(O-K3) Associations Between Sex Steroid Hormones and Cardiac Arrest Outcomes

Objectives: To characterize the temporal trajectories in sex steroids (estrogens [estrone and estradiol], progesterone, and testosterone) in the post-return of spontaneous circulation (ROSC) phase and determine associations with survival and neurological outcomes.

Background: Sudden cardiac arrest (SCA) is one of the leading causes of death in both males and females although females tend to have better outcomes. Despite previous work which has shown that biological sex dictates physiological and molecular processes in cardiovascular disease, there has been a paucity of research on understanding sex differences specifically in SCA. While sex steroids influence cardiovascular disease, and low level of testosterone and high level of estradiol in pre-clinical studies has been shown to be associated with the risk of SCA, little is known about their changes after a cardiac arrest, and their association to outcomes.

Methods: Under an approved IRB protocol, patients greater than 18 years of age, with a witnessed cardiac arrest and sustained ROSC were eligible to participate in the study. Post-ROSC plasma samples from SCA patients were collected between May 2018-March 2020 at four serial time points (0, 6, 24, 48h). Quantitative sex hormone analysis was performed using Liquid Chromatography Mass Spectroscopy (LCMS). Demographics, cardiac arrest characteristics, clinical data in the pre-hospital care and during hospital course were also collected. Baseline and clinical characteristics were stratified by sex and presented using frequencies for categorical variables and means for continuous variables. Chi-square or fisher exact test was used to test differences for categorical variables while T-test was used for differences in continuous variables. Median and interquartile ranges were reported and differences between groups were determined using Wilcoxon rank sum test.Trends were examined for each sex hormone over the 48 hours and stratified by sex, survival, neurological recovery (cerebral performance category [CPC]), and rhythm type. A repeated measures analyses with Generalized Estimating Equation (GEE) models were used to determine the association between sex hormones and their ratios with outcomes, with p< 0.05 indicating significance.

Results: A total of 65 patients were included in the analyses, 33 (51%) men and 32 (49%) women, with 62.7% of women categorized as menopausal. There were no differences in demographic and clinical characteristics between males and females. Plasma estrone continued to rise across the 48 hours, and estradiol remained fairly flat across time, whereas progesterone and testosterone peaked at 6 hours. Estradiol at 24 hours and testosterone at all time points were higher in males compared to females, while progesterone trended higher in females but not significantly different from males. Survivors had lower concentrations of estradiol at 1 and 24 hours relative to non-survivors. Testosterone concentrations were lower in patients with good neurological recovery (CPC 1-2) at 1, 6, and 24 hours compared with those with poor neurological recovery (CPC 3-5). Similarly at 1 hour, testosterone concentration was lower in non-shockable compared to shockable rhythms. There was a trend towards a lower estradiol level predicting survival (β=-2.44, 95% CI= -5.09, 0.21, p=0.067) regardless of sex and after adjusting for sex, time, age (β=-13.80, 95% CI= -28.98, 1.38, p=0.075). Females were associated with better neurological recovery compared to males with or without adjusting for estrone (β= 1.67, 95% CI=0.12, 3.21), estradiol (β= 1.63, 95% CI=0.11, 3.15), or progesterone (β= 1.80, 95% CI=0.23, 3.38) but not testosterone (β= 1.19, 95% CI=-0.45, 2.82). An increase in T/E2 ratio was also associated with good neurological outcome in males (β= 0.03, 95% CI=0.002, 0.066) but not in females (β= -0.01, 95% CI= 0.03, -0.67).

Conclusions: Our study reveals that lower level of hormones, especially estradiol, may indicate survival from OHCA. Sex differences may be more evident for estradiol and testosterone concentrations but not estrone and progesterone in the first 48 hours after ROSC. Females may have good neurological recovery over 48 hours compared to male irrespective of hormonal level.

Funding (Optional): Primary author acknowledges support from the UIC Building Interdisciplinary Research Careers in Women's Health (BIRCWH) Grant K12HD101373 from the National Institutes of Health (NIH) Office of Research on Women’s Health (ORWH). Primary author also acknowledges funding from Zoll Foundation grant