General Discussion and Future Perspectives | 191 Figure 2. Integration of multimodality data The displayed data are from an early ARVC patient who underwent CMR, ECG imaging and echocardiography on the same day. The carrier of a pathogenic variant was diagnosed with ARVC based on family history (major TFC), prolonged terminal activation duration on the ECG (minor TFC) and >500 premature ventricular beats on the surface ECG (minor TFC). CMR showed no signs of fibrosis, a preserved ejection fraction of both ventricles and no regional akinesia or dyskinesia. ECG imaging showed relatively homogeneous electrical activation with the subtricuspid segment of the RV lateral wall and the basal segment of the anterolateral being the latest activated regions. Echocardiographic deformation imaging showed indeed slightly delayed mechanical activation of these areas. Besides, longitudinal strain was clearly diminished in the subtricuspid region with slight post-systolic shortening. In the Digital Twin model, these deformation abnormalities were estimated to result from decreased myocardial compliance, rather than an electrical disease substrate. Achilles heels of the heart The human heart has adapted to highly specific requirements in order to survive under all kinds of extreme conditions.19 Although evolution lead to an intricate design which seems optimally adapted to our needs, the cardiac diseases discussed in this thesis reveal several potential weak spots or “Achilles heels” of the heart. The most extensively discussed weak spot is the thin RV free wall, more specifically the subtricuspid segment. The early and predominant impairment of the subtricuspid segment was a consistent finding in ARVC patients with a pathogenic variant in desmosomal genes, which became especially evident in Chapter 6. Besides the thin aspect of the RV free wall, the anatomical location of the subtricuspid segment may result in disproportionally high wall stress. Swiss researchers used silicone anatomical RV models of ARVC patients and healthy controls to evaluate wall shear stress in different segments.20 They observed the highest wall shear stress in the RV outflow tract, followed by the subtricuspid region. In general, these are the earliest affected regions in ARVC and a common origin of arrhythmia.21 On the other hand, wall shear stress in the RV apex and septal region was negligible in the silicone RV models. In the LV, completing the so-called triangle of dysplasia, a common predisposition site for ARVC disease manifestation is the basal segment of the LV posterolateral wall.21,22 The fact that this region mirrors the subtricuspid segment of the RV lateral wall on the left side might support similar hypotheses; systolic flow direction from apex to base might result in disproportionally high wall stress in both the RV and LV basal segments. 9
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