(P011) MECHANISMS OF SEXUAL DIMORPHISM IN CARDIOVASCULAR DISEASE: LITERATURE REVIEW AND PROPOSED FUTURE DIRECTIONS

Background: Numerous reports have described important sex-based differences in the clinical presentation and outcome of patients with heart disease. Trials are ongoing to further understand these observations and to evaluate various approaches towards their clinical management. However, an understanding of the basic mechanisms that result in the sexually dimorphic expression of cardiovascular disease remain lacking. To this end, we performed a narrative review of the literature to organize and describe these basic processes systematically.

METHODS AND RESULTS: A narrative review of the literature was performed by 2 independent investigators (SS & YL) searching electronic databases for studies on the pathophysiologic mechanisms of sex-specific differences in cardiac disease. Studies were included for review based on independent reviewer judgement and the aid of a senior investigator (ZL) if required. Findings from select studies were analyzed and included in the narrative review through a description of key findings alongside an interpretation of the results in relation to other studies and datasets included in the review. Overall, we found 2 overarching domains within the available data that described the mechanisms leading to sex-specific differences in cardiovascular disease: genetic and hormonal (Table 1). Genetic mechanisms sub-divided into sex chromosome-based differences and gene expression differences. The data for sex chromosome-based differences describe mechanisms of early cardiac development that modify the risk of downstream cardiac disease, based mainly on the pattern of X or Y chromosomes present. The evidence for gene expression differences describe patterns of sex-specific gene expression profiles that lead to differences in processes such as cardiac contractility, calcium handling, and electrophysiology that differentially predispose to cardiac disease based on sex. Moreover, we include data on hormonal mechanisms which include sex-specific differential activation of membrane-bound or nuclear receptors to influence cardiovascular risk across the lifespan as hormonal levels wax and wane with age, pharmacologic therapy (e.g. oral contraception), and non-cardiac conditions (e.g. hypogonadism in males and polycystic ovarian syndrome in females). Lastly, based on this review of the currently available literature, we propose future directions for investigation including applications for induced pluripotent stem cell technologies.

Conclusion: Review of the available evidence base suggests that mechanisms of sexual dimorphism in the manifestation of cardiovascular diseases are based largely on genetic and hormonal differences between sexes. These results can inform future research directions to further our understanding in this area and to drive improvements within the clinical management of patients with cardiac disease across the sexes.