Electromechanical Substrate Characterization in ARVC | 63 1. Following the revised 2010 TFC5, AC can be divided into three consecutive clinical stages: a) subclinical (concealed) stage with absence of any 2010 TFC, except for harbouring a pathogenic mutation; b) electrical stage, with only electrocardiographic (ECG) or Holter abnormalities; and c) structural stage, with structural abnormalities on non-invasive imaging, regardless of the history of ventricular arrhythmias or presence of ECG or Holter abnormalities.5,13 2. Based on the pattern of basal RVfw deformation following the predefined criteria published by Mast et al.4 A Type-I pattern is defined as normal deformation; a Type-II pattern is characterized by delayed onset of shortening, reduced systolic peak strain and minor postsystolic shortening; a Type-III pattern is characterized by little or no systolic peak strain, predominantly systolic stretching and major post-systolic shortening. 3. Based on RV mechanical dispersion (RVMD), an index of segmental heterogeneity in contraction in the RVfw and IVS. RVMD was calculated on 6 segments of the RV, including the IVS, and defined as the standard deviation of the segmental time intervals from onset Q/R on the surface ECG to peak negative strain.7 A previously established cut-off value of 30ms14 was used in this study to define a group with low and high RVMD. Computer Simulations Regional RV, IVS, and LV myocardial deformation were simulated using the CircAdapt model15, which is a closed-loop lumped parameter computer model of the human heart and circulation. It enables simulation of cardiac hemodynamics and regional wall mechanics, using a phenomenological model describing active and passive myofibre mechanics.16 Ventricular interactions are modelled using the TriSeg model using the concept of conservation of energy.17 LVfw and IVS were modelled as a single segment representing the mechanics of the entire wall. Three RVfw segments representing the apical, mid-ventricular, and basal regions were modelled using the previously validated MultiPatch model.16 Patient-Specific Simulation Protocol Computer simulations were personalized by automatically tuning model parameters to optimize the modelled myofibre strain to measured longitudinal strain (Figure 1). A parameter subset with 21 parameters essential for modelling regional RVfw, IVS, and LVfw deformation in AC mutation carriers was previously identified8 and shown in Supplementary Table 1. CO and heart rate (HR) were direct input parameters of the model and thereby set from the measurements. The former was obtained from CMR data, while the latter was obtained from the RV focused 4-chamber view. The other 19 parameters describe the size of the RVfw, IVS, and LVfw (3 model parameters), myocardial twitch duration and thus relative systolic duration (1 parameter), and three regional tissue properties per myocardial segment being contractility, compliance, and activation delay (i.e. 15 model parameters in total). Objective function The objective function describes the agreement between modelled and measured strain. Measured strain is by definition relative to the stretch on , which is defined as the onset of the QRS complex, obtained from ECG. This cannot be modelled in CircAdapt. Therefore, t =t0 4
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