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Title: The effects of progressive heart failure on the Na/K ATPase and intracellular calcium regulation
Author: Ke, Hung-Yen
ISNI:       0000 0004 5989 4475
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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The aim of this thesis is to investigate the effects of progressive heart failure on the function of the Na/K ATPase and intracellular calcium regulation. Progressive heart failure was induced in male guinea pigs by constriction of the ascending aorta. Sham operations were carried out on the control group. Hearts were harvested and used for various experiments at 30, 60, and 150 days after the aortic constriction operation. Echocardiography was performed on unanaesthetized guinea pigs to monitor in vivo changes of contractile function. Significantly smaller fractional shortening was noted after aortic constriction although this remained stable during the progression of disease until the 150 day end point when fractional shortening decreased greatly and circulatory insufficiency presented. Heart weight : body weight ratio increased 60 days after the operation, but the lung weight : body weight ratio only increased at the 150 day end point. Electrophysiological measurements of action potential duration (APD), Ca transients, SR Ca content, and Na/K ATPase current were performed to investigate alterations of Ca regulation during the progression of heart failure using enzymatically isolated ventricular cardiac myocytes. In end-stage heart failure, APD remained prolonged and the function of other mechanisms all declined. These results supported the view that compensated hypertrophy developed at 60 days after aortic constriction, and decompensation with end stage heart failure occurred about 150 days after the operation. At the compensated hypertrophy stage, only Na/K ATPase pump function declined but other mechanisms were enhanced or were the same as the situation prior to the constriction. These results suggested that alteration of Na/K ATPase function might assist the compensation phase and may trigger the decompensatory progression. Since t-tubule remodelling was also observed early in the heart failure progression in other study, we used membrane staining with wheat germ agglutinin (WGA) to investigate the change of t-tubule density and regularity in guinea pigs with heart failure. Our results showed a decrease in density and disorganization with regular but narrower intervals of t-tubule arrangement. Immunocytochemical staining of the α1 and α2 isoforms of the Na/K ATPase was further carried out to study their distribution in the sarcolemma when the heart fails. The results showed decreased expression of both α1 and α2 isoforms, which is compatible with our functional findings of Na/K ATPase pump current decline. Furthermore, corresponding to WGA membrane staining, α2 isoforms were found to colocalize with t-tubules. These finding suggested that alteration of Na/K ATPase pump function occurs early in the progression of hypertrophy toward heart failure, and α2 isoforms may play a more prominent role in regulating Ca handling.
Supervisor: MacLeod, Kenneth Sponsor: Government of China
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral