Mast cell stabilization decreases cardiomyocyte and LV function in dogs with isolated mitral regurgitation.
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.
Pat
Betty
B
Department of Medicine, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
Killingsworth
Cheryl
C
Chen
Yuanwen
Y
Gladden
James D
JD
Walcott
Greg
G
Powell
Pamela C
PC
Denney
Thomas
T
Gupta
Himanshu
H
Desai
Ravi
R
Tillson
Michael
M
Dillon
A Ray
AR
Dell'italia
Louis J
LJ
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
D000318:Adrenergic beta-Agonists; D018926:Anti-Allergic Agents; D003094:Collagen; D007545:Isoproterenol; D007665:Ketotifen
J Am Coll Cardiol. 2002 Apr 17;39(8):1380-3
11955859
Am J Physiol. 1996 Dec;271(6 Pt 2):H2689-700
8997332
Int J Cardiovasc Imaging. 2002 Feb;18(1):539-42
12135124
Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H632-7
15388501
J Exp Med. 2002 Feb 4;195(3):375-81
11828013
J Mol Cell Cardiol. 2003 Mar;35(3):311-9
12676546
Nat Med. 2007 Jun;13(6):719-24
17546038
Am J Physiol. 1997 Aug;273(2 Pt 2):H961-70
9277516
Circulation. 1985 May;71(5):994-1009
3986986
J Biol Chem. 1997 Oct 10;272(41):25628-35
9325284
Circulation. 1981 Jun;63(6):1223-7
7014027
Immunol Rev. 2007 Jun;217:141-54
17498057
J Am Coll Cardiol. 2007 Feb 20;49(7):811-21
17306712
J Biol Chem. 2005 Mar 11;280(10):9291-6
15615702
Am J Physiol Regul Integr Comp Physiol. 2008 Mar;294(3):R689-98
18184767
J Hypertens. 2003 Oct;21(10):1935-44
14508201
Am J Physiol Regul Integr Comp Physiol. 2004 Oct;287(4):R969-80
15231494
Circulation. 1987 Jun;75(6):1310-9
3568333
Respiration. 1984;45(4):411-21
6206536
Am J Physiol. 1995 Dec;269(6 Pt 2):H2065-73
8594918
J Card Fail. 2005 Sep;11(7):548-56
16198252
Am J Physiol Heart Circ Physiol. 2000 Jul;279(1):H250-9
10899064
Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H518-25
12124196
Pflugers Arch. 1994 Oct;428(5-6):433-8
7838664
J Dermatol Sci. 2008 Jan;49(1):7-19
18024086