Differential effects of mechano-electric feedback mechanisms on whole-heart activation, repolarization, and tension.

The human heart is subject to highly variable amounts of strain during day-to-day activities and needs to adapt to a wide range of physiological demands. This adaptation is driven by an autoregulatory loop that includes both electrical and the mechanical components. In particular, mechanical forces are known to feed back into the cardiac electrophysiology system, which can result in pro- and anti-arrhythmic effects. Despite the widespread use of computational modelling and simulation for cardiac electrophysiology research, the majority of in silico experiments ignore this mechano-electric feedback entirely due to the high computational cost associated with solving cardiac mechanics. In this study, we therefore use an electromechanically coupled whole-heart model to investigate the differential and combined effects of electromechanical feedback mechanisms with a focus on their physiological relevance during sinus rhythm. In particular, we consider troponin-bound calcium, the effect of deformation on the tissue diffusion tensor, and stretch-activated channels. We found that activation of the myocardium was only significantly affected when including deformation into the diffusion term of the monodomain equation. Repolarization, on the other hand, was influenced by both troponin-bound calcium and stretch-activated channels and resulted in steeper repolarization gradients in the atria. The latter also caused afterdepolarizations in the atria. Due to its central role for tension development, calcium bound to troponin affected stroke volume and pressure. In conclusion, we found that mechano-electric feedback changes activation and repolarization patterns throughout the heart during sinus rhythm and lead to a markedly more heterogeneous electrophysiological substrate. KEY POINTS: The electrophysiological and mechanical function of the heart are tightly interrelated by excitation-contraction coupling (ECC) in the forward direction and mechano-electric feedback (MEF) in the reverse direction. While ECC is considered in many state-of-the-art computational models of cardiac electromechanics, less is known about the effect of different MEF mechanisms. Accounting for calcium bound to troponin increases stroke volume and delays repolarization. Geometry-mediated MEF leads to more heterogeneous activation and repolarization with steeper gradients. Both effects combine in an additive way. Non-selective stretch-activated channels as an additional MEF mechanism lead to heterogeneous diastolic transmembrane voltage, higher developed tension and delayed repolarization or afterdepolarizations in highly stretched parts of the atria. The differential and combined effects of these three MEF mechanisms during sinus rhythm activation in a human four-chamber heart model may have implications for arrhythmogenesis, both in terms of substrate (repolarization gradients) and triggers (ectopy).

The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-Chamber Heart Model.

PURPOSE: Atrial fibrillation is one of the most frequent cardiac arrhythmias in the industrialized world and ablation therapy is the method of choice for many patients. However, ablation scars alter the electrophysiological activation and the mechanical behavior of the affected atria. Different ablation strategies with the aim to terminate atrial fibrillation and prevent its recurrence exist but their impact on the performance of the heart is often neglected. METHODS: In this work, we present a simulation study analyzing five commonly used ablation scar patterns and their combinations in the left atrium regarding their impact on the pumping function of the heart using an electromechanical whole-heart model. We analyzed how the altered atrial activation and increased stiffness due to the ablation scars affect atrial as well as ventricular contraction and relaxation. RESULTS: We found that systolic and diastolic function of the left atrium is impaired by ablation scars and that the reduction of atrial stroke volume of up to 11.43% depends linearly on the amount of inactivated tissue. Consequently, the end-diastolic volume of the left ventricle, and thus stroke volume, was reduced by up to 1.4 and 1.8%, respectively. During ventricular systole, left atrial pressure was increased by up to 20% due to changes in the atrial activation sequence and the stiffening of scar tissue. CONCLUSION: This study provides biomechanical evidence that atrial ablation has acute effects not only on atrial contraction but also on ventricular performance. Therefore, the position and extent of ablation scars is not only important for the termination of arrhythmias but is also determining long-term pumping efficiency. If confirmed in larger cohorts, these results have the potential to help tailoring ablation strategies towards minimal global cardiovascular impairment.

Efficient time splitting schemes for the monodomain equation in cardiac electrophysiology.

Approximating the fast dynamics of depolarization waves in the human heart described by the monodomain model is numerically challenging. Splitting methods for the PDE-ODE coupling enable the computation with very fine space and time discretizations. Here, we compare different splitting approaches regarding convergence, accuracy, and efficiency. Simulations were performed for a benchmark problem with the Beeler-Reuter cell model on a truncated ellipsoid approximating the left ventricle including a localized stimulation. For this configuration, we provide a reference solution for the transmembrane potential. We found a semi-implicit approach with state variable interpolation to be the most efficient scheme. The results are transferred to a more physiological setup using a bi-ventricular domain with a complex external stimulation pattern to evaluate the accuracy of the activation time for different resolutions in space and time.

Dyssynchronous Left Ventricular Activation is Insufficient for the Breakdown of Wringing Rotation.

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.

Causes of altered ventricular mechanics in hypertrophic cardiomyopathy: an in-silico study.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is typically caused by mutations in sarcomeric genes leading to cardiomyocyte disarray, replacement fibrosis, impaired contractility, and elevated filling pressures. These varying tissue properties are associated with certain strain patterns that may allow to establish a diagnosis by means of non-invasive imaging without the necessity of harmful myocardial biopsies or contrast agent application. With a numerical study, we aim to answer: how the variability in each of these mechanisms contributes to altered mechanics of the left ventricle (LV) and if the deformation obtained in in-silico experiments is comparable to values reported from clinical measurements. METHODS: We conducted an in-silico sensitivity study on physiological and pathological mechanisms potentially underlying the clinical HCM phenotype. The deformation of the four-chamber heart models was simulated using a finite-element mechanical solver with a sliding boundary condition to mimic the tissue surrounding the heart. Furthermore, a closed-loop circulatory model delivered the pressure values acting on the endocardium. Deformation measures and mechanical behavior of the heart models were evaluated globally and regionally. RESULTS: Hypertrophy of the LV affected the course of strain, strain rate, and wall thickening-the root-mean-squared difference of the wall thickening between control (mean thickness 10 mm) and hypertrophic geometries (17 mm) was >10%. A reduction of active force development by 40% led to less overall deformation: maximal radial strain reduced from 26 to 21%. A fivefold increase in tissue stiffness caused a more homogeneous distribution of the strain values among 17 heart segments. Fiber disarray led to minor changes in the circumferential and radial strain. A combination of pathological mechanisms led to reduced and slower deformation of the LV and halved the longitudinal shortening of the LA. CONCLUSIONS: This study uses a computer model to determine the changes in LV deformation caused by pathological mechanisms that are presumed to underlay HCM. This knowledge can complement imaging-derived information to obtain a more accurate diagnosis of HCM.

Sequential Coupling Shows Minor Effects of Fluid Dynamics on Myocardial Deformation in a Realistic Whole-Heart Model.

Background: The human heart is a masterpiece of the highest complexity coordinating multi-physics aspects on a multi-scale range. Thus, modeling the cardiac function in silico to reproduce physiological characteristics and diseases remains challenging. Especially the complex simulation of the blood's hemodynamics and its interaction with the myocardial tissue requires a high accuracy of the underlying computational models and solvers. These demanding aspects make whole-heart fully-coupled simulations computationally highly expensive and call for simpler but still accurate models. While the mechanical deformation during the heart cycle drives the blood flow, less is known about the feedback of the blood flow onto the myocardial tissue. Methods and Results: To solve the fluid-structure interaction problem, we suggest a cycle-to-cycle coupling of the structural deformation and the fluid dynamics. In a first step, the displacement of the endocardial wall in the mechanical simulation serves as a unidirectional boundary condition for the fluid simulation. After a complete heart cycle of fluid simulation, a spatially resolved pressure factor (PF) is extracted and returned to the next iteration of the solid mechanical simulation, closing the loop of the iterative coupling procedure. All simulations were performed on an individualized whole heart geometry. The effect of the sequential coupling was assessed by global measures such as the change in deformation and-as an example of diagnostically relevant information-the particle residence time. The mechanical displacement was up to 2 mm after the first iteration. In the second iteration, the deviation was in the sub-millimeter range, implying that already one iteration of the proposed cycle-to-cycle coupling is sufficient to converge to a coupled limit cycle. Conclusion: Cycle-to-cycle coupling between cardiac mechanics and fluid dynamics can be a promising approach to account for fluid-structure interaction with low computational effort. In an individualized healthy whole-heart model, one iteration sufficed to obtain converged and physiologically plausible results.