EDITORIAL

Quantifying is believing: Techniques

for evaluating transthyretin cardiac amyloidosis
burden for expanded clinical applications
Robert J. H. Miller, MD ,a and Nowell Fine, MD, SMa
a
Libin Cardiovascular Institute and Department of Cardiac Sciences, University of Calgary,
Calgary, AB, Canada

Received Nov 15, 2021; accepted Nov 16, 2021

doi:10.1007/s12350-021-02880-8

threshold established relative to aortic blood pool

See related article, https://doi.org/10.10
activity. The authors demonstrated high diagnostic
07/s12350-021-02857-7. accuracy for CPV using a threshold of 1.29 aortic blood
pool activity (CPV1.2), with area under the receiver-
operating characteristic curve (AUC) of 0.96. AUC was
The clinical use of bone radiotracer imaging for the numerically lower for CPV using a threshold of 1.4
diagnosis of transthyretin cardiac amyloidosis (ATTR- (AUC 0.89) as well as heart contralateral lung (H/CL)
CM) is growing exponentially.1,2 The combination of ratio (AUC 0.91). A major strength of the study is that
highly accurate non-invasive testing and targeted ther- all patients underwent endomyocardial biopsy or had
apies which demonstrate clinical benefit,3,4 has created a positive genetic testing (with other evidence of car-
perfect storm for increasing use and ongoing advance- diomyopathy) to adjudicate a diagnosis of ATTR-CM.
ment of the technique. As a result, patients with less These promising results support the concept that quan-
advanced disease are being referred for imaging tification of bone radiotracer uptake is feasible and has
including patients with identified genetic mutations high diagnostic accuracy for the detection of ATTR-
during cascade screening without evidence of heart CM.
failure.5,6 With changing referral patterns, there has been There are a few limitations to this study which
increasing focus on the need to confirm diffuse should be acknowledged.8 The population sample was
myocardial radiotracer uptake on single photon emission relatively small and as a result diagnostic accuracy was
computed tomography (SPECT) imaging to ensure not statistically different between any of the proposed
accurate diagnosis.2,7 With the growing importance of methods.8 Therefore, larger studies are needed to more
SPECT, there have also been several efforts at quanti- conclusively demonstrate the high diagnostic accuracy
fying radiotracer uptake from the images. of CPV. The proposed measurements are dependent on
In this issue of the Journal of Nuclear CardiologyÒ, placement of volumes of interest, which could be subject
Watanabe et al present one method for volumetric to interobserver variability leading to some variability in
quantification of 99mtechnetium pyrophosphate (99mTc- measurements. However, our group described a similar
PYP) activity.8 The authors included 25 patients who method, using SPECT images, with low interobserver
underwent SPECT with computed tomography (CT) variability and excellent agreement on the presence of
attenuation correction imaging. Using SPECT-CT ima- abnormal activity.9 This task would be simplified with
ges, cardiac pyrophosphate volume (CPV) was the use of CT attenuation correction images to provide
measured as the volume of 99mTc-PYP activity above a anatomic localization, making this limitation relatively
minor. Lastly, the authors applied their analysis to
images performed 3 hours post radiotracer injection, and
Reprint requests: Robert J. H. Miller, MD, Libin Cardiovascular
Institute and Department of Cardiac Sciences, University of Calgary, additional studies are needed to determine if the pro-
Calgary, AB, Canada; robert.miller@albertahealthservices.ca, posed method, and threshold values for CPV, could be
robert.miller@ahs.ca similarly applied to SPECT/CT imaging performed at 1
J Nucl Cardiol or 2-hours.10
1071-3581/$34.00
There are now several methods which have been
Copyright Ó 2021 The Author(s) under exclusive licence to American
Society of Nuclear Cardiology proposed to quantify bone radiotracer uptake from
 Miller and Fine Journal of Nuclear CardiologyÒ
Quantitative analysis for cardiac amyloidosis

Table 1. Selected studies investigating quantitative single photon emission computed tomography
image analysis

Study Isotope Measurement Results

Ramsay et al HMDP SUVmax Patients with ATTR-CM had higher SUVmax compared to patients
(2018)16 without ATTR-CM
Scully et al DPD SUVpeak, Diagnostic accuracy 0.999 for SUVpeak and SUV retention index.
(2020)15 SUV retention SUVpeak had good correlation with ECV by CT (r2 = 0.73)
index
Dorbala et al PYP SUVmean, SUVmax, All measures had diagnostic accuracy [ 0.96. Moderate
(2020)12 CAA, %ID correlations with LVMI (r2 = 0.105–0.235) and good
correlations with ECV by CMR (r2 = 0.619–0.762)
Ben Haim DPD SUVmax, SUVmean Both methods had perfect accuracy for distinguishing grade 0
et al above threshold uptake. One patient with AL had abnormal quantitation.
(2021)13
Miller et al PYP VOI, CPA CPA and VOI had diagnostic accuracy of 0.996. Moderate
(2021)9 correlations with LVEF (r2 = 0.176). Associated with heart
failure hospitalizations
Ren et al PYP SUVmax SUVmax significantly higher in patients with ATTR-CM compared
(2021)14 to AL. Higher SUVmax with increasing planar grade
Roshankar PYP VOI, CPA Moderate correlations with native T1 (r2 = 0.502–0.617) and
et al ECV by CMR (r2 = 0.515). Associated with heart failure
(2021)11 hospitalization or cardiovascular death.
Watanabe PYP SUVmax, CPV1.2, Diagnostic accuracy 0.96 for CPV1.2 and 0.89 for CPV1.4.
et al CPV1.4 Moderate correlations with LVEF (r2 = 0.36) and LVPWTd
(2021)8 (r2 = 0.46)

CAA, cardiac amyloid activity, CMR, cardiovascular magnetic resonance, CPA, cardiac pyrophosphate activity, CPV, cardiac
pyrophosphate volume, CT, computed tomography, DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid, ECV, extracellular
volume, HMDP, hydroxymethylene diphosphonate, LVEF, left ventricular ejection fraction, LVPWTd, left ventricular posterior wall
thickness at end-diastole, PYP, pyrophosphate, SUV, standardized uptake value, VOI, volume of involvement

SPECT imaging.8,9,11–16 A few of these studies are visual interpretation of SPECT seems to be the optimal
outlined in Table 1. Some methods are based on mea- method for disease diagnosis since it has similarly high
suring maximal standardized uptake volumes (SUVmax). diagnostic accuracy compared to these quantitative
However, there may be some inaccuracy to SUVmax approaches and is substantially simpler to perform.
measurements with SPECT compared to positron In the absence of differences in diagnostic accuracy,
emission tomography due to lower spatial resolution and it is necessary to consider the larger potential clinical
partial volume effects.17 Other efforts, like the one application and utility to determine which one mea-
proposed by Watanabe et al, are based on volumetric surement has the greatest efficacy. Quantitative
measurements. Volumetric measurements quantify assessment of bone radiotracer uptake could potentially
either volume of activity above a threshold or attempt to be used to non-invasively stage severity of disease,
quantify both volume and intensity of abnormal activity. estimate risk of cardiovascular events, or assess response
Volumetric measurements are potentially subject to to therapy. Correlations with other measures of disease
interobserver variability related to region of interest severity may be helpful in establishing these clinical
placement. Regardless, studies consistently demonstrate roles. Watanabe et al demonstrated correlations between
high diagnostic accuracy for these techniques with CPV and left ventricular ejection fraction. We demon-
AUCs ranging from 0.96 to 0.999. The minor variations strated that cardiac pyrophosphate activity (CPA) was
in AUC are most likely related to differences in referral correlated with left ventricular hypertrophy and left
patterns among these largely single center studies, and it ventricular ejection fraction.9 More recently we
is unlikely that one superior measure could be estab- demonstrated that CPA was also correlated with burden
lished on the basis of diagnostic accuracy alone. In fact, of late gadolinium enhancement and native myocardial
Journal of Nuclear CardiologyÒ Miller and Fine
Quantitative analysis for cardiac amyloidosis

T1 using cardiovascular magnetic resonance (CMR) therapeutic, on cardiac parameters in patients with hereditary
imaging.11 Dorbala et al demonstrated significant cor- transthyretin-mediated amyloidosis. Circulation 2019;139:431-43.
5. Fine NM, Davis MK, Anderson K, Delgado DH, Giraldeau G,
relations with extracellular volume estimates from Kitchlu A, et al. Canadian Cardiovascular Society/Canadian Heart
CMR.12 Many of the previously discussed studies have Failure Society joint position statement on the evaluation and
also demonstrated associations with clinical outcomes; management of patients with cardiac amyloidosis. Can J Cardiol
however, the patient sample sizes preclude making firm 2020;36:322-34.
conclusions based on these results. Overall, these studies 6. Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine NM,
et al. Screening for transthyretin amyloid cardiomyopathy in
provide some confidence that these measures may be everyday practice. JACC Heart Fail 2019;7:709-16.
useful for assessing disease burden non-invasively. 7. Dorbala S, Ando Y, Bokhari S, Dispenzieri A, Falk RH, Ferrari
Ultimately, beyond accurate diagnosis, the most VA, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI
important question is whether quantitative methods can expert consensus recommendations for multimodality imaging in
be used clinically to alter patient management and cardiac amyloidosis: Evidence base and standardized methods of
imaging. Circ Cardiovasc Imaging 2021;14:e000029.
improve patient outcomes. Given the significant cost 8. Watanabe S, Nakajima K, Hiroshi W, Yoneyama H, Yoshida S,
associated with novel disease-modifying therapies for Komatsu J, et al. Volumetric evaluation of 99mTc-pyrophosphate
ATTR-CM,18 methods to identify patients most likely to SPECT/CT for transthyretin cardiac amyloidosis: methodology
benefit could improve selection criteria, decreasing costs and correlation with cardiac functional parameters. J Nucl Cardiol
and improving patient outcomes. Alternatively, quanti- 2021;62:137.
9. Miller RJH, Cadet S, Mah D, Pournazari P, Chan D, Fine NM,
tative imaging could be used to determine response to et al. Diagnostic and prognostic value of Technetium-99m
therapy, an important knowledge gap in clinical prac- pyrophosphate uptake quantitation for transthyretin cardiac amy-
tice.19 Fontana et al demonstrated that quantification of loidosis. J Nucl Cardiol 2021. https://doi.org/10.1007/s12350-021-
SPECT/CT images, using measurement of precent 02563-4.
injected dose, decreased over time in a cohort of 16 10. Sperry BW, Burgett E, Bybee KA, McGhie AI, O’Keefe JH, Saeed
IM, et al. Technetium pyrophosphate nuclear scintigraphy for
patients with hereditary ATTR-CM treated with Pati- cardiac amyloidosis: Imaging at 1 vs 3 hours and planar vs
siran.20 Therefore, these techniques may be able to help SPECT/CT. J Nucl Cardiol 2020;27:1802-7.
identify patients who are not responding and could be 11. Roshankar G, White GC, Cadet S, Fine NM, Chan D, White JA,
switched to an alternative agent earlier before the onset et al. Quantitative technetium pyrophosphate and cardiovascular
of irreversible organ damage. Given the rate of progress magnetic resonance in patients with suspected cardiac amyloido-
sis. J Nucl Cardiol 2021. https://doi.org/10.1007/s12350-021-
in the field of nuclear imaging for ATTR-CM, it’s likely 02806-4.
that one or more of these clinical roles will become more 12. Dorbala S, Park MA, Cuddy S, Singh V, Sullivan K, Kim S, et al.
established in the near future. Absolute quantitation of cardiac (99m)Tc-pyrophosphate using
cadmium-zinc-telluride-based SPECT/CT. J Nucl Med
2021;62:716-22.
Disclosure 13. Ben-Haim S, Chicheportiche A, Goshen E, Arad M, Smekhov M,
Menezes LJ, et al. Quantitative SPECT/CT parameters of
Dr. Miller reports consulting support from Alnylam and myocardial 99mTechnetium-3,3-diphosphono-1,2-propanodicar-
Pfizer and research support from Pfizer. Dr. Fine reports boxylic acid (DPD) uptake in suspected cardiac transthyretin
research and consulting support from Pfizer, Akcea, Ionis, amyloidosis. EJNMMI Res 2021;11:86.
Alnylam, and Eidos. 14. Ren C, Ren J, Tian Z, Du Y, Hao Z, Zhang Z, et al. Assessment of
cardiac amyloidosis with (99m)Tc-pyrophosphate (PYP) quanti-
tative SPECT. EJNMMI Phys 2021. https://doi.org/10.1186/
s40658-020-00342-7.
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 Miller and Fine Journal of Nuclear CardiologyÒ
Quantitative analysis for cardiac amyloidosis

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