title: Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration.
abstract: BACKGROUND
  Catecholamines increase cardiac contractility, but exposure to high concentrations or prolonged exposures can cause cardiac injury. A recent study demonstrated that a single subcutaneous injection of isoproterenol (ISO; 200 mg/kg) in mice causes acute myocyte death (8%-10%) with complete cardiac repair within a month. Cardiac regeneration was via endogenous cKit(+) cardiac stem cell-mediated new myocyte formation.
  
  
  OBJECTIVE
  Our goal was to validate this simple injury/regeneration system and use it to study the biology of newly forming adult cardiac myocytes.
  
  
  RESULTS
  C57BL/6 mice (n=173) were treated with single injections of vehicle, 200 or 300 mg/kg ISO, or 2 daily doses of 200 mg/kg ISO for 6 days. Echocardiography revealed transiently increased systolic function and unaltered diastolic function 1 day after single ISO injection. Single ISO injections also caused membrane injury in ≈10% of myocytes, but few of these myocytes appeared to be necrotic. Circulating troponin I levels after ISO were elevated, further documenting myocyte damage. However, myocyte apoptosis was not increased after ISO injury. Heart weight to body weight ratio and fibrosis were also not altered 28 days after ISO injection. Single- or multiple-dose ISO injury was not associated with an increase in the percentage of 5-ethynyl-2'-deoxyuridine-labeled myocytes. Furthermore, ISO injections did not increase new myocytes in cKit(+/Cre)×R-GFP transgenic mice.
  
  
  CONCLUSIONS
  A single dose of ISO causes injury in ≈10% of the cardiomyocytes. However, most of these myocytes seem to recover and do not elicit cKit(+) cardiac stem cell-derived myocyte regeneration.
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Markus
authors.initials: M
authors.lastname: Wallner
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Jason M
authors.initials: JM
authors.lastname: Duran
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Constantine D
authors.initials: CD
authors.lastname: Troupes
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Davy
authors.initials: D
authors.lastname: Vanhoutte
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Giulia
authors.initials: G
authors.lastname: Borghetti
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Vagnozzi
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Polina
authors.initials: P
authors.lastname: Gross
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Trappanese
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Hajime
authors.initials: H
authors.lastname: Kubo
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Amir
authors.initials: A
authors.lastname: Toib
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Sharp
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Shavonn C
authors.initials: SC
authors.lastname: Harper
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Michael A
authors.initials: MA
authors.lastname: Volkert
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Timothy
authors.initials: T
authors.lastname: Starosta
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Eric A
authors.initials: EA
authors.lastname: Feldsott
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Remus M
authors.initials: RM
authors.lastname: Berretta
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Mary F
authors.initials: MF
authors.lastname: Barbe
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.).
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: From the Cardiovascular Research Center (M.W., J.M.D., S.M., C.D.T., G.B., P.G., D.M.T., H.K., T.E.S., S.C.H., M.A.V., T.S., E.A.F., R.M.B., T.W., S.R.H.), Department of Clinical Sciences (D.Y.), and Department of Anatomy and Cell Biology (M.F.B.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, OH (D.V., R.J.V., J.D.M.); Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA (A.T.); Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.D.M.); and Department of Internal Medicine, University of California San Diego Medical Center, San Diego, CA (J.M.D.). srhouser@temple.edu.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000008:administration & dosage / Q000633:toxicity; D007545:Isoproterenol / Q000008:administration & dosage* / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D012038:Regeneration / Q000187:drug effects* / Q000502:physiology
chemical_list: D002395:Catecholamines; D007545:Isoproterenol
keywords: catecholamine; drug; heart failure; myocardium; remodeling