# Multi-Modality Cardiovascular Imaging Assessment in Fabry Disease
## 3 Diagnosis: Tissue Characterization in Early Disease
### Transthoracic Echocardiography  
Reduction in age-adjusted tissue Doppler (TDI) systolic (s') velocity and early myocardial relaxation velocity (e') is a consistent early finding in FD cardiomyopathy(see Figure 4). Case-cohort studies have demonstrated a reduction in both s' and e' in gene-positive, phenotype negative patients compared to normal controls. This reduction was intermediate in size compared to that found in gene-positive patients with LVH. This has been demonstrated not only in sarcomeric HCM mutations [21], but also in a study of 20 patients with FD (10 with LVH, 10 without) and 10 age- and sex-matched controls, a reduction that takes place regardless of gender and mutation. Subsequent histological examination of endomyocardial biopsies demonstrated that reductions in TDI velocities were proportionate to the accumulation of sphingolipid in the gene+/LVH+ group and the gene+/LVH- group compared to controls. Furthermore, the observed reduced tissue velocities in the gene+/LVH- group correlated with higher LV end-diastolic filling pressures during cardiac catheterization [22]. Moreover, introduction of therapy based on reduced TDI velocities before development of LVH may be advantageous. In a study of 76 patients, the finding of reduced s' and e' prior to onset of LVH was not only replicated but the severity of reduction was also found to be inversely proportional to the risk of developing LVH. When comparing LVH- patients, 80% went on to develop abnormal TDI without ERT compared with 33% on ERT [23]. The limitation of TDI in clinical practice is that, although case-control studies consistently differentiate gene+/LVH+ from gene+/LVH- and controls, the absolute difference between the groups is small. In particular, there is considerable overlap between the values for gene+/LVH- cases and controls, meaning that defining those with an early phenotype on which to make a solid judgement about introducing treatment is difficult.  
Both Doppler-derived and 2D speckle tracking measurements of strain and strain rate are further useful developments for early detection of subclinical regional and longitudinal dysfunction in FD (see Figure 5) [24]. Impaired regional and longitudinal global longitudinal strain (GLS) has been used to quantify response to ERT [25]. In a prospective study of 16 patients with FD, longitudinal and radial strain and strain rates were significantly impaired compared to normal controls but improved over a 12 month period of treatment with ERT [24]. In an extended study of 32 FD patients over 3 years, there was evidence of benefit of early ERT based on functional improvement in 2D speckle tracking according to the presence or absence of fibrosis--in those with fibrosis documented on late enhancement imaging, both radial and longitudinal peak systolic strain rate continued to decline despite treatment, but improved in those without fibrosis [26]. These data provided some of the first evidence to suggest ERT was no longer effective when introduced later in the course of FD cardiomyopathy  
Figure 4: Pulsed-wave Doppler and TDI TTE in a patient with Fabry cardiomyopathy. **(A)**: Pulsed-wave Doppler through the mitral valve leaflets showing E/A 0.7 and deceleration time 143 ms with LA dilatation; **(B)**: Lateral TDI showing reduced lateral s′ and e′ velocities; **(C)**: Septal TDI showing reduced septal s′ and e′ velocities.  
Novel technologies are emerging in identifying myocardial fibrosis in both ischaemic and non-ischaemic cardiomyopathies [27], including the use of contrast-enhanced 3D TTE, speckle tracking 3D TTE, pulse cancellation ultrasound technique, and radiomic-based analysis. Their application has not been tested in FD specifically but provides an area of future work to identify fibrosis and scar associated with FCM which enables clinicians to stage and prognosticate with both TTE and CMR.