Sex Differences Following Cardiac Arrest: A Conceptual Framework for Mechanisms and Translational Targets

Biological sex is increasingly recognized as a fundamental variable in cardiovascular and cerebrovascular disease, yet its integration into our understanding of post-cardiac arrest brain injury (PCABI) pathophysiology remains limited. Although mortality following cardiac arrest remains universally high, males have a higher lifetime incidence while females experience disproportionately poor survival and neurological outcomes, particularly after menopause. Rather than a binary difference, evidence indicates three possible functionally distinct risk profiles: males with relatively stable neurological vulnerability across the lifespan, premenopausal females with apparent neuroprotection, and postmenopausal females at increased risk of neurological sequelae. Neurological injury is the primary determinant of survival and long-term function after cardiac arrest, yet mechanisms underlying sex differences in PCABI remain poorly defined. To address this, this review integrates clinical observations with experimental and translational evidence to develop a conceptual framework for hypothesis generation in sex-specific PCABI. We examine differences in arrest etiology, resuscitation, and post-resuscitation care, drawing on pathophysiological insights from myocardial infarction and ischemic stroke to contextualize PCABI-relevant pathways. Across the phases of ischemic depolarization, reperfusion repolarization, dysregulation, and recovery/repair, we synthesize biologically plausible mechanisms through which hormones, autonomic regulation, vascular reactivity, immune responses, and excitotoxic signaling may shape diverging patterns of injury and recovery. We identify key calls to action for research priorities and propose strategies to incorporate sex- and age-informed frameworks into PCABI research. Specifically, our calls to action will address the inclusion of sex and age-disaggregated analyses into research designs, develop generalizable and standardized assessments for hormonal status to assist with phenotyping and consider confounding by disparities in healthcare access or delivery between sexes. Treating sex as a primary biological variable, rather than a covariate or supplementary analysis, will be essential for advancing precision critical care and improving outcomes following cardiac arrest.