Role of estrogen in diastolic dysfunction

Abstract

The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure. While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science have implicated activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue ANG II and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces ROS that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen-insufficient or -deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence showing that estrogen modulates the tissue RAAS and NOS system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 (GPR30; also called G protein-coupled estrogen receptor 1). Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD as well as inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS system, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic heart failure that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications.

Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality

“…Within the same population, there was evidence for increased risk of hypertension, abdominal obesity and high glucose levels, in postmenopausal women; however, risk did not vary with duration since menopause. Conversely, no increased risk of obesity, hypertension or diabetes was found in Chinese women who were more than 2 years post-menopause compared with women less than 1 year post-menopause 13 . Similarly, within the same study, systolic and diastolic blood pressure, BMI, WHR, and glucose levels did not vary with time since menopause.…”

“…The findings of these studies, therefore, were only qualitatively reviewed. In a Chinese population 13 , relative to women less than 1 year post menopause, women 2-6 years post menopause were at a greater risk of CVD, with evidence for an increased risk after 6 years. In the same study, there was also evidence for a greater risk of CHD and stroke more than 1 year post menopause.…”

“…Early loss of the ovarian function through menopause may lead to long term activation of the renin-angiotensinaldosterone system, leading to endothelial dysfunction, inflammation and immune dysfunction, and therefore causing vascular damage 13,18 . This process may be partially mediated via the membrane G protein-coupled estrogen receptor 13 . Also, menopause marks the start of a biological mechanism, led by hormonal changes, which causes tissue damage and organ dysfunction 10 .…”

“…In a health vessel, estrogens are involved in the relaxation and expansion of blood vessels, helping to accommodate blood flow, and consequently, decreased levels of oestrogen would result in stiffer blood vessels 12 . Furthermore, loss of the ovarian function through menopause is associated with the activation of the renin-angiotensinaldosterone system, leading to downstream endothelial dysfunction, inflammation and immune dysfunction 13 . These processes are associated with obesity, diabetes and hypertension 13 .…”

“…Furthermore, loss of the ovarian function through menopause is associated with the activation of the renin-angiotensinaldosterone system, leading to downstream endothelial dysfunction, inflammation and immune dysfunction 13 . These processes are associated with obesity, diabetes and hypertension 13 . Thus, early menopause has been hypothesized to be detrimental to cardiovascular health, due to the early cessation of the protective effect of endogenous oestrogen.…”