Atrial fibrillation (AF) is the most common heart rhythm disease and affects 1% of the US population. The incidence and prevalence of AF rise with age to affect nearly 8% of octogenarians. It is a major public health burden and associated with higher risks of mortality and morbidity including stroke, heart failure, embolic events, dementia and impaired quality of life. There is no effective strategy for the prevention and treatment of AF since the molecular mechanisms and the mechanistic therapeutic targets are not known. The goal of this proposal is to investigate the role of mitochondria in the mechanisms of AF and to define the novel mitochondrial targets for prevention and treatment. The structural and electrical integrity of atrial myocardium is essential for prevention of AF and that is dependent upon normal mitochondrial function. Mitochondrial dysfunction causes metabolic and oxidative stress in association with ATP depletion, disruption of ionic currents and increased reactive oxygen species generation. The applicant has demonstrated that impaired mitochondrial energetics and oxidative stress induce arrhythmias and myocyte loss. Activation of mitochondrial ATP-sensitive potassium channel (mitoKATP) and uncoupling proteins (UCP) protect cardiomyocytes by attenuating oxidative stress and preserving mitochondrial bioenergetics. However, it is unclear as to whether mitochondrial dysfunction plays a role in the development and progression of AF. The central hypothesis of this proposal is that mitochondrial dysfunction precedes the initiation and the progression of AF by causing progressive atrial remodeling and electrical instability due to impaired energetics and oxidative stress. To test this, we will evaluate the molecular and cellular changes associated with the onset of AF, and determine whether two mitochondrial pathways UCP and mitoKATP are disrupted in AF, and whether they can be reversed with therapy. This hypothesis will be tested by using two distinct animal models: a) mice with disruption of the liver kinase B1 protein (LKB1) that develop AF, and b) pigs with rapid atrial pacing that develop AF.
The Specific Aims are:
Specific Aim 1 : Determine the role of atrial mitochondrial dysfunction in the onset and progression of paroxysmal AF.
Specific Aim 2 : Investigate whether mitoKATP dysfunction causes AF and whether modulation of mitoKATP prevents the development of AF.
Specific Aim 3 : Determine the role of MIM-driven oxidative stress and mitochondrial UCPs in the development of AF and identify the efficacy of UCPs in prevention of AF. This project presents an original approach for understanding the cellular mechanisms of AF and identifying the novel molecular targets for the prevention and treatment of AF. Our ultimate goal is to develop effective clinical interventions for the prevention and treatment of AF by targeting mitochondrial mechanisms of AF. Characterization of the role of mitochondria in the mechanism of AF will provide a framework and an opportunity to develop novel therapies for this debilitating disease.

Public Health Relevance

As a major public health burden, atrial fibrillation is the most common heart rhythm disorder affecting more than 2.2 million Americans and causing increased risk of death and disability. This project investigates the molecular mechanism of atrial fibrillaton and novel therapies for prevention and treatment of this devastating disease. The investigator aims to discover the role of mitochondrial dysfunction as a molecular cause of atrial fibrillation and the mitochondrial molecular targets for development of new therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1)
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Carlson, Drew E
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State University of New York at Buffalo
Internal Medicine/Medicine
Schools of Medicine
United States
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Deshmukh, Amrish; Bhatia, Ankit; Anyanwu, Emeka et al. (2018) Incidence and Outcomes of Postoperative Atrial Fibrillation After Left Ventricular Assist Device. ASAIO J 64:581-585
Bukari, Abdallah; Nayak, Hemal; Aziz, Zaid et al. (2017) Impact of race and gender on clinical outcomes of catheter ablation in patients with atrial fibrillation. Pacing Clin Electrophysiol 40:1073-1079
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Ozcan, Cevher; Battaglia, Emily; Young, Rebeccah et al. (2015) LKB1 knockout mouse develops spontaneous atrial fibrillation and provides mechanistic insights into human disease process. J Am Heart Assoc 4:e001733