Abstract 18171: HCN Channel Distribution in the Human Sinoatrial Node and Latent Atrial Pacemakers (Best of Basic Science Abstract)
Background: The hyperpolarization-activated current, If, plays an important role in cardiac pacemaker cells. However, the distribution and expression of HCN isoforms in the human SAN and latent atrial pacemaker clusters is unknown.
Methods: Human atria and entire SAN complexes were isolated from failing (n=5) and non-failing (n=9) human hearts cardioplegically-arrested in the operating room. Three dimensional intramural SAN structure was identified as the fibrotic compact region around the SAN artery with Connexin43-negative pacemaker cardiomyocytes visualized in Masson’s trichrome and immunostained cryosections. Pure SAN tissue was precisely isolated from the frozen SAN cryo blocks using a 16G biopsy needle (Figure). Atrial tissues from different locations were fresh frozen in liquid nitrogen. Immunoblot and immunostaining were used to study the expression pattern of HCN isoforms.
Results: Three HCN isoform proteins were detected in the atria and SAN (Figure). HCN1 was predominantly distributed in all the human SAN with a 125.1±40.2 (n=12) expression ratio of SAN to right atrial free wall (RAFW). HCN2 and HCN4 expression levels were higher in SAN than atria with ratios of 6.1±0.9 and 4.6±0.6 (n=12), respectively. HCN2 expression but not HCN1/4 in the latent atrial pacemakers from the right atrioventricular ring (RR) area was significantly higher than in RAFW, with the band density ratio of RR/RAFW= 2.4±0.4 (n=12).
Conclusions: This is the first study to conduct precise molecular mapping of the human SAN by isolating pure pacemaker SAN tissue. HCN1 was almost exclusively expressed in SAN and may play a critical role in determining the leading pacemaker in human SAN. Even HCN2 and HCN4 expression is higher in the SAN than RAFW, these isoforms are less SAN-specific than HCN1. SAN and latent atrial pacemakers have different HCN expression patterns, suggesting the utility of HCN isoform specific blockers to selectively modify sinus rhythm or atrial ectopic rhythms.
Author Disclosures: N. Li: None. T.A. Csepe: None. B.J. Hansen: None. H. Dobrzynski: None. R.S. Higgins: None. A. Kilic: None. P.J. Mohler: None. P.M. Janssen: None. M.R. Rosen: None. B.J. Biesiadecki: None. V.V. Fedorov: None.
- © 2015 by American Heart Association, Inc.