Journal of Cardiovascular Development and Disease Review Development and Function of the Cardiac Conduction System in Health and Disease David S. Park and Glenn I. Fishman * Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA; [email protected] * Correspondence: glenn.fi[email protected]; Tel.: +01-212-263-3967 Academic Editor: Robert E. Poelmann Received: 26 March 2017; Accepted: 1 June 2017; Published: 7 June 2017 Abstract: The generation and propagation of the cardiac impulse is the central function of the cardiac conduction system (CCS). Impulse initiation occurs in nodal tissues that have high levels of automaticity, but slow conduction properties. Rapid impulse propagation is a feature of the ventricular conduction system, which is essential for synchronized contraction of the ventricular chambers. When functioning properly, the CCS produces ~2.4 billion heartbeats during a human lifetime and orchestrates the flow of cardiac impulses, designed to maximize cardiac output. Abnormal impulse initiation or propagation can result in brady- and tachy-arrhythmias, producing an array of symptoms, including syncope, heart failure or sudden cardiac death. Underlying the functional diversity of the CCS are gene regulatory networks that direct cell fate towards a nodal or a fast conduction gene program. In this review, we will discuss our current understanding of the transcriptional networks that dictate the components of the CCS, the growth factor-dependent signaling pathways that orchestrate some of these transcriptional hierarchies and the effect of aberrant transcription factor expression on mammalian conduction disease. Keywords: cardiac conduction system development; ventricular conduction system; gene regulatory networks 1. Introduction The CCS is functionally divided into the impulse generating, but slowly conducting nodal cells and the rapidly-conducting ventricular conduction system (VCS); as visualized using various conduction system reporter mice (Figure1). The dominant pacemaker is the sinus node (SN) located at the junction between the superior vena cava and the right atrium (RA). Upon exiting the SN, impulses travel rapidly through the atrial myocardium, ensuring synchronous contraction of the atrial chambers. The cardiac impulse then slows in the atrioventricular node (AVN), which is the last point of communication between the atria and ventricles, providing adequate time for ventricular filling. The impulse accelerates again as it enters the penetrating His bundle, which traverses the central fibrous body crossing the annulus fibrosus that electrically isolates atria from ventricles, and then, rapidly disseminates throughout the ventricular myocardium using the VCS, also referred to as the His-Purkinje system (HPS). The VCS includes the His bundle, left and right bundle branches and distal Purkinje fiber network. The HPS allows for: (1) apex-to-basal ventricular contraction; (2) left and right ventricular synchrony; and (3) intraventricular synchrony. This coordinated electrical activity is highly conserved in all mammalian species and is essential to maintain optimal stroke volume. J. Cardiovasc. Dev. Dis. 2017, 4, 7; doi:10.3390/jcdd4020007 www.mdpi.com/journal/jcdd J.J. Cardiovasc. Cardiovasc. Dev. Dev. Dis. Dis. 20172017, ,44, ,7 7 22 of of 16 16 FigureFigure 1 1.. CardiacCardiac conduction conduction system system (CCS) (CCS) reporter reporter mice. mice. ( (AA)) Contactin2 Contactin2-eGFP-eGFP demonstrating demonstrating CCS CCS componentscomponents ( (ReproducedReproduced with permissionpermission fromfrom [ 1[1]);]); ( B(B)) cardiac cardiac conduction conduction system system reporter-LacZ reporter-LacZ in in an anembryonic embryonic day d 17.5ay 17.5 heart heart (Reproduced (Reproduced with with permission permission from from [2]); ( C[2,]D);) ( co-expressionC,D) co-expression of Etv1-nuclear of Etv1- nuclearLacZ (C LacZ) in a ( Contactin2-EGFP;C) in a Contactin2- (EGFPD) background; (D) background delineating delineating the left the ventricular left ventricular conduction conduction system. system.AV, atrioventricular. AV, atrioventricular. TheThe formation formation of of the the CCS CCS occurs occurs simultaneously simultaneously with with cardiac cardiac development development [ [33]] (Figure (Figure 22).). Heart formationformation begins begins as as a alinear linear tube tube that that maintains maintains circulation circulation via peristaltic via peristaltic contraction. contraction. At this At stage, this thestage, linear the heart linear tube heart is tubecomposed is composed of primary of primary heart field heart myocardium field myocardium and conducts and conducts impulses impulses slowly. Electrocardiographicslowly. Electrocardiographic (ECG) recordings (ECG) recordings at this at stage this stage in developing in developing chicks chicks show show a asinusoidal sinusoidal wwaveform.aveform. At At the the onset onset of of looping looping morphogenesis, morphogenesis, the the ECG ECG morphology morphology changes changes to to show show distinct distinct P P wavewavess ( (representsrepresents atrial atrial activation activation on on ECG ECG)) and and QRS QRS wave wavess ( (representsrepresents HPS HPS-dependent-dependent ventricular ventricular activationactivation on on ECG ECG)) that that are are separated separated by a by PQ a or PQ PR or interval PR interval (represents (represents cumulative cumulative measure measure of atrial, of AVNatrial, and AVN HPS and-dependent HPS-dependent ventricular ventricular activation activation time on time ECG on). ECG).At the At same the sametime, time,the atrial the atrialand ventricularand ventricular electrocardiogram electrocardiogram signals signals acquire acquire high high frequency frequency waveforms, waveforms, indicative indicative of of rapid rapid conduction.conduction. Rapid Rapid conduction conduction is is a a h hallmarkallmark feature feature of of cardiac cardiac chamber chamber formation, formation, where where pectinated pectinated myocardiummyocardium of of the the atria atria and and trabeculated trabeculated myocardium myocardium in in the the ventricles ventricles adopt adopt a a fast fast conduction conduction phenotype.phenotype. SubendocardialSubendocardial trabeculated trabeculated cardiomyocytes cardiomyocytes in the ventriclesin the ventricles undergo furtherundergo specification further specificatito form theon highly to form specialized the highly VCS, specialized whereas in theVCS atria,, whereas the pectinated in the atrialatria, myocardiumthe pectinated maintains atrial myocardiumthe fast conduction maintains phenotype the withoutfast conduction further specification. phenotype Thewithout atrioventricular further (AV)specification. junction formsThe atrioventriculara constriction called (AV) thejunction AV canal forms (AVC) a constriction that maintains called thethe slowAV canal conduction (AVC) that phenotype maintains ofthe the linearslow conductionheart tube, servingphenotype as the of nascentthe linear AVN. heart Eventually, tube, serving epicardial as the cellsnascent ingress AVN. into Eventually, the ventricular epicardial aspect cellsof AV ingress junctional into myocardiumthe ventricular giving aspect rise of to AV the junctional annulus fibrosus, myocardium except giving in the dorsalrise to aspect, the annulus where fibrosus,the AVN maintainsexcept in electricalthe dorsal continuity aspect, withwhere the t penetratinghe AVN maintains His bundle. electrical The remaining continuity AV junctionalwith the penetratingmyocardium His remains bundle. into The adulthood remaining as theAV AVjunctional ring bundles myocardium [4]. remains into adulthood as the AV ring bundles [4]. J. Cardiovasc. Dev. Dis. 2017, 4, 7 3 of 16 J. Cardiovasc. Dev. Dis. 2017, 4, 7 3 of 16 FigureFigure 2. 2. SchematicSchematic of of chicken chicken heart heart development development and and corresponding corresponding electrocardiograms electrocardiograms at at somite somite stagesstages shown. shown. (A (A) )Somite Somite S Stagetage 11 11 (11 (11-S);-S); (B (B) 18) 18-S;-S; (C (C) 20) 20-S;-S; and and (D (D) 33) 33-S-S (Reproduced (Reproduced with with permission permission fromfrom [3 [3])]).. TheThe gene gene regulatory regulatory networks networks that that govern govern CCS CCSdevelopment development are tightly are tightly orchestrated orchestrated in a tissue in- a specifictissue-specific and time and-dependent time-dependent manner, manner, producing producing distinct distinct nodal and nodal fast and conduction fast conduction phenotypes. phenotypes. The nodesThe nodes display display high highlevels levels of automaticity of automaticity driven driven by bya dual a dual clock clock mechanism: mechanism: the the voltage voltage clock clock (hyperpolarization(hyperpolarization-activated-activated cyclic cyclic nucleotide nucleotide-gated-gated cation cation channel channel (Hcn4 (Hcn4)))) [5 [5] ]and and the the calcium calcium cloc clockk (ryanodine(ryanodine receptor receptor (Ryr2 (Ryr2),), the the sodium sodium-calcium-calcium exchanger exchanger (Ncx (Ncx) )and and the the voltage voltage-dependent-dependent calcium calcium channel,channel, TT type, type, alpha alpha 1G 1G subunit subunit (Cacna1g (Cacna1g)) [))6] [. 6The]. The slow slow conduction conduction properties properties of nodal of nodal tissue tissue are determinedare determined by the by near the absence near absence of the cardiac of the cardiacsodium sodiumchannel pore channel forming pore subunit forming