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Division of Cardiology, McGill University Health Centre, Montreal, Quebec, CanadaDepartment of Internal Medicine, Division of Cardiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Eastern Province, Saudi Arabia
Cardiac amyloidosis (CA) is characterized by the aggregation of misfolded proteins forming amyloid fibrils depositing in the myocardium and other cardiac structures leading to an infiltrative cardiomyopathy. There are two major subtypes of CA with different management and prognosis: transthyretin (ATTR) and amyloid light-chain (AL) amyloidosis.(
Fine NM, Davis MK, Anderson K, Delgado DH, Giraldeau G, Kitchlu A, et al. Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis. Can J Cardiol. 2020;36(3):322-34.
) A high clinical index of suspicion is the foundation for diagnosing CA; however, cardiac imaging is critical for its diagnosis in suspected patients.(
Fine NM, Davis MK, Anderson K, Delgado DH, Giraldeau G, Kitchlu A, et al. Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis. Can J Cardiol. 2020;36(3):322-34.
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
) We present a rare case of biopsy-proven CA with positive uptake of 18F-fluorodeoxyglucose (18F-FDG) PET tracer.
Case Presentation:
The patient is a 69-year-old female with a known history of type-2 diabetes mellitus, hypertension, dyslipidemia, bilateral carpal tunnel syndrome, and suspected sarcoidosis with previous anterior uveitis. Her diagnosis of sarcoidosis was suspected based on prior chest computed tomography (CT) scans, demonstrating mediastinal lymphadenopathy suggestive of sarcoidosis with no evidence of interstitial lung disease and normal pulmonary function tests. She had a family history of dilated cardiomyopathy in her mother and pulmonary sarcoidosis in two sisters. Her medications included aspirin, losartan, amlodipine, rosuvastatin, and metformin.
She was in her usual state of health with no cardiac complaints until August 2020, when she developed atypical chest discomfort and shoulder pains. She denied any exertional chest pain, shortness of breath, or other cardiac symptoms. Her electrocardiogram (ECG) showed normal sinus rhythm, right bundle branch block, and left anterior fascicular block (Figure 1A). A transthoracic echocardiogram (TTE) was requested, demonstrating concentric left ventricular (LV) remodeling with a left ventricular ejection fraction (LVEF) of 60-65%, moderate diastolic dysfunction, and severely reduced global longitudinal strain (GLS) of -11.6% with preservation of the apex suggestive of CA. (Figure 1B) Given these echocardiographic findings, she was referred to cardiology for further workup.
Figure 1ECG and Multimodality Imaging. Figure 1. ECG (A), Echocardiography (B), PYP Scan (C), CMR (D), FDG-PET (E). (A) ECG demonstrating normal sinus rhythm, left axis deviation, right bundle branch block, and left anterior fascicular block. B1) Apical Four-Chamber View on echocardiogram demonstrating concentric left ventricular (LV) remodeling, moderate left atrial (LA) enlargement, mild thickening of aortic and mitral valve leaflets. B2) Strain imaging demonstrating severely reduced global longitudinal strain (GLS) of -11.6% with preservation of the apex suggestive of cardiac amyloidosis. C1) PYP scan demonstrating diffusely increased activity throughout the left heart, of greater intensity than the rib cage, localizing to the myocardium, indicating a Perugini score of 3. C2) SPECT Images demonstrating increased uptake localizing to the myocardium. D1&D2) 4-Chamber long-axis CMR image, D3) Apical short-axis view, D4) 3-Chamber vertical long-axis view demonstrating almost circumferential subendocardial LGE. E1, E2, and E3) FDG PET/CT demonstrating low-grade heterogeneous diffuse radiotracer accumulation in the left ventricular wall more in the anterolateral wall.
The clinical suspicion for amyloid arose; thus, serum protein electrophoresis (SPEP), serum free light chains (FLC), and a technetium-99m pyrophosphate scintigraphy (99mTc-PYP) scan were requested. Her SPEP and serum FLC were negative, with no evidence of hematologic dyscrasias. Her high-sensitivity troponin-I (hsTN-I) was mildly elevated at 26.6 ng/L (Normal <17.5 ng/L). Her subsequent 99mTc-PYP and associated single-photon emission computerized tomography (SPECT) of the thorax demonstrated increased activity throughout the left heart greater than the rib cage localizing to the myocardium, indicating a Perugini score of 3 (Figure 1C). She also underwent cardiac magnetic imaging (CMR), which demonstrated normal biventricular volume and systolic function and concentric remodeling/ thickening of the LV up to 14 mm thickness. There was also an almost circumferential subendocardial LGE pattern involving the anterior, lateral and inferior wall with septal mid myocardial LGE. This pattern of circumferential subendocardial LGE is in keeping with CA. (Figure 1D) However, given the patient’s history of suspected sarcoidosis and being confounded by two possible infiltrative etiologies (Sarcoid and Amyloid), an 18FDG-PET/CT scan was arranged to see if there was both myocardial uptake and/or uptake in the lymph nodes. The 18FDG-PET/CT showed low-grade heterogeneous diffuse radiotracer accumulation in the left ventricular wall radiotracer uptake, possibly related to sarcoidosis or ATTR-CA associated with inflammatory changes of lymphohistiocytic infiltration around the amyloid protein deposition in the myocardium (Figure 1E).
In view of the prior pyrophosphate scan findings, amyloidosis with an inflammatory component was more suspected. The patient eventually underwent an endomyocardial biopsy with proteomic analysis by mass spectrometry of Congo red positive areas indicating amyloid deposition of ATTR-type Amyloidosis. She remained asymptomatic with NYHA I symptoms and did not require diuretics. She was started on Diflunisal with the plan to start Tafamidis for mortality benefit.
Discussion:
The initial workup for CA should include a 12-lead ECG, troponin, brain natriuretic peptide (BNP)/ N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac imaging, namely TTE. Screening for plasma cell dyscrasia is important to ensure early referral to hematology-oncology for initiation of appropriate chemotherapy.(
Fine NM, Davis MK, Anderson K, Delgado DH, Giraldeau G, Kitchlu A, et al. Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis. Can J Cardiol. 2020;36(3):322-34.
) Despite using serum biomarkers for risk assessment of CA, the biomarkers themselves are non-specific. For this reason, imaging remains a requisite component of the diagnostic algorithm for CA.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
) Different cardiac imaging modalities are being used as complementary to each other and play a crucial role in the diagnostic evaluation of patients with suspected CA.(
Fine NM, Davis MK, Anderson K, Delgado DH, Giraldeau G, Kitchlu A, et al. Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis. Can J Cardiol. 2020;36(3):322-34.
Echocardiography remains an excellent initial screening modality for cardiomyopathies, given its safety and accessibility. The most common finding is increased LV wall thickness (>12 mm).(
) The suspicion grows when combined with increased LV wall mass, typical LV longitudinal strain pattern, mitral annular tissue doppler imaging < 5 cm/sec, biatrial enlargement, small pericardial or pleural effusion, and severe aortic stenosis (AS), especially in paradoxical, low-flow, low-gradient severe AS.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
) Deformation imaging using GLS calculations has enhanced the utility of echocardiography. CA has a classic diffusely decreased GLS with relative apical sparing and is the best predicting parameter for CA by echocardiography.
A comprehensive CMR evaluation for CA includes morphologic and functional assessment of the cardiac chambers using cine imaging, evaluation of native T1 signal, assessment of LGE, and extracellular volume (ECV) measurement. It helps diagnose CA, especially when echocardiography is indeterminant.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
) The primary purpose of CMR in CA is to exclude or confirm the presence of cardiac amyloid by its ability to characterize myocardial tissue, especially in undifferentiated increased ventricular thickness. The amyloid protein deposition in the myocardium significantly prolongs the T1 relaxation time, increasing native myocardial T1 values and detecting CA with a sensitivity of 90% and a specificity of 87%.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
) Deposited amyloid fibrils have an affinity for gadolinium-based agents, usually resulting in diffuse subendocardial gadolinium uptake. A CMR-based LGE pattern has been shown to have a diagnostic sensitivity of 85% and specificity of 92%.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
) In LGE imaging, when nulling the myocardium is attempted (making the myocardium dark and blood pool bright), the blood pool and amyloid-infiltrated myocardium null together, giving an appearance of a dark blood pool suggestive of CA.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
) Comparing T1 values pre and post-contrast allows for estimating the ECV, which is elevated in CA (≥40%) and has been shown to most closely mirror the amyloid burden and treatment response.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
The use of nuclear imaging for the diagnosis of CA also plays a crucial and unique role. Of the bone-seeking radiotracers, 99mTc-PYP is the most studied for its use in CA imaging. It is the first radiotracer demonstrating high sensitivity and specificity for differentiating ATTR from AL-CA. Radiotracer uptake is graded visually by comparing the cardiac uptake to bone on planar images. In the absence of monoclonal proteins in the blood and urine, a Grade 2 or 3 positive Perugini score is highly specific for diagnosing ATTR-CA without needing a biopsy with a specificity and positive predictive value >98%.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
) The utility of PET scans for diagnosing CA has been studied with conflicting evidence depending on the tracer, which could suggest its unsuitability.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
) FDG uptake is usually significant in conditions with inflammation and the presence of mononuclear cells making FDG-PET a reliable imaging modality to detect hematologic malignancy, but its evidence is lacking for its use in amyloidosis.(
) In cardiac sarcoidosis, 18F-FDG accumulates in active cardiac sarcoidosis lesions, usually giving a typical patchy uptake and correlates with overall prognosis. 18F-FDG uptake helps monitor disease activity and response to therapy. Performing whole-body 18F-FDG PET/CT helps evaluate extracardiac involvement, an essential step in assessing sarcoidosis.(
Positive 18F-FDG uptake in CA is rare and only reported in case reports described in (Table 1). The pattern of 18F-FDG uptake in reported cases was diffuse rather than patchy. In a case series describing ten patients with AL amyloidosis and FDG PET uptake patterns, three had known cardiac involvement with FDG uptake in other organs involved but no uptake in the heart.(
) In another study of 15 patients with histologically confirmed AL amyloidosis, ten patients had cardiac involvement with diffuse myocardial uptake of FDG.(
) Only one case report was found of ATTR-CA in a 73 year-old-male undergoing FDG PET for lung cancer staging, demonstrating tracer uptake in the left ventricle, although the test was limited with suboptimal diet preparation.(
) Recently, new amyloid-directed molecule tracers (ADMT) (18F-florbetapir, 18F-florbetaben, and 11C-Pittsburgh Compound B (PIB)) showed success in imaging B-amyloid plaques in Alzheimer’s patients, thus holds promise in CA detection.(
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
Our case is the first confirmed ATTR-CA case with positive FDG uptake by PET scan with proper preparation with a 14-hour fast, a low-carbohydrate diet 24 hours before the study and ensuring blood glucose levels <11.1 mmol/L at the time of the study. The complexity in our case is the fact that the patient has a history of suspected sarcoidosis with a suggestive echocardiogram and CMR for CA, with a very positive 99mTc-PYP in the absence of hematologic markers, but also a weakly positive 18F-FDG-PET scan which could be representative of either cardiac amyloidosis and/or sarcoidosis or a false positive result from inadequate glucose suppression. In the literature the PET positive amyloid cases were usually associated with AL type with only one other case of ATTR, which could have been a false positive result, similar to our case. The endomyocardial biopsy confirmed the diagnosis of CA. The inflammation process, suggested by the FDG uptake, may play a role in detecting CA, but more data and studies are required.
Conclusion:
CA with a positive uptake on FDG-PET is very infrequent and potentially misleading. It is more commonly seen in AL CA. To our best knowledge, this is the first confirmed case of ATTR CA with a weakly positive PET uptake with proper preparation described in the literature which could be because of the ATTR-protein itself, the inflammatory process like in AL, or a false positive result in ATTR similar to a previous reported case in the literature. This case highlights the importance and limitations of multimodality imaging in its current state in diagnosing cardiomyopathies with further development required. This case is an important contribution to the literature on the role of multimodality imaging in CA and an essential reminder not to exclude CA in patients with a positive FDG uptake pattern on PET.
Fine NM, Davis MK, Anderson K, Delgado DH, Giraldeau G, Kitchlu A, et al. Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis. Can J Cardiol. 2020;36(3):322-34.
ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging.
Funding: The authors report no funding resources relevant to the content
Disclosures: The authors have no conflict of interest to disclose
Novel Teaching Points:
-Despite advancements in multimodality imaging, there are still limitations; thus, cardiac imaging modalities must be used complementary to each other. A tissue biopsy may be required despite best efforts.
-FDG-PET positivity in cases of CA is more likely associated with AL type rather than ATTR type and is likely related to the associated inflammatory process and less likely the co-existent of two different infiltrative diseases.
-PET scan for detection of CA is likely more useful using ADMT, rather than FDG tracers, for which more studies are needed.
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