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

Purpose We 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. Methods Aortic 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. Results Adjusted 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). Conclusion There 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.

Sympathetic neural responses to sleep disorders and insufficiencies

Short sleep duration and poor sleep quality are associated with cardiovascular risk, and sympathetic nervous system (SNS) dysfunction appears to be a key contributor. The present review will characterize sympathetic function across several sleep disorders and insufficiencies in humans, including sleep deprivation, insomnia, narcolepsy, and obstructive sleep apnea (OSA). We will focus on direct assessments of sympathetic activation (e.g., plasma norepinephrine and muscle sympathetic nerve activity), but include heart rate variability (HRV) when direct assessments are lacking. The review also emphasizes sex as a key biological variable. Experimental models of total sleep deprivation and sleep restriction are converging to support epidemiological studies reporting an association between short sleep duration and hypertension, especially in women. A systemic increase of SNS activity via plasma norepinephrine is present with insomnia, and has also been confirmed with direct, regionally-specific evidence from microneurographic studies. Narcolepsy is characterized by autonomic dysfunction via both HRV and microneurographic studies, but with opposing conclusions regarding SNS activation. Robust sympathoexcitation is well documented in OSA, and is related to baroreflex and chemoreflex dysfunction. Treatment of OSA with continuous positive airway pressure results in sympathoinhibition. In summary, sleep disorders and insufficiencies are often characterized by sympathoexcitation and/or sympathetic/baroreflex dysfunction, with several studies suggesting women may be at heightened risk.

The Role of Central Command in the Increase in Muscle Sympathetic Nerve Activity to Contracting Muscle During High Intensity Isometric Exercise

We previously demonstrated that muscle sympathetic nerve activity (MSNA) increases to contracting muscle as well as to non-contracting muscle, but this was only assessed during isometric exercise at ∼10% of maximum voluntary contraction (MVC). Given that high-intensity isometric contractions will release more metabolites, we tested the hypothesis that the metaboreflex is expressed in the contracting muscle during high-intensity but not low-intensity exercise. MSNA was recorded continuously via a tungsten microelectrode inserted percutaneously into the right common peroneal nerve in 12 participants, performing isometric dorsiflexion of the right ankle at 10, 20, 30, 40, and 50% MVC for 2 min. Contractions were immediately followed by 6 min of post-exercise ischemia (PEI); 6 min of recovery separated contractions. Cross-correlation analysis was performed between the negative-going sympathetic spikes of the raw neurogram and the ECG. MSNA increased as contraction intensity increased, reaching mean values (± SD) of 207 ± 210 spikes/min at 10% MVC (P = 0.04), 270 ± 189 spikes/min at 20% MVC (P &lt; 0.01), 538 ± 329 spikes/min at 30% MVC (P &lt; 0.01), 816 ± 551 spikes/min at 40% MVC (P &lt; 0.01), and 1,097 ± 782 spikes/min at 50% MVC (P &lt; 0.01). Mean arterial pressure also increased in an intensity-dependent manner from 76 ± 3 mmHg at rest to 90 ± 6 mmHg (P &lt; 0.01) during contractions of 50% MVC. At all contraction intensities, blood pressure remained elevated during PEI, but MSNA returned to pre-contraction levels, indicating that the metaboreflex does not contribute to the increase in MSNA to contracting muscle even at these high contraction intensities.

Low-Dose Fentanyl Does Not Alter Muscle Sympathetic Nerve Activity, Blood Pressure, or Tolerance During Progressive Central Hypovolemia

Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a pre-syncopal limited progressive lower-body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg•min), which was compared between trials using a paired, two-tailed t-test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model (time [LBNP stage] x trial). LBNP tolerance was not different between trials (Fentanyl: 647 ± 386 vs. Placebo: 676 ± 295 mmHg•min, P=0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: p<0.01, trial: p=0.29, interaction: p=0.94) and reductions in mean BP (time: p<0.01, trial: p=0.50, interaction: p=0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.

Low-Dose Fentanyl Reduces Pain Perception, Muscle Sympathetic Nerve Activity Responses, and Blood Pressure Responses During the Cold Pressor Test

Our knowledge about how low-dose (analgesic) fentanyl affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose fentanyl influences human autonomic cardiovascular responses during painful stimuli in humans. Therefore, we tested the hypothesis that low-dose fentanyl reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-three adults (10F/13M; 27±7 y; 26±3 kg•m-2, mean ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed a cold pressor test (CPT; hand in ~0.4 °C ice bath for two minutes) before and five minutes after drug/placebo administration (75 μg fentanyl or saline). We compared pain perception (100 mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography, 11 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and post-drug/placebo time points) using paired, two-tailed t-tests. Before drug/placebo administration, perceived pain (p=0.8287), Δ MSNA burst frequency (p=0.7587), and Δ mean BP (p=0.8649) during the CPT were not different between trials. After the drug/placebo administration, fentanyl attenuated perceived pain (36 vs. 66 mm, p<0.0001), Δ MSNA burst frequency (9 vs. 17 bursts/minute, p=0.0054), and Δ mean BP (7 vs. 13 mmHg, p=0.0174) during the CPT compared to placebo. Fentanyl-induced reductions in pain perception and Δ mean BP were moderately related (r=0.40, p=0.0641). These data provide valuable information regarding how low-dose fentanyl reduces autonomic cardiovascular responses during an experimental painful stimulus.

An open-source application for the standardized burst identification from the integrated muscle sympathetic neurogram.

Muscle sympathetic nerve activity (MSNA) can be acquired from humans using the technique of microneurography. The resulting integrated neurogram displays pulse-synchronous bursts of sympathetic activity which undergoes processing for standard MSNA metrics including burst frequency, height, area, incidence, total activity and latency. The procedure for detecting bursts of MSNA and calculating burst metrics is tedious and differs widely amongst laboratories world-wide. We sought to develop an open-source, cross-platform web application that provides a standardized approach for burst identification and a tool to increase research reproducibility for those measuring MSNA. We compared the performance of this web application against a manual scoring approach under conditions of rest, chemoreflex activation (N = 9, 20 min isocapnic hypoxia), and metaboreflex activation (N = 13, 2 min isometric handgrip exercise and 4 min post exercise circulatory occlusion). The intraclass correlation coefficient (ICC) indicated good to strong agreement between scoring approaches for burst frequency (ICC = 0.92 - 0.99), incidence (ICC = 0.94 - 0.99), height (ICC = 0.76 - 0.88), total activity (ICC = 0.85 - 0.99), and latency (ICC = 0.97 - 0.99). Agreement with burst area was poor to moderate (ICC = 0.04 - 0.67) but changes in burst area were similar with chemoreflex and metaboreflex activation. Scoring using the web application was highly efficient and provided data visualization tools which expedited data processing and the analysis of MSNA. We recommend the open-source web application be adopted by the community for the analysis of MSNA.

Blood pressure oscillations impact signal-averaged sympathetic transduction of blood pressure: implications for the association with resting sympathetic outflow

The current signal-averaging technique for calculating sympathetic transduction of blood pressure does not consider the arterial pressure at which each muscle sympathetic burst occurs. A burst firing when mean arterial pressure is above the operating pressure was associated with a decrease in blood pressure. Thus, individuals with higher muscle sympathetic nerve activity demonstrate a reduced sympathetic transduction owing to the weighted contribution of more sympathetic bursts at higher levels of arterial pressure.

Effect of pulmonary vein isolation on left atrial remodeling and muscle sympathetic nerve activity in patients with atrial fibrillation

Background Catheter ablation (CA) for atrial fibrillation (AF) improves left ventricular function and induces left atrium reverse remodeling (LARR). CA is also associated with the modulation of ganglionated plexi in the left atrium (LA), including stretch-sensitive sympathetic and parasympathetic nerve mechanoreceptors. Increased filling pressure and enlargement of LA stimulate stretch-sensitive sympathetic nerve mechanoreceptors in heart failure, which contribute augmented sympathetic nerve activity. However, little is known about an effect of CA on the interaction between the changes of LARR and sympathetic nerve activity. Purpose To test the hypothesis that CA induce the reduction in sympathetic nerve activity in accordance with LARR in patients with atrial fibrillation. Methods This study was conducted as a retrospective, observational study. Twenty-eight AF patients (65.4±12.1 years old) were included in this study. We measured mean blood pressure (BP), heart rate (HR), brain natriuretic peptide (BNP), and direct recording of muscle sympathetic nerve activity (MSNA) using microneurography technique before and 12 weeks after CA. Echocardiogram was also performed to assess LARR and left ventricular function. To evaluate the interaction between LARR and MSNA, AF patients were divided into two groups by presence (LARR group; n=18) and absence (no LARR group; n=10) of LARR according to left atrium volume index (LAVi) following CA. Results No significant differences were observed at baseline in BP, MSNA and LAVi between two groups. BP did not change significantly after CA in both groups. HR significantly increased in the LARR group (63.1±5.7 vs 69.9±7.8, p&lt;0.01) compared to no LARR group. CA significantly reduced MSNA in the LARR group (37.8±10.1 vs 24.9±8.8 bursts/min, p&lt;0.01), but there was no significant change in the no LARR group. The septal E/e' ratio (11.3±3.8 vs 9.8±2.9, p&lt;0.05), left ventricular end-systolic volume index (LVESVi) (24.4±11.9 vs 19.6±7.8 ml/m2, p&lt;0.05) and Ln BNP (4.0±1.2 vs 3.3±1.0 log/pg/ml, p&lt;0.05) were also significantly improved in the LARR group. On the other hand, in the no LARR group, there were no significancy in the changes of the septal E/e' ratio, LVESVi and Ln BNP. LVEF was not significantly changed in both two groups. Conclusion Our study shows CA reduced MSNA accompanied by LARR in AF patients. The reduction in MSNA, septal E/e' ratio, LVESVi and Ln BNP were all more pronounced in the LARR group compared to the no LARR group. These findings suggest that LARR is associated with the reduction in MSNA in AF patients, which was attributed to CA-induced modulation of stretch-sensitive sympathetic nerve mechanoreceptors. FUNDunding Acknowledgement Type of funding sources: None.

Oscillatory Pattern of Sympathetic Nerve Bursts Is Associated With Baroreflex Function in Heart Failure Patients With Reduced Ejection Fraction

Sympathetic hyperactivation and baroreflex dysfunction are hallmarks of heart failure with reduced ejection fraction (HFrEF). However, it is unknown whether the progressive loss of phasic activity of sympathetic nerve bursts is associated with baroreflex dysfunction in HFrEF patients. Therefore, we investigated the association between the oscillatory pattern of muscle sympathetic nerve activity (LFMSNA/HFMSNA) and the gain and coupling of the sympathetic baroreflex function in HFrEF patients. In a sample of 139 HFrEF patients, two groups were selected according to the level of LFMSNA/HFMSNA index: (1) Lower LFMSNA/HFMSNA (lower terciles, n = 46, aged 53 ± 1 y) and (2) Higher LFMSNA/HFMSNA (upper terciles, n = 47, aged 52 ± 2 y). Heart rate (ECG), arterial pressure (oscillometric method), and muscle sympathetic nerve activity (microneurography) were recorded for 10 min in patients while resting. Spectral analysis of muscle sympathetic nerve activity was conducted to assess the LFMSNA/HFMSNA, and cross-spectral analysis between diastolic arterial pressure, and muscle sympathetic nerve activity was conducted to assess the sympathetic baroreflex function. HFrEF patients with lower LFMSNA/HFMSNA had reduced left ventricular ejection fraction (26 ± 1 vs. 29 ± 1%, P = 0.03), gain (0.15 ± 0.03 vs. 0.30 ± 0.04 a.u./mmHg, P &lt; 0.001) and coupling of sympathetic baroreflex function (0.26 ± 0.03 vs. 0.56 ± 0.04%, P &lt; 0.001) and increased muscle sympathetic nerve activity (48 ± 2 vs. 41 ± 2 bursts/min, P &lt; 0.01) and heart rate (71 ± 2 vs. 61 ± 2 bpm, P &lt; 0.001) compared with HFrEF patients with higher LFMSNA/HFMSNA. Further analysis showed an association between the LFMSNA/HFMSNA with coupling of sympathetic baroreflex function (R = 0.56, P &lt; 0.001) and left ventricular ejection fraction (R = 0.23, P = 0.02). In conclusion, there is a direct association between LFMSNA/HFMSNA and sympathetic baroreflex function and muscle sympathetic nerve activity in HFrEF patients. This finding has clinical implications, because left ventricular ejection fraction is less in the HFrEF patients with lower LFMSNA/HFMSNA.

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.