Abstract:

Cardiac resynchronization therapy is a valuable tool to restore left ventricular function in patients experiencing dyssynchronous ventricular activation. However, the non-responder rate is still as high as 40%. Recent studies suggest that left ventricular torsion or specifically the lack thereof might be a good predictor for the response of cardiac resynchronization therapy. Since left ventricular torsion is governed by the muscle fiber orientation and the heterogeneous electromechanical activation of the myocardium, understanding the relation between these components and the ability to measure them is vital. To analyze if locally altered electromechanical activation in heart failure patients affects left ventricular torsion, we conducted a simulation study on 27 personalized left ventricular models. Electroanatomical maps and late gadolinium enhanced magnetic resonance imaging data informed our in-silico model cohort. The angle of rotation was evaluated in every material point of the model and averaged values were used to classify the rotation as clockwise or counterclockwise in each segment and sector of the left ventricle. 88% of the patient models (n = 24) were classified as a wringing rotation and 12% (n = 3) as a rigid-body-type rotation. Comparison to classification based on in vivo rotational NOGA XP maps showed no correlation. Thus, isolated changes of the electromechanical activation sequence in the left ventricle are not sufficient to reproduce the rotation pattern changes observed in vivo and suggest that further patho-mechanisms are involved.

Abstract:

Atrial fibrillation (AF) is the most common supra-ventricular tachycardia. Despite not fully understanding all mechanisms leading to AF, atrial dilation and thus cellular stretch are identified as risk factors. It is suspected that the influence of stretch-activated ion channels (SACs) on electrophysiological cellular properties connects atrial stretch and the pathogenesis of AF, among other contributing factors. Therefore, this work investigates the possible relationship between SACs and AF in silico. In addition, this also provides a better understanding of SACs in general. For this purpose, a model was implemented that distinguished between a K+-selective component and a non-selective component. Then conditions were identified that triggered stretch-induced action potentials (APs) on the cellular level and in coupled whole heart simulations. In the specific case of a constant stretch application at the cellular level, a problematic time-dependent depolarization of the transmembrane voltage was observed. This issue is not yet critically discussed in literature but was addressed to be able to perform whole heart simulations with a physiological atrial pre-stretch of λ ≈ 1.10 m/m. Adaptations of the channel conductances for the non-selective SAC current and the rectifying K+ current (IK1) were required to overcome the problem of excited states in continuously stretched cells. On the tissue level, a homogeneous distribution of SACs was considered in healthy as well as in pathological conditions on a whole heart geometry. In healthy tissue, the impact of SACs was varied to understand the effects of this channel type. This was done by scaling the sensitivity of the channel conductance towards stretch which led to ectopic beats for GSAC,NS ≥ 0.39 nS/pF. Pathological tissue conditions were simulated with GSAC,NS = 0.33 nS/pF to prevent spontaneous activity. Additionally, different aspects of cardiac remodeling were considered to represent tissue adaptations in the presence of AF. No ectopic activity was triggered with an ionic remodeling due to a faster repolarization mainly attributed to the adapted channel conductance of IK1. Only a reduction of the tissue conductivity in the myocardium of the atria to 40 % of the healthy conductivity initiated extrasystoles. Simulations of reduced basic cycle lengths showed unphysiological behavior and, therefore, revealed a lack of ability of the current simulation setup towards investigations using increased heart rates. In summary, the myocardium in cranial regions as well as close to the atrioventricular valves was identified as vulnerable towards triggering stretch-induced APs and causing conduction blocks that could lead to chaotic ectopic excitation propagations. Therefore, this simulation setup might be able to initiate AF if reentries are present additionally. To conclude, the amount and timing of atrial stretch were identified as equally important contributors to ectopic activity. Additionally, the simulations provide evidence to support the presumed connection between SACs and AF.