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PloS One 2022Simplified nonlinear models of biological cells are widely used in computational electrophysiology. The models reproduce qualitatively many of the characteristics of...
Simplified nonlinear models of biological cells are widely used in computational electrophysiology. The models reproduce qualitatively many of the characteristics of various organs, such as the heart, brain, and intestine. In contrast to complex cellular ion-channel models, the simplified models usually contain a small number of variables and parameters, which facilitates nonlinear analysis and reduces computational load. In this paper, we consider pacemaking variants of the Aliev-Panfilov and Corrado two-variable excitable cell models. We conducted a numerical simulation study of these models and investigated the main nonlinear dynamic features of both isolated cells and 1D coupled pacemaker-excitable systems. Simulations of the 2D sinoatrial node and 3D intestine tissue as application examples of combined pacemaker-excitable systems demonstrated results similar to obtained previously. The uniform formulation for the conventional excitable cell models and proposed pacemaker models allows a convenient and easy implementation for the construction of personalized physiological models, inverse tissue modeling, and development of real-time simulation systems for various organs that contain both pacemaker and excitable cells.
Topics: Action Potentials; Computer Simulation; Ion Channels; Models, Cardiovascular; Sinoatrial Node
PubMed: 35404982
DOI: 10.1371/journal.pone.0257935 -
Channels (Austin, Tex.) 2018Potassium currents determine the resting membrane potential and govern repolarisation in cardiac myocytes. Here, we review the various currents in the sinoatrial node... (Review)
Review
Potassium currents determine the resting membrane potential and govern repolarisation in cardiac myocytes. Here, we review the various currents in the sinoatrial node focussing on their molecular and cellular properties and their role in pacemaking and heart rate control. We also describe how our recent finding of a novel ATP-sensitive potassium channel population in these cells fits into this picture.
Topics: Animals; Heart Rate; Humans; Potassium Channels; Sinoatrial Node
PubMed: 30301404
DOI: 10.1080/19336950.2018.1532255 -
Circulation Journal : Official Journal... 2012The results presented by Shinohara et al(1) suggests that both the membrane clock and the Ca(2+) clock contribute to sinus node automaticity. Which is dominant depends...
The results presented by Shinohara et al(1) suggests that both the membrane clock and the Ca(2+) clock contribute to sinus node automaticity. Which is dominant depends on the region within the sinus node and the condition of the SNS. When you change the way you look at things, the things you look at change. This new hypothesis is very attractive, because it combines the membrane and Ca(2+) clocks. In fact, supporting data have been reported by the same parties.(11,12) Supportive studies by others are warranted.
Topics: Animals; Biological Clocks; Calcium; Male; Potassium; Sinoatrial Node; Tachycardia, Sinus
PubMed: 22185712
DOI: 10.1253/circj.cj-11-1354 -
Circulation Research May 2024Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of... (Review)
Review
Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease-including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating Ī²-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate-sensitive hyperpolarization-activated current (I) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate-dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.
Topics: Humans; Animals; Heart Rate; Sinoatrial Node; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Biological Clocks
PubMed: 38723033
DOI: 10.1161/CIRCRESAHA.123.323250 -
JACC. Clinical Electrophysiology Nov 2022
Topics: Humans; Sinoatrial Node; Heart Failure; Electrocardiography
PubMed: 36424001
DOI: 10.1016/j.jacep.2022.09.001 -
The Tohoku Journal of Experimental... Mar 2018The formation and conduction of electrocardiosignals and the synchronous contraction of atria and ventricles with rhythmicity are both triggered and regulated by the... (Review)
Review
The formation and conduction of electrocardiosignals and the synchronous contraction of atria and ventricles with rhythmicity are both triggered and regulated by the cardiac conduction system (CCS). Defect of this system will lead to various types of cardiac arrhythmias. In recent years, the research progress of molecular genetics and developmental biology revealed a clearer understanding of differentiation and development of the cardiac conduction system and their regulatory mechanisms. Short stature homeobox 2 (Shox2) transcription factor, encoded by Shox2 gene in the mouse, is crucial in the formation and differentiation of the sinoatrial node (SAN). Shox2 drives embryonic development processes and is widely expressed in the appendicular skeleton, palate, temporomandibular joints, and heart. Mutations of Shox2 can lead to dysembryoplasia and abnormal phenotypes, including bradycardiac arrhythmia. In this review, we provide a summary of the latest research progress on the regulatory effects of the Shox2 gene in differentiation and development processes of the cardiac conduction system, hoping to deepen the knowledge and understanding of this systematic process based on the cardiac conduction system. Overall, the Shox2 gene is intimately involved in the differentiation and development of cardiac conduction system, especially sinoatrial node. We also summarize the current information about human SHOX2. This review article provides a new direction in biological pacemaker therapies.
Topics: Amino Acid Sequence; Animals; Base Sequence; Biological Clocks; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Heart Conduction System; Homeodomain Proteins; Humans; Mice; Sinoatrial Node
PubMed: 29503396
DOI: 10.1620/tjem.244.177 -
Circulation. Arrhythmia and... Oct 2021Each heartbeat that pumps blood throughout the body is initiated by an electrical impulse generated in the sinoatrial node (SAN). However, a number of disease conditions... (Review)
Review
Each heartbeat that pumps blood throughout the body is initiated by an electrical impulse generated in the sinoatrial node (SAN). However, a number of disease conditions can hamper the ability of the SAN's pacemaker cells to generate consistent action potentials and maintain an orderly conduction path, leading to arrhythmias. For symptomatic patients, current treatments rely on implantation of an electronic pacing device. However, complications inherent to the indwelling hardware give pause to categorical use of device therapy for a subset of populations, including pediatric patients or those with temporary pacing needs. Cellular-based biological pacemakers, derived in vitro or in situ, could function as a therapeutic alternative to current electronic pacemakers. Understanding how biological pacemakers measure up to the SAN would facilitate defining and demonstrating its advantages over current treatments. In this review, we discuss recent approaches to creating biological pacemakers and delineate design criteria to guide future progress based on insights from basic biology of the SAN. We emphasize the need for long-term efficacy in vivo via maintenance of relevant proteins, source-sink balance, a niche reflective of the native SAN microenvironment, and chronotropic competence. With a focus on such criteria, combined with delivery methods tailored for disease indications, clinical implementation will be attainable.
Topics: Action Potentials; Arrhythmias, Cardiac; Biological Clocks; Humans; Prosthesis Design; Sinoatrial Node
PubMed: 34592837
DOI: 10.1161/CIRCEP.121.009957 -
GeroScience Feb 2022The cardiac pacemaker ignites and coordinates the contraction of the whole heart, uninterruptedly, throughout our entire life. Pacemaker rate is constantly tuned by the... (Review)
Review
The cardiac pacemaker ignites and coordinates the contraction of the whole heart, uninterruptedly, throughout our entire life. Pacemaker rate is constantly tuned by the autonomous nervous system to maintain body homeostasis. Sympathetic and parasympathetic terminals act over the pacemaker cells as the accelerator and the brake pedals, increasing or reducing the firing rate of pacemaker cells to match physiological demands. Despite the remarkable reliability of this tissue, the pacemaker is not exempt from the detrimental effects of aging. Mammals experience a natural and continuous decrease in the pacemaker rate throughout the entire lifespan. Why the pacemaker rhythm slows with age is poorly understood. Neural control of the pacemaker is remodeled from birth to adulthood, with strong evidence of age-related dysfunction that leads to a downshift of the pacemaker. Such evidence includes remodeling of pacemaker tissue architecture, alterations in the innervation, changes in the sympathetic acceleration and the parasympathetic deceleration, and alterations in the responsiveness of pacemaker cells to adrenergic and cholinergic modulation. In this review, we revisit the main evidence on the neural control of the pacemaker at the tissue and cellular level and the effects of aging on shaping this neural control.
Topics: Aging; Animals; Heart Rate; Reproducibility of Results; Sinoatrial Node
PubMed: 34292477
DOI: 10.1007/s11357-021-00420-3 -
Progress in Biophysics and Molecular... 2008Voltage-gated Na+ channels are transmembrane proteins that produce the fast inward Na+ current responsible for the depolarization phase of the cardiac action potential.... (Review)
Review
Voltage-gated Na+ channels are transmembrane proteins that produce the fast inward Na+ current responsible for the depolarization phase of the cardiac action potential. They play fundamental roles in the initiation, propagation, and maintenance of normal cardiac rhythm. Inherited mutations in SCN5A, the gene encoding the pore-forming alpha-subunit of the cardiac-type Na+ channel, result in a spectrum of disease entities termed Na+ channelopathies. These include multiple arrhythmic syndromes, such as the long QT syndrome type 3 (LQT3), Brugada syndrome (BrS), an inherited cardiac conduction defect (CCD), sudden infant death syndrome (SIDS) and sick sinus syndrome (SSS). To date, mutational analyses have revealed more than 200 distinct mutations in SCN5A, of which at least 20 mutations are associated with sinus node dysfunction including SSS. This review summarizes recent findings bearing upon: (i) the functional role of distinct voltage-gated Na+ currents in sino-atrial node pacemaker function; (ii) genetic Na+ channelopathy and its relationship to sinus node dysfunction.
Topics: Animals; Humans; Mice; Models, Molecular; Muscle Proteins; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Sick Sinus Syndrome; Sinoatrial Node; Sodium Channels
PubMed: 19027778
DOI: 10.1016/j.pbiomolbio.2008.10.003 -
Progress in Biophysics and Molecular... 2008Cardiac pacemaking in the sinoatrial (SA) node and atrioventricular (AV) node is generated by an interplay of many ionic currents, one of which is the funny pacemaker... (Comparative Study)
Comparative Study Review
Cardiac pacemaking in the sinoatrial (SA) node and atrioventricular (AV) node is generated by an interplay of many ionic currents, one of which is the funny pacemaker current (If). To understand the functional role of If in two different pacemakers, comparative studies of spontaneous activity and expression of the HCN channel in mouse SA node and AV node were performed. The intrinsic cycle length (CL) is 179+/-2.7 ms (n=5) in SA node and 258+/-18.7 ms (n=5) in AV node. Blocking of If current by 1 micromol/L ZD7288 increased the CL to 258+/-18.7 ms (n=5) and 447+/-92.4 ms (n=5) in SA node and AV node, respectively. However, the major HCN channel, HCN4 expressed at low level in the AV node compared to the SA node. To clarify the discrepancy between the functional importance of If and expression level of HCN4 channel, a SA node cell model was used. Increasing the If conductance resulted in decreasing in the CL in the model, which explains the high pacemaking rate and high expression of HCN channel in the SA node. Resistance to the blocking of If in the SA node might result from compensating effects from other currents (especially voltage sensitive currents) involved in pacemaking. The computer simulation shows that the difference in the intrinsic CL could explain the difference in response to If blocking in these two cardiac nodes.
Topics: Action Potentials; Animals; Atrioventricular Node; Biological Clocks; Humans; Sinoatrial Node
PubMed: 17905415
DOI: 10.1016/j.pbiomolbio.2007.07.009