The role of 17β-estradiol and estrogen receptors in regulation of Ca(2+) channels and mitochondrial function in cardiomyocytes

Numerous epidemiological, clinical, and animal studies showed that cardiac function and manifestation of cardiovascular diseases (CVDs) are different between males and females. The underlying reasons for these sex differences are definitely multifactorial, but major evidence points to a causal role of the sex steroid hormone 17β-estradiol (E2) and its receptors (ER) in the physiology and pathophysiology of the heart. Interestingly, it has been shown that cardiac calcium (Ca(2+)) ion channels and mitochondrial function are regulated in a sex-specific manner. Accurate mitochondrial function and Ca(2+) signaling are of utmost importance for adequate heart function and crucial to maintaining the cardiovascular health. Due to the highly sensitive nature of these processes in the heart, this review article highlights the current knowledge regarding sex dimorphisms in the heart implicating the importance of E2 and ERs in the regulation of cardiac mitochondrial function and Ca(2+) ion channels, thus the contractility. In particular, we provide an overview of in-vitro and in-vivo studies using either E2 deficiency; ER deficiency or selective ER activation, which suggest that E2 and ERs are strongly involved in these processes. In this context, this review also discusses the divergent E2-responses resulting from the activation of different ER subtypes in these processes. Detailed understanding of the E2 and ER-mediated molecular and cellular mechanisms in the heart under physiological and pathological conditions may help to design more specifically targeted drugs for the management of CVDs in men and women

Socioeconomic status and adverse birth outcomes: a population-based Canadian sample

This study assessed the strength of the association between socioeconomic status (SES) and low birth weight (LBW) and preterm birth (PTB) in Southwestern Ontario. Utilizing perinatal and neonatal databases at the London Health Science Centre, maternal postal codes were entered into a Geographic Information System to determine home neighbourhoods. Neighbourhoods were defined by dissemination areas (DAs). Median household income for each DA was extracted from the latest Canadian Census and linked to each mother. All singleton infants born between February 2009 and February 2014 were included. Of 26,654 live singleton births, 6.4% were LBW and 9.7% were PTB. Top risk factors for LBW were: maternal amphetamine use, chronic hypertension and maternal marijuana use (OR respectively: 17.51, 3.18, 2.72); previously diagnosed diabetes, maternal narcotic use and insulin-controlled gestational diabetes predicted PTB (OR respectively: 17.95, 2.69, 2.42). Overall, SES had little impact on adverse birth outcomes, although low maternal education increased the likelihood of a LBW neonate (OR: 1.01)

Cardiomyocyte-specific estrogen receptor alpha increases angiogenesis, lymphangiogenesis and reduces fibrosis in the female mouse heart post-myocardial infarction

Experimental studies showed that 17{beta}-estradiol (E2) and activated Estrogen Receptors (ER) protect the heart from ischemic injury. However, the underlying molecular mechanisms are not well understood. To investigate the role of ER{alpha} in cardiomyocytes in the setting of myocardial ischemia, we generated transgenic mice with cardiomyocyte-specific overexpression of ER-{alpha} (ER{alpha}-OE) and subjected them to Myocardial Infarction (MI). At the basal level, female and male ER{alpha}-OE mice showed increased Left Ventricular (LV) mass, LV volume and cardiomyocyte length. Two weeks after MI, LV volume was significantly increased and LV wall thickness decreased in female and male WT-mice and male ER{alpha}-OE, but not in female ER{alpha}-OE mice. ER{alpha}-OE enhanced expression of angiogenesis and lymphangiogenesis markers (Vegf, Lyve-1), and neovascularization in the peri-infarct area in both sexes. However, attenuated level of fibrosis and higher phosphorylation of JNK signaling pathway could be detected only in female ER{alpha}-OE after MI. In conclusion, our study indicates that ER{alpha} protects female mouse cardiomyocytes from the sequelae of ischemia through induction of neovascularization in a paracrine fashion and impaired fibrosis, which together may contribute to the attenuation of cardiac remodelling

Sex-dependent regulation of fibrosis and inflammation in human left ventricular remodelling under pressure overload

AIMS: Women with aortic stenosis develop a more concentric form of LV hypertrophy than men. However, the molecular factors underlying sex differences in LV remodelling are incompletely understood. We took an unbiased approach to identify sex-specific patterns in gene expression and pathway regulation, and confirmed the most prominent findings in human hearts. METHODS AND RESULTS: Echocardiography was performed in 104 patients (53.8% women) with aortic stenosis before aortic valve replacement. LV mass, LV end-diastolic diameter, and relative wall thickness were included in a factor analysis to generate an index classifying LV remodelling as adaptive or maladaptive. Maladaptive remodelling was present in 64.6% of male and in 32.7% of female patients (P < 0.01). Genome-wide expression profiling of LV samples was performed in a representative subgroup of 19 patients (52.6% women) compared with samples from healthy controls (n = 18). Transcriptome characterization revealed that fibrosis-related genes/pathways were induced in male overloaded ventricles, while extracellular matrix-related and inflammatory genes/pathways were repressed in female overloaded ventricles (adjusted P < 0.05). We confirmed gene regulation by quantitative real-time reverse transcription-polymerase chain reaction and immunoblotting analysis, and we further demonstrate the relevance of our findings by histological documentation of higher fibrosis in men than in women. CONCLUSION: We conclude that in pressure overload distinct molecular processes are regulated between men and women. Maladaptive LV remodelling occurs more frequently in men and is associated with greater activation of profibrotic and inflammatory markers. Collectively, sex-specific regulation of these processes may contribute to sex differences in the progression to heart failure

Factors that influence excessive gestational weight gain: Moving beyond assessment and counselling

One in four Canadian adults is obese, and more women are entering pregnancy with a higher body mass index (BMI) than in the past. Pregnant women who are overweight or obese have a higher risk of pregnancy-related complications than women of normal weight. Gestational weight gain (GWG) is also associated with childhood obesity. Although the factors influencing weight gain during pregnancy are multifaceted, little is known about the social inequality of GWG. This review will address some of the socioeconomic factors and maternal characteristics influencing weight gain and the impact that excessive GWG has on health outcomes such as post-partum weight retention. The effects of an overweight or obese pre-pregnancy BMI on GWG and neonatal outcomes will also be addressed. The timing of weight gain is also important, as recommendations now include trimester-specific guidelines. While not conclusive, preliminary evidence suggests that excessive weight gain during the first trimester is most detrimental

Longer and better lives for patients with atrial fibrillation: the 9th AFNET/EHRA consensus conference.

AIMS: Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). METHODS AND RESULTS: Eighty-three international experts met in Münster for 2 days in September 2023. Key findings are as follows: (i) Active rhythm management should be part of the default initial treatment for all suitable patients with AF. (ii) Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes and also increases major but non-lethal bleeding. (iii) More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics, and imaging can support this. (iv) The presence of AF should trigger systematic workup and comprehensive treatment of concomitant cardiovascular conditions. (v) Machine learning algorithms have been used to improve detection or likely development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF. CONCLUSIONS: Patients with AF and a low arrhythmia burden have a lower risk of stroke and other cardiovascular events than those with a high arrhythmia burden. Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF

Targeted basic research to highlight the role of estrogen and estrogen receptors in the cardiovascular system

Epidemiological, clinical and animal studies revealed that sex differences exist in the manifestation and outcome of cardiovascular disease (CVD). The underlying molecular mechanisms implicated in these sex differences are not fully understood. The reasons for sex differences in CVD are definitely multifactorial, but major evidence points to the contribution of sex steroid hormone, 17β-estradiol (E2), and its receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). In this review, we summarize past and present studies that implicate E2 and ER as important determinants of sexual dimorphism in the physiology and pathophysiology of the heart. In particular, we give an overview of studies aimed to reveal the role of E2 and ER in the physiology of the observed sex differences in CVD using ER knock-out mice. Finally, we discuss recent findings from novel transgenic mouse models, which have provided new information on the sexual dimorphic roles of ER specifically in cardiomyocytes under pathological conditions

Effects of aging on cardiac extracellular matrix in men and women

PURPOSE: Aging has severe implications for tissue damage and is a major risk factor for disease. However, the effects of aging on cardiac extracellular matrix (ECM) components in individuals free of cardiovascular disease are incompletely understood. We aimed at the characterization of the effects of aging on major ECM proteins in the heart of men and women. EXPERIMENTAL DESIGN: Left ventricular (LV) samples of nondiseased human hearts technically unusable for transplantation obtained from general organ donors (n = 31; age 17-68 years; 48% women) were used for protein isolation. We separated the group into 17-40 years (n = 7 men and 7 women) and 50-68 years (n = 9 men and 8 women). RESULTS: Analysis of ECM proteins demonstrated an age-dependent sex-specific regulation of collagen type I and III (interaction p < 0.05), type VI (interaction p = 0.01), tissue inhibitor of metalloproteinase 3 (interaction p < 0.05), SMAD2 (interaction p < 0.05), and SMAD3 (interaction p = 0.001). Overall, the levels of these proteins in younger individuals were lower in women than men, while in older individuals they were higher in women than men. CONCLUSIONS AND CLINICAL RELEVANCE: This age-mediated myocardial ECM remodeling might play a key role in the limited ability of the aging heart to adapt adequately to altered work load and to respond to tissue damage. Therapeutic agents that target ECM homeostasis represent promising prevention strategies