Atrial fibrillation (AF) is the most common cardiac arrhythmia of clinical significance, and it often results in devastating outcomes. Current treatment is often ineffective, and there is a critical need for an improved understanding of the molecular mechanisms causing AF and novel strategies to treat it. Abundant evidence links oxidative stress and reactive oxygen species (ROS) to the pathogenesis and progression of AF, including increased risk during inflammation. The strongest genetic risk factors are chromosome 4q25 variants near PITX2, now recognized to encode an antioxidant stress response. Nonetheless, upstream therapy to target oxidative stress has been ineffective. Reactive lipid peroxidation metabolites are a major component of ROS-related injury, and the most reactive products generated, dicarbonyl compounds known as isolevuglandins (IsoLGs), react almost instantaneously with proteins to induce multiple effects that drive disease. The overarching hypothesis of this project is that these reactive lipid metabolites are the principal drivers of oxidative injury in AF, making them potential therapeutic targets. Dicarbonyl scavengers have been identified that preemptively bind IsoLGs before they can interact with biologic targets; the best studied scavenger is 2-hydroxybenzylamine or 2-HOBA. We have accumulated compelling evidence that IsoLGs play a critical role in the pathogenesis of AF: they are formed in in vitro and in vivo models associated with AF susceptibility, including rapidly-stimulated atrial cells, and mice with hypertension, obesity, or familial AF; and 2-HOBA reduces isoLG adducts and AF inducibility. In Aim 1, we will test the hypothesis that inflammation promotes AF susceptibility due to generation of atrial IsoLGs. The model we will use is mice lacking the lymphocyte adaptor protein LNK, in which inflammation, oxidative stress, and inducible AF are enhanced. In Aim 2, we will test the hypothesis that a major driver for AF susceptibility due to Pitx2 loss of function is increased ROS and IsoLG production, and this is enhanced by the common AF risk factors of hypertension, obesity, and inflammation. By scavenging dicarbonyls preemptively, 2-HOBA provides a novel tool to strengthen the hypothesis that dicarbonyls contribute to the pathogenesis of AF. Importantly, dicarbonyl scavengers represent a potential paradigm shift in the pharmacologic strategy for the prevention of AF by blocking its pathogenesis.
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2018 → 06/30/2022|