Atrial fibrillation (AF), an age-related cardiac arrhythmia, increases risk of stroke and death. AF can occur in the absence of structural heart disease, but is often associated with CAD, hypertension, and heart failure. Systemic inflammatory markers are elevated in AF patients, and tend to be more elevated in those with persistent than with paroxysmal AF. Inflammatory mechanisms promote atrial remodeling that increases AF persistence and risk of morbidity.
To evaluate AF mechanisms, we study the cellular, biochemical and histologic properties of atrial tissues from surgical patients and from experimental animal models. We study the expression and function of ion channels and other proteins that underlie atrial electrical activity, and evaluate the signaling pathways and genes that are altered in AF. As AF is a highly heritable but complex disease, expression array studies are combined with DNA SNP arrays and DNA/RNA sequencing to assess the impact of genetic variation on mRNA and protein expression. Imaging techniques are used to explore the distribution of inflammatory mediators, inflammatory cells, markers of oxidant stress, and the links to altered atrial architecture. Animal models are used to explore the impact of high rate electrical activity and inflammation.
The combination of approaches will help us to identify and evaluate novel pathways that promote AF and which may be targeted for intervention, in an effort to decrease its incidence and clinical impact.
Atrial fibrillation (AF) is a common age related arrhythmia that can cause shortness of breath, an irregular heart beat, stroke and heart failure. There are approximately 3 million Americans with AF at present, and the number affected is expected to increase to 12-15 million by 2050.
While not immediately life-threatening, AF is a significant medical and economic burden. With the expected rise in AF prevalence due to the aging of the population, efforts to slow the increase in AF are critically important.
Studies in our group are focused on determining the functional pathways by which genetic variations (single nucleotide polymorphisms, SNPs) lead to increased risk of AF. We are using state of the art tools and techniques to characterize how AF-related SNPs affect the expression of genes in human atrial tissues and in relevant preclinical studies.
We seek to identify the signaling pathways affected by these genes, in an effort to identify novel targets for pharmacologic intervention that can help to slow the progression of AF and/or decrease its burden.
Selected recent publications:
K Kusunose, Y Zhang, TN Mazgalev, DR Van Wagoner, JD Thomas, ZB Popovic. Impact of Vagal Nerve Stimulation on Left Atrial Structure and Function in a Canine High-Rate Pacing Model. Circ. Heart Fail., 2014. PMID:24397925
N. Rozmaritsa, T. Christ, D. R. Van Wagoner, H. Haase, J. P. Stasch, K. Matschke, and U. Ravens. Attenuated response of ICa,L to nitric oxide in atrial fibrillation. Cardiovasc Res, 2014. PMID:24336332
F. Mayyas, K. H. Alzoubi, and D. R. Van Wagoner. Impact of aldosterone antagonists on the substrate for atrial fibrillation: Aldosterone promotes oxidative stress and atrial structural/electrical remodeling. Int.J Cardiol, 15;168:5135-42, 2013. PMID:23993726
N. Tan, M. K. Chung, J. D. Smith, J. Hsu, D. Serre, D. W. Newton, L. Castel, E. Soltesz, G. Pettersson, A. M. Gillinov, D. R. Van Wagoner, and J. Barnard. Weighted gene coexpression network analysis of human left atrial tissue identifies gene modules associated with atrial fibrillation. Circ Cardiovasc Genet 6:362-371, 2013. PMID:23863953
Ellinor, PT et al. Meta-analysis identifies six new susceptibility loci for atrial fibrillation. Nat Genet 2012; 44:670-675. PMID:22544366
M. Harada, X. Luo, X. Y. Qi, A. Tadevosyan, A. Maguy, B. Ordog, J. Ledoux, T. Kato, P. Naud, N. Voigt, Y. Shi, K. Kamiya, T. Murohara, I. Kodama, J. C. Tardif, U. Schotten, D. R. Van Wagoner, D. Dobrev, and S. Nattel. Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circ. 126 (17):2051-2064, 2012. PMID:22992321
F. Mayyas, S. Sakurai, R. Ram, J. Rennison, E.S. Hwang, L. Castel, B. Lovano, M.L. Brennan, D. Bibus, B. Lands, J. Barnard, M.K. Chung, and D.R. Van Wagoner. Dietary ω3 fatty acids modulate the substrate for post-operative atrial fibrillation in a canine cardiac surgery model . Cardiovasc Res. 89 (4):852-861, 2011. PMID:21123218
F. Mayyas, M. Niebauer, A. Zurick, J. Barnard, A.M. Gillinov, M.K. Chung, and D.R. Van Wagoner. Association of left atrial endothelin-1 with atrial rhythm, size and fibrosis in patients with structural heart disease. Circ.Arrhythm.Electrophysiol. 3 (4):369-379, 2010. PMID:20495015
Y. Zhang, Z.B. Popovic, S. Bibevski, I. Fakhry, D.A. Sica, D.R. Van Wagoner, and T.N. Mazgalev. Chronic Vagus Nerve Stimulation Improves Autonomic Control and Attenuates Systemic Inflammation and Heart Failure Progression in a Canine High-Rate Pacing Model. Circ Heart Fail 2 (6):692-699, 2009. PMID:19919995
C.A. Carnes, P.M. Janssen, M.L. Ruehr, H. Nakayama, T. Nakayama, H. Haase, J.A. Bauer, M.K. Chung, I.M. Fearon, A.M. Gillinov, R.L. Hamlin, and D.R. Van Wagoner. Atrial glutathione content, calcium current and contractility. J Biol.Chem. 282 (38):28063-28073, 2007. PMID:17656369