Inherited Conduction System Abnormalities -- One Group of Diseases, Many Genes

Cordula M. Wolf, M.D.; Charles I. Berul, M.D.


J Cardiovasc Electrophysiol. 2006;17(4):446-455. 

In This Article

Abstract and Introduction

The cardiac conduction system can be anatomically, developmentally, and molecularly distinguished from the working myocardium. Abnormalities in cardiac conduction can occur due to a variety of factors, including developmental and congenital defects, acquired injury or ischemia of portions of the conduction system, or less commonly due to inherited diseases that alter cardiac conduction system function. So called 'idiopathic' conduction system degeneration may have familial clustering, and therefore is consistent with a hereditary basis. This 'Molecular Perspectives' will highlight several diverse mechanisms of isolated conduction system disease as well as conduction system degeneration associated with other cardiac and non-cardiac disorders. The first part of this review focuses on channelopathies associated with conduction system disease. Human genetic studies have identified mutations in the sodium channel SCN5A gene causing tachyarrhythmia disorders, as well as progressive cardiac conduction system diseases, or overlapping syndromes. Next, the importance of embryonic developmental genes such as homeobox and T-box transcription factors are highlighted in conduction system development and function. Conduction system diseases associated with multisystem disorders, such as muscular and myotonic dystrophies, will be described. Last, a new glycogen storage cardiomyopathy associated with ventricular preexcitation and progressive conduction system degeneration will be reviewed. There are a myriad of mutations identified in genes encoding cardiac transcription factors, ion channels, gap junctions, energy metabolism regulators, lamins and other structural proteins. Understanding of the molecular and ionic mechanisms underlying cardiac conduction is essential for the appreciation of the pathogenesis of conduction abnormalities in structurally normal and altered hearts.

The heart achieves the coordinated contraction of the atrial and ventricular chambers due to the precise timing of the cardiac conduction system (CCS), a specialized complex and heterogeneous network of cells that initiate and allow propagation of action potentials through the heart. Inherited conduction system diseases can be life threatening and, although relatively uncommon overall, are known cause of mortality and morbidity in selected populations. Knowledge derived from human genetics and from experimental studies in engineered animal models has led to the discovery of multiple molecular defects responsible for progressive conduction system diseases. Some inherited arrhythmias are caused by a malfunction of proteins that are related to the initiation or propagation of electrical activity.

The normal cardiac impulse of the vertebrate heart originates in the pacemaker cells of the sinoatrial node, located in the right atrium.[1] The impulse is then conducted through the atrium to the atrioventricular junction from where, after a delay, the electrical signal is propagated to the ventricles along bundles of specialized conduction tissue to the distal Purkinje fibers, which ramify among the contractile myocardium. The tips of the Purkinje fibers are electrically coupled to muscle cells and the working myocytes are longitudinally connected via gap junctions, thereby initiating a coordinated, efficient contraction of the ventricles.[2]

The slow-conducting SA and AV nodes take developmental origin from the slow-conducting embryonic inflow tract and atrioventricular canal region.[3] Nodal cells have less well-organized actin and myosin filaments and a poorly developed sarcoplasmic reticulum.[4,5] Although atrial and ventricular myocytes maintain a stable resting voltage level at the termination of an action potential, the nodal cells are characterized by slow and spontaneous diastolic depolarization, or automaticity, which is the basis of their pacemaking activity[6] (Fig. 1). During this phase, the membrane slowly depolarizes until the threshold for a new action potential is reached. The ion channels If and ICa,T are responsible for this slow depolarization in phase 4 (Fig. 1). In contrast to nonpacemaker cells, SA and AV nodal cells predominantly use calcium channels for the initial upstroke in phase 0 (Fig. 1) and lack sodium ion channels for the rapid initial upstroke in phase 1 of their action potentials.[7] The SA node is a complex and nonuniform tissue. There is regional heterogeneity of the mammalian sinoatrial node in terms of cell morphology, pacemaker activity, action potential configuration and conduction, densities of ionic currents (INa, ICa,L, Ito, Iks, If), expression of gap junction proteins (Cx40, Cx43, Cx45), and autonomic regulation. With maturation, the SA nodal function deteriorates and the intrinsic heart rate declines. Experimental studies in rabbits and cats have shown that there is an age-related increase in action potential duration due to changes in the density of specific ionic currents.[8]

Action potential in nodal cells. The action potential of nodal conduction system cells differs in phase 4 from a cardiomyocyte action potential (upper panel). The relevant ion currents are pictured crossing the cell membrane (middle). A slow upstroke phase replaces the stable resting phase 4, allowing the cell to spontaneously depolarize. The initial upstroke is caused by calcium instead of sodium influx. The corresponding electrocardiographic ventricular activity is shown below.

The ventricular conduction system comprises the His bundle, the left and right bundle branches, and the peripheral Purkinje network. The main function of this peripheral network of conduction cells is to rapidly distribute an impulse throughout ventricular muscle, thereby synchronizing contraction of the ventricular chambers. Voltage-gated Na+ channels are essential for the amplitude and upstroke velocity of the cardiac action potential, which are important determinants for impulse propagation and conduction velocity throughout the fast conducting conduction system and the working myocardium.[9] The speed of depolarization (e.g., slope phase 0) is a determinant of conduction velocity. The His bundle is found in the AV junction area, but its molecular phenotype shows most of the characteristics of the working ventricular myocardium,[10] displaying a high conduction velocity compared to the slower conducting AV nodal tissue.