Mechanisms of sex differences in atrial fibrillation: role of hormones and differences in electrophysiology, structure, function, and remodelling

Odening, Katja E.; Deiß, Sebastian; Dilling-Boer, Dagmara; Didenko, Maxim; Eriksson, Urs; Nedios, Sotirios; Ng, Fu Siong; Roca‐Luque, Ivo; Borque, Pepa Sánchez; Vernooy, Kevin; Wijnmaalen, Adrianus P.; Yorgun, Hikmet

doi:10.1093/europace/euy215

Cited by 88 publications

(66 citation statements)

References 144 publications

(138 reference statements)

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“…Moreover, the peaked levels of 2hG and 3hG at range of 81~90 ages suggested that glucose loading duration was prolonged by aging. Interestingly, men had a higher 2hG than women did, which is consistent with the gender difference of AF incidence [33]. Previous study had shown excess LPS led to age-associated hyperglycemia by inducing mitochondrial dysfunction, cellular senescence and adipose tissue dysfunction [45].…”

Section: Discussionsupporting

confidence: 80%

“…Moreover, the peak glucose levels ( Figure 6B) and 2hG levels (Additional File 1:FigureS6A) in responding to OGTT were also progressively higher with aging. Interestingly, 2hG levels rise with increasing ages in both sexes, reaching higher levels in the men than women with same age (Additional File 1:FigureS6B), which is consistent with the gender difference of AF incidence [33]. The similar trend of aging phenotype still exists in DM and NDM patients, but 2hG levels were always higher in DM than NDM (Additional File 1:FigureS6C).…”

Section: Lps and Excess Glucose Synergistically Enhanced Nlrp3-in Ammsupporting

confidence: 75%

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Age-Related Changes in the Gut Microbiota Promote Atrial Fibrillation

Zhang¹,

Zhang²,

Luo³

et al. 2020

Preprint

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Background: Aging is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-associated diseases. However, whether age-associated gut microbial dysbiosis contributes to AF is still unknown. The aim of this study was to evaluate the effect of gut microbiota on the susceptibility of aging-induced AF and to elucidate the underlying mechanisms. Results: The gut microbiota profiling of fecal samples in aged (22-24 months old) and young (2-3 months old) rats was performed by 16S ribosomal RNA gene analysis. A rat model of fecal microbiota transplantation (FMT) was established for analyzing the possible role of age-associated gut microbial dysbiosis in AF. Here, we found that aging process led to marked shift of the microbiota spectrum. The microbiota in young rats following FMT resembled that of aged microbiota and transmitted the increased AF susceptibility by elevation of circulating lipopolysaccharide (LPS). The mechanism for LPS-driven atrial pro-arrhythmic action was dependent on the activation of atrial nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing (NLRP3)-inflammasome. Inhibition of inflammasome by MCC950 resulted in lower atrial fibrosis and AF susceptibility. In addition, atrial fibrosis, plasma LPS concentration, plasma glucose to oral glucose tolerance test (OGTT), intestinal permeability, and gut pathology were significantly increased in elderly human subjects. Finally, altering the microbiota in aged recipient to resemble that of young restored the intestinal barrier dysfunction and LPS and impaired glucose tolerance, and the worse outcomes of aged dysbiosis on atrial fibrosis and AF susceptibility were abrogated. Conclusions: These data suggest that age-associated microbial dysbiosis induces circulating LPS and impairs glucose tolerance, and thereby promotes AF susceptibility through enhanced activity of atrial NLRP3-inflammasome.

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Section: Discussionsupporting

confidence: 80%

Section: Lps and Excess Glucose Synergistically Enhanced Nlrp3-in Ammsupporting

confidence: 75%

Age-Related Changes in the Gut Microbiota Promote Atrial Fibrillation

Zhang¹,

Zhang²,

Luo³

et al. 2020

Preprint

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“…According to a 2019 update article from the American Heart Association, almost one in three adult men have some type of cardiovascular disease (10). Women are known to suffer cardiac disease 10-20 years later than men, which supports the hypothesis that physiological estrogen levels confer cardioprotective effects (11)(12)(13)(14). In the past decades, the effect of sex-related steroid hormones on the cardiovascular system has been predominantly focused on estrogen actions, whereas research concerning the beneficial cardiac effects of androgens has been limited.…”

Section: Introductionmentioning

confidence: 91%

Androgen-Regulated Cardiac Metabolism in Aging Men

2020

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The prevalence of cardiovascular mortality is higher in men than in age-matched premenopausal women. Gender differences are linked to circulating sex-related steroid hormone levels and their cardio-specific actions, which are critical factors involved in the prevalence and features of age-associated cardiovascular disease. In women, estrogens have been described as cardioprotective agents, while in men, testosterone is the main sex steroid hormone. The effects of testosterone as a metabolic regulator and cardioprotective agent in aging men are poorly understood. With advancing age, testosterone levels gradually decrease in men, an effect associated with increasing fat mass, decrease in lean body mass, dyslipidemia, insulin resistance and adjustment in energy substrate metabolism. Aging is associated with a decline in metabolism, characterized by modifications in cardiac function, excitation-contraction coupling, and lower efficacy to generate energy. Testosterone deficiency-as found in elderly men-rapidly becomes an epidemic condition, associated with prominent cardiometabolic disorders. Therefore, it is highly probable that senior men showing low testosterone levels will display symptoms of androgen deficiency, presenting an unfavorable metabolic profile and increased cardiovascular risk. Moreover, recent reports establish that testosterone replacement improves cardiomyocyte bioenergetics, increases glucose metabolism and reduces insulin resistance in elderly men. Thus, testosterone-related metabolic signaling and gene expression may constitute relevant therapeutic target for preventing, or treating, age-and gender-related cardiometabolic diseases in men. Here, we will discuss the impact of current evidence showing how cardiac metabolism is regulated by androgen levels in aging men.

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“…Nevertheless, a better understanding of the modifiable biomarkers, including an altered thyroid status, and molecular factors, including autoantibodies, may provide us with a chance to prevent AF or to tailor the treatment to avoid harmful consequences. It is noteworthy that women have worse and often atypical symptoms, as well as a higher risk for stroke and death, associated with AF compared to the risk in men [61].…”

Section: A Short Overview On Afmentioning

confidence: 99%

Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism

Tribulová

Kurahara

Hlivák

et al. 2020

IJMS

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A perennial task is to prevent the occurrence and/or recurrence of most frequent or life-threatening cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF). VF may be lethal in cases without an implantable cardioverter defibrillator or with failure of this device. Incidences of AF, even the asymptomatic ones, jeopardize the patient’s life due to its complication, notably the high risk of embolic stroke. Therefore, there has been a growing interest in subclinical AF screening and searching for novel electrophysiological and molecular markers. Considering the worldwide increase in cases of thyroid dysfunction and diseases, including thyroid carcinoma, we aimed to explore the implication of thyroid hormones in pro-arrhythmic signaling in the pathophysiological setting. The present review provides updated information about the impact of altered thyroid status on both the occurrence and recurrence of cardiac arrhythmias, predominantly AF. Moreover, it emphasizes the importance of both thyroid status monitoring and AF screening in the general population, as well as in patients with thyroid dysfunction and malignancies. Real-world data on early AF identification in relation to thyroid function are scarce. Even though symptomatic AF is rare in patients with thyroid malignancies, who are under thyroid suppressive therapy, clinicians should be aware of potential interaction with asymptomatic AF. It may prevent adverse consequences and improve the quality of life. This issue may be challenging for an updated registry of AF in clinical practice. Thyroid hormones should be considered a biomarker for cardiac arrhythmias screening and their tailored management because of their multifaceted cellular actions.

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Mechanisms of sex differences in atrial fibrillation: role of hormones and differences in electrophysiology, structure, function, and remodelling

Cited by 88 publications

References 144 publications

Age-Related Changes in the Gut Microbiota Promote Atrial Fibrillation

Age-Related Changes in the Gut Microbiota Promote Atrial Fibrillation

Androgen-Regulated Cardiac Metabolism in Aging Men

Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism

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