Sympathetic Neural Activity Research Articles

Actigraphy-based sleep and muscle sympathetic nerve activity in humans.

Short and insufficient sleep are prevalent and associated with cardiovascular disease, with the sympathetic nervous system as a suspected mediator. The purpose of the present study was to investigate the association between objective, actigraphy-based total sleep time (TST), sleep efficiency (SE), and cardiovascular and sympathetic regulation in healthy adults. We hypothesized that short TST and low SE would be associated with elevated resting blood pressure, heart rate (HR), and muscle sympathetic nerve activity (MSNA). Participants included 94 individuals [46 males, 48 females, age: 30 ± 15 yr, body mass index (BMI): 26 ± 4 kg/m2]. All participants underwent at least 7 days of at-home, wristwatch actigraphy monitoring (avg: 10 ± 3 days). Seated blood pressures were assessed using brachial blood pressure measurements, followed by a 10-minute supine autonomic testing session consisting of continuous HR (electrocardiogram), beat-by-beat blood pressure (finger plethysmograph), and MSNA (microneurography) monitoring. Partial correlations were used to determine the relationship between sleep and cardiovascular parameters while accounting for the influence of age, sex, and BMI. TST was not associated with MAP (R = -0.105, P = 0.321), HR (R = 0.093, P = 0.383), or MSNA burst frequency (BF; R = -0.168, P = 0.112) and burst incidence (BI; R = -0.162, P = 0.124). Similarly, SE was not associated with MAP (R = -0.088, P = 0.408), HR (R = -0.118, P = 0.263), MSNA BF (R = 0.038, P = 0.723), or MSNA BI (R = 0.079, P = 0.459). In contrast to recent preliminary findings, our results do not support a significant association between actigraphy-based sleep duration or efficiency and measures of resting blood pressure, heart rate, and MSNA.NEW & NOTEWORTHY The present study investigated the independent association between actigraphy-based sleep duration, efficiency, and measures of blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) in adult males and females. Contrary to our hypothesis, the findings do not support an independent association between habitual sleep and cardiovascular or sympathetic neural activity. However, these findings do not preclude a potential association between these parameters in populations with sleep disorders and/or cardiovascular disease.

Mitochondria-targeted sonodynamic modulation of neuroinflammation to protect against myocardial ischemia‒reperfusion injury

Sympathetic hyperactivation and inflammatory responses are the main causes of myocardial ischemia‒reperfusion (I/R) injury and myocardial I/R-related ventricular arrhythmias (VAs). Previous studies have demonstrated that light-emitting diodes (LEDs) could modulate post-I/R neuroinflammation, thus providing protection against myocardial I/R injury. Nevertheless, further applications of LEDs are constrained due to the low penetration depth (<1 cm) and potential phototoxicity. Low-intensity focused ultrasound (LIFU), an emerging noninvasive neuromodulation strategy with deeper penetration depth (∼10 cm), has been confirmed to modulate sympathetic nerve activity and inflammatory responses. Sonodynamic therapy (SDT), which combines LIFU with sonosensitizers, confers additional advantages, including superior therapeutic efficacy, precise localization of neuronal modulation and negligible side effects. Herein, LIFU and SDT were introduced to modulate post-myocardial I/R neuroinflammation to protect against myocardial I/R injury. The results indicated that LIFU and SDT inhibited sympathetic neural activity, suppressed the activation of astrocytes and microglia, and promoted microglial polarization towards the M2 phenotype, thereby attenuating myocardial I/R injury and preventing I/R-related malignant VAs. These insights suggest that LIFU and SDT inspire a noninvasive and efficient neuroinflammatory modulation strategy with great clinical translation potential thus benefiting more patients with myocardial I/R in the future. Statement of significanceMyocardial ischemia-reperfusion (I/R) may cause I/R injury and I/R-induced ventricular arrhythmias. Sympathetic hyperactivation and inflammatory response play an adverse effect in myocardial I/R injury. Previous studies have shown that light emitting diode (LED) can regulate I/R-induced neuroinflammation, thus playing a myocardial protective role. However, due to the low penetration depth and potential phototoxicity of LED, it is difficult to achieve clinical translation. Herein, we introduced sonodynamic modulation of neuroinflammation to protect against myocardial I/R injury, based on mitochondria-targeted nanosonosensitizers (CCNU980 NPs). We demonstrated that sonodynamic modulation could promote microglial autophagy, thereby preventing myocardial I/R injury and I/R-induced ventricular arrhythmias. This is the first example of sonodynamic modulation of myocardial I/R-induced neuroinflammation, providing a novel strategy for clinical translation.

The Effects of Obstructive Sleep Apnea on the Cardiovascular System: A Comprehensive Review.

Obstructive sleep apnea (OSA) is an increasingly relevant cause of cardiovascular morbidity worldwide. Although the association between OSA and the cardiovascular system is well-known, the extent of its effects is still a topic of interest, including pathophysiologic mechanisms, cardiovascular sequelae, and OSA therapies and their effects. Commonly described mechanisms of cardiovascular etiologies revolve around sympathetic activation, inflammation, and intermittent hypoxia resulting from OSA. Ultimately, these effects lead to manifestations in the cardiovascular system, such as arrhythmias, hypertension, and heart failure, among others. The resulting sequelae of OSA may also have differential effects based on gender and age; several studies suggest female gender to have more susceptibility to cardiovascular mortality, as well as an increase in age. Furthermore, several therapies for OSA, both established and emerging, show a reduction in cardiovascular morbidity and may even reduce cardiovascular burden. Namely, the establishment of CPAP has led to improvement in hypertension and cardiac function in patients with heart failure and even reduced the progression of early stages of atherosclerosis. Effective management of OSA decreases abnormal neural sympathetic activity, which results in better rhythm control and blood pressure control, both in waking and sleep cycles. With newer therapies for OSA, its effects on the cardiovascular system may be significantly reduced or even reversed after long-term management. The vast extent of OSA on the cardiovascular system, as well as current and future therapeutic strategies, will be described in detail in this review.

Oxidative Products of Catecholamines During Heightened Sympathetic Activity Due to Congestive Heart Failure: Possible Role of Antioxidants.

The past several decades have shown the functional status of sympathetic activity in congestive heart failure. The results, particularly through clinical and basic studies in heart failure, indicate an increased sympathetic neural activity. The definitive and compelling evidence of the involvement of catecholamines is the demonstration that many drugs that are therapeutically useful in the treatment of heart failure also affect the sympathetic nervous system at various sites, including its synthesis, release and uptake of catecholamines and a decreased plasma norepinephrine level. Although it is not surprising that the sympathetic system is altered as cardiac function is compromised in heart failure, it now appears that this system may overreact in chronic situations. The detrimental cardiovascular problems result in the production of aminochrome and free radicals. Antioxidant therapy to target the production of aminochrome from autooxidation of catecholamines should provide an insight into the future therapeutic goal in situations like congestive heart failure.

Neural recordings can differentiate between spontaneously metastasizing melanomas and melanomas with low metastatic potential.

Multiple studies report that melanomas are innervated tumors with sensory and sympathetic fibers where these neural fibers play crucial functional roles in tumor growth and metastasis with branch specificity. Yet there is no study which reports the direct neural recording and its pattern during in-vivo progression of the cancer. We performed daily neural recordings from male and female mice bearing orthotopic metastasizing- melanomas and melanomas with low metastatic poential, derived from B16-F10 and B16-F1 cells, respectively. Further, to explore the origins of neural activity, 6-Hydroxidopamine mediated chemical sympathectomy was performed followed by daily microneurographic recordings. We also performed the daily bioluminescent imaging to track in vivo growth of primary tumors and distant metastasis to the cranial area. Our results show that metastasizing tumors display high levels of neural activity while tumors with low metastatic potential lack it indicating that the presence of neural activity is linked to the metastasizing potential of the tumors. Moreover, the neural activity is not continuous over the tumor progression and has a sex-specific temporal patterns where males have two peaks of high neural activity while females show a single peak. The neural peak activity originated in peripheral sympathetic nerves as sympathectomy completely eliminated the peak activity in both sexes. Peak activities were highly correlated with the distant metastasis in both sexes. These results show that sympathetic neural activity is crucially involved in tumor metastasis and has sex-specific role in malignancy initiation.

Comparison of time domain indices of heart rate variability between alcohol-dependent individuals and non-alcoholic subjects

Background: Alcohol dependence develops because of repeated alcohol intake. Alcohol damages the cardiac autonomic nerve fibers leading to autonomic imbalance, resulting in reduced heart rate variability (HRV). HRV refers to the complex beat-to-beat variation in the heart rate, produced by the interplay of sympathetic and parasympathetic neural activity at the Sino-atrial node. Our body works effectively in parasympathetic activity dominance. The time domain indices of HRV are specific markers of parasympathetic activity. A decrease in the time domain parameters indicates reduced parasympathetic activity in the heart, indicating cardiac autonomic dysfunction with vagal neuropathy. Aims and Objectives: The objectives of the study are as follows: (1) To assess the HRV in alcohol-dependent individuals using time domain indices. (2) To compare the HRV between alcoholic-dependent individuals and non-alcoholic subjects. Materials and Methods: A total of 110 individuals in the age group of 20–55 years were recruited for our study. Among them, 55 were alcohol-dependent individuals selected based on the diagnostic and statistical manual-IV, international classification of diseases-10 criteria, and 55 age and gender-matched volunteers were selected as healthy non-alcoholic controls. Short-term HRV was recorded in a supine posture, and the results were interpreted. Statistical analysis was done using the software SPSS version 21.0. Results: Our results showed a significant reduction in the time-domain parameters of HRV – SDNN, RMSSD, NN50, and pNN50 in the alcohol-dependent individuals compared to the controls, suggesting reduced parasympathetic activity in the heart indicating cardiac autonomic neuropathy. Conclusion: Alcohol affects the cardiac autonomic status leading to sudden death due to arrhythmias. HRV can be used as a non-invasive test to assess cardiac autonomic dysfunction and its biofeedback can help alcohol-dependent individuals to adopt healthy lifestyle measures.

Postmenopausal Lumbar Spine Osteoporosis in Hungarian Women is Characterised By Increased Serum Levels of Nerve Growth Factor

Purpose: In addition to its neuronal specificity, nerve growth factor (NGF) plays a role in immuno-inflammatory events. Cells involved in osteoporosis, in particular mesenchymal stem/stromal cells and monocytes/macrophages, are capable of producing NGF. The question was whether NGF might be involved in osteoporotic bone loss independent of age. Methods: Sixty postmenopausal Hungarian women were studied for serum NGF-β and MCP-1 levels, total lumbar spine and forearm osteoporosis, and femoral neck osteoporosis. Biochemical data were measured by enzyme-linked immunosorbent assay and presented as geometric mean (95% CI). Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) and T-score values in three bone regions. Multiple regression analysis was used to identify the independent variables involved in the elevated NGF-β levels. Results: Serum NGF-β levels were significantly increased in the osteoporotic subgroup compared to the normal and osteopenic subgroups [15.85(8.99-27.91) vs. 12.42(8.28-18.64) pg/ml, p&lt;0.004 and 12.49(9.36-16.65) pg/ml, p&lt;0.002, respectively] in the total lumbar spine region. Using multiple regression analysis, serum MCP-1 levels alone and their interaction with lumbar spine BMD were significant with elevated serum NGF-β levels, age was not included in the model. Increased serum NGF-β levels were restricted to the lumbar spine, but not to forearm and femoral neck osteoporosis. Conclusion: Increased serum NGF-β levels were associated with the severity of lumbar spine osteoporosis. Increased sympathetic and sensory neural activity may contribute to the presence of pain and neuropathy in osteoporosis.

Low-intensity focused ultrasound modulation of the paraventricular nucleus to prevent myocardial infarction–induced ventricular arrhythmia

BackgroundOur previous study showed that light-emitting diode modulation of the hypothalamic paraventricular nucleus (PVN), which is the control center of the sympathetic nervous system, might attenuate neuroinflammation in the PVN and prevent ventricular arrhythmias (VAs) after myocardial infarction (MI). Low-intensity focused ultrasound (LIFU) has deeper penetration than does light-emitting diode, while its effect on the PVN has not been reported. ObjectiveThis study aimed to explore the effect of LIFU modulation of the PVN on the inducibility of post-MI VAs. MethodsFifty-four Sprague-Dawley rats were randomly divided into acute control (n = 12, 22.22%), acute MI (AMI, n = 12, 22.22%), AMI + LIFU (n = 12, 22.22%), chronic control (n = 6, 11.11%), chronic MI (CMI, n = 6, 11.11%), and CMI + LIFU (n = 6, 11.11%) groups. MI was induced by left anterior artery ligation, and electrocardiographic recording for 0.5 hours after MI and programmed electrophysiological stimulation were used to test the vulnerability of VAs. Peripheral sympathetic neural activity was assessed by measuring left stellate ganglion neural activity. Finally, hearts and brains were extracted for Western blotting and histopathological analysis, respectively. ResultsCompared with the AMI group, AMI-induced VAs (P < .05) and left stellate ganglion neural activity (P < .05) were significantly attenuated in the AMI + LIFU group. In addition, LIFU resulted in a significant reduction of microglial activation in the PVN and expression of inflammatory cytokines in the peri-ischemic myocardium. In the CMI + LIFU group, there was no obvious tissue damage in the brain. ConclusionLIFU modulation of the PVN may prevent the incidence of post-MI VAs by attenuating MI-induced sympathetic neural activation and inflammatory response.

Ischemia-reperfusion myocardial infarction induces remodeling of left cardiac-projecting stellate ganglia neurons.

Neurons in the stellate ganglion (SG) provide sympathetic innervation to the heart, brown adipose tissue (BAT), and other organs. Sympathetic innervation to the heart becomes hyperactive following myocardial infarction (MI). The impact of MI on the morphology of cardiac sympathetic neurons is not known, but we hypothesized that MI would stimulate increased cell and dendritic tree size in cardiac neurons. In this study, we examined the effects of ischemia-reperfusion MI on sympathetic neurons using dual retrograde tracing methods to allow detailed characterization of cardiac- and BAT-projecting neurons. Different fluorescently conjugated cholera toxin subunit B (CTb) tracers were injected into the pericardium and the interscapular BAT pads, respectively. Experimental animals received a 45-min occlusion of the left anterior descending coronary artery and controls received sham surgery. One week later, hearts were collected for assessment of MI infarct and SGs were collected for morphological or electrophysiological analysis. Cardiac-projecting SG neurons from MI mice had smaller cell bodies and shorter dendritic trees compared with sham animals, specifically on the left side ipsilateral to the MI. BAT-projecting neurons were not altered by MI, demonstrating the subpopulation specificity of the response. The normal size and distribution differences between BAT- and cardiac-projecting stellate ganglion neurons were not altered by MI. Patch-clamp recordings from cardiac-projecting left SG neurons revealed increased spontaneous excitatory postsynaptic currents despite the decrease in cell and dendritic tree size. Thus, increased dendritic tree size does not contribute to the enhanced sympathetic neural activity seen after MI.NEW & NOTEWORTHY Myocardial infarction (MI) causes structural and functional changes specifically in stellate ganglion neurons that project to the heart, but not in cells that project to brown adipose fat tissue.

Abstract 17565: Sympathetic Neural Overactivity, Endothelial Dysfunction, Aortic Stiffening, and Diminished Exercise Capacity in Breast Cancer Survivors Treated With Doxorubicin and Trastuzumab-Based Chemotherapy

Introduction: Previous evidence demonstrates that breast cancer (BC) survivors who were treated with doxorubicin and trastuzumab-based chemotherapy have an increased risk of developing cardiovascular (CV) disease at least 7 years after completion of cancer treatment. The reasons for the increased CV disease risk are not completely understood, a constellation of physiological changes may contribute. We hypothesized that BC survivors compared with age- and body mass index (BMI), sex -matched healthy controls, exhibit sympathetic neural overactivity, vascular endothelial dysfunction, aortic stiffening, and diminished exercise capacity. Methods: Twelve women BC survivors, treated with doxorubicin and trastuzumab (age=48±2 years and BMI=28±2 Kg/m 2 ) and fourteen women control subjects (age=46±1 years and BMI=27±1 Kg/m 2 ) were studied. Muscle sympathetic nerve activity (MSNA, Microneurography), endothelium-dependent dilation (brachial artery flow-mediated dilation, BAFMD), aortic stiffness (carotid-femoral pulse wave velocity, CFPWV), blood pressure (BP, Finometer), heart rate (HR, Electrocardiogram), and peak oxygen uptake (V˙O 2 peak, Cardiopulmonary exercise testing) were measured. Results: BC survivors were evaluated 8±2 years after the completion of cancer treatment. Burst frequency and burst incidence of MSNA were higher and BAFMD and V˙O 2 peak were lower in BC survivors than in controls ( p &lt;0.001). There were not differences between the groups in CFPWV, BP, and HR ( p &gt;0.05). MSNA burst frequency and burst incidence were inversely associated with V˙O 2 peak or BAFMD ( p &lt;0.05). Conclusion: Our findings demonstrate that BC survivors have an augmented sympathetic neural activity, endothelial dysfunction, and attenuated exercise capacity, which may help to explain, at least in part, the increased CV risk in this population. Therefore, it is urgent to establish therapeutic strategies (e.g., physical exercise rehabilitation) to restore or alleviate these cardiovascular changes in BC survivors.

Klotho Null Mutation Indirectly Leads to Age-Related Lacrimal Gland Degeneration in Mutant Mice.

The Klotho null mutation is known to lead to accelerated aging in many organs, but its effects on tear secretion and lacrimal gland (LG) senescence have not been addressed. This study investigated whether the Klotho null mutation would lead to a dry eye status and the outcome of LG without Klotho function. The Klotho (-/-) mutant mice showed reduced LG size and tear volume on the 8th week, as compared to their littermates (+/+, +/-). Hematoxylin-Eosin and Masson's trichrome staining were performed to determine morphological changes and collagen deposition. Traits of LG aging, including acinar atrophy, thickened capsules, and more collagen depositions, were observed. Immunohistochemical detections for Klotho, α-SMA, MDA, 8-OHdG, vasoactive intestinal polypeptide (VIP), tyrosine hydroxylase (TH), MMP-2, MMP-9, and FGF-23 were performed and compared among the three genotypes (+/+, +/-, -/-) at 6 and 8 weeks of age for mechanism analyses. Unexpectedly, the Klotho protein was not detected in the LG of all the three genotypes, indicating indirect effects from the Klotho null mutation. Further analyses showed abundant MDA and 8-OHdG detected in the Klotho (-/-) LG on the 8th week, indicating elevated oxidative stress. In addition, both sympathetic and parasympathetic neural transducing activities, as represented by TH and VIP expression, respectively, and α-SMA were increased in LGs with Klotho mutations. Furthermore, MMP-2 and MMP-9 expression were elevated, with FGF-23 expression being decreased on the 8th week in the Klotho (-/-) LG. In conclusion, characteristics of age-related LG degeneration were found in the Klotho null mutant mice. These traits support the use of Klotho mutant mice as a model of age-related dry eye disease.

Concomitantly higher resting arterial blood pressure and transduction of sympathetic neural activity in human obesity without hypertension.

Central (abdominal) obesity is associated with elevated adrenergic activity and arterial blood pressure (BP). Therefore, we tested the hypothesis that transduction of spontaneous muscle sympathetic nerve activity (MSNA) to BP, that is, sympathetic transduction, is augmented in abdominal obesity (increased waist circumference) and positively related to prevailing BP. Young/middle-aged obese (32 ± 7 years; BMI: 36 ± 5 kg/m2, n = 14) and nonobese (29 ± 10 years; BMI: 23 ± 4 kg/m2, n = 14) without hypertension (24-h ambulatory average BP < 130/80 mmHg) were included. MSNA (microneurography) and beat-to-beat BP (finger cuff) were measured continuously and the increase in mean arterial pressure (MAP) during 15 cardiac cycles following MSNA bursts of different patterns (single, multiples) and amplitude (quartiles) was signal-averaged over a 10 min baseline period. MSNA burst frequency was not significantly higher in obese vs. nonobese (21 ± 3 vs. 17 ± 3 bursts/min, P = 0.34). However, resting supine BP was significantly higher in obese compared with nonobese (systolic: 127 ± 3 vs. 114 ± 3; diastolic: 76 ± 2 vs. 64 ± 1 mmHg, both P < 0.01). Importantly, obese showed greater increases in MAP following multiple MSNA bursts (P = 0.02) and MSNA bursts of higher amplitude (P = 0.02), but not single MSNA bursts (P = 0.24), compared with nonobese when adjusting for MSNA burst frequency. The increase in MAP following higher amplitude bursts among all participants was associated with higher resting supine systolic (R = 0.48; P = 0.01) and diastolic (R = 0.48; P = 0.01) BP when controlling for MSNA burst frequency, but not when also controlling for waist circumference (P > 0.05). In contrast, sympathetic transduction was not correlated with 24-h ambulatory average BP. Sympathetic transduction to BP is augmented in abdominal obesity and positively related to higher resting supine BP but not 24-h ambulatory average BP.

Effects of sacubitril-valsartan on clinical, echocardiographic and polygraphic parameters in patients affected by heart failure with reduced ejection fraction and sleep apnea

Abstract Background Heart failure with reduced ejection fraction (HFrEF) is a clinical condition frequently diagnosed in clinical practice. In patients affected by HFrEF, sleep apnea (SA) can be detected among the most frequent comorbidities. Sacubitril–valsartan (sac/val) association has been proven to be effective in reducing disease progression and all-cause mortality in HFrEF patients. Sac/val treatment can potentially attenuate SA development via several pathophysiologic mechanisms, including improvement of global hemodynamics, reduction of extracellular fluid overload, and decrease of sympathetic neural activity. Purpose The aim of this work is to evaluate the effects of a 6-month therapy with sac/val on hemodynamic and metabolic parameters, as well as on the occurrence of apnea/hypopnea and oxygen saturation in patients with HFrEF and SA, already treated with CPAP. Methods We recruited 132 patients affected by HFrEF and SA, already under treatment with continuous positive airway pressure (CPAP), which was discontinued 24 hours before the scheduled study timepoints. Physical examination, echocardiography, nocturnal cardio-respiratory monitoring, and laboratory tests were performed in each patient at baseline and after a 6-month treatment with sac/val. Results After 6 months, sac/val induced statistically significant changes in clinical, hemodynamic, biohumoral (NT-proBNP, serum electrolytes, creatinine and uric acid), and echocardiographic parameters. In particular, cardiac index (CI), both atrial and ventricular volumes and global longitudinal strain (GLS) improved. Moreover, polysomnography, carried out during a temporary CPAP interruption, revealed a significant reduction in global apnea-hypopnea index (AHI) value (p&amp;lt;0.0001), central AHI (p&amp;lt;0.0001), obstructive AHI (p&amp;lt;0.0001), oxygen desaturation index (ODI) (p&amp;lt;0.0001), and percentage time of saturation below 90% (TC90) (p&amp;lt;0.0001). The changes of CI, estimated glomerular filtration rate (eGFR), NT-proBNP and tricuspid annular plane excursion (TAPSE) contributed to 23.6%, 7.6%, 7.3% and 4.8% of AHI variability, respectively, and the whole model accounted for a 43.3% of AHI variation. Conclusions Our results suggest that treatment with sac/val is able to significantly improve the cardiorespiratory performance of patients with HFrEF and SA, integrating the positive impact of CPAP. Thus, both CPAP and sac/val therapy may synergistically contribute to lower the risks of both cardiac and pulmonary complications in HFrEF patients with SA. Funding Acknowledgement Type of funding sources: None.

Orexin, Sleep, Sympathetic Neural Activity, and Cardiovascular Function.

Inadequate sleep duration and quality are associated with reduced cardiovascular health and increased mortality. Experimental evidence points to the sympathetic nervous system as a key mediator in the observed relationship between poor sleep and cardiovascular dysfunction. However, brain mechanisms underpinning the impaired sympathetic function associated with poor sleep remain unclear. Recent evidence suggests the central orexin system, particularly orexins A and B and their receptors, have a key regulatory role for sleep in animal and human models. While orexin system activity has been observed to significantly impact sympathetic regulation in animals, the extension of these findings to humans has been difficult due to an inability to directly assess orexin system activity in humans. However, direct measures of sympathetic activity in populations with narcolepsy and chronic insomnia, 2 sleep disorders associated with deficient and excessive orexin neural activity, have allowed indirect assessment of the relationships between orexin, sleep, and sympathetic regulation. Further, the recent pharmaceutical development of dual orexin receptor antagonists for use in clinical insomnia populations offers an unprecedented opportunity to examine the mechanistic role of orexin in sleep and cardiovascular health in humans. The current review assesses the role of orexin in both sleep and sympathetic regulation from a translational perspective, spanning animal and human studies. The review concludes with future research directions necessary to fully elucidate the mechanistic role for orexin in sleep and sympathetic regulation in humans.

Abstract 052: Central Gain For Sympathetic Outflow Is Increased In Postural Tachycardia Syndrome

White noise perturbations using neck suction (NS) can be applied to identify open loop transfer function in a closed loop baroreflex system. It allows an estimation of central arc transfer function (H1) which represents how afferent baroreceptor information is translated into sympathetic outflow and peripheral arc transfer function (H2) which describes how muscle sympathetic nerve activity (MSNA) affects blood pressure (BP). We hypothesize that patients with postural tachycardia syndrome (POTS) have elevated central gain compared to healthy controls (CONT). We recorded raw MSNA and continuous finger BP during randomized NS (0 to -50 mmHg, 0.03-0.3 Hz) and controlled breathing at 0.25 Hz for 6 minutes in 10 female POTS and 9 female CONT. Both groups were matched for age (28.4±2.1 vs. 31.9±3.0 p=0.80) and BMI (23.0±0.7 vs 24.5±1.0, p=0.25). We derived the continuous spike rate using wavelet-based denoising. We estimated median central gain in H1 and peripheral gain in H2 for low (LF: 0.04-0.15 Hz) and high (HF: 0.15-0.4 Hz) frequency ranges (Figure). We found that POTS have significantly higher central gain in LF range (2.44±0.38 vs 1.53±0.24 spikes/s/mmHg, p=0.028, MN±SE) but not in HF range (9.02±3.02 vs. 5.06±0.52 spikes/s/mmHg, p=0.604). Median peripheral gains were comparable in LF (0.68±0.15 vs 0.58±0.09 mmHg/spikes/s, p&gt;0.99) and HF ranges (0.18±0.02 vs 0.21±0.03 mmHg/spikes/s, p=0.497). Our results indicate that POTS have higher recruitment of neural sympathetic spike activity during BP oscillations in the LF range. This could explain why higher sympathetic activation/modulation and greater BP fluctuations in the LF range are found during upright in POTS.

Longitudinal observations of sympathetic neural activity and hemodynamics during 6 months recovery from SARS-CoV-2 infection.

Cross‐sectional data indicate that acute SARS‐CoV‐2 infection increases resting muscle sympathetic nerve activity (MSNA) and alters hemodynamic responses to orthostasis in young adults. However, the longitudinal impact of contracting SARS‐CoV‐2 on autonomic function remains unclear. The aim of this study was to longitudinally track MSNA, sympathetic transduction to blood pressure (BP), and hemodynamics over 6 months following SARS‐CoV‐2 infection. Young adults positive with SARS‐CoV‐2 reported to the laboratory three times over 6 months (V1:41 ± 17, V2:108 ± 21, V3:173 ± 16 days post‐infection). MSNA, systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were measured at rest, during a cold pressor test (CPT), and at 30° head‐up tilt (HUT). Basal SBP (p = 0.019) and DBP (p < 0.001) decreased throughout the 6 months, whereas basal MSNA and HR were not different. Basal sympathetic transduction to BP and estimates of baroreflex sensitivity did not change over time. SBP and DBP were lower during CPT (SBP: p = 0.016, DBP: p = 0.007) and HUT at V3 compared with V1 (SBP: p = 0.041, DBP: p = 0.017), with largely no changes in MSNA. There was a trend toward a visit‐by‐time interaction for burst incidence (p = 0.055) during HUT, wherein at baseline immediately prior to tilting, burst incidence was lower at V3 compared with V1 (p = 0.014), but there were no differences between visits in the 30 HUT position. These results support impairments to cardiovascular health, and potentially autonomic function, which may improve over time. However, the improvements in BP over 6 months recovery from mild SARS‐CoV‐2 infection are likely not a direct result of changes in sympathetic activity.

Sympathetic neural reactivity to the Trier social stress test.

Sympathetic responsiveness to laboratory mental stress is highly variable, making interpretations of its role in stress reactivity challenging. The present study assessed muscle sympathetic nerve activity (MSNA, microneurography) responsiveness to the Trier social stress test (TSST), which employs an anticipatory stress phase, followed by a public speaking and mental arithmetic task. We hypothesized that sympathetic reactivity to the anticipatory phase would offer a more uniform response between individuals due to elimination of confounds (i.e. respiratory changes, muscle movement, etc.) observed during more common stress tasks. Participants included 26healthy adults (11men, 15 women, age: 25±6years, body mass index: 24±3kg/m2 ). Continuous heart rate (electrocardiogram) and beat-to-beat blood pressure (finger plethysmography) were recorded from all participants, while MSNA recordings were obtained in 20 participants. MSNA burst frequency was significantly reduced during anticipatory stress. During the speech, although burst frequency was unchanged, total MSNA was significantly increased. Changes in diastolic arterial pressure were predictive of changes in MSNA during anticipatory (β=-0.680, P=0.001), but not the speech (P=0.318) or mental maths (P=0.051) phases. Lastly, sympathetic reactivity to anticipatory stress was predictive of subsequent reactivity to both speech (β=0.740, P=0.0002) and maths (β=0.663, P=0.001). In conclusion, anticipatory social stress may offer a more versatile means of assessing sympathetic reactivity to mental stress in the absence of confounds and appears to predict reactivity to subsequent mental stress paradigms. KEY POINTS: Cardiovascular reactivity to laboratory mental stress is predictive of future health outcomes. However, reactivity of the sympathetic nervous system to mental stress is highly variable. The current study assessed peripheral muscle sympathetic nerve activity in response to the Trier social stress test, a psychosocial stressor that includes anticipatory stress, public speaking and mental arithmetic. Our findings demonstrate that sympathetic neural activity is consistently reduced during anticipatory stress. Conversely, the classically observed inter-individual variability of sympathetic responsiveness was observed during speech and maths tasks. Additionally, sympathetic reactivity to the anticipatory period accurately predicted how an individual would respond to both speech and maths tasks, outlining the utility of anticipatory stress in future research surrounding stress reactivity. Utilization of the Trier social stress test in autonomic physiology may offer an alternative assessment of sympathetic responsiveness to stress with more consistent inter-individual responsiveness and may be a useful tool for further investigation of stress reactivity.

Central regulation of body fluid homeostasis.

Extracellular fluids, including blood, lymphatic fluid, and cerebrospinal fluid, are collectively called body fluids. The Na+ concentration ([Na+]) in body fluids is maintained at 135–145 mM and is broadly conserved among terrestrial animals. Homeostatic osmoregulation by Na+ is vital for life because severe hyper- or hypotonicity elicits irreversible organ damage and lethal neurological trauma. To achieve “body fluid homeostasis” or “Na homeostasis”, the brain continuously monitors [Na+] in body fluids and controls water/salt intake and water/salt excretion by the kidneys. These physiological functions are primarily regulated based on information on [Na+] and relevant circulating hormones, such as angiotensin II, aldosterone, and vasopressin. In this review, we discuss sensing mechanisms for [Na+] and hormones in the brain that control water/salt intake behaviors, together with the responsible sensors (receptors) and relevant neural pathways. We also describe mechanisms in the brain by which [Na+] increases in body fluids activate the sympathetic neural activity leading to hypertension.

Recruiting "clean" chronic insomnia participants: the unicorn of sleep research.

Recruiting "clean" chronic insomnia participants: the unicorn of sleep research.

Associations of Reduced Sympathetic Neural Activity and Elevated Baroreflex Sensitivity With Non-Rapid Eye Movement Sleep: Evidence From Electroencephalogram- and Electrocardiogram-Based Sleep Staging.

Autonomic neural controls in sleep regulation have been previously demonstrated; however, whether these alternations can be observed by different sleep staging approaches remains unclear. Two established methods for sleep staging-the standardized visual scoring and the cardiopulmonary coupling (CPC) analysis based on electrocardiogram-were used to explore the cardiovascular profiles of sleep. Overnight polysomnography was recorded together with continuous beat-to-beat blood pressure. Cortical activity, heart rate variability, blood pressure variability, and baroreflex sensitivity during sleep stages from 24 nights of sleep were obtained from 15 normotensive participants and analyzed. Non-rapid eye movement sleep (NREM) from visual scoring and restful sleep (RS) of CPC both showed the highest delta power of electroencephalogram (EEG) and lowest beta activity of EEG in comparison with other sleep stages (p < .001); likewise, the lowest total power of heart rate variability and suppressed vascular-sympathetic activity, reflected by low-frequency power of blood pressure variability, as well as a trend in elevated baroreflex sensitivity, were observed in the NREM or RS. This suppressed vascular-sympathetic activity during stable sleep further exhibited a significant correlation with increased slow-wave activity (NREM: r = -0.292 ± 0.34, p = .002; RS: r = -0.209 ± 0.30, p = .010). Autonomic nervous system is evidently associated with stable sleep, as indicated by the similar findings obtained from sleep stages categorized by standardized visual scoring or CPC analysis. Such association between cardiovascular neural activity and sleep EEGs can be observed regardless of the sleep staging approach followed.