On the Basis of Sex: The Role of Sex chromosomal complement in Atrial Fibrillation and Dementia

PROJECT SUMMARY/ ABSTRACT Age and female sex are independent risk factors for stroke and dementia due to atrial fibrillation. Why women are more susceptible to dementia when they have atrial fibrillation is unclear. This proposal aims to identify the underlying pathophysiology of atrial fibrillation that leads to dementia, in animals of both sexes. We will use four core genotype and wild type mice to study sex differences in atrial fibrillation related dementia. The four-core genotype mouse model will be used to dissect the role of sex hormones from that of the sex chromosomal complement. In this model, the testes determining gene, Sry, is present on autosome instead of being on the Y chromosome, therefore, we obtain the four core genotypes; XX and XY males and; XX and XY females. We will use state of the art mouse ambulatory electrocardiogram, trans-esophageal atrial pacing and optical mapping to detect sex differences in atrial fibrillation burden and cardiac electrophysiology. To study inflammation/fibrosis in the atrial substrate, we will use MRI, ELISA, immunohistochemistry and flow cytometry to quantify myeloid cells. We will assess sexual dimorphism in chronic atrial fibrillation induced inflammatory injury in the brain using MRI, behavioral tests, histology and flow cytometry (to assess microglia). These studies will help us identify XX/XY gene directed inflammatory pathways that may be important sex specific drug targets. Our study will also use aged mice with fibrin gene deletion, and wild-type mice treated with a pharmacological inhibitor of fibrosis. We will use Pirfenidone, (a drug that is currently approved for use in pulmonary fibrosis), to identify the complex sex specific role of atrial inflammation and fibrosis on atrial fibrillation burden and inflammation of the neurovascular unit which may lead to dementia. The ultimate goal of this study is to prevent the morbidity from atrial fibrillation related dementia in elderly women. Patients with atrial fibrillation use anticoagulants for stroke prevention, but those have a high bleeding risk, are incompletely protective and have unclear benefits on cognitive decline from atrial fibrillation. It is important to understand the contributions of sex chromosomal complement in the atrial fibrillation related heart brain axis, as this would assist in the development of new sex-specific atrial fibrillation and dementia preventative therapies.