Heart failure (HF), a clinical syndrome that develops as a consequence of heart disease from multiple etiologies, now affects almost six million Americans, presenting an imminent need for further research addressing the pathophysiology of this pervasive disease. One of the most damaging consequences of HF is an elevation in sympathetic nervous system (SNS) activity, which is expressed through alpha adrenergic receptors located on the vascular smooth muscle, promoting peripheral vasoconstriction. In HF patients, chronic sympathetic vasoconstriction acts to limit blood flow in the exercising muscle, promoting exercise intolerance, inactivity, and a subsequent acceleration in disease progression. Fortunately, disease-related sympathoexcitation may be remediable. Among the most influential modulators of peripheral SNS expression is the nitric oxide (NO) pathway, located at the interface between the vascular smooth muscle and the vascular endothelium. Though NO is perhaps best known for its transient vasodilator effects, recent studies have identified a clear role for this substance as an inhibitor of both central SNS activity and peripheral expression at the level of the alpha adrenergic receptor. Interventions focused on improving NO bioavailability may thus offer a new, unexplored strategy for inhibiting SNS overactivity in HF. A series of experiments using innovative methodologies are proposed to explore the contribution of the alpha adrenergic pathway to vasoconstriction in these patients and to subsequently evaluate the beneficial role of disruptions in oxidative stress (via AOx administration) on sympathetic vasoconstriction in this patient group.
Specific Aim 1 will explore the hypothesis that peripheral alpha adrenergic vasoconstriction is overactive in HF. Intra-arterial drug infusions (alpha-adrenergic agonists/antagonists) will be undertaken to pharmacologically probe disease-related changes in alpha adrenergic-mediated vasoconstriction, both at rest and during exercise.
Specific Aim 2 will study the direct and modulatory effects of oxidative stress on skeletal muscle vasoconstriction. It is hypothesized that acute AOx administration (intra-arterial Vitamin C) will promote vasodilation at rest and during exercise in an NO-dependent manner. We also hypothesize that chronic oral AOx administration (Vitamins C [1000mg], E [400 IU], and Alpha Lipoic Acid [600 mg], daily for 8 weeks) will reduce circulating free radical levels and subsequently improve NO bioavailability, which will in turn lessen peripheral vasoconstriction through inhibition of alpha adrenergic-mediated vasoconstriction. Successfully defining how sympathetic vasoconstriction is altered in HF is an important step towards better patient care, as we anticipate that findings from the proposed work may serve to refine current strategies for the treatment of peripheral blood flow dysregulation in HF, ultimately leading to enhanced quality of life in this cohort.

Public Health Relevance

Heart disease is the leading cause of death in the United States, accounting for one in every four deaths in 2010 and costing over $300 billion annually in health care, medication, and lost productivity. The proposed project seeks to examine the mechanisms leading to chronic peripheral vasoconstriction in HF, with the hope that this knowledge will improve the level of physical activity and reduce symptoms in these patients. Findings from these studies may thus serve to refine important aspects of clinical care in HF, ultimately leading to enhanced quality of life and reduced morbidity and mortality in this cohort.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Desvigne-Nickens, Patrice
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University of Utah
Internal Medicine/Medicine
Schools of Medicine
Salt Lake City
United States
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Barrett-O'Keefe, Zachary; Lee, Joshua F; Berbert, Amanda et al. (2018) Metaboreceptor activation in heart failure with reduced ejection fraction: Linking cardiac and peripheral vascular haemodynamics. Exp Physiol 103:807-818
Clifton, Heather L; Machin, Daniel R; Groot, H Jonathan et al. (2018) Attenuated nitric oxide bioavailability in systemic sclerosis: Evidence from the novel assessment of passive leg movement. Exp Physiol 103:1412-1424
Hureau, Thomas J; Weavil, Joshua C; Thurston, Taylor S et al. (2018) Identifying the role of group III/IV muscle afferents in the carotid baroreflex control of mean arterial pressure and heart rate during exercise. J Physiol 596:1373-1384
Wray, D Walter; Amann, Markus; Richardson, Russell S (2017) Peripheral vascular function, oxygen delivery and utilization: the impact of oxidative stress in aging and heart failure with reduced ejection fraction. Heart Fail Rev 22:149-166
Nishiyama, Steven K; Zhao, Jia; Wray, D Walter et al. (2017) Vascular function and endothelin-1: tipping the balance between vasodilation and vasoconstriction. J Appl Physiol (1985) 122:354-360
Machin, Daniel R; Clifton, Heather L; Richardson, Russell S et al. (2017) Acute oral tetrahydrobiopterin administration ameliorates endothelial dysfunction in systemic sclerosis. Clin Exp Rheumatol 35 Suppl 106:167-172
Lee, Joshua F; Barrett-O'Keefe, Zachary; Garten, Ryan S et al. (2016) Evidence of microvascular dysfunction in heart failure with preserved ejection fraction. Heart 102:278-84
Gifford, Jayson R; Garten, Ryan S; Nelson, Ashley D et al. (2016) Symmorphosis and skeletal muscle V?O2 max : in vivo and in vitro measures reveal differing constraints in the exercise-trained and untrained human. J Physiol 594:1741-51
Trinity, Joel D; Barrett-O'Keefe, Zachary; Ives, Stephen J et al. (2016) Endogenous endothelin-1 and femoral artery shear rate: impact of age and implications for atherosclerosis. J Hypertens 34:266-73
Machin, Daniel R; Clifton, Heather L; Garten, Ryan S et al. (2016) Exercise-induced brachial artery blood flow and vascular function is impaired in systemic sclerosis. Am J Physiol Heart Circ Physiol 311:H1375-H1381

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