Abstract 962: Beta-1 Adrenergic Receptor Blockade Improves Cardiomyocyte Function but not Remodeling in Chronic Canine Mitral Regurgitation
Introduction: Volume overload and chronic sympathetic stimulation induced by mitral regurgitation (MR) result in cardiac remodeling, which translates to diminished function and heart failure. We sought to determine isolated myocyte length and function in the presence of Beta-adrenergic stimulation and chronic blockade. We hypothesized that
Beta-1 adrenergic receptor blockade would improve intrinsic myocyte function in volume overload MR and
changes in intracellular calcium (Ca) transients would parallel myocyte function and remodeling.
Methods: MR was induced in 9 dogs in which 4 received no treatment and 5 were treated with the oral Beta-1 receptor blocker metoprolol for 4 months. Six normal dogs served as controls. Hearts were removed and left ventricular myocytes isolated by enzymatic digestion. Cells were incubated in 5 microM fluo 3-AM ester and field stimulated at 1000 ms cycle length. Following baseline measurements, some cells were exposed to 25 nM isoproterenol. Cell shortening was recorded using a video edge detection system and Ca transients were recorded using a photomultiplier tube. Data are presented as mean+/−SEM.
Results: In MR + Beta-1 blocked myocytes, isoproterenol stimulation increased percent shortening 215+/−84% and Ca transients 21+/−9% compared to baseline (P<0.05). In contrast, isoproterenol-induced percent shortening was similar between control (56+/−11%) and MR (50+/−20%) myocytes but Fmax/Fo was significantly less in MR (3+/−2% increase from baseline) compared to control cells (13+/−3%) following isoproterenol.
Conclusions: Chronic MR results in decreased myocyte contractile function and decreased Ca transients. Beta-1 blockade improved myocyte function along with a marked isoproterenol enhanced contractile response and calcium transient. Cardiomyocyte remodeling was not improved by Beta-1 receptor blockade, suggesting a disconnect between remodeling and myocyte function in volume overload MR.