Key result
Isoproterenol-induced ischemia drives ~124% higher mortality and worse systolic dysfunction in males versus females.
Why the study?
Previous studies highlighted sex hormone roles in cardioprotective pathways, but early sex-specific functional and proteomic changes following myocardial ischemia required investigation using an unbiased approach.
In a rat model of myocardial ischemia, males developed more pronounced systolic dysfunction while females developed more severe diastolic impairment, accompanied by sex-specific proteomic and hormonal alterations.
Early post-ischemic sex differences in rat cardiac function and proteomics; leaves open translation to human sex-specific interventions.
BACKGROUND: Reduced cardiovascular risk in premenopausal women has been the focus of research in recent decades. Previous hypothesis-driven experiments have highlighted the role of sex hormones on distinct inflammatory responses, mitochondrial proteins, extracellular remodeling and estrogen-mediated cardioprotective signaling pathways related to post-ischemic recovery, which were associated with better cardiac functional outcomes in females. We aimed to investigate the early, sex-specific functional and proteomic changes following myocardial ischemia in an unbiased approach. METHODS: Ischemia was induced in male (M-Isch) and female (F-Isch) rats with sc. injection of isoproterenol (85 mg/kg) daily for 2 days, while controls (M-Co, F-Co) received sc. saline solution. At 48 h after the first injection pressure-volume analysis was carried out to assess left ventricular function. FFPE tissue slides were scanned and analyzed digitally, while myocardial proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using isobaric labeling. Concentrations of circulating steroid hormones were measured with LC-MS/MS. Feature selection (PLS and PLS-DA) was used to examine associations among functional, proteomic and hormonal datasets. RESULTS: Induction of ischemia resulted in 38% vs 17% mortality in M-Isch and F-Isch respectively. The extent of ischemic damage to surviving rats was comparable between the sexes. Systolic dysfunction was more pronounced in males, while females developed a more severe impairment of diastolic function. 2224 proteins were quantified, with 520 showing sex-specific differential regulation. Our analysis identified transcriptional, cytoskeletal, contractile, and mitochondrial proteins, molecular chaperones and the extracellular matrix as sources of disparity between the sexes. Bioinformatics highlighted possible associations of estrogens and their metabolites with early functional and proteomic alterations. CONCLUSIONS: Our study has highlighted sex-specific alterations in systolic and diastolic function shortly after ischemia, and provided a comprehensive look at the underlying proteomic changes and the influence of estrogens and their metabolites. According to our bioinformatic analysis, inflammatory, mitochondrial, chaperone, cytoskeletal, extracellular and matricellular proteins are major sources of intersex disparity, and may be promising targets for early sex-specific pharmacologic interventions.
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Barta et al. (2021) studied Myocardial ischemia (n=53). Isoproterenol vs. Saline was evaluated on Mortality and left ventricular function. Isoproterenol-induced myocardial ischemia resulted in 38% mortality in males versus 17% in females, with males showing more pronounced systolic dysfunction and females exhibiting more severe diastolic impairment.
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