title: Molecular Mapping of Sinoatrial Node HCN Channel Expression in the Human Heart.
abstract: BACKGROUND
  The hyperpolarization-activated current, If, plays an important role in sinoatrial node (SAN) pacemaking. Surprisingly, the distribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in human SAN has only been investigated at the mRNA level. Our aim was to define the expression pattern of HCN proteins in human SAN and different atrial regions.
  
  
  RESULTS
  Entire SAN complexes were isolated from failing (n=5) and nonfailing (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 Connexin 43-negative pacemaker cardiomyocytes visualized in Masson's trichrome and immunostained cryosections. SAN protein was precisely isolated from the adjacent frozen SAN tissue blocks using a 16G biopsy needle. The purity of the SAN protein was confirmed by Connexin 43 immunoblot. All 3 HCN isoform proteins were detected in SAN. HCN1 was predominantly distributed in the human SAN with a 125.1±40.2 (n=12) expression ratio of SAN to right atrium. HCN2 and HCN4 expression levels were higher in SAN than in atria, with SAN to right atrium ratios of 6.1±0.9 and 4.6±0.6 (n=12), respectively.
  
  
  CONCLUSIONS
  This is the first study to conduct precise 3D molecular mapping of the human SAN by isolating pure pacemaker SAN tissue. All 3 cardiac HCN isoforms had higher expression in the SAN than in the atria. HCN1 was almost exclusively expressed in SAN, emphasizing its utility as a new specific molecular marker of the human SAN and as a potential target of specific treatments intended to modify sinus rhythm.
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Ning
authors: N
authors: Li
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Thomas A
authors: TA
authors: Csepe
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Brian J
authors: BJ
authors: Hansen
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Halina
authors: H
authors: Dobrzynski
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Robert S D
authors: RS
authors: Higgins
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Ahmet
authors: A
authors: Kilic
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Peter J
authors: PJ
authors: Mohler
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Paul M L
authors: PM
authors: Janssen
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Michael R
authors: MR
authors: Rosen
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.).
authors: Brandon J
authors: BJ
authors: Biesiadecki
authors: From the Department of Physiology & Cell Biology and Dorothy M. Davis Heart & Lung Research Institute (N.L., T.A.C., B.J.H., P.J.M., P.M.L.J., B.J.B., V.V.F.), Department of Surgery and Dorothy M. Davis Heart & Lung Research Institute (R.S.D.H., A.K.), The Ohio State University Wexner Medical Center, Columbus; Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom (H.D.); and Departments of Pharmacology and Pediatrics, Columbia University, New York, NY (M.R.R.). vadim.fedorov@osumc.edu fedorov.2@osu.edu.
authors: Vadim V
authors: VV
authors: Fedorov
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012849:Sinoatrial Node / Q000378:metabolism*
chemical_list: C578665:HCN1 protein, human; C578710:HCN2 protein, human; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D020033:Protein Isoforms
keywords: HCN pacemaker channels; heart failure; human heart; sinoatrial node; sinus node dysfunction