Cardiac Amyloid Imaging with Tc-99m PYP - Challenges and Potential Solutions

Guest Bloggers: Vivek Singh, DO and Renee P. Bullock-Palmer, MD, FACC, FAHA, FASNC, FASE, FSCCT, Deborah Heart and Lung Center, Browns Mills, NJ *****
Cardiac Amyloidosis (CA) refers to abnormal deposition of misfolded proteins that occur specifically in the heart. This is a progressive disorder which can lead to nearly irreversible damage in the heart, typically in the form of cardiomyopathy and/or arrhythmias. There are two major types of Cardiac Amyloidosis: Light-Chain (AL) Amyloidosis and Transthyretin (ATTR) Amyloidosis, of which ATTR Amyloidosis can be further subdivided into Wild-Type and Mutant ATTR. It is important to distinguish each subtype of CA as early as possible due to the implications each may have involving possible therapies and familial genetic testing.
CA is not as uncommon as once postulated and remains a relatively underdiagnosed pathologic process. Over three decades ago, it was shown that the bone avid radiotracer Technetium-99m pyrophosphate (Tc-99m) PYP can be used to non-invasively diagnose Transthyretin CA (TTR-CA).1,2 Furthermore, there have been several published studies within the realm of Nuclear Cardiology in the last 10 years that show that Tc-99m PYP scintigraphy with single photon emission computed tomography (SPECT) can accurately differentiate TTR-CA from AL Cardiac Amyloidosis (AL-CA).(3,4) One of these was demonstrated by Bokhari et al. who showed that Tc-99m PYP scintigraphy can be used to differentiate TTR-CA from AL-CA with a sensitivity of 97% and a specificity of 100%.3 To add to this, Gillmore et al. had shown that when Tc-99m PYP scintigraphy was performed along with serum and urine clonal analysis to exclude monoclonal gammopathy, the combined findings of grade 2 or 3 myocardial radiotracer uptake on scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for TTR-CA of 100% (positive predictive value confidence interval, 98.0 to 100).4 Even though endomyocardial biopsy is still considered the gold-standard at diagnosing CA, these studies show that it is feasible to forego invasive testing with non-invasive nuclear cardiac imaging when diagnosing TTR-CA.4
Tc-99m PYP scintigraphy with SPECT is the current preferred method in cardiac imaging in the United States for diagnosing TTR-CA. It is important to understand how this test is properly performed and interpreted before discussing any challenges it may bring. When a patient presents for testing, the first step involves an injection of Tc-99m PYP into a peripheral vein. The Tc-99m PYP gives off gamma rays as it moves throughout the body and after one hour, planar and SPECT imaging are taken to determine where the Tc-99m PYP has collected in the body. If there is evidence of blood pool activity, optional delayed imaging should be acquired after three hours as per the most recent ASNC Practice Points regarding Tc-99m PYP for TTR-CA.5,6 Once images are obtained, both semiquantitative and quantitative approaches are performed to evaluate uptake in the heart. The semiquantitative grading involves using the Perugini scale to compare heart to rib uptake: grade 0 is no cardiac and normal rib uptake; grade 1 is cardiac less than rib uptake; grade 2 is cardiac equal to rib uptake; and grade 3 is cardiac greater than rib uptake with mild/absent rib uptake. Quantitative analysis involves comparison of mean counts as determined by a region of interest placed over the heart and compared with a similar sized region of interest placed over the contralateral chest. In the absence of a light chain abnormality, the Tc-99m PYP scan is diagnostic of TTR-CA if there is grade 2 to 3 cardiac uptake or a heart/contralateral chest ratio >1.5.5,6  As stated previously, studies have shown that Tc-99m PYP has distinct affinity for binding to transthyretin proteins.3 However, Tc-99m PYP also has high affinity for areas of bone with altered osteogenesis, damaged myocardial cells (usually after acute MI), and red blood cells, specifically visualized in areas of blood pooling. Therefore, it is important that SPECT images are obtained and assessed in all positive scans to confirm that uptake represents myocardial retention of the tracer and not blood pool uptake6 (Figure 1). Concomitant collection of serum free light chain concentration and serum and urine immunofixation should be obtained in all patients undergoing imaging to rule out AL-CA as Tc-99m PYP does not typically detect the presence of AL-CA.(6,7,8,9) Regardless, Tc-99m PYP with SPECT imaging has demonstrated excellent diagnostic accuracy for TTR-CA without the need for invasive procedures.4

Figure 1. Case example of patient with Tc99m- pyrophosphate scan with planar and SPECT imaging that was positive for TTR type cardiac amyloidosis (TTR-CA). The planar images (A) show a quantitative heart to contralateral lung (H/CL) ratio of 1.86 which is strongly suggestive of TTR-CA. Diffuse myocardial uptake was confirmed on SPECT (B) including Cardiac SPECT (C) images with a visual semi quantitative score of Grade 3 with myocardial uptake being greater than rib uptake. SPECT images also ruled out blood pool uptake.

Figure 2. Case example of a patient who had a Tc99m- pyrophosphate scan with SPECT imaging (A) and planar imaging (B) that were equivocal for TTR type cardiac amyloidosis (TTR-CA) due to blood pool uptake.
There are also various challenges to keep in mind when using Tc-99m PYP as a diagnostic tool for TTR-CA. One of the most common challenges that occurs with the use of Tc-99m PYP is false positive testing due to blood pool uptake (Figure 2). Since Tc-99m PYP has affinity for red blood cells, chambers of the heart with pooling of blood can show uptake of Tc-99m PYP which can be misinterpreted as a positive study. In addition, uptake by overlying breast tissue, degenerative bone disease, parenchymal lung processes such as consolidation and atelectasis, and attenuation from overlying devices on the chest wall can all result in false positives when using planar imaging alone.10 Another common issue with the use of Tc-99m PYP is that, often, patients are not appropriately ruled out for AL-CA using clonal analysis. This can result in the diagnosis of AL-CA being missed. Since Tc-99m PYP has a high affinity for damaged myocardial cells, patients who have had a previous myocardial infarction can also have false positive testing, though this uptake is usually seen as focal and not diffuse.5,6  There have also been reports of Hydroxychloroquine toxicity causing false positives.11 As per the 2019 ASNC Practice Points regarding Tc-99m PYP for TTR-CA5, patient selection is crucial and Tc-99m PYP should be considered in the following clinical situations:
  • Individuals with heart failure and unexplained increase in left ventricular wall thickness.5
  • African-Americans over the age of 60 years with unexplained recurrent heart failure with preserved left ventricular ejection fraction (HFpEF) or with increased left ventricular wall thickness (>12 mm).5
  • Individuals over the age of 60 years with unexplained heart failure with preserved ejection fraction.5
  • Individuals, especially elderly males, with unexplained neuropathy, bilateral carpal tunnel syndrome or atrial arrhythmias in the absence of usual risk factors, and signs/symptoms of heart failure.5
  • Evaluation of cardiac involvement in individuals with known or suspected familial amyloidosis.5
  • Diagnosis of TTR-CA in individuals with cardiac MRI or echocardiography consistent with CA.5
  • Patients with suspected TTR-CA and contraindications to cardiac MRI such as renal insufficiency or presence of a non-MRI compatible cardiac device.5
Finally, once the diagnosis of TTR-CA is reached, it is important to remember to perform genetic testing for the transthyretin gene because the presence of a pathologic mutation can affect clinical trial options, predict sites of organ involvement, and have relevance for family members.12
Some of the above challenges with Tc-99m PYP for TTR-CA have been addressed with recent advancements in nuclear imaging as well as education among the medical community. The use of SPECT/CT imaging concomitantly with planar imaging, helps to minimize false positive Tc-99m PYP scans from blood pooling.5,6,10 Even with use of conventional SPECT imaging there are still a proportion of studies where blood pool uptake cannot be confidently ruled out. Cadmium zinc telluride (CZT) SPECT-CT systems show promise with regards to precise location of radiotracer uptake to determine whether or not there is blood pool uptake and can also be used to quantify myocardial radiotracer uptake. An editorial published in October 2019 by Ramsay et al. discussed how CZT SPECT-CT systems can be useful to quantify radiotracer uptake of PYP in the myocardium when assessing for the presence of TTR-CA.13 A small study published recently by Wojtylak et al. showed that combined SPECT-CT technique is useful to more precisely localize the area of radiotracer uptake of PYP with improved image quality and use of cardiac CT to localize the myocardium which could potentially improve the diagnostic ability of these studies when compared to studies done with conventional gamma cameras.14 However, CZT SPECT-CT systems are not as widely available when compared with gamma camera systems. For labs that do not have this latest camera system, dual-isotope imaging with Tl-201/Tc-99m may be useful in more precise localization of the myocardium to determine myocardial uptake and to more confidently rule out blood pool uptake. In a study published by Tamarappoo et al. in 2019, it was shown that dual-isotope imaging improves visual localization of radiotracer uptake to determine whether or not blood pool uptake is present and therefore decreases the rate of equivocal studies.15 This study also showed that dual-isotope imaging with Tl-201/Tc-99m was a significantly better predictor of TTR-CA when compared with single isotope Tc-99m-PYP imaging.15 There are also currently several other radiotracers with different imaging modalities, such as PET, being studied to determine their efficacy in regards to the diagnosis of CA.6
With this technology evolving so rapidly, it is important to properly educate clinicians who refer their patients for Tc-99m PYP scintigraphy. These clinicians need to be aware of the recommended patient selection for Tc-99m PYP scans, required co-testing, and how to appropriately manage follow-up care once results are obtained. One specific solution would be to implement a system where an electronic medical record can automatically add-on a plasma cell clonal analysis lab order set when Tc-99m PYP testing is initially ordered. This is frequently overlooked and can ultimately result in a missed diagnosis. It is also important to make this recommendation of performing clonal analysis to rule out AL-CA in all Tc-99m-PYP study reports regardless of the results. This was a recommendation made in the latest edition of the ASNC PYP Practice Points document.5 The same is true with regards to the recommendation of genetic testing for patients diagnosed with TTR-CA to differentiate mutant variants of this disease from the wild-type form. Providing this recommendation for genetic testing in the report upon the interpretation of a positive Tc-99m PYP study may be helpful to remind providers to perform this vital part of the diagnostic pathway for these patients. Table 1 outlines the challenges and potential solutions when diagnosing TTR-CA with Tc-99m-PYP Cardiac SPECT imaging.
Table 1. An outline of the challenges and potential solutions when diagnosing TTR-CA with Tc-99m-PYP Cardiac SPECT imaging


Potential Solutions

Difficulty determining blood pool uptake from myocardial uptake resulting in equivocal studies or false positive studies

  1. Use of Cardiac SPECT imaging5,6

  2. Use of SPECT/CT hybrid imaging13,14

  3. Use of Tl-201/Tc-99m PYP dual isotope imaging15

Lack of performing concomitant clonal analysis to rule out the presence of AL-cardiac amyloidosis when performing Tc-99m PYP imaging for TTR-cardiac amyloidosis

  1. Use of clonal analysis order set and prompts in the electronic medical record upon ordering Tc-99m PYP imaging for TTR-cardiac amyloidosis

  2. Provider education

Lack of performing genetic testing to determine the presence of wild-type vs. mutant forms of TTR-CA for patients diagnosed with TTR-CA after positive Tc-99m PYP test

  1. Provider education

  2. Providing this recommendation in the report upon the interpretation of a positive Tc-99m PYP study

Inappropriate referrals of patients with low likelihood for the presence of TTR-CA

  1. Provider education and raising awareness

The use of Tc-99m PYP scintigraphy has set the stage for non-invasive diagnosis of TTR-CA, especially with the addition of plasma cell clonal analysis. Although challenges do exist with interpretation of testing as well as ensuring a complete and proper workup, recent advancements in the field of nuclear cardiology have allowed for this to be a reliable method to detect TTR-CA, a disease process that has thus far been under recognized among clinicians.16
1. Wizenberg TA, Muz J, Sohn YH, Samlowski W, Weissler AM. Value of positive myocardial technetium-99m-pyrophosphate scintigraphy in the noninvasive diagnosis of cardiac amyloidosis. Am Heart J 1982;103(4 Pt 1):468-73.
2. Gertz MA, Brown ML, Hauser MF, Kyle RA. Utility of technetium Tc 99m pyrophosphate bone scanning in cardiac amyloidosis. Arch Intern Med 1987;147(6):1039-44.
3. Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-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.
4. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133(24):2404-12.
5. Dorbala S, Bokhari S, Miller E, Bullock-Palmer R, Soman P, Thompson R. ASNC Practice Points: 99mTechnetium-Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis (American Society of Nuclear Cardiology website). 2019. Available at Accessed February 2019.
6.  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;26:2065-123.
7. Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, Chang PP, Eisen HJ, Nair AP, Nativi-Nicolau J, Ruberg FL; Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association. American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Circulation. 2020 Jul 7;142(1):e7-e22. doi: 10.1161/CIR.0000000000000792. Epub 2020 Jun 1. PMID: 32476490
8. Castano A, Haq M, Narotsky DL, Goldsmith J, Weinberg RL, Morgenstern R, Pozniakoff T, Ruberg FL, Miller EJ, Berk JL, et al. Multicenter study of planar technetium 99m pyrophosphate cardiac imaging: predicting survival for patients with ATTR cardiac amyloidosis. JAMA Cardiol. 2016;1:880–889. doi: 10.1001/jamacardio.2016.2839.
9. Palladini G, Russo P, Bosoni T, Verga L, Sarais G, Lavatelli F, Nuvolone M, Obici L, Casarini S, Donadei S, et al. Identification of amyloidogenic light chains requires the combination of serum-free light chain assay with immunofixation of serum and urine. Clin Chem. 2009;55:499–504. doi 10.1373/clinchem.2008.117143.
10. Alkordy, T., Romsa, J., & Akincioglu, C. (2020). Tc-99m-PYP Planar Scan Pitfalls in the Assessment of Cardiac Amyloidosis. Journal of Nuclear Medicine, 61(1). Abstract May 2020
11. Chang ICY, Bois JP, Bois MC, Maleszewski JJ, Johnson GB, Grogan M. Hydroxychloroquine-Mediated Cardiotoxicity With a False-Positive 99mTechnetium-Labeled Pyrophosphate Scan for Transthyretin-Related Cardiac Amyloidosis. Circ Cardiovasc Imaging. 2018 Jan;11(1):e007059. doi: 10.1161/CIRCIMAGING.117.007059. PMID: 29288196.
12. Witteles, R. (2016, July 7). Cardiac Amyloidosis [Web log post]. Retrieved January 25,     
2021, from
13.  Ramsay, S.C., Cuscaden, C. The current status of quantitative SPECT/CT in the assessment of transthyretin cardiac amyloidosis. J. Nucl. Cardiol. 27, 1464–1468 (2020).
14. Wojtylak P, Avril N and Kardan A. Feasibility and initial experience in the utilization of a fully digital CZT SPECT/CT system for the diagnosis of transthyretin cardiac amyloidosis (ATTR). Journal of Nuclear Medicine May 2020, 61 (supplement 1) 3040;
15. Tamarappoo B, Otaki Y, Manabe O, Hyun M, Cantu S, Arnson Y, Gransar H, Hayes SW, Friedman JD, Thomson L, Slomka P, Dey D, Vescio R, Patel J, Berman DS.Simultaneous Tc-99m PYP/Tl-201 dual-isotope SPECT myocardial imaging in patients with suspected cardiac amyloidosis. J Nucl Cardiol. 2020 Feb;27(1):28-37. doi: 10.1007/s12350-019-01753-5. Epub 2019 Jun 6. PMID: 31172386
16. Galant NJ, Westermark P, Higaki JN, Chakrabartty A. Transthyretin amyloidosis: an under-recognized neuropathy and cardiomyopathy. Clin Sci (Lond). 2017 Mar 1;131(5):395-409. doi: 10.1042/CS20160413. PMID: 28213611 Review.
Vivek Singh, DO
First year cardiology fellow at Deborah Heart and Lung Center, Browns Mills, NJ 08015
Renee P. Bullock-Palmer, MD, FACC, FAHA, FASNC, FASE, FSCCT
Chair of ASNC's Social Media Task Force committee. Attending Cardiologist. Director of Non-Invasive Cardiac Imaging, Director of the Women's Heart Center, Deborah Heart and Lung Center, Browns Mills, NJ

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