Electro-mechanical cardiac computational modelling of the human and rabbit – from cell to heart to ECG

Abstract: Cardiovascular research has been thriving over the last decades, as heart-related diseases have become one of the main causes of mortality in the Western world. In order to better understand the function of the heart in healthy and diseased states, computational modeling has emerged as a helpful tool alongside classic in-vivo and in-vitro findings. Here, mathematical descriptions of biological mechanisms can be used to analyse, enhance, or interpret measured data but also as a stand-alone tool to generate new perspectives and hypotheses. The present work shows three projects in more detail, where computational modeling was used to scale findings from ion channel to single cell to whole heart levels and even ECG, as well as to translate them across species.

The first-presented work is focused on the cardiac muscarinic receptor (M2R) which plays a central role in the regulation of heart rate as part of the parasympathetic nervous system. Experimental work identified that the receptors affinity towards acetylcholine (ACh), a chemical transmitter, is voltage dependent. A property that could explain the thus far unexplained behaviour of the M2R regulated IK,ACh current in response to different voltages. To incorporate these effects, I extended an existing Markovian model of the M2R to include said effects and incorporated it into a human sinus node (SN) model. Using this new model, I was able to show how low concentrations of ACh slow down the beating rate without shortening the duration of the action potential, a response that was previously accredited to the ACh sensitivity of the pacemaker current $I_f$. Further, I was able to investigate alterations in the voltage sensitivity due to pathologies and their cascading effect on heart rate regulation. This project highlights the translational capabilities of computational modeling, as the response in respect to low ACh is something that only comes into play due to the intrinsically lower beating rate of human SN cells compared to SN cells in smaller mammals that are normally investigated.

The second-presented work aims to bridge the gap between classical lab work, computational modeling, and the clinics. The rabbit is one of the most used animal models in the scope of classical lab work to investigate electrophysiological function and dysfunction. Using techniques such as patch clamping, the dynamics of single ion channels and the overall membrane voltage can be measured. Computational modeling can then be used as a way to compliment these findings on a single cell or tissue levels. With this project, I aimed at extending this scope to the ECG level. In order to do so, a new volumetric model of the heart and torso was created, based on computed tomography imaging. Further, as a way to parameterize the underlying electrophysiological properties, we measured the body surface potentials, using a self-fabricated 32-Lead ECG-vest. With the help of the new model and the measured signals, I was then able to optimize the ventricular activation sequence as well as investigate the feasibility of different repolarization gradients in respect to the measured ECG data.

The third-presented work showcases the unique possibility of computational models to split biological processes into their physical components to assess their respective contribution to the overall dynamics. Normally, when ECG signals are calculated based on the simulated electrical activity of the heart, a static representation of the heart is used. But by doings so, the impact of cardiac contraction, which leads to a movement of the electrical sources which are responsible for the measured signals, is ignored. To investigate this impact further, I developed a four chamber electro-mechanical model of the human heart. On the electrophysiological side, this model was used to reproduce ECG signals, which showed a strong correlation with measured ones. As for the mechanical function, my model accurately recreated all major features of pressure and volume dynamics, as well as an atrioventricular plane displacement and ventricular rotation similar to measured data. By comparing the 'dynamic' with different 'static' approaches, I was then able to determine that the influence of cardiac contraction on the ECG should not be overlooked, especially in terms of parameterization of repolarization dynamics

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2023

Klassifikation und Themen

• Schlagwort: Computersimulation ; Herz ; Elektrokardiografie ; Elektrophysiologie ; Modell ; Numerisches Modell ; Mathematisches Modell ; Elektrophysiologie ; Herz ; Simulation ; Finite-Elemente-Methode ; Elektrokardiografie ; Herzmuskel

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2023
• Urheber: Moss, Kai Robin
• Beteiligte Personen und Organisationen: Pastewka, Lars ; Pastewka, Lars ; Kohl, Peter ; Albert-Ludwigs-Universität Freiburg. Fakultät für Angewandte Wissenschaften ; Institut für Experimentelle Kardiovaskuläre Medizin

Weitere Informationen

• DOI: 10.6094/UNIFR/235767
• URN: urn:nbn:de:bsz:25-freidok-2357671
• Rechteinformation: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 2025-03-25T13:47:03+0100