{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:15:53Z","timestamp":1790835353318,"version":"4.1.0"},"reference-count":116,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2019,6,30]],"date-time":"2019-06-30T00:00:00Z","timestamp":1561852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heart failure (HF) frequently coexists with atrial fibrillation (AF) and dysfunction of the sinoatrial node (SAN), the natural pacemaker. HF is associated with chronic adrenergic stimulation, neurohormonal activation, abnormal intracellular calcium handling, elevated cardiac filling pressure and atrial stretch, and fibrosis. Pulmonary veins (PVs), which are the points of onset of ectopic electrical activity, are the most crucial AF triggers. A crosstalk between the SAN and PVs determines PV arrhythmogenesis. HF has different effects on SAN and PV electrophysiological characteristics, which critically modulate the development of AF and sick sinus syndrome. This review provides updates to improve our current understanding of the effects of HF in the electrical activity of the SAN and PVs as well as therapeutic implications for AF.<\/jats:p>","DOI":"10.3390\/ijms20133224","type":"journal-article","created":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T03:23:59Z","timestamp":1561951439000},"page":"3224","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Heart Failure Differentially Modulates Natural (Sinoatrial Node) and Ectopic (Pulmonary Veins) Pacemakers: Mechanism and Therapeutic Implication for Atrial Fibrillation"],"prefix":"10.3390","volume":"20","author":[{"given":"Chao-Shun","family":"Chan","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11042, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Kuo","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan"},{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao-Chang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Yu","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei City 22174, Taiwan"},{"name":"School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City 24257, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Ann","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11042, Taiwan"},{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"},{"name":"Cardiovascular Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1056\/NEJM199711063371906","article-title":"Cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities","volume":"337","author":"Braunwald","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1001\/jama.1994.03510350050036","article-title":"Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study","volume":"271","author":"Benjamin","year":"1994","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1093\/eurjhf\/hfp085","article-title":"A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure","volume":"11","author":"Mamas","year":"2009","journal-title":"Eur. J. Heart Fail."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2920","DOI":"10.1161\/01.CIR.0000072767.89944.6E","article-title":"Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study","volume":"107","author":"Wang","year":"2003","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1161\/CIRCULATIONAHA.111.019893","article-title":"Atrial fibrillation pathophysiology: implications for management","volume":"124","author":"Iwasaki","year":"2011","journal-title":"Circulation"},{"key":"ref_6","first-page":"865","article-title":"The pathophysiology of atrial fibrillation in heart failure","volume":"3","author":"Wongcharoen","year":"2012","journal-title":"J. Innov. Card. Rhythm Manag."},{"key":"ref_7","first-page":"3250","article-title":"Atrial fibrillation in heart failure: what should we do?","volume":"36","author":"Kotecha","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.ejheart.2005.11.007","article-title":"Previously known and newly diagnosed atrial fibrillation: a major risk indicator after a myocardial infarction complicated by heart failure or left ventricular dysfunction","volume":"8","author":"Swedberg","year":"2006","journal-title":"Eur. J. Heart Fail."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/S0002-9149(00)01324-2","article-title":"Prognosis of congestive heart failure after prior myocardial infarction in older person with atrial fibrillation versus sinus rhythm","volume":"87","author":"Aronow","year":"2001","journal-title":"Am. J. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.hlc.2017.05.117","article-title":"Atrial fibrillation and heart failure - cause or effect?","volume":"26","author":"Prabhu","year":"2017","journal-title":"Heart Lung Circ."},{"key":"ref_11","first-page":"751","article-title":"Atrial fibrillation and heart failure: A review of the intersection of two cardiac epidemics","volume":"6","author":"Park","year":"2013","journal-title":"J. Atr. Fibrillation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4277","DOI":"10.1093\/eurheartj\/ehy626","article-title":"Prognostic implications of atrial fibrillation in heart failure with reduced, mid-range, and preserved ejection fraction: a report from 14\u2009964 patients in the European Society of Cardiology Heart Failure Long-Term Registry","volume":"39","author":"Zafrir","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1097\/CRD.0000000000000131","article-title":"Heart failure with preserved, mid-range, and reduced ejection fraction: The misleading definition of the new guidelines","volume":"25","author":"Fedele","year":"2017","journal-title":"Cardiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1016\/j.jacc.2014.02.552","article-title":"Heart failure: TNM-like classification","volume":"63","author":"Fedele","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1056\/NEJMoa0708789","article-title":"Rhythm control versus rate control for atrial fibrillation and heart failure","volume":"358","author":"Roy","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1093\/europace\/euw295","article-title":"2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS","volume":"18","author":"Kirchhof","year":"2016","journal-title":"Europace"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1056\/NEJM199809033391003","article-title":"Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins","volume":"339","author":"Shah","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1161\/01.CIR.100.18.1879","article-title":"Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation","volume":"100","author":"Chen","year":"1999","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1161\/01.CIR.102.21.2619","article-title":"Circumferential radiofrequency ablation of pulmonary vein ostia: a new anatomic approach for curing atrial fibrillation","volume":"102","author":"Pappone","year":"2000","journal-title":"Circulation"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1161\/CIRCRESAHA.114.303772","article-title":"Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy","volume":"114","author":"Chen","year":"2014","journal-title":"Circ. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1016\/j.hrthm.2007.06.023","article-title":"Aging increases pulmonary veins arrhythmogenesis and susceptibility to calcium regulation agents","volume":"4","author":"Wongcharoen","year":"2007","journal-title":"Heart Rhythm"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4658","DOI":"10.1016\/j.ijcard.2013.07.183","article-title":"Distinctive sodium and calcium regulation associated with sex differences in atrial electrophysiology of rabbits","volume":"168","author":"Tsai","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1161\/CIRCULATIONAHA.106.616011","article-title":"New insights into pacemaker activity: promoting understanding of sick sinus syndrome","volume":"115","author":"Dobrzynski","year":"2007","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1161\/01.CIR.16.1.20","article-title":"Disease of the sinoatrial node associated with bradycardia, asystole, syncope, and paroxysmal atrial fibrillation","volume":"16","author":"Birchfield","year":"1957","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/europace\/eus219","article-title":"Sinus node dysfunction in atrial fibrillation patients: the evidence of regional atrial substrate remodelling","volume":"151","author":"Chang","year":"2013","journal-title":"Europace"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.ijcard.2014.03.009","article-title":"Sinoatrial node electrical activity modulates pulmonary vein arrhythmogenesis","volume":"173","author":"Chen","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/0002-8703(54)90211-2","article-title":"Functional anatomy and \u2018throttle valve\u2019 action of the pulmonary veins","volume":"47","author":"Burch","year":"1954","journal-title":"Am. Heart J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1161\/01.CIR.34.3.412","article-title":"The junction between the left atrium and the pulmonary veins. An anatomic study of human hearts","volume":"34","author":"Nathan","year":"1966","journal-title":"Circulation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0008-6363(01)00532-6","article-title":"Basic and clinical electrophysiology of pulmonary vein ectopy","volume":"54","author":"Ho","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/S0735-1097(03)00918-5","article-title":"Morphology of atrial myocardium in human pulmonary veins: a postmortem analysis in patients with and without atrial fibrillation","volume":"42","author":"Hassink","year":"2003","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.jacep.2017.11.011","article-title":"Pulmonary vein sleeve length and association with body mass index and sex in atrial fibrillation","volume":"4","author":"Ellis","year":"2018","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1111\/jce.13286","article-title":"Structural relation between the superior vena cava and pulmonary veins in patients with atrial fibrillation","volume":"28","author":"Yoshida","year":"2017","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0008-6363(00)00179-6","article-title":"Arrhythmogenic activity of cardiac muscle in pulmonary veins of the dog: implication for the genesis of atrial fibrillation","volume":"48","author":"Chen","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.jecm.2011.04.004","article-title":"Ion channel remodeling in pulmonary vein arrhythmogenesis for atrial fibrillation","volume":"3","author":"Lin","year":"2011","journal-title":"J. Exp. Clin. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1111\/j.1540-8167.2009.01480.x","article-title":"Heterogeneous expression of potassium currents and pacemaker currents potentially regulates arrhythmogenesis of pulmonary vein cardiomyocytes","volume":"20","author":"Chen","year":"2009","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.cardiores.2004.07.025","article-title":"Identifying and understanding the role of pulmonary vein activity in atrial fibrillation","volume":"64","author":"Khan","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1046\/j.1540-8167.2004.03399.x","article-title":"T-type calcium current in electrical activity of cardiomyocytes isolated from rabbit pulmonary vein","volume":"15","author":"Chen","year":"2004","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1113\/jphysiol.2003.046417","article-title":"Cellular electrophysiology of canine pulmonary vein cardiomyocytes: action potential and ionic current properties","volume":"551","author":"Ehrlich","year":"2003","journal-title":"J. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1161\/hc4801.099736","article-title":"Effects of rapid atrial pacing on the arrhythmogenic activity of single cardiomyocytes from pulmonary veins: Implication in initiation of atrial fibrillation","volume":"104","author":"Chen","year":"2001","journal-title":"Circulation"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1159\/000092569","article-title":"Connexins in the sinoatrial and atrioventricular nodes","volume":"42","author":"Boyett","year":"2006","journal-title":"Adv. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/S0008-6363(02)00490-X","article-title":"Tissue structure and connexin expression of canine pulmonary veins","volume":"55","author":"Verheule","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/(SICI)1097-0185(199702)247:2<289::AID-AR15>3.0.CO;2-L","article-title":"Gross and microscopic anatomy of the human intrinsic cardiac nervous system","volume":"247","author":"Armour","year":"1997","journal-title":"Anat. Rec."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"26e34","DOI":"10.1007\/s395-002-8384-6","article-title":"Electrophysiology of single cardiomyocytes isolated from rabbit pulmonary veins: implication in initiation of focal atrial fibrillation","volume":"97","author":"Chen","year":"2002","journal-title":"Basic Res. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1208505","DOI":"10.1155\/2019\/1208505","article-title":"Triggers for atrial fibrillation: The role of anxiety","volume":"2019","author":"Severino","year":"2019","journal-title":"Cardiol. Res. Pract."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.jacc.2005.12.023","article-title":"Sodium-calcium exchange initiated by the Ca2+ transient: An arrhythmia trigger within pulmonary veins","volume":"47","author":"Patterson","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"497e508","DOI":"10.1016\/j.cardiores.2006.02.026","article-title":"Effects of a Na+\/Ca2+ exchanger inhibitor on pulmonary vein electrical activity and ouabain-induced arrhythmogenicity","volume":"70","author":"Wongcharoen","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1937e43","DOI":"10.1161\/01.CIR.0000062645.38670.BD","article-title":"Pacing-induced spontaneous activity in myocardial sleeves of pulmonary veins after treatment with ryanodine","volume":"107","author":"Honjo","year":"2003","journal-title":"Circulation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"915e25","DOI":"10.1038\/sj.bjp.0707564","article-title":"K201, a novel antiarrhythmic drug on calcium handling and arrhythmogenic activity of pulmonary vein cardiomyocytes","volume":"153","author":"Chen","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.lfs.2008.06.014","article-title":"Increased Ca2+ sparks and sarcoplasmic reticulum Ca2+ stores potentially determine the spontaneous activity of pulmonary vein cardiomyocytes","volume":"83","author":"Chang","year":"2008","journal-title":"Life Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/sj.bjp.0706445","article-title":"Angiotensin II and angiotensin II receptor blocker modulate the arrhythmogenic activity of pulmonary veins","volume":"147","author":"Chen","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1007\/s00395-011-0206-8","article-title":"Electromechanical effects of the direct renin inhibitor (aliskiren) on the pulmonary vein and atrium","volume":"106","author":"Tsai","year":"2011","journal-title":"Basic Res. Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0079-6107(03)00009-9","article-title":"Cardiac fibroblasts and the mechano-electric feedback mechanism in healthy and diseased hearts","volume":"82","author":"Kamkin","year":"2003","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1161\/01.CIR.101.11.1274","article-title":"Pulmonary vein morphology in patients with paroxysmal atrial fibrillation initiated by ectopic beats originating from the pulmonary veins: implications for catheter ablation","volume":"101","author":"Lin","year":"2000","journal-title":"Circulation"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1023\/A:1019561820830","article-title":"Dilatation as a marker of pulmonary veins initiating atrial fibrillation","volume":"6","author":"Yamane","year":"2002","journal-title":"J. Interv. Card. Electrophysiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1536\/jhj.45.81","article-title":"Pulmonary vein dimensions and variation of branching pattern in patients with paroxysmal atrial fibrillation using magnetic resonance angiography","volume":"45","author":"Takase","year":"2004","journal-title":"Jpn. Heart J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1152\/physrev.00014.2006","article-title":"Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation","volume":"87","author":"Nattel","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1046\/j.1540-8167.2001.00809.x","article-title":"Pulmonary vein dilation in patients with atrial fibrillation: detection by magnetic resonance imaging","volume":"12","author":"Tsao","year":"2001","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1136\/hrt.2006.089359","article-title":"Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins","volume":"93","author":"Chang","year":"2007","journal-title":"Heart"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1161\/01.CIR.0000086979.39843.7B","article-title":"Intra-atrial pressure increases rate and organization of waves emanating from the superior pulmonary veins during atrial fibrillation","volume":"108","author":"Kalifa","year":"2003","journal-title":"Circulation"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ijcard.2014.06.054","article-title":"Testosterone replacement increases aged pulmonary vein and left atrium arrhythmogenesis with enhanced adrenergic activity","volume":"176","author":"Tsai","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1161\/01.CIR.0000056765.97013.5E","article-title":"Correlation between anatomy and electrical activation in canine pulmonary veins","volume":"107","author":"Hamabe","year":"2003","journal-title":"Circulation"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.yjmcc.2013.03.008","article-title":"Extracellular matrix of collagen modulates arrhythmogenic activity of pulmonary veins through p38 MAPK activation","volume":"59","author":"Lu","year":"2013","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_63","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_64","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1016\/S0006-3495(86)83559-7","article-title":"Propagation through electrically coupled cells. How a small SA node drives a large atrium","volume":"50","author":"Joyner","year":"1986","journal-title":"Biophys. J."},{"key":"ref_65","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_66","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1161\/CIRCULATIONAHA.116.018011","article-title":"Sinus node and atrial arrhythmias","volume":"133","author":"John","year":"2016","journal-title":"Circulation"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1161\/01.CIR.63.1.80","article-title":"Coexistence of sick sinus rhythm and atrial flutter-fibrillation","volume":"63","author":"Gomes","year":"1981","journal-title":"Circulation"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1161\/01.CIR.94.11.2953","article-title":"Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs: electrophysiological remodeling","volume":"94","author":"Elvan","year":"1996","journal-title":"Circulation"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1046\/j.1540-8167.2002.00584.x","article-title":"Short-term rapid atrial pacing produces electrical remodeling of sinus node function in humans","volume":"13","author":"Hadian","year":"2002","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1161\/CIRCULATIONAHA.108.789677","article-title":"Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome","volume":"119","author":"Yeh","year":"2009","journal-title":"Circulation"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1161\/01.CIR.91.5.1588","article-title":"Chronic rapid atrial pacing. Structural, functional, and electrophysiological characteristics of a new model of sustained atrial fibrillation","volume":"91","author":"Morillo","year":"1995","journal-title":"Circulation"},{"key":"ref_72","first-page":"30","article-title":"Sinus node dysfunction in atrial fibrillation: cause or effect?","volume":"1","author":"Kezerashvili","year":"2008","journal-title":"J. Atr. Fibrillation"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1136\/hrt.34.5.520","article-title":"Pathology of atrial fibrillation in man","volume":"34","author":"Davies","year":"1972","journal-title":"Br. Heart J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1161\/01.CIR.64.4.832","article-title":"Role of Autonomic Regulatory Mechanisms in Sinoatrial Conduction and Sinus Node Automaticity in Sick Sinus Syndrome","volume":"64","author":"Kang","year":"1981","journal-title":"Circulation"},{"key":"ref_75","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_76","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1161\/CIRCEP.113.000267","article-title":"Low heart rates predict incident atrial fibrillation in healthy middle-aged men","volume":"6","author":"Grundvold","year":"2013","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.hlc.2015.04.185","article-title":"Slow Heart Rate Predicts New Occurrence of Atrial Fibrillation","volume":"11","author":"Hai","year":"2015","journal-title":"Heart Lung Circ."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.amjcard.2018.03.025","article-title":"Usefulness of a low resting heart rate to predict recurrence of atrial fibrillation after catheter ablation in people \u226565 years of age","volume":"122","author":"Wu","year":"2018","journal-title":"Am. J. Cardiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1001\/jama.1968.03150030101028","article-title":"The sick sinus syndrome in atrial disease","volume":"206","author":"Ferrer","year":"1968","journal-title":"JAMA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1161\/01.CIR.0000090685.13169.07","article-title":"Reverse remodeling of sinus node function after catheter ablation of atrial fibrillation in patients with prolonged sinus pauses","volume":"108","author":"Hocini","year":"2003","journal-title":"Circulation"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.1056\/NEJMoa013040","article-title":"Ventricular pacing or dual-chamber pacing for sinus-node dysfunction","volume":"346","author":"Lamas","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ijcard.2014.05.043","article-title":"Sinus node dysfunction and atrial fibrillation: which one dominates?","volume":"175","author":"Amasyali","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1113\/jphysiol.1981.sp013718","article-title":"Electrical activity of the pulmonary vein and its interaction with the right atrium in the guinea-pig","volume":"314","author":"Cheung","year":"1981","journal-title":"J. Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.ijcard.2016.07.027","article-title":"Gap junction modifiers regulate electrical activities of the sinoatrial node and pulmonary vein: Therapeutic implications in atrial arrhythmogenesis","volume":"221","author":"Chang","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1056\/NEJMoa0708234","article-title":"Pulmonary-vein isolation for atrial fibrillation in patients with heart failure","volume":"359","author":"Khan","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1016\/j.jacc.2013.01.069","article-title":"A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure","volume":"61","author":"Jones","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1161\/CIRCULATIONAHA.115.019406","article-title":"Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial","volume":"133","author":"Mohanty","year":"2016","journal-title":"Circulation"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1056\/NEJMoa1707855","article-title":"Catheter ablation for atrial fibrillation with heart failure","volume":"378","author":"Marrouche","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1093\/eurheartj\/ehz284","article-title":"Effect of catheter ablation on pre-existing abnormalities of left atrial systolic, diastolic, and neurohormonal functions in patients with chronic heart failure and atrial fibrillation","volume":"40","author":"Packer","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.cardfail.2018.09.016","article-title":"Heart failure differentially modulates the effects of ivabradine on the electrical activity of the sinoatrial node and pulmonary veins","volume":"24","author":"Chan","year":"2018","journal-title":"J. Card. Fail."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1111\/j.1540-8167.2011.02126.x","article-title":"Heart failure enhanced pulmonary vein arrhythmogenesis and dysregulated sodium and calcium homeostasis with increased calcium sparks","volume":"22","author":"Chang","year":"2011","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1111\/j.1440-1681.2011.05553.x","article-title":"Heart failure enhances arrhythmogenesis in pulmonary veins","volume":"38","author":"Chang","year":"2011","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1161\/01.CIR.0000139336.69955.AB","article-title":"Remodeling of sinus node function in patients with congestive heart failure: reduction in sinus node reserve","volume":"110","author":"Sanders","year":"2004","journal-title":"Circulation"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1161\/01.CIR.0000083719.51661.B9","article-title":"Ionic remodeling of sinoatrial node cells by heart failure","volume":"108","author":"Verkerk","year":"2003","journal-title":"Circulation"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cardiores.2005.02.011","article-title":"Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model","volume":"66","author":"Zicha","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"771","DOI":"10.3892\/etm.2016.4015","article-title":"Heart failure modulates electropharmacological characteristics of sinoatrial nodes","volume":"13","author":"Chang","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"H1805","DOI":"10.1152\/ajpheart.00723.2010","article-title":"Ca2+ clock malfunction in a canine model of pacing-induced heart failure","volume":"299","author":"Shinohara","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1161\/CIRCHEARTFAILURE.110.957647","article-title":"Changes in ion channel gene expression underlying heart failure-induced sinoatrial node dysfunction","volume":"4","author":"Yanni","year":"2011","journal-title":"Circ. Heart Fail."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1161\/CIRCHEARTFAILURE.114.001667","article-title":"Left atrial remodeling and function in advanced heart failure with preserved or reduced ejection fraction","volume":"8","author":"Melenovsky","year":"2015","journal-title":"Circ. Heart Fail."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1093\/cvr\/cvp216","article-title":"Chronic heart failure and the substrate for atrial fibrillation","volume":"84","author":"Sridhar","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1152\/ajplegacy.1966.211.5.1192","article-title":"Effect of stretch on the isolated cat sinoatrial node","volume":"211","author":"Lange","year":"1966","journal-title":"Am. J. Physiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1152\/ajplegacy.1966.211.5.1197","article-title":"Effects of localized stretch of the sinoatrial node region of the dog heart","volume":"211","author":"Brooks","year":"1966","journal-title":"Am. J. Physiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S1357-2725(99)00004-7","article-title":"Heat stress proteins and myocardial protection: experimental model or potential clinical tool?","volume":"31","author":"Gray","year":"1999","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.hrthm.2015.12.005","article-title":"Electrolyte disturbances differentially regulate sinoatrial node and pulmonary vein electrical activity: A contribution to hypokalemia- or hyponatremia-induced atrial fibrillation","volume":"13","author":"Lu","year":"2016","journal-title":"Heart Rhythm"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1016\/S0140-6736(14)61373-8","article-title":"Beta-Blockers in Heart Failure Collaborative Group. Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis","volume":"384","author":"Kotecha","year":"2014","journal-title":"Lancet"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1093\/eurheartj\/ehw128","article-title":"2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure","volume":"37","author":"Ponikowski","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.2165\/00003495-200464160-00003","article-title":"Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease","volume":"64","author":"Camm","year":"2004","journal-title":"Drugs"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1016\/j.jacc.2013.07.027","article-title":"Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients","volume":"62","author":"Reil","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1093\/eurheartj\/ehr311","article-title":"Effects of selective heart rate reduction with ivabradine on left ventricular remodeling and function: results from the SHIFT echocardiography sub-study","volume":"32","author":"Tardif","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/S0140-6736(10)61198-1","article-title":"Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study","volume":"376","author":"Swedberg","year":"2010","journal-title":"Lancet"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1093\/eurheartj\/eht101","article-title":"Effect of ivabradine in patients with left-ventricular systolic dysfunction: a pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials","volume":"34","author":"Fox","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_112","first-page":"3291","article-title":"Bradycardia and atrial fibrillation in patients with stable coronary artery disease treated with ivabradine: an analysis from the SIGNIFY study","volume":"36","author":"Fox","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1136\/heartjnl-2014-305482","article-title":"Atrial fibrillation associated with ivabradine treatment: meta-analysis of randomized controlled trials","volume":"100","author":"Martin","year":"2014","journal-title":"Heart"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.pharmthera.2011.11.003","article-title":"Role of ranolazine in angina, heart failure, arrhythmias, and diabetes","volume":"133","author":"Sossalla","year":"2010","journal-title":"Pharmacol. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2330","DOI":"10.1016\/j.jacc.2009.12.055","article-title":"Altered Na+ currents in atrial fibrillation effects of ranolazine on arrhythmias and contractility in human atrial myocardium","volume":"55","author":"Sossalla","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_116","first-page":"66","article-title":"Ranolazine preserves and improves left ventricular ejection fraction and autonomic measures when added to guideline-driven therapy in chronic heart failure","volume":"9","author":"Murray","year":"2014","journal-title":"Heart Int."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/13\/3224\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:02:41Z","timestamp":1760187761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/13\/3224"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,30]]},"references-count":116,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["ijms20133224"],"URL":"https:\/\/doi.org\/10.3390\/ijms20133224","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,30]]}}}