Adaptation of the Calcium-dependent Tension Development in Ventricular Cardiomyocytes

Today a variety of models describe the physiological behavior of the heart on a cellular level. The intracellular calcium concentration plays an important role, since it is the main driver for the active contraction of the heart. Due to different implementations of the calcium dynamics, simulating cardiac electromechanics can lead to severely different behaviors of the active tension when coupling the same tension model with different electrophysiological models. To handle these variations, we present an optimization tool that adapts the parameters of the most recent, human based tension model. The goal is to generate a physiologically valid tension development when coupled to an electrophysiological cellular model independent of the specifics of that model's calcium transient. In this work, we focus on a ventricular cell model. In order to identify the calcium-sensitive parameters, a sensitivity analysis of the tension model was carried out. In a further step, the cell model was adapted to reproduce the sarcomere length-dependent behavior of troponin C. With a maximum relative deviation of 20.3% per defined characteristic of the tension development, satisfactory results could be obtained for isometric twitch tension. Considering the length-dependent troponin handling, physiological behavior could be reproduced. In conclusion, we propose an algorithm to adapt the tension development model to any calcium transient input to achieve a physiologically valid active contraction on a cellular level. As a proof of concept, the algorithm is successfully applied to one of the most recent human ventricular cell models. This is an important step towards fully coupled electromechanical heart models, which are a valuable tool in personalized health care.

Deterministic and Stochastic Cellular Mechanisms Contributing to Carbon Monoxide Induced Ventricular Arrhythmias

Chronic exposure to low levels of Carbon Monoxide is associated with an increased risk of cardiac arrhythmia. Microelectrode recordings from rat and guinea pig single isolated ventricular myocytes exposed to CO releasing molecule CORM-2 and excited at 0.2/s show repolarisation changes that develop over hundreds of seconds: action potential prolongation by delayed repolarisation, EADs, multiple EADs and oscillations around the plateau, leading to irreversible repolarisation failure. The measured direct effects of CO on currents in these cells, and ion channels expressed in mammalian systems showed an increase in prolonged late Na+, and a decrease in the maximal T- and L-type Ca++. peak and late Na+, ultra-rapid delayed, delayed rectifier, and the inward rectifier K+ currents. Incorporation of these CO induced changes in maximal currents in ventricular cell models; (Gattoni et al., J. Physiol., 2016, 594, 4193–4224) (rat) and (Luo and Rudy, Circ. Res., 1994, 74, 1071–1096) (guinea-pig) and human endo-, mid-myo- and epi-cardial (O’Hara et al., PLoS Comput. Biol., 2011, 7, e1002061) models, by changes in maximal ionic conductance reproduces these repolarisation abnormalities. Simulations of cell populations with Gaussian distributions of maximal conductance parameters predict a CO induced increase in APD and its variability. Incorporation of these predicted CO induced conductance changes in human ventricular cell electrophysiology into ventricular tissue and wall models give changes in indices for the probability of the initiation of re-entrant arrhythmia.

Simulating Notch-Dome Morphology of Action Potential of Ventricular Cell: How the Speeds of Positive and Negative Feedbacks on Transmembrane Voltage Can Influence the Health of a Cell?

Ventricular action potential is well-known because of its plateau phase with a spike-notch-dome morphology. As such, the morphology of action potential is necessary for ensuring a correct heart functioning. Any distraction from normal notch-dome morphology may trigger a circus movement reentry in the form of lethal ventricular fibrillation. When the epicardial action potential dome propagates from a site where it is maintained to regions where it has been lost, it gives rise to the proposed mechanism for the Brugada syndrome. Despite the impact of notch-dome dynamics on the heart function, no independent and explicit research has been performed on the simulation of notch-dome dynamics and morphology. In this paper, using a novel mathematical approach, a three-state variable model is proposed; we show that our proposed model not only can simulate morphology of action potential of ventricular cells but also can propose a biological reasonable tool for controlling of the morphology of action potential spike-notch-dome. We show that the processes of activation and inactivation of ionic gating variables (as positive or negative feedbacks on the voltage of cell membrane) and the ratio of their speeds (time constants) can be treated as a reasonable biological tool for simulating ventricular cell notch-dome. This finding may led to a new insight to the quantification of the health of a ventricular cell and may also propose a new drug therapy strategy for cardiac diseases.

Reciprocal interaction between IK1 and If in biological pacemakers: A simulation study

Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current treatment of PD using implanted electronic pacemaker has some limitations, such as finite battery life and the risk of repeated surgery. As such, the biological pacemaker has been proposed as a potential alternative to the electronic pacemaker for PD treatment. Experimentally it has been shown that bio-engineered pacemaker cells can be generated from non-rhythmic ventricular myocytes (VMs) by knocking down genes related to the inward rectifier potassium channel current (IK1) or by overexpressing hyperpolarization-activated cyclic nucleotide gated channel genes responsible for the “funny” current (If). Such approaches can turn the VM cells into rhythmic pacemaker cells. However, it is unclear if a bio-engineered pacemaker based on the modification of IK1- and If-related channels simultaneously would enhance the ability and stability of bio-engineered pacemaking action potentials (APs). This study aimed to investigate by a computational approach the combined effects of modifying IK1 and If density on the initiation of pacemaking activity in human ventricular cell models. First, the possible mechanism(s) responsible for VMs to generate spontaneous pacemaking APs by changing the density of IK1 and If were investigated. Then the integral action of targeting both IK1 and If simultaneously on the pacemaking APs was analysed. Our results showed a reciprocal interaction between IK1 and If on generating stable and robust pacemaking APs in VMs. In addition, we thoroughly investigated the dynamical behaviours of automatic rhythms in VMs in the IK1 and If parameter space, providing optimal parameter ranges for a robust pacemaker cell. In conclusion, to the best of our knowledge, this study provides a novel theoretical basis for generating stable and robust pacemaker cells from non-pacemaking VMs, which may be helpful in designing engineered biological pacemakers for application purposes.Author SummaryPacemaking dysfunction has become one of the most serious cardiac diseases, which may result in arrhythmia and even death. The treatment of pacemaking dysfunction by electronic pacemaker has saved millions of people in the past fifty years. But not every patient can benefit from it because of possible limitations, such as surgical implication and lack of response to autonomic stimulus. The development of bio-pacemaker based on gene engineering technology provides a promising alternative to electronic pacemaker by manipulating the gene expression of cardiac cells. However, it is still unclear how a stable and robust bio-pacemaker can be generated. The present study aims to elucidate possible mechanisms responsible for a bio-engineered pacemaker by using a computational electrophysiological model of pacemaking cells based on modifying ion channel properties of IK1 and incorporating If in a human ventricular cell model, mimicking experimental approaches of gene engineering. Using the model, possible pacemaking mechanisms in non-pacemaking cells, as well as factors responsible for generating robust and stable biological pacemaker, were investigated. It was shown that the reciprocal interaction between reduction of IK1 and incorporation of If played an important role for producing robust and stable pacemaking. This study provides a novel insight into understanding of the initiation of pacemaking behaviours in non-rhythmic cardiac myocytes, providing a theoretical basis for experimental designing of biological pacemakers.