Atrial fibrillation (AF) is the most common heart rhythm disturbance encountered in clinical practice, affecting approximately 2.3 million people in the United States. AF is an independent risk factor for stroke, congestive heart failure and mortality. Current therapies for AF are inadequate and are associated with limited long term success rates and significant risks. Although many risk factors for AF have been identified, our understanding of the underlying pathogenic mechanisms of AF remains elusive. The public health burden of AF, combined with significant gaps in our knowledge of its pathogenesis and the lack of effective treatment, underscore the critical need for new research into its pathogenesis. A recent 2015 NHLBI document outlining strategic research priorities proposed that the identification of novel targets for drug development was a high priority of research to reduce human disease. This proposal sets out to address this priority area by identifying a unifying mechanistic explanation for the pathogenesis of AF, potentially forming the basis for designing novel targeted therapies to prevent or reverse this prevalent human disease. There is accumulating evidence to suggest that autoimmune mechanisms could be implicated in the pathogenesis of AF. Our own preliminary data suggest that autoimmune diseases as a group are more prevalent in patients with AF than non-AF controls. Therefore, the central hypothesis of this proposal is that AF is an autoimmune-mediated disease. The overall objectives of this application are to determine whether autoimmune diseases are associated with AF development and to identify specific diagnostic and prognostic biomarkers that will improve the ability to accurately predict risk of AF development.
In aim 1, we will analyze epidemiologic data from Olmsted County, Minnesota to estimate the prevalence of autoimmune diseases (in aggregate) in patients with incident AF and thereby establish their association with AF.
In aim 2, we will prospectively enroll patients with and without AF and determine their serum cytokine levels and assess the functional responses of T cells on the basis of cytokine production after in vitro T-cell specific stimulation, using state-of-the-art Luminex bead-based multiplex technology. The proposed work is significant because a better understanding of the interactions between autoimmune mechanisms and AF is expected to have broad translational value by 1) enhancing our ability to identify individuals at risk of AF and 2) facilitating the development of novel, targeted therapies for the management and prevention of AF. The proposed translational research is innovative because it seeks to identify a novel causative biologic pathway for the development of AF, using a multidisciplinary approach. At the completion of these aims, the role of autoimmune mechanisms in the pathogenesis of AF will be established and the cytokines profiles of individuals at risk of developing AF will be characterized. Therefore, this proposal will enable better stratification of at-risk patients, and provide a framework for advancement of translational investigations in this field to promote health and reduce the burden of cardiovascular disease.

Public Health Relevance

The proposed research is relevant to public health because it seeks to provide novel insights into the mechanism of atrial fibrillation (AF) and lay the groundwork for developing novel, targeted therapy for the prevention or reversal of AF. Completion of these aims will enable better risk stratification of patients and may identify new mechanisms of AF development. This translational investigation is integrally related to the NHLBI Global Health Strategic Plan to reduce the global burdens imposed by cardiovascular diseases because it is the initial step in the process of reducing the burden of a common human disease and contributing to individualized, cost-effective care.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL135288-02
Application #
9406346
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Meadows, Tawanna
Project Start
2017-01-01
Project End
2021-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Kim, Kye Hun; Miranda, William R; Sinak, Larry J et al. (2018) Effusive-Constrictive Pericarditis After Pericardiocentesis: Incidence, Associated Findings, and Natural History. JACC Cardiovasc Imaging 11:534-541
Lee, Hon-Chi; Melduni, Rowlens M (2018) Autoimmunity and cardiac arrhythmias in endemic pemphigus foliaceus-Association, correlation, or causation? Heart Rhythm 15:732-733
Wysokinski, W E; Cohoon, K P; Melduni, R M et al. (2018) Association between P-selectin levels and left atrial blood stasis in patients with nonvalvular atrial fibrillation. Thromb Res 172:4-8
Melduni, Rowlens M; Gersh, Bernard J; Wysokinski, Waldemar E et al. (2018) Real-Time Pathophysiologic Correlates of Left Atrial Appendage Thrombus in Patients Who Underwent Transesophageal-Guided Electrical Cardioversion for Atrial Fibrillation. Am J Cardiol 121:1540-1547
Yao, Xiaoxi; Gersh, Bernard J; Holmes Jr, David R et al. (2018) Association of Surgical Left Atrial Appendage Occlusion With Subsequent Stroke and Mortality Among Patients Undergoing Cardiac Surgery. JAMA 319:2116-2126
Johnsrud, Daniel O; Melduni, Rowlens M; Lahr, Brian et al. (2018) Evaluation of anticoagulation use and subsequent stroke in patients with atrial fibrillation after empiric surgical left atrial appendage closure: A retrospective case-control study. Clin Cardiol :
Egbe, Alexander C; Asirvatham, Samuel J; Connolly, Heidi M et al. (2017) Outcomes of Direct Current Cardioversion in Adults With Congenital Heart Disease. Am J Cardiol 119:1468-1472
Wysokinski, Waldemar E; Cohoon, Kevin P; Konik, Ewa A et al. (2017) Effect of atrial fibrillation duration on plasma von Willebrand factor level. Eur J Haematol 99:569-576
Melduni, Rowlens M; Schaff, Hartzell V; Lee, Hon-Chi et al. (2017) Impact of Left Atrial Appendage Closure During Cardiac Surgery on the Occurrence of Early Postoperative Atrial Fibrillation, Stroke, and Mortality: A Propensity Score-Matched Analysis of 10?633 Patients. Circulation 135:366-378
Vaidya, Vaibhav R; Prueksaritanond, Suartcha; Bois, John P et al. (2017) Impact of acute left ventricular apical thrombus on cardioversion for atrial fibrillation. Echocardiography 34:1708-1711

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