Original Article
Quantitative 99mTc-DPD-SPECT/CT assessment of cardiac amyloidosis

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Abstract

Introduction

Transthyretin (ATTR) amyloidosis is responsible for the majority of cardiac amyloidosis (CA) cases and can be reliably diagnosed with bone scintigraphy and the visual Perugini score. We aimed to implement a quantification method of cardiac amyloid deposits in patients with suspected cardiac amyloidosis and to compare performance to visual scoring.

Methods and materials

136 patients received 99mTc-DPD-bone scintigraphy including SPECT/CT of the thorax in case of suspicion of cardiac amyloidosis. Imaging phantom studies were performed to determine the scaling factor for standardized uptake value (SUV) quantification from SPECT/CT. Myocardial tracer uptake was quantified in a whole heart volume of interest.

Results

Forty-five patients were diagnosed with CA. A strong relationship between cardiac SUVmax and Perugini score was found (Spearman r 0.75, p < 0.0001). Additionally, tracer uptake in bone decreased with increasing cardiac SUVmax and Perugini score (p < 0.0001). ROC analysis revealed good performance of the SUVmax for the detection of ATTR-CA with AUC of 0.96 ± 0.02 (p < 0.0001) with sensitivity 98.7% and specificity 87.2%.

Conclusion

We demonstrate an accessible and accurate quantitative SPECT approach in CA. Quantitative assessment of the cardiac tracer uptake may improve diagnostic accuracy and risk classification. This method may enable monitoring and assessment of therapy response in patients with ATTR amyloidosis.

Introduction

Cardiac amyloidosis (CA) is an underdetected cause for heart failure which has significantly gained attention in the past years.1,2 Systemic amyloidosis is a disorder that leads to extracellular deposition of misfolded proteins affecting organ function. In the vast majority of cases light-chain (AL) or transthyretin (ATTR) amyloid deposits are responsible for CA, leading to systolic and diastolic dysfunction, hypertrophy, arrhythmias, conduction blocks, and heart failure. Cardiac involvement is the most significant prognostic factor in patients with amyloidosis.3, 4, 5, 6, 7 AL amyloidosis can be treated with different anti-plasma cell regimens.8 In case of hematological response5 organ responses with improving organ function are possible. In ATTR amyloidosis disease specific therapeutic approaches include transthyretin stabilizers or transthyretin gene silencers.

Until recently endomyocardial biopsy has been the “gold standard” for diagnosing all types of cardiac amyloidosis, but non-invasive strategies are emerging.3,9,10 It has been known for few years now that accumulation of bone-seeking radiopharmaceuticals like 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) have very high accuracy in diagnosing ATTR amyloidosis. In 2005, a visual scoring system known as the Perugini score was introduced.11 In 2016, a large multicenter study showed that substantial cardiac radiotracer uptake (Perugini score >1) on bone scintigraphy yields a specificity of 100% for cardiac ATTR amyloidosis when plasma cell disease is excluded.3 In light of these findings, new diagnostic algorithms were implemented, and bone scintigraphy is becoming increasingly important in the diagnostic and differentiation of cardiac amyloidosis often obviating the need for endomyocardial biopsy.12

Currently the visual interpretation and scoring of the myocardial uptake of 99mTc-phosphate tracers based on Perugini is the standard in clinical practice. Nonetheless, there are certain limitations due to lack of reliable quantification and frequent neglection of SPECT/CT data.

Methods for quantitative SPECT have been emerging in the last years but “real-life” applications are still lacking. The previous unavailability of accurate SPECT reconstructions is being increasingly replaced by hybrid SPECT/CT systems, which can be setup for true quantification or are intrinsically capable of tracer quantification.13

Quantification of cardiac tracer uptake could enhance diagnostic capabilities of bone scintigraphy and allow assessment of disease progression and therapy response. So far only a few studies have investigated different approaches to (semi-)quantify tracer uptake in cardiac amyloidosis.14, 15, 16 A recent study showed similar or slightly better sensitivity and specificity for detection of transthyretin amyloidosis with semiquantitative parameters compared to visual scoring.17 First approaches for true quantitative SPECT/CT in CA have been reported using commercially available SPECT/CT quantification methods.16,18 These methods either rely on manually adjusted volume of interests or threshold based isocontours, which are prone to misinterpretation in patients with low or no cardiac tracer uptake.16,18 Further these methods are bound to commercially available software solutions and not easily transferable to other institutions. Despite that, their results showed the feasibility of this technique. The aim of this study was to implement an accessible, accurate and robust whole heart quantification method for cardiac amyloid deposits in patients with suspected cardiac amyloidosis and to compare results to visual Perugini scoring.

Section snippets

Study population

Between 10/2017 and 05/2020 149 patients with suspected CA were referred to the nuclear medicine facility. 136 patients were imaged with a 99mTc-DPD scintigraphy including SPECT/CT of the thorax in the routine diagnostic workup of suspected CA (Figure 1) and were included in the quantitative assessment. CA was diagnosed according to the Gillmore Criteria3 by endomyocardial biopsy or bone scans and analysis of protein electrophoresis, serum free light-chain assay and immunofixation in urine and

Study population

The study included 136 patients (89 male, 47 female) with a mean age of 76 ± 10 years. Patients were injected with a mean activity of 99mTc-DPD of 523 ± 27 MBq (range 484-635). Late static images approximately 3h p.i. were used for analysis. Most patients was referred for 99mTc-DPD scintigraphy because of heart failure with preserved ejection fraction (n = 69) or reduced ejection fraction (n = 58), nine patients were referred due to extracardiac amyloid deposits and six patients with suspected

Discussion

In this study we propose a whole heart quantitative assessment of cardiac DPD tracer uptake in a large group of patients. Further, the diagnostic performance is comparable to the Perugini scoring system with partially higher sensitivity for the detection of CA.

Quantitative approaches may further increase the diagnostic value of bone scintigraphy for CA and have the potential to more thoroughly assess the burden of amyloid deposits, which is crucial to better risk-stratify patients with CA and

New Knowledge Gained

To our knowledge this is the first study using a whole heart delineation for 99mTc-DPD SPECT/CT quantification in large cohort with suspected cardiac amyloidosis. Whole heart SPECT/CT absolute quantification shows strong correlation with the visual Perugini score and high diagnostic performance with SUVmax cut-off >6.1. Specificity of our approach can be increased to 99% by ruling out elevated monoclonal proteins. This method is accessible and easily implementable at other centers.

Funding

Open Access funding enabled and organized by Projekt DEAL.

Disclosure

L. K. is consultant for BTG and AAA and received fees from Sanofi outside of the submitted work. T.R: has nothing to disclose. P.F.C. has nothing to disclose. W.J. has nothing to disclose. D.K. has nothing to disclose. M.M. is consultant for Boston Scientific and received fees outside from the submitted work. T.H: has nothing to disclose. P.L. has nothing to disclose. C.R. reports grants and other from Pfizer, other from Alnylam, other from GE, personal fees from Pharmtrace, other from Siemens,

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    Maria Papathanasiou and Christoph Rischpler are senior authors contributed equally.

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