Clinical factors, such as obesity, hypertension, diabetes, coronary artery disease, and aging, contribute to AF risk. These comorbidities all represent states of elevated oxidative stress and inflammation, but clinical trials of antioxidants have not prevented AF. We present here, and in the Murray Basic Project, strong evidence implicating the generation of highly reactive lipid metabolites during oxidative stress as a driver for AF, and identify small molecules interfering with this pathway that, in multiple experimental settings, prevent AF. Vanderbilt has for decades been an international center of excellence in eicosanoid biology, identifying pathways of lipid metabolism contributing to diverse human disease. Work here identified highly reactive metabolites, isolevuglandins (isoLGs), generated by peroxidation of arachidonic acid during oxidative stress. IsoLGs avidly bind to macromolecules leading to cell death, and small molecules have been developed that rapidly 'scavenge' IsoLGs and thereby prevent tissue injury. The best studied scavenger is 2-hyroxylbenzamine (2-HOBA), and work in the Murray Basic Project has demonstrated that experimental models of hypertension, obesity, and inflammation are accompanied by high levels of isoLG adducts and inducible AF, and both are inhibited by 2-HOBA. A Phase I trial of 2-HOBA has shown no adverse effects, and therefore we propose here a first-in-AF clinical trial to test 2-HOBA as a treatment for AF. To study a population enriched for oxidative-stress mediated AF, we have selected patients undergoing AF ablation. Ablation reduces AF in the long term, but immediately following the procedure, the inflammation generated by extensive atrial tissue injury leads to elevation of isoLG adducts and recurrence of AF in 50% of patients within 30 days. Therefore, we propose to test the hypothesis that treatment with 2-HOBA reduces early recurrence of AF (clinical endpoint, Aim 1) and circulating levels of IsoLG-adducts (biochemical endpoint, Aim 2) in patients undergoing AF ablation. Aim 3 builds on the recent observation that PITX2, a gene strongly associated with AF risk, generates an anti-oxidant program after myocardial injury. Accordingly, we will explore whether genetic variation at the 4q25/PITX2 locus modulates response to 2-HOBA. These studies will support the advancement of IsoLG scavengers such as 2-HOBA as a new treatment for AF that targets a major common mechanism, inflammation and oxidative stress.
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2018 → 06/30/2022|