Functional, Anatomical, and Molecular Investigation of the Cardiac Conduction System and Arrhythmogenic Atrioventricular Ring Tissue in the Rat Heart

Abstract

BackgroundThe cardiac conduction system consists of the sinus node, nodal extensions, atrioventricular (AV) node, penetrating bundle, bundle branches, and Purkinje fibers. Node‐like AV ring tissue also exists at the AV junctions, and the right and left rings unite at the retroaortic node. The study aims were to (1) construct a 3‐dimensional anatomical model of the AV rings and retroaortic node, (2) map electrical activation in the right ring and study its action potential characteristics, and (3) examine gene expression in the right ring and retroaortic node.Methods and ResultsThree‐dimensional reconstruction (based on magnetic resonance imaging, histology, and immunohistochemistry) showed the extent and organization of the specialized tissues (eg, how the AV rings form the right and left nodal extensions into the AV node). Multiextracellular electrode array and microelectrode mapping of isolated right ring preparations revealed robust spontaneous activity with characteristic diastolic depolarization. Using laser microdissection gene expression measured at the mRNA level (using quantitative PCR) and protein level (using immunohistochemistry and Western blotting) showed that the right ring and retroaortic node, like the sinus node and AV node but, unlike ventricular muscle, had statistically significant higher expression of key transcription factors (including Tbx3, Msx2, and Id2) and ion channels (including HCN4, Cav3.1, Cav3.2, Kv1.5, SK1, Kir3.1, and Kir3.4) and lower expression of other key ion channels (Nav1.5 and Kir2.1).ConclusionsThe AV rings and retroaortic node possess gene expression profiles similar to that of the AV node. Ion channel expression and electrophysiological recordings show the AV rings could act as ectopic pacemakers and a source of atrial tachycardia.

Molecular Mapping of Sinoatrial Node HCN Channel Expression in the Human Heart

“…Consistent with these observations, we observed heterogeneous HCN2 distribution in SAN and adjacent atrial tissue, with 6 times higher expression in SAN than RAFW, and expression 2 times higher in latent atrial pacemaker (RR) 30 than non-pacemaker regions (RAFW). Studies in animals 30 and our preliminary optical mapping experiments 31 revealed nodal-type action potentials and ectopic activity in the RR region that were depressed by I f blockade 31 . We suggest that HCN2 may be important for both primary (SAN) and latent (RR) pacemaker automaticity in the human heart.…”

Potassium channels related to primary aldosteronism: Expression similarities and differences between human and rat adrenals

“…The role of KCNJ5 in mice has been previously studied in the heart (Liang et al, 2014; Mesirca et al, 2013) and in a mouse cardiac muscle cell line (Nobles et al, 2010). In rats, KCNJ5 has also been studied in cardiac tissue (Atkinson et al, 2013; Bingen et al, 2013), and in kidney tissue of obese rats (Kang et al, 2013). However, to date, no studies have investigated the role of KCNJ5 in the adrenal cortex or in aldosterone regulation in rodents.…”

Ion Channels in the Heart

“…This conclusion results from studies in which the AVN was dissected from surrounding atrial and His tissue, resulting in a dramatic acceleration of rate (260). In the human, rabbit, and rat, HCN4 is abundantly expressed throughout the AVN (27) and is likely responsible for I f in the AVN and thus an important player in pacemaking. Interestingly, knock-out of HCN4 not only causes sinus bradycardia, but also high-degree AV block (36), suggesting that I f also plays an important role in normal AVN conduction.…”