title: Mast cell stabilization decreases cardiomyocyte and LV function in dogs with isolated mitral regurgitation.
abstract: BACKGROUND
  Mast cells are increased in isolated mitral regurgitation (MR) in the dog and may mediate extracellular matrix loss and left ventricular (LV) dilatation. We tested the hypothesis that mast cell stabilization would attenuate LV remodeling and improve function in the MR dog.
  
  
  RESULTS
  MR was induced in adult dogs randomized to no treatment (MR, n = 5) or to the mast cell stabilizer, ketotifen (MR + MCS, n = 4) for 4 months. LV hemodynamics were obtained at baseline and after 4 months of MR and magnetic resonance imaging (MRI) was performed at sacrifice. MRI-derived, serial, short-axis LV end-diastolic (ED) and end-systolic (ES) volumes, LVED volume/mass ratio, and LV 3-dimensional radius/wall thickness were increased in MR and MR + MCS dogs compared with normal dogs (n = 6) (P < .05). Interstitial collagen was decreased by 30% in both MR and MR + MCS versus normal dogs (P < .05). LV contractility by LV maximum time-varying elastance was significantly depressed in MR and MR + MCS dogs. Furthermore, cardiomyocyte fractional shortening was decreased in MR versus normal dogs and further depressed in MR + MCS dogs (P < .05). In vitro administration of ketotifen to normal cardiomyocytes also significantly decreased fractional shortening and calcium transients.
  
  
  CONCLUSIONS
  Chronic mast cell stabilization did not attenuate eccentric LV remodeling or collagen loss in MR. However, MCS therapy had a detrimental effect on LV function because of a direct negative inotropic effect on cardiomyocyte function.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Pat
authors.forename: Cheryl
authors.initials: C
authors.lastname: Killingsworth
authors.forename: Yuanwen
authors.initials: Y
authors.lastname: Chen
authors.forename: James D
authors.initials: JD
authors.lastname: Gladden
authors.forename: Greg
authors.initials: G
authors.lastname: Walcott
authors.forename: Pamela C
authors.initials: PC
authors.lastname: Powell
authors.forename: Thomas
authors.initials: T
authors.lastname: Denney
authors.forename: Himanshu
authors.initials: H
authors.lastname: Gupta
authors.forename: Ravi
authors.initials: R
authors.lastname: Desai
authors.forename: Michael
authors.initials: M
authors.lastname: Tillson
authors.forename: A Ray
authors.initials: AR
authors.lastname: Dillon
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'italia
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D018926:Anti-Allergic Agents / Q000627:therapeutic use; D003094:Collagen / Q000187:drug effects; D004285:Dogs; D005109:Extracellular Matrix; D006352:Heart Ventricles / Q000187:drug effects* / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D007665:Ketotifen / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008407:Mast Cells / Q000187:drug effects*; D008944:Mitral Valve Insufficiency / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling
chemical_list: D000318:Adrenergic beta-Agonists; D018926:Anti-Allergic Agents; D003094:Collagen; D007545:Isoproterenol; D007665:Ketotifen
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