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Page 2 of 11 Pica et al. Vessel Plus 2022;6:10 https://dx.doi.org/10.20517/2574-1209.2021.81

[3]
Cardiac dysfunction results from infiltration, but there is also evidence for a toxic effect of light chains .
ATTR amyloidosis is most commonly from wild-type protein, with age-related misfolding (ATTRwt) and
less commonly from variant TTR (ATTRv), caused by a germline mutation in ATTR gene. ATTRwt often
involves the heart, with a prevalence around 15% in the seventh decade in patients with heart failure and
preserved EF or in association with severe aortic stenosis . ATTRv presents at an earlier age, following a
[4-6]
varied clinical course depending on the specific mutation inherited, with either cardiomyopathy or
polyneuropathy. ATTR has a median survival of 3-4 years from presentation in patients with predominantly
[7,8]
cardiomyopathy .
Endomyocardial biopsy is the reference standard for diagnosing CA, with histopathological evidence of
diffuse infiltration of the subendocardial layer and sometimes a patchy or transmural pattern.
Immunoelectron microscopy, immunohistochemistry, or mass spectrometry can identify TTR and AL fibril
types, and DNA analysis is used to differentiate ATTRv from ATTRwt, thus identifying causative
mutations.

Besides limited availability, invasiveness, and requirement of expertise, a biopsy sample may not be
[9]
representative of the entire heart, particularly in the early stages, with focal deposits . The expert consensus
statement for the diagnosis of cardiac amyloidosis recommends a positive biopsy for amyloid fibrils. In
[10]
the absence of endomyocardial biopsy-proven disease, cardiac amyloidosis can be diagnosed using a
combination of extracardiac biopsy, Tc-PYP/DPD scintigraphy, myocardial uptake of targeted positron
emission tomography amyloid tracers, echocardiographic, and/or CMR findings.

Very importantly, Tc-PYP/DPD scintigraphy consistent with ATTR cardiac amyloidosis combined with
suggestive Echo or CMR findings obviates the need for invasive biopsy, allowing a clinical diagnosis of
[11]
ATTR cardiac amyloidosis in the absence of serum and/or urine light chains . Otherwise, the presence of a
clonal plasma cell process makes a histological diagnosis still mandatory.

CA is an increasing focus for the imaging community, driven by expensive new therapeutic options,
increasing survival in AL, and wider recognition of ATTR amyloidosis in the elderly; hence, early diagnosis
of CA and typing of fibrils are critical.

Available imaging modalities offer substantial advantages for non-invasive diagnosis and estimation of
amyloid burden, and they can be easily repeated in the follow-up, with complementary information.

The combination of ECG low voltages with LV thickening is highly suggestive for CA . ATTR often shows
[12]
more severe, asymmetric hypertrophy and systolic dysfunction as compared to AL, presenting with
[13]
moderate symmetric hypertrophy, sometimes with non-hypertrophic LV . Small ventricles, enlarged atria,
diastolic dysfunction, right ventricular hypertrophy, thickened valves and interatrial septum, and pericardial
and pleural effusions are also common.

Besides a fundamental role for the initial screening, echocardiography may be non-specific, particularly in
earlier stages. Over the years, more specific echocardiographic features have been recognized, such as
[13]
reduction in LV longitudinal strain (LS). Global LS is significantly impaired in CA even with normal EF ,
and AL-CA showed worse strain values as compared with ATTR-CA . A regional pattern that spares the
[13]
apex, giving the characteristic “bull’s-eye” appearance on strain polar maps, is sensitive (93%) and specific
(82%) to distinguish CA from other causes of LVH . However, although echocardiography can provide an
[14]
assessment of the likelihood of cardiac amyloid infiltration, it cannot be considered a definitive diagnostic