Grant: CIHR Fellowship

Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide and is associated with increased morbidity, mortality, and socio-economic burden. AF affects 1-2% of the general population and with an incidence expected to double by 2060. While AF is tightly linked to aging and cardiovascular (CV) disease (i.e., heart failure, valve disease), its origins are complex, but are fundamentally linked to altered structural and/or electrical remodeling of the atria. Importantly, most conditions linked to AF are associated with elevated atrial pressures and atrial stretch, which is a powerful stimulus for adverse atrial remodeling. It is well-established that the pro-inflammatory and mechanosensitive cytokine tumor necrosis factor alpha (TNFa) is a critical factor in cardiac remodeling, fibrosis, arrhythmias, and inflammation seen in heart disease as well as athletes with AF, and an enhanced inflammatory response is typically observed in AF patients. While previous work from our group established the requirement of TNFa in exercise-induced adverse atrial remodeling and AF vulnerability in mice, the overlap in pathways mediating arrhythmogenesis in exercise and CV disease is undeniable. My research seeks to translate our exercise findings to more clinically-relevant models of heart disease, including a mouse model of aortic regurgitation (AR), which is characterized by cardiac volume overload, dilatation, elevated atrial pressures, fibrosis, and AF. As AR patients have one of the highest risks of AF, AR offers a clinically-relevant model to study atrial stretch-dependent TNFa-mediated AF pathogenesis. This mechanistic link will be assessed by: 1) assessing the molecular and cellular basis for TNFa-mediated adverse atrial remodeling in CV disease; 2) identifying novel pathways involved in the TNFa-dependent differential effects of AR on the atria with a goal towards developing novel interventions; and 3) translating our findings to CV patients.