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.

We have previously shown in rabbit that the pacemaker of the heart (the sinus node) is widespread and matches the wide distribution of the leading pacemaker site within the right atrium. There is, however, uncertainty about the precise location of the pacemaker in human heart, and its spatial relationships with the surrounding right atrial muscle. Therefore, the aim of the current study was to investigate the distribution of the sinus node tissue in a series of healthy human hearts and, for one of the hearts to construct a computer three-dimensional anatomical model of the sinus node, including the likely orientation of myocytes. A combination of experimental techniques-diffusion tensor magnetic resonance imaging (DT-MRI), histology, immunohistochemistry, image processing and computer modelling-was used. Our data show that the sinus node was larger than in previous studies and, most importantly, we identified a previously unknown area running alongside the sinus node (the ''paranodal area"), which is even more extensive than the sinus node. This area possesses properties of both nodal and atrial tissues and may have a role in pacemaking. For example, it could explain the wide spread distribution of the leading pacemaker site in human right atrium, a phenomenon known as the wandering pacemaker observed in clinics. In summary, a Additional Supporting Information may be found in the online version of this article.Abbreviations used: AM ¼ Atrial muscle; ANP ¼ Atrial natriuretic peptide; Ao ¼ Aorta; Cx40, Cx43 ¼ Connexin 40 and 43; 3D ¼ Three-dimensional; DT-MRI ¼ Diffusion tensor magnetic resonance imaging; HCN4 ¼ Ion channel responsible for hyperpolarization-activated or 'funny' current, I f ; IVC ¼ Inferior vena cava; Kir2.1 ¼ Ion channel responsible for background inward rectifier K þ current, I K1 ; Kir6.2 ¼ Ion channel responsible for ATP-sensitive K þ current, I KATP ; Kv1.4 ¼ Ion channel responsible for transient outward K þ current, I to ; LAA ¼ Left atrial appendage; MiRP2 ¼ Accessory protein for K þ channels; N av1.5, Nav 1 ¼ Na þ channel responsible for inward Na þ current, I Na ; PA ¼ Pulmonary artery; PV ¼ Pulmonary vein; RA ¼ Right atrium; RAA ¼ Right atrial appendage; RV ¼ Right ventricle; SCV ¼ Superior caval vein; SK2 ¼ Ion channel responsible for Ca 2þ -activated K þ current, I KCa ; TASK1 Twin-pore domain K þ channel; Tbx3 ¼ Transcription factor; TC ¼ Terminal crest.

Sudden cardiac death remains one of the most serious medical challenges in Western countries. Increasing evidence in recent years has demonstrated that the n-3 polyunsaturated fatty acids (PUFAs) can prevent fatal ventricular arrhythmias in experimental animals and probably in humans. Dietary supplement of fish oils or intravenous infusion of the n-3 PUFAs prevents ventricular fibrillation caused by ischemia/reperfusion. Similar antiarrhythmic effects of these fatty acids are also observed in cultured mammalian cardiomyocytes. Based on clinical observations and experimental studies in vitro and in vivo, several mechanisms have been postulated for the antiarrhythmic effect of the n-3 PUFAs. The data from our laboratory and others have shown that the n-3 PUFAs are able to affect the activities of cardiac ion channels. The modulation of channel activities, especially voltage-gated Na(+) and L-type Ca(2+) channels, by the n-3 fatty acids may explain, at least partially, the antiarrhythmic action. It is not clear, however, whether one or more than one mechanism involves the beneficial effect of the n-3 PUFAs on the heart. This article summarizes our recent studies on the specific effects of the n-3 PUFAs on cardiac ion channels. In addition, the effect of the n-3 PUFAs on the human hyperpolarization-activated cyclic-nucleotide-modulated channel is presented.

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