Molecular Investigation into the Human Atrioventricular Node in Heart Failure

Abstract

The atrioventricular node (AVN), the molecular basis has been studied in animal models; however, the human AVN remains poorly explored at the molecular level in heart failure patients. We studied ex vivo donor human hearts rejected for transplantation (n=6) and end-stage failing hearts with cardiomyopathy of various etiologies (n=6). Microdissection and quantitative PCR (qPCR) were used to anatomically map mRNA expression in both failing and non-failing hearts from tissue sections through the AVN, atrial and ventricular muscle. In the failing ventricle significant (P<0.05) downregulation is apparent for vimentin, hERG and Kir3.4 and trend to downregulation for Nav1.5, Cav1.2, Tbx3, Kir2.1, NCX1, Cx43 and Cx45. In the failing atrium, there is non-significant trend in upregulation for Nav1.5, HCN2, Cav3.1, Kv1.5, Kir3.1, RYR2 and significant upregulation for Cx40 and trend in downregulation for hERG, Kir2.1 and NCX1, and significant downregulation for HCN4 and Kir3.4. In the failing AVN there is significant (P<0.05) downregulation for vimentin, collagen, Tbx3, Kir3.1, Kir3.4, Cx45 and HCN4; there is also trend toward downregulation for HCN2, Kv1.5, Kir2.1 and RYR2. In the failing AVN there is significant (P<0.05) upregulation for Cx40, HCN1 and Cav3.1; and trend in upregulation for Nav1.5 and Cx43. For several transcripts, we also analysed corresponding protein expression via immunofluorescence. The protein expression data on the AVN for HCN1, Cav3.1 and Cx40 support qPCR data. Remodelling of AVN in heart failure might contribute to prolonged AV conduction time and could explain the prolonged PR interval that occurs in heart failure patients.

At the Atrioventricular Crossroads: Dual Pathway Electrophysiology in the Atrioventricular Node and its underlying Heterogeneities

“…The expression profiles of their various isoforms are summarised in PB and INE cells, at levels significantly higher than in AM and VM. 27,28 Ca v 3.3 has a more uniform distribution through the AVN region and its expression is also comparable to AM and VM. 27,28 Calcium Handling Proteins…”

“…Several groups have studied Cx expression patterns in the human AVN. 11,27,28 Total protein and mRNA levels of Cx40, Cx43 and/or Cx45 were assessed qualitatively and quantitatively in these studies. Representative Cx43 immunolabelled sections are shown in Figure 2B, alongside their serially sectioned histological images (Figure 2A).…”

“…Interestingly, the left nodal extension was also reported to be longer in pathological states such as dilated cardiomyopathy. 11,27,28 The expression profile for Cx43 in the human AVN is shown in Figure 2C. To summarise, although Cx43 is highly…”

“…32 Of these, HCN4 is the HCN2 and HCN3 were uniformly expressed throughout the myocardium and AVN cells; however, the latter was expressed at very low levels. 27,28 Sodium Channels…”

“…40 The level of sodium calcium exchanger isoform 1 mRNA was reported to be similar in AVN tissue relative to AM and VM; however, there was a slight upregulation in the CN and a small downregulation in the INE regions specifically. 27,28 The sarcoplasmic reticulum calcium release and uptake channel expression was also previously investigated. While Greener et al 28 reported a lower abundance of ryanodine receptor 2 in AVN cells versus myocytes, Dobrzynski et al 27 hERG mRNA expression in the AM, AVN cells and VM were reported to be uniform by Greener et al 28 but Dobrzynski et al 27 reported that hERG mRNA expression was significantly higher in VM.…”