Original Article
18F-flutemetamol positron emission tomography in cardiac amyloidosis

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Abstract

Purpose

Bone-tracer scintigraphy has an established role in diagnosis of cardiac amyloidosis (CA) as it detects transthyretin amyloidosis (ATTR). Positron emission tomography (PET) with amyloid tracers has shown high sensitivity for detection of both ATTR and light-chain (AL) CA. We aimed to investigate the accuracy of 18F-flutemetamol in CA.

Methods

We enrolled patients with CA or non-amyloid heart failure (NA-HF), who underwent cardiac 18F-flutemetamol PET/MRI or PET/CT. Myocardial and blood pool standardized tracer uptake values (SUV) were estimated. Late gadolinium enhancement (LGE) and T1 mapping/ extracellular volume (ECV) estimation were performed.

Results

We included 17 patients (12 with CA, 5 with NA-HF). PET/MRI was conducted in 13 patients, while PET/CT was conducted in 4. LGE was detected in 8 of 9 CA patients. Global relaxation time and ECV were higher in CA (1448 vs. 1326, P = 0.02 and 58.9 vs. 33.7%, P = 0.006, respectively). Positive PET studies were demonstrated in 2 of 12 patients with CA (AL and ATTR). Maximal and mean SUV did not differ between groups (2.21 vs. 1.69, P = 0.18 and 1.73 vs. 1.30, P = 0.13).

Conclusion

Although protein-independent binding is supported by our results, the diagnostic yield of PET was low. We demonstrate here for the first time the low sensitivity of PET for CA.

Introduction

Cardiac amyloidosis (CA) is nowadays recognized as a major cause of heart failure (HF) with high mortality rates.1 For a long time, CA was considered a rare entity, mainly associated with immunoglobulin light-chain derived amyloid (AL) due to plasma cell dyscrasias. During the recent years, transthyretin amyloidosis (ATTR) was shown to be highly prevalent among older patients with left ventricular hypertrophy, HF with preserved ejection fraction and severe aortic valve stenosis, and represents probably the most underdiagnosed heart disease to date.2, 3, 4, 5 These two distinct disease phenotypes account for the overwhelming majority of CA cases and both are associated with a dismal prognosis. In AL-CA median survival can be < 6 months from the time of diagnosis depending on the severity of cardiac involvement.6 ATTR amyloidosis has a longer disease course with a median survival of 3.6 years for the acquired, wild-type disease and varying prognosis for the hereditary type of disease, depending on the underlying transthyretin gene mutation.7

The evolution of cardiac imaging techniques has contributed substantially to the raised awareness of the disease. Cardiac magnetic resonance imaging (MRI) is an established diagnostic method for myocardial disease. It enables tissue characterization and facilitates differential diagnosis of myocardial hypertrophy.8 Bone-tracer scintigraphy was the first method to enable non-invasive diagnosis of CA. Following the publication of a large-scale study on its diagnostic accuracy compared to endomyocardial biopsy, scintigraphy has played a pivotal role in redirecting the diagnostic pathway from the catheterization laboratory and the pathology bench to the outpatient setting and is now integrated in the diagnostic algorithm for the evaluation of patients with suspected CA.9,10 Despite this paradigm shift, bone-tracer scintigraphy does not enable non-invasive diagnosis of AL-CA and scarce data exist regarding its diagnostic yield at an early disease stage.

Aiming to fill this gap, positron emission tomography (PET) bears hope for the non-invasive diagnosis of both ATTR- and AL-CA by utilizing tracers with amyloid-specific affinity. Furthermore, due to its superior spatial resolution, quantitative analysis of tracer uptake has the potential to accurately estimate myocardial amyloid burden, facilitate prognosis and assess disease progression and response to therapy. Previous explorative studies demonstrated a high diagnostic accuracy of cardiac PET/CT for the detection of amyloid deposits of both ATTR and AL type in the heart.11, 12, 13, 14, 15, 16, 17, 18 A meta-analysis reported a sensitivity of 95% and a specificity of 98% for the detection of CA.19 The aim of the present study was to estimate the diagnostic accuracy of the amyloid-binding tracer 18F-flutemetamol in CA by using integrated PET/MR or low-dose PET/CT imaging protocols.

Section snippets

Study Patients and Study Design

We retrospectively included patients who presented at our clinic with suspected cardiac amyloidosis and underwent off-label 18F-flutemetamol PET/MRI or low-dose PET/CT as part of a comprehensive diagnostic evaluation for suspected CA. Patients were included in this retrospective analysis only if the diagnosis of CA was confirmed or excluded via established diagnostic methods i.e., myocardial biopsy or the combination of laboratory examinations with bone-tracer scintigraphy. Accordingly,

Results

Our analysis included 17 patients who underwent cardiac 18F-flutemetamol PET imaging, 12 patients with CA and 5 with NA-HF. The study patients received an integrated 18F-flutemetamol PET/MR (n = 13) or a low-dose 18F-flutemetamol PET/CT (n = 4). The selection of the imaging method is demonstrated in Figure 1. 18F-flutemetamol PET/MRI was the preferred imaging method and was substituted by 18F-flutemetamol PET/CT due to non-conditional implanted devices in 4 patients. Among the amyloidosis

Discussion

Radionuclide imaging with bone-avid tracers has emerged as a valuable diagnostic tool for the diagnosis of CA and has even replaced endomyocardial biopsy in certain clinical scenarios. Although the mechanism of tracer uptake and the selectivity of bone-avid tracers for ATTR are not completely understood, their accuracy has been well described.27 The method is widely available at a reasonable cost, but its value is confined to ATTR-CA. Detection of both AL and ATTR-CA with 18F- and 11C-labeled

New Knowledge Gained

In contrast to other available amyloid PET tracers the sensitivity of 18F-Flutemetamol for the diagnosis of cardiac amyloidosis was low > 30 minutes post injection. The appropriate imaging protocol for this specific radiotracer still needs to be defined, as tracer kinetics in myocardium and biologic properties of amyloid deposits may influence its diagnostic accuracy.

Funding

Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Universitätsmedizin Essen Clinician Scientist Academy (UMEA)/ German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) under Grant FU356/12-1 to MP and the DFG under Grant LU2139/2-1 to PL and under Grant RA969/12-1 to TR.

Conflicts of interest

The authors have no conflicts of interest.

Ethics Approval

The study was approved by the local institutional review board for retrospective data analysis (registry number: 19-5786-BO).

Data Availability

Clinical and image data are available for review upon request.

Funding

Open Access funding enabled and organized by Projekt DEAL.

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  • Cited by (0)

    Maria Papathanasiou and Lukas Kessler first authors contributed equally to this work.

    Peter Luedike and Christoph Rischpler senior authors contributed equally to this work.

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