Writing Group Members

Sharmila Dorbala, MD, MPH, FASNC (Chair)a

Yukio Ando, MD, PhDb

Sabahat Bokhari, MDc

Angela Dispenzieri, MDd

Rodney H. Falk, MDa

Victor A. Ferrari, MDe

Marianna Fontana, PhDf

Olivier Gheysens, MD, PhDg

Julian D. Gillmore, MD, PhDf

Andor W.J.M. Glaudemans, MD, PhDh

Mazen A. Hanna, MDi

Bouke P.C. Hazenberg, MD, PhDj

Arnt V. Kristen, MDk

Raymond Y. Kwong, MD, MPHa

Mathew S. Maurer, MDc

Giampaolo Merlini, MDl,l1

Edward J. Miller, MD, PhDm

James C. Moon, MDf

Venkatesh L. Murthy, MD, PhDn

C. Cristina Quarta, MD, PhDf

Claudio Rapezzi, MDo

Frederick L. Ruberg, MDp

Sanjiv J. Shah, MDq

Riemer H.J.A. Slart, MDh

Hein J. Verberne, MD, PhDr

Jamieson M. Bourque, MD, MHS, FASNC (Co-Chair)s

  1. aCardiac Amyloidosis Program, Cardiovascular Imaging Program, Departments of Medicine and Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. bDepartment of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan. cColumbia University Medical Center/New York Presbyterian Hospital, Columbia University, NY, USA. dDivision of Hematology, Division of Cardiovascular Diseases, and Department of Radiology, Division of Nuclear Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA. ePerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. fNational Amyloidosis Centre, Division of Medicine, University College London, London, United Kingdom. gNuclear Medicine and Molecular Imaging, University Hospitals Leuven, Leuven, Belgium. hMedical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. iDepartment of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA. jDepartment of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. kDepartment of Cardiology, University of Heidelberg, Heidelberg, Germany. lAmyloidosis Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy. l1Department of Molecular Medicine, University of Pavia, Italy. mCardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA. nFrankel Cardiovascular Center, Michigan Medicine, Ann Arbor, MI, USA. oCardiology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater-University of Bologna, Bologna, Italy. pAmyloidosis Center and Section of Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA. qFeinberg School of Medicine, Northwestern University, Chicago, IL, USA. rAmsterdam UMC, University of Amsterdam, Department of Radiology and Nuclear Medicine, Amsterdam, The Netherlands. sCardiovascular Imaging Center, Departments of Medicine and Radiology, University of Virginia, Charlottesville, VA, USA.

Introduction

Cardiac amyloidosis is increasingly recognized as an important cause of heart failure with preserved ejection fraction (EF)1 and carries a high morbidity and mortality.2,3 Emerging imaging methods have facilitated earlier diagnosis4,5,6 and improved prognostication7,8 and management. The diagnostic criteria for cardiac amyloidosis, however, need to be updated to include these novel imaging tools.

A multi-societal writing group with expertise in cardiovascular imaging and cardiac amyloidosis has been assembled by the American Society of Nuclear Cardiology (ASNC) with representatives from the American College of Cardiology (ACC), the American Heart Association (AHA), the American Society of Echocardiography (ASE), the European Association of Nuclear Medicine (EANM), the Heart Failure Society of America (HFSA), the International Society of Amyloidosis (ISA), the Society of Cardiovascular Magnetic Resonance imaging (SCMR), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). This writing group has established consensus recommendations on imaging cardiac amyloidosis from this panel of multidisciplinary experts. Part 1 documents the evidence base for multimodality imaging in cardiac amyloidosis and defines standardized imaging protocols. Part 2 has the following aims:

  1. 1)

    Develop consensus diagnostic criteria for cardiac amyloidosis incorporating advanced echocardiography, cardiovascular magnetic resonance (CMR), and radionuclide imaging.

  2. 2)

    Identify consensus clinical indications for noninvasive imaging in cardiac amyloidosis to guide patient management through a rigorous application of the modified Delphi method.

  3. 3)

    Address the appropriate utilization of echocardiography, CMR, and radionuclide imaging in these clinical scenarios.

Diagnostic Criteria, Clinical Indications, and Appropriate Utilization

Expert consensus criteria were developed based on histologic, clinical, and imaging features with accompanying certainty of recommendation. The appropriate utilization of multiple imaging modalities was assessed using clinical scenarios that represent diverse patient presentations and address the diagnostic and prognostic capabilities of noninvasive imaging. The goal of this document is to determine which modalities may be reasonable for a specific indication rather than to identify one test that is best.

Methods

In order to accomplish this goal, a rating panel of clinical experts in cardiac amyloidosis was assembled. As recommended by the RAND-UCLA Appropriateness Manual, this group included representatives from relevant clinical societies, all of whom have extensive expertise in the management of cardiac amyloidosis.9 The group was recruited internationally from diverse geographical locations. All group representatives practice in academic settings, which is typical given the clinical complexity of this disorder. Experts with extensive imaging expertise were expressly excluded from this panel to prevent bias in the scoring process, as experts with expertise in a single imaging modality might tend to rate their favored imaging modality as more appropriate than the remainder. The final ratings panel included seven clinical experts.9 This group developed expert consensus recommendations on criteria for the diagnosis of cardiac amyloidosis via histologic, imaging, and cardiac biomarkers. The rating panel then engaged in an exercise using the modified Delphi technique for a robust evaluation of appropriateness.10

Indication Development

A standardized approach was used to ensure inclusion of the majority of clinical scenarios encountered in the evaluation and management of cardiac amyloidosis. Despite best efforts, however, the writing group acknowledges that clinical presentations vary, and not every relevant clinical scenario is represented. These scenarios were organized into several broad categories representing key areas of cardiac amyloidosis clinical care:

  • Assessment for cardiac involvement in asymptomatic individuals;

  • Screening for cardiac amyloidosis in patients with symptomatic heart failure;

  • Evaluation of biopsy-proven light chain (AL) and amyloidogenic transthyretin (ATTR) cardiac amyloidosis;

  • Follow-up testing for new or worsening cardiac symptoms;

  • Other diverse clinical scenarios/conditions; and

  • Prior testing suggestive of cardiac amyloidosis.

Once a final list was developed, the larger writing group, comprised of imaging experts in the various disciplines, provided feedback prior to the final indication determination.

Rating Process

Once the indications were finalized, the rating panel scored them independently. For each indication, the rating panel was asked to rate its appropriateness in the evaluation and management of cardiac amyloidosis. The following definition of appropriate use was adapted from prior appropriate use documents11,12,13:

An appropriate imaging study is one in which the expected incremental information, combined with clinical judgement, exceeds the expected negative consequences by a sufficiently wide margin for a specific indication that the procedure is generally considered acceptable care and a reasonable approach for the indication.14

The rating group used a scale from 1 to 9. These scores were divided into three general categories: Appropriate (A), May Be Appropriate (M), or Rarely Appropriate (R) in accordance with published appropriate use criteria methodology and prior appropriate use documents.12,15,16,17

Appropriate (Score 7-9)

An indication scored from 7 to 9 represents an appropriate option for management of patients in this population due to benefits generally outweighing risks; it should be viewed as an effective option for individual care plans, although the imaging procedure may not always be necessary depending on physician judgement and patient-specific preferences (i.e., the procedure is generally acceptable and is generally reasonable for the indication).

May Be Appropriate (Score 4-6)

An indication scored from 4 to 6 is considered at times an appropriate option for management of patients in this population due to variable evidence or agreement regarding the risk-benefit ratio, potential benefit based on practice experience in the absence of evidence, and/or variability in the population; the effectiveness of this indication for individual care must be determined by a patient’s physician in consultation with the patient based on additional clinical variables and judgement along with patient preferences (i.e., the procedure may be acceptable and may be reasonable for the indication). A categorization of May Be Appropriate may also imply that further research and/or patient information is needed to classify the indication definitively.

Rarely Appropriate (Score 1-3)

An indication scored from 1 to 3 is rarely an appropriate option for management of patients in this population for this clinical indication due to a lack of a clear benefit/risk advantage; it is rarely an effective option for individual care plans; exceptions should have documentation of the clinical reasons for proceeding with this care option (i.e., procedure is not generally acceptable and is not generally reasonable for the indication).

The division of the scores into these three broad categories is somewhat arbitrary, and the raters were instructed to consider the numeric range as a continuum. Recognizing that there is variability in many patient factors, local practice patterns, and a lack of data on use of imaging across clinical scenarios and indications, the rating panel members were asked to independently rate the appropriateness of using each imaging modality for the general category and the specific clinical indication based on the best available evidence, including guidelines and key references wherever possible.10

After rating the indications independently, the total results were tabulated, and each rater was provided with their individual scores and de-identified scores from all other panel members. The panel was convened for conference calls for discussion of each indication. The clinical indications were modified if needed based on the discussion. This meeting was facilitated by non-rating representatives of the writing panel who served as unbiased moderators and facilitated group dynamics to optimize the process. The moderators were free of significant relationships with industry and were unbiased relative to the topics under consideration. Following the meeting, panel members were asked to independently provide their scores for each clinical indication in a second round of ratings, taking into consideration the discussion from the call. For indications with continued significant dispersion of scores, a second conference call and third round of ratings occurred.

Median scores were calculated. A median panel score of 7 to 9 without disagreement was considered “Appropriate.” A median panel score of 1 to 3 without disagreement was considered “Rarely Appropriate.” A median panel score of 4 to 6 or any median with disagreement was classified as “May Be Appropriate.” Agreement was classified as having no more than two panelists provide ratings in an alternate category (this corresponded to > 70% consensus).9,16

Assumptions

The following list of assumptions to be followed was adapted from methodology recommendations and prior appropriate use documents and was communicated to the expert rating panel members prior to their rating of the indications.12,15,17,18

  1. 1.

    All imaging studies are assumed to be locally available and to be performed in accredited imaging laboratories in accordance with published criteria for quality cardiac diagnostic testing using state-of-the-art, certified imaging equipment.

  2. 2.

    All imaging is assumed to be performed according to the standard of care as defined by the peer-reviewed medical literature.

  3. 3.

    All interpreting physicians are qualified and certified to supervise the imaging procedure and appropriately report the findings.

  4. 4.

    In clinical scenarios, the clinical status listed is assumed to be valid as stated (asymptomatic patients are truly asymptomatic) and no extenuating circumstances are to be taken into consideration (patient willingness to receive treatment, clinical stability) unless specifically noted.

  5. 5.

    Appropriateness should be rated independently of the appropriateness of any prior diagnostic imaging that may have been performed.

  6. 6.

    All patients are assumed to be receiving optimal therapy conforming to current standards of care, including contemporary heart failure therapy and cardiovascular risk-factor modification, unless specifically noted.

  7. 7.

    Imaging indicated for surveillance to assess disease progression or response to therapy is assumed to be performed solely because the indicated time period elapsed rather than due to any change in clinical circumstances.

  8. 8.

    Radiation risk was not considered. Although theoretical concerns have been raised that diagnostic imaging-related ionizing radiation may result eventually in an increased risk of cancer in the exposed population, this has not been proven. Moreover, in this population with high risk for heart failure and neuropathy, the benefit of a small dose of radiation was felt to outweigh the risk, especially when compared to a strategy with invasive endomyocardial biopsy. This risk can be minimized by preventing inappropriate use and by optimizing studies with the lowest radiation dose possible.19

  9. 9.

    Cost of the imaging procedures is not to be considered in accordance with recommended appropriateness scoring methods.9 Cost is recognized to be an important issue from a policy perspective, but expert physician appropriateness rating has been shown to agree with cost-effectiveness models.20,21

Definitions

  1. 1.

    No cardiac symptoms

The absence of the following symptoms was used to indicate that no cardiac symptoms are present. These include chest pain, fatigue, effort intolerance, shortness of breath, palpitations, dizziness/lightheadedness, syncope, orthopnea, paroxysmal nocturnal dyspnea, bloating, leg swelling, leg or jaw claudication.

  1. 2.

    TTR gene carrier

A TTR gene carrier refers to individuals who harbor one of the more than 120 mutations in the transthyretin gene that have been associated with the development of transthyretin amyloidosis.22

  1. 3.

    Recurrent testing

Recurrent testing refers to performance of the same imaging modality more than once, excluding non-diagnostic studies, to identify cardiac involvement in the setting of prior negative testing; the interval between studies is not addressed.

  1. 4.

    Biopsy-proven AL cardiac amyloidosis

The diagnosis of AL amyloidosis requires a positive tissue biopsy showing amyloid deposits in the presence of clinical, imaging, or laboratory signs of organ involvement. The amyloid deposits should exhibit a characteristic affinity for Congo red staining with birefringence under polarized light. Typing of AL amyloidosis is confirmed on immunohistochemistry and/or mass spectroscopy. Electron microscopy of amyloid deposits is rarely performed but reveals prototypic rigid, nonbranching 10- to 12-nm width fibrils. Amyloid deposits can be detected at accessible sites, such as abdominal fat, bone marrow, or minor salivary glands, and the biopsy of the involved organ is not always necessary.23

  1. 5.

    Abnormal NT-proBNP and Troponin T

Cardiac biomarkers (N terminal—pro brain natriuretic peptide, NT-proBNP and troponins) are used for staging with different cutoffs.24,25,26 In AL amyloidosis, NT-proBNP has > 99% diagnostic sensitivity, with all patients with heart involvement having an elevated (≥ 332 ng/L) NT-proBNP.27

  1. 6.

    Monoclonal gammopathy of uncertain significance (MGUS)

A premalignant, clonal plasma cell disorder characterized by the presence of a usually small monoclonal (M) protein and < 10% clonal plasma cell clones in the bone marrow in the absence of multiple myeloma or related lymphoplasmacytic malignancies.28,29

  1. 7.

    Abnormal free light chains (FLCs)

Abnormal FLCs are defined by an abnormal serum Kappa and Lambda immunoglobulin FLC ratio. The reference interval of FLC ratio may vary by the assay method used or in the setting of renal failure. The reference range of the FLC ratio as measured by Binding Site is between 0.26 and 1.65 in patients with normal renal function or between 0.31 and 3.7 in patients with renal failure. The reference range of the FLC ratio as measured by Siemens is between 0.31 and 1.56.

  1. 8.

    Symptomatic heart failure

Symptomatic heart failure refers to patients who have New York Heart Association (NYHA) Class II or greater symptoms adapted from Dolghin et al30 from original source.31

  1. 9.

    Unexplained heart failure

Unexplained heart failure refers to heart failure without a known etiology, in particular, ischemic heart disease or valvular heart disease.

  1. 10.

    Increased wall thickness

Echo mean left ventricular (LV) wall thickness of > 12 mm with no other known cardiac cause.23

  1. 11.

    Preserved LV ejection fraction

Heart failure with preserved ejection fraction is defined per ACC/AHA heart failure guidelines as an LV ejection fraction of ≥40%.32

  1. 12.

    Low-flow aortic stenosis

A low-flow aortic stenosis was defined as low transvalvular mean aortic gradient (≤ 40 mmHg) or stroke volume index of < 35 mL/m2 in the context of reduced LV ejection fraction (classical low flow) or preserved LV ejection fraction (paradoxical low flow).33

  1. 13.

    Unexplained peripheral sensorimotor neuropathy

Patient-reported paresthesias typical for this type of neuropathy in which no known cause has been identified (e.g., diabetes, alcohol abuse, or toxicity).

  1. 14.

    Known or suspected familial amyloidosis

Documented amyloidosis in one or more closely related family members, such as a parent, brother or sister, uncle or aunt, and particularly so if a mutation of an amyloidogenic protein has been identified. In addition, an unexplained clinical picture of peripheral polyneuropathy and/or cardiomyopathy in several family members in a number of generations.

  1. 15.

    Biopsy-proven ATTR cardiac amyloidosis

Endomyocardial biopsy showing amyloid deposits, which are confirmed on immunohistochemistry and/or mass spectroscopy to be transthyretin.

  1. 16.

    Contraindication to Cardiac Magnetic Resonance (CMR)

As the CMR scanner generates a very powerful static magnetic field, certain implanted cardiac devices and ferromagnetic prostheses may pose a safety concern from movement, arrhythmia induction, or tissue heating from the magnetic fields. Each device must be evaluated on an individual basis for safety before proceeding with CMR. Due to a potential risk of nephrogenic systemic fibrosis, gadolinium use is contraindicated in individuals with estimated glomerular filtration rate (GFR) < 30 ml/min/1.73 m2.34

  1. 17.

    Unexplained bilateral carpal tunnel syndrome

Carpal tunnel syndrome is defined as a symptomatic compression neuropathy of the median nerve at the level of the wrist, characterized physiologically by evidence of increased pressure within the carpal tunnel and decreased function of the nerve at that level.35 Bilateral carpal tunnel syndrome in the absence of rheumatoid arthritis or known trauma is defined as unexplained.

  1. 18.

    Unexplained biceps tendon rupture

Biceps tendon rupture in the absence of trauma, such as severe heavy lifting.

  1. 19.

    Echo, CMR, or 99mTc-PYP/DPD/HMDP imaging study suggestive of cardiac amyloidosis

An echocardiogram, CMR, or 99mTc-pyrophosphate (99mTc-PYP)/99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD)/99mTc-hydroxymethylenediphosphonate (99mTc-HMDP) radionuclide imaging study with findings of cardiac amyloidosis as specified in Table 1, Expert Consensus Recommendations for Diagnosis of Cardiac Amyloidosis.

Table 1 Expert consensus recommendations for diagnosis of cardiac amyloidosis
Full size table

Diagnostic Criteria for Cardiac Amyloidosis

The current diagnosis of cardiac amyloidosis is not standardized. A multicenter consensus paper has proposed a diagnostic algorithm for the evaluation of ATTR cardiac amyloidosis incorporating echocardiography, CMR, and bone-avid radiotracers;36 however, no formal diagnostic criteria have been reported. An international consensus document on AL amyloidosis defines cardiac involvement by either endomyocardial biopsy or by systemic biopsy demonstrating AL amyloid and elevated LV wall thickness on echocardiography without alternative cardiac cause.23 However, advances in noninvasive imaging and cardiac biomarkers in cardiac amyloidosis during the past two decades have led to improved methods of assessment beyond echocardiographic wall thickness. These tools have extensive validation in the literature, as described above, but were not included in the consensus document. They allow for more sensitive and earlier detection of disease. Therefore, there is a need for updated diagnostic criteria that incorporate these novel methods. Expert consensus recommendations for criteria for diagnosis of cardiac amyloidosis are provided in Table 1 with accompanying certainty of recommendation. Cardiac amyloidosis is confirmed with a positive endomyocardial biopsy for amyloid fibrils. In the absence of endomyocardial biopsy-proven disease, cardiac amyloidosis can be diagnosed using a combination of extracardiac biopsy, 99mTc-PYP/DPD/HMDP scintigraphy, myocardial uptake of targeted positron emission tomography (PET) amyloid tracers, and echocardiographic and CMR findings as shown in Table 1. In the absence of a clonal plasma cell process, 99mTc-PYP/DPD/HMDP scintigraphy consistent with ATTR cardiac amyloidosis combined with consistent echo or CMR findings obviates the need for invasive endomyocardial or extracardiac biopsy.

Appropriate Utilization of Multimodality Imaging in Cardiac Amyloidosis

The appropriate utilization ratings for echocardiography, CMR, and radionuclide scintigraphy (99mTc-PYP/DPD/HMDP) for the 32 clinical indications are provided in Table 2. There were 30 evaluable indications for echocardiography, of which 27 were rated as “Appropriate” and 3 “May Be Appropriate.” Cardiac magnetic resonance likewise had 30 evaluable indications, of which 19 were rated as “Appropriate,” 9 as “May Be Appropriate,” and 2 as “Rarely Appropriate.” 99mTc-PYP/DPD/HMDP scintigraphy had 31 evaluable indications, of which 10 were “Appropriate,” 6 were “May Be Appropriate,” and 15 “Rarely Appropriate.” Echocardiography was rated as “Appropriate” for all assessed clinical indications except for some more frequent intervals of assessment of cardiac response to therapy or disease progression, which were rated as “May Be Appropriate.” Except for new onset symptomatic heart failure, CMR had more mixed ratings. 99mTc-PYP/DPD/HMDP scintigraphy was rated as “Appropriate” or “May Be Appropriate” for all indications other than those involving suspected light-chain amyloidosis or biopsy-proven AL or ATTR cardiac amyloidosis, which were classified as “Rarely Appropriate.”

Table 2 Appropriate utilization rating of multimodality imaging for the assessment of cardiac amyloidosis
Full size table

Although cost considerations, radiation risk, and availability of technology were not considered during the rating process, the rating panel did want to emphasize that these issues may influence the choice of imaging modality, particularly with regard to the frequency of repeat testing. The panel also wanted to stress the importance of consideration of referral to specialized amyloidosis centers, particularly in familial amyloidosis, AL cardiac amyloidosis, or for consideration of novel therapies.

Clinical Scenario #1: Identifying Cardiac Involvement: No Cardiac Symptoms

For asymptomatic gene carriers, echocardiography and radionuclide scintigraphy (99mTc-PYP/DPD/HMDP) were rated as “Appropriate,” while CMR was rated “May Be Appropriate.” Because the age of onset and phenotypic manifestation of disease vary by the type of mutation, imaging was determined by the panel to be appropriate in some situations but not for others, resulting in a rating of “May Be Appropriate.” In particular, the panel discussed that extracellular volume (ECV) assessment by CMR has the potential to identify disease earlier in asymptomatic gene carriers compared with echocardiography. For asymptomatic patients with elevated cardiac biomarkers and either biopsy-proven systemic AL amyloidosis or MGUS with abnormal FLC levels, echocardiography and CMR were rated as “Appropriate,” but 99mTc-PYP/DPD/HMDP scintigraphy was “Rarely Appropriate.” The panel discussed that the magnitude of biomarker abnormality should play a role in determining the use of imaging. In particular, due to the high prevalence of MGUS, as well as ATTR wild-type (ATTRwt) in older individuals, use of imaging may be guided by serum biomarker levels, particularly in AL amyloidosis patients, in whom NT-proBNP is a sensitive marker of cardiac involvement.

Clinical Scenario #2: Screening for Cardiac Amyloidosis: New Symptomatic Heart Failure

In the nine clinical indications encompassing patients with new symptomatic heart failure considered in this document, echocardiography and CMR were rated as uniformly “Appropriate” for screening for cardiac amyloidosis. This is consistent with the appropriate rating given to CMR and echocardiography for evaluation of newly suspected heart failure in the most recent appropriate utilization report addressing heart failure.1899mTc-PYP/DPD/HMDP scintigraphy was also “Appropriate” for all of these indications except the two addressing patients in whom AL cardiac amyloidosis is suspected due to elevated FLC levels or monoclonal gammopathy, in whom bone scintigraphy alone is insufficient to establish the type of cardiac amyloidosis and for whom a biopsy is required. 99mTc-PYP/DPD/HMDP scintigraphy may occasionally be considered prior to endomyocardial biopsy in instances where ATTR cardiac amyloidosis is in the differential diagnosis. The panel discussed that individuals with unexplained peripheral sensorimotor neuropathy should have diabetes mellitus and other causes of neuropathy excluded as a cause and may benefit from FLC level testing or genetic sequencing of amyloidogenic proteins to guide need for imaging.

Clinical Scenarios #3 and #4: Evaluation of Biopsy-Proven AL and ATTR Cardiac Amyloidosis

Although biopsy-proven AL and ATTR cardiac amyloidosis qualifies as a definitive diagnosis, imaging was still considered to assess amyloid burden, response to therapy, or eligibility for stem cell transplant. For these indications, 99mTc-PYP/DPD/HMDP scintigraphy is not performed clinically and was rated as “Rarely Appropriate.” For quantifying cardiac amyloid burden, echocardiography and CMR were rated as “Appropriate.” With regard to assessing cardiac response to therapy and disease progression in AL and ATTR cardiac amyloidosis, the raters agreed that assessment every 24 months was “Appropriate.” More frequent evaluation varied across expert amyloidosis centers.

Clinical Scenario #5: Follow-Up Testing: New or Worsening Cardiac Symptoms

In TTR gene carriers or patients with AL or ATTR amyloidosis who have new or worsening cardiac symptoms, the panel rated echocardiography, CMR, and 99mTc-PYP/DPD/HMDP scintigraphy as “Appropriate.” 99mTc-PYP/DPD/HMDP scintigraphy was rated as “Rarely Appropriate” for patients with AL amyloidosis. Notably, ATTR cardiac amyloidosis has been reported in long-term survivors of AL amyloidosis, and 99mTc-PYP/DPD/HMDP scintigraphy may have a potential role in those rare instances.37

Clinical Scenario #6: Other Indications and Prior Testing

The rating panel evaluated several clinical indications emerging as high risk for potential cardiac amyloidosis and rated echocardiography as “Appropriate” and CMR and 99mTc-PYP/DPD/HMDP scintigraphy as “May Be Appropriate.” The evolving literature suggesting possible ATTR cardiac amyloidosis in patients with bilateral carpal tunnel syndrome, biceps tendon rupture, and unexplained neuropathy suggest that CMR and 99mTc-PYP/DPD/HMDP scintigraphy likely have a clinical role. However, the panel chose a rating of “May Be Appropriate” due to the lack of definitive evidence and the need for more research to clarify the prevalence of cardiac amyloidosis and the role of imaging in these subgroups and other emerging high-risk cohorts (e.g., transcutaneous aortic valve replacement [TAVR],5 hip and knee arthroplasty38).

Clinical Scenario #7: Prior Testing Suggestive of Cardiac Amyloidosis

In patients with an echocardiogram suggestive of cardiac amyloidosis, CMR was rated as “Appropriate” and likewise echocardiography was “Appropriate” with a suggestive CMR. 99mTc-PYP/DPD/HMDP scintigraphy was rated as “May Be Appropriate,” as its use should be limited to suspected cases of ATTR cardiac amyloidosis. It should be noted that the most common clinical scenario is an older adult with an echo consistent with cardiac amyloidosis; in this group, the best test would likely be 99mTc-PYP/DPD/HMDP scintigraphy due to the high incidence of ATTR cardiac amyloidosis.

Summary

In Part 2 of this consensus statement, a panel of international experts have established the diagnostic criteria, clinical indications, and appropriate utilization of echocardiography, CMR, and radionuclide imaging for the assessment of cardiac amyloidosis. We hope that prospective clinical trials will validate these diagnostic criteria and appropriate utilization recommendations and will support guideline development.

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, Prothena Bioscience

   

Sharmila Dorbala, MD, MPH

GE Healthcare

Pfizer

 

GE Healthcare, Proclara Biosciences, Advanced Accelerator Applications

Pfizer

 

Rodney H. Falk, MD

  

Alnylam, Ionis, Akcea Therapeutics, Eidos Therapeutics

  

Julian D. Gillmore, MD, PhD

Alnylam, GlaxoSmithKline

    

Raymond Y. Kwong, MD, MPH

 

Siemens Medical Systems, Bayer, GlaxoSmithKline, Alynlam, Myokardia, the SCMR

   

Mathew S. Maurer, MD

Prothena Biosciences, GlaxoSmithKline, Ionis

Pfizer, Alnylam

   

Giampaolo Merlini, MD

Prothena Biosciences, Pfizer, 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 Biosciences, 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, Merck, MyoKardia, Novartis, Sanofi, United Therapeutics Corp.

Pfizer

 
  1. All other contributors have nothing relevant to disclose