Background— Although we know much about the molecular makeup of the sinus node (SN) in small mammals, little is known about it in humans. The aims of the present study were to investigate the expression of ion channels in the human SN and to use the data to predict electrical activity. Methods and Results— Quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence were used to analyze 6 human tissue samples. Messenger RNA (mRNA) for 120 ion channels (and some related proteins) was measured in the SN, a novel paranodal area, and the right atrium (RA). The results showed, for example, that in the SN compared with the RA, there was a lower expression of Na v 1.5, K v 4.3, K v 1.5, ERG, K ir 2.1, K ir 6.2, RyR2, SERCA2a, Cx40, and Cx43 mRNAs but a higher expression of Ca v 1.3, Ca v 3.1, HCN1, and HCN4 mRNAs. The expression pattern of many ion channels in the paranodal area was intermediate between that of the SN and RA; however, compared with the SN and RA, the paranodal area showed greater expression of K v 4.2, K ir 6.1, TASK1, SK2, and MiRP2. Expression of ion channel proteins was in agreement with expression of the corresponding mRNAs. The levels of mRNA in the SN, as a percentage of those in the RA, were used to estimate conductances of key ionic currents as a percentage of those in a mathematical model of human atrial action potential. The resulting SN model successfully produced pacemaking. Conclusions— Ion channels show a complex and heterogeneous pattern of expression in the SN, paranodal area, and RA in humans, and the expression pattern is appropriate to explain pacemaking.

Background-There is an effort to build an anatomically and biophysically detailed virtual heart, and, although there are models for the atria and ventricles, there is no model for the sinoatrial node (SAN

Abstract-The aim of the study was to identify ion channel transcripts expressed in the sinoatrial node (SAN), the pacemaker of the heart. Functionally, the SAN can be divided into central and peripheral regions (center is adapted for pacemaking only, whereas periphery is adapted to protect center and drive atrial muscle as well as pacemaking) and the aim was to study expression in both regions. In rabbit tissue, the abundance of 30 transcripts (including transcripts for connexin, Na ϩ , Ca 2ϩ , hyperpolarization-activated cation and K ϩ channels, and related Ca 2ϩ handling proteins) was measured using quantitative PCR and the distribution of selected transcripts was visualized using in situ hybridization. Quantification of individual transcripts (quantitative PCR) showed that there are significant differences in the abundance of 63% of the transcripts studied between the SAN and atrial muscle, and cluster analysis showed that the transcript profile of the SAN is significantly different from that of atrial muscle. There are apparent isoform switches on moving from atrial muscle to the SAN center: RYR2 to RYR3, Na v 1.5 to Na v 1.1, Ca v 1.2 to Ca v 1.3 and K v 1.4 to K v 4.2. The transcript profile of the SAN periphery is intermediate between that of the SAN center and atrial muscle. For example, Na v 1.5 messenger RNA is expressed in the SAN periphery (as it is in atrial muscle), but not in the SAN center, and this is probably related to the need of the SAN periphery to drive the surrounding atrial muscle. (Circ Res. 2006;99:1384-1393.)Key Words: sinoatrial node Ⅲ pacemaker Ⅲ Na ϩ channels Ⅲ Ca 2ϩ channels Ⅲ HCN channels Ⅲ K ϩ channels T his is the centenary of the discovery of the sinoatrial node (SAN), the pacemaker of the heart, by Keith and Flack. 1 Early intracellular recordings of pacemaker and action potentials in the SAN were made by de Carvalho et al in 1959 2 and, in the Ϸ50 years since then, a wealth of data has been accumulated concerning the pacemaker and action potentials in the SAN and the underlying ionic currents. 3,4 However, little is known about the molecular basis of ionic currents in the SAN and the aim of this study was to measure the abundance of messenger RNAs (mRNAs) coding for ion channels and related proteins in the SAN. The study was performed on rabbit, because of the existence of extensive functional data from this species: the early study of de Carvalho et al, 2 as well as the majority of the studies on SAN since, 3,4 have been performed on rabbit.The SAN is a complex and heterogeneous tissue. 5 The action potential is first initiated in the center of the SAN. 4 It then propagates from the leading pacemaker site in the center to the periphery of the SAN (where SAN connects to atrial muscle) and then onto the atrial muscle of the crista terminalis and right atrial free wall. 4 The SAN center is adapted for pacemaking: it has poor electrical coupling to protect it from the inhibitory hyperpolarizing influence of surrounding atrial muscle and it has a complement of ionic currents...