The effect of estrogen on intracellular Ca2+ and Na+ regulation in heart failure
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Published version
Author(s)
Firth, J
Yang, H-Y
Francis, A
Islam, N
MacLeod, K
Type
Journal Article
Abstract
Background: Under-representation of women in heart failure (HF) trials and contradictory findings of estrogen supplementation highlight the need to investigate the involvement of estrogen in the progression of heart failure. Objectives: To characterize the influence of estrogen on cardiac function during the onset of heart failure in a controlled animal model that lacks traditional comorbidities. Methods: HF was induced by aortic constriction (AC) in female guinea pigs. Selected AC animals were ovariectomized (ACOV) and a group of these received 17β-estradiol (ACOV+E) supplementation. 150 days post-AC surgery, left ventricular myocytes were isolated and their electrophysiology and Ca2+ and Na+ regulation examined. Results: ACOV animals heart weight/body weight ratios increased by 11% and in vivo fractional shortening decreased by 14% compared with the AC group, suggesting greater impairment of cardiac function in the absence of estrogen. Action potential duration increased in all three HF groups, the extent of the changes being estrogen-dependent. Myocytes from ACOV animals had reduced Ca2+ transient amplitudes, slower transient decay kinetics, decreased SR Ca2+ contents but increased Ca2+ spark frequencies and spark-mediated SR leak compared with the AC and ACOV+E groups. The Na+/K+ ATPase current densities and Na+ extrusion rates were reduced by 13% and 19%, respectively, in parallel with a 17% increase in INa,L current densities in the ACOV group compared with the AC group. Conclusions: Long-term absence of ovarian hormones exacerbates the decline in cardiac function during the progression to HF. Estrogen supplementation reverses these aggravating effects.
Date Issued
2020-09
Date Acceptance
2020-06-23
ISSN
2452-302X
Publisher
Elsevier
Start Page
901
End Page
912
Journal / Book Title
JACC: Basic to Translational Science
Volume
5
Issue
9
Copyright Statement
© 2020 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICANCOLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDERTHE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Sponsor
British Heart Foundation
British Heart Foundation
Identifier
https://www.sciencedirect.com/science/article/pii/S2452302X20303041?via%3Dihub
Grant Number
SP/16/2/32004
FS/17/73/33186
Subjects
AC, aortic constriction
ACOV+E, aortic constriction with ovariectomy, supplemented with 17β-estradiol
ACOV, aortic constriction with ovariectomy
FS, fractional shortening
ICa, l-type Ca2+ channel current (cadmium-sensitive)
INa,L, late Na+ current (ranolazine-sensitive)
NCX, Na+/Ca2+ exchange
OV, ovariectomy
SERCA, Sarco/endoplasmic reticulum Ca2+-ATPase
SR, sarcoplasmic reticulum
calcium regulation
cardiomyocytes
estrogen
excitation-contraction coupling
female
heart failure
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
Publication Status
Published
Date Publish Online
2020-09-02