Electromechanical Substrate Characterization in ARVC | 61 INTRODUCTION Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder characterized by fibrofatty replacement of primarily the right ventricular (RV) myocardium, which predisposes to ventricular arrhythmias and sudden cardiac death in young individuals.1,2 Variable disease expression is found in familial AC3, ranging from sudden cardiac death (SCD) in young individuals to a lifelong absence of any phenotype. To prevent apparently healthy AC mutation carriers from SCD, early detection of potentially pro-arrhythmic tissue substrates is important. Using speckle-tracking echocardiography, our groups4 found distinct regional RV deformation abnormalities in AC mutation carriers. Predominantly the basal (subtricuspid) part of the RV free wall was affected, even in the absence of electrocardiographic or structural 2010 Task Force Criteria (TFC)5. Using computer simulations, it was hypothesized that these deformation abnormalities resulted from a decreased contractility and an increased stiffness within this segment. In a follow-up study, these RV deformation abnormalities were found to be associated with AC disease progression.6 Another approach, as reported by Sarvari et al.7 showed that RV mechanical dispersion, defined as the standard deviation in time-to-peak strain, is a marker for arrhythmic events in AC patients. The latter study demonstrate the prognostic value of RV longitudinal strain, while the disease substrates underlying the deformation abnormalities remain unknown. Together with the first study by Mast et al.4, these studies suggest that identification of the disease substrate causing RV deformation abnormalities could be used to better understand disease progression and support risk stratification. Patient-specific characterization of the electromechanical disease substrates in early-stage AC may lead to better arrhythmic risk stratification and ultimately to the identification of possible therapeutic targets, thereby enabling personalized medicine. Since invasive tissue characterization is accompanied by important risks, and is rarely performed, non-invasive ways of tissue characterization should be investigated. The aim of this study is to non-invasively estimate the pathophysiological substrates underlying regional deformation abnormalities in the individual AC mutation carrier, using imaging-based patient-specific computer simulations. We use a parameter estimation protocol based on a previously established framework8 which simulates myocardial deformation to identify regional tissue properties. METHODS Patient Cohort This study was performed on a previously reported consecutive cohort of pathogenic desmosomal mutation carriers, who were evaluated at the UMC Utrecht in the Netherlands between 2006 and 2015.4 During this period, 87 subjects carrying a pathogenic plakophilin-2 (PKP2), desmoglein-2 (DSG2), or desmoplakin (DSP) mutation were evaluated. Additionally, 20 healthy volunteers were included as control subjects. The study was approved by the local institutional ethics review board. The echocardiographic protocol has been detailed elsewhere.9 Briefly, all echocardiographic data were obtained on a Vivid 7 or Vivid E9 ultrasound machine (GE Vingmed Ultrasound, Horten, Norway) using a broadband M3S transducer and were analysed for fulfilling 2010 TFC for structural abnormalities.5 Only exams during sinus rhythm were eligible for inclusion. 4
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