G. Bernasochi

Sex and sex hormones in cardiac stress—Mechanistic insights

Important sex differences in the onset and characteristics of cardiovascular disease are evident, yet the mechanistic details remain unresolved. Men are more susceptible to cardiovascular disease earlier in life, though younger women who have a cardiovascular event are more likely to experience adverse outcomes. Emerging evidence is prompting a re-examination of the conventional view that estrogen is protective and testosterone a liability. The heart expresses both androgen and estrogen receptors and is functionally responsive to circulating sex steroids. New evidence of cardiac aromatase expression indicates local estrogen production may also exert autocrine/paracrine actions in the heart. Cardiomyocyte contractility studies suggest testosterone and estrogen have contrasting inotropic actions, and modulate Ca(2+) handling and transient characteristics. Experimentally, sex differences are also evident in cardiac stress responses. Female hearts are generally less susceptible to acute ischemic damage and associated arrhythmias, and generally are more resistant to stress-induced hypertrophy and heart failure, attributed to the cardioprotective actions of estrogen. However, more recent data show that testosterone can also improve acute post-ischemic outcomes and facilitate myocardial function and survival in chronic post-infarction. The myocardial actions of sex steroids are complex and context dependent. A greater mechanistic understanding of the specific actions of systemic/local sex steroids in different cardiovascular disease states has potential to lead to the development of cardiac therapies targeted specifically for men and women.

Myocardial and Cardiomyocyte Stress Resilience Is Enhanced in Aromatase-Deficient Female Mouse Hearts Through CaMKIIδ Activation

The role of sex steroids in cardioprotection is contentious, with large clinical trials investigating hormone supplementation failing to deliver outcomes expected from observational studies. Mechanistic understanding of androgen/estrogen myocardial actions is lacking. Using a genetic model of aromatase tissue deficiency (ArKO) in female mice, the goal of this investigation was to evaluate the capacity of a shift in cardiac endogenous steroid conversion to influence ischemia-reperfusion resilience by optimizing cardiomyocyte Ca2+ handling responses. In isolated normoxic cardiomyocytes, basal Ca2+ transient amplitude and extent of shortening were greater in ArKO myocytes, with preservation of diastolic Ca2+ levels. Isolated ArKO cardiomyocytes exposed to a high Ca2+ load exhibited greater Ca2+ transient and contractile amplitudes, associated with a greater postrest spontaneous sarcoplasmic reticulum Ca2+ load-release. Microarray differential gene expression analysis of normoxic ventricular tissues from ArKO vs wild-type identified a significant influence of aromatase on genes involved in cardiac Ca2+ handling and signaling [including calmodulin dependent kinase II (CaMKII)-δ], myofilament structure and function, glucose uptake and signaling, and enzymes controlling phosphorylation-specific posttranslational modification status. CaMKII expression was not changed in ventricular tissues, although CaMKIIδ activation and phosphorylation of downstream targets was enhanced in ArKO hearts subjected to ischemia-reperfusion. Overall, this investigation shows that relative withdrawal of estrogen in favor of testosterone through genetically induced tissue aromatase deficiency in females modifies the gene expression profile to effect inotropic support via optimized Ca2+ handling in response to stress, with a modest impact on basal function. Consideration of aromatase inhibition, acutely or chronically, may have a role in cardioprotection, of particular relevance to women.

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

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 Womens 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.