Key result
Calcineurin blockade with cyclosporine completely inhibited cardiac hypertrophy in mice subjected to 5 weeks of pressure overload, maintaining normal LV size and systolic function.
Why the study?
Does calcineurin inhibition with cyclosporine prevent cardiac hypertrophy and maintain ventricular function in mice with surgically induced pressure overload?
Does calcineurin inhibition with cyclosporine prevent cardiac hypertrophy and maintain ventricular function in mice with surgically induced pressure overload?
Calcineurin blockade with cyclosporine prevents left ventricular hypertrophy due to pressure overload in mice without compromising systolic function or survival, challenging the concept that hypertrophy is a required compensatory response.
Answers are grounded in this paper and cite their sources.
Does not support clinical use of cyclosporine; challenges compensatory role of hypertrophy and leaves translation to humans open.
BACKGROUND: Cardiac hypertrophy is considered a necessary compensatory response to sustained elevations of left ventricular (LV) wall stress. METHODS AND RESULTS: To test this, we inhibited calcineurin with cyclosporine (CsA) in the setting of surgically induced pressure overload in mice and examined in vivo parameters of ventricular volume and function using echocardiography. Normalized heart mass increased 45% by 5 weeks after thoracic aortic banding (TAB; heart weight/body weight, 8.3+/-0.9 mg/g [mean+/-SEM] versus 5. 7+/-0.1 mg/g unbanded, P<0.05). Similar increases were documented in the cell-surface area of isolated LV myocytes. In mice subjected to TAB+CsA treatment, we observed complete inhibition of hypertrophy (heart weight/body weight, 5.2+/-0.3 mg/g at 5 weeks) and myocyte surface area (endocardial and epicardial fractions). The mice tolerated abolition of hypertrophy with no signs of cardiovascular compromise, and 5-week mortality was not different from that of banded mice injected with vehicle (TAB+Veh). Despite abolition of hypertrophy by CsA (LV mass by echo, 83+/-5 mg versus 83+/-2 mg unbanded), chamber size (end-diastolic volume, 33+/-6 microL versus 37+/-1 microL unbanded), and systolic ejection performance (ejection fraction, 97+/-2% versus 97+/-1% unbanded) were normal. LV mass differed significantly in TAB+Veh animals (103+/-5 mg, P<0.05), but chamber volume (end-diastolic volume, 44+/-6 microL), ejection fraction (92+/-2%), and transstenotic pressure gradients (70+/-14 mm Hg in TAB+Veh versus 77+/-11 mm Hg in TAB+CsA) were not different. CONCLUSIONS: In this experimental setting, calcineurin blockade with CsA prevented LV hypertrophy due to pressure overload. TAB mice treated with CsA maintain normal LV size and systolic function.
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Hill et al. (2000) studied Surgically induced pressure overload. Cyclosporine (CsA) vs. Vehicle (TAB+Veh) or unbanded mice was evaluated on Cardiac hypertrophy (heart weight/body weight) (p=<0.05). Calcineurin blockade with cyclosporine completely inhibited cardiac hypertrophy in mice subjected to 5 weeks of pressure overload, maintaining normal LV size and systolic function.
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