Hereditary transthyretin (hATTR) amyloidosis is a rare, multisystemic, progressive disease characterized by the accumulation of abnormal transthyretin protein (TTR) in various tissues and organs. It is an autosomal dominant disease that is endemic to certain geographical regions.

Affected individuals inherit mutations to the TTR gene which lead to decreased folding stability of the TTR homotetramer, favoring its dissociation into partially unfolded species that self-assemble into amyloid fibrils.1 The most common mutation worldwide is Val30Met, in endemic and nonendemic countries, although over 130 distinct mutations have been identified in 29 different countries—with the vast majority being pathogenic.1,2 In the United States, the most common mutations from most to least prevalent are V122I, T60A, and V30M.3

The clinical features of hATTR are heterogenous and multisystemic. Symptoms include gastrointestinal dysfunction, autonomic dysfunction, ocular manifestations, carpal tunnel syndrome, polyneuropathy, compromised renal function, and cardiac manifestations. Patients with hATTR who harbor an S23N, L11M, T60A, V122I, or I68L mutation are more likely to present with cardiac features.4

Cardiac involvement may take the form of cardiomyopathy, conduction block, or arrhythmia. Some mutations are more strongly correlated with cardiac manifestations than others. For instance, the Val122Ile mutation is associated with cardiac disease in approximately 97% of cases.3

Cardiac amyloidosis is a form of restrictive cardiomyopathy that results from the accumulation of amyloid fibrils within the myocardium producing a clinically diverse range of systemic diseases. There are 2 classes of amyloid proteins responsible for cardiac amyloidosis: amyloid immunoglobulin light chain (AL) and amyloid transthyretin (ATTR). ATTR is further subdivided into wild-type (ATTRwt) and hereditary (ATTRv). ATTRv amyloidosis (“v” for variant) results from the accumulation of defective TTR due to inherited mutations seen in hATTR.

Read more about the epidemiology of hATTR

The clinical course, prognosis, and treatment approach in cardiac amyloidosis are highly heterogeneous. AL amyloidosis is a rapidly progressive disease that involves the heart in up to 75% of patients, with a median survival of less than 6 months if untreated. ATTRv amyloidosis follows a more variable course depending on the specific gene mutation present, involves different organ systems, and displays age-dependent penetrance (the clinical phenotype develops as age advances). ATTRv and ATTRwt cardiac amyloidosis are important causes of diastolic heart failure that remain widely unrecognized.5

Shortcomings in Standardization

The diagnosis of cardiac amyloidosis is a challenge due to several factors. These include clinical overlap with common diseases that result in myocardial thickening and the unfamiliarity with proper diagnostic algorithms that generally accompanies rare diseases.

Medical technology has made monumental leaps over the past 2 decades and the list of noninvasive imaging options for evaluating cardiac amyloidosis is ever-growing. However, there was previously little guidance available to healthcare professionals on standardized imaging pathways in cardiac amyloidosis, which may contribute to delayed diagnosis and increased morbidity. 

The American Society of Nuclear Cardiology (ASNC) has assembled a writing group with expertise in cardiovascular imaging and amyloidosis to produce a comprehensive review of evidence on cardiac imaging and defined standardized technical protocols for the acquisition, interpretation, and reporting of these noninvasive imaging techniques in the evaluation of cardiac amyloidosis. Additionally, a consensus statement addresses the development of consensus diagnostic criteria for cardiac amyloidosis, identifies consensus clinical indications, and provides ratings on appropriate utilization in these clinical scenarios.5

Imaging in Cardiac Amyloidosis

Imaging remains a requisite component of the diagnostic algorithm for cardiac amyloidosis. It can capture the cardiac functional impairment caused by amyloid infiltration, assess hemodynamic status, and may directly visualize cardiac remodeling during therapy.5 Several tools and techniques are available to clinicians.

Echocardiography

Echocardiography plays a key role in the noninvasive diagnosis of cardiac amyloidosis. Its use focuses on visualizing morphological findings related to amyloid infiltration, especially thickened left ventricle (LV) walls of more than 1.2 cm in the absence of other plausible causes of LV hypertrophy. These findings when paired with low-voltage electrocardiogram (ECG) are suggestive of cardiac amyloidosis. Echocardiographic parameters should be combined with electrocardiographic, clinical, biomarker, and other imaging findings to maximize diagnostic accuracy.5

Comprehensive 2D echocardiography including quantitative tissue Doppler imaging (TDI) is a requirement for all patients with unexplained LV wall thickening and clinical suspicion of cardiac amyloidosis.5 Speckle-tracking strain analysis (strain image) should also be performed when available.5

Parameters for acquisition and reporting include LV wall thickness, myocardial echogenicity, atrial size and function, interatrial septum and valves, presence of pericardial effusion, diastolic function, and estimated pulmonary artery (PA) systolic pressure and right atrial (RA) pressure. There are several abnormal parameters that may be seen in cardiac amyloidosis: 5

  • Increased LV wall thickness (>1.2 cm) and increased relative wall thickness (>0.42). Increased LV wall thickness relative to QRS voltage on ECG is especially suggestive.
  • Increased myocardial echogenicity may be seen as sparkling or having a hyper-refractile texture; however, these findings are not highly specific for cardiac amyloidosis and may be observed in other infiltrative cardiomyopathies and end-stage renal disease.
  • Abnormal atrial enlargement and dysfunction is a nonspecific but important supportive finding and offers insight into stroke and embolic risk.
  • Thickening of the interatrial septum is another suggestive but nonspecific finding.
  • Diastolic dysfunction of grade 2 or worse with a high ratio of early to late atrial mitral flow velocities (E/A ratio) and a reduced early mitral flow (E) velocity deceleration time of less than 150 ms. Diastolic dysfunction on Doppler is a useful prognostic indicator. A severely reduced A wave (late atrial mitral velocity) can be due to left atrial failure, which can be helpful in determining the risk of stroke.
  • Estimated PA systolic and RA pressure are important parameters to estimate volume status and optimize diuretic dosing. Increased pressure is more than 35 mmHg for PA and at least 10 mmHg for RA.
  • Reduced tissue Doppler s’, e’, and a’ velocities (<5 cm/s) can be useful and is usually suggestive of the diagnosis, but sensitivity may be suboptimal in early disease. A reduction in s’, e’, and a’ TDI velocities is called the “5-5-5” sign.

When available, strain imaging is recommended. A decreased global longitudinal LV strain (absolute value <15%) and a positive “cherry-on-the-top” sign on longitudinal strain bullseye map are suggestive. The latter appears when there is preservation of apical longitudinal strain with severely abnormal basal and mid-LV longitudinal strain.5

Read more about testing for hATTR.

An echocardiogram report that is strongly suggestive of cardiac amyloidosis is one with 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. Features that are not suggestive are a normal LV wall thickness, normal LV mass normal atrial size, septal or lateral tissue Doppler e’ velocity >10 cm/s. Echocardiogram is not capable of differentiating AL from TTR cardiac amyloidosis. Plasma cell dyscrasia with serum and urine immunofixation and serum flow cytometry assay may be used to exclude AL amyloidosis. ATTR cardiac amyloidosis can be excluded with 99mTc-PYP/DPD/HMDP (see below). 5

Cardiac Magnetic Resonance

Cardiac magnetic resonance (CMR) imaging allows for noninvasive, high-resolution morphologic and functional assessment. A comprehensive CMR-based evaluation of cardiac structure and function and myocardial tissue characterization is helpful in the diagnosis of cardiac amyloidosis. That includes assessment of all 4 chambers using cine imaging, evaluation of native T1 signal (assessed on noncontrast T1 mapping), assessment of late gadolinium enhancement (LGE), and extracellular volume (ECV) measurement.

New LGE imaging techniques using phase-sensitive inversion recovery sequence (PSIR) reduce operator dependency (a pitfall of traditional LGE) and grant LGE superior sensitivity and specificity compared to echocardiogram or CMR functional assessment. A recent meta-analysis estimated a sensitivity of 85% and a specificity of 92% for CMR-based LGE in diagnosing cardiac amyloidosis.

Typical CMR findings in patients with established cardiac amyloidosis include diffuse LGE, “nulling of myocardium before or at the same inversion time as the blood pool,” and extensive ECV expansion. AL cardiac amyloidosis is associated with predominant subendocardial LGE while transmural LGE is more prevalent in ATTR cardiac amyloidosis; however, this is not sufficient to distinguish between both entities since these patterns may be seen in either situation. CMR parameters should be considered in clinical context with electrocardiographic, clinical, biomarker, and other imaging findings to maximize diagnostic accuracy.5  

Required parameters for standardization interpretation and reporting of CMR for cardiac amyloidosis include LV function and morphology (encompassing LV function, wall thickness, stroke volume index, mass, atrial size, and function based on Simpson’s method, and presence of pericardial effusion) and amyloid imaging using LGE. Amyloid imaging using myocardial signal suppression pattern and amyloid quantitation using native T1 mapping precontrast and T1 mapping postcontrast (estimates ECV) are recommended parameters for acquisition and reporting.  

CMR findings that are strongly suggestive of cardiac amyloidosis include increased LV wall thickness, increased LV mass, biatrial enlargement, typical diffuse or global LGE pattern, difficulty in achieving myocardial nulling, significantly increased ECV (>0.40), and small pericardial and/or pleural effusions.

Radionuclide Imaging

Bone-Avid Radiotracers for Cardiac Scintigraphy: 99mTc-PYP/DPD/HMDP

99mTc-PYP/DPD/HMDP cardiac uptake has a positive correlation with LV wall thickness and mass, troponin T, N-terminal-pro brain natriuretic peptide (NT-proBNP), and ECV. It correlates negatively with LV ejection fraction.

A multicenter study using 99mTc-PYP found that a heart-to-contralateral lung (H/CL) ratio of more than 1.5 was associated with worse survival in patients with ATTR cardiac amyloidosis. Other imaging parameters associated with a worse prognosis include increased LV mass, lower global longitudinal strain, increased right ventricular wall thickness, and higher native T1 and ECV.

The imaging procedure involves the intravenous infusion of 99mTc-PYP, 99mTc-DPD, or 99mTc-HMDP followed by obtaining a SPECT/CT of the chest at 1 hour (early), or 2 or 3 hours (late). Images with no myocardial uptake and normal bone uptake are categorized as grade 0. If myocardial uptake is less than rib uptake, grade 1 is assigned. Grade 2 uptake refers to imaging in which myocardial uptake is equal to rib uptake and grade 3 is assigned when myocardial uptake exceeds rib uptake with mild/absent rib uptake. A 99mTc-PYP/DPD/HMDP uptake of grade 2 or 3 is strongly suggestive of cardiac amyloidosis.

H/CL lung uptake ratio assessment is performed when applicable which is calculated as the fraction of heart circular ROI (region of interest) mean counts to contralateral lung ROI mean counts. H/CL ratios of ≥1.5 at 1 hour can accurately identify ATTR cardiac amyloidosis if myocardial PYP uptake is visually confirmed on SPECT and systemic amyloidosis is excluded. ATTR cardiac amyloidosis can also be identified by an H/CL ratio of ≥1.3 at 3 hours.5

Autonomic Myocardial Innervation Imaging: I-mIGB scintigraphy

Patients with ATTR cardiac amyloidosis, especially ATTRv, may develop cardiac sympathetic denervation, which is associated with decreased survival. I-mIGB cardiac uptake compared to background (heart-to-mediastinal ratio [HMR]) is used as an indirect method of evaluating amyloid infiltration in the sympathetic nervous system of the heart. A late decreased HMR of less than 1.6 is associated with a poor prognosis and can be used to select ATTRv patients who are candidates for liver transplantation. The role of late-HMR reduction in AL and ATTRwt patients with cardiac involvement is unclear.5

Consensus Algorithm for Noninvasive Diagnosis of Cardiac Amyloidosis

After reviewing all available data, a consensus algorithm has been developed by the ASNC for the noninvasive diagnosis of cardiac amyloidosis. They are described in the steps below.5

Step 1: Diagnostic Suspicion

Recognizing the clinical features of amyloidosis (cardiac and systemic forms) is paramount. Clinical symptoms include heart failure, peripheral/autonomic neuropathy, macroglossia, carpal tunnel syndrome, periorbital bruising, stroke, atrial fibrillation, postural hypotension, fatigue, weight loss, pedal edema, renal dysfunction, diarrhea, and constipation.

Step 2: Evaluate for Cardiac Involvement

To evaluate for cardiac involvement, perform ECG, ECHO, and/or CMR. Typical findings in cardiac amyloidosis for each imaging modality are discussed above.

Step 3: Bone scintigraphy with 99mTc-PYP/DPD/HMDP + Serum and urine immunofixation + serum free light chain assay.

Serum and urine immunofixation and serum free light chain assays are performed to detect abnormal clonal abnormalities and are combined with bone scintigraphy with 99mTc-PYP/DPD/HMDP to determine amyloidosis type.  Among patients with suspected cardiac amyloidosis, grade 2 or 3 uptake of 99mTc-PYP/DPD/HMDP in the absence of a clonal abnormality is highly specific to diagnose ATTR cardiac amyloidosis, avoiding the need for endomyocardial biopsy. The presence of monoclonal protein in grade 2 or 3 uptake requires specialized assessment for diagnosis involving histological confirmation and amyloid protein typing.

See additional information on hATTR guidelines.

Specialized assessment is also required in patients with grade 1 uptake regardless of monoclonal protein presence and for grade 0 uptake with positive monoclonal protein. Grade 0 uptake with no monoclonal protein makes cardiac amyloidosis of any type unlikely.

Step 4: TTR genotyping (if necessary)

Patients with grade 2-3 uptake of 99mTc-PYP/DPD/HMDP without monoclonal protein are likely suffering from TTR amyloidosis. TTR genotyping is necessary to reveal if the patient is suffering from ATTRv or ATTRwt amyloidosis.

This diagnostic algorithm, for the first time, offers clear guidance and standardization for multimodal, noninvasive imaging for patients with cardiac amyloidosis. It is the goal of the authors that this consensus algorithm improves diagnostic accuracy and patient outcomes in patients with this disease.

References

1.         Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overview. Neurol Sci. Published online November 14, 2020. doi:10.1007/s10072-020-04889-2

2.        Luigetti M, Romano A, Paolantonio AD, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. TCRM. 2020;16:109-123. doi:10.2147/TCRM.S219979

3.         Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017:23-S0.

4.         What is hereditary ATTR amyloidosis (hATTR)? hATTR Amyloidosis. Accessed October 21, 2022.

5.         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. Circ Cardiovasc Imaging. 2021;14(7):e000029. doi:10.1161/HCI.0000000000000029