Cyclosporine attenuates pressure-overload hypertrophy in mice while enhancing susceptibility to decompensation and heart failure

Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload, Recently, a calcineurin pathway mediating LVH and its p revention by cyclosporine was reported. We examined whether calcineurin med iates LVH due to pressure overload in mice. Pressure overload was induced b y aortic banding in 53 mice (32 treated with cyclosporine [25 mg . kg(-1) . d(-1)], 21 treated with vehicle). There were 17 sham-operated mice (9 trea ted with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, L V weight to body weight was greater in the nontreatment banded group (4.39/-0.16 mg/g) than in the cyclosporine-treated banded group (3.95+/-0.14 mg/ g, P<0.05), with both groups being greater compared with the entire group o f sham-operated mice (3.02+/-0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine-tr eated (49.6+/-6.1 mm Hg) and nontreatment groups (48.7+/-4.6 mm Hg). Althou gh LV systolic pressure was lower in the cyclosporine-treated banded animal s, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774+/-656 mm Hg/s) than in the non treatment banded group (6604+/-516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery, Deaths cause d by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treate d group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after b anding; LV ejection fraction measured with echocardiography was lower (P<0. 05) in the cyclosporine-treated banded group (66+/-3.0%) than in the nontre atment blinded group (79+/-1.5%), whereas LV systolic wall stresses were si milar. Calcineurin phosphatase activity was depressed similarly in both cyc losporine-treated groups compared with both nontreatment groups. Thus, cycl osporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resu lting in reduced LV wall stress and function and increased susceptibility t o decompensation and heart failure.