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Cardiac Scintigraphy and Screening for Transthyretin Cardiac Amyloidosis

2021; Lippincott Williams & Wilkins; Volume: 144; Issue: 13 Linguagem: Inglês

10.1161/circulationaha.121.055517

1524-4539

Matthew J. Maurer, Frederick L. Ruberg,

Parathyroid Disorders and Treatments

HomeCirculationVol. 144, No. 13Cardiac Scintigraphy and Screening for Transthyretin Cardiac Amyloidosis Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBCardiac Scintigraphy and Screening for Transthyretin Cardiac AmyloidosisCaveat Emptor Mathew S. Maurer, MD and Frederick L. Ruberg, MD Mathew S. MaurerMathew S. Maurer Correspondence to: Mathew S. Maurer, Clinical Cardiovascular Research Laboratory for the Elderly, Columbia University Irving Medical Center, New York Presbyterian Hospital, 622 West 168th St, PH 12 Stem Room 134, New York, NY 10032. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1867-0526 Columbia University Irving Medical Center, New York (M.S.M.). and Frederick L. RubergFrederick L. Ruberg https://orcid.org/0000-0002-6424-4413 Boston University School of Medicine, Boston Medical Center, MA (F.L.R.). Originally published27 Sep 2021https://doi.org/10.1161/CIRCULATIONAHA.121.055517Circulation. 2021;144:1005–1007A growing body of evidence convincingly demonstrates that transthyretin cardiac amyloidosis (ATTR-CA) is an underdiagnosed cause of heart failure with preserved ejection fraction.1 With the advent and widespread availability of US Food and Drug Administration–approved therapies for ATTR-CA and evidence suggesting enhanced efficacy if administered early in the course of the disease, there has been an intense focus on "screening" for ATTR-CA that leverages noninvasive cardiac scintigraphy with bone-seeking tracers to identify early disease. The attraction of scintigraphy using technetium-based bone-avid radiotracers includes low cost, relative ease of administration and interpretation, availability, minimal radiation dose, and avoidance of a cardiac biopsy. Whereas such an approach seems logical and appropriate on the basis of data highlighting the excellent performance characteristics of cardiac scintigraphy with evidence-based multisocietal guidelines endorsing its appropriate use,2 we have concerns regarding the widespread and inappropriate application of scintigraphy in populations that do not have features suggestive of ATTR-CA (Figure). We, and others, have observed an alarmingly increasing rate of false-positive results seen at amyloidosis specialty referral centers.3Download figureDownload PowerPointFigure. Suggested steps for optimal use of cardiac scintigraphy to diagnose transthyretin cardiac amyloidosis. (1) Clinicians should identify clinical features suggestive of the phenotype of cardiac amyloidosis to (2) increase pretest probability, which will enhance positive predictive value and avoid false-positive results, and (3) assess for monoclonal proteins to exclude light chain (AL) amyloidosis, use single photon-emission computed (SPECT) tomography imaging to confirm myocardial retention of isotope, and use delayed imaging (eg, after 3 hours) especially in lower prevalence populations undergoing testing to minimize the confounding effect of blood pool tracer retention on scan interpretation. AV indicates atrioventricular; NPV, negative predictive value; PPV, positive predictive value; and TTR, transthyretin.The seminal article that delineated a nonbiopsy approach for the diagnosis of ATTR-CA evaluated 2 retrospective cohorts of patients gleaned from 9 international referral centers for cardiac amyloidosis.4 One cohort included 374 participants who underwent scintigraphy and an endomyocardial biopsy (the gold standard diagnostic test) in whom the prevalence of ATTR-CA was 70%. An additional 843 participants underwent cardiac scintigraphy without an endomyocardial biopsy. Collectively, in the 1,217 participants studied, with an overall prevalence of ATTR-CA of 44%, the diagnostic performance of positive scan result (semiquantitative grade 2 or 3) was excellent, conferring a sensitivity of 90.4%, specificity of 97.1%, negative predictive value of 92.9%, and positive predictive value (PPV) of 96%. When a positive scan result was combined with the absence of monoclonal proteins by serum and urine testing (thereby excluding light-chain amyloidosis, which was the most common cause of false-positive scan), the specificity and PPV were 100%. When using scintigraphy for nonbiopsy diagnosis, uptake noted on planar imaging must be verified as myocardial (and not in the ventricular cavity or "blood pool") by single photon-emission computed tomography. On the basis of these data, clinical providers have embraced this nonbiopsy approach for the diagnosis of ATTR-CA in populations deemed to be at high risk, such as older adults with cardiovascular conditions (eg, heart failure with preserved ejection fraction, atrial fibrillation, conduction disease), especially when accompanied by other noncardiac ATTR manifestations, such as carpal tunnel syndrome or spinal stenosis. The multisocietal guidelines that outline appropriate use of scintigraphy clearly stipulate the proper clinical scenarios for use as well as the scenarios in which the test should not be applied. Our experience is that providers are not adhering to this well-vetted guidance, resulting in increasing misdiagnoses, particularly in the context of planar imaging alone.Diagnostic tests are often validated in populations with a high prevalence of the disease of interest, often with advanced phenotypes. Cardiac scintigraphy for ATTR-CA is no exception. The problems arising from spectrum and bias in the initial evaluation of diagnostic tests were predicted by Ransohoff and Feinstein5 to result in lower values for PPV and negative predictive value over time when a test is subsequently applied to populations with lower prevalence and less severe disease. They note that initial observations of diagnostic performance "often produced misleading results such that tests initially regarded as valuable were later rejected as worthless." Such events are all too familiar in the practice of cardiovascular medicine. In the assessments of noninvasive stress testing for identification of significant coronary artery disease, initial patient populations with known multivessel coronary artery disease (eg, severe spectrum) and those with a high prevalence of disease were studied. When stress testing was performed in populations with lower disease prevalence, the same issues were observed, as PPV declined as patients with less severe coronary artery disease were studied.Thus, while we remain strong proponents of the appropriate use of cardiac scintigraphy as a noninvasive test to diagnose ATTR-CA, we are compelled to issue this warning. If one applies the test characteristics determined from a population with a prevalence of disease of ≈50% to a population in which the prevalence of disease is 5% or less (screening), the PPV will decline from 96% to 62.1% (Figure). A large percentage of positive imaging results will thus be false-positive. Thus, for appropriate use, the population evaluated with scintigraphy must have features suggestive of the known clinical phenotype of ATTR-CA. We suggest that this includes older patients (>60 years), increased ventricular wall thickness (at least 12 mm or greater), and a nondilated left ventricle along with other red flags (apical sparing longitudinal strain pattern, orthopedic manifestations [eg, carpal tunnel syndrome, lumbar spinal stenosis, or a biceps tendon rupture], persistently positive troponin, atrioventricular conduction block, or peripheral or autonomic neuropathy). Cardiac scintigraphy testing for ATTR-CA should not be performed in patients with dilated cardiomyopathy, severe ischemic heart disease, or dilated left ventricles without increased wall thickness, or another known cause of heart failure. Cardiac scintigraphy is preferably performed with delayed (eg, 3 hours) imaging to minimize the effect of tracer retained in the blood pool, must include single photon-emission computed tomography imaging, and must be accompanied by testing for a plasma cell disorder to exclude light-chain amyloidosis. Failure to follow all these recommendations will not only result in misdiagnoses but will incur significant clinical as well as financial consequences owing to high treatment copayments and inappropriate downstream testing while undermining the confidence among clinicians of scintigraphy as a method to achieve noninvasive ATTR-CA diagnosis even if applied appropriately. Cardiac scintigraphy affords great potential as a diagnostic test for early-stage ATTR-CA but use comes with the risk of great peril. All responsible parties including government regulators, industry partners, insurance payors, and academic societies should coordinate and work together to guide clinicians down the proper path.Sources of FundingDr Maurer receives grant support from National Institutes of Health grants R01HL139671, R21AG058348, and K24AG036778. He has had consulting income from Pfizer, Eidos, Prothena, Akcea, and Alnylam, and his institution received clinical trial funding from Pfizer, Prothena, Eidos, and Alnylam. Dr Ruberg received research grant support from National Institutes of Health grant R01HL139671, Pfizer, Akcea Therapeutics, and Alnylam Therapeutics and consulting income from Attralus and Alexion.Disclosures None.Footnoteshttps://www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1007.Correspondence to: Mathew S. Maurer, Clinical Cardiovascular Research Laboratory for the Elderly, Columbia University Irving Medical Center, New York Presbyterian Hospital, 622 West 168th St, PH 12 Stem Room 134, New York, NY 10032. Email [email protected]columbia.eduReferences1. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review.J Am Coll Cardiol. 2019; 73:2872–2891. doi: 10.1016/j.jacc.2019.04.003CrossrefMedlineGoogle Scholar2. Dorbala S, Ando Y, Bokhari S, Dispenzieri A, Falk RH, Ferrari VA, Fontana M, Gheysens O, Gillmore JD, Glaudemans AWJM, et al.. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 2 of 2: diagnostic criteria and appropriate utilization.J Card Fail. 2019; 25:854–865. doi: 10.1016/j.cardfail.2019.08.002CrossrefMedlineGoogle Scholar3. Hanna M, Ruberg FL, Maurer MS, Dispenzieri A, Dorbala S, Falk RH, Hoffman J, Jaber W, Soman P, Witteles RM, et al.. Cardiac scintigraphy with technetium-99m-labeled bone-seeking tracers for suspected amyloidosis: JACC review topic of the week.J Am Coll Cardiol. 2020; 75:2851–2862. doi: 10.1016/j.jacc.2020.04.022CrossrefMedlineGoogle Scholar4. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, et al.. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.Circulation. 2016; 133:2404–2412. doi: 10.1161/CIRCULATIONAHA.116.021612LinkGoogle Scholar5. Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests.N Engl J Med. 1978; 299:926–930. doi: 10.1056/NEJM197810262991705CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails September 28, 2021Vol 144, Issue 13Article InformationMetrics Download: 2,531 © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.055517PMID: 34570590 Originally publishedSeptember 27, 2021 PDF download