Ryan M. Broxterman

Incidence Rate of Cardiovascular Disease End Points in the National Aeronautics and Space Administration Astronaut Corps

Background It is unknown whether the astronaut occupation or exposure to microgravity influences the risk of long‐term cardiovascular disease (CVD). This study explored the effects of being a career National Aeronautics and Space Administration (NASA) astronaut on the risk for clinical CVD end points. Methods and Results During the Longitudinal Study of Astronaut Health, data were collected on 310 NASA astronauts and 981 nonastronaut NASA employees. The nonastronauts were matched to the astronauts on age, sex, and body mass index, to evaluate acute and chronic morbidity and mortality. The primary outcomes were composites of clinical CVD end points (myocardial infarction, congestive heart failure, stroke, and coronary artery bypass surgery) or coronary artery disease (CAD) end points (myocardial infarction and coronary artery bypass surgery). Of the astronauts, 5.2% had a clinical CVD end point and 2.9% had a CAD end point compared with the nonastronaut comparisons with 4.7% and 3.1% having CVD and CAD end points, respectively. In the multivariate models adjusted for traditional risk factors, astronauts had a similar risk of CVD compared with nonastronauts (adjusted hazard ratio, 1.08; 95% CI, 0.60–1.93; P=0.80). Risk of a CAD end point was similar between groups (hazard ratio, 0.97; CI, 0.45–2.08; P=0.93). In astronauts with early spaceflight experience, the risk of CVD (hazard ratio, 0.80; CI, 0.25–2.56; P=0.71) and CAD (hazard ratio, 1.23; CI: 0.27–5.61; P=0.79) compared with astronauts with no experience were not different. Conclusions These findings suggest that being an astronaut is not associated with increased long‐term risk of CVD development.

Identifying the role of group III/IV muscle afferents in the carotid baroreflex control of mean arterial pressure and heart rate during exercise

We investigated the contribution of group III/IV muscle afferents to carotid baroreflex resetting during electrically evoked (no central command) and voluntary (requiring central command) isometric knee extension exercise. Lumbar intrathecal fentanyl was used to attenuate the central projection of μ‐opioid receptor‐sensitive group III/IV leg muscle afferent feedback. Spontaneous carotid baroreflex control was assessed by loading and unloading the carotid baroreceptors with a variable pressure neck chamber. Group III/IV muscle afferents did not influence spontaneous carotid baroreflex responsiveness at rest or during exercise. Afferent feedback accounted for at least 50% of the exercise‐induced increase in the carotid baroreflex blood pressure and heart rate operating points, adjustments that are critical for an appropriate cardiovascular response to exercise. These findings suggest that group III/IV muscle afferent feedback is, independent of central command, critical for the resetting of the carotid baroreflex blood pressure and heart rate operating points, but not for spontaneous baroreflex responsiveness.

SINGLE PASSIVE LEG MOVEMENT INDUCED-HYPEREMIA: A SIMPLE VASCULAR FUNCTION ASSESSMENT WITHOUT A CHRONOTROPIC RESPONSE

Passive leg movement (PLM)-induced hyperemia is a novel approach to assess vascular function, with a potential clinical role. However, in some instances, the varying chronotropic response induced by PLM has been proposed to be a potentially confounding factor. Therefore, we simplified and modified the PLM model to require just a single PLM (sPLM), an approach that may evoke a peripheral hemodynamic response, allowing a vascular function assessment, but at the same time minimizing central responses. To both characterize and assess the utility of sPLM, in 12 healthy subjects, we measured heart rate (HR), stroke volume, cardiac output (CO), mean arterial pressure (MAP), leg blood flow (LBF), and calculated leg vascular conductance (LVC) during both standard PLM, consisting of passive knee flexion and extension performed at 1 Hz for 60 s, and sPLM, consisting of only a single passive knee flexion and extension over 1 s. During PLM, MAP transiently decreased (5 ± 1 mmHg), whereas both HR and CO increased from baseline (6.0 ± 1.1 beats/min, and 0.8 ± 0.01 l/min, respectively). Following sPLM, MAP fell similarly (5 ± 2 mmHg; P = 0.8), but neither HR nor CO responses were identifiable. The peak LBF and LVC response was similar for PLM (993 ± 189 ml/min; 11.9 ± 1.5 ml·min-1·mmHg-1, respectively) and sPLM (878 ± 119 ml/min; 10.9 ± 1.6 ml·min-1·mmHg-1, respectively). Thus sPLM represents a variant of the PLM approach to assess vascular function that is more easily performed and evokes a peripheral stimulus that induces a significant hyperemia, but does not generate a potentially confounding, chronotropic response, which may make sPLM more useful clinically. NEW & NOTEWORTHY Using the single passive leg movement (PLM) technique, a variant of the vascular function assessment PLM, we have identified a novel peripheral vascular assessment method that is more easily performed than PLM, which, by not evoking potentially confounding central hemodynamic responses, may be more useful clinically.

Bioenergetics and ATP Synthesis during Exercise: Role of Group III/IV Muscle Afferents

Purpose The purpose of this study was to investigate the role of the group III/IV muscle afferents in the bioenergetics of exercising skeletal muscle beyond constraining the magnitude of metabolic perturbation. Methods Eight healthy men performed intermittent isometric knee-extensor exercise to task failure at ~58% maximal voluntary contraction under control conditions (CTRL) and with lumbar intrathecal fentanyl to attenuate group III/IV leg muscle afferents (FENT). Intramuscular concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), diprotonated phosphate (H2PO4−), adenosine triphosphate (ATP), and pH were determined using phosphorous magnetic resonance spectroscopy (31P-MRS). Results The magnitude of metabolic perturbation was significantly greater in FENT compared with CTRL for [Pi] (37.8 ± 16.8 vs 28.6 ± 8.6 mM), [H2PO4−] (24.3 ± 12.2 vs 17.9 ± 7.1 mM), and [ATP] (75.8% ± 17.5% vs 81.9% ± 15.8% of baseline), whereas there was no significant difference in [PCr] (4.5 ± 2.4 vs 4.4 ± 2.3 mM) or pH (6.51 ± 0.10 vs 6.54 ± 0.14). The rate of perturbation in [PCr], [Pi], [H2PO4−], and pH was significantly faster in FENT compared with CTRL. Oxidative ATP synthesis was not significantly different between conditions. However, anaerobic ATP synthesis, through augmented creatine kinase and glycolysis reactions, was significantly greater in FENT than in CTRL, resulting in a significantly greater ATP cost of contraction (0.049 ± 0.016 vs 0.038 ± 0.010 mM·min−1·N−1). Conclusion Group III/IV muscle afferents not only constrain the magnitude of perturbation in intramuscular Pi, H2PO4−, and ATP during small muscle mass exercise but also seem to play a role in maintaining efficient skeletal muscle contractile function in men.

Commentaries on Viewpoint: Could small-diameter muscle afferents be responsible for the ergogenic effect of limb ischemic preconditioning?

TO THE EDITOR: Cruz and colleagues (3) suggested that the ergogenic effect of ischemic preconditioning (IP) is in part caused by a reduced activity of sensory muscle afferents (SMA). This is an intriguing hypothesis that also further highlights some important implications of SMA for endurance performance. However, given the complex and integrative role of SMA, some points should be considered. First, unlike IP, spinal blockade of SMA did not provide any ergogenic effect on healthy subjects (1, 2), albeit the last most probably has a stronger suppression of SMA activity. Second, blockade of SMA demonstrated that perception of effort (RPE) is independent of SMA activity (4) and therefore changes in RPE after IP, should not be caused by a reduced activity of SMA. Finally, the ergogenic effect of IP might be also caused by a placebo effect. Indeed, the inability to effectively perform a sham-control IP treatment still remains. The placebo effect mainly relies on the assumption that participant believes that the intervention will alter results. For IP treatment, sham procedure commonly involves a very low cuff pressure that does not induce the same sensation experienced during IP treatment. Therefore participant expectancy about the treatment is unpredictable and might explain the improvement in performance and/or an altered pacing strategy (3, 5). Accordingly, future experiments should deserve more attention to reduce this confounding variable. In conclusion, future studies are required to confirm this hypothesis and more research is needed to understand the physiological mechanisms responsible for the ergogenic effect of IP on exercise performance.

Effect of adipose tissue thickness, muscle site, and sex on near-infrared spectroscopy derived total-[hemoglobin + myoglobin]

Craig JC, Broxterman RM, Wilcox SL, Chen C, Barstow TJ. Effect of adipose tissue thickness, muscle site, and sex on near-infrared spectroscopy derived total-[hemoglobin + myoglobin]. J Appl Physiol 123: 1571-1578, 2017. First published September 21, 2017; doi: 10.1152/japplphysiol.00207.2017 .-Adipose tissue thickness (ATT) attenuates signals from near-infrared spectroscopy (NIRS) and diminishes the absolute quantification of underlying tissues by contemporary NIRS devices. Based on the relationship between NIRS-derived total-[hemoglobin + myoglobin] (total-[Hb + Mb]) and ATT, we tested the hypotheses that the correction factor for ATT 1) is muscle site specific; 2) does not differ between men and women; and that 3) exclusion of the shortest source-detector distance from data analysis increases total-[Hb + Mb]. Fourteen healthy subjects (7 men) rested in a neutral body position (supine or prone) while measurements of total-[Hb + Mb] and ATT were taken at four muscles common to resting and exercise studies: vastus lateralis (VL), rectus femoris (RF), gastrocnemius (GS), and flexor digitorum superficialis (FDS). ATT averaged 6.0 ± 0.4 mm across all muscles. Every muscle showed a negative slope ( r2: 0.6-0.94; P < 0.01) for total-[Hb + Mb] as a function of ATT: VL (-34 μM/mm), RF (-26 μM/mm), GS (-54 μM/mm), and FDS (-33 μM/mm). The projected total-[Hb + Mb] at 0 mm ATT ( y-intercept) was 452, 372, 620, and 456 μM for VL, RF, GS, and FDS, respectively. No differences were found between the sexes within VL, RF, or FDS, but men had a greater projected total-[Hb + Mb] at 0 mm for GS (688 ± 44 vs. 552 ± 40 μM; P < 0.05). Exclusion of the shortest source-detector distance increased total-[Hb + Mb] by 12 ± 1 μM ( P < 0.05). The present findings demonstrate that total-[Hb + Mb] should be corrected for ATT using muscle site-specific factors which are not sex specific, except in the case of GS. NEW & NOTEWORTHY Near-infrared spectroscopy (NIRS) is an important tool for physiologists and clinicians. However, adipose tissue greatly attenuates the signals from these devices. Correcting for this attenuation has been suggested based on the strength of the relationship between NIRS-derived measurements and the adipose tissue thickness. We show that this relationship is unique to the muscle site of interest but may not be sex specific. Accurate quantification of underlying tissue mandates researchers correct for adipose tissue thickness.

Single passive leg movement assessment of vascular function: Contribution of nitric oxide

Broxterman RM, Trinity JD, Gifford JR, Kwon OS, Kithas AC, Hydren JR, Nelson AD, Morgan DE, Jessop JE, Bledsoe AD, Richardson RS. Single passive leg movement assessment of vascular function: contribution of nitric oxide. J Appl Physiol 123: 1468-1476, 2017. First published August 31, 2017; doi:10.1152/japplphysiol.00533.2017.-The assessment of passive leg movement (PLM)-induced leg blood flow (LBF) and vascular conductance (LVC) is a novel approach to assess vascular function that has recently been simplified to only a single PLM (sPLM), thereby increasing the clinical utility of this technique. As the physiological mechanisms mediating the robust increase in LBF and LVC with sPLM are unknown, we tested the hypothesis that nitric oxide (NO) is a major contributor to the sPLM-induced LBF and LVC response. In nine healthy men, sPLM was performed with and without NO synthase inhibition by intra-arterial infusion of NG-monomethyl-l-arginine (l-NMMA). Doppler ultrasound and femoral arterial pressure were used to determine LBF and LVC, which were characterized by the peak change (ΔLBFpeak and ΔLVCpeak) and area under the curve (LBFAUC and LVCAUC). l-NMMA significantly attenuated ΔLBFpeak [492 ± 153 (l-NMMA) vs. 719 ± 238 (control) ml/min], LBFAUC [57 ± 34 (l NMMA) vs. 147 ± 63 (control) ml], ΔLVCpeak [4.7 ± 1.1 (l-NMMA) vs. 8.0 ± 3.0 (control) ml·min-1·mmHg-1], and LVCAUC [0.5 ± 0.3 (l-NMMA) vs. 1.6 ± 0.9 (control) ml/mmHg]. The magnitude of the NO contribution to LBF and LVC was significantly correlated with the magnitude of the control responses ( r = 0.94 for ΔLBFpeak, r = 0.85 for LBFAUC, r = 0.94 for ΔLVCpeak, and r = 0.95 for LVCAUC). These data establish that the sPLM-induced hyperemic and vasodilatory response is predominantly (~65%) NO-mediated. As such, sPLM appears to be a promising, simple, in vivo assessment of NO-mediated vascular function and NO bioavailability. NEW & NOTEWORTHY Passive leg movement (PLM), a novel assessment of vascular function, has been simplified to a single PLM (sPLM), thereby increasing the clinical utility of this technique. However, the role of nitric oxide (NO) in mediating the robust sPLM hemodynamic responses is unknown. This study revealed that sPLM induces a hyperemic and vasodilatory response that is predominantly NO-mediated and, as such, appears to be a promising simple, in vivo, clinical assessment of NO-mediated vascular function and, therefore, NO bioavailability.

Influence of group III/IV muscle afferents on small muscle mass exercise performance: a bioenergetics perspective

This investigation assessed the influence of group III/IV muscle afferents on small muscle mass exercise performance from a skeletal muscle bioenergetics perspective. Group III/IV muscle afferent feedback was attenuated with lumbar intrathecal fentanyl during intermittent isometric single‐leg knee‐extensor all‐out exercise, while 31P‐MRS was used to assess skeletal muscle bioenergetics. Attenuation of group III/IV muscle afferent feedback improved exercise performance during the first minute of exercise, due to an increase in total ATP production with no change in the ATP cost of contraction. However, exercise performance was not altered during the remainder of the protocol, despite a sustained increase in total ATP production, due to an exacerbated ATP cost of contraction. These findings reveal that group III/IV muscle afferents directly limit exercise performance during small muscle mass exercise, but, due to their critical role in maintaining skeletal muscle contractile efficiency, with time, the benefit of attenuating the muscle afferents is negated.

Decreases in maximal oxygen uptake following long-duration spaceflight: Role of convective and diffusive O2 transport mechanisms

We have previously predicted that the decrease in maximal oxygen uptake (V̇o2max) that accompanies time in microgravity reflects decrements in both convective and diffusive O2 transport to the mitochondria of the contracting myocytes. The aim of this investigation was therefore to quantify the relative changes in convective O2 transport (Q̇o2) and O2 diffusing capacity (Do2) following long-duration spaceflight. In nine astronauts, resting hemoglobin concentration ([Hb]), V̇o2max, maximal cardiac output (Q̇Tmax), and differences in arterial and venous O2 contents ([Formula: see text]-[Formula: see text]) were obtained retrospectively for International Space Station Increments 19-33 (April 2009-November 2012). Q̇o2 and Do2 were calculated from these variables via integration of Ficks Principle of Mass Conservation and Ficks Law of Diffusion. V̇o2max significantly decreased from pre- to postflight (-53.9 ± 45.5%, P = 0.008). The significant decrease in Q̇Tmax (-7.8 ± 9.1%, P = 0.05), despite an unchanged [Hb], resulted in a significantly decreased Q̇o2 (-11.4 ± 10.5%, P = 0.02). Do2 significantly decreased from pre- to postflight by -27.5 ± 24.5% (P = 0.04), as did the peak [Formula: see text]-[Formula: see text] (-9.2 ± 7.5%, P = 0.007). With the use of linear regression analysis, changes in V̇o2max were significantly correlated with changes in Do2 (R2 = 0.47; P = 0.04). These data suggest that spaceflight decreases both convective and diffusive O2 transport. These results have practical implications for future long-duration space missions and highlight the need to resolve the specific mechanisms underlying these spaceflight-induced changes along the O2 transport pathway.NEW & NOTEWORTHY Long-duration spaceflight elicited a significant decrease in maximal oxygen uptake. Given the adverse physiological adaptations to microgravity along the O2 transport pathway that have been reported, an integrative approach to the determinants of postflight maximal oxygen uptake is needed. We demonstrate that both convective and diffusive oxygen transport are decreased following ~6 mo International Space Station missions.

Oxygen delivery and the restoration of the muscle energetic balance following exercise: Implications for delayed muscle recovery in patients with COPD

Patients with chronic obstructive pulmonary disease (COPD) experience a delayed recovery from skeletal muscle fatigue following exhaustive exercise that likely contributes to their progressive loss of mobility. As this phenomenon is not well understood, this study sought to examine postexercise peripheral oxygen (O2) transport and muscle metabolism dynamics in patients with COPD, two important determinants of muscle recovery. Twenty-four subjects, 12 nonhypoxemic patients with COPD and 12 healthy subjects with a sedentary lifestyle, performed dynamic plantar flexion exercise at 40% of the maximal work rate (WRmax) with phosphorus magnetic resonance spectroscopy (31P-MRS), near-infrared spectroscopy (NIRS), and vascular Doppler ultrasound assessments. The mean response time of limb blood flow at the offset of exercise was significantly prolonged in patients with COPD (controls: 56 ± 27 s; COPD: 120 ± 87 s; P < 0.05). In contrast, the postexercise time constant for capillary blood flow was not significantly different between groups (controls: 49 ± 23 s; COPD: 51 ± 21 s; P > 0.05). The initial postexercise convective O2 delivery (controls: 0.15 ± 0.06 l/min; COPD: 0.15 ± 0.06 l/min) and the corresponding oxidative adenosine triphosphate (ATP) demand (controls: 14 ± 6 mM/min; COPD: 14 ± 6 mM/min) in the calf were not significantly different between controls and patients with COPD (P > 0.05). The phosphocreatine resynthesis time constant (controls: 46 ± 20 s; COPD: 49 ± 21 s), peak mitochondrial phosphorylation rate, and initial proton efflux were also not significantly different between groups (P > 0.05). Therefore, despite perturbed peripheral hemodynamics, intracellular O2 availability, proton efflux, and aerobic metabolism recovery in the skeletal muscle of nonhypoxemic patients with COPD are preserved following plantar flexion exercise and thus are unlikely to contribute to the delayed recovery from exercise in this population.