Monocyte-Derived Macrophages Aggravate Cardiac Dysfunction After Ischemic Stroke in Mice.

BACKGROUND: Cardiac damage induced by ischemic stroke, such as arrhythmia, cardiac dysfunction, and even cardiac arrest, is referred to as cerebral-cardiac syndrome (CCS). Cardiac macrophages are reported to be closely associated with stroke-induced cardiac damage. However, the role of macrophage subsets in CCS is still unclear due to their heterogeneity. Sympathetic nerves play a significant role in regulating macrophages in cardiovascular disease. However, the role of macrophage subsets and sympathetic nerves in CCS is still unclear. METHODS AND RESULTS: In this study, a middle cerebral artery occlusion mouse model was used to simulate ischemic stroke. ECG and echocardiography were used to assess cardiac function. We used Cx3cr1GFPCcr2RFP mice and NLRP3-deficient mice in combination with Smart-seq2 RNA sequencing to confirm the role of macrophage subsets in CCS. We demonstrated that ischemic stroke-induced cardiac damage is characterized by severe cardiac dysfunction and robust infiltration of monocyte-derived macrophages into the heart. Subsequently, we identified that cardiac monocyte-derived macrophages displayed a proinflammatory profile. We also observed that cardiac dysfunction was rescued in ischemic stroke mice by blocking macrophage infiltration using a CCR2 antagonist and NLRP3-deficient mice. In addition, a cardiac sympathetic nerve retrograde tracer and a sympathectomy method were used to explore the relationship between sympathetic nerves and cardiac macrophages. We found that cardiac sympathetic nerves are significantly activated after ischemic stroke, which contributes to the infiltration of monocyte-derived macrophages and subsequent cardiac dysfunction. CONCLUSIONS: Our findings suggest a potential pathogenesis of CCS involving the cardiac sympathetic nerve-monocyte-derived macrophage axis.

Sympathetic Neurofunction Testing in Gestational Hypertension and Relationship with Developing Preeclampsia and Eclampsia: Real-world Evidences from Clinical Pharmacology Clinics.

BACKGROUND: Gestational hypertension carries a high-risk for adverse maternal and fetal outcomes, and it can also develop into preeclampsia. A relative decrease in parasympathetic and increase in sympathetic activity has been seen in normal pregnancy which returns to baseline after delivery. The present study aimed to detect any abnormality in sympathetic neurofunction in gestational hypertension and to identify its possible association with the development of preeclampsia/eclampsia. METHODS: A prospective, observational study was carried out among gestational hypertensive patients between 24 and 26 weeks of gestation, who were sent to clinical pharmacology clinics for autonomic neurofunction testing, along with their 24-hour urinary protein testing reports. Preisometric handgrip (IHG) and post-IHG differences in diastolic blood pressure (DBP) were noted. The association between Δ DBP and the development of eclampsia/preeclampsia was probed. RESULTS: A total of 52 pregnancy-induced hypertension (PIH) participants, both multigravida (n = 15) and primigravida (n = 37) were included in one arm (PIH arm), and 52 matched (age and gravida) pregnant women, those do not have PIH included in another arm for comparative analysis. On comparing the PIH arm and normal arm, prehand grip DBP (p ≤ 0.0001), posthand grip DBP, and Δ DBP were significantly higher in the PIH arm. Correlation between Δ DBP and 24 hours' proteinuria was observed in the PIH arm, with a significant positive correlation. CONCLUSION: A high-rise in DBP post-IHG exercise is associated with gestational hypertensive mothers and this rise is strongly correlated with the development of preeclampsia and eclampsia, which suggests that addressing sympathetic hyperactivity could be a potential area to target therapeutics while managing gestational hypertension.

Biomarker Periodic Repolarization Dynamics Indicates Enhanced Risk for Arrhythmias and Sudden Cardiac Death in Myocardial Infarction in Pigs.

BACKGROUND: Periodic repolarization dynamics (PRD) is an electrocardiographic biomarker that captures repolarization instability in the low frequency spectrum and is believed to estimate the sympathetic effect on the ventricular myocardium. High PRD indicates an increased risk for postischemic sudden cardiac death (SCD). However, a direct link between PRD and proarrhythmogenic autonomic remodeling has not yet been shown. METHODS AND RESULTS: We investigated autonomic remodeling in pigs with myocardial infarction (MI)-related ischemic heart failure induced by balloon occlusion of the left anterior descending artery (n=17) compared with pigs without MI (n=11). Thirty days after MI, pigs demonstrated enhanced sympathetic innervation in the infarct area, border zone, and remote left ventricle paralleled by altered expression of autonomic marker genes/proteins. PRD was enhanced 30 days after MI compared with baseline (pre-MI versus post-MI: 1.75±0.30 deg2 versus 3.29±0.79 deg2, P<0.05) reflecting pronounced autonomic alterations on the level of the ventricular myocardium. Pigs with MI-related ventricular fibrillation and SCD had significantly higher pre-MI PRD than pigs without tachyarrhythmias, suggesting a potential role for PRD as a predictive biomarker for ischemia-related arrhythmias (no ventricular fibrillation versus ventricular fibrillation: 1.50±0.39 deg2 versus 3.18±0.53 deg2 [P<0.05]; no SCD versus SCD: 1.67±0.32 deg2 versus 3.91±0.63 deg2 [P<0.01]). CONCLUSIONS: We demonstrate that ischemic heart failure leads to significant proarrhythmogenic autonomic remodeling. The concomitant elevation of PRD levels in pigs with ischemic heart failure and pigs with MI-related ventricular fibrillation/SCD suggests PRD as a biomarker for autonomic remodeling and as a potential predictive biomarker for ventricular arrhythmias/survival in the context of MI.

Decreased levels of hydrogen sulfide in the hypothalamic paraventricular nucleus contribute to sympathetic hyperactivity induced by cerebral infarction.

Paroxysmal sympathetic hyperactivity (PSH) is a common clinical feature secondary to ischemic stroke (IS), but its mechanism is poorly understood. We aimed to investigate the role of H2S in the pathogenesis of PSH. IS patients were divided into malignant (MCI) and non-malignant cerebral infarction (NMCI) group. IS in rats was induced by the right middle cerebral artery occlusion (MCAO). H2S donor (NaHS) or inhibitor (aminooxy-acetic acid, AOAA) were microinjected into the hypothalamic paraventricular nucleus (PVN). Compared with the NMCI group, patients in the MCI group showed PSH, including tachycardia, hypertension, and more plasma norepinephrine (NE) that was positively correlated with levels of creatine kinase, glutamate transaminase, and creatinine respectively. The 1-year survival rate of patients with high plasma NE levels was lower. The hypothalamus of rats with MCAO showed increased activity, especially in the PVN region. The levels of H2S in PVN of the rats with MCAO were reduced, while the blood pressure and renal sympathetic discharge were increased, which could be ameliorated by NaHS and exacerbated by AOAA. NaHS completely reduced the disulfide bond of NMDAR1 in PC12 cells. The inhibition of NMDAR by MK-801 microinjected in PVN of rats with MCAO also could lower blood pressure and renal sympathetic discharge. In conclusion, PSH may be associated with disease progression and survival in patients with IS. Decreased levels of H2S in PVN were involved in regulating sympathetic efferent activity after cerebral infarction. Our results might provide a new strategy and target for the prevention and treatment of PSH.

Chronic nicotine exposure is associated with electrophysiological and sympathetic remodeling in the intact rabbit heart.

Nicotine is the primary addictive component of tobacco products. Through its actions on the heart and autonomic nervous system, nicotine exposure is associated with electrophysiological changes and increased arrhythmia susceptibility. To assess the underlying mechanisms, we treated rabbits with transdermal nicotine (NIC, 21 mg/day) or control (CT) patches for 28 days before performing dual optical mapping of transmembrane potential (RH237) and intracellular Ca2+ (Rhod-2 AM) in isolated hearts with intact sympathetic innervation. Sympathetic nerve stimulation (SNS) was performed at the first to third thoracic vertebrae, and ß-adrenergic responsiveness was additionally evaluated following norepinephrine (NE) perfusion. Baseline ex vivo heart rate (HR) and SNS stimulation threshold were higher in NIC versus CT (P = 0.004 and P = 0.003, respectively). Action potential duration alternans emerged at longer pacing cycle lengths (PCL) in NIC versus CT at baseline (P = 0.002) and during SNS (P = 0.0003), with similar results obtained for Ca2+ transient alternans. SNS shortened the PCL at which alternans emerged in CT but not in NIC hearts. NIC-exposed hearts tended to have slower and reduced HR responses to NE perfusion, but ventricular responses to NE were comparable between groups. Although fibrosis was unaltered, NIC hearts had lower sympathetic nerve density (P = 0.03) but no difference in NE content versus CT. These results suggest both sympathetic hypoinnervation of the myocardium and regional differences in ß-adrenergic responsiveness with NIC. This autonomic remodeling may contribute to the increased risk of arrhythmias associated with nicotine exposure, which may be further exacerbated with long-term use.NEW & NOTEWORTHY Here, we show that chronic nicotine exposure was associated with increased heart rate, increased susceptibility to alternans, and reduced sympathetic electrophysiological responses in the intact rabbit heart. We suggest that this was due to sympathetic hypoinnervation of the myocardium and diminished ß-adrenergic responsiveness of the sinoatrial node following nicotine treatment. Though these differences did not result in increased arrhythmia propensity in our study, we hypothesize that prolonged nicotine exposure may exacerbate this proarrhythmic remodeling.

Neuroimmune modulation mediated by IL-6: A potential target for the treatment of ischemia-induced ventricular arrhythmias.

BACKGROUND: Neural remodeling in the left stellate ganglion (LSG), as mediated by neuroimmune reactions, promotes cardiac sympathetic nerve activity (SNA) and thus increases the incidence of ventricular arrhythmias (VAs). Interleukin-6 (IL-6) is an important factor of the neuroimmune interaction. OBJECTIVE: The present study explored the effects of IL-6 on LSG hyperactivity and the incidence of VAs. METHODS: Eighteen beagles were randomly allocated to a control group (saline with myocardial infarction [MI], n = 6), adeno-associated virus (AAV) group (AAV with MI, n = 6), and IL-6 group (overexpression of IL-6 via AAV vector with MI, n = 6). Ambulatory electrocardiography was performed before and 30 days after AAV microinjection into the LSG. LSG function and ventricular electrophysiology were assessed at 31 days after surgery, and a canine MI model was established. Samples of the LSG were collected for immunofluorescence staining and molecular biological evaluation. Blood samples and 24-hour Holter data were obtained from 24 patients with acute MI on the day after they underwent percutaneous coronary intervention to assess the correlation between IL-6 levels and SNA. RESULTS: IL-6 overexpression increased cardiac SNA and worsened postinfarction VAs. Furthermore, sustained IL-6 overexpression enhanced LSG function, promoted expression of nerve growth factor, c-fos, and fos B in the LSG, and activated the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway. Clinical sample analysis revealed a correlation between serum IL-6 levels and heart rate variability frequency domain index as well as T-wave alternans. CONCLUSION: IL-6 levels are correlated with cardiac SNA. Chronic overexpression of IL-6 mediates LSG neural remodeling through the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway, elevating the risk of VA after MI.

Exaggerated renal sympathetic nerve and pressor responses during spontaneously occurring motor activity in hypertensive rats.

Stimulation of the mesencephalic locomotor region elicits exaggerated sympathetic nerve and pressor responses in spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto rats (WKY). This suggests that central command or its influence on vasomotor centers is augmented in hypertension. The decerebrate animal model possesses an ability to evoke intermittent bouts of spontaneously occurring motor activity (SpMA) and generates cardiovascular responses associated with the SpMA. It remains unknown whether the changes in sympathetic nerve activity and hemodynamics during SpMA are altered by hypertension. To test the hypothesis that the responses in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during SpMA are exaggerated with hypertension, this study aimed to compare the responses in decerebrate, paralyzed SHR, WKY, and normotensive Sprague-Dawley (SD) rats. In all strains, an abrupt increase in RSNA occurred in synchronization with tibial motor discharge (an index of motor activity) and was followed by rises in MAP and heart rate. The centrally evoked increase in RSNA and MAP during SpMA was much greater (306 ± 110%) in SHR than WKY (187 ± 146%) and SD (165 ± 44%). Although resting baroreflex-mediated changes in RSNA were not different across strains, mechanically or pharmacologically induced elevations in MAP attenuated or abolished the RSNA increase during SpMA in WKY and SD but had no effect in SHR. It is likely that the exaggerated sympathetic nerve and pressor responses during SpMA in SHR are induced along a central command pathway independent of the arterial baroreflex and/or result from central command-induced inhibition of the baroreflex.

Diagnosis of colonic dysmotility associated with autonomic dysfunction in patients with chronic refractory constipation.

We report the first study assessing human colon manometric features and their correlations with changes in autonomic functioning in patients with refractory chronic constipation prior to consideration of surgical intervention. High-resolution colonic manometry (HRCM) with simultaneous heart rate variability (HRV) was performed in 14 patients, and the resulting features were compared to healthy subjects. Patients were categorized into three groups that had normal, weak, or no high amplitude propagating pressure waves (HAPWs) to any intervention. We found mild vagal pathway impairment presented as lower HAPW amplitude in the proximal colon in response to proximal colon balloon distention. Left colon dysmotility was observed in 71% of patients, with features of (1) less left colon HAPWs, (2) lower left colon HAPW amplitudes (69.8 vs 102.3 mmHg), (3) impaired coloanal coordination, (4) left colon hypertonicity in patients with coccyx injury. Patients showed the following autonomic dysfunction: (1) high sympathetic tone at baseline, (2) high sympathetic reactivity to active standing and meal, (3) correlation of low parasympathetic reactivity to the meal with absence of the coloanal reflex, (4) lower parasympathetic and higher sympathetic activity during occurrence of HAPWs. In conclusion, left colon dysmotility and high sympathetic tone and reactivity, more so than vagal pathway impairment, play important roles in refractory chronic constipation and suggests sacral neuromodulation as a possible treatment.

Paroxysmal Sympathetic Hyperactivity in Patients Victims of Traumatic Brain Injury: Literature Review

The present literature review aims to present the physiology of paroxysmal sympathetic hyperactivity (PSH) as well as its clinical course, conceptualizing them, and establishing its diagnosis and treatment. Paroxysmal sympathetic hyperactivity is a rare syndrome, which often presents after an acute traumatic brain injury. Characterized by a hyperactivity of the sympathetic nervous system, when diagnosed in its pure form, its symptomatologic presentation is through tachycardia, tachypnea, hyperthermia, hypertension, dystonia, and sialorrhea. The treatment of PSH is basically pharmacological, using central nervous system suppressors; however, the nonmedication approach is closely associated with a reduction in external stimuli, such as visual and auditory stimuli. Mismanagement can lead to the development of serious cardiovascular and diencephalic complications, and the need for neurosurgeons and neurointensivists to know about PSH is evident in order to provide a fast and accurate treatment of this syndrome.

Sympathovagal equilibrium analysis in patients with COVID-19 / Análisis del equilibrio simpatovagal en pacientes con COVID-19

Introduction: With the increase of COVID-19 cases, an unusual manifestation for this type of virus began to appear anosmia and dysgeusia, which could indicate a neurologic alteration. In this context, it seems likely that subclinical manifestations of baroreflex involvement occur. The vegetative nervous system carries out the regulation of the baroreflex through the balance between sympathetic and parasympathetic activity. The objective of this study is to verify whether patients with COVID-19 present alteration of this equilibrium. Material and methods: Patients included had a confirmed diagnosis of COVID-19 admitted to the Internal Medicine Department of JB Iturraspe Hospital. A Holter recording was performed at rest for 5 minutes, determining the variables in the frequency domain using Fourier transform analysis. We excluded patients with diabetes, medicated with drugs that modify heart rate or with a history of irradiation to the neck. Results: 68 patients were studied. The mean age was 49±13 years. The median systolic blood pressure was 120 mmHg and the diastolic blood pressure 80 mmHg. The heart rate was 76±13 beats per minute and the median respiratory rate was 24 (16 to 40). Anosmia was observed in 22% and dysgeusia in 19% The variables in the frequency domain were: Low-frequency power (LF) 135.8ms2 (13.7-2861.7); High-frequency power (HF), 89.04ms2 (4.1-5234.4), LFnu 57.5±22.3, HFnu 43.1±22.6. LF:HF 2.1±2. 41.2% of the patients had a high LF:HF. Conclusions: LF and HF components can be obtained through frequency analysis. The relationship between these two elements would thus represent the sympathovagal balance and is expressed as the LF/HF ratio. We observed that 41.2% of the studied patients showed elevated LF/HF ratio. The 41.2% of the patients presented an increased LF:HF ratio, which could be interpreted as an alteration in autonomic function (AU)

Introducción: Con el aumento de casos de COVID-19, unas manifestaciones inusuales para este tipo de virus como la anosmia y disgeusia comenzaron a aparecer, lo que podría indicar una alteración neurológica. En este contexto, parece probable que se produzcan manifestaciones subclínicas de afectación barorrefleja. El sistema nervioso vegetativo lleva a cabo la regulación del barorreflejo a través del equilibrio entre la actividad simpática y parasimpática. El objetivo de este estudio es verificar si los pacientes con COVID-19 presentan alteración de este equilibrio. Material y métodos: Se evaluaron pacientes con diagnóstico confirmado de COVID-19 ingresados en el Servicio de Medicina Interna del Hospital JB Iturraspe. Se realizó un registro Holter en reposo durante 5 minutos, determinando las variables en el dominio de la frecuencia mediante análisis por transformada de Fourier. Se excluyeron pacientes con diabetes, medicados con fármacos que modifican la frecuencia cardiaca o con antecedentes de irradiación al cuello. Resultados: Se estudiaron 68 pacientes. La edad media fue de 49±13 años. La mediana de la presión arterial sistólica fue de 120 mmHg y la diastólica de 80 mmHg. La frecuencia cardiaca fue de 76±13 latidos por minuto y la mediana de la frecuencia respiratoria fue de 24 (16 a 40). Se observó anosmia en 22% y disgeusia en 19% Las variables en el dominio frecuencial fueron: Potencia de baja frecuencia (LF) 135,8ms2 (13,7-2861,7); Potencia de alta frecuencia (HF), 89,04 ms2 (4,1-5234,4), LFnu 57,5±22,3, HFnu 43,1±22,6. LF:HF 2.1±2. El 41,2% de los pacientes tenían una relación LF:HF alta. Conclusiones: Los componentes de LF y HF se pueden obtener a través del análisis de frecuencia. La relación entre estos dos elementos representaría así el equilibrio simpatovagal y se expresa como la relación LF/HF (AU)

High-resolution structure-function mapping of intact hearts reveals altered sympathetic control of infarct border zones.

Remodeling of injured sympathetic nerves on the heart after myocardial infarction (MI) contributes to adverse outcomes such as sudden arrhythmic death, yet the underlying structural mechanisms are poorly understood. We sought to examine microstructural changes on the heart after MI and to directly link these changes with electrical dysfunction. We developed a high-resolution pipeline for anatomically precise alignment of electrical maps with structural myofiber and nerve-fiber maps created by customized computer vision algorithms. Using this integrative approach in a mouse model, we identified distinct structure-function correlates to objectively delineate the infarct border zone, a known source of arrhythmias after MI. During tyramine-induced sympathetic nerve activation, we demonstrated regional patterns of altered electrical conduction aligned directly with altered neuroeffector junction distribution, pointing to potential neural substrates for cardiac arrhythmia. This study establishes a synergistic framework for examining structure-function relationships after MI with microscopic precision that has potential to advance understanding of arrhythmogenic mechanisms.

Effect of liver resection-induced increases in hepatic venous pressure gradient on development of postoperative acute kidney injury.

BACKGROUND: The impact of changes in portal pressure before and after liver resection (defined as ΔHVPG) on postoperative kidney function remains unknown. Therefore, we investigated the effect of ΔHVPG on (i) the incidence of postoperative AKI and (ii) the renin-angiotensin system (RAAS) and sympathetic nervous system (SNS) activity. METHODS: We included 30 patients undergoing partial liver resection. Our primary outcome was postoperative AKI according to KDIGO criteria. For our secondary outcome we assessed the plasma renin, aldosterone, noradrenaline, adrenaline, dopamine and vasopressin concentrations prior and 2 h after induction of anaesthesia, on the first and fifth postoperative day. HVPG was measured prior and immediately after liver resection. RESULTS: ΔHVPG could be measured in 21 patients with 12 patients HVPG showing increases in HVPG (∆HVPG≥1 mmHg) while 9 patients remained stable. AKI developed in 7/12 of patients with increasing HVPG, but only in 2/9 of patients with stable ΔHVPG (p = 0.302). Noradrenalin levels were significantly higher in patients with increasing ΔHVPG than in patients with stable ΔHVPG. (p = 0.009). Biomarkers reflecting RAAS and SNS activity remained similar in patients with increasing vs. stable ΔHVPG. CONCLUSIONS: Patients with increased HVPG had higher postoperative creatinine concentrations, however, the incidence of AKI was similar between patients with increased versus stable HVPG.

Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation.

BACKGROUND: Initial orthostatic hypotension (IOH) is defined by a large drop in blood pressure (BP) within 15 s of standing. IOH often presents during an active stand, but not with a passive tilt, suggesting that a muscle activation reflex involving lower body muscles plays an important role. To our knowledge, there is no literature exploring how sympathetic activation affects IOH. We hypothesized involuntary muscle contractions before standing would significantly reduce the drop in BP seen in IOH while increasing sympathetic activity would not. METHODS: Study participants performed 4 sit-to-stand maneuvers including a mental stress test (serial 7 mental arithmetic stress test), cold pressor test, electrical stimulation, and no intervention. Continuous heart rate and beat-to-beat BP were measured. Cardiac output and systemic vascular resistance were estimated from these waveforms. Data are presented as mean±SD. RESULTS: A total of 23 female IOH participants (31±8 years) completed the study. The drops in systolic BP following the serial 7 mental arithmetic stress test (-26±12 mm Hg; P=0.004), cold pressor test (-20±15 mm Hg; P<0.001), and electrical stimulation (-28±12 mm Hg; P=0.01) were significantly reduced compared with no intervention (-34±11 mm Hg). The drops in systemic vascular resistance following the serial 7 mental arithmetic stress test (-391±206 dyne×s/cm5; P=0.006) and cold pressor test (-386±179 dyne×s/cm5; P=0.011) were significantly reduced compared with no intervention (-488±173 dyne×s/cm5). Cardiac output was significantly increased upon standing (7±2 L/min) compared with during the sit (6±1 L/min; P<0.001) for electrical stimulation. CONCLUSION: Sympathetic activation mitigates the BP response in IOH, while involuntary muscle contraction mitigates the BP response and reduces symptoms. Active muscle contractions may induce both of these mechanisms of action in their pretreatment of IOH. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03970551.

Sympathetic neural responses to sleep disorders and insufficiencies.

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

Central sympathetic nerve activation in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a life-threatening condition, and although its two main complications-cerebral vasospasm (CVS)/delayed cerebral ischemia (DCI) and early brain injury (EBI)-have been widely studied, prognosis has not improved over time. The sympathetic nerve (SN) system is important for the regulation of cardiovascular function and is closely associated with cerebral vessels and the regulation of cerebral blood flow and cerebrovascular function; thus, excessive SN activation leads to a rapid breakdown of homeostasis in the brain. In the hyperacute phase, patients with SAH can experience possibly lethal conditions that are thought to be associated with SN activation (catecholamine surge)-related arrhythmia, neurogenic pulmonary edema, and irreversible injury to the hypothalamus and brainstem. Although the role of the SN system in SAH has long been investigated and considerable evidence has been collected, the exact pathophysiology remains undetermined, mainly because the relationships between the SN system and SAH are complicated, and many SN-modulating factors are involved. Thus, research concerning these relationships needs to explore novel findings that correlate with the relevant concepts based on past reliable evidence. Here, we explore the role of the central SN (CSN) system in SAH pathophysiology and provide a comprehensive review of the functional CSN network; brain injury in hyperacute phase involving the CSN system; pathophysiological overlap between the CSN system and the two major SAH complications, CVS/DCI and EBI; CSN-modulating factors; and SAH-related extracerebral organ injury. Further studies are warranted to determine the specific roles of the CSN system in the brain injuries associated with SAH.

Successful continuous positive airway pressure treatment reduces skin sympathetic nerve activity in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with cardiovascular diseases and increased sympathetic tone. We previously demonstrated that patients with OSA have increased skin sympathetic nerve activity (SKNA). OBJECTIVE: The purpose of this study was to test the hypothesis that continuous positive airway pressure (CPAP) treatment reduces SKNA. METHODS: The electrocardiogram, SKNA, and polysomnographic recording were recorded simultaneously in 9 patients with OSA. After baseline recording, CPAP titration was performed and the pressure was adjusted gradually for the optimal treatment, defined by reducing the apnea-hypopnea index (AHI) to ≤5/h. Otherwise the treatment was considered suboptimal (AHI > 5/h). Fast Fourier transform analyses were performed to investigate the frequency spectrum of SKNA. RESULTS: There were very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations in SKNA. The HF oscillation matched the frequency of respiration. OSA episodes were more frequently associated with the VLF and LF than with the HF oscillations of SKNA. Compared with baseline, CPAP significantly decreased the arousal index and AHI and increased the minimal and mean oxyhemoglobin levels. Optimal treatment significantly increased the dominant frequency and reduced the heart rate, average SKNA (aSKNA), SKNA burst duration, and total burst area. The dominant frequency negatively correlated with aSKNA. CONCLUSION: VLF, LF, and HF oscillations are observed in human SKNA recordings. Among them, VLF and LF oscillations are associated with OSA while HF oscillations are associated with normal breathing. CPAP therapy reduces aSKNA and shifts the frequency of SKNA oscillation from VLF or LF to HF.

Effect of extracellular hyperosmolality on sweat rate during metaboreflex activation in passively heated young men.

Metaboreflex activation augments sweating during mild-to-moderate hyperthermia in euhydrated (isosmotic isovolemic) individuals. Recent work indicates that extracellular hyperosmolality may augment metaboreflex-mediated elevations in sympathetic nervous activity. Our primary objective was, therefore, to test the hypothesis that extracellular hyperosmolality would exacerbate metaboreflex-mediated increases in sweat rate. On two separate occasions, 12 young men [means (SD): 25 (5) yr] received a 90-min intravenous infusion of either 0.9% saline (isosmotic condition, ISO) or 3.0% saline (hyperosmotic condition, HYP), resulting in a postinfusion serum osmolality of 290 (3) and 301 (7) mosmol/kgH2O, respectively. A whole body water perfusion suit was then used to increase esophageal temperature by 0.8°C above resting. Participants then performed a metaboreflex activation protocol consisting of 90-s isometric handgrip exercise (40% of their predetermined maximum voluntary contraction), followed by 150 s of brachial occlusion (trapping produced metabolites within the limb). Metaboreflex-induced sweating was quantified as the change in global sweat rate (from preisometric handgrip exercise to brachial occlusion), estimated as the surface area-weighted average of local sweat rate on the abdomen, axilla, chest, bicep, quadriceps, and calf, measured using ventilated capsules (3.8 cm2). We also explored whether this response differed between body regions. The change in global sweat rate due to metaboreflex activation was significantly greater in HYP compared with ISO (0.03 mg/min/cm2 [95% confidence interval: 0.00, 0.06]; P = 0.047), but was not modulated by body region (site × condition interaction: P = 0.679). These findings indicate that extracellular hyperosmolality augments metaboreflex-induced increases in global sweat rate, with no evidence for region-specific differences.