Circulation: Cardiovascular Imaging 1 EXPERT CONSENSUS RECOMMENDATIONS 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

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Circulation: Cardiovascular Imaging is available at www.ahajournals.org/journal/circimaging
Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021
*Cardiac Amyloidosis Program, Cardiovascular Imaging Program, Departments of Radiology and Medicine, Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA. †Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan. ‡Columbia University Medical Center/New York
Presbyterian Hospital, Columbia University, NY. §Division of Hematology, Division of Cardiovascular Diseases, and Department of Radiology, Division of Nuclear
Medicine, Department of Medicine, Mayo Clinic, Rochester, MN. ∥Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. ¶National Amyloidosis
Centre, Division of Medicine, University College London, London, United Kingdom. #Nuclear Medicine and Molecular Imaging, University Hospitals Leuven, Leuven,
Belgium. **Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen,
The Netherlands. ††Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH. ‡‡Department of Rheumatology & Clinical Immunology, University
of Groningen, University Medical Center Groningen, Groningen, The Netherlands. §§Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
∥∥Amyloidosis Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy. ∥∥1Department
of Molecular Medicine, University of Pavia, Italy. ¶¶Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT. ##Frankel Cardiovascular Center,
Michigan Medicine, Ann Arbor, MI. ***Cardiology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater-University of Bologna, Bologna,
Italy. †††Amyloidosis Center and Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston,
MA. ‡‡‡Feinberg School of Medicine, Northwestern University, Chicago, IL. §§§Amsterdam UMC, University of Amsterdam, Department of Radiology and Nuclear
Medicine, Amsterdam, The Netherlands. ∥∥∥Cardiovascular Imaging Center, Departments of Medicine and Radiology, University of Virginia, Charlottesville, VA.
The American Heart Association requests that this document be cited as follows: Dorbala S, Ando Y, Bokhari S, Dispenzieri A, Falk RH, Ferrari VA, Fontana M,
Gheysens O, Gillmore JD, Glaudemans AWJM, Hanna MA, Hazenberg BPC, Kristen AV, Kwong RY, Maurer MS, Merlini G, Miller EJ, Moon JC, Murthy VL, Quarta CC,
Rapezzi C, Ruberg FL, Shah SJ, Slart RHJA, Verberne HJ, Bourque JM. 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. Circ Cardiovasc Imaging. 2021;14:e000029. DOI:
10.1161/HCI.0000000000000029
© 2021 American Society of Nuclear Cardiology, Heart Failure Society of America, and American Heart Association, Inc.
EXPERT CONSENSUS RECOMMENDATIONS
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
Sharmila Dorbala, MD, MPH, FASNC, Chair*; Yukio Ando, MD, PhD†; Sabahat Bokhari, MD‡; Angela Dispenzieri, MD§;
Rodney H. Falk, MD*; Victor A. Ferrari, MD∥; Marianna Fontana, PhD¶; Olivier Gheysens, MD, PhD#; Julian D. Gillmore, MD, PhD¶;
Andor W. J. M. Glaudemans, MD, PhD**; Mazen A. Hanna, MD††; Bouke P. C. Hazenberg, MD, PhD‡‡; Arnt V. Kristen, MD§§;
Raymond Y. Kwong, MD, MPH*; Mathew S. Maurer, MD‡; Giampaolo Merlini, MD∥∥,∥∥1; Edward J. Miller, MD, PhD¶¶;
James C. Moon, MD¶; Venkatesh L. Murthy, MD, PhD##; C. Cristina Quarta, MD, PhD¶; Claudio Rapezzi, MD***;
Frederick L. Ruberg, MD†††; Sanjiv J. Shah, MD‡‡‡; Riemer H. J. A. Slart, MD**; Hein J. Verberne, MD, PhD§§§;
Jamieson M. Bourque, MD, MHS, FASNC, Co-Chair∥∥∥
Key Words: AHA Scientific Statements ◼ cardiac amyloidosis ◼ diagnosis ◼ appropriate use ◼ expert consensus ◼ multimodality
Circulation: Cardiovascular ImagingCCIMcirccvimCirc: Cardiovasc ImagingHCICIRCCVIMCirculation: Cardiovascular Imaging1941-96511942-0080Lippincott Williams &
WilkinsHagerstown, MD
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PREAMBLE
Cardiac amyloidosis is a form of restrictive infiltrative car-
diomyopathy that confers significant mortality. Due to the
relative rarity of cardiac amyloidosis, clinical and diagnos-
tic expertise in the recognition and evaluation of individu-
als with suspected amyloidosis is mostly limited to a few
expert centers. Electrocardiography, echocardiography,
and radionuclide imaging have been used for the evalua-
tion of cardiac amyloidosis for over 40 years.1-3 Although
cardiovascular magnetic resonance (CMR) has also been
in clinical practice for several decades, it was not applied to
cardiac amyloidosis until the late 1990s. Despite an abun-
dance of diagnostic imaging options, cardiac amyloidosis
remains largely underrecognized or delayed in diagnosis.4
While advanced imaging options for noninvasive evalua-
tion have substantially expanded, the evidence is predomi-
nately confined to single-center small studies or limited
multicenter larger experiences, and there continues to be
no clear consensus on standardized imaging pathways
in cardiac amyloidosis. This lack of guidance is particu-
larly problematic given that there are numerous emerg-
ing therapeutic options for this morbid disease, increasing
the importance of accurate recognition at earlier stages.
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Imaging provides non-invasive tools for follow-up of dis-
ease remission/progression complementing clinical eval-
uation. Additional areas not defined include appropriate
clinical indications for imaging, optimal imaging utilization
by clinical presentation, accepted imaging methods, accu-
rate image interpretation, and comprehensive and clear
reporting. Prospective randomized clinical trial data for the
diagnosis of amyloidosis and for imaging-based strate-
gies for treatment are not available. A consensus of expert
opinion is greatly needed to guide the appropriate clinical
utilization of imaging in cardiac amyloidosis.
INTRODUCTION
The American Society of Nuclear Cardiology (ASNC) has
assembled a writing group with expertise in cardiovascu-
lar imaging and amyloidosis, with representatives from the
American College of Cardiology (ACC), the American Heart
Association (AHA), the American Society of Echocardiog-
raphy (ASE), the European Association of Nuclear Medicine
(EANM), the Heart Failure Society of America (HFSA), the
International Society of Amyloidosis (ISA), the Society for
Cardiovascular Magnetic Resonance (SCMR), and the Soci-
ety of Nuclear Medicine and Molecular Imaging (SNMMI).
This writing group has developed a joint expert consensus
document on imaging cardiac amyloidosis, divided into two
parts. Part 1 has the following aims:
1. Perform and document a comprehensive review of
existing evidence on the utility of echocardiogra-
phy, CMR, and radionuclide imaging in screening,
diagnosis, and management of cardiac amyloidosis.
2. Define standardized technical protocols for the
acquisition, interpretation, and reporting of these
noninvasive imaging techniques in the evaluation
of cardiac amyloidosis.
Part 2 of this expert consensus statement addresses
the development of consensus diagnostic criteria for
cardiac amyloidosis, identifies consensus clinical indica-
tions, and provides ratings on appropriate utilization in
these clinical scenarios.
Purpose of the Expert Consensus Document
The overall goal of this multi-societal expert consensus
document on noninvasive cardiovascular imaging in car-
diac amyloidosis is to standardize the selection and per-
formance of echocardiography, CMR, and radionuclide
imaging in the evaluation of this highly morbid condition,
and thereby improve healthcare quality and outcomes of
individuals with known or suspected cardiac amyloidosis.
We hope that research generated to validate the recom-
mendations of this consensus document will form the
basis for evidence-based guidelines on cardiac amyloi-
dosis imaging within the next few years.
OVERVIEW OF CARDIAC AMYLOIDOSIS
Cardiac amyloidosis is a cardiomyopathy that results in
restrictive physiology from the myocardial accumulation of
misfolded protein deposits, termed amyloid fibrils, causing
a clinically diverse spectrum of systemic diseases. Most
cases of cardiac amyloidosis result from two protein pre-
cursors: amyloid immunoglobulin light chain (AL), in which
the misfolded protein is a monoclonal immunoglobulin light
chain typically produced by bone marrow plasma cells,
and amyloid transthyretin (ATTR) amyloidosis, in which the
misfolded protein is transthyretin (TTR), a serum transport
protein for thyroid hormone and retinol that is synthesized
primarily by the liver.3 ATTR amyloidosis is further subtyped
by the sequence of the TTR protein into wild-type (ATTRwt)
or hereditary (ATTRv), the latter resulting from genetic vari-
ants in the TTR gene.5,6 Cardiac involvement in systemic
AL amyloidosis is common (up to 75%, depending on diag-
nostic criteria),7 and in the case of ATTRwt amyloidosis, is
the dominant clinical feature seen in all cases.
The different types of cardiac amyloidosis display sig-
nificant heterogeneity in clinical course, prognosis, and
treatment approach.8 AL amyloidosis is characterized by
a rapidly progressive clinical course, and if untreated, the
median survival is less than 6 months. ATTRv amyloido-
sis follows a varied clinical course depending upon the
specific mutation inherited with either cardiomyopathy
and/or sensory/autonomic polyneuropathy.9 Further-
more, ATTR amyloidosis (both wild-type and hereditary)
is characterized by an age-dependent penetrance, with
the clinical phenotype developing as age advances.
The diagnosis of cardiac amyloidosis remains challeng-
ing owing to a number of factors, which include the relative
rarity of the disease, clinical overlap with more common dis-
eases that result in thickening of the myocardium (ie, hyper-
tension, chronic renal failure, hypertrophic cardiomyopathy,
aortic stenosis), unfamiliarity with the proper diagnostic
algorithm, and a perceived lack of definitive treatment. While
systemic AL amyloidosis is indeed a rare disease affecting
approximately 8 to 1210,11 per million person years, and as
high as 40.5 per million person years in 2015,12 ATTRwt
cardiac amyloidosis appears quite common, with recent
reports using contemporary diagnostic strategies that place
Abbreviations
AL Amyloid immunoglobulin light chain
ATTR Amyloid transthyretin
DPD
99mTc-3,3-diphosphono-1,2-propanodi-
carboxylic acid
ECV Extracellular volume
EF Ejection fraction
HMDP Hydroxymethylenediphosphonate
LGE Late gadolinium enhancement
LV Left ventricular
PYP Pyrophosphate
Tc 99mTechnetium
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 3
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
the prevalence in as many as 10% to 16% of older patients
with heart failure or with aortic stenosis.13-15 In addition, the
most common mutation associated with ATTRv amyloido-
sis has been reproducibly demonstrated in 3.4% of African
Americans.16 While the penetrance remains disputed, this
suggests there are approximately 2 million people in the
United States who are carriers of an amyloidogenic muta-
tion and are at risk for cardiac amyloidosis. It is clear both
ATTRv and ATTRwt cardiac amyloidosis are underrecog-
nized, yet important causes of diastolic heart failure.17
Treatment options are rapidly expanding. Anti-plasma
cell therapeutics have extended median survival in AL
amyloidosis beyond 5 years, 7 with increasing survival
beyond 10 years. We are potentially nearing a similar sea
change in the management of ATTR amyloidosis. ATTR
amyloidosis was previously only treated by solid-organ
transplantation, as conventional highly effective heart-
failure therapy is poorly tolerated and contraindicated in
advanced cardiac amyloidosis. Although early clinical tri-
als of amyloid specific antibodies have been unsuccessful
to date,18-20 one remains under study in a Phase I clinical
trial.21 Novel therapeutics that suppress TTR expression
have been studied in Phase 3 clinical trials and received
FDA approval18,19 for ATTRv with polyneuropathy. Addi-
tionally, a randomized clinical trial of TTR stabilizer therapy
demonstrated a reduction in all-cause mortality in ATTR
cardiomyopathy22; this agent has recently received FDA
approval for ATTR cardiomyopathy. As these exciting pros-
pects move into the clinical realm, it is evident early diagno-
sis will be essential to afford the most effective treatment
options for both AL and ATTR cardiac amyloidosis.
BIOMARKERS AND BIOPSY IN CARDIAC
AMYLOIDOSIS
Despite these advances in treatment, the challenge per-
sists to increase recognition and achieve effective, timely
diagnosis. In the past, a diagnosis of cardiac amyloidosis
required an endomyocardial biopsy, which remains the
gold standard, as it is virtually 100% accurate, assum-
ing appropriate sampling, for the detection of amyloid
deposits.23 Specific identification of the precursor protein
can be accomplished from the tissue specimen through
immunohistochemistry, albeit with limitations,24 or laser-
capture tandem mass spectrometry (LC/MS/MS). This
latter technique is considered the definitive test for pre-
cursor protein identification.25 While ATTR cardiac amyloi-
dosis can now be diagnosed accurately without the need
of cardiac biopsy,3 AL amyloidosis requires demonstration
of light-chain amyloid fibrils in tissue (although not nec-
essarily the heart) prior to administration of chemother-
apy. Even for ATTR cardiac amyloidosis, a cardiac biopsy
remains necessary in the context of equivocal imaging or
the co-existence of a monoclonal gammopathy.
Clinical suspicion of cardiac amyloidosis can be raised
by the constellation of clinical signs and symptoms, specific
demographics (ie, age, race, country of family origin), electro-
cardiography, and suggestive non-invasive imaging findings.
Endomyocardial biopsy, although highly sensitive (100%),23
is impractical as a screening test for cardiac amyloidosis,
given its inherent risk and requirement of pathologic exper-
tise, which is limited to a few academic centers. Other limita-
tions of endomyocardial biopsy include: inability to quantify
whole-heart amyloid burden, inability to evaluate systemic
disease burden, and, for these same reasons, limited assess-
ment of response to therapy. Thus, contemporary imaging
techniques, including CMR, radionuclide imaging with bone-
avid radiotracers, and echocardiography with longitudinal
strain quantification, have evolved as the principal means for
diagnosis and management of cardiac amyloidosis.
The current diagnostic approach for cardiac amyloidosis
involves the use of one or more of these imaging modalities in
conjunction with assessment of a plasma-cell disorder (Fig-
ure 1).3 Serum plasma electrophoresis is an insensitive test
for AL amyloidosis and thus is unreliable for diagnosing AL
amyloidosis. Serum and urine immunofixation and the mea-
surement of serum free light chains (FLC) are necessary for
the diagnosis of AL amyloidosis. In cases of confirmed ATTR
amyloidosis, TTR gene sequencing is performed to establish
ATTRwt vs ATTRv. In AL amyloidosis, the concentration of
the affected FLC, in conjunction with serum N-terminal-pro
brain natriuretic peptide (NT-proBNP) and cardiac troponin
T or I, can be utilized to assign a disease stage that confers
highly reproducible prognostic information.26 Furthermore,
a cardiac staging system based on NT-proBNP and car-
diac troponins (along with differential FLC levels) allows the
stratification of patients into stages widely used in clinical
practice for modulating the therapy intensity in AL amyloido-
sis.26 A European study identified a stage 3b subgroup with
very advanced cardiac involvement; these patients had high
concentrations of NT-proBNP (>8500 ng/L) and a very
poor prognosis, which warrants further study.27 Furthermore,
a reduction in FLC following anti-plasma cell treatment,
termed a hematologic response, is typically followed within
6 to 12 months by a reduction in NT-pro-BNP and tropo-
nin, termed an organ-specific response, which is associated
with improved symptoms of heart failure and extended sur-
vival.28 The FLC-based and NT-proBNP-based hematology
and cardiac responses have been extensively validated in
AL amyloidosis.29 In ATTR cardiac amyloidosis, NT-pro-BNP,
cardiac troponin, and estimated glomerular filtration rate
have also been validated as diagnostic markers in different
risk-prediction models,30-32 with changes in NT pro-BNP
useful to follow disease progression.18,22 Biomarker evalu-
ation is an integral part of the management of patients with
AL and ATTR cardiac amyloidosis.
EVOLUTION OF IMAGING IN CARDIAC
AMYLOIDOSIS
Despite the widespread utilization of serum biomarkers
for risk assessment of cardiac amyloidosis, biomarkers
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
themselves are non-specific for the diagnosis of amyloido-
sis. This lack of specificity is primarily due to confounding
by renal function and overlap with other cardiomyopathies
that also result in abnormalities of NT-pro BNP and tropo-
nin. For this reason, imaging remains a requisite component
of the diagnostic algorithm for cardiac amyloidosis. In addi-
tion, imaging alone captures the cardiac functional impair-
ment caused by amyloid infiltration and affords insight into
hemodynamics. Finally, imaging has the potential to directly
visualize cardiac remodeling that may result from both FLC
reduction, TTR stabilization/suppression, and/or the anti-
amyloid specific therapies in development. This consensus
document serves as means to summarize the interpretation
and application of multimodal imaging in cardiac amyloidosis.
The first descriptions of echocardiographic findings in
cardiac amyloidosis were reported more than 40 years
ago.1,33 Since that time, echocardiography has become
a standard part of the diagnostic assessment in patients
with suspected or confirmed cardiac amyloidosis.34-37 The
initial studies of echocardiography in cardiac amyloido-
sis occurred when only M-mode echocardiography was
routinely available and predated the advent of clinical
2D and Doppler echocardiography. Nevertheless, these
early studies recognized many of the findings of cardiac
amyloidosis still used today in clinical practice,34-41 along
with more recent advances as discussed in subsequent
sections.1,33 Echocardiography has the advantage of
portability, bedside availability, conspicuous presence,
Figure 1. Systematic evaluation of cardiac amyloidosis.
A comprehensive evaluation of cardiac amyloidosis includes consideration of clinical symptoms, evaluation of cardiac involvement (biomarkers
and cardiac imaging), evaluation of systemic amyloidosis (serum, urine testing, and biopsy), followed by typing of amyloid deposits into AL or
ATTR, and documentation of mutations in patients with ATTR amyloidosis. *Clinical symptoms: heart failure, peripheral/autonomic neuropathy,
macroglossia, carpal tunnel syndrome, periorbital bruising, stroke, atrial fibrillation, postural hypotension, fatigue, weight loss, pedal edema, renal
dysfunction, diarrhea, constipation. †Evaluation for cardiac amyloidosis: ECG, ECHO, CMR, EMB, 99mTc-PYP/DPD/H MDP/123I-mIBG/
PET, NT-proBNP, troponin T. ‡Evaluation for systemic amyloidosis: AL: detect plasma cell clone: serum and urine immunofixation, serum
FLC assay and immunoglobulin analysis; AL: detect systemic organ involvement: 24-hour urine protein, Alkaline phosphatase, eGFR, cardiac
biomarkers (NT-proBN P, troponins); Tissue biopsy: EM B/Fatpad/ Bone marrow/Other with Congo red staining. §Confirm Amyloidosis Type:
ATTR: IHC and MS of Biopsy or 99mTc- PYP/DPD/HMDP Grade 2 or 3 if a clonal process is excluded; AL: MS or IHC of Biopsy. ¥Confirm TTR
Mutation in Patients with ATTR amyloidosis: genetic testing for TTR mutations. AL, amyloid light chain; ATTR, amyloid transthyretin; CMR,
cardiac magnetic resonance imaging; DPD, -3,3-diphosphono-1,2-propanodicarboxylic acid; ECG, electrocardiogram; EMB, endomyocardial
biopsy; ECHO, echocardiogram; eGFR, estimated glomerular filtration rate; HMDP, hydroxymethylenediphosphonate; IHC, immunohistochemistry;
mIBG, meta-iodobenzylguanidine; MS, mass spectroscopy; v, hereditary; PYP, pyrophosphate; Tc, technetium; wt, wild-type.
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
and superior diastolic function assessment. Thus, while
echocardiography is not sufficient by itself, to make the
diagnosis of cardiac amyloidosis, it is an essential part of
the diagnostic evaluation and ongoing management of
patients with this disorder.
Cardiovascular magnetic resonance in cardiac amy-
loidosis provides structural and functional information
that complements echocardiography.42 Cardiovascular
magnetic resonance may have advantages when acous-
tic windows are poor, for characterization of the right
ventricle, tissue characterization based on the contrast-
enhanced patterns of myocardial infiltration, and precise
quantification of cardiac chamber volumes and ventricu-
lar mass. However, CMR with late gadolinium enhance-
ment (LGE) may be relatively contraindicated in patients
with suspected cardiac amyloidosis and concomitant
renal failure—a frequent occurrence. Moreover, in cen-
ters where CMR scanning in patients with pacemakers is
not yet routine, echocardiography may be the only option
for imaging cardiac structure and function. Although
both the echocardiographic and CMR assessment of
structure and function alone may be non-specific, some
features provide more specificity, including biventricular
long axis function impairment, apical sparing, reduced
stroke volume index, pericardial effusion, marked biatrial
enlargement, atrial appendage thrombus in sinus rhythm,
sparkling texture of the myocardium, and/or dispropor-
tionate increase in left ventricular (LV) mass for elec-
trocardiogram (ECG) voltages. Given the limitations of
assessment of structure and function alone (by echo or
CMR), tissue characterization by CMR adds high value,
as discussed in subsequent sections.
Radionuclide imaging provides critical information
on amyloid type that complements cardiac structural
and functional characterization by echocardiography
and CMR. It has long been appreciated that there is a
unique myocardial uptake pattern in amyloid by scintigra-
phy with 99mTechnetium (Tc)-bisphosphonate derivatives
(99mTc-pyrophosphate [PYP], 99mTc-3,3-diphosphono-
1,2-propanodicarboxylic acid (99mTc-DPD), 99mTc hydroxy-
methylene- diphosphonate [99mTc-HMDP]). Many studies
dating from the 1970s and 80s suggested 99mTc-PYP
could assist in diagnosing amyloidosis.2,43-48 However,
there was variable diagnostic accuracy, which limited early
use of the technique, owing to the study of mixed patients
populations with undifferentiated ATTR and AL subtypes.
Subsequent studies comparing 99mTc-bisphosphonate
scintigraphy to gold standard endomyocardial biopsy
discovered that ATTR cardiac amyloidosis has avidity for
bone radiotracers, whereas AL cardiac amyloidosis has
minimal or no avidity for these tracers. Therefore, bone-
avid radiotracers can definitively diagnose amyloid type
when a plasma cell dyscrasia is excluded. Recognition
of preferential ATTR binding to bone-avid 99mTc-bisphos-
phonate-based radiotracers resulted in renewed interest
and greater clinical application of cardiac scintigraphy
with 99mTc-PYP, 99mTc-DPD, and 99mTc-HMDP. Although
there is no direct comparison between these tracers, the
information available suggests they can be used inter-
changeably. This is fortunate, given that there is limited
access to 99mTc-DPD and 99mTc-HDMP in the United
States and 99mTc-PYP in Europe.
EVIDENCE BASE FOR CARDIAC
AMYLOIDOSIS IMAGING
Diagnosis
Cardiac amyloidosis is substantially underdiagnosed
due to varied clinical manifestations, especially in the
early stages of disease. An ideal non-invasive diagnostic
method would identify cardiac involvement in amyloidosis
and would also confirm the etiologic subtype. No existing
diagnostic tools can provide this information individually,
necessitating a multimodality cardiac imaging approach.
Echocardiography
Echocardiography plays a major role in the non-invasive
diagnosis of cardiac amyloidosis due to its assessment
of structure and function and its pervasive use in patients
with concerning cardiac symptoms. The evaluation of
cardiac amyloidosis using echocardiography focuses on
morphological findings related to amyloid infiltration, in
particular, thickened LV walls >1.2 cm in the absence
of any other plausible causes of LV hypertrophy (Fig-
ure 2).28 Although increased LV mass in the setting of
low voltage ECG is suggestive of cardiac amyloidosis, a
definitive distinction by echocardiography of amyloidosis
from hypertrophic cardiomyopathy or other causes of LV
hypertrophy is challenging.49 Other echocardiographic
findings that suggest infiltrative disease include normal
to small LV cavity size; biatrial enlargement and dysfunc-
tion41; left atrial and left atrial appendage stasis and
thrombi; thickened valves; right ventricular and interatrial
septal thickening; pericardial effusion; and a restrictive
transmitral Doppler filling pattern.50-54 Several of these
features, including an overt restrictive mitral inflow pat-
tern are uncommon until late in the disease process.34,51
However, reduced LV systolic thickening, filling pressures,
cardiac output,38 early diastolic dysfunction,39,40 and
signs of raised filling pressures are commonly seen.34,52
A granular sparkling appearance of the myocardial walls
may be appreciated, but it is not considered a highly spe-
cific finding and can be seen in other conditions, such
as end-stage renal disease. The echocardiographic shift
from fundamental to harmonic imaging has confounded
this phenotype.
Tissue Doppler imaging (TDI) and speckle-tracking
echocardiography (STE) refine the non-invasive recogni-
tion of cardiac amyloidosis by quantitating longitudinal
systolic function.51,55,56 A pattern of reduced longitudinal
shortening with preserved LV ejection fraction and radial
shortening is characteristic of cardiac amyloidosis and
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
can differentiate it from other causes of increased LV
wall thickness. Longitudinal systolic function is commonly
impaired, even in the earlier phases of the disease, when
radial thickening and circumferential shortening are still
preserved.34,51,57-62 Both AL and ATTR cardiac amyloido-
sis patients demonstrate a typical pattern of distribution
of STE-derived longitudinal strain in which basal LV seg-
ments are severely impaired while apical segments are
relatively spared (Figure 3).51,63 Conversely, patients with
other causes of LV hypertrophy (ie, aortic stenosis, hyper-
trophic cardiomyopathy) typically show reduced LV longi-
tudinal strain in the regions of maximal hypertrophy.63,64
Another abnormal quantitative measure of LV contrac-
tility in cardiac amyloidosis is the myocardial contraction
fraction (MCF), the ratio of stroke volume to myocardial
volume. The MCF is an index of the volumetric shortening
of the myocardium that is independent of chamber size
and geometry and highly correlated with LV longitudinal
strain.65-67 Abnormalities beyond the left ventricle can
also suggest cardiac amyloidosis. Recently, it has been
reported that the stroke volume index has a prognos-
tic performance similar to LV strain in predicting survival
in AL cardiac amyloidosis, independently of biomarker
staging. Because the stroke volume index is routinely
calculated and widely available, it could serve as the pre-
ferred echocardiographic measure to predict outcomes
in AL cardiac amyloidosis patients. Left atrial reservoir
and pump functions measured by strain are frequently
impaired, irrespective of left atrial size, suggesting that
both raised LV filling pressures and direct atrial amyloid
infiltration (as documented by CMR studies) contribute to
left atrial dysfunction.41,68 This dysfunction may result in
Figure 2. Characteristic appearance of cardiac amyloidosis on echocardiography.
(A)-(D) 2D echocardiography. (A) (parasternal long axis) and (B) (parasternal short axis) demonstrate increased LV wall thickness with a
sparkling texture of the myocardium (yellow arrows) in a patient with primary (AL) cardiac amyloidosis. Also, note the small pericardial effusion
(white arrows), which is often seen in patients with cardiac amyloidosis. (C) (apical 4-chamber view) demonstrates increased biventricular
wall thickness, biatrial enlargement, and increased thickening of the interatrial septum (yellow arrow) and mitral valve leaflets (white arrow) in a
patient with wild-type transthyretin cardiac amyloidosis. (D) Tissue Doppler imaging (TDI) tracing taken at the septal mitral annulus in a patient
with ATTR cardiac amyloidosis. The TDI tracings shows the ‘‘5-5-5’’ sign (s’ [systolic], e’ [early diastolic], and a’ [late (atrial) diastolic] tissue
velocities are all <5 cm/s), which is seen in patients with more advanced cardiac amyloidosis. The dotted lines denote the 5 cm/s cut-off for
systolic and diastolic tissue velocities. In addition to the decreased tissue velocities, isovolumic contraction and relaxation times (IVCT and
IVRT, respectively) are increased and ejection time (ET) is decreased, findings also seen in patients with cardiac amyloidosis especially as the
disease becomes more advanced.
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
the formation of atrial and atrial appendage thrombi, even
in the setting of normal sinus rhythm, exposing patients to
higher relative risk for embolic strokes. Although data are
not available, clinical experience from major amyloidosis
centers suggest the highly thrombogenic milieu of the left
atrium increases cardioembolic risk in these patients.69
The right ventricle is often affected due to a combination
of increased afterload from pulmonary hypertension and
intrinsic right ventricular amyloid infiltration, resulting in
reduced tricuspid annular plane systolic excursion, tissue
Doppler systolic velocity, and longitudinal strain.70
As echocardiographic findings lack the tissue char-
acterization provided by CMR, echocardiographic diag-
nosis of cardiac amyloidosis relies on the presence of
highly suggestive findings that can confirm diagnostic
suspicion.34,71 Table 1 lists the echocardiographic param-
eters for acquisition, interpretation, and reporting in car-
diac amyloidosis. Moreover, abnormal parameters are
provided that suggest cardiac amyloidosis and warrant
further evaluation. The combination of these echocar-
diographic “red flags” with other parameters, such as
abnormal cardiac biomarkers and electrocardiographic
findings, maximizes diagnostic accuracy.72 For instance,
the combination of pericardial effusion and symmetric LV
wall thickening in the presence of low or normal QRS
voltages should prompt a strong suspicion of cardiac
amyloidosis.50,72 ,73 In particular, the ratio of QRS voltage
to echocardiographic LV wall thickness is useful in diag-
nosing cardiac amyloidosis.49
Key Recommendations for Diagnosis:
Echocardiography
• Comprehensive 2D echocardiography, including
quantitative tissue Doppler and speckle-tracking
strain analysis (when available) should be performed
in all patients with unexplained LV wall thickening
and a clinical suspicion of cardiac amyloidosis.
• To increase identification of this underdiagnosed
disease, any echocardiographic abnormalities sug-
gestive of cardiac amyloidosis should prompt further
evaluation.
• Echocardiographic parameters should be combined
with electrocardiographic, clinical, biomarker, and other
imaging findings to maximize diagnostic accuracy.
Figure 3. Left ventricular longitudinal strain abnormalities.
(A) (apical 4-chamber view), (B) (apical 2-chamber view), (C) (apical 3-chamber view) all show abnormal longitudinal strain in the basal and mid
segments with relative preservation in the apical segments (purple and green curves, white arrows) in a patient with ATTRv cardiac amyloidosis.
(D) shows the corresponding bullseye map of the longitudinal strain pattern throughout the left ventricle with the ‘‘cherry-on-the-top’’ sign (red
denotes normal longitudinal strain at the apex and pink/blue denotes abnormal longitudinal strain at the mid/basal left ventricle).
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Cardiac Magnetic Resonance
Cardiac magnetic resonance has a central role in the
non-invasive diagnosis of cardiac amyloidosis due to its
ability to provide tissue characterization in addition to
high-resolution morphologic and functional assessment.
Cardiac magnetic resonance offers value in two clinical
scenarios: the differentiation of cardiac amyloidosis from
other cardiomyopathic processes with increased wall
thickening and potentially in detection of early cardiac
involvement in patients with evidence of systemic amyloi-
dosis. A comprehensive CMR evaluation for cardiac amy-
loidosis includes morphologic and functional assessment
of the left and right ventricles and atria using cine imag-
ing, evaluation of native T1 signal (assessed on non-con-
trast T1 mapping), assessment of LGE, and extracellular
volume (ECV) measurement. Overall, current published
Table 1. Standardized Acquisition, Interpretation, and Reporting of Echocardiography for Cardiac Amyloidosis
Parameter for Acquisition
and Reporting Abnormal Parameter Notes
Recommendations
for Reporting
2D, Color, and Spectral Doppler Imaging Required
LV wall thickness Increased LV wall thickness (>1.2 cm) and
increased relative wall thickness (>0.42)
Increased LV wall thickness relative to ECG QRS
voltage is particularly suggestive
Required
Myocardial echogenicity Increased echogenicity of the myocardium
(sparkling, hyper-refractile “texture” of the
myocardium)
Not highly specific (differential diagnosis includes
ESRD or other infiltrative cardiomyopathies). How-
ever, this finding in conjunction with severely reduced
longitudinal function of the LV is highly suggestive.
Required
Atrial size and function Atrial enlargement and dysfunction Non-specific but important finding to support the
diagnosis and potentially provide insight into risk for
stroke or arterial embolism
Required
Interatrial septum and
valves
Thickening of the interatrial septum and
valves (>0.5 cm)
Non-specific but suggestive of the diagnosis Required
Pericardial effusion Pericardial effusion Non-specific, but when coupled with other echo signs
is suggestive of the diagnosis
Required
Diastolic function Grade 2 or worse diastolic dysfunction with
high E/A ratio (>1.5) and reduced E decel-
eration time (<150 ms)
Doppler diastolic function is helpful in determining
prognosis. Severely reduced A wave velocity can be
due to LA failure, which can be helpful in determining
risk of stroke.
Required
Estimated PA systolic and
right atrial pressure
Increased pressures (>35mmHg for PA,
≥10mmHg for RA)
These are important parameters to estimate volume
status and optimize diuretic dosing.
Required
Tissue Doppler Imaging Required
Tissue Doppler velocities Reduced tissue Doppler s', e', and a' veloci-
ties (all <5 cm/s)
If present, the “5-5-5” sign (all TDI velocities <5 cm/s)
can be useful and is typically highly suggestive of the
diagnosis but may not be sensitive for the diagnosis in
early forms of the disease
Required
Strain Imaging Recommended
Longitudinal LV strain Decreased global longitudinal LV strain (ab-
solute value less than −15%)
2D and STE shows characteristic appearance of
myocardial deformation in patients with cardiac amy-
loidosis
Recommended
Longitudinal LV strain bulls-
eye map
“Cherry-on-the-top” sign on STE longitudinal
strain bullseye map (preservation of apical
longitudinal strain with severely abnormal
basal and mid-LV longitudinal strain)
Characteristic bullseye pattern is likely the most
specific sign to rule in the diagnosis of cardiac amy-
loidosis (but still does not differentiate ATTR vs. AL
amyloidosis)
Recommended
Reporting
An overall interpretation of the echo findings into categories of:
1. Not suggestive: Normal LV wall thickness, normal LV mass normal atrial size, septal or lateral tissue Doppler e' velocity >10 cm/s
2. Strongly suggestive: Increased LV wall thickness, increased LV mass, typical LV longitudinal strain pattern, mitral annular TDI
<5 cm/s, biatrial enlargement, small A wave in sinus rhythm, small pericardial and or pleural effusions
3. Equivocal: Findings not described above
Required
Interpret the echo results in the context of prior evaluation. Recommended
Provide follow-up recommendations:
Strongly suggestive echocardiographic findings cannot distinguish AL from TTR cardiac amyloidosis. Endomyocardial biopsy is not
always indicated in patients with strongly suggestive echo findings. Please see Part 2, Table 1 “Expert Consensus Recommendations
for Diagnosis of Cardiac Amyloidosis” for indications for endomyocardial biopsy.
Consider evaluation (1) to exclude AL amyloidosis, evaluate for plasma cell dyscrasia (serum and urine immunofixation, serum FLC as-
say) and (2) to exclude ATTR cardiac amyloidosis, consider imaging with 99mTc-PYP/DPD/ HMDP.
Recommended
2D, 2 dimensional; A, late (atrial) mitral inflow velocity; AL, amyloid light chain; ATTR, amyloid transthyretin; E, early mitral inflow velocity; E/A, ratio of early to late (atrial)
mitral inflow velocities; ECG, electrocardiogram; ESRD, end-stage renal disease; IVCT, isovolumic contraction time; IVRT, isovolumic relaxation time; LA, left atrial; LV, left
ventricular; PA, pulmonary artery; RA, right atrium; STE, speckle-tracking echocardiography; TDI, tissue Doppler imaging.
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
reports from single-center studies demonstrated hetero-
geneity in study design, sample size, and types of amy-
loidosis included. See the Appendix for a summary of the
published literature on diagnosis of cardiac amyloidosis
using CMR.
Maceira et al described a typical LGE pattern in car-
diac amyloidosis of global subendocardial enhance-
ment.74 Initial observations were that nulling—rendering
remote myocardium dark—was difficult in cardiac amyloi-
dosis. The blood pool and myocardium null together due
to expansion of the extra cellular myocardial volume (from
amyloid infiltration) which approaches plasma volume.
An inversion time scout (TI-scout) technique (obtaining a
series of images with various inversion time values) could
be useful to select the optimal inversion time for the LGE
sequence.75 Traditional LGE imaging techniques, how-
ever, can be difficult to acquire and interpret in cardiac
amyloidosis. Late gadolinium enhancement using the
widely available relatively new phase-sensitive inver-
sion recovery sequence (PSIR) eliminates the need to
optimize null-point settings, making LGE in cardiac amy-
loidosis more robust and operator independent. Using
the PSIR technique, LGE is significantly more specific
and sensitive than echo or CMR functional assessment.
Although multiple LGE distributions have been described
in cardiac amyloidosis, subendocardial and transmural
LGE patterns predominate. Both patterns are present
in AL and ATTR cardiac amyloidosis, but to different
extents, with subendocardial LGE being more prevalent
in AL and transmural LGE more prevalent in ATTR car-
diac amyloidosis.76 Late gadolinium enhancement shows
an initial basal predilection but with biventricular trans-
murality in advanced disease.77-80
At 4 minutes post-gadolinium administration, a sub-
endocardial-blood T1 difference of 191 ms detected
cardiac amyloidosis at 90% and 87% sensitivity and
specificity, respectively.74 In several studies where the
results of an endomyocardial biopsy has been used as
a reference standard, a typical LGE pattern has con-
sistently been shown to have a diagnostic sensitivity of
85% to 90%.74,77,78,80-82 However, the true specificity of
LGE in diagnosing cardiac amyloidosis with reference
to histologic evidence cannot be accurately determined,
given verification bias (typically only positive CMR cases
are referred for endomyocardial biopsy). A recent meta-
analysis based on seven published studies, estimated a
sensitivity and specificity of 85% and 92%, respectively,
for CMR-based LGE in diagnosing cardiac amyloidosis.83
Other CMR methods include native (non-contrast)82,84
and post-contrast T1 mapping,85 left atrial LGE,68 and
qualitative visual T1 comparison between the myocar-
dium and cardiac blood pool.79 The method of a nulling
comparison between the myocardium and the blood
pool allows a rapid confirmation of cardiac amyloidosis
diagnosis as an adjunct to LGE findings, at an excellent
sensitivity but a moderate specificity.79 Late gadolinium
enhancement in non-ischemic cardiomyopathies, espe-
cially cardiac amyloidosis, is not easy to quantify; there-
fore, using LGE to track changes over time can be
difficult. T1 mapping is a new technique where a direct
quantitative signal from the myocardium is measured,
either pre-contrast (native T1) or post-contrast (ECV).86
T1 mapping before and after contrast administration
allows a quantitative measure of the contrast exchange
between the blood pool and the expanded extracellular
compartment, thus permitting an incremental character-
ization and detection of the degree of infiltration.
Native T1 may find particular utility when adminis-
tration of contrast is contraindicated. Of note, a recent
report demonstrated that native myocardial T1 measured
by the shortened modified look-locker inversion recov-
ery (ShMOLLI) method achieved a diagnostic sensitivity
and specificity of 92% and 91%, respectively.82 Native
T1, however, is a composite signal from the extra- and
intracellular space, and administration of contrast with
ECV measurement enables us to isolate the signal from
the extracellular space.86 Amyloidosis is an exemplar of
interstitial disease, and this is reflected by substantial
elevation of ECV in patients with AL and ATTR cardiac
amyloidosis.85,87 Extracellular volume is also elevated
even when conventional testing and LGE suggest no
cardiac involvement, highlighting a potential role of ECV
as an early disease marker.88 Both native T1 and ECV
track a variety of markers of disease activity, and there
is early evidence they could be used to track changes in
amyloid burden over time.
Advanced techniques, such as T2 mapping and per-
fusion are being used to assess additional aspects of
the cardiac amyloidosis phenotype, including myocardial
edema89 and coronary microvascular dysfunction. Using
a combination of CMR features, a measure of the likeli-
hood of cardiac amyloid type (ATTR vs AL), and likelihood
of ATTR vs AL can be gleaned90,91; but, this is typically not
sufficient for excluding AL cardiac amyloidosis. Free light
chains combined with cardiac scintigraphy with bone
tracers have advantages over echo and CMR for differ-
entiation of the type of cardiac amyloidosis.3
Key Recommendations for Diagnosis: Cardiac
Magnetic Resonance
1. Comprehensive CMR-based evaluation of cardiac
structure, function, and myocardial tissue charac-
terization is helpful for diagnosis of cardiac amyloi-
dosis, particularly when echocardiographic findings
are suggestive or indeterminate.
2. In patients with biopsy-proven systemic amyloido-
sis, typical CMR findings, including diffuse LGE,
nulling of myocardium before or at the same inver-
sion time as the blood pool, and extensive ECV
expansion are combined with structural findings
of increased wall thickness and myocardial mass
to diagnose cardiac involvement. In the absence
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 10
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
of documented systemic amyloidosis, typical CMR
features should prompt further evaluation for car-
diac amyloidosis.
3. Cardiovascular magnetic resonance, however, is
typically unable to definitively distinguish AL from
ATTR cardiac amyloidosis.
4. Cardiovascular magnetic resonance parameters
should be combined with electrocardiographic,
clinical, biomarker, and other imaging findings to
maximize diagnostic accuracy.
Radionuclide Imaging
Radionuclide imaging plays a unique role in the non-inva-
sive diagnosis of cardiac amyloidosis. A variety of 99mTc-
labeled diphosphonate and PYP (bone-avid) compounds
diagnose ATTR cardiac amyloidosis with high sensitivity
and specificity.3 Targeted amyloid binding 18F-positron
emission tomography (PET) tracers are highly specific
to image amyloid deposits and appear to bind to both
AL and ATTR.92-96 123I-meta-iodobenzylguanidine (mIBG),
an established tracer for imaging myocardial denerva-
tion, has been utilized to image myocardial denervation in
familial ATTR cardiac amyloidosis.97, 9 8 A substantial addi-
tional benefit of radionuclide evaluation of cardiac amy-
loidosis is that whole-body imaging can be performed
concurrently, allowing evaluation of multi-organ systemic
involvement.
The explanation for this differential uptake in ATTR
vs AL cardiac amyloidosis is unknown, but it has been
suggested that the preferential uptake by ATTR may be
a result of higher calcium content.99,100 Furthermore, the
type of mutation and the result of the proteolysis of myo-
cardial fibers (full-length only vs full length plus C-ter-
minal ATTR fragments) also modulate uptake of bone
radiotracers by amyloid fibrils.100
Bone-Avid Radiotracers for Cardiac Scintigraphy:
99mTc-PYP/DPD/HMDP
Systematic evaluation of diphosphonate radiotracers
suggests that cardiac uptake of 99mTc-PYP, 99mTc-DPD,
and 99mTc-HMDP are remarkably sensitive (but not com-
pletely specific) for ATTR cardiac amyloidosis.3,31,100-106
Notably in the absence of cardiac amyloidosis (or previ-
ous myocardial infarction), there is no myocardial uptake
of bone tracers; therefore, cardiac scintigraphy with
bone-avid radiotracers may reliably distinguish cardiac
amyloidosis from other entities that mimic cardiac amyloi-
dosis, such as hypertrophic cardiomyopathy.31,102 Cardiac
scintigraphy with bone-avid radiotracers is particularly
sensitive in the early identification of ATTR cardiac
amyloidosis, including carriers without apparent car-
diac involvement by other diagnostic techniques.105,107,108
Furthermore, 99mTc-DPD/HMDP allow the possibility of
detecting extra-cardiac (skeletal muscle and lung) amy-
loid infiltration.109,110 See the Appendix for a full summary
of the published literature on diagnosis of ATTR cardiac
amyloidosis using 99mTc-PYP/DPD/HMDP.
A multicenter experience in 1498 patients showed a
positive predictive value for ATTR cardiac amyloidosis of
100% (95% confidence interval, 98.0-100) in patients
with an echocardiogram or CMR consistent with or sug-
gestive of cardiac amyloidosis, and absence of monoclo-
nal protein using urine and serum, with serum FLC assay
and immunofixation electrophoresis.3 A recent bivariate
meta-analysis confirmed the accuracy of bone scintig-
raphy in the assessment of ATTR cardiac amyloidosis.111
Again, these high sensitivities and specificities were
reported from major centers of expertise and in patients
with advanced stages of the disease, and often with New
York Heart Association (NYHA) heart failure greater than
Class II. The yield of 99mTc-PYP/DPD/HMDP cardiac
scintigraphy in patients with earlier stages of disease or
with pre-clinical disease is yet to be confirmed.
Several diagnostic parameters have been evaluated
on cardiac scintigraphy with bone-avid tracers. The ratio
of heart-to-contralateral (H/CL) lung uptake (semi-
quantitative scoring), heart-to-whole-body (H/WB)
retention, and a heart-to-bone ratio (visual grade) have
been assessed at both 1 and 3 hours (see Standard-
ized Imaging Techniques). Early work by Perugini and
colleagues found that a visual grade ≥2 on 99mTc-DPD
(ie, moderate or strong myocardial uptake) was 100%
sensitive to identify ATTR cardiac amyloidosis and 100%
specific to distinguish from AL and control subjects.112
Subsequent studies have confirmed the high sensitivity
to detect ATTR cardiac amyloidosis and showed that mild
uptake of 99mTc-DPD (Grade 1) may be noted in patients
with other subtypes of cardiac amyloidosis (ie, AL, Amy-
loid A amyloidosis, and Apolipoprotein A1).43,106 Rape-
zzi et al105 evaluated the ratio of heart-to-whole-body
retention of 99mTc-DPD, on the late (3-hour) images, in
patients with TTR mutation, and demonstrated that indi-
viduals with increased LV myocardial wall thickness >1.2
cm had much higher heart-to-whole-body retention ratio
compared to individuals with normal LV wall thickness.
In a single-center experience, Bokhari et al113 identified
a very high diagnostic accuracy (area under the curve
of 0.992, P<0.0001) for visual Grade ≥2 and a H/CL
ratio ≥1.5 on 1-hour images to distinguish ATTR from
AL cardiac amyloidosis.3,111 A H/CL ratio ≥1.3 has been
proposed to distinguish ATTR accurately from AL cardiac
amyloidosis on the late (3-hour) 99mTc-PYP images.114
The recently-developed consensus algorithm for
non-invasive diagnosis of cardiac amyloidosis attributes
a central role to 99mTc-PYP/DPD/HMDP cardiac scin-
tigraphy (Figure 4).3 If cardiac amyloidosis is suspected
clinically or based on echocardiography/CMR, blood and
urine should be analyzed for evidence of a monoclonal
protein and 99mTc-PYP/DPD/HMDP cardiac scintigra-
phy should be considered if ATTR cardiac amyloidosis is
suspected. If both tests are negative, then current evi-
dence suggests that cardiac amyloidosis is very unlikely.
It is still possible, however, for patients with ATTRv to have
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 11
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
negative findings on DPD scintigraphy105 in case of some
rare non-V30M mutations and in some V30M mutations
with early onset and only full-length TTR fibrils.115 In the
presence of a Grade 2 or 3 positive 99mTc-PYP/DPD/
HMDP cardiac scan (see section on standardized imag-
ing techniques) without evidence for monoclonal proteins
in blood and urine, a diagnosis of ATTR cardiac amyloido-
sis can be made without a biopsy (specificity and positive
predictive value >98%).3 For those patients with evidence
of a plasma cell dyscrasia, a histological diagnosis is still
required because the presence of low-grade uptake on a
99mTc-PYP/DPD/HMDP scan is not 100% specific for
ATTR cardiac amyloidosis, and substantial uptake (Grade
2 or 3) has been reported in more than 20% of patients
with AL cardiac amyloidosis.3 The writing group would like
to emphasize the importance of excluding monoclonal
process with serum/urine immunofixation and a serum
FLC assay in all patients with suspected amyloidosis.
99mTc-PYP/DPD/HMDP scintigraphy has been
recently used to detect ATTR cardiac amyloidosis in pre-
viously unexplored clinical settings, including heart failure
with preserved ejection fraction (prevalence 15%)13,15
and severe degenerative aortic stenosis,14,116 including
the “paradoxical low-flow low-gradient” subtype (18%).117
Based on the utility of cardiac scans with SPECT
bone-avid radiotracers, there has been interest in
18F-NaF, a PET bone radiotracer, for imaging cardiac
amyloidosis.118,119 Early reports, however, suggest limited
utility for imaging ATTR cardiac amyloidosis, and further
studies are warranted to examine its utility.
Amyloid Binding Radiotracers
Several amyloid binding SPECT and PET radiotrac-
ers are available for amyloidosis imaging. 99mTc-
aprotinin120-122 and 123I-serum amyloid P-component
(123I-SAP)123 were originally developed to image sys-
temic amyloidosis but have limited availability. They
have not been useful to image cardiac amyloidosis due
to poor signal-to-noise ratio123 and concerns for risk
of bovine encephalopathy.121 In contrast, several PET
amyloid-binding radiotracers, structurally similar to thio-
flavin-T and likely binding to the amyloid fibril structure,
approved for imaging beta amyloid in Alzheimer’s dis-
ease,124 have been successfully used to image cardiac
amyloidosis. 11C-Pittsburgh compound B (PIB) was
one of the first PET radiotracers developed for beta-
amyloid imaging but is limited in availability to sites
with a cyclotron. 18F-florbetapir, 18F-florbetaben, and
18F-flutemetamol developed subsequently and are cur-
rently FDA approved for beta-amyloid imaging and are
widely commercially available. Several additional tracers
are still under development.125
Figure 4. Consensus algorithm for noninvasive diagnosis of cardiac amyloidosis.
This algorithm provides an approach to the evaluation of patients with cardiac amyloidosis. Among patients with suspected cardiac amyloidosis,
Grade 2 or 3 uptake of 99mTc-PYP/DPD/HMDP uptake in the absence of a clonal abnormality is highly specific to diagnose ATTR cardiac
amyloidosis avoiding the need for endomyocardial biopsy. Patients with any abnormal serum/ urine immunofixation or a positive serum free light
chain assay should be referred for further evaluation to a hematologist ideally with amyloidosis experience. (Figure reproduced with permission
from Gillmore JD, et al. Circulation. 2016;133:2404-2412.)
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
11C-PIB,92,95 18F-florbetapir,93,96 and 18F-florbetaben94
have been evaluated in patients with AL and ATTR car-
diac amyloidosis. In these pilot studies, high cardiac
radiotracer uptake was consistently reported in patients
with cardiac amyloidosis compared to controls, including
hypertensive controls. A target to background (LV myo-
cardium to blood pool) ratio >1.5 and a retention index of
>0.025 min-1 with 18F-florbetapir93 and 18F-florbetaben94
have been shown to separate patients with cardiac amy-
loidosis from controls without amyloidosis. Myocardial
retention of 11C-PIB,92 18F-florbetapir,93 and 18F-florbe-
taben94 was significantly greater in cardiac amyloidosis
patients compared to controls. In one study, although
18F-florbetapir myocardial retention index was lower in
ATTR compared to AL cases, definitive subtype differen-
tiation was not feasible93; similar findings were confirmed
with 18F-florbetaben.95 Although not studied serially,
retention of 11C-PIB was lower in AL cardiac amyloidosis
patients treated with chemotherapy as compared to those
who did not undergo treatment,95 suggesting it is pos-
sible this radiotracer will be useful for disease monitoring.
Finally, unlike echocardiography or CMR, amyloid-binding
PET tracers can image systemic amyloid deposits in vari-
ous other organs126,127 and offer the potential to quantify
the load of amyloidosis in the whole body.
As literature on PET amyloid-binding radiotracers is
limited, sections on risk assessment and standardized
protocols are not provided for these radiotracers.
Autonomic Myocardial Innervation Imaging
Patients with amyloidosis are prone to autonomic dys-
function from amyloid infiltration of myocardial and nerve
conduction tissue, resulting in rhythm disorders.128 Auto-
nomic dysfunction is most common in ATTR cardiac
amyloidosis, particularly ATTRv, where it has been stud-
ied extensively.129,130 Notably, cardiac dysautonomia may
occur independent of the presence of a typical restric-
tive cardiomyopathy.131 In patients with ATTRwt cardiac
amyloidosis, polyneuropathy and dysautonomia are less
common, seen in approximately 9%.132 While AL cardiac
amyloidosis patients less commonly manifest autonomic
dysfunction,133 it may develop as a complication of AL
amyloidosis treatment.134 Therefore, autonomic denerva-
tion is a non-specific finding. 123I-mIBG scintigraphy is
not able to discriminate between cardiac amyloidosis
subtypes nor differentiate cardiac amyloidosis from other
forms of cardiomyopathy.135 However, cardiac dener-
vation evidenced by mIBG occurs earlier than amyloid
deposit detection by diphosphonate scintigraphy in TTR
mutation carriers.136 Although secondary (Amyloid A, AA)
amyloidosis rarely shows cardiac manifestations, myo-
cardial denervation has been reported in one study.135
While amyloid infiltration of the cardiac autonomic system
cannot be directly imaged, multiple tracers assess autonomic
myocardial denervation, including 123I-mIBG, 124I-mIBG,
N-[3-Bromo-4-3-[18F-]fluoro-propoxy)-benzyl]-guanidine
LM1195, and 11C-hydroxy-ephedrine. 123I-mIBG, a chemi-
cally modified analogue of norepinephrine, is stored in
vesicles in presynaptic sympathetic nerve terminals and
is not further catabolized. 123I-mIBG has been specifically
studied in cardiac amyloidosis, and semi-quantitative analy-
sis of 123I-mIBG cardiac uptake compared to background
(heart-to-mediastinal ratio [HMR]), provides indirect infor-
mation of amyloid infiltration in the sympathetic nerve sys-
tem.97,98,130,135,137-141 Decreased HMR at 4 hours after tracer
administration (late HMR) reflects the degree of sympa-
thetic dystonia, and is an independent prognostic factor in
the development of ventricular dysrhythmia. PET imaging
of sympathetic innervation in cardiac amyloidosis has not
yet been studied. See the Appendix for a summary of the
published literature on assessment of autonomic myocar-
dial innervation imaging in amyloidosis using 123I-mIBG.
Myocardial Perfusion Imaging
Angina, in the absence of coronary artery disease, is com-
mon in patients with cardiac amyloidosis. Endothelial142 and
microvascular dysfunction143 have been described and may
precede the clinical diagnosis of cardiac amyloidosis.143,144
In one study, focal and global subendocardial hypoperfu-
sion at rest and post-vasodilator stress were ubiquitous in
patients with AL and ATTR cardiac amyloidosis.145 Absolute
myocardial blood flow145 and coronary flow reserve144,145
are substantially reduced in patients with cardiac amyloido-
sis, despite absence of epicardial coronary artery disease.
Whether coronary microvascular dysfunction improve after
successful anti-amyloid therapy is not known.
Key Recommendations for Diagnosis: Radionuclide
Imaging
• Myocardial imaging with 99mTc-PYP/DPD/HMDP,
in the appropriate clinical context, is highly sensitive
and specific to diagnose ATTR cardiac amyloidosis
and may aid in its early detection.
• In the absence of a light-chain clone, myocardial
uptake of 99mTc-PYP/DPD/HMDP of Grade ≥2 is
diagnostic of ATTR cardiac amyloidosis, obviating
the need for endomyocardial biopsy.
• To facilitate early diagnosis of ATTR cardiac amyloi-
dosis, cardiac 99mTc-PYP/DPD/HMDP scintigraphy
should be more broadly considered in patients with
unexplained increased LV wall thickness, heart fail-
ure with preserved ejection fraction, familial amyloid
polyneuropathy (FAP), family history of amyloidosis,
degenerative aortic stenosis with low-flow low gra-
dient in the elderly, and a history of bilateral carpal
tunnel syndrome.
• 123I-mIBG can detect cardiac denervation in patients
with hereditary ATTR amyloidosis.
Assessment of Prognosis
Cardiac involvement is common in systemic AL and
ATTR amyloidosis and markedly impacts quality of life
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
and outcome.146 Thus, cardiac assessment in patients
with systemic amyloidosis is crucial for risk stratifica-
tion and treatment decisions. Imaging plays a key role
in risk stratification of patients with AL and ATTR car-
diac amyloidosis and may add to the existing clinical and
biomarker-based risk stratification as discussed previ-
ously (see section “Biomarkers and Biopsy in Cardiac
Amyloidosis”).
Echocardiography
Abnormalities in several echocardiographic imaging
parameters (eg, LV longitudinal strain, early mitral inflow
[E-wave], deceleration time, myocardial performance
index, pericardial effusion) are associated with worse
outcomes and should alert the clinician to the potential
of advanced disease.9,50,59,65,70,147-165 At the present time,
however, there is no formal staging system for ATTRv,
ATTRwt, or AL cardiac amyloidosis that uses echocardio-
graphic parameters. Therefore, echocardiography find-
ings in isolation should not be used to determine risk in
the individual patient with cardiac amyloidosis. Additional
studies to assess the optimal risk-stratification algorithm
that incorporates multiple echocardiographic param-
eters are needed. Moreover, further study is needed to
demonstrate the incremental value of echocardiographic
parameters over simple clinical markers (eg, New York
Heart Association functional class, B-type natriuretic
peptide, troponin, glomerular filtration rate) and radionu-
clide and CMR imaging findings. See the Appendix for
a summary of the published literature on the prognostic
value of echocardiography in cardiac amyloidosis.
Cardiac Magnetic Resonance
Multiple CMR measures have prognostic significance
in cardiac amyloidosis, including LGE presence and
pattern, native T1, post-contrast T1, and multiple mor-
phologic parameters.166 Despite the excellent discrimi-
native capacity of LGE, conflicting results were initially
reported describing its prognostic impact in cardiac
amyloidosis.78,80,81,167 At that time, LGE patterns of car-
diac amyloidosis were heterogeneous due to non-stan-
dardized acquisition and analysis. The transition to more
robust LGE approaches, such as PSIR,168 has markedly
improved image quality. This tool has provided insight into
progression of both AL and ATTR cardiac amyloidosis
through visualization of a continuum of amyloid accumu-
lation as determined by progression of the LGE pattern
from normal to subendocardial to transmural.76,169 As a
result, several studies now show that the LGE pattern
can serve as an independent predictor of prognosis after
adjustments for echocardiographic characteristics and
blood biomarkers (NT-proBNP and troponin) have been
performed.170 Importantly, the LGE pattern confers prog-
nosis in both AL and ATTR cardiac amyloidosis. Despite
its prognostic usefulness, LGE does not lend itself read-
ily toward quantification of myocardial infiltration, owing
to different patterns and signal intensities. Thus, the
capacity of LGE to track changes accurately over time
and monitor response to treatment is unknown. Paramet-
ric T1 mapping has the potential to overcome these limi-
tations.86 Recent studies have shown that higher native
myocardial T1 can accurately stratify worse prognosis in
AL cardiac amyloidosis171 but not in ATTR cardiac amy-
loidosis.87 Alternatively, T1-derived ECV has been associ-
ated with prognosis in AL and ATTR cardiac amyloidosis
after adjustment for known independent predictors.171,172
T2 mapping, a measure of myocardial edema, adds a
third dimension to the tissue characterization; in patients
with AL cardiac amyloidosis, it is an independent predic-
tor of prognosis.89 See the Appendix for a summary of
the published literature on the prognostic value of CMR
in cardiac amyloidosis.
Radionuclide Imaging
The prognostic role of 99mTc-PYP/DPD/HMDP scintigra-
phy and 123I-mIBG have been explored in several studies.
99mTc-PYP/DPD/HMDP cardiac uptake moderately cor-
relates positively with LV wall thickness and mass, tropo-
nin T, NT-proBNP, and ECV; it correlates negatively with
LV ejection fraction.31,102,105,173-175 The degree of cardiac
uptake correlates with overall mortality and survival free
from major adverse cardiac events. Multiple semi-quan-
titative markers of cardiac uptake have been studied,
including heart and heart-to-whole-body retention,105,174
heart/skull ratio, 102 H/CL ratio,1 73 and visual scoring.175
In a multicenter study using 99mTc-PYP, an H/CL ratio of
>1.5 was associated with worse survival among patients
with ATTR cardiac amyloidosis.173 Similar data was found
in a single-center study in patients with suspected ATTR
cardiac amyloidosis,175 and these same authors found that
regional variability of 99mTc-PYP uptake may also predict
mortality.176 In all these studies, combining the degree of
cardiac uptake with an anatomical (interventricular septal
thickness) or functional (Class NYHA, NT-proBNP) vari-
able improved prognostic risk stratification. Of note, visual
grading of 99mTc-PYP/DPD/HMDP has not been shown
to be an independent predictor of outcomes.31,114
Cardiac sympathetic denervation is associated with
decreased survival in ATTRv cardiac amyloidosis.129,131 A
late decreased HMR <1.6 portends a poor prognosis and
can be used to identify ATTRv cardiac amyloidosis patients
who would benefit from liver transplantation.131 After liver
transplantation, cardiac sympathetic denervation does not
appear to progress138 and has questionable independent
prognostic significance.131 The prognostic relevance of
late-HMR reduction is less clear in AL and ATTRwt car-
diac amyloidosis.135,138-140 See the Appendix for a summary
of the published literature on the prognostic value of radio-
nuclide imaging in ATTR cardiac amyloidosis.
Key Recommendations for Assessment of Prognosis
• Multiple imaging parameters predict a worse prog-
nosis, including increased LV mass, lower global
longitudinal strain, increased right ventricular wall
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 14
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
thickness, higher native T1 and ECV, higher H/CL
ratio, and 123I-mIBG increased HMR and delayed
washout rate.
• Although not formally incorporated into current risk-
assessment algorithms, radionuclide results should
be combined with electrocardiographic, clinical,
biomarker, and other imaging findings for optimal
prognostication.
Management
The ideal method for evaluating the time course of the dis-
ease and the response to treatment, particularly disease-
modifying treatments, should provide a precise quantitative
measure of systemic and cardiac amyloid burden. In AL
cardiac amyloidosis, cardiac response is assessed using
the serum NT-proBNP concentration, a substantial reduc-
tion of which consistently predicts clinical improvement
and extended survival.177 However, the advent of anti-amy-
loid therapies demands the development of imaging tech-
niques that can estimate the amyloid burden in the heart.
Echocardiography remains the cornerstone of serial
assessment of LV dysfunction in patients with heart fail-
ure. However, there is relatively little information in the
echocardiographic cardiac amyloidosis literature regard-
ing assessment of disease progression and response to
therapy. A few studies have shown potential benefit for the
use of echocardiography in the following areas: (1) to dem-
onstrate changes in cardiac disease in response to treat-
ment in patients with AL cardiac amyloidosis29,178,179; (2)
to determine whether patients with cardiac amyloidosis
need to be anticoagulated for stroke prophylaxis; (3) to
diagnose progressive cardiac involvement after liver trans-
plantation in patients with ATTRv amyloidosis180-182; and
(4) to assess LV ejection fraction in patients with AL amy-
loidosis being considered for stem-cell transplantation.183
Due to a higher incidence of cardiac thrombi in patients
with cardiac amyloidosis, some centers consider a trans-
esophageal echocardiogram prior to cardioversion of atrial
arrhythmias, even in patients on therapeutic anticoagula-
tion. Emerging data suggests that echocardiographic LV
global longitudinal strain may be a marker of disease pro-
gression and response to therapy.184 In contrast, T1 map-
ping with ECV measurement by CMR can track multiple
parameters of structural change (amyloid burden and car-
diomyocyte response). In a small retrospective study, the
prevalence of a decrease in LV mass and ECV on CMR
was higher in patients with AL cardiac amyloidosis and
a complete response or very good partial response to
chemotherapy.88 The quantitative nature of CMR makes
it a promising tool to monitor disease progression and
response to therapy. Although 99mTc-PYP/DPD/HMDP
scintigraphy correlates well with anatomic and functional
variables, this technique has not been definitively proven
to quantify changes in response to current therapies, and
thus repeat studies are not typically clinically useful.185
Positron emission tomography is inherently more sensi-
tive and quantitative, and holds the possibility of monitor-
ing response to therapy with PET amyloid-binding tracers
once adequately studied. Serial myocardial denervation
studies have been studied in ATTRv amyloidosis to guide
timing of liver transplantation.186 Experience with implant-
able cardioverter defibrillators (ICDs) in cardiac amyloido-
sis is limited,187,188 and the indication for ICD implantation
in these patients is unclear even in the setting of myocar-
dial denervation. Prospective studies are needed in this
area. The role of imaging to guide referral to cardiac trans-
plantation and monitor for recurrence post-transplant is
not well elucidated and needs further study.
Notably, none of the imaging techniques have been
validated for assessing response to therapy, and no study
has correlated changes in imaging findings after therapy
with survival.
Key Recommendations for Management
• Transthoracic echocardiography is reasonable to
monitor disease progression and/or response to
therapy in cardiac amyloidosis because echocar-
diography is often done clinically for other reasons
(ie, heart failure management).
• Transthoracic echocardiography (for the evaluation
of left atrial size and function) and transesopha-
geal echocardiography (for the evaluation of the left
atrial appendage) are useful to guide initiation and
management of anticoagulation in patients with car-
diac amyloidosis.
• Cardiovascular magnetic resonance assessment of
LV wall thickness, LV mass, and particularly ECV is
emerging as a tool to assess disease progression
and response to therapy.
• Serial SPECT 99mTc-PYP/DPD/HMDP scintigraphy
is currently not recommended to assess disease
progression or response to therapy.
STANDARDIZED IMAGING TECHNIQUES
Extensive research has been performed in cardiac amy-
loidosis using varied protocols without a clear consensus.
This section will provide recommendations for standard-
ized image acquisition, interpretation, and reporting in the
assessment of cardiac amyloidosis using echocardiog-
raphy, CMR, and radionuclide imaging. Standardization
would facilitate comparability and reproducibility within
and across institutions and enable pooling of data for
research purposes.
Echocardiography
2D Echocardiography
2D and Doppler echocardiographic acquisition in patients
with suspected or known cardiac amyloidosis should fol-
low the ASE/European Association of Cardiovascular
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 15
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Imaging (EACVI) guidelines,40,189 and all standard trans-
thoracic echocardiography views should be obtained.
Required and optional reporting recommendations are
provided in Table 1. When reporting results of the echo-
cardiogram in this population, it is important to distin-
guish other forms of LV hypertrophy from increased LV
wall thickness due to amyloid infiltration. Therefore, the
report should include not only wall-thickness measure-
ments but also qualitative assessment of the “texture” of
the myocardium. Other morphologic features that can be
helpful for the diagnosis of cardiac amyloidosis (eg, atrial
enlargement; increased relative wall thickness defined
as two times posterior wall thickness/LV end-diastolic
dimension; thickening of the interatrial septum and/or
valves; and the presence of a pericardial effusion) should
also be reported. The visual assessment of the loss of
longitudinal motion of the heart on 2D imaging (ie, mini-
mal descent of the base in the apical views) can be help-
ful to include in the report as it increases the likelihood
of cardiac amyloidosis.
In patients with cardiac amyloidosis, right ventricular
involvement confers a worse prognosis; thus, right ven-
tricular wall thickness (measured in the subcostal view at
end-diastole) and assessment of right ventricular systolic
function should be included in the report.189 On Doppler
assessment, evaluation of diastolic function (mitral inflow
velocities, early mitral inflow [E] deceleration time, and
early diastolic relaxation velocity on tissue Doppler imag-
ing (TDI), [see section below]) should be reported.39,40
In addition, estimation of hemodynamics (including right
atrial pressure, pulmonary artery systolic pressure, LV fill-
ing pressure [based on E/e' ratio], and cardiac output
[based on LV outflow tract diameter, velocity-time inte-
gral (on pulse wave Doppler)]) is helpful for the manage-
ment of heart failure.38
Tissue Doppler Echocardiography
Accurate tissue Doppler images should be obtained
per ASE and EACVI recommendations.40 As shown
in Figure 2, in the setting of cardiac amyloidosis, s', e',
and a' velocities are all often reduced, and should be
reported. The right ventricular free wall TDI should be
measured, and the s' velocity reported as a measure of
right ventricular longitudinal systolic function (<10 cm/s
is abnormal).190 In addition, isovolumic relaxation and
contraction times are increased, and ejection time is
decreased. Although not widely used in clinical practice,
these three indices can be combined to calculate the
myocardial performance index (ejection time/[isovolumic
relaxation time+isovolumic contraction time]), which is
also reduced in the majority of patients with overt cardiac
amyloidosis.165
Speckle-Tracking (Strain) Echocardiography
High-quality longitudinal strain STE LV curves should
be obtained in the apical 2-, 3-, and 4-chamber views at
frame rates of 50-80 fps with good endocardial border
definition (Figure 3). Right ventricular free wall strain is
calculated as the average of the basal, mid, and apical lon-
gitudinal segmental strains. The curves for the left atrium
should be generated using P-P gating, if the patient is
in normal sinus rhythm. In patients with atrial fibrillation
or other rhythm with a lack of P waves, there will be no
booster component to the left atrial strain curve, and the
left atrial conduit and reservoir strains will be equal to
each other.191,192 Emerging literature (scientific abstract
not yet published) suggests that transesophageal echo-
cardiography should be considered in patients with sus-
pected cardiac amyloidosis and distal embolization to
rule out left atrial and left atrial appendage thrombi even
in the setting of normal sinus rhythm.
Ideally, in all patients with suspected or known car-
diac amyloidosis, the global LV longitudinal strain value
(which is calculated using the peak negative instanta-
neous average of the 18 longitudinal segmental strains
[6 in each of the apical views]) should be reported.193,194
In addition, a description and assessment of the pattern
displayed on the global longitudinal strain bullseye map
(as shown in Figure 3) should be included in the report.63
Right ventricular free wall strain can also be reported. If
left atrial strain is performed, the values of the reservoir,
conduit, and booster strains can be reported.
Key Recommendations for Standardized Imaging
Techniques: Echocardiography
• Echocardiograms in patients with suspected or
known cardiac amyloidosis should be obtained
using ASE/EACVI guidelines on comprehensive
echocardiography.
• Reporting should include assessment of wall thick-
ness and myocardial “texture”; thickening of other
cardiac structures; pericardial effusion; tissue
Doppler velocities (s', e', and a'); diastolic function;
and hemodynamics.
• Speckle-tracking echocardiography should be
performed routinely in patients with suspected or
known cardiac amyloidosis when available, and
efforts should be made to optimize the apical 2D
imaging views for speckle-tracking analysis. The
global longitudinal strain and pattern of segmental
strains (ie, ‘bullseye’ map) should be reported. RV
and LA strain can be reported when performed.
• An overall reporting on likelihood of amyloidosis
based on imaging findings is recommended (not
suggestive, strongly suggestive, or equivocal for
cardiac amyloidosis).
Cardiac Magnetic Resonance
Structure and Function
Cardiovascular magnetic resonance assessment of
structure and function in patients with suspected or
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 16
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
known cardiac amyloidosis follows well-standardized
protocols (Table 2).195 Image interpretation and reporting
should highlight effusions, atrial thrombi, long axis func-
tion, and stroke volumes in addition to LV and right ven-
tricular ejection fraction. These and other parameters are
specified in Table 3.
Late Gadolinium Enhancement
Protocols for LGE assessment in cardiac amyloidosis are
likewise well-defined.195 Late gadolinium enhancement
visualizes the extracellular space expansion that occurs
in cardiac amyloidosis. Late gadolinium enhancement
imaging depends on “nulling” of normal myocardium in
order to detect LGE from slowed gadolinium washout
(thus signal enhancement) in abnormal tissue. Initial
LGE evaluation of cardiac amyloidosis was challenging
due to similar nulling of both the myocardium and blood
pool. The more recent PSIR technique, which ensures
appropriate nulling, overcomes this limitation.76,168 There
are two phenomena that are unique to the LGE assess-
ment of cardiac amyloidosis. First, there is rapid move-
ment of gadolinium into the ECV due to the high burden
of amyloid protein. This results in myocardial nulling prior
to or concurrent with the blood pool, which can be identi-
fied visually on the TI scout.79 Second, there is a global
delayed washout of gadolinium from the ECV, resulting
in diffuse LGE at time points at which LGE are typically
assessed in scar imaging.74
A limitation of LGE assessment in cardiac amyloidosis
is the requirement for gadolinium administration in the
setting of a high coincidence of renal failure in ATTR and
AL amyloidosis due to age and multiple myeloma and
renal involvement, respectively. Cyclic gadolinium agents
need to be administered to decrease risk of nephro-
genic systemic fibrosis and other complications. Par-
tially protein-bound contrast agents (gadolinium-BOPTA
MultiHance®) should not be used, as neither the ECV
technique nor the characteristic amyloid LGE pattern are
reliable.169
T1 and T2 Mapping
In contrast to LGE, T1 and T2 mapping techniques are
quantitative tools. Their acquisition has been standardized
in a recent consensus statement.86,196 Per this guideline,
T1 map acquisition is recommended in two short-axis
slices and a 4-chamber view before and after contrast;
T2 map acquisition is recommended in one mid-short-
axis slice. Use of local reference ranges and quality con-
trol phantoms has been emphasized. A potential concern
is the time required for these multiple acquisitions.
T1 mapping can measure the longitudinal magneti-
zation of the myocardium before contrast (native T1). In
addition, by measuring T1 before and after contrast and
correcting for the blood volume of distribution (1-hema-
tocrit), ECV can be derived (Figure 5). In combination with
pre-contrast T1, an approach using one post-contrast T1
has been validated in cardiac amyloidosis197 and is used by
many centers. Other centers perform serial post-contrast
measurements, as the fidelity of mapping the myocardial
vs blood exchange of contrast may be improved.198 T1
mapping has advanced from a cumbersome multi breath-
hold technique with contrast infusion; current techniques
require a single breath-hold and generate an ECV map
automatically, in some cases without the need for hema-
tocrit sampling or off-line processing.199,200
More recently, CMR with multiparametric mapping has
been driving a change in disease understanding: cardiac
amyloidosis is not a disease of solely infiltration. T2 map-
ping, a marker of myocardial edema, has been highlight-
ing other processes in the myocardium—a possible new
aspect of the evolution of the myocardial phenotype in
cardiac amyloidosis.89
Other techniques may also add value: perfusion is pro-
foundly abnormal in cardiac amyloidosis with vasodila-
tor stress revealing marked endo to epicardial gradients
(Figure 5).201
Key Recommendations for Standardized Imaging
Techniques: CMR
• Cardiovascular magnetic resonance should be per-
formed using standard parameters, as listed in this
section.
Table 2. Recommendations for Standardized Acquisition of
CMR in Cardiac Amyloidosis
#
Protocol
Step
Sequence Tech-
nique Note
1 Cine function Retrospectively
gated cine
2-, 4- and 3-chamber and
short-axis stack cines per
SCMR guidelines
2 Native T1
mapping
(pre-contrast)
Quality controlled T1
mapping sequence
Mid and basal short-axis
and apical 4-chamber
views as per SCMR clini-
cal recommendations
3 T2 Minimum mid-short axis,
consider multiple views
4 Contrast type Gadolinium-based
non-protein bound
cyclic contrast agent
(0.1–0.2 mmol/kg)
5 T1 mapping
post-contrast
(ECV estima-
tion)
Quality controlled T1
mapping sequence
Mid and basal short-axis
and apical 4-chamber
Should be acquired at
least 10- minutes post-
contrast
Sampling scheme can
be varied post-contrast
to optimize for short T1
times post-contrast
6 TI scout TI scout
7LGE Phase-sensitive
inversion recovery
(PSIR) LGE imaging
is recommended
2-, 4-, and 3-chamber
and short-axis stack per
SCMR
The overall imaging protocol as described above will take approximately 45-60
minutes. This table provides a general guide to the steps of a CMR imaging proto-
col. Some variation between sites may exist. Each of these sequences assesses a
unique myocardial characteristic as discussed in the text and Table 3.
ECV, extracellular volume; SCM R, Society for Cardiovascular Magnetic Resonance.
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 3. Recommendations for Standardized Interpretation and Reporting of CMR for Cardiac Amyloidosis
Parameter for Acquisition
and Reporting Criteria Notes
Recommendations
for Reporting
LV function and morphology
LV function Biventricular long-axis impairment with rela-
tive apical functional sparing
Although LV ejection fraction is typically preserved in cardiac
amyloidosis, a reduced LV ejection fraction may be seen in
advanced cases
Required
LV wall thickness Increased LV wall thickness: >laboratory
ULN for sex on SSFP cine C MR205 and in-
creased relative wall thickness >0.42 cm
Increased LV wall thickness is suggestive in the presence of
normal or low QRS voltage on ECG and/or concomit ant in-
creased right ventricular wall thickness
While increased LV wall thickness is typically concentric, it can
be asymmetric in ATTR cardiac amyloidosis172
Required
Stroke volume index LV stroke volume index (<35 mL/m2) A low stroke volume index is non-specific but suggestive of
cardiac amyloidosis
Required
LV mass LV mass ≥91 g/m2 for men and ≥78 g/m2
for women (with papillary muscle included
as part of LV mass measurement)206
To quantify myocardial and amyloid mass Required
Atrial size and function
(based on Simpson’s
method)
Increased left atrial volume >163 mL for
men and >131 mL for women206 Increased
right atrial volume >85 mL/m2206
Reduced atrial function: <29% for men and
<35% for women.206
Non-specific but important finding to support the diagnosis
and potentially provide insight into risk for stroke or arterial
embolism
Required
Pericardial effusion Pericardial effusion Non-specific, but when coupled with other CMR signs is sug-
gestive of the diagnosis, especially in the setting of normal LV
ejection fraction
Required
Amyloid Imaging
LGE imaging Abnormal LGE Pattern
Diffuse LGE
Subendocardial LGE
Patchy LGE
Difficulty in achieving myocardial nulling
over a range of inversion times
Dark blood pool signal
Standard mag-IR LGE imaging is not recommended given
difficulty in selecting the optimal inversion time (TI). Phase-
sensitive reconstruction is preferred
Data acquisition should be obtained in every other RR interval
Quantification of LGE is challenging in amyloidosis and is not
recommended for routine clinical practice.
Required
Myocardial signal sup-
pression pattern
Abnormal myocardial signal suppression
pattern
Myocardium nulls before blood pool on Look
Locker, Cine IR, or TI scout sequences
Recommended
Amyloid quantitation
Native T1 mapping
(pre-contrast)
Abnormal T1 mapping (criteria may vary based
on the sequence used [MOLLI, ShMOLLI]
and the field strength of the magnet)
Assess interstitial amyloid accumulation without gadolinium
Reference range should be based on a site’s local calibrated
values on specific field strengths.
Recommended
T1 mapping post-con-
trast (ECV estimation)
ECV >0.40 is highly suggestive of cardiac
amyloidosis
Assess expansion of ECV from interstitial amyloid accumulation
A. 1 pre- and 1 post- contrast measurement (15-min post-
contrast injection)
B. 1 pre- and 3 post- contrast measurements (5-, 15-, and
25-min post contrast injection)
A. Recommended
B. Optional
Reporting of CMR Findings in Cardiac Amyloidosis
An overall interpretation of the CMR findings into categories of:
Not suggestive: Normal LV wall thickness, normal LV mass, no ventricular LGE, normal atrial size
Strongly suggestive: Increase LV wall thickness, increased LV mass, biatrial enlargement, typical diffuse or global LGE pattern, dif-
ficulty in achieving myocardial nulling, significantly increased ECV (>0.40), small pericardial and or pleural effusions
Equivocal: Findings not described above.
Required
Interpret the CMR results in the context of prior evaluation. Recommended
Provide follow-up recommendations:
Strongly suggestive CMR findings cannot distinguish AL from ATTR cardiac amyloidosis.
Endomyocardial biopsy is frequently unnecessary in patients with strongly suggestive CMR findings and histologically defined sys-
temic amyloidosis or diagnostic 99mTc-PYP/DPD/HMDP imaging.
Consider evaluation (1) to exclude AL amyloidosis, evaluate for plasma cell dyscrasia (serum and urine immunofixation, serum FLC
assay) and (2) to exclude ATTR cardiac amyloidosis, consider imaging with 99mTc-PYP/DPD/ HMDP.
Recommended
T2 mapping is currently not part of the standard clinical amyloidosis imaging protocol.
AL, amyloid light chain; ATTR, amyloid transthyretin; CMR, cardiac magnetic resonance imaging; ECV, extracellular volume; EF, ejection fraction; FLC, free light chain; LGE, late
gadolinium enhancement; LV, left ventricular; MOLLI, modified Look-Locker inversion recovery; SSFP, steady state free precession; ShMOLLI, Shortened MOdified Look-Locker
Inversion Recovery; ULN, upper limit of normal and per Ref. 205 at mid-cavity level ULN for women/men were 7 mm/9 mm (long axis) and 7 mm/8 mm (short axis), respectively.
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
• Cardiac structure, function, and PSIR LGE should
be assessed and reported per SCMR guidelines.
• Cardiac amyloidosis-specific CMR markers, such
as native T1 mapping and ECV, should be assessed
and reported when available, as discussed in this
document.
• An overall reporting on likelihood of cardiac amyloi-
dosis based on imaging findings is recommended
(eg, not suggestive, strongly suggestive, or equivo-
cal for cardiac amyloidosis).
Radionuclide Imaging
99mTc-PYP/DPD/HM DP Imaging
Recommendations for standardized radionuclide image
acquisition for cardiac amyloidosis using 99mTc-PYP/
DPD/HMDP are provided in Table 4. Images should be
acquired early (1 hour) or late (2-3 hours). There is a
stepwise approach to interpretation as shown in Table 5.
The first step of interpretation is to visually confirm dif-
fuse myocardial radiotracer uptake and differentiate this
uptake from residual blood pool activity or overlapping
bone using SPECT and planar images.
If myocardial uptake is confirmed visually, there are
two approaches to differentiate AL from ATTR cardiac
amyloidosis, depending on the tracer used and time
between injection and scan acquisition. The 1-hour
approach has been validated for 99mTc-PYP and involves
generation of an elliptical/circular region of interest (ROI)
over the heart on the anterior planar images with care
to avoid sternal overlap and with size adjusted to maxi-
mize coverage of the heart without inclusion of adjacent
lung. This ROI should be mirrored over the contralateral
chest to adjust for background and rib uptake (Figure 6).
A semi-quantitative H/CL ratio is calculated as a ratio-
of-heart ROI mean counts to contralateral chest ROI
mean counts; a ratio of ≥1.5 at 1 hour can accurately
differentiate ATTR cardiac amyloidosis from AL cardiac
amyloidosis.113
Alternatively, a 2- or 3-hour approach can be used (as
typically performed for 99mTc-DPD/HMDP) in which a
visual grading scale is used (Table 5). Grade 2 or Grade
3 myocardial uptake of 99mTc-PYP/DPD/HMDP, in the
absence of a clonal disorder, is diagnostic of ATTR cardiac
amyloidosis (Figure 7). Both planar and SPECT imaging
should be reviewed and interpreted using visual and quan-
titative approaches irrespective of the timing of acquisition.
SPECT imaging is necessary for studies that show
planar myocardial uptake because they can help differ-
entiate myocardial uptake from blood pool or overlying
Figure 5. Characteristic appearance of cardiac amyloidosis on CMR.
Two patients [upper and lower row, (A) and (B)] with cardiac amyloidosis: similar mass (cine), but significantly different amyloid burden, with
the patient at the bottom (B) showing a significant higher amyloid burden (higher native T1, higher ECV, transmural LGE) and lower myocardial
resting perfusion (also, after adjusting for ECV expansion). (C) Inversion scout images in two patients, upper row amyloid, lower row non-
amyloid control. These images show a distinct pattern of myocardial and blood pool nulling. In the non-amyloid subject, the blood pool nulls
prior to myocardium; in contrast, in the subject with cardiac amyloidosis, the myocardium nulls prior to the blood pool.
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
bone uptake. Interpretation should also include comment
on focal vs diffuse radiotracer uptake; diffuse uptake is
typically consistent with cardiac amyloidosis, while focal
uptake may represent early cardiac amyloidosis but has
also been described in acute or subacute myocardial
Table 4. Recommendations for Standardized Acquisition of
99mTc-PYP/DPD/H MDP for Cardiac Amyloidosis
Imaging Procedures Parameters Recommendation
Preparation No specific preparation.
No fasting required.
Required
Scan Rest scan Required
Dose 99mTc-PYP: 10–20 mCi
(370–740 MBq) intravenously
99mTc-DPD: 10–20 mCi
(370–740 MBq) intravenously
99mTc-HMDP: 10–20 mCi
(370–740 MBq) intravenously
Recommended
Time between injection
and acquisition:
99mTc-PYP/DPD/HMDP
2 or 3 h Recommended
Time between injection
and acquisition:
99mTc-PYP only
1 h Optional. If excess
blood pool activity
noted on 1-h images,
3-h imaging is
recommended.
See below regarding
image type.
General imaging parameters*
Field of view Heart
Chest
Required
Optional for planar
CT attenuation
correction
Heart Recommended
SPECT/CT fusion im-
ages helpful to
localize tracer uptake
to the myocardium
Image type: planar Chest
2 or 3 h
Recommended
1-h planar-only imaging
is not recommended
Image type: SP ECT Heart Required
Position Supine
Upright
Required
Optional
Energy window 140 keV, 15–20% Required
Collimators Low energy, high resolution Recommended
Matrix-Planar 256×256 Recommended
Matrix-SPECT 128×128 (at least 64 by
64 is required)
Recommended
Pixel size 2.3–6.5 mm Recommended
Planar imaging specific parameters*
Number of views† Anterior and lateral Required
Detector configuration 90° Recommended
Image duration (count
based)
750,000 counts Recommended
Magnification 1.46 for large field of view
systems
1.0 for small field of view
systems
Recommended with
goal of achieving rec-
ommended pixel size
Recommended
SPECT imaging specific parameters*
Angular range/detector
configuration
180°/90° Minimum required
Angular range/detector
configuration
360°/180° Optional, recommend-
ed if large FOV camera
is available
EC G gating Off; Non-gated imaging Recommended
Number of views/detector 40/32 Recommended
Time per stop 20 s/25 s Recommended
Magnification 1.46 (180° angular range)
1.0 (360° angular range)
Recommended
Adapted from Ref. 207.
ECG, electrocardiogram; PYP, pyrophosphate.
*Parameters for NaI SPECT scanners. †Anterior and lateral views are obtained
at the same time; lateral planar views or SPECT imaging may help separate sternal
from myocardial uptake.
Table 5. Recommendations for Interpretation of 99mTc-PYP/
DPD/ HMDP for Cardiac Amyloidosis
Step 1: Visual interpretation
Evaluate planar and SPECT images to confirm diffuse radiotracer uptake
in the myocardium.
Differentiate myocardial radiotracer uptake from residual blood pool activ-
ity, focal myocardial infarct, and overlapping bone (eg, from rib hot spots
from fractures) on SPECT images. If excess blood-pool activity is noted,
recommend repeat SPECT imaging at 3 h.
If myocardial tracer uptake is visually present on SPECT, proceed to step
2, semi-quantitative visual grading. If no myocardial tracer uptake is pres-
ent on SPECT, the visual grade is 0.
Step 2: Semi-quantitative grading to distinguish AL from ATTR cardiac amy-
loidosis (1- or 3-hour approach)
Examine planar and SPECT images for relative tracer uptake in the myo-
cardium relative to ribs and grade using the following scale:
Grade 0 No myocardial uptake and normal bone
uptake
Grade 1 Myocardial uptake less than rib uptake
Grade 2 Myocardial uptake equal to rib uptake
Grade 3 Myocardial uptake greater than rib uptake
with mild/absent rib uptake
Step 3: Heart/contralateral lung uptake ratio assessment (when applicable)
A circular ROI should be drawn over the heart on the anterior planar
images with care to avoid sternal overlap and with size adjusted to
maximize coverage of the heart without inclusion of adjacent lung. This
ROI (same size) should be mirrored over the contralateral chest without
inclusion of the right ventricle, to adjust for background and rib uptake
(see Fig. 6*). The heart and contralateral ROIs should be drawn above
the diaphragm.
An H/CL ratio is calculated as the fraction of heart RO I mean counts to
contralateral lung ROI mean counts.
H/CL ratios of ≥1.5 at 1 h can accurately identify ATTR cardiac amy-
loidosis if myocardial PYP uptake is visually confirmed on SPECT and
systemic AL amyloidosis is excluded.114 An H/CL ratio of ≥1.3 at 3 h can
identify ATTR cardiac amyloidosis.
NOTE: Diagnosis of ATTR cardiac amyloidosis cannot be made solely
based on H/CL ratio alone with PYP. H/CL ratio is not recommended
if there is absence of myocardial uptake on SPECT. Additionally, if the
visual grade is 2 or 3, diagnosis is confirmed and H/CL ratio assessment
is not necessary. H/CL ratio is typically concordant with visual grade. If
discordant or the visual grade is equivocal, H/CL ratio may be helpful to
classify equivocal visual grade 1 vs 2 as positive or negative.
See Fig. 7.* Grade 2 or Grade 3 uptake is consistent with ATTR cardiac
amyloidosis if a monoclonal plasma cell dyscrasia is excluded, as this
degree of uptake can be seen in >20% of patients with AL cardiac amy-
loidosis.3 Grade 0 and Grade 1 uptake may be observed in AL cardiac
amyloidosis and warrants further evaluation to exclude AL amyloidosis.3
The writing group would like to emphasize the importance of excluding a
monoclonal process with serum/urine immunofixation and a serum-free
light-chains assay in all patients with suspected amyloidosis.
Of note: 99mTc-PYP/DPD/HM DP uptake could be seen in other causes
of myocardial injury, including pericarditis, myocardial infarction (regional
uptake), and chemotherapy or drug-associated myocardial toxicity.
Adapted from Ref. 207.
AL, amyloid light chain; ATTR, amyloid transthyretin; H/CL, heart/contralateral
lung; ROI, region of interest.
*Fig. 6 and 7 refer to figures in the original document.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 20
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
infarction. Guidelines for standardized reporting are pro-
vided in Table 6.
An H/CL ratio may be falsely low in patients who
had suffered a prior large remote myocardial infarction;
myocardial uptake of the tracer will be limited to non-
infarcted zone. Careful evaluation of these imaging using
SPECT and non-planar image display are recommended
to visualize regional uptake.
123I-mIBG Sympathetic Innervation Tracer
An overview of the imaging acquisition parameters for
123I-mIBG is available in the Appendix. Sources of vari-
ability in late HMR include non-homogeneity in 123I-mIBG
imaging acquisition; differing gamma camera systems;
and low- vs medium-energy collimators.131,186,202,203 Rec-
ommendations for the reporting of 123I-mIBG are pro-
vided in the Appendix and are predominately based on
the HMR and washout-rate quantification. As with 99mTc-
PYP/DPD/HMDP, SPECT imaging is of value in addition
to planar imaging to evaluate regional cardiac sympathetic
innervation abnormalities. The majority of patients (in both
AL and ATTR cardiac amyloidosis) with low HMR show
reduced tracer accumulation in the inferolateral seg-
ments.97,98,130,135,137,139 This, however, is not a finding spe-
cific to cardiac amyloidosis; reduced radiotracer uptake in
the inferolateral myocardial wall is also reported in healthy
control subjects due to physiological over projection of
123I-mIBG accumulation of the liver into this region.204 Also,
this technique should be avoided in patients with sus-
pected cardiac amyloidosis and prior myocardial infarction.
Key Recommendations for Standardized Image
Techniques: Radionuclide Imaging
• 99mTc-PYP/DPD/HMDP and 123I-mIBG imaging
should be performed using standard protocols as
discussed in this section.
• SPECT imaging is useful particularly in posi-
tive or equivocal cases to differentiate myocardial
from blood pool signal and to describe regional
heterogeneity.
• Visual and semi-quantitative interpretation of 99mTc -
PYP/DPD/HMDP planar and SPECT images
should be employed to evaluate heart-to-bone ratio
and/or H/CL lung ratio. The HMR is used to inter-
pret 123I-mIBG images.
Figure 6. Characteristic appearance of cardiac amyloidosis on 99mTc-PYP/DPD/H MDP imaging.
Semi-quantitative H/CL Ratio on 9 9mTc-PYP Planar Imaging. Anterior planar chest views one hour after injection of 99mTc-PYP a patient with
Grade 3 (A), and Grade 0 (B) 99mTc-PYP uptake. On the right are the corresponding H/CL (heart/contralateral lung) lung-ratio methodology with
measurement of mean counts per pixel for target (heart) and background (contralateral chest). As shown in this figure, the ROIs (region of interest)
should be positioned to minimize overlap with sternal or focal rib uptake and maximize coverage of the heart without including adjacent lung.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 21
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
• An overall reporting on likelihood of amyloidosis
based on imaging findings is recommended (eg, not
suggestive, strongly suggestive, or equivocal for car-
diac amyloidosis and for extra-cardiac findings).
FUTURE DIRECTIONS
The field of imaging in cardiac amyloidosis is expanding
rapidly and more research is needed in several key areas.
• Early detection with imaging remains an unmet need
in cardiac amyloidosis, and techniques that identify
disease at an earlier stage are needed. 99mTc PYP/
DPD/HMDP have the potential for early detection
of ATTR cardiac amyloidosis prior to echocardiogra-
phy and CMR. This needs to be further validated.
• Molecular imaging techniques, including amyloid
binding PET radionuclide tracers and ECV by CMR
are particularly well suited to detect early disease.
Further studies are needed.
• Early detection of cardiac amyloidosis could allow
targeted therapy prior to symptom onset and improve
clinical outcomes. This needs to be studied further.
Figure 7. 99mTc-PYP/DPD/HMDP.
Anterior planar chest images (Top row), SPECT cardiac imaging (Middle row) and planar whole-body imaging (Bottom row). Cardiac uptake is
visually compared with surrounding ribs for a visual grading score as described in Table 5. Images with Grade 0, Grade 1, Grade 2, and Grade
3 myocardial uptake of 99mTc-PYP are shown. (Top panel provided by ASNC Cardiac Amyloidosis Practice Points.209)
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 22
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
• Methods for quantitative assessment of systemic
and cardiac burden of amyloidosis are needed. ECV
assessment by CMR, and 18F-labelled PET tracers
have the potential to provide accurate quantification
but require additional evaluation and more wide-
spread dissemination of technology and broader
clinical use to reach their full potential.
• Precise detection of changes in the burden of car-
diac amyloidosis using imaging can allow evaluation
of the efficacy of emerging novel therapies aimed at
stabilization and even resorption of amyloid fibrils.
• Advanced echocardiography, including 3D echocar-
diographic strain, dynamic echocardiography, left atrial
mechanics, and automated, machine learning-based
methods over standard approaches are being investigated.
• Prospective studies evaluating the incremental diag-
nostic and prognostic value of non-invasive imaging
techniques, including advanced echocardiographic
methods, 99mTc PYP/DPD/HMDP, 123I-mIBG, and
CMR should be undertaken. The incremental value
of imaging markers over clinical and laboratory
markers needs to be studied further.
• The majority of existing literature arises from small,
single-center studies of highly selected patients.
Multicenter studies, including larger patient cohorts
and standardized imaging methods, are needed to
advance the evaluation and management of cardiac
amyloidosis. In particular, large prospective studies
are needed to validate the clinical utility of cardiac
imaging in assessing the response to therapy and
predicting clinical outcome.
SUMMARY
The purpose of Part 1 of this consensus statement has
been to establish the available diagnostic and prognos-
tic literature for imaging in cardiac amyloidosis and pro-
vide comprehensive expert recommendations based on
this evidence and expert opinion regarding the role of
imaging in cardiac amyloidosis, including standardized
image acquisition, interpretation, and reporting. We hope
that use of these consensus recommendations on stan-
dardized imaging techniques will improve patient care
and outcomes. We also hope we have identified gaps in
the literature that can spur relevant research to broaden
our understanding of this complex disease and support
guideline development.
APPENDIX
A summary of literature that supports the recommen-
dations provided in this consensus statement on the
prognostic value of echocardiography (Table 7); diag-
nostic and prognostic value of CMR (Tables 8 and 9),
and diagnostic and prognostic value of radionuclide
imaging with 99mTc- PYP/DPD/HMDP (Tables 10, 11,
12, 13, and 14) in the evaluation of cardiac amyloidosis
are provided in the Appendix. The diagnostic value, prog-
nostic value, standardized image acquisition and report-
ing of 123I-mIBG in cardiac amyloidosis are provided in
Tables 15, 16, 17, and 18.
Tables 7 through 18 are located after the References
section, beginning on page 31.
Table 6. Recommendations for Standardized Reporting of 99mTc-PYP/DPD/H MDP Imaging for Cardiac Amyloidosis
Parameters Elements
Demographics Patient name, age, sex, reason for the test, date of study, prior imaging procedures, biopsy results if available (Required)
Methods Imaging technique, radiotracer dose and mode of administration, interval between injection and scan, scan technique (planar and
SPECT) (Required)
Findings Image quality
Visual scan interpretation (Required)
Semi-quantitative interpretation in relation to rib uptake (Required)
Quantitative findings H/CL lung ratio (Optional; recommended for positive scans)
Ancillary findings Whole-body imaging if planar whole-body images are acquired (Optional)
Interpret CT for attenuation correction if SPECT/CT scanners are used (Recommended)
Conclusions 1. An overall interpretation of the findings into categories of (1) not suggestive of ATTR cardiac amyloidosis; (2) strongly suggestive of
ATTR cardiac amyloidosis; or (3) equivocal for ATTR cardiac amyloidosis after exclusion of a systemic plasma cell dyscrasia (Required)
a. Not suggestive: A semi-quantit ative visual grade of 0.
b. Equivocal: If diffuse myocardial uptake of 99mTc-PYP/DPD/HM DP is visually confirmed and the semi-quantitative visual grade is 1
or there is interpretive uncertainty of grade 1 versus grade 2 on visual grading.
c. Strongly suggestive: If diffuse myocardial uptake of 99mTc-PYP/DPD/HM DP is visually confirmed, a semi-quantitative visual grade
of 2 or 3.
2. Statement that evaluation for AL amyloidosis by serum FLCs, serum, and urine immunofixation is recommended in all patients under-
going 99mTc-PYP/DPD/HMDP scans for cardiac amyloidosis. (Required)
3. Statement that results should be interpreted in the context of prior evaluation and referral to a hematologist or amyloidosis expert is
recommended if either:
a. Recommended echo/CMR is strongly suggestive of cardiac amyloidosis and 99mTc- PYP/DPD/HMDP is not suggestive or
equivocal and/or
b. FLCs are abnormal or equivocal. (Recommended)
Adapted from Ref. 207.
AL, amyloid light chain; ATTR, amyloid transthyretin; CMR, cardiovascular magnetic resonance; echo, echocardiography; FLC, free light chain; H/CL, heart-to-contra-
lateral lung ratio.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 23
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
ADDENDUM
There are 2 primary reasons for an addendum. First, since
the original publication of this article,236 the Acknowledg-
ments now include Dr. Richard Cheng and Dr. Roy John,
who critically reviewed the article but were inadvertently
not listed as reviewers.
Second, since the original publication236 and intro-
duction of approved therapies for transthyretin cardiac
amyloidosis (ATTR-CA), the clinical use of bone tracer
cardiac scintigraphy has been extended to populations
with lower prevalence of ATTR-CA. Numerous observa-
tions have raised concerns about (1) incorrect diagno-
sis of ATTR-CA based on 99mTc-pyrophosphate (PYP)
planar imaging and heart-to-contralateral lung (H/CL)
ratio without confirmation of diffuse myocardial uptake
on SPECT imaging at some sites; (2) excess blood pool
activity on the 1-hour planar and SPECT images being
interpreted as positive scans; and (3) missed diagno-
sis of light chain (AL) amyloidosis, as serum-free light
chain studies and serum and urine immunofixation
electrophoresis studies may not be recommended in
the 99mTc-PYP/-3,3-diphosphono-1,2-propanodicar-
boxylic acid/hydroxymethylene diphosphonate (99mTc-
PYP/DPD/HMDP) report. Incorrect diagnosis leads
to inappropriate therapy and worse patient outcomes.
SPECT and planar imaging performed at 3 hour maxi-
mize specificity.114,237,238 Additionally, technical param-
eters have been updated.
This addendum clarifies the protocols, interpretation,
and reporting of 99mTc-PYP imaging:
1. Acquisition (Table 4):
a. The time between injection of 99mTc-PYP and
scan is revised: 2- or 3-hour imaging is recom-
mended, and 1-hour imaging is optional (Table
4). If excess blood pool activity is noted, 3-hour
imaging is recommended. The timing between
injection and scanning is now consistent for
99mTc-PYP, -DPD, and -HMDP. We recognize
some experienced centers that have become
proficient at 1-hour scanning; the recommen-
dation for 2- or 3-hour imaging is particularly
important for centers starting new Tc-PYP
programs.
b. SPECT imaging is required in all studies (irre-
spective of time between injection and scan) to
highlight the importance of directly visualizing
tracer uptake in the myocardium.
c. 1-hour planar-only imaging is not recommended.
d. Emerging literature suggests that cadmium
zinc telluride (CZT) SPECT can also be used
for 99mTc-PYP/DPD/HMDP imaging.239,240
2. Interpretation (Table 5):
a. Planar imaging and H/CL ratio alone are
insufficient for diagnosis of ATTR cardiac
amyloidosis. SPECT imaging is necessary to
identify myocardial uptake of 99mTc-PYP/DPD/
HMDP.
b. Repeat imaging is recommended at 3 hours if
excess blood pool activity is noted.
c. The steps in Table 5 clarify that visual grad-
ing on planar and SPECT imaging is the pri-
mary method for diagnosis of ATTR cardiac
amyloidosis.
d. Recommendations are clarified for ease of
interpretation.
3. Reporting (Table 6):
a. Diffuse myocardial uptake should be visualized
to report a positive scan.
b. The criterion for H/CL ratio >1.5 as strongly
positive has been removed (consistent with
diagnostic criteria listed in the “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,”241 where H/CL ratio was not listed).
c. Conclusions have been clarified.
Tables 4, 5, and 6 reflect these clarifications.
ARTICLE INFORMATION
This document was approved for publication by the governing body of the Ameri-
can Society of Nuclear Cardiology (ASNC) and was endorsed by the American
College of Cardiology (ACC), the American Heart Association (AHA), American
Society of Echocardiography (ASE), the European Association of Nuclear Medi-
cine (EANM), the Heart Failure Society of America (HFSA), the International So-
ciety of Amyloidosis (ISA), the Society for Cardiovascular Magnetic Resonance
(SCMR), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI).
This document was approved by the American Heart Association Science Advi-
sory and Coordinating Committee on July 8, 2019.
This article has been copublished in the Journal of Nuclear Cardiology and the
Journal of Cardiac Failure.
“Part 2—Diagnostic Criteria and Appropriate Utilization” is available at:
https://www.ahajournals.org/doi/10.1161/HCI.0000000000000030
A copy of the document is available at https://professional.heart.org/
statements by using either “Search for Guidelines & Statements” or the
“Browse by Topic” area. To purchase additional reprints, call 215-356-2721 or
email Meredith.Edelman@wolterskluwer.com.
The expert peer review of AHA-commissioned documents (eg, scientific
statements, clinical practice guidelines, systematic reviews) is conducted by the
AHA Office of Science Operations. For more on AHA statements and guidelines
development, visit https://professional.heart.org/statements. Select the “Guide-
lines & Statements” drop-down menu, then click “Publication Development.”
Permissions: Multiple copies, modification, alteration, enhancement, and/or
distribution of this document are not permitted without the express permission of
the American Heart Association. Instructions for obtaining permission are located
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quest Form” appears in the second paragraph (https://www.heart.org/en/about-
us/statements-and-policies/copyright-request-form).
Acknowledgments
We would like to thank the reviewers of this document for their input, which has sig-
nificantly improved the quality of this document, including Renée P. Bullock-Palmer,
MD, FACC, FASNC, FASE, FSCCT; Dennis A. Calnon, MD, FASNC; Richard Cheng,
MD; Marcelo F. Di Carli, MD; Martha Grogan, MD; Phillip Hawkins, PhD, FMedSci;
Wael A. Jaber, MD, FACC, FAHA; Roy John, MD; Prem Soman, MD, FASNC; James
E. Udelson, MD, FACC; Ashutosh D. Wechalekar, DM, MRCP, FRCPath.
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
REFERENCES
1. Child JS, Levisman JA, Abbasi AS, MacAlpin RN. Echocardiographic mani-
festations of infiltrative cardiomyopathy. A report of seven cases due to
amyloid. Chest 1976;70:726–31.
2. Braun SD, Lisbona R, Novales-Diaz JA, Sniderman A. Myocardial uptake of
99mTc-phosphate tracer in amyloidosis. Clin Nucl Med 1979;4:244–5.
3. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et
al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation
2016;133:2404–12.
4. Alexander KM, Orav J, Singh A, Jacob SA, Menon A, Padera RF, et al. Geographic
disparities in reported US amyloidosis mortality from 1979 to 2015: Potential
underdetection of cardiac amyloidosis. JAMA Cardiol 2018;3:865–70.
5. Sipe JD, Benson MD, Buxbaum JN, Ikeda SI, Merlini G, Saraiva MJ, et al.
Amyloid fibril proteins and amyloidosis: Chemical identification and clini-
cal classification International Society of Amyloidosis 2016 Nomenclature
Guidelines. Amyloid 2016;23:209–13.
6. Benson MD, Buxbaum JN, Eisenberg DS, Merlini G, Saraiva MJM,
Sekijima Y, et al. Amyloid nomenclature2018: Recommendations by the
International Society of Amyloidosis (ISA) nomenclature committee. Amy-
loid 2019;2019:1–5.
7. Muchtar E, Gertz MA, Kumar SK, Lacy MQ, Dingli D, Buadi FK, et al. Improved
outcomes for newly diagnosed AL amyloidosis over the years 2000–2014:
Cracking the glass ceiling of early death. Blood 2017;129:2111–9.
8. Siddiqi OK, Ruberg FL. Cardiac amyloidosis: An update on pathophysiology,
diagnosis, and treatment. Trends Cardiovasc Med 2018;28:10–21.
9. Perlini S, Salinaro F, Musca F, Mussinelli R, Boldrini M, Raimondi A, et al.
Prognostic value of depressed midwall systolic function in cardiac light-
chain amyloidosis. J Hypertens 2014;32:1121–31 discussion 1131.
10. Kyle RA, Linos A, Beard CM, Linke RP, Gertz MA, O’Fallon WM, et al.
Incidence and natural history of primary systemic amyloidosis in Olmsted
County, Minnesota, 1950 through 1989. Blood 1992;79:1817–22.
11. Pinney JH, Smith CJ, Taube JB, Lachmann HJ, Venner CP, Gibbs SD, et al.
Systemic amyloidosis in England: An epidemiological study. Br J Haematol
2013;161:525–32.
12. Quock TP, Yan T, Chang E, Guthrie S, Broder MS. Epidemiology of
AL amyloidosis: A real-world study using US claims data. Blood Adv
2018;2:1046–53.
13. Gonzalez-Lopez E, Gallego-Delgado M, Guzzo-Merello G,
de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, et al. Wild-type transthyre-
tin amyloidosis as a cause of heart failure with preserved ejection fraction.
Eur Heart J 2015;36:2585–94.
14. Castano A, Narotsky DL, Hamid N, Khalique OK, Morgenstern R, DeLuca A,
et al. Unveiling transthyretin cardiac amyloidosis and its predictors among
elderly patients with severe aortic stenosis undergoing transcatheter aortic
valve replacement. Eur Heart J 2017;38:2879–87.
15. Bennani Smires Y, Victor G, Ribes D, Berry M, Cognet T, Mejean S, et
al. Pilot study for left ventricular imaging phenotype of patients over
65 years old with heart failure and preserved ejection fraction: The
high prevalence of amyloid cardiomyopathy. Int J Cardiovasc Imaging
2016;32:1403–13.
16. Jacobson DR, Alexander AA, Tagoe C, Buxbaum JN. Prevalence of the amy-
loidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans.
Amyloid 2015;22:171–4.
17. Dungu JN, Papadopoulou SA, Wykes K, Mahmood I, Marshall J,
Valencia O, et al. Afro-Caribbean heart failure in the United Kingdom: Cause,
outcomes, and ATTR V122I cardiac amyloidosis. Circ Heart Fail 2016.
https://doi.org/10.1161/CIRCH EARTFAILURE.116.003352.
Disclosures
Authors Advisory Board Research Grant Consulting Fee Honoraria
Stock
Ownership
Jamieson M. Bourque, MD Astellas Pfizer Locus
Health
Angela Dispenzieri, MD Celgene, Takeda, Janssen, Pfizer,
Alnylam Pharmaceuticals, Pro-
thena Bioscience
Sharmila Dorbala, MD,
MPH
GE Healthcare GE Healthcare, Proclara Biosci-
ences, Advanced Accelerator
Applications
Pfizer
Pfizer
Rodney H. Falk, MD Alnylam, Ionis, Akcea Therapeu-
tics, Eidos Therapeutics
Julian D. Gillmore, MD, PhD Alnylam, GlaxoSmithKline
Raymond Y. Kwong, MD,
MPH
Siemens Medical Systems, Bayer,
GlaxoSmithKline, Alynlam, Myo-
kardia, the SCMR
Mathew S. Maurer, MD Prothena Biosciences,
GlaxoSmithKline, Ionis
Pfizer, Alnylam
Giampaolo Merlini, MD Prothena Biosciences, Pfiz-
er, Ionis Pharmaceuticals
Edward J. Miller, MD, PhD Bracco Diagnostics GE Healthcare, Pfizer
Venkatesh L. Murthy, MD,
PhD
INVIA Medical Imaging Solutions Ionetix, Bracco
Diagnostics
General
Electric
Claudio Rapezzi, MD Alnylam, Prothena Biosci-
ences, GlaxoSmithKline
Pfizer
Frederick L. Ruberg, MD Caelum Biosciences, Alynlam,
Prothena Biosciences
Sanjiv J. Shah, MD Actelion, AstraZeneca, Corvia
Medical
Actelion, Amgen, AstraZeneca,
Bayer, Boehringer-Ingelheim,
Cardiora, Eisai, Gilead Sciences,
Ironwood Pharmaceuticals, Mer-
ck, MyoKardia, Novartis, Sanofi,
United Therapeutics Corp.
Pfizer
All other contributors have nothing relevant to disclose.
Downloaded from http://ahajournals.org by on July 2, 2021

Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 25
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
18. Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Ueda M, Kristen AV,
et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis.
N Engl J Med 2018;379:11–21.
19. Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK,
et al. Inotersen treatment for patients with hereditary transthyretin amyloido-
sis. N Engl J Med 2018;379:22–31.
20. Richards DB, Cookson LM, Berges AC, Barton SV, Lane T, Ritter JM, et al.
Therapeutic clearance of amyloid by antibodies to serum amyloid P compo-
nent. N Engl J Med 2015;373:1106–14.
21. Comenzo RL, Vosburgh E, Simms RW, Bergethon P, Sarnacki D,
Finn K, et al. Dose-intensive melphalan with blood stem cell support for
the treatment of AL amyloidosis: one-year follow-up in five patients. Blood
1996;88:2801–6.
22. Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G,
Waddington-Cruz M, et al. Tafamidis treatment for patients with transthyre-
tin amyloid cardiomyopathy. N Engl J Med 2018;379:1007–16.
23. Pellikka PA, Holmes DR Jr, Edwards WD, Nishimura RA, Tajik AJ, Kyle RA.
Endomyocardial biopsy in 30 patients with primary amyloidosis and sus-
pected cardiac involvement. Arch Intern Med 1988;148:662–6.
24. Satoskar AA, Efebera Y, Hasan A, Brodsky S, Nadasdy G, Dogan A, et al.
Strong transthyretin immunostaining: potential pitfall in cardiac amyloid typ-
ing. Am J Surg Pathol 2011;35:1685–90.
25. Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR 3rd,
Dogan A. Classification of amyloidosis by laser microdissection and mass
spectrometry-based proteomic analysis in clinical biopsy specimens. Blood
2009;114:4957–9.
26. Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Colby C, et al.
Revised prognostic staging system for light chain amyloidosis incorporating
cardiac biomarkers and serum free light chain measurements. J Clin Oncol
2012;30:989–95.
27. Wechalekar AD, Schonland SO, Kastritis E, Gillmore JD, Dimopoulos MA,
Lane T, et al. A European collaborative study of treatment outcomes in 346
patients with cardiac stage III AL amyloidosis. Blood 2013;121:3420–7.
28. Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN,
et al. Definition of organ involvement and treatment response in immuno-
globulin light chain amyloidosis (AL): a consensus opinion from the 10th
International Symposium on Amyloid and Amyloidosis, Tours, France, 18–22
April 2004. Am J Hematol 2005;79:319–28.
29. Madan S, Kumar SK, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al.
High-dose melphalan and peripheral blood stem cell transplantation for light-
chain amyloidosis with cardiac involvement. Blood 2012;119:1117–22.
30. Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, et al. Natural
history of wild-type transthyretin cardiac amyloidosis and risk stratification
using a novel staging system. J Am Coll Cardiol 2016;68:1014–20.
31. Hutt DF, Fontana M, Burniston M, Quigley AM, Petrie A, Ross JC, et al. Prog-
nostic utility of the Perugini grading of 99mTc-DPD scintigraphy in trans-
thyretin (ATTR) amyloidosis and its relationship with skeletal muscle and
soft tissue amyloid. Eur Heart J Cardiovasc Imaging 2017;18:1344–50.
32. Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ,
Martinez-Naharro A, et al. A new staging system for cardiac transthyretin
amyloidosis. Eur Heart J 2018;39:2799–806.
33. Chew C, Ziady GM, Raphael MJ, Oakley CM. The functional defect in amy-
loid heart disease the “stiff heart” syndrome. Am J Cardiol 1975;36:438–44.
34. Falk RH, Quarta CC. Echocardiography in cardiac amyloidosis. Heart Fail
Rev 2015;20:125–31.
35. Ruberg FL, Maurer MS, Judge DP, Zeldenrust S, Skinner M, Kim AY, et al.
Prospective evaluation of the morbidity and mortality of wild-type and V122I
mutant transthyretin amyloid cardiomyopathy: The Transthyretin Amyloido-
sis Cardiac Study (TRACS). Am Heart J 2012;164:e1.
36. Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) car-
diac amyloidosis: A review of diagnosis and therapy. J Am Coll Cardiol
2016;68:1323–41.
37. Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet
2016;387:2641–54.
38. Kirkpatrick JN, Lang RM. Heart failure: hemodynamic assessment using
echocardiography. Curr Cardiol Rep 2008;10:240–6.
39. Mitter SS, Shah SJ, Thomas JD. A test in context: E/A and E/e’ to
assess diastolic dysfunction and LV filling pressure. J Am Coll Cardiol
2017;69:1451–64.
40. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H,
Edvardsen T, et al. Recommendations for the evaluation of left ventricular
diastolic function by echocardiography: An update from the American Soci-
ety of Echocardiography and the European Association of Cardiovascular
Imaging. J Am Soc Echocardiogr 2016;29:277–314.
41. Nochioka K, Quarta CC, Claggett B, Roca GQ, Rapezzi C, Falk RH, et al. Left
atrial structure and function in cardiac amyloidosis. Eur Heart J Cardiovasc
Imaging 2017;18:1128–37.
42. Banypersad SM, Moon J C, Whelan C, Hawkins PN, Wechalekar AD. Updates
in cardiac amyloidosis: A review. J Am Heart Assoc 2012;1:e000364.
43. Falk RH, Lee VW, Rubinow A, Hood WB Jr, Cohen AS. Sensitivity of tech-
netium-99m-pyrophosphate scintigraphy in diagnosing cardiac amyloidosis.
Am Heart J 1983;51:826–30.
44. Gertz MA, Brown ML, Hauser MF, Kyle RA. Utility of technetium Tc 99m
pyrophosphate bone scanning in cardiac amyloidosis. Arch Intern Med
1987;147:1039–44.
45. Hartmann A, Frenkel J, Hopf R, Baum RP, Hör G, Schneider M, et al. Is
technetium-99 m-pyrophosphate scintigraphy valuable in the diagnosis of
cardiac amyloidosis? Int J Card Imaging 1990;5:227–31.
46. Schiff S, Bateman T, Moffatt R, Davidson R, Berman D. Diagnostic consider-
ations in cardiomyopathy: Unique scintigraphic pattern of diffuse biventricu-
lar technetium-99m-pyrophosphate uptake in amyloid heart disease. Am
Heart J 1982;103:562–3.
47. Wizenberg TA, Muz J, Sohn YH, Samlowski W, Weissler AM. Value of positive
myocardial technetium-99m-pyrophosphate scintigraphy in the noninvasive
diagnosis of cardiac amyloidosis. Am Heart J 1982;103:468–73.
48. Yamamoto Y, Onoguchi M, Haramoto M, Kodani N, Komatsu A, Kitagaki H,
et al. Novel method for quantitative evaluation of cardiac amyloidosis using
(201)TlCl and (99m)Tc-PYP SPECT. Ann Nucl Med 2012;26:634–43.
49. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: Character-
ization by a distinctive voltage/mass relation. Am J Cardiol 1982;49:9–13.
50. Cueto-Garcia L, Reeder GS, Kyle RA, Wood DL, Seward JB, Naessens J, et
al. Echocardiographic findings in systemic amyloidosis: spectrum of cardiac
involvement and relation to survival. J Am Coll Cardiol 1985;6:737–43.
51. Quarta CC, Solomon SD, Uraizee I, Kruger J, Longhi S, Ferlito M, et al. Left
ventricular structure and function in transthyretin-related vs light-chain car-
diac amyloidosis. Circulation 2014;129:1840–9.
52. Rapezzi C, Merlini G, Quarta CC, Riva L, Longhi S, Leone O, et al. Systemic
cardiac amyloidoses: Disease profiles and clinical courses of the 3 main
types. Circulation 2009;120:1203–12.
53. Siqueira-Filho AG, Cunha CL, Tajik AJ, Seward JB, Schattenberg TT,
Giuliani ER. M-mode and two-dimensional echocardiographic features in
cardiac amyloidosis. Circulation 1981;63:188–96.
54. Gonzalez-Lopez E, Gagliardi C, Dominguez F, Quarta CC, de Haro-Del Moral FJ,
Milandri A, et al. Clinical characteristics of wild-type transthyretin cardiac
amyloidosis: Disproving myths. Eur Heart J 2017;38:1895–904.
55. Buss SJ, Emami M, Mereles D, Korosoglou G, Kristen AV, Voss A, et al.
Longitudinal left ventricular function for prediction of survival in systemic
light-chain amyloidosis: Incremental value compared with clinical and bio-
chemical markers. J Am Coll Cardiol 2012;60:1067–76.
56. Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function
assessed by tissue velocity, strain, and strain rate tissue Doppler echo-
cardiography in patients with AL (primary) cardiac amyloidosis. Circulation
2003;107:2446–52.
57. Koyama J, Ray-Sequin PA, Davidoff R, Falk RH. Usefulness of pulsed tissue
Doppler imaging for evaluating systolic and diastolic left ventricular function
in patients with AL (primary) amyloidosis. Am J Cardiol 2002;89:1067–71.
58. Sallach JA, Klein AL. Tissue Doppler imaging in the evaluation of patients
with cardiac amyloidosis. Curr Opin Cardiol 2004;19:464–71.
59. Bellavia D, Abraham RS, Pellikka PA, Dispenzieri A, Burnett JC Jr,
Al-Zahrani GB, et al. Utility of Doppler myocardial imaging, cardiac biomark-
ers, and clonal immunoglobulin genes to assess left ventricular performance
and stratify risk following peripheral blood stem cell transplantation in
patients with systemic light chain amyloidosis (Al). J Am Soc Echocardiogr
2011;24:444–54.
60. Bellavia D, Abraham TP, Pellikka PA, Al-Zahrani GB, Dispenzieri A,
Oh JK, et al. Detection of left ventricular systolic dysfunction in cardiac
amyloidosis with strain rate echocardiography. J Am Soc Echocardiogr
2007;20:1194–202.
61. Bellavia D, Pellikka PA, Abraham TP, Al-Zahrani GB, Dispenzieri A, Oh JK,
et al. Evidence of impaired left ventricular systolic function by Doppler myo-
cardial imaging in patients with systemic amyloidosis and no evidence of
cardiac involvement by standard two-dimensional and Doppler echocar-
diography. Am J Cardiol 2008;101:1039–45.
62. Bellavia D, Pellikka PA, Al-Zahrani GB, Abraham TP, Dispenzieri A,
Miyazaki C, et al. Independent predictors of survival in primary systemic
(Al) amyloidosis, including cardiac biomarkers and left ventricular
strain imaging: an observational cohort study. J Am Soc Echocardiogr
2010;23:643–52.
Downloaded from http://ahajournals.org by on July 2, 2021

Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 26
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
63. Phelan D, Collier P, Thavendiranathan P, Popovic ZB, Hanna M, Plana JC,
et al. Relative apical sparing of longitudinal strain using two-dimensional
speckle-tracking echocardiography is both sensitive and specific for the
diagnosis of cardiac amyloidosis. Heart 2012;98:1442–8.
64. Liu D, Hu K, Niemann M, Herrmann S, Cikes M, Stork S, et al. Effect of com-
bined systolic and diastolic functional parameter assessment for differentia-
tion of cardiac amyloidosis from other causes of concentric left ventricular
hypertrophy. Circ Cardiovasc Imaging 2013;6:1066–72.
65. Tendler A, Helmke S, Teruya S, Alvarez J, Maurer MS. The myocardial
contraction fraction is superior to ejection fraction in predicting survival in
patients with AL cardiac amyloidosis. Amyloid 2015;22:61–6.
66. Arenja N, Fritz T, Andre F, Riffel JH, Aus dem Siepen F, Ochs M, et al. Myo-
cardial contraction fraction derived from cardiovascular magnetic reso-
nance cine images-reference values and performance in patients with heart
failure and left ventricular hypertrophy. Eur Heart J Cardiovasc Imaging
2017;18:1414–22.
67. Milani P, Dispenzieri A, Scott CG, Gertz MA, Perlini S, Mussinelli R, et al. Inde-
pendent prognostic value of stroke volume index in patients with immuno-
globulin light chain amyloidosis. Circ Cardiovasc Imaging 2018;11:e006588.
68. Kwong RY, Heydari B, Abbasi S, Steel K, Al-Mallah M, Wu H, et al. Charac-
terization of Cardiac Amyloidosis by Atrial Late Gadolinium Enhancement
Using Contrast-Enhanced Cardiac Magnetic Resonance Imaging and Cor-
relation With Left Atrial Conduit and Contractile Function. Am J Cardiol.
2015;116:622–9.
69. El-Am E, Dispenzieri A, Grogan M, Ammash N, Melduni R, White R, et al.
Outcomes of direct current cardioversion in adults with cardiac amyloidosis.
Eur Heart J 2018.
70. Bellavia D, Pellikka PA, Dispenzieri A, Scott CG, Al-Zahrani GB, Grogan M, et
al. Comparison of right ventricular longitudinal strain imaging, tricuspid annular
plane systolic excursion, and cardiac biomarkers for early diagnosis of cardiac
involvement and risk stratification in primary systematic (AL) amyloidosis: A
5-year cohort study. Eur Heart J Cardiovasc Imaging 2012;13:680–9.
71. Rapezzi C, Lorenzini M, Longhi S, Milandri A, Gagliardi C, Bartolomei I, et al.
Cardiac amyloidosis: The great pretender. Heart Fail Rev 2015;20:117–24.
72. Damy T, Maurer MS, Rapezzi C, Plante-Bordeneuve V, Karayal ON,
Mundayat R, et al. Clinical, ECG and echocardiographic clues to the diagno-
sis of TTR-related cardiomyopathy. Open Heart 2016;3:e000289.
73. Rahman JE, Helou EF, Gelzer-Bell R, Thompson RE, Kuo C, Rodriguez ER,
et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll
Cardiol 2004;43:410–5.
74. Maceira AM, Joshi J, Prasad SK, Moon JC, Perugini E, Harding I, et al.
Cardiovascular magnetic resonance in cardiac amyloidosis. Circulation
2005;111:186–93.
75. Pandey T, Jambhekar K, Shaikh R, Lensing S, Viswamitra S. Utility of the
inversion scout sequence (TI scout) in diagnosing myocardial amyloid infil-
tration. Int J Cardiovasc Imaging 2013;29:103–12.
76. Fontana M, Pica S, Reant P, Abdel-Gadir A, Treibel TA, Banypersad SM, et al.
Prognostic value of late gadolinium enhancement cardiovascular magnetic
resonance in cardiac amyloidosis. Circulation 2015;132:1570–9.
77. Vogelsberg H, Mahrholdt H, Deluigi CC, Yilmaz A, Kispert EM, Greulich S, et
al. Cardiovascular magnetic resonance in clinically suspected cardiac amy-
loidosis: Noninvasive imaging compared to endomyocardial biopsy. J Am
Coll Cardiol 2008;51:1022–30.
78. Syed IS, Glockner JF, Feng D, Araoz PA, Martinez MW, Edwards WD, et al.
Role of cardiac magnetic resonance imaging in the detection of cardiac
amyloidosis. JACC Cardiovasc Imaging 2010;3:155–64.
79. White JA, Kim HW, Shah D, Fine N, Kim KY, Wendell DC, et al. CMR imaging
with rapid visual T1 assessment predicts mortality in patients suspected of
cardiac amyloidosis. JACC Cardiovasc Imaging 2014;7:143–56.
80. Ruberg FL, Appelbaum E, Davidoff R, Ozonoff A, Kissinger KV, Harrigan C,
et al. Diagnostic and prognostic utility of cardiovascular magnetic resonance
imaging in light-chain cardiac amyloidosis. Am J Cardiol 2009;103:544–9.
81. Austin BA, Tang WH, Rodriguez ER, Tan C, Flamm SD, Taylor DO, et al.
Delayed hyper-enhancement magnetic resonance imaging provides incre-
mental diagnostic and prognostic utility in suspected cardiac amyloidosis.
JACC Cardiovasc Imaging 2009;2:1369–77.
82. Karamitsos TD, Piechnik SK, Banypersad SM, Fontana M, Ntusi NB,
Ferreira VM, et al. Noncontrast T1 mapping for the diagnosis of cardiac
amyloidosis. JACC Cardiovasc Imaging 2013;6:488–97.
83. Zhao L, Tian Z, Fang Q. Diagnostic accuracy of cardiovascular magnetic
resonance for patients with suspected cardiac amyloidosis: A systematic
review and meta-analysis. BMC Cardiovasc Disord 2016;16:129.
84. Fontana M, Banypersad SM, Treibel TA, Maestrini V, Sado DM, White SK, et
al. Native T1 mapping in transthyretin amyloidosis. JACC Cardiovasc Imag-
ing 2014;7:157–65.
85. Banypersad SM, Sado DM, Flett AS, Gibbs SD, Pinney JH, Maestrini V, et
al. Quantification of myocardial extracellular volume fraction in systemic AL
amyloidosis: an equilibrium contrast cardiovascular magnetic resonance
study. Circ Cardiovasc Imaging 2013;6:34–9.
86. Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T,
Kellman P, et al. Clinical recommendations for cardiovascular magnetic
resonance mapping of T1, T2, T2* and extracellular volume: A consen-
sus statement by the Society for Cardiovascular Magnetic Resonance
(SCMR) endorsed by the European Association for Cardiovascular Imag-
ing (EACVI). J Cardiovasc Magn Reson 2018;20:9.
87. Martinez-Naharro A, Kotecha T, Norrington K,
Boldrini M, Rezk T, Quarta C, et al. Native T1 and extracellular volume
in transthyretin amyloidosis. JACC Cardiovasc Imaging 2019;12:810–9.
https://doi.org/10.1016/j.jcmg.2018.02.006.
88. Martinez-Naharro A, Abdel-Gadir A, Treibel TA, Zumbo G, Knight DS,
Rosmini S, et al. CMR-verified regression of cardiac AL amyloid after che-
motherapy. JACC Cardiovasc Imaging 2018;11:152–4.
89. Kotecha T, Martinez-Naharro A, Treibel TA, Francis R, Nordin S,
Abdel-Gadir A, et al. Myocardial edema and prognosis in amyloidosis. J Am
Coll Cardiol 2018;71:2919–31.
90. Fontana M, Banypersad SM, Treibel TA, Abdel-Gadir A, Maestrini V, Lane T,
et al. Differential myocyte responses in patients with cardiac transthyretin
amyloidosis and light-chain amyloidosis: A cardiac MR imaging study. Radi-
ology 2015;277:388–97.
91. Dungu JN, Valencia O, Pinney JH, Gibbs SD, Rowczenio D, Gilbertson JA,
et al. CMR-based differentiation of AL and ATTR cardiac amyloidosis.
JACC Cardiovasc Imaging 2014;7:133–42.
92. Antoni G, Lubberink M, Estrada S, Axelsson J, Carlson K, Lindsjo L, et al. In
vivo visualization of amyloid deposits in the heart with 11C-PIB and PET. J
Nucl Med 2013;54:213–20.
93. Dorbala S, Vangala D, Semer J, Strader C, Bruyere JR, Di Carli MF, et al.
Imaging cardiac amyloidosis: a pilot study using (18)F-florbetapir positron
emission tomography. Eur J Nucl Med Mol Imaging 2014;41:1652–62.
94. Law WP, Wang WY, Moore PT, Mollee PN, Ng AC. Cardiac amyloid imaging
with 18F-florbetaben positron emission tomography: A pilot study. J Nucl
Med 2016;57:1733–9.
95. Lee SP, Lee ES, Choi H, Im HJ, Koh Y, Lee MH, et al. (11)C-Pittsburgh
B PET imaging in cardiac amyloidosis. JACC Cardiovasc Imaging
2015;8:50–9.
96. Osborne DR, Acuff SN, Stuckey A, Wall JS. A routine PET/CT protocol
with streamlined calculations for assessing cardiac amyloidosis using (18)
F-florbetapir. Front Cardiovasc Med 2015;2:23.
97. Nakata T, Shimamoto K, Yonekura S, Kobayashi N, Sugiyama T, Imai K, et
al. Cardiac sympathetic denervation in transthyretin-related familial amy-
loidotic polyneuropathy: detection with iodine-123-MIBG. J Nucl Med
1995;36:1040–2.
98. Tanaka M, Hongo M, Kinoshita O, Takabayashi Y, Fujii T, Yazaki Y, et al.
Iodine-123 metaiodobenzylguanidine scintigraphic assessment of myocar-
dial sympathetic innervation in patients with familial amyloid polyneuropa-
thy. J Am Coll Cardiol 1997;29:168–74.
99. Pepys MB, Dyck RF, de Beer FC, Skinner M, Cohen AS. Binding of
serum amyloid P-component (SAP) by amyloid fibrils. Clin Exp Immunol
1979;38:284–93.
100. Suhr OB, Lundgren E, Westermark P. One mutation, two distinct disease
variants: unravelling the impact of transthyretin amyloid fibril composition. J
Intern Med 2017;281:337–47.
101. Cappelli F, Gallini C, Di Mario C, Costanzo E N, Vaggelli L, Tutino F, et al. Accu-
racy of 99mTc-hydroxymethylene diphosphonate scintigraphy for diagno-
sis of transthyretin cardiac amyloidosis. J Nucl Cardiol 2019;26:497–504.
https://doi.org/10.1007/s12350-017-0922-z.
102. Galat A, Rosso J, Guellich A, Van Der Gucht A, Rappeneau S, Bodez D,
et al. Usefulness of (99m)Tc-HMDP scintigraphy for the etiologic diag-
nosis and prognosis of cardiac amyloidosis. Amyloid 2015;22:210–20.
https://doi.org/10.3109/13506129.2015.1072089.
103. Quarta CC, Guidalotti PL, Longhi S, Pettinato C, Leone O, Ferlini A, et
al. Defining the diagnosis in echocardiographically suspected senile
systemic amyloidosis. JACC Cardiovasc Imaging 2012;5:755–8.
https://doi.org/10.1016/j.jcmg.2012.02.015.
104. Rapezzi C, Guidalotti P, Salvi F, Riva L, Perugini E. Usefulness of 99mTc-
DPD scintigraphy in cardiac amyloidosis. J Am Coll Cardiol 2008;51:1509–
10. https://doi.org/10.1016/j.jacc.2007.12.038 author reply 1510.
105. Rapezzi C, Quarta CC, Guidalotti PL, Pettinato C, Fanti S, Leone O, et al.
Role of (99m)Tc-DPD scintigraphy in diagnosis and prognosis of heredi-
tary transthyretin-related cardiac amyloidosis. JACC Cardiovasc Imaging
2011;4:659–70. https://doi.org/10.1016/j.jcmg.2011.03.016.
Downloaded from http://ahajournals.org by on July 2, 2021

Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 27
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
106. Hutt DF, Quigley AM, Page J, Hall ML, Burniston M, Gopaul D, et al. Util-
ity and limitations of 3,3-diphosphono-1,2-propanodicarboxylic acid
scintigraphy in systemic amyloidosis. Eur Heart J Cardiovasc Imaging
2014;15:1289–98. https://doi.org/10.1093/ehjci/jeu107.
107. Haq M, Pawar S, Berk JL, Miller EJ, Ruberg FL. Can (99m)Tc-pyro-
phosphate aid in early detection of cardiac involvement in asymptomatic
variant TTR amyloidosis? JACC Cardiovasc Imaging 2017;10:713–4.
https://doi.org/10.1016/j.jcmg.2016.06.003.
108. Glaudemans AW, van Rheenen RW, van den Berg MP, Noordzij W, Koole M,
Blokzijl H, et al. Bone scintigraphy with (99m)technetium-hydroxymethylene
diphosphonate allows early diagnosis of cardiac involvement in patients
with transthyretin-derived systemic amyloidosis. Amyloid 2014;21:35–44.
https://doi.org/10.3109/13506129.2013.871250.
109. Hutt DF, Gilbertson J, Quigley AM, Wechalekar AD. (99m)Tc-DPD scin-
tigraphy as a novel imaging modality for identification of skeletal muscle
amyloid deposition in light-chain amyloidosis. Amyloid 2016;23:134–5.
https://doi.org/10.3109/13506129.2016.
110. Bach-Gansmo T, Wien TN, Londalen A, Halvorsen E. Myocardial uptake of
bone scintigraphic agents associated with increased pulmonary uptake.
Clin Physiol Funct Imaging 2016;36:237–41.
111. Treglia G, Glaudemans A, Bertagna F, Hazenberg BPC,
Erba PA, Giubbini R, et al. Diagnostic accuracy of bone scintigraphy in
the assessment of cardiac transthyretin-related amyloidosis: a bivari-
ate meta-analysis. Eur J Nucl Med Mol Imaging 2018;45:1945–55.
https://doi.org/10.1007/s00259-018-4013-4.
112. Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L, et al. Non-
invasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-di-
phosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol
2005;46:1076–84.
113. Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)
Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amy-
loidosis from the transthyretin-related familial and senile cardiac amyloido-
ses. Circ Cardiovasc Imaging 2013;6:195–201.
114. Castano A, Haq M, Narotsky DL, Goldsmith J, Weinberg RL, Morgenstern R,
et al. Multicenter study of planar technetium 99m pyrophosphate cardiac
imaging: Predicting survival for patients with ATTR cardiac amyloidosis. JAMA
Cardiol 2016;1:880–9. https://doi.org/10.1001/jamacardio.2016.2839.
115. Pilebro B, Arvidsson S, Lindqvist P, Sundstrom T, Westermark P, Antoni G,
et al. Positron emission tomography (PET) utilizing Pittsburgh compound
B (PIB) for detection of amyloid heart deposits in hereditary transthyretin
amyloidosis (ATTR). J Nucl Cardiol 2018;25:240–8.
116. Treibel TA, Fontana M, Gilbertson JA, Castelletti S,
White SK, Scully PR, et al. Occult transthyretin cardiac amyloid in severe
calcific aortic stenosis: Prevalence and prognosis in patients undergo-
ing surgical aortic valve replacement. Circ Cardiovasc Imaging 2016.
https://doi.org/10.1161/CIRCI MAGING.116.005066.
117. Longhi S, Lorenzini M, Gagliardi C, Milandri A, Marzocchi A, Marrozzini C, et
al. Coexistence of degenerative aortic stenosis and wild-type transthyretin-
related cardiac amyloidosis. JACC Cardiovasc Imaging 2016;9:325–7.
https://doi.org/10.1016/j.jcmg.2015.04.012.
118. Morgenstern R, Yeh R, Castano A, Maurer MS, Bokhari S. (18)Fluorine
sodium fluoride positron emission tomography, a potential biomarker of
transthyretin cardiac amyloidosis. J Nucl Cardiol 2018;25:1559–67.
https://doi.org/10.1007/s12350-017-0799-x.
119. Van Der Gucht A, Galat A, Rosso J, Guellich A, Garot J, Bodez D, et al.
18F]-NaF PET/CT imaging in cardiac amyloidosis. J Nucl Cardiol
2016;23:846–9.
120. Aprile C, Marinone G, Saponaro R, Bonino C, Merlini G. Cardiac and pleu-
ropulmonary AL amyloid imaging with technetium-99m labelled aprotinin.
Eur J Nucl Med 1995;22:1393–401.
121. Han S, Chong V, Murray T, McDonagh T, Hunter J, Poon FW, et al. Pre-
liminary experience of 99mTc-Aprotinin scintigraphy in amyloidosis. Eur J
Haematol 2007;79:494–500.
122. Schaadt BK, Hendel HW, Gimsing P, Jonsson V, Pedersen H, Hesse B.
99mTc-aprotinin scintigraphy in amyloidosis. J Nucl Med 2003;44:177–83.
123. Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis
by scintigraphy with 123I-labeled serum amyloid P component. N Engl J
Med 1990;323:508–13.
124. Minoshima S, Drzezga AE, Barthel H, Bohnen N, Djekidel M, Lewis DH, et
al. SNMM I procedure standard/EANM practice guideline for amyloid PET
imaging of the brain 1.0. J Nucl Med 2016;57:1316–22.
125. Sundaram GSM, Dhavale DD, Prior JL, Yan P, Cirrito J, Rath NP, et al.
Fluselenamyl: a novel benzoselenazole derivative for PET detection of
amyloid plaques (AÎ2) in Alzheimer’s disease. Sci Rep 2016;6:35636.
126. Wagner T, Page J, Burniston M, Skillen A, Ross JC, Manwani R, et al. Extracar-
diac (18)F-florbetapir imaging in patients with systemic amyloidosis: More
than hearts and minds. Eur J Nucl Med Mol Imaging 2018;45:1129–38.
127. Ezawa N, Katoh N, Oguchi K, Yoshinaga T, Yazaki M, Sekijima Y. Visualiza-
tion of multiple organ amyloid involvement in systemic amyloidosis using
(11)C-PiB PET imaging. Eur J Nucl Med Mol Imaging 2018;45:452–61.
https://doi.org/10.1007/s00259-017-3814-1.
128. Goldstein DS. Cardiac dysautonomia and survival in hereditary transthyre-
tin amyloidosis. JACC Cardiovasc Imaging 2016;9:1442–5.
129. Coutinho MC, Cortez-Dias N, Cantinho G, Conceicao I, Oliveira A,
Bordalo e Sa A, et al. Reduced myocardial 123-iodine metaiodobenzylgua-
nidine uptake: A prognostic marker in familial amyloid polyneuropathy. Circ
Cardiovasc Imaging 2013;6:627–36.
130. Delahaye N, Dinanian S, Slama MS, Mzabi H, Samuel D, Adams D, et
al. Cardiac sympathetic denervation in familial amyloid polyneuropathy
assessed by iodine-123 metaiodobenzylguanidine scintigraphy and heart
rate variability. Eur J Nucl Med 1999;26:416–24.
131. Algalarrondo V, Antonini T, Theaudin M, Chemla D, Benmalek A, Lacroix C,
et al. Cardiac dysautonomia predicts long-term survival in hereditary trans-
thyretin amyloidosis after liver transplantation. JACC Cardiovasc Imaging
2016;9:1432–41.
132. Pinney J H, Whelan CJ, Petrie A, Dungu J, Banypersad SM, Sattianayagam P,
et al. Senile systemic amyloidosis: Clinical features at presentation and out-
come. J Am Heart Assoc 2013;2:e000098.
133. Dingli D, Tan TS, Kumar SK, Buadi FK, Dispenzieri A, Hayman SR, et al.
Stem cell transplantation in patients with autonomic neuropathy due to
primary (AL) amyloidosis. Neurology 2010;74:913–8.
134. Wechalekar AD, Gillmore JD, Bird J, Cavenagh J, Hawkins S, Kazmi M,
et al. Guidelines on the management of AL amyloidosis. Br J Haematol
2015;168:186–206.
135. Noordzij W, Glaudemans AW, van Rheenen RW, Hazenberg BP, Tio RA,
Dierckx RA, et al. (123)I-Labelled metaiodobenzylguanidine for the evalu-
ation of cardiac sympathetic denervation in early stage amyloidosis. Eur J
Nucl Med Mol Imaging 2012;39:1609–17.
136. Piekarski E, Chequer R, Algalarrondo V, Eliahou L, Mahida B, Vigne J, et
al. Cardiac denervation evidenced by MIBG occurs earlier than amyloid
deposits detection by diphosphonate scintigraphy in TTR mutation carriers.
Eur J Nucl Med Mol Imaging 2018;45:1108–18.
137. Arbab AS, Koizumi K, Toyama K, Arai T, Yoshitomi T, Araki T. Scan findings
of various myocardial SPECT agents in a case of amyloid polyneuropathy
with suspected myocardial involvement. Ann Nucl Med 1997;11:139–41.
138. Delahaye N, Rouzet F, Sarda L, Tamas C, Dinanian S, Plante-Bordeneuve V,
et al. Impact of liver transplantation on cardiac autonomic denervation in
familial amyloid polyneuropathy. Medicine 2006;85:229–38.
139. Hongo M, Urushibata K, Kai R, Takahashi W, Koizumi T, Uchikawa S, et
al. Iodine-123 metaiodobenzylguanidine scintigraphic analysis of myocar-
dial sympathetic innervation in patients with AL (primary) amyloidosis. Am
Heart J 2002;144:122–9.
140. Lekakis J, Dimopoulos MA, Prassopoulos V, Mavrikakis M, Gerali S,
Sifakis N, et al. Myocardial adrenergic denervation in patients with primary
(AL) amyloidosis. Amyloid 2003;10:117–20.
141. Watanabe H, Misu K, Hirayama M, Hattori N, Yoshihara T, Doyu M, et al.
Low cardiac 123I-MIBG uptake in late-onset familial amyloid polyneuropa-
thy type I (TTR Met30). J Neurol 2001;248:627–9.
142. Migrino RQ, Truran S, Gutterman DD, Franco DA, Bright M,
Schlundt B, et al. Human microvascular dysfunction and apoptotic injury
induced by AL amyloidosis light chain proteins. J Physiol Heart Circ Physiol
2011;301:H2305–12.
143. Modesto KM, Dispenzieri A, Gertz M, Cauduro SA, Khandheria BK,
Seward JB, et al. Vascular abnormalities in primary amyloidosis. Eur Heart
J 2007;28:1019–24.
144. Al Suwaidi J, Velianou JL, Gertz MA, Cannon RO 3rd, Higano ST,
Holmes DR Jr, et al. Systemic amyloidosis presenting with angina pectoris.
Ann Intern Med 1999;131:838–41.
145. Dorbala S, Vangala D, Bruyere J Jr, Quarta C, Kruger J, Padera R, et al.
Coronary microvascular dysfunction is related to abnormalities in myo-
cardial structure and function in cardiac amyloidosis. JACC Heart Fail
2014;2:358–67.
146. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circula-
tion 2005;112:2047–60.
147. Barros- Gomes S, Williams B, Nhola LF, Grogan M, Maalouf JF, Dispenzieri A,
et al. Prognosis of light chain amyloidosis with preserved LVEF: Added
value of 2D speckle-tracking echocardiography to the current prognostic
staging system. JACC Cardiovasc Imaging 2017;10:398–407.
Downloaded from http://ahajournals.org by on July 2, 2021

Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 28
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
148. Bodez D, Ternacle J, Guellich A, Galat A, Lim P, Radu C, et al. Prognostic
value of right ventricular systolic function in cardiac amyloidosis. Amyloid
2016;23:158–67.
149. Cappelli F, Porciani MC, Bergesio F, Perlini S, Attana P, Moggi Pignone A,
et al. Right ventricular function in AL amyloidosis: Characteristics and prog-
nostic implication. Eur Heart J Cardiovasc Imaging 2012;13:416–22.
150. Damy T, Jaccard A, Guellich A, Lavergne D, Galat A, Deux JF, et al. Identi-
fication of prognostic markers in transthyretin and AL cardiac amyloidosis.
Amyloid 2016;23:194–202.
151. Hu K, Liu D, Nordbeck P, Cikes M, Stork S, Kramer B, et al. Impact of
monitoring longitudinal systolic strain changes during serial echocardiogra-
phy on outcome in patients with AL amyloidosis. Int J Cardiovasc Imaging
2015;31:1401–12.
152. Koyama J, Falk RH. Prognostic significance of strain Doppler imaging in
light-chain amyloidosis. JACC Cardiovasc Imaging 2010;3:333–42.
153. Koyama J, Ray-Sequin PA, Falk RH. Prognostic significance of ultrasound
myocardial tissue characterization in patients with cardiac amyloidosis. Cir-
culation 2002;106:556–61.
154. Kristen AV, Scherer K, Buss S, aus dem Siepen F, Haufe S, Bauer R, et
al. Noninvasive risk stratification of patients with transthyretin amyloidosis.
JACC Cardiovasc Imaging 2014;7:502–10.
155. Liu D, Hu K, Herrmann S, Cikes M, Ertl G, Weidemann F, et al. Value of tissue
Doppler-derived Tei index and two-dimensional speckle tracking imaging
derived longitudinal strain on predicting outcome of patients with light-
chain cardiac amyloidosis. Int J Cardiovasc Imaging 2017;33:837–45.
156. Liu D, Hu K, Stork S, Herrmann S, Kramer B, Cikes M, et al. Predictive value
of assessing diastolic strain rate on survival in cardiac amyloidosis patients
with preserved ejection fraction. PloS ONE 2014;9:e115910.
157. Migrino RQ, Harmann L, Christenson R, Hari P. Clinical and imaging predic-
tors of 1-year and long-term mortality in light chain (AL) amyloidosis: A
5-year follow-up study. Heart Vessel 2014;29:793–800.
158. Mohty D, Petitalot V, Magne J, Fadel BM, Boulogne C, Rouabhia D, et al.
Left atrial function in patients with light chain amyloidosis: A transthoracic
3D speckle tracking imaging study. J Cardiol 2018;71:419–27.
159. Mohty D, Pibarot P, Dumesnil JG, Darodes N, Lavergne D, Echahidi N, et
al. Left atrial size is an independent predictor of overall survival in patients
with primary systemic amyloidosis. Arch Cardiovasc Dis 2011;104:611–8.
160. Mohty D, Pradel S, Magne J, Fadel B, Boulogne C, Petitalot V, et al. Preva-
lence and prognostic impact of left-sided valve thickening in systemic light-
chain amyloidosis. Clin Res Cardiol 2017;106:331–40.
161. Ochs MM, Riffel J, Kristen AV, Hegenbart U, Schonland S, Hardt SE, et al.
Anterior aortic plane systolic excursion: A novel indicator of transplant-
free survival in systemic light-chain amyloidosis. J Am Soc Echocardiogr
2016;29:1188–96.
162. Riffel JH, Mereles D, Emami M, Korosoglou G, Kristen AV, Aurich M, et
al. Prognostic significance of semiautomatic quantification of left ven-
tricular long axis shortening in systemic light-chain amyloidosis. Amyloid
2015;22:45–53.
163. Senapati A, Sperry BW, Grodin JL, Kusunose K, Thavendiranathan P,
Jaber W, et al. Prognostic implication of relative regional strain ratio in
cardiac amyloidosis. Heart 2016;102:748–54.
164. Siepen FAD, Bauer R, Voss A, Hein S, Aurich M, Riffel J, et al. Predictors
of survival stratification in patients with wild-type cardiac amyloidosis. Clin
Res Cardiol 2018;107:158–69.
165. Tei C, Dujardin KS, Hodge DO, Kyle RA, Tajik AJ, Seward JB. Doppler index
combining systolic and diastolic myocardial performance: Clinical value in
cardiac amyloidosis. J Am Coll Cardiol 1996;28:658–64.
166. Kwong RY, Jerosch-Herold M. CMR and amyloid cardiomyopathy: Are we
getting closer to the biology? JACC Cardiovasc Imaging 2014;7:166–8.
167. Mekinian A, Lions C, Leleu X, Duhamel A, Lamblin N, Coiteux V, et al. Prog-
nosis assessment of cardiac involvement in systemic AL amyloidosis by
magnetic resonance imaging. Am J Med 2010;123:864–8.
168. Kellman P, Arai AE, McVeigh ER, Aletras AH. Phase-sensitive inversion
recovery for detecting myocardial infarction using gadolinium-delayed
hyperenhancement. Magn Reson Med 2002;47:372–83.
169. Fontana M, Treibel TA, Martinez-Naharro A, Rosmini S, Kwong RY,
Gillmore JD, et al. A case report in cardiovascular magnetic resonance:
The contrast agent matters in amyloid. BMC Med Imaging 2017;17:3.
170. Raina S, Lensing SY, Nairooz RS, Pothineni NV, Hakeem A, Bhatti S, et al.
Prognostic value of late gadolinium enhancement CMR in systemic amy-
loidosis. JACC Cardiovasc Imaging 2016;9:1267–77.
171. Banypersad SM, Fontana M, Maestrini V, Sado DM, Captur G, Petrie A, et
al. T1 mapping and survival in systemic light-chain amyloidosis. Eur Heart
J 2015;36:244–51.
172. Martinez-Naharro A, Treibel TA, Abdel-Gadir A, Bulluck H, Zumbo G,
Knight DS, et al. Magnetic resonance in transthyretin cardiac amyloidosis.
J Am Coll Cardiol 2017;70:466–77.
173. Castano A, Haq M, Narotsky DL, Goldsmith J, Weinberg RL,
Morgenstern R, et al. Multicenter study of planar technetium 99m pyro-
phosphate cardiac imaging. JAMA Cardiol 2016;1:880–9. https://doi.org/
10.1001/jamacardio.2016.2839.
174. Kristen AV, Haufe S, Schonland SO, Hegenbart U, Schnabel PA,
Rocken C, et al. Skeletal scintigraphy indicates disease severity of car-
diac involvement in patients with senile systemic amyloidosis. Int J Cardiol
2013;164:179–84.
175. Vranian MN, Sperry BW, Hanna M, Hachamovitch R, Ikram A, Brunken RC,
et al. Technetium pyrophosphate uptake in transthyretin cardiac amyloido-
sis: Associations with echocardiographic disease severity and outcomes. J
Nucl Cardiol 2017. https://doi.org/10.1007/s12350-016-0768-9b.
176. Sperry BW, Tamarappoo BK, Oldan JD, Javed O, Culver DA, Brunken R, et al.
Prognostic impact of extent, severity, and heterogeneity of abnormalities on
(18)F-FDG PET scans for suspected cardiac sarcoidosis. JACC Cardiovasc
Imaging 2018;11:336–45. https://doi.org/10.1016/j.jcmg.2017.04.020.
177. Merlini G, Lousada I, Ando Y, Dispenzieri A, Gertz MA, Grogan M, et al.
Rationale, application and clinical qualification for NT-proBNP as a sur-
rogate end point in pivotal clinical trials in patients with AL amyloidosis.
Leukemia 2016;30:1979–86.
178. Fitzgerald BT, Bashford J, Newbigin K, Scalia GM. Regression of cardiac
amyloidosis following stem cell transplantation: A comparison between
echocardiography and cardiac magnetic resonance imaging in long-term
survivors. Int J Cardiol Heart Vasc 2017;14:53–7.
179. Dubrey SW, Burke M M, Khaghani A, Hawkins PN, Yacoub M H, Banner NR.
Long term results of heart transplantation in patients with amyloid heart
disease. Heart 2001;85:202–7.
180. Liepnieks JJ, Benson MD. Progression of cardiac amyloid deposition in
hereditary transthyretin amyloidosis patients after liver transplantation.
Amyloid 2007;14:277–82.
181. Okamoto S, Zhao Y, Lindqvist P, Backman C, Ericzon BG,
Wijayatunga P, et al. Development of cardiomyopathy after liver transplan-
tation in Swedish hereditary transthyretin amyloidosis (ATTR) patients.
Amyloid 2011;18:200–5.
182. Olofsson BO, Backman C, Karp K, Suhr OB. Progression of cardiomyopa-
thy after liver transplantation in patients with familial amyloidotic polyneu-
ropathy, Portuguese type. Transplantation 2002;73:745–51.
183. Comenzo RL, Vosburgh E, Falk RH, Sanchorawala V, Reisinger J, Dubrey S,
et al. Dose-intensive melphalan with blood stem-cell support for the treat-
ment of AL (amyloid light-chain) amyloidosis: Survival and responses in 25
patients. Blood 1998;91:3662–70.
184. Patel MR, White RD, Abbara S, Bluemke DA, Herfkens RJ, Picard M, et
al. 2013 ACCF/ACR/ASE/ASNC/SCCT/SCMR appropriate utilization of
cardiovascular imaging in heart failure: A joint report of the American Col-
lege of Radiology Appropriateness Criteria Committee and the American
College of Cardiology Foundation Appropriate Use Criteria Task Force. J
Am Coll Cardiol 2013;61:2207–31.
185. Castaño A, DeLuca A, Weinberg R, Pozniakoff T, Blaner WS, Pirmohamed A,
et al. Serial scanning with technetium pyrophosphate ((99m)Tc-PYP) in
advanced ATTR cardiac amyloidosis. J Nucl Cardiol 2016;23:1355–63.
186. Azevedo Coutinho MDC, Cortez-Dias N, Cantinho G, Conceicao I,
Guimaraes T, Lima da Silva G, et al. Progression of myocardial sympa-
thetic denervation assessed by (123)I-MIBG imaging in familial amyloid
polyneuropathy and the effect of liver transplantation. Rev Port Cardiol
2017;36:333–40.
187. Lin G, Dispenzieri A, Kyle R, Grogan M, Brady PA. Implantable cardioverter
defibrillators in patients with cardiac amyloidosis. J Cardiovasc Electro-
physiol 2013;24:793–8.
188. Varr BC, Zarafshar S, Coakley T, Liedtke M, Lafayette RA, Arai S, et al.
Implantable cardioverter-defibrillator placement in patients with cardiac
amyloidosis. Heart Rhythm 2014;11:158–62.
189. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al.
Recommendations for cardiac chamber quantification by echocardiogra-
phy in adults: An update from the American Society of Echocardiography
and the European Association of Cardiovascular Imaging. Eur Heart J Car-
diovasc Imaging 2015;16:233–70.
190. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD,
Chandrasekaran K, et al. Guidelines for the echocardiographic assess-
ment of the right heart in adults: A report from the American Society of
Echocardiography endorsed by the European Association of Echocar-
diography, a registered branch of the European Society of Cardiology,
Downloaded from http://ahajournals.org by on July 2, 2021

Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 29
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
and the Canadian Society of Echocardiography. J Am Soc Echocardiogr
2010;23:685–713(quiz 86–8).
191. Cianciulli TF, Saccheri MC, Lax JA, Bermann AM, Ferreiro DE. Two-dimen-
sional speckle tracking echocardiography for the assessment of atrial
function. World J Cardiol 2010;2:163–70.
192. Kowallick JT, Lotz J, Hasenfuss G, Schuster A. Left atrial physiol-
ogy and pathophysiology: Role of deformation imaging. World J Cardiol
2015;7:299–305.
193. Mor-Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G,
et al. Current and evolving echocardiographic techniques for the quantita-
tive evaluation of cardiac mechanics: ASE/EAE consensus statement on
methodology and indications endorsed by the Japanese Society of Echo-
cardiography. J Am Soc Echocardiogr 2011;24:277–313.
194. Voigt JU, Pedrizzetti G, Lysyansky P, Marwick TH, Houle H, Baumann R,
et al. Definitions for a common standard for 2D speckle tracking echo-
cardiography: Consensus document of the EACVI/ASE/Industry Task
Force to standardize deformation imaging. J Am Soc Echocardiogr
2015;28:183–93.
195. Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E, Society for Cardio-
vascular Magnetic Resonance Board of Trustees Task Force on Standard-
ized P. Standardized cardiovascular magnetic resonance (CMR) protocols
2013 update. J Cardiovasc Magn Reson 2013;15:91.
196. Moon JC, Messroghli DR, Kellman P, Piechnik SK, Robson MD, Ugander M,
et al. Myocardial T1 mapping and extracellular volume quantification: A
Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Work-
ing Group of the European Society of Cardiology consensus statement. J
Cardiovasc Magn Reson 2013;15:92.
197. Zumbo G, Barton SV, Thompson D, Sun M, Abdel-Gadir A, Treibel TA, et
al. Extracellular volume with bolus-only technique in amyloidosis patients:
Diagnostic accuracy, correlation with other clinical cardiac measures, and
ability to track changes in amyloid load over time. J Magn Reson Imaging
2018;47:1677–84.
198. Neilan TG, Coelho-Filho OR, Shah RV, Abbasi SA, Heydari B, Watanabe E,
et al. Myocardial extracellular volume fraction from T1 measurements in
healthy volunteers and mice: Relationship to aging and cardiac dimensions.
JACC Cardiovasc Imaging 2013;6:672–83.
199. Flett AS, Hayward MP, Ashworth MT, Hansen MS, Taylor AM, Elliott PM, et
al. Equilibrium contrast cardiovascular magnetic resonance for the mea-
surement of diffuse myocardial fibrosis: Preliminary validation in humans.
Circulation 2010;122:138–44.
200. Treibel TA, Fontana M, Maestrini V, Castelletti S, Rosmini S, Simpson J, et al.
Automatic measurement of the myocardial interstitium: Synthetic extracel-
lular volume quantification without hematocrit sampling. JACC Cardiovasc
Imaging 2016;9:54–63.
201. Li R, Yang ZG, Wen LY, Liu X, Xu HY, Zhang Q, et al. Regional myocar-
dial microvascular dysfunction in cardiac amyloid light-chain amyloidosis:
Assessment with 3T cardiovascular magnetic resonance. J Cardiovasc
Magn Reson 2016;18:16.
202. Flotats A, Carrio I, Agostini D, Le Guludec D, Marcassa C, Schafers M, et
al. Proposal for standardization of 123I-metaiodobenzylguanidine (MIBG)
cardiac sympathetic imaging by the EANM Cardiovascular Committee and
the European Council of Nuclear Cardiology. Eur J Nucl Med Mol Imaging
2010;37:1802–12.
203. Inoue Y, Abe Y, Kikuchi K, Matsunaga K, Masuda R, Nishiyama K. Correc-
tion of collimator-dependent differences in the heart-to-mediastinum ratio
in (123)I-metaiodobenzylguanidine cardiac sympathetic imaging: Determi-
nation of conversion equations using point-source imaging. J Nucl Cardiol
2017;24:1725–36.
204. Nakajima K, Matsumoto N, Kasai T, Matsuo S, Kiso K, Okuda K. Normal
values and standardization of parameters in nuclear cardiology: Japanese
Society of Nuclear Medicine working group database. Ann Nucl Med
2016;30:188–99. https://doi.org/10.1007/s12149-016-1065-z.
205. Kawel N, Turkbey EB, Carr JJ, Eng J, Gomes AS, Hundley WG, et al. Normal
left ventricular myocardial thickness for middle-aged and older subjects
with steady-state free precession cardiac magnetic resonance: The multi-
ethnic study of atherosclerosis. Circ Cardiovasc Imaging 2012;5:500–8.
https://doi.org/10.1161/CIRCI MAGING.112.973560.
206. Kawel-Boehm N, Maceira A, Valsangiacomo-Buechel ER, Vogel-Claussen J,
Turkbey EB, Williams R, et al. Normal values for cardiovascular magnetic
resonance in adults and children. J Cardiovasc Magn Reson 2015;17:29.
207. Dorbala S, Bokhari S, Miller E, Bullock-Palmer R, Soman P, Thompson R.
ASNC Practice Points: 99mTechnetium-pyrophosphate imaging for trans-
thyretin cardiac amyloidosis. Released February 27, 2019. https://www.
asnc.org/files/19110%20ASNC%20Amyloid%20Practice%20
Points%20WEB(2).pdf.
208. Kristen AV, Perz JB, Schonland SO, Hansen A, Hegenbart U, Sack FU, et
al. Rapid progression of left ventricular wall thickness predicts mortality in
cardiac light-chain amyloidosis. J Heart Lung Transplant 2007;26:1313–9.
209. Maceira AM, Prasad SK, Hawkins PN, Roughton M, Pennell DJ. Cardiovas-
cular magnetic resonance and prognosis in cardiac amyloidosis. J Cardio-
vasc Magn Reson 2008;10:54.
210. Migrino RQ, Christenson R, Szabo A, Bright M, Truran S, Hari P. Prognostic
implication of late gadolinium enhancement on cardiac MRI in light chain
(AL) amyloidosis on long term follow up. BMC Med Phys 2009;9:5.
211. Lin L, Li X, Feng J, Shen KN, Tian Z, Sun J, et al. The prognostic value of
T1 mapping and late gadolinium enhancement cardiovascular magnetic
resonance imaging in patients with light chain amyloidosis. J Cardiovasc
Magn Reson 2018;20:2.
212. Lee VW, Caldarone AG, Falk RH, Rubinow A, Cohen AS. Amyloidosis of
heart and liver: comparison of Tc-99m pyrophosphate and Tc-99m methy-
lene diphosphonate for detection. Radiology 1983;148:239–42.
213. Eriksson P, Backman C, Bjerle P, Eriksson A, Holm S, Olofsson BO. Non-
invasive assessment of the presence and severity of cardiac amyloidosis. A
study in familial amyloidosis with polyneuropathy by cross sectional echo-
cardiography and technetium-99m pyrophosphate scintigraphy. Br Heart J
1984;52:321–6.
214. Leinonen H, Totterman KJ, Korppi-Tommola T, Korhola O. Negative myo-
cardial technetium-99m pyrophosphate scintigraphy in amyloid heart
disease associated with type AA systemic amyloidosis. Am J Cardiol
1984;53:380–1.
215. Falk RH, Lee VW, Rubinow A, Skinner M, Cohen AS. Cardiac technetium-
99m pyrophosphate scintigraphy in familial amyloidosis. Am Heart J
1984;54:1150–1.
216. Hongo M, Hirayama J, Fujii T, Yamada H, Okubo S, Kusama S, et al. Early
identification of amyloid heart disease by technetium-99m-pyrophosphate
scintigraphy: A study with familial amyloid polyneuropathy. Am Heart J
1987;113:654–62.
217. Goldstein SA, Lindsay J Jr, Chandeysson PL, Nolan NG. Usefulness of
technetium pyrophosphate scintigraphy in demonstrating cardiac amyloi-
dosis in persons aged 85 years and older. Am J Cardiol 1989;63:752–3.
218. Fournier C, Grimon G, Rinaldi JP, et al. Usefulness of technetium-99m
pyrophosphate myocardial scintigraphy in amyloid polyneuropathy and cor-
relation with echocardiography. Am J Cardiol 1993;72:854–7.
219. Puille M, Altland K, Linke RP, Steen-Müller MK, Kiett R, Steiner D, et al.
99mTc-DPD scintigraphy in transthyretin-related familial amyloidotic poly-
neuropathy. Eur J Nucl Med Mol Imaging 2002;29:376–9.
220. Rapezzi C, Quarta CC, Guidalotti PL, Longhi S, Pettinato C, Leone A, et al.
Usefulness and limitations of 99mTc-3,3-diphosphono-1,2-propanodicar-
boxylic acid scintigraphy in the aetiological diagnosis of amyloidotic car-
diomyopathy. Eur J Nucl Med Mol Imaging 2011;38:470–8.
221. de Haro-del Moral FJ, Sanchez-Lajusticia A, Gomez-Bueno M,
Garcia-Pavia P, Salas-Anton C, Segovia-Cubero J. Role of cardiac scintig-
raphy with 99mTc-DPD in the differentiation of cardiac amyloidosis sub-
type. Rev Esp Cardiol (Engl Ed) 2012;65:440–6.
222. Ferreira SG, Rocha AM, Moreira do Nascimento OJ, Mesquita CT. Role of
99mTc-DPD scintigraphy on discrimination of familial cardiac amyloidosis.
Int J Cardiol 2016;203:885–7.
223. Pilebro B, Suhr OB, Naslund U, Westermark P, Lindqvist P, Sundstrom T.
(99m)Tc-DPD uptake reflects amyloid fibril composition in hereditary trans-
thyretin amyloidosis. Ups J Med Sci 2016;121:17–24.
224. Abulizi M, Cottereau AS, Guellich A, Vandeventer S,
Galat A, Van Der Gucht A, et al. Early-phase myocardial uptake inten-
sity of 99mTc-HMDP vs 99mTc-DPD in patients with hereditary trans-
thyretin-related cardiac amyloidosis. J Nucl Cardiol 2018;25:217–22.
https://doi.org/10.1007/s12350-016-0707-9.
225. Galat A, Van der Gucht A, Guellich A, Bodez D, Cottereau AS, Guendouz S,
et al. Early phase 99Tc-HMDP scintigraphy for the diagnosis and typ-
ing of cardiac amyloidosis. JACC Cardiovasc Imaging 2017;10:601–3.
https://doi.org/10.1016/j.jcmg.2016.05.007.
226. Van Der Gucht A, Cottereau AS, Abulizi M, Guellich A, Blanc-Durand P,
Israel JM, et al. Apical sparing pattern of left ventricular myocardial (99m)
Tc-HMDP uptake in patients with transthyretin cardiac amyloidosis. J
Nucl Cardiol 2018;25:2072–9. https://doi.org/10.1007/s12350-017-
0894-z.
227. Moore PT, Burrage MK, Mackenzie E, Law WP, Korczyk D, Mollee P. The
utility of (99m)Tc-DPD scintigraphy in the diagnosis of cardiac amyloidosis:
An Australian experience. Heart Lung Circ 2017;26:1183–90.
228. Longhi S, Guidalotti PL, Quarta CC, Gagliardi C, Milandri A, Lorenzini M, et
al. Identification of TTR-related subclinical amyloidosis with 99mTc-DPD
scintigraphy. JACC Cardiovasc Imaging 2014;7:531–2.
Downloaded from http://ahajournals.org by on July 2, 2021

Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 30
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
229. Galat A, Guellich A, Bodez D, Slama M, Dijos M, Zeitoun DM, et al. Aortic
stenosis and transthyretin cardiac amyloidosis: the chicken or the egg? Eur
Heart J 2016;37:3525–31. https://doi.org/10.1093/eurheartj/ehw033.
230. Sperry BW, Vranian MN, Tower-Rader A, Hachamovitch R, Hanna M,
Brunken R, et al. Regional variation in technetium pyrophosphate uptake in
transthyretin cardiac amyloidosis and impact on mortality. JACC Cardiovasc
Imaging 2018;11:234–42. https://doi.org/10.1016/j.jcmg.2017.06.020.
231. Delahaye N, Le Guludec D, Dinanian S, Delforge J, Slama MS, Sarda L,
et al. Myocardial muscarinic receptor upregulation and normal response
to isoproterenol in denervated hearts by familial amyloid polyneuropathy.
Circulation 2001;104:2911–26.
232. Coutinho CA, Conceicao I, Almeida A, Cantinho G, Sargento L,
Vagueiro MC. Early detection of sympathetic myocardial denervation in
patients with familial amyloid polyneuropathy type I. Rev Port Cardiol
2004;23:201–11.
233. Algalarrondo V, Eliahou L, Thierry I, Bouzeman A, Dasoveanu M,
Sebag C, et al. Circadian rhythm of blood pressure reflects the severity of
cardiac impairment in familial amyloid polyneuropathy. Arch Cardiovasc Dis
2012;105:281–90.
234. Takahashi R, Ono K, Shibata S, Nakamura K, Komatsu J, Ikeda Y, et al. Effi-
cacy of diflunisal on autonomic dysfunction of late-onset familial amyloid
polyneuropathy (TTR Val30Met) in a Japanese endemic area. J Neurol Sci
2014;345:231–5. https://doi.org/10.1016/j.jns.2014.07.017.
235. Henzlova MJ, Duvall WL, Einstein AJ, Travin MI, Verberne HJ. ASNC imag-
ing guidelines for SPECT nuclear cardiology procedures: Stress, protocols,
and tracers. J Nucl Cardiol 2016;23:606–39.
236. Dorbala S, Ando Y, Bokhari S, Dispenzieri A, Falk RH, Ferrari VA, et al.
ASNC/AHA/ASE/EAN M/HFSA/ISA/SCMR/SNMMI expert consensus
recommendations for multimodality imaging in cardiac amyloidosis: part 1
of 2—evidence base and standardized methods of imaging. J Nucl Cardiol
2019;26:2065–2123. https://doi.org/10.1007/s12350-019-01760-6
237. Sperry BW, Burgett E, Bybee KA, McGhie AI, O’Keefe JH, Saeed IM, et
al. Technetium pyrophosphate nuclear scintigraphy for cardiac amyloi-
dosis: Imaging at 1 vs 3 hours and planar vs SPECT/CT. J Nucl Cardiol
2020;27:1802–7. https://doi.org/10.1007/s12350-020-02139-8
238. Masri A, Bukhari S, Ahmad S, Nieves R, Eisele YS, Follansbee W, et al.
Efficient 1-hour technetium-99m pyrophosphate imaging protocol for the
diagnosis of transthyretin cardiac amyloidosis. Circ Cardiovasc Imaging
2020;13:e010249. https://doi.org/10.1161/CIRCIMAGING.119.010249
239. Tamarappoo B, Otaki Y, Manabe O, Hyun M, Cantu S, Arnson Y, et al.
Simultaneous Tc-99m PYP/Tl-201 dual-isotope SPECT myocardial
imaging in patients with suspected cardiac amyloidosis. J Nucl Cardiol
2020;27:28–37.
240. Manrique A, Dudoignon D, Brun S, N’Ganoa C, Cassol E, Legallois D, et al.
Quantification of myocardial (99m)Tc-labeled bisphosphonate uptake with
cadmium zinc telluride camera in patients with transthyretin-related cardiac
amyloidosis. EJNMMI Res 2019;9:117.
241. Dorbala S, Ando Y, Bokhari S, Dispenzieri A, Falk RH, Ferrari VA, et al.
ASNC/AHA/ASE/EAN M/HFSA/ISA/SCMR/SNMMI expert consensus
recommendations for multimodality imaging in cardiac amyloidosis: part 2
of 2—diagnostic criteria and appropriate utilization, Circ Cardiovasc Imaging
2021;14:e000030. https://doi.org/10.1161/HCI.0000000000000030
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 31
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 7. Key Literature Summarizing the Utility of Echocardiography for Risk Assessment in Cardiac Amyloidosis
First Author Year
N
Patients
N
Controls Design
Follow-Up
Period
(Months) Outcome
Event Rate (An-
nualized)
Hazard
Ratio Comments
Left ventricle
Mohty160 2017 63 87 Retrospective 24 (range
0–216)
All-cause mortality Year 1: 31% 2.29 Left-sided valve time
thickening
Siepen164 2018 191 0 Retrospective 26.2±1.7 All-cause mortality Year 1: 3.7% 0. 173 MAPSE ≤8.8 mm
Liu156 2014 41 21 Retrospective 16 (quartiles
5–35)
All-cause mortality Year 1: 33% 7. 5 Longitudinal early dia-
stolic strain rate Cut-off
0.85
Barros-
Gomes147
2017 63 87 Retrospective 40.8 (31.2–
51.6)
All-cause mortality Year 1: 11% 4.71 GLSGE ≥14.81%
Ochs161 2016 36 53 Retrospective 12 Transplant-free
survival
Year 1: 36% 0.66 AAPSE <5 mm
Senapati163 2016 49 48 Retrospective 21.2
(quartiles
5.7–34.3)
All-cause mortality
or heart transplan-
tation
Year 1: 31% 2.45 RRSR ≥1.19; 59 AL,
38 ATTR
Tendler65 2015 36
AL 34
ATTR 32
22 Retrospective 22.3±21.4 Event-free survival Year 1: 45% 2.841
AL 3.39
ATTR1.26
MCF <30, AL and
ATTR
Riffel162 2015 50 70 Retrospective 12 All-cause mortality
or heart transplan-
tation
Year 1: 42% 0.67 Long axis shortening
≥5.8
Hu151 2015 8 16 Retrospective 16 (7.3–
15.7)
All-cause mortality 67% during
follow-up
5.47 LSsys >3%
Liu155 2017 19 39 Retrospective 12 All-cause mortality Year 1: 21% 8.48 Tei index ≥0.9
Perlini92014 221 121 Retrospective 18.4 All-cause mortality n. a. x2 58.2 Midwall fractional short-
ening ≤12.04%
Migrino157 2014 27 15 Prospective 60 months All-cause mortality Year 1: 40.9% 5.07 Left ventricular ejection
time ≤240 ms
Bellavia59 2011 23 28 Prospective 3 4 (0.9–64) All-cause mortality 32% during
follow-up
6.5 Vk II–III or the Vk VI
gene family vs Vk or Vλ-
I families
Koyama152 2010 70 49 Prospective 6.2±4.5 All-cause mortality Year 1: not giv-
en(26.9% during
follow-up)
Basal systolic strain
strain ≤13%
Kristen208 2007 17 22 Retrospective 24.7±3.1 All-cause mort ality
and heart transplant
Year-1: 27.9% n.a. Progression of LV wall
thickness <0.2mm/month
Koyama153 2002 133 75 Retrospective 10.2±5.2 All-cause n.a. 25.6 CV-IB ≤5.35 dB
Tei 153 1996 45 45 Retrospective 3 6 months All-cause mortality n.a. Chi square
4.6
Tei index ≤0.77
Cueto- Garcia50 1985 71 44 Retrospective n.a. All-cause mortality CHF 83% no
CHF 41%
n.a. CHF
Left atrium
Mohty160 2017 77 39 Prospective 19±10 (IQR
9–26)
All-cause mortality 8 0±5 0.94 3D positive atrial longi-
tudinal strain >14%
Mohty159 2011 53 58 Retrospective 33.6±34.8 All-cause mortality Year 1: 28.9% 2.47 AL
Right ventricle
Bodez148 2016 82 47 Prospective 8 (2–16) Death, heart trans-
plant, acute heart
failure
Year 1: 16.3% 0.85 TAPSE ≥14 mm
Bellavia70 2012 47 59 Prospective 53 (0.6–75) All-cause mortality Year 1: 49% 1.3 Strain rate of the RV
free wall middle seg-
ment ≥- 1.37/s
Cappelli149 2012 52 31 Prospective 19±12 (me-
dian 20)
Cardiac death Year 1: 11.5%
(missing values
not mentioned
1.128 RV longitudinal strain
>9%
Other Damy150 2016 84 149 Reprospective 17 (6–35) All-cause mortality Year 2: 53% (AL)
58% (ATTRwt)
28% (ATTRv)
2.25 Pericardial effusion
AL, light-chain amyloidosis; ATTR, transthyretin amyloidosis; ATTRv, amyloidosis due to transthyretin gene mutations, ATTRwt, amyloidosis due to deposition of wild-type trans-
thyretin (senile amyloidosis); AAPSE, anterior aortic plane systolic excursion; CV-1B, cyclic variation of integrated back scatter; CHF, congestive heart failure; GLS, global longitudinal
strain; LV, left ventricular; LSsys, longitudinal strain; GLSGE, global longitudinal strain; MCF, myocardial contraction fraction; MAPSE, mitral annular plane systolic excursion; n.a., not
available; N number; RV, right ventricular; RRSR, relative regional strain ratio; TAPSE, tricuspid annular plane systolic excursion.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 32
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 8. Key Literature Summarizing the Diagnostic Value of CMR for Cardiac Amyloidosis
First
Author Year
N
Patients
N
Controls Patient Cohort
ATT R /
AL Method Criterion Sensitivity Specificity Comments
Maceira74 2005 30 16 Systemic (extracar-
diac) amyloidosis con-
firmed by non-cardiac
histology and cardiac
involvement by Echo-
cardiographic criteria
AL/
ATTR
LGE, T1
mapping
at 4 min-
utes after
contrast
Subendocar-
dium-blood
T1 difference
of 191 ms at
4 minutes af-
ter injection
90% 87% Limitations of a
cohort controlled
study, small
sample size, and
selection bias
Vogels-
berg77
2008 33 0 Suspected cardiac
amyloidosis patients
referred for to undergo
both endomyocardial
biopsy and CMR
Did
not
specify
LGE Diffuse sub-
endocardial
LGE involve-
ment
80% 94% Small sample
size and selection
bias
Austin81 2009 47 0 Suspected cardiac
amyloidosis patients
AL/
ATTR
LGE Diffuse sub-
endocardial
LGE involve-
ment
88% 90% LGE more ac-
curate than ECG
and TTE param-
eters combined
Ruberg80 2009 28 0 Systemic (extracar-
diac) AL amyloidosis
patients with variable
cardiac involvement
AL LGE Presence
and size of
LGE (6 SD
threshold)
86% 86%
Syed78 2010 120 0 Systemic (extracar-
diac) AL amyloidosis
confirmed either by
cardiac histology
(n=35) or monoclonal
protein/plasma cell ab-
normalities (n=85)
AL/
ATTR
LGE Any LGE ab-
normality
Cardiac
histology
group:
LGE sensi-
tivity 97%
in detect-
ing CA by
EMB
NA Non-cardiac
histology group:
LGE abnormality
more prevalent
than echocardio-
graphic criteria
of CA (69% vs
58%)
Karamitsos82 2013 53 53 (36
normal
and 17
pts with
aortic
stenosis)
Systemic (extracar-
diac) AL amyloidosis
patients with variable
cardiac involvement
AL Native T1
mapping
(ShMOLLI)
Native T1
value 1020
ms
92% 91%
White79 2014 90 64 pts
with
HHD
Suspected cardiac
amyloidosis patients
AL/
ATTR
Visual T1
assess-
ment
Myocar-
dial T1 curve
crosses the
null point
before blood
T1 curve
100% 70%
Kwong68 2015 22 37 pts
with
HHD
and 22
pts With
DCM
Systemic amyloidosis
confirmed by cardiac
histology
AL/
ATTR
Left atrial
LGE >1/3
all left
atrial seg-
ments
Number of
left atrial seg-
ments with
abnormal
LGE
76% 94% Limitations of a
cohort controlled
study, small
sample size, and
selection bias
Zhao83 2016 257 0 Meta-analysis of 7
published studies
AL/
ATTR
LGE Presence of
a typical LGE
pattern
85% 92% Binary LGE clas-
sification, a lack
of consideration
of cardiac amyloi-
dosis subtypes,
lack of T1 map-
ping data, limita-
tions of a meta-
analysis
Martinez-
Naharro172
2017 313 0 ATTR cardiac amy-
loidosis pts corrobo-
rated by 99Tc SPECT
(n=201) or TTR
mutation
(n=12) and AL car-
diac amyloidosis pts
(n=50)
AL/
ATTR
Asym-
metric
increase in
LV septal
thickness,
typical
LGE pat-
tern
79% NA Asymmetrical
increase in septal
wall thickness
is common and
LGE typical in
ATTR
AL, light chain amyloidosis; ATTR, transthyretin amyloidosis; CMR, cardiac magnetic resonance imaging; DCM, dilated cardiomyopathy; ECG, electrocardiogram; HH D,
hypertensive heart disease; LGE, late gadolinium enhancement; LV, left ventricular; NA, not applicable; SD, standard deviation; ShMOLLI, Shortened MOdified Look-
Locker Inversion recovery; TTE, transthoracic echocardiography; TTR, transthyretin.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 33
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 9. Key Literature Summarizing the Utility of CMR for Risk Assessment in Cardiac Amyloidosis
First Author Year
N
Patients Design
Followup
Period
(Months) CMR Sequence Outcome Event Rate
Odds Ratio
or Hazard
Ratio Comments
Late gadolinium enhancement (LGE)
Maceira209 2008 29 (25 AL,
4 ATTR)
Prospective 20 2D, Segmented IR GE
sequence (LGE); IR
segmented FISP cine
30 ms/frame
All-cause
mortality
LGE
+
0.35
LGE
−
0.37
OR 0.90* LGE not predic-
tive, mortality
was predicted
by gadolinium
kinetics
Migrino210 2009 29 (all AL) Prospective 29 PS IR (LGE) All-cause
mortality
0.25 0 OR 19.84* LGE predicted
mortality
Austin81 2009 25 (15 AL,
9 ATTR,1
miscella-
neous)
Retrospective 12 PSIR (LGE) All-cause
mortality
0.48 0.25 OR 2.73* LGE predicted
mortality
Ruberg80 2009 28 (all AL) Prospective 29 2D, spoiled segmented
IR GE sequence (LGE)
All-cause
mortality
0.09 0.05 OR 2.13* LGE did not pre-
dict morality
Mekinian167 2010 29 (All AL) Retrospective 32 IR GE (LGE). Used the
LL sequence to define
CMR+and CM R–
All-cause
mortality
0.38 0.04 OR
132.60*
Abnormal nulling
on the LL se-
quence predicted
mortality
White79 2014 46 (41 AL,
2 ATTR,
three mis-
cellaneous)
Prospective 29 2D, segmented IR GE
sequence (LGE). TI
scout (T1 visual as-
sessment)
All-cause
mortality
0.32 0.10 OR 9.75* Diffuse enhance-
ment by visual T1
assessment pre-
dicted mortality
Fontana90 2015 250 (119
AL, 122
ATTR, 9
mutation
carriers)
Prospective 24 PSIR (43% of patients),
magnitude-IR LGE. Post
contrast T1 at equilib-
rium of contrast used to
offset errors in nulling
before adoption of PSIR
All-cause
mortality
0.16 0.05 OR 4.44* Transmural LGE
predicted mor-
tality
T1, T2 mapping
Kotecha89 2018 286 (100
AL, 163
ATTR, 12
suspected
ATTR, 11
mutation
carriers)
Prospective 23 T2 mapping All-cause
mortality
0.26 HR 1.48
for 3 ms
change
T2 is a predictor
of prognosis in
AL amyloidosis,
not in ATTR
Martinez-
Naharro87
2018 227 (215
ATTR, 12
mutation
carriers)
Prospective 32 T1 mapping ShMOLLI All-cause
mortality
0.42 HR Native
T1 (59 ms
change)
1.22 HR
ECV (0.03
change)
1.16
Native T1 and
ECV predicted
mortality, only
ECV remained
independent
after adjusting for
known predictors
Lin211 2018 82 (all AL) Prospective 8 T1 mapping MOLLI All-cause
mortality
0.26 HR ECV
(>0.44)
7.25 HR
LGE+ 4.80
ECV and LGE
predicted mortal-
ity. Native T1
did not predict
mortality
Banypersad171 2015 100 (all AL) Prospective 23 T1 mapping ShMOLLI All-cause
mortality
0.25 HR ECV
(>0.45)
3.84 HR na-
tive Native
T1 (>1044
ms) 5.39
Native T1 and
ECV predicted
mortality
Martinez-
Naharro172
2017 292 (263
ATTR, 17
suspected
ATTR, 12
mutation
carriers)
Prospective 19 T1 mapping ShMOLLI
or MOLLI
All-cause
mortality
0.22 HR ECV
(0.03
increase)
1.16
ECV predicted
mortality
AL, light-chain amyloidosis; ATTR, transthyretin-related amyloidosis; LGE, late gadolinium enhancement; PSIR, phase sensitive inversion recovery; LL, look locker; IR,
inversion recovery; GE, gradient echo.
*OR from Raina et al.170
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 10. Key Literature Summarizing the Diagnostic Value of 99mTc-PYP Radionuclide Imaging for Cardiac Amyloidosis
First Author Year
N
Patients
N
Controls
Planar/
SPE CT Patient Cohort
Amyloidosis
Type Criterion Sensitivity Specificity Comments
Wizenberg47 1982 10 0 Planar Biopsy proven Not defined ≥2+ 100% –
Falk43 1983 20 Planar Biopsy proven AL ≥2+ 91% 90%
Lee212 1983 7 10 Planar Biopsy proven AL ≥2+ 86% 100% MDP lower sensitiv-
ity vs PYP
Eriksson213 1984 12 0 FA P ATTR ≥2+ 33% –
Leinonen214 1984 6 0 Planar Systemic amyloid 5 AA
1 ATTR
≥2+ 0 –
Falk215 1984 9 0 Planar FA P ATTR ≥2+ 77.7% –
Gertz44 1987 34 Planar/
SPECT
Biopsy proven Not defined ≥1+ 21%
(Retro)
85%*
(Prosp)
25%
Hongo216 1987 15 Planar/
SPECT
FAP ATTR ≥2+ 67% 95%
Goldstein217 1989 32 0 Planar Elderly ≥85 yrs
screening for AT-
TRwt
ATTR ≥2+ 12.5% –
Hartmann45 1990 7 Planar/
first
pass
Not defined ≥2+ 71.4%
Fournier218 1993 9 6 Planar FAP Majority ATTR Scinti-
graphic
index
–
Yamamoto48 2012 13 37 Planar/
SPECT
CHF, LVH, Sus-
pected cardiac
amyloidosis
Not defined PYP
score
85% 95%
Bokhari113 2013 45 Planar/
SPECT
Biopsy proven AL/ATTR ≥2+ 97%
(ATTR)
17% (AL)
100% ATTR vs AL
Castano114 2016 121 16 Planar Retrospective ATTR/AL H/CL;
visual
91% 92% Multicenter
Gillmore32016 1217 360 Planar Retrospective,
referral centers
ATTR/AL H/CL,
visual
74% 100% + PYP and absence
of monoclonal gam-
mopathy
AL, light chain amyloidosis; ATTR, transthyretin amyloidosis; AA, Apo serum amyloid A; CHF, congestive heart failure; CL, contralateral; DPD, 3,3-diphosphono-1,2-
propanodicarboxylic acid; HMDP, hydroxymethylene diphosphonate; H, heart; H/CL, heart/contralateral lung; LVH, left ventricular hypertrophy; FAP, familial amyloid
polyneuropathy; PYP, 99mTc pyrophosphate; DPD, 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD); HM DP, 99mTc-hydroxymethylene diphosphonate; MDP,
99mTc-methylene diphosphonate.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 35
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 11. Key Literature Summarizing the Diagnostic Value of 99mTc-DPD/ HMDP Radionuclide Imaging for Cardiac Amyloidosis
First
Author Year
N
Patients
N
Controls Isotope
Planar/
SPE CT
Patient Cohort/
Diagnostic
Standard
ATTR/AL/
Others Criterion Sensitivity Specificity Comments
Puille219 2002 8 10 DPD Planar/
SPECT
Prospective/
rectal biopsy with
IHC+genotyping
ATTRv HR
WBR
H/WB
– – HR/WBR>>in ATTR
pts (vs controls)
(P<0.001)
Perugini112 2005 25 10 DPD Planar/
SPECT
Prospective/
cardiac biopsy
with IHC+
genotyping+
echo
ATTR
AL
(a) HR; H/
WB
(b) Visual
score ≥1
(a) >in
ATTR
(b) 100%
for
ATTR
(b) 100% Evaluation
of diagnostic
accuracy in
the etiological
diagnosis
(identification of
ATTR pts)
Rapezzi105 2011 40 23 DPD Planar/
SPECT
Retrospective/
FPA or cardiac
biopsy+
genotyping+
echo
ATTRv Moderate/in-
tense cardiac
uptake (visual
score ≥2)
100% in
pts with
CA
– 4/23 pts without
cardiac amyloido-
sis had a positive
bonescan (early
diagnosis)
Rapezzi220 2011 79 15 DPD Planar/
SPECT
Retrospective/
FPA or cardiac
biopsy+
genotyping+
echo
ATTR
AL
(a) HR
(b) H/WB
(c) Visual
score ≥1
(a)
>in
ATTR
(b) 71% in
AL+
ATTR
pts
(c) 100%
in ATTR
pts
(a)
(b) 100%
(c) –
Evaluation of diag-
nostic accuracy in
the etiological diag-
nosis (identification
of ATTR pts)
Quarta103 2012 46 16 DPD Planar/
SPECT
Prospective/Car-
diac biopsy+
genotyping
ATTRwt Visual score
≥2
100% 100% Evaluation of the
diagnostic accuracy
in the differential
diagnosis with other
cardiomy-opathies
mimicking cardiac
amyloidosis
De Haro221 2012 19 – DPD Planar/
SPECT
Retrospective/
various organ
biopsy+
genotyping+
echo
ATTR
AL
Visual score
≥2
100% 100% Evaluation of the
diagnostic accuracy
in the etiological
diagnosis (identifica-
tion of ATTR pts)
Hutt106 2014 321 – DPD Planar/
SPECT
Prospective/sus-
pected or proven
(biopsy driven)
amyloidosis—
cardiac amyloido-
sis diagnosed by
echo/CMR
ATTR
AL
AA
Other
Visual score
≥1
100% (for
detecting
ATTR pts
with car-
diac amy-
loidosis)
– In 85 pts amyloido-
sis was ultimately
excluded
Ferreira222 2015 19 – DPD/
MDP
Planar/
SPECT
Prospective/
echo+geno-typing
ATTR Visual score
≥1 (DPD)
50% 94% Evaluated accuracy
in detecting CA
Galat102 2015 69 52 (oth-
er CMP
[37 with
LVH;
15 no
LVH])
HMDP Planar/
SPECT
Prospective/vari-
ous organ biopsy
with IHC+
genotyping+
echo
ATTR
AL
(a) Visual score
≥1 (amy-
loidosis vs
control)
(b) Visual score
≥2 (identi-
fication of
ATTR pts
with cardiac
amyloidosis)
(a) 75%
(b) 83%
(a) 100%
(b) 100%
Evaluation of diag-
nostic accuracy in
the etiological diag-
nosis (in identifica-
tion of ATTR pts)
All ATTRv without
cardiac amyloidosis
and carriers had no
cardiac uptake
Pilebro22 2016 55 – DPD Planar/
SPECT
Retrospective/
FPA or cardiac
biopsy
ATTRv Visual score – – Evaluation of dif-
ferent cardiac
uptake according
to amyloid fibril type
(strong association
between DPD up-
take and fibrils type)
(Continued )
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 36
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Abulizi224 2016 6 – HMDP
vs DPD
Planar/
SPECT
Prospective/
various organ
biopsy+
genotyping
ATTRv H/mediasti-
num
– – HMDP and DPD
showed comparable
cardiac uptake
Galat225 2016 135 31 (pts
with
LVH)
HMDP
(early
vs late
phase)
Planar/
SPECT
Prospective/vari-
ous organ biopsy
with IHC+
genotyping+
echo
ATTR
AL
a) H/Mediasti-
num
>1.210 (early
phase)
100% (for
detecting
ATTR pts
vs AL)
100% (for
detecting
ATTR pts
vs AL)
All controls had no
cardiac uptake
Cappelli101 2017 65 20 HMDP Planar/
SPECT
Retrospective/
various organ bi-
opsy with IHC+
genotyping+
echo
ATTR
AL
Visual score
≥1
100% (for
detecting
ATTR pts
vs AL)
100% Evaluation of diag-
nostic accuracy in
the etiological diag-
nosis (identification
of ATTR pts)
Van Der
Gucht226
2017 61 – HMDP Planar/
SPECT
Prospective/ vari-
ous organ biopsy
with IHC+
genotyping+
echo
ATTR Cardiac
uptake in the
early phase
100% – Evaluation of LV
distribution of early
phase uptake
Moore227 2017 21 – DPD Planar/
SPECT
Prospective/vari-
ous organ biopsy
with IHC+
genotyping+
echo
ATTR
AL
Visual score
≥1
100% (for
detecting
ATTR pts
vs AL)
87% Evaluation of diag-
nostic accuracy in
the etiological diag-
nosis (identification
of TTR pts)
AL, light chain amyloidosis; ATTRv, transthyretin amyloidosis mutant; ATTRwt, transthyretin amyloidosis wild type; AF, atrial fibrillation; CMR, cardiac magnetic reso-
nance imaging; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; FPA, fat pad aspiration; IHC, immunohistochemistry; HMDP, hydroxymethylene diphosphonate;
HCM, hyper- trophic cardiomyopathy; HR, heart retention; H, heart; N, number; TTR, transthyretin; WBR, whole-body retention; WB, whole body.
Table 11. Continued
First
Author Year
N
Patients
N
Controls Isotope
Planar/
SPE CT
Patient Cohort/
Diagnostic
Standard
ATTR/AL/
Others Criterion Sensitivity Specificity Comments
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Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 12. Key Literature Summarizing the Role of Radionuclide Imaging in Screening for Cardiac Amyloidosis in Selected
Settings
First
Author Year
Clinical
Setting N Pts. Isotope
Planar/
SPE CT
Type of Study and
Patient Selection
N Pts.
With CAc
Prevalence
of CA
Criterion
for CA
Reference
Diagnosis
of CA Comments
Longhi228 2014 Bone-
scan for
noncardiac
reasons
12 400 DPD Planar/
SPECT
Retrospective/
patients with a
positive bone scan
were contacted for
a cardiac evaluation
14 ATTR
CA
1.4% in men
in the 9th
decade
Visual
score ≥2
Echo+EMB+
genotyping
Gonzalez13 2015 Hosp. pts
HFpEF
120 DPD Planar/
SPECT
Prospective-con-
secutive pts/
Pts with HFpEF
and LVH (echo)
16
ATTRwt
13%
(16/120)
Visual
score ≥2
Genotyping+
EMB or extra
cardiac tissues
Bennani
Smires15
2016 Hosp. pts
HFpEF
49 DPD Planar/
SPECT
Prospective-con-
secutive pts/Pts
with HFpEF and
no CAD
9 ATTRwt
5 AL 10%
(5/49)
18% (9/49) Visual
score=3;
H/WB
CMR+
genotyping+
various
organ biopsy
(for AL diag-
nosis)
Selected pts
underwent
a cardiac
screening
Longhi117 2016 Severe AS
evaluated
for AVR
43 DPD Planar/
SPECT
Prospective/Pts
with ≥1 of the fol-
lowing echo “red
flags*”
5 ATTRwt 12% (5/43) Visual
score ≥2
EMB+
genotyping
2/5 low flow-
low gradient,
reduced
LV E F
2/5 low flow-
low gradient,
preserved
LV E F
Galat229 2016 CA+
moderate/
severe AS
16 HMDP Planar/
SPECT
Retrospective/
Pts with moder-
ate/severe aortic
stenosis+CA (diag-
nosed by bonescan
in 62%)
ATTR – Visual
score ≥2
EMB in 38%
(6 pts)
87% low
flowlow gra-
dient
Treibel116 2016 Pts with
severe AS,
eval. For
AVR
146 DPD Planar/
SPECT
Prospective/Pts
with intra-operative
(during AVR) car-
diac biopsy+IHC/
MS
6
ATTRwt
4.1%
(6/146)
Visual
score ≥1
Echo+MR+
bone scan+
genotyping
4/6 pts with
a positive
biopsy evalu-
ated for CA
(2 pts died
before evalu-
ation)
AL, light chain amyloidosis, ATTRv, transthyretin amyloidosis mutant; ATTRwt, transthyretin amyloidosis wild type; AVR, aortic valve replacement; AV, atrioventricular;
CAD, coronary artery disease; AS, aortic stenosis; EMB, endomyocardial biopsy; eval, evaluated; FAP, familial amyloid polyneuropathy; IHC, immunohistochemistry; HR,,
heart retention; H, heart; HFpEF, heart failure with preserved ejection fraction; HMDP, hydroxymethylene diphosphonate; DPD, 3,3-diphosphono-1,2-propanodicarboxylic
acid; PYP, pyrophosphate; LV, left ventricle; LVEF, left ventricular ejection fraction; MS, mass spectrometry; N, number; Pts, patients; RV, right ventricle; SPECT, single
photon emission computed tomography; TTR, transthyretin; WBR, whole-body ratio; WB, whole body.
*red flags=increased thickness of AV valves, interatrial septum or RV free wall, pericardial effusion, myocardial granular sparkling.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 38
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 13. Key Literature Summarizing the Prognostic Value of 99mTc-DPD/HMD P Radionuclide Imaging for Cardiac
Amyloidosis
First
Author Year
N
Patients
Follow-Up
Duration Isotope
Planar/
SPE CT
Type of Study
and Patient
Population
ATTRv/AT-
TRwt
Prognostic
Scintigraph-
ic Criterion
Prognostic Role
Confirmed at Mul-
tivariable Analysis
(Yes/No)
Hutt31 2017 602 29.6 months DPD Planar/
SPECT
Retrospective/all pts who
received a bone-scan to
evaluate for cardiac amy-
loidosis
225 ATTRv;
377 ATTRwt
Visual score
(N pts):
No
Univariable predictors; age; 6MWT; LVEF; troponinT; NT-proBNP; NYHA class; Echo performance status; GFR; SBP;
Multivariable predictors: echo performance status; GFR; evaluation of the prognostic role of the scintigraphic visual score; survival was significantly longer in
score 0 pts (absence of cardiac amyloidosis) compared to score 1-2-3 pts.
Galat102 2015 121 111 [50-
343] days
HMDP Planar/
SPECT
Prospective/Consecutive
pts with suspected car-
diac amyloidosis
55 ATTR
(m+wt) car-
diac amyloi-
dosis
H/Skull a. None
b. NYHA III-IV
c. NYHA III-IV
Comments: Cox’s regression uni- and multivariate analysis were performed and prognosis was assessed in terms of predictors of MACE. a) model with
scintigraphic+echo variables; (b) model with scintigraphic+echo+clinical variables; c) model with scintigraphic+echo+clinical+biological variables
Univariable predictors: NYHA class; LVEF; E /e´; NTproBNP; TroponinT
Multivariable predictors: (a) none; (b) class NYHA III-IV; (c) class NYHA III-IV
Kristen174 2013 36 27.4 [0.1–
106.2]
DPD Planar/
SPECT
Retrospective/con-
secutive pts with ATTRwt
(20/36 underwent bone-
scan)
ATTRwt HR; Visual
score
N/A
Comments: diastolic dysfunction; univariate Kaplan–Meier analysis was performed
Rapezzi105 2011 63 14 [6.2–32]
months
DPD Planar/
SPECT
Retrospective/consecu-
tive pts with ATTRv with/
without cardiac amyloi-
dosis
ATTRv H R; H/WB No
Univariable: age; left atrial diameter; LV wall thickness; LV M/V; NYHA class; low QR S; voltage; restrictive filling pattern; HR; H /WB
Multivariable: age; restrictive filling pattern
Cox’s regression uni- and multivariate analysis were performed; prognosis was assessed in terms of predictors of MACE
AA, amyloid A amyloidosis; AF disease, Anderson–Fabry disease; AL, light-chain amyloidosis; ATTR, transthyretin-related amyloidosis; ATTRv, amyloidosis due to
transthyretin gene mutations; ATTRwt, amyloidosis due to deposition of wild-type transthyretin (senile amyloidosis); AV, atrio-ventricular; AVR, aortic valve replacement;
CMP cardiomyopathies; echo, echocardiogram; FPA, fat pad aspiration; GFR, glomerular filtration rate; HR, heart retention; H/WB, heart/whole body; HCM, hypertrophic
cardiomyopathy; HFpEF, heart failure with preserved ejection fraction; IHC, immunohistochemistry; LVH, left ventricle hypertrophy; LVEF, left ventricular ejection fraction;
LVM/V, left ventricle mass/volume ratio; mBMI, modified body mass index; MS, mass spectrometry; NYHA, New York Heart Association; MACE, major adverse cardiac
events; RV, right ventricle; SBP, systolic blood pressure; TAVR, transcatheter aortic valve replacement; WBR, whole-body retention.
Table 14. Key Literature Summarizing the Utility of 99mTc-PYP Radionuclide Imaging for Risk Assessment in Cardiac
Amyloidosis
First Author Year
N
Patients
N
Controls Design Follow-Up Period Outcome
Hazard
Ratio Comments
Vranian175 2017 75 27 Retrospective Not specified Correlation to echo/
biomarkers
Not given PYP predicted mortality in suspect-
ed ATTR, but not confirmed ATTR
Sperry230 2017 54 0 Retrospective Up to 4 years (me-
dian 1.8 years)
Regional PYP up-
take by SPECT
0.73
Castano114 2016 121 16 Retrospective 5 years Mortality 3.91 Multicenter registry
AS, aortic stenosis; ATTR, transthyretin amyloidosis; PYP, pyrophosphate; SPECT, single photon emission computed tomography.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 39
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 15. Key Literature Summarizing the Diagnostic Value of 123I-MIBG Radionuclide Imaging for Cardiac Amyloidosis
First Author Year
N
Patients
N
Controls
Planar/
SPE CT
Patient Co-
hort ATTR/AL Criterion Comments/Pt Outcome
Tanaka et al98 1997 12 15 Planar/
SPECT
Prospective ATTRv Cardiac
tracer accu-
mulation
No cardiac tracer accumulation in 8 of 12
Mean FU 15.5±5.8 months: no lethal arrhythmia, no
cardiac death
Delahaye et al130 1999 17 12 Planar/
SPECT
Consecutive ATTRv Late HMR Mean late HM R in patients 1.36±0.26 vs in healthy
controls 1.98±0.35 (P<0.001), no difference in
washout
Delahaye et al231 2001 21 12 Planar/
SPECT
Consecutive ATTRv Muscarinic
receptor den-
sity
Late HMP
Mean muscarinic receptor density was higher in
patients than in control subjects: B’max, 35.5±8.9 vs
26.1±6.7pmol/mL (P=0.003)
Mean late HMR in patients 1.43±0.28 vs in healthy
controls 1.98±0.35 (P<0.001), mean wash-out
29±6.8% vs 21±6% (P=0.003). Individual mus-
carinic receptor density did not correlate with late
HMR
Watanabe et al141 2001 4 10 Planar/
SPECT
Prospective ATTRv Late H MR Mean late HMR in patients 1.1±0.2, vs 2.4±0.2 in
health controls (P value N/A)
Hongo et al139 2002 25 12 Planar/
SPECT
Prospective AL Late HMR Mean late H MR in patients without autonomic neu-
ropathy 1.53±0.06 vs in with autonomic neuropathy
1.29±0.05 (P<0.001), mean wash-out 42±4.8% vs
31±4.0% (P<0.001)
Lekakis et al140 2003 3 23 Planar Retrospective AL Late HM R Mean late HMR 1.33±0.1 vs in 2.13±0.2 healthy
controls (P value N/A)
Coutinho et al232 2004 34 – Planar Prospective ATTRv Late HMR Mean late HMR 1.75±0.5 in all patients. Mean late
HMR in patients without neuropathy 2.2±0.5 vs pa-
tients with neuropathy 1.5±0.4 (P=0.001)
Delahaye et al138 2006 31 12 Planar/
SPECT
Prospective ATTRv Late H MR Mean late HMR 6 months before liver transplanta-
tion 1.45±0.29, vs 1.98±0.35 of controls (P<0.001)
No cardiac death or lethal arrhythmia reported.
Neuronal worsening in FAP patients after liver trans-
plantation
Algalarrondo et al233 2012 32 – Planar Retrospective ATTRv Late HMR Late HMR ≤1.6 in 26 out of 32 patients
No cardiac death or lethal arrhythmia reported
Noordzij et al135 2012 61 9 Planar Consecutive AL
AA
ATTR
Late HMR Mean late H MR in all patients 2.3±0.75 vs healthy
control subjects 2.9±0.58 (P<0.005). Mean late
HMR in ATTR patients 1.7±0.75 vs AL patients
2.4±0.75 (P<0.05)
Mean wash-out in patients 8.6±14% vs in
healthy control subjects−2.1±10% (P<0.05)
Coutinho et al129 2013 143 – Planar Longitudinal
consecutive
ATTRv Late HMR Mean late HMR 1.83±0.43, and mean wash-out
47±11%
Mean FU 5.5 years: hazard ratio all-cause mortality
7 if HMR<1.6, progressive increase in 5-year mortal-
ity with decrease in late HMR
Takahashi et al234 2014 6 – Planar Prospective ATTRv Late HMR Mean late HMR at baseline 1.7±0.9 (P=0.004)
No cardiac death or lethal arrhythmia reported
Algalarrondo et al131 2016 215 – Planar Retrospective
ATTRv
ATTRv Late HMR Median late HMR 1.49 (inter-quartile range 1.24–
1.74, range 0.97–2.52)
Median FU 5.9 years after liver transplantation:
5-year survival 64% if late HMR ≤1.43, vs 93% if
HMR>1.43 (P<0.0001)
Azevedo Coutinho
et al186
2017 232 – Planar Prospective ATTRv Late HMR Initial assessment: mean late HMR 1.83±0.03, me-
dian wash-out 2.5 (inter-quartile
range−2.3 to 8.5)
Median FU 4.5 years (inter-quartile
range 2.1–7.7 years)
Initial HMR<1.55: H R mortality 9.36
(95% CI 4.27–20.56, P<0.001)
Initial HMR 1.55–1.83: H R mortality 4.27 (95% CI
1.68–9.05, P=0.002).
AA, amyloid A; AL, amyloid light chain; ATTRv, hereditary transthyretin amyloidosis; FU, followup; HMR, heart-to-mediastinal ratio; H R, hazard ratio; Pt, patient.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 40
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 16. Key Literature Summarizing the Utility of 123I-MIBG Radionuclide Imaging for Risk Assessment in Cardiac Amyloidosis
First
Author Year
N
Patients
N
Controls Design
Follow-Up
Period Outcome
Event Rate
(Annualized)
Hazard Ratio
(95% CI) Comments
Azevedo Coutinho et al186 2017 232 – Prospective ob-
servational
4.5 years All-cause
mortality
38 (1171.5
patient years)
HR 0.183 (95%
CI 0.075–0.450)
Late H/M multivari-
able predictor
Liver transplantation
patients (n=70)
Algalarrondo et al131 2016 215 82 (no
MIBG)
Consecutive 5.9 years All-cause
mortality
84 pts in total HR 0.049 (95%
CI 0.014–0.170)
Late H/M univari-
able predictor
Liver transplantation
patients (n=65)
Coutinho et al129 2013 143 – Prospective
longitudinal con-
secutive
5.5 years All-cause
mortality
32 total
(22.4%)
HR, 0.18 (95%
CI 0.06–0.57)
Liver transplantation
patients (n=53)
CI, confidence interval; HR, hazard ratio; H/ M, heart to mediastinal ratio.
Table 17. Recommendations for Standardized Acquisition of 123I-MIBG for Cardiac Amyloidosis
Imaging Procedures Parameters Recommendation
Preparation No fasting required
Withdrawal of certain drugs: readers are referred to Ref. 235
Oral thyroid blockage 30 min before administration 123I-MIB G: Lu-
gol solution (130 mg adults, body weight adjusted children) OR po-
tassium perchlorate (500 mg adults, body weight adjusted children)
Preferred
Scan Rest scan Preferred
Dose of 123I-MIBG 370 MBq (10 mCi) intravenously Preferred
Time between injection and acquisition 15 min Preferred
3–4 h
General imaging parameters
Field of view Heart Preferred
Chest Preferred
Image type SPECT Preferred
Planar Preferred
Position Supine Standard
Upright Optional
Energy window 159 keV, 15–20% Standard
Collimators Medium energy, high resolution Preferred
Low energy, high resolution Optional
Matrix 128×128 (maximum 256×256) Standard
Pixel size 4.5–6.4 mm Standard
Planar imaging specific parameters
Number of views* Anterior Standard
Detector configuration Planar Standard
Image duration (count based) 10 min Standard
Magnification 1.45 Standard
SPECT imaging specific parameters
Angular range 180° Standard
Detector configuration 90° Standard
Angular range 360° Optional
Detector configuration 180° Optional
ECG gating Off; Nongated imaging Standard
Number of views/detector 64 over 180° Standard
Time per stop 20 s Standard
Magnification 1.0 Standard
For details on 123I-MIBG imaging, readers are referred to Ref. 235.
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Circ Cardiovasc Imaging. 2021;14:e000029. DOI: 10.1161/HCI.0000000000000029 July 2021 41
Multimodality Imaging in Cardiac AmyloidosisDorbala et al
Table 18. Recommendations for 123I-MIBG Imaging Reporting
Parameters Elements
Demographics Patient name, age, sex, reason for the test, date of study, prior imaging procedures, biopsy results if available (required)
Methods Imaging technique, radiotracer dose and mode of administration, interval between injection and scan, scan technique (planar and
SPECT) (required)
Findings Image quality
Thyroid uptake
Visual scan interpretation (required)
Semi-quantitative interpretation heart-to-mediastinum (H/ M) (required):
Regions of interest (ROIs) are drawn over the heart (including the cavity) and the upper mediastinum (avoiding the thyroid gland)
in the planar anterior view. Average counts per pixel (CPP) in the myocardium are divided by average counts per pixel in the me-
diastinum. The myocardial washout rate (WR) from initial to late images is also calculated, and expressed as a percentage, as the
rate of decrease in myocardial counts over time between early and late imaging (normalized to mediastinal activity)
Ancillary findings On planar imaging and SPECT (optional)
Interpret CT for attenuation correction if SPECT/CT scanners are used (recommended)
Conclusions The appearance of images should be described succinctly, including a statement on quality if suboptimal. Sympathetic activity
SPECT defects should be classified in terms of location relative to myocardial walls, extent and severity. Other abnormalities that
should be mentioned are LV dilatation, increased lung uptake of tracer, or significant noncardiopulmonary tracer uptake. The find-
ings should be integrated with the clinical data to reach a final interpretation. A comparison with any previous study should be
included
Normal values for late H/M ratio and WR vary in relation to age (inversely for the late H /M ratio, directly for the WR) and image
acquisition (LEHR vs M E collimation and acquisition time)
In general:
A WR >20% between early and late imaging is considered as abnormal
A late H/M ratio <1.60 is abnormal, between 1.6 0 and 1.85 equivocal, and >1.85 as normal (LEHR collimator)
H, heart; LEHR, low energy high resolution; M, mediastinum; ME, medium energy; LV, left ventricular; SPECT, single photon emission computed tomography; WR,
wash out rate.
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