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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01HL118313-01A1
Application #
8632342
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Desvigne-Nickens, Patrice
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Barrett-O'Keefe, Zachary; Lee, Joshua F; Berbert, Amanda et al. (2014) Hemodynamic responses to small muscle mass exercise in heart failure patients with reduced ejection fraction. Am J Physiol Heart Circ Physiol 307:H1512-20