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 (ECM) 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 MR was induced in adult dogs randomized to no treatment (MR, n = 9) or to mast cell stabilizer, ketotifen (MR+MCS, n = 6) for four months. LV hemodynamics was obtained after four months of MR and magnetic resonance imaging (MRI) was performed at sacrifice. Results MRI-derived serial short axis LV end-diastolic (ED) and end-systolic (ES) volumes, LVED volume/mass ratio, and LV three-dimensional radius/wall thickness were increased in MR and MR+MCS dogs compared to normal dogs (n = 6) (P < 0.05). Interstitial collagen was decreased by 30% in both MR and MR+MCS vs. normal dogs (P < 0.05). 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 vs. normal dogs and further depressed in MR+MCS dogs (P < 0.05). 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 due a direct negative inotropic effect on cardiomyocyte function.

Intracrine angiotensin II functions originate from noncanonical pathways in the human heart

“…THE HEART AND ANGIOTENSIN- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) chymase inhibitors can target other enzymes in the pathophysiology of left ventricular remodeling and thus may synergize with ACE inhibition or AT 1 receptor blockade in the treatment of heart failure. Finally, our new finding of chymase within the cardiomyocyte during volume overload in the rat opens up an entirely new potential mechanism for Ang II formation and proteasemediated destructive actions within the cell that are untouched by ACE inhibitors or AT 1 receptor blockers that act on the cell surface (102). The presence of the chymase-Ang-(1-12) pathway is further exemplified by the failure to achieve additional benefit when more complete blockade of the canonical pathway was obtained with the renin inhibitor aliskerin in patients with heart failure (88).…”

“…Mast cells contain a plethora of mediators, of which the most important in tissue injury are mast cell proteases including tryptase, chymase, and dipeptidyl peptidase I (DPP I), in addition to TNF-␣, and stem cell factor (SCF), which are responsible for recruitment of macrophages and neutrophils (22,104). Targeting mast cells with mast cell stabilizers resulted in left ventricular and cardiomyocyte dysfunction in dogs with mitral regurgitation due to inherent calcium-entry blocking effects of mast cell stabilizers (102). As indicated by chymase's multiple actions (Fig.…”

Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling

“…Another potential concern is that chronic mast cell stabilization in chronic MR in the dog results in a decrease in LV systolic function that is further verified in isolated adult dog cardiomyocytes, where mast cell stabilization causes a marked depression of the cardiomyocyte calcium transient and fractional shortening. 245 As a result, inhibiting chymase or a combination of proteases is a more appropriate therapeutic approach. Such an approach is now especially enticing given that cells other than mast cells produce excessive chymase under pathologic stimuli such as hypoxia, 246,247 hemodynamic stretch, 152 and excessive glucose.…”

Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs

“…No clinical signs developed in either treated or untreated groups, and although cardiac enlargement was less in the treated dogs, cardiac function was significantly impaired providing no support for this therapeutic approach. 11 To further understand the role of the collagen matrix loss in MR, a unique oral chymase inhibitor was utilized in dogs with mild MR of 4-months duration. With cMRI, a >40% increase in LV EDV was noted in both treated and control dogs, which was associated with a 25% loss of collagen in the LV matrix of both groups.…”