Electromechanical Substrate Characterization in ARVC | 71 are related to increased regional heterogeneity in contractility and compliance without a heterogeneity in activation delay.4 AC mutation carriers classified with structural abnormalities according to the 2010 TFC, being wall motion abnormalities such as akinesia, dyskinesia, or aneurysm in combination with RV dilatation or impaired RV systolic function measured by either CMR or echocardiography.5 These structural abnormalities result from fibrofatty replacements of the RV myocardium, which affects regional wall motion and eventually global RV systolic function.2 Also our computer simulations revealed the largest heterogeneity of RVfw tissue properties in the patients with structural stage disease, with the basal region of the RVfw being most affected by the disease. The few structural stage subjects with a relatively low heterogeneity of RV tissue properties showed highly impaired RV deformation with decreased contractility and compliance in all three segments, suggesting highly advanced AC disease. Our patient-specific simulations suggested that the RV apex-to-base heterogeneity of mechanical behaviour in the more advanced AC disease stages is mostly due to decreased basal contractility and compliance. Several potential causes for AC-related changes in active and passive myocardial tissue properties have been identified in clinical and pre-clinical studies. One is the fibrofatty replacement of the myocardium2, which results in loss of contractile function and a change in passive tissue behaviour. Besides, Cerrone et al. found altered calcium transients in mice with a loss of PKP2 expression, including an increased calcium transient with an increased time-to-peak and a slower decay23, suggesting a change in contractile function. To identify the exact (sub)cellular mechanisms underlying the regional RV deformation abnormalities in AC subjects beyond changes of tissue contractility and compliance, a more complex model of the myocardial electromechanics is needed. In previous clinical studies, RVMD was associated with arrhythmic outcome.7 In our modelling study, a higher RVMD was associated with an increased heterogeneity of contractility in the RVfw, but not with myocardial compliance. These contractile abnormalities could reflect calcium handling abnormalities, which form a possible pro-arrhythmic substrate. Interestingly, using the classification defined by Mast et al.4, an abnormal Type-III deformation pattern was reproduced by both abnormal contractility and abnormal compliance. Where RVMD is based only on timing of the longitudinal strain, the pattern classification is based on information of both timing and amplitude. Our computer simulations suggest that both classifications can detect a different kind of tissue substrate. An RVfw apex-to-base heterogeneity was already present in the deformation measurements of healthy controls, resulting in heterogeneity in estimated tissue properties. Some level of ‘physiological’ heterogeneity in deformation is to be expected, since regional differences of ventricular tissue properties, such as activation delay24, action potential morphology25, and wall thickness26, also exist in healthy hearts. Because the control group and subclinical group have a similar heterogeneity in tissue properties, it can be assumed that the observed heterogeneity in regional RV tissue properties is not abnormal. Study Limitations Estimations are based on the average CO obtained from CMR and on regional LV and RV strain obtained from speckle tracking echocardiography. CMR volumes were used because they provided the most reliable non-invasive estimation of CO and ventricular volumes. Because the CMR and the echocardiographic examination cannot be performed simultaneously, there is a potential mismatch between the two measurements. This mismatch might result in 4
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