Associate Editor: P. Molenaar
Structure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues

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Abstract

It is now over 100 years since the discovery of the cardiac conduction system, consisting of three main parts, the sinus node, the atrioventricular node and the His–Purkinje system. The system is vital for the initiation and coordination of the heartbeat. Over the last decade, immense strides have been made in our understanding of the cardiac conduction system and these recent developments are reviewed here. It has been shown that the system has a unique embryological origin, distinct from that of the working myocardium, and is more extensive than originally thought with additional structures: atrioventricular rings, a third node (so called retroaortic node) and pulmonary and aortic sleeves. It has been shown that the expression of ion channels, intracellular Ca2+-handling proteins and gap junction channels in the system is specialised (different from that in the ordinary working myocardium), but appropriate to explain the functioning of the system, although there is continued debate concerning the ionic basis of pacemaking. We are beginning to understand the mechanisms (fibrosis and remodelling of ion channels and related proteins) responsible for dysfunction of the system (bradycardia, heart block and bundle branch block) associated with atrial fibrillation and heart failure and even athletic training. Equally, we are beginning to appreciate how naturally occurring mutations in ion channels cause congenital cardiac conduction system dysfunction. Finally, current therapies, the status of a new therapeutic strategy (use of a specific heart rate lowering drug) and a potential new therapeutic strategy (biopacemaking) are reviewed.

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

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