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Confirming a transthyretin cardiac amyloidosis* diagnosis

*Also known as transthyretin amyloid cardiomyopathy (ATTR-CM).

Nuclear scintigraphy with 99mTechnetium pyrophosphate (99mTc-PYP)†—a noninvasive approach1

Nuclear scintigraphy using both planar and single-photon emission computer tomography (SPECT) imaging is a noninvasive and commonly available diagnostic tool.2 Using nuclear scintigraphy with bone-avid radiotracers, such as 99mTc-PYP,†can identify ATTR cardiac amyloidosis with high sensitivity and specificity.2

†99mTc-PYP is not FDA approved for the diagnosis of ATTR cardiac amyloidosis. Please consult individual labeling for risks.3

A multicenter international study at amyloid centers of excellence demonstrated 100% positive predictive value for ATTR cardiac amyloidosis using visual grade 2 or 3 with concurrent testing to rule out immunoglobulin light chain (AL) amyloidosis.1,4

Evidence for nuclear scintigraphy2
  • Provides a unique myocardial uptake pattern in amyloid
  • May identify transthyretin amyloidosis (ATTR) deposits early in the course of disease 
  • According to the expert recommendations, SPECT imaging is required in all studies (irrespective of time between injection and scan) to ensure direct visualization of tracer uptake in the myocardium 
Multisocietal expert consensus recommendations for diagnosing ATTR cardiac amyloidosis with nuclear scintigraphy2‡
  • 99mTc-PYP† has avidity for cardiac amyloid deposits
  • The recommended time between injection of 99mTc-PYP† and scan is 2 or 3 hours; 1-hour planar-only imaging is not recommended
  • Both planar and SPECT imaging should be reviewed and interpreted using visual and quantitative approaches irrespective of the timing of acquisition, when applicable
3-step interpretation of 99mTc-PYP† images to diagnose ATTR cardiac amyloidosis:Step 1: Visual interpretation2
  • Evaluate planar and SPECT images to confirm diffuse radiotracer uptake in the myocardium
  • Differentiate myocardial radiotracer uptake from residual blood pool activity, focal myocardial infarction, and overlapping bone (eg, from rib hot spots from fractures) on SPECT images
  • If excess blood pool activity is noted, recommend repeating SPECT imaging at 3 hours
Step 2: Semiquantitative2
  • Visual grading comparison to bone (rib) uptake at 1 or 3 hours
  • Examine planar and SPECT images for tracer uptake in the myocardium relative to ribs and grade using the following scale:
Illustrative representation.
  • Visual scoring method in relation to bone (rib) uptake at 3 hours
    • Strongly suggestive of ATTR cardiac amyloidosis: visual grade of ≥2 on planar and SPECT images with concurrent testing to rule out AL
    • Not suggestive or equivocal of ATTR cardiac amyloidosis: visual grade of <2

When cardiac amyloidosis is suspected, grade 2 or 3 myocardial uptake with concurrent testing to rule out AL is diagnostic of ATTR cardiac amyloidosis, as this degree of uptake is seen in >20% of patients with AL.§

 
Step 3: Quantitative grading (when applicable)2
  • Diagnosis of ATTR cardiac amyloidosis cannot be made solely based on heart-to-contralateral lung (H/CL) ratio alone. H/CL ratio is not recommended if there is absence of myocardial uptake on SPECT imaging.
  • H/CL ratio is typically concordant with visual grade
    • If the visual grade is 2 or 3, diagnosis is confirmed, and H/CL ratio assessment is not necessary
    • If discordant, or the visual grade is equivocal, H/CL ratio may be helpful to classify equivocal visual grade 1 vs 2 as positive or negative
  • A circular region of interest (ROI) should be drawn over the heart on anterior planar images, avoiding sternal overlap and size adjusted to maximize coverage of the heart without including the adjacent lung. The same ROI should be mirrored over the contralateral chest without including the right ventricle, then the heart and contralateral lung ROIs should be drawn above the diaphragm.
  • An H/CL ratio is calculated as the fraction of heart ROI mean counts to contralateral lung ROI mean counts
    • H/CL ratios of ≥1.5 at 1 hour can accurately identify ATTR cardiac amyloidosis if myocardial 99mTc-PYP* uptake is visually confirmed on SPECT imaging and systemic AL amyloidosis is excluded
    • An H/CL ratio of ≥1.3 at 3 hours can identify ATTR cardiac amyloidosis
Quantification of cardiac 99mTc-PYP* uptake using H/CL ratio5Illustrative representation. Rule out AL by testing for presence of monoclonal protein via serum and urine immunofixation and serum free light chain assay.4Endomyocardial biopsy (EMB)—an invasive approach1

If clinical suspicion for cardiac amyloidosis remains high despite a negative or inconclusive scintigraphy scan, consider EMB, as biopsy with Congo red histology and apple-green birefringence can be used to diagnose ATTR cardiac amyloidosis.4

 Congo red staining of myocardial tissue on light microscopy and apple-green birefringence on polarized light microscopy images

Illustrative representation.

Important considerations:

  • To determine amyloid type, immunohistochemistry tests and/or mass spectrometry should be performed1
  • Risk of complications and the need for specialized centers and expertise may contribute to a diagnostic delay1,4,6
Genetic testing—critical for patients and their families
  • V122I is the most frequent in the US and is carried by 3%-4% of African Americans, though not all will develop the disease7-9
  • Genetic testing is used to determine if the disease is hereditary due to a mutation in the TTR gene or if it is wild-type8-12
  • Genetic counseling and gene sequencing are recommended following confirmation of ATTR cardiac amyloidosis8-12
Diagnosis of hATTR-CM in an index patient should prompt genetic counseling and testing of family members.12

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Written by a writing group of experts in cardiovascular imaging and amyloidosis assembled by the American Society of Nuclear Cardiology and endorsed by 9 societies including the American College of Cardiology, American Heart Association, American Society of Echocardiography, European Association of Nuclear Medicine, Heart Failure Society of America, International Society for Amyloidosis, Society for Cardiovascular Magnetic Resonance, and Society of Nuclear Medicine and Molecular Imaging.99mTc-PYP uptake could be seen in other causes of myocardial injury, including pericarditis, myocardial infarction (regional uptake), and chemotherapy- or drug-associated myocardial toxicity.2ATTR=transthyretin amyloidosis.
References:Bokhari S, Castaño A, Pozniakoff T, et al. 99mTc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidosis. Circ Cardiovasc Imaging. 2013;6(2):195-201.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. Circ Cardiovasc Imaging. 2021;14(7):e000029.Miller EJ, Campisi R, Shah NR, et al. Radiopharmaceutical supply disruptions and the use of 99mTc-hydroxymethylene diphosphonate as an alternative to 99mTc-pyrophosphate for the diagnosis of transthyretin cardiac amyloidosis: an ASNC Information Statement. J Nucl Cardiol. 2022;29(5):2748-2760.Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412.Hanson CA, Bourque JM. Nuclear Scintigraphy for cardiac amyloidosis assessment in current clinical practice. DAIC. July 22, 2019. Accessed February 16, 2022. https://www.dicardiology.com/article/nuclear-scintigraphy-cardiac-amyloidosis-assessment-current-clinical-practiceNarotsky 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.Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid. 2015;22(2):171-174.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.Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (transthyretin amyloid outcome survey). J Am Coll Cardiol. 2016;68(2):161-172.Alreshq R, Ruberg F. Clinical approach to genetic testing in amyloid cardiomyopathy: from mechanism to effective therapies. Curr Opin Cardiol. 2021;36(3):309-317.Gillmore JD, Reilly MM, Coats CJ, et al. Clinical and genetic evaluation of people with or at risk of hereditary ATTR amyloidosis: an expert opinion and consensus on best practice in Ireland and the UK. Adv Ther. 2022;39(6):2292-2301.Conceição I, Damy T, Romero M, et al. Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations. Amyloid. 2019;26(1):3-9.
Diagnosis American Society of Nuclear Cardiology (ASNC) webinar on PYP 

Experts from ASNC share important information about interpreting and reporting PYP scans.

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Explore the latest about diagnosing ATTR cardiac amyloidosis using nuclear scintigraphy from the experts at the American Society of Nuclear Cardiology (ASNC).

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