Chronic Estrogen Supplementation Following Ovariectomy Improves the Emotional Stress-Induced Cardiovascular Responses by Indirect Action on the Nervous System and by Direct Action on the Heart

Abstract

he incidence of cardiovascular diseases is low in pre-menopausal women, whereas it is increased in post-menopausal women. Estrogen supplementation therapy prevented the increase of cardiovascular diseases in post-menopausal women, 1 while recent metaanalysis of randomized trials showed no significant merits. 2 Effects of estrogen on cardiovascular diseases were attributed principally to the modification of serum lipid concentration and coagulation pathways, while direct actions of estrogen on the cardiovascular system contributed substantially to the cardiovascular protective effects of estrogen because estrogen receptors (ER and ER ) are expressed in the blood vessels and in the heart. 3,4 Both ER and ER are also widely expressed in the central nervous system. 5 Estrogen plays crucial roles in sexual behavior, learning and memory processes, protection against ischemic insults and modulation of autonomic nervous function. 6 In fact, a reduction of estrogen levels following menopause might increase the vulnerability of women to stress while estrogen supplementation attenuates the exaggerated response to stress or to increased sympathoadrenal activity. 7 A unique form of acute cardiac attack called "takotsubo cardiomyopathy", or "transient left ventricular apical ballooning" similarly occurs predominantly in postmenopausal women in association with emotional or physical stress. [8][9][10][11][12][13][14] Although the etiology of this syndrome is yet to be clarified, an increase of serum norepinephrine, epinephrine and neuropeptide Y levels at the onset of takotsubo cardiomyopathy compared with acute myocardial infarction suggests that the exaggerated sympathoadrenal activation triggered by stress is the primary cause of this cardiomyopathy. 9,10 Immobilization stress (IMO) in the rat provides an excellent animal model of emotional stress, which activates the hypothalamic-pituitary-adrenocortical system and the sympathoadrenal system. 15 We have succeeded in developing a model of this clinical condition in rats. [16][17][18][19][20] The characteristic changes such as elevation of Circ J 2007; 71: 565 -573 (Received September 19, 2006; revised manuscript received January 9, 2007; accepted January 23, 2007 Background Takotsubo cardiomyopathy is triggered by emotional or physical stress especially in postmenopausal women. A reduction in estrogen levels following menopause might underlie the high incidence of takotsubo cardiomyopathy. Methods and ResultsThe left ventricular contraction between ovariectomized rats (OVX) and OVX with estrogen supplementation (OVX + E) while subjected to immobilization stress (IMO) was compared. The IMO in combination with general anesthesia impaired the left ventricular contraction in both OVX and OVX + E. Estrogen supplementation tended to improve the IMO-induced cardiac dysfunction and significantly attenuated the increase of blood pressure and heart rate. To understand the protective mechanism of estrogen, the expression of c-fos mRNA, a marker of cellular activation was compared. ...

Protective Effects of Estrogen Against Reperfusion Arrhythmias Following Severe Myocardial Ischemia in Rats

“…19 Accumulating experimental and clinical evidence indicates that estrogens are actively involved in protecting the cardiovascular system against ischemic injury and RA. 6,8,20, 21 Although the biological effects of estrogen are less well defined in males than in females, a growing body of clinical evidence demonstrates that endogenous estrogen may protect cardiovascular health not only in female but also in male patients. 7,8 Therefore, understanding the pathophysiological mechanism of RA and how sex hormones protect the heart against RA is important not only for the prevention and control of RA but also for estrogen replacement therapy.…”

Reversible Dilated Cardiomyopathy: Into the Thaumaturgy of the Heart—Part 1

“…Estrogen hormones appear to be clearly protective in animal models, while the cardiodepressive effects of cathecolamine-excess are exacerbated in ovariectomized animals. 33 Myocytes express alpha and beta estrogen receptors. Estrogens increase production of cardioprotective factors such as AN, heat shock proteins, and protect the heart from toxic effects of catecholamine, calcium overload and oxidative stress.…”

Stress-Induced Cardiomyopathy: Clinical Observations

“…This strong female predominance has been strongly associated with estrogen deficiency. Indeed, ovariectomised rats without estradiol supplementation exposed to immobilization stress had reduced left ventricular systolic function and increased heart rate and blood pressure in comparison with rats that were supplemented with estradiol (Ueyama et al, 2007). They also demonstrated that chronic supplementation with estrogen attenuated stress-induced sympatho-adrenal outflow from the brain to the heart (indirect action on the nervous system) and upregulated cardioprotective substances such as atrial natriuretic peptide and heat shock protein 70 in the heart (direct action on the heart).…”