General Discussion and Future Perspectives | 189 examinations and to evaluate disease progression over time. Since both measurements and model estimations introduce uncertainty, in Chapter 5 the introduction of uncertainty to estimations of tissue properties is described. This was a necessary step towards longitudinal follow-up of the disease substrates presented in Chapter 6. The heterogeneity in estimated tissue properties progressed over time in early ARVC subjects in different age groups. While case studies showed that heterogeneity in regional tissue properties in the Digital Twin preceded overt disease and arrhythmia, the added value of absolute values of estimated properties was still limited. Since the model is based on deformation characteristics, which are load dependent, more information on loading conditions during the examination will probably support the interpretation of absolute values, rather than heterogeneity alone. In addition to the phenomenological model used in our Digital Twin approach, computer modelling can also further elucidate the electromechanical coupling which is a central component in the pathophysiology of ARVC.13 With the coupling between an electromechanical cardiomyocyte model and a mechanical sarcomere model, myocardial deformation can be related to disease specific changes in cellular electrophysiology and calcium handling within cardiomyocytes.14 RVfw strain [%] LVfw+IVS strain [%] Digital twin Contractility Compliance Activation Delay Individually estimated RVfw tissue properties Measurements RVfw strain [%] LVfw+IVS strain [%] Included Measurements Strain | HR EDV | EF | RVD fully automatic uncertainty quantification Algorithm Legend RVfw IVS LVfw Base Mid Apex θ w Time [ms] Time [ms] Figure 1. The Digital Twin model as was used after introducing uncertainty into the algorithm15 Non-invasive measurements were used as input for a fully automated algorithm. The Digital Twin estimated individual tissue properties for the three segments of the RV free wall (RVfw), the inverventricular septum (IVS) and the LV free wall (LVfw). HR = heart rate, EDV = end diastolic volume, EF = ejection fraction, RVD = RV diameter. Multimodality approach While a diagnosis of DCM or HCM can usually be made based on one single imaging modality, diagnosis of ARVC and risk assessment in all genetic cardiomyopathies requires a multimodality approach. The aforementioned electromechanical coupling illustrates that both imaging and electrocardiographic diagnostics are needed to perform a complete risk assessment. Over the years, the Utrecht University has developed into a unique environment for ARVC research since 9
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