Induced Pacemaker Activity in Virtual Mammalian Ventricular Cells

Computers in Cardiology, 2005

Tong

Garratt

et al. 2005

Down-regulation of Kir2.1 channel reduces the inward-rectifier potassium current (i K1 ), and transforms excitable ventricular myocytes to pacemaker cells. This provides a possible bio-technique to induce a biological pacemaker, as an alternative to an implantable electronic pacemaker. However there are two fundamental issues: (i) the stability of the pacemaker activity; (ii) the critical size of the biological pacemaker necessary for robust pacing and driving the surrounding ventricular muscle. In this study, we address the two issues by computer modelling.

“…These conclusions are model independent. Similar results have been obtained using several other biophysically detailed models [5]. …”

Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Stability of genetically engineered cardiac pacemaker - role of intracellular CA/sup 2+/ handling

Computers in Cardiology, 2005

Tong

Garratt

et al. 2005

“…Computational modelling offers a means to investigate different approaches to generating stable pacemaking activity. It has been used to study possible roles of down-regulating I K1 in VMs (45)(46)(47) and combined action of overexpression of I f with down-regulation of I K1 in inducing spontaneous pacemaking activity in SAN (42). Bifurcation analysis has also been used to explore the effect of changes in some individual ion channel current on the pacemaking activities of SAN cells (48) and genesis of automaticity in VMs (46,49), showing the role of I K1 , I f , I st and Na + /Ca 2+ exchange current (I NaCa ) in modulating the initiation and stability of pacemaking activity (49).…”

Section: Introductionmentioning

confidence: 99%

Reciprocal interaction between I_K1and I_fin biological pacemakers: A simulation study

Wang

et al. 2020

Preprint

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.

“…Benson et al also analyzed the autorhythmicity induced by I K1 [6] using the Luo-Rudy model. In an independent study, Tong et al [7] implemented the ten Tusscher et al model [8] of human ventricular cells to study the stability of ventricular automaticity with I K1 reduction. All of these experimental and simulation studies suggested that biological pacemakers may be created from ventricular cells by suppression of I K1 and modulation of other currents, which could be potentially used to replace the electrical pacemakers, which have many disadvantages, such as imposed limitation on the exercise tolerance, cardiac rate-response to emotion, need for replacement and possibility of infection [9].…”

Section: Introductionmentioning

confidence: 99%

Simulation of ventricular automaticity induced by reducing inward-rectifier K⁺ current

Wang

2014 IEEE International Conference on Bioinformatics and Biomedicine (BIBM)

et al. 2014

Turning non-autonomic ventricular cells into pacemaking cells is believed to hold the key for making a biopacemaker that could potentially treat patients with cardiac conduction diseases. In this article, we analyze the effects of various membrane ion channel currents on ventricular automaticity induced by reducing the inward-rectifier K + current (I K1 ). It was found that the L-type calcium current (I CaL ), rather than the fast sodium current (I Na ), plays a major role in the rapid depolarization phase of the action potential. With a small I CaL , the automaticity of cells failed due to incompletion of the rapid depolarization. However, during the slow depolarization phase of the action potential, the background sodium current (I bNa) , background calcium current (I bCa ) and Na + /Ca 2+ exchanger current (I NaCa ) were playing more important roles. In 2D simulations, the automatic ventricular excitations arising from I K1 reduction only couldn't propagate; it required other currents to be modulated at the same time for driving the surrounding cardiac tissues.