Short communication
Pericardial adipose and aromatase: A new translational target for aging, obesity and arrhythmogenesis?

https://doi.org/10.1016/j.yjmcc.2017.08.006Get rights and content

Highlights

  • Human atrial myocardial and pericardial adipose tissues express aromatase.

  • Capacity for local cardiac estrogen synthesis increases substantially in aged rodents.

  • Aging/adiposity identified as aromatase-associated arrhythmogenic predisposing factors

  • 17β-Estradiol exposure promotes atrial arrhythmic activity.

  • Potential new mechanistic paradigm for understanding sex steroids and cardiopathology

Abstract

A correlation exists between the extent of pericardial adipose and atrial fibrillation (AF) risk, though the underlying mechanisms remain unclear. Selected adipose depots express high levels of aromatase, capable of converting androgens to estrogens – no studies have investigated aromatase occurrence/expression regulation in pericardial adipose. The Women's Health Initiative reported that estrogen-only therapy in women elevated AF incidence, indicating augmented estrogenic influence may exacerbate cardiac vulnerability. The aim of this study was to identify the occurrence of pericardial adipose aromatase, evaluate the age- and sex-dependency of local cardiac steroid synthesis capacity and seek preliminary experimental evidence of a link between pericardial adipose aromatase capacity and arrhythmogenic vulnerability. Both human atrial appendage and epicardial adipose exhibited immunoblot aromatase expression. In rodents, myocardium and pericardial adipose aromatase expression increased > 20-fold relative to young controls. Comparing young, aged and aged-high fat diet animals, a significant positive correlation was determined between the total aromatase content of pericardial adipose and the occurrence/duration of triggered atrial arrhythmias. Incidence and duration of arrhythmias were increased in hearts perfused with 17β-estradiol. This study provides novel report of pericardial adipose aromatase expression. We show that aromatase expression is remarkably upregulated with aging, and aromatase estrogen conversion capacity significantly elevated with obesity-related cardiac adiposity. Our studies suggest an association between adiposity, aromatase estrogenic capacity and atrial arrhythmogenicity – additional investigation is required to establish causality. The potential impact of these findings may be considerable, and suggests that focus on local cardiac steroid conversion (rather than systemic levels) may yield translational outcomes.

Introduction

Adipose is a major endocrine organ which releases a range of bioactive agents [1].

Selected adipose depots have been established as sites of sex steroid metabolism [1]. Subcutaneous and visceral adipose express high levels of aromatase, capable of converting androgens to estrogens [1]. No studies to date have investigated aromatase occurrence or expression regulation in pericardial adipose. Aging and obesity are both associated with a marked increase in pericardial adipose deposition, and represent significant cardiac risk factors [2]. With ongoing rises in obesity rate and life expectancy, there is considerable interest in identifying the underlying cellular mechanisms by which pericardial adipose accumulation may exert pathogenic influence.

Clinically, a correlation between the extent of pericardial adipose (constituting both epicardial and paracardial) and atrial fibrillation (AF) risk has now been established [2]. AF is the most common sustained arrhythmia, and is particularly prevalent in the aged population [3]. Cather ablation procedures have been successful in treating paroxysmal AF, though high rates for repeat procedures highlight the necessity for new adjunct therapies or stand-alone preventative measures.

Investigations relating to adipose accumulation and AF have focused on the identification of pro-inflammatory and pro-fibrotic mediators produced by epicardial adipose [2]. These mediators have been proposed to exert paracrine actions on atrial myocardium, culminating in the fibrosis, scarring and conduction heterogeneity which contribute to the atrial structural substrate for AF [2]. Our contention is that, beyond adipokines, other adipocyte/myocyte-related metabolites may constitute important paracrine mediators. A possible role for regulated pericardial adipose aromatase modulation of local tissue steroid levels has not been previously considered – in physiological or pathophysiological settings. Similarly, the potential for pericardial adipose influence on AF induction risk through modulation of local estrogen synthetic capacity has not yet been explored.

Observational studies of cardiovascular disease have supported the conventional view of estrogen ‘protection’, yet clinical trial outcomes (including the Women's Health Initiative, WHI) have not demonstrated definitive benefit of estrogen supplementation and in some cases provided qualified evidence of increased risk [4]. The WHI reported that estrogen-only therapy in women elevated AF incidence through unknown mechanisms [5], indicating that augmented estrogenic influence may exacerbate cardiac vulnerability.

Experimentally, we and others have shown that in the heart, estrogens influence electromechanical properties, myocyte viability signaling and disease progression [6]. We have also previously identified aromatase expression in rodent ventricular tissues, and demonstrated that aromatase transgenic and knockout animals exhibit distinct cardiac phenotypes with differential arrhythmogenicity [7], [8].

These previous findings suggest the concept of a local cardiac androgen-estrogen system exerting an important role in cardiac disease etiology. Building on these earlier findings, we now report the expression of aromatase in both pericardial adipose and myocardium in human and rodents. We show that a substantial increase in the total aromatase capacity of pericardial adipose in hearts of aged and high-fat diet fed mice correlates with a heightened atrial arrhythmia vulnerability, and that acute 17β-estradiol treatment significantly augments incidence/duration of atrial arrhythmias.

Section snippets

Methods

A detailed methodology is available in the online supplement. Briefly, rodents were anesthetized with an intra-peritoneal injection of sodium pentobarbitone (70 mg/kg) and sodium heparin (200 IU/kg) prior to heart excision. Experiments were conducted and animals handled in the manner specified by the NHMRC/CSIRO/ACC Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (2013) and the EU Directive 2010/63/EU for animal experiments, with approval and oversight of the

Pericardial adipose – a depot of estrogen synthesis capacity in the heart

Aromatase protein expression was assessed in human and rodent myocardium and pericardial adipose by immunoblotting. Atrial appendage and pericardial adipose from coronary artery bypass graft patients expressed aromatase (Fig. 1A), indicating a capacity for these tissues to synthesise estrogens locally. Aromatase was also expressed in adult (8 week) rat myocardium (Fig. 1B; n = 5) and pericardial adipose (Fig. 1B; n = 6). Expression was consistently greater in females compared with males across all

Discussion

This Short communication delivers a number of new and potentially important findings, drawing on clinical and experimental investigations. We report the novel observation that human atrial myocardial and pericardial adipose tissues express aromatase and thus possess capacity for localised estrogen synthesis. Our data demonstrate that myocardial aromatase expression is developmentally and sex modulated, with levels in aged rodents very substantially increased (with female levels consistently

Conclusions

In summary, this study provides novel report of pericardial adipose aromatase expression – in both human and rodent. We show that aromatase expression is remarkably upregulated with aging (Fig. 1C), and that total aromatase estrogen conversion capacity is significantly elevated with obesity-related cardiac adiposity (Fig. 1F). Further, we explore an association between adiposity, aromatase estrogenic capacity and atrial arrhythmogenicity in the rodent ex vivo setting.

The potential impact of

Funding sources

Research support provided through National Health and Medical Research Councill (LMDD, SBH, JMK, JRB; #1099352), Australian Research Council (LMDD, LJP, MT; DP160102404) and Victorian Government Operational Infrastructure Support Program (ED). Fellowship support provided through National Health and Medical Research Council (ED; #550905).

Disclosures

None declared.

References (16)

There are more references available in the full text version of this article.

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LMDD and JRB contributed equally to this work.

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