Mast cell stabilization decreases cardiomyocyte and LV function in dogs with isolated mitral regurgitation

J Card Fail. 2010 Sep;16(9):769-76. doi: 10.1016/j.cardfail.2010.05.005. Epub 2010 Jul 1.

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.

Methods and 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Analysis of Variance
  • Animals
  • Anti-Allergic Agents / therapeutic use
  • Collagen / drug effects
  • Dogs
  • Extracellular Matrix
  • Heart Ventricles / drug effects*
  • Heart Ventricles / pathology
  • Hemodynamics / drug effects
  • Isoproterenol / pharmacology
  • Ketotifen / therapeutic use
  • Magnetic Resonance Imaging
  • Mast Cells / drug effects*
  • Mitral Valve Insufficiency / physiopathology*
  • Myocytes, Cardiac / drug effects*
  • Ventricular Function, Left / drug effects*
  • Ventricular Remodeling

Substances

  • Adrenergic beta-Agonists
  • Anti-Allergic Agents
  • Collagen
  • Isoproterenol
  • Ketotifen