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Aguiar. Rare Dis Orphan Drugs J 2024;3:13 https://dx.doi.org/10.20517/rdodj.2023.56 Page 11 of 29

Late gadolinium enhancement
LGE imaging techniques using cardiac MRI are the gold standard for non-invasive detection of focal
[131]
replacement fibrosis in the myocardium .

Between 31% and 77% of patients with FD disease may present LGE, with a characteristic mid-myocardial
distribution (sparing the subendocardium) in the inferolateral basal and mid basal segments of the LV wall,
that seems to be specific to FD cardiomyopathy [82,83,93,122,125,131-136] . Additionally, in FD, LGE was correlated
with histologic findings (myocardial collagen deposition) from autopsy . A greater proportion of male
[137]
patients present larger amounts of LGE in cardiac MRI [83,131,133] ; it was reported previously that only female
patients might present LGE with normal LV mass , but recent reports showed that this is also true for
[138]
some male patients [82,83,133,139] .

Several studies have reported a significant correlation between the amount of LGE and LV
mass [93,122,131,133,140,141] , and LGE correlates with abnormalities in regional myocardial function assessed by
speckle-tracking imaging studies [93,122,123,135,138,142] . However, the sensitivity of LGE to detect early cardiac
involvement, as expected due to the identification of irreversible replacement fibrosis, is limited: LGE is
uncommon in patients showing only TDI abnormalities (without LV hypertrophy) [93,143] .

Cardiac fibrosis, evaluated by LGE in cardiac MRI, tends to increase progressively, mainly in patients with
[82]
larger LGE volumes at baseline, even in patients with stable LV mass . Moreover, the annual increase in
LGE during the follow-up is an independent predictor of malignant ventricular arrhythmias, with sudden
cardiac deaths only occurring in the group of patients with LGE . Other studies confirmed that the
[144]
presence and the extent of LGE, as well as maximal wall thickness, are associated with a greater risk of
adverse cardiac events in FD patients [145,146] .

ERT does not seem to have any effect on LGE: the amount of LGE significantly increased in patients treated
for 12 months with agalsidase β (no patients without LGE at baseline developed LGE during ERT), and LV
mass only significantly decreased in patients without LGE at baseline . These results were further
[122]
confirmed with longer treatment periods, also showing some patients developing LGE even during
[144]
treatment with ERT . Moreover, as previously mentioned, the presence of LGE is one of the most
important predictors of response to ERT in terms of myocardial function and exercise capacity . Similar
[125]
results were found with migalastat, with no patients without LGE at baseline developing LGE during
treatment, but with an increase in LGE in patients who initially present LGE .
[147]
T1 mapping
A novel technique, T1 mapping, enables the measurement of native myocardial T1 (non-contrast
myocardial T1) and T1 after administration of gadolinium contrast. Native T1 allows for a better
characterization of the myocardium content, with increased values in the setting of fibrosis, edema, or
amyloid deposits and decreased values in iron overload or lipid storage. Measurement of T1 with
extracellular gadolinium-based contrast agents gives additional information about the extracellular volume
fraction and has been studied for assessment of diffuse fibrosis, with good histological correlations .
[148]
However, in FD, it has been more extensively studied as an imaging biomarker for early detection of cardiac
involvement and for distinguishing FD from other etiologies of concentric remodeling and hypertrophy
(due to lipid storage, yielding low native T1) , rather than for evaluation of diffuse fibrosis [150-154] .
[149]

Very high (> 95%) diagnostic accuracy of native T1 in distinguishing between FD cardiomyopathy and
other forms of cardiomyopathy has been reported [85,152,153,155,156] . Septal native T1 is low in around 90% of the