Sympathetic nervous system activation and heart failure:Current state of evidence and the pathophysiology in the light of novel biomarkers

Heart failure(HF)is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues.The sympathetic nervous system(SNS)is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes,circulating and neuronal catecholamine spillover,attenuated parasympathetic response,and augmented sympathetic outflow to the heart,kidneys and skeletal muscles.When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis,maladaptive ventricular and vascular remodeling,arrhythmogenesis,and poor prognosis in patients with HF.These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities.Therefore,this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF.Finally,special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.

Differences in sympathetic nervous system activity and NMDA receptor levels within the hypothalamic paraventricular nucleus in rats with differential ejaculatory behavior

Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system （SNS） activity and expression of N-methyI-D-aspartic acid （NMDA） receptors in the paraventricular nucleus of the hypothalamus （PVN）. Male rats were classified as ＂sluggish,＂ ＂normal,＂ and ＂rapid＂ ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460±480 mV, 1660±600 mV, and 1680±490 mV, respectively （P = 0.71）. However, SNS sensitivity was remarkably different between the groups （P 〈 0.01）, being 28.9% ± 8.1% in ＂sluggish,＂ 48.4%±7.5% in ＂normal,＂ and 88.7% ~ 7.4% in ＂rapid＂ groups. Compared with ＂normal＂ ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of ＂rapid＂ ejaculators was significantly higher, whereas it was significantly lower in ＂sluggish＂ ejaculators （P = 0.01）. In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity （r = 0.876, P = 0.02）. This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.

Effects of the Hand Care Therapy that Used Natural Herb Oil on Autonomic Nervous System against All People Concerned

Multi-sensory stimulation is beneficial to a wide variety of conditions typical of geriatric patients. Some therapies for elderly people are based on the philosophy that the activities to be carried out will also be stimulating to the senses. On the other hand, the dynamics of the senses plays an important role beyond mere reason and sensibility in people’s lives. The hand care therapy that used natural herb oil is the alternative medicine that utilized a plant or its essential oil, which is used in various application scenes. In our past study, the hand care therapy that used natural herb oil demonstrated the effectiveness for elderly people. In this study, we examined influences on psychological condition of the side to treatment on. On the evaluation with question paper, baseline of POMS factor and TMD average were similar to pre-HCT. In post-HCT, T-A, A-H, F and C which were negative factors decreased than pre significantly. The forward factor V did not have significant difference, but the mean increased. Furthermore, the TMD (total mood distance) score generally decreased and changed in the balance of good feelings. On the objective evaluation, temporal change differences in the PNS (Parasympathetic Nervous System) during the relaxed state and following the induced stress state were monitored using ECG (electrocardiograph). The SNS (Sympathetic Nervous System) of students in HCT has decreased, and the PNS was confirmed to increase. For the tendency in SNS, the changes during the HCT were small. There were no significant changes in rSO2 (regional oxygen saturation) by HCT. BVI (blood volume information) showed significantly big values at left hand treatment and after HCT than BL, indicating that peripheral circulation of the blood flow quantity of the student increased. Generally, it was shown that the subjective emotional evaluation of the hand care treatment side, the objective autonomic nervous system change, and the coronal blood flow were all good. In Japan, the global pandemic of COVID-19 disrupts human interaction, and there are concerns about physical, cognitive, and mental deterioration. The use of hand care therapy has been shown to be an effective technique for building quality communication for both recipients and performers.

Inhibition of central sympathetic nervous tone improves cardiomyocyte contraction by increasing the response of beta 2-adrenergic receptor in aged rats

In the present study,selective β1-adrenergic receptor antagonist CGP20712A and selective β2-adrenergic receptor antagonist ICI 118551 were administered to isolated cardiomyocytes from young （4-6 months）,aged （18-20 months）,and clonidine-pretreated aged （18-20 months） Sprague-Dawley rats.Cardiomyocyte contraction amplitude was measured to assess cardiomyocyte response to the β-adrenergic receptor agonist,isoprenaline.CGP20712A reduced cardiomyocyte contraction amplitude in young and aged groups and significantly reduced contraction amplitude in cells from young rats.ICI 118551 had no effect on cardiomyocyte contraction amplitude in young rats,but significantly decreased contraction amplitude in the aged groups,in particular in the clonidine-pretreated aged rats.Results demonstrated that reduced central sympathetic tone improved cardiomyocyte contraction in aged rats by improving the response of β2-adrenergic receptor to isoprenaline.

Brachial arteries sympathetic innervation: A contribution to anatomical knowledge

BACKGROUND The sympathetic nervous system makes medium and large peripheral arteries smaller to slow the blood flowing through them.AIM To observe brachial artery sympathetic innervation.METHODS We developed a neurophysiological autonomous test that measured the effects of peripheral sympathetic fibres on peripheral arteries.Our specific objective was to find the sympathetic innervation of the brachial artery.To accomplish this purpose,the brachial artery baseline diameter and flow rate were measured in the right arm of the patients.Afterwards,electrical stimulus was applied to the medial nerve for 5 s.Through electrical sympathetic activation,the vessel diameter and overall flow rate will decrease.After 7 d,a similar experiment was repeated using the ulnar nerve.RESULTS The differences in diameter and flow rate of the brachial artery in response to median and ulnar nerve activation were compared.In the total group,no significant difference in diameter was seen between medial and ulnar nerve stimulation(P=0.648).The difference in absolute slowdown of flow rate between median nerve stimulation and ulnar nerve stimulation was not statistically significant for the entire group(P=0.733).CONCLUSION As a target organ,the brachial artery receives an equal amount of sympathetic innervation from the median and the ulnar nerves.

Molecular chaperones in stroke-induced immunosuppression

Stroke-induced immunosuppression is a process that leads to peripheral suppression of the immune system after a stroke and belongs to the central nervous system injury-induced immunosuppressive syndrome.Stroke-induced immunosuppression leads to increased susceptibility to post-stroke infections,such as urinary tract infections and stroke-associated pneumonia,worsening prognosis.Molecular chaperones are a large class of proteins that are able to maintain proteostasis by directing the folding of nascent polypeptide chains,refolding misfolded proteins,and targeting misfolded proteins for degradation.Various molecular chaperones have been shown to play roles in stroke-induced immunosuppression by modulating the activity of other molecular chaperones,cochaperones,and their associated pathways.This review summarizes the role of molecular chaperones in stroke-induced immunosuppression and discusses new approaches to restore host immune defense after stroke.

Impact of Manipulative Treatment on Professional Drivers

The experimental research, presented in the study, focuses on track tests with the aim of highlighting changes in lap times after manipulative treatment of drainage of the glymphatic system and stimulation of the sympathetic nervous system. Introduction: The experimental research, presented in this study, focuses on analyzing the potential effects of a manipulative treatment on the performance of a professional driver. The main objective is to evaluate the change in lap times after the application of the treatment, trying to understand whether it can actually positively influence the driver’s performance. The study stands an important opportunity to extend knowledge, regarding the use of manipulative therapies in the context of optimized driving skills. The results obtained could provide useful insights and contribute to improving the performance of professional drivers by offering new perspectives and strategies to improve their performance. Leveraging a rigorous scientific approach and a sample of highly skilled drivers, the research aims to provide concrete evidence on the effectiveness of manipulative treatment in driving skills. Monitoring lap times before and after the intervention also capture any temporary or long-term effects of the treatment, ensuring a thorough and reliable analysis of the results. Materials and methods: 15 professional drivers, aged 18 to 36 years, with at least 10 years of experience as drivers, participated in this study. The test consisted of analyzing lap times before and after treatment.

Cerebral ischemia and neuroregeneration

Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke （a form of cerebral ischemia）-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics （i.e., tissue plasminogen activator） and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies again st stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism（s） underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies （i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells） as it relates to cerebral ischemia.

Liver cirrhosis and arterial hypertension

Characteristic findings in patients with cirrhosis are vasodilatation with low overall systemic vascular resistance, high arterial compliance, increased cardiac output, secondary activation of counter-regulatory systems （renin-angiotensin-aldosterone system, sympathetic nervous system, release of vasopressin）, and resistance to vasopressors. The vasodilatory state is mediated through adrenomedullin, calcitonin generelated peptide, nitric oxide, and other vasodilators, and is most pronounced in the splanchnic area. This constitutes an effective （although relative） counterbalance to increased arterial blood pressure. This review considers the alterations in systemic hemodynamics in patients with cirrhosis in relation to essential hypertension and arterial hypertension of the renal origin. Subjects with arterial hypertension （essential, secondary） may become normotensive during the development of cirrhosis, and arterial hypertension is rarely manifested in patients with cirrhosis, even in cases with renovascular disease and high circulating renin activity. There is much dispute as to the understanding of homoeostatic regulation in cirrhotic patients with manifest arterial hypertension. This most likely includes the combination of vasodilatation and vasoconstriction in parallel.

Angiotensin receptor blocker neprilysin inhibitors

Heart failure(HF)is a clinical syndrome that results from a structural or functional cardiac disorder that reduces the ability of the ventricle of the heart to fill with,or eject,blood.It is a multifaceted clinical condition that affects up to 2%of the population in the developed world,and is linked to significant morbidity and mortality;it is therefore considered a major concern for public health.Regarding the mechanism of HF,three neurohumoral factors-the reninangiotensin-aldosterone system,the sympathetic nervous system,and natriuretic peptides—are related to the pathology of chronic HF(CHF),and the targets of treatment.Angiotensin receptor blocker and neprilysin inhibitor(angiotensinreceptor neprilysin inhibitor),namely sacubitril/valsartan(SAC/VAL),has been introduced as a treatment for CHF.SAC/VAL is an efficacious,safe,and costeffective therapy that improves quality of life and longevity in patients with HF with reduced ejection fraction(HFrEF),and reduces hospital admissions.An inhospital initiation strategy offers a potential new avenue to improve the clinical uptake of SAC/VAL.In the last five years,SAC/VAL has been established as a cornerstone component of comprehensive disease-modifying medical therapy in the management of chronic HFrEF.On the other hand,further work,with carefully designed and controlled preclinical studies,is necessary for understanding the molecular mechanisms,effects,and confirmation of issues such as long-term safety in both human and animal models.

肾脏去神经技术:历史,现状和前景（英文）

Renal denervation is a new technique approved effective for resistant-hypertension treatment.The common renal denervation system consists of a generator and a flexible catheter.During this minimally invasive procedure,the interventionalist uses a steerable catheter with a radio frequency(RF)energy electrode tip.The RF energy is delivered to the renal artery via standard femoral artery access.A series of 2-minute ablation are delivered in each renal artery to distroy the nerves system.The procedure does not involve a permanent device implant.By deactivating the renal nerves,and therefore reducing sympathetic nerve transmission,a significant and reliable reduction in blood pressure could be achieved.In this review,potential complications and future sights of renal denervation are also discussed.

Comparison of a 5 F Microtube-Irrigated Ablation Catheter and a General Ablation Catheter in the Treatment of Resistant Hypertension with Renal Denervation

Objective:To assess the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with resistant hypertension using a 5 F microtube-irrigated ablation catheter.Methods:Sixty patients with resistant hypertension were divided into two groups:a microtube-irrigated ablation catheter group and a general ablation catheter group.We conducted 12-month follow-up of all patients and recorded clinical blood pressure,ambulatory blood pressure,medication use,and biochemistry test results in both groups at the baseline and at the 12-month follow-up.Results:All patients underwent renal denervation.At the 6-month follow-up,ambulatory blood pressure in the mi-crotube-irrigated ablation catheter group was signifi cantly lower than in the general ablation catheter group(systolic blood pressure 142.0±14.4 mmHg vs.150.8±17.9 mmHg,P=0.04;diastolic blood pressure 81.2±7.0 mmHg vs.87.6±8.0 mmHg,P=0.002).At the 12-month follow-up,the between-group difference in ambulatory blood pressure was not statistically signifi cant.At the 12-month follow-up,the number of antihypertensive drugs and diuretics used in the microtube-irrigated ablation catheter group was less than in the general ablation catheter group(P=0.043).There was no statistical difference between the two groups in the results of biochemistry tests and echocardiography.Conclusion:The microtube-irrigated ablation catheter is more effective in treating hypertension than the general ablation catheter at the 6-month follow up and thus fewer antihypertensive drugs were used in the microtube-irrigated ablation catheter group than in the general ablation catheter group.

Peripheral BDNF Regulates Somatosensory–Sympathetic Coupling in Brachial Plexus Avulsion-Induced Neuropathic Pain

Brachial plexus avulsion(BPA)is a combined injury involving the central and peripheral nervous systems.Patients with BPA often experience severe neuropathic pain(NP)in the affected limb.NP is insensitive to the existing treatments,which makes it a challenge to researchers and clinicians.Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction,which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP.However,the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear.In this study,through using a novel BPA C7 root avulsion mouse model,we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased,and the markers of sympathetic nervous system activity includingα1 andα2 adrenergic receptors(α1-AR andα2-AR)also increased after BPA.The phenomenon of superexcitation of the sympathetic nervous system,including hypothermia and edema of the affected extremity,was also observed in BPA mice by using CatWalk gait analysis,an infrared thermometer,and an edema evaluation.Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice.Further,intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice.In another branch experiment,we also found the elevated expression of BDNF,TrκB,TH,α1-AR,andα2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry.Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP.This study also opens a novel analgesic target(BDNF)in the treatment of this pain with fewer complications,which has great potential for clinical transformation.

Cardiovascular autonomic neuropathy in diabetes:Pathophysiology,clinical assessment and implications

Cardiovascular autonomic neuropathy(CAN)is a debilitating condition that mainly occurs in long-standing type 2 diabetes patients but can manifest earlier,even before diabetes is diagnosed.CAN is a microvascular complication that results from lesions of the sympathetic and parasympathetic nerve fibers,which innervate the heart and blood vessels and promote alterations in cardiovascular autonomic control.The entire mechanism is still not elucidated,but several aspects of the pathophysiology of CAN have already been described,such as the production of advanced glycation end products,reactive oxygen species,nuclear factor kappa B,and pro-inflammatory cytokines.This microvascular complication is an important risk factor for silent myocardial ischemia,chronic kidney disease,myocardial dysfunction,major cardiovascular events,cardiac arrhythmias,and sudden death.It has also been suggested that,compared to other traditional cardiovascular risk factors,CAN progression may have a greater impact on cardiovascular disease development.However,CAN might be subclinical for several years,and a late diagnosis increases the mortality risk.The duration of the transition period from the subclinical to clinical stage remains unknown,but the progression of CAN is associated with a poor prognosis.Several tests can be used for CAN diagnosis,such as heart rate variability(HRV),cardiovascular autonomic reflex tests,and myocardial scintigraphy.Currently,it has already been described that CAN could be detected even during the subclinical stage through a reduction in HRV,which is a non-invasive test with a lower operating cost.Therefore,considering that diabetes mellitus is a global epidemic and that diabetic neuropathy is the most common chronic complication of diabetes,the early identification and treatment of CAN could be a key point to mitigate the morbidity and mortality associated with this long-lasting condition.

Specific acupuncture stimulation of Shenshu(BL23)affects sympathetic nervous activity-associated plasma renin concentration changes

OBJECTIVE:To examine whether specific stimulation of Shenshu(BL23)affects sympathetic nervous activity(SNA)-associated plasma renin concentration(PRC).METHODS:Eight healthy volunteers participated in three pattern conditions in random order:control(Cont),stimulation of Shenshu(BL23),and stimulation of sham point(Sham).All participants were initially in the supine position for>60 min,and then remained in the standing position during the experimental procedure to increase SNA.An electrocardiogram was used to calculate low frequency/high frequency(LF/HF)ratio;blood was collected to analyze PRC.RESULTS:The LF/HF ratio was significantly increased in the standing position when compared with the supine position(P<0.01).There was no difference in LF/HF ratio during or after stimulation of Shenshu(BL23)in the standing position when compared with before the stimulation in the supine position;however,the LF/HF ratio was significantly increased in Cont and Sham conditions(P<0.01).There was no difference in PRC after stimulation of Shenshu(BL23)in the standing position when compared with before the stimulation in the supine position;however,there was a significant increase in PRC in the Cont and Sham conditions(Cont P<0.05,Sham P<0.01).CONCLUSION:Our results demonstrated that specific acupuncture stimulation of Shenshu(BL23)in the standing position decreased SNA-associated PRC,which was not observed during acupuncture stimulation of the sham point.

Effects of sympathetic histamine on vasomotor responses of blood vessels in rabbit ear to electrical stimulation

Objective To investigate the effects of histamine receptor antagonists on vasoconstriction induced by electrical stimulation （ES） on posterior auricular nerve,and to explore the pre-and post-synaptic effects of sympathetic histamine on the vasomotor responses of vascular smooth muscle in rabbit ear.Methods ES was applied to posterior auricular nerves of the whole rabbit ear at 10 Hz,20 Hz and 40 Hz,respectively.Besides,the whole ear was perfused with different histamine receptor antagonists under constant perfusion pressure,and the changes in the flow rate of perfusate were observed.Results The flow rate of venous outflow was decreased by ES at all the 3 frequencies.The ES-induced vasoconstriction at 20 Hz and 40 Hz could be partly inhibited by H1 receptor antagonist chlorpheniramine （P0.05） .After exhaustion of histamine in mast cells by pretreatment with specific mast cell degranulator compound 48/80,chlorpheniramine could still inhibit the ES-induced flow rate reduction.In contrast,H2 receptor antagonist cimetidine could enhance the 40-Hz ES-induced flow rate reduction （P 0.05） .Moreover,ES-induced vasoconstriction at the 3 frequencies could all be enhanced by H3 receptor antagonist thioperamide （P0.05） .Conclusion Stimulation on the auricular nerve may evoke histamine release from sympathetic nerves rather than from mast cells.Moreover,the functions of sympathetic histamine vary from pre-synaptic modulation to post-synaptic vasoconstriction or vasodilatation,via activation of different histamine receptors.

Overview of the Association Between Non-Alcoholic Fatty Liver Disease and Hypertension

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its prevalence is rising. NAFLD is closely associated with metabolic syndrome, with both conditions sharing common clinical characteristics such as obesity, insulin resistance, type 2 diabetes mellitus, hypertension, and hypertriglyceridemia. Several observational studies have evaluated the relationship between NAFLD and hypertension, with the overall evidence suggesting a bidirectional relationship. It is hypothesized that activation of the sympathetic nervous and renin-angiotensin systems, observed in NAFLD with or without insulin resistance promotes the development of hypertension. In patients with hypertension, activation of these systems can lead to hepatic fibrosis and progressive inflammation through increased oxidative stress and activation of hepatic stellate cells and Kupffer cells. The present review examines the pathophysiologic and clinical evidence supporting the bidirectional association between NAFLD and hypertension.

Value of sympathetic skin response test in the early diagnosis of diabetic neuropathy

Background Diabetic neuropathy is common in diabetes mellitus. The early stage of diabetic neuropathy is often symptomless and difficult to be treated. The aim of this study was to assess the correlation between the results of the sympathetic skin response (SSR) test and the development of diabetic neuropathy, and explore the use of SSR as an objective basis for the early diagnosis of diabetic neuropathy. Methods The latencies and amplitudes of initiation and of the N and P waves were determined by SSR testing of the extremities of 80 diabetic patients and 30 healthy controls. Results The latencies of initiation and of the N and P waves were significantly (P<0.001) longer in diabetic patients than in the controls, while there was no significant difference in the amplitudes (P>0.05). All but two patients (97.5%) demonstrated abnormal SSR in at least one limb. Conclusions SSR can detect early dysfunction of the small sympathetic fibers in people affected by diabetes mellitus, and may be a useful electrophysiological test for the early diagnosis of diabetic neuropathy.

Renal sympathetic denervation for the treatment of resistant hypertension with chronic renal failure： first-in-man experience

A39-year-old man with resistant hypertension,presented with headache and dizziness at theemergency department on January 6, 2012. The patient had a history of hypertension for 3 years, his highest blood pressure was 250/110 mmHg, and he was taking antihypertensive medication regimens for at least 6 months. A mitral replacement by bioprosthetic valve had been implanted 6 months before. The patient was in chronic renal failure （CRF） uremia, maintenance of which he underwent the standard hemodialysis treatment three times a week for 6 months.