Dynamic Leg Exercise Research Articles

Age Comparisons of Cardiac Work During Exercise in Women: Insight from Acute β1 Adrenergic Blockade

Postmenopausal women exhibit exaggerated increases in blood pressure during activities of daily living and exercise. The decreased size and increased stiffening of postmenopausal women's hearts elevate myocardial oxygen demand when compared to age-matched men and younger cohorts. Together, this poses a risk to the safety of, and capacity for, exercise in postmenopausal women. We recently studied the effects of esmolol, a fast-acting, cardio-selective β1 antagonist, on oxygen transport variables during dynamic exercise in healthy young (Y) and older (O) women to better understand differences in cardiovascular responses to exercise. Objective: Determine the effects of acute cardiac specific blockade on myocardial oxygen demand (rate pressure product, RPP) and cardiac work (CW) in healthy young premenopausal and older postmenopausal women. Methods: Thirteen healthy young (20-32 yr) and older postmenopausal (58-70 yr) women performed moderate (85% of lactate threshold) and heavy (50% between lactate threshold and the respiratory compensation point) recumbent leg cycling exercise during IV infusion of saline or esmolol in randomized order. Whole body oxygen consumption (VO2, indirect calorimetry), brachial systolic blood pressure (SBP, automated cuff), heart rate (HR, ECG), and cardiac output (CO, bioimpedance) were measured continuously. RPP (HR×SBP), CW (CO×SBP), and cardiac effciency (CE, CW/VO2) were calculated. Mixed model repeated measures ANOVAs were used to determine the effect of treatment and age group. Results: Power outputs were lower in O vs. Y at both moderate (45±9W and 72±15W, p<0.001) and heavy (81±21W vs. 117±32W, p<0.001) intensities. During the saline trial CO was lower (p<0.001), and RPP was higher (p<0.001) in the O vs. Y group during both intensities. There was a main effect of treatment on RPP, CW, and CE. Esmolol reduced RPP (4638±775 SD, p<0.001), CW (547±89, p<0.001) and CE (1682±62, p<0.001) in both O and Y. There was a main effect of age group on CE, pairwise comparisons showed CE was lower in O than Y (441±112, p<0.001). Conclusions: Older postmenopausal women experience higher myocardial oxygen demand and perform more cardiac work for a given whole body liter oxygen consumed during dynamic leg exercise compared to younger premenopausal women. Acute β1 adrenergic blockade narrows the gap between central cardiovascular function in young and old women and provides a powerful tool to investigate age-related cardiovascular differences. NIH R21 AG054940. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of sex and menstrual cycle phase on celiac artery blood flow during dynamic moderate-intensity leg exercise in young individuals.

The purpose of this study was to clarify the effect of sex and menstrual cycle phase on celiac artery blood flow during dynamic exercise in healthy young humans. Eleven healthy young females (21 ± 2 yr, means ± SD) and 10 males (23 ± 3 yr) performed dynamic knee-extension and -flexion exercises at 30% of heart rate reserve for 4 min. The percent changes from baseline (Δ) for mean arterial blood pressure (MAP), mean blood flow (celMBF) in the celiac artery, and celiac vascular conductance (celVC) during exercise were calculated. Arterial blood pressure was measured using an automated sphygmomanometer, and celiac artery blood flow was recorded by Doppler ultrasonography. Female subjects performed the exercise test in the early follicular phase (EF) and in the midluteal phase (ML) of their menstrual cycle. The increase in MAP during exercise was not significantly (P > 0.05) different between sexes or between menstrual cycle phases (ΔMAP, EF in females: +16.6 ± 6.4%, ML in females: +20.2 ± 11.7%, and males: +19.9 ± 12.2%). The celMBF decreased during exercise in each group, but the response was not significantly (P > 0.05) different between sexes or between menstrual cycle phases (ΔcelMBF, EF in females: -24.6 ± 15.5%, ML in females: -25.2 ± 18.7%, and males: -29.2 ± 4.0%). The celVC decreased during dynamic exercise in each group, with no significant (P > 0.05) difference in the responses between sexes or between menstrual cycle phases (ΔcelVC, EF in females: -38.3 ± 15.0%, ML in females: -41.5 ± 19.1%, and males: -43.4 ± 7.2%). These results suggest that sex and menstrual cycle phase have minimal influence on hemodynamic responses in the splanchnic artery during dynamic moderate-intensity exercise in young healthy individuals.NEW & NOTEWORTHY During dynamic exercise, splanchnic organ blood flow is reduced from resting values. Whether sex and menstrual cycle phase influence splanchnic blood flow responses during exercise remains unknown. We show that the decrease in celiac artery blood flow during dynamic leg exercise does not differ between young females and males or between menstrual cycle phases. In young individuals, sex and menstrual cycle have minimal influence on splanchnic artery hemodynamic responses during dynamic moderate-intensity leg exercise.

Cardiovascular reflex contributions to sympathetic inhibition during low intensity dynamic leg exercise in healthy middle-age.

Aging augments resting muscle sympathetic nerve activity (MSNA) and sympatho-inhibition during mild dynamic 1-leg exercise. To elucidate which reflexes elicit exercise-induced inhibition, we recruited 19 (9 men) healthy volunteers (mean age 56 ± 9 SD years), assessed their peak oxygen uptake (VO2peak ), and, on another day, measured heart rate (HR), blood pressure (BP) and MSNA (microneurography) at rest and during 1-leg cycling (2 min each at 0 load and 30%-40% VO2peak ), 3 times: (1) seated +2 min of postexercise circulatory occlusion (PECO) (elicit muscle metaboreflex); (2) supine (stimulate cardiopulmonary baroreflexes);and (3) seated, breathing 32% oxygen (suppress peripheral chemoreceptor reflex). While seated, MSNA decreased similarly during mild and moderate exercise (p < 0.001) with no increase during PECO (p = 0.44). Supine posture lowered resting MSNA (main effect p = 0.01) BP and HR. MSNA fell further (p = 0.04) along with diastolic BP and HR during mild, not moderate, supine cycling. Hyperoxia attenuated resting (main effect p = 0.01), but not exercise MSNA. In healthy middle-age, the cardiopulmonary baroreflex and arterial chemoreflex modulate resting MSNA, but contrary to previous observations in young subjects, without counter-regulatory offset by the sympatho-excitatory metaboreflex, resulting in an augmented sympatho-inhibitory response to mild dynamic leg exercise.

Sex differences in blood pressure and inactive limb blood flow responses during dynamic leg exercise with increased inspiratory muscle work.

We hypothesized that, compared with young males, young females have a smaller decrease in blood flow to the inactive limb, accompanied by a smaller increase in arterial blood pressure, during dynamic exercise with increased inspiratory muscle work. Young males and females performed dynamic knee-extension and -flexion exercises for 10 min (spontaneous breathing for 5 min and voluntary hyperpnoea with or without inspiratory resistance for 5 min). Mean arterial blood pressure (MAP) and mean blood flow (MBF) in the brachial artery were continuously measured by means of finger photoplethysmography and Doppler ultrasound, respectively. No sex differences were found in the ΔMAP and ΔMBF (Δ: from baseline) during exercise without inspiratory resistance. In contrast, the ΔMAP during exercise with inspiratory resistive breathing was greater (P < 0.05) in males (+31.3 ± 2.1 mmHg, mean ± SE) than females (+18.9 ± 3.2 mmHg). The MBF during exercise with inspiratory resistance did not change in males (-4.4 ± 10.6 mL/min), whereas it significantly increased in females (+25.2 ± 15.4 mL/min). These results suggest that an attenuated inspiratory muscle-induced metaboreflex in young females affects blood flow distribution during submaximal dynamic leg exercise.

Pericardial fat is adversely related to cardio-mechanical interaction in heart failure with preserved ejection fraction: implications for exercise intolerance

Abstract Background Exercise intolerance is the primary manifestation in heart failure with preserved ejection fraction (HFpEF); however, the pathophysiologic mechanism(s) remains incompletely understood. Excess cardiac adiposity may physically constrain the myocardium, resulting in adverse Cardio-Mechanical Interaction (i.e., greater left ventricular eccentricity); a phenomenon only expected to worsen during exercise, with increased respiratory excursion and hemodynamic load. Evidence for this hypothesis, however, remains limited to a small number of observations, from a single group, made only under resting conditions using transthoracic echocardiography. Purpose To evaluate the relationship between pericardial fat and cardio-mechanical interaction in HFpEF at rest and during exercise using high resolution cardiac magnetic resonance imaging (cMRI). Methods We performed real-time (ungated), free-breathing cinematic imaging of the left ventricular (LV) short axis in 11 individuals with HFpEF (4M/7F, BMI: 36±6, age: 69±4 years). Imaging was performed at rest and during dynamic leg exercise (30 Watts) using an MRI-compatible ergometer (Ergospect, Austria). Epicardial and paracardial fat area were measured using high resolution cine images in the horizontal long axis imaging plane, with epicardial fat defined as the adipose tissue within the pericardium and paracardial fat defined as the adipose tissue outside of the pericardium (Figure 1A); the sum of which defined pericardial fat area. The LV eccentricity index was calculated as the ratio of LV short axis diameter parallel to the septum (anteroposterior dimension, AP) to the LV short axis diameter perpendicular to the septum (septolateral dimension, SL, Figure 1A) at mid-ventricular level, during inspiration at end-diastole. Results At rest, adverse cardio-mechanical interaction (i.e., AP/SL &amp;gt;1.0) was observed in 5 of the 11 cases. In those with adverse cardio-mechanical interaction both epicardial and paracardial fat area were significantly higher, resulting in greater pericardial fat area (Figure 1B). While epicardial fat area was not related to LV eccentricity index (R2=0.19, P=0.18), we observed a strong correlation between paracardial fat area and LV eccentricity index (R2=0.93, P&amp;lt;0.01), and pericardial fat area and LV eccentricity index (R2=0.86, P&amp;lt;0.01, Figure 1C). In contrast to our hypothesis, however, supine exercise did not exacerbate cardio-mechanical interaction, with LV eccentricity index remaining elevated in 4 of the 5 original cases, improving the fifth case (1.1 to 0.9, rest to exercise). Conclusions Taken together, these data extend prior reports of adverse cardio-mechanical interaction in HFpEF, showing greater contribution from paracardial fat versus epicardial fat. Future studies are needed to examine cardio-mechanical interaction during upright exercise in HFpEF patients. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): National Institutes of Health

Exercise hemodynamics by echocardiography and right heart catheterization in patients with chronic thromboembolic pulmonary disease

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is an important cause of pulmonary hypertension (PH). A subclinical form of PH is referred to as exercise-induced pulmonary hypertension (EIPH), and its prevalence in patients with chronic thromboembolic pulmonary disease (CTEPD) without pulmonary hypertension at rest is unknown. Purpose To explore the occurrence of exercise-induced pulmonary hypertension (PH) in patients with CTEPD and compare exercise echocardiography with right heart catheterization (RHC). Methods In total, 16 patients with CTEPD, all diagnosed after pulmonary embolism, underwent exercise echocardiography and exercise RHC with dynamic supine leg exercise using a cycle ergometer. CTEPH at rest was defined as mean pulmonary artery pressure (mPAP) &amp;gt;20 mmHg and pulmonary vascular resistance (PVR) ≥3WU. EIPH by RHC was defined as mPAP &amp;gt;30 mmHg with total pulmonary resistance (TPR) ≥3 WU. Based on these criteria, our patients with CTEPD are presented by a flow chart (Figure 1). Systolic pulmonary artery pressure by echocardiography was calculated by tricuspid regurgitation peak velocity (TR V max) and the Bernoulli formula: 4 × (TR V)2. The RHC examination followed the exercise echocardiography within 2 hours. Groups were compared with independent sample t-test. Results Four patients (25%) were diagnosed with EIPH by exercise RHC. Patients with EIPH had a mean mPAP at peak exercise of 40.5 mmHg (range 38 to 43mmHg) and TPR of 3.7 WU (range 3.0 to 4.3 WU). The same patients also had a higher TR V max at peak exercise during exercise echocardiography compared to the patients without EIPH (Table 2). None of the patients had signs of elevated left-sided filling pressure during exercise by RHC, and none had left ventricular diastolic dysfunction during exercise by echocardiography. Conclusion In total, 4 of 16 patients with CTEPD were diagnosed with EIPH. The same four patients also had abnormal pulmonary artery pressure rise during exercise echocardiography and invasive RHC. These findings suggest that exercise echocardiography may be useful for screening patients with CTEPD and suspected EIPH. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Ostfold Hospital Trust

Exercise-induced pulmonary hypertension assessed by echocardiography in patients with chronic thromboembolic pulmonary disease

Abstract Background Many patients with chronic thromboembolic pulmonary disease (CTEPD) without pulmonary hypertension (PH) at rest suffer from exercise intolerance. Exercise echocardiography, which is a noninvasive examination, may have potential to discover exercise-induced PH in these patients, however, its role is scarcely explored in this population. Purpose To determine the occurrence of abnormal pulmonary pressure during rest and by exercise echocardiography in patients with CTEPD. Methods In total, 24 patients with CTEPD, all diagnosed after pulmonary embolism, underwent exercise echocardiography with dynamic supine leg exercise using a cycle ergometer. In addition, all participants underwent a modified incremental shuttle walk test (mISWT), pulmonary function tests and measurement of NT pro-BNP. Systolic pulmonary arterial pressure (sPAP) &amp;gt;50 mmHg by echocardiography during exercise was chosen as cutoff to define exercise-induced pulmonary hypertension (EIPH). Left ventricular diastolic dysfunction during stress was defined according to the American Society of Cardiology guidelines from 2016. Mean pulmonary artery pressure was estimated by sPAP measurements using the Chemla formula (0.61 x sPAP + 2 mmHg), and pulmonary vascular resistance (PVR) by the Doppler method (5.19 x TRV2/TVI RVOT − 0.4) proposed by Abbas et al. [1]. Subjects with heart failure with reduced or preserved ejection fraction, significant valvular heart disease, chronic pulmonary disease and chronic thromboembolic pulmonary hypertension were excluded. Results 11 (46%) of the patients had EIPH at peak exercise (range 50 to 89 mmHg). PVR at peak exercise ranged from 2.6 to 5.9 WU, whereas 10 had PVR &amp;gt;3.0 WU. None had unmasked left ventricular diastolic dysfunction during exercise, resting tricuspid regurgitation peak velocity (TR V max) &amp;gt;3.4m/s, or a high probability of PH at rest. Three patients had TR V max between 2.9 and 3.4m/s or intermediate probability of PH. All patients had normal biventricular systolic function at rest and during exercise (Table 2). Conclusion Patients with CTEPD had normal pulmonary pressures at rest. However, approximately half of the patients showed abnormal rise in pulmonary pressure during exercise, which may explain or contribute to the exercise intolerance in these patients. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Ostfold Hospital Trust

Sympathetic vasomotor outflow during low-intensity leg cycling in healthy older males.

What is the central question of this study? Sympathetic vasomotor outflow is reduced during low-intensity dynamic leg exercise in younger individuals: does ageing influence the sympathoinhibitory effect during low-intensity leg cycling? What is the main finding and its importance? Muscle sympathetic nerve activity during low-intensity cycling decreased in older males, as seen in young males. It is possible that cardiopulmonary baroreflex-mediated inhibition of sympathetic vasomotor outflow during dynamic leg exercise is preserved in healthy older males. Muscle sympathetic nerve activity (MSNA) is reduced during low-intensity dynamic leg exercise in young males. It is suggested that this inhibition is mediated by loading of the cardiopulmonary baroreceptors. The purpose of this study was to clarify the impact of age on MSNA during dynamic leg exercise. Nine younger males (YM, mean±SD, 20±1years) and nine older males (OM, 72±3years) completed the study. The subjects performed two 4-min cycling exercises at 10% of their heart rate reserve using a cycle ergometer in a semirecumbent position (MSNA and estimated central venous pressure (eCVP) trials). MSNA was recorded via microneurography of the left radial nerve. The CVP was estimated based on peripheral venous pressure, which was monitored using a cannula in the right large antecubital vein. The magnitude of the increase in mean arterial blood pressure during leg cycling was larger in OM (+9.3±5.5mmHg) compared with YM (+2.8±4.7mmHg). MSNA burst frequency was decreased during cycling in both YM (-8.1±3.8bursts/min) and OM (-10.6±3.3bursts/min), but no significant difference was found between the two groups. The eCVP increased during exercise in both groups, and there was no difference in the changes in eCVP between YM (+1.1±0.4mmHg) and OM (+1.2±0.7mmHg). These data indicate that inhibition of sympathetic vasomotor outflow during low-intensity cycling appears in OM as seen in YM. It is possible that the muscle pump-induced loading of the cardiopulmonary baroreflex is preserved during cycling in healthy older males.

Evaluation of Exercise‐Induced Changes in Lung Water Density in Heart Failure with Preserved Ejection Fraction

The primary chronic symptom of heart failure with preserved ejection fraction (HFpEF) is severe exercise intolerance, often associated with dyspnea upon exertion. Here we examine the role of pulmonary congestion, by measuring lung water density (LWD, %) using a previously validated magnetic resonance imaging (MRI) approach. First, in 6 healthy reference controls (3 M/3 F, BMI: 23 ± 3 kg/m2, age: 24 ± 4 years) LWD was measured at rest and in response to six minutes of moderate intensity dynamic leg exercise, using an MRI compatible exercise ergometer. LWD decreased in all six healthy reference controls immediately following exercise (from 24.8 ± 3.0% to 18.9 ± 4.2%, p=0.003), while returning to baseline ten minutes after exercise cessation. Next, we assessed exercise‐induced changes in LWD in 10 individuals with HFpEF (4 M/6 F, BMI: 35 ± 6 kg/m2, age: 69 ± 5 years), following the same experimental protocol. In contrast to the reference control participants, LWD remained unchanged from baseline immediately after exercise (22.8 ± 4.1% vs. 21.9 ± 5.2%, respectively), and tended to increase above baseline ten minutes after exercise cessation (25.2 ± 7.7%). Together, the data support the use of cardiovascular MRI in evaluating LWD at rest and in response to exercise. More work is needed to determine whether changes in LWD contribute to exercise intolerance in HFpEF.

Heart failure-specific inverse relationship between the muscle sympathetic response to dynamic leg exercise and V̇O2peak

During 1-leg cycling, contralateral muscle sympathetic nerve activity (MSNA) falls in healthy adults but increases in most with reduced ejection fraction heart failure (HFrEF). We hypothesized that their peak oxygen uptake (V̇O2peak) relates inversely to their MSNA response to exercise. Twenty-nine patients (6 women; 63 ± 9 years; left ventricular ejection fraction: 30 ± 7%; V̇O2peak: 78 ± 23 percent age-predicted (%V̇O2peak); mean ± SD) and 21 healthy adults (9 women; 58 ± 7 years; 115 ± 29%V̇O2peak) performed 2min of mild- ("loadless") and moderate-intensity ("loaded") 1-leg cycling. Heart rate, blood pressure (BP), contralateral leg MSNA and perceived exertion rate (RPE) were recorded. Resting MSNA burst frequency (BF) was higher (p < 0.01) in HFrEF (51 ± 11 vs 44 ± 7 bursts·min-1). Exercise heart rate, BP and RPE responses at either intensity were similar between groups. In minute 2 of "loadless" and "loaded" cycling, group mean BF fell from baseline values in controls (-5 ± 6 and -7 ± 7 bursts·min-1, respectively) but rose in HFrEF (+5 ± 7 and +5 ± 10 bursts·min-1). However, in 10 of the latter cohort, BF fell, similarly to controls. An inverse relationship between ΔBF from baseline to "loaded" cycling and %V̇O2peak was present in patients (r = -0.43, p < 0.05) but absent in controls (r = 0.07, p = 0.77). In HFrEF, ∼18% of variance in %V̇O2peak can be attributed to the change in BF elicited by exercise. Novelty: Unlike healthy individuals, in the majority of heart failure patients with reduced ejection fraction (HFrEF), 1-leg cycling increases muscle sympathetic nerve activity (MSNA). In HFrEF, ∼18% of age-predicted peak oxygen uptake (V̇O2peak) can be attributed to changes in MSNA elicited by low-intensity exercise. This relationship is absent in healthy adults.

Interaction between the muscle metaboreflex and central command - A clearer picture of cardiorespiratory control during exercise.

Neural control of the circulatory and ventilatory responses to exercise has been an intriguing area of investigation for well over 100 years. However, development of experimental protocols that clarify mechanisms and their relative importance has proved difficult because of the likelihood of redundancy and the complexity of central integration. In this issue of Experimental Physiology, Lam, Greenhough, Nazari, White, & Bruce (2019) met this challenge with an elegant and cleverly designed study in humans that improves our understanding of the contribution of metabolically sensitive neural feedback from active skeletal muscle to the cardiorespiratory response to dynamic exercise. Ventilation and heart rate responses to exercise occur rapidly to a level well matched to the workload. Descending neural signals from higher brain centres (i.e. central command) have a prominent role in increasing ventilation and heart rate in proportion to the effort exerted (Goodwin, McCloskey, & Mitchell, 1972). When examining the contribution of metabolically sensitive neural feedback from active skeletal muscle (i.e. the metaboreflex) in isolation after exercise, which effectively increases blood pressure, the ventilatory and heart rate responses generally trend towards resting values. Given this, the observation that ventilation and heart rate rapidly return towards resting levels during metaboreflex isolation (i.e. postexercise ischaemia) has led some to suggest that the muscle metaboreflex has little influence on both ventilation and heart rate. Countering evidence shows a contribution of the afferent feedback from contracting skeletal muscle to the ventilatory and heart rate response to dynamic leg exercise that is attenuated by pharmacological blockade (Amann et al. 2010). These findings seem to suggest that the metaboreflex can contribute to the ventilatory response to exercise, but only in certain conditions. The study by Lam et al. (2019) provides insight into this mechanism by demonstrating metaboreflex control of exercise ventilation and heart rate only when central command is engaged, i.e. during exercise. To demonstrate this, the authors used an innovative and creative study protocol, in which cardiorespiratory responses to left-legged cycling were followed by right-legged cycling with and without left leg postexercise circulatory occlusion (PECO). Relative to baseline, ventilation was elevated during leg cycling, as expected, but was heightened further during concomitant PECO, particularly at higher workloads. Indeed, ventilation returned to baseline when PECO was performed in a separate protocol without right-legged cycling. Central respiratory drive is modified by many afferent inputs during exercise. However, chemosensitive structures in the medulla and carotid bodies responsible for ventilatory responses to hypoxia and hypercapnia probably make a small contribution to the ventilatory response to mild- and moderate-intensity exercise because arterial , and pH remain relatively constant. Indeed, end-tidal CO2 () was not increased with higher intensity single-legged cycling. In fact, single-legged cycling combined with PECO significantly reduced , probably as a result of greater ventilation relative to CO2 production. Thus, if lower arterial were to be confirmed ( is not necessarily equivalent to arterial ), it would suggest opposite signalling from the muscle metaboreflex and central chemoreflex and perhaps an overall underestimation of metaboreflex-mediated increases in ventilation. However, little is known regarding the potential interaction between the muscle metaboreflex and central and peripheral chemoreceptor input to modulate exercise ventilation. Advancements in the field often create more questions than answers, and the study by Lam et al. (2019) is no exception. An exaggerated ventilatory response to exercise is characteristic of patients with heart failure, chronic obstructive pulmonary disease and pulmonary hypertension. The obvious question is, to what extent does the metaboreflex contribute? Also, exaggerated sympathetic responses (not assessed in the study by Lam et al., 2019) to isolated muscle metaboreflex activation have been documented in patient populations with high prevalence, such as hypertension, heart failure and diabetes. Future studies are needed to determine the extent to which the interaction between the metaboreflex and central command augments the sympathetic response beyond what is observed during isolated metaboreflex activation in these patient populations. To this end, the authors are to be commended on moving a step forwards in our understanding of the role of the skeletal muscle metaboreflex in controlling ventilation and heart rate during exercise in healthy humans.

Effects of dynamic arm and leg exercise on muscle sympathetic nerve activity and vascular conductance in the inactive leg.

The influence of muscle sympathetic nerve activity (MSNA) responses on local vascular conductance during exercise are not well established. Variations in exercise mode and active muscle mass can produce divergent MSNA responses. Therefore, we sought to examine the effects of small- versus large-muscle mass dynamic exercise on vascular conductance and MSNA responses in the inactive limb. Thirty-five participants completed two study visits in a randomized order. During visit 1, superficial femoral artery (SFA) blood flow (Doppler ultrasound) was assessed at rest and during steady-state rhythmic handgrip (RHG; 1:1 duty cycle, 40% maximal voluntary contraction), one-leg cycling (17 ± 3% peak power output), and concurrent exercise at the same intensities. During visit 2, MSNA (contralateral fibular nerve microneurography) was acquired successfully in 12/35 participants during the same exercise modes. SFA blood flow increased during RHG (P < 0.0001) and concurrent exercise (P = 0.03) but not cycling (P = 0.91). SFA vascular conductance was unchanged during RHG (P = 0.88) but reduced similarly during concurrent and cycling exercise (both P < 0.003). RHG increased MSNA burst frequency (P = 0.04) without altering burst amplitude (P = 0.69) or total MSNA (P = 0.26). In contrast, cycling and concurrent exercise had no effects on MSNA burst frequency (both P ≥ 0.10) but increased burst amplitude (both P ≤ 0.001) and total MSNA (both P ≤ 0.007). Across all exercise modes, the changes in MSNA burst amplitude and SFA vascular conductance were correlated negatively (r = -0.43, P = 0.02). In summary, the functional vascular consequences of alterations in sympathetic outflow to skeletal muscle are most closely associated with changes in MSNA burst amplitude, but not frequency, during low-intensity dynamic exercise.NEW & NOTEWORTHY Low-intensity small- versus large-muscle mass exercise can elicit divergent effects on muscle sympathetic nerve activity (MSNA). We examined the relationships between changes in MSNA (burst frequency and amplitude) and superficial femoral artery (SFA) vascular conductance during rhythmic handgrip, one-leg cycling, and concurrent exercise in the inactive leg. Only changes in MSNA burst amplitude were inversely associated with SFA vascular conductance responses. This result highlights the functional importance of measuring MSNA burst amplitude during exercise.

Muscle sympathetic nerve activity during exercise.

Appropriate cardiovascular adjustment is necessary to meet the metabolic demands of working skeletal muscle during exercise. The sympathetic nervous system plays a crucial role in the regulation of arterial blood pressure and blood flow during exercise, and several important neural mechanisms are responsible for changes in sympathetic vasomotor outflow. Changes in sympathetic vasomotor outflow (i.e., muscle sympathetic nerve activity: MSNA) in inactive muscles during exercise differ depending on the exercise mode (static or dynamic), intensity, duration, and various environmental conditions (e.g., hot and cold environments or hypoxic). In 1991, Seals and Victor [6] reviewed MSNA responses to static and dynamic exercise with small muscle mass. This review provides an updated comprehensive overview on the MSNA response to exercise including large-muscle, dynamic leg exercise, e.g., two-legged cycling, and its regulatory mechanisms in healthy humans.

Effect of Dynamic Eccentric Leg Exercise Training on Functional Fitness and Arterial Stiffness in Older Adults

Eccentric exercise is shown to offer musculoskeletal benefits in multiple populations, but little is known about the effect of chronic dynamic eccentric exercise training in older adults concerning functional physical fitness and cardiovascular health. Therefore, the purpose of this study was to determine if twelve weeks of dynamic eccentric leg exercise (Eccentron) could improve functional fitness and reduce arterial stiffness. Thirteen older adults (ages 65–79 years; M = 70±1) performed dynamic eccentric leg exercise twice per week at a light to somewhat hard rating of perceived exertion. Exercise duration increased from five minutes per session in the first week to 25 minutes per session during the final week. Timed up and go test significantly improved from pre‐ to post‐training (5.7±0.2 vs. 5.3±0.1 s; p&lt;0.05). Likewise, Berg Balance Score was statistically (p&lt;0.05) improved from pre‐ to post‐training. Participants demonstrated non‐significant increases in single‐leg knee extensor strength (43.0±2.6 vs. 45.2±2.8 kg; p=0.26). Aortic arterial stiffness, assessed via carotid‐femoral pulse wave velocity, did not change from pre‐ to post‐eccentric exercise training (8.6±0.7 vs. 9.2±0.5 m/s; p=0.44). Similarly, leg arterial stiffness, assessed as femoral to dorsalis pedis pulse wave velocity, was unchanged (9.9±0.8 vs. 9.2±0.5 m/s; p=0.31). Our results demonstrate how 12‐weeks of eccentric training can positively influence functional physical fitness measures in older adults without a negative influence on arterial stiffness. Significant improvements in timed up and go and the Berg Balance Score, and non‐significant increases in leg extensor strength, suggests that older adults could improve their agility and balance, and reduce their risk of falling through eccentric leg exercise.Support or Funding InformationSupported by the Portage Health Foundation and Michigan Tech Research Excellence Fund.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of Dynamic Arm and Leg Exercise on Muscle Sympathetic Nerve Activity and Vascular Conductance in the Inactive Leg

The aim of this study was to comprehensively assess the effects of rhythmic handgrip (RHG), one‐leg cycling, and concurrent arm and leg exercise on muscle sympathetic nerve activity (MSNA) and vascular conductance responses in the inactive leg. Thirty‐five participants completed two study visits in a randomized order. During visit 1, hemodynamic (Finometer) and superficial femoral artery (SFA) blood flow (Doppler ultrasound) measurements were assessed at rest and during 3 min of RHG (1:1 duty cycle; 40% MVC), one‐leg cycling (17 ± 3% peak power output), and concurrent exercise at the same intensities. During visit 2, hemodynamic and MSNA (fibular nerve microneurography) measurements were acquired during the same exercise modes (MSNA; n=12). SFA blood flow and MSNA were both acquired in the inactive leg. Heart rate, blood pressure, cardiac output, and respiration rate increased during each exercise mode (all, P&lt;0.0001), with the largest increases during concurrent exercise (all, P&lt;0.006); no differences were detected between visit 1 and 2 (all, P&gt;0.05). SFA mean blood flow increased during RHG (Δ24 ± 30 ml/min, P&lt;0.0001) and concurrent exercise (Δ10 ± 38 ml/min, P=0.03) but not cycling (Δ2.3 ± 30 ml/min, P=0.9). SFA vascular conductance was unchanged during RHG (Δ0.02 ± 0.29 ml·min−1·mmHg−1, P=0.9) but reduced similarly during concurrent and cycling exercise (Δ−0.14 ± 0.33 ml·min−1·mmHg−1; Δ−0.14 ± 0.38 ml·min−1·mmHg−1, P&lt;0.003). RHG increased MSNA burst frequency (Δ4 ± 8 burst/min, P=0.04) without altering burst amplitude (Δ7 ± 14 %, P=0.7) or total MSNA (Δ40 ± 40 %, P=0.07). In contrast, cycling and concurrent exercise had no effects on MSNA burst frequency (Δ−3 ± 6 burst/min and Δ4 ± 6 burst/min, P≥0.1) but increased burst amplitude (Δ34 ± 30 %; Δ31 ± 31 %, P≤0.001) and total MSNA (Δ59 ± 63 %; Δ94 ± 100 %, P≤0.007). In conclusion, during one‐leg cycling or concurrent exercise, reductions in inactive leg SFA vascular conductance occurred in parallel with increases in burst amplitude and total MSNA but not burst frequency. Exercise studies relying solely on measures of MSNA burst occurrence may not accurately reflect the corresponding changes in vascular conductance.Support or Funding InformationResearch was supported by a Natural Science and Engineering Research Council (NSERC) of Canada Discovery Grant (P.J.M; #06019), the Canada Foundation for Innovation (P.J.M.; #34379), and the Ontario Ministry of Research, Innovation, and Science (P.J.M. #34379).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Microneurographic characterization of sympathetic responses during 1-leg exercise in young and middle-aged humans.

Muscle sympathetic nerve activity (MSNA) at rest increases with age. However, the influence of age on MSNA recorded during dynamic leg exercise is unknown. We tested the hypothesis that aging attenuates the sympatho-inhibitory response observed in young subjects performing mild to moderate 1-leg cycling. After predetermining peak oxygen uptake, we compared contra-lateral fibular nerve MSNA during 2 min each of mild (unloaded) and moderate (30%-40% of the work rate at peak oxygen uptake, halved for single leg) 1-leg cycling in 18 young (age, 23 ± 1 years (mean ± SE)) and 18 middle-aged (age, 57 ± 2 years) sex-matched healthy subjects. Mean height, weight, resting heart rate, systolic blood pressure, and percent predicted peak oxygen uptake were similar between groups. Middle-aged subjects had higher resting MSNA burst frequency and incidence (P < 0.001) and diastolic blood pressure (P = 0.04). During moderate 1-leg cycling, older subjects' systolic blood pressure increased more (+21 ± 5 vs. +10 ± 1 mm Hg; P = 0.02) and their fall in MSNA burst incidence was amplified (-19 ± 2 vs. -11 ± 2 bursts/100 heart beats; P = 0.01) but because heart rate rose less (+15 ± 3 vs. +19 ± 2 bpm; P = 0.03), exercise induced similar reductions in burst frequency (P = 0.25). Contrary to our initial hypothesis, with advancing age, mild- to moderate-intensity dynamic leg exercise elicits a greater rise in systolic blood pressure and a larger fall in MSNA.

Impact of acute dynamic exercise on radial artery low-flow mediated constriction in humans

PurposeA “low-flow mediated constriction” (L-FMC) is evoked in the radial artery by the inflation of an ipsilateral wrist cuff to a supra-systolic pressure. We sought to test the hypothesis that the radial artery L-FMC response is augmented immediately following acute dynamic leg exercise in young healthy individuals.MethodsTen healthy and recreationally active men (23 ± 4 years) undertook a 30-min trial of incremental dynamic leg cycling exercise (10 min at 50, 100 and 150 W) and a 30-min time control trial (seated rest). Trials were randomly assigned and performed on separate days. Radial artery characteristics (diameter, blood flow and shear rate) were assessed throughout each trial, with L-FMC and flow-mediated vasodilatation (FMD) assessments conducted prior to and immediately following (10 min) trials.ResultsDynamic leg cycling exercise increased radial artery blood flow, along with mean, retrograde and anterograde shear rate (P < 0.05). Blood flow profiles were unchanged during the time control trial (P > 0.05). Following exercise L-FMC was increased (mean [SD]; − 5.6 [3.3] vs. − 10.1 [3.8] %, P < 0.05), while it was not different in the time control condition (− 8.1 [3.2] vs. − 6.7 [3.4] %, P > 0.05). FMD was not different following either the exercise or time control trials (P > 0.05), but the composite end-point of L-FMC + FMD was enhanced post-exercise (P < 0.05).ConclusionsDynamic exercise with a large muscle mass acutely augments the vasoconstrictor response of the radial artery in response to a reduction in blood flow (L-FMC) in young healthy individuals. The time course of this post-exercise response and the underlying vasoregulatory mechanisms require elucidation.

Abstract 721: The Exercise Pressor Response to Lower Extremity Dynamic Exercise is Accompanied by an Abnormal Change in Total Peripheral Resistance in Peripheral Arterial Disease Subjects

Patients with peripheral arterial disease (PAD) have an exaggerated pressor response to dynamic exercise of the affected limb. We tested the hypothesis that this response is mediated by an increase in total peripheral resistance (TPR). We measured heart rate, blood pressure, stroke volume, cardiac output (CO), and total peripheral resistance (TPR) during exercise in 9 subjects with PAD and 9 age matched controls using continuous finger arterial pressure monitoring (Finometer). Finometer derived values were adjusted to values obtained by echocardiography, and brachial pressure at baseline. The average age and ABI was 65 ± 7 and 1.06 ± 0.07 in controls, and 66 ± 7 and 0.64 ± 0.08 in PAD. Participants performed dynamic plantar flexion at progressive workloads of 2 to 12kg (increased by 1kg/min until onset of fatigue/pain) using their symptomatic leg or leg with lower ABI. Those who reached 12kg continued exercise at a constant load until onset of fatigue/pain or a maximum of 4 minutes. Participants were then asked to perform an isometric handgrip exercise at 30% of maximum voluntary contraction (MVC) until fatigue. Results are shown in Table 1. There were no differences in hemodynamic parameters at baseline. The average weight at end of plantar flexion was 12.0 ± 0.2 and 9.2 ± 2.5 kg (p&lt;0.0001) for control and PAD. Perceived exertion (Borg scale) and pain (NPRS scale) at end of exercise was 15 ± 2 and 0, and 15 ± 2 and 6 ± 3 in control and PAD. Plantar flexion elicited a significantly higher rise in blood pressure in PAD compared to control. TPR decreased in controls, but slightly increased in PAD. In contrast, isometric handgrip elicited a similar pressor response, as well as changes in CO and TPR in both groups. We conclude that the exaggerated pressor response in PAD is mediated by an abnormal response in TPR, which counteracts the normal vasodilatory response to dynamic leg exercise seen in controls. This response appears to be specific to dynamic plantar flexion exercise in PAD.

High-intensity muscle metaboreflex activation attenuates cardiopulmonary baroreflex-mediated inhibition of muscle sympathetic nerve activity.

Previous studies have shown that muscle sympathetic nerve activity (MSNA) is reduced during low- and mild-intensity dynamic leg exercise. It has been suggested that such inhibition is mediated by loading of the cardiopulmonary baroreceptors and that this effect is overridden by muscle metaboreflex activation with higher-intensity exercise. However, limited data are available regarding the interaction between the cardiopulmonary baroreflex and the muscle metaboreflex. Therefore, we tested the hypothesis that cardiopulmonary baroreflex-mediated inhibition of MSNA is attenuated during high-intensity muscle metaboreflex activation. In nine young men, MSNA (right peroneal nerve), mean arterial pressure (MAP), and thoracic impedance were recorded. Graded isolation of muscle metaboreflex activation was achieved via postexercise ischemia (PEI) following low (PEI-L)-, moderate (PEI-M)-, and high (PEI-H)-intensity isometric handgrip performed at 20, 30, and 40% maximum voluntary contraction, respectively. Lower-body positive pressure (LBPP, +10 Torr) was applied at rest and during PEI, to load the cardiopulmonary baroreceptors. Handgrip exercise elicited intensity-dependent increases in MSNA and MAP that were maintained during PEI, indicating a graded muscle metaboreflex activation. LBPP at rest significantly decreased MSNA burst frequency (BF: -36.7 ± 4.7%, mean ± SE, P < 0.05), whereas MAP was unchanged. When LBPP was applied during PEI, MSNA BF decreased significantly at PEI-L (-40.0 ± 9.2%, P < 0.05) and PEI-M (-27.0 ± 6.3%, P < 0.05), but not at PEI-H (+1.9 ± 7.1%, P > 0.05). These results suggest that low- and moderate-intensity muscle metaboreflex activation does not modulate the inhibition of MSNA by cardiopulmonary baroreceptor loading, whereas high-intensity metaboreflex activation can override cardiopulmonary baroreflex-mediated inhibition of sympathetic vasomotor outflow. NEW & NOTEWORTHY The interaction between the sympathoinhibitory influence of cardiopulmonary baroreflex and sympathoexcitatory effect of skeletal muscle metaboreflex is not completely understood. In the current study, light- to moderate-intensity muscle metaboreflex activation did not modulate the suppression of muscle sympathetic nerve activity by cardiopulmonary baroreceptor loading, whereas high-intensity muscle metaboreflex activation attenuated the cardiopulmonary baroreflex-mediated inhibition of muscle sympathetic nerve activity. These results provide important information concerning the neural reflex mechanisms regulating sympathetic vasomotor outflow during exercise.

High Intensity Muscle Metaboreflex Activation Blunts Cardiopulmonary Baroreflex Control of Sympathetic Vasomotor Outflow

Muscle sympathetic nerve activity (MSNA) is reduced during low intensity dynamic leg exercise. This reduction in MSNA has been attributed to loading of the cardiopulmonary baroreflex with increased venous return and it has been suggested that such inhibition is overridden with higher intensity exercise due to muscle metaboreflex activation. However, limited data are available regarding the interaction between the cardiopulmonary baroreflex and the muscle metaboreflex. Herein, we tested the hypothesis that cardiopulmonary baroreflex control of MSNA is attenuated when the muscle metaboreflex is strongly activated. In eight healthy young men, MSNA (right peroneal nerve), mean arterial blood pressure (MAP, Finometer), heart rate (ECG), and thoracic impedance were recorded. Graded isolation of the muscle metaboreflex was achieved by post‐exercise ischemia (PEI) following low‐ (PEI‐L), moderate‐ (PEI‐M) and high‐ (PEI‐H) intensity isometric handgrip performed at 20%, 30% and 40% maximum voluntary contraction, respectively. Lower‐body positive pressure (LBPP, +10 mmHg), to load the cardiopulmonary baroreflex, was applied at rest and during PEI. Handgrip exercise elicited intensity‐dependent increases in MSNA and MAP that were maintained during PEI indicating a graded muscle metaboreflex activation. LBPP at rest significantly decreased MSNA burst frequency and total activity (total activity: −39.5 ± 5.7%, mean ± SE, P &lt; 0.05), while MAP was unchanged. When LBPP was applied during PEI, MSNA burst frequency and total activity decreased significantly at PEI‐L (total activity: −41.8 ± 10.6%, P &lt; 0.05) and PEI‐M (total activity: −34.7 ± 8.6%, P &lt; 0.05), but not at PEI‐H (total activity: −11.8 ± 8.6%, n.s., one‐way repeated measures ANOVA: F = 5.07, P &lt; 0.05). Thoracic admittance, which was calculated from thoracic impedance as an index of central blood volume, was not changed during handgrip or PEI alone, whereas LBPP evoked similar increases in thoracic admittance during all conditions (rest: +5.4±0.8, PEI‐L: +5.8±0.5, +PEI‐M: +5.4±0.5, PEI‐H: +5.8±0.5 S·10−4, one‐way repeated measures ANOVA: F = 0.38, n.s.). These preliminary findings suggest that high intensity muscle metaboreflex activation attenuates cardiopulmonary baroreflex control of sympathetic vasomotor outflow.Support or Funding InformationNIH R01 HL127071 JSPS KAKENHI Grant Number JP16KK0201This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.