This SFRN node will build on extensive methods development and preliminary data to test the hypothesis that the principal mediators of oxidative stress injury in AF are reactive lipid species that can be targeted therapeutically. Decades of expertise in arachidonic acid metabolite pharmacology at Vanderbilt has identified biomarkers of oxidative stress (isoprostanes) and more recently has implicated isolevuglandins (isoLGs) as highly reactive lipid metabolites that cause tissue damage by generation of isoLG adducts with macromolecules (proteins, DNA). In mouse models of obesity and hypertension, we have shown elevated levels of isoLG-protein adducts and readily inducible AF, and both are inhibited by isoLG scavengers such as 2-hydroxybenzylamine (2-HOBA), but not by the inactive analog 4-HOBA. We propose 3 inter-related Projects that focus on the role of inflammation in AF, and a training core that builds on an environment of excellence in formal training programs in cardiovascular medicine and across the institution in basic, translational, and population science:1)Murray Basic Project: Reactive lipid metabolites as mediators of AF susceptibility in clinical and genetic risk models. We will build on preliminary data to establish the effects of 2- and 4-HOBA on isoLG adducts and AF inducibility in mice key AF risk factors, including inflammation and deficiency of Pitx2 (a gene implicated in AF risk and more recently as a regulator of an anti-oxidant gene program). 2)Michaud Clinical Project: A first-in-AF trial of a reactive lipid metabolite scavenger. We will extend hypothesis testing by conducting a clinical trial of 2-HOBA in patients undergoing AF ablation, assessing both circulating isoLG-adduct levels and early AF recurrence. 3)Roden Population Project: Identifying AF subtypes driven by inflammation. We will use novel association methods we have developed to examine the role of inflammatory markers in AF susceptibility across the whole AF population and targeted subsets. In the Clinical and Population Projects, and in the Training Program, we partner with investigators at Lipscomb University, a non-research-intensive institution with whom we have ongoing collaborations. We pride ourselves on a very strong commitment to and track record in collaborative science both within the institution and with others in national networks, and look forward to being productive members of this timely SFRN.
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2018 → 06/30/2022|