Muscle Sympathetic Nerve Activity Burst Research Articles

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.

The Effect of Menstrual Cycle Phase on Neural Recruitment Patterns during Acute Chemoreflex Stress

We have shown previously that muscle sympathetic nerve activity (MSNA) responses to acute chemoreflex stress are augmented during the early follicular (EF) phase of the menstrual cycle relative to the midluteal (ML) phase in young healthy women. Interestingly, these differences were most pronounced in terms of MSNA burst amplitude, which may imply that neural recruitment strategies are affected by menstrual cycle phase. Therefore, the purpose of this retrospective analysis was to test the hypothesis that the recruitment of large action potential (AP) clusters occurs to a greater extent during the EF phase of the menstrual cycle compared with the ML phase. MSNA data (microneurography) from 7 young healthy women (aged 23±3 years; body mass index 23±3 kg/m2) were examined at rest and during a voluntary end‐inspiratory apnea which followed a rebreathing protocol to an end‐tidal PO2 of 65 Torr. These data were collected during the EF and ML phases. APs were identified from the filtered MSNA signal using a custom wavelet deconstruction approach which quantified AP firing frequencies (overall AP frequency and AP content per integrated burst). The identified APs were also binned in accordance to peak to peak amplitude to determine individual AP clusters (Scott’s rule). Resting AP frequency and AP content per MSNA burst were not different between menstrual cycle phases (APs/min: P=0.23; APs/burst: P=0.26). Similarly, the number of identified AP clusters at rest did not differ between the EF and ML phases (8±4 vs10±4 clusters; P=0.16). During apnea, changes in AP frequency and AP content per MSNA burst (i.e. expressed relative to baseline) were greater during the EF phase than the ML phase (ΔAPs/min: P=0.02; ΔAPs/burst: P=0.02). Similarly, apnea‐induced recruitment of new AP clusters (i.e. clusters which were not activated at baseline) was greater during the EF phase compared to the ML phase (ΔAP clusters: +6±8 vs+2±6 clusters; P=0.009). Taken together, these findings confirm that augmented integrated MSNA reactivity to chemoreflex stress during the EF phase of the menstrual cycle is mediated by a greater recruitment of latent subpopulations of larger sympathetic neurons relative to the ML phase. We speculate that the change in the gonadal hormone profile between EF (i.e. low estradiol, progesterone) and ML (i.e. elevated estradiol and progesterone) may be associated with centrally‐mediated alterations to neural outflow during chemoreflex stress, although further research is certainly required to address this hypothesis.

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.

Sympathetic transduction of blood pressure during graded lower body negative pressure

IntroductionCross‐sectional work has demonstrated that participants with high resting muscle sympathetic nerve activity (MSNA) have lower resting sympathetic transduction of blood pressure (BP), and a larger proportion of sympathetic bursts firing above the BP set‐point (or mean BP). However, to date, most of these observations have been evaluated between participants with different levels of resting MSNA. The objective of the current study is to evaluate the influence of acute elevations in MSNA on sympathetic transduction of BP in young healthy adults using graded lower body negative pressure (LBNP). We hypothesize that sympathetic transduction will decrease during acute elevations in MSNA due to an increased proportion of MSNA bursts firing above the BP set‐point.MethodsTen (1 female) young healthy participants underwent 8 minutes of quiet rest, followed by a graded LBNP protocol consisting of 8‐minute stages at ‐10, ‐20, and ‐30mmHg. Beat‐to‐beat heart rate and BP were quantified using single‐lead electrocardiography and finger photoplethysmography, respectively, while MSNA was quantified using fibular nerve microneurography. Sympathetic transduction was quantified in the time (signal‐averaging) and frequency (MSNA‐diastolic BP low frequency [LF: 0.04‐0.15 Hz] transfer function magnitude) domains. Tertiles of diastolic BP were determined for each participant, and the proportion of MSNA bursts firings within each BP tertile were quantified.ResultsMSNA burst frequency increased progressively during graded LBNP (from 15±7 to 17±7, 22±7, and 27±9 bursts/min; P<0.01), while the proportion of MSNA bursts firing in the highest BP tertile remained stable (19±7, 18±9, 19±9, 19±7 %; P=0.72). Sympathetic transduction of BP was unchanged during LBNP (from 2.1±1.1 to 2.3±1.5, 2.1±1.2, and 2.0±1.1 mmHg; P=0.51), while the BP responses to non‐burst cardiac cycles decreased progressively (from ‐0.7±0.5 to ‐0.9±0.5, ‐1.0±0.4, and ‐1.4±0.7 mmHg; P<0.01). The difference between burst and non‐burst cardiac cycles (from 2.8±1.4 to 3.2±1.9, 3.1±1.5, and 3.4±1.3 mmHg; P=0.26) and the MSNA‐diastolic BP transfer function magnitude (from 0.14±0.09 to 0.14±0.06, 0.14±0.06, and 0.13±0.07 au/mmHg; P=0.40) were also unchanged during LBNP. Lastly, the change in the proportion of MSNA bursts firing in the largest BP tertile was associated with the change in signal‐averaged sympathetic transduction across each stage of LBNP (r= ‐0.79, ‐0.78, ‐0.81; P≤0.01).ConclusionSympathetic transduction of diastolic BP is unchanged during graded LBNP due to the heterogenous inter‐individual responses in the gating of bursts to diastolic BP. The proportion of bursts firing at high BPs are associated with changes in sympathetic transduction of BP. The determinants of gating MSNA burst occurrence by the arterial baroreflex and its capacity for modulation warrant further study.

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.

Sleep Disturbance and Sympathetic Reactivity in Menopausal Women

IntroductionCardiovascular disease (CVD) is the leading cause of death in women. Sleep disturbances (DS), such as insomnia or frequent nocturnal awakenings, may increase the risk of CVD. Prior work suggests that autonomic blood pressure (BP) dysregulation in postmenopausal women may exaggerate risk of hypertension (HTN) and CVD. In addition, individuals with greater BP and sympathetic neural responses to stressors, such as a cold pressor test (CPT), demonstrate future risk for HTN development. Further, when exposed to 24‐hour sleep deprivation, older women, but not older men, demonstrate greater sympathetic activity. It is unknown, however, if women who experience DS demonstrate a greater sympathetic reactivity to a CPT. The purpose of this study was to determine if postmenopausal women with DS exhibit sympathetic reactivity to a CPT compared to women without DS.MethodsEighteen women (62±1yrs old; mean±SE) participated in two study visits. Visit 1: Informed consent and medical and health questionnaires. Visit 2: DS was assessed by the Menopause‐Specific Quality of Life questionnaire. Participants were classified as having disturbed sleep (DS; n=10) or non‐disturbed sleep (NDS; n=8) based on a scale of 1 indicating ‘none’ and 2‐8 being how bothersome it is. The study was conducted in the morning after overnight fast and abstinence of alcohol, caffeine, and exercise. Muscle sympathetic nerve activity (MSNA) was measured from the peroneal nerve using microneurography. Heart rate (HR) via 3‐lead electrocardiography, MSNA, and beat‐to‐beat BP using a non‐invasive finger cuff were measured during a 10‐min quiet rest and a two‐min CPT of the left hand.ResultsMenopause onset ranged from 40‐57yrs (50±1yrs). Body mass index was similar between groups (DS=25±1kg/m2, NDS=24±2kg/m2, p=0.53). MSNA burst incidence (bursts/100 heart beats, hb) increased throughout the CPT (time effect, p<0.01), but increases were not significantly different between DS (Δ19±6b/100hb; 95% CI [7,31]) and NDS (Δ11±6b/100hb; 95% CI [‐2,24]) (time*group, p=0.36) groups. Systolic BP, Diastolic BP and HR increased similarly (p>0.05) during the CPT for both groups. Sleep difficulty score was correlated with resting diastolic BP (r=0.43, p=0.03) and trended to correlate with the age of menopause (r= ‐0.37, p=0.05).ConclusionThese findings suggest that women with DS do not demonstrate greater sympathetic reactivity to a CPT, however, we did observe that DS was linked to greater diastolic BP at rest and appeared to be more bothersome for women who completed menopause at an earlier age. These findings suggest a pathway by which disrupted sleep may contribute to the future development of HTN and CVD in postmenopausal women.

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.

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.

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.

The feasibility of baroreflex sensitivity measurements in heart failure subjects: The role of slow-patterned breathing.

Increased muscle sympathetic nerve activity (MSNA) indicates an adverse outcome in heart failure. Decreased baroreflex modulation of MSNA is a well-known feature of the disease. The determinability of cardiovagal baroreflex sensitivity (BRS) in heart failure is low, however, the determinability of sympathetic BRS is not known. We have assessed the spontaneous, MSNA burst incidence-based baroreflex index (BRSsymp) in 33 stable heart failure patients and in 10 healthy controls using the traditional r ≥ .5 cutoff for acceptable individual diastolic pressure-burst incidence slopes, and also a more stringent r ≥ .7 cutoff. We have also assessed the influence of 6/min breathing. The determinability of BRSsymp in heart failure patients was 64% during spontaneous breathing with r ≥ .5 cutoff, and 39% using the r ≥ .7 cutoff. The determinability of these indices further decreased during 6/min breathing, dropping to 29% with the r ≥ .7 cutoff. In contrast, the determinability of the cardiovagal BRS indices increased significantly with 6/min breathing (from 24% to 66%; p < .001). Patients who still had determinable BRSsymp at the r ≥ .7 cutoff had a significantly lower baseline burst incidence than those with an undeterminable index (70 ± 14 vs. 89 ± 10 burst/100 cycles; p < .002). Neither the 6/min breathing, nor the r ≥ .7 cutoff limit influenced the high availability of BRSsymp in healthy subjects. The determinability of BRSsymp in heart failure patients is limited, especially with the 0.7 limit for correlation. Undeterminable BRSsymp in patients is associated with higher sympathetic activity. 6/min breathing improves the determinability of cardiovagal BRS indices, but not that of BRSsymp.

Autoencoded deep features for semi-automatic, weakly supervised physiological signal labelling

Background and aimsMachine Learning is transforming data processing in medical research and clinical practice. Missing data labels are a common limitation to training Machine Learning models. To overcome missing labels in a large dataset of microneurography recordings, a novel autoencoder based semi-supervised, iterative group-labelling methodology was developed. MethodsAutoencoders were systematically optimised to extract features from a dataset of 478621 signal excerpts from human microneurography recordings. Selected features were clusters with k-means and randomly selected representations of the corresponding original signals labelled as valid or non-valid muscle sympathetic nerve activity (MSNA) bursts in an iterative, purifying procedure by an expert rater. A deep neural network was trained based on the fully labelled dataset. ResultsThree autoencoders, two based on fully connected neural networks and one based on convolutional neural network, were chosen for feature learning. Iterative clustering followed by labelling of complete clusters resulted in all 478621 signal peak excerpts being labelled as valid or non-valid within 13 iterations. Neural networks trained with the labelled dataset achieved, in a cross validation step with a testing dataset not included in training, on average 93.13% accuracy and 91% area under the receiver operating curve (AUC ROC). DiscussionThe described labelling procedure enabled efficient labelling of a large dataset of physiological signal based on expert ratings. The procedure based on autoencoders may be broadly applicable to a wide range of datasets without labels that require expert input and may be utilised for Machine Learning applications if weak-labels were available.

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?

Menstrual cycle effects on sympathetic neural burst amplitude distribution during orthostasis in young women.

Fluctuations in ovarian hormones during the menstrual cycle impact muscle sympathetic nerve activity burst frequency and burst incidence at rest. The purpose of this study was to investigate menstrual cycle effects on sympathetic neural burst amplitude distribution during an orthostatic challenge in young women. This study included 11 healthy women (33 ± 10years [mean ± standard deviation]). Muscle sympathetic nerve activity was measured in the supine position as baseline measurement and during 5 min of 60° upright tilting, during the early follicular phase (low estrogen and progesterone) and mid-luteal phase (high estrogen and progesterone) of the menstrual cycle. Relative burst amplitude distribution of muscle sympathetic nerve activity was characterized by the mean, median, skewness, and kurtosis. From the supine to upright position, mean and median values of relative burst amplitude increased (both P < 0.05), regardless of phases of the menstrual cycle (P = 0.5 and P = 0.7, respectively). In comparison, during the early follicular phase, skewness and kurtosis remained unchanged (P = 0.6 and P = 0.3, respectively) and kurtosis decreased (1.25 ± 1.11 supine vs. -0.03 ± 0.73 upright; P = 0.02); there was no change in skewness during the mid-luteal phase (P = 0.4). In response to orthostasis, while the symmetry and tailedness/peakness of burst amplitude distribution do not change during the early follicular phase, the distribution during the mid-luteal phase becomes flatter with a lower but broader peak. The latter result suggests that the firing probability of large axon action potentials in response to orthostatic challenge is higher when estrogen and progesterone levels are elevated. The role of changes in sympathetic neural burst amplitude distribution in orthostatic tolerance remains to be determined.

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.

Sympathetic-transduction in untreated hypertension

Transduction of muscle sympathetic nerve activity (MSNA) into vascular tone varies with age and sex. Older normotensive men have reduced sympathetic transduction so that a given level of MSNA causes less arteriole vasoconstriction. Whether sympathetic transduction is altered in hypertension (HTN) is not known. We investigated whether sympathetic transduction is impaired in untreated hypertensive men compared to normotensive controls. Eight untreated hypertensive men and 10 normotensive men (age 50 ± 15 years vs. 45 ± 12 years (mean ± SD); p = 0.19, body mass index (BMI) 24.7 ± 2.7 kg/m2 vs. 26.0 ± 4.2 kg/m2; p = 0.21) were recruited. MSNA was recorded from the peroneal nerve using microneurography; beat-to-beat blood pressure (BP; Finapres) and heart rate (ECG) were recorded simultaneously at rest for 10 min. Sympathetic-transduction was quantified using a previously described method. The relationship between MSNA burst area and subsequent diastolic BP was measured for each participant with the slope of the regression indicating sympathetic transduction. MSNA was higher in the hypertensive group compared to normotensives (73 ± 17 bursts/100 heartbeats vs. 49 ± 19 bursts/100 heart bursts; p = 0.007). Sympathetic-transduction was lower in the hypertensive versus normotensive group (0.04%/mmHg/s vs. 0.11%/mmHg/s, respectively; R = 0.622; p = 0.006). In summary, hypertensive men had lower sympathetic transduction compared to normotensive individuals suggesting that higher levels of MSNA are needed to cause the same level of vasoconstrictor tone.