Abstract
Background
This study was to investigate the significance of 11C-Pittsburgh B (PIB) PET/CT in patients with suspected cardiac amyloidosis compared with 99mTc-aprotinin scintigraphy.
Methods
Thirteen consecutive patients with suspected cardiac amyloidosis were considered for enrolment in this prospective pilot study. Participants were scheduled to undergo a series of 11C-PIB PET/CT and 99mTc-aprotinin within a 2-month period. Finally, we evaluated nine cases who underwent both imaging modalities, and compared imaging results with clinical and pathological results and prognosis.
Results
Six of the 9 patients who underwent both imaging modalities were diagnosed with amyloidosis, of whom 3 patients were diagnosed with cardiac amyloidosis from endomyocardial biopsy. These 3 patients with positive 11C-PIB uptake at the left ventricle wall showed worsening of cardiac function progressing in the short term or death caused by acute exacerbation of chronic heart failure. Six of 8 patients with positive uptake on 99mTc-aprotinin presented with amyloid deposition in the left ventricle wall, but symptoms remained stable if results of 11C-PIB were not positive.
Conclusion
In a small sample of subjects, the present study showed that 11C-PIB accumulation in myocardium indicated cardiac amyloidosis with poor prognosis. Uptake of 11C-PIB may be related to progressive amyloid deposition to the heart and can predict patient prognosis.
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Background
Cardiac amyloidosis is a myocardial disease characterized by extracellular amyloid infiltration in the heart, resulting in cardiomyopathy, heart failure, and atrial and ventricular arrhythmias, and tends to present a poor prognosis with a short median survival in the absence of treatment.1 Histopathological diagnosis with Congo Red stain in a biopsy of tissue has been conducted for the final diagnosis of amyloidosis.2 Although endomyocardial biopsy is the standard for diagnosis, early diagnosis with non-invasive imaging has been expected to improve the care of patients with cardiac amyloidosis.
Aprotinin (Trasylol; Bayer Pharmaceuticals, Müllerstr, Berlin) is a small bovine protein that acts as a basic pancreatic trypsin inhibitor. Aprotinin is used as an anti-coagulant drug and has been available for the prophylaxis and treatment of major blood loss during complex surgery.3 Proteinase inhibitors have been detected within amyloid deposits, allowing binding of amyloid to aprotinin. Aprile, et al. described the first evaluation of 99mTc-aprotinin for the imaging of amyloid deposit in patients with AL amyloidosis, and as a potential tracer for detecting cardiac amyloid.4 Pittsburgh B (PIB) compound, a derivative of thioflavin T, has been used for imaging β-amyloid in Alzheimer’s disease 5 and is believed to bind to amyloid fibrils of any type.6 A few recent studies have shown that 11C-PIB positron emission tomography/ computed tomography (PET/CT) could visualize cardiac amyloidosis in several types of amyloid (AL k, AL l, and transthyretin origin). 7,8 However, we reported a mismatch between results of 11C-PIB and 99mTc-aprotinin in the myocardium in patient with amyloidosis, and whether 11C-PIB uptake is relevant to amyloid deposition remains unclear.9 The aim of this pilot study was to evaluate the significance of 11C-PIB-positive findings in patients with cardiac amyloidosis, compared to positive findings for 99mTc-aprotinin, which binds specifically to amyloid.
Materials and Method
Patients Selection
All patients provided written informed consent to participate in this prospective study, and the study was approved by the institutional review board at our hospital in accordance with the Declaration of Helsinki. Each patient was referred to our hospital with suspected cardiac amyloidosis by US and/or MRI or systematic amyloidosis related to multiple myeloma. A total of 13 consecutive patients were assessed for eligibility for this prospective study from August 2010 to August 2016, which consisted of a series of 11C-PIB PET/CT and 99mTc-aprotinin scintigraphy. Four of the 13 patients did not undergo 99mTc-aprotinin, because treatment was initiated for multiple myeloma in three patients, and the purity of 99mTc-aprotinin was lower than 90% in one case, which did not fulfill the quality standards for the tracer. Finally, we analyzed nine patients (3 women, 6 men; mean age ± standard deviation (SD), 64 ± 14 years) who underwent both 11C-PIB PET/CT and 99mTc-aprotinin scintigraphy. The difference in time between 11C-PIB PET/CT and 99mTc-aprotinin scintigraphy was mean age ± standard deviation 33.4 ± 32.8 days (range 4 to 117 days). Amyloid deposition was histopathologically diagnosed by biopsy specimens stained with Congo red dye. Enrolled patients were followed up for maximum 21 months (mean ± SD: 264 ± 189 days, range 32 to 633 days) in terms of progressing of cardiac function and/or cardiac symptom.
Imaging Protocol
99mTc-Aprotinin scintigraphy
Planar and tomographic imaging were performed 90 min after a 2-mL injection containing 740 MBq of 99mTc-aprotinin (mean radiochemical purity, 98.6%; range 95.7% to 99.8%). Acquisition included anterior and posterior whole-body scans (11 to 13 cm/min) and regional static imaging (acquisition time, 5 to 7 min per image) obtained with a single-photon emission computed tomography/computed tomography (SPECT/CT) system (Infinia Hawkeye4; GE Health Care, Milwaukee, WI). The camera was equipped with a low-energy, high-resolution parallel-hole collimator. SPECT tomograms of the chest were also obtained for all patients. Images were taken on a 512 × 512 matrix for static views and on a 128 × 128 matrix for SPECT images.
11C-PIB PET/CT
Injection of 11C-PIB (620 ± 168 MBq; range 366 to 746 MBq) was performed after an emission scan, 40 min after tracer injection using a PET/CT scanner (Discovery 600M; GE Health Care). After low-dose CT, PET scan was performed in 3-dimensional mode for 20 min. PET images were reconstructed on 192 × 192 matrices using an ordered-subset expectation maximization method (4 iterations, 8 subsets) with application of a 4-mm Gaussian filter.
Image Interpretation and Analysis
Images were reviewed by two board-certified nuclear medicine specialists. Accumulation of each tracer in myocardium was determined by visual interpretation. The reference 99mTc-aprotinin image for visual interpretation referred to the image of a control subject is presented in the article by Han et al.10 If the obtained image showed intense focal uptake that was not confirmed in the reference image, the result was regarded as positive 99mTc-aprotinin uptake. A positive 11C-PIB result was defined as 11C-PIB uptake by myocardium higher than that in the blood pool. These findings were compared with the final clinical and histopathological diagnoses. Images were displayed on trans-axial, coronal, and sagittal planes with 5-mm slice thickness.
Volume of interests (VOIs) with 10 mm diameter were carefully positioned on the highest uptake points in myocardium as identified visually on trans-axial 11C-PIB images, and the standardized uptake value (SUV) was measured. As for the measurement of uptake in the blood pool, a 10-mm diameter VOI was placed centrally within the ascending aorta.
Statistical Analysis
The Mann-Whitney U test was used to evaluate differences in 11C-PIB uptake between 11C-PIB-positive and 11C-PIB-negative case, and between amyloid-positive and amyloid-negative cases. A two-sided value of P < 0.05 was considered significant.
Results
Patient characteristics are shown in Table 1. Three patients with positive 11C-PIB uptake in the left ventricle wall showed worsening of cardiac function progressing in the short term or death caused by acute exacerbation of chronic cardiac failure. Six of the 8 patients with positive uptake on 99mTc-aprotinin suspected amyloid deposition in the left ventricular wall, but myocardial symptoms consistently remained stable if results of 11C-PIB were not positive. One case showing negative findings on both 11C-PIB and 99mTc-aprotinin at the cardiac wall had no evidence of amyloid deposition on pathological diagnosis or according to clinical status. Representative images are shown in Figures 1, 2, and 3.
All four cases that underwent 11C-PIB alone showed negative findings on 11C-PIB PET/CT, and cardiac function was stable for at least 6 months according to clinical diagnosis.
The SUVmax and SUVmean of 11C-PIB uptake in the myocardium were 5.1 ± 1.7 and 4.1 ± 0.9, respectively (P = 0.02), in 11C-PIB-positive cases, significantly higher than the 1.2 ± 0.6 and 0.8 ± 0.2, respectively (P = 0.02) in 11C-PIB-negative cases. Uptake in the ascending aorta showed no significant difference between 11C-PIB-positive and 11C-PIB-negative cases (SUVmax: 1.2 ± 0.2 vs 1.2 ± 0.6, P = 1.00; SUVmean: 0.8 ± 0.3 and 0.9 ± 0.1, P = 1.00). Myocardium-to-background (blood pool) ratios with SUVmax and SUVmean of 11C-PIB uptake were 2.7 ± 2.0 and 2.0 ± 1.3, respectively, in 11C-PIB-positive cases, tending to be higher than the 1.1 ± 0.4 and 0.9 ± 0.3, respectively, in 11C-PIB-negative cases, but these differences were not significant (P = 0.22 and P = 0.39, respectively).
Discussion
In a small sample of subjects, this preliminary study showed that 11C-PIB accumulation in the myocardium indicated cardiac amyloidosis with poor prognosis. Uptake of 11C-PIB may relate to progressive amyloid deposition in the myocardium and can predict patient prognosis. Theoretically, 11C-PIB can bind with conformational dependence to amyloid fibrils of any type.5 Antoni et al. first reported that 11C-PIB could detect deposition of several types of amyloid (AL k, AL l, and transthyretin origin) in the heart, representing a usage of 11C-PIB beyond detection of brain amyloid.7 Lee et al. reported a value of 11C PIB for the diagnosis of cardiac amyloidosis and the possibility of using this tracer as a surrogate for active light chain deposition in the myocardium.11 A recent study reported that 11C-PIB could bind to TTR-related amyloidosis (ATTR) amyloid and seems to bind much more strongly to type B than to type A fibrils of ATTR.12 The quantitative aspects of 11C-PIB binding to ATTR amyloid might depend on fibril type, rather than amyloid burden.
A significant increase in 11C-PIB uptake was found in patients with amyloidosis, whereas myocardial blood flow was significantly reduced. The author concluded that increased 11C-PIB is associated with decreased myocardial blood flow.7 As a result, 11C-PIB accumulation is independent of cardiac blood flow. In our study, positive 11C-PIB uptake could be seen in three of the 8 cases with 99mTc-aprotinin-positive results in myocardium, and prognosis of all three cases was quite poor.
Given the ability of 99mTc-aprotinin to detect amyloid deposits in myocardium,13,14 this tracer appears valuable for the imaging of myocardial amyloid. In a study by Han, all 5 patients (out of 35 examined) who had histologically confirmed heart amyloidosis showed positive uptake of 99mTc-aprotinin in the myocardium.10 In our study, 99mTc-aprotinin scintigraphy showed positive findings in all 5 patients with histologically confirmed amyloid deposit.
Based on such findings, 99mTc-aprotinin scintigraphy appears to offer a sensitive, specific diagnostic modality for patients with amyloidosis. However, this tracer is not widely used in cardiac surgery due to concerns over safety.15,16 Our results showed that 99mTc-aprotinin might yield false-positive findings or amyloid deposition unrelated to patient prognosis.
All patients in our study showed AL-type amyloidosis. Median survival from onset of heart failure has been reported as approximately 6 months,17 but recent therapies can prolong remission and extend life.18 Early diagnosis using 11C-PIB PET/CT may be critical for achieving better outcomes in patients with cardiac amyloidosis.
Limitations
The key limitation was that this study was performed on a small number of patients. The 11C-PiB myocardial retention index advocated by the Uppsala University group7 and a full compartmental analysis of 11C-PIB PET data could not be performed in this study. Cardiac MRI is not performed routinely due to the prevalence of pacemaker carriers. Not all patients were investigated for concomitant amyloid deposition, even though AL cardiac amyloidosis is part of a systemic disease that most commonly affects the kidney.
Conclusions
This present study evaluated the significance of 11C-Pittsburgh B (PIB) positron emission tomography in patients with suspected cardiac amyloidosis compared with 99mTc-aprotinin scintigraphy. Our result showed that 11C-PIB accumulation in myocardium indicated cardiac amyloidosis with poor prognosis. Uptake of 11C-PIB may be related to progressive amyloid deposition to the heart and can predict patient prognosis.
New Knowledge Gained
11C-PIB accumulation in myocardium indicated cardiac amyloidosis with poor prognosis. Uptake of 11C-PIB may be related to progressive amyloid deposition to the heart and can predict patient prognosis.
Abbreviations
- PIB:
-
Pittsburgh B
- PET/CT:
-
Positron emission tomography/ computed tomography
- SPECT/CT:
-
Single-photon emission computed tomography/computed tomography
- VOIs:
-
Volume of interests
- SUV:
-
Standardized uptake value
- ATTR:
-
TTR-related amyloidosis
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Minamimoto, R., Awaya, T., Iwama, K. et al. Significance of 11C-PIB PET/CT in cardiac amyloidosis compared with 99mTc-aprotinin scintigraphy: A pilot study. J. Nucl. Cardiol. 27, 202–209 (2020). https://doi.org/10.1007/s12350-018-1260-5
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DOI: https://doi.org/10.1007/s12350-018-1260-5