Paul J. Fadel

New insights into central cardiovascular control during exercise in humans: a central command update

The autonomic adjustments to exercise are mediated by central signals from the higher brain (central command) and by a peripheral reflex arising from working skeletal muscle (exercise pressor reflex), with further modulation provided by the arterial baroreflex. Although it is clear that central command, the exercise pressor reflex and the arterial baroreflex are all requisite for eliciting appropriate cardiovascular adjustments to exercise, this review will be limited primarily to discussion of central command. Central modulation of the cardiovascular system via descending signals from higher brain centres has been well recognized for over a century, yet the specific regions of the human brain involved in this exercise‐related response have remained speculative. Brain mapping studies during exercise as well as non‐exercise conditions have provided information towards establishing the cerebral cortical structures in the human brain specifically involved in cardiovascular control. The purpose of this review is to provide an update of current concepts on central command in humans, with a particular emphasis on the regions of the brain identified to alter autonomic outflow and result in cardiovascular adjustments.

Arterial baroreflex resetting during exercise: a current perspective

Within the past 20 years numerous animal and human experiments have provided supportive evidence of arterial baroreflex resetting during exercise. In addition, it has been demonstrated that both the feedforward mechanism of central command and the feedback mechanism associated with skeletal muscle afferents (the exercise pressor reflex) play both independent and interactive roles in the resetting of the arterial baroreflex with exercise. A fundamental alteration associated with baroreflex resetting during exercise is the movement of the operating point of the reflex away from the centring point and closer to the threshold, thereby increasing the ability of the reflex to buffer hypertensive stimuli. Recent studies suggest that central command and the cardiopulmonary baroreceptors may play a role in this movement of the operating point on the baroreflex–heart rate and baroreflex–blood pressure curve, respectively. Current research is focusing on the investigation of central neural mechanisms involved in cardiovascular control, including use of electrophysiological and molecular biological techniques in rat and mouse models to investigate baroreflex resetting as well as use of state of the art brain imaging techniques in humans. However, the purpose of this review is to describe the role of the arterial baroreflex in the regulation of arterial blood pressure during physical activity from a historical perspective with a particular emphasis on human investigations.

Simvastatin impairs exercise training adaptations.

OBJECTIVES This study sought to determine if simvastatin impairs exercise training adaptations. BACKGROUND Statins are commonly prescribed in combination with therapeutic lifestyle changes, including exercise, to reduce cardiovascular disease risk in patients with metabolic syndrome. Statin use has been linked to skeletal muscle myopathy and impaired mitochondrial function, but it is unclear whether statin use alters adaptations to exercise training. METHODS This study examined the effects of simvastatin on changes in cardiorespiratory fitness and skeletal muscle mitochondrial content in response to aerobic exercise training. Sedentary overweight or obese adults with at least 2 metabolic syndrome risk factors (defined according to National Cholesterol Education Panel Adult Treatment Panel III criteria) were randomized to 12 weeks of aerobic exercise training or to exercise in combination with simvastatin (40 mg/day). The primary outcomes were cardiorespiratory fitness and skeletal muscle (vastus lateralis) mitochondrial content (citrate synthase enzyme activity). RESULTS Thirty-seven participants (exercise plus statins: n = 18; exercise only: n = 19) completed the study. Cardiorespiratory fitness increased by 10% (p < 0.05) in response to exercise training alone, but was blunted by the addition of simvastatin resulting in only a 1.5% increase (p < 0.005 for group by time interaction). Similarly, skeletal muscle citrate synthase activity increased by 13% in the exercise-only group (p < 0.05), but decreased by 4.5% in the simvastatin-plus-exercise group (p < 0.05 for group-by-time interaction). CONCLUSIONS Simvastatin attenuates increases in cardiorespiratory fitness and skeletal muscle mitochondrial content when combined with exercise training in overweight or obese patients at risk of the metabolic syndrome. (Exercise, Statins, and the Metabolic Syndrome; NCT01700530).

Baroreflex‐Mediated Changes in Cardiac Output and Vascular Conductance in Response to Alterations in Carotid Sinus Pressure during Exercise in Humans

We sought to quantify the contribution of cardiac output (Q) and total vascular conductance (TVC) to carotid baroreflex (CBR)‐mediated changes in mean arterial pressure (MAP) during mild to heavy exercise. CBR function was determined in eight subjects (25 ± 1 years) at rest and during three cycle exercise trials at heart rates (HRs) of 90, 120 and 150 beats min−1 performed in random order. Acute changes in carotid sinus transmural pressure were evoked using 5 s pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr (+5.33 to −10.67 kPa). Beat‐to‐beat changes in HR and MAP were recorded throughout. In addition, stroke volume (SV) was estimated using the Modelflow method, which incorporates a non‐linear, three‐element model of the aortic input impedance to compute an aortic flow waveform from the arterial pressure wave. The application of NP and NS did not cause any significant changes in SV either at rest or during exercise. Thus, CBR‐mediated alterations in Q were solely due to reflex changes in HR. In fact, a decrease in the carotid‐HR response range from 26 ± 7 beats min−1 at rest to 7 ± 1 beats min−1 during heavy exercise (P= 0.001) reduced the contribution of Q to the CBR‐mediated change in MAP. More importantly, at the time of the peak MAP response, the contribution of TVC to the CBR‐mediated change in MAP was increased from 74 ± 14 % at rest to 118 ± 6 % (P= 0.017) during heavy exercise. Collectively, these findings indicate that alterations in vasomotion are the primary means by which the CBR regulates blood pressure during mild to heavy exercise.

Central sympathetic overactivity: Maladies and mechanisms

There is growing evidence to suggest that many disease states are accompanied by chronic elevations in sympathetic nerve activity. The present review will specifically focus on central sympathetic overactivity and highlight three main areas of interest: 1) the pathological consequences of excessive sympathetic nerve activity; 2) the potential role of centrally derived nitric oxide in the genesis of neural dysregulation in disease; and 3) the promise of several novel therapeutic strategies targeting central sympathetic overactivity. The findings from both animal and human studies will be discussed and integrated in an attempt to provide a concise update on current work and ideas in these important areas.

Exaggerated sympathetic and pressor responses to handgrip exercise in older hypertensive humans: role of the muscle metaboreflex

Recent animal studies have reported that exercise pressor reflex (EPR)-mediated increases in blood pressure are exaggerated in hypertensive (HTN) rodents. Whether these findings can be extended to human hypertension remains unclear. Mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and venous metabolites were measured in normotensive (NTN; n = 23; 60 ± 1 yr) and HTN (n = 15; 63 ± 1 yr) subjects at baseline, and during static handgrip at 30 and 40% maximal voluntary contraction (MVC) followed by a period of postexercise ischemia (PEI) to isolate the metabolic component of the EPR. Changes in MAP from baseline were augmented in HTN subjects during both 30 and 40% MVC handgrip (P < 0.05 for both), and these group differences were maintained during PEI (30% PEI trial: Δ15 ± 2 NTN vs. Δ19 ± 2 HTN mmHg; 40% PEI trial: Δ16 ± 1 NTN vs. Δ23 ± 2 HTN mmHg; P < 0.05 for both). Similarly, in HTN subjects, MSNA burst frequency was greater during 30 and 40% MVC handgrip (P < 0.05 for both), and these differences were maintained during PEI [30% PEI trial: 35 ± 2 (NTN) vs. 44 ± 2 (HTN) bursts/min; 40% PEI trial: 36 ± 2 (NTN) vs. 48 ± 2 (HTN) bursts/min; P < 0.05 for both]. No group differences in metabolites were observed. MAP and MSNA responses to a cold pressor test were not different between groups, suggesting no group differences in generalized sympathetic responsiveness. In summary, compared with NTN subjects, HTN adults exhibit exaggerated sympathetic and pressor responses to handgrip exercise that are maintained during PEI, indicating that activation of the metabolic component of the EPR is augmented in older HTN humans.

Increased muscle sympathetic nerve activity acutely alters conduit artery shear rate patterns

Escalating evidence indicates that disturbed flow patterns, characterized by the presence of retrograde and oscillatory shear stress, induce a proatherogenic endothelial cell phenotype; however, the mechanisms underlying oscillatory shear profiles in peripheral conduit arteries are not fully understood. We tested the hypothesis that acute elevations in muscle sympathetic nerve activity (MSNA) are accompanied by increases in conduit artery retrograde and oscillatory shear. Fourteen healthy men (25 +/- 1 yr) performed three sympathoexcitatory maneuvers: graded lower body negative pressure (LBNP) from 0 to -40 Torr, cold pressor test (CPT), and 35% maximal voluntary contraction handgrip followed by postexercise ischemia (PEI). MSNA (microneurography; peroneal nerve), arterial blood pressure (finger photoplethysmography), and brachial artery velocity and diameter (duplex Doppler ultrasound) in the contralateral arm were recorded continuously. All maneuvers elicited significant increases in MSNA total activity from baseline (P < 0.05). Retrograde shear (-3.96 +/- 1.2 baseline vs. -8.15 +/- 1.8 s(-1), -40 LBNP, P < 0.05) and oscillatory shear index (0.09 +/- 0.02 baseline vs. 0.20 +/- 0.02 arbitrary units, -40 LBNP, P < 0.05) were progressively augmented during graded LBNP. In contrast, during CPT and PEI, in which MSNA and blood pressure were concomitantly increased (P < 0.05), minimal or no changes in retrograde and oscillatory shear were noted. These data suggest that acute elevations in MSNA are associated with an increase in conduit artery retrograde and oscillatory shear, an effect that may be influenced by concurrent increases in arterial blood pressure. Future studies should examine the complex interaction between MSNA, arterial blood pressure, and other potential modulatory factors of shear rate patterns.

Recent insights into carotid baroreflex function in humans using the variable pressure neck chamber

The variable pressure neck chamber has provided an invaluable research tool for the non‐invasive assessment of carotid baroreflex (CBR) function in human investigations. The ability to construct complete stimulus‐response curves and define specific parameters of the reflex function curve permits statistical comparisons of baroreflex function between different experimental conditions, such as rest and exercise. Results have convincingly indicated that the CBR stimulus‐response curve is reset during exercise in an intensity‐dependent manner to functionally operate around the prevailing pressure elicited by the exercise workload. Furthermore, both at rest and during exercise, alterations in stroke volume do not contribute importantly to the maintenance of arterial blood pressure by the carotid baroreceptors, and therefore, any reflex‐induced changes in cardiac output (Q) are the result of CBR‐mediated changes in heart rate. However, more importantly, the CBR‐induced changes in mean arterial pressure (MAP) are primarily mediated by alterations in vascular conductance with only minimal contributions from Q to the initial reflex MAP response. Thus, the capacity of the CBR to regulate blood pressure depends critically on its ability to alter vascular tone both at rest and during exercise. This review will emphasize the utility of the variable pressure neck chamber to assess CBR function in human experimental investigations and the mechanisms by which the CBR responds to alterations in arterial blood pressure both at rest and during exercise.

Effects of partial neuromuscular blockade on carotid baroreflex function during exercise in humans

1 This investigation was designed to determine the contribution of central command to the resetting of the carotid baroreflex during static and dynamic exercise in humans. 2 Thirteen subjects performed 3.5 min of static one‐legged exercise (20 % maximal voluntary contraction) and 7 min dynamic cycling (20 % maximal oxygen uptake) under two conditions: control (no intervention) and with partial neuromuscular blockade (to increase central command influence) using Norcuron (curare). Carotid baroreflex function was determined at rest and during steady‐state exercise using a rapid neck pressure/neck suction technique. Whole‐body Norcuron was repeatedly administered to effectively reduce hand‐grip strength by approximately 50 % of control. 3 Partial neuromuscular blockade increased heart rate, mean arterial pressure, perceived exertion, lactate concentration and plasma noradrenaline concentration during both static and dynamic exercise when compared to control (P < 0.05). No effect was seen at rest. Carotid baroreflex resetting was augmented from control static and dynamic exercise by partial neuromuscular blockade without alterations in gain (P < 0.05). In addition, the operating point of the reflex was relocated away from the centring point (i.e. closer to threshold) during exercise by partial neuromuscular blockade (P < 0.05). 4 These findings suggest that central command actively resets the carotid baroreflex during dynamic and static exercise.

Human investigations into the arterial and cardiopulmonary baroreflexes during exercise.

After considerable debate and key experimental evidence, the importance of the arterial baroreflex in contributing to and maintaining the appropriate neural cardiovascular adjustments to exercise is now well accepted. Indeed, the arterial baroreflex resets during exercise in an intensity‐dependent manner to continue to regulate blood pressure as effectively as at rest. Studies have indicated that the exercise resetting of the arterial baroreflex is mediated by both the feedforward mechanism of central command and the feedback mechanism associated with skeletal muscle afferents (the exercise pressor reflex). Another perhaps less appreciated neural mechanism involved in evoking and maintaining neural cardiovascular responses to exercise is the cardiopulmonary baroreflex. The limited information available regarding the cardiopulmonary baroreflex during exercise provides evidence for a role in mediating sympathetic nerve activity and blood pressure responses. In addition, recent investigations have demonstrated an interaction between cardiopulmonary baroreceptors and the arterial baroreflex during dynamic exercise, which contributes to the magnitude of exercise‐induced increases in blood pressure as well as the resetting of the arterial baroreflex. Furthermore, neural inputs from the cardiopulmonary baroreceptors appear to play an important role in establishing the operating point of the arterial baroreflex. This symposium review highlights recent studies in these important areas indicating that the interactions of four neural mechanisms (central command, the exercise pressor reflex, the arterial baroreflex and cardiopulmonary baroreflex) are integral in mediating the neural cardiovascular adjustments to exercise.