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Page 8 of 29 Aguiar. Rare Dis Orphan Drugs J 2024;3:13 https://dx.doi.org/10.20517/rdodj.2023.56

FABRY DISEASE CARDIOMYOPATHY BIOMARKERS
Currently, imaging techniques are the most commonly used biomarkers of cardiac injury in FD, but some
biochemical biomarkers are also used in clinical practice [Table 3].

Troponin
Role in clinical monitoring
Cardiac troponins are well-validated biomarkers of cardiomyocyte injury. New generation/high-sensitivity
assays for cardiac troponin T enable the identification of minimal cardiac injury and have been associated
with poor outcomes in cardiomyopathies other than ischemic heart disease [77,78] . Two studies evaluating the
performance of troponin I as a biomarker of FD cardiomyopathy have shown that this analyte was elevated
in 21%-37% of the patients, with a very high diagnostic accuracy for LV hypertrophy or late gadolinium
enhancement (LGE) in cardiac magnetic resonance imaging (MRI) [79,80] . Comparable results were obtained
with high-sensitivity troponin T [81-85] and one study showed a strong correlation with T2 in basal
inferolateral wall ; in a retrospective analysis, over a follow-up period of 3.9 years, patients with elevated
[86]
[81]
troponin at baseline had significantly increasing replacement fibrosis .
Role in the assessment of treatment response
High-sensitivity troponin T remained stable in the first 12 months after ERT initiation, while increased in
untreated patients or in treated patients with advanced cardiomyopathy . This biomarker also remained
[87]
[88]
stable within the first 18 months after migalastat initiation .
Brain natriuretic peptide
Role in clinical monitoring and assessment of treatment response
Brain natriuretic peptide and the N-terminal fragment of its prohormone (NT-proBNP) have an established
role in determining the diagnosis and prognosis of heart failure [89,90] . NT-proBNP was evaluated as a
biomarker of early cardiac involvement in FD, showing significant correlations with parameters of diastolic
dysfunction and LV wall thickness [91,92] . Other studies showed that NT-proBNP is significantly higher in
patients with LGE in cardiac MRI and presented a significant correlation with the amount of LGE and the
T2 in the basal inferolateral wall and an inverse correlation with native T1 [83,86,93] . NT-proBNP remained
stable after ERT or migalastat initiation [87,88] .

Echocardiography
Nonetheless, cardiac imaging techniques are the mainstay in the assessment of FD cardiomyopathy.
Conventional two-dimensional and Doppler echocardiography is the standard imaging tool in the
identification and staging of cardiac involvement in FD disease, but it is not suitable for detecting subtle
myocardial dysfunction in the early course of FD cardiomyopathy [94,95] . Therefore, advanced
echocardiography techniques, such as tissue Doppler imaging (TDI) and strain and strain rate (SR) speckle-
tracking based echocardiography have been used in early cardiac involvement that precedes overt LV
hypertrophy and appearance of replacement myocardial fibrosis. Recently, an echocardiographic-based
staging of FD cardiomyopathy was proposed and was demonstrated to have clear prognostic value. FD
cardiomyopathy was categorized into four stages: stage 0 (no cardiac involvement); stage 1 (LV
hypertrophy); stage 2 (left atrium enlargement); stage 3 (ventricular impairment, defined as LV ejection
[96]
fraction < 50% or E/e′ ≥ 15 or TAPSE < 17 mm) .
Tissue Doppler imaging
There are several studies establishing the added value of TDI in the early detection of FD
cardiomyopathy [97-103] . In the first study on the evaluation of TDI in FD cardiomyopathy, it was reported that
echocardiography did not show any difference between FD patients without LV hypertrophy and controls