title: Recreating an artificial biological pacemaker: insights from a theoretical model.
abstract: BACKGROUND
  Normal cardiac rhythm is critically dependent on the sinoatrial (SA) node, the natural biological pacemaker. Although recent studies have focused on the development of "artificial" biological pacemakers using gene transfer, less is known about the functional consequences of such interventions.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the electrophysiological consequences of two approaches used to create a biological pacemaker: overexpression of the hyperpolarization-activated cyclic nucleotide gated channel (HCN "pacemaker" channels) and suppression of the inward-rectifier potassium current, I(K1).
  
  
  METHODS
  We used a linear multicellular Luo-Rudy (LRd) AP model consisting of 130 ventricular cells connected by resistive gap junctions. To induce automaticity, I(K1) current was reduced or I(f) (HCN) current was introduced in endocardial and midmyocardial (M) cells.
  
  
  RESULTS
  Similar to the previously published results for a single LRd model, myocyte I(K1) suppression induced automaticity in the fiber. While introduction of I(f) also resulted in automaticity, the main differences between I(K1) suppression and I(f) expression were (1) a relatively more gradual phase 4 depolarization with HCN expression, (2) stabilization of cycle lengths during I(K1) suppression, but not during HCN expression, and (3) responsiveness to beta-adrenergic stimulation during HCN expression, but not during I(K1) suppression. Upon further investigation, we found that cycle length instability during HCN expression was primarily due to a gradual reduction of intracellular potassium ([K(+)](i)) from its baseline value of 142 mM to 120 mM in 600 beats and subsequent alteration of potassium-dependent ionic currents. A twofold increase in HCN expression also led to a similar behavior. We attribute this decrease in [K(+)](i) to a large I(K1) during phase 4 depolarization. When intracellular [K(+)](i) loss was minimized, cycle lengths stabilized during HCN expression.
  
  
  CONCLUSIONS
  Our results help to further understand the electrophysiologic consequences as well as some of the challenges associated with the creation of biological pacemakers using HCN and I(K1) gene transfer strategies.
authors.affiliation: Cardiovascular Research Institute, University of Pittsburgh, Pennsylvania, USA. viswanathanp2@upmc.edu
authors.forename: Prakash C
authors.initials: PC
authors.lastname: Viswanathan
authors.forename: James A
authors.initials: JA
authors.lastname: Coles
authors.forename: Vinod
authors.initials: V
authors.lastname: Sharma
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Sigg
mesh_terms: D000200:Action Potentials / Q000502:physiology; D054815:Cyclic Nucleotide-Gated Cation Channels; D018014:Gene Transfer Techniques; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D007473:Ion Channels / Q000096:biosynthesis* / Q000235:genetics; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010138:Pacemaker, Artificial; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels; D015398:Signal Transduction / Q000502:physiology
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D011188:Potassium