Gender and cardiovascular disease: Are sex-biased miRNA networks a driving force behind heart failure with preserved ejection fraction in women?

Cardiovascular disease (CVD) is the primary cause of death among men and women worldwide. Nevertheless, our comprehension of how CVD progresses in women and elicits clinical outcomes is lacking, leading CVD to be under-diagnosed and under-treated in women. A clear example of this differential presentation of CVD pathophysiologies in females is the strikingly higher prevalence of heart failure with preserved ejection fraction (HFpEF). Women with a history of pre-eclampsia or those who present with co-morbidities such as obesity, hypertension, and diabetes mellitus are at increased risk of developing HFpEF. Long understood to be a critical CVD risk factor, our understanding of how gender differentially affects the development of CVD has been greatly expanded by extensive genomic and transcriptomic studies. These studies uncovered a pivotal role for differential microRNA (miRNA) expression in response to systemic inflammation, where their co-ordinated expression forms a post-transcriptional regulatory network that instigates microcirculation defects. Importantly, the potential sex-biased expression of the given miRNAs may explain sex-specific cardiovascular pathophysiologies in women, such as HFpEF. Sex-biased miRNAs are regulated by oestrogen (E2) in their transcription and processing or are expressed from loci on the X-chromosome due to incomplete X-chromosome inactivation. Interestingly, while E2-induced miRNAs predominantly appear to serve protective functions, it could be argued that many X-linked miRNAs have been found to challenge microvascular and myocardial integrity. Therefore, menopausal E2 deficiency, resulting in protective miRNA loss, and the augmentation of X-linked miRNA expression, may well contribute to the molecular mechanisms that underlie the female-specific cardiovascular aetiology in HFpEF.