Measured Muscle Sympathetic Nerve Activity Research Articles

1541-P: Sympathetic Nervous System Activity in Response to Food Ingestion Is Impacted by Obesity

Studies have shown that sympathetic nervous system activity (SNSA) may differ in obese (OB) compared to lean individuals. In addition, increased (SNSA) has been observed after ingestion of food. However, it remains unclear whether obesity alters post-meal (SNSA). We tested the hypothesis that (SNSA) is increased post-meal in OB individuals. We used a dual strategy to assess SNSA: i) a whole-body PET radiotracer ([11C]MRB) in combination with CT imaging (PET-CT). [11C]MRB binds to norepinephrine (NE) transporter allowing measurement of NE release from SNS. ii) Skeletal muscle microneurography to measure muscle sympathetic nerve activity (MSNA). Participants underwent two PET-CT and MSNA visits: fasting and mixed meal test (MMT). We ​​examined 5 subjects, 3F/2M, age 41±7 years (2 OB) and 3 normal weight (NW). During the MSNA fasting visit, RR intervals were longer at 15 minutes (P=0.03), while opposite findings were observed with MMT, which diminished between 15 until 60 minutes indicating increased heart rate (HR). We also observed increased total MSNA area/burst at 60 min after MMT (P<0.02). No statistically significant differences in MSNA were observed between OB and NW. PET-CT of deltoid muscle (n=4, 2 OB and 2 NW) showed changes in distribution volume ratio (DVR) between days (MMT - fasting) were correlated with BMI (R2=0.71, P=0.16). DVR changes in both NW were reduced, while both OB were increased (P=0.01), suggesting that OB had less endogenous NE competing with [11C]MRB to bind at the NE transporter compared to NW. These preliminary data suggest that MSNA increases following MMT in both NW and OB subjects which may be further impacted by obesity. Disclosure T.J.Chung: None. J.Deajon-jackson: None. J.Bini: None. H.Song: None. E.Sanchez rangel: None. C.W.Yeckel: None. J.J.Hwang: None. N.Stachenfeld: None. R.Belfort-deaguiar: Research Support; Fractyl Health, Inc., Silver Palate Kitchens. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R56DK129344)

Acute Exposure to Diesel Exhaust Increases Muscle Sympathetic Nerve Activity in Humans.

BackgroundDiesel exhaust (DE) emissions are a major contributor to ambient air pollution and are strongly associated with cardiovascular morbidity and mortality. Exposure to traffic‐related particulate matter is linked with acute adverse cardiovascular events; however, the mechanisms are not fully understood. We examined the role of the autonomic nervous system during exposure to DE that has previously only been indirectly investigated.Methods and ResultsUsing microneurography, we measured muscle sympathetic nerve activity (MSNA) directly in the peroneal nerve of 16 healthy individuals. MSNA, heart rate, and respiration were recorded while subjects rested breathing filtered air, filtered air with an exposure mask, and standardized diluted DE (300 µg/m3) through the exposure mask. Heart rate variability was assessed from an ECG. DE inhalation rapidly causes an increase in number of MSNA bursts as well as the size of bursts within 10 minutes, peaking by 30 minutes (P<0.001), compared with baseline filtered air with an exposure mask. No significant changes occurred in heart rate variability indices during DE exposure; however, MSNA frequency correlated negatively with total power (r 2=0.294, P=0.03) and low frequency (r 2=0.258, P=0.045). Heart rate correlated positively with MSNA frequency (r 2=0.268, P=0.04) and the change in percentage of larger bursts (burst amplitude, height >50% of the maximum burst) from filtered air with an exposure mask (r 2=0.368, P=0.013).ConclusionsOur study provides direct evidence for the rapid modulation of the autonomic nervous system after exposure to DE, with an increase in MSNA. The quick increase in sympathetic outflow may explain the strong epidemiological data associating traffic‐related particulate matter to acute adverse cardiovascular events such as myocardial infarction.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT02892279.

The sympathetic muscle metaboreflex is not different in the third trimester in normotensive pregnant women.

Isometric handgrip (IHG) is used to assess sympathetic nervous system responses to exercise and may be useful at predicting hypertension in both pregnant and nonpregnant populations. We previously observed altered sympathetic nervous system control of blood pressure in late pregnancy. Therefore, we measured muscle sympathetic nerve activity (MSNA) and blood pressure during muscle metaboreflex activation (IHG) in normotensive pregnant women in the third trimester compared with in healthy nonpregnant women. Further, 19 pregnant (32 ± 3 wk gestation) and 14 nonpregnant women were matched for age, non/prepregnant body mass index (BMI), and parity. MSNA (microneurography), heart rate (ECG), and arterial blood pressure (Finometer) were continuously recorded during 10 min of rest, and then during 2 min of IHG at 30% of maximal voluntary contraction, and 2 min of postexercise circulatory occlusion (PECO). Baseline sympathetic nerve activity (SNA) was elevated in pregnant (41 ± 11 bursts/min) compared with nonpregnant women (27 ± 9 bursts/min; P = 0.005); however, the sympathetic baroreflex gain and neurovascular transduction were not different between groups (P = 0.62 and P = 0.32, respectively). During IHG and PECO, there were no significant differences in the pressor responses (ΔMAP) between groups, (P = 0.25, main effect of group) nor was the sympathetic response different between groups (interaction effect: P = 0.16, 0.25, and 0.27 for burst frequency, burst incidence, and total SNA, respectively). These data suggest that pregnant women who have maintained sympathetic baroreflex and neurovascular transduction also have similar sympathetic and pressor responses during exercise.NEW & NOTEWORTHY We compared sympathetic nervous system activation by muscle metaboreflex between pregnant women in the third trimester and nonpregnant women. We show that the sympathetic nerve activity and associated pressor responses to isometric handgrip and post-exercise circulatory occlusion are not different between third-trimester pregnant and nonpregnant women. These data suggest that unlike other reflexes (e.g., cold pressor test or head-up tilt), metaboreflex control is maintained in pregnant women.

Autonomic Reactivity to Acute Mental Stress Differs Between Women and Men with Post Traumatic Stress Disorder (PTSD)

Over 7 million Americans are affected by post‐traumatic stress disorder (PTSD), a debilitating mental illness that is associated with significant cardiovascular disease risk. Women are twice as likely as men to develop PTSD after a traumatic event. A prior study from our laboratory showed that sympathetic nervous system reactivity during combat related and non‐combat related stress is heightened in PTSD; however, this study was conducted in a predominantly male cohort and did not consider the potential influence of sex on neural cardiovascular function in PTSD. The aim of the current study was to determine if women with PTSD have heightened blood pressure (BP), heart rate (HR), and sympathetic reactivity to acute mental stress than men with PTSD. We recruited 15 women and 18 men clinically diagnosed with PTSD and confirmed using the Clinician Administered PTSD Scale (CAPS) and PTSD Checklist‐Military (PCL‐M) surveys. We measured muscle sympathetic nerve activity (MSNA), continuous BP, HR and heart rate variability (HRV) at baseline and during 3 minutes of mental arithmetic. Women and men were matched for race, age (41±2 vs 38±2 years, p=0.191), body mass index (31±2 vs 29±2 kg/m2, p=0.368), CAPS (71 ±9 vs 74 ±4, p=0.732) and PCLM (57 ±5 vs 68 ±4, p=0.129) scores. Likewise, baseline systolic BP (131±5 vs 128±4 mmHg), diastolic BP (76±4 vs 74±2 mmHg) and HR (70±3 vs 64±2 beats/min) were comparable (P&gt;0.05) between women and men. Although resting HRV measures were not different between groups (p&gt;0.05), resting MSNA was higher (p=0.008) in women compared to men (27±3 vs 16±3 bursts/min). In response to mental arithmetic, systolic BP reactivity was higher in women compared to men (Δ+5.1±1 versus Δ+2.2±1 mm Hg, p&lt;0.001). Diastolic BP (p=0.366) and HR (p=0.170) responses were not different. However, MSNA reactivity was higher (p=0.04) in women compared to men (Δ15.2±5 versus Δ6.4±3 bursts/min), suggesting an exaggerated sympathetic response to acute stress. Although RMSSD reactivity was similar between both groups (p=0.347), HF response to mental stress was blunted (p=0.05) in women compared to men, suggesting a greater withdrawal of parasympathetic control of the heart during acute stress. In summary, women with PTSD show an exaggerated blood pressure and sympathetic response to acute mental stress coupled with a blunted parasympathetic control of the heart. These results provide important insight into the physiological mechanisms linking the high risk of PTSD in women and the associated cardiovascular disease and hypertension risk.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) Grant R01 HL135183; NIH R61 AT010457, VA Merit I01CX001065, the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Decatur, Georgia, and the APS STRIDE Undergraduate Summer Research Fellowship, grant program number NHLBI; 1 R25 HL115473‐01.

Early onset neurocirculatory response to static handgrip is associated with greater blood pressure variability in women with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric illness that is more prevalent in women, and accumulating evidence suggests a link between PTSD and future development of cardiovascular disease. The underlying mechanisms are unclear, but augmented sympathetic reactivity to daily stressors may be involved. We measured muscle sympathetic nerve activity (MSNA), blood pressure (BP), and heart rate responses in 14 women with PTSD and 14 healthy women (controls) during static handgrip (SHG) exercise to fatigue at 40% of maximal voluntary contraction (MVC). Two minutes of postexercise circulatory arrest (PECA) was followed immediately after SHG to fatigue. MVC and the time to fatigue during SHG did not differ between groups (both P > 0.05). At the first 30 s of SHG, women with PTSD showed augmented sympathetic neural [mean ± SD, ∆MSNA burst frequency (BF): 5 ± 4 vs. 2 ± 3 bursts/30 s, P = 0.02 and ∆MSNA total activity (TA): 82 ± 58 vs. 25 ± 38 arbitrary units/30 s, P = 0.004] and pressor (∆systolic BP: 10 ± 5 vs. 4 ± 3 mmHg, P = 0.003) responses compared with controls. However, MSNA and BP responses at fatigue and during PECA were not different between groups. More interestingly, the augmented initial neural and pressor responses to SHG were associated with greater awake systolic BP variability during ambulation in women with PTSD (MSNA BF: r = 0.55, MSNA TA: r = 0.62, and SBP: r = 0.69, all P < 0.05). These results suggest that early onset exercise pressor response in women with PTSD may be attributed to enhanced mechano- rather than metaboreflexes, which might contribute to the mechanisms underlying the link between PTSD and cardiovascular risk.NEW & NOTEWORTHY The novel findings of the current study are that women with posttraumatic stress disorder (PTSD) exhibited augmented sympathetic neural and pressor responses at the first 30 s of submaximal isometric muscle contraction. More interestingly, exaggerated neurocirculatory responses at the onset of muscle contraction were associated with greater ambulatory awake systolic blood pressure fluctuations in women with PTSD. Our findings expand the knowledge on the physiological mechanisms that perhaps contribute to increased risk of cardiovascular disease in such a population.

Symptom Severity Impacts Inflammation and Sympathetic Over‐activity in Post‐Traumatic Stress Disorder (PTSD)

Patients with post‐traumatic stress disorder (PTSD) are at significantly higher risk of developing hypertension and cardiovascular disease. Low‐grade inflammation and overactive sympathetic nervous system (SNS) activity are suggested as contributing mechanisms. Our prior studies showed that while SNS reactivity during stress is heightened in PTSD, resting MSNA and inflammation was not elevated in young combat Veterans with PTSD as a group; however, prior results did not take into account the potential influence of PTSD symptom severity on neural cardiovascular function. The aim of the current study was to determine if PTSD patients with greater PTSD symptoms measured via the gold‐standard clinician administered PTSD scale (CAPS) have higher SNS activity and inflammation compared to PTSD patients with less severe symptoms. To answer this question, we recruited 21 veterans clinically diagnosed with PTSD (mean CAPS score, 68±4). We measured muscle sympathetic nerve activity (MSNA) via microneurography and blood pressure using standard technique. We collected blood samples to measure serum levels of two inflammatory biomarkers: highly sensitive C‐reactive protein (hsCRP) and interleukin‐6 (IL‐6). For data analysis, the participants were grouped based on the median CAPS score of 70, with the low CAPS group (L‐CAPS) having a score ≤ 70 and the high CAPS group (H‐CAPS) having a score &gt; 70. The two groups (L‐CAPS, n=11; H‐CAPS, n=10) were matched for age, body mass index (BMI) and selective serotonin reuptake inhibitor (SSRI) prescription. Resting blood pressure and heart rate were similar between the two groups. However, the H‐CAPS group had a significantly greater MSNA at baseline when quantified as both burst frequency (26±5 vs 13±2 bursts/min, p= 0.011) and burst incidence (35±6 vs 21±3 bursts/100hb, p= 0.022) compared to the L‐CAPS group. Similarly, hsCRP (2.02±0.71 vs 0.74±0.18, p= 0.036) and IL‐6 (5.44±1.86 vs 2.35±0.73, p= 0.055) levels were higher in the H‐CAPS group compared to the L‐CAPS group. Furthermore, the levels of hsCRP (r= 0.766, p&lt; 0.001) and IL‐6 (r= 0.594, p=0.007) were positively correlated with MSNA. When the groups were analyzed separately, the correlation between MSNA and hsCRP was stronger in the H‐CAPS group (r=0.822, p=0.012) than the L‐CAPS group (r=0.604, p=0.065). These results suggest that the severity of PTSD is associated with chronically increased MSNA and inflammation, and SNS overactivity may be mechanistically linked to inflammation in severe PTSD.Support or Funding InformationSupported by NIH HL‐098744, NIH DK‐00756, VA Merit I01CX001065, AHA 15CSA24340001This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sympathoexcitation and impaired arterial baroreflex sensitivity are linked to vascular inflammation in individuals with elevated resting blood pressure.

Elevated Resting Blood Pressure (ERBP) in the prehypertensive range is associated with increased risk of hypertension and cardiovascular disease, the mechanisms of which remain unclear. Prior studies have suggested that ERBP may be associated with overactivation and dysregulation of the sympathetic nervous system (SNS). We hypothesized that compared to normotensives (≤120/80 mmHg), ERBP (120/80–139/89 mmHg) has higher SNS activity, impaired arterial baroreflex sensitivity (BRS), and increased vascular inflammation. Twenty‐nine participants were studied: 16 otherwise healthy individuals with ERBP (blood pressure (BP) 130 ± 2/85 ± 2 mmHg) and 13 matched normotensive controls (mean BP 114 ± 2/73 ± 2 mmHg). We measured muscle sympathetic nerve activity (MSNA), beat‐to‐beat BP, and continuous electrocardiogram at rest and during arterial BRS testing via the modified Oxford technique. Blood was analyzed for the following biomarkers of vascular inflammation: lipoprotein‐associated phospholipase A2 (Lp‐PLA2), E‐selectin, and intercellular adhesion molecule 1 (ICAM‐1). Resting MSNA burst frequency (22 ± 2 vs. 16 ± 2 bursts/min, P = 0.036) and burst incidence (36 ± 3 vs. 25 ± 3 bursts/100 heart beats, P = 0.025) were higher in ERBP compared to controls. Cardiovagal BRS was blunted in ERBP compared to controls (13 ± 2 vs. 20 ± 3 msec/mmHg, P = 0.032), while there was no difference in sympathetic BRS between groups. Lp‐PLA2 (169 ± 8 vs. 142 ± 9 nmol/min/mL, P = 0.020) and E‐selectin (6.89 ± 0.6 vs. 4.45 ± 0.51 ng/mL, P = 0.004) were higher in ERBP versus controls. E‐selectin (r = 0.501, P = 0.011) and ICAM‐1 (r = 0.481, P = 0.015) were positively correlated with MSNA, while E‐selectin was negatively correlated with cardiovagal BRS (r = −0.427, P = 0.030). These findings demonstrate that individuals with ERBP have SNS overactivity and impaired arterial BRS that are linked to biomarkers of vascular inflammation.

P28-3 - Effect of Central Sympathetic Nerve Activity on Weight Change in Patients With Chronic Heart Failure

Background: Body weight loss or cardiac cachexia is associated with poor prognosis. Although the causes of cardiac cachexia are not fully determined, sympathetic overactivation might be implicated in the development of muscle wasting. Recently, it has been shown that beta blocker treatment attenuated the development and promoted a partial reversal of body weight loss in patients with heart failure (HF). Methods: We prospectively evaluated changes in body weight in 108 nonedematous patients with HF and reduced ejection fraction (EF <0.45) who were measured muscle sympathetic nerve activity (MSNA). Any data of body weights during follow-up were excluded from analyses if edema were present. Patients were divided into 3 groups according to MSNA level (low, middle and high groups). Significant weight loss was defined as follow: weight loss of at least 5% in 12 months. Results: Usage and dose of beta blockers were similar in 3 groups. Mean left ventricular ejection fraction were 34%, 32%, 30% in low, middle and high MSNA groups, respectively. Interestingly, significant weight loss was frequently observed in high MSNA groups (33%) in compared to middle and low MSNA groups (6% and 3%, respectively, P < .001 for χ test). Conclusion: Sympathetic overactivation might promote cachexia in patients with HF and reduced ejection fraction.

Ventilation inhibits sympathetic action potential recruitment even during severe chemoreflex stress.

This study investigated the influence of ventilation on sympathetic action potential (AP) discharge patterns during varying levels of high chemoreflex stress. In seven trained breath-hold divers (age 33 ± 12 yr), we measured muscle sympathetic nerve activity (MSNA) at baseline, during preparatory rebreathing (RBR), and during 1) functional residual capacity apnea (FRCApnea) and 2) continued RBR. Data from RBR were analyzed at matched (i.e., to FRCApnea) hemoglobin saturation (HbSat) levels (RBRMatched) or more severe levels (RBREnd). A third protocol compared alternating periods (30 s) of FRC and RBR (FRC-RBRALT). Subjects continued each protocol until 85% volitional tolerance. AP patterns in MSNA (i.e., providing the true neural content of each sympathetic burst) were studied using wavelet-based methodology. First, for similar levels of chemoreflex stress (both HbSat: 71 ± 6%; P = NS), RBRMatched was associated with reduced AP frequency and APs per burst compared with FRCApnea (both P < 0.001). When APs were binned according to peak-to-peak amplitude (i.e., into clusters), total AP clusters increased during FRCApnea (+10 ± 2; P < 0.001) but not during RBRMatched (+1 ± 2; P = NS). Second, despite more severe chemoreflex stress during RBREnd (HbSat: 56 ± 13 vs. 71 ± 6%; P < 0.001), RBREnd was associated with a restrained increase in the APs per burst (FRCApnea: +18 ± 7; RBREnd: +11 ± 5) and total AP clusters (FRCApnea: +10 ± 2; RBREnd: +6 ± 4) (both P < 0.01). During FRC-RBRALT, all periods of FRC elicited sympathetic AP recruitment (all P < 0.001), whereas all periods of RBR were associated with complete withdrawal of AP recruitment (all P = NS). Presently, we demonstrate that ventilation per se restrains and/or inhibits sympathetic axonal recruitment during high, and even extreme, chemoreflex stress.NEW & NOTEWORTHY The current study demonstrates that the sympathetic neural recruitment patterns observed during chemoreflex activation induced by rebreathing or apnea are restrained and/or inhibited by the act of ventilation per se, despite similar, or even greater, levels of severe chemoreflex stress. Therefore, ventilation modulates not only the timing of sympathetic bursts but also the within-burst axonal recruitment normally observed during progressive chemoreflex stress.

Effects of face cooling on pulse waveform and sympathetic activity in hypertensive subjects.

Adverse cardiovascular events occur more frequently during cold weather. To test the hypothesis that cold exposure would lead to increased sympathetic activity and impaired hemodynamic control, we measured muscle sympathetic nerve activity and hemodynamic parameters in nine men with hypertension before and during trigeminal stimulation and facial cooling. The procedure increased blood pressure (p<0.01), aortic hemodynamic parameters (p<0.01), and muscle sympathetic nerve activity (p<0.05). These results suggest that sympathetic activation during cold exposure in hypertensive subjects may increase the risk of cardiovascular events during cold weather.

Effects of postural change from supine to head-up tilt on the skin sympathetic nerve activity component synchronised with the cardiac cycle in warmed men.

Humans are unique in controlling body temperature in a hot environment by a large amount of skin blood flow; however, the decrease in total peripheral resistance due to systemic cutaneous vasodilatation and the reduction of venous return to the heart due to blood pooling in the cutaneous vein threatens blood pressure maintenance in the upright position, and occasionally causes heat syncope. Against this condition, cutaneous vasodilatation is reportedly suppressed to maintain arterial pressure; however, the nerve activity responsible for this phenomenon has not been identified. In the present study, we found that the skin sympathetic nerve activity component that was synchronised with the cardiac cycle increased in hyperthermia, but the increase was suppressed when the posture was changed from supine to head-up tilt. The profile of the component agreed with that of cutaneous vasodilatation. Thus, the component might contribute to the prevention of heat syncope in humans. In humans, the cutaneous vasodilatation response to hyperthermia has been suggested to be suppressed by baroreflexes to maintain arterial pressure when the posture is changed from supine to upright, and if the reflexes do not function sufficiently, it can cause heat syncope. However, the efferent signals of the reflexes have not been identified. To identify the signals, we continuously measured skin sympathetic nerve activity (SSNA; microneurography), right atrial volume (RAV; echocardiography, the baroreceptors for the reflexes are reportedly located in the right atrium), cutaneous vascular conductance on the chest (CVCchest ; laser Doppler flowmetry), and oesophageal temperature (Toes ; thermocouple) in young men before and after passive warming with a perfusion suit, during which periods the posture was changed from supine to 30deg head-up tilt positions. During these periods, we also simultaneously measured muscle sympathetic nerve activity (MSNA) to distinguish the SSNA from MSNA. We found that an increase in Toes by ∼0.7°C (P<0.0001) increased the total SSNA (P<0.005); however, the head-up tilt in hyperthermia did not change the total SSNA (P>0.26) although an increase in CVCchest (P<0.019) was suppressed and RAV was reduced (P<0.008). In contrast, the SSNA component synchronised with the cardiac cycle increased in hyperthermia (P<0.015), but decreased with the postural change (P<0.017). The SSNA component during the postural change before and after warming was highly correlated with the CVCchest (r=0.817, P<0.0001), but the MSNA component was not (r=0.359, P=0.085). Thus, the SSNA component synchronised with the cardiac cycle appeared to be involved in suppressing cutaneous vasodilatation during postural changes.

Neural control of blood flow during exercise in human metabolic syndrome

α-Adrenergic-mediated vasoconstriction is greater during simulated exercise in animal models of metabolic syndrome (MetSyn) when compared with control animals. In an attempt to translate such findings to humans, we hypothesized that adults with MetSyn (n=14, 35±3years old) would exhibit greater α-adrenergic responsiveness during exercise when compared with age-matched healthy control subjects (n=16, 31±3years old). We measured muscle sympathetic nerve activity (MSNA; microneurography) and forearm blood flow (Doppler ultrasound) during dynamic forearm exercise (15% of maximal voluntary contraction). α-Adrenergic agonists (phenylephrine and clonidine) and an antagonist (phentolamine) were infused intra-arterially to assess α-adrenergic receptor responsiveness and restraint, respectively. Resting MSNA was ∼35% higher in adults with MetSyn (P<0.05), but did not change in either group with dynamic exercise. Clonidine-mediated vasoconstriction was greater in adults with MetSyn (P<0.01). Group differences in vascular responses to phenylephrine and phentolamine were not detected (P>0.05). Interestingly, exercise-mediated vasodilatation was greater in MetSyn (P<0.05). Adults with MetSyn exhibit greater resting MSNA and clonidine-mediated vasoconstriction, yet preserved functional sympatholysis and higher exercise blood flow during low-intensity hand-grip exercise when compared with age-matched healthy control subjects. These results suggest that adults with MetSyn exhibit compensatory vascular control mechanisms capable of preserving blood flow responses to exercise in the face of augmented sympathetic adrenergic activity.

Sympathetic nerve activity and peripheral vasodilator capacity in young and older men

Interindividual variability in sympathetic nerve activity (SNA) has provided insight into integrative mechanisms contributing to blood pressure (BP) regulation in humans. In young people, the influence of high SNA on BP is balanced by lower cardiac output and less adrenergic vasoconstrictor responsiveness. Older people have higher SNA and higher BP. We hypothesized that SNA has a restraining effect on peripheral vasodilator responsiveness in young and older men, such that individuals with higher tonic SNA would show less forearm vasodilatation to exogenous vasodilators. We measured muscle SNA (MSNA; microneurography) and forearm vasodilator responses to intra-arterial infusions of acetylcholine (ACh; endothelium dependent) and sodium nitroprusside (SNP; endothelium independent) in 13 young (age; 27 ± 1 yr) and 16 older (61 ± 2 yr) men. Forearm vascular conductance (FVC) responses to ACh were lower in the older men at the two highest doses (2 and 4 μg·100 ml(-1)·min(-1); Δ395 ± 81 vs. 592 ± 87% and 412 ± 87 vs. 616 ± 132%, P < 0.05), and MSNA was higher (64 ± 4 vs. 41 ± 2 bursts/100 hb; P < 0.05). There was no difference in the FVC response to SNP between young and older men (P > 0.05). In young men, there was an inverse relationship between resting MSNA and FVC responses (%change) to both ACh and SNP (r = -0.83 and r = -0.83, respectively; P < 0.05). In older men, however, this relationship was not observed. Tonic SNA may act to restrain vasodilator responses in young men, whereas in older men a lack of such restraint may be protective against the pressor effects of higher SNA.

Transcatheter Aortic Valve Implantation Reduces Sympathetic Activity and Normalizes Arterial Spontaneous Baroreflex in Patients With Aortic Stenosis

This study sought to measure muscle sympathetic nerve activity (MSNA) in patients with aortic stenosis (AS) before and after transcatheter aortic valve implantation (TAVI) and to compare MSNA with that of control patients. TAVI is an emerging therapeutic option in patients with severe AS at high risk of open heart surgery. Whether patients with AS have increased sympathetic activity remains to be established, and the effects of TAVI on the sympathetic nervous system are also unknown. We prospectively enrolled 14 patients with severe symptomatic AS treated by TAVI. Fourteen control patients matched for age, body mass index, and unscathed of AS were also included. All patients underwent MSNA and arterial baroreflex gain assessment at baseline and 1 week after TAVI for AS patients. Patients with AS had lower blood pressure (BP) levels, a significant increase in MSNA (61.0±1.7 burst/min vs. 55.4 ± 1.4 burst/min; p < 0.05), and a decrease in arterial baroreflex gain (2.13± 0.14% burst/mm Hg vs. 3.32 ± 0.19% burst/mm Hg; p < 0.01) compared with matched control patients. The TAVI procedures induced an increase in BP associated with a significant decrease in MSNA (from 61.0 ± 1.7 burst/min to 54.1 ± 1.0 burst/min; p < 0.01) and was associated with a significant increase in arterial baroreflex gain (from 2.13 ± 0.14% burst/mm Hg to 3.49 ± 0.33% burst/mm Hg; p < 0.01). We report for the first time, through direct measurement of nerve activity, that patients with AS have increased sympathetic nervous system activity associated with a decrease in sympathetic baroreflex gain and that TAVI normalizes these parameters. This study provides evidence of a new beneficial effect of TAVI, namely, normalization of sympathetic nervous system hyperactivity.

Effect of acute hyperthyroidism on blood flow, muscle oxygenation, and sympathetic nerve activity during dynamic handgrip

Hyperthyroidism induces marked changes in hemodynamics. Although considerable research has been done to study the effect of hyperthyroidism on the cardiovascular system, few studies have isolated the short-term, nongenomic effects of thyroid hormone on cardiovascular responses to exercise. We used near-infrared spectroscopy to measure muscle oxygenation, Doppler ultrasound to measure skeletal muscle blood flow, and microneurography to measure muscle sympathetic nerve activity (MSNA) during fatiguing dynamic handgrip in twelve healthy males (26 ± 1 years). Subjects were measured separately in both the euthyroid state, and acute hyperthyroid state (approximately ten times the normal levels of T3), induced by oral dosage of 300 μg of triiodothyronine (T3). Forearm blood flow was increased as a function of exercise time in the euthyroid and hyperthyroid state (Δ161.8 ± 45.0 mL/min and Δ140.7 ± 16.3 mL/min, respectively) but there was no significant difference between trials. Forearm vascular conductance (FVC) also increased as a function of exercise time with no significant difference between treatments at submaximal exercise but was significantly less with T3 treatment. MSNA was not different at rest or during submaximal exercise; however, MSNA was significantly greater at fatigue during the hyperthyroid state. Muscle oxyhemoglobin concentration was decreased during exercise in both euthyroid and hyperthyroid states (Δ19.7 ± 10.8% and Δ14.8 ± 9.6%, respectively); whereas deoxyhemoglobin concentration was increased (Δ50.0 ± 4.1% and Δ50.0 ± 6.2%, respectively). These results indicate that T3 had no direct effect on skeletal muscle oxygenation or blood flow during dynamic exercise, but elicited greater MSNA and lower FVC during fatiguing exercise.

393 NEUROADRENERGIC DYSFUNCTION ALONG THE DIABETIC CONTINUUM

Background: Neuroadrenergic function in type 2 diabetic (T2D) patients is poorly characterized, particularly in the early stages of disease, before the onset of peripheral neuropathy. We therefore compared sympathetic nervous system (SNS) activity at rest and during a standard oral glucose tolerance test (OGTT) in obese metabolic syndrome (MetS) subjects classified using WHO criteria as glucose intolerant (IGT) or treatment naïve T2D. Design and methods: Untreated subjects (17 IGT, 17 T2D) matched for age (mean 59 ± 1 yr), gender, body mass index (32.4 ± 0.6 kg/m2) and family history of diabetes were studied. We measured muscle sympathetic nerve activity (MSNA) by microneurography, whole-body noradrenaline kinetics by isotope dilution, neuronal noradrenaline re-uptake as the steady state tritiated 3,4-dihydroxyphenylglycol to tritiated noradrenaline ratio (3H-DHPG: 3H-NA), insulin sensitivity by euglycaemic hyperinsulinemic clamp (M/I) and MetS components. Results: T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats, P = 0.05) and arterial noradrenaline levels (264 ± 33 versus 167 ± 16 pg/ml, P = 0.02), lower plasma noadrenaline clearance (by 17%, P = 0.03) and reduced neuronal re-uptake compared with IGT subjects (by 46%, P = 0.04). Moreover, noradrenaline spillover responses to glucose ingestion were significantly blunted in T2D subjects. The M/I value independently predicted whole-body noadrenaline spillover (r = −0.47, P = 0.008), whilst fasting insulin level related to neuronal noradrenaline re-uptake (r = −0.35, P = 0.047). Conclusions: These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness and altered noradrenaline disposition.

Changes in peripheral but not central pulse wave velocity with estradiol administration is positively correlated with muscle sympathetic nerve activity

To investigate how estrogen affects autonomic and cardiovascular function, we measured muscle sympathetic nerve activity (MSNA), and central and peripheral pulse wave velocities (PWV) in 8 young healthy women after 3 days of endogenous sex hormone suppression (via gonadotropin‐releasing hormone antagonism). Five subjects continued hormone suppression for 2 days, combined with 0.2mg/day transdermal estradiol, and were retested. Estradiol administration decreased peripheral PWV (p&lt;0.05), a finding that does not exist during normal menstrual fluctuations. There was no change in central PWV (p=0.27). In addition, we used linear regression analyses to explore the relationship between MSNA and PWV. Across all subjects and conditions, peripheral (brachial‐ankle) PWV was positively correlated with MSNA bursts/min (R2=0.33, p=0.05) and bursts/100 heartbeats (R2=0.39, p=0.03), whereas no relationships existed between central (carotid‐femoral) PWV and MSNA parameters (bursts/min, R2&lt;0.01, p=0.90; and bursts/100 heartbeats, R2&lt;0.01, p=0.77). These data suggest sympathetic outflow to the peripheral arteries may explain the changes in peripheral PWV with estrogen administration. Degree of sympathetic innervation in the specific arteries studied may explain the differences between peripheral and central PWV measurements.Supported by NIH Grant HL081671.

Resting sympathetic outflow does not predict the morning blood pressure surge in hypertension

The blood pressure (BP) rise on awakening (morning surge) might be a predictor of hypertension-related cardiovascular complications. Previous studies suggest that the autonomic nervous system may contribute to the early morning BP increase. We tested the hypothesis that resting sympathetic outflow [assessed by direct measures of intraneural sympathetic nerve activity (SNA)] may help predict the morning BP surge in hypertension. We measured muscle SNA (MSNA), heart rate (HR) and BP during undisturbed supine rest in 68 newly diagnosed untreated hypertensive patients (53 men and 15 women, age 40 ± 3 years, BMI 27 ± 1 kg/m(2), mean ± SEM). The morning BP surge was defined as the difference between the morning BP and the pre-awake BP. SBP averaged 143 ± 3 mmHg for daytime and 126 ± 2 mmHg for night-time. Mean HR was 81 ± 2 beats/min for daytime and 69 ± 2 beats/min for night-time. Average MSNA was 32 ± 2 bursts/min., SBP morning surge 19 ± 2 mmHg and HR morning surge 14 ± 2 beats/min. In univariate analysis, MSNA correlated with daytime SBP (r = 0.28, P = 0.02); night-time SBP (r = 0.26, P = 0.03); daytime HR (r = 0.28, P = 0.02); and night-time HR (r = 0.26, P = 0.03). Multivariate analysis, taking into consideration age, BMI and sex, revealed that MSNA was independently related to both daytime (P = 0.006) and night-time HR (P = 0.02), but not to ambulatory SBP. The morning surge of SBP and HR was not related to MSNA (r = 0.01 and r = 0.07, respectively, P = NS). In patients with essential hypertension, MSNA is related to both daytime and night-time HR, but not to the morning BP surge.

Sympathetic nerve activity during deep brain stimulation

Electrical ‘deep brain’ stimulation (DBS) in humans has previously been shown to alter cardiovascular parameters such as blood pressure, pulse pressure and the response of blood pressure to standing. An alteration in the autonomic nervous system is likely to be responsible for these changes. The aim of this study was to directly measure muscle sympathetic nerve activity (MSNA) in humans with electrodes simultaneously stimulating the periaqueductal grey (PAG) and other areas known to modulate arterial blood pressure. MSNA has been successfully recorded in nine patients with electrodes in the PAG (n=4) and the subthalamic nucleus (STN) (n=5). Our preliminary results show, that when stimulating the PAG, the occurrence of sympathetic bursts remained unchanged, while the burst amplitude distribution demonstrated a transfer from low amplitude bursts towards a greater number of medium to high amplitude bursts during stimulation. Blood pressure variability changed in parallel with changes in MSNA. Stimulation of the STN resulted in unchanged burst amplitude distribution, whereas the occurrence of sympathetic bursts changed, which was paralleled by alterations in blood pressure and heart rate. Evidence of a differentiated control of occurrence and strength of sympathetic bursts has been reported previously. While it is not known how the differentiated control of sympathetic bursts is brought about, it has been suggested that the baroreflex modulation of sympathetic outflow occurs at two CNS locations. Our preliminary results on the effects of DBS of the STN and PAG on efferent sympathetic nerve traffic are in line with previous findings of a differentiated control of occurrence and strength of sympathetic bursts. But importantly, as modulation of sympathetic outflow is vital in the regulation of arterial blood pressure, our results may shed light on cardiovascular central neurocircuitry responsible for cardiovascular modulation.

The use of real-time ultrasound in microneurography

The use of microneurography to measure muscle sympathetic nerve activity has provided important insights in human physiology. However, placing microelectrodes into nerves can be challenging, particularly in certain patient populations. In this paper, we describe the use of real-time ultrasound guidance to assist with microneurography, including advantages, disadvantages, and proper training.