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Abstract Background Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival. Methods In this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20). Results Ex vivo cytokine production capacity of TNF, IL-6 and IL-1β was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1β after BCS (p = .041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p = .045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p = .003 and p = .041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p = .038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1β and TNF on POD3 (r = .408; p = .011 and r = .500; p = .001, respectively). Conclusions This pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation.

Background: Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival. Methods: In this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20). Results: Ex vivo cytokine production capacity of TNF, IL-6 and IL-1β was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1β after BCS (p =.041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p =.045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p =.003 and p =.041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p =.038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1β and TNF on POD3 (r =.408; p =.011 and r =.500; p =.001, respectively). Conclusions: This pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with cardiovascular-related mortality, leading to a higher mortality rate compared the general population. However, few reports have examined cardiovascular events in non-obese MASLD mouse models. Through the present study, we highlight a non-obese steatohepatitis mouse model with cardiac dysfunction produced using co-diet ethanol added to a high-fat/high-cholesterol diet (STHD-01) for 6 or 12 weeks. Incorporating ethanol into the STHD-01 diet regimen intensifies liver issues, such as inflammation and fibrosis, as well as cardiac dysfunction, potentially due to enhanced sympathetic nervous system activity. Alcohol, even when completely metabolized on the day of drinking, is a factor that exacerbates the progression of non-obese MASLD and cardiac dysfunction. Non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with cardiovascular-related mortality, leading to a higher mortality rate compared to the general population. However, few reports have examined cardiovascular events in non-obese MASLD mouse models. In this study we created a mouse model to mimic this condition. In this study involving seven-week-old C57BL/6J male mice, two dietary conditions were tested: a standard high-fat/high-cholesterol diet (STHD-01) and a combined diet of STHD-01 and ethanol. Over periods of 6 and 12 weeks, we analyzed the effects on liver and cardiac tissues using various staining techniques and PCR. Echocardiography and blood tests were also performed to assess cardiac function and liver damage. The results showed that mice on the ethanol-supplemented STHD-01 diet developed signs of steatohepatitis and cardiac dysfunction, along with increased sympathetic activity, as early as 6 weeks. At 12 weeks, more pronounced exacerbations accompanied with cardiac dilation, advanced liver fibrosis, and activated myocardial fibrosis with sympathetic activation were observed. This mouse model effectively replicated non-obese MASLD and cardiac dysfunction over a 12-week period using a combined diet of STHD-01 and ethanol. This dietary approach highlighted that both liver inflammation and fibrosis, as well as cardiac dysfunction, could be significantly worsened due to the activation of the sympathetic nervous system. Our results indicate that alcohol, even when completely metabolized on the day of drinking, exacerbates the progression of non-obese MASLD and cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Suppression (i.e., inhibiting one's emotional expression) has typically been associated with social and physiological costs. However, recent theorizing calls into question the inevitability of these costs. The present study takes a more nuanced approach and examines the social and physiological correlates of spontaneous (i.e., uninstructed) suppression when considering two potentially critical factors: the valence of the suppressed emotions (i.e., negative vs. positive) and the valence of the emotional context in which emotions are suppressed (i.e., negative conversation vs. positive conversation). Specifically, dating couples (N = 196 couples) completed both a negatively-valenced and a positively-valenced conversation in the laboratory while their autonomic-physiological responses were recorded. After each conversation, participants rated 1) the extent to which they had suppressed their negative and positive emotions, 2) the quality of the conversation, and 3) how connected they felt with their partner. We used Actor-Partner Interdependence Models to estimate actor effects (e.g., association of one's own suppression and one's own connectedness) and partner effects (e.g., association of one's partner's suppression and one's own connectedness). Suppression was associated with lower conversation quality and connectedness for the actors but largely not for the partners, regardless of the valence of the suppressed emotions and of the context, even when adjusting for felt emotion. Additionally, suppression was consistently not associated with physiological responses of actors or partners. Together, these findings suggest that, during emotional conversations with one's romantic partner, spontaneous (unlike instructed) suppression is associated with social but not physiological costs for the self but not one's partner.

Maternal obesity increases the risk of adverse pregnancy outcomes. The mechanisms that contribute to this elevated risk are unclear but may be related to greater activity of the sympathetic nervous system, which is associated with hypertensive disorders of pregnancy. We hypothesized that resting muscle sympathetic nerve activity (MSNA) would be greater in women with obesity during pregnancy when compared with normal-weight women. Blood pressure, heart rate, and MSNA were recorded during 5 min of supine rest in 14 normal-weight women [body mass index (BMI) 22.1 ± 2.1 (SD) kg/m²] and 14 women with obesity (BMI 33.9 ± 3.5 kg/m²) during (early and late) pregnancy and postpartum. All women had uncomplicated pregnancies. Resting MSNA burst frequency was not different between groups during early (normal weight 17 ± 10 vs. obesity 22 ± 15 bursts/min, P = 0.35) but was significantly greater in the obesity group during late pregnancy (23 ± 13 vs. 35 ± 15 bursts/min, P = 0.031) and not different postpartum (10 ± 6 vs. 9 ± 7 bursts/min, P = 0.74). These findings were also apparent when comparing burst incidence and total activity. Although still within the normotensive range, systolic blood pressure was greater in the obesity group across all time points (P = 0.002). Diastolic blood pressure was lower during pregnancy compared with postpartum (P < 0.001) and not different between groups (P = 0.488). Heart rate increased throughout pregnancy in both groups (P < 0.001). Our findings suggest that maternal obesity is associated with greater increases in sympathetic activity even during uncomplicated pregnancy. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy. NEW & NOTEWORTHY The impact of maternal obesity on resting muscle sympathetic nerve activity was examined during (early and late) and after uncomplicated pregnancy. Resting muscle sympathetic nerve activity is not different during early pregnancy or postpartum but is significantly elevated in women with obesity during late pregnancy when compared with normal-weight women. Future research is needed to determine if this is linked with an increased risk of adverse outcomes or is required to maintain homeostasis in pregnancy. [ABSTRACT FROM AUTHOR]

Objectives: Yokukansan (YKS) is a traditional Japanese Kampo medicine approved by the Ministry of Health, Labour and Welfare of Japan. Recently, in addition to its indications as a drug treatment, YKS has been shown to have ameliorative effects on various psychological and behavioral responses such as anxiety, aggression, and stress responses. Stress exposure activates not only the hypothalamic-pituitary-adrenal axis but also the sympathetic nervous system. Sympathetic activation in brain regions such as the paraventricular hypothalamic nucleus (PVN) stimulates elevation of plasma catecholamine (noradrenaline and adrenaline) levels. We previously reported that various stress-related neuropeptides and several kinds of stressors, such as restraint stress (RS), increase plasma catecholamine and that brain prostanoids and their synthases mediate these responses in rats. In the present study, to determine if YKS treatment can affect stress-induced sympathetic activation, we examined the effects of YKS treatment on the RSinduced elevation of plasma catecholamine levels and related prostanoid production in the PVN of rats. Methods: YKS (1000 mg/10 mL/kg, p.o.) or vehicle was administered to rats daily for 14 days, and all rats were exposed to RS for 60 min on day 14. Before and during stress exposure on day 14, blood samples and PVN dialysates were collected and analyzed by high-performance liquid chromatography and liquid chromatography-ion trap tandem mass spectrometry, respectively. Results: Our results showed that repeated administration of YKS suppressed the RS-induced increase in plasma adrenaline but not noradrenaline. Furthermore, YKS administration also suppressed the RS-induced elevation of both prostaglandin E2 and thromboxane B2 levels in the PVN. In addition, we found that repeated administration of YKS suppressed the RS-induced increase in serotonin, gamma-aminobutyric acid, and acetylcholine in the PVN. Conclusion: Our results suggest that YKS can ameliorate stress-induced sympathetic activation via inhibition of stress responses in the brain. [ABSTRACT FROM AUTHOR]

A prevalent condition linked to an elevated risk of cardiovascular disease is sleep apnea. This review examines the connections between cardiac risk, the sympathetic nervous system, and sleep apnea. The increased risk of hypertension, arrhythmias, myocardial infarction, and heart failure was highlighted in the pathophysiology of sleep apnea and its effect on sympathetic activation. It is also important to consider potential processes such as oxidative stress, inflammation, endothelial dysfunction, and autonomic imbalance that may relate sleep apnea-induced sympathetic activation to cardiac risk. With implications for creating innovative diagnostic and treatment approaches to lessen the cardiovascular effects of sleep apnea, the goal of this investigation is to improve the understanding of the intricate link between sympathetic activity, cardiac risk, and sleep apnea. This study aimed to clarify the complex relationship between cardiovascular health and sleep apnea by synthesizing the available research and highlighting the crucial role played by the sympathetic nervous system in moderating this relationship. Our thorough investigation may have important therapeutic ramifications that will direct the creation of focused therapies to enhance cardiovascular outcomes in sleep apnea sufferers.

Introduction: There are 1.5 million new mild traumatic brain injuries (mTBI) annually in the US, with many of the injured experiencing long-term consequences lasting months after the injury. Although the post injury mechanisms are not well understood, current knowledge indicates peripheral immune system activation as a causal link between mTBI and long-term side effects. Through a variety of mechanisms, peripheral innate immune cells are recruited to the CNS after TBI to repair and heal the injured tissue; however, the recruitment and activation of these cells leads to further inflammation. Emerging evidence suggests sympathetic nervous system (SNS) activity plays a substantial role in the recruitment of immune cells post injury. Methods: We sought to identify the peripheral innate immune response after repeated TBIs in addition to repurposing the nonselective beta blocker propranolol as a novel mTBI therapy to limit SNS activity and mTBI pathophysiology in the mouse. Mice underwent repetitive mTBI or sham injury followed by i.p. saline or propranolol. Isolated mRNA derived from femur bone marrow of mice was assayed for changes in gene expression at one day, one week, and four weeks using Nanostring nCounter® stem cell characterization panel. Results: Differential gene expression analysis for bone marrow uncovered significant changes in many genes following drug alone, mTBI alone and drug combined with mTBI. Discussion: Our data displays changes in mRNA at various timepoints, most pronounced in the mTBI propranolol group, suggesting a single dose propranolol injection as a viable future mTBI therapy in the acute setting. [ABSTRACT FROM AUTHOR]

Objective: Cardiovascular events show morning preference and sex differences, and are related to aging and type 2 diabetes. We assessed circadian variations and sex differences in vascular conductance (VC) and blood flow (BF) regulations following a brief bout of forearm ischemia. Methods: Young healthy individuals (H18‐30) and elderly without (H50‐80) and with type 2 diabetes (T2DM50‐80) of both sexes were included. Forearm VC and BF, and mean arterial pressure (MAP) at baseline and following circulatory reperfusion were measured at 6 a.m. and 9 p.m. Results: In the morning compared to evening, following reperfusion, the VC and BF increments were similar in H18‐30 (p>.71), but lower in H50‐80 (p<.001) and T2DM50‐80 (p<.01). VC and BF following circulatory reperfusion were higher in men than women in H18‐30 (p<.001), but similar between sexes in the older groups (p>.23). Conclusions: Forearm vasodilation following reperfusion is attenuated in the morning in the elderly, impairing BF towards an ischemic area. Diabetes does not affect the circadian regulation of VC and BF, but that of MAP. There are sex differences in VC and BF at baseline and after circulatory reperfusion at a young age, being greater in men, which disappear with aging without being affected by diabetes. [ABSTRACT FROM AUTHOR]

Non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with cardiovascular-related mortality, leading to a higher mortality rate compared to the general population. However, few reports have examined cardiovascular events in non-obese MASLD mouse models. In this study we created a mouse model to mimic this condition. In this study involving seven-week-old C57BL/6J male mice, two dietary conditions were tested: a standard high-fat/high-cholesterol diet (STHD-01) and a combined diet of STHD-01 and ethanol. Over periods of 6 and 12 weeks, we analyzed the effects on liver and cardiac tissues using various staining techniques and PCR. Echocardiography and blood tests were also performed to assess cardiac function and liver damage. The results showed that mice on the ethanol-supplemented STHD-01 diet developed signs of steatohepatitis and cardiac dysfunction, along with increased sympathetic activity, as early as 6 weeks. At 12 weeks, more pronounced exacerbations accompanied with cardiac dilation, advanced liver fibrosis, and activated myocardial fibrosis with sympathetic activation were observed. This mouse model effectively replicated non-obese MASLD and cardiac dysfunction over a 12-week period using a combined diet of STHD-01 and ethanol. This dietary approach highlighted that both liver inflammation and fibrosis, as well as cardiac dysfunction, could be significantly worsened due to the activation of the sympathetic nervous system. Our results indicate that alcohol, even when completely metabolized on the day of drinking, exacerbates the progression of non-obese MASLD and cardiac dysfunction.

IntroductionThere are 1.5 million new mild traumatic brain injuries (mTBI) annually in the US, with many of the injured experiencing long-term consequences lasting months after the injury. Although the post injury mechanisms are not well understood, current knowledge indicates peripheral immune system activation as a causal link between mTBI and long-term side effects. Through a variety of mechanisms, peripheral innate immune cells are recruited to the CNS after TBI to repair and heal the injured tissue; however, the recruitment and activation of these cells leads to further inflammation. Emerging evidence suggests sympathetic nervous system (SNS) activity plays a substantial role in the recruitment of immune cells post injury.MethodsWe sought to identify the peripheral innate immune response after repeated TBIs in addition to repurposing the nonselective beta blocker propranolol as a novel mTBI therapy to limit SNS activity and mTBI pathophysiology in the mouse. Mice underwent repetitive mTBI or sham injury followed by i.p. saline or propranolol. Isolated mRNA derived from femur bone marrow of mice was assayed for changes in gene expression at one day, one week, and four weeks using Nanostring nCounter® stem cell characterization panel.ResultsDifferential gene expression analysis for bone marrow uncovered significant changes in many genes following drug alone, mTBI alone and drug combined with mTBI.DiscussionOur data displays changes in mRNA at various timepoints, most pronounced in the mTBI propranolol group, suggesting a single dose propranolol injection as a viable future mTBI therapy in the acute setting.

Sowohl im Tier- als auch Menschenversuch wurde gezeigt, wie emotionaler Stress sich auf myofasziale Eigenschaften auswirkt. Erst in den letzten Jahren wendet sich die Forschung hierbei gezielt den zahlreichen sympathischen Nervenendigungen in den Faszien zu. Es wird vermutet, dass diese Nervenendigungen nicht nur die Mikrozirkulation regulieren, sondern auch mit dem Immunsystem interagieren. Fasziale Fibroblasten wirken als notwendige Teamplayer im Zusammenspiel zwischen Emotionen, Vegetativum, Immunsystem, Entzündungsreaktion und dem enterischen sowie faszialen Mikrobiom. Erste manualtherapeutische Tierversuche deuten an, über welche pro- und antientzündlichen Botenstoffe eine positive Wirkung auf dieses dynamische Wechselspiel bewirkt werden kann. Both animal and human experiments have shown how emotional stress affects myofascial properties. Only in recent years has research turned to the numerous sympathetic nerve endings in the fascia. It is believed that these not only regulate microcirculation, but also interact with the immune system. Fascial fibroblasts act as necessary team players in the interplay between emotions, the autonomic nervous system, immune regulation, the inflammatory response, and the enteric as well as fascial microbiome. First manualtherapeutic animal experiments indicate which pro- and anti-inflammatory messenger substances tend to express positive effects on this dynamic interplay. [ABSTRACT FROM AUTHOR]

Key pointsCardiac electrophysiology and Ca2+ handling change rapidly during the fight-or-flight response to meet physiological demands. Despite dramatic differences in cardiac electrophysiology, the cardiac fight-or-flight response is highly conserved across species. In this study, we performed physiological sympathetic nerve stimulation (SNS) while optically mapping cardiac action potentials and intracellular Ca2+ transients in innervated mouse and rabbit hearts. Despite similar heart rate and Ca2+ handling responses between mouse and rabbit hearts, we found notable species differences in spatio-temporal repolarization dynamics during SNS. Species-specific computational models revealed that these electrophysiological differences allowed for enhanced Ca2+ handling (i.e. enhanced inotropy) in each species, suggesting that electrophysiological responses are fine-tuned across species to produce optimal cardiac fight-or-flight responses.AbstractSympathetic activation of the heart results in positive chronotropy and inotropy, which together rapidly increase cardiac output. The precise mechanisms that produce the electrophysiological and Ca2+ handling changes underlying chronotropic and inotropic responses have been studied in detail in isolated cardiac myocytes. However, few studies have examined the dynamic effects of physiological sympathetic nerve activation on cardiac action potentials (APs) and intracellular Ca2+ transients (CaTs) in the intact heart. Here, we performed bilateral sympathetic nerve stimulation (SNS) in fully innervated, Langendorff-perfused rabbit and mouse hearts. Dual optical mapping with voltage- and Ca2+ -sensitive dyes allowed for analysis of spatio-temporal AP and CaT dynamics. The rabbit heart responded to SNS with a monotonic increase in heart rate (HR), monotonic decreases in AP and CaT duration (APD, CaTD), and a monotonic increase in CaT amplitude. The mouse heart had similar HR and CaT responses; however, a pronounced biphasic APD response occurred, with initial prolongation (50.9 ± 5.1 ms at t = 0 s vs. 60.6 ± 4.1 ms at t = 15 s, P

Introduction: An impact of the sympathetic nervous system in the higher rate of cardiovascular events in the early morning compared to the evening has been claimed. Augmented sympathetic vasoconstriction increases cardiovascular risk by augmenting pulse pressure and cardiac afterload. Type 2 diabetes (T2DM) further increases sympathetic neurovascular transduction and cardiovascular risk. Aim: We assessed whether peripheral vasoconstriction triggered by a standardized sympathetic stressor is augmented at 6am vs 9pm in adults between 50–80 years with type 2 diabetes (T2DM50-80) vs healthy ones (H50-80). Methods: Mean values of sympathetic vasoconstrictor responsiveness (SVR), vascular conductance (VC), brachial artery blood flow, and mean arterial pressure were measured on the contralateral forearm over two 5-minute bouts of rest and handgrip-mediated sympathetic stimulation, respectively. Results: Although baseline VC values were lower (p < 0.01) in the morning vs evening in both groups, SVR values in response to sympathoexcitation were similar in H50-80 (− 0.43 ± 12.44 vs − 2.57 ± 11.63 %, p = 0.73) and T2DM50-80 (+6.64 ± 10.67 vs +5.21 ± 7.64 %, p = 0.90), but higher (p < 0.01) in T2DM50-80 vs H50-80 at both day hours. Individuals with T2DM reported positive SVR values and VC change-scores, while healthy individuals reported statistically different (p < 0.02) negative SVR values and VC change-scores. Conclusion: Peripheral vasoconstriction triggered by a standardized sympathetic stressor is similar between morning and evening, regardless of T2DM and different baseline VC values. However, peripheral vasoconstriction responsiveness is blunted in individuals with T2DM as handgrip-mediated sympathoexcitation induces vasodilation in the contralateral forearm in adults with T2DM and vasoconstriction in healthy age-matched controls, highlighting a neurovascular response altered by T2DM. [ABSTRACT FROM AUTHOR]

Purpose: Augmented central arterial stiffness (CAS) increases cardiovascular risk. CAS can be augmented by physical exercise and sympathetic activation (SYMP) induced by stressful stimuli. Interestingly, sympathetic vasoconstriction triggered by a sympathetic stimulant is augmented immediately after a strenuous half-marathon compared to at rest. This study assessed whether CAS also augments more post- than pre-half-marathon in response to SYMP. Such assessment takes on relevance considering the growing popularity of strenuous, long-distance endurance exercises. Methods: 13 healthy recreational runners (age 46.1 ± 6.5 years; V ′ O 2 max 54.23 ± 9.31 mlO2/min/kg) provided the following measurements prior to and within 10 min following a strenuous half-marathon: beat-by-beat aortic pulse wave velocity (aPWV; index of CAS), mean blood pressure, and heart rate assessment. Measures were performed at rest and during a 2 min handgrip-mediated SYMP. The effects of the half-marathon and SYMP were assessed by two-way repeated-measures ANOVA. Results: Measurements of the aPWV pre- and post-race were not significantly different (7.5 ± 0.8 vs 7.8 ± 0.8 m/s, p = 0.34; pre- vs post-race). 2 min of SYMP increased the baseline aPWV post-race (7.8 ± 0.8 vs 8.4 ± 0.8, p = 0.003; rest vs SYMP) but not pre-race (7.5 ± 0.8 vs 7.9 ± 0.9, p = 0.21). Conclusion: The baseline aPWV assessed 7 to 8 min after a strenuous half-marathon is similar to that pre-race in healthy runners. This agrees with previous studies suggesting CAS being at or below resting values > 5 min following completion of aerobic exercises. The same sympathetic stressor augments CAS to a greater extent 8–10 min post-race than pre-race, suggesting a greater post-exercise stiffening of central artery segments triggered by the same task. [ABSTRACT FROM AUTHOR]

Despite the contemporary treatment of acute coronary syndromes, arrhythmic complications occurring prior to medical attendance remain significant, mandating in-depth understanding of the underlying mechanisms. Sympathetic activation has long been known to play a key role in the pathophysiology of ischemia-induced arrhythmias, but the regulating factors remain under investigation. Several lines of evidence implicate the endothelin system (a family of three isopeptides and two specific receptors) as an important modulator of sympathetic activation in the setting of acute coronary syndromes. Such interaction is present in the heart and in the adrenal medulla, whereas less is known on the effects of the endothelin system on the central autonomic network. This article summarizes the current state-of-the-art, placing emphasis on early-phase arrhythmogenesis, and highlights potential areas of future research. [ABSTRACT FROM AUTHOR]

Suppression (i.e., inhibiting one's emotional expression) has typically been associated with social and physiological costs. However, recent theorizing calls into question the inevitability of these costs. The present study takes a more nuanced approach and examines the social and physiological correlates of spontaneous (i.e., uninstructed) suppression when considering two potentially critical factors: the valence of the suppressed emotions (i.e., negative vs. positive) and the valence of the emotional context in which emotions are suppressed (i.e., negative conversation vs. positive conversation). Specifically, dating couples (N = 196 couples) completed both a negatively-valenced and a positively-valenced conversation in the laboratory while their autonomic-physiological responses were recorded. After each conversation, participants rated 1) the extent to which they had suppressed their negative and positive emotions, 2) the quality of the conversation, and 3) how connected they felt with their partner. We used Actor-Partner Interdependence Models to estimate actor effects (e.g., association of one's own suppression and one's own connectedness) and partner effects (e.g., association of one's partner's suppression and one's own connectedness). Suppression was associated with lower conversation quality and connectedness for the actors but largely not for the partners, regardless of the valence of the suppressed emotions and of the context, even when adjusting for felt emotion. Additionally, suppression was consistently not associated with physiological responses of actors or partners. Together, these findings suggest that, during emotional conversations with one's romantic partner, spontaneous (unlike instructed) suppression is associated with social but not physiological costs for the self but not one's partner. • We measured spontaneous suppression in negative and positive in-lab conversations. • We measured spontaneous suppression of negative and positive emotions. • Spontaneous suppression was linked with worse social outcomes for the self. • Spontaneous suppression was not robustly linked with social outcomes for the partner. • Spontaneous suppression was not linked with physiological activation. [ABSTRACT FROM AUTHOR]

Aim: Sepsis results in high mortality and is associated with organ dysfunction caused by infection. The present study aimed to elucidate whether early-stage sympathetic activation is associated with the prognosis of sepsis and its possible mechanisms., Methods: Patients with sepsis and healthy controls were included. Sepsis in rats was induced by lipopolysaccharide. Dexmedetomidine, a α2-adrenergic receptor agonist, was used in patients and rats with sepsis to evaluate the role of the sympathetic nervous system in sepsis. Holter monitoring was used to detect heart rate variability, while plasma samples were obtained to measure levels of norepinephrine and inflammatory markers. Mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded. Immunofluorescence was used to detect the activation of neurons in the rostral ventrolateral medulla (RVLM)., Results: In patients with sepsis, plasma levels of norepinephrine and interleukin-1β were higher compared with those in controls and positively correlated with acute physiology and chronic health evaluation (APACHEII). SDNN and SDANN were significantly reduced as well as negatively correlated with APACHEII. Meanwhile, rats with sepsis showed increased of sympathetic outflow and plasma levels of norepinephrine, with increased c-fos levels in the RVLM. Treatment with dexmedetomidine could improve prognosis. Lesion of tyrosine hydroxylase-positive neurons in the RVLM attenuated sympathetic activation and target organs damage in septic rats as well as improved survival., Conclusion: The results suggest that tyrosine hydroxylase-positive neurons in the RVLM might contribute to the prognosis of sepsis via activation of the sympathetic nervous system, while dexmedetomidine could ameliorate sepsis via inhibiting sympathetic activation., Competing Interests: Declaration of competing interest The author(s) declare no competing interests for the article of Tyrosine Hydroxylase-Positive Neurons in the Rostral Ventrolateral Medulla Mediate Sympathetic Activation in Sepsis., (Copyright © 2024. Published by Elsevier Inc.)

Obstructive sleep apnea (OSA) is associated with many cardiovascular and metabolic diseases. Sleep apnea causes intermittent hypoxemia, chest pressure fluctuations and a reaction from the cerebral cortex in the form of a short awakening during sleep (EEG-activation). The consequences of pathological pathways are studied in experimental models involving cell cultures, animals, and healthy volunteers. At present, the negative impact of intermittent hypoxemia on a variety of pathophysiological disorders of the heart and blood vessels (vascular tone fluctuations, thickening of the intimamedia complex in the vascular wall, direct damaging effect on the myocardium) has a great evidence base. Two other pathological components of OSA (pressure fluctuations and EEG-activation) can also affect cardiovascular system, mainly affecting the increase in blood pressure and changing cardiac hemodynamics. Although these reactions are considered separately in the review, with the development of sleep apnea they occur sequentially and are closely interrelated. As a result, these pathological pathways trigger further pathophysiological mechanisms acting on the heart and blood vessels. It is known that these include excessive sympathetic activation, inflammation, oxidative stress and metabolic dysregulation. In many respects being links of one process, these mechanisms can trigger damage to the vascular wall, contributing to the formation of atherosclerotic lesions. The accumulated data with varying degrees of reliability confirm the participation of OSA through these processes in the formation of cardiovascular disorders. There are factors limiting direct evidence of this interaction (sleep deprivation, causing similar changes, as well as the inability to share the contribution of other risk factors for cardiovascular diseases, in particular arterial hypertension, obesity, which are often associated with OSA). It is necessary to continue the study of processes that implement the pathological effect of OSA on the cardiovascular system.

The incidence of cardiovascular events is higher in the morning than in the evening and differs between sexes. We tested the hypothesis that aortic stiffness, a compelling cardiovascular risk factor, increases in the morning than in the evening in young, healthy individuals between 18 and 30 years (H18–30) or in older individuals between 50 and 80 years, either healthy (H50–80) or with type 2 diabetes (T2DM50–80). Sex differences were also investigated. Carotid-femoral pulse wave velocity (cf-PWV) recorded via Doppler Ultrasound, blood pressure and heart rate were checked at 6 a.m. and 9 p.m., at rest and during acute sympathetic activation triggered by handgrip exercise. Cf-PWV values were lower in the morning compared to the evening in all groups (p < 0.01) at rest and lower (p = 0.008) in H18–30 but similar (p > 0.267) in the older groups during sympathetic activation. At rest, cf-PWV values were lower in young women compared to young men (p = 0.001); however, this trend was reversed in the older groups (p < 0.04). During sympathetic activation, the cf-PWV was lower in women in H18–30 (p = 0.001), similar between sexes in H50–80 (p = 0.122), and higher in women in T2DM50–80 (p = 0.004). These data do not support the hypothesis that aortic stiffness increases in the morning compared to the evening within any of the considered groups in both rest and sympathetic activation conditions. There are differences between the sexes, which vary according to age and diabetes status. In particular, aortic stiffness is higher in older women than in men with diabetes during acute stress.

Background: Nonalcoholic steatohepatitis is the inflammatory subtype of nonalcoholic fatty liver disease with a high risk of progression to liver fibrosis. We investigated metabolic steatohepatitis with advanced liver fibrosis in apolipoprotein E/low‐density lipoprotein receptor double‐knockout (AL) mice fed a co‐diet of ethanol with a low‐carbohydrate–high‐protein‐high‐fat atherogenic diet (AD) for 16 weeks. We also examined the underlying mechanisms, especially hepatic sympathetic activation, involved in the effects. Methods: We maintained 12‐week‐old male AL mice on AD and a standard chow diet (SCD) with or without ethanol treatment for 16 weeks. Age‐matched male C57BL/6J mice on SCD without ethanol treatment served as controls. We conducted blood biochemical, histopathological, and fluorescence immunohistochemical, and reverse transcriptase polymerase chain reaction studies. Results: AL mice showed significant hyperlipidemia. AD induced increased body weight, hepatic steatosis, and hepatic damage; ethanol and the AD co‐diet resulted in hepatic sympathetic activation accompanied by hepatic steatosis, lobular inflammation, bridging fibrosis, and hepatic damage. Hepatic Kupffer cells (KCs) and hepatic stellate cells (HSCs), which showed sympathetic activation, produced 4.4‐ to 9.4‐fold more inflammatory factors (KC and KC‐derived tumor necrosis factor‐α, and chemokine [C‐C motif] ligand 2) and 2.0‐ to 32.0‐fold more fibrosis factors (HSC and HSC‐derived transforming growth factor β1 and collagen 1a1); all p < 0.05 vs. controls. Conclusions: We created a model of metabolic steatohepatitis with advanced liver fibrosis from coexisting hyperlipidemia and hepatic sympathetic activation in AL mice on a co‐diet of ethanol and AD. KCs and HSCs became the cellular targets of hepatic sympathetic activation, which could play a role in the initiation and progression of metabolic steatohepatitis with advanced liver fibrosis. [ABSTRACT FROM AUTHOR]

Purpose of Review: To update on definition, diagnosis, prevalence, patient characteristics, pathophysiology, and treatment of refractory hypertension (RfHTN). Recent Findings: Refractory hypertension (RfHTN) is defined as blood pressure (BP) that is uncontrolled despite using ≥ 5 antihypertensive medications of different classes, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist (MRA) at maximal or maximally tolerated doses. This new phenotype is different from resistant hypertension (RHTN), defined as BP that is uncontrolled despite using ≥ 3 medications, commonly a long-acting calcium channel blocker (CCB), a blocker of the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]), and a diuretic. The RHTN phenotype includes controlled RHTN, BP that is controlled on 4 or more medications. RfHTN is largely attributable to increased sympathetic activity, unlike RHTN, which is mainly due to increased intravascular fluid volume frequently caused by hyperaldosteronism and chronic excessive sodium ingestion. Compared to those with controlled RHTN, patients with RfHTN have a higher prevalence of target organ damage and do not have elevated aldosterone levels. Ongoing clinical trials are assessing the safety and efficacy of using devices to aid with BP control in patients with RfHTN. Summary: RfHTN is a separate entity from RHTN and is generally attributable to increased sympathetic activity. [ABSTRACT FROM AUTHOR]

Baixin Chen,1,2 Virend K Somers,3 Xiangdong Tang,4 Yun Li1,2 1Department of Sleep Medicine, Shantou University Mental Health Center, Shantou University Medical College, Shantou, People’s Republic of China; 2Sleep Medicine Center, Shantou University Medical College, Shantou, People’s Republic of China; 3Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA; 4Sleep Medicine Center, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Yun LiDepartment of Sleep Medicine, Shantou University Mental Health Center, Shantou University Medical College, Shantou, People’s Republic of ChinaEmail s_liyun@stu.edu.cnBackground: Sympathetic activation is a primary mechanism mediating increased blood pressure (BP) in obstructive sleep apnea (OSA). However, the relationships between overweight/obesity, sympathetic activation and BP in OSA are not well understood. We hypothesized that increased sympathetic drive is associated with increased BP in normal weight, but not in overweight/obese males with OSA. We therefore examined the effects of body mass index (BMI) on the association between sympathetic activation and BP in males with OSA.Methods: We studied 115 males with OSA recruited consecutively from clinic. Twenty-four-hour urinary norepinephrine was used to assess sympathetic activation. Blood pressure was measured both in the evening and in the morning. Hypertension was defined based on either BP measurements or an existing diagnosis. Linear and logistic regressions were conducted to examine the associations between sympathetic activation and both BP and risk of hypertension.Results: We found 24-hour urinary norepinephrine levels were associated with systolic and diastolic BP (SBP, β=0.157, p=0.082; DBP, β=0.212, p=0.023) and mean arterial pressure (MAP, β=0.198, p=0.032) after adjusting for confounders. Interestingly, these associations were modified by overweight/obesity. After adjusting for confounders, increased 24-hour urinary norepinephrine levels were significantly associated with elevated SBP (β=0.454, p=0.012), DBP (β=0.399, p=0.041), and MAP (β=0.432, p=0.023) in normal weight, but not in overweight/obese patients (all p> 0.2). Similar findings were observed in the associations between 24-hour urinary norepinephrine levels and hypertension.Conclusion: Sympathetic activation is associated with elevated BP in normal weight but not in overweight/obese males with OSA, suggesting that BMI may moderate the association between sympathetic activation and BP in males with OSA.Keywords: obesity, overweight, sympathetic activation, blood pressure, hypertension, obstructive sleep apnea

Background: Acute psychological stressors such as anger can precipitate ventricular arrhythmias, but the mechanism is incompletely understood. Quantification of regional myocardial sympathetic activity with 123I-metaiodobenzylguanidine (123I-mIBG) SPECT imaging in conjunction with perfusion imaging during mental stress may identify a mismatch between perfusion and sympathetic activity that may exacerbate a mismatch between perfusion and sympathetic activity that could create a milieu of increased vulnerability to ventricular arrhythmia. Methods: Five men with ischemic cardiomyopathy (ICM), and five age-matched healthy male controls underwent serial 123I-mIBG and 99mTc-Tetrofosmin SPECT/CT imaging during an anger recall mental stress task and dual isotope imaging was repeated approximately 1 week later during rest. Images were reconstructed using an iterative reconstruction algorithm with CT-based attenuation correction. The mismatch of left ventricular myocardial 123I-mIBG and 99mTc-Tetrofosmin was assessed along with radiotracer heterogeneity and the 123I-mIBG heart-to-mediastinal ratios (HMR) were calculated using custom software developed at Yale. Results: The hemodynamic response to mental stress was similar in both groups. The resting-HMR was greater in healthy control subjects (3.67 ± 0.95) than those with ICM (3.18 ± 0.68, P =.04). Anger recall significantly decreased the HMR in ICM patients (2.62 ± 0.3, P =.04), but not in normal subjects. The heterogeneity of 123I-mIBG uptake in the myocardium was significantly increased in ICM patients during mental stress (26% ± 8.23% vs. rest: 19.62% ± 9.56%; P =.01), whereas the 99mTc-Tetrofosmin uptake pattern was unchanged. Conclusion: Mental stress decreased the 123I-mIBG HMR, increased mismatch between sympathetic activity and myocardial perfusion, and increased the heterogeneity of 123I-mIBG uptake in ICM patients, while there was no significant change in myocardial defect size or the heterogeneity of 99mTc-Tetrofosmin perfusion. The changes observed in this proof-of-concept study may provide valuable information about the trigger–substrate interaction and the potential vulnerability for ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

The role of α1-adrenergic receptors (α-ARs) in the regulation of myocardial function is less well-understood than that of β-ARs. Previous reports in the mouse heart have described that α1-adrenergic stimulation shortens action potential duration in isolated cells or tissues, in contrast to prolongation of the action potential reported in most other mammalian hearts. It has since become appreciated, however, that the mouse heart exhibits marked variation in inotropic response to α1-adrenergic stimulation between ventricles and even individual cardiomyocytes. We investigated the effects of α1-adrenergic stimulation on action potential duration at 80% of repolarization in the right and left ventricles of Langendorff-perfused mouse hearts using optical mapping. In hearts under β-adrenergic blockade (propranolol), phenylephrine or noradrenaline perfusion both increased action potential duration in both ventricles. The increased action potential duration was partially reversed by subsequent perfusion with the α-adrenergic antagonist phentolamine (1 μmol L−1). These data show that α1-receptor stimulation may lead to a prolonging of action potential in the mouse heart and thereby refine our understanding of how action potential duration adjusts during sympathetic stimulation.

A prevalent condition linked to an elevated risk of cardiovascular disease is sleep apnea. This review examines the connections between cardiac risk, the sympathetic nervous system, and sleep apnea. The increased risk of hypertension, arrhythmias, myocardial infarction, and heart failure was highlighted in the pathophysiology of sleep apnea and its effect on sympathetic activation. It is also important to consider potential processes such as oxidative stress, inflammation, endothelial dysfunction, and autonomic imbalance that may relate sleep apnea-induced sympathetic activation to cardiac risk. With implications for creating innovative diagnostic and treatment approaches to lessen the cardiovascular effects of sleep apnea, the goal of this investigation is to improve the understanding of the intricate link between sympathetic activity, cardiac risk, and sleep apnea. This study aimed to clarify the complex relationship between cardiovascular health and sleep apnea by synthesizing the available research and highlighting the crucial role played by the sympathetic nervous system in moderating this relationship. Our thorough investigation may have important therapeutic ramifications that will direct the creation of focused therapies to enhance cardiovascular outcomes in sleep apnea sufferers.

Matching arousal level to the motor activity of an animal is important for efficiently allocating cognitive resources and metabolic supply in response to behavioral demands, but how the brain coordinates changes in arousal and wakefulness in response to motor activity remains an unclear phenomenon. We hypothesized that the locus coeruleus (LC), as the primary source of cortical norepinephrine (NE) and promoter of cortical and sympathetic arousal, is well-positioned to mediate movement-arousal coupling. Here, using a combination of physiological recordings, fiber photometry, optogenetics, and behavioral tracking, we show that the LC NE activation is tightly coupled to the return of organized movements during waking from an anesthetized state. Moreover, in an awake animal, movement initiations are coupled to LC NE activation, while movement arrests, to LC NE deactivation. We also report that LC NE activity covaries with the depth of anesthesia and that LC NE photoactivation leads to sympathetic activation, consistent with its role in mediating increased arousal. Together, these studies reveal a more nuanced, modulatory role that LC NE plays in coordinating movement and arousal., Competing Interests: DECLARATION OF INTERESTS The authors have declared no competing interest.

Background: Sham-controlled trials demonstrated safety and efficacy of renal denervation (RDN) to lower blood pressure (BP). Association of baseline heart rate with BP reduction after RDN is incompletely understood.Objectives: The purpose of this analysis was to evaluate the impact of baseline heart rate on BP reduction without antihypertensive medications in the SPYRAL HTN-OFF MED (Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications) Pivotal trial.Methods: Patients removed from any antihypertensive medications were enrolled with office systolic blood pressure (SBP) ≥150 and <180 mm Hg and randomized 1:1 to RDN or sham control. Patients were separated according to baseline office heart rate <70 or ≥70 beats/min. BP changes from baseline to 3 months between treatment arms were adjusted for baseline SBP using analysis of covariance.Results: Scatter plots of 3-month changes in 24-hour and office SBP illustrate a wide range of changes in SBP for different baseline heart rates. Treatment difference at 3 months between RDN and sham control with baseline office heart rate ≥70 beats/min for 24-hour SBP was -6.2 mm Hg (95% CI: -9.0 to -3.5 mm Hg) (P < 0.001) and for baseline office heart rate <70 beats/min it was -0.1 mm Hg (-3.8 to 3.6 mm Hg) (P = 0.97) with an interaction P value of 0.008. Results were similar for changes in office, daytime, and nighttime SBP at 3 months, with a greater reduction in SBP with baseline office heart rate ≥70 beats/min.Conclusions: Reduction in mean office, 24-hour, daytime, and nighttime SBP for RDN at 3 months was greater with baseline office heart rate ≥70 than <70 beats/min, suggesting an association between baseline heart rate and BP reduction after RDN. (SPYRAL PIVOTAL-SPYRAL HTN-OFF MED Study; NCT02439749). [ABSTRACT FROM AUTHOR]

Despite the contemporary treatment of acute coronary syndromes, arrhythmic complications occurring prior to medical attendance remain significant, mandating in-depth understanding of the underlying mechanisms. Sympathetic activation has long been known to play a key role in the pathophysiology of ischemia-induced arrhythmias, but the regulating factors remain under investigation. Several lines of evidence implicate the endothelin system (a family of three isopeptides and two specific receptors) as an important modulator of sympathetic activation in the setting of acute coronary syndromes. Such interaction is present in the heart and in the adrenal medulla, whereas less is known on the effects of the endothelin system on the central autonomic network. This article summarizes the current state-of-the-art, placing emphasis on early-phase arrhythmogenesis, and highlights potential areas of future research.

Takotsubo syndrome (TTS) is estimated to account for 1–3% of all patients presenting with suspected ST-segment elevation myocardial infarction. A sudden surge in sympathetic nervous system is considered the cause of TTS. Nonetheless, no specific recommendations have been provided regarding β-blocking therapy. Apart from specific contra-indications (severe LV dysfunction, hypotension, bradycardia and corrected QT interval >500 ms), treatment with a β-blocker seems reasonable until full recovery of LV ejection fraction, though evidence is limited to a few animal studies, case reports or observational studies. In this review, we will reappraise the rationale for β-blocker therapy in TTS and speculate on the pathophysiologic basis for preferring non-selective agents with vasodilating activity over β 1 -selective drugs. [ABSTRACT FROM AUTHOR]

Baroreflex and chemoreflex act through the autonomic nervous system, which is involved with the neural regulation of inflammation. The present study reports the effects of reflex physiological sympathetic activation in endotoxemic rats using bilateral carotid occlusion (BCO), a physiological approach involving the baroreflex and chemoreflex mechanisms and the influence of the baroreceptors and peripheral chemoreceptors in the cardiovascular and systemic inflammatory responses. After lipopolysaccharide (LPS) administration, the arterial pressure was recorded during 360 min in unanesthetized rats, and serial blood samples were collected to analyze the plasma cytokine levels. BCO elicited the reflex activation of the sympathetic nervous system, providing the following outcomes: (I) increased the power of the low-frequency band in the spectrum of the systolic arterial pressure during the BCO period; (II) reduced the levels of pro-inflammatory cytokines in plasma, including the tumor necrosis factor (TNF) and the interleukin (IL)-1β; (III) increased the plasma levels of anti-inflammatory cytokine IL-10, 90 min after LPS administration. Moreover, selective baroreceptor or chemoreceptor denervation deactivated mechanosensitive and chemical sensors, respectively, and decreased the release of the LPS-induced cytokine but did not alter the BCO modulatory effects. These results show, for the first time, that physiological reflex activation of the sympathetic circuit decreases the inflammatory response in endotoxemic rats and suggest a novel function for the baroreceptors as immunosensors during the systemic inflammation.

Baroreflex and chemoreflex act through the autonomic nervous system, which is involved with the neural regulation of inflammation. The present study reports the effects of reflex physiological sympathetic activation in endotoxemic rats using bilateral carotid occlusion (BCO), a physiological approach involving the baroreflex and chemoreflex mechanisms and the influence of the baroreceptors and peripheral chemoreceptors in the cardiovascular and systemic inflammatory responses. After lipopolysaccharide (LPS) administration, the arterial pressure was recorded during 360 min in unanesthetized rats, and serial blood samples were collected to analyze the plasma cytokine levels. BCO elicited the reflex activation of the sympathetic nervous system, providing the following outcomes: (I) increased the power of the low-frequency band in the spectrum of the systolic arterial pressure during the BCO period; (II) reduced the levels of pro-inflammatory cytokines in plasma, including the tumor necrosis factor (TNF) and the interleukin (IL)-1 β ; (III) increased the plasma levels of anti-inflammatory cytokine IL-10, 90 min after LPS administration. Moreover, selective baroreceptor or chemoreceptor denervation deactivated mechanosensitive and chemical sensors, respectively, and decreased the release of the LPS-induced cytokine but did not alter the BCO modulatory effects. These results show, for the first time, that physiological reflex activation of the sympathetic circuit decreases the inflammatory response in endotoxemic rats and suggest a novel function for the baroreceptors as immunosensors during the systemic inflammation. [ABSTRACT FROM AUTHOR]

High intensity, low volume inspiratory muscle strength training (IMST) has favorable effects on casual systolic blood pressure and systemic vascular resistance. However, the acute effects of IMST on heart rate (HR), blood pressure (BP), and sympathetic regulation of vascular resistance and the trajectory of post exercise recovery are not known. We recruited 14 young adults (7 women/7 men, age: 22 ± 2 years) to perform a single bout of high intensity IMST (inspiratory resistance set at 75% of maximal inspiratory pressure) importantly, female and male subjects were matched in regard to the target inspiratory pressure and target inspiratory muscle work per breath. We recorded HR, beat-to-beat changes in BP and postganglionic, muscle sympathetic nerve activities (MSNA) continuously throughout baseline, a single bout of IMST (comprising five sets of 6 inspiratory efforts) and in recovery. We show that one bout of IMST does not effect a change in BP, however, it effects a significant increase in HR (68.4 ± 11.7 beats/min versus 85.4 ± 13.6 beats/min; P < 0.001) and a significant decline in MSNA (6.8 ± 1.1 bursts/15 s bin; P < 0.001 versus 3.6 ± 0.6 bursts/15 s bin) relative to baseline. Remarkably, among men MSNA rebounded to baseline levels within the first minute of recovery, however, in women, MSNA suppression persisted for 5 min. We show that in healthy young adults, high intensity, low volume respiratory training results in the acute suppression of MSNA. Importantly, MSNA suppression is of greater magnitude and longer duration in women than in men. NEW & NOTEWORTHY Previous studies show 6 weeks of high intensity, low volume inspiratory muscle strength training (IMST) lowers blood pressure (BP) and systemic vascular resistance in young adults. However, the acute response to IMST is unknown. We characterized BP, heart rate, and sympathetic nervous activity (SNA) in healthy young adults at baseline, during IMST, and in recovery. There was no acute effect of IMST on BP, however, there was significant IMST-related suppression of SNA that was of greater magnitude in women than men. [ABSTRACT FROM AUTHOR]

Acupuncture, which is widely used as a complementary and alternative medicine, has been expected to be beneficial for the treatment of hypertension. However, the antihypertensive effect of acupuncture is still under debate. In the present study, the blood pressure induced by handgrip stress were evaluated using power spectral frequency analysis and hormone examination. This study, which recruited 6 normotensive participants, was designed as a randomized crossover trial of two interventions; electroacupuncture and sham-electroacupuncture. Intervention was delivered as 5 sessions over 2 consecutive weeks. The first electroacupuncture immediately before handgrip exercise did not affect the rates of increase in blood pressure and heart rate. Also, neither increase in LF/HF ratio, as sympathetic nerve activity, nor decrease in HF value, as parasympathetic nerve activity, by handgrip stress was significantly inhibited by a single intervention of electroacupuncture. In addition, 5 repeated electroacupuncture sessions did not attenuate the elevation of blood pressure after handgrip stress, and did not suppress the increase in LF/HF ratio and decrease in HF value. Also, electroacupuncture did not influence the changes in plasma concentrations of renin, aldosterone, norepinephrine, and epinephrine after handgrip stress. No difference was observed in the rate of change in each parameter after handgrip stress between the electroacupuncture treatment group and the sham-electroacupuncture group. The present study did not show any suppressive effect on stress-induced response of blood pressure as well as sympathetic nerve activity. The obtained findings showed no beneficial effects of acupuncture on hypertension as a standalone therapy, consistent with suggestions by previous systematic reviews and meta-analyses. Research with larger sample sizes or higher-quality randomized controlled trials are expected, and a conclusion on the utility of acupuncture treatment for hypertension should be carefully made. [ABSTRACT FROM AUTHOR]

One in three Americans suffer from kidney diseases such as chronic kidney disease, and one of the etiologies is suggested to be long-term renal hypoxia. Interestingly, sympathetic nervous system activation evokes a renal vasoconstrictor effect that may limit oxygen delivery to the kidney. In this report, we sought to determine if sympathetic activation evoked by lower body negatiive pressure (LBNP) would decrease cortical and medullary oxygenation in humans. LBNP was activated in a graded fashion (LBNP; -10, -20, and -30mmHg), as renal oxygenation was measured (T2*, blood oxygen level dependent, BOLD MRI; n = 8). At a separate time, renal blood flow velocity (RBV) to the kidney was measured (n = 13) as LBNP was instituted. LBNP significantly reduced RBV (P = 0.041) at -30mmHg of LBNP (Δ-8.17 ± 3.75 cm/s). Moreover, both renal medullary and cortical T2* were reduced with the graded LBNP application (main effect for the level of LBNP P = 0.0008). During recovery, RBV rapidly returned to baseline, whereas medullary T2* remained depressed into the first minute of recovery. In conclusion, sympathetic activation reduces renal blood flow and leads to a significant decrease in oxygenation in the renal cortex and medulla. [ABSTRACT FROM AUTHOR]

Indirect and direct approaches to assess sympathetic neural function in man have shown that congestive heart failure is characterized by a marked adrenergic overdrive. Although compensatory in the initial phases of the disease, with time the sympathetic overactivity exerts adverse cardiovascular effects, favoring the disease progression and promoting the occurrence of non-fatal and fatal cardiovascular events. This explains why the adrenergic overactivity has become an important target of the therapeutic interventions adopted in the managementof the disease. The present paper will examine the impact of therapeutic approaches, used in the management of heart failure, on the sympathetic activation characterizing the disease. After a brief mention of the sympathetic effects of non-pharmacological interventions and procedural approches, particular emphasis will be given to the effects of pharmacological interventions and device treatments (renal denervation and carotid baroreceptor stimulation), which became in recent years a promising tool for the management of the disease. The clinical implications as well as the unsolved aspects related to the sympathomodulatory interventions in heart failure management will be finally discussed. • Sympathetic activation characterizes heart failure worsening prognosis. • Drugs currently employed in the treatment of the disease may affect the sympathetic overactivity. • Device-based interventions have been shown to exert favorable effects on sympathetic overactivity. [ABSTRACT FROM AUTHOR]

BACKGROUND Sleep‐disordered breathing is associated with a poor prognosis (mortality) in patients with ischemic cardiomyopathy. The understanding of mechanisms linking intermittent hypoxia (IH), the key feature of sleep‐disordered breathing, to ischemic cardiomyopathy progression is crucial for identifying specific actionable therapeutic targets. The aims of the present study were (1) to evaluate the impact of IH on the time course evolution of cardiac remodeling and contractile dysfunction in a rat model of ischemic cardiomyopathy; and (2) to determine the impact of IH on sympathetic activity, hypoxia inducible factor‐1 activation, and endoplasmic reticulum stress in the time course of ischemic cardiomyopathy progression. METHODS AND RESULTS Ischemic cardiomyopathy was induced by a permanent ligature of the left coronary artery in male Wistar rats (rats with myocardial infarction). Rats with myocardial infarction were then exposed to either IH or normoxia for up to 12 weeks. Cardiac remodeling and function were analyzed by Sirius red and wheat germ agglutinin staining, ultrasonography, and cardiac catheterization. Sympathetic activity was evaluated by spectral analysis of blood pressure variability. Hypoxia‐inducible factor‐1α activation and burden of endoplasmic reticulum stress were characterized by Western blots. Long‐term IH exposure precipitated cardiac remodeling (hypertrophy and interstitial fibrosis) and contractile dysfunction during the time course evolution of ischemic cardiomyopathy in rodents. Among associated mechanisms, we identified the early occurrence and persistence of sympathetic activation, associated with sustained hypoxia‐inducible factor‐1α expression and a delayed pro‐apoptotic endoplasmic reticulum stress. CONCLUSIONS Our data provide the demonstration of the deleterious impact of IH on post–myocardial infarction remodeling and contractile dysfunction. Further studies are needed to evaluate whether targeting sympathetic nervous system or HIF‐1 overactivities could limit these effects and improve management of coexisting ischemic cardiomyopathy and sleep‐disordered breathing.

The aim of this work was to relate the activation of the sympathetic and parasympathetic nervous systems with the skin temperature (Tsk) of the lower limbs after a resistance training exercise. Under controlled conditions, the average Tsk in the areas of the anterior and posterior thighs, knees and legs was obtained with a thermal imager and the parasympathetic and sympathetic activation was registered with an Omegawave® device on 20 healthy and trained male volunteers (25.39 ± 8.21 years) before exercise, immediately after standard resistance training (3 exercises (2 quadriceps + 1 hamstrings) × 4 sets × 10 repetitions (70% 1RM), 90-sec recovery) and after 20 min of recovery. The results showed a significant effect of exercise and recovery on Tsk in all regions of interest (ROIs) considered (p < 0.05) and strong inverse relationships between sympathetic and parasympathetic activation values. Significant results were found for the total variation of Tsk (p < 0.05) with highly positive values for subjects with lower sympathetic activation and almost null or even negative values for those with higher sympathetic activation. Sympathetic activity was a significant predictor of total Tsk variation in the anterior thigh, posterior thigh and anterior knee but not in the posterior knee, anterior leg, and posterior leg. Baseline Tsk was a significant predictor of total Tsk variation the all ROIs except in the posterior knee. Tsk measured by thermography could be used to estimate the level of participation of muscle areas in exercise and registering the level of sympathetic activation before exercise could be interesting in predicting the athlete’s physiological response to strength training.

The review presents a modern view on stress as a risk factor for the development of arterial hypertension (AH). A variety pathogenic mechanisms responsible for increase of blood pressure during stress exposure are described in detail. The importance of the sympathetic activation as a key link in the development of stress-induced AH and initiation of a cascade of pathophysiological reactions that realize their adverse effects at the level of the whole organism is underlined. Particular attention is paid to worksite AH as a variant of stress-induced hypertension due to its wide prevalence and association with an increased risk of cardiovascular complications, primarily myocardial infarction and stroke. Epidemiological data and results of recent metanalysis are presented, indicating the high significance of job strain as a risk factor for adverse cardiovascular events. The actual psychological stress reduction programs are described. Possibilities of using β-blockers in patients with stress-induced hypertension as drugs affecting the central pathogenetic trigger of this disease are considered. The advantages of using bisoprolol as a highly selective β-blocker are considered taking into account the available body of evidence for its effectiveness in patients with worksite AH, as well as its metabolic neutrality and target-organ protective properties.

Heart failure is associated with profound sympathetic overactivation, which initially develops as an adaptive effect that supports cardiac contractile function. Nevertheless, in the long term, sympathetic activation promotes detrimental myocardial changes, and therefore contributes to systolic dysfunction and poor clinical prognosis. The current knowledge about the mechanisms of these maladaptive effects largely stems from the animal studies that utilized a model of heart failure induced by chronic administration of adrenergic agonists. In this model, sustained adrenergic overactivation was found to induce cardiac hypertrophy owing to the increased protein synthesis in cardiac myocytes, and to promote myocardial fibrosis by stimulating collagen production in cardiac fibroblasts. Catecholamines also produce toxic effects leading to the myocyte cell death via necrosis and apoptosis. Systolic dysfunction in the setting of adrenergic overactivation is partly attributed to the eccentric ventricular chamber remodeling, an effect related to the increased activity of matrix metalloproteinases which digest cross-linked collagen, and promote myocyte slippage. At the cellular level, cardiac contractile failure is linked to the impaired calcium handling. Beta-adreneregic stimulation causes hyperphosphorylation of the ryanodine receptor (RyR2) via cAMP-protein kinase A-dependent mechanism, which increases RyR2 open probability, and hence contributes to the calcium leakage, resulting in depleted sarcoplasmic reticulum calcium stores. This change is further exacerbated owing to the decreased SERCA2a expression in failing cardiac myocytes, which impairs sarcoplasmic reticulum calcium uptake in diastole. Overall, myocardial structural changes upon sustained adrenergic overactivation are related to the increased activity of the renin-angiotensin-aldosterone system, stimulation of the myocardial growth factors, and increased expression of cytokines. The adrenergic cellular growth-promoting effects are mediated through the mitogen-activated protein kinase signaling pathway, transient up-regulation of the immediate-early genes, and activation of transcription factors. These effects translate to the increased synthesis of contractile proteins and their assembly into the organized sarcomeric units in cardiac myocytes.

Previous work has shown lowered casual blood pressure after just 6 wk of inspiratory muscle strength training (IMST), suggesting IMST as a potential therapeutic in the prevention/treatment of hypertension. In this study, we assessed the effects of IMST on cardiovascular parameters in older, overweight adults diagnosed with moderate and severe obstructive sleep apnea (OSA). Subjects were randomly assigned to one of two interventions 1) high-intensity IMST (n = 15, 75% maximal inspiratory pressure), or 2) a control intervention (n = 10, 15% maximum inspiratory pressure). Subjects in both groups trained at home completing 30 training breaths/day, 5 days/wk for 6 wk. Pre- and posttraining measures included maximal inspiratory pressure, casual and ambulatory blood pressures, spontaneous cardiac baroreflex sensitivity, and muscle sympathetic nerve activity. Men and women in the high-intensity IMST group exhibited reductions in casual systolic (SBP), diastolic (DBP), and mean arterial blood pressures (MAP) [SBP: -8.82 ± 4.98 mmHg; DBP: -4.69 ± 2.81 mmHg; and MAP: -6.06 ± 1.03 mmHg; P < 0.002] and nighttime SBP (pre: -12.00 ± 8.20 mmHg; P < 0.01). Muscle sympathetic nerve activities also were lower (-6.97 ± 2.29 bursts/min-1; P = 0.01 and -9.55 ± 2.42 bursts/100 heartbeats; P = 0.002) by week 6. Conversely, subjects allocated to the control group showed no change in casual blood pressure or muscle sympathetic nerve activity and a trend toward higher overnight blood pressures. A short course of high-intensity IMST may offer significant respiratory and cardiovascular benefits for older, overweight adults with OSA. [ABSTRACT FROM AUTHOR]

Sudden drops in pulse wave amplitude (PWA) measured by finger photoplethysmography (PPG) are known to reflect peripheral vasoconstriction resulting from sympathetic activation. Previous work demonstrated that sympathetic activations during sleep typically accompany the occurrence of pathological respiratory and motor events, and their alteration may be associated with the arising of metabolic and cardiovascular diseases. Importantly, PWA-drops often occur in the absence of visually identifiable cortical micro-arousals and may thus represent a more accurate marker of sleep disruption/fragmentation. In this light, an objective and reproducible quantification and characterization of sleep-related PWA-drops may offer a valuable, non-invasive approach for the diagnostic and prognostic evaluation of patients with sleep disorders. However, the manual identification of PWA-drops represents a time-consuming practice potentially associated with high intra/inter-scorer variability. Since validated algorithms are not readily available for research and clinical purposes, here we present a novel automated approach to detect and characterize significant drops in the PWA-signal. The algorithm was tested against expert human scorers who visually inspected corresponding PPG-recordings. Results demonstrated that the algorithm reliably detects PWA-drops and is able to characterize them in terms of parameters with a potential physiological and clinical relevance, including timing, amplitude, duration and slopes. The method is completely user-independent, processes all-night PSG-data, automatically dealing with potential artefacts, sensor loss/displacements, and stage-dependent variability in PWA-time-series. Such characteristics make this method a valuable candidate for the comparative investigation of large clinical datasets, to gain a better insight into the reciprocal links between sympathetic activity, sleep-related alterations, and metabolic and cardiovascular diseases. [ABSTRACT FROM AUTHOR]