More Like this

1. A Cellular Automata Model for Dynamics and Control of Cardiac Arrhythmias

   Danny Gallenberger, Min Xiong (October 2020, ASME 2020 Dynamic Systems and Control Conference)

   null (Ed.)

   As a leading cause of death in 325,000 adults per year in the United States, a significant proportion of sudden cardiac arrest (SCA) result from arrhythmias. To better understand the onset of arrhythmias and its potential treatment with more rapid and effective control approaches, a two-dimensional 50 × 50 cellular automata (CA) model is used in this study to illustrate the propagation of electrical waves across its tissue, and a constant diastolic interval (DI) control mechanism is adopted to help stabilize and prevent cardiac arrhythmias. Simulations of various scenarios including normal conduction and spiral waves in the presence of scar, normal conduction and alternans under control conditions are shown. The results validate that the CA model and constant DI control method are very efficient and effective in the study of dynamics and control of cardiac arrhythmias. 

   more » « less
2. Arrhythmogenic Effects of Genetic Mutations Affecting Potassium Channels in Human Atrial Fibrillation: A Simulation Study

   https://doi.org/10.3389/fphys.2021.681943  

   Belletti, Rebecca; Romero, Lucia; Martinez-Mateu, Laura; Cherry, Elizabeth M.; Fenton, Flavio H.; Saiz, Javier (May 2021, Frontiers in Physiology)

   null (Ed.)

   Genetic mutations in genes encoding for potassium channel protein structures have been recently associated with episodes of atrial fibrillation in asymptomatic patients. The aim of this study is to investigate the potential arrhythmogenicity of three gain-of-function mutations related to atrial fibrillation—namely, KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M—using modeling and simulation of the electrophysiological activity of the heart. A genetic algorithm was used to tune the parameters’ value of the original ionic currents to reproduce the alterations experimentally observed caused by the mutations. The effects on action potentials, ionic currents, and restitution properties were analyzed using versions of the Courtemanche human atrial myocyte model in different tissues: pulmonary vein, right, and left atrium. Atrial susceptibility of the tissues to spiral wave generation was also investigated studying the temporal vulnerability. The presence of the three mutations resulted in an overall more arrhythmogenic substrate. Higher current density, action potential duration shortening, and flattening of the restitution curves were the major effects of the three mutations at the single-cell level. The genetic mutations at the tissue level induced a higher temporal vulnerability to the rotor’s initiation and progression, by sustaining spiral waves that perpetuate until the end of the simulation. The mutation with the highest pro-arrhythmic effects, exhibiting the widest sustained VW and the smallest meandering rotor’s tip areas, was KCNE3-V17M. Moreover, the increased susceptibility to arrhythmias and rotor’s stability was tissue-dependent. Pulmonary vein tissues were more prone to rotor’s initiation, while in left atrium tissues rotors were more easily sustained. Re-entries were also progressively more stable in pulmonary vein tissue, followed by the left atrium, and finally the right atrium. The presence of the genetic mutations increased the susceptibility to arrhythmias by promoting the rotor’s initiation and maintenance. The study provides useful insights into the mechanisms underlying fibrillatory events caused by KCNH2 T895M, KCNH2 T436M, and KCNE3-V17M and might aid the planning of patient-specific targeted therapies. 

   more » « less
3. Experimental studies of spiral wave teleportation in a light sensitive Belousov–Zhabotinsky system

   https://doi.org/10.1063/5.0216649  

   Tyler, Shannyn A; Mersing, David; Fenton, Flavio H; Tinsley, Mark R; Showalter, Kenneth (September 2024, Chaos: An Interdisciplinary Journal of Nonlinear Science)

   Cardiac arrythmias are a form of heart disease that contributes toward making heart disease a significant cause of death globally. Irregular rhythms associated with cardiac arrythmias are thought to arise due to singularities in the heart tissue that generate reentrant waves in the underlying excitable medium. A normal approach to removing such singularities is to apply a high voltage electric shock, which effectively resets the phase of the cardiac cells. A concern with the use of this defibrillation technique is that the high-energy shock can cause lasting damage to the heart tissue. Various theoretical works have investigated lower-energy alternatives to defibrillation. In this work, we demonstrate the effectiveness of a low-energy defibrillation method in an experimental 2D Belousov–Zhabotinsky (BZ) system. When implemented as a 2D spatial reaction, the BZ reaction serves as an effective analog of general excitable media and supports regular and reentrant wave activity. The defibrillation technique employed involves targeted low-energy perturbations that can be used to “teleport” and/or annihilate singularities present in the excitable BZ medium. 

   more » « less
4. Clinical Potential of Beat‐to‐Beat Diastolic Interval Control in Preventing Cardiac Arrhythmias

   https://doi.org/10.1161/JAHA.121.020750  

   Kulkarni, Kanchan; Walton, Richard D.; Armoundas, Antonis A.; Tolkacheva, Elena G. (June 2021, Journal of the American Heart Association)

   null (Ed.)

   Abstract Life‐threatening ventricular arrhythmias and sudden cardiac death are often preceded by cardiac alternans, a beat‐to‐beat oscillation in the T‐wave morphology or duration. However, given the spatiotemporal and structural complexity of the human heart, designing algorithms to effectively suppress alternans and prevent fatal rhythms is challenging. Recently, an antiarrhythmic constant diastolic interval pacing protocol was proposed and shown to be effective in suppressing alternans in 0‐, 1‐, and 2‐dimensional in silico studies as well as in ex vivo whole heart experiments. Herein, we provide a systematic review of the electrophysiological conditions and mechanisms that enable constant diastolic interval pacing to be an effective antiarrhythmic pacing strategy. We also demonstrate a successful translation of the constant diastolic interval pacing protocol into an ECG‐based real‐time control system capable of modulating beat‐to‐beat cardiac electrical activity and preventing alternans. Furthermore, we present evidence of the clinical utility of real‐time alternans suppression in reducing arrhythmia susceptibility in vivo. We provide a comprehensive overview of this promising pacing technique, which can potentially be translated into a clinically viable device that could radically improve the quality of life of patients experiencing abnormal cardiac rhythms. 

   more » « less
5. Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N-terminal domains

   Yue, Benny; Haddad, Bassam G.; Khan, Umair; Chen, Hongchong; Atalla, Mena; Zhang, Ze; Zuckerman, Daniel M.; Reichow, Steve L.; Bai, Donglin (April 2021, The journal of physiology)

   null (Ed.)

   Connexins form intercellular communication channels, known as gap junctions (GJs), that facilitate diverse physiological roles, from long-range electrical and chemical coupling to coordinating development and nutrient exchange. GJs formed by different connexin isoforms harbour unique channel properties that have not been fully defined mechanistically. Recent structural studies on Cx46 and Cx50 defined a novel and stable open state and implicated the amino-terminal (NT) domain as a major contributor for isoform-specific functional differences between these closely related lens connexins. To better understand these differences, we constructed models corresponding to wildtype Cx50 and Cx46 GJs, NT domain swapped chimeras, and point variants at the 9th residue for comparative molecular dynamics (MD) simulation and electrophysiology studies. All constructs formed functional GJ channels, except the chimeric Cx46-50NT variant, which correlated with an introduced steric clash and increased dynamical behaviour (instability) of the NT domain observed by MD simulation. Single channel conductance correlated well with free-energy landscapes predicted by MD, but resulted in a surprisingly greater degree of effect. Additionally, we observed significant effects on transjunctional voltage-dependent gating (Vj gating) and/or open state dwell times induced by the designed NT domain variants. Together, these studies indicate intra- and inter-subunit interactions involving both hydrophobic and charged residues within the NT domains of Cx46 and Cx50 play important roles in defining GJ open state stability and single channel conductance, and establish the open state Cx46/50 structural models as archetypes for structure–function studies targeted at elucidating GJ channel mechanisms and the molecular basis of cataract-linked connexin variants. 

   more » « less