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ATTR-CMATTR-CMATTR-CM HomeAbout ATTR-CMMechanism of DiseaseWild-Type ATTR-CMHereditary ATTR-CMSuspect ATTR-CMDetect ATTR-CMResourcesMaterialsVideosTreatment Option
Detect ATTR-CM

What is nuclear scintigraphy?

Nuclear scintigraphy using both planar and single-photon emission computed tomography (SPECT) imaging is a noninvasive, commonly available diagnostic tool with high sensitivity and specificity for ATTR-CM when combined with testing to rule out immunoglobulin light chain (AL) amyloidosis.1-3

To facilitate early diagnosis of ATTR-CM, nuclear scinitigraphy should be more broadly considered in patients with the following3:

  • Unexplained increased left ventricular (LV) wall thickness
  • Heart failure with preserved ejection fraction (HFpEF)
  • Familial amyloid polyneuropathy
  • Family history of amyloidosis
  • Low-flow, low-gradient degenerative aortic stenosis in the elderly
  • History of bilateral carpal tunnel syndrome
Nuclear scintigraphy and the importance of collaboration

David Wolinksy, MD, FACC, MASNC, Section Head, Nuclear Cardiology, Cleveland Clinic Florida, and Past President, American Society of Nuclear Cardiology

Evidence for nuclear scintigraphy
  • Nuclear scintigraphy with 99mTc-PYP/99mTc-DPD/99mTc-HMDP* provides a unique myocardial uptake pattern in amyloid3
  • Nuclear scintigraphy may identify ATTR deposits early in the course of disease3
  • Studies comparing 99mTc-PYP/99mTc-DPD/99mTc-HMDP* scintigraphy with endomyocardial biopsy (EMB) found that bone radiotracers have avidity for ATTR deposits, whereas avidity for immunoglobulin light chain amyloid fibril protein (AL) cardiac amyloid deposits is minimal or absent3
  • According to the expert recommendations, SPECT imaging is required in all studies (irrespective of time between injection and scan) to ensure direct visualisation of tracer uptake in the myocardium3
Specificity of nuclear scintigraphy for ATTR-CM​​​​​​​A multicentre international study of scintigraphy at amyloid centres of excellence demonstrated 100% specificity for ATTR-CM using visual grade 2 or 3 with concurrent testing to rule out AL amyloidosis.1 ​​​​​​​99mTc-PYP/99mTc-DPD/99mTc-HMDP is not approved for the diagnosis of ATTR-CM. Please consult individual labelling for risks.Important considerations for the acquisition of 99mTc-PYP/99mTc-DPD/99mTc-HMDP* imagingMultisocietal expert consensus recommendations for diagnosing ATTR-CM with nuclear scintigraphy3†
  • 99mTc-PYP/99mTc-DPD/99mTc-HMDP* has avidity for cardiac amyloid deposits3
  • The recommended time between injection of 99mTc-PYP/99mTc-DPD/99mTc-HMDP* and scan is 2 or 3 hours3; 1-hour planar-only imaging is not recommended3
  • Both planar and SPECT imaging should be reviewed and interpreted using visual and quantitative approaches irrespective of the timing of acquisition3
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 of Amyloidosis, Society for Cardiovascular Magnetic Resonance, and Society of Nuclear Medicine and Molecular Imaging.
Step 1: Visual interpretation3
  • Evaluate planar and SPECT images to confirm diffuse radiotracer uptake in the myocardium
  • Differentiate myocardial radiotracer uptake from residual blood pool activity, focal myocardial infarct, 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

If myocardial tracer uptake is visually present on SPECT, proceed to step 2, semiquantitative visual grading

Illustrative representation of 99mTc-PYP/99mTc-DPD/99mTc-HMDP* uptake. ​​​​​

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

If no myocardial tracer uptake is present on SPECT, the visual grade is 0

Illustrative representation of 99mTc-PYP/99mTc-DPD/99mTc-HMDP* uptake.

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

Step 2: Semiquantitative  
  • Semiquantitative visual grading comparison to bone (rib) uptake at 3 hours3
  • Examine planar and SPECT images for tracer uptake in the myocardium relative to ribs and grade using the following scale:

Illustrative representation of 99mTc-PYP/99mTc-DPD/99mTc-HMDP* uptake.
Adapted from Dorbala et al. Expert consensus recommendations for multimodality imaging in cardiac amyloidosis. J Nucl Cardiol. 2019.

Visual scoring method in relation to bone (rib) uptake at 3 hours3

  • Strongly suggestive of ATTR-CM: Visual grade of ≥2 on planar and SPECT images with concurrent testing to rule out AL3
  • Not suggestive or equivocal of ATTR-CM: Visual grade of <23

When cardiac amyloidosis is suspected, Grade 2 or 3 myocardial uptake with concurrent testing to rule out AL is diagnostic of ATTR-CM.3*†

99mTc-PYP/99mTc-DPD/99mTc-HMDP uptake could be seen in other causes of myocardial injury, including pericarditis, myocardial infarction (regional uptake), and chemotherapy- or drug-associated myocardial toxicity.Rule out AL: testing for presence of monoclonal protein via serum and urine immunofixation (IFE) and serum free light chain (SFLC) assay.1
Step 3: H/CL uptake ratio assessment (when applicable)3  Diagnosis of ATTR-CM 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 grade3
  • 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
An H/CL ratio is calculated as the fraction of heart region of interest (ROI) mean counts to contralateral lung ROI mean counts3
  • H/CL ratios of ≥1.5 at 1 hour can accurately identify ATTR-CM 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 ratio4

Illustrative representation.

99mTc-PYP/99mTc-DPD/99mTc-HMDP is not approved for the diagnosis of ATTR-CM. Please consult individual labelling for risks.

99mTc-DPD, 99mtechnetium-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid; 99mTc-HMDP, 99mtechnetium-labelled hydroxymethylene diphosphonate; 99mTc-PYP, 99mtechnetium-labelled pyrophosphate. 

Review more information about nuclear scintigraphy. Download Loading

EMB—An invasive approach to diagnosing ATTR-CM

If clinical suspicion for cardiac amyloidosis remains high despite a negative or inconclusive scintigraphy scan, consider EMB.1
EMB requires histology with positive Congo red staining with apple-green birefringence, which is also used to diagnose ATTR-CM.1,5

Congo red staining of myocardial tissue on light microscopy and apple-green birefringence on polarised light microscopy images1 Congo red positive staining for amyloid myocardial biopsy image Apple-green birefringence  myocardial biopsy image Illustrative representation.
  • To determine amyloid type, immunohistochemistry (IHC) tests and/or mass spectrometry should be performed1
  • Risk of complications and the need for specialised centres and expertise may contribute to a diagnostic delay1,5

Genetic testing—used in the ATTR-CM diagnostic process

  • Used to determine if the disease is hereditary due to a mutation in the TTR gene or if it is wild-type6
  • Genetic counselling and gene sequencing are recommended following confirmation of ATTR-CM6
The diagnostic flowchart takes you through the first signs of ATTR-CM to diagnosis7

An approach for patients with suspected cardiac amyloidosis that includes testing for monoclonal protein followed by scintigraphy and/or biopsy7

Dr. Detective Series: Detecting ATTR-CM

Meet Dr. Detective, a cardiologist who specialises in diagnosing tough cases. Watch as he detects ATTR-CM in his patients.

Encountering ATTR-CM

Raising suspicion of ATTR-CM

Detecting ATTR-CM

ATTR-CM Resources > LoadingReferences: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 Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. 99mTc-Pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging. 2013;6(2):195-201. doi:10.1161/CIRCIMAGING.112.000132Dorbala 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(6):2065-2123. doi:10.1007/s12350-019-01760-6. Addendum: J Nucl Cardiol. Published online July 1, 2021. doi:10.1007/s12350-020-02455-zAmerican Society of Nuclear Cardiology (ASNC). ASNC practice points: 99mTechnetium-pyrophosphate imaging for transthyretin cardiac amyloidosis. Available at: © 2019 American Society of Nuclear Cardiology. 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. doi:10.1016/j.cjca.2016.05.008Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377. doi:10.1161/CIRCULATIONAHA.116.024438 Maurer MS, Bokhari S, Damy T, et al. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail. 2019;12(9):1-11. doi:10.1161/CIRCHEARTFAILURE.119.006075
ATTR-CM What imaging modalities help raise suspicion of ATTR-CM?

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