Associate Editor: P. MolenaarStructure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues
Introduction
The cardiac conduction system consists of the sinus (or sinuatrial or sinoatrial) node, the atrioventricular (AV) conduction axis (including the AV node), its right and left bundle branches, and the terminal Purkinje network. All of these structures, made up of specialised cardiac myocytes, have unique anatomical, molecular and functional properties that permit them to work collectively as the electrical system of the heart. The system has been the subject of extensive studies since its elucidation in the first decade of the 20th century. Recent advances in technologies have aided our further understanding of this specialised system of the heart. In particular, other myocytes with comparable properties, such as the AV ring tissue and myocytes in the ventricular outflow tracts, especially the right ventricular outflow tract, have attracted notice because of their arrhythmogenic properties. A common feature of the different tissues of the cardiac conduction system is the ability to show pacemaking and Fig. 1 shows the perhaps surprising widespread distribution of tissues with pacemaking potentiality in the heart. Our aim in this review is to describe our current understanding of the expanded concept of the cardiac conduction system, in terms of anatomy, function and clinical relevance. So-called channelopathies related to the cardiac conduction system are also discussed.
Section snippets
Cardiac conduction system in relation to working myocardium
The heart initially forms as a midline tube ventral to the foregut at the stage of embryonic folding. Its cells are derived from visceral mesoderm, with the cells forming a linear primary heart tube containing the primordium for little more than the left ventricle, or even less (Cai et al., 2003, Aanhaanen et al., 2009). Ongoing development depends on the addition of cells to the primary tube from the heart-forming areas at both the venous and arterial poles (Fig. 2A). At this early
Sinus node
In health, the sinus node is the pacemaker of the mammalian heart. Even more than 100 years after its first description by Keith & Flack in, 1907, the molecular mechanisms underlying its pacemaker potential are hotly disputed (e.g., Monfredi et al., 2010a, Monfredi et al., 2010b).
Anatomy
In the normal postnatal heart, the atrial and ventricular muscle masses are separated at the AV junctions by connective tissues, with the plane of insulation thus formed crossed only by the AV conduction axis, thus allowing normal conduction of the action potential generated by the sinus node to the ventricles. In addition to the histologically-specialised tissues forming the AV conduction axis, we now know that additional histologically specialised rings encircle the orifices of the tricuspid
Right ventricular outflow tract: anatomy, function and clinical relevance
The right ventricular outflow tract is an intriguing region of the heart, with an embryological development and anatomy that is unique (see Section 2), and subsequently an electrophysiological phenotype that contributes disproportionately to arrhythmias in the adult heart.
Channelopathies in humans responsible for dysfunction of the cardiac conduction system
In humans, naturally occurring mutations (inherited or acquired) in ion channels or associated proteins are the cause of a variety of cardiac arrhythmias, including arrhythmias arising from dysfunction of the cardiac conduction system. Channel (or channel-related) genes, mutations in which are associated with dysfunction of the cardiac conduction system, are listed in the first part of Table 3. Mutations in other genes (non-channel related) giving rise to cardiac conduction system dysfunction
Conclusions
Over the last few decades, as well as developing a greater understanding of the embryonic development and anatomy of the cardiac conduction system, we have learnt much about the cardiac conduction system at the molecular level, from the transcription factors determining its embryological development to the ion channels and related proteins underlying its electrical activity. Clinically, a picture is emerging of dysfunction of the cardiac conduction system in various disease states, such as
Conflict of Interest
The authors declare that there are no conflicts of interests.
Glossary
- A, N, NH
- types of myocyte at the atrioventricular node
- ANK2
- ankyrin 2
- AV
- atrioventricular
- AVNRT
- atrioventricular nodal reentrant tachycardia
- CASQ2
- calsequestrin 2
- Cav1.2 (CACNA1C)
- principal L-type Ca2+ channel and gene
- Cav1.3
- auxiliary L-type Ca2+ channel
- Cav3.1/Cav3.2
- T-type Ca2+ channels
- ClC-2
- hyperpolarization-activated Cl− channel
- CPVT
- catecholaminergic polymorphic ventricular tachycardia
- Cx30.2, Cx40, Cx43, Cx45
- connexins 30.2, 40, 43 and 45
- DAD
- delayed afterdepolarization
- DNA
- deoxyribonucleic acid
- dV/dtmax
- maximum
References (338)
- et al.
KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes
Am J Hum Genet
(2002) - et al.
3D virtual human atria: A computational platform for studying clinical atrial fibrillation
Prog Biophys Mol Biol
(2011) - et al.
Ionic mechanisms for electrical heterogeneity between rabbit Purkinje fiber and ventricular cells
Biophys J
(2010) - et al.
Anatomical and molecular mapping of the left and right ventricular His–Purkinje conduction networks
J Mol Cell Cardiol
(2011) - et al.
Catheter ablation of bundle branch reentrant ventricular tachycardia
Hear Rhythm
(2008) - et al.
Analysis of the electrophysiological effects of ambasilide, a new antiarrhythmic agent, in canine isolated ventricular muscle and purkinje fibers
Gen Pharmacol
(2000) - et al.
Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial
Lancet
(2010) - et al.
2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart
Hear Rhythm
(2004) - et al.
Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart
Dev Cell
(2003) - et al.
A step towards characterisation of electrophysiological profile of torsadogenic drugs
J Pharmacol Toxicol Methods
(2011)
Arrhythmia and right heart disease: From genetic basis to clinical practice
Rev Esp Cardiol
Inhibition of spontaneous activity of rabbit atrioventricular node cells by KB-R7943 and inhibitors of sarcoplasmic reticulum Ca(2+) ATPase
Cell Calcium
If in non-pacemaker cells: Role and pharmacological implications
Pharmacol Res
The properties of the pacemaker current If in human ventricular myocytes are modulated by cardiac disease
J Mol Cell Cardiol
Torsades de pointes complicating atrioventricular block: Evidence for a genetic predisposition
Hear Rhythm
Early and delayed afterdepolarizations in rabbit heart Purkinje cells viewed by confocal microscopy
Cell Calcium
Architectural plan for the heart: Early patterning and delineation of the chambers and the nodes
Trends Cardiovasc Med
A gata-6 gene heart-region-specific enhancer provides a novel means to mark and probe a discrete component of the mouse cardiac conduction system
Mech Dev
The Tbx2+ primary myocardium of the atrioventricular canal forms the atrioventricular node and the base of the left ventricle
Circ Res
Calcium-antagonist drugs
N Engl J Med
Evidence for gender differences in electrophysiological properties of canine Purkinje fibres
Br J Pharmacol
Gender differences in the slow delayed (IKs) but not in inward (IK1) rectifier K+ currents of canine Purkinje fibre cardiac action potential: key roles for IKs, beta-adrenoceptor stimulation, pacing rate and gender
Br J Pharmacol
Diagnosis and treatment of sick sinus syndrome
Am Fam Physician
Age-related changes in structure and relative collagen content of the human and feline sinoatrial node. A comparative study
Eur Heart J
Effect of verapamil and diltiazem on calcium-dependent electrical activity in cardiac Purkinje fibres
Br J Pharmacol
What should we call the ‘crista’?
Br Heart J
Atrioventricular ring specialized tissue in the normal heart
Eur J Cardiol
A combined morphological and electrophysiological study of the atrioventricular node of the rabbit heart
Circ Res
The morphology of the cardiac conduction system
Novartis Found Symp
Anatomy of the human atrioventricular junctions revisited
Anat Rec
Mahaim, Kent and abnormal atrioventricular conduction
Cardiovasc Res
The clinical anatomy of tetralogy of fallot
Cardiol Young
The anatomy of the cardiac conduction system
Clin Anat
Distribution of the Purkinje fibres in the sheep heart
Anat Rec (Hoboken)
Brugada syndrome
Pacing Clin Electrophysiol
Electrophysiology of single heart cells from the rabbit tricuspid valve
J Physiol
Action potential characteristics and arrhythmogenic properties of the cardiac conduction system of the murine heart
Circ Res
Role of the Purkinje system in spontaneous ventricular tachycardia during acute ischemia in a canine model
Circulation
Idiopathic outflow tract tachycardias: Current perspectives
Herz
Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists
Eur Heart J
Apoptosis in the developing mouse heart
Dev Dyn
Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4
Proc Natl Acad Sci U S A
Eelctrophysiologic and ultrastructural characteristics of the canine tricuspid valve
Am J Physiol
Inhibitory G protein overexpression provides physiologically relevant heart rate control in persistent atrial fibrillation
Circulation
Role of subendocardial Purkinje network in triggering torsade de pointes arrhythmia in experimental long QT syndrome
Europace
Sinus node dysfunction: pathophysiology, clinical features, evaluation, and treatment
Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)
J Clin Invest
Purkinje-muscle reentry as a mechanism of polymorphic ventricular arrhythmias in a 3-dimensional model of the ventricles
Circ Res
Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system
Circ Res
Expanding spectrum of human RYR2-related disease: new electrocardiographic, structural, and genetic features
Circulation
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