to bone (rib) uptake at 3 hours14
    • Cardiac uptake is evaluated using a visual scoring method in relation to bone uptake
    • Images are graded as 0 to 3:
      • Grade 0 no cardiac uptake and normal bone uptake
      • Grade 1 uptake less than rib uptake
      • Grade 2 uptake equal to rib uptake
      • Grade 2–3 uptake is strongly suggestive of TTR amyloidosis

X-ray profiles of four bodies labelled A, B, C, D, with graphs beneath them indicating skeletal muscle uptake of 99mTc-DPD

Cardiac and skeletal muscle uptake of 99mTc-DPD with a line count profile created by drawing an ROI across an area of thigh (4.5 cm wide) on the anterior whole body image.15

Hutt DF, Quigley A-M, Page J et al. Utility and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy in systemic amyloidosis, European Heart Journal - Cardiovascular Imaging 2014; 15 (11): 1289-1298, by permission of Oxford University Press on behalf of the European Society of Cardiology.

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

  • Quantitative approach: myocardial to contralateral lung (H/CL) ratio of uptake at 1 hour14

X-ray profile of two lungs showing a positive uptake on the left and CT measurements on the right

  • H/CL >1.5 uptake is strongly suggestive of TTR amyloidosis14

 

 

 

Referenced with permission from ASNC. © 2019 American society of Nuclear cardiology

| A diagnostic algorithm for patients with suspected ATTR-CM

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

A flow diagram with yes/no decision points showing the path taken to detect 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.
Adapted with permission from Wolters Kluwer Health, Inc.: Gillmore JD, Maurer MS, Falk RH, et al., Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis, Circulation, 133, 24, 2404-2412.
https://www.ahajournals.org/doi/epub/10.1161/CIRCULATIONAHA.116.021612

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


 

Footnotes

AApoAI = apolipoprotein A-I

References

  1. 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. 
  2. Cyrille NB, Goldsmith J, Alvarez J, Maurer MS. Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis. Am J Cardiol. 2014; 114(7): 1089–1093. 
  3. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation. 2012; 126(10): 1286–1300. 
  4. Rapezzi C, Lorenzini M, Longhi S et al. Cardiac amyloidosis: the great pretender. Heart Fail Rev. 2015; 20(2): 117–124. 
  5. Quarta CC, Solomon D, Uraizee I et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014; 129(18): 1840–1849. 
  6. Ternacle J, Bodez D, Guellich A et al. Causes and consequences of longitudinal LV dysfunction assessed by 2D strain echocardiography in cardiac amyloidosis. JACC Cardiovasc Imaging. 2016; 9(2): 126–138. 
  7. Siddiqi OK, Ruberg FL. Cardiac amyloidosis: an update on pathophysiology, diagnosis, and treatment. Trends Cardiovasc Med. 2018; 28(1): 10–21. 
  8. Donnelly JP, Hanna M. Cardiac amyloidosis : An update on diagnosis and treatment. Cleve Clin J Med. 2017; 84(12 Suppl 3): 12–26.
  9. Witteles RM, Bokhari S, Damy T et al.  Screening for Transthyretin Amyloid Cardiomyopathy in Everyday Practice. JACC Heart Fail. 2019; 7(8): 709–716.
  10.  Brunjes DL, Castano A, Clemons A et al.  Transthyretin Cardiac Amyloidosis in Older Americans. J Card Fail. 2016; 22(12): 996–1003.
  11. Gillmore JD, Maurer MS, Falk RH et al.  Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016; 133(24): 2404–2412.
  12. Hawkins PN, Ando Y, Dispenzeri A et al.  Evolving landscape in the management of transthyretin amyloidosis. Ann Med. 2015; 47(8): 625–38.
  13. Maurer MS, Elliott P, Comenzo R et al. Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis. Circulation. 2017; 135(14): 1357–1377.
  14. American Society of Nuclear Cardiology (ASNC). ASNC practice points: 99mTechnetium-pyrophosphate imaging for transthyretin cardiac amyloidosis. Available at: https://www.asnc.org/files/19110%20ASNC%20Amyloid%20Practice%20Points%20WEB(2).pdf © 2019.
  15. Hutt DF, Quigley AM, Page J et al. Utility and limitations of 3,3-diphosphono-1, 2-propanodicarboxylic acid scintigraphy in systemic amyloidosis. Eur Heart J – Cardiovasc Imaging. 2014; 15: 1289–1298.

PP-VYN-GBR-0185. March 2020

Click here for Vyndaqel ▼ (tafamidis) prescribing information