Muscle Sympathetic Nerve Activity Burst Frequency Research Articles

Resistance Breathing and Sympathetic Nerve Activity During Simulated Hemorrhage in Humans

BackgroundResistance breathing amplifies the respiratory pump during inspiration, so may be an effective intervention for treatment of hemorrhagic injuries. In animal studies of actual hemorrhage, and human studies of simulated hemorrhage, resistance breathing protects arterial pressure, and improves tolerance to this stress. Anecdotally, resistance breathing also increases the coupling between sympathetic nerve activity and arterial pressure. The impact of resistance breathing on overall sympathetic nerve activity, however, has not been examined. We tested the hypothesis that resistance breathing increases sympathetic nerve activity during simulated hemorrhage in healthy humans.MethodsLower body negative pressure (LBNP) was used to simulate hemorrhage in five human subjects (3M, 2F; 29.2 ± 6.8 y). Two experiments were conducted (randomized order): 1) a control condition in which LBNP was applied at 3 mmHg/min until the onset of presyncope, and 2) a resistance breathing condition in which the same LBNP protocol was used, but subjects breathed through a resistance device (set at ‐7 cm.H2O) during the final stages of the protocol. Arterial pressure and muscle sympathetic nerve activity (MSNA) of the radial nerve were monitored continuously. Bursts frequency (bursts/min) and burst incidence (burst/ 100 heart beats) were used to quantify MSNA. Coupling between diastolic arterial pressure (DAP) and MSNA was assessed by transfer function analysis coherence within the low frequency range (0.04‐0.15 Hz). Two‐way repeated measures ANOVAs were conducted for assessment of responses in the control and resistance breathing conditions, between baseline and at matched time points late in the LBNP protocol.ResultsWhile LBNP induced increases in both MSNA burst frequency (P=0.003) and burst incidence (P=0.06), there was no effect of resistance breathing on MSNA for either index during LBNP (control, 57.9 ± 25.9 bursts/min vs. resistance breathing, 50.6 ± 21.7 bursts/min, P=0.99; control, 55.6 ± 25.6 b/100 heart beats vs. resistance breathing, 42.3 ± 18.3 b/100 heart beats, P=0.42). Additionally, there was no effect of resistance breathing on DAP (control, 73.2 ± 9.9 mmHg vs. resistance breathing, 72.8 ± 4.4 mmHg; P=0.99), or coherence between MSNA and DAP during LBNP (control, 0.53 ± 0.21 vs. resistance breathing, 0.69 ± 0.17; P=0.46).ConclusionContrary to our hypothesis, resistance breathing had no effect on sympathetic nerve activity during LBNP. A limitation of this study is the low sample size (N=5), and high variability of MSNA. Future investigations with a larger sample size are needed to determine if respiratory dynamics can influence the coupling between MSNA and arterial pressure.

Morning Cardiovascular and Sympathetic Reactivity to Cold Pressor Test After Evening Binge Drinking: Sex Differences

Heavy alcohol consumption, including binge drinking, is associated with increased cardiovascular risk There is consistent evidence for increased muscle sympathetic nerve activity (MSNA) after acute alcohol consumption, and recent evidence for augmented sympathetic reactivity the morning after evening binge drinking. Given well documented differences in neural cardiovascular control between men and women, we hypothesized that women would exhibit augmented morning cardiovascular and sympathetic neural reactivity to cold stress following evening binge alcohol consumption. Thirty volunteers (15 women, 15 men; 25±1 years; 27±1 kg/m2) participated in the present study. Utilizing a randomized, cross‐over design, participants visited the laboratory for fluid control and alcohol sessions separated by ~1 month. The alcohol dose was based upon biological sex and body weight (1 g/kg dose in men and 0.85 g/kg dose in women). Beverage consumption occurred at 8:00pm and 9:00pm to simulate binge alcohol consumption (i.e., 4‐5 drink equivalent), with lights out at 11:00pm. An 8‐hour sleep opportunity was allotted from 11:00pm to 7:00am for overnight polysomnography (NATUS, Middleton, WI). Following lights on, twenty‐two (10 women, 12 men) participants were instrumented for a morning autonomic study with measurements of muscle sympathetic nerve activity (MSNA; microneurography), beat‐to‐beat blood pressure (finger plethysmography), and heart rate (electrocardiogram). MSNA, blood pressure, and heart rate were measured during a 3‐minute baseline, 2‐minute cold pressor test (CPT), and 3‐minute recovery. MSNA was scored and confirmed by one trained investigator (JR Carter). Statistical analysis included repeated measures ANOVA with condition and time as within subject factors and sex as a between subject factor (α = 0.05). Total sleep time and sleep efficiency were reduced following binge alcohol consumption in both sexes (condition: p < 0.05), but women had more frequent arousals following alcohol consumption (condition × sex: p = 0.008). During CPT, women exhibited an augmented pressor response via mean arterial pressure following evening binge alcohol consumption compared to fluid control, while men did not (condition × time × sex: p = 0.010). MSNA burst frequency was elevated during CPT following evening binge alcohol consumption compared to fluid control (condition × time: p = 0.033), but this was not different between sexes. Heart rate reactivity was not different across conditions (condition × time: p = 0.405) or between sexes (condition × time × sex: p = 0.818). In conclusion, our results indicate that evening binge drinking results in augmented cardiovascular reactivity in women compared to men, but these differences do not appear to be mediated via sympathetic neural reactivity.

Obesity‐related higher blood pressure is associated with augmented transduction of spontaneous muscle sympathetic nerve activity

Central obesity is associated with elevated adrenergic activity and arterial blood pressure (BP). Therefore, we tested the hypothesis that transduction of spontaneous muscle sympathetic nerve activity (MSNA) to BP, i.e., sympathetic transduction, would be augmented in central obesity (increased waist circumference) and positively related to resting BP. Young/middle‐age obese (n=14) or non‐obese (n=14) adults without hypertension (average ambulatory 24‐hr BP<130/80 mmHg) were included. MSNA (microneurography) and BP (finger cuff) were measured continuously for 10 min (supine) and bursts of MSNA were grouped into quartiles of burst clusters (1, 2, 3, 4+bursts) and burst amplitude. Beat‐to‐beat mean arterial pressure (MAP) was signal‐averaged over 10 cardiac cycles following each burst of MSNA. MSNA burst frequency was similar between obese and non‐obese (21±3vs.17±3 bursts/min, P=0.34). However, supine BP was significantly higher in obese compared with non‐obese (systolic: 127±3vs.114±3; diastolic: 76±2vs.64±1 mmHg, both P<0.01). Importantly, obese showed greater MAP responses to clusters of bursts compared with non‐obese (e.g.,4th quartile: 4.5±0.4vs.3.3±0.4 mmHg, P=0.05), but did not show greater MAP responses to higher burst amplitude (P=0.13). MAP responses to clusters of bursts were positively correlated with systolic BP when controlling for age, sex, and MSNA (R=0.43, P=0.03), but this correlation was abolished when also controlling for BMI (R=0.20, P=0.34). Diastolic BP was only weakly correlated with MAP responses to clusters of bursts (R=0.27, P=0.20). These findings suggest that the pressor response to clustered bursts of MSNA (i.e., sympathetic transduction) is augmented in central obesity and may contribute to the obesity‐related rise in supine systolic BP.

Lower blood pressure, but not muscle sympathetic nerve activity, in female compared to male adults during progressive central hypovolemia

INTRODUCTIONRapid adjustments in cardiac output and sympathetically‐mediated vasoconstriction are critical to prevent blood pressure (BP) from falling during central hypovolemia. Female adults have a reduced ability to tolerate central hypovolemia (i.e., orthostatic hypotension), potentially due to reduced sympathetically‐mediated vasoconstriction. However, there are minimal data evaluating sex differences in muscle sympathetic nerve activity (MSNA) during pre‐syncopal limited central hypovolemia. Therefore, the purpose of this study was to compare autonomic cardiovascular responses during central hypovolemia between sexes. We tested the hypothesis that young healthy female, compared to male, adults would have a lower tolerance to progressive hypovolemia, accompanied by attenuated MSNA responses.METHODSTwenty‐eight female (28±8 years old, 170±7 cm, 75±8 kg, BMI: 26±3 kg/m2) and 31 male (age: 30±5 years old, height: 176±6 cm, mass: 82±9 kg, BMI: 26±3 kg/m2) adults completed a staged lower‐body negative pressure (LBNP) protocol. The LBNP protocol started at minus 40 mmHg (LBNP40) and was further reduced by 10 mmHg every 3 minutes until the participant reached pre‐syncope. MSNA (radial nerve), heart rate, and BP were collected continuously throughout the protocol. LBNP tolerance was quantified as a cumulative stress index (mmHg*min) and was compared between sexes using a two‐tailed Mann‐Whitney test. MSNA, heart rate, and BP responses during LBNP were compared between sexes (LBNP stage [repeated measure] x sex) using mixed‐model analysis of variance tests.RESULTSConsistent with prior findings, female adults had a lower tolerance to progressive LBNP (female: 513±283 vs. male: 929±357 mmHg*min, p<0.0001). Due to more females reaching pre‐syncope sooner in the protocol, we compared responses during the early stages of LBNP. At these early LBNP stages (LBNP40 & LBNP50), significant interactions for heart rate and BP were observed (heart rate: p<0.0001, BP: p=0.0464). Post‐hoc analyses revealed a significantly higher heart rate (98±20 vs. 82±15 bpm, p<0.0001) and lower mean BP (80±11 vs. 87±7 mmHg, p = 0.0343) in females at LBNP50. However, MSNA burst frequency responses were not different between sexes at the assessed time points (female vs. male; Baseline: 14±9 vs. 17±10, LBNP40: 29±14 vs. 34±12, LBNP50: 34±16 vs. 35±16 bursts/min; sex: p=0.2685, interaction: p=0.2334, stage: p<0.0001).DISCUSSIONConsistent with previous reports, this study demonstrated a lower tolerance to progressive central hypovolemia in female compared to male adults. However, contrary to our hypothesis, there was no difference in MSNA burst frequency between sexes, despite lower BP in female adults during the early stages of LBNP. These findings support the need for future studies to explore other mechanisms contributing to sex differences in tolerance to central hypovolemia.

Muscle Sympathetic Nerve Reactivity to Trier Social Stress Test

Muscle sympathetic nerve activity (MSNA) responses to laboratory mental stress are highly variable, making characterization of the sympathoneural response difficult to infer. However, most commonly used mental stress tasks (i.e., mental arithmetic, Stroop Color Word Task, etc.) are primarily cognitive tasks. Further, interpretation of MSNA reactivity to these stressors can be challenging due to irregular breathing patterns, limb movement, etc. The current study assesses MSNA reactivity to the Trier Social Stress Test (TSST), an ecologically valid evaluative social stress task that utilizes an anticipatory stress period free of confounds such as irregular breathing and movement found in other mental stress tasks. The primary purpose of the present study was to assess MSNA during the stress‐anticipation period, as well as during the socially evaluated portion of the task. We hypothesized that MSNA would be elevated during both phases of the task. Sixteen healthy adults (12 female, 26 ± 1 years, 24 ± 1 kg/m2) participated in a morning autonomic function test consisting of simultaneous recordings of heart rate (HR, electrocardiogram), beat‐to‐beat blood pressure (finger plethysmography), and MSNA (microneurography) during a 10‐minute resting baseline followed by the TSST. The TSST consists of a speech preparation period (5 min), a public speech (5 min), and mental arithmetic task (5 min) in front of two laboratory judges and video recording. After completion of the TSST, participants were assessed throughout a 5‐minute recovery. MSNA was obtained throughout all tasks in 12 individuals. Compared to baseline, mean arterial pressure (MAP) significantly increased during the anticipatory phase (Δ8 ± 2 mmHg, p<.001), increased further during the speech (Δ25 ± 3 mmHg, p<.001) and arithmetic (Δ23 ± 3 mmHg, p<.001), and returned to anticipatory levels during recovery (Δ10 ± 1 mmHg, p<.001). Similarly, HR was elevated during the anticipatory (Δ8 ± 2 bpm, p=.002), and increased further during the speech (Δ24 ± 5 bpm, p<.001) and arithmetic (Δ19 ± 4 bpm, p<.001) phases, but fully returned to baseline levels during recovery (Δ2 ± 1 bpm p=.232). MSNA burst frequency was significantly reduced during the anticipatory phase (Δ‐5 ± 2 bursts/min, p=.014) and tended to be reduced during mental arithmetic (Δ‐5 ± 2 bursts/min, p=.058), while MSNA burst incidence was reduced during the anticipatory (Δ‐9 ± 3 bursts/100hb, p=.008) and arithmetic (Δ‐11 ± 4 bursts/100hb, p=.016) phases. In 7 individuals, MSNA signal quality allowed assessment of MSNA total area. While total MSNA appeared to increase during the speech portion of the TSST, this effect did not reach significance (Δ8906 ± 4547 arbitrary units, p=.098). Contrary to our hypothesis, while blood pressure and HR were significantly elevated, MSNA was reduced in response to social stress, likely due to baroreflex inhibition. Further, our findings exhibit previously observed inter‐individual variability in MSNA responsiveness to mental stress, even during anticipatory stress, suggesting that this variability is conserved between various laboratory stressors.

Sympathetic Responses to Chemoreflex Stress in Lean Women with Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive‐aged women, affecting ~10% of premenopausal women. Women with PCOS present with myriad cardiovascular risk factors including greater muscle sympathetic nerve activity (MSNA), however this has yet to be assessed during periods of reactivity. Interestingly, there is limited evidence to suggest that testosterone (i.e. free testosterone), which is elevated in ~75% of women with PCOS, may play a role in mediating greater MSNA in PCOS. Therefore, the purpose of this study was to test the hypotheses that (a) women with PCOS would exhibit greater MSNA reactivity in response to acute stress relative to control (CTRL) women, and (b) MSNA reactivity to stress would be positively correlated with elevated testosterone levels. We tested 4 lean women with PCOS and 4 CTRL women (age: 20±1 vs. 23±3 yrs, P=0.12; BMI: 25±3 vs.24±2 kg/m2, P=0.41). Heart rate (3‐lead ECG), beat‐by‐beat blood pressure (Finapres) and MSNA (microneurography at the peroneal nerve) were measured during 3‐min of quiet rest and during a maximal voluntary end‐expiratory breath hold. Analyses were performed comparing baseline to the latter half of the apnea, in which sympathetic reactivity was the greatest. Baseline mean arterial pressure (MAP) was similar between PCOS and CTRL (87±7 vs.86±5 mmHg, P=0.97), as were MSNA burst frequency (BF) and MSNA burst incidence (BI) (BF: 7±5 vs. 10±7 bursts/min, P=0.51; BI: 10±8 vs. 16±10 bursts/100hb, P=0.50). Apnea induced increases in MAP and MSNA in both groups (main effects of condition: MAP, P<0.05; BF, P<0.01; BI, P<0.01). However, MSNA during apnea was higher in women with PCOS compared to CTRL women (BF: 55±7 vs.35±12 bursts/min, P<0.05; BI: 81±18 vs.50±13 bursts/100hb, P<0.05). When all participants were pooled together, a trend towards a positive modest correlation between serum free testosterone concentrations and MSNA BI during apnea was observed (R2=0.33; P=0.18). These preliminary data provide some evidence that elevated testosterone levels observed in women with PCOS may contribute to greater sympathetic reactivity, although this requires further study. Importantly, despite greater MSNA responses to apnea, women with PCOS demonstrated similar BP responses to the CTRL group. These findings suggest that these young lean women with PCOS may benefit from an offsetting of high MSNA, which may be mediated by blunted neurovascular transduction.

Hypoxia‐induced sympathetic long‐term facilitation is mediated by a rightward shift in sympathetic action potential amplitude distribution and baroreflex resetting of action potential clusters

IntroductionBaroreflex resetting permits sympathetic long‐term facilitation (sLTF) following hypoxia. Muscle sympathetic nerve activity (MSNA) bursts are generated by synchronous discharge of varying‐amplitude action potentials (APs), with medium APs under strong baroreflex control. AP discharge strategies and baroreflex control of AP clusters facilitating sLTF is unknown. We hypothesized that recruitment of previously latent, large‐amplitude APs and baroreflex resetting of AP cluster operating points (OPs) would mediate sLTF following acute hypoxia.MethodsEight men (age = 24±3 yrs; BMI = 24±3 kg/m2) were exposed to 20 min isocapnic hypoxia (PETO2: 47±2 mmHg) and 30 min recovery. Blood pressure (BP; photoplethysmography) and MSNA (fibular microneurography) were acquired during baseline, hypoxia, early (first 5‐min) and late recovery (last 5‐min). Multi‐unit MSNA burst frequency (BF) and total activity (TA) were quantified. A continuous wavelet transform with matched mother wavelet was used to extract sympathetic APs. AP frequency, AP amplitude (normalized % of largest baseline AP amplitude), percent APs occurring outside a MSNA burst (% asynchronous APs) and total AP clusters was calculated. The proportion of APs firing in small (1‐3), medium (4‐6) and large (7‐10) normalized cluster sizes was assessed. Baroreflex OP was measured by plotting the intersection point of mean cluster incidence and mean diastolic BP (DBP). Friedman repeated‐measures analysis of variance on ranks was used to determine the effect of condition (baseline, hypoxia, early, late). Data are means ± standard deviation or 95% confidence intervals.ResultsHypoxia increased BF (P<0.01), TA (P<0.01), AP frequency (Δ124{‐30, 279} AP/min, P<0.05), AP amplitude (Δ3{1, 5} %, P<0.05) and decreased asynchronous APs (Δ‐10{‐17, ‐4} %, P<0.03). Compared to baseline, BF (P<0.03), TA (P<0.02) and AP amplitude (early: Δ3{0, 5} %, P<0.05; late: Δ4{1, 6} %, P<0.05) was elevated during recovery while asynchronous APs (early: Δ‐9{‐16, ‐3} %, P<0.03; late: Δ‐7{‐14, ‐1} %, P<0.03) were reduced. The total number of AP clusters was increased (P<0.05) with no one condition different compared to baseline (hypoxia: Δ3{‐1, 7} clusters; early and late: Δ3{‐1, 6} clusters, P>0.10). Proportion of APs in small clusters was reduced in hypoxia (hypoxia: 44±18 %, P<0.05), early (46±21 %, P<0.05) and late recovery (44±17 %, P<0.05) compared with baseline (53±20 %) while the proportion of APs in large clusters was increased in early recovery (7±6 %, P<0.05) compared with baseline (5±5 %). Baroreflex OPs were shifted rightward for all AP clusters in recovery (baseline DBP: 63±5; early DBP: 64±5; late DBP: 65±4, mmHg; P<0.05) with no effect on slope (P>0.20).ConclusionsHypoxia‐induced sLTF is mediated by reduced asynchronous AP firing, a proportional shift toward large‐amplitude AP activity, and baroreflex resetting of AP clusters to higher OPs.

Impact of Maternal Obesity on Resting Muscle Sympathetic Nerve Activity during Normotensive Pregnancy

Maternal obesity increases the risk of adverse pregnancy outcomes. The mechanisms that contribute to this elevated risk are unclear but may be related to overactivation of the sympathetic nervous system. Indeed, sympathetic activation during pregnancy is now regarded as a normal adaptation to maintain homeostasis. However, sympathetic overactivation is associated with gestational hypertensive disorders. It is unknown whether the health related problems linked to maternal obesity (i.e., inflammation, insulin resistance, dyslipidemia) results in sympathetic overactivation during pregnancy. We hypothesized that maternal obesity would induce greater increases in resting muscle sympathetic nerve activity (MSNA) during pregnancy when compared with normal‐weight women.Blood pressure (BP), heart rate and MSNA (microneurography) were recorded during 5 min of supine rest in 14 normal‐weight (Age 30±1.6 [SE] yrs; BMI 22.1±0.6 kg/m2) and 14 obese (Age 28±0.8 yrs; BMI 33.9±1.0 kg/m2) women during early pregnancy (5‐12 weeks), late pregnancy (32 to 34 weeks) and 6‐10 weeks postpartum.Gestational weight gain from early to late pregnancy was not significantly different between groups (11.8±0.9 kg vs. 9.2±2.1 kg, P=0.23). Resting MSNA burst frequency was not different between normal‐weight and obese groups during early pregnancy (17±3 bursts/min vs. 22±4 bursts/min, P=0.35) or postpartum (10±2 bursts/min vs. 8±2 bursts/min P=0.74) but was significantly greater in the obese group during late pregnancy (23±4 bursts/min vs. 35±4 bursts/min, Figure A, P=0.031). There were no significant changes in resting MSNA from early to late pregnancy in the normal‐weight group (P=0.67) whereas the obese group had significant increases in MSNA from early to late pregnancy (P=0.002). These findings were also apparent when MSNA was characterized as burst incidence and total activity (Figure B and C). Although still within the normotensive range, women with obesity had greater levels of systolic BP when compared with normal‐weight women across all time points (Figure D, group main effect P=0.002). Diastolic BP was lower during pregnancy when compared with postpartum and this was similar between groups (Figure E, gestation main effect P<0.001). Heart rate was greater during early pregnancy when compared with postpartum and increased similarly in both groups during late pregnancy (Figure F, gestation main effect P<0.001).These findings suggest that maternal obesity is associated with greater increases in sympathetic activation even during normotensive pregnancy and may play a role in the increased risk of adverse maternal and fetal outcomes in women with obesity.

Sympathetic transduction of blood pressure during graded lower body negative pressure in young healthy adults.

Sympathetic transduction of blood pressure (BP) is correlated negatively with resting muscle sympathetic nerve activity (MSNA) in cross-sectional data, but the acute effects of increasing MSNA are unclear. Sixteen (4 female) healthy adults (26 ± 3 years) underwent continuous measurement of heart rate, BP, and MSNA at rest and during graded lower body negative pressure (LBNP) at -10, -20, and -30 mmHg. Sympathetic transduction of BP was quantified in the time (signal averaging) and frequency (MSNA-BP gain) domains. The proportions of MSNA bursts firing within each tertile of BP were calculated. As expected, LBNP increased MSNA burst frequency (P < 0.01) and burst amplitude (P < 0.02), although the proportions of MSNA bursts firing across each BP tertile remained stable (all P > 0.44). The MSNA-diastolic BP low-frequency transfer function gain (P = 0.25) was unchanged during LBNP; the spectral coherence was increased (P = 0.03). Signal-averaged sympathetic transduction of diastolic BP was unchanged (from 2.1 ± 1.0 at rest to 2.4 ± 1.5, 2.2 ± 1.3, and 2.3 ± 1.4 mmHg; P = 0.43) during LBNP, but diastolic BP responses following nonburst cardiac cycles progressively decreased (from -0.8 ± 0.4 at rest to -1.0 ± 0.6, -1.2 ± 0.6, and -1.6 ± 0.9 mmHg; P < 0.01). As a result, the difference between MSNA burst and nonburst diastolic BP responses was increased (from 2.9 ± 1.4 at rest to 3.4 ± 1.9, 3.4 ± 1.9, and 3.9 ± 2.1 mmHg; P < 0.01). In conclusion, acute increases in MSNA using LBNP did not alter traditional signal-averaged or frequency-domain measures of sympathetic transduction of BP or the proportion of MSNA bursts firing at different BP levels. The factors that determine changes in the firing of MSNA bursts relative to oscillations in BP require further investigation.

Aortic haemodynamics: the effects of habitual endurance exercise, age and muscle sympathetic vasomotor outflow in healthy men

PurposeWe determined the effect of habitual endurance exercise and age on aortic pulse wave velocity (aPWV), augmentation pressure (AP) and systolic blood pressure (aSBP), with statistical adjustments of aPWV and AP for heart rate and aortic mean arterial pressure, when appropriate. Furthermore, we assessed whether muscle sympathetic nerve activity (MSNA) correlates with AP in young and middle-aged men.MethodsAortic PWV, AP, aortic blood pressure (applanation tonometry; SphygmoCor) and MSNA (peroneal microneurography) were recorded in 46 normotensive men who were either young or middle-aged and endurance-trained runners or recreationally active nonrunners (10 nonrunners and 13 runners within each age-group). Between-group differences and relationships between variables were assessed via ANOVA/ANCOVA and Pearson product-moment correlation coefficients, respectively.ResultsAdjusted aPWV and adjusted AP were similar between runners and nonrunners in both age groups (all, P > 0.05), but higher with age (all, P < 0.001), with a greater effect size for the age-related difference in AP in runners (Hedges’ g, 3.6 vs 2.6). aSBP was lower in young (P = 0.009; g = 2.6), but not middle-aged (P = 0.341; g = 1.1), runners compared to nonrunners. MSNA burst frequency did not correlate with AP in either age group (young: r = 0.00, P = 0.994; middle-aged: r = − 0.11, P = 0.604).ConclusionThere is an age-dependent effect of habitual exercise on aortic haemodynamics, with lower aSBP in young runners compared to nonrunners only. Statistical adjustment of aPWV and AP markedly influenced the outcomes of this study, highlighting the importance of performing these analyses. Further, peripheral sympathetic vasomotor outflow and AP were not correlated in young or middle-aged normotensive men.

Sympathoinhibitory effect of sacubitril-valsartan in heart failure with reduced ejection fraction: A pilot study.

Chronic sympathetic nervous system (SNS) overactivity, characteristic of heart failure (HF) with reduced ejection fraction (HFrEF), is associated with poor prognosis and contributes to increased mortality risk. Sacubitril-valsartan is a recently approved, first-in-class, angiotensin receptor neprilysin inhibitor (ARNI) drug that markedly reduces the risks of death from cardiovascular causes and hospitalization for HF in patients with HFrEF, but the physiological mechanisms underlying these benefits are not fully understood. This single-arm, open-label, prospective study sought to test the hypothesis that short-term treatment with sacubitril-valsartan reduces SNS activity, measured directly via muscle sympathetic nerve activity (MSNA), in patients with HFrEF. MSNA, heart rate (HR), and arterial blood pressure (BP) were assessed in stable Class II and III patients with HFrEF (n=9, 69±8yrs.; 28.6±3.6kg/m2) on contemporary, guideline-directed medical treatment who were subsequently started on sacubitril-valsartan. These measurements were repeated after two months of treatment with sacubitril-valsartan. Sacubitril-valsartan reduced MSNA burst frequency (baseline: 43±10 bursts/min; 2-month: 36±10 bursts/min, p=0.05) and burst incidence (baseline: 68±16 bursts/100 heartbeats; 2-month: 55±16 bursts/100 heartbeats, p=0.02), while HR and BP were unchanged following the treatment (p>0.05). These preliminary findings provide new evidence regarding the ability of sacubitril-valsartan to rapidly reduce SNS activity in patients with HFrEF, suggesting the presence of a novel sympathoinhibitory effect of this new drug class.

Does COVID‐19 influence the sympathetic regulation of blood pressure?

Does COVID‐19 influence the sympathetic regulation of blood pressure?

Sympathetic vasoconstrictor activity before and after left ventricular assist device implantation in patients with end-stage heart failure.

Sympathetic overactivity, which predicts poor outcome in patients with heart failure, normalizes following cardiac transplantation. We tested the hypothesis that haemodynamic improvement following left ventricular assist device (LVAD) implantation is also associated with reductions in centrally generated sympathetic activity. In eight patients with heart failure (two women, six men, age 44-66 years), we continuously recorded electrocardiogram, beat-to-beat finger blood pressure, respiration, and muscle sympathetic nerve activity (MSNA) before and after implantation of the continuous-flow LVAD devices HeartWare HVAD (n= 4) and HeartMate II (n= 2), and the non-continuous-flow device HeartMate 3 (n= 2). LVAD implantation increased cardiac output by 1.29 ± 0.88 L/min (P= 0.060) and mean arterial pressure by 16.2± 7.9 mmHg (P< 0.001), while reducing pulse pressure by 25.3± 9.8 mmHg (P< 0.001). LVAD implantation did not change MSNA burst frequency (-1.3± 7.5 bursts/min, P= 0.636), total activity (+0.62 ± 1.83 au, P= 0.369), or normalized activity (+0.63 ± 4.23, P= 0.685). MSNA burst incidence was decreased (-7.8± 9.3 bursts/100 heart beats, P= 0.049). However, cardiac ectopy altered MSNA bursting patterns that could be mistaken for sympatholysis. Implantation of current design LVAD does not consistently normalize sympathetic activity in patients with end-stage heart failure despite haemodynamic improvement.

COVID-19 is getting on our nerves: sympathetic neural activity and haemodynamics in young adults recovering from SARS-CoV-2.

Key points The impact of SARS‐CoV‐2 infection on autonomic and cardiovascular function in otherwise healthy individuals is unknown.For the first time it is shown that young adults recovering from SARS‐CoV‐2 have elevated resting sympathetic activity, but similar heart rate and blood pressure, compared with control subjects.Survivors of SARS‐CoV‐2 also exhibit similar sympathetic nerve activity and haemodynamics, but decreased pain perception, during a cold pressor test compared with healthy controls.Further, these individuals display higher sympathetic nerve activity throughout an orthostatic challenge, as well as an exaggerated heart rate response to orthostasis.If similar autonomic dysregulation, like that found here in young individuals, is present in older adults following SARS‐CoV‐2 infection, there may be substantial adverse implications for cardiovascular health. The novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) can elicit systemic adverse physiological effects. However, the impact of SARS‐CoV‐2 on autonomic and cardiovascular function in otherwise healthy individuals remains unclear. Young adults who tested positive for SARS‐CoV‐2 (COV+; n = 16, 8 F) visited the laboratory 35 ± 16 days following diagnosis. Muscle sympathetic nerve activity (MSNA), systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were measured in participants at rest and during a 2 min cold pressor test (CPT) and 5 min each at 30° and 60° head‐up tilt (HUT). Data were compared with age‐matched healthy controls (CON; n = 14, 9 F). COV+ participants (18.2 ± 6.6 bursts min−1) had higher resting MSNA burst frequency compared with CON (12.7 ± 3.4 bursts min−1) (P = 0.020), as well as higher MSNA burst incidence and total activity. Resting HR, SBP and DBP were not different. During CPT, there were no differences in MSNA, HR, SBP or DBP between groups. COV+ participants reported less pain during the CPT compared with CON (5.7 ± 1.8 vs. 7.2 ± 1.9 a.u., P = 0.036). MSNA was higher in COV+ compared with CON during HUT. There was a group‐by‐position interaction in MSNA burst incidence, as well as HR, in response to HUT. These results indicate resting sympathetic activity, but not HR or BP, may be elevated following SARS‐CoV‐2 infection. Further, cardiovascular and perceptual responses to physiological stress may be altered, including both exaggerated (orthostasis) and suppressed (pain perception) responses, compared with healthy young adults.

Signal-averaged resting sympathetic transduction of blood pressure: is it time to account for prevailing muscle sympathetic burst frequency?

Calculating the blood pressure (BP) response to a burst of muscle sympathetic nerve activity (MSNA), termed sympathetic transduction, may be influenced by an individual's resting burst frequency. We examined the relationships between sympathetic transduction and MSNA in 107 healthy males and females and developed a normalized sympathetic transduction metric to incorporate resting MSNA. Burst-triggered signal averaging was used to calculate the peak diastolic BP response following each MSNA burst (sympathetic transduction of BP) and following incorporation of MSNA burst cluster patterns and amplitudes (sympathetic transduction slope). MSNA burst frequency was negatively correlated with sympathetic transduction of BP (r = -0.42; P < 0.01) and the sympathetic transduction slope (r = -0.66; P < 0.01), independent of sex. MSNA burst amplitude was unrelated to sympathetic transduction of BP in males (r = 0.04; P = 0.78), but positively correlated in females (r = 0.44; P < 0.01) and with the sympathetic transduction slope in all participants (r = 0.42; P < 0.01). To control for MSNA, the linear regression slope of the log-log relationship between sympathetic transduction and MSNA burst frequency was used as a correction exponent. In subanalysis of males (38 ± 10 vs. 14 ± 4 bursts/min) and females (28 ± 5 vs. 12 ± 4 bursts/min) with high versus low MSNA, sympathetic transduction of BP and sympathetic transduction slope were lower in participants with high MSNA (all P < 0.05). In contrast, normalized sympathetic transduction of BP and normalized sympathetic transduction slope were similar in males and females with high versus low MSNA (all P > 0.22). We propose that incorporating MSNA burst frequency into the calculation of sympathetic transduction will allow comparisons between participants with varying levels of resting MSNA.

Muscle Metaboreflex Control of Sympathetic Activity Is Preserved after Acute Intermittent Hypercapnic Hypoxia.

In normotensive patients with obstructive sleep apnea (OSA), the muscle sympathetic nerve activity (MSNA) response to exercise is increased while metaboreflex control of MSNA is decreased. We tested the hypotheses that acute intermittent hypercapnic hypoxia (IHH) in males free from OSA and associated comorbidities would augment the MSNA response to exercise but attenuate the change in MSNA during metaboreflex activation. Thirteen healthy males (age = 24 ± 4 yr) were exposed to 40 min of IHH. Before and after IHH, the pressor response to exercise was studied during 2 min of isometric handgrip exercise (at 30% maximal voluntary contraction), whereas the metaboreflex was studied during 4 min of postexercise circulatory occlusion (PECO). Mean arterial pressure (MAP), heart rate (HR), and fibular MSNA were recorded continuously. MSNA was quantified as burst frequency (BF) and total activity (TA). Mixed effects linear models were used to compare the exercise pressor and metaboreflex before and after IHH. As expected, IHH led to significant increases in MSNA BF, TA, and MAP at baseline and throughout exercise and PECO. However, during handgrip exercise, the change from baseline in MAP, HR, MSNA BF, and TA was similar before and after IHH (All P > 0.31). During PECO, the change from baseline in MSNA BF and TA was similar after IHH, whereas the change from baseline in MAP (Δ14 mm Hg, 95% CI = 7-19, vs Δ16 mm Hg, 95% CI = 10-21; P < 0.01) was modestly increased. After acute IHH, MSNA response to handgrip exercise and metaboreflex activation were preserved in healthy young males despite overall increases in resting MSNA and MAP. Chronic IHH and comorbidities often associated with OSA may be required to modulate the exercise pressor reflex and metaboreflex.

Aerobic fitness is inversely associated with neurohemodynamic transduction and blood pressure variability in older adults.

Higher aerobic fitness is independently associated with better cardiovascular health in older adults. The transduction of muscle sympathetic nerve activity (MSNA) into mean arterial pressure (MAP) responses provides important insight regarding beat-by-beat neural circulatory control. Aerobic fitness is negatively associated with peak MAP responses to spontaneous MSNA in young males. Whether this relationship exists in older adults is known. We tested the hypothesis that aerobic fitness was inversely related to sympathetic neurohemodynamic transduction and blood pressure variability (BPV) in older adults. Relative peak oxygen consumption (V̇O2peak, indirect calorimetry) was assessed in 22 older adults (13 males, 65 ± 5years, 36.3 ± 11.5ml/kg/min). Peroneal MSNA (microneurography) and arterial pressure (finger photoplethysmography) were recorded during ≥ 10-min of rest. BPV was assessed using the average real variability index. MAP was tracked for 12 cardiac cycles following heartbeats associated with MSNA bursts (i.e., peak ΔMAP). Peak ΔMAP responses (0.9 ± 0.6mmHg) were negatively associated (all, P < 0.04) with resting burst frequency (30 ± 11 bursts/min; R = -0.47) and burst incidence (54 ± 22 bursts/100 heartbeats; R = -0.51), but positively associated with BPV (ρ = 0.47). V̇O2peak was inversely related to the pressor responses to spontaneous bursts (R = -0.47, P = 0.03) and BPV (ρ = -0.54, P = 0.01), positively related to burst incidence (R = 0.42, P = 0.05), but unrelated to MSNA burst frequency (P = 0.20). The V̇O2peak-BPV relationship remained after controlling for burst frequency, peak ΔMAP, age, and sex. Lower V̇O2peak was associated with augmented neurohemodynamic transduction and BPV in older adults. These negative hemodynamic outcomes highlight the importance of higher aerobic fitness with ageing for optimal cardiovascular health.

Influence of Family History of Hypertension on Muscle Metaboreflex Activation in Young Healthy Non‐Hispanic White and Black Men

Activation of skeletal muscle afferents (i.e., the muscle metaboreflex) contributes importantly to the blood pressure and muscle sympathetic nerve activity (MSNA) responses evoked during exercise. Previous studies have demonstrated that non-Hispanic Black (BK) individuals have a heightened pressor response during exercise compared to White (WH) individuals. In addition, there is evidence to suggest that normotensive individuals with a family history of hypertension (+FHH) have exaggerated increases in blood pressure and MSNA during exercise. However, the mechanism(s) contributing to exaggerated responses during exercise in BK individuals and those with a +FHH remain unclear. Therefore, we tested the hypothesis that individuals with a +FHH would have an exaggerated muscle metaboreflex activation compared to those with a -FHH and these responses would be further augmented in BK individuals with a +FHH. Twenty-three WH (-FHH, n=12; +FHH, n=11) and twenty-two BK (-FHH n=10; +FHH, n=12) healthy young men performed 2 min of static handgrip at 40% of maximal voluntary contraction, followed by 2 min of post-exercise ischemia (PEI) to isolate muscle metaboreflex activation. Beat-to-beat arterial blood pressure (finger photoplethysmography), heart rate (ECG), and MSNA (peroneal nerve microneurography) were measured. Resting mean arterial pressure (MAP, p=0.89) and MSNA burst frequency (p=0.76) were similar between all groups. During PEI, WH+FHH had significantly exaggerated MAP (-FHH: Δ23±2 vs +FHH: Δ33±3 mmHg, p=0.01) and MSNA (-FHH: Δ17±2 vs +FHH: Δ28±3 bursts/min, p=0.02) responses compared to WH-FHH. In contrast, PEI responses were similar between BK-FHH and BK+FHH for both MAP (-FHH: Δ26±1 vs +FHH: Δ25±2 mmHg, p=0.79) and MSNA (-FHH: Δ25±3 vs +FHH: Δ20±3 bursts/min, p=0.26). In summary, in contrast to our hypothesis, +FHH did not appear to affect responses in BK individuals, whereas WH men with a +FHH exhibited heightened muscle metaboreflex-mediated pressor and sympatho-excitatory responses compared to WH men with a -FHH.

The Influence of OSA Treatment on Muscle Sympathetic Nerve Activity: A Systematic Review and Meta‐Analysis

Introduction Obstructive Sleep Apnea (OSA) is commonly treated with Continuous Positive Airway Pressure (CPAP) therapy, which reduces the number of airway obstructions while sleeping. Recently, diet and exercise interventions have been explored as a possible alternative treatment for OSA. Microneurography is a technique used to measure efferent postganglionic muscle sympathetic nerve activity (MSNA) via direct interneural recordings. CPAP therapy and diet and exercise interventions reduce disease severity, but their influence on MSNA is less clear. Purpose The present meta-analysis aims to examine the influence of type and length of treatment for OSA on MSNA. Methods A structured search of electronic databases was performed by a research librarian. Two reviewers independently assessed the titles of abstracts of articles; studies meeting eligibility criteria were selected for full-text review. Two reviewers independently extracted the data and assessed the quality of the studies using Joanna Briggs Institute Critical Appraisal of Evidence Effectiveness tool. Review Manager v5.3 was used to conduct the statistical analyses, and significance was set at P < 0.05. Results Evidence from 10 interventions (n=186) shows CPAP therapy significantly decreases MSNA burst frequency in individuals with OSA (Mean Difference, +12.6 bursts/min; 95% CI, 10.1-15.2 bursts/min; I2 = 39%). The same is shown for burst incidence in 6 studies (n=113) (MD, +21.5 bursts/100 hbs; 95% CI, 18.6-24.5 bursts/100 hbs; I2 = 0%). Reductions in MSNA (burst frequency and burst incidence) were seen for all time points of CPAP therapy: 1, 6, and 12 months. Data from 5 studies shows a significant decrease in burst frequency following diet and exercise intervention (n=68) (MD, +9.86 bursts/min; 95% CI, 5.37-14.35 bursts/min; I2 = 75%). A meta-regression analysis identified a relationship between CPAP therapy length and burst frequency (R2 = 0.329, p = 0.003). Conclusion CPAP therapy decreases MSNA in individuals with OSA, and a relationship exists between length of treatment and sympathetic activity. However, a significant reduction in sympathetic activity was also seen as a result of diet and exercise interventions; although, only burst frequency data was reported. More data is needed to determine optimal treatment type and length.

Muscle Sympathetic Nerve Activity is Elevated in Females with Physical Menopause Symptoms

Introduction Multiple symptoms accompany menopause, including vasomotor symptoms (VMS), physical symptoms, psychosocial symptoms and sexual dysfunction. Previous studies show that experiencing VMS may increase the risks for hypertension and cardiovascular disease (CVD); however, it is unclear whether physical menopausal symptoms, such as weight gain, lack of energy, or reduced muscular strength, contribute to CVD risk. Furthermore, muscle sympathetic nerve activity (MSNA) is elevated with CVD, but the relationship between menopause symptoms and MSNA is unknown. Thus, the aim of our study was to determine if physical menopausal symptoms are correlated with MSNA in postmenopausal females. Methods Eight postmenopausal females (age 63±1yr; menopause age 53±2yr) attended two study visits. The first visit included written informed consent, completion of the Menopause-Specific Quality of Life (MENQOL) and Minnesota Leisure Time Physical Activity (MLTPAQ) Questionnaires, and blood draws to measure sex hormone levels. The MENQOL asks participants to rate how bothered they feel in four areas of symptoms: vasomotor (i.e., VMS), psychosocial, physical, and sexual. The absence of a symptom corresponds with a score of 1 point, whereas a present symptom is rated according to how bothersome it is and is scored from 2-8 points. The MLTPAQ estimates caloric expenditure based on reported habitual physical activity. The second visit was conducted in the morning after an overnight fast and abstinence of alcohol, caffeine and exercise for 12 hours and included measurements of continuous noninvasive BP, heart rate via a 3-lead electrocardiography (ADInstruments, Colorado Springs, CO) and MSNA of the peroneal nerve via microneurography during a 10-minute period of quiet rest. Results Total MENQOL scores ranged from 1.3-2.4 on a 1-8 scale; physical symptom scores ranged from 1.1 to 3.4; and VMS ranged from 1.0-1.7. Body mass index (BMI, kg/m2) was 24±2. Levels of estradiol, total estrogens, testosterone, total estrogens: testosterone ratio, and MLTPAQ were not different between the females. Average mean arterial pressure was (101±5mmHg) and MSNA burst frequency was 29 bursts/min). In addition, MSNA burst frequency correlated with the MENQOL scores for physical symptoms (r=0.73, p=0.04), but not other menopausal symptoms, including VMS (p>0.05), indicating that females with more severe physical symptoms had greater MSNA. Conclusion Although females with VMS have greater CVD risk than those without VMS, data from this small sample of females suggests that reported physical symptoms rather than VMS were elevated with resting MSNA and were strongly associated with MSNA. These findings suggest that females who experience physical menopause symptoms may demonstrate autonomic dysregulation which could contribute to CVD risk.