Cardiac Amyloidosis Imaging, Part 1: Amyloidosis Etiology and Image Acquisition PDF

CONTINUING EDUCATION Cardiac Amyloidosis Imaging, Part 1: Amyloidosis Etiology and Image Acquisition Monica Embry-Dierson1, Mary Beth Farrell2, Eric Schockling3, Jaime Warren4, and Scott Jerome5 1 Noninvasive Cardiology, Norton Audubon Hospital, Louisville, Kentucky; 2Intersocietal Accreditation Commission, Ellicott City, Maryland; 3Outpatient Cardiovascular Diagnostics, Norton Healthcare, LLC, Louisville, Kentucky; 4MedAxiom, Neptune Beach, Florida; and 5University of Maryland School of Medicine, Westminster, Maryland CE credit: For CE credit, you can access the test for this article, as well as additional JNMT CE tests, online at https://www.snmmilearningcenter.org. Complete the test online no later than June 2026. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 80% of the questions correctly to receive 1.0 CEH (Continuing Education Hour) credit. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certiﬁcate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test. Key Words: cardiac amyloid imaging; cardiac amyloidosis; transthyr- Cardiac amyloidosis is a systemic form of amyloidosis in which etin; light-chain; 99mTc-pyrophosphate protein-based inﬁltrates are deposited in myocardial extracellular J Nucl Med Technol 2023; 51:83–89 space. The accumulation of amyloid ﬁbrils causes the myocardium DOI: 10.2967/jnmt.123.265415 to thicken and stiffen, leading to diastolic dysfunction and, eventu- ally, heart failure. Until recently, cardiac amyloidosis was consid- ered rare. However, the recent adoption of noninvasive diagnostic testing, including 99mTc-pyrophosphate imaging, has revealed a previously undiagnosed sizable disease prevalence. Light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR), the 2 pri- A myloidosis is a collection of diseases characterized by deposits of protein-based inﬁltrates within the body’s tis- mary types, account for 95% of cardiac amyloidosis diagnoses. AL results from plasma cell dyscrasia and has a very poor prognosis. sues. There are several amyloid subtypes based on the type The usual treatment for cardiac AL is chemotherapy and immuno- of protein deposited (1). Until recently, cardiac amyloidosis therapy. Cardiac ATTR is more chronic, usually resulting from age- was considered rare in the United States. However, the related instability and misfolding of the transthyretin protein. ATTR increased use of noninvasive diagnostic testing, such as is treated by managing heart failure and using new pharmacothera- 99m Tc-pyrophosphate imaging, has led to increased diagno- peutic drugs. 99mTc-pyrophosphate imaging can efﬁciently and ses of what may have otherwise been unrecognized cases of effectively distinguish between ATTR and cardiac AL. Although the exact mechanism of myocardial 99mTc-pyrophosphate uptake is cardiac amyloidosis (2). Attention to detail is imperative unknown, it is believed to bind to amyloid plaque microcalciﬁca- when gathering the patient’s history, administering the tions. 99mTc-pyrophosphate imaging has a 97% sensitivity and radiopharmaceutical, and acquiring images to ensure quality nearly 100% sensitivity for identifying cardiac ATTR when the AL and accurate diagnosis of the disease. form of the disease is ruled out through serum free light-chain and This article is the ﬁrst part of a 3-part series in this issue of serum and urine protein electrophoresis with immunoﬁxation test- the Journal of Nuclear Medicine Technology examining the ing. Although there are no published 99mTc-pyrophosphate cardiac utility of 99mTc-pyrophosphate imaging to diagnose cardiac amyloidosis imaging guidelines, the American Society of Nuclear Cardiology, Society of Nuclear Medicine and Molecular Imaging, amyloidosis. Part 1 begins with a discussion of the etiology and others have published consensus recommendations to stan- of amyloidosis in general and then details cardiac amyloid- dardize test performance and interpretation. This article, part 1 of osis, including information about the types, prevalence, signs a 3-part series in this issue of the Journal of Nuclear Medicine and symptoms, and disease course. The last section of part 1 Technology, describes amyloidosis etiology and cardiac amyloid- outlines the 99mTc-pyrophosphate image acquisition protocol. osis characteristics, including the types, prevalence, signs and Part 2 explains the processing and quantiﬁcation of 99mTc- symptoms, and disease course. It further explains the scan acqui- sition protocol. Part 2 of the series focuses on image/data quantiﬁ- pyrophosphate scans, including semiquantitative grading and cation and technical considerations. Finally, part 3 describes scan heart–to–contralateral-lung ratios, and discusses several proto- interpretation, along with the diagnosis and treatment of cardiac col technical considerations (3). Finally, part 3 concludes the amyloidosis. series by discussing scan interpretation, cardiac amyloidosis diagnosis, and treatment (4). WHAT IS AMYLOIDOSIS? Received Jan. 5, 2023; revision accepted Feb. 16, 2023. For correspondence or reprints, contact Mary Beth Farrell (marybethfarrell2016@ gmail.com). Amyloidosis refers to a collective group of rare diseases COPYRIGHT ! 2023 by the Society of Nuclear Medicine and Molecular Imaging. in which there are deposits of protein-based inﬁltrates CARDIAC AMYLOIDOSIS, PART 1: ACQUISITION ! Embry-Dierson et al. 83 within the extracellular tissue space (1). Proteins perform a transthyretin amyloidosis (ATTR), and serum amyloid A wide range of essential functions throughout the body, such amyloidosis. AL is caused by an overabundance and mis- as catalyzing chemical reactions, providing structural support, folding of light-chain proteins. Light-chain proteins are regulating cellular membrane transport, protecting against dis- antibody components or immunoglobulins (immune system eases, and coordinating cell signaling pathways (5). It is esti- proteins in serum and cells) produced by plasma cells in the mated that there are as many as 100,000 different proteins in bone marrow that ﬁght off infection. There are 2 types of the human body (6). Proteins fold and bend into precise light chains: k and l. shapes based on the sequence of amino acids. A protein’s spe- Although light-chain amyloid ﬁbrils can build up in any ciﬁc function is directly related to its 3-dimensional shape. organ, they most frequently affect the heart and kidneys. Proteins must maintain their speciﬁc shape (5). If the pro- However, light-chain ﬁbrils can also accumulate in periph- tein loses its normal shape, or misfolds, it cannot function eral nerves (e.g., carpal tunnel syndrome), liver, skin, and properly. Usually, when proteins misfold, the body disassem- the gastrointestinal system. AL is acquired and typically bles and removes them with specialized enzymes called diagnosed in individuals over 50 y old. It is lethal because proteasomes. However, if the body does not remove the mis- of its rapid progression (Fig. 1). folded proteins, they can accumulate within various organs in ATTR results from the misfolding of the transthyretin the extracellular tissue. In amyloid disease, long, unbranched protein, a protein that used to be called prealbumin. The strings of misfolded proteins, called ﬁbrils, several micro- ATTR protein is generated by the liver and involved in meters in length, have an extremely stable structure resistant the transportation of thyroxine (a hormone secreted by the to dismantling and removal by cellular processes (2). thyroid gland affecting digestion, heart function, muscle The accumulation of amyloid ﬁbrils eventually impairs function, brain development, and bone maintenance) and the affected organ’s function. Think of it like a neighbor- retinol-binding protein (a protein responsible for transport- hood with a stockpile of broken-down, junked cars parked ing vitamin A) (7). ATTR can affect multiple organs, on the streets (the amyloid ﬁbrils are the junked end- including the heart, peripheral nerves, and autonomic ner- product of the misfolded proteins). The junked cars stock- vous system. When amyloid is deposited in the autonomic pile, blocking the parking places and the driving lanes for nervous system, it can affect bladder, digestive, and genital normally operating cars. Eventually, trafﬁc ceases, and the function. neighborhood shuts down. In amyloid, the ﬁbrils displace Serum amyloid A amyloidosis is caused by misfolding of normally functioning structures in a similar fashion. serum amyloid A protein and ﬁbril formation. Serum amyloid Amyloid ﬁbrils can deposit in any tissue or organ in the A protein is produced in the liver and is involved in inﬂam- body, such as the brain, skin, or heart, causing amyloidosis matory responses. It commonly deposits in the kidney and (5). Different clinical manifestations and diseases result, liver and can affect individuals at any age. It can be involved depending on the organ and protein deposited (2). For in long-term inﬂammatory conditions such as rheumatoid example, the deposition of b-amyloid proteins between arthritis, Crohn disease, tuberculosis, or osteomyelitis. brain neurons creates plaques that block communication Because many types of amyloidosis can affect different and disrupt cell function in Alzheimer disease. As another and multiple organs and tissues, causing a plethora of example, deposits of serum amyloid A protein in the kidney symptoms, it can be challenging to diagnose. For example, or liver can cause long-term inﬂammatory conditions. amyloidosis affecting the kidneys can cause fatigue, as can Over 30 different amyloid diseases have been identiﬁed. amyloidosis affecting the heart. As another example, amy- Interestingly, all amyloid is morphologically or structurally loidosis of the heart can cause shortness of breath, but so similar despite the abnormal protein involved. How amyloid can amyloidosis of the respiratory system. can be morphologically homogeneous compared with the heterogeneity of organ involvement and clinical syndromes WHAT IS CARDIAC AMYLOIDOSIS? is a mystery. Cardiac amyloidosis is a systemic form of amyloidosis in which the protein-based inﬁltrates deposit in myocardial TYPES tissue along with other tissues throughout the body. The Classiﬁcation of amyloid is based on the abnormal pro- accumulation of amyloid ﬁbrils causes the myocardium to tein involved and whether it is conﬁned to a single organ thicken and stiffen, leading to diastolic dysfunction. Dia- (localized) or spread throughout the body (systemic) (5). stolic dysfunction progresses to restrictive cardiomyopathy Localized, or organ-speciﬁc, amyloidosis involves a single and, eventually, congestive heart failure (8). organ. Although it can occur in any organ or tissue, amy- Until recently, cardiac amyloidosis was considered rare. loidosis frequently affects the skin, bladder, eyes, lungs, or However, the recent adoption of noninvasive diagnostic test- brain. Alzheimer disease, which affects the brain, is the ing has revealed a previously undiagnosed sizable prevalence most recognized localized form of the disease. of the disease (2). Cardiac amyloidosis has been identiﬁed The most common types of systemic amyloidosis include as a primary cause of heart failure, particularly unexplained monoclonal immunoglobulin light-chain amyloidosis (AL), heart failure with preserved ejection fraction (HFpEF) in 84 JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY ! Vol. 51 ! No. 2 ! June 2023 Unfortunately, cardiac AL, with its poor prognosis, has a median survival of 6 mo from the onset of heart failure if left untreated (13). Treatment focuses on symptom management and the suppres- sion of additional light-chain production and usually entails chemotherapy and immunotherapy. Fortunately, cardiac AL is relatively rare. Men and women are diagnosed at about the same rate, and diagnosis typi- cally occurs in patients between the ages of 40 and 80 y (2). Cardiac AL can be associated with other immunoglobulin- related diseases, such as multiple mye- loma (9). Cardiac ATTR Compared with cardiac AL, there is less evidence of direct toxic effects asso- ciated with cardiac ATTR. It is subdi- vided into wild-type ATTR, previously called senile amyloidosis, and variant, or hereditary, ATTR. FIGURE 1. Amyloid molecular mechanisms and imaging characteristics. Source, pro- Wild-type ATTR is the most com- tein, misfolding, ﬁbril formation, and deposition are depicted for cardiac ATTR and AL. In mon type of cardiac amyloidosis and is ATTR (both wild-type and variant), transthyretin proteins are secreted by liver, fold considered a chronic disease that occurs abnormally, and form ﬁbrils that are deposited in myocardium. In AL, immunoglobulin with aging. Wild-type ATTR accounts light-chain proteins misfold and form ﬁbrils that are also deposited in myocardium. Echocardiography, CMR, and PET can detect both types of cardiac amyloidosis. How- for about 80% of cardiac amyloidosis ever, nuclear imaging with bone-seeking tracers can differentiate between ATTR and AL, cases. Although the overall prevalence although there is evidence to suggest that a percentage of AL will be positive on nuclear in the general population has not been imaging. TTR 5 transthyretin; Wt 5 wild-type. (Adapted from (2).) ﬁrmly established, on autopsy, nearly 30% of patients over 75 y old with the elderly (9). Cardiac amyloidosis is so unrecognized and HFpEF without an antemortem suspicion of amyloid disease underdiagnosed that recent research suggests most patients were found to have wild-type ATTR (14). Similarly, wild- experience a delay of 2 or more years from when a patient type ATTR has been found in 13% of hospitalized patients ﬁrst presents to a physician to when cardiac amyloidosis is diagnosed (2). Two subtypes, AL and ATTR, make up approximately 95% of all cardiac amyloid diagnoses (Fig. 2) (10). Other forms of systemic amyloidosis, such as serum amyloid A amyloidosis, rarely affect the heart. The responsible proteins, the phenotypic expression (observable traits), therapy, and prognosis differ vastly between AL and ATTR. Therefore, differentiation between the two is essential. However, if left untreated, both types can lead to heart failure and reduced life expectancy (11). Cardiac AL AL results from plasma cell dyscrasia, the unregulated prolif- eration of a single plasma cell clone (2). AL prognosis, in gen- eral, is a function of the number and severity of organs involved. However, cardiac involvement harbors the worst prognosis because it has a rapid clinical progression and is rarely diag- FIGURE 2. Common types of cardiac amyloidosis. Two kinds nosed before symptoms appear. Furthermore, the emergence of amyloidosis account for approximately 95% of all cardiac amy- of symptoms often signals advanced organ involvement (12). loidosis cases: AL and ATTR. CARDIAC AMYLOIDOSIS, PART 1: ACQUISITION ! Embry-Dierson et al. 85 with HFpEF and left ventricular wall thickness greater than rhythms; lightheadedness; abdominal distension; and a sense 1.2 cm (15). of overall weakness and fatigue (19). If amyloid is deposited Wild-type ATTR occurs predominantly in people over in the heart valves, it can lead to regurgitation or stenosis. It is 70 y old and affects men more often than women (16). not uncommon to discover that patients being treated for Although the factors behind the lower prevalence in women severe aortic stenosis also have ATTR. Treatment for both have not been elucidated, one study suggested hormonal types of cardiac ATTR includes the management of heart protection for women against wild-type ATTR (17). Wild- failure symptoms and arrhythmias. In addition, new pharma- type ATTR is clinically associated with bilateral carpal tun- cotherapeutic drugs are available that can help silence, stabi- nel syndrome, aortic stenosis, atrial ﬁbrillation, and other lize, or break down errant proteins. conditions resulting in increased wall thickness (1). The Because amyloidosis is a systemic disease, patients may— median survival from diagnosis is 57 mo (13). depending on the type of amyloidosis—experience other Variant ATTR is inherited from a genetic mutation in the symptoms, often called red ﬂags, such as numbness, tingling, transthyretin gene that affects the amino acid sequence and or pain in the hands or feet. Patients with cardiac amyloidosis predisposes the protein to misfolding (16). Over 120 variant may have skin changes, such as thickness or easy bruising. ATTR genotypic mutations have been identiﬁed (18). World- Some patients with AL may demonstrate purple patches wide, the most common mutation is V30M, which is associ- around the eyes (periorbital purpura), sometimes called panda ated more with sensory or autonomic neuropathy than with or raccoon eyes (20). Macroglossia, an enlarged tongue that cardiomyopathy. In the United States, the V122I mutation, looks rippled along the edge, is a symptom in patients with which is more likely to cause cardiomyopathy, is more com- AL (21). Finally, because AL can affect the kidneys and gas- mon. Again, although the exact prevalence is unknown, it is trointestinal tract, patients may experience increased or de- estimated that 2 million people in the United States are carriers creased urination, diarrhea, or constipation (22). and that 3%–4% of African Americans carry the gene (2). 99M Like wild-type cardiac ATTR, variant cardiac ATTR is TC-PYROPHOSPHATE SCAN ACQUISITION more common in men and is usually diagnosed between the Because cardiac amyloidosis eventually results in cardiac ages of 55 and 75 y (1). It is also associated with bilateral dysfunction, a debilitating disease, and because the treatment carpal tunnel syndrome along with polyneuropathy. The options vastly differ between ATTR and AL, it is critical to median survival from diagnosis is 31 mo for the V122I form diagnose and differentiate between them. 99mTc-pyrophosphate and 69 mo for other forms of variant ATTR (Table 1) (13). imaging can efﬁciently and effectively distinguish between ATTR and cardiac AL. Although the exact mechanism under- SIGNS AND SYMPTOMS OF CARDIAC AMYLOIDOSIS lying 99mTc-pyrophosphate uptake in cardiac amyloidosis is If left untreated, all forms of cardiac amyloidosis eventually unknown, it has been hypothesized that ATTR amyloid plaque result in heart failure due to the restrictive nature of the disease contains a higher concentration of microcalciﬁcations that and diastolic dysfunction. Thus, many patients experience bind with the pyrophosphate, allowing for improved uptake on the classic symptoms of heart failure, including shortness of nuclear cardiac imaging (Fig. 3) (23). 99mTc-pyrophosphate breath during exertion and when lying down; swelling in the imaging has a 97% sensitivity and nearly 100% speciﬁcity for feet, ankles, and legs; orthostatic hypotension; irregular heart identifying cardiac ATTR when the AL form of the disease is TABLE 1 Cardiac Amyloidosis Subtypes and Clinical Characteristics Frequency of Other organ Age Sex cardiac involvement or Associated Subtype Cause Protein range (y) frequency involvement conditions conditions AL Plasma cell Immunoglobulin 40–80 Men 5 70% Heart, kidney, Multiple myeloma dyscrasia light chain women gastrointestinal, tongue, nerves, liver, soft tissue Wild-type Aging Transthyretin.70 Men. 100% Heart, peripheral Bilateral carpal ATTR women nerves tunnel syndrome, lumbar spinal stenosis, atrial ﬁbrillation, biceps tendon rupture Variant Inherited Transthyretin 55–75 Men. 30%–100% Heart, nerves Bilateral carpal ATTR genetic women (depending tunnel mutation on mutation) syndrome, polyneuropathy 86 JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY ! Vol. 51 ! No. 2 ! June 2023 Patients with signs of heart failure and a history of bilateral carpal tunnel syndrome, unexplained neuropathy, or atrial arrhythmias are also candidates for 99mTc-pyrophosphate imaging (19). In addition, 99mTc-pyrophosphate im- aging is indicated to differentiate vari- ant from wild-type cardiac ATTR in patients with a suspected or known family history of amyloidosis. Finally, patients who are believed to have cardiac FIGURE 3. Abnormal planar and SPECT 99mTc-pyrophosphate cardiac amyloidosis ATTR but have contraindications to car- scans. (A) 99mTc-pyrophosphate planar anterior image showing avid myocardial uptake. diac MRI, such as implantable devices (B) SPECT short-axis (top), vertical long-axis (middle), and horizontal long-axis (bottom) or renal insufﬁciency, are candidates for images of same patient showing diffuse myocardial uptake. This scan is considered 99mTc-pyrophosphate imaging (2). diagnostic of ATTR cardiomyopathy if serum and urine studies for AL are negative. (Rep- There are no known contraindica- rinted from (2).) tions speciﬁc to 99mTc-pyrophosphate imaging other than the usual nuclear ruled out by the serum free light-chain ratio and serum and medicine procedure cautions related to pregnancy, breast- urine protein electrophoresis with immunoﬁxation tests (dis- feeding, and other recent nuclear medicine scans. cussed in part 3). Patient Preparation and Education There are no speciﬁc patient restrictions before 99mTc- Protocol Note pyrophosphate imaging. Patients may eat, drink, and take In the literature, several radiopharmaceuticals and imaging their medications as usual. However, at the time of appoint- protocols have been used for cardiac amyloidosis imaging ment scheduling, patients should be warned about the 3-h over the past 40 y (24). However, with the recent renewed delay between injection and imaging. interest in radionuclide imaging, the multitude of protocols A thorough patient medical history is crucial for accurate and lack of standardization have caused confusion and mis- interpretation of 99mTc-pyrophosphate cardiac amyloidosis diagnosis. In response, the American Society of Nuclear scans (24). The level of detail required is substantially more Cardiology and several other professional medical societies, than necessary for other types of nuclear medicine scans. including the Society of Nuclear Medicine and Molecular Thus, a standardized history sheet is useful in ensuring col- Imaging, published “ASNC/AHA/ASE/EANM/HFSA/ISA/ lection of complete information. SCMR/SNMMI Expert Consensus Recommendations for The patient interview should include past medical problems, Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2— speciﬁcally those related to heart failure and other cardiac dis- Evidence Base and Standardized Methods of Imaging” in eases. The past medical history should also elicit information 2019. The goal was to standardize performance and interpreta- pertaining to bilateral carpal tunnel syndrome, lumbar spinal tion to improve quality and patient outcomes (24). In 2021, stenosis, orthopedic procedures, biceps tendon rupture, American Society of Nuclear Cardiology and the other unexplained peripheral neuropathy, and autonomic dysfunc- societies published an addendum to the recommendations to tion. In addition, the record needs to include any family history further reﬁne 99mTc-pyrophosphate imaging (25). The protocol of amyloidosis, cardiomyopathy, or polyneuropathy. described below follows those recommendations. Documentation of current symptoms, even if they do not seem heart-speciﬁc, is necessary to diagnose cardiac amyloid- Indications and Contraindications osis. Particular attention must be paid to signs and symptoms A variety of patient populations may be scheduled for 99m of heart failure, such as shortness of breath, lower-extremity Tc-pyrophosphate cardiac amyloidosis imaging. How- edema, weakness, fatigue, or irregular heartbeat. Finally, the ever, patients with certain diagnoses present more often than results of any previous diagnostic tests, including echocardi- others. Many patients with suspected cardiac amyloidosis ography, cardiac MRI, electrocardiography, and clinical labo- have classic symptoms of heart failure. These patients also ratory testing, must be noted. often present with unexplained increased left ventricle thick- ness. Thus, the primary indication for 99mTc-pyrophosphate Radiopharmaceutical imaging is the evaluation of patients with heart failure and A variety of 99mTc-diphosphonate and pyrophosphate bone- increased left ventricular wall thickness not associated with seeking agents, speciﬁcally 99mTc-pyrophosphate, 99mTc-3,3- other conditions or reasons. 99mTc-pyrophosphate imaging is diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD), and & 99m also indicated for men over 60 y old who may be African Tc-hydroxymethylene diphosphonate (99mTc-HMDP), can Americans or patients with HFpEF (2). be used to diagnose ATTR cardiomyopathy (24). In the Introduction of HeartFatire CARDIAC AMYLOIDOSIS, PART 1: ACQUISITION ! Embry-Dierson et al. 87 99m absence of cardiac amyloidosis or subacute myocardial infarc- Tc-pyrophosphate in the bone continues to increase over tion, these bone tracers do not accumulate in the myocardium. time. However, myocardial uptake in amyloid disease peaks Thus, radionuclide imaging can differentiate cardiac amyloid- at about 1 h and then slowly begins to decline. The 99mTc- osis from other conditions that mimic it, such as hypertrophic pyrophosphate blood pool clearance rate depends on bone cardiomyopathy. metabolism and renal function. The higher the bone metabo- Although no studies to date have directly compared the 3 lism along with normal renal function, the faster the 99mTc- tracers, the published literature suggests they can be used inter- pyrophosphate clears from the blood pool, improving the pyP changeably. 99mTc-DPD and 99mTc-HMDP are predominantly semiquantitative and quantitative interpretation of the study. used in Europe because 99mTc-pyrophosphate is not available there. 99mTc-pyrophosphate is used in the United States Acquisition 99m because the Food and Drug Administration has not approved After intravenous injection of the Tc-pyrophosphate, 99m Tc-DPD and there is limited access to 99mTc-HMDP. both planar and SPECT images of the patient’s chest are 99m Tc-methylene diphosphonate, although widely available in obtained 3 h later (26). Imaging is usually performed on a the United States, has a signiﬁcantly lower sensitivity and standard dual-head g-camera using a 90" detector conﬁgura- should not be used for cardiac amyloid imaging. tion (27). However, recent research demonstrated that 99mTc- The recommended dose is 370–740 MBq (10–20 mCi) pyrophosphate imaging and 3-dimensional semiquantitative administered intravenously. The total radiation exposure from analysis of the images is feasible using newer cadmium-zinc- a 555-MBq (15-mCi) dose is approximately 3 mSv (26). telluride cameras (28). 99m Tc-pyrophosphate clears from the blood pool, with rapid Although imaging can be performed on a camera with a uptake in the bone and myocardium (27). Accumulation of small ﬁeld of view, positioning is more difﬁcult (27) and the TABLE 2 99m Tc-Pyrophosphate Cardiac Amyloidosis Imaging Parameters Parameter Characteristics Standard/optional/preferred Camera type Large-ﬁeld-of-view g-camera Standard Cadmium zinc telluride Optional* Energy peak 140 keV Standard Energy window 15%–20% Standard Collimator Low-energy, all-purpose Standard Patient position Supine Standard Field of view Heart/chest Standard Injection-to-imaging time 3h Standard 1h Optional Planar Acquisition type Static Standard Whole-body imaging Optional† Detector conﬁguration 90" Standard Views Anterior and left lateral Standard Number of views 2 Standard Counts per view 750,000 Standard Matrix 256 3 256 Standard Magniﬁcation 1.46 SPECT or SPECT/CT* Acquisition type Step and shoot or continuous Standard Patient position Supine Standard Upright Optional Orbit 180" /90" Standard 360" /180" Optional Matrix 128 3 128 (minimum, 64 3 64) Standard Magniﬁcation 1.46 (180" orbit) Standard 1.0 (360" orbit) Optional Pixel size 2.3–6.5 mm Standard Projections per detector 40/32 Standard Time per projection 20 s/25 s Standard CT attenuation correction Heart Preferred *Parameters deﬁned for g-cameras as parameters for cadmium-zinc-telluride cameras have not been ﬁrmly established. † Whole-body imaging is not useful when imaging with 99mTc-pyrophosphate. 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J Nucl Med. 2019;60(suppl 1):2068. and characteristics of cardiac amyloid disease so that tech- 24. Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/ nologists understand how the intricacies of the disease SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2—evidence base and standardized methods of affect test performance. This article further provides a tech- imaging. Circ Cardiovasc Imaging. 2021;14:e000029. nical foundation for study acquisition. Part 2 details how to 25. Dorbala S, Ando Y, Bokhari S, et al. Addendum to ASNC/AHA/ASE/EANM/ process and quantify the images and justiﬁes some of the HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2—evidence base and standardized meth- technical considerations of 99mTc-pyrophosphate cardiac ods of imaging. J Nucl Cardiol. 2021;28:1769–1774. amyloidosis imaging. Finally, part 3 puts acquisition and 26. ASNC cardiac amyloidosis practice points: 99m technetium-pyrophosphate imaging for data quantiﬁcation together to describe study interpretation transthyretin cardiac amyloidosis. American Society of Nuclear Cardiology website. https://www.asnc.org/ﬁles/19110%20ASNC%20Amyloid%20Practice%20Points%20 and the diagnosis and treatment of cardiac amyloidosis. WEB.pdf. Published February 2016. Updated February 2019. Accessed April 11, 2023. 27. Bokhari S, Cerqueira MD. Tc-99m-PYP imaging for cardiac amyloidosis: deﬁning REFERENCES the best protocol before the ﬂood gates burst. J Nucl Cardiol. 2020;27:1816–1819. 28. Manrique A, Dudoignon D, Brun S, et al. Quantiﬁcation of myocardial 99mTc- 1. Witteles RM, Bokhari S, Damy T, et al. Screening for transthyretin amyloid cardio- labeled bisphosphonate uptake with cadmium zinc telluride camera in patients with myopathy in everyday practice. JACC Heart Fail. 2019;7:709–716. transthyretin-related cardiac amyloidosis. EJNMMI Res. 2019;9:117. CARDIAC AMYLOIDOSIS, PART 1: ACQUISITION ! Embry-Dierson et al. 89 CONTINUING EDUCATION TEST: Cardiac Amyloidosis Imaging, Part 1: Amyloidosis Etiology and Image Acquisition 1. Which of the following is not a function of proteins? A. Cellular membrane transport regulation. B. Chemical reaction inhibition. gi 59 C. Disease protection. D. Structural support. 2. Which type of cardiac amyloidosis is the most common? A. β-amyloid. B. Light-chain. you 93 C. Monoclonal immunoglobulin. Da D. Transthyretin. 3. The usual treatment for cardiac AL is… A. Chemotherapy. B. Hormone therapy. g C. Radiation therapy. 59 D. Symptom management. Page 1 of 3 4. Patients with cardiac amyloidosis are often also diagnosed with… A. Alzheimer disease. B. Angioimmunoblastic lymphoma. g4 C. Bilateral carpal tunnel syndrome. Py D. Polycystic kidney disease. 5. All the following symptoms are typical of cardiac amyloidosis diagnosis except… A. Edema in the feet and ankles. B. Irregular heart rhythms. gi C. Nausea and vomiting. 99 D. Shortness of breath. 6. Which of the following is true regarding the diagnosis of cardiac AL? A. Men are diagnosed more often than women. B. Men and women are diagnosed at the same rate. as C. Women are diagnosed more often than men. pa D. Women are rarely diagnosed. Page 2 of 3 7. What is the required patient preparation for 99mTc-pyrophosphate cardiac amyloidosis imaging? A. Nothing to eat or drink after midnight. B. No -blockers for 48 h. ot C. No caffeine for 12 h before the study. 99 D. No patient preparation is necessary. 8. Which of the following has the lowest sensitivity for detecting cardiac amyloidosis? A. 99mTc-DPD. B. 99mTc-HDMP. C. 99mTc-methylene diphosphonate. page D. 99mTc-pyrophosphate. 9. What is the optimum time between injection and imaging for 99mTc-pyrophosphate cardiac amyloidosis scanning? A. No delay needed because imaging can immediately follow the injection. B. 30 min after injection. C. 1 h after injection. D. 3 h after injection. 1988 10. Which views are recommended for 99mTc-pyrophosphate cardiac amyloidosis imaging? A. Anterior and left lateral planar. B. Anterior and left lateral planar and SPECT. C. SPECT. g 19 D. Whole-body planar and left lateral. Page 3 of 3

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