Abstract 17318: Caspase Inhibition Prevents Hypertrophy and Improves Cardiac Function with Chronic Pressure Overload

It is widely held that a major mechanism underlying the transition from stable left ventricular (LV) function to failure is myocyte loss through apoptosis. To test this hypothesis, we examined the effects of chronic transverse aortic constriction (TAC) in C57BL/6 mice with or without administration of the caspase inhibitor (CI) (Z-Asp-2,6-DCBMk) delivered through an intraperitoneal osmotic minipump. In mice treated with CI, LV function (LV ejection fraction) was preserved (73±1%) compared with the vehicle group (52±7%) (p<0.05) after 2 weeks of TAC. One possibility was that CI prevented apoptosis of myocytes and thereby improved LV function. This was not likely, since with CI, apoptosis was reduced, but relatively trivially in myocytes; using double staining with TUNEL and wheat germ agglutinin, only 7% of the reduced cellular apoptosis in the heart could be attributed to myocytes as compared with 93% of non-myocytes protected. Furthermore, if myocyte apoptosis protection was the mechanism, then LV mass would likely have been larger with CI. However, the reverse occurred, i.e., CI actually prevented LV hypertrophy; LV weight/tibial length did not increase significantly with CI after TAC (5.26±0.30) vs. sham (4.95±0.30) as opposed to vehicle after TAC (7.49±0.43). This was not because of differences in LV/aortic pressure gradient in CI (102±4mmHg) vs. vehicle (100±2mmHg), but likely due to protected LV wall stress, which was less (p<0.05) in the CI group (70.2±9.9 Kdyn/cm 2 ) than vehicle (132.2±19.4 Kdyn/cm 2 ). Therefore, the mechanism for improved function with TAC and CI was likely related to an effect of CI on myocytes. Accordingly, we examined isolated myocytes using a Langendorff perfusion apparatus, and measured isolated myocyte contractility by an optical edge-tracking method. After TAC the contractility (% of cell length) under 1mM calcium was increased in CI (15.5±1.2%) compared to vehicle (10.2±1.4%) (p<0.01). Thus, CI improved LV function after chronic pressure overload, not by protecting against myocyte apoptosis, but rather by improving myocyte contractile function resulting in reduced LV wall stress and hypertrophy.