Atrial fibrillation (AF) represents one of the most common arrhythmias clinically and is associated with a significant increase in morbidity and mortality, yet, current treatment paradigms remain inadequate. Treatment with conventional antiarrhythmic drugs generally carries a high risk of proarrhythmia. Moreover, prevalence of AF is increasing due to the aging population. We were the first to demonstrate beneficial effects of a novel class of anti-inflammatory agent, soluble epoxide hydrolase (sEH) inhibitors, in clinically relevant models of cardiac hypertrophy and failure. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and MI models. During the last funding cycle, we demonstrate that treatment with sEHIs prevents cardiac fibroblast (CF) proliferation, fibrosis, adverse cardiac remodeling, and AF. These results demonstrate broader salutary effects in cardiac remodeling (not limited to myocyte hypertrophy alone) of this novel class of compounds. The goal of the competing renewal is to test the hypothesis that an increase in the level of endogenous EETs by sEHIs represents a completely unexplored avenue to modify atrial fibrosis by reducing CF proliferation and activation. The proposal represents a bench-to-bedside multidisciplinary study to determine the mechanism and efficacy of using sEHIs for the treatment of AF.
Atrial fibrillation (AF) represents one of the most common arrhythmias clinically and is associated with a significant increase in morbidity and mortality, yet, current treatment paradigms have proven largely inadequate. The goal of the current study is to test new upstream therapeutic targets to modify atrial fibrosis and electrical remodeling in AF.
|Yeo, Khung-Keong; Armstrong, Ehrin J; López, Javier E et al. (2018) Aspirin and clopidogrel high on-treatment platelet reactivity and genetic predictors in peripheral arterial disease. Catheter Cardiovasc Interv 91:1308-1317|
|Hegyi, Bence; Bossuyt, Julie; Griffiths, Leigh G et al. (2018) Complex electrophysiological remodeling in postinfarction ischemic heart failure. Proc Natl Acad Sci U S A 115:E3036-E3044|
|Zhang, Xiao-Dong; Coulibaly, Zana A; Chen, Wei Chun et al. (2018) Coupling of SK channels, L-type Ca2+ channels, and ryanodine receptors in cardiomyocytes. Sci Rep 8:4670|
|Gluck, Jessica M; Herren, Anthony W; Yechikov, Sergey et al. (2017) Biochemical and biomechanical properties of the pacemaking sinoatrial node extracellular matrix are distinct from contractile left ventricular matrix. PLoS One 12:e0185125|
|Frederich, Bert J; Timofeyev, Valeriy; Thai, Phung N et al. (2017) Electrotaxis of cardiac progenitor cells, cardiac fibroblasts, and induced pluripotent stem cell-derived cardiac progenitor cells requires serum and is directed via PI3'K pathways. Heart Rhythm 14:1685-1692|
|Sirish, Padmini; Ledford, Hannah A; Timofeyev, Valeriy et al. (2017) Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6. Circ Arrhythm Electrophysiol 10:|
|López, Javier E; Sharma, Janhavi; Avila, Jorge et al. (2017) Novel large-particle FACS purification of adult ventricular myocytes reveals accumulation of myosin and actin disproportionate to cell size and proteome in normal post-weaning development. J Mol Cell Cardiol 111:114-122|
|Zhang, Zheng; Ledford, Hannah A; Park, Seojin et al. (2017) Distinct subcellular mechanisms for the enhancement of the surface membrane expression of SK2 channel by its interacting proteins, ?-actinin2 and filamin A. J Physiol 595:2271-2284|
|Sirish, Padmini; Li, Ning; Timofeyev, Valeriy et al. (2016) Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. Circ Arrhythm Electrophysiol 9:|
|Awasthi, Samir; Izu, Leighton T; Mao, Ziliang et al. (2016) Multimodal SHG-2PF Imaging of Microdomain Ca2+-Contraction Coupling in Live Cardiac Myocytes. Circ Res 118:e19-28|
Showing the most recent 10 out of 67 publications