Objective To better understand the hemodynamic and autonomic reflex abnormalities in heart-failure patients (HF), we investigated the influence of group III/IV muscle afferents on their cardiovascular response to rhythmic exercise. Methods Nine HF-patients (NYHA class-II, mean left ventricular ejection-fraction: 27±3%) performed single leg knee-extensor exercise (25/50/80% peak-workload) under control conditions and with lumbar intrathecal fentanyl impairing μ-opioid receptor-sensitive muscle afferents. Results Cardiac-output (Q) and femoral blood-flow (QL) were determined, and arterial/venous blood samples collected at each workload. Exercise-induced fatigue was estimated via pre/post-exercise changes in quadriceps strength. There were no hemodynamic differences between conditions at rest. During exercise, Q was 8–13% lower with Fentanyl-blockade, secondary to significant reductions in stroke volume and heart rate. Lower norepinephrine spillover during exercise with Fentanyl revealed an attenuated sympathetic outflow that likely contributed to the 25% increase in leg vascular conductance (p<0.05). Despite a concomitant 4% reduction in blood pressure, QL was 10–14% higher and end-exercise fatigue attenuated by 30% with Fentanyl-blockade (p<0.05). Conclusion/Practice/Implications Although group III/IV muscle afferents play a critical role for central hemodynamics in HF-patients, it also appears that these sensory neurons cause excessive sympatho-excitation impairing QL which likely contributes to the exercise intolerance in this population.

Wray DW, Witman MA, Ives SJ, McDaniel J, Fjeldstad AS, Trinity JD, Conklin JD, Supiano MA, Richardson RS. Progressive handgrip exercise: evidence of nitric oxide-dependent vasodilation and blood flow regulation in humans. Am J Physiol Heart Circ Physiol 300: H1101-H1107, 2011. First published January 7, 2011 doi:10.1152/ajpheart.01115.2010.-In the peripheral circulation, nitric oxide (NO) is released in response to shear stress across vascular endothelial cells. We sought to assess the degree to which NO contributes to exercise-induced vasodilation in the brachial artery (BA) and to determine the potential of this approach to noninvasively evaluate NO bioavailability. In eight young (25 Ϯ 1 yr) healthy volunteers, we used ultrasound Doppler to examine BA vasodilation in response to handgrip exercise (4,8,12,16,20, and 24 kg) with and without endothelial NO synthase blockade [intra-Higher exercise intensities evoked significant BA vasodilation (4 -12%) that was positively correlated with the hyperemic stimulus (r ϭ 0.98 Ϯ 0.003, slope ϭ 0.005 Ϯ 0.001). During NO blockade, BA vasodilation at the highest exercise intensity was reduced by ϳ70% despite similar exercise-induced increases in shear rate (control, ϩ224 Ϯ 30 s Ϫ1 ; L-NMMA, ϩ259 Ϯ 46 s Ϫ1 ). The relationship and slope of BA vasodilation with increasing shear rate was likewise reduced (r ϭ 0.48 Ϯ 0.1, slope ϭ 0.0007 Ϯ 0.0005). We conclude that endothelial NO synthase inhibition with L-NMMA abolishes the relationship between shear stress and BA vasodilation during handgrip exercise, providing clear evidence of NO-dependent vasodilation in this experimental model. These results support this paradigm as a novel and valid approach for a noninvasive assessment of NO-dependent vasodilation in humans. endothelium; endothelial nitric oxide synthase; N G -monomethyl-Larginine MEASUREMENT OF BRACHIAL ARTERY (BA) flow-mediated vasodilation (FMD) following ischemic cuff occlusion, first described by Celermajer et al. (1), has been widely used in recent years as a noninvasive means of evaluating endothelial function in a research setting (10,15,17,20,36). The assessment of endothelial function via FMD has been proposed to represent a functional bioassay for endothelium-derived nitric oxide (NO) bioavailability in humans (7, 16), though there is new evidence challenging the view that FMD is a reliable and selective index of endothelial NO function (23). Earlier work demonstrated a positive correlation between endothelium-dependent vasodilation of the brachial and coronary arteries (32), a finding that has fueled the ongoing interest in a noninvasive evaluation of NO bioactivity in humans.The uncertainty surrounding conventional FMD testing has raised the question of whether a more robust and comprehensive experimental paradigm might be adopted for the noninvasive determination of vascular health. One such approach is dynamic handgrip exercise, first described by Shoemaker et al. (29), which elevates shear stress through the BA and produces a subsequent vasodilation. We ...

Key pointsr The concept of symmorphosis predicts that the capacity of each step of the oxygen cascade is attuned to the task demanded of it during aerobic exercise at maximal rates of oxygen consumption (V O 2 max ) such that no single process is limiting or in excess atV O 2 max .r The present study challenges the applicability of this concept to humans by revealing clear, albeit very different, limitations and excesses in oxygen supply and consumption among untrained and endurance-trained humans.r Among untrained individuals,V O 2 max is limited by the capacity of the mitochondria to consume oxygen, despite an excess of oxygen supply, whereas, among trained individuals,V O 2 max is limited by the supply of oxygen to the mitochondria, despite an excess of mitochondrial respiratory capacity. AbstractThe concept of symmorphosis postulates a matching of structural capacity to functional demand within a defined physiological system, regardless of endurance exercise training status. Whether this concept applies to oxygen (O 2 ) supply and demand during maximal skeletal muscle O 2 consumption (V O 2 max ) in humans is unclear. Therefore, in vitro skeletal muscle mitochondrialV O 2 max ( MitoVO 2 max , mitochondrial respiration of fibres biopsied from vastus lateralis) was compared with in vivo skeletal muscleV O 2 max during single leg knee extensor exercise ( KEVO 2 max , direct Fick by femoral arterial and venous blood samples and Doppler ultrasound blood flow measurements) and whole-bodyV O 2 max during cycling ( BodyVO 2 max , indirect calorimetry) in 10 endurance exercise-trained and 10 untrained young males. In untrained subjects, during KE exercise, maximal O 2 supply ( KEQ O 2max ) exceeded (462 ± 37 ml kg −1 min −1 , P < 0.05) and KEVO 2 max matched (340 ± 22 ml kg −1 min −1 , P > 0.05) MitoVO 2 max (364 ± 16 ml kg −1 min −1 ). Conversely, in trained subjects, both KEQ O 2max (557 ± 35 ml kg −1 min −1 ) and KEVO 2 max (458 ± 24 ml kg −1 min −1 ) fell far short of MitoVO 2 max (743 ± 35 ml kg −1 min −1 , P < 0.05). Although MitoVO 2 max was related to KEVO 2 max (r = 0.69, P < 0.05) and BodyVO 2 max (r = 0.91, P < 0.05) in untrained subjects, these variables were entirely unrelated in trained subjects. Therefore, in untrained subjects,V O 2 max is limited by mitochondrial O 2 demand, with evidence of adequate O 2 supply, whereas, in trained subjects, an exercise training-induced mitochondrial reserve results in skeletal muscleV untrained and trained humans and challenge the concept of symmorphosis as it applies to O 2 supply and demand in humans. Abbreviations BIOPS, biopsy preservation fluid; Body, whole-body; KE, knee extensor; Mito, mitochondrial;Q O 2max , maximum specific oxygen uptake rate;V O2max , maximal oxygen uptake; WR max , maximum work rate.

Aging is associated with a pro-oxidant state and a decline in endothelial function. Whether acute, enteral antioxidant treatment can reverse this decrement in vascular function is not well known. Flow-mediated vasodilation and reactive hyperemia were evaluated following consumption of either placebo or an oral antioxidant cocktail (Vitamin C, 1000mg; Vitamin E, 600 I.U.; Alpha-lipoic acid, 600 mg) in 87 healthy volunteers (42 young, 25 ± 1 yrs; 45 older, 71 ± 1 yrs) using a double-blind, crossover design. Blood velocity and brachial artery diameter (ultrasound Doppler) were assessed before and after 5-min forearm circulatory arrest. Serum markers of lipid peroxidation, total antioxidant capacity, endogenous antioxidant activity, and Vitamin C were assayed, and plasma nitrate, nitrite, and 3-nitrotyrosine were determined. In the placebo trial, an age-related reduction in brachial artery vasodilation was evident (young: 7.4 ± 0.6 %; older: 5.2 ± 0.4 %). Following antioxidant consumption, flow-mediated vasodilation improved in older subjects (5.2 ± 0.4 %, placebo: 8.2 ± 0.6 %, antioxidant) but declined in the young (7.4 ± 0.6 %, placebo; 5.8 ± 0.6 %, antioxidant). Reactive hyperemia was reduced with age, but antioxidant administration did not alter the response in either group. Together, these data demonstrate that antioxidant consumption acutely restores endothelial function in the elderly, while disrupting normal endothelium-dependent vasodilation in the young, and suggest that this age-related impairment is due, at least in part, to free radicals.

Chronic obstructive pulmonary disease is characterized by low pulmonary function, inflammation, free-radical production, vascular dysfunction and subsequently a greater incidence of cardiovascular disease. By administering an acute oral antioxidant cocktail to patients with chronic obstructive pulmonary disease (n=30) and controls (n=30), we sought to determine the role of redox balance in the vascular dysfunction of these patients. Using a double blind, randomized, placebo controlled, crossover design, patients with chronic obstructive pulmonary disease and controls ingested placebo or the antioxidant cocktail (Vitamin-C, Vitamin-E, α-lipoic acid) after which brachial artery flow mediated dilation and carotid-radial pulse wave velocity were assessed using ultrasound Doppler. The patients exhibited lower baseline antioxidant levels (Vitamin-C and superoxide dismutase activity) and higher levels of oxidative stress (Thiobarbituic acid reactive species) in comparison to controls. The patients also displayed lower basal flow mediated dilation (p<0.05), which was significantly improved with antioxidant cocktail (3.1±0.5 vs. 4.7±0.6 %, p<0.05, placebo vs. antioxidant cocktail), but not controls (6.7±0.6 vs. 6.9±0.7 %, p>0.05, placebo vs. antioxidant cocktail). The antioxidant cocktail also improved pulse wave velocity in the patients (14±1 vs. 11±1 m·s−1, p<0.05, placebo vs. antioxidant cocktail), while not affecting controls (11±2 vs. 10±1 m·s−1, p>0.05, placebo vs. antioxidant). Patients with chronic obstructive pulmonary disease exhibit vascular dysfunction, likely mediated by an altered redox balance, which can be acutely mitigated by an oral antioxidant. Therefore, free radically-mediated vascular dysfunction may be an important mechanism contributing to this population’s greater risk and incidence of cardiovascular disease.

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Background Peripheral endothelial function is recognized to be impaired in patients with heart failure with reduced ejection fraction (HFrEF), but the peripheral vascular effects of continuous-flow left ventricular assist device (LVAD) implantation, now employed as either a bridge-to-transplantation or as a destination therapy, remain unclear. Using flow-mediated vasodilation (FMD) and reactive hyperemia (RH), this study aimed to provide greater insight into LVAD-induced changes in peripheral vascular function. Methods and Results Sixty-eight subjects (13 New York Heart Association (NYHA) Class II HFrEF patients, 19 NYHA Class III/IV HFrEF patients, 20 NYHA Class III/IV HFrEF patients post-LVAD implantation, and 16 healthy age-matched controls) underwent FMD and RH testing in the brachial artery with blood flow velocity, artery diameters, and pulsatility index (PI) assessed by ultrasound Doppler. PI was significantly lower in the LVAD group (2.0 ± 0.4) compared to both the HFrEF II, (8.6 ± 0.8) and HFrEF III/IV (8.1 ± 0.9) patients, who, in turn, were significantly lower than the controls (12.8 ± 0.9). Likewise, LVAD %FMD/shear rate (0.09 ± 0.01 %Δ/s−1) was significantly reduced compared to all other groups (controls, 0.24 ± 0.03; HFrEF II, 0.17 ± 0.02 and HFrEF III/IV, 0.13 ± 0.02 %Δ/s−1) and %FMD/shear rate was significantly correlated with PI (r=0.45). RH was unremarkable across groups. Conclusions Although central hemodynamics are improved in patients with HFrEF by a continuous-flow LVAD, peripheral vascular function is further compromised, likely due, at least in part, to the reduction in pulsatility that is a characteristic of such a mechanical assist device.

Previous studies have determined that premenopausal women exhibit an attenuated metaboreflex; however, little is known about sex specificity of the mechanoreflex. Thus, we sought to determine if sex differences exist in the central and peripheral hemodynamic responses to passive limb movement. Second-by-second measurements of heart rate, stroke volume, cardiac output (CO), mean arterial pressure, and femoral artery blood flow (FBF) were recorded during 3 min of supine passive knee extension in 24 young healthy subjects (12 women and 12 men). Normalization of CO and stroke volume to body surface area, expressed as cardiac index and stroke index, eliminated differences in baseline central hemodynamics, whereas, peripherally, basal FBF and femoral vascular conductance were similar between the sexes. In response to passive limb movement, women displayed significantly attenuated peak central hemodynamic responses compared with men (heart rate: 9.0 ± 1 vs. 14.8 ± 2% change, stroke index: 4.5 ± 0.6 vs. 7.8 ± 1.2% change, cardiac index: 9.6 ± 1 vs. 17.2 ± 2% change, all P < 0.05), whereas movement induced similar increases in peak FBF (167 ± 32 vs. 193 ± 17% change) and femoral vascular conductance (172 ± 31 vs. 203 ± 16% change) in both sexes (women vs. men, respectively). Additionally, there was a significant positive relationship between individual peak FBF and peak CO response to passive movement in men but not in women. Thus, although both sexes exhibited similar movement-induced hyperemia and peripheral vasodilatory function, the central hemodynamic response was blunted in women, implying an attenuated mechanoreflex. Therefore, this study reveals that, as already recognized with the metaboreflex, there is likely a sex-specific attenuation of the mechanoreflex in women.