Development of the Pacemaker Tissues of the Heart

Abstract

Pacemaker and conduction system myocytes play crucial roles in initiating and regulating the contraction of the cardiac chambers. Genetic defects, acquired diseases, and aging cause dysfunction of the pacemaker and conduction tissues, emphasizing the clinical necessity to understand the molecular and cellular mechanisms of their development and homeostasis. Although all cardiac myocytes of the developing heart initially possess pacemaker properties, the majority differentiates into working myocardium. Only small populations of embryonic myocytes will form the sinus node and the atrioventricular node and bundle. Recent efforts have revealed that the development of these nodal regions is achieved by highly localized suppression of working muscle differentiation, and have identified transcriptional repressors that mediate this process. This review will summarize and reflect new experimental findings on the cellular origin and the molecular control of differentiation and morphogenesis of the pacemaker tissues of the heart. It will also shed light on the etiology of inborn and acquired errors of nodal tissues. (Circ Res. 2010;106:240-254.)Key Words: conduction system Ⅲ pacemaker Ⅲ sinus venosus Ⅲ atrioventricular canal Ⅲ development T he contractions of the heart are initiated and coordinated by electric signals from pacemaker tissues. At the entrance of the right atrium, sinus node (sinoatrial node [SAN]) myocytes generate the impulse to activate the atrial myocardium. After rapid propagation through the atria, the impulse is delayed in the atrioventricular node (AVN) and further propagated to the fast-conducting atrioventricular bundle (AVB), bundle branches (BB), and Purkinje fiber network, from which the mass of the ventricular working myocardium is activated. The components of the conduction system contain cardiomyocytes with pacemaker activity and other specific nodal properties that discriminate them from atrial and ventricular working myocardium (Figure 1). The SAN serves as the primary pacemaker, whereas the AVN and ventricular conduction system act as secondary (accessory) pacemakers to secure Original

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels

“…This structure displays increasing levels of high conduction proteins (CX40) while sustaining the levels of primitive marker Tbx3. As the AV canal shrinks, another fast conduction system is required to supply the growing ventricles [1] . The "peripheral ventricular conduction system" is the last element of the conduction system to differentiate.…”

“…Only a small population of embryonic cardiomyocytes form SAN, AVN and the bundle of His [1] . In this short review, we survey the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity.…”

Competing Oscillators in Cardiac Pacemaking

“…The other contributions to this issue make valuable contributions to the debate at the tissue level, particularly concerning the use of imaging with voltage-or calcium-sensitive indicators 13 and the insights that come from studying the development of pacemaker tissues. 14 These studies show that integrative physiology of pacemaker activity does not end with analysis of cellular activity. In fact, it has been evident since the first electrophysiological mapping work that the sinus node acts as more than just a few thousand cells beating in synchrony.…”

Cardiomyogenesis of embryonic stem cells upon purinergic receptor activation by ADP and ATP

“…Different isoforms of connexin proteins are expressed in different types of cardiac cells. For example Cx43, a fast conductance protein is expressed in the working myocardium, whereas Cx45 and Cx 30.2 as low conductance velocity connexin proteins are preferentially expressed in the cardiac conduction system [58]. If the differentiation of sinus node-like cells is upregulated after exposure of cells to ADP or ATP, an enhancement of corresponding gap junction proteins was expected.…”