Abstract 3016: Oral Chymase Inhibitor TEI-F00806 Improves in vitro and in vivo Cardiac Function in Volume Overload Mitral Regurgitation in the Dog
Data suggest that angiotensin II production in the cardiac interstitium is chymase dependent and that chymase is an important modulator of eccentric left ventricular (LV) remodeling in chronic volume overload secondary to mitral regurgitation (MR). We hypothesized that chymase inhibition would improve LV function and intrinsic myocyte function in volume overload MR by limiting extracellular matrix degradation and adverse cardiac remodeling.
Methods and Results: Eight adult mongrel dogs were subjected to MR without treatment and 8 were subjected to MR with treatment with the oral chymase inhibitor TEI-F00806 (100 mg/kg BID; MR+CI) for 4 months. Seven unoperated normal dogs served as controls. In vivo cardiac function was determined in anesthetized dogs using an LV impedance catheter followed by euthanasia. Hearts were removed and LV myocytes isolated by enzymatic digestion. Cells were incubated in 5 μM fluo 3-AM ester and field stimulated at 1000 ms cycle length. Cell shortening was recorded using a video edge detector and Ca transients were recorded using a photomultiplier tube. Measurements included
LV cardiomyocyte functional analysis,
picric acid sirius red histopathological quantification of LV endocardial and epicardial interstitial collagen, and
LV end-systolic pressure-volume measurement to define LV contractility in vivo by LV Emax. Compared to MR dogs, the percent LV myocyte shortening in MR+CI had significantly improved without an improvement in calcium transients. LV Emax was depressed in MR and normalized in MR + CI dogs. There was a 25% increase in LV mass and a similar 50% decrease in LV endocardial and epicardial interstitial collagen in MR and MR + CI dogs. MR dogs had greater LV cardiomyocyte elongation.
Conclusions: Chymase inhibition improved isolated cardiomyocyte function and LV contractility in chronic MR in the dog. This was not achieved with a decrease in interstitial collagen suggesting a direct effect on cardiomyocyte function.