Abstract 16055: A Decrease in Na/K ATPase Function Occurs before Changes to Calcium Handling in a Guinea-Pig Model of Progressive Heart Failure
Although the underlying cellular mechanisms of heart failure are gradually being better understood, the changes to these mechanisms during the progression of hypertrophy toward heart failure have not been well studied. The study uses a well characterised model of hypertrophy and heart failure in the guinea-pig - aortic constriction (AC) and electrophysiological and fluorescence techniques to measure the function of Na and Ca regulatory proteins at 30, 60 and 150 days after AC. Compensated hypertrophy develops at 60 days after AC and after 150 days heart failure is well defined (heart weight and lung weight: body weight ratios significantly increased (by 50% and 76% respectively), in vivo echocardiography confirms LV wall hypertrophy and decreased fractional shortening (74.3 ± 1.6%, N=5, sham vs 47.9 ± 5.4%, N=10, 150 day AC, P < 0.01). Ventricular myocyte action potential duration increases during the development of hypertrophy and continues to increase as the hearts fail. Voltage clamp experiments were used to assess Na/K ATPase current, SR Ca content and Ca transients in cells isolated from 30, 60, and 150 days sham and AC hearts. Na/K ATPase current decreases after the initial development of hypertrophy. The current recorded 30 days after aortic banding is not different from sham but the current recorded 60 and 150 days after aortic banding is significantly smaller (1.10 ± 0.16 A.F-1, N=15, sham vs 0.54 ± 0.10 A.F-1, N=13, 60 day AC, P < 0.05; 0.86 ± 0.13 A.F-1, N=25, sham vs 0.51 ± 0.06 A.F-1, N=15, 150 day AC, P < 0.05). SR Ca content increases in the compensated hypertrophy stage (22 ± 4 µM.l-1, N=5, sham vs 44 ± 6 µM.l-1, N=17, 60 day AC, P < 0.05) and then decreases in heart failure (32 ± 4 µM.l-1, N=7, sham vs 15 ± 3 µM.l-1, N=8, 150 day AC, P < 0.01). The size of Ca transients do not change until the latest time point (F/F0=4.36 ± 0.69, N=12, sham vs 3.87 ± 0.13,N=13, 60 day AC, P = 0.47; F/F0=3.83 ± 0.41, N=16, sham vs 2.35 ± 0.25, N=14, 150 day AC, P < 0.01). The decline in Na/K ATPase current occurs early in the progression of dysfunction following AC and may trigger a variety of changes in cellular Ca handling and contractile function.
- © 2012 by American Heart Association, Inc.