The association between enlarged perivascular spaces and muscle sympathetic nerve activity in normotensive and hypertensive humans.

What is the central question of this study?Muscle sympathetic nerve activity (MSNA) is well known to be modulated by the arterial baroreceptors and respiration, but what are the magnitudes of cardiac and respiratory modulation of skin sympathetic nerve activity (SSNA), which primarily subserves thermoregulation?What is the main finding and what is its importance?Using direct microelectrode recordings of MSNA and SSNA in awake humans, we show that the magnitude of respiratory modulation of SSNA is identical to that of MSNA, the primary difference between the two sources of sympathetic outflow being the greater cardiac modulation of MSNA. This emphasises the role of the baroreceptors in entraining sympathetic outflow to muscle. It is well known that microelectrode recordings of skin sympathetic nerve activity (SSNA) in awake human subjects reveal spontaneous bursts of activity with no overt modulation by changes in blood pressure or respiration, in contrast to the clear cardiac and respiratory modulation of muscle sympathetic nerve activity (MSNA). However, cross-correlation analysis has revealed that, like individual muscle vasoconstrictor neurones, the firing of individual cutaneous vasoconstrictor neurones is temporally coupled to both the cardiac and respiratory rhythms during cold-induced cutaneous vasoconstriction, and the same is true of single sudomotor neurones during heat-induced sweating. Here, we used cross-correlation analysis to determine whether SSNA exhibits cardiac and respiratory modulation in thermoneutral conditions and to compare respiratory and cardiac modulation of SSNA with that of MSNA. Oligounitary recordings of spontaneous SSNA (n = 20) and MSNA (n = 18) were obtained during quiet, unrestrained breathing. Respiration was recorded by a strain-gauge transducer around the chest and ECG recorded by surface electrodes. Respiratory and cardiac modulation of SSNA and MSNA were quantified by fitting polynomial equations to the cross-correlation histograms constructed between the sympathetic spikes and respiration or ECG. The amplitude of the respiratory modulation (52.5 ± 3.4%) of SSNA was not significantly different from the amplitude of the cardiac modulation (46.6 ± 3.2%). Both were comparable to the respiratory modulation of MSNA (47.7 ± 4.2%), while cardiac modulation of MSNA was significantly higher (89.8 ± 1.5%). We conclude that SSNA and MSNA share similar levels of respiratory modulation, the primary difference between the two sources of sympathetic outflow being the marked cardiac modulation of MSNA provided by the baroreceptors.

Many patients with severe obstructive sleep apnea (OSA) do not complain of excessive daytime sleepiness (EDS), possibly due to increased sympathetic nervous activity (SNA) and accompanying heightened alertness. We hypothesized that in patients with OSA, those without subjective EDS (Epworth Sleepiness Scale, ESS score < 11) would have higher very low frequency (VLF) heart rate variability (HRV) during sleep, reflecting greater sympathetic heart rate modulation than patients with an ESS score ≥ 11. Patients with severe OSA (AHI ≥ 30: 26 with and 65 without heart failure) were divided into those with and without EDS. Heart rate (HR) signals were acquired in stage 2 sleep during periods of recurrent apneas and hypopneas and submitted to coarse graining spectral analysis, which extracts harmonic, neurally mediated contributions to HRV from total spectral power. Because the apnea-hyperpnea cycle entrains muscle SNA at VLF (0 to 0.04 Hz), VLF power was our principal between-group comparison. Subjects without EDS had higher harmonic VLF power (944 ± 839 vs 447 ± 461 msec(2), p = 0.003) than those with EDS, irrespective of the presence or absence of heart failure (1218 ± 944 vs 426 ± 299 msec(2), p = 0.043, and 1029 ± 873 vs 503 ± 533 msec(2), p = 0.003, respectively). ESS scores correlated inversely with VLF power in all (r = -0.294, p = 0.005) and in heart failure subjects (r = -0.468, p = 0.016). Patients with severe OSA but without EDS have higher VLF-HRV than those with EDS. This finding suggests that patients with severe OSA but without EDS have greater sympathetic modulation of HRV than those with EDS that may reflect elevated adrenergically mediated alertness. Taranto Montemurro L; Floras JS; Picton P; Kasai T; Alshaer H; Gabriel JM; Bradley TD. Relationship of heart rate variability to sleepiness in patients with obstructive sleep apnea with and without heart failure.

Sympathetic excitation characterizes heart failure, but the underlying mechanisms remain unknown. Abnormal baroreflex restraint of sympathetic neural outflow has been proposed, since baroreflexes are known to be abnormal in heart failure. The purpose of this study was to determine if sympathetic activation in humans with heart failure is limited to regions governed by the baroreflexes or is generalized to other regions free from baroreflex control. We report the first direct recordings of skin sympathetic nerve activity (free from baroreflex control) in humans with heart failure and compare simultaneous skin and muscle (baroreflex-dependent) sympathetic peroneal nerve activity in six patients with severe heart failure (mean left ventricular ejection fraction, 0.19 +/- 0.06) and in six age-matched normal control subjects. Although muscle sympathetic nerve activity was markedly increased in heart failure patients (heart failure versus controls, 69 +/- 3 versus 21 +/- 2 bursts per minute; P < .001), skin sympathetic nerve activity was not increased (heart failure versus controls, 12 +/- 1 versus 15 +/- 1 bursts per minute; P = NS). The finding that skin sympathetic nerve activity in contrast to muscle sympathetic nerve activity is not increased in heart failure supports the concept that an altered reflex system, such as the baroreflexes, with nonuniform effects on muscle and skin sympathetic nerve activity, underlies sympatho-excitation in heart failure.

Obesity prevalence is soaring in industrialized countries and progressively increasing in the developing world. Altered patterns of nutrition and reduction in work-related energy expenditure have led to obesity becoming a truly global health issue. The central thermodynamic formulation for the origins of obesity, a mismatched energy balance equation, with an excess of dietary calorie intake over body energy expenditure, is a first step in the understanding of this phenomenon but leaves the diverse causal issues unexplored. Dietary calorie intake is modified by multiple social, economic, and cultural issues. Similarly, the reduction in energy expenditure in recent decades has complex origins, deriving from demographic and social change, which includes third-world transition from a labor-intensive agricultural economy to an industrial base, the introduction of household labor-saving devices, the popularity of transportation modes not reliant on physical effort, and from changed recreational habits, particularly in childhood (computer games instead of physical games). The prevalence of childhood obesity is escalating, having whimsically but not entirely unrealistically been attributed to “potato chips and computer chips.” Obesity and hypertension are intimately associated, and both very commonly coexist in individual patients with insulin resistance, hyperinsulinemia, and hyperlipidemia, this clustering of adverse health factors1 being designated the metabolic syndrome. The pathophysiological mechanisms by which obesity leads to hypertension remain uncertain. Understanding these processes might, perhaps, provide a more rational basis for drug treatment of obesity-related hypertension. Attempts at reduction in body weight, although pivotal in the treatment of obesity-related hypertension, more often than not fail, so that antihypertensive drug therapy is often needed. This review analyses the proposition that obesity is characterized by activation of the sympathetic nervous system and that obesity-related hypertension is, in fact, neurogenic, being initiated and sustained by neural mechanisms. At one time, this idea would have been held to fly in the …

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Essential hypertension, obesity, and congestive heart failure are characterized by an increase in muscle sympathetic nerve activity. Whether in these conditions skin sympathetic nerve activity is also increased has never been systematically examined, however. In 10 untreated mild essential hypertensive, 12 untreated normotensive obese, 10 mild (New York Heart Association class II) heart failure, and 10 normotensive lean healthy control subjects, we measured beat-to-beat arterial blood pressure (Finapres technique), body mass index, and postganglionic sympathetic nerve activity in skeletal muscle and skin areas (microneurographic technique, peroneal nerve). The muscle and skin nerve measurements were made in a randomized sequence. All data were obtained with the subject supine in a quiet, semidark environment at constant temperature over two periods of 30 minutes each, separated by a 20- to 30-minute interval. Blood pressure was increased only in hypertensive and body mass index only in obese subjects. Muscle sympathetic nerve activity quantified as bursts/min was markedly and significantly (P<.01) greater in essential hypertensive (33.3+/-1.7), obese (42.2+/-2.8), and congestive heart failure subjects (55.8+/-4.3) in comparison with control subjects (23.9+/-1.6). This was the case also for muscle sympathetic nerve activity, quantified as bursts per 100 heart beats. In contrast, skin sympathetic nerve activity (bursts per minute) was superimposable in hypertensive, obese, heart failure, and control subjects, its ability to increase being documented in all four groups by the marked response to an acoustic stimulus. Thus, in various diseases, muscle but not skin sympathetic activity is increased, with the sympathetic activation not being uniformly distributed over the whole cardiovascular system.

Dynamic arterial baroreflex function during high intensity exercise in humans: insights into sympathetic control

Introduction: Augmented sympathetic nerve activity (SNA) in hypertension (HT) is regarded as a therapeutic target, but there is few non-invasive markers to evaluate SNA in clinical practice. It is reported to associate with SNA which increased arterial reflected wave plays the important role in disease progression in HT, and it is reported to associate with SNA. Recently, Arterial Velocity Pulse Index (AVI) are developed as an index of arterial reflected waves, however the relationship between AVI and SNA is still uncertain. Methods: Patients with essential HT and matched non-hypertensive control subjects were included in this study. HT was diagnosed as systolic blood pressure (SBP) ≧ 140 mmHg or diastolic blood pressure (DBP) ≧ 90 mmHg. Patients with secondary HT was excluded. AVI was measured from left upper arm by NAS-1000 (Nihon Koden, Japan). SNA was evaluated by direct recording of muscle sympathetic nerve activity (MSNA) from peroneal nerves. Results: 50 HT patients and 50 control subjects were included. Age, SBP and DBP were significantly increased in HT group compared to control (Age 63±14 vs 42±16 years, p&lt;0.001; SBP 144±16 vs 115±9 mmHg, p&lt;0.001; DBP 80±14 vs 67±9 mmHg, p&lt;0.001). MSNA and AVI were significantly increased in HT group compared to control (MSNA 34±10 vs 25±8 bursts/min, p&lt;0.05; AVI 28±9 vs 17±5, p&lt;0.05). In univariate analysis, AVI was significantly correlated with MSNA, age, and SBP in HT group. However, no significant relationship was observed between AVI and MSNA in multivariate analysis. Therefore, HT group was divided into two groups according to their severity (group 1, SBP&lt;160mmHg, N=30; group 2, SBP&gt;160 mmHg, N=20). AVI in group 1 showed significantly correlation with MSNA (r=0.49, p&lt;0.05), but no correlation was seen in group 2. Conclusions: AVI was significantly increased in patients with HT compared to control, and AVI is significantly associated with MSNA in HT patients with SBP&lt;160mmHg. These results indicate that AVI is helpful to estimate augmented SNA in patients with mild or moderate hypertension. Further study is warranted to exam the relationship AVI and SNA in reality.

Left atrial radiofrequency catheter ablation (RFCA) is a therapy for atrial fibrillation. RFCA may alter sensory input from left atrium and pulmonary veins. It is speculated that RFCA may alter autonomic afferents and alter indices of sympathetic function. Although prior studies have shown that RFCA may alter autonomic function, which was assessed with heart rate variability (HRV), the effects of left atrial RFCA on sympathetic nerve activity have not been assessed. In this study, we hypothesized that RFCA would raise muscle sympathetic nerve activity (MSNA) during and after the RFCA procedure. Total of 18 patients (16 M, 2 F, 57 ± 3 years, 181 ± 2 cm, 97 ± 5 kg) were studied. In Protocol 1 (n = 10), the ECG, BP and MSNA from the peroneal nerve were recorded through the RFCA procedure in the electrophysiology laboratory. In Protocol 2 (n = 8), ECG, BP and MSNA were recorded before (within one week) and one day after the RFCA in a research laboratory. In Protocol 1, MSNA was obtained prior (n = 9), during (n = 3) and just post (within 15 min, n = 7) the RFCA procedure. Compared to prior RFCA, MSNA decreased during (28.4 ± 3.7 to 16.0 ± 2.6 bursts/min, P &lt; 0.05) and just post (28.6 ± 3.1 to 16.5 ± 4.1 bursts/min, P &lt; 0.05) the RFCA. Cardiac sympathetic tone (HRV) also decreased (prior, during, post LF/HF: 0.64 ± 0.15, 0.49 ± 0.11, 0.16 ± 0.04, P &lt; 0.05, n = 10). Vagal tone (HRV indexes: RMSSD, SDSD, HF) increased during RFCA (all P &lt; 0.05, n = 10). In Protocol 2, MSNA increased one day after RFCA (21.3 ± 3.7 to 35.7 ± 2.6 bursts/min, P &lt; 0.05, n = 6), and blood pressure did not change. Vagal tone (HRV indexes) decreased (all P &lt; 0.05, n = 8), while LF/HF also tended (P = 0.09, n = 8) to decrease one day after RFCA. Despite body motions and electronic noise during the RFCA procedure, we successfully obtained MSNA recordings during the RFCA procedure. The MSNA data suggest that the sympathetic activity is suppressed, and the HRV indexes suggest that the vagal tone is activated during the procedure. We speculate that the radiofrequency energy stimulates the vagal afferents, which in turn induces the observed effects during the procedure. Our data suggest the RFCA induces autonomic denervation in the heart and induces decreases in vagal and cardiac sympathetic tone one day post procedure. The rise in the sympathetic output to muscle after the procedure may represent a compensatory response to maintain blood pressure.Support or Funding InformationSupported by American Heart Association Grant 15GRNT24480051 (Cui), Penn State Heart and Vascular Institute Penny A. Garban Endowment (Cui), National Institutes of Health Grants P01 HL096570 (Sinoway) and UL1 TR000127 (Sinoway).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Relevance of differential control of sympathorespiratory response magnitudes in clinical assessments.

Smoking and cardiovascular risk: new mechanisms and further evidence for a 'guilty' verdict.

Radiofrequency catheter ablation (RFCA) is a frequently performed procedure in patients with atrial fibrillation. Prior studies have shown that the RFCA may directly stimulate vagal afferents during the procedure, whereas the vagal tone assessed by heart rate variability (HRV) is lowered weeks after the RFCA procedure. The effects of RFCA performed in the left atrium on sympathetic nerve activity have not been assessed. In the present study, we hypothesized that RFCA would lower muscle sympathetic nerve activity (MSNA) during ablation and would raise MSNA 1 day postablation. A total of 18 patients were studied. In protocol 1 ( n = 10), electrocardiogram, blood pressure, and MSNA in the peroneal nerve were recorded through the RFCA procedure performed in the electrophysiology laboratory. In protocol 2, eight patients were studied before the procedure and 1 day postablation. RFCA led to a decrease in MSNA immediately after the procedure (25.4 ± 3.2 to 17.2 ± 3.8 bursts/min, P < 0.05). Cardiac parasympathetic activity was determined using indexes of HRV and increased during the procedure. One day postablation, MSNA was above baseline values (21.3 ± 3.7 to 35.7 ± 2.6 bursts/min, P < 0.05). HRV indexes of cardiac parasympathetic activity fell, and the HRV index of sympathovagal balance was not significantly altered. The results show that RFCA raised cardiac parasympathetic activity and decreased MSNA during the procedure. One day postablation, MSNA rose and cardiac parasympathetic activity fell. In addition, RFCA evokes differentiated sympathetic responses directed to the heart and skeletal muscles. NEW & NOTEWORTHY The effects of radiofrequency catheter ablation performed in the left atrium on muscle sympathetic nerve activity (MSNA) have not been assessed. The results of this study show that radiofrequency catheter ablation raised cardiac parasympathetic activity and decreased MSNA during the procedure. One day postablation, MSNA rose and cardiac parasympathetic activity fell. We speculate that the partial autonomic afferent denervation induces these effects on autonomic activity.

Different contribution of sympathetic nerve activity to arterial velocity pulse index in hypertensive patients with and without diastolic dysfunction

The purpose of this experiment was to examine the effects of the endogenous opioid system on forearm muscle pain and muscle sympathetic nerve activity (MSNA) during dynamic fatiguing exercise. Twelve college-age men (24 +/- 4 yr) performed graded (1-min stages; 30 contractions/min) handgrip to fatigue 1 h after the ingestion of either 60 mg codeine, 50 mg naltrexone, or placebo. Pain (0-10 scale) and exertion (0-10 and 6-20 scales) intensities were measured during the last 15 s of each minute of exercise and every 15 s during recovery. MSNA was measured continuously from the peroneal nerve in the left leg. Pain threshold occurred earlier [1.8 +/- 1, 2. 2 +/- 1, 2.2 +/- 1 J: codeine, naltrexone, and placebo, respectively] and was associated with a lower rating of perceived exertion (RPE) (2.7 +/- 2, 3.6 +/- 2, 3.8 +/- 2: codeine, naltrexone, and placebo, respectively) in the codeine condition compared with either the naltrexone or placebo conditions. There were no main effects (i.e., drugs) or interaction (i.e., drugs x time) for either forearm muscle pain or RPE during exercise [pain: F (2, 22) = 0.69, P = 0.51]. There was no effect of drug on MSNA, heart rate, or blood pressure during baseline, exercise, or recovery. Peak exercise MSNA responses were 21 +/- 1, 21 +/- 2.0, and 21 +/- 2.0 bursts/30 s for codeine, naltrexone, and placebo conditions, respectively. Peak mean arterial pressure responses were 135 +/- 4, 131 +/- 3, and 132 +/- 4 mmHg for codeine, naltrexone, and placebo conditions, respectively. It is concluded that neither 60 mg codeine nor 50 mg naltrexone has an effect on forearm muscle pain, exertion, or MSNA during high- intensity handgrip to fatigue.

Stretching our understanding of baroreflex control in humans: evidence of a positive feedback pulmonary baroreflex.