Decompensated heart failure challenges the ability of the lungs to maintain fluid homeostasis and can result in alveolar flooding and death;however, not all patients with decompensated heart failure develop pulmonary edema, despite similar clinical characteristics, suggesting a genetic influence on susceptibility to pulmonary edema in this population. In the lungs, alveolar Na+ and fluid clearance are primarily regulated by the activity of epithelial Na+ channels (ENaC). The activity and number of ENaCs are regulated by ?2 adrenergic receptors (ADRB2s). Stimulation of the ADRB2s by an endogenous (epinephrine) or exogenous agonist increases alveolar fluid clearance. Therefore, there are three key proteins involved in alveolar fluid clearance: ADRB2s, ENaCs, and epinephrine. There are common functional variants in the genes that encode the ADRB2, the alpha subunit of the ENaC, and phenylethanolamine N- methyltransferase (PNMT, which converts norepinephrine to epinephrine). It remains unclear what effects of these genes will be on patients with heart failure. Our long term goal is to determine appropriate therapeutic interventions for improving ion and lung fluid regulation in disease based on genetic information. The objective in this proposal is to determine the influence of genetic variation on lung Na+ and fluid handling, which is likely to have significant clinical applications, particularly in patients with heart failure who have an elevated adrenergic drive. Our central hypothesis is that genetic variation of the ADRB2, ENaC, and PNMT will influence baseline lung fluid and lung fluid clearance in response to a ?-agonist. The rationale for the proposed research is that determining how these genes regulate lung fluid in heart failure will allow for personalization of current therapy as well as utilization of alternative therapies to reduce the susceptibility of pulmonary edema in heart failure. This proposal is significant because we will explore the therapeutic effects of stimulation of the ?2-adrenergic receptors on lung fluid balance, and how genetic variation can influence this therapeutic response. This will add to the understanding of specific therapies used to reduce the risk of pulmonary edema in patients with HF. The research proposed is innovative because we will be testing the influence of genetic variation of ADRB2, ENaC and PNMT (which have not been explored together in patients with HF) on lung ion and fluid regulation in HF, we are determining how multiple genes interact together to influence lung fluid balance in patients with HF, and, finally, we have recently developed a new technique to assess lung ion and fluid changes which we will couple with existing methods to expand techniques that can be used to assess changes in lung water.

Public Health Relevance

The proposed research is relevant to public health because complications from heart failure (HF), including symptoms of pulmonary edema, are the number one reason for hospital admissions in the United States. Understanding the genetic influence to this susceptibility is key for therapeutic progress in HF. Thus, the proposed research is relevant to the NIH mission in that it will translate clinical research obtained in a laboratory setting in HF patients to clinical practice.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Harabin, Andrea L
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University of Arizona
Schools of Pharmacy
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Van Iterson, Erik H; Baker, Sarah E; Wheatley, Courtney M et al. (2018) Exercise Stroke Volume in Adult Cystic Fibrosis: A Comparison of Acetylene Pulmonary Uptake and Oxygen Pulse. Clin Med Insights Circ Respir Pulm Med 12:1179548418790564
Van Iterson, Erik H; Johnson, Bruce D; Joyner, Michael J et al. (2017) V?o2 kinetics associated with moderate-intensity exercise in heart failure: impact of intrathecal fentanyl inhibition of group III/IV locomotor muscle afferents. Am J Physiol Heart Circ Physiol 313:H114-H124
Van Iterson, Erik H; Olson, Thomas P; Borlaug, Barry A et al. (2017) Comparisons of Noninvasive Methods Used to Assess Exercise Stroke Volume in Heart Failure with Preserved Ejection Fraction. Med Sci Sports Exerc 49:1758-1768
Kelley, Eli F; Johnson, Bruce D; Snyder, Eric M (2017) Beta-2 Adrenergic Receptor Genotype Influences Power Output in Healthy Subjects. J Strength Cond Res 31:2053-2059
Van Iterson, Erik H; Wheatley, Courtney M; Baker, Sarah E et al. (2016) The relationship between cardiac hemodynamics and exercise tolerance in cystic fibrosis. Heart Lung 45:283-90
Van Iterson, Erik H; Wheatley, Courtney M; Baker, Sarah E et al. (2016) The Coupling of Peripheral Blood Pressure and Ventilatory Responses during Exercise in Young Adults with Cystic Fibrosis. PLoS One 11:e0168490
Van Iterson, Erik H; Karpen, Stephen R; Baker, Sarah E et al. (2015) Impaired cardiac and peripheral hemodynamic responses to inhaled ??-agonist in cystic fibrosis. Respir Res 16:103
Snyder, Eric M; Van Iterson, Erik H; Olson, Thomas P (2015) Clinical Classification of Heart Failure Patients Using Cardiac Function during Exercise. Exerc Sport Sci Rev 43:204-13
Wheatley, Courtney M; Baker, Sarah E; Morgan, Mary A et al. (2015) Moderate intensity exercise mediates comparable increases in exhaled chloride as albuterol in individuals with cystic fibrosis. Respir Med 109:1001-11
Wheatley, Courtney M; Baker, Sarah E; Morgan, Mary A et al. (2015) Effects of exercise intensity compared to albuterol in individuals with cystic fibrosis. Respir Med 109:463-74

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