Mast Cell Stabilization with Beta-Adrenergic Receptor Blockade Attenuates Dysfunctional Cardiac Remodeling in Canine Mitral Valve Regurgitation
Dogs with induced mitral valve regurgitation (MR) have been shown to lose myocardial collagen, develop mast cell infiltrates in the LV wall, undergo cardiomyocyte lengthening and to use an inherent renin-angiotensin system (RAS) unaffected by systemic ACE inhibitors. The mechanism of this dysfunctional cardiac remodeling secondary to volume overload appears distinct from changes resulting from cardiogenic or pressure overload remodeling. The goal was to characterize this cardiac remodeling (structurally and molecularly) in order to compare these findings with hemodynamic studies, and the geometric changes and LV wall stress obtained through cardiac magnetic resonance imaging (c-MRI). Study groups included normal dogs (n=14), dogs with MR (n=9) without medication, dogs with MR (n=6) receiving a β1-receptor blockade (β1-RB), and dogs with MR (n=6) receiving β1-RB and a mast cell stabilizer (MCS).
Mild mitral regurgitation (MR) was induced by chordae tendonae rupture. Sufficient regurgitation was achieved when dogs had 1) a 6-12% decrease in forward stroke volume (SV), 2) increased LV EDP or decreased LV ESP, 3) increase pulmonary artery wedge (Paw), and an auscultable mitral murmur. Hemodynamic parameters were collected before and immediately after MR induction and again at 4 months. C-MRI images (Picker Vista 1.0 T magnet; DICOM images; 8mm slices) were collected during the cardiac cycle before MR induction and again at 4 months.
Treatment with β1-RB improved isolated cardiomyocyte fractional shortening and B-receptor responsiveness, but did not attenuate increases in cardiomyocyte length or LV-EDV or affect eccentric LV remodeling. Improved cardiomyocyte function did not translate to benefits in LV wall stress, load dependent LV fractional shortening, or peak LV dP/dt. Treatment with β1-RB (with or without MCS) attenuated epicardial extracellular collagen loss but not endocardial collagen loss, by picric acid-Sirius red assay (Type I&III). Treatment with β1-RB+MCS normalized cardiomyocyte length and restored Ca++ transients. LV peak +dP/dt was decreased in β1-RB treated dogs compared to baseline but was normalized in dogs receiving β1-RB+MCS.
All groups had increased LV mass and total SV compared to baseline. Forward SV compared to baseline was decreased in MR and β1-RB dogs, but was preserved in β1-RB+MSC dogs. 3-D MRI images showed an increase in LV-EDV and LV 3-D radius/wall thickness in MR and β1-RB dogs, but these and LV-ED wall stress were decreased in β1-RB+MCS dogs compared to MR.
These data suggest use of β1-RB and MCS in dogs with MR induced volume overload does attenuate dysfunctional LV and cardiomyocyte remodeling and improves LV function and geometry, without attenuating the previously described interstitial collagen loss. The effect of MCS may be directly on cardiomyocytes or through preservation of cardiomyocyte-collagen scaffolding proteins affecting outside-in signaling and eccentric remodeling.