Journal of Cardiac Failure
Volume 16, Issue 9 , Pages 769-776, September 2010

Mast Cell Stabilization Decreases Cardiomyocyte and LV Function in Dogs With Isolated Mitral Regurgitation

  • Betty Pat, PhD

      Affiliations

    • Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL
    • ,
  • Cheryl Killingsworth, DVM, PhD

      Affiliations

    • Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL
    • ,
  • Yuanwen Chen, MD, PhD

      Affiliations

    • Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL
    • Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    • ,
  • James D. Gladden, BS

      Affiliations

    • Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL
    • ,
  • Greg Walcott, MD

      Affiliations

    • Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL
    • ,
  • Pamela C. Powell, MS

      Affiliations

    • Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL
    • ,
  • Thomas Denney, PhD

      Affiliations

    • Department of Electrical Engineering, Auburn University, Auburn, AL
    • ,
  • Himanshu Gupta, MD

      Affiliations

    • Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL
    • ,
  • Ravi Desai, MD

      Affiliations

    • Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL
    • ,
  • Michael Tillson, DVM

      Affiliations

    • College of Veterinary Medicine, Auburn University, Auburn, AL
    • ,
  • A. Ray Dillon, DVM

      Affiliations

    • College of Veterinary Medicine, Auburn University, Auburn, AL
    • ,
  • Louis J. Dell'Italia, MD

      Affiliations

    • Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL
    • Department of Veteran Affairs, University of Alabama at Birmingham (UAB), Birmingham, AL
    • Corresponding Author InformationReprint requests: Louis J. Dell'Italia, MD, UAB Center for Heart Failure Research, Department of Medicine, Division of Cardiology, 434 BMR2, 901 19th Street South, Birmingham, AL 35294-2180. Tel: (205) 934-0850; Fax: (205) 996-2586.

Received 30 September 2009; received in revised form 4 May 2010; accepted 6 May 2010. published online 02 July 2010.

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.

Key Words: Heart failure, mast cells, calcium, myocyte

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 Supported by the Office of Research and Development, Medical Service, Department of Veteran Affairs (LJD) and National Heart, Lung and Blood Institute Grant Specialized Centers of Clinically Orientated Research grant in Cardiac Dysfunction P50HL077100.

 See page 776 for disclosure information.

PII: S1071-9164(10)00211-3

doi:10.1016/j.cardfail.2010.05.005

Journal of Cardiac Failure
Volume 16, Issue 9 , Pages 769-776, September 2010

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