Abstract
Objectives
Cardiac amyloidosis (CA) is a type of systemic amyloidosis. Amyloid-targeting positron emission tomography (PET) has shown potential as an imaging method for CA. However, the optimal imaging protocol and role of 18F-florbetaben (FBB) PET in the diagnosis and subtyping of CA have yet to be determined.
Methods
Patients with suspected CA who had positive or equivocal results of technetium-99m pyrophosphate (PYP) scintigraphy were enrolled for dynamic and late FBB PET imaging. In addition to visual assessment, a kinetic modeling-based approach including target-to-background ratio (TBR) and myocardial retention fraction (RF) of serial images reconstructed from a 20-min dynamic acquisition, and a late image at 110 min post-injection were performed. We compared FBB PET measures of four typical patients with light chain amyloidosis (AL), wild-type transthyretin amyloidosis (ATTRwt), variant transthyretin amyloidosis (ATTRv), and heart failure, respectively. We also reviewed the literature on the clinical use of amyloid PET in CA.
Results
Myocardial tracer retention was only found in the AL patient on the late images. TBR and RF were highest in the AL patient followed by the ATTRwt patient, and lowest in the ATTRv and non-CA patients.
Conclusions
FBB PET has potential in the detection and non-invasive subtyping of CA, especially in subjects with equivocal PYP findings or monoclonal gammopathy.
Keywords: 18F-florbetaben (FBB), Heart failure, Light-chain cardiac amyloidosis (AL-CA), Positron emission tomography (PET), Transthyretin cardiac amyloidosis (ATTR-CA)
Abbreviations
11C-PiB, Carbon-11 Pittsburgh compound B
99mTc-PYP, Technetium-99m pyrophosphate
AL-CA, Light chain cardiac amyloidosis
ATTR-CA, Transthyretin cardiac amyloidosis
ATTRv, Variant transthyretin amyloidosis
ATTRwt, Wild-type transthyretin amyloidosis
CA, Cardiac amyloidosis
EF, Ejection fraction
FBB, 18F-florbetaben
H/CL, Heart-to-contralateral lung
HFpEF, Heart failure with preserved ejection fraction
LA, Left atrium
LV, Left ventricle
NT-proBNP, N-terminal pro-B-type natriuretic peptide
PET, Positron emission tomography
RF, Retention fraction
SPECT, Single-photon emission computed tomography
SUVmean, Mean standard uptake value
TBR, Target-to-background ratio
TTR, Transthyretin
INTRODUCTION
Cardiac amyloidosis (CA) is characterized by the extracellular deposition of insoluble amyloid fibrils in the myocardium. Light chain cardiac amyloidosis (AL-CA) and transthyretin cardiac amyloidosis (ATTR-CA) are the two primary subtypes of CA, where AL-CA stems from the aggregation of misfolded immunoglobulin light chain produced by monoclonal plasma cells, and ATTR-CA arises due to misfolded transthyretin (TTR) protein. ATTR-CA is further categorized into wild-type (ATTRwt) or variant type (ATTRv), and it is increasingly recognized as the cause of heart failure with preserved ejection fraction (HFpEF) in older populations.1,2 The treatment options for CA differ based on the subtypes of amyloid deposition,3 and the efficacy of disease-modifying medications decreases in the advanced stages of the disease.4 An early diagnosis and accurate subtyping of CA are crucial for the effective management of these patients.
Endomyocardial biopsy coupled with immunohistochemistry or mass spectroscopy is currently considered the gold standard for the definitive diagnosis of CA.5 However, this method is invasive, carries the risk of complications, requires specialized expertise, and is not clinically practical to evaluate disease extent and treatment response. In contrast, bone-avid radiotracer scintigraphy allows for the non-invasive diagnosis of ATTR-CA, and it has shown high diagnostic accuracy, particularly after excluding the possibility of plasma cell dyscrasia by serum free light chain assay and urine and serum immunofixation electrophoresis.6,7 In addition, it has led to a paradigm shift in that ATTR-CA can now be effectively diagnosed without the need for a tissue biopsy. Nonetheless, the binding mechanism is not amyloid-specific, potentially limiting the diagnostic accuracy due to delayed blood pool clearance, myocardial infarcts, and high uptake in the ribs. Moreover, these tracers are not useful for diagnosing AL-CA, cannot detect CA early, and have limited use in prognostication, monitoring, and assessing the therapy response in patients with CA.
Amyloid positron emission tomography (PET) is used to detect β-amyloid deposition in the brains of Alzheimer’s disease patients. These radiotracers bind specifically to the β-pleated-sheet structure,8 suggesting the ability of quantitative measures of amyloid PET to highlight pathological changes at the earliest stages of the CA continuum and generate more sensitive thresholds, as well as improving diagnostic confidence around established binary cutoff values. While previous studies have demonstrated the ability of amyloid PET tracers to detect amyloid deposits in the myocardium,9-11 the diagnostic and prognostic value of amyloid PET for CA along with the imaging protocol and quantitative assessments remain to be established, because these PET tracers are still investigational and the sample sizes of these studies were rather small. In addition, differences may exist between different amyloid PET tracers.
The aim of this study was to evaluate the feasibility of kinetic modeling-based approaches using 18F-florbetaben (FBB) dynamic and late PET images in patients with suspected CA, and to discuss the potential role in the diagnostic algorithm of CA. We present four cases with suspected CA who underwent serial clinical evaluations and both technetium-99m pyrophosphate (PYP) scans and amyloid PET with FBB, and were ultimately found to have distinct diagnoses.
METHODS
In this ongoing prospective observational study, patients with a positive or equivocal PYP scan but still a high clinical suspicion of CA have been enrolled since June 2021. The suspicion of CA was based on the red-flag signs proposed in the updated guidelines in Taiwan.12,13 The patients subsequently underwent an FBB cardiac PET study, and we analyzed the clinical information and measures of the PYP scans and FBB PET. This study was approved by the Institutional Review Board of Far Eastern Memorial Hospital (IRB. No. 110068-F), and written informed consent was obtained from all patients. This pilot study included four representative cases with different disease entities (AL-CA, non-CA, ATTRv-CA and ATTRwt-CA).
FBB PET/CT image acquisition and analyses
Dynamic PET acquisition of the cardiac region began simultaneously with the intravenous administration of 299.7 Mbq of FBB and continued for 20 min. This was followed by a late whole-body static acquisition at 110 min post-injection. In addition to the late images, static cardiac images were reconstructed from dynamic data collected between 3-6 min, 10-13 min, and 17-20 min for serial visual comparisons.
For the calculation of mean standard uptake value (SUVmean), a region of interest for the left ventricular (LV) myocardium was automatically generated using the iso-contouring function provided in PMOD Cardiac PET Analysis software (version 4.2, PMOD Technologies Ltd., Zurich, Switzerland). The region of interest for the blood pool was obtained by placing a circular region of interest in the left atrium (LA). After the SUVmean values had been obtained, the time-activity curves of the myocardium and the blood pool were plotted to allow for better comparisons. The target-to-background ratio (TBR), representing the contrast between the myocardium and background, was calculated as LV myocardium SUVmean divided by blood pool SUVmean.
To enable direct comparisons of myocardial tracer retention among patients, the retention fraction (RF) was computed for each frame during dynamic acquisition. The RF denotes the fraction of total tracer delivered to the myocardium that is retained, and it was calculated using the formula:
where CT is the concentration of tracer in myocardial tissue, Cp is the concentration of tracer in plasma, tb is the beginning time, and te is the ending time.
RESULTS
Case 1
A 70-year-old women who had previously been diagnosed with paroxysmal atrial fibrillation and had received breast-conserving therapy for left breast cancer 7 years previously, presented with palpitation, hypotension, syncope and progressive dyspnea on exertion. Transthoracic echocardiography revealed an LV ejection fraction (EF) of 59%, normal-sized LA and LV, LV asymmetrical septal hypertrophy (interventricular septum = 16 mm, posterior wall = 10 mm), and diastolic dysfunction. A blood examination showed elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (2049 pg/mL) and troponin-T. A serum free light chain assay showed increased free lambda light chain and decreased kappa/lambda ratio. The presence of IgG lambda monoclonal gammopathy was confirmed through serum and urine immunofixation electrophoresis. The subsequent diagnosis of multiple myeloma was based on 12% clonal plasma cells present in a bone marrow biopsy and evidence of end-organ damage in the heart and kidneys. The overall likelihood of cardiac amyloidosis according to the PYP scan was equivocal, with a visual grade of 1 at 3 hours (myocardial uptake less than rib uptake). Multiple myeloma with AL-CA was considered under the impression of symptoms of HFpEF, elevated cardiac biomarkers, and increased wall thickness on echocardiography, along with an equivocal PYP scan (Figure 1A). The FBB PET/CT scan showed marked myocardial uptake throughout the dynamic phase (Figure 1A) that persisted into the late image (Figure 2A). A chemotherapy regimen consisting of bortezomib, thalidomide, and dexamethasone was initiated, and subsequent follow-up examinations demonstrated significantly diminished IgG lambda monoclonal gammopathy and significantly improved heart failure symptoms and biomarkers.
Figure 1.
(A) Case 1, AL-CA. Equivocal PYP scan (left panel). 18F-florbetaben amyloid PET showed intense myocardial uptake throughout the early dynamic phase (right panel). (B) Case 2, non-CA. PYP scan was equivocal with delayed clearance of blood pool activity and mild myocardial uptake on 3-hour SPECT image (left panel). Amyloid PET also showed delayed clearance of blood pool activity in the early dynamic phase, with tracer washout from the myocardium by the end of the dynamic phase (right panel). (C) Case 3, ATTRv-CA carrier or early ATTRv-CA. Equivocal PYP scan (left panel). Amyloid PET showed homogeneous tracer distribution in the myocardium in the early phase, with tracer washout by the end of the dynamic phase (right panel). (D) Case 4, ATTRwt-CA. Positive PYP scan, with a visual grade of 2 at 3 hours (left panel). Amyloid PET showed rather weak tracer retention in the myocardium at the end of the dynamic phase (right panel). AL-CA, light-chain cardiac amyloidosis; ATTRv-CA, variant transthyretin cardiac amyloidosis; ATTRwt-CA, wild-type transthyretin cardiac amyloidosis; CA, cardiac amyloidosis; PET, positron emission tomography; PYP, pyrophosphate; SPECT, single-photon emission computed tomography.
Figure 2.
High myocardial tracer retention on the late image (110 min post-injection) was noted in the patient with AL-CA (A), but not in the patient with non-CA heart failure (B), the ATTRv-CA carrier (C), or the patient with ATTRwt-CA (D). The highest retention fraction in the myocardium was observed in the patient with AL-CA (red) compared to the other patients in our series (E). AL-CA, light-chain cardiac amyloidosis; ATTRv-CA, variant transthyretin cardiac amyloidosis; ATTRwt-CA, wild-type transthyretin cardiac amyloidosis; CA, cardiac amyloidosis.
Case 2
A 65-year-old women with a history of hypertension, hyperlipidemia, and coronary artery disease presented with dyspnea on exertion, weakness, and numbness in the right lower extremity. Echocardiography revealed an LVEF of 70%, dilated LA, dilated right atrium and dilated right ventricle, normal-sized LV, normal LV wall thickness (interventricular septum = 8 mm, posterior wall = 8 mm), LV diastolic dysfunction, and a secundum atrial septal defect. A blood examination showed an elevated level of NT-proBNP (278 pg/mL). Plasma cell dyscrasia was ruled out due to normal results of both serum free light chain assay and serum and urine immunofixation electrophoresis. The result of the PYP scan was equivocal for ATTR-CA (Figure 1B). Despite a heart-to-contralateral lung (H/CL) ratio of 1.51 at 1 hour and 1.35 at 3 hours, with a visual grade of 2 at both 1 and 3 hours, visual inspection of single-photon emission computed tomography (SPECT) images revealed no myocardial uptake. This absence of uptake indicated a false-positive quantitative interpretation, likely due to residual activity in the blood pool, thereby rendering the result equivocal. Subsequent FBB PET showed a rapid washout of initial myocardial uptake, which became invisible by the end of the dynamic phase (Figure 1B). Notably, delayed clearance of the radiotracer from the blood pool was observed during early dynamic imaging. This delay may have been related to the existence of heart failure, intracardiac shunting and pulmonary hypertension, which may also have explained the increase in myocardial activity on the previous PYP scan.
Transcatheter closure of the atrial septal defect was performed, and her condition remained stable without specific treatment for CA. Three years later, a follow-up PYP scan revealed a downgrade in quantitative parameters, with an H/CL ratio of 1.20 at 1 hour and 1.14 at 3 hours, and a visual grade of 2 at 1 hour and 1 at 3 hours, confirming the absence of ATTR pathology.
Case 3
A 59-year-old women with a family history of ATTRv-CA, specifically the TTR V122I variant, presented with chest discomfort and numbness of the fingertips. Her mother had been diagnosed with ATTRv-CA with heart failure when she was in her 80s, and genetic testing confirmed that the patient was a TTR V122I variant carrier. Echocardiography revealed an LVEF of 68%, with normal-sized LA and LV, and normal LV wall thickness (interventricular septum = 10 mm, posterior wall = 8 mm). The result of the PYP scan was equivocal for ATTR-CA, with a visual grade of 1 at 3 hours (Figure 1C). FBB PET showed homogeneous myocardial uptake with rapid washout, and no myocardial tracer retention was noted at the end of the dynamic phase (Figure 1C) or on the late image (Figure 2C). We also noted faint diffuse uptake in the mediastinum but not the myocardium on the late image. Correlation with the dynamic images could avoid false-positive interpretation, as the tracer had washed out from the myocardium by the end of the dynamic phase. Cardiac MRI showed a diffuse high T1 value in the myocardium (native T1 mapping = 1120-1180 ms, normal range in our institution = 1026.5 at 1.5 Tesla) and elevated extracellular volume (42-47%). Notably, no late gadolinium enhancement was observed in the myocardium, suggesting early-stage ATTRv-CA without obvious scar formation.
Case 4
A 77-year-old man with a history of hypertension, diabetes, hyperlipidemia, and pontine ischemic stroke, presented with progressive dyspnea on exertion, palpitation, and leg edema. Echocardiography showed an LVEF of 58%, dilated LA, dilated right atrium, normal-sized LV, and LV concentric hypertrophy (interventricular septum = 15 mm, posterior wall = 12 mm). A blood examination showed an elevated level of NT-proBNP (398 pg/mL). Plasma cell dyscrasia was ruled out due to normal results of both serum free light chain assay and serum and urine immunofixation electrophoresis. The PYP scan strongly suggested ATTR-CA (Figure 1D). Genetic testing was negative for mutations. Under the impression of ATTRwt-CA, FBB PET showed rapid washout of initial myocardial uptake, with minimal tracer retained at the end of the dynamic phase (Figure 1D). No myocardial uptake was observed on the late image (Figure 2D). In addition, the segmental RF of dynamic imaging showed relatively lower tracer uptake in the apex and apical segments of the myocardium compared to the mid and basal segments (Figure 3).
Figure 3.
Case 4, ATTRwt-CA. The time-activity curves of myocardial segments in AHA 17-segmentation model (A) and the polar map of retention fraction (B) at the end of the dynamic phase revealed the lowest tracer uptake in the apex, demonstrating a basal-to-apical gradient. ATTRwt-CA, wild-type transthyretin cardiac amyloidosis.
In the quantitative evaluation, we observed a significantly high RF in the patient with AL-CA throughout the dynamic phase (Figure 2E). The RFs at the end of dynamic acquisition were 0.96, 0.52, 0.50, and 0.49 for the patients with AL-CA, non-CA, ATTRv-CA, and ATTRwt-CA, respectively, and the TBRs at the end of dynamic acquisition were 3.00, 1.48, 1.38, and 2.02, respectively.
DISCUSSION
While ATTR-CA can often be diagnosed non-invasively, the diagnosis of AL-CA frequently requires histological confirmation. Furthermore, concomitant monoclonal gammopathy has been reported in 39% of patients with ATTRwt amyloidosis and 49% of patients with V122I ATTRv amyloidosis.14 This presents a diagnostic dilemma in the imaging-based subtyping of CA using PYP scans, especially in patients with a visual grade of ≥ 1 on PYP scan, as both ATTR-CA and AL-CA cannot be ruled out in this scenario.12 A previous study demonstrated the potential of FBB PET to differentiate between AL-CA, ATTR-CA, and non-CA controls.15 In our case series, myocardial uptake was visualized in the patients with AL-CA and ATTRwt-CA at the end of the dynamic phase, while myocardial retention on late images was only observed in the patient with AL-CA. Although TBR was markedly higher in the patient with AL-CA, it was only slightly higher in the patient with ATTRwt-CA than in the early ATTRv-CA and non-CA patients. Given the distinct myocardial avidity for FBB, amyloid PET may serve as a complementary tool to PYP scans in the diagnosis and subtyping of CA. This observation aligns with the findings of a previous study in Japan,16 where the combination of positive Carbon-11 Pittsburgh compound B (11C-PiB) PET and negative PYP scan was observed in all patients with AL-CA, and the combination of negative 11C-PiB and positive PYP uptake accurately identified all patients with ATTRwt-CA. This potential diagnostic combination is particularly relevant in patients with multiple myeloma, as the presence of monoclonal gammopathy precludes the diagnosis of ATTR-CA based on a positive PYP scan, and the coexistence of multiple myeloma and ATTR-CA has been reported.17
The RF of FBB PET was higher in the patient with AL-CA, but not in the patients with ATTR-CA compared to the non-CA patient with heart failure. A similar result was reported in a previous study from Genovesi et al.,15 in which the retention index was higher in patients with AL-CA than in patients with ATTR-CA or non-CA conditions, but no difference was observed between patients with ATTR-CA and non-CA conditions. In our case series, a substantial difference in the tracer RF in AL-CA versus other conditions was observed early in the imaging process, when TBR remained high in all patients, limiting visual comparisons due to subjectivity. Thus, this quantitative parameter has the potential to facilitate a shorter imaging protocol by eliminating the need for a late static image, while maintaining the specificity to rule out AL-CA reliably. Moreover, previous studies18,19 have reported a correlation between myocardial retention of FBB and the severity of myocardial dysfunction in patients diagnosed with CA, and a correlation between alterations in myocardial retention during follow-up and treatment response.
In the patient with ATTRwt-CA, the myocardial uptake of FBB was highest in the basal segment, exhibiting a basal-to-apical gradient in the early images. This predominantly basal distribution of amyloid fibrils may explain the "cherry-on-top" pattern on strain echocardiogram, where LV longitudinal strain is relatively preserved in the apex.20 Of note, this unique apical sparing pattern has also been reported in ATTR patients on bone PET using 18F-NaF.21
Interestingly, in the only ATTRv-CA carrier in our case series, the clearance of blood pool activity was faster, and the distribution of myocardial radiotracer activity was very homogeneous when she had no significant heart failure symptoms and normal echocardiographic findings. This phenomenon is likely attributable to preserved cardiac output and coronary microvascular function. Cardiac MRI showed the absence of scarring but characteristic findings of increased native T1 and extracellular volume, indicative of early-stage disease. Although a β-pleated-sheet structure is ubiquitous in amyloid fibrils, variations in the components and configuration of amyloid fibrils among subtypes may contribute to the observed heterogeneity in the avidity of amyloid tracers. Of note, negative 11C-PiB PET results were reported in a patient with biopsy-proven CA.22
In patients with symptomatic heart failure or impaired renal function, the delayed clearance of radiotracers from the blood pool is a potential source of false-positive interpretations in planar PYP scans. While delayed 3-hour images are recommended in cases with marked blood pool activity on initial 1-hour images,13 persistent blood pool activity is not uncommon.23 In our second case, CA was excluded due to only mild myocardial uptake on 3-hour SPECT in the first PYP scan, improvement in symptoms and downgrading of visual grade on follow-up PYP scan after atrial septal defect occlusion and heart failure treatment without any ATTR-CA disease-modifying treatment. As non-CA controls have been associated with a lower TBR in previous studies,11,14,24 this quantitative method facilitated by amyloid PET may have allowed for a more straightforward negative interpretation in this patient. Although the myocardial SUVmean was similar, the TBR was actually lower in this patient compared to the patient with ATTR-CA, indicating the retention of radiotracer activity in the blood pool. However, larger studies are needed to determine an optimal cutoff of TBR.
Pathologic confirmation is the most reliable diagnostic method, and an extracardiac biopsy cannot determine the presence or type of amyloid in the heart, although the risk is lower. The amyloid PET features of CA may be helpful in diagnosing and subtyping CA in patients with high clinical suspicion. Moreover, the imaging findings of amyloidosis may precede the clinical manifestations, providing important diagnostic and prognostic information. This is the first amyloid cardiac PET case series in Taiwan. The selected cases are representative of distinct disease entities, providing insights into a variety of scenarios that may be encountered in the diagnosis of CA. The limitation of our case series is the absence of endomyocardial biopsy and small sample size. Nonetheless, for the patient with suspected AL-CA, the diagnosis was inferred from the improvement in cardiac symptoms and biomarkers following the initiation of chemotherapy. In the patient with ATTRwt-CA, the diagnosis could be established with suggestive clinical presentations, echocardiographic findings, a positive PYP scan, and the absence of plasma cell dyscrasia, in accordance with updated guidelines.25 In the patient with suspected ATTRv-CA, endomyocardial biopsy was not performed because she was asymptomatic for heart failure, and she hesitated to undergo an invasive procedure. However, the presence of amyloidosis deposition was suggested by cardiac MRI.
In summary, we demonstrated the feasibility of using a kinetic modeling-based approach and the FBB PET imaging protocol for CA subtyping, and proposed the position of amyloid PET in the diagnostic algorithm of CA (Central Illustration). Amyloid PET may be helpful in demonstrating amyloid deposition when cardiac MR is contraindicated or unavailable, in differentiating between amyloid subtypes, and also in identifying cardiac and extracardiac sites for histological confirmation. However, due to the high cost and limited availability of the radiotracer, there is currently a lack of large-scale trials and widespread clinical application of amyloid PET. Future studies with a larger number of cases are required to validate the diagnostic performance in patients suspected with CA.
Central Illustration.
18F-florbetaben amyloid PET potentially aids in the differential diagnosis of AL-CA and ATTR-CA in patients with monoclonal gammopathy. When CMR is contraindicated or unavailable, amyloid PET can serve as an alternative tool to differentiate between CA and non-CA and between ATTR-CA and AL-CA, and a whole-body scan may be able to identify the cardiac and extracardiac amyloid deposition for biopsy. In patients with monoclonal gammopathy, myocardial amyloid uptake on late FBB PET images highly suggests light chain amyloid deposition in the myocardium. In patients without monoclonal gammopathy, an increased TBR during the dynamic phase suggests ATTR deposition. AL-CA, light chain cardiac amyloidosis; ATTR-CA, transthyretin cardiac amyloidosis; CA, cardiac amyloidosis; CMR, cardiac magnetic resonance; PET, positron emission tomography; PYP, pyrophosphate; TBR, target-to-background ratio.
NEW KNOWLEDGE GAINED
Dynamic FBB PET with late imaging offers a non-invasive and quantitative tool to complement PYP scans in the diagnosis and subtyping of CA. In cases with monoclonal gammopathy, PYP scans are less diagnostic, and cardiac MRI cannot differentiate ATTR-CA and AL-CA. AL-CA is highly suggested in patients with delayed myocardial uptake on amyloid PET, and it can be reliably diagnosed in the presence of extracardiac light chain deposition. In patients with suspected ATTR-CA who have equivocal myocardial PYP uptake or prolonged blood pool activity on SPECT/CT, FBB PET with quantitative measurements may serve as an alternative to cardiac MRI or invasive endomyocardial biopsy.
DECLARATION OF CONFLICTS OF INTEREST
The authors declare no conflicts of interest.
Acknowledgments
The study was partly supported by grant MOST110-2314-B-418-005-MY3 from the Ministry of Science and Technology of Taiwan, and mutual fund FEMH 110-2314-B-418-005-MY from Far Eastern Memorial Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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