The Anatomy and Physiology of the Sinoatrial Node—A Contemporary Review

The sinoatrial node is the primary pacemaker of the heart. Nodal dysfunction with aging, heart failure, atrial fibrillation, and even endurance athletic training can lead to a wide variety of pathological clinical syndromes. Recent work utilizing molecular markers to map the extent of the node, along with the delineation of a novel paranodal area intermediate in characteristics between the node and the surrounding atrial muscle, has shown that pacemaker tissue is more widely spread in the right atrium than previously appreciated. This can explain the phenomenon of a “wandering pacemaker” and concomitant changes in the P‐wave morphology. Extensive knowledge now exists regarding the molecular architecture of the node (in particular, the expression of ion channels) and how this relates to pacemaking. This review is an up‐to‐date summary of the current state of our appreciation of the above topics. (PACE 2010; 1392–1406)

[1]  B. Lüderitz,et al.  Conduction disturbances and increased atrial vulnerability in Connexin40-deficient mice analyzed by transesophageal stimulation. , 1999, Circulation.

[2]  K. Arakawa,et al.  Electrophysiological Properties in Chronic Lone Atrial Fibrillation , 1991, Circulation.

[3]  M. Taylor,et al.  Reconstruction of the human sinoatrial node , 1967, The Anatomical record.

[4]  D. Allen,et al.  Store-Operated Ca2+ Influx and Expression of TRPC Genes in Mouse Sinoatrial Node , 2007, Circulation research.

[5]  J. Cho,et al.  Clinical Characteristics of Hypervagotonic Sinus Node Dysfunction , 2004, The Korean journal of internal medicine.

[6]  P. Sanders,et al.  Effect of Chronic Right Atrial Stretch on Atrial Electrical Remodeling in Patients With an Atrial Septal Defect , 2003, Circulation.

[7]  H. Kasanuki,et al.  Association of sick sinus syndrome with hyperinsulinemia and insulin resistance in patients with non-insulin-dependent diabetes mellitus: report of four cases. , 1995, Internal medicine.

[8]  H Honjo,et al.  The sinoatrial node, a heterogeneous pacemaker structure. , 2000, Cardiovascular research.

[9]  O. Naseer,et al.  Short‐term effects of streptozotocin‐induced diabetes on the electrocardiogram, physical activity and body temperature in rats , 2005, Experimental physiology.

[10]  Robert H. Anderson,et al.  New insights into pacemaker activity: promoting understanding of sick sinus syndrome. , 2007, Circulation.

[11]  J. Boineau,et al.  Origin of the Sinus Impulse , 1996, Journal of cardiovascular electrophysiology.

[12]  Å. Kilbom,et al.  Role of the adrenergic nervous system in development of training-induced bradycardia. , 1977, Acta physiologica Scandinavica.

[13]  J. Kalman,et al.  Aging and sinoatrial node dysfunction: musings on the not-so-funny side. , 2007, Circulation.

[14]  A. Nisbet.  The electrophysiology of the atrioventricular node in normal and failing rabbit hearts , 2008 .

[15]  Richard P. Harvey,et al.  Molecular Pathway for the Localized Formation of the Sinoatrial Node , 2007, Circulation research.

[16]  J. Olgin,et al.  "Cristal tachycardias": origin of right atrial tachycardias from the crista terminalis identified by intracardiac echocardiography. , 1998, Journal of the American College of Cardiology.

[17]  P. D. Lucas,et al.  A comparison between atria from control and streptozotocin‐diabetic rats: The effects of dietary myoinositol , 1988, British journal of pharmacology.

[18]  H. Zhang,et al.  Connexins in the sinoatrial and atrioventricular nodes. , 2006, Advances in cardiology.

[19]  A. Wilde,et al.  Contribution of Sodium Channel Mutations to Bradycardia and Sinus Node Dysfunction in LQT3 Families , 2003, Circulation research.

[20]  J. Olgin,et al.  Short‐Term Rapid Atrial Pacing Produces Electrical Remodeling of Sinus Node Function in Humans , 2002, Journal of cardiovascular electrophysiology.

[21]  F C Howarth,et al.  EFFECTS OF INSULIN TREATMENT ON HEART RHYTHM, BODY TEMPERATURE AND PHYSICAL ACTIVITY IN STREPTOZOTOCIN‐INDUCED DIABETIC RAT , 2006, Clinical and experimental pharmacology & physiology.

[22]  T. N. James,et al.  Comparative Ultrastructure of the Sinus Node in Man and Dog , 1966, Circulation.

[23]  M. Brignole,et al.  Sick sinus syndrome. , 2002, Clinics in geriatric medicine.

[24]  H. Jongsma,et al.  Functional and morphological organization of the guinea-pig sinoatrial node compared with the rabbit sinoatrial node. , 1985, Journal of molecular and cellular cardiology.

[25]  S. Nattel,et al.  Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. , 2005, Cardiovascular research.

[26]  P B Corr,et al.  Demonstration of a widely distributed atrial pacemaker complex in the human heart. , 1988, Circulation.

[27]  M. Biel,et al.  A family of hyperpolarization-activated mammalian cation channels , 1998, Nature.

[28]  M. Boyett,et al.  Distribution of ion channel transcripts in the rabbit atrioventricular node as studied using in situ hybridisation and quantitative PCR , 2006 .

[29]  J. Jarmakani,et al.  Sinus node dysfunction in children, adolescents, and young adults. , 1978, Pediatrics.

[30]  M. Boyett,et al.  Ageing‐dependent remodelling of ion channel and Ca2+ clock genes underlying sino‐atrial node pacemaking , 2011, Experimental physiology.

[31]  R B Schuessler,et al.  Primary negativity does not predict dominant pacemaker location: implications for sinoatrial conduction. , 1995, The American journal of physiology.

[32]  S. Syverud,et al.  Cardiac pacing. , 1988, Emergency medicine clinics of North America.

[33]  D DiFrancesco,et al.  Reciprocal role of the inward currents ib, Na and if in controlling and stabilizing pacemaker frequency of rabbit sino-atrial node cells , 1992, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[34]  H Honjo,et al.  Variation in effects of Cs+, UL-FS-49, and ZD-7288 within sinoatrial node. , 1997, The American journal of physiology.

[35]  W. Catterall,et al.  An unexpected requirement for brain-type sodium channels for control of heart rate in the mouse sinoatrial node , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Robert H. Anderson,et al.  New insights into Sick Sinus Syndrome , 2007 .

[37]  D. Bandorski,et al.  Incidence of Coronary Artery Disease and Necessity of Revascularization in Symptomatic Patients Requiring Permanent Pacemaker Implantation , 2008, Medizinische Klinik.

[38]  D P Zipes,et al.  Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling. , 1996, Circulation.

[39]  F. Morady,et al.  Radiofrequency catheter ablation of inappropriate sinus tachycardia guided by activation mapping. , 2000, Journal of the American College of Cardiology.

[40]  L N Bouman,et al.  Electrophysiology of the ageing rabbit and cat sinoatrial node--a comparative study. , 1993, European heart journal.

[41]  J. Kugler,et al.  Sinoatrial Conduction in Children An Index of Sinoatrial Node Function , 1979, Circulation.

[42]  D. Noble,et al.  Requirement of neuronal‐ and cardiac‐type sodium channels for murine sinoatrial node pacemaking , 2004, The Journal of physiology.

[43]  Henggui Zhang,et al.  Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a , 2005, The Journal of physiology.

[44]  T. C. West,et al.  Ultramicroelectrode recording from the cardiac pacemaker. , 1955, The Journal of pharmacology and experimental therapeutics.

[45]  D. Shah,et al.  Reverse Remodeling of Sinus Node Function After Catheter Ablation of Atrial Fibrillation in Patients With Prolonged Sinus Pauses , 2003, Circulation.

[46]  H. Tan,et al.  Is sodium current present in human sinoatrial node cells? , 2009, International journal of biological sciences.

[47]  Robert H. Anderson,et al.  The extent of the specialized atrioventricular ring tissues. , 2009, Heart rhythm.

[48]  M. Lev.  Aging changes in the human sinoatrial node. , 1954, Journal of gerontology.

[49]  E. Lakatta,et al.  Sinoatrial Nodal Cell Ryanodine Receptor and Na + -Ca 2+ Exchanger: Molecular Partners in Pacemaker Regulation , 2001, Circulation research.

[50]  D. DiFrancesco.  Chapter 12 – Pacemaker Channels and Normal Automaticity , 2004 .

[51]  P. Sanders,et al.  Remodeling of Sinus Node Function in Patients With Congestive Heart Failure: Reduction in Sinus Node Reserve , 2004, Circulation.

[52]  F. Howarth,et al.  Altered expression of gap junction connexin proteins may partly underlie heart rhythm disturbances in the streptozotocin-induced diabetic rat heart , 2007, Molecular and Cellular Biochemistry.

[53]  P. Boyden,et al.  Aged atria: electrical remodeling conducive to atrial fibrillation , 2009, Journal of Interventional Cardiac Electrophysiology.

[54]  M. Link,et al.  Report of the NASPE Policy Conference on Arrhythmias and the Athlete , 2001, Journal of cardiovascular electrophysiology.

[55]  J. Borer,et al.  Antianginal and Antiischemic Effects of Ivabradine, an If Inhibitor, in Stable Angina: A Randomized, Double-Blind, Multicentered, Placebo-Controlled Trial , 2003, Circulation.

[56]  P. Sanders,et al.  Electrophysiologic and electroanatomic changes in the human atrium associated with age. , 2004, Journal of the American College of Cardiology.

[57]  A. Giordano,et al.  Mechanisms and immediate outcome of in-hospital cardiac arrest in patients with advanced heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. , 2001, The American journal of cardiology.

[58]  D. DiFrancesco,et al.  Heart rate reduction via selective 'funny' channel blockers. , 2007, Current opinion in pharmacology.

[59]  W. Fisher,et al.  Radiofrequency catheter modification of sinus pacemaker function guided by intracardiac echocardiography. , 1995, Circulation.

[60]  M. Biel,et al.  The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[61]  R. Kennedy,et al.  Effects of streptozotocin-induced diabetes on heart rate, blood pressure and cardiac autonomic nervous control. , 1998, Journal of the autonomic nervous system.

[62]  L. Hatle,et al.  Sinus arrest in acute myocardial infarction , 1971, British heart journal.

[63]  J. Jalife,et al.  Cardiac Electrophysiology: From Cell to Bedside , 1990 .

[64]  Tetsuo Sakai,et al.  Anatomical diversity and age-related histological changes in the human right atrial posterolateral wall. , 2004, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[65]  Halina Dobrzynski,et al.  Differential Expression of Ion Channel Transcripts in Atrial Muscle and Sinoatrial Node in Rabbit , 2006, Circulation research.

[66]  J. Brugada,et al.  Endurance sport practice as a risk factor for atrial fibrillation and atrial flutter , 2008, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[67]  H Honjo,et al.  Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node. , 1997, The American journal of physiology.

[68]  J. Engel,et al.  Congenital Deafness and Sinoatrial Node Dysfunction in Mice Lacking Class D L-Type Ca2+ Channels , 2000, Cell.

[69]  D DiFrancesco,et al.  A new interpretation of the pace‐maker current in calf Purkinje fibres. , 1981, The Journal of physiology.

[70]  H. Mond,et al.  Electrical remodeling of the atria following loss of atrioventricular synchrony: a long-term study in humans. , 1999, Circulation.

[71]  D. Radford,et al.  Sick sinus syndrome. Symptomatic cases in children. , 1975, Archives of disease in childhood.

[72]  M. Boyett,et al.  Intracellular Ca2+ and pacemaking within the rabbit sinoatrial node: heterogeneity of role and control , 2004, The Journal of physiology.

[73]  R. Podlaha,et al.  The prevalence of diabetes mellitus and other risk factors of atherosclerosis in bradycardia requiring pacemaker treatment. , 1992, Hormone and metabolic research. Supplement series.

[74]  A. Wilde,et al.  A single Na(+) channel mutation causing both long-QT and Brugada syndromes. , 1999, Circulation research.

[75]  N. Hagiwara,et al.  Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino‐atrial node cells. , 1988, The Journal of physiology.

[76]  A. Moorman,et al.  Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria. , 2007, Genes & development.

[77]  S. Siegelbaum,et al.  Molecular mechanism of cAMP modulation of HCN pacemaker channels , 2001, Nature.

[78]  M. Boyett.  ‘And the beat goes on’ The cardiac conduction system: the wiring system of the heart , 2009, Experimental physiology.

[79]  W. Stevenson,et al.  Sudden Death Prevention in Patients With Advanced Ventricular Dysfunction , 1993, Circulation.

[80]  M. Boyett,et al.  Structural remodelling of the sinoatrial node in obese old rats , 2010, Journal of molecular and cellular cardiology.

[81]  H. Brown,et al.  How does adrenaline accelerate the heart? , 1979, Nature.

[82]  J. Olgin,et al.  Radiofrequency catheter modification of the sinus node for "inappropriate" sinus tachycardia. , 1995, Circulation.

[83]  Henggui Zhang,et al.  Computer Three-Dimensional Reconstruction of the Atrioventricular Node , 2008, Circulation research.

[84]  G. Breithardt,et al.  Pacemaker channel dysfunction in a patient with sinus node disease. , 2003, The Journal of clinical investigation.

[85]  A. Moorman,et al.  The transcriptional repressor Tbx3 delineates the developing central conduction system of the heart. , 2004, Cardiovascular research.

[86]  M. Boyett,et al.  Declining Into Failure: The Age-Dependent Loss of the L-Type Calcium Channel Within the Sinoatrial Node , 2007, Circulation.

[87]  F. Howarth,et al.  Effects of carbenoxolone on heart rhythm, contractility and intracellular calcium in streptozotocin-induced diabetic rat , 2006, Molecular and Cellular Biochemistry.

[88]  E. Bozler.  THE INITIATION OF IMPULSES IN CARDIAC MUSCLE , 1943 .

[89]  H. Ector,et al.  Sick sinus syndrome in childhood. , 1980, British heart journal.

[90]  Tomaso Gnecchi-Ruscone,et al.  Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. , 2006, The New England journal of medicine.

[91]  Mark R Boyett,et al.  Ageing‐related changes of connexins and conduction within the sinoatrial node , 2004, The Journal of physiology.

[92]  D DiFrancesco,et al.  A study of the ionic nature of the pace‐maker current in calf Purkinje fibres. , 1981, The Journal of physiology.

[93]  H. Brown,et al.  Cardiac pacemaking in the sinoatrial node. , 1993, Physiological reviews.

[94]  Stefan Herrmann,et al.  HCN4 provides a ‘depolarization reserve’ and is not required for heart rate acceleration in mice , 2007, The EMBO journal.

[95]  M. Davies,et al.  Quantitative study of ageing changes in the human sinoatrial node and internodal tracts. , 1972, British heart journal.

[96]  K. Suma.  Sunao Tawara: A Father of Modern Cardiology , 2001, Pacing and clinical electrophysiology : PACE.

[97]  A Keith,et al.  The Form and Nature of the Muscular Connections between the Primary Divisions of the Vertebrate Heart. , 1907, Journal of anatomy and physiology.

[98]  Vadim V Fedorov,et al.  Structural and Functional Evidence for Discrete Exit Pathways That Connect the Canine Sinoatrial Node and Atria , 2009, Circulation research.

[99]  A. Garson,et al.  Symptomatic sick sinus syndrome in children and adolescents as the only manifestation of cardiac abnormality or associated with unoperated congenital heart disease. , 1983, The American journal of cardiology.

[100]  J. Ribeiro,et al.  Intrinsic sinus and atrioventricular node electrophysiologic adaptations in endurance athletes. , 2002, Journal of the American College of Cardiology.

[101]  L. Bouman,et al.  Age-related changes in structure and relative collagen content of the human and feline sinoatrial node. A comparative study. , 1995, European heart journal.

[102]  K. R. Anderson,et al.  Location and vascular supply of sinus node in human heart. , 1979, British heart journal.

[103]  F C Howarth,et al.  Long‐term effects of streptozotocin‐induced diabetes on the electrocardiogram, physical activity and body temperature in rats , 2005, Experimental physiology.

[104]  S. Nattel,et al.  Funny Current Downregulation and Sinus Node Dysfunction Associated With Atrial Tachyarrhythmia: A Molecular Basis for Tachycardia-Bradycardia Syndrome , 2009, Circulation.

[105]  H. Morita,et al.  Functional Characterization of a Trafficking-defective HCN4 Mutation, D553N, Associated with Cardiac Arrhythmia* , 2004, Journal of Biological Chemistry.

[106]  M. Boyett,et al.  Effect of aging on gene expression in the rat sinoatrial node , 2006 .

[107]  B. Uretsky,et al.  Primary prevention of sudden cardiac death in heart failure: will the solution be shocking? , 1997, Journal of the American College of Cardiology.

[108]  A. Wilde,et al.  A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. , 2005, Journal of molecular and cellular cardiology.

[109]  P. Varghese,et al.  Spectrum of sinus node dysfunction in two siblings. , 1976, American heart journal.

[110]  Richard B Schuessler,et al.  Abnormal Sinus Node Function in Clinical Arrhythmias , 2003, Journal of cardiovascular electrophysiology.

[111]  N. Goldschlager,et al.  Medical progress : cardiac pacing , 1996 .

[112]  N. Linker,et al.  Chronic sinoatrial disorder (sick sinus syndrome): a possible result of cardiac ischaemia. , 1987, British heart journal.

[113]  V. Rich.  Personal communication , 1989, Nature.

[114]  Hee-Sup Shin,et al.  Bradycardia and Slowing of the Atrioventricular Conduction in Mice Lacking CaV3.1/&agr;1G T-Type Calcium Channels , 2006, Circulation research.

[115]  H. Jongsma,et al.  A Cardiac Sodium Channel Mutation Cosegregates With a Rare Connexin40 Genotype in Familial Atrial Standstill , 2003, Circulation research.

[116]  A. George,et al.  Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). , 2003, The Journal of clinical investigation.

[117]  M. Masson-Pévét,et al.  Sinus node and atrium cells from the rabbit heart: a quantitative electron microscopic description after electrophysiological localization. , 1979, Journal of molecular and cellular cardiology.

[118]  P. Vardas,et al.  Sinus Pacemaker Function after Cardioversion of Chronic Atrial Fibrillation: Is Sinus Node Remodeling Related with Recurrence? , 2001, Journal of cardiovascular electrophysiology.

[119]  E. Lakatta,et al.  Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function. , 2008, Cardiovascular research.

[120]  T. N. James,et al.  Anatomy of the human sinus node , 1961, The Anatomical record.

[121]  G. Billman,et al.  Heart rate adaptation to exercise training in cardiac-denervated dogs. , 1982, Journal of applied physiology: respiratory, environmental and exercise physiology.

[122]  B. Seifert,et al.  Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists. , 2007, European heart journal.

[123]  D. Sánchez-Quintana,et al.  Sinus node revisited in the era of electroanatomical mapping and catheter ablation , 2005, Heart.

[124]  Robert H. Anderson,et al.  Molecular Architecture of the Human Sinus Node: Insights Into the Function of the Cardiac Pacemaker , 2009, Circulation.