114 | Chapter 6 the LV and RV, but progression was more pronounced in the RV. This is in line with expectations, since primarily the RV myocardium is affected by fibrofatty replacement in ARVC.1,2 From Figure 3 it can be appreciated that RV deformation types are a robust classification method during serial analyses, enabling detection of disease progression over time. This confirms that once abnormal, RV deformation patterns remain abnormal, as was previously shown in another cohort of ARVC patients with two sequential echocardiographic examinations.30 Our segmental analysis consistently showed that all deformation parameters were worse in the basal segment and progressed over time from base to apex. This is in line with previous studies in other cohorts, which showed that the subtricuspid segment of the RV lateral wall is the earliest and most severely affected area in ARVC.13,19,30,31 It is conceivable that longitudinal strain also slightly deteriorates over time in healthy individuals. While this has been shown for LV GLS32, the deterioration is small and probably not clinically relevant in the RV free wall33. Importantly, the prolonged time to onset of shortening and post-systolic shortening, as observed in ARVC patients, are not observed in physiologic aging of the myocardium. Progression of RV tissue substrates Definitive diagnosis of ARVC is based on the presence of transmural fibro-fatty replacement of RV myocardium at biopsy, autopsy, or surgery.1,34 Since histology is not available in the vast majority of patients, TFC guide the diagnosis of ARVC.15 The use of personalized computational modelling can give more insight in the patient’s underlying myocardial disease substrate through the estimated tissue properties being directly related to intrinsic myocardial function and composition.20,23,35 In the current study, we applied this Digital Twin approach on serial echocardiographic examinations in a large cohort to gain insight into the evolution of early myocardial disease substrates in ARVC. On a group level, we found increasing heterogeneity of both contractility, compliance, and activation delay in all three age-groups, indicating the progression of local RV tissue substrates. We presented two case studies of patients from the cohort. The first (Figure 4A) showed progression of deformation abnormalities, which were, according to estimations in the Digital Twin, caused by decreased contractility and to a lesser degree decreased compliance. The patient had no VA during follow-up. In the second case (Figure 4B), the patient experienced VA while having no overt structural phenotype according to conventional TFC. RV deformation abnormalities preceded the arrhythmic event and heterogeneity was most pronounced in the activation delay. These cases illustrate the potential use of the modelling approach on a patient-specific basis, as specific estimated tissue abnormalities which are present prior to an arrhythmic event may have predictive value. The number of events in this study on subjects with early-stage ARVC was, however, too low to draw any firm conclusions from these findings. Clinical implications Prevention of SCD is the most important goal of ARVC screening. Prior studies report SCD rates up to 23% at presentation, mainly in young ARVC patients.3,4 Cascade genetic screening provides clinicians with an increasing group of patients at risk of severe arrhythmic events, but without an overt phenotype at first evaluation. Since there is a clear correlation between structural disease expression and the risk of arrhythmias, these patients undergo frequent cardiac evaluations to detect early signs of disease penetrance. A recent expert consensus statement recommended clinical evaluation of relatives at risk with 12-lead ECG, ambulatory
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