Nearly 37% of all Veterans are clinically hypertensive, making hypertension the most common medical condition in the VA Health Care System. Importantly, of the 67 million Americans diagnosed with hypertension only 31 million are being effectively treated, leaving 36 million (54%) Americans with uncontrolled hypertension. 1. Hypertension is a major risk factor for cardiovascular disease and when left untreated leads to the development of heart failure, coronary heart disease, peripheral artery disease, stroke, and renal disease2, 3. Exercise and regular physical activity are considered the cornerstones of prevention and management of hypertension 2-4. Unfortunately, individuals with hypertension exhibit marked exercise intolerance5 and are characterized by an exaggerated or greater than normal physiologic increase in blood pressure during exercise (i.e. exercise pressor reflex or EPR)6-8. This excessive EPR increases the risk of adverse cardiovascular events such as myocardial infarction, cardiac arrest, or stroke during or immediately after exercise 7, 8 and is an established risk factor for cardiovascular morbidity and mortality 9, 10. This paradox is poorly understood, but it is highly likely that free radical production and the subsequent increase in oxidative stress plays a significant role in this response11-13. We have recently identified that afferent fibers, located in the skeletal muscle, play an essential role in regulating the cardiovascular response to exercise by increasing heart rate and blood pressure14. A process that in other pathologies, such as heart failure, has been documented to be influenced by oxidative stress. In hypertension these afferent fibers may be oversensitive to the free radical stimulus resulting in excessive increases in heart rate and blood pressure, ultimately leading to impaired blood flow and exercise intolerance.
Two aims are proposed, the first will confirm a role of free radicals and oxidative stress in the exaggerated EPR in hypertension and the second will utilize an antioxidant cocktail to ameliorate the effects of an exaggerated EPR in hypertensive patients allowing the safe performance of a clinical exercise rehabilitation program which will then itself attenuate the EPR and reduce the level of hypertension.

Public Health Relevance

Hypertension affects 37% of the Veteran population, making it the most common medical condition treated by the VA Health Care System. Physical activity is the first line of defense in the treatment and management of hypertension. Unfortunately, individuals with hypertension have marked exercise intolerance and exhibit exaggerated increases in blood pressure during exercise (exercise pressor reflex or EPR) leading to increased risk of stroke and heart attack. The cause of this exaggerated EPR is not known but it is highly likely that free radical production and the subsequent increase in oxidative stress plays a significant role. Two aims are proposed, the first will confirm a role of free radicals and oxidative stress in the exaggerate EPR in hypertension and the second will utilize an antioxidant cocktail to ameliorate the effects of an exaggerated EPR in hypertensive patients allowing the safe performance of a clinical exercise rehabilitation program which will then itself attenuate the EPR and reduce the level of hypertension.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (I21)
Project #
1I21RX001433-01
Application #
8634540
Study Section
Special Emphasis Panel (RRDS)
Project Start
2014-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA Salt Lake City Healthcare System
Department
Type
DUNS #
009094756
City
Salt Lake City
State
UT
Country
United States
Zip Code
84148
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
Broxterman, Ryan M; Layec, Gwenael; Hureau, Thomas J et al. (2017) Bioenergetics and ATP Synthesis during Exercise: Role of Group III/IV Muscle Afferents. Med Sci Sports Exerc 49:2404-2413
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
Groot, H Jonathan; Rossman, Matthew J; Garten, Ryan S et al. (2016) The Effect of Physical Activity on Passive Leg Movement-Induced Vasodilation with Age. Med Sci Sports Exerc 48:1548-57
Lee, Joshua F; Barrett-O'Keefe, Zachary; Nelson, Ashley D et al. (2016) Impaired skeletal muscle vasodilation during exercise in heart failure with preserved ejection fraction. Int J Cardiol 211:14-21
Richardson, Russell S; Wary, Claire; Wray, D Walter et al. (2015) MRS Evidence of Adequate O? Supply in Human Skeletal Muscle at the Onset of Exercise. Med Sci Sports Exerc 47:2299-307
Trinity, Joel D; Groot, H Jonathan; Layec, Gwenael et al. (2014) Impact of age and body position on the contribution of nitric oxide to femoral artery shear rate: implications for atherosclerosis. Hypertension 63:1019-25
Ives, Stephen J; Harris, Ryan A; Witman, Melissa A H et al. (2014) Vascular dysfunction and chronic obstructive pulmonary disease: the role of redox balance. Hypertension 63:459-67