Reduces Muscle Sympathetic Nerve Activity Research Articles

The Impact of Exercise Training on Muscle Sympathetic Nerve Activity: A Systematic Review and Meta-Analysis.

The purpose of this systematic review and meta-analysis was to examine the effects of exercise training on muscle sympathetic nerve activity (MSNA) in humans. Studies included exercise interventions (randomized controlled trials [RCTs], non-randomized controlled trials [non-RCTs] or pre-to-post intervention) that reported on adults (>18 years) where MSNA was directly assessed using microneurography, and relevant outcomes were assessed (MSNA [total activity, burst frequency, burst incidence, amplitude], heart rate, blood pressure [systolic blood pressure, diastolic blood pressure, or mean blood pressure], and aerobic capacity [maximal or peak oxygen consumption]). 40 intervention studies (n=1,253 individuals) were included. RCTs of exercise compared to no exercise illustrated that those randomized to the exercise intervention had a significant reduction in MSNA burst frequency and incidence compared to controls. This reduction in burst frequency was not different between individuals with cardiovascular disease compared to those without. However, the reduction in burst incidence was greater in those with cardiovascular disease (9 RCTs studies, n = 234, MD -21.08 bursts/100 hbs; 95% CI -16.51, -25.66; I2 = 63%) compared to those without (6 RCTs, n = 192, MD -10.92 bursts/100 hbs; 95% CI -4.12, -17.73; I2 = 76%). Meta-regression analyses demonstrated a dose-response relationship where individuals with higher burst frequency and incidence pre-intervention had a greater reduction in values post-intervention. These findings suggest that exercise training reduces muscle sympathetic nerve activity, which may be valuable for improving cardiovascular health.

Effect of Sex on Sympatho-inhibitors and Non-inhibitor Phenotypes during Acute Hyperoxia

Acute hyperoxia (i.e., breathing air consisting of 100% oxygen, O2) reduces muscle sympathetic nerve activity (MSNA), positioning hyperoxia as a potential anti-hypertensive therapeutic. However, the link between hyperoxia and MSNA has not been established in females. We tested the hypothesis that males would exhibit greater reductions in MSNA during hyperoxia than females. We tested healthy females (n=18, 27±5yr, body mass index [BMI] 23±3kg/m2) and males (n=13, 27±5yr, 25±3kg/m2) of similar age (P=0.99) and BMI (P=0.08). Integrated MSNA, blood pressure, and end-tidal O2 (ETO2) and CO2 (ETCO2) were measured during normal room air breathing (BSL; 3-min) and hyperoxic breathing (100% O2; 3-min). Integrated MSNA was quantified as burst frequency (BF; bursts/min), amplitude (BA; a.u.), and total MSNA (a.u.); blood pressure was quantified as mean arterial pressure (MAP). Baseline MSNA BF was not different between females and males (24±7 vs 23±8 bursts/min, respectively, P=0.68); MAP was lower in females than males (85±7 vs 93±7 mmHg; p<0.01). Hyperoxia increased ETO2 (effect of cond: p<0.01) and reduced ETCO2 (effect of cond: p<0.01) in a manner similar between sexes for ETO2 (sex*cond: P=0.56) whereas ETCO2 decreased more in females than males (sex*cond: P=0.01). Overall, hyperoxia evoked reductions in MSNA BF (effect of cond: P=0.02) but not BA (effect of cond: P=0.80) or total MSNA (effect of cond: P=0.26). Nadir MSNA responses during hyperoxia unveiled sex differences insofar as total MSNA was reduced consistently only in males (sex*cond: P=0.04); within the females we observed the presence of sympatho-inhibitors and non-inhibitors. Whereas female and male inhibitors reduced total MSNA via substantial reductions in BF and non-significant reductions in BA, female non-inhibitors demonstrated limited reductions in BF (P=0.11 vs inhibitors) coupled with increases in BA (p<0.01 vs inhibitors), resulting in no net change in total MSNA (p<0.01 vs inhibitors). Overall, these findings indicate sex differences exist in the sympathetic response to hyperoxia, in marked variability in the female sympathetic response to acute hyperoxia. The Women and Children's Health Research Institute. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Neural-Cardiovascular Responses to Orthostasis Following 8-Weeks of Home-Based Lower Leg Heating in Older Women with Hypertension

Background: Hypertension remains a significant health problem for older women (≥60 y). Though effective blood pressure (BP) interventions exist (e.g., exercise, medication), adherence to these options is low. Lower leg heat therapy represents a promising and easily implementable adjuvant treatment that may offer cardioprotective benefits. However, no studies have investigated lower leg heat therapy’s effects on BP and neural-cardiovascular function, let alone in older women with hypertension. Accordingly, we hypothesized that 8-weeks of home-based lower leg heat therapy in older women with hypertension would 1) reduce ambulatory BP and 2) reduce muscle sympathetic nerve activity (MSNA) while augmenting cardiac output and stroke volume during graded head-up tilt (HUT). Methods: Forty older women with hypertension (69 ± 5 y [mean±SD]) were randomized to either heat therapy (INT, 42°C; n = 20) or a thermoneutral control (CON, 35°C; n = 20). Each woman completed 8 wks of at-home sessions (~4/wk; 45 min/session) immersing their legs ~33 cm in a portable spa bath. 24-h ambulatory BP was measured pre- (PRE) and post-intervention (POST). A subset of women (n = 18 for each group) completed supine rest and 5 min of 30° and 60° HUT at each time point, whereby laboratory heart rate, systolic and diastolic BP, MSNA burst frequency and incidence (microneurography), cardiac output (acetylene rebreathing), and stroke volume (cardiac output/heart rate) were measured. Results: Between INT and CON, PRE ambulatory awake systolic BP (140 ± 7 vs. 142 ± 6 mmHg; P = 0.34) and diastolic BP (80 ± 6 vs. 79 ± 6 mmHg; P = 0.51) were not different, nor were PRE supine systolic BP, diastolic BP, or heart rate (all P > 0.05). PRE supine resting MSNA burst frequency (36 ± 13 vs. 33 ± 16 bursts/min), MSNA burst incidence (54 ± 19 vs. 51 ± 22 bursts/100 heartbeats), cardiac output (4.9 ± 0.9 vs. 5.1 ± 1.0 L/min), and stroke volume (72 ± 15 vs. 76 ± 15 mL/beat) were not different between groups (all P > 0.05). From PRE to POST neither ambulatory awake systolic nor diastolic BP differed between groups (all P > 0.05). Despite this, POST laboratory systolic and diastolic BP were greater in INT (both P < 0.05) but not in CON (both P > 0.05) during HUT. POST laboratory heart rate was reduced in INT ( P = 0.025), and trended greater in CON ( P = 0.065) across HUT. Neither MSNA burst frequency nor burst incidence changed during HUT PRE to POST (all P > 0.05). Despite no PRE to POST differences in cardiac output in either group (all P > 0.05), INT had a greater overall POST stroke volume throughout HUT ( P = 0.011), while CON had a reduced stroke volume during 60° HUT ( P = 0.036). Conclusions: Contrary to our hypotheses, 8-weeks of home-based lower leg heat therapy did not improve ambulatory BP or HUT MSNA and cardiac output in older women with hypertension. However, women completing INT appeared to have a greater stroke volume and lower heart rate during HUT. Accordingly, these data suggest that 8-weeks of lower leg heat therapy in older women with hypertension may improve cardiac function during orthostasis without significant changes in sympathetic outflow or ambulatory BP. Supported by the National Institutes of Health (R01AG059314 and F32HL167556). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effective non-invasive ventilation reduces muscle sympathetic nerve activity in patients with stable hypercapnic COPD.

Increased sympathetic drive is of prognostic significance in chronic obstructive pulmonary disease (COPD) but its determinants remain poorly understood. One potential mechanism may be chemoreflex-mediated adrenergic stimulation caused by sustained hypercapnia. This study determined the impact of non-invasive ventilation (NIV) on muscle sympathetic nerve activity (MSNA) in patients with stable hypercapnic COPD. Ten patients (age 70 ± 7years, GOLD stage3-4) receiving long-term NIV (mean inspiratory positive airway pressure 21 ± 7cmH2O) underwent invasive MSNA measurement via the peroneal nerve during spontaneous breathing and NIV. Compared with spontaneous breathing, NIV significantly reduced hypercapnia (PaCO2 51.5 ± 6.9 vs 42.6 ± 6.1mmHg, p < 0.0001) along with the burst rate (64.4 ± 20.9 vs 59.2 ± 19.9 bursts/min, p = 0.03) and burst incidence (81.7 ± 29.3 vs 74.1 ± 26.9 bursts/100heartbeats, p = 0.04) of MSNA. This shows for the first time that correcting hypercapnia with NIV decreases MSNA in COPD.

The Effects of Transcutaneous Vagal Nerve Stimulation on Dynamic Cerebral Autoregulation

PurposeTranscutaneous vagal nerve stimulation (tVNS) applied to the cervical branch of the vagus nerve is FDA‐approved to treat migraine and cluster headache. tVNS applied to the auricle branch of the vagus nerve (tVNSab) reduces muscle sympathetic nerve activity and improves cardiac parasympathetic activity after one session in healthy participants. Given the use of tVNS to treat cerebral disorders and its effects on autonomic function, we postulated that tVNSab might be beneficial for cerebral vascular function. We tested the hypotheses that tVNSab will increase resting middle cerebral artery blood flow velocity (MCAv) and improve dynamic cerebral autoregulation (dCA) during a repeated squat‐to‐stand procedure.MethodsSeven healthy participants (age: 20 ± 3 y; BMI:19 ± 7 kg/m2; 3 women) completed two randomized experimental visits on separate days. One visit consisted of tVNSab using a transcutaneous electrical nerve stimulation device (pulse width = 200 ms; pulse frequency = 30 Hz) with electrodes attached to the tragus of each ear. A time‐control visit (SHAM) was conducted with electrodes attached to the tragus but no current was applied. Mean arterial pressure (MAP; photoplethysmography), the partial pressure of end‐tidal carbon dioxide (PETCO2; capnography) and MCAv (transcranial Doppler ultrasound) were measured continuously. After 45 min of resting tVNS or SHAM, subjects performed a repeated squat‐to‐stand maneuver at a frequency of 0.05 Hz for 5 min while tVNSab or SHAM continued. Resting conductance values for the MCA (MCAc) were calculated as MCAv/MAP. MCA dCA was assessed during the squat‐to‐stand maneuver using spectral analyses to obtain coherence, gain, and phase values in the very low frequency (VLF) and low frequency (LF) bands. Spectral analysis gain was also assessed using normalized units (gainn), defined as beat to beat values divided by the mean value relative to changes in blood pressure. Data are presented as mean ± SD.ResultsThere were no differences between tVNSab and SHAM for MAP (tVNSab: 103 ± 8; SHAM: 102 ± 12 mmHg; P=0.41), PETCO2 (tVNSab: 35 ± 5; SHAM: 36 ± 2 mmHg; P=0.42), MCAv (tVNSab: 61.5 ± 9.2; SHAM: 58.7 ± 13.3 cm/s, P=0.36) or MCAc (tVNSab: 0.60 ± 0.08; SHAM: 0.59 ± 0.19 cm/s/mmHg, P=0.46) during baseline. There were no differences between conditions for coherence at VLF (tVNSab: 0.43 ± 0.14; SHAM: 0.45 ± 0.34; P=0.44) or LF (tVNSab: 0.65 ± 0.17; SHAM: 0.72 ± 0.13; P=0.06). Phase in the VLF (tVNSab: 0.35 ± 0.32; SHAM: 0.33 ± 0.36 rad; P=0.44) and LF (tVNSab: 0.28 ± 0.23; SHAM: 0.30 ± 0.16 rad; P=0.36) were not different. Gain (tVNSab: 0.56 ± 0.30; SHAM: 0.56 ± 0.54 cm/s/mmHg; P=0.50) and gainn (tVNSab: 0.99 ± 0.53; SHAM: 0.85 ± 0.84 %/mmHg; P=0.37) in the VLF were not different. However, gain (tVNSab: 0.76 ± 0.14; SHAM: 0.86 ± 0.17 cm/s/mmHg; P=0.02) and gainn (tVNSab: 1.22 ± 0.16; SHAM: 1.35 ± 0.23 %/mmHg; P=0.04) in the LF were lower during tVNSab.ConclusiontVNSab did not alter resting cerebral vascular responses. However, MCA LF gain was lower during tVNSab versus SHAM. These preliminary data indicate that dCA in a major intracranial cerebral artery might be improved during a single session of tVNSab. Further research regarding the influence of chronic tVNSab on cerebral vascular function is warranted.

Reduced Muscle Sympathetic Nerve Activity Response To A Cold Pressor Test In Multiple Sclerosis

Reduced Muscle Sympathetic Nerve Activity Response To A Cold Pressor Test In Multiple Sclerosis

Treatment with Sacubitril‐Valsartan Reduces Muscle Sympathetic Nerve Activity and Improves Functional Capacity in Heart Failure Patients with Reduced Ejection Fraction

BackgroundChronic sympathetic overactivity and reduced functional capacity, characteristics of heart failure with reduced ejection fraction (HFrEF), are associated with poor prognosis and an increased risk of mortality in this patient group. Sacubitril‐valsartan, a recently approved angiotensin receptor neprilysin inhibitor (ARNI), reduces the risk of death from cardiovascular causes or hospitalization for heart failure in patients with HFrEF, but the mechanisms underlying its benefits are not fully understood. This study tested the hypothesis that treatment with sacubitril‐valsartan reduces muscle sympathetic nerve system activity and improves functional capacity in patients with HFrEF.MethodsIn nine Class II and III patients with HFrEF (69±3 yrs; 28.6±1.2 kg/m2), measurements of muscle sympathetic nerve activity (MSNA), functional capacity (six‐minute walk test (6MWT) distance), and blood pressure (BP) were performed at baseline prior to being transitioned to sacubitril‐valsartan. The measurements were repeated after two months of treatment with sacubitril‐valsartan.ResultsSacubitril‐valsartan treatment reduced MSNA burst frequency (baseline: 43±3 bursts/min; 2‐month: 36±3 bursts/min, p=0.05) and burst incidence (baseline: 68±5 bursts/min; 2‐month: 55±5 bursts/min, p=0.02), as well as improved 6MWT distance (baseline: 446±26 m; 2‐month: 500±30 m, p&lt;0.001). The changes in MSNA burst frequency and burst incidence were not correlated with the change in 6MWT distance (r=0.13 and r=0.11, respectively; both p&gt;0.05). No changes in BP were observed with the treatment (p&gt;0.05).ConclusionSacubitril‐valsartan reduced sympathetic nervous system activity and improved functional capacity in patients with HFrEF, providing new evidence for the potential favorable effect of this new drug class on autonomic and functional outcomes in this patient group.Support or Funding InformationThis project is funded in part by the National Institutes of Health (HL118313; D.W.W., R56AG057584; R.S.R., T32HL139451; R.S.R. (recipient) and K.B. (trainee)), the U.S. Department of Veterans Affairs (I01RX001311; D.W.W., I01RX001697; R.S.R., I01RX002323; R.S.R., I21RX001433; R.S.R., I01RX000182; R.S.R.), and the American Heart Association (18POST33960192; K.B.).

High‐intensity interval training decreases muscle sympathetic nerve activity and improves peripheral vascular function in patients with heart failure with reduced ejection fraction

BackgroundModerate intensity continuous exercise (MICT) has been shown to reduce muscle sympathetic nerve activity (MSNA) in heart failure patients with reduced ejection fraction (HFrEF). However, the effects of high‐intensity interval training (HIIT) on MSNA in HFrEF patients are unknown. We hypothesized that reductions in MSNA would be greater following HIIT than MICT and correspond with improvements in peripheral vascular function.MethodsHFrEF patients (30 ‐ 65 years), left ventricular ejection fraction ≤ 40%, Functional Classes II–III, were randomized into HIIT, MICT or no training (NT) three times/week for 12 weeks. MSNA was assessed by microneurography. Brachial artery flow‐mediated dilation (FMD), blood flow and vascular conductance were assessed by ultrasonography, blood pressure (BP) and heart rate (HR) by plethysmography and peak oxygen uptake (V̇O2peak) by a cardiopulmonary exercise test.ResultsBoth, HIIT and MICT, led to reductions in MSNA (frequency and incidence burst) relative to NT (p&lt;0.05). However, the reduction in MSNA was more pronounced following HIIT than MICT (p&lt;0.05). Increases in brachial artery FMD, resting blood flow and conductance were also greater following HIIT than MICT (p&lt;0.05), while V̇O2peak increased similarly following HIIT and MICT relative to NT. No changes in BP or HR were observed in either exercise condition. Further analysis showed a negative correlation between changes in MSNA and FMD following the interventions (r=−0.60, p=0.005).ConclusionOur findings indicate that 12 weeks of HIIT is superior to MICT in reducing sympathetic overactivity and improving vascular function in patients with HFrEF, despite similar increases in exercise capacity.Support or Funding InformationFAPESP Grants (2014/11671‐6 and 2017/25613‐6)

Device-guided slow breathing reduces blood pressure and sympathetic activity in young normotensive individuals of both sexes.

Slow breathing (SLOWB) is recommended for use as an adjuvant treatment for hypertension. However, the extent to which blood pressure (BP) responses to SLOWB differ between men and women are not well-established. Therefore, we tested the hypothesis that an acute bout of SLOWB would induce larger decreases in BP in males than in females, given that males typically have higher resting BP. We also examined autonomic contributors to reduced BP during SLOWB; that is, muscle sympathetic nerve activity and spontaneous cardiovagal (sequence method) and vascular sympathetic baroreflex sensitivity. We tested normotensive females (n = 10, age: 22 ± 2 y, body mass index: 22 ± 2 kg/m2) and males (n = 12, age: 23 ± 3 y, body mass index: 26 ± 4 kg/m2). Subjects were tested at baseline and during the last 5 min of a 15-min RESPeRATE-guided SLOWB session. Overall, SLOWB reduced systolic BP by 3.2 ± 0.8 mmHg (main effect, P < 0.01). Females had lower systolic BP (main effect, P = 0.02); we observed no interaction between sex and SLOWB. SLOWB also reduced muscle sympathetic nerve activity burst incidence by -5.0 ± 1.4 bursts/100 heartbeats (main effect, P < 0.01). Although females tended to have lower burst incidence (main effect, P = 0.1), there was no interaction between sex and SLOWB. Cardiovagal baroreflex sensitivity improved during SLOWB (21.0 vs. 36.0 ms/mmHg, P = 0.03) with no effect of sex. Despite lower overall BP in females, our data support a lack of basement effect on SLOWB-induced reductions in BP, as SLOWB was equally effective in reducing BP in males and females. Our findings support the efficacy of the RESPeRATE device for reducing BP in both sexes, even in young, normotensive individuals.NEW & NOTEWORTHY We provide support for the effectiveness of device-guided slow breathing for blood pressure reduction in young normotensive women and men. Despite having lower baseline blood pressure and sympathetic nerve activity, women experienced equivalent reductions in both measures in response to RESPeRATE-guided slow breathing as men. Thus, slow breathing appears to be effective in young healthy normotensive individuals of both sexes and may be an ideal preventative therapy against future hypertension.

Femoral vascular conductance and peroneal muscle sympathetic nerve activity responses to acute epidural spinal cord stimulation in humans.

What is the central question of this research? Does acute spinal cord stimulation increase vascular conductance and decrease muscle sympathetic nerve activity in the lower limbs of humans? What is the main finding and its importance? Acute spinal cord stimulation led to a rapid rise in femoral vascular conductance, and peroneal muscle sympathetic nerve activity demonstrated a delayed reduction that was not associated with the initial increase in femoral vascular conductance. These findings suggest that neural mechanisms in addition to attenuated muscle sympathetic nerve activity might be involved in the initial increase in femoral vascular conductance during acute spinal cord stimulation. Clinical cases have indicated an increase in peripheral blood flow after continuous epidural spinal cord stimulation (SCS) and that reduced muscle sympathetic nerve activity (MSNA) might be a potential mechanism. However, no studies in humans have directly examined the effects of acute SCS (<60min) on vascular conductance and MSNA. In study 1, we tested the hypothesis that acute SCS (<60min) of the thoracic spine would lead to increased common femoral vascular conductance, but not brachial vascular conductance, in 11 patients who previously underwent surgical SCS implantation for management of neuropathic pain. Throughout 60min of SCS, common femoral artery conductance was elevated and significantly different from brachial artery conductance [in millilitres per minute: 15min, change (Δ) 26±37 versus Δ-2±19%; 30min, Δ28±45 versus Δ0±26%; 45min, Δ48±43 versus Δ2±21%; 60min, Δ36±61 versus Δ1±24%; and 15min post-SCS, Δ51±64 versus Δ6±33%; P=0.013]. A similar examination in a patient with cervical SCS revealed minimal changes in vascular conductance. In study 2, we examined whether acute SCS reduces peroneal MSNA in a subset of SCS patients (n=5). The MSNA burst incidence in response to acute SCS gradually declined and was significantly reduced at 45 and 60min of SCS (in bursts per 100heart beats: 15min, Δ-1±12%; 30min, Δ-14±12%; 45min, Δ-19±16%; 60min, Δ-24±18%; and 15min post-SCS: Δ-11±7%; P=0.015). These data demonstrate that acute SCS rapidly increases femoral vascular conductance and reduces peroneal MSNA. The gradual reduction in peroneal MSNA observed during acute SCS suggests that neural mechanisms in addition to attenuated MSNA might be involved in the acute increase in femoral vascular conductance.

Carotid chemoreceptor control of muscle sympathetic nerve activity in hypobaric hypoxia.

What is the central question of this study? High-altitude hypoxia increases muscle sympathetic nerve activity (MSNA), but whether intravenous infusion of dopamine, to blunt the responsiveness of the carotid chemoreceptors, reduces MSNA at high altitude is not known. What is the main finding and its importance? Muscle sympathetic nerve activity was elevated after 15-17days of high-altitude hypoxia (3454m) compared with values at 'sea level' (432m). However, intravenous dopamine infusion to blunt the responsiveness of the carotid chemoreceptors did not significantly decrease MSNA either at sea level or at high altitude, suggesting that high-altitude sympathoexcitation arises via a different mechanism. High-altitude hypoxia causes pronounced sympathoexcitation, but the underlying mechanisms remain unclear. We tested the hypothesis that i.v. infusion of dopamine to attenuate carotid chemoreceptor responsiveness would reduce muscle sympathetic nerve activity (MSNA) at high altitude. Nine healthy individuals [mean (SD); 26 (4) years of age] were studied at 'sea level' (SL; Zurich) and at high altitude (ALT; 3454m; 15-17days after arrival), both while breathing the ambient air and during an acute incremental hypoxia test (eight 3min stages; partial pressure of end-tidal O2 90-45mmHg). Intravenous infusions of dopamine (3μgkg-1 min-1 ) and placebo (saline) were administered on both study days, according to a single-blind randomized cross-over design. Sojourn to high altitude decreased the partial pressure of end-tidal O2 (to ∼60mmHg) and increased minute ventilation [V̇E; mean±SEM, SL versus ALT: saline, 8.6±0.5 versus 11.3±0.6lmin-1 ; dopamine, 8.2±0.5 versus 10.6±0.8lmin-1 ; P<0.05] and MSNA burst frequency by ∼80% [SL versus ALT: saline, 16±3 versus 28±4burstsmin-1 ; dopamine, 16±4 versus 31±4burstsmin-1 ; P<0.05) when breathing the ambient air, but were not different with dopamine. Increases in MSNA burst frequency and V̇E during the acute incremental hypoxia test were greater at ALT than SL (P<0.05). Dopamine did not affect the magnitude of the MSNA burst frequency response to acute incremental hypoxia at either SL or ALT. However, V̇E was lower with dopamine than saline administration throughout the acute incremental hypoxia test at ALT. These data indicate that i.v. infusion of low-dose dopamine to blunt the responsiveness of the carotid chemoreceptors does not significantly decrease MSNA at high altitude.

L‐arginine Infusion Reduces Muscle Sympathetic Nerve Activity and Blood Pressure in Patients with Chronic Kidney Disease

An overactive sympathetic nervous system is a known cardiovascular risk factor present in chronic kidney disease (CKD) patients. However, limited effort has been directed at identifying the mechanisms contributing to sympathetic overactivity in CKD. Herein, we examined a potential role for accumulation of the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) in driving the high sympathetic nerve activity (SNA) present in CKD. ADMA is elevated in CKD and is a strong, independent predictor of future cardiovascular events in these patients. Much of the work with ADMA has been correlational in nature with a focus on the well‐known vascular endothelial properties of nitric oxide. However, increasing functional evidence indicates that NO is also a key signaling molecule involved in the tonic restraint of sympathetic outflow from the brainstem. Thus, it is possible that NO synthase inhibition with elevated endogenous ADMA contributes to sympathetic overactivity in CKD patients. We tested the hypothesis that overcoming accumulation of endogenous ADMA with acute L‐arginine infusion reduces sympathetic overactivity in CKD patients. In 5 hypertensive CKD patients, muscle SNA (peroneal nerve microneurography), blood pressure (BP; finger photoplethysmography), and heart rate (ECG) were measured before, during, and 45 minutes after systemic intravenous infusion of L‐arginine, the natural substrate for NO synthase, at a dose of 250 mg/kg over 20 minutes. Following L‐arginine infusion, mean BP was reduced (111±4 mmHg, baseline vs. 105±4 mmHg, L‐arginine; P=0.009). Likewise, MSNA was significantly decreased with L‐arginine (70±4 bursts per 100 heart beats, baseline vs. 59±6 bursts per 100 heart beats, L‐arginine; P=0.023). The concomitant decrease in MSNA and BP strongly implicates a central sympathetic effect of L‐arginine. If L‐arginine was only restoring peripheral NO production, the endothelial‐mediated reduction in mean BP due to peripheral vasodilation would be accompanied by an arterial baroreflex‐mediated increase in MSNA. These preliminary findings of simultaneous reductions in MSNA and BP suggest that L‐arginine restores central NO production in CKD patients supporting a role for ADMA in mediating sympathetic overactivity and hypertension in CKD patients.Support or Funding InformationNIH R01 HL127071

Effects of chronic carotid baroreceptor activation on arterial stiffness in severe heart failure.

Heart failure with reduced ejection fraction (HFrEF) is characterized by activation of the sympathetic nervous system and increased arterial stiffness, leading to an impaired ventricular-vascular coupling. Baroreflex activation therapy (BAT) has been shown to reduce muscle sympathetic nerve activity (MSNA) and improve clinical status of patients with HFrEF. The purpose of this investigation was to determine the effects of BAT on arterial stiffness in HFrEF. MSNA, clinical variables, and parameters of central blood pressure (BP) and arterial stiffness were collected in 18 NYHA Class III HFrEF patients, nine receiving BAT and nine continuing with optimal medical management alone. Patients were followed for 3months, with measurements at that time compared to baseline evaluation. Baseline characteristics of the groups were well matched. At 3months, BAT did not improve central BP and arterial stiffness despite a significant amelioration of MSNA, NYHA class, Minnesota living with heart failure questionnaire score, number of heart failure medications and six-minute walking distance. The control group exhibited no significant changes in all the measured variables. Despite significant reductions in MSNA and clinical improvement, BAT does not appear to chronically modify arterial stiffness within this HFrEF cohort. Additional study is required to determine if this result applies to the HFrEF population as a whole.

Acute Response to Unilateral Unipolar Electrical Carotid Sinus Stimulation in Patients With Resistant Arterial Hypertension.

Bilateral bipolar electric carotid sinus stimulation acutely reduced muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant arterial hypertension but is no longer available. The second-generation device uses a smaller unilateral unipolar disk electrode to reduce invasiveness while saving battery life. We hypothesized that the second-generation device acutely lowers BP and MSNA in treatment-resistant hypertensive patients. Eighteen treatment-resistant hypertensive patients (9 women/9 men; 53±11 years; 33±5 kg/m(2)) on stable medications have been included in the study. We monitored finger and brachial BP, heart rate, and MSNA. Without stimulation, BP was 165±31/91±18 mm Hg, heart rate was 75±17 bpm, and MSNA was 48±14 bursts per minute. Acute stimulation with intensities producing side effects that were tolerable in the short term elicited interindividually variable changes in systolic BP (-16.9±15.0 mm Hg; range, 0.0 to -40.8 mm Hg; P=0.002), heart rate (-3.6±3.6 bpm; P=0.004), and MSNA (-2.0±5.8 bursts per minute; P=0.375). Stimulation intensities had to be lowered in 12 patients to avoid side effects at the expense of efficacy (systolic BP, -6.3±7.0 mm Hg; range, 2.8 to -14.5 mm Hg; P=0.028 and heart rate, -1.5±2.3 bpm; P=0.078; comparison against responses with side effects). Reductions in diastolic BP and MSNA (total activity) were correlated (r(2)=0.329; P=0.025). In our patient cohort, unilateral unipolar electric baroreflex stimulation acutely lowered BP. However, side effects may limit efficacy. The approach should be tested in a controlled comparative study.

Abstract P152: Acute Effect of Unilateral Unipolar Electrical Carotid Sinus Stimulation in Patients with Treatment-Resistant Arterial Hypertension

Electrical carotid sinus stimulation has been developed for treatment of resistant arterial hypertension. The first-generation device (Rheos™) relying on bilateral placement of bipolar electrodes acutely reduced muscle sympathetic nerve activity (MSNA) and blood pressure (BP) but is no longer available. The second-generation device (Neo™) utilizes a smaller unilateral unipolar disk electrode to reduce invasiveness while saving battery life. We tested acute effects of the latter on BP and MSNA. We studied 18 treatment-resistant hypertensive patients (9 women, 53±11 years, 34±5 kg/m 2 ) on stable medication who had been implanted with the second-generation device. We assessed acute BP (oscillometry), heart rate (HR, ECG), and MSNA (microneurography) responses to electrical stimulation in the supine position. Without stimulation, BP was 165±31/91±18 mmHg, HR was 75±17 bpm, and MSNA was 48±14 bursts/min. Acute stimulation with intensities producing side effects that were tolerable in the short term elicited variable changes in systolic BP (SBP: -16.9±15.0 mmHg, range: 0.0 to -40.8 mmHg, p=0.002), HR (-3.6±3.6 bpm, p=0.004), and MSNA (-1.9±5.3 bursts/min, p=0.194). Stimulation intensities had to be lowered in 12 patients to avoid side effects at the expense of efficacy (SBP: -6.3±7.0 mmHg, range: 2.8 to -14.5 mmHg, p=0.028; HR: -1.5±2.3 bpm, p=0.078; comparison against responses with side effects). Reductions in diastolic BP and MSNA (total activity) tended to be correlated (r 2 =0.202, p=0.093). In our patient cohort, unilateral unipolar electrical baroreflex stimulation acutely lowered BP. Side effects may limit efficacy. The novel approach should be tested in a controlled comparative study.

Increase in paced heart rate reduces muscle sympathetic nerve activity in heart failure patients treated with cardiac resynchronization therapy.

To test the hypothesis that acute increased biventricularly (BiV) paced heart rate (pHR) results in decreased muscle sympathetic nerve activity (MSNA), and that dyssynchronous pacing (AAI) attenuates this effect, in heart failure patients receiving cardiac resynchronization therapy (CRT). Fourteen CRT patients (NYHA II-III, 12 males, mean EF 28 ± 14%) were recruited. Three different pHRs (50-90 b.p.m.) were randomly programmed in BiV- and AAI-pacing modes. Muscle sympathetic nerve activity (total sympathetic nerve activity/min (units) and number of bursts/100 RR) were recorded from the peroneal nerve using a microelectrode. In addition, cardiac output (CO) and mean blood pressure (mBP) were measured. With BiV pacing, the total MSNA/min was lower at 70 b.p.m. (-7 ± 21%, P = 0.18) and 90 b.p.m. (-29 ± 18%, P = 0.01) compared with at 50 b.p.m. (280 ± 180 U). Similarly, bursts/100RR decreased with increased BiV pHR. Cardiac output (3.7 L/min at 50 b.p.m., +12 ± 12% at 70 b.p.m., and +18 ± 19% at 90 b.p.m.) and mBP (78 ± 11 mmHg at 50 b.p.m., +6 ± 6% at 70 b.p.m. and +11 ± 8% at 90 b.p.m.) increased significantly at elevated pHRs in BiV-pacing mode. The effect on MSNA, CO, and mBP was less pronounced in AAImode but we found no significant differences between the pacing modes. Increased pHR acutely reduces MSNA and improves haemodynamics in HF patients treated with CRT with no evident differences between BiV- and AAI-pacing modes. Further studies are warranted to guide the programming of basic pHR in CRT patients.

Acute cyclooxygenase inhibition does not alter muscle sympathetic nerve activity or forearm vasodilator responsiveness in lean and obese adults.

Obesity is often characterized by chronic inflammation that may contribute to increased cardiovascular risk via sympathoexcitation and decreased vasodilator responsiveness. We hypothesized that obese individuals would have greater indices of inflammation compared with lean controls, and that cyclooxygenase inhibition using ibuprofen would reduce muscle sympathetic nerve activity (MSNA) and increase forearm blood flow in these subjects. We measured MSNA, inflammatory biomarkers (C‐reactive protein [CRP] and Interleukin‐6 [IL‐6]), and forearm vasodilator responses to brachial artery acetylcholine and sodium nitroprusside in 13 men and women (7 lean; 6 obese) on two separate study days: control (CON) and after 800 mg ibuprofen (IBU). CRP (1.7 ± 0.4 vs. 0.6 ± 0.3 mg/L; P < 0.05) and IL‐6 (4.1 ± 1.5 vs. 1.0 ± 0.1pg/mL; P < 0.05) were higher in the obese group during CON and tended to decrease with IBU (IL‐6: P < 0.05; CRP: P = 0.14). MSNA was not different between groups during CON (26 ± 4 bursts/100 heart beats (lean) versus 26 ± 4 bursts/100 heart beats (obese); P = 0.50) or IBU (25 ± 4 bursts/100 heart beats (lean) versus 30 ± 5 bursts/100 heart beats (obese); P = 0.25), and was not altered by IBU. Forearm vasodilator responses were unaffected by IBU in both groups. In summary, an acute dose of ibuprofen did not alter sympathetic nerve activity or forearm blood flow responses in healthy obese individuals, suggesting that the cyclooxygenase pathway is not a major contributor to these variables in this group.

Sustained sympathetic and blood pressure reduction 1 year after renal denervation in patients with resistant hypertension.

Renal denervation (RDN) reduces muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in resistant hypertension. Although a persistent BP-lowering effect has been demonstrated, the long-term effect on MSNA remains elusive. We investigated whether RDN influences MSNA over time. Office BP and MSNA were obtained at baseline, 3, 6, and 12 months after RDN in 35 patients with resistant hypertension. Office BP averaged 166±22/88±19 mm Hg, despite the use of an average of 4.8±2.1 antihypertensive drugs. Baseline MSNA was 51±11 bursts/min ≈2- to 3-fold higher than the level observed in healthy controls. Mean office systolic and diastolic BP significantly decreased by -12.6±18.3/-6.5±9.2, -16.1±25.6/-8.6±12.9, and -21.2±29.1/-11.1±12.9 mm Hg (P<0.001 for both systolic BP and diastolic BP) with RDN at 3-, 6-, and 12-month follow-up, respectively. MSNA was reduced by -8±12, -6±12, and -6±11 bursts/min (P<0.01) at 3-, 6-, and 12-month follow-up. The reduction in MSNA was maintained, despite a progressive fall in BP over time. No such changes were observed in 7 control subjects at 6-month follow-up. These findings confirm previous reports on the favorable effects of RDN on elevated BP and demonstrate sustained reduction of central sympathetic outflow ≤1-year follow-up in patients with resistant hypertension and high baseline MSNA. These observations are compatible with the hypothesis of a substantial contribution of afferent renal nerve signaling to increased BP in resistant hypertension and argue against a relevant reinnervation at 1 year after procedure.

Role of the carotid chemoreceptors in insulin‐mediated sympathoexcitation in humans (873.7)

Objective: Given recent evidence from rodents supporting a novel role for the carotid bodies in insulin‐mediated sympathoexcitation, we sought to determine whether carotid chemoreceptor desensitization would reduce muscle sympathetic nerve activity (MSNA) during hyperinsulinemia in humans. Methods: Young, healthy subjects (n=4, 30±2 yrs) breathed hyperoxic gas (End‐tidal O2 = 100%, PaO2 505±13 mmHg) for 15 min at baseline and during steady‐state hyperinsulinemia (5±1 vs 53±1 µU/mL). Hyperinsulinemia was achieved using a 90‐min hyperinsulinemic (1 mU/kg FFM/min), euglycemic (108±4 mg/dL) clamp. CO2 was maintained at resting levels (PaCO2 41±1 mmHg). Changes in heart rate, blood pressure, minute ventilation, and MSNA (microneurography of the peroneal nerve) were assessed. Results: Hyperinsulinemia increased MSNA [burst frequency (p&lt;0.01), burst incidence (p=0.02), total activity (p=0.02)]. Hyperoxia decreased heart rate (p=0.01) and minute ventilation (p=0.11), and increased mean blood pressure (p=0.04). Consistent with our hypothesis, the effect of hyperoxia on MSNA (Δ) was different between baseline and hyperinsulinemia (burst frequency, p=0.03; burst incidence, p=0.10). Conclusion: These data are the first to suggest the carotid chemoreceptors may contribute to insulin‐mediated sympathoexcitation in humans.Grant Funding Source: Supported by: NIH R01 DK090541 (MJJ), NIH T32 DK07352 (JKL)

Renal nerve ablation reduces augmentation index in patients with resistant hypertension

Renal denervation (RDN) has been demonstrated to reduce muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant hypertension. Whether alterations of arterial stiffness may contribute to BP-lowering effects of RDN is unknown. We measured office BP and arterial stiffness using fingertip tonometry-derived augmentation index (EndoPAT2000) at baseline and at 3-month follow-up in 50 consecutive patients with resistant hypertension. Forty patients received RDN and 10 patients served as controls. MSNA was obtained in 20 RDN and 10 non-RDN patients. Baseline BP averaged 170/92 ± 19/15 mmHg (RDN) and 171/93 ± 14/8 mmHg (non-RDN) despite the use of 4.9 ± 1.9 and 4.4 ± 2.0 antihypertensive drugs, respectively. RDN significantly reduced SBP (170 ± 19 vs. 154 ± 25 mmHg; P < 0.001) and DBP (92 ± 15 vs. 84 ± 16 mmHg; P<0.001), augmentation index (30.6 ± 23.8 vs. 22.7 ± 22.4%; P=0.002), AI@75 corrected for heart rate (22.4 ± 21.6 vs. 14.4 ± 20.7; P=0.002) and MSNA (80 ± 15 vs. 71 ± 18 bursts/100 heartbeats; P<0.01). Changes in AI@75 with RDN were unrelated to SBP (r=0.043; P = 0.79), and DBP (r = 0.092; P = 0.57) and MSNA changes (r = -0.17; P = 0.49). No changes in BP, augmentation index, AI@75 or MSNA were observed in the non-RDN group. RDN results in a substantial and rapid reduction in augmentation index, which appears to be independent of BP and MSNA changes. These findings are indicative of a beneficial effect of RDN on arterial stiffness in patients with resistant hypertension and may contribute to the sustained BP-lowering effect of RDN.