The cardiac muscarinic receptor (M2R) regulates heart rate, in part, by modulating the acetylcholine (ACh) activated K+ current IK,ACh through dissociation of G-proteins, that in turn activate KACh channels. Recently, M2Rs were noted to exhibit intrinsic voltage sensitivity, i.e. their affinity for ligands varies in a voltage dependent manner. The voltage sensitivity of M2R implies that the affinity for ACh (and thus the ACh effect) varies throughout the time course of a cardiac electrical cycle. The aim of this study was to investigate the contribution of M2R voltage sensitivity to the rate and shape of the human sinus node action potentials in physiological and pathophysiological conditions. We developed a Markovian model of the IK,ACh modulation by voltage and integrated it into a computational model of human sinus node. We performed simulations with the integrated model varying ACh concentration and voltage sensitivity. Low ACh exerted a larger effect on IK,ACh at hyperpolarized versus depolarized membrane voltages. This led to a slowing of the pacemaker rate due to an attenuated slope of phase 4 depolarization with only marginal effect on action potential duration and amplitude. We also simulated the theoretical effects of genetic variants that alter the voltage sensitivity of M2R. Modest negative shifts in voltage sensitivity, predicted to increase the affinity of the receptor for ACh, slowed the rate of phase 4 depolarization and slowed heart rate, while modest positive shifts increased heart rate. These simulations support our hypothesis that altered M2R voltage sensitivity contributes to disease and provide a novel mechanistic foundation to study clinical disorders such as atrial fibrillation and inappropriate sinus tachycardia.
Mathematical models of the human heart are evolving to become a cornerstone of precision medicine and support clinical decision making by providing a powerful tool to understand the mechanisms underlying pathophysiological conditions. In this study, we present a detailed mathematical description of a fully coupled multi-scale model of the human heart, including electrophysiology, mechanics, and a closed-loop model of circulation. State-of-the-art models based on human physiology are used to describe membrane kinetics, excitation-contraction coupling and active tension generation in the atria and the ventricles. Furthermore, we highlight ways to adapt this framework to patient specific measurements to build digital twins. The validity of the model is demonstrated through simulations on a personalized whole heart geometry based on magnetic resonance imaging data of a healthy volunteer. Additionally, the fully coupled model was employed to evaluate the effects of a typical atrial ablation scar on the cardiovascular system. With this work, we provide an adaptable multi-scale model that allows a comprehensive personalization from ion channels to the organ level enabling digital twin modeling
The heart rate is mediated by the G protein-coupled muscarinic receptor (M2R) activating the acetylcholine (ACh)-dependent K+ current (IKACh). Here, a novel model for IKACh gating is presented based on recent findings that M2R agonist binding is voltage-sensitive. Furthermore, ACh and pilocarpine (Pilo) manifest opposite voltage-dependent IKACh modulation. In a previous work, a 4-state Markov model of M2R reconstructing the voltage-dependent change in agonist affinity was proposed. In this work, a 2-state Markov model of IKACh gating purely dependent on the Gβγ concentration is proposed. IKACh is modeled based on the description of Zhang et al. Measurement data are used to parametrize the combined M2R and IKACh model for both ACh and Pilo. The channel model has a linear Gβγ dependent forward and a constant backward rate. For ACh and Pilo, optimal values of model parameters are found reconstructing the measured opposite voltage-dependent change in agonist affinity. The combined model is able to reconstruct the measured data regarding the agonist and voltage-dependent properties of the M2R-IKACh channel complex. In future studies, this channel will be integrated in a sinus node model to investigate the effect of the channel properties on heart rate
Student Theses (2)
R. Moss. Effects of the Long-QT-syndrome on the mechanical deformation in a computational rabbit model.. Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT). Masterarbeit. 2015
In this work it is shown that electromechanical coupling has a major influence on a whole heart level.It is shown that a higher tension development due to ion channel density variations on a single cell level does not subsequently lead to a higher or lower tension development in a cellular complex but rather in a faster or respectively slower tension development. A change in heterogeneities of ion channel density in the ventricles might therefore be identified by a change in the duration of the systole in relation to the heart cycle length. Hence, the incorporation of the stretch based influences on the tension development shows to be very promising. \\Additionally, heterogeneities which have a major influence on the electrophysiological behavior, such as the blocking of \IKr\ which leads to a prolonged QT-interval as it is the case in LQT2, might not influence the tension development directly. Changes in the behavior of the ventricles during contraction might result from either a different excitation pattern or changes in the intracellular calcium release at the beginning of the action potential due to remodeling. \\During the systole of the heart cycle, the modeled behavior is not far away from measured data. Nevertheless, during the diastole the modeled relaxation of the ventricles showed little likeliness to measured data, thus no real conclusion could be made on the impact of heterogeneities during this time interval. Without a doubt, the model still has room for improvement but this work can be seen as more than just a simple proof of concept. Further investigations into the subject of electrophysiological heterogeneities and their respective influence on the behavior of the ventricles during contraction are highly likely to one day aid physicians diagnosing diseases such as Long-QT-Syndrome.
R. Moss. Simulation of the chronotropic effect of voltage dependent M2 receptor agonist binding on the rabbit sinus node and atrium. Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT). Bachelorarbeit. 2012
The normal heart rate is mediated by the G-protein-coupled, acetylcholine (ACh)- activated inward rectifier K+ current (IK,ACh). A unique feature of IK,ACh is the so- called relaxation gating property that contributes to increased current at hyperpolarized membrane potentials. This Bachelor thesis is considering a novel explanation for IK,ACh relaxation based upon recent findings that G-protein-coupled receptors are intrinsically voltage sensitive and that the muscarinic agonists acetylcholine and pilocarpine manifest opposite voltage-dependent IK,ACh modulation. Based on experimental and computa- tional findings, [Moreno-Galindo et al., 2011] proposed that IK,ACh relaxation represents a voltage-dependent change in agonist affinity as a consequence of a voltage-dependent conformational change in the muscarinic receptor.