Amyloidoses are protein-folding disorders in which more than one organ is infiltrated by proteinaceous deposits known as amyloid. The deposits are derived from one of several amyloidogenic precursor proteins, and the prognosis of the disease is determined both by the organ(s) involved and the type of amyloid. Amyloid involvement of the heart, cardiac amyloidosis, carries the worst prognosis of any involved organ, and light-chain (AL) amyloidosis is the most serious form of the disease.¹ Cardiac amyloidosis may be due to myocardial deposition of transthyretin protein derived from the liver known as transthyretin cardiac amyloidosis (ATTR) or may be due to AL amyloidosis with myocardial deposition of immunoglobulin light-chain proteins derived from a clone of plasma cells.¹

Clinical features suggestive of cardiac amyloidosis are recurrent unexplained heart failure, particularly in African Americans males >60 years old with preserved left ventricular ejection fraction, an unexplained increase in left ventricular wall thickness (>12 mm), and a restrictive left ventricular filling pattern suggestive of increased filling pressures. There is usually left atrial dysfunction in the absence of atrial fibrillation and an abnormal global longitudinal strain (GLS) with apical sparing pattern.² Other clinical features may include peripheral/autonomic neuropathy, macroglossia, carpal tunnel syndrome, periorbital bruising, stroke, postural hypotension, fatigue, weight loss, pedal edema, renal dysfunction, diarrhea, and constipation.³ On cardiac magnetic resonance imaging (CMR), diffuse late gadolinium enhancement as well as nulling of myocardium before or at the same inversion time as the blood pool and extensive extracellular volume (ECV) expansion are combined with structural findings of increased wall thickness and myocardial mass to diagnose cardiac amyloidosis.³ Of note, echocardiography and CMR are unable to differentiate ATTR from AL amyloidosis.

Compared with CMR and echocardiography, cardiac planar and single-photon emission computed tomography (SPECT) imaging with bone avid radiotracers such as technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) and technetium-99m pyrophosphate (99mTc-PYP) is unique in being able to noninvasively differentiate ATTR from AL amyloidosis with a great degree of accuracy, particularly when performed with adjunctive clonal analysis with free light chain immunofixation to exclude AL amyloidosis with a 100% positive predictive value (confidence interval 98.0-100).^4,5

ATTR has significant cardiac involvement compared with AL amyloidosis and is often associated with bilateral carpal tunnel syndrome and neuropathy.² ATTR may be wild type (normal) transthyretin (ATTRwt) or mutant (hereditary) transthyretin (ATTRm). ATTRwt has a marked male predominance, with a male-to-female prevalence ratio of 15:1, and usually occurs at >65 years of age.² ATTRwt has more frequent cardiac involvement and is usually preceded by carpal tunnel syndrome by 5-10 years.² ATTRm usually occurs at a younger age (>40 years) and may occur in either males or females, with a slight male predominance.² There is a common African American variant of ATTRm that has a prevalence of 3-4% in the US African American population and is due to a mutation in the Val122Ile gene.² This variant of ATTRm usually occurs at an older age (60-65 years) compared with the other forms of ATTRm.²

The population prevalence of ATTR is less certain. ATTR may not be as rare as previously thought. Autopsy data have demonstrated that among adults >80 years of age, 25% have transthyretin amyloid deposits in the myocardium. Among patients with heart failure with preserved left ventricular ejection fraction, autopsy data reveal amyloid deposits in 32% of those >75 years of age compared with 8% of those <75 years of age.⁶

The use of bone avid radiotracers such as 99mTc-DPD/PYP in accurately differentiating ATTR from AL amyloidosis has dramatically changed the diagnostic and management approach for cardiac amyloidosis, which was often previously challenging to diagnose noninvasively. The development of novel therapies for ATTR have heightened the importance of early and accurate diagnosis of this disease with cardiac imaging. A multimodality cardiac imaging approach and thorough clinical evaluation are vital in the diagnosis, prognostication, treatment, and follow-up of these patients. This has led to the conception and ultimate publication of the multi-societal cardiac amyloidosis imaging consensus statements.^3,7 The following are the top 10 points to remember when diagnosing, assessing prognosis, and determining therapeutic response of cardiac amyloidosis with cardiac imaging.

The following are the top 10 points to remember when diagnosing, assessing prognosis, and determining therapeutic response of cardiac amyloidosis with cardiac imaging:

1. 99mTc-DPD/PYP planar and SPECT imaging is useful in diagnosing ATTR but does not exclude the presence of AL amyloidosis. In patients with ATTR, transthyretin proteinaceous deposits in the myocardium have a very strong affinity for bone avid radiotracers such as 99mTc-DPD/PYP; this is contrasted with patients with AL amyloidosis in whom the plasma cell-derived protein deposits do not share the same affinity.8 When performing 99mTc-DPD/PYP to diagnose ATTR, plasma cell clonal analysis with serum and urine immunofixation, serum free light chain assay, and immunoglobulin analysis should be performed for all patients regardless of the 99mTc-PYP scan results to rule out AL amyloidosis.³
2. Equivocal 99mTc-DPD/PYP results may occur in early ATTR or in AL amyloidosis. Equivocal 99mTc-DPD/PYP results, defined as a Perugini Grade 1 uptake in the myocardium, may represent AL amyloidosis or early ATTR. Therefore, these patients will need further specialized assessment for diagnosing cardiac amyloidosis; histological confirmation and typing of cardiac amyloidosis are recommended.³
3. SPECT imaging is useful when performing 99mTc-DPD/PYP imaging. SPECT imaging should be considered to avoid erroneous results due to blood pool uptake and to confirm myocardial radiotracer uptake. SPECT is also useful to avoid overlap of bone uptake, to distinguish blood pool activity from myocardial activity, to assess the distribution of myocardial 99mTc-PYP uptake in individuals with positive planar scans, to identify 99mTc-PYP uptake in the interventricular septum (commonly involved in amyloidosis), and to quantify the degree of myocardial uptake by comparison to rib uptake.⁹
4. 99mTc-DPD/PYP is not recommended in monitoring therapeutic response. There is a paucity of research data on the use of serial imaging with bone avid radiotracers in the detection of disease progression or improvement of disease state with treatment. A small, single-center study involving 20 patients and use of 99mTc-PYP did not show any significant change in myocardial radiotracer retention despite clinical progression of the disease as determined by New York Heart Association functional class, laboratory biomarkers, echocardiographic parameters, progression to cardiac transplantation, and/or death. Therefore, serial SPECT 99mTc-DPD/PYP scintigraphy is currently not recommended to assess disease progression or response to therapy.^3,10
5. Novel SPECT radiotracers and cardiac positron emission tomography radiotracers such as 123 I-metaiodobenzylguanidine and florbetapir, have shown promise in being able to follow response to treatment and assess prognosis, respectively. Patients with amyloidosis are prone to autonomic dysfunction from amyloid infiltration of myocardial and nerve conduction tissue, resulting in rhythm disorders. Autonomic dysfunction is most common in ATTR and particularly in ATTRm, in which it has been studied extensively.³ Notably, cardiac dysautonomia may occur independent of the presence of a typical restrictive cardiomyopathy. In patients with ATTRwt, polyneuropathy and dysautonomia are less common, seen in approximately 9% of cases.³ Cardiac denervation evidenced by 123 I-metaiodobenzylguanidine occurs earlier than amyloid deposition detection by 99mTc-DPD/PYP scintigraphy in ATTRm and thus allows for earlier detection and treatment of the disease. 123 I-metaiodobenzylguanidine has been specifically studied in cardiac amyloidosis, and semi-quantitative analysis of I-metaiodobenzylguanidine cardiac uptake compared to background (heart-to-mediastinum ratio) provides indirect information of amyloid infiltration in the sympathetic nerve system.³ Decreased heart-to-mediastinum ratio at 4 hours after tracer administration (late heart-to-mediastinum ratio) reflects the degree of sympathetic dystonia and is an independent prognostic factor in the development of ventricular dysrhythmia.³ Positron emission tomography tracers (18F-florbetapir and 18F-florbetaben) show promising results to detect and monitor the progression of cardiac amyloidosis.¹⁰ However, these are not yet ready for regular clinical use.¹⁰ More research is necessary in this area to determine the best diagnostic strategy to monitor disease progression or regression.
6. The absence of the classical apical sparing GLS pattern on echocardiography does not rule out the presence of cardiac amyloidosis. Abnormal GLS in the mid and basal walls of the left ventricle with normal values in the apex, known as the apical sparing pattern (or "cherry on top" pattern), is 93% sensitive and 82% specific in identifying patients with cardiac amyloidosis. This pattern does not differentiate ATTR from AL amyloidosis. Although the sensitivity and specificity are relatively high, if clinical suspicion is high, the absence of this pattern does not rule out cardiac amyloidosis.¹¹
7. Echocardiography and CMR with ECV may be useful in monitoring response to therapy. Transthoracic echocardiography with GLS imaging is reasonable to monitor disease progression and/or response to therapy in cardiac amyloidosis. CMR assessment of left ventricular wall thickness and mass as well as assessment of ECV is emerging as a tool to assess disease progression and response to therapy.³
8. Genotype testing is important for patients diagnosed with ATTR. ATTR may be due to ATTRwt or ATTRm. There are more than 100 genetic variants of ATTR that are associated with amyloidosis. However, only a few of these variants, including Val30Met, Thr60Ala, Ser77Tyr, and Val122Ile, are responsible for the majority of cases of hereditary ATTR globally.¹² Inheritance is autosomal dominant with variable penetrance.¹² Patients who are diagnosed with ATTR should have genotype testing to determine if these patients have ATTRm and determine the genotypic variation because this determines treatment options and has consequences regarding familial inheritance for patients' relatives. Screening for ATTR is also appropriate for individuals with known or suspected familial amyloidosis presenting with new symptomatic heart failure.⁷
9. There are special patient populations with clinical characteristics that are secondary to cardiac amyloidosis who have an increased incidence of ATTR. These populations include patients with unexplained peripheral sensorimotor neuropathy, bilateral carpal tunnel syndrome, spontaneous biceps tendon rupture, or familial amyloid polyneuropathy or transthyretin amyloid polyneuropathy. Familial amyloid polyneuropathy is a rare, inherited, and progressive disease caused by the abnormal deposits of proteins or amyloids around peripheral nerves and other tissues. Familial amyloid polyneuropathy was first identified in 1952, when it was observed in several families in Portugal.¹³ Val30Met is the most common mutation and the only one found in large foci of patients. Foci of patients have also been found in Japan and Sweden.¹³ In these patients, it may be appropriate to screen for the presence of ATTR if they present with symptomatic heart failure.⁷ ATTR is prevalent in 16% of patients (4% in females and 22% in males) with severe low-flow, low-gradient calcific aortic valve stenosis undergoing transcatheter aortic valve replacement who have a mildly reduced left ventricular ejection fraction. These patients had an average tissue Doppler mitral annular s' of less than 6 cm/second, and this finding may therefore prompt 99mTc-PYP imaging and subsequent testing for ATTR. There is a need for further prospective studies to determine outcomes after transcatheter aortic valve replacement in patients with and without ATTR.¹⁴
10. Coronary microvascular dysfunction is often severe in cardiac amyloidosis and may be reversible. Even in the absence of epicardial coronary artery disease, coronary microvascular dysfunction is very prevalent in patients with cardiac amyloidosis. Of note, almost all subjects with cardiac amyloidosis (>95%) had significantly reduced peak stress myocardial blood flow (<1.3 ml/g/min) (p < 0.0001). This may explain symptoms of angina in these patients. There is a need for further research in this area to determine if specific therapy directed at cardiac amyloidosis may improve coronary microvascular function in amyloidosis.¹⁵

Conclusion

As the field of cardiac amyloidosis evolves with more timely and accurate diagnosis, we are learning more about this disease. Development of therapeutic options for ATTR has given hope to many of these patients. This field is rapidly evolving, and imagers need to stay up to date with the latest guidelines.

References

1. Bullock-Palmer RP. Diagnosing cardiac amyloidosis: A wealth of new possibilities with nuclear cardiac imaging. J Nucl Cardiol 2019;May 13:[Epub ahead of print].
2. Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. J Am Coll Cardiol 2016;68:1323-41.
3. Dorbala S, Ando Y, Bokhari S, et al. 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. J Nucl Cardiol 2019;26:2065-123.
4. Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging 2013;6:195-201.
5. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation 2016;133:2404-12.
6. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis. Circulation 2017;135:1357-77.
7. Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 2 of 2-Diagnostic Criteria and Appropriate Utilization. J Card Fail 2019;25:854-65.
8. Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46:1076-84.
9. Dorbala S, Bokhari S, Miller E, Bullock-Palmer R, Soman P, Thompson R. ASNC Practice Points: 99mTechnetium-Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis (American Society of Nuclear Cardiology website). 2019. Available at https://www.asnc.org/Files/Amyloid/ASNC%20Practice%20Point-99mTechnetium-Pyrophosphate.2019.pdf. Accessed February 2019.
10. Singh V, Falk R, Di Carli MF, Kijewski M, Rapezzi C, Dorbala S. State-of-the-art radionuclide imaging in cardiac transthyretin amyloidosis. J Nucl Cardiol 2019;26:158-73.
11. Phelan D, Collier P, Thavendiranathan P, 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.
12. Patel KS, Hawkins PN. Cardiac amyloidosis: where are we today? J Intern Med 2015;278:126-44.
13. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis 2013;8:31.
14. Castaño A, Narotsky DL, Hamid N, 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. Dorbala S, Vangala D, Bruyere J Jr, et al. Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis. JACC Heart Fail 2014;2:358-67.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Heart Transplant, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Computed Tomography, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Nuclear Imaging

Keywords: Diagnostic Imaging, Cardiac Imaging Techniques, Amyloid, Amyloid Neuropathies, Familial, Amyloidogenic Proteins, Amyloidosis, African Americans, Aortic Valve Stenosis, Aniline Compounds, Autopsy, Atrial Fibrillation, Biomarkers, Cardiomyopathy, Restrictive, Carpal Tunnel Syndrome, Confidence Intervals, Consensus, Contrast Media, Coronary Artery Disease, Denervation, Diphosphates, Dystonia, Echocardiography, Disease Progression, Ethylene Glycols, Fatigue, Edema, Follow-Up Studies, Genotype, Heart Failure, Heart Transplantation, Heart Ventricles, Hypotension, Orthostatic, Immunoglobulin Light Chains, Gadolinium, Kidney Diseases, Liver, Macroglossia, Mediastinum, Magnetic Resonance Imaging, Neural Conduction, Penetrance, Plaque, Amyloid, Plasma Cells, Polyneuropathies, Myocardium, Positron-Emission Tomography, Positron-Emission Tomography, Prevalence, Prealbumin, Primary Dysautonomias, Prognosis, Prospective Studies, Radionuclide Imaging, Stilbenes, Reference Values, Stroke, Stroke Volume, Technetium, Technetium Tc 99m Medronate, Technetium Tc 99m Pyrophosphate, Tendons, Tomography, Emission-Computed, Transcatheter Aortic Valve Replacement, Weight Loss

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