Understanding the Exercise-Hypertension Paradox
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. However, individuals with hypertension have impaired muscle blood flow and exhibit exaggerated increases in blood pressure during exercise (exercise pressor reflex or EPR) leading to exercise intolerance and increased risk of stroke and heart attack. The cause of these impairments 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; Aim 1 will identify the physiological consequences of elevated oxidative stress in hypertension, and Aim 2 will utilize an antioxidant treatment to ameliorate the effects of an exaggerated EPR allowing the safe performance of a clinical exercise rehabilitation program which will then, itself, attenuate the EPR and reduce hypertension.
Dietary Supplement: Oral Antioxidant
Other: Exercise rehabilitation
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Basic Science
|Official Title:||Understanding the Exercise-Hypertension Paradox: Implication for Rehabilitation|
- Blood Pressure [ Time Frame: Immediate to 8 weeks ] [ Designated as safety issue: No ]Blood pressure with be assessed prior to the study intervention and during exercise (Aim #1). Additionally, blood pressure will be assessed following 8 weeks of exercise rehabilitation
|Study Start Date:||February 2014|
|Estimated Study Completion Date:||December 2019|
|Estimated Primary Completion Date:||February 2018 (Final data collection date for primary outcome measure)|
Experimental: Specific Aim #1
Specific Aim 1: Determine the consequences of oxidative stress on skeletal muscle afferent feedback and muscle blood flow during exercise in hypertension. Hypothesis: Afferent feedback sensitivity, determined by passive leg movement (isolation of mechanoreceptor sensitivity) and post exercise circulatory occlusion (isolation of metaboreceptor sensitivity) will be greater in hypertension leading to the exaggerated EPR. Muscle blood flow, assessed by Doppler ultrasound during multiple exercise intensities, will be impaired in hypertension leading to exercise intolerance. Reductions in oxidative stress, achieved by an oral antioxidant treatment (Vitamins C, E and alpha lipoic acid), will reduce afferent fiber sensitivity and improve muscle blood flow in hypertension. Additionally, venous endothelial cells will express elevated markers of oxidative stress providing novel evidence that the vascular endothelium contributes to the greater oxidative stress in hypertension.
Dietary Supplement: Oral Antioxidant
Consisting of vitamins C, E and alpha lipoic acid.
Experimental: Specific Aim #2
Specific Aim 2: Determine the remediable effect of combined antioxidant treatment and exercise rehabilitation in the treatment of hypertension. Hypothesis: Acute antioxidant treatment administered prior to exercise in hypertensive patients will ameliorate the exaggerated EPR resulting in a normal and safe blood pressure response to exercise-based rehabilitation. This two-pronged approach (antioxidants and exercise training) will result in a safely achieved reduction in skeletal muscle afferent feedback facilitating improved exercise tolerance, improved muscle blood flow and ultimately reduced cardiovascular risk in this population.
Dietary Supplement: Oral Antioxidant
Consisting of vitamins C, E and alpha lipoic acid.Other: Exercise rehabilitation
8 weeks of exercise rehabilitation
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 less than half are being effectively treated for their condition. Hypertension constitutes 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 disease. Exercise and regular physical activity are considered the cornerstones of prevention and management of hypertension. However, individuals with hypertension exhibit exercise intolerance characterized by impaired skeletal muscle blood flow and heightened afferent fiber sensitivity leading to an exaggerated or greater than normal physiologic increase in blood pressure during exercise (i.e. exercise pressor reflex or EPR). This imbalance between the beneficial effects of exercise and exercise intolerance creates an interesting paradox, the causes and consequences of which are poorly understood. The etiology of hypertension is undoubtedly complex, however a common denominator in this condition, elevated oxidative stress, may contribute to impaired muscle blood flow and heightened skeletal muscle afferent feedback leading to the exaggerated EPR. Previous work from our laboratory and others suggests that elevated oxidative stress associated with aging impairs muscle blood flow. Additionally, free radicals, the initiators of oxidative stress, can directly stimulate skeletal muscle afferent fibers leading to the exaggerated EPR. Importantly, the role of oxidative stress in regulating muscle blood flow and afferent fiber function in human hypertension has not been determined. Preliminary studies support a significant role of oxidative stress in impairing muscle blood flow and contributing to the exaggerated EPR in hypertension. With this information as context two aims are proposed that will systematically identify the consequences of elevated oxidative stress in hypertension. Specific Aim 1 will determine the consequences of oxidative stress by examining how elevated free radicals contribute to heightened skeletal muscle afferent feedback and impaired muscle blood flow during exercise in hypertension leading to the exaggerated EPR. Additionally, vascular endothelial cells collected from an antecubital vein will provide novel insight regarding the endothelium as potential source of elevated oxidative stress in hypertension. Specific Aim 2 will determine the effectiveness of combined antioxidant therapy and exercise rehabilitation in the treatment of hypertension. The overall goal of this proposal is to provide novel information regarding the role of oxidative stress as a critical regulator of cardiovascular and hemodynamic responses to exercise in hypertension. By identifying potential causes and consequences of oxidative stress, important insight will be gained facilitating the development of novel approaches and therapeutic strategies for the treatment of hypertension. Importantly, the practical applications tested in these studies (i.e. antioxidant treatment and combined exercise rehabilitation) are designed to identify and document effective countermeasures to aid in the treatment and management of hypertension allowing for the safe performance of exercise in a large number of Veterans.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02034422
|Contact: Amy Rogers||(801) firstname.lastname@example.org|
|United States, Utah|
|VA Salt Lake City Health Care System, Salt Lake City, UT||Recruiting|
|Salt Lake City, Utah, United States, 84148|
|Contact: Amy Rogers (801) 582-1565 email@example.com|
|Principal Investigator: Joel Douglas Trinity, PhD|
|Principal Investigator:||Joel Douglas Trinity, PhD||VA Salt Lake City Health Care System, Salt Lake City, UT|