title: Methodological approaches in the investigation of sex &amp; gender in cardiovascular disease
Creators: name: Connelly, Paul James
Publisher: name: University of Glasgow
Year: 2024

description: Background: Differences exist in the presentation, pathophysiology, management, and outcomes of cardiovascular conditions in men and women. These differences may arise from sex-dependent factors such as chromosomal complement, regulation of sex hormones, and sex-specific factors like pregnancy. Beyond sex, gender, a multifaceted psychosocial concept, also has an impact on cardiovascular health and disease. Transgender individuals experience incongruence between the sex they were assigned at birth and their gender identity. These individuals may engage with gender-affirming hormone therapy (GAHT), such as oestrogen or testosterone, and the effects of such treatments upon cardiovascular health have yet to be determined, and may provide insight into cardiovascular pathophysiology. 

Aims: This thesis aims to enhance our understanding of the role of sex and gender in cardiovascular disease, including transgender cardiovascular health, through a range of methodological approaches. 

Methods: Chapter 3) A systematic review assessing the influence of GAHT upon the blood pressure of transgender individuals is undertaken; Chapter 4) The Gender and Sex Determinants of Cardiovascular Disease: From Bench to BeyondPremature Acute Coronary Syndrome (GENESIS-PRAXY) gender stratification questionnaire is adapted and applied to a UK sample of cisgender individuals (n=446) to construct a gender score via principal component analysis (PCA); Chapter 5) A bioinformatic analysis of sex and gender stratified differentially expressed microRNA (miRNAs) in human plasma of individuals (n=36), derived from the original GENESIS-PRAXY study, who have experienced acute coronary syndrome (ACS) is undertaken; Chapter 6) A descriptive analysis of the Vascular Effects of Sex Steroids in Transgender Adults (VESSEL) study, which utilises a range of vascular phenotyping procedures (e.g. flow-mediated dilatation, peripheral artery tonometry, and pulse wave analysis (PWA) and velocity (PWV)) in transgender individuals using long-term GAHT compared to cisgender individuals is presented. 

Results: Chapter 3) The systematic review identified 14 studies including 1,309 transgender individuals, which demonstrated broadly no change in blood pressure in transmasculine individuals using testosterone. Both increases and decreases were observed within the transfeminine population using oestrogen therapy. These studies were of limited quality due to their uncontrolled pre-post design, lack of intervention and blood pressure measurement standardisation, inadequate follow up and small sample sizes; Chapter 4) The gender stratification analysis demonstrated a continuum of gender scores in this population derived from five gender-related questionnaire instruments. Gender score distributions were distinct from the GENESIS-PRAXY analysis, highlighting that gender and its related factors are dynamic and context dependent; Chapter 5) miR-664a-5p, miR-36135p, miR-382-5p, miR-134-5p, miR-10b-5p, miR-885-5p, miR-206, and miR-32-5p were found to be differentially expressed in females versus males in ACS. Many of these miRNA and associated gene networks demonstrate a number of roles important to ACS pathophysiology including the regulation of vascular smooth muscle cell proliferation, endothelial injury and inflammation, atherosclerosis progression. miR-3605-5p and miR-4467 were differentially expressed in males with feminine versus masculine gender characteristics; Chapter 6) Due to the impact of coronavirus disease 2019 (COVID-19), the VESSEL study was discontinued prematurely, however, the feasibility of local recruitment of transgender participants is demonstrated. 

Discussion: This thesis expands our appreciation of the means by which gender can be measured and its potential influence, in addition to sex, upon epigenomic regulation in cardiovascular disease. Moreover, it improves our understanding of limitations and barriers in conducting research in transgender populations. Overall, this thesis provides valuable insight into the methodological approaches used the investigation of sex and gender in cardiovascular disease, which can be applied in future cardiovascular research in cisgender and transgender populations.