Right Ventricular Functional Abnormalities in ARVC | 33 INTRODUCTION Arrhythmogenic cardiomyopathy (AC, also known as arrhythmogenic right ventricular cardiomyopathy (ARVC)) is an inheritable cardiomyopathy, characterized by life-threatening ventricular arrhythmias (VA) and progressive cardiac failure.1 In the classical phenotype, pathogenic mutations encoding for desmosomal proteins lead to primarily right ventricular (RV) myocyte loss and replacement by fibrofatty tissue.2,3 Already in the early stage of the disease, life-threatening arrhythmias can occur, making it a leading cause of sudden cardiac death amongst young, seemingly healthy, individuals.2,3,4 Early detection of the disease is thus of great importance. Currently, AC is diagnosed according to a complex set of criteria, defined in the 2010 revised Task Force Criteria (TFC), in which cardiac imaging has an important role.5 In addition to conventional imaging parameters, as incorporated in the 2010 TFC, echocardiographic deformation imaging has been described for detection of subtle phenotypic expressions in early AC as well as for risk prediction regarding ventricular arrhythmias.6-11 The technique has been applied to the RV in AC patients in different ways: by recognition of deformation patterns of the RV subtricuspid area6,7, and by using the mechanical dispersion, a measure of heterogeneous contraction, as a parameter of disease expression8-10. These two methods have successfully been tested in separate cohorts of the centers where they were developed, but are not yet implemented in clinical care outside of these centers. In order to advance RV deformation imaging closer to standard clinical care in AC, it is pivotal to show that these results are not only achieved in one center. To date, the value of RV deformation patterns and mechanical dispersion has never been externally validated. Furthermore, the association between RV deformation patterns and ventricular arrhythmias has not been investigated previously, and it is not known whether the two methods measure essentially the same phenomenon or if combining the two methods adds value to risk stratification of VA. We aimed to perform an external validation of the association between RV deformation patterns and disease stage in AC. Furthermore, we aimed to validate mechanical dispersion as a marker of ventricular arrhythmias. Finally, we wanted to explore the added value of combining the parameters. METHODS Study design and population This study was conducted in two academic referral centers for AC in Europe. We used an AC cohort from the University Medical Center Utrecht in the Netherlands and an age- and sex matched AC cohort from the Oslo University Hospital in Norway. Probands underwent genetic testing as described previously12, and cascade genetic screening was performed in family members of genotype positive probands. The Utrecht cohort consisted of 80 AC probands and genotype positive family members with an echocardiographic examination including RV deformation imaging in Utrecht between 2006 and 2015, who have been reported previously.6 During this period, 87 subjects were evaluated, of which 7 were excluded due to inadequate image quality for RV deformation analyses. The Oslo cohort also consisted of 80 AC probands and genotype positive family members. By matching to the Utrecht subjects based on age and sex, the Oslo subjects were selected from a previously reported cohort of 144 subjects which 3
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