The time-course of vascular adaptations following localized short term exercise training

This is a series of 3 experiments in the area of vasoreactivity. The first study investigated the stability and reproducibility of brachial artery flow-mediated dilation (BAFMD). Twenty-six healthy volunteers underwent 3 scans on 2 days, performed by 2 ultrasonographers, and analyzed by 2 readers. All subjects were tested between 7 and 11am after refraining from food and exercise. Average baseline diameter was 3.48±0.53mm, which increased to 3.71±0.57mm (6.58±4.15%) at peak dilation. ICCC\u27s for days, testers and readers were 0.9188, 0.9394, and 0.8982 respectively. To detect a difference in vasoreactivity of 60% (two-tailed), e.g. 5% vasodilation versus 8% vasodilation, at 90% power, 23 and 10 subjects would be required for cross-sectional and pre-post designs, respectively. These data indicate adequate stability and reproducibility of the BAFMD technique under controlled conditions. The second study investigated the relation between BAFMD and normal plasma fibrinogen (PF) in 30 non-smoking, healthy, volunteers (41±12 yr.; range:22-57). Results indicated a 6.08% increase (range:-3.58 to 17.48%) in BAFMD. Correlation analysis indicated significant inverse relationships for BAFMD and age r=-0.417 (p=0.02), and for BAFMD and PF r=-0.56 (p=0.001). Stepwise multiple regression including PF, age, total cholesterol and blood pressure revealed PF as the predominant predictor for BAFMD with 31% of the variance accounted for by BAFMD =22.61-(0.05836*PF), with no other variables entered. The final study examined the time-course of changes in BAFMD in response to a localized exercise training protocol. Fourteen healthy males (age: 26±5.7) underwent BAFMD assessment prior to, during and following 4 weeks (5 days per week) of 60% maximal voluntary contraction handgrip training of the non-dominant arm. Following training, paired t-tests revealed a 62% increase in BAFMD for the trained arm (6.2±3.0% to 10±4.1%), compared to baseline (p=0.0004), and a 100% difference (10±4.1% vs. 4.6±4.4%) between arms (p=0.0001). An increase in BAFMD (6.2±3.0% to 8.25±2.4%), was evident following 4 days of training (p=0.015), although individual participant variability reduced the statistical power of these findings. There were no changes in hemodynamic, autonomic and hematological variables, suggesting the improvement was a locally mediated process

Impact of inactivity and exercise on the vasculature in humans

The effects of inactivity and exercise training on established and novel cardiovascular risk factors are relatively modest and do not account for the impact of inactivity and exercise on vascular risk. We examine evidence that inactivity and exercise have direct effects on both vasculature function and structure in humans. Physical deconditioning is associated with enhanced vasoconstrictor tone and has profound and rapid effects on arterial remodelling in both large and smaller arteries. Evidence for an effect of deconditioning on vasodilator function is less consistent. Studies of the impact of exercise training suggest that both functional and structural remodelling adaptations occur and that the magnitude and time-course of these changes depends upon training duration and intensity and the vessel beds involved. Inactivity and exercise have direct “vascular deconditioning and conditioning” effects which likely modify cardiovascular risk

Role of vascular hyperpolarization in muscle blood flow regulation in healthy humans

2013 Spring.Includes bibliographical references.The following investigation composes a series of experiments with the overall aim of determining the role for vascular hyperpolarization via activation of inwardly-rectifying potassium (KIR) channels and Na+/K+-ATPase in the regulation of vascular tone in response to muscle contractions and ischaemia in young, healthy humans. We tested the general hypothesis that activation of KIR channels and Na+/K+-ATPase contributes in large part to the vasodilatory, hyperaemic, and sympatholytic responses observed in these conditions and this contribution is greater than that of other vasodilators, specifically nitric oxide (NO) and prostaglandins (PGs). The specific aims of each experiment were: 1) to determine whether K+-stimulated vascular hyperpolarization via activation of KIR channels and Na+/K+-ATPase mediates contraction-induced rapid vasodilatation in the human forearm; 2) to determine whether vascular hyperpolarization via activation of KIR channels and Na+/K+-ATPase contributes to the hyperaemic response at the onset of repeated muscle contractions, as well as to steady-state forearm blood flow during rhythmic handgrip exercise; 3) to determine whether vascular hyperpolarization via activation of KIR channels and Na+/K+-ATPase contributes to the observed blunting of sympathetically-mediated vasoconstriction that occurs during moderate intensity rhythmic forearm exercise; and 4) to determine whether vascular hyperpolarization via activation of KIR channels and Na+/K+-ATPase contributes to the observed reactive hyperaemia that occurs in the human forearm following release of temporary ischaemia. Our collective findings demonstrate a significant contribution of KIR channels and Na+/K+-ATPase activation to rapid vasodilatation following a single muscle contraction, the onset of exercise hyperaemia in response to repeated muscle contractions, steady-state muscle blood flow during rhythmic handgrip exercise and reactive hyperaemia following temporary ischaemia. In contrast to our hypothesis, we did not observe a significant contribution of KIR channels and Na+/K+-ATPase to the observed blunting of sympathetic α-adrenergic vasoconstriction that occurs during handgrip exercise. In all studies, any role of NO and PGs was modest, if present at all. Taken together, our findings indicate that during a variety of vasodilatory stimuli, there is a large contribution of pathways that are independent of NO and PGs, specifically activation of KIR channels and Na+/K+-ATPase. Hyperpolarization via activation of KIR channels and Na+/K+-ATPase represents a novel mechanistic pathway in the understanding of in vivo regulation of muscle blood flow in response to contractions and ischaemia. These findings may provide insight into understanding impaired vascular function in patient populations and as such, could represent a novel therapeutic target for reversing microvascular dysfunction

Exercise and peripheral vascular function in health and disease

“Chronic disease will never reach its clinical horizon to compromise health if it is attacked at its origin” [1]. Knowledge that one’s risk for cardiovascular events is related to the severity of endothelial dysfunction, and evidence that exercise training can improve endothelial function, has prompted speculation that measures of vascular function may serve as a “barometer” for cardiovascular health. This dissertation consists of three experiments intended to study vascular function and the manner in which it may influence or may be influenced by physical function. Project one examined the influence of high and low volume circuit weight training on forearm vascular function. Thirty-five individuals participated in a program consisting of 3 sessions/week for 5 weeks. Results indicated significant but similar strength gains in both groups (Hand Grip: Ä15.55%, Knee Extension: Ä21.00%, Bench Press: Ä35.31%; p\u3c0.05). Reactive hyperemic responses, a measure of vascular function, only changed in those individuals with the lowest pre-training vascular measures, independent of group assignment. Project two examined the link between vascular and physical function in peripheral neuropathy patients. Reactive hyperemic responses were significantly related to the time up and go test (r=-0.31, p=0.02) and the 6-minute walk distance (r=0.37, p=0.007). These data suggest a link between measures of vascular and physical function in these patients, indicating that those with better vascular function have greater physical function. Project three examined the effects of an acute bout of exercise on nitric oxide, oxidative stress and anti-oxidants, and brachial vasoreactivity, before, at peak exercise, and in recovery, in trained individuals. The results indicated a significant increase in reactive oxygen species and peroxynitrite, and a decrease in the anti-oxidant glutathione peroxidase at peak exercise. Brachial vasoreactivity was significantly lower immediately after exercise, but returned to pre-exercise levels at 20 minutes into recovery. These findings suggest an acute bout of exercise contributes to a significant rise in oxidative stress, which can in part be buffered by anti-oxidants systems, but may cause temporary blunting of arterial reactivity. Collectively, these findings indicate the importance of examining vascular function, and its controllers, and may extend the current understanding of preserving and/or maintaining vascular health

Plasma nitrite reserve and vascular function before and after handgrip training in patients with heart failure

There is a direct relationship between vascular health and physical function. The controllers of this relationship are unclear, but appear to involve biomechanical and biochemical influences on the vascular wall. Purpose: The purpose of this dissertation was twofold: (1) to explore the relationship between vascular health and physical function in three populations (elderly, young and chronic heart failure patients); and (2) to determine the modifying role of physical activity, inactivity and exercise training on controllers of this relationship. Methods: Four projects were designed to address 3 key issues in exercise vascular biology, including the influence of the pattern of blood flow on the vasculature; the effects of exercise training with blood flow restriction vascular function; and the influence of exercise training on vascular function in individuals with known disease. Results: Projects 1 and 2 indicate an increase in oscillatory shear within the vasculature with aging. This appears to be associated with lower physical function. Those individuals who maintain a higher amount of daily physical activity have more favorable blood flow pattern and higher vascular function. Project 3 indicates that localized exercise training with blood flow restriction dissociates vascular and muscle gains leading to enhanced muscular strength but diminished vascular function. The controller involved in the lower vascular function may be reduced shear stress during exercise. The controller that contributes to greater muscle strength during blood flow restriction remains unknown. Project 4 concludes that localized exercise training significantly improves vascular function and muscular strength in heart failure patients, although the gains are less than in age-matched individuals. The underlying controllers are unclear but may involve localized increases in shear stress and reduced oxidative stress. However, the benefits of exercise training are transient with vascular function returning to pre-training levels within 4 weeks after cessation of the training stimulus. Conclusion: These projects confirm a direct relationship between vascular health and physical function. This relationship is modifiable with physical activity levels and exercise training. It appears that intermittent shear stress, as seen with acute exercise, and oxidative stress serve as important stewards of the relationship between vascular and physical function

Vascular function, physical performance and aging

This is a series of three experiments with brachial artery flow-mediated dilation (BAFMD) as the major outcome variable. The first study examined the temporal response of the brachial artery diameter following forearm occlusion in sixteen young (28±8 years) and fifteen older (85±8 years) men. Following release of the pressure cuff there is a significant reduction in brachial diameter compared to baseline, followed by a rapid increase to a PEAK. When comparing the magnitude of the decrease in diameter and the BAFMD between Young and Old, older subjects demonstrated a blunted response. A significant relation was noted between the magnitude of decrease and BAFMD (r=- 0.44, p= 0.04). Specific features of the biphasic pattern are blunted in older adults compared with younger subjects. The magnitude of the drop in diameter following forearm occlusion correlates with the magnitude of the BAFMD. The second study examined the relation between BAFMD and the total score from the Continuous Scale Physical Function Performance Test (PFP-10). Sixty-four men (84±11years) were studied. BAFMD was associated with the total PFP-10 score (r = 0.45, p = 0.0001) and age (r = -0.36, p = 0.003). When individuals were categorized based on their PFP-10 score, those in the highest functional class, exhibited the highest BAFMD, compared to those in the middle class, who had greater vasoreactivity than those in the lowest functional class. The final study examined the effects of four weeks of unilateral handgrip exercise training on BAFMD and the features of the vasoreactivity curve. Twelve men (81±5 years) were studied before, during and after four weeks of handgrip training of the non-dominant arm. Following training, a 40% increase in BAFMD was observed in the trained arm only. Significant improvements in BAFMD were observed after the second week of training (p=0.024). Also, BAFMD was significantly related to the estimated shear rate (r=0.341, p\u3c0.001). A biphasic pattern was not observed in the present study. A significant improvement in BAFMD was observed following unilateral handgrip training. These improvements take place very rapidly and may be partly mediated through increases in shear stress resulting from changes in resistance vessel function

Arterial and venous adaptations to short-term handgrip exercise training

Four studies on vascular and exercise physiology are presented in this document. The 1st study examined the relationships between measures of fitness and FVF in 55 young [22.6 ± 3.5 years] adults. Estimated VO2peak correlated with arterial inflow (Ainf) [r=0.54; p=0.012] and resting venous outflow (Vout) [r=0.56; p=0.016]. Lastly, HG strength was associated with Vcap [r=0.57; p=0.007] and Vout [r=0.67; p=0.001]. The 2nd study examined the relationship between FVF and exercise tolerance (ExT) in 20 patients with HF [age: 59 ± 13 years] and 10 age-matched controls [age: 51 ± 16 years. The ExT was measured as the maximum walking distance (MWD) in 6 minutes. FVF [Ainf: HF 15.3 ± 6; controls 22 ± 6.7; Vcap: HF 1.4 ± 0.5; controls 2.0 ± 0.4; Vout: HF 24.5 ± 9.4; controls 33 ± 10 mL · 100 mL tissue-1 · min-1; and forearm vascular resistance: HF 7.8 ± 3; controls 4.6 ± 1.4U] indices and MWD [HF: 178 ± 65 m; controls: 562 ± 136m, P = .0001] were different between groups. Correlation analysis revealed significant associations between FVF indices and MWD. The 3rd study examined the effect of 25% (LO) and 75% (HI) of MVC short-term HG exercise training on FVF in 28 healthy men [Age:23±4.3]. The 4-week program consisted of non-dominant HG exercise performed 5 d/wk for 20-min. Training resulted in increased Ainf in the non-dominant arm in the LO and HI groups by 16.51% and 20.72%, respectively. The final study examined the time-course FVF adaptations to HG exercise training in 17 men [Age: 22.6 ± 3.5]. The HG exercise was performed in the non-dominant arm 5 d/wk for 20-min at 60% of MVC. The 2 X 5 ANOVA revealed arms X visits interaction for Ainf [p=0.02], while the LSD post-hoc demonstrated unilateral increase in Ainf following the 1st week. Additional 2 X 5 split-plot ANOVA tests revealed arms X visits interaction [p=0.04] for venous compliance (Vcomp) with LSD post-hoc demonstrating a decrease in trained arm Vcomp in visit 2 followed by an increase in visit 4 and return to baseline level at visit 5

Vascular adaptation to exercise in humans: Role of hemodynamic stimuli

On the 400th anniversary of Harvey’s Lumleian lectures, this review focuses on “hemodynamic” forces associated with the movement of blood through arteries in humans and the functional and structural adaptations that result from repeated episodic exposure to such stimuli. The late 20th century discovery that endothelial cells modify arterial tone via paracrine transduction provoked studies exploring the direct mechanical effects of blood flow and pressure on vascular function and adaptation in vivo. In this review, we address the impact of distinct hemodynamic signals that occur in response to exercise, the interrelationships between these signals, the nature of the adaptive responses that manifest under different physiological conditions, and the implications for human health. Exercise modifies blood flow, luminal shear stress, arterial pressure, and tangential wall stress, all of which can transduce changes in arterial function, diameter, and wall thickness. There are important clinical implications of the adaptation that occurs as a consequence of repeated hemodynamic stimulation associated with exercise training in humans, including impacts on atherosclerotic risk in conduit arteries, the control of blood pressure in resistance vessels, oxygen delivery and diffusion, and microvascular health. Exercise training studies have demonstrated that direct hemodynamic impacts on the health of the artery wall contribute to the well-established decrease in cardiovascular risk attributed to physical activity. © 2017 the American Physiological Society

Limb tissue haemodynamic responses and regulation in the heat-stressed human: role of local vs. central thermosensitive mechanisms at rest and during small muscle mass exercise

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University LondonLimb haemodynamic responses during heat-stress and the importance of local vs. central temperature-sensitive mechanisms towards their regulation remain poorly understood, both at a whole-limb level and within individual tissues (i.e. skeletal muscle and skin). The aims of this thesis were to 1) investigate the haemodynamic responses at rest to direct thermal challenges both at a local level and during progressive elevations in systemic heat stress, 2) to ascertain the contribution of local vs. systemic mechanisms towards this regulation, and 3) to investigate the same responses during single-legged small-muscle mass exercise to near maximal levels. Results from Chapters 4 and 5 characterised the haemodynamic responses during isolated cooling and heating of the arm and leg, and provided evidence of alterations in both skin and skeletal muscle blood flow controlled solely through local temperature-sensitive mechanisms. While local cooling led to modest decreases in limb blood flow due to decreases in mean blood velocity alone, increases during heating occurred as a result of an increased antegrade flow, a diminished retrograde flow, and a reduction in the potentially pro-atherogenic oscillatory shear index. In Chapter 6, whole-body heating with isolated single leg cooling displayed the continued control of limb blood flow via local thermosensitive mechanisms alone, as cooled leg blood flow remained unchanged despite significant elevations in core temperature, cardiac output, and opposing heated leg blood flow. Furthermore, elevations in heated leg V̇O2 suggested a possible metabolic contribution to the observed skeletal muscle hyperaemic response. During incremental single-legged knee-extensor exercise to near maximal levels, blood flow was determined by a combination of metabolic workload and local tissue temperatures, regardless of whether systemic heat stress was present. Chapter 7 revealed that whilst skin and muscle blood flow in the leg continued to increase in line with local temperatures to levels of severe heat stress, rapid cooling of the leg when hyperthermic resulted in a similar reverse response in muscle tissues only, as skin blood flow remained elevated despite the abolition of high skin and subcutaneous temperatures. In addition, evidence was provided that moderate levels of whole-body heat stress provided little additional benefit to anti-atherogenic shear profiles than that experienced during isolated limb heating alone. Taken together, these findings suggest that local thermosensitive mechanisms dominate limb blood flow control during direct rapid heating in humans both at rest and during small muscle mass exercise, but that underlying central mechanisms may act to maintain flow when local temperatures are reduced in the face of high core temperatures