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  1. ASNC PRACTICE POINTS 99mTechnetium-Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis OVERVIEW diagnosis is confirmed by endomyocardial biopsy and typing of amyloid fibrils as needed. The purpose of this document is to identify the critical components involved in performing 99mTechnetium- pyrophosphate (99mTc-PYP) imaging for the evaluation of cardiac transthyretin amyloidosis (ATTR). • Several studies confirm the high sensitivity and specificity of 99mTc-bone compound scintigraphy [99mTc- 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) or PYP(2, 3)] for cardiac ATTR amyloidosis; recent studies highlight the value of DPD and/or PYP in differentiating cardiac ATTR from AL amyloidosis (4). BACKGROUND • The majority of individuals with cardiac amyloidosis have myocardial amyloid deposits formed from misfolded light chain (AL) or transthyretin (TTR) proteins. Diagnosis of amyloidosis and differentiation between the types is important for prognosis, therapy, and genetic counseling. • A distinct advantage of 99mTc-PYP imaging, even when echocardiography and CMR are diagnostic for cardiac amyloidoisis, is its ability to specifically identify ATTR cardiac amyloidosis non-invasively and thereby guide patient management (5). PATIENT SELECTION • Cardiac TTR amyloidosis, the focus of this practice points document, is an under‐diagnosed cause of heart failure. • Individuals with heart failure and unexplained increase in left ventricular wall thickness. • Amyloid derived from wild-type TTR results in a restrictive cardiomyopathy, most commonly presenting in men in their early 70’s onwards, but occasionally seen as young as age 60. Although almost 1 in 4 males > 80 years have some TTR-derived amyloid deposits at autopsy, the clinical significance of a mild degree of deposition is unknown--generally clinical manifestations of heart failure occur once enough amyloid has been deposited to cause LV wall thickening (1). • African-Americans over the age of 60 years with heart failure, unexplained or with increased left ventricular wall thickness (>12 mm). • Individuals over the age of 60 years with unexplained heart failure with preserved ejection fraction. • Individuals, especially elderly males, with unexplained neuropathy, bilateral carpal tunnel syndrome or atrial arrhythmias in the absence of usual risk factors, and signs/symptoms of heart failure. • Approximately 3 – 4% among US African Americans have a common inherited mutation of the TTR gene (Val122Ile), which produces a restrictive cardiomyopathy in a minority, but may contribute to heart failure in a higher proportion (1). • Evaluation of cardiac involvement in individuals with known or suspected familial amyloidosis. • Diagnosis of cardiac ATTR in individuals with CMR or echocardiography consistent with cardiac amyloidosis. • Cardiac amyloidosis should be suspected in individuals with heart failure and thickened ventricles with grade 2 or greater diastolic dysfunction on echocardiography or typical findings on cardiac magnetic resonance imaging (CMR; diffuse late gadolinium enhancement, ECV expansion or characteristic T-1 relaxation times); • Patients with suspected cardiac ATTR amyloidosis and contraindications to CMR such as renal insufficiency or an implantable cardiac device (5).

  2. ASNC PRACTICE POINTS 99mTechnetium-Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis OBTAINING THE RADIOTRACER IMAGING PROCEDURE 99mTc-PYP is readily available as unit doses from commercial radiopharmaceutical distributors or as kits for preparation (TechneScan PYPTM, Mallinkcrodt, St. Louis, MO). • Commonly used imaging procedures for 99mTc-PYP imaging are shown in Table 1. Individual centers can modify imaging procedures based on local camera capabilities and expertise. • • Kits containing 5 or 30 single-use vials are commercially available. Each 10 ml vial contains 11.9 mg of sodium pyrophosphate and 3.2 mg of stannous chloride and 4.4 mg of total tin, and this kit is approved for bone, cardiac (for the detection of myocardial infarction), and blood pool (radionuclide ventriculography and GI bleeding) imaging (see package insert for details of reconstitution of 99mTc-PYP). • Cardiac or chest SPECT and planar images are obtained one hour after injection of 99mTc-PYP using the parameters listed in Table 1. If persistent blood pool activity is noted on one hour images (e.g., renal failure), delayed images may be obtained at 3 hours. • Planar imaging is rapid, simple to perform, and useful for visual interpretation and quantification of the degree of myocardial uptake (see image interpretation) by heart to lung ratio or comparison to rib uptake. • The total body effective dose from 15 mCi of 99mTc-PYP is estimated at 3.2 mSv. • SPECT imaging may be helpful to 99mTc-DPD is not available for clinical use in the United States. Although there are no large studies directly comparing the agents, the principles in this document apply similarly to 99mTc-DPD and 99mTc-PYP imaging. • 1. avoid overlap of bone uptake 2. distinguish blood pool activity from myocardial activity(3) 3. assess the distribution of myocardial 99mTc-PYP uptake in individuals with positive planar scans TEST PREPARATION 4. identify 99mTc-PYP uptake in the interventricular septum (commonly involved in amyloidosis) and • No specific test preparation is required. 5. quantify the degree of myocardial uptake by comparison to rib uptake. • Whole body planar imaging may be helpful to identify uptake of 99mTc-PYP in the shoulder and hip girdles (a specific sign of systemic ATTR amyloidosis) (6) and should be considered adjunctive and optional in addition to standard cardiac-centered imaging, based on local expertize. • The value of 99mTc-PYP imaging with the newer “cardiac only” SPECT cameras needs further validation (due to inability to accurately display bone and lung 99m Tc-PYP uptake with these systems; see image interpretation section).

  3. ASNC PRACTICE POINTS 99mTechnetium-Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis IMAGE INTERPRETATION Table 1. Imaging Parameters for Cardiac 99mTc-PYP Imaging • The anterior and lateral planar images as well as the rotating projection images and reconstructed SPECT images are reviewed in standard cardiac imaging planes using commercial software. Myocardial 99mTc-PYP uptake patterns are categorized as absent, focal, diffuse or focal on diffuse. Scans with focal 99mTc-PYP uptake could represent rib fracture or previous myocardial infarction. Following a myocardial infarction, myocardial 99mTc-PYP uptake may be positive for upto 7 days and rarely may remain persistently positive. Imaging procedures Preparation Parameters No specific preparation. No fasting required. Rest scan 10-20 mCi intravenously Recommended: 1-hour SPECT and planar; Optional: 3-hour SPECT or planar • Scan Dose of 99mTc-PYP Time between injection and acquisition Imaging parameters Field of view • Recommended: Cardiac or chest; Optional: Wholebody planar Recommended: Cardiac or chest SPECT and planar imaging Supine 140 keV, 15-20% Low energy, high resolution 64 X 64 minimum 3.5 – 6.5 mm Quantifying myocardial 99mTc-PYP Uptake There are two approaches to quantification: Image type 1. Quantitative: myocardial to contralateral lung ratio of uptake at 1 hour • Circular target regions of interest (ROI) are drawn over the heart on the planar images and are mirrored over the contralateral chest to account for background and ribs (see Figure 1). • Total and absolute mean counts are measured in each ROI. A heart to contralateral (H/CL) ratio is calculated as the fraction of heart ROI mean counts to contralateral chest ROI mean counts. • H/CL ratios of ≥ 1.5 at one hour are classified as ATTR positive and ratios < 1.5 as ATTR negative (4). Position Energy window Collimators Matrix Pixel size Planar imaging specific parameters Number of views* Anterior, Lateral, and Left Anterior Oblique 90 degrees Detector configuration Image duration (count based) Magnification SPECT imaging specific parameters Angular range Detector configuration ECG gating Number of views/ detector Time per stop Magnification 2. Semi-quantitative: visual comparison to bone (rib) uptake at 3 hours 750,000 counts Cardiac uptake of 99mTc-PYP is evaluated using a semi- quantitative visual scoring method in relation to bone uptake (Table 2 and Figure 2). Based on previously publishedresults, visual scores of greater than or equal to 2 on planar (2, 3) or SPECT images at 3 hours(6) are classified as ATTR positive, and scores of less than 2 as ATTR negative. 1.46 360 degrees 180 degrees Off; Nongated imaging 40 While grade 2-3 or H/CL >1.5 uptake is strongly suggestive of TTR amyloidosis, any degree of 99mTc-PYP uptake can also be seen in AL amyloidosis, and as such a complete evaluation is warranted to exclude this diagnosis. 20 seconds 1.0 In clinical practice both semi-quantitative visual scoring and H/CL are used. *Anterior and lateral views can be obtained at the same time using a 90 degree detector configuration; lateral planar views or SPECT imaging may help separate sternal from myocardial uptake.

  4. ASNC PRACTICE POINTS 99mTechnetium-Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis REPORTING The report should include all elements of an ideal report as per standard ASNC guidelines. Table 2. Semi-quantitative Visual Grading of Myocardial 99mTc-PYP Uptake by Comparison to Bone(rib) Uptake Grade Grade 0 Grade 1 Grade 2 Grade 3 Myocardial 99mTc-PYP Uptake no uptake and normal bone uptake uptake less than rib uptake uptake equal to rib uptake uptake greater than rib uptake with mild/ absent rib uptake Table 3. Myocardial 99mTc-PYP Imaging Guideline for Reporting Parameters Demographics Elements Patient name, age, sex, reason for the test, date of study, prior imaging procedures, biopsy results if available (required) Imaging technique, radiotracer dose and mode of administration, interval between injection and scan, scan technique (planar and SPECT) (required) Figure 1. Quantitation of Cardiac 99mTc-PYP Uptake Using Heart to Contralateral Lung (H/CL) Ratio Methods Findings Image quality Visual scan interpretation (required) Semi-quantitative interpretation in relation to rib uptake (required) Quantitative findings heart to contralateral lung ratio (optional; recommended for positive scans) Whole body imaging if planar whole body images are acquired (optional) Interpret CT for attenuation correction if SPECT/CT scanners are used (recommended) 1. An overall interpretation of the findings into categories of 1) not suggestive of TTR amyloidosis; 2) strongly suggestive of TTR amyloidosis or 3) equivocal for TTR amyloidosis a. Not suggestive: A semi-quantitative visual score of 0 or H/CL ratio < 1. b. Strongly suggestive: A semi-quantitative visual score of 2 or 3 or H/CL ratio >1.5 c. Equivocal: A semi-quantitative visual score of 1 or H/CL ratio 1-1.5 2. Interpret the results in the context of prior evaluation a. If echo/CMR are strongly positive, and 99mTc‐ PYP negative, consider further evaluation including endomyocardial biopsy Ancillary findings Figure 2. Grading 99mTc-PYP Uptake on Planar and SPECT Images Conclusions Of note: A negative or mildly positive PYP does not exclude AL amyloid. In addition, equivocal results could represent AL amyloid or early TTR amyloid

  5. ASNC PRACTICE POINTS 99mTechnetium-Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis BILLING ASNC would recommend: • For planar with SPECT report CPT 78803 Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s); tomographic (SPECT). REFERENCES: (1) Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012;126:1286-300. (2) Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. Journal of the American College of Cardiology 2005;46:1076-84. • When reporting CPT 78803, planar imaging of a limited area or multiple areas should be included with the SPECT. (3) Gertz MA, Brown ML, Hauser MF, Kyle RA. Utility of technetium Tc 99m pyrophosphate bone scanning in cardiac amyloidosis. Archives of internal medicine 1987;147:1039-44. • For the HCPCS level II code report A9538 99mTc- pyrophosphate, diagnostic, per study dose, up to 25 millicuries. (4) Bokhari S, Castano A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin- related familial and senile cardiac amyloidoses. Circulation Cardiovascular imaging 2013;6:195-201. • For a single planar imaging session alone (without a SPECT study), report CPT 78800 Radiopharmaceutical localization of tumor or distribution of radiopharmaceutical agent(s); limited area. (5) Falk RH, Quarta CC, Dorbala S. How to image cardiac amyloidosis. Circulation Cardiovascular imaging 2014;7:552-62. (6) Hutt DF, Quigley AM, Page J, Hall ML, Burniston M, Gopaul D et al. Utility and limitations of 3,3-diphosphono-1,2- propanodicarboxylic acid scintigraphy in systemic amyloidosis. European heart journal cardiovascular Imaging 2014;15:1289-98. ASNC thanks the following members for their contributions to this document: Writing Group: Sharmila Dorbala, MD (Chair) Sabahat Bokhari, MD Edward Miller, MD Renee Bullock-Palmer, MD Prem Soman, MD Randall Thompson, MD Reviewers: Rodney Falk, MD Martha Grogan, MD Matthew Maurer, MD Frederick Ruberg, MD