{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T00:31:23Z","timestamp":1793233883632,"version":"4.5.0"},"reference-count":120,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T00:00:00Z","timestamp":1618272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["16SDG29120011"],"award-info":[{"award-number":["16SDG29120011"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17POST33370089"],"award-info":[{"award-number":["17POST33370089"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01HL141214-01"],"award-info":[{"award-number":["1R01HL141214-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wisconsin Partnership Program","award":["4140 grant"],"award-info":[{"award-number":["4140 grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>The sinoatrial node (SAN), the primary pacemaker of the heart, consists of a heterogeneous population of specialized cardiac myocytes that can spontaneously produce action potentials, generating the rhythm of the heart and coordinating heart contractions. Spontaneous beating can be observed from very early embryonic stage and under a series of genetic programing, the complex heterogeneous SAN cells are formed with specific biomarker proteins and generate robust automaticity. The SAN is capable to adjust its pacemaking rate in response to environmental and autonomic changes to regulate the heart\u2019s performance and maintain physiological needs of the body. Importantly, the origin of the action potential in the SAN is not static, but rather dynamically changes according to the prevailing conditions. Changes in the heart rate are associated with a shift of the leading pacemaker location within the SAN and accompanied by alterations in P wave morphology and PQ interval on ECG. Pacemaker shift occurs in response to different interventions: neurohormonal modulation, cardiac glycosides, pharmacological agents, mechanical stretch, a change in temperature, and a change in extracellular electrolyte concentrations. It was linked with the presence of distinct anatomically and functionally defined intranodal pacemaker clusters that are responsible for the generation of the heart rhythm at different rates. Recent studies indicate that on the cellular level, different pacemaker clusters rely on a complex interplay between the calcium (referred to local subsarcolemmal Ca2+ releases generated by the sarcoplasmic reticulum via ryanodine receptors) and voltage (referred to sarcolemmal electrogenic proteins) components of so-called \u201ccoupled clock pacemaker system\u201d that is used to describe a complex mechanism of SAN pacemaking. In this review, we examine the structural, functional, and molecular evidence for hierarchical pacemaker clustering within the SAN. We also demonstrate the unique molecular signatures of intranodal pacemaker clusters, highlighting their importance for physiological rhythm regulation as well as their role in the development of SAN dysfunction, also known as sick sinus syndrome.<\/jats:p>","DOI":"10.3390\/jcdd8040043","type":"journal-article","created":{"date-parts":[[2021,4,13]],"date-time":"2021-04-13T05:31:37Z","timestamp":1618291897000},"page":"43","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Cellular and Molecular Mechanisms of Functional Hierarchy of Pacemaker Clusters in the Sinoatrial Node: New Insights into Sick Sinus Syndrome"],"prefix":"10.3390","volume":"8","author":[{"given":"Di","family":"Lang","sequence":"first","affiliation":[{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey V.","family":"Glukhov","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1161\/01.RES.46.1.11","article-title":"Functional and morphological organization of the rabbit sinus node","volume":"46","author":"Bleeker","year":"1980","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1046\/j.1540-8167.2003.02307.x","article-title":"Sophisticated architecture is required for the sinoatrial node to perform its normal pacemaker function","volume":"14","author":"Boyett","year":"2003","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/BF02125744","article-title":"The mammalian sinoatrial node","volume":"1","author":"Opthof","year":"1988","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"eaam5607","DOI":"10.1126\/scitranslmed.aam5607","article-title":"Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure","volume":"9","author":"Li","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/S0008-6363(00)00135-8","article-title":"The sinoatrial node, a heterogeneous pacemaker structure","volume":"47","author":"Boyett","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1113\/eph8602100","article-title":"Pacemaker shift in the rabbit sinoatrial node in response to vagal nerve stimulation","volume":"86","author":"Shibata","year":"2001","journal-title":"Exp. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.jelectrocard.2011.08.010","article-title":"Spatiotemporal control of heart rate in a rabbit heart","volume":"44","author":"Lang","year":"2011","journal-title":"J. Electrocardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1172\/JCI65268","article-title":"Diabetes increases mortality after myocardial infarction by oxidizing CaMKII","volume":"123","author":"Luo","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"H403","DOI":"10.1152\/ajpheart.00253.2016","article-title":"Electrophysiological heterogeneity of pacemaker cells in the rabbit intercaval region, including the SA node: Insights from recording multiple ion currents in each cell","volume":"314","author":"Monfredi","year":"2018","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"345a","DOI":"10.1016\/j.bpj.2019.11.1994","article-title":"Hierarchical Pacemaker Clustering within the Rabbit Sinoatrial Node is Driven by Dynamic Interaction between the Components of the Coupled-Clock System","volume":"118","author":"Yuan","year":"2020","journal-title":"Biophys. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1152\/ajplegacy.1967.212.2.407","article-title":"Location of pacemaker in chick embryo heart at the time of initiation of heartbeat","volume":"212","year":"1967","journal-title":"Am. J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1152\/physrev.1991.71.1.53","article-title":"Optical approaches to ontogeny of electrical activity and related functional organization during early heart development","volume":"71","author":"Kamino","year":"1991","journal-title":"Physiol. Rev."},{"key":"ref_13","first-page":"575","article-title":"Observations on the development of the electrocardiogram","volume":"160","author":"Paff","year":"1968","journal-title":"Anat. Rec. Adv. Integr. Anat. Evol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1161\/CIRCRESAHA.110.223917","article-title":"Neuregulin\/ErbB Signaling Regulates Cardiac Subtype Specification in Differentiating Human Embryonic Stem Cells","volume":"107","author":"Zhu","year":"2010","journal-title":"Circ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s11010-013-1764-x","article-title":"Genetic isolation of stem cell-derived pacemaker-nodal cardiac myocytes","volume":"383","author":"Hashem","year":"2013","journal-title":"Mol. Cell. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, H., Lau, D.H., Shlapakova, I.N., Zhao, X., Danilo, P., Robinson, R.B., Cohen, I.S., Qu, D., Xu, Z., and Rosen, M.R. (2011). Implantation of Sinoatrial Node Cells into Canine Right Ventricle: Biological Pacing Appears Limited by the Substrate, SAGE Publications.","DOI":"10.3727\/096368911X565038"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/0002-9149(70)90580-1","article-title":"The morphologic development of the sinoatrial node in the mouse","volume":"25","author":"Gessner","year":"1970","journal-title":"Am. J. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1161\/CIRCRESAHA.109.205419","article-title":"Development of the Pacemaker Tissues of the Heart","volume":"106","author":"Christoffels","year":"2010","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1161\/01.CIR.59.5.879","article-title":"The cardiac conduction system in situs ambiguus","volume":"59","author":"Dickinson","year":"1979","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cardiores.2006.07.026","article-title":"Extended atrial conduction system characterised by the expression of the HCN4 channel and connexin45","volume":"72","author":"Yamamoto","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.cardiores.2006.11.016","article-title":"Organisation of the mouse sinoatrial node: Structure and expression of HCN channels","volume":"73","author":"Liu","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.yjmcc.2009.04.009","article-title":"Distribution of the pacemaker HCN4 channel mRNA and protein in the rabbit sinoatrial node","volume":"47","author":"Brioschi","year":"2009","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1038\/ncb2824","article-title":"A HCN4+ cardiomyogenic progenitor derived from the first heart field and human pluripotent stem cells","volume":"15","author":"Abramczuk","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/S1567-133X(03)00125-X","article-title":"Expression of the hyperpolarization-activated cyclic nucleotide-gated cation channel HCN4 during mouse heart development","volume":"3","author":"Shi","year":"2003","journal-title":"Gene Expr. Patterns"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15235","DOI":"10.1073\/pnas.2434235100","article-title":"The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart","volume":"100","author":"Stieber","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/0006-8993(88)90707-X","article-title":"Heart conduction system: A neural crest derivative?","volume":"457","author":"Gorza","year":"1988","journal-title":"Brain Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1161\/01.RES.68.6.1638","article-title":"Spatial distribution of connexin43, the major cardiac gap junction protein, in the developing and adult rat heart","volume":"68","author":"Fromaget","year":"1991","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1124\/pr.114.009597","article-title":"Stem Cell\u2013Derived Nodal-Like Cardiomyocytes as a Novel Pharmacologic Tool: Insights from Sinoatrial Node Development and Function","volume":"67","author":"Barbuti","year":"2015","journal-title":"Pharmacol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.cardiores.2004.01.030","article-title":"The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart","volume":"62","author":"Hoogaars","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1101\/gad.416007","article-title":"Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria","volume":"21","author":"Hoogaars","year":"2007","journal-title":"Genes Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.ydbio.2008.12.028","article-title":"Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5","volume":"327","author":"Yu","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1161\/CIRCRESAHA.108.187062","article-title":"Formation of the Sinus Node Head and Differentiation of Sinus Node Myocardium Are Independently Regulated by Tbx18 and Tbx3","volume":"104","author":"Wiese","year":"2009","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3256","DOI":"10.1172\/JCI68257","article-title":"Transcription factor ISL1 is essential for pacemaker development and function","volume":"125","author":"Liang","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1161\/CIRCRESAHA.120.317145","article-title":"ATAC-Seq Reveals an Isl1 Enhancer That Regulates Sinoatrial Node Development and Function","volume":"127","author":"Galang","year":"2020","journal-title":"Circ. Res."},{"key":"ref_35","first-page":"371","article-title":"Reconstruction of the human sinoatrial node","volume":"159","author":"Truex","year":"1967","journal-title":"Anat. Rec. Adv. Integr. Anat. Evol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1161\/01.RES.39.1.76","article-title":"Spontaneous action potentials of cells in the canine sinus node","volume":"39","author":"Woods","year":"1976","journal-title":"Circ. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Anderson, R.H., Yen, H.S., Becker, A.E., and Gosling, J.A. (1978). The Development of the Sinoatrial Node. The Sinus Node, Springer.","DOI":"10.1007\/978-94-009-9715-8_14"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1111\/j.1540-8167.1998.tb00097.x","article-title":"The architecture of the sinus node, the atrioventricular conduction axis, and the internodal atrial myocardium","volume":"9","author":"Anderson","year":"1998","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1093\/cvr\/19.5.304","article-title":"Electrophysiological study of the two main pacemaker mechanisms in the rabbit sinus node","volume":"19","author":"Kreitner","year":"1985","journal-title":"Cardiovasc. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/BF00586730","article-title":"Pacemaker shift in the sino-atrial node during vagal stimulation","volume":"302","author":"Bouman","year":"1968","journal-title":"Pfl\u00fcger Arch."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Bouman, L., Mackaay, A., Bleeker, W., and Becher, A. (1978). Pacemaker Shifts in the Sinus Node: Effects of Vagal Stimulation, Temperature and Reduction of Extracellular Calcium. The Sinus Node, Springer.","DOI":"10.1007\/978-94-009-9715-8_20"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1161\/CIRCEP.113.000404","article-title":"Sinoatrial node reentry in a canine chronic left ventricular infarct model: Role of intranodal fibrosis and heterogeneity of refractoriness","volume":"6","author":"Glukhov","year":"2013","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_43","unstructured":"Shinohara, T., Park, H.W., Joung, B., Maruyama, M., Chua, S.K., Han, S., Shen, M.J., Chen, P.-S., and Lin, S.-F. (2011). Selective sinoatrial node optical mapping and the mechanism of sinus rate acceleration. Circ. J., 1111041458."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"H634","DOI":"10.1152\/ajpheart.00347.2010","article-title":"Tachybradycardia in the isolated canine right atrium induced by chronic sympathetic stimulation and pacemaker current inhibition","volume":"299","author":"Joung","year":"2010","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1113\/JP276876","article-title":"Shift of leading pacemaker site during reflex vagal stimulation and altered electrical source-to-sink balance","volume":"597","author":"Ashton","year":"2019","journal-title":"J. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1111\/j.1540-8167.1996.tb00524.x","article-title":"Origin of the Sinus Impulse","volume":"7","author":"Schuessler","year":"1996","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_47","first-page":"R483","article-title":"P-wave morphology and atrial activation in the domestic fowl","volume":"239","author":"Hill","year":"1980","journal-title":"Am. J. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"H482","DOI":"10.1152\/ajpheart.00756.2009","article-title":"Functional anatomy of the murine sinus node: High-resolution optical mapping of ankyrin-B heterozygous mice","volume":"299","author":"Glukhov","year":"2010","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1093\/eurheartj\/eht452","article-title":"Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex1","volume":"36","author":"Glukhov","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.hrthm.2012.09.012","article-title":"Tachy-brady arrhythmias: The critical role of adenosine-induced sinoatrial conduction block in post-tachycardia pauses","volume":"10","author":"Lou","year":"2013","journal-title":"Heart Rhythm"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1161\/CIRCULATIONAHA.108.817379","article-title":"Intracellular Calcium Dynamics and the Acceleration of Sinus Rhythm by \u03b2-Adrenergic Stimulation","volume":"119","author":"Joung","year":"2009","journal-title":"Circulation"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1161\/CIRCULATIONAHA.109.935288","article-title":"Complex Interactions Between the Sinoatrial Node and Atrium During Reentrant Arrhythmias in the Canine Heart","volume":"122","author":"Fedorov","year":"2010","journal-title":"Circulation"},{"key":"ref_53","first-page":"e3275","article-title":"Optical Mapping of Action Potentials and Calcium Transients in the Mouse Heart","volume":"2011","author":"Lang","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1161\/CIRCEP.114.002065","article-title":"Arrhythmogenic remodeling of beta2 versus beta1 adrenergic signaling in the human failing heart","volume":"8","author":"Lang","year":"2015","journal-title":"Circ. Arrhythm Electrophysiol."},{"key":"ref_55","first-page":"e54773","article-title":"High-resolution Optical Mapping of the Mouse Sino-atrial Node","volume":"2016","author":"Lang","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Janardhan, A.H., Lang, D., and Efimov, I.R. (2012). Optical Mapping of the Sinoatrial Node and Atrioventricular Node. Card. Mapp., 79\u201389.","DOI":"10.1002\/9781118481585.ch9"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1161\/01.RES.46.3.406","article-title":"The effect of ouabain on the isolated sinus node preparation of the rabbit studied with microelectrodes","volume":"46","author":"Steinbeck","year":"1980","journal-title":"Circ. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"H2793","DOI":"10.1152\/ajpheart.1997.272.6.H2793","article-title":"Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node","volume":"272","author":"Kodama","year":"1997","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0022-2828(84)80714-2","article-title":"Pacemaker cell types in the rabbit sinus node: A correlative ultrastructural and electrophysiological study","volume":"16","author":"Massonpevet","year":"1984","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"H1773","DOI":"10.1152\/ajpheart.00892.2011","article-title":"Conduction barriers and pathways of the sinoatrial pacemaker complex: Their role in normal rhythm and atrial arrhythmias","volume":"302","author":"Fedorov","year":"2012","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1016\/j.jacc.2010.03.098","article-title":"Optical Mapping of the Isolated Coronary-Perfused Human Sinus Node","volume":"56","author":"Fedorov","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5555","DOI":"10.1038\/s41467-020-19304-9","article-title":"cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells","volume":"11","author":"Fenske","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1113\/jphysiol.1984.sp015461","article-title":"Mutual entrainment and electrical coupling as mechanisms for synchronous firing of rabbit sino-atrial pace-maker cells","volume":"356","author":"Jalife","year":"1984","journal-title":"J. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1161\/01.RES.58.5.706","article-title":"Dynamic interactions and mutual synchronization of sinoatrial node pacemaker cells. A mathematical model","volume":"58","author":"Michaels","year":"1986","journal-title":"Circ. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1113\/jphysiol.1996.sp021728","article-title":"Correlation between electrical activity and the size of rabbit sino-atrial node cells","volume":"496","author":"Honjo","year":"1996","journal-title":"J. Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1161\/01.RES.73.3.473","article-title":"Immunohistochemical delineation of the conduction system. I: The sinoatrial node","volume":"73","author":"Oosthoek","year":"1993","journal-title":"Circ. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1161\/01.RES.45.5.621","article-title":"The plasma membrane of leading pacemaker cells in the rabbit sinus node. A qualitative and quantitative ultrastructural analysis","volume":"45","author":"Bleeker","year":"1979","journal-title":"Circ. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1161\/01.CIR.34.1.139","article-title":"Comparative Ultrastructure of the Sinus Node in Man and Dog","volume":"34","author":"James","year":"1966","journal-title":"Circulation"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.3389\/fphys.2018.01686","article-title":"Functional Microdomains in Heart\u2019s Pacemaker: A Step beyond Classical Electrophysiology and Remodeling","volume":"9","author":"Lang","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1177\/002215540205000303","article-title":"Heterogeneous Expression of Ca2+Handling Proteins in Rabbit Sinoatrial Node","volume":"50","author":"Musa","year":"2002","journal-title":"J. Histochem. Cytochem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"H686","DOI":"10.1152\/ajpheart.1999.276.2.H686","article-title":"Downward gradient in action potential duration along conduction path in and around the sinoatrial node","volume":"276","author":"Boyett","year":"1999","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_72","first-page":"H793","article-title":"Regional differences in effects of E-4031 within the sinoatrial node","volume":"276","author":"Kodama","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1161\/CIRCULATIONAHA.115.018131","article-title":"Direct Evidence for Microdomain-Specific Localization and Remodeling of Functional L-Type Calcium Channels in Rat and Human Atrial Myocytes","volume":"132","author":"Glukhov","year":"2015","journal-title":"Circulation"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1161\/CIRCRESAHA.117.312050","article-title":"Calcium-Dependent Arrhythmogenic Foci Created by Weakly Coupled Myocytes in the Failing Heart","volume":"121","author":"Lang","year":"2017","journal-title":"Circ. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1161\/CIRCRESAHA.110.220517","article-title":"Sarcoplasmic Reticulum Ca2+ Pumping Kinetics Regulates Timing of Local Ca2+ Releases and Spontaneous Beating Rate of Rabbit Sinoatrial Node Pacemaker Cells","volume":"107","author":"Vinogradova","year":"2010","journal-title":"Circ. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ceca.2018.07.002","article-title":"Heterogeneity of calcium clock functions in dormant, dysrhythmically and rhythmically firing single pacemaker cells isolated from SA node","volume":"74","author":"Kim","year":"2018","journal-title":"Cell Calcium"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"eaap7608","DOI":"10.1126\/scisignal.aap7608","article-title":"A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells","volume":"11","author":"Tsutsui","year":"2018","journal-title":"Sci. Signal."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/j.1748-1716.2009.01963.x","article-title":"Modulation of rabbit sinoatrial node activation sequence by acetylcholine and isoproterenol investigated with optical mapping technique","volume":"196","author":"Abramochkin","year":"2009","journal-title":"Acta Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1161\/CIRCEP.115.003070","article-title":"Molecular Mapping of Sinoatrial Node HCN Channel Expression in the Human Heart","volume":"8","author":"Li","year":"2015","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.pbiomolbio.2005.05.001","article-title":"Serious workings of the funny current","volume":"90","author":"DiFrancesco","year":"2006","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1161\/01.RES.0000204575.94040.d1","article-title":"High Basal Protein Kinase A\u2013Dependent Phosphorylation Drives Rhythmic Internal Ca2+ Store Oscillations and Spontaneous Beating of Cardiac Pacemaker Cells","volume":"98","author":"Vinogradova","year":"2006","journal-title":"Circ. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"H532","DOI":"10.1152\/ajpheart.00765.2015","article-title":"CaMKII-dependent phosphorylation regulates basal cardiac pacemaker function via modulation of local Ca2+ releases","volume":"311","author":"Li","year":"2016","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1016\/j.yjmcc.2011.07.028","article-title":"A full range of mouse sinoatrial node AP firing rates requires protein kinase A-dependent calcium signaling","volume":"51","author":"Liu","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1161\/CIRCULATIONAHA.111.083584","article-title":"Ca2+ -Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2","volume":"126","author":"Boink","year":"2012","journal-title":"Circulation"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3999","DOI":"10.1172\/JCI88241","article-title":"Axial tubule junctions control rapid calcium signaling in atria","volume":"126","author":"Brandenburg","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.3389\/fphys.2018.01227","article-title":"Axial Tubule Junctions Activate Atrial Ca2+ Release Across Species","volume":"9","author":"Brandenburg","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_87","first-page":"125","article-title":"The T-tubule system in the specialized and general myocardium of the rat","volume":"127","author":"Ayettey","year":"1978","journal-title":"J. Anat."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1097\/00005344-199809000-00012","article-title":"Local Cholinergic Suppression of Pacemaker Activity in the Rabbit Sinoatrial Node","volume":"32","author":"Vinogradova","year":"1998","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"H612","DOI":"10.1152\/ajpheart.00022.2006","article-title":"Postganglionic nerve stimulation induces temporal inhibition of excitability in rabbit sinoatrial node","volume":"291","author":"Fedorov","year":"2006","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/0022-2828(78)90409-1","article-title":"Dual excitatory channels in the sinus node","volume":"10","author":"Lipsius","year":"1978","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1161\/CIRCRESAHA.107.153676","article-title":"Calcium Cycling Protein Density and Functional Importance to Automaticity of Isolated Sinoatrial Nodal Cells Are Independent of Cell Size","volume":"100","author":"Lyashkov","year":"2007","journal-title":"Circ. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0140-6736(01)74711-3","article-title":"Recent researches on the anatomy of the heart","volume":"175","author":"Keith","year":"1910","journal-title":"Lancet"},{"key":"ref_93","first-page":"453","article-title":"The disposition, morphology and innervation of cardiac specialized tissue in the guinea-pig","volume":"111","author":"Anderson","year":"1972","journal-title":"J. Anat."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.autneu.2016.08.006","article-title":"Characterization of the intrinsic cardiac nervous system","volume":"199","author":"Wake","year":"2016","journal-title":"Auton. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1161\/01.RES.32.3.393","article-title":"Selective In Situ Parasympathetic Control of the Canine Sinoatrial and Atrioventricular Nodes","volume":"32","author":"Lazzara","year":"1973","journal-title":"Circ. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"H949","DOI":"10.1152\/ajpheart.01340.2008","article-title":"Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca2+ cycling and I(KACh)","volume":"297","author":"Lyashkov","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/aja.1001850108","article-title":"Morphological study of the innervation pattern of the rabbit sinoatrial node","volume":"185","author":"Roberts","year":"1989","journal-title":"Am. J. Anat."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1161\/01.RES.77.5.957","article-title":"Relative densities of muscarinic cholinergic and beta-adrenergic receptors in the canine sinoatrial node and their relation to sites of pacemaker activity","volume":"77","author":"Beau","year":"1995","journal-title":"Circ. Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1046\/j.1440-1681.2002.03714.x","article-title":"Heterogeneous Distribution Of \u03b2-Adrenoceptors and Muscarinic Receptors In The Sinoatrial Node And Right Atrium Of The Dog","volume":"29","author":"Kurogouchi","year":"2002","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s10517-005-0420-1","article-title":"Relative Distribution Densities of Cholinergic and Adrenoceptor Structures in the Central Part of the Sinoatrial Node in Rat Heart","volume":"140","author":"Sutyagin","year":"2005","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/BF02278013","article-title":"Accentuated antagonism in the control of human heart rate","volume":"10","author":"Uijtdehaage","year":"2000","journal-title":"Clin. Auton. Res."},{"key":"ref_102","first-page":"335","article-title":"Sympathetic-parasympathetic interaction and accentuated antagonism in conscious dogs","volume":"260","author":"Vanoli","year":"1991","journal-title":"Am. J. Physiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1161\/CIRCEP.112.970517","article-title":"Familial evaluation in catecholaminergic polymorphic ventricular tachycardia: Disease penetrance and expression in cardiac ryanodine receptor mutation-carrying relatives","volume":"5","author":"Nederend","year":"2012","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1161\/CIRCULATIONAHA.111.075382","article-title":"Paradoxical Effect of Increased Diastolic Ca2+ Release and Decreased Sinoatrial Node Activity in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia","volume":"126","author":"Neco","year":"2012","journal-title":"Circulation"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1161\/01.CIR.0000152100.04087.DB","article-title":"Computer Three-Dimensional Reconstruction of the Sinoatrial Node","volume":"111","author":"Dobrzynski","year":"2005","journal-title":"Circulation"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1161\/01.RES.17.5.449","article-title":"Action of Driving Stimuli from Intrinsic and Extrinsic Sources on in Situ Cardiac Pacemaker Tissues","volume":"17","author":"Lange","year":"1965","journal-title":"Circ. Res."},{"key":"ref_107","unstructured":"Hoffman, B., and Cranefield, P.F. (1960). Electrophysiology of the Heart, McGraw-Hill."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1161\/01.CIR.77.6.1221","article-title":"Demonstration of a widely distributed atrial pacemaker complex in the human heart","volume":"77","author":"Boineau","year":"1988","journal-title":"Circulation"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1161\/01.CIR.58.6.1036","article-title":"Multicentric origin of the atrial depolarization wave: The pacemaker complex. Relation to dynamics of atrial conduction, P-wave changes and heart rate control","volume":"58","author":"Boineau","year":"1978","journal-title":"Circulation"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.jacc.2003.09.030","article-title":"Roles of adrenergic and cholinergic stimulation in spontaneous atrial fibrillation in dogs","volume":"43","author":"Sharifov","year":"2004","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_111","unstructured":"Fedorov, V.V., Trifonova, O.P., Glukhov, A.V., Rosen, M.R., and Rosenshtraukh, L.V. (2005). The role of mechano-electrical feedback in the cholinergic atrial fibrillation initiation. Mechanosensitivity in Cells and Tissues, Academia Publishing House Ltd."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1113\/jphysiol.1883.sp000121","article-title":"On the Innervation of the Heart, with especial reference to the Heart of the Tortoise","volume":"4","author":"Gaskell","year":"1883","journal-title":"J. Physiol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"592229","DOI":"10.3389\/fphys.2021.592229","article-title":"Structural and Functional Properties of Subsidiary Atrial Pacemakers in a Goat Model of Sinus Node Disease","volume":"12","author":"Soattin","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1093\/cvr\/cvt164","article-title":"Characterization of a right atrial subsidiary pacemaker and acceleration of the pacing rate by HCN over-expression","volume":"100","author":"Morris","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1152\/japplphysiol.00616.2003","article-title":"Parasympathetic control of the heart. II. A novel interganglionic intrinsic cardiac circuit mediates neural control of heart rate","volume":"96","author":"Gray","year":"2004","journal-title":"J. Appl. Physiol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"6141","DOI":"10.1113\/JP276508","article-title":"TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome","volume":"596","author":"Choudhury","year":"2018","journal-title":"J. Physiol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0735-1097(84)80098-4","article-title":"Alterations in subsidiary pacemaker function after prolonged subsidiary pacemaker dominance in the canine right atrium","volume":"4","author":"Rozanski","year":"1984","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S0735-1097(97)00492-0","article-title":"\u201cCristal tachycardias\u201d: Origin of right atrial tachycardias from the crista terminalis identified by intracardiac echocardiography","volume":"31","author":"Kalman","year":"1998","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.accreview.2005.08.071","article-title":"Focal Atrial Tachycardia From the Ostium of the Coronary Sinus. Electrocardiographic and Electrophysiological Characterization and Radiofrequency Ablation","volume":"14","author":"Kistler","year":"2005","journal-title":"ACC Curr. J. Rev."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/S0735-1097(02)02071-5","article-title":"Clinical and electrophysiologic characteristics of left septal atrial tachycardia","volume":"40","author":"Marrouche","year":"2002","journal-title":"J. Am. Coll. Cardiol."}],"container-title":["Journal of Cardiovascular Development and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2308-3425\/8\/4\/43\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:47:18Z","timestamp":1760161638000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2308-3425\/8\/4\/43"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,13]]},"references-count":120,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["jcdd8040043"],"URL":"https:\/\/doi.org\/10.3390\/jcdd8040043","relation":{},"ISSN":["2308-3425"],"issn-type":[{"value":"2308-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,13]]}}}