Muscle Metaboreflex Activation Research Articles

Sex Differences in Left Ventricular Stroke Volume During Muscle Metaboreflex Activation

Introduction: Muscle metaboreflex activation (MMA) increases blood pressure, possibly by disproportionate increases in left ventricular (LV) stroke volume (SV) in males compared to females due to greater grip strength and metabolite production. The purpose of this study was to determine the effect of sex on SV during isolated MMA using cardiac MRI in young healthy adults. We hypothesized that SV would increase during MMA to a greater degree in males compared to females, and that this effect would be negated by accounting for grip strength. Methods: Ten males [23(2) yrs] and 10 females [26(5) yrs] underwent cardiac MRI during rest, 30% maximal voluntary contraction (MVC) isometric handgrip exercise (6 min), and isolation of MMA with brachial cuff circulatory occlusion (6 min). SV, end-systolic (ESV) and end-diastolic volumes (EDV) were measured by 2- and 4-chamber cine images and indexed (i) to body surface area to account for body size. Heart rate (HR, ECG) and mean arterial pressure (MAP, brachial cuff) were recorded. Cardiac output index (COi) and total peripheral resistance (TPR) were calculated. Analyses included ANOVA (sex × condition), ANCOVA [100% MVC (M=49(13) kg, F=26(7) kg) covariate], and linear regression. Results: SVi decreased from rest to MMA in males [67(8) to 61(5) mL/m2, p=0.0001] but not females [59(9) to 59(7) mL/m2, p=0.998; interaction p=0.002]. Notably, the reduction in SVi during MMA in males ( p=0.002) but not females ( p=0.957) remained with ANCOVA using MVC as the covariate (interaction p=0.021). ESVi increased during MMA in males [39(5) to 48(10) mL/m2, p<0.0001] but not females [32(5) to 36(6) mL/m2, p=0.092; interaction p=0.029]. MMA decreased both EDVi ( p=0.004) and COi ( p=0.045) and increased both MAP ( p<0.0001) and TPR ( p<0.0001) pooled across sex. HR did not change with MMA in either sex (all p≥0.093). Linear regression revealed significant relationships between ΔSVi and ΔESVi in males ( p=0.002, R2=0.709) but not females ( p=0.223, R2=0.179) and between ΔSVi and ΔTPR in males ( p=0.005, R2=0.649) but not females ( p=0.522, R2=0.053). Conclusions: MMA lowers SVi in males but not females, even when accounting for grip strength and despite similar pressor responses in both groups. These findings from gold-standard MRI suggest differential LV responses to MMA between sexes, potentially related to greater sensitivity to increased TPR in males than females. Thus, sex differences in blood pressure control during MMA may be impacted by differences in LV afterload sensitivity. Further, the blood pressure response to MMA may be primarily mediated through TPR and not CO in healthy young adults. Heart and Stroke Foundation of Canada. 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.

The Arterial Baroreflex Buffers Muscle Metaboreflex-Induced Coronary Vasoconstriction

The ability to increase cardiac output and thereby skeletal muscle blood flow during dynamic exercise is paramount to maintaining exercise workload. Increases in cardiac output are driven via increases in heart rate, ventricular function, and central blood volume mobilization which raises arterial blood pressure, in part, due to activation of the muscle metaboreflex. The increase in cardiac sympathetic tone also activates coronary vascular alpha-adrenergic receptors which restrains increases in coronary blood flow which limits increases in ventricular function. During submaximal dynamic exercise, the muscle metaboreflex acts primarily to raise cardiac output with little net peripheral vasoconstriction. However, after sinoaortic baroreceptor denervation (SAD), the muscle metaboreflex causes increases in both cardiac output and total peripheral resistance indicating that the baroreflex buffers the muscle metaboreflex mainly via restraint of peripheral vasoconstriction. To what degree the arterial baroreflex restrains muscle metaboreflex-induced coronary vasoconstriction is unknown. Therefore, we utilized our chronically instrumented canine model to evaluate if SAD would significantly impact muscle metaboreflex-induced coronary vasoconstriction. Canines were chronically instrumented to measure cardiac output, left circumflex coronary artery blood flow, hindlimb blood flow and arterial blood pressure. During steady-state mild treadmill exercise (3.2 kph, 0% grade) the muscle metaboreflex was activated via partial inflation of vascular occluders placed distal to the hindlimb blood flow probe. Metaboreflex activation caused substantial increases in cardiac output, heart rate, cardiac power, coronary blood flow, and arterial blood pressure. Assessment of coronary vasodilation was performed via linear regression of the relationship between coronary vascular conductance (CVC; coronary blood flow/mean arterial pressure) vs. cardiac power (CP, an index of O2 demand). Experiments were performed at least 2 weeks after chronic bilateral SAD. Muscle metaboreflex activation after SAD caused a significantly greater pressor response driven by increases in both cardiac output and total peripheral resistance. Furthermore, after SAD the slope of the CVC-CP relationship was significantly lower during muscle metaboreflex activation (0.072 ml/min/mmHg/Watt, control vs 0.033 ml/min/mmHg/Watt, SAD; p<0.05) We conclude that the arterial baroreflex buffers the muscle metaboreflex and restrains the reflex coronary vasoconstriction. This baroreflex-induced restraint of metaboreflex mediated coronary vasoconstriction potentially limits metaboreflex-induced reductions myocardial oxygen delivery. Augmented coronary vasoconstriction with metaboreflex activation after SAD likely contributes to the smaller role of cardiac output in mediating the rise in arterial blood pressure after SAD, and provides further evidence that baroreflex buffering of metaboreflex responses improves cardiac function. Thus, reduced baroreflex function in heart failure may contribute to the accentuated metaboreflex coronary vasoconstriction which impairs ventricular performance during exercise in heart failure. This work was supported by the National Heart, Lung and, Blood Institute grants HL-055473, HL-126706. 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.

Central motor output does not interact with muscle metaboreceptors input for ventilation regulation during dynamic exercise in health humans

INTRODUCTION: The muscle metaboreflex typically does not contribute to ventilation regulation when activated in isolation at rest via post-exercise circulatory occlusion (PECO), but it might synergistically interact with other mechanisms operating during voluntary exercise. Efferent signals from brain areas involved in the motor control of appendicular skeletal muscles to the medulla (i.e., central command) supposedly contribute to ventilation regulation during voluntary exercise. Therefore, we sought to test the hypothesis that central motor output interacts with muscle metaboreceptor input, generating a greater ventilatory response to PECO during voluntary exercise than electrically-induced involuntary exercise. METHODS: Thirteen healthy adults (4 women, age: 26 ± 5 years) participated in the study. Each participant completed four experiments in random order. Two experiments were accomplished per visit at 30-minute intervals. The interval between visits was at least two and at most seven days. The muscle metaboreflex was activated by rhythmic handgrip exercise with the dominant hand at 60% of the maximal voluntary contraction force with a 2-s duty cycle. Then, the muscle metaboreflex remained active for a 4-minute recovery period via PECO, or it was inactivated via free circulation to the exercised arm. During the last 2-minutes of the handgrip exercise recovery, participants either performed unilateral voluntary plantar flexion with the dominant leg to generate central motor output or the dominant leg’s calf was involuntarily activated by electrical stimulation not to have central motor output. Voluntary and involuntary calf contractions were performed at the same external workload. A rebreathing circuit maintained isocapnia throughout all experiments. A bidirectional turbine measured breath-by-breath airflow. Heart rate was measured via ECG, and arterial pressure by auscultation in a resting arm. RESULTS: Ventilation, heart rate, and arterial pressure increased during handgrip exercise similarly in all experiments. PECO-induced muscle metaboreflex activation maintained ventilation (Δ = 5.4 ± 5.2 l/min, P = 0.003), heart rate (Δ = 6.6 ± 8.0 bpm, P = 0.011) and systolic arterial pressure (Δ = 28.4 ± 14.8 mmHg, P < 0.001) elevated above the control handgrip exercise recovery with free circulation to the exercised arm. The ventilation response to voluntary plantar flexion was greater when PECO was present in the arm than when it was absent (Δ = 8.3 ± 5.6 l/min vs. 4.5 ± 2.7 l/min, P = 0.006), reproducing previous findings. However, the ventilation response to voluntary and involuntary plantar flexion with a PECO background was similar (Δ = 8.3 ± 5.6 l/min vs. 8.2 ± 6.3 l/min, P = 1.000). CONCLUSION: The data do not support that an interaction between central motor output and muscle metaboreceptors input is obligatory to generate a ventilatory response to PECO during voluntary exercise. FINANCIAL SUPPORT: grant 2023/07135-0, São Paulo Research Foundation (FAPESP); Scientific production award from the National Council for Scientific and Technological Development (CNPq; Process: 310110/2019-0). 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.

Muscle metaboreflex stimulates the cardiac sympathetic afferent reflex causing positive feedback amplification of sympathetic activity: effect of heart failure.

Exercise intolerance is a hallmark symptom of heart failure and to a large extent stems from reductions in cardiac output that occur due to the inherent ventricular dysfunction coupled with enhanced muscle metaboreflex-induced functional coronary vasoconstriction, which limits increases in coronary blood flow. This creates a further mismatch between O2 delivery and O2 demand, which may activate the cardiac sympathetic afferent reflex (CSAR), causing amplification of the already increased sympathetic activity in a positive-feedback fashion. We used our chronically instrumented conscious canine model to evaluate if chronic ablation of afferents responsible for the CSAR would attenuate the gain of muscle metaboreflex before and after induction of heart failure. After afferent ablation, the gain of the muscle metaboreflex control of mean arterial pressure was significantly reduced before (-239.5 ± 16 to -95.2 ± 8 mmHg/L/min) and after the induction of heart failure (-185.6 ± 14 to -95.7 ± 12 mmHg/L/min). Similar results were observed for the strength (gain) of muscle metaboreflex control of heart rate, cardiac output, and ventricular contractility. Thus, we conclude that the CSAR contributes significantly to the strength of the muscle metaboreflex in normal animals with heart failure serving as an effective positive-feedback amplifier thereby further increasing sympathetic activity.NEW & NOTEWORTHY The powerful pressor responses from the CSAR arise via O2 delivery versus O2 demand imbalance. Muscle metaboreflex activation (MMA) simultaneously elicits coronary vasoconstriction (which is augmented in heart failure) and profound increases in cardiac work thereby upsetting oxygen balance. Whether MMA activates the CSAR thereby amplifying MMA responses is unknown. We observed that removal of the CSAR afferents attenuated the strength of the muscle metaboreflex in normal and subjects with heart failure.

Augmented sympathoexcitation slows postexercise heart rate recovery.

Slow heart rate recovery following exercise may be influenced by persistent sympathoexcitation. This study examined 1) the effect of muscle metaboreflex activation (MMA) on heart rate recovery following dynamic exercise; and 2) whether the effect of MMA on heart rate recovery is reversible by reducing sympathoexcitation [baroreflex activation via phenylephrine (PE)] in canines. Twenty-two young adults completed control and MMA protocols during cycle ergometry at 110% ventilatory threshold with 5 min recovery. Heart rate recovery kinetics [tau (τ), amplitude, end-exercise, and end-recovery heart rate] and root mean square of successive differences (RMSSD) were measured. Five chronically instrumented canines completed control, MMA (50%-60% imposed reduction in hindlimb blood flow), and MMA with end-exercise PE infusion (MMA + PE) protocols during moderate exercise (6.4 km·h-1) and 3 min recovery. Heart rate recovery kinetics and MAP were measured. MAP increased during MMA versus control in canines (P < 0.001). Heart rate recovery τ was slower during MMA versus control in humans (17% slower; P = 0.011) and canines (150% slower; P = 0.002). Heart rate recovery τ was faster during MMA + PE versus MMA (40% faster; P = 0.034) and was similar to control in canines (P = 0.426). Amplitude, end-exercise, and end-recovery heart rate were similar between conditions in humans (all P ≥ 0.122) and in canines (all P ≥ 0.084). MMA decreased RMSSD in early recovery (P = 0.004). MMA-induced sympathoexcitation slows heart rate recovery and this effect is markedly attenuated with PE. Therefore, elevated sympathoexcitation via MMA impairs heart rate recovery and inhibition of this stimulus normalizes, in part, heart rate recovery.NEW & NOTEWORTHY Augmented sympathoexcitation, via muscle metaboreflex activation, functionally slows heart rate recovery in both young healthy adults and chronically instrumented canines. Furthermore, elevated sympathoexcitation corresponded with lower parasympathetic activity, as assessed by heart rate variability, during the first 3 min of recovery. Finally, sympathoinhibition, via phenylephrine infusion, normalizes heart rate recovery during muscle metaboreflex activation.

Muscle metaboreflex control of left ventricular systolic function in heart failure with reduced ejection fraction.

Heart failure with reduced ejection fraction (HFrEF) exhibits exaggerated sympathoexcitation and altered cardiac and vascular responses to muscle metaboreflex activation (MMA). However, left ventricular (LV) responses to MMA are not well studied in patients with HFrEF. The purpose of this study was to examine LV function during MMA using cardiac magnetic resonance imaging (MRI) in patients with HFrEF. Thirteen patients with HFrEF and 18 healthy age-matched controls underwent cardiac MRI during rest and MMA. MMA protocol included 6 min of isometric handgrip exercise followed by 6-min of brachial postexercise circulatory occlusion. LV stroke volume index (SVi), end-systolic volume index (ESVi), end-diastolic volume index (EDVi), and global longitudinal strain (GLS) were measured by two- and four-chamber cine images. Volumes were indexed to body surface area. Heart rate (via ECG) and brachial mean arterial pressure (MAP) were recorded. Cardiac output and total peripheral resistance (TPR) were calculated. SVi decreased during MMA in HFrEF (P = 0.037) but not in controls (P = 0.392). ESVi (P = 0.007) and heart rate (P < 0.001) increased during MMA in HFrEF but not controls (P ≥ 0.170). TPR (P = 0.021) and MAP (P < 0.001) increased during MMA in both groups. Cardiac output (P = 0.946), EDVi (P = 0.177), and GLS (P = 0.619) were maintained from rest to MMA in both groups. Despite similarly maintained cardiac output, LV strain, and increased TPR in HFrEF and control groups, SVi decreased, and heart rate increased during MMA in patients with HFrEF. These findings suggest an impaired contractility reserve in response to increased TPR during MMA in HFrEF.NEW & NOTEWORTHY Stroke volume decreases and end-systolic volume increases during muscle metaboreflex activation in patients with heart failure with reduced ejection fraction (HFrEF), suggesting impaired contractile reserve during muscle metaboreflex activation in patients with HFrEF. Total peripheral resistance increases similarly during muscle metaboreflex activation in patients with HFrEF compared to controls, indicating normal levels of peripheral vasoconstriction during muscle metaboreflex activation in patients with HFrEF.

Blood flow restriction training activates the muscle metaboreflex during low-intensity sustained exercise.

Blood flow restriction training (BFRT) employs partial vascular occlusion of exercising muscle and has been shown to increase muscle performance while using reduced workload and training time. Numerous studies have demonstrated that BFRT increases muscle hypertrophy, mitochondrial function, and beneficial vascular adaptations. However, changes in cardiovascular hemodynamics during the exercise protocol remain unknown, as most studies measured blood pressure before the onset and after the cessation of exercise. With reduced perfusion to the exercising muscle during BFRT, the resultant accumulation of metabolites within the ischemic muscle could potentially trigger a large reflex increase in blood pressure, termed the muscle metaboreflex. At low workloads, this pressor response occurs primarily via increases in cardiac output. However, when increases in cardiac output are limited (e.g., heart failure or during severe exercise), the reflex shifts to peripheral vasoconstriction as the primary mechanism to increase blood pressure, potentially increasing the risk of a cardiovascular event. Using our chronically instrumented conscious canine model, we utilized a 60% reduction in femoral blood pressure applied to the hindlimbs during steady-state treadmill exercise (3.2 km/h) to reproduce the ischemic environment observed during BFRT. We observed significant increases in heart rate (+19 ± 3 beats/min), stroke volume (+2.52 ± 1.2 mL), cardiac output (+1.21 ± 0.2 L/min), mean arterial pressure (+18.2 ± 2.4 mmHg), stroke work (+1.93 ± 0.2 L/mmHg), and nonischemic vascular conductance (+3.62 ± 1.7 mL/mmHg), indicating activation of the muscle metaboreflex.NEW & NOTEWORTHY Blood flow restriction training (BFRT) increases muscle mass, strength, and endurance. There has been minimal consideration of the reflex cardiovascular responses that could be elicited during BFRT sessions. We showed that during low-intensity exercise BFRT may trigger large reflex increases in blood pressure and sympathetic activity due to muscle metaboreflex activation. Thus, we urge caution when employing BFRT, especially in patients in whom exaggerated cardiovascular responses may occur that could cause sudden, adverse cardiovascular events.

Sympathetic Activity and Diastolic Dysfunction in HFrEF: Muscle metaboreflex induced changes in left ventricle passive filling pressure

During exercise, activation of afferents within active skeletal muscle improves cardiovascular performance through reflex increases in cardiac output (CO), ventricular function, and central blood volume mobilization - termed the muscle metaboreflex. In heart failure (HF) ventricular function is depressed and muscle metaboreflex activation (MMA) does little to improve ventricular performance. In HF reflex characteristics shift to from cardio-centric mediated increases in mean arterial pressure via increases in ventricular function and central blood volume mobilization, to profound vasoconstriction of not only the peripheral circulation but also the myocardium which thereby further limits increases in contractility. Impaired increases in CO during MMA in HF are not a result of reductions in preload, but are primarily a result of reduced contractile function via pathology and enhanced negative reflex characteristics. In HF, there are attenuated improvements in the rate of left ventricular relaxation just after the cessation of contraction during MMA vs. that observed in healthy subjects. To what degree MMA also induces alterations in passive left ventricular filling is unknown. We sought to determine if rate of rise in left ventricular passive filling pressure (LVPFR) (an index of ventricular stiffness) during MMA in HF was significantly increased, thus suggesting not only pathological but sympathetically mediated ventricular stiffening. Using conscious, chronically instrumented canines who were observed before and after the induction of HF via rapid ventricular pacing we analyzed 10 ventricular beats in each experiment taken from steady state values at rest, during volitional exercise (3.2 km/hr), and during volitional exercise (3.2 km/hr) with MMA achieved via imposed reductions in hindlimb blood flow by ~ 50%. From these 10 beats the rate of ventricular filling pressure was assessed prior to the atrial kick. We observed in healthy subjects that neither exercise nor MMA significantly altered LVPFR. In HF the LVPFR was significantly increased from rest to exercise (312 ± 54 to 449 ± 76 mmHg/sec) and in response to MMA (449 ± 76 to 726 ± 111 mmHg/sec). The effect of heart failure on LVPFR at rest (217 ± 22 vs 312 ± 54 mmHg/sec P=0.051) and during exercise (288 ± 47 to 449 ± 76 mmHg/sec P=0.059) approached significance, but only reached significance during MMA (385 ± 58 to 726 ± 111 mmHg/sec P= 0.030) when compared to healthy controls. We conclude that in HF, MMA significantly increases the LVPFR thereby indicating reflex mediated increases in ventricular stiffness in addition to those induced as a result of HF. Increases in ventricular stiffness during MMA may be an additional mechanism that limits CO, reducing peripheral perfusion during exercise and potentially leading to sudden cardiac death. This project was funded by NHLBI grant HL-055473. This is the full abstract presented at the American Physiology Summit 2023 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.

Ventilatory response to peripheral chemoreflex and muscle metaboreflex during static handgrip in healthy humans: evidence of hyperadditive integration.

What is the central question of this study? What is the effect of peripheral chemoreflex and muscle metaboreflex integration on ventilation regulation, and what is the effect of integration on breathing-related sensations and emotions? What is the main finding and its importance? Peripheral chemoreflex and muscle metaboreflex coactivation during isocapnic static handgrip exercise appeared to elicit a hyperadditive effect with regard to ventilation and an additive effect with regard to breathing-related sensations and emotions. These findings reveal the nature of the integration between two neural mechanisms that operate during small-muscle static exercise performed under hypoxia. Exercise augments the hypoxia-induced ventilatory response in an exercise intensity-dependent manner. A mutual influence of hypoxia-induced peripheral chemoreflex activation and exercise-induced muscle metaboreflex activation might mediate the augmentation phenomenon. However, the nature of these reflexes' integration (i.e., hyperadditive, additive or hypoadditive) remains unclear, and the coactivation effect on breathing-related sensations and emotions has not been explored. Accordingly, we investigated the effect of peripheral chemoreflex and muscle metaboreflex coactivation on ventilatory variables and breathing-related sensations and emotions during exercise. Fourteen healthy adults performed 2-min isocapnic static handgrip, first with the non-dominant hand and immediately after with the dominant hand. During the dominant hand exercise, we (a) did not manipulate either reflex (control); (b) activated the peripheral chemoreflex by hypoxia; (c) activated the muscle metaboreflex in the non-dominant arm by post-exercise circulatory occlusion (PECO); or (d) coactivated both reflexes by simultaneous hypoxia and PECO use. Ventilation response to coactivation of reflexes (mean±SD, 13±6l/min) was greater than the sum of responses to separated activations of reflexes (mean±SD, 8±8l/min, P=0.005). Breathing-related sensory and emotional responses were similar between coactivation of reflexes and the sum of separate activations of reflexes. Thus, the peripheral chemoreflex and muscle metaboreflex integration during exercise appeared to be hyperadditive with regard to ventilation and additive with regard to breathing-related sensations and emotions in healthy adults.

Blood Pressure Responses to Postexercise Circulatory Occlusion Are Attenuated After Exercise-Induced Muscle Weakness.

Exercise blood pressure (BP) responses are thought to be determined by relative exercise intensity (percent maximal voluntary contraction (MVC) strength). However, cross-sectional studies report that during a static contraction, higher absolute force is associated with greater BP responses to relative intensity exercise and subsequent muscle metaboreflex activation with postexercise circulatory occlusion (PECO). We hypothesized that a bout of unaccustomed eccentric exercise would reduce knee extensor MVC and subsequently attenuate BP responses to PECO. Continuous BP, heart rate, muscle oxygenation, and knee extensor electromyography were recorded in 21 young healthy individuals (female, n = 10) during 2 min of 20% MVC static knee extension exercise and 2 min of PECO, performed before and 24 h after 300 maximal knee extensor eccentric contractions to cause exercise-induced muscle weakness. As a control, 14 participants repeated the eccentric exercise 4 wks later to test whether BP responses were altered when exercise-induced muscle weakness was attenuated via the protective effects of the repeated bout effect. Eccentric exercise reduced MVC in all participants (144 ± 43 vs 110 ± 34 N·m, P < 0.0001). BP responses to matched relative intensity static exercise (lower absolute force) were unchanged after eccentric exercise ( P > 0.99) but were attenuated during PECO (systolic BP: 18 ± 10 vs 12 ± 9 mm Hg, P = 0.02). Exercise-induced muscle weakness modulated the deoxygenated hemoglobin response to static exercise (64% ± 22% vs 46% ± 22%, P = 0.04). When repeated after 4 wks, exercise-induced weakness after eccentric exercise was attenuated (-21.6% ± 14.3% vs -9.3 ± 9.7, P = 0.0002) and BP responses to PECO were not different from control values (all, P > 0.96). BP responses to muscle metaboreflex activation, but not exercise, are attenuated by exercise-induced muscle weakness, indicating a contribution of absolute exercise intensity on muscle metaboreflex activation.

The 'normal' adjustment of oxygen delivery to small muscle mass exercise is not optimized for muscle contractile function.

Oxygen delivery is viewed as tightly coupled to demand in exercise below critical power because increasing oxygen delivery does not increase . However, whether the 'normal' adjustment of oxygen delivery to small muscle mass exercise in the heavy intensity domain is optimal for excitation-contraction coupling is currently unknown. In 20 participants (10 female), a remote skeletal muscle (i.e. tibialis anterior) metaboreflex was (Hyperperfusion condition) or was not (Control condition) activated for 4min during both force of contraction (experimental model 1) and muscle activation-targeted (experimental model 2) rhythmic forearm handgrip exercise. Analysis was completed on the combined data from both experimental models. After 30s of remote skeletal muscle metaboreflex activation, mean arterial blood pressure, forearm blood flow and muscle oxygenation were increased and remained increased until metaboreflex discontinuation. While oxygen delivery was elevated, the muscle activation to force of contraction ratio was improved. Upon metaboreflex discontinuation, forearm oxygen delivery and the muscle activation and force of contraction ratio rapidly (within 30s) returned to control levels. These findings demonstrate that (a) the metaboreflex was effective at increasing forearm muscle oxygen delivery and oxygenation, (b) the muscle activation to force of contraction ratio was improved with increased oxygen delivery, and (c) in the heavy exercise intensity domain, the normal matching of oxygen delivery to metabolic demand is not optimal for muscle excitation-contraction coupling. These results suggest that the nature of vasoregulation in exercising muscle is such that it does not support optimal perfusion for excitation-contraction coupling. KEY POINTS: Oxygen delivery is viewed as tightly coupled to demand in exercise below critical power because increasing oxygen delivery does not increase the rate of oxygen uptake. Whether the 'normal' adjustment of oxygen delivery in small muscle mass exercise below critical power is optimal for excitation-contraction coupling is not known. Here we show in humans that increasing oxygen delivery above 'normal' improves excitation-contraction coupling. These results suggest that, in the heavy exercise intensity domain, the 'normal' matching of oxygen delivery to metabolic demand is not optimal for muscle excitation-contraction coupling. Therefore, the nature of vasoregulation in exercising muscle is such that it does not support optimal perfusion for excitation-contraction coupling.

Muscle metaboreflex activation during hypercapnia modifies nonlinear heart rhythm dynamics, increasing the complexity of the sinus node autonomic regulation in humans.

Muscle metaboreflex activation during hypercapnia leads to enhanced pressive effects that are poorly understood while autonomic responses including baroreflex function are not documented. Thus, we assessed heart rate variability (HRV) that is partly due to autonomic influences on sinus node with linear tools (spectral analysis of instantaneous heart period), baroreflex set point and sensitivity with the heart period-arterial pressure transfer function and sequences methods, and system coupling through the complexity of RR interval dynamics with nonlinear tools (Poincaré plots and approximate entropy (ApEn)). We studied ten healthy young men at rest and then during muscle metaboreflex activation (MMA, postexercise muscle ischemia) and hypercapnia (HCA, PetCO2 = + 10mmHg from baseline) separately and combined (MMA + HCA). The strongest pressive responses were observed during MMA + HCA, while baroreflex sensitivity was similarly lowered in the three experimental conditions. HRV was significantly different in MMA + HCA compared to MMA and HCA separately, with the lowest total power spectrum (p < 0.05), including very low frequency (p < 0.05), low frequency (p < 0.05), and high frequency (tendency) power spectra decreases, and the lowest Poincaré plot short-term variability index (SD1): SD1 = 36.2ms (MMA + HCA) vs. SD1 = 43.1ms (MMA, p < 0.05) and SD1 = 46.1ms (HCA, p < 0.05). Moreover, RR interval dynamic complexity was significantly increased only in the MMA + HCA condition (ApEn increased from 1.04 ± 0.04, 1.07 ± 0.02, and 1.05 ± 0.03 to 1.10 ± 0.03, 1.13 ± 0.04, and 1.17 ± 0.03 in MMA, HCA, and MMA + HCA conditions, respectively; p < 0.01). These results suggest that in healthy young men, muscle metaboreflex activation during hypercapnia leads to interactions that reduce parasympathetic influence on the sinus node activity but complexify its dynamics.

Inspiratory and leg muscle blood flows during inspiratory muscle metaboreflex activation in heart failure with preserved ejection fraction.

The purpose of this study was to determine the cardiovascular consequences elicited by activation of the inspiratory muscle metaboreflex in patients with heart failure with preserved ejection fraction (HFpEF) and controls. Patients with HFpEF (n = 15; 69 ± 10 yr; 33 ± 4 kg/m2) and controls (n = 14; 70 ± 8 yr; 28 ± 4 kg/m2) performed an inspiratory loading trial at 60% maximal inspiratory pressure (PIMAX) until task failure. Mean arterial pressure (MAP) was measured continuously. Near-infrared spectroscopy and bolus injections of indocyanine green dye were used to determine the percent change in blood flow index (%ΔBFI) from baseline to the final minute of inspiratory loading in the vastus lateralis and sternocleidomastoid muscles. Vascular resistance index (VRI) was calculated. Time to task failure was shorter in HFpEF than in controls (339 ± 197 s vs. 626 ± 403 s; P = 0.02). Compared with controls, patients with HFpEF had a greater increase from baseline in MAP (16 ± 7 vs. 10 ± 6 mmHg) and vastus lateralis VRI (76 ± 45 vs. 32 ± 19%) as well as a greater decrease in vastus lateralis %ΔBFI (-32 ± 14 vs. -17 ± 9%) (all, P < 0.05). Sternocleidomastoid %ΔBFI normalized to absolute inspiratory pressure was higher in HFpEF compared with controls (8.0 ± 5.0 vs. 4.0 ± 1.9% per cmH2O·s; P = 0.03). These data indicate that patients with HFpEF exhibit exaggerated cardiovascular responses with inspiratory muscle metaboreflex activation compared with controls.NEW & NOTEWORTHY Respiratory muscle dysfunction is thought to contribute to exercise intolerance in heart failure with preserved ejection fraction (HFpEF); however, the underlying mechanisms are unknown. In the present study, patients with HFpEF had greater increases in leg muscle vascular resistance index and greater decreases in leg muscle blood flow index compared with controls during inspiratory resistive breathing (to activate the metaboreflex). Furthermore, respiratory muscle blood flow index responses normalized to pressure generation during inspiratory resistive breathing were exaggerated in HFpEF compared with controls.

Impact Of Age On Aortic Pressure And Pressure Waves Responses To Metaboreflex Activation In Women

INTRODUCTION: Aging and hypertension are related to exaggerated peripheral blood pressure (BP) responses to exercise and metaboreflex activation (post-exercise muscle ischemia, PEMI). Postmenopausal (POST) women have greater risk of heart failure with preserved ejection fraction due to increased aortic pulsatile load on the left ventricle induced by increased systolic BP (SBP) and decreased diastolic BP (DBP) at rest. Age-related aortic stiffening augments pressures of the forward (Pf) and the reflected wave (Pb) traveling from peripheral arteries to the aorta. Increases in Pf and Pb contribute to elevated aortic SBP and pulse pressure (PP) responses to exercise, increasing the risk for cardiovascular events. However, the influence of Pf and Pb on aortic pulsatile load during isometric handgrip (IHG) and PEMI in normotensive premenopausal (PRE) and POST women have not been examined. PURPOSE: To investigate the effect of age on aortic BP, Pf, and Pb during IHG and PEMI in normotensive PRE and POST women. METHODS: Fifteen PRE (age: 24 ± 1 years) and 16 POST women (age: 59 ± 1 years) participated in this study. Brachial BP was obtained using an automated device and radial arterial tonometry was used to capture aortic waveforms to estimate aortic BP and pressure waves at rest, during a 2-min IHG at 30% of maximal force, and during a 3-min PEMI. RESULTS: BP responses to IHG were similar in both groups. Brachial PP (POST: Δ9 ± 1 mmHg vs PRE: Δ0 ± 2 mmHg, P < 0.01), aortic PP (POST: Δ8 ± 1 mmHg vs PRE: Δ3 ± 2 mmHg, P = 0.03), Pf (POST: Δ6 ± 1 mmHg vs PRE: Δ0 ± 1 mmHg, P < 0.01), and Pb (POST: Δ5 ± 1 mmHg vs PRE: Δ2 ± 1 mmHg, P = 0.02) responses to PEMI were significantly increased in POST compared to PRE women. Aortic DBP (POST: Δ6 ± 1 mmHg vs PRE: Δ11 ± 2 mmHg, P = 0.04) responses to PEMI was significantly lower in POST than PRE women. Brachial and aortic SBP significantly (P < 0.001) increased during PEMI in both PRE and POST women, but there was no difference (P > 0.05) between groups. CONCLUSION: Normotensive POST women have augmented aortic PP response to PEMI compared to PRE women due to increases in pressure of the forward and backward waves and a decrease in DBP. Our findings suggest that the age-related increase in muscle metaboreflex activation does not induce a systolic overload and the increase in aortic PP is attributed to reduced DBP in normotensive POST women.

Arterial Baroreceptor Denervation Enhances Muscle Metaboreflex Induced Increases in Effective Arterial Elastance Without Worsening Stoke Work During Dynamic Exercise in Heart Failure

Optimal energy transfer from the left ventricle to the systemic circulation is paramount to the maintenance of workload performance during exercise. This interaction between the heart and circulation is quantified by the ventricular‐vascular coupling relationship which is the ratio of direct assessments of arterial and ventricular elastance. During exercise, increases in both arterial and ventricular elastance occur as a result of sympatho‐excitatory efferent responses brought about by activation of metabosensitive skeletal muscle afferents ‐ termed the muscle metaboreflex. In heart failure, ventricular elastance is reduced and arterial elastance is increased causing ventricular‐vascular uncoupling at rest and further sympatho‐activation elicited by the muscle metaboreflex worsens this relationship through profound systemic vasoconstriction. Recent studies have concluded that the arterial baroreflex substantially buffers vasoconstriction within peripheral vascular beds. In heart failure, the arterial baroreflex buffering capacity is significantly reduced and muscle metaboreflex induced vasoconstriction is enhanced. To what extent this shift in metaboreflex control of peripheral sympathetic tone affects ventricular‐vascular coupling is unknown. We examined the effect of sino‐aortic baroreceptor denervation (SAD) on the ventricular‐vascular relationship at rest and during moderate dynamic exercise (6.4 km/h 10% grade) in chronically instrument conscious canines before and after the induction of heart failure to determine whether loss of baroreflex buffering engendered further uncoupling of the ventricular‐vascular relationship in heart failure. Increases in effective arterial elastance (Ea), were significantly enhanced during muscle metaboreflex activation after SAD (0.5 ± 0.1 mmHg/ml to 2.0 ± 0.4 mmHg/mL). Furthermore, SAD elicited a significant increase in the ability to improve stroke work during muscle metaboreflex activation (2.7 ± 0.1 L*mmHg to 3.5 ± 0.1 L*mmHg) suggesting that even without the arterial baroreflex muscle metaboreflex activation in healthy subjects maintains ventricular‐vascular coupling. In heart failure, SAD elicited a 2‐fold increase in Ea during muscle metaboreflex activation (0.9 ± 0.2 mmHg/ml to 1.8 ± 0.2 mmHg/ml). Stroke work did not improve during muscle metaboreflex activation in heart failure with SAD. Thus, enhanced increases in Ea are likely not matched by ventricular elastance thereby exacerbating the already uncoupled ventricular‐vascular relationship. We conclude that the arterial baroreflex actively restrains increases in Ea and stroke work during muscle metaboreflex activation and SAD does not appear to significantly impact the ventricular‐vascular relationship in healthy subjects. In heart failure, the arterial baroreflex retains some degree of restraint over metaboreflex induced increases in Ea and thus is likely a mechanism which prevents worsening of the already impaired energy transfer from the left ventricle to the systemic circulation.

Impaired Sympathetic Neural Recruitment During Skeletal Muscle Metaboreflex Activation in Women with Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that is more prevalent in women than men and has been linked to an elevated risk of developing cardiovascular disease. Although the physiological mechanisms are unclear, it is thought that exaggerated neuro‐cardiovascular reactivity is partially responsible. Indeed, women with PTSD demonstrate exaggerated muscle sympathetic nerve activity (MSNA) responses at the onset of exercise. However, it is unknown whether PTSD modifies the underlying sympathetic action potentials (AP) coding patterns that comprise the integrated MSNA signal during fatiguing exercise in women. We therefore hypothesized that women with PTSD will exhibit exaggerated MSNA and AP recruitment compared to women without PTSD during fatiguing handgrip exercise. MSNA and AP discharge patterns (via microneurography and a continuous wavelet transform) were assessed in eleven women with PTSD (43±11 [SD] years) and thirteen women without PTSD (Controls; 40±8 years) during isometric handgrip exercise (IHG) to fatigue at 40% of maximal voluntary contraction (MVC) force, followed by 2 minutes of post‐exercise circulatory occlusion (PECO), and three minutes of recovery. The IHG time was divided equally into five stages. IHG duration (P=0.867) and MVC (P=0.226) were similar between both groups. PTSD did not modify the increase in MSNA and AP frequency or incidence during IHG and PECO (all group‐by‐stage interactions: P=0.294‐0.380). Conversely, throughout IHG and PECO, AP content per burst was greater in the Controls compared to women with PTSD (main effect of group: P=0.026). Furthermore, relative to Controls, women with PTSD were unable to increase the number of AP clusters per burst during the first (Controls: ∆1.3±1.2 vs. PTSD: ∆‐0.2±0.8 clusters/burst; P=0.016) and last minute (Controls: ∆1.2±1.1 vs. PTSD: ∆‐0.1±0.8 clusters/burst; P=0.022) of PECO, and recruited fewer subpopulations of previously silent axons during the first (Controls: ∆5±4 vs. PTSD: ∆1±2 clusters; P=0.020) and last minute (Controls: ∆4±2 vs. PTSD: ∆1±2 clusters; P=0.021) of PECO. Lastly, although an interaction effect was observed for the AP cluster size‐latency relationship during IHG and PECO (P=0.042), post‐hoc analyses revealed that PTSD did not modify this relationship (all P=0.658‐0.999). These data indicate that the central features of sympathetic outflow are impaired in women with PTSD during skeletal muscle metaboreflex activation.

Cardiorespiratory responses to muscle metaboreflex activation in fibrosing interstitial lung disease.

New Findings What is the central question of this study? We determined whether sensory feedback from metabolically sensitive skeletal muscle afferents (metaboreflex) causes a greater ventilatory response and higher dyspnoea ratings in fibrosing interstitial lung disease (FILD). What is the main finding and its importance? Ventilatory responses and dyspnoea ratings during handgrip exercise and metaboreflex isolation were not different in FILD and control groups. Blood pressure and heart rate responses to handgrip were attenuated in FILD but not different to controls during metaboreflex isolation. These findings suggest that the muscle metaboreflex contribution to the respiratory response to exercise is not altered in FILD. Exercise limitation and dyspnoea are hallmarks of fibrosing interstitial lung disease (FILD); however, the physiological mechanisms are poorly understood. In other respiratory diseases, there is evidence that an augmented muscle metaboreflex may be implicated. We hypothesized that metaboreflex activation in FILD would result in elevated ventilation and dyspnoea ratings compared to healthy controls, due to augmented muscle metaboreflex. Sixteen FILD patients (three women, 69±14 years; mean±SD) and 16 age‐matched controls (four women, 67±7 years) were recruited. In a randomized cross‐over design, participants completed two min of rhythmic handgrip followed by either (i) two min of post‐exercise circulatory occlusion (PECO trial) to isolate muscle metaboreflex activation, or (ii) rested for four min (Control trial). Minute ventilation (V˙E; pneumotachometer), dyspnoea ratings (0–10 Borg scale), mean arterial pressure (MAP; finger photoplethysmography) and heart rate (HR; electrocardiogram) were measured. V˙E was higher in the FILD group at baseline and exercise increased V˙E similarly in both groups. V˙E remained elevated during PECO, but there was no between‐group difference in the magnitude of this response (ΔV˙E FILD 4.2 ± 2.5 L·min–1 vs. controls 3.6 ± 2.4 L·min–1, P = 0.596). At the end of PECO, dyspnoea ratings in FILD were similar to controls (1.0 ± 1.3 units vs. 0.5 ± 1.1 units). Exercise increased MAP and HR (P < 0.05) in both groups; however, responses were lower in FILD. Collectively, these findings suggest that there is not an augmented effect of the muscle metaboreflex on breathing and dyspnoea in FILD, but haemodynamic responses to handgrip are reduced relative to controls.

Arterial Baroreflex Inhibits Muscle Metaboreflex Induced Increases in Effective Arterial Elastance: Implications for Ventricular-Vascular Coupling.

The ventricular-vascular relationship assesses the efficacy of energy transferred from the left ventricle to the systemic circulation and is quantified as the ratio of effective arterial elastance to maximal left ventricular elastance. This relationship is maintained during exercise via reflex increases in cardiovascular performance raising both arterial and ventricular elastance in parallel. These changes are, in part, due to reflexes engendered by activation of metabosensitive skeletal muscle afferents—termed the muscle metaboreflex. However, in heart failure, ventricular-vascular uncoupling is apparent and muscle metaboreflex activation worsens this relationship through enhanced systemic vasoconstriction markedly increasing effective arterial elastance which is unaccompanied by substantial increases in ventricular function. This enhanced arterial vasoconstriction is, in part, due to significant reductions in cardiac performance induced by heart failure causing over—stimulation of the metaboreflex due to under perfusion of active skeletal muscle, but also as a result of reduced baroreflex buffering of the muscle metaboreflex-induced peripheral sympatho-activation. To what extent the arterial baroreflex modifies the metaboreflex-induced changes in effective arterial elastance is unknown. We investigated in chronically instrumented conscious canines if removal of baroreflex input via sino-aortic baroreceptor denervation (SAD) would significantly enhance effective arterial elastance in normal animals and whether this would be amplified after induction of heart failure. We observed that effective arterial elastance (Ea), was significantly increased during muscle metaboreflex activation after SAD (0.4 ± 0.1 mmHg/mL to 1.4 ± 0.3 mmHg/mL). In heart failure, metaboreflex activation caused exaggerated increases in Ea and in this setting, SAD significantly increased the rise in Ea elicited by muscle metaboreflex activation (1.3 ± 0.3 mmHg/mL to 2.3 ± 0.3 mmHg/mL). Thus, we conclude that the arterial baroreflex does buffer muscle metaboreflex induced increases in Ea and this buffering likely has effects on the ventricular-vascular coupling.

Hemodynamic responses to neuromuscular electrical stimulation and to metaboreflex activation.

Metabolites produced during muscle exercise can sensitize types III and IV fibers, which account for increasing blood pressure (BP) and vascular resistance in non-exercising limbs, as well as for redistributing the blood flow to active muscles; reflex response is called metaboreflex. Neuromuscular electrical stimulation (NMES) induces greater local muscle metabolic demand than voluntary isometric contractions. Metabolic accumulation is essential to activate muscle metaboreflex; thus, the hypothesis of the current study is that one NMES session can induce metaboreflex with different hemodynamic responses in upper and lower limbs. Objective - to investigate whether one acute NMES session could activate metaboreflex by inducing different hemodynamic responses between arms and legs. Twenty (20) healthy subjects (mean age = 47.7±9.4 years, 13 women, mean body mass index = 26 ± 3 kg/m2) participated in this randomized crossover study. All participants were subjected to two NMES interventions, one in the upper limbs (UPL) and the other in the lower limbs (LL). Mean blood pressure (MBP), blood flow (BF) and vascular resistance (VR) were used to selectively evaluate metaboreflex responses at baseline, during NMES interventions, and recovery periods with, and without, postexercise circulatory occlusion (PECO+ and PECO-, respectively) through the area under the curve (AUC) in VR. MBP increased by 13% during UPL interventions and only remained high during PECO+. Changes in MBP were not observed in LL, although BF in the contralateral leg has decreased by 14% during PECO+ protocol. Muscle metaboreflex activation (AUC differences in VR between PECO+ and PECO-) was not different between UPL and LL (P=0.655). Acute NMES session has induced similar metaboreflex activation in both arms and legs, although hemodynamic responses differed between interventions.

Investigating the control of exercise hyperpnoea: A synergy of contributions.

Investigating the control of exercise hyperpnoea: A synergy of contributions.