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

T2 mapping sequences, able to quantify myocardial edema, showed higher mean T2 values in both AL and
[37]
ATTR . Increased myocardial T2 values correlated with the presence of edema on histology, in the absence
[37]
of significant inflammation . Patients with untreated AL amyloidosis showed the greatest increase in
myocardial T2, but there was substantial overlap of T2 values between subtypes. Figure 3 shows a
comprehensive CMR assessment of patients with cardiac amyloidosis.

Due to its unique tissue characterization, CMR has a highly important role in the diagnostic evaluation of
suspected cardiac amyloidosis, in fact, the addition of LGE and mapping imaging can significantly
contribute to diagnosis of AL CA, especially when echocardiography is not conclusive. In ATTR patients,
bone scintigraphy Perugini Grade 2 or 3 with a suggestive echocardiogram is often diagnostic, but in
uncertain cases CMR examination is recommended and could be useful to detect early disease [22,31,32,38,39] .

STAGING OF CARDIAC INVOLVEMENT
Staging of cardiac involvement
Staging of CA is currently based on echocardiography and blood biomarkers, with limited accuracy when
confounders (hypertension, renal failure, and atrial fibrillation) are present [40-42] . Furthermore, none of these
parameters quantify the amyloid burden.

CMR explores the continuum of amyloid infiltration, showing correlation with clinical, bio-humoral, and
morpho-functional parameters, possibly representing a useful tool for early detection and stratification of
cardiac involvement.

First, LGE can be present in a proportion of patients in which routine assessment is not suggestive for
CA , contributing to earlier detection of CA, but it can also be focal or even absent in early stages. With
[38]
disease worsening, LGE transmural extent increases, and this is paralleled by higher T1 and ECV
values [31,32,43] .

Moreover, a limitation of LGE imaging is that it is not a quantitative marker in amyloidosis, owing to often
diffuse infiltration, thus limiting its capability to precisely track changes of myocardial substrate.
Quantitative T1 mapping overcomes these limitations, being an easy quantitative tool and more sensitive to
early disease than LGE.

Native T1 is very high in advanced disease, it is less in early stages, and, in this setting, ECV estimation
appears to be the most accurate parameter. ECV identified early CA in AL with values of ~0.40 and no other
evidence of cardiac involvement (no LGE, wall thickening, or biomarker elevation). This was also shown in
ATTR, where ECV was increased in a proportion of patients with possible ATTR (Perugini Grade 1) and no
LGE [31,32,43] .

The accuracy and precision of ECV measurements in the evaluation of substrate changes in the individual
patient suggest the potential role of this marker for staging purposes.

Some limitations of parametric mapping need to be highlighted. Different CMR systems, field strength, and
T1 mapping sequences have different normal ranges. Current recommendations are for normal reference
ranges to be defined locally and to perform phantoms quality control regularly at each center. Although
ECV demonstrated lower dependence on field strength, sequence choice, and imaging parameters, this is an
obstacle for the implementation of mapping in clinical practice. Further work is required to obviate the
need for local reference ranges, enabling the establishment of T1 and ECV reference standard to facilitate