Predominance of Heart Failure With Preserved Ejection Fraction in Postmenopausal Women: Intra- and Extra-Cardiomyocyte Maladaptive Alterations Scaffolded by Estrogen Deficiency

Abstract

Heart failure (HF) remains a public health concern as it is associated with high morbidity and death rates. In particular, heart failure with preserved ejection fraction (HFpEF) represents the dominant (>50%) form of HF and mostly occurring among postmenopausal women. Hence, the initiation and progression of the left ventricular diastolic dysfunctions (LVDD) (a typically clinical manifestation of HFpEF) in postmenopausal women have been attributed to estrogen deficiency and the loss of its residue cardioprotective effects. In this review, from a pathophysiological and immunological standpoint, we discuss the probable multiple pathomechanisms resulting in HFpEF, which are facilitated by estrogen deficiency. The initial discussions recap estrogen and estrogen receptors (ERs) and β-adrenergic receptors (βARs) signaling under physiological/pathological states to facilitate cardiac function/dysfunction, respectively. By reconciling these prior discussions, attempts were made to explain how the loss of estrogen facilitates the disruptions both ERs and βARs-mediated signaling responsible for; the modulation of intra-cardiomyocyte calcium homeostasis, maintenance of cardiomyocyte cytoskeletal and extracellular matrix, the adaptive regulation of coronary microvascular endothelial functions and myocardial inflammatory responses. By scaffolding the disruption of these crucial intra- and extra-cardiomyocyte physiological functions, estrogen deficiency has been demonstrated to cause LVDD and increase the incidence of HFpEF in postmenopausal women. Finally, updates on the advancements in treatment interventions for the prevention of HFpEF were highlighted.

ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress

“…However, elevated fibroblasts can result in fibroblast activation, both mechanically by altered activation patterns and chemically by inflammatory mediators ( Wang et al, 2002 ). Notably, elevated TNFα and IL-6 secretions from macrophages, T and B lymphocytes during chronic inflammation also contributes to the aggravation of cardiac fibrosis as these cytokines stimulate fibroblast proliferation, differentiation to myofibroblast, and their migration ( Wang et al, 2002 ; Adekunle et al, 2021 ). Also, TGF-β plays a vital role in ECM remodeling, cell mobility, and modulation of immune function.…”

“…It can exist in two main forms, namely, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) ( Van Linthout and Tschöpe, 2017 ; Adu-Amankwaah et al, 2021b ). HFpEF is accompanied by diastolic dysfunction characterized by impaired ventricle relaxation and filling, increased ventricle stiffness, and elevated filling pressure to respond to pressure overload ( Adekunle et al, 2021 ). On the flip side, HFrEF is associated with systolic dysfunction characterized by impaired left ventricular contractility, resulting in a reduced ejection fraction ( Tanai and Frantz, 2015 ).…”

The Role of Estrogens and Vitamin D in Cardiomyocyte Protection: A Female Perspective

“…Women are more frequently affected by hypertension (which likely contributes to the different left ventricular dysfunction and arterial stiffness) and are more prone to cardiometabolic syndrome (which exacerbates sex-related bias in cardiac disease occurrence) and disease sequelae, as addressed later in this manuscript. In particular, left ventricular diastolic dysfunction, the typical clinical presentation of HF with preserved ejection fraction (HFpEF) predominant in women, seems to be facilitated by estrogen deficiency, affecting intra-cellular calcium homeostasis, cyto-skeleton and extra-cellular matrix rearrangements [ 15 ].…”

A Systematic Review and Meta-Analysis of Phytoestrogen Protects Against Myocardial Ischemia/Reperfusion Injury: Pre-Clinical Evidence From Small Animal Studies

“…But this cardiovascular protection declines after menopause, with myocardial infarction being the primary cause of mortality in older women ( Wenger, 2016 ). Estrogen deficiency has been shown to play an important role in the development of cardiovascular diseases such as MIRI ( Deschamps et al, 2010 ; Sivasinprasasn et al, 2016 ), atherosclerosis ( Kassi et al, 2015 ; Hajializadeh and Khaksari, 2021 ), heart failure (( Hajializadeh and Khaksari, 2021 ), ( Adekunle et al, 2021 )), atrial fibrillation ( Bretler et al, 2012 ; Odening et al, 2019 ), hypertension ( Colafella and Denton, 2018 ; Srivaratharajah and Abramson, 2019 ), myocardial fibrosis ( Medzikovic et al, 2019 ), cardiac hypertrophy ( Hajializadeh and Khaksari, 2021 ), and Takotsubo syndrome ( Pelliccia et al, 2017 ). However, the use of estrogen or estrogen replacement therapy for an extended period can raise the risk of gynecological cancers ( Stevenson et al, 2009 ; Narod, 2011 ).…”