Evolution of right ventricular tissue abnormalities in early-stage Arrhythmogenic Cardiomyopathy: an imaging-based patient-specific modeling study

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): (NWO-ZonMw, VIDI grant 016.176.340) and Dutch Heart Foundation (2015T082) Introduction Arrhythmogenic Cardiomyopathy (AC) is an inherited cardiac disease which is characterized by life-threatening ventricular arrhythmias and progressive cardiac dysfunction. Early disease detection and risk stratification is important as geno-positive subjects with and without symptoms may suffer from sudden cardiac death. We propose a patient-specific computer modelling approach using clinical imaging data, to non-invasively quantify regional ventricular tissue abnormalities during follow-up. Purpose To non-invasively reveal the development of myocardial disease substrates underlying the regional RV deformation abnormalities in individual AC mutation carriers. Methods In 2 individuals carrying a plakophilin-2 mutation, regional longitudinal deformation patterns of the RV free wall (RVfw, Figure top row strain panels) , interventricular septum (IVS) and left ventricular free wall (LVfw) were obtained using speckle-tracking echocardiography at baseline during follow-up (4.2 and 9.9 years) and used as input for our Bayesian-based computational framework (Figure Left). This framework generates Digital Twins based on the CircAdapt model of the cardiovascular system which allows estimation of regional tissue properties and its associated uncertainties. The Digital Twins at baseline and during follow-up reveal evolution of the investigated regional tissue properties myocardial contractility, compliance, activation delay, and work. Results This framework was able to reproduce the regional deformation patterns measured at baseline and during follow-up (Figure second row strain panels). Both patients developed abnormal basal deformation patterns during follow-up. Our model revealed this was paired with an increase in heterogeneity in tissue properties. In Patient 1, heterogeneity in contractility developed (75kPa/s [p=.228] at baseline to 347kPa/s [p<.001] at last follow-up). No activation delay was present in this subject (p = 0.188 and p = 0.242 at baseline and at last follow-up). Heterogeneity in compliance developed from 0.11 (p=.014) to 0.49 /kPa (p=.002). Heterogeneity in work-density increased from 1927 (p<.001) to 5497kPa (p<.001). Patient 2 did not develop a contractile substrate (p=.336 and p=.104 for baseline and last follow-up) or delayed basal activation (p=.336 and p=.190 for baseline and last follow-up). Heterogeneity in compliance and work did both develop from 0.04 (p=.070) to 0.1 /kPa (p=.004) and from 865 (p=.100) to 2504kPa (p < 0.001), respectively. Conclusion Our patient-specific modelling approach is able to reveal individual myocardial substrates including uncertainty underlying the regional RV deformation abnormalities and allows investigation of substrate development. Early abnormalities in RV longitudinal strain are most likely caused by increased heterogeneity in tissue compliance. Future studies will investigate whether this approach can improve early detection and risk stratification in geno-positive subjects. Abstract Figure.