Sympathetic Activity Research Articles

5131 Vanishing Act: Uncommon Case Of Pheochromocytoma With Positive Biochemical Work-up With Absence Of Tumor And Medullary Tissue

Abstract Disclosure: N. Chan: None. R. Kaufman: None. N. Farhat: None. G.Y. Kim: None. Pheochromocytomas are rare neuroendocrine tumors derived from adrenal chromaffin cells that result in hyperactivity of the sympathetic nervous system. In the United States, they occur in about 0.05% to 0.1% patients with sustained hypertension. We are presenting a case of a patient with biochemical evidence of pheochromocytoma, but surgical pathology revealed absence of tumor and residual normal medulla.80-year-old female with a history of follicular lymphoma and hypertension presented for evaluation of an incidental right-sided adrenal nodule noted on a PET-CT. She had a history of hypertension managed on lisinopril 40 mg, amlodipine 10 mg and atenolol 100 mg daily. She denied a history of weakness, dizziness, headaches, palpitations, or easy bruising. Workup was negative for primary aldosteronism and Cushing’s Syndrome. Plasma normetanephrines was high at 675.7 pg/mL (0-285.2 pg/mL). 24-hour urinary normetanephrine was also elevated at 562 ug/g (0-400 ug/g). CT abdomen and pelvis with and without contrast revealed a 1.4 cm right adrenal nodule approximately 16 Hounsfield units. These findings were suggestive of pheochromocytoma. She was pre-treated with alpha blockade and subsequently had a robotically assisted laparoscopic right adrenalectomy. Postoperatively, the patient was hypotensive and required vasopressors. She was eventually weaned off vasopressors and discharged on lisinopril 20 mg daily. Soon after discharge, the patient was complaining of hypotension and this dose was halved. 4 weeks postoperatively, laboratory evaluation showed normalization of plasma normetanephrines to 0.83 nmol/L (0-0.89 nmol/L). Surgical pathology revealed an infarcted benign adrenal cortical proliferative lesion with background of cortical hyperplasia, fibrotic adrenal medullary region, and hemosiderin deposition. There was no identifiable medullary neoplasm and no residual medulla.Pheochromocytomas are highly vascular tumors as angiogenesis is a critical step in tumor growth, which can lead to frequent infarcts. This case shows classic biochemical evidence of pheochromocytoma. Interestingly, the resulting clinical examination displayed obliteration of the medullary tissue. Complete disappearance of both tumor and residual normal medulla is extraordinarily rare. The pre-operative hormonal levels in association with findings of complete absence of neoplastic and nonneoplastic medullary tissue cannot be explained. Presentation: 6/1/2024

9398 Early Identification of Impending Thyroid Storm Leading to Improved Thyrotoxic Induce Cardiomyopathy

Abstract Disclosure: D.H. Sacoto: None. D. Patel: None. A. De Rosairo: None. K. Madani: None. B. Singh: None. A. Bonilla Campos: None. R. Belokovskaya: None. F. Alberto A.: None. Introduction: Heart failure can be the leading presentation in 6% of thyroid storm cases and is the leading cause of death, particularly in elderly patients. However, its importance lies in symptom control and heart function reversibility once the euthyroid state is achieved. We present a caseof thyroid storm-induced atrial fibrillation (Afib) leading to severe systolic dysfunction. Case: A 61-year-old female with a history of Graves’ disease (GD) presented to the ED with two months of palpitations and one week of shortness of breath. There were bibasilar lung crackles, irregular heart rhythm, pedal edema, and thyromegaly at the examination. EKG was consistent with Afib with rapid ventricular response (123-135 beats per minute); She was tachypneic (respiratory rate: 40 per minute) and hypoxemic (87% O2 saturation), which required bilevel positive airway pressure. Otherwise, hemodynamically stable (BP: 127/106 mmHg). Laboratories showed negative troponin T (<0.010 ng/mL, n <0.01 ng/mL). However, elevation of Pro-B-type natriuretic peptide (6000 pg/mL, n <125 pg/mL), an x-ray displaying bibasilar pleural effusions and an echocardiogram demonstrating a severely reduced ejection fraction (EF) (21%, n 50-70%), myocardial perfusion scan was normal. Thyroid evaluation showed a suppressed TSH (<0.01 uIU/mL, n 0.27-4.20 uIU/mL) with elevated free T4 (5.8 ng/dL, n 0.9-1.8 ng/dL), free T3 (202 ng/dL, n 2.0-4.4 ng/dL), and TSI (8.25 IU/L, n 0-0.55 IU/L). A thyroid ultrasound revealed increased vascular flow on the left thyroid lobe. A Burh-Schakowsky score of 45 points was consistent with impending thyroid storm. She was started on methimazole, cholestyramine, and propranolol. Three months follow-up, she was asymptomatic, TSH normalized (4.12 uIU/mL), and mild improvement of cardiac EF 25%. Discussion: A thyroid storm in the setting of GD often presents after precipitating factors such as surgery, infection, or, as in our case, anti-thyroid medication non-compliance. Increased thyroid hormone levels upregulate cardiac β receptors, enhancing sensitivity to sympathetic innervation. These can shorten the refractory period of cardiomyocytes, leading to tachyarrhythmias, with Afib occurring in 20% of patients. Chronic tachycardia finally impairs left ventricle function, with heart failure as an outcome. A high index of suspicion and the ability of early diagnosis of impending thyroid storm is critical since the first laboratory confirmation is often delayed, and second, either anti-thyroid medication, radioactive iodine ablation or thyroidectomy, in addition to non-selective beta-blockers, can reverse cardiac dysfunction and lead to clinical improvement as early as 12 -Twenty-four hours of medical treatment. In our case, the early diagnosis and treatment of thyroid storm, in addition to the rate control prevented a deadly outcome and contributed to the improvement of heart failure. Presentation: 6/1/2024

8688 Pseudopheochromocytoma Due To Severe Obstructive Sleep Apnea

Abstract Disclosure: L.M. José: None. M. Ataide: None. F. Aratani: None. S. Beeby: None. G.F. Fagundes: None. F. Coelho: None. F. Ledesma: None. A. Latronico: None. B.B. Mendonca: None. M.C. Fragoso: None. M.Q. Almeida: None. Background: Obstructive sleep apnea (OSA) represents an independent risk factor for cardiovascular disease, and it is associated with a wide range of conditions, such as resistant hypertension and primary aldosteronism (PA). Patients with sleep apnea have a higher sympathetic activity during wakefulness due to chronic hypoxia. We present the case of pseudopheochromocytoma caused by severe OSA in an obese patient with RH and PA.Clinical Case: A 58-year-old female Brazilian patient was referred to an endocrinologist to investigate a 1.8 cm right adrenal nodule at computed tomography (CT) performed to investigate abdominal pain. Her medical history includes resistant hypertension diagnosed at 27 years of age, type 2 diabetes, dyslipidemia, Class II obesity, a previous acute myocardial infarction, and severe OSA (apnea-hypopnea index 61.6/hour). She has used irregularly the continuous positive airway pressure (CPAP) therapy at night. She is currently using carvedilol 50 mg bid, chlorthalidone 25 mg, olmesartan 40 mg, amlodipine 10 mg, spironolactone 50 mg, clonidine 0.2 mg tid, hydralazine 50 mg every 6 hours, acetylsalicylic acid 100 mg, atorvastatin 80 mg, and metformin XR 1000 mg. At physical examination, she had BMI 37 kg/m2, BP 150 x 90 mmHg, HR 64 bpm, and no signs of Cushing syndrome. Abdominal CT revealed a right adrenal nodule measuring 1.8 cm with 18 Hounsfield unit (HU) in the pre-contrast phase, reaching a density of 117 HU at the arterial phase and showing an absolute washout of 65% and a relative washout of 56%. A nodular thickening of 1.4 cm (-4 HU) at the left adrenal gland was also displayed at CT scan. Hormone evaluation showed basal cortisol 7 µg/dL, ACTH 15.7 pg/mL, DHEAS 1152 ng/mL (189-2050 ng/mL), 1 mg overnight dexamethasone suppression test 2.3 ug/dL, aldosterone 9.9 ng/dL, direct renin concentration 36.8 uIU/mL, plasma metanephrines 0.3 nmol/L (<0.5 nmol/L) and plasma normetanephrines 1.3 nmol/L (<0.9 nmol/L). It was not possible to change anti-hypertensive medications to investigate PA. A 0.3 mg clonidine suppression test did not suppress normetanephrine levels, confirming the biochemical diagnosis of pheochromocytoma. Then, alpha-blockade with doxazosin 4 mg was started and the patient underwent right adrenalectomy. Pathological examination revealed an adenoma with immunohistochemistry positive for CYP11B2. BP control was achieved with only two medications and aldosterone decreased to 3 ng/dL confirming PA. Plasma normetanephrine levels remained elevated post-surgery and only normalized after the CPAP regular use.Clinical lessons: Chronic activation of sympathetic autonomic drive in OSA can increase norepinephrine and normetanephrine levels. OSA is a very prevalent disease and it is frequently associated with RH. Therefore, OSA should be considered a possible cause of pseudopheochromocytoma in hypertensive patients. Presentation: 6/3/2024

6692 Proarrhythmic Risk Of Hypoglycemia; A Case Of Insulin-Induced Hypoglycemia Provoking Torsade De Pointes-Cardiac Arrest

Abstract Disclosure: A.M. San Hernandez: None. A. Adelkhanova: None. H. Ashraf: None. J. Aguayo Herrera: None. M.F. Siddiqui: None. Introduction: Torsade de Pointes is a life-threatening polymorphic ventricular tachycardia which is associated with QTc prolongation caused by medications, metabolic and electrolyte abnormalities. Very few cases of hypoglycemia causing QTc prolongation and Torsades de Pointes have been reported in the literature. Although the mechanism is unclear, the effects of low blood glucose have been proposed to induce a sympathetic response, hypokalemia and calcium disturbances. We report a case of an insulin-induced hypoglycemia causing Torsades de Pointes cardiac arrest, highlighting the proarrhythmic risk of hypoglycemia. Case presentation: A 57-year-old female with a history of Insulin-dependent Type 2 Diabetes Mellitus (DM) was brought in by EMS due to severe symptomatic hypoglycemia (POC blood glucose of 30 mg/dL), requiring treatment with dextrose. Patient reported reduced oral intake due to vomiting for 1 week and continued insulin administration without self-monitoring of blood glucose. Laboratory work up on presentation revealed severe hypoglycemia VBG= 55 mg/dL and mild hypomagnesemia Mg=1.4mg/dL (Ref Range 1.7-2.2mg/dl) which was treated. There was no hypokalemia or hypocalcemia. ECG showed sinus rhythm with prolonged QTc interval of 573ms and non-specific ST changes.Few hours later, patient developed torsades de pointes, requiring ACLS resuscitation. ROSC was achieved after two rounds of CPR. Patient received dextrose infusion to maintain euglycemic state. She was not taking any QTc prolonging medication. There was no history of autoimmune disease. Except for hypoglycemia, no other metabolic abnormality could be identified. Cardiac and pulmonary etiologies of cardiac arrest were ruled out. Post-ROSC ECG showed sinus tachycardia with normalization of QTc to 454ms. Thus, Insulin-induced hypoglycemia was appointed as the main culprit for her cardiac arrest, in the setting of QTc prolongation. Patient received diabetes self-management and hypoglycemia education. Conclusion: Several studies support strong correlation between hypoglycemia and arrhythmic events during bedtime in people with diabetes “The dead in bed syndrome”. Hypoglycemia causes an acquired long QT syndrome independent of other risk factors such as cardiac autonomic neuropathy. Possible mechanisms include; sympathoadrenal activation, which regulates potassium, calcium and chloride channels or altered autonomic regulation caused by hypoglycemia itself regardless of the effect of insulin or hypokalemia. QT prolongation is a risk factor for sudden cardiac death by causing torsades de pointes ventricular tachycardia (VT).People with insulin dependent diabetes are at high risk of hypoglycemia and should be cautioned about the proarrhythmic risk of hypoglycemia. Education is crucial, and Continuous glucose monitor (CGM) is a valuable tool to be use in such a patient population. Presentation: 6/3/2024

Examining hypothalamic-pituitary-adrenal axis genetic variation on cortisol and alpha-amylase reactivity during an explicit negative-evaluative stress induction.

Prior work consistently links additive genetic variation in the hypothalamic-pituitary-adrenal (HPA) axis-a multilocus genetic profile score (MGPS)-to depression risk in the context of stress exposure. However, despite that HPA MGPS variants were selected based on evidence that they elevate cortisol reactivity, there are surprisingly few tests of whether an HPA MGPS elevates cortisol reactivity to lab-based stress. Similarly, despite neurobiological connections and coordination between the HPA axis and the sympathetic nervous system (e.g., in the paraventricular nucleus and locus coeruleus), no work has tested whether an HPA MGPS influences sympathetic nervous system reactivity to stress. We investigated whether an HPA MGPS moderates the relation between lab-based stress and: (1) HPA activity indexed by cortisol, and/or (2) sympathetic activity indexed by salivary alpha-amylase, sAA. Emerging adults (N=152; mean age=19.5, largest subsample 44.4% Black/African American) were randomly assigned to one of two Trier Social Stress Test variations, a non-evaluative control, or an explicitly negative-evaluative condition. Participants provided DNA and repeated saliva samples for sAA and cortisol. The HPA MGPS did not significantly moderate the relationship between stress condition and cortisol or sAA reactivity, respectively; moreover, post-hoc tests highlight that individual polymorphisms showed non-significant effects in opposite directions from each other, cancelling out in aggregate. Findings suggest that the HPA MGPS's associations with cortisol reactivity are not as straightforward as initially believed. We speculate that the relationships of some HPA variants to biomarker reactivity may vary between modest lab-based stressors and the explicit negative-evaluative induction used here.

Acute Alcohol Consumption and Arrhythmias in Young Adults: The MunichBREW II Study.

and aims: Acute excessive alcohol intake may cause the holiday heart syndrome, characterized by cardiac arrhythmias including atrial fibrillation. Since underlying data are scarce, the study aimed to prospectively investigate the temporal course of occurring cardiac arrhythmias following binge drinking in young adults. A total of 202 volunteers planning acute alcohol consumption with expected peak breath alcohol concentrations (BAC) of ≥1.2 g/kg were enrolled. The study comprised 48-hour electrocardiogram (ECG) monitoring covering baseline (hour 0), 'drinking period' (hours 1-5), 'recovery period' (hours 6-19), and two control periods corresponding to 24 hours after the 'drinking' and 'recovery periods', respectively. Acute alcohol intake was monitored by BAC measurements during the 'drinking period'. ECGs were analyzed for mean heart rate, atrial tachycardia, premature atrial complexes (PAC), premature ventricular complexes (PVC), and heart rate variability (HRV) measures. Data revealed an increase in heart rate and an excess of atrial tachycardias with increasing alcohol intake. HRV analysis indicated an autonomic modulation with sympathetic activation during alcohol consumption and the subsequent 'recovery period', followed by parasympathetic predominance thereafter. PACs occurred significantly more frequently in the 'control periods', whereas PVCs were more frequent in the 'drinking period'. Ten participants experienced notable arrhythmic episodes, including atrial fibrillation and ventricular tachycardias, primarily during the 'recovery period'. The study demonstrates the impact of binge drinking on heart rate alterations and increased atrial tachycardias during 'drinking period', and the occurrence of clinically relevant arrythmias during the 'recovery period', emphasizing the holiday heart syndrome as a health concern.

Interleukin-2 improves insulin sensitivity through hypothalamic sympathetic activation in obese mice

BackgroundIL-2 regulates T cell differentiation: low-dose IL-2 induces immunoregulatory Treg differentiation, while high-dose IL-2 acts as a potent activator of cytotoxic T cells and NK cells. Therefore, high-dose IL-2 has been studied for use in cancer immunotherapy. We aimed to utilize low-dose IL-2 to treat inflammatory diseases such as obesity and insulin resistance, which involve low-grade chronic inflammation.Main bodySystemic administration of low-dose IL-2 increased Treg cells and decreased inflammation in gonadal white adipose tissue (gWAT), leading to improved insulin sensitivity in high-fat diet-fed obese mice. Additionally, central administration of IL-2 significantly enhanced insulin sensitivity through the activation of the sympathetic nervous system. The sympathetic signaling induced by central IL-2 administration not only decreased interferon γ (IFNγ) + Th1 cells and the expression of pro-inflammatory cytokines, including Il-1β, Il-6, and Il-8, but also increased CD4 + CD25 + FoxP3 + Treg cells and Tgfβ expression in the gWAT of obese mice. These phenomena were accompanied by hypothalamic microgliosis and activation of pro-opiomelanocortin neurons. Furthermore, sympathetic denervation in gWAT reversed the enhanced insulin sensitivity and immune cell polarization induced by central IL-2 administration.ConclusionOverall, we demonstrated that IL-2 improves insulin sensitivity through two mechanisms: direct action on CD4 + T cells and via the neuro-immune axis triggered by hypothalamic microgliosis.

Renal nerves in physiology, pathophysiology and interoception.

Sympathetic efferent renal nerves have key roles in the regulation of kidney function and blood pressure. Increased renal sympathetic nerve activity is thought to contribute to hypertension by promoting renal sodium retention, renin release and renal vasoconstriction. This hypothesis led to the development of catheter-based renal denervation (RDN) for the treatment of hypertension. Two RDN devices that ablate both efferent and afferent renal nerves received FDA approval for this indication in 2023. However, in animal models, selective ablation of afferent renal nerves resulted in comparable anti-hypertensive effects to ablation of efferent and afferent renal nerves and was associated with a reduction in sympathetic nerve activity. Selective afferent RDN also improved kidney function in a chronic kidney disease model. Notably, the beneficial effects of RDN extend beyond hypertension and chronic kidney disease to other clinical conditions that are associated with elevated sympathetic nerve activity, including heart failure and arrhythmia. These findings suggest that the kidney is an interoceptive organ, as increased renal sensory nerve activity modulates sympathetic activity to other organs. Future studies are needed to translate this knowledge into novel therapies for the treatment of hypertension and other cardiorenal diseases.

Persistence of post-stress blood pressure elevation requires activation of astrocytes

The reflexive excitation of the sympathetic nervous system in response to psychological stress leads to elevated blood pressure, a condition that persists even after the stress has been alleviated. This sustained increase in blood pressure, which may contribute to the pathophysiology of hypertension, could be linked to neural plasticity in sympathetic nervous activity. Given the critical role of astrocytes in various forms of neural plasticity, we investigated their involvement in maintaining elevated blood pressure during the post-stress phase. Specifically, we examined the effects of arundic acid, an astrocytic inhibitor, on blood pressure and heart rate responses to air-jet stress. First, we confirmed that the inhibitory effect of arundic acid is specific to astrocytes. Using c-Fos immunohistology, we then observed that psychological stress activates neurons in cardiovascular brain regions, and that this stress-induced neuronal activation was suppressed by arundic acid pre-treatment in rats. By evaluating astrocytic process thickness, we also confirmed that astrocytes in the cardiovascular brain regions were activated by stress, and this activation was blocked by arundic acid pre-treatment. Next, we conducted blood pressure measurements on unanesthetized, unrestrained rats. Air-jet stress elevated blood pressure, which remained high for a significant period during the post-stress phase. However, pre-treatment with arundic acid, which inhibited astrocytic activation, suppressed stress-induced blood pressure elevation both during and after stress. In contrast, arundic acid had no significant impact on heart rate. These findings suggest that both neurons and astrocytes play integral roles in stress-induced blood pressure elevation and its persistence after stress, offering new insights into the pathophysiological mechanisms underlying hypertension.

To the issue of vagosympathetic balance assessment in patients with facial phlegmon

Objective. To assess the influence of the autonomic nervous system tone on the activity of the inflammatory process in facial phlegmon. Materials and methods. A group of patients with facial phlegmon (n = 74) was divided into two parts according to the predominant type of ANS. To identify the dominant type of ANS the method of A.M. Vayne was used. The content of leukocytes and their types was assessed in peripheral blood samples. The concentration of glucose, total protein, C-reactive protein was determined in the patients` blood serum. Statistical data processing was carried out using Student's t-test. Results. Significant differences in laboratory parameters of patients with facial phlegmons with different types of the autonomic nervous system are demonstrated. In patients with prevailing sympathetic division, leukocytosis with a shift of the formula to the left was more pronounced. When the parasympathetic division dominated, a higher concentration of C-reactive protein was observed. Conclusion. Assessment of the autonomic nervous system tone in case of facial phlegmons indicates its significant impact on the activity of the inflammatory process, which affects the duration of inpatient treatment.

Role of the Kölliker-Fuse/parabrachial complex in the generation of postinspiratory vagal and sympathetic nerve activities and their recruitment by hypoxemic stimuli in the rat.

In the rat, the activity of laryngeal adductor muscles, the crural diaphragm, and sympathetic vasomotor neurons is entrained to the postinspiratory (post-I) phase of the respiratory cycle, a mechanism thought to enhance cardiorespiratory efficiency. The identity of the central neurons responsible for transmitting respiratory activity to these outputs remains unresolved. Here we explore the contribution of the Kölliker-Fuse/parabrachial nuclei (KF-PBN) in the generation of post-I activity in vagal and sympathetic outputs under steady-state conditions and during acute hypoxemia, a condition that potently recruits post-I activity. In artificially ventilated, vagotomized, and urethane-anesthetized rats, bilateral KF-PBN inhibition by microinjection of the GABAA receptor agonist isoguvacine evoked stereotypical responses on respiratory pattern, characterized by a reduction in phrenic nerve burst amplitude, a modest lengthening of inspiratory time, and an increase in breath-to-breath variability, while post-I vagal nerve activity was abolished and post-I sympathetic nerve activity diminished. During acute hypoxemia, KF-PBN inhibition attenuated tachypneic responses and completely abolished post-I vagal activity while preserving respiratory-sympathetic coupling. Furthermore, KF-PBN inhibition disrupted the decline in respiratory frequency that normally follows resumption of oxygenation. These findings suggest that the KF-PBN is a critical hub for the distribution of post-I activities to vagal and sympathetic outputs and is an important contributor to the dynamic adjustments to respiratory patterns that occur in response to acute hypoxia. Although KF-PBN appears essential for post-I vagal activity, it only partially contributes to post-I sympathetic nerve activity, suggesting the contribution of multiple neural pathways to respiratory-sympathetic coupling.NEW & NOTEWORTHY Inhibition of neurons in the pontine Kölliker-Fuse/parabrachial complex (KF-PBN) differentially inhibited postinspiratory (post-I) activity in vagal and sympathetic outputs. The strong recruitment of post-I vagal activity that occurs in response to hypoxemia is selectively abolished by KF-PBN inhibition. This suggests that 1) post-I activity in vagal and sympathetic outputs may be generated by partially independent mechanisms and 2) neurons in the KF-PBN are a preeminent source of drive for the generation of eupneic post-I activity.

An Optimized Liquid Chromatography-Mass Spectrometry Method for Ganglioside Analysis in Cell Lines.

Gangliosides are glycosphingolipids composed of a sialylated glycan head group and a ceramide backbone. These anionic lipids form lipid rafts and play crucial roles in regulating various proteins involved in signal transduction, adhesion, and cell-cell recognition. Neuroblastoma, a pediatric cancer of the sympathetic nervous system, is treated with intensive chemotherapy, radiation, and an antibody targeting the GD2 ganglioside. Gangliosides are critical in neuroblastoma development and serve as therapeutic targets, making it essential to establish a reliable, rapid, and cost-effective method for profiling gangliosides, particularly one capable of isomeric separation of intact species. In this study, liquid chromatography-mass spectrometry (LC-MS) was optimized using standard gangliosides, followed by the optimization of sphingolipid extraction methods from cell lines by comparing Folch and absolute methanol extraction techniques. Percent recovery and the number of identified sphingolipids were used to evaluate the analytical merits of these methods. A standard gangliosides calibration curve demonstrated excellent linearity (R2 = 0.9961-0.9975). The ZIC-HILIC column provided the best separation of ganglioside GD1 isomers with a 25 min runtime. GD1a elutes before GD1b on the ZIC-HILIC column. Absolute methanol yielded better percent recovery (96 ± 7) and identified 121 different sphingolipids, the highest number between the two extraction methods. The optimized method was applied to profile gangliosides in neuroblastoma (COG-N-683), pancreatic cancer (PSN1), breast cancer (MDA-MB-231BR), and brain tumor (CRL-1620) cell lines. The ganglioside profile of the neuroblastoma cell line COG-N-683 showed an inverse relationship between GD1 and GD2. Ceramide, Hex1Cer, GM1, and GM3 were highly abundant in CRL-1620, PSN1, and MDA-MB-231BR, respectively. These results suggest that our method provides a sensitive, reliable, and high-throughput workflow for ganglioside profiling across different cell types.

Tyrosine hydroxylase-positive neurons in the rostral ventrolateral medulla mediate sympathetic activation in sepsis

AimSepsis 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. MethodsPatients 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). ResultsIn 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. ConclusionThe 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.

Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity.

The mechanisms underlying obesity-induced insulin resistance remain incompletely understood, as impaired cellular insulin signaling, traditionally considered the primary driver of insulin resistance, does not always accompany impaired insulin action. Overnutrition rapidly increases plasma norepinephrine (NE), suggesting overactivation of the sympathetic nervous system (SNS). However, the role of the SNS in obesity is controversial, as both increased and decreased SNS activity (SNA) have been reported. Here, we show that reducing catecholamine (CA) release from the SNS protects against overnutrition-induced insulin resistance as well as hyperglucagonemia, adipose tissue dysfunction, and fatty liver disease, as we demonstrate utilizing a mouse model of inducible and peripherally restricted deletion of tyrosine hydroxylase (th; THΔper). A key mechanism through which heightened SNA induces insulin resistance is by triggering adipose tissue lipolysis. Increased SNA emerges as a critical driver in the pathogenesis of overnutrition-induced insulin resistance and metabolic disease independent of cellular insulin signaling.

Neuro- and immuno-modulation mediated by the cardiac sympathetic nerve: a novel insight into the anti-ischemic efficacy of acupuncture.

Communication between sympathetic nerves and the immune system is a crucial and active process during myocardial ischemia (MI), as myocardial damage and inflammatory stimuli concurrently occur. Sympathetic nerves undergo structural and functional changes after MI, leading to adverse left ventricular (LV) remodeling and heart failure (HF). The complex inflammatory response to MI, including local myocardial anti-inflammatory repair and systemic immune reactions, plays a key role in adverse LV remodeling. Here, we review the progressive structural and electrophysiological remodeling of the LV and the involvement of sympathetic tone in complex and dynamic processes that are susceptible to MI pathological conditions. Acupuncture has been reported to effectively improve cardiac function, eliminate arrhythmia, and mitigate adverse LV remodeling via somatosensory regulation after MI. Moreover, acupuncture has an anti-inflammatory effect on the pathological process of myocardial ischemia. In this Review, we aim to summarize the involvement of sympathetic nerve activation in the neuro-immune modulation of structural and functional cardiac changes after MI. As a noninvasive method for sympathetic regulation, acupuncture is an ideal option because of its anti-ischemic efficacy. A better understanding of the neural circuitry that regulates cardiac function and immune responses following MI could reveal novel targets for acupuncture treatment.

Binge Alcohol Consumption Elevates Sympathetic Transduction to Blood Pressure: A Randomized Controlled Trial.

Alcohol consumption is associated with cardiovascular disease, and the sympathetic nervous system is a suspected mediator. The present study investigated sympathetic transduction of muscle sympathetic nerve activity to blood pressure at rest and in response to cold pressor test following evening binge alcohol or fluid control, with the hypothesis that sympathetic transduction would be elevated the morning after binge alcohol consumption. Using a randomized, fluid-controlled (FC) crossover design, 26 healthy adults (12 male, 14 female, 25±6 years, 27±4 kg/m2) received an evening binge alcohol dose and a FC. All participants underwent next-morning autonomic-cardiovascular testing consisting of muscle sympathetic nerve activity, beat-to-beat blood pressure, and heart rate during a 10-minute rest period and a 2-minute cold pressor test. Sympathetic transduction was assessed at rest and during the cold pressor test in both experimental conditions. Evening alcohol increased heart rate (FC: 60±9 versus alcohol: 64±9 bpm; P=0.010) but did not alter resting mean arterial pressure (FC: 80±6 versus alcohol: 80±7 mm Hg; P=0.857) or muscle sympathetic nerve activity (FC: 18±9 versus alcohol: 20±8 bursts/min; P=0.283). Sympathetic transduction to mean arterial pressure (time×condition; P=0.003), diastolic blood pressure (time×condition; P=0.010), and total vascular conductance (time×condition; P=0.004) was augmented after alcohol at rest. Sympathetic transduction during the cold pressor test was also elevated after evening binge alcohol consumption (P=0.002). These findings suggest that evening binge alcohol consumption leads to augmented morning-after sympathetic transduction of muscle sympathetic nerve activity to blood pressure, highlighting a new mechanism whereby chronic or excessive alcohol consumption contributes to cardiovascular disease progression via altered end-organ responsiveness to sympathetic neural outflow. URL: https://clinicaltrials.gov/study/NCT03567434; Unique identifier: NCT03567434.

Impact of neonatal hyperoxia on adult cardiac autonomic function in rats: Role of angiotensin II type 1 receptor activation

Individuals born preterm present altered cardiac autonomic function, a risk factor to heart diseases. Neonatal renin-angiotensin-system activation contributes to adult cardiomyopathy in rats exposed to neonatal hyperoxia, a well-established model of preterm birth-related conditions. Central angiotensin II receptor activation is a key modulator of the autonomic drive to the heart. Whether neonatal hyperoxia leads to alteration of the cardiac autonomic function through activation of the angiotensin II receptor type 1 (AT1) is unknown and was examined in the present study.Sprague-Dawley pups were exposed to hyperoxia or room air from postnatal days 3–10. AT1 antagonist losartan or water was given orally postnatal days 8–10. Blood pressure, autonomic function, left ventricular sympathetic innervation, β-adrenergic-receptors expression, and AT1 expression in the solitary-tract-nucleus were examined in adult rats.Neonatal hyperoxia led to loss of day-night blood pressure variation, decreased heart rate variability, increased sympathovagal balance, increased AT1 expression in the solitary-tract, decreased left ventricle sympathetic innervation, and increased β1-adrenergic-receptor protein expression. Losartan prevented the autonomic changes and AT1 expression in the solitary-tract but did not impact the loss of circadian blood pressure variation nor the changes in sympathetic innervation and in β1-adrenergic-receptor expression.In conclusion, neonatal hyperoxia leads to both central autonomic and cardiac sympathetic changes, partly programmed by neonatal activation of the renin-angiotensin system.

Activated sympathetic nerve post stroke downregulates Toll-like receptor 5 and disrupts the gut mucosal barrier

The gut permeability significantly increases after ischemic stroke, partly due to disrupted mucosal barrier, but the mechanism remains elusive. Here, we found that the mucus disruption starts at 2h post stroke, whereas goblet cell functions remain intact. Meanwhile, the flagellated bacteria Helicobacter thrives and penetrates in the mucus layer. Elimination of the mucosal microbiota or transplantation of Helicobacter in germ-free mice reveals an important role of the mucosal microbiota in mucus disruption. The bacterial invasion is due to downregulated Toll-like receptor 5 (TLR5) and its downstream products flagellin-specific IgA and antimicrobial peptides. Knockdown of intestinal TLR5 increases the abundance of flagellated bacteria and exacerbates mucus injury. Intestinal TLR5 is downregulated by the activation of sympathetic nerve. Serum noradrenaline level is positively associated with flagellin level in patients with stroke and patients' prognosis. These findings reveal a neural pathway in which the sympathetic nerve disrupts the mucosal barrier, providing potential therapeutic targets for stroke injury.

“Assessment Of Cardiac Autonomic Dysfunction In Children With Cerebral Palsy Using Heart Rate Variability”

Background: Cardiac autonomic imbalance in children with CP might be due to primary brain insult, vary with different levels of Gross Motor Functional Classification System or may alter with multimodal therapies in various types of cerebral palsy (1,2) . It is important to understand and to create awareness that autonomic impairment in children with CP is in part due to sedentary lifestyle (3).HRV(Heart Rate Variability) in cerebral palsy is recognized as an important tool for monitoring cardiovascular health, in which autonomic imbalance is characterized by reduced HRV (i.e. regarded as increased cardiac sympathetic activity and decreased vagal modulation) (4,5) . Of the research that does exist, each study discusses only very few parameters of the autonomic nervous system, thus providing opportunities for further research and hence the need for the study. Materials and Methods: This is a cross-sectional case control study of 51 children with Cerebral Palsy (CP) and 51 normal children, conducted at District Early Intervention Centre (DEIC) in the Department of Paediatrics, Vani Vilas hospital. These 51 cases were assessed and classified based on their demographic features, etiology, type of CP, GMFCS scale and with the objectives of assessing the heart rate variability (HRV) in children with cerebral palsy and compare it with controls in both supine position and after a stress test, and also to correlate the obtained parameters with GMFCS level, type of CP using a systematically designed proforma. Results: Results of the study showed that of the children with CP studied, 62% were male children, and majority of were between 6-8 years of age (58%), and it was found that the most common etiology for CP in our study was due to perinatal asphyxia (43%), and 80% of the children had history of NICU admission. Of the 51 cerebral palsy children studied 72% were in GMFCS levels 3 and 4, regarding the topographical classification majority had spastic quadriplegia (58.8%) followed by spastic diplegia (15.7%). Study revealed that cerebral palsy children had significantly lower HRV, higher sympathetic activity, autonomic response deficit to stress test, and higher autonomic dysfunction when compared to normal children. Among cases, HRV was lowest with spastic quadriplegia and triplegic CP, in functional classification HRV was lowest among GMFCS 4 and 3. Conclusion: Cerebral palsy children had significantly higher sympathetic activity and less cardiac vagal modulation compared to normal children in supine position and there was existence of autonomic response deficit in cerebral palsy children after stress test, higher the motor impairment, higher was the sympathetic activity

The sympathetic nervous system drives hyperinflammatory responses to Clostridioides difficile infection

Clostridioides difficile infection (CDI) is a leading cause of hospital-acquired infections in the United States, known for triggering severe disease by hyperactivation of the host response. In this study, we determine the impact of the sympathetic nervous system (SNS) on CDI disease severity. Mouse models of CDI are administered inhibitors of SNS activity prior to CDI. Chemical sympathectomy or pharmacological inhibition of norepinephrine synthesis greatly reduces mortality and disease severity in the CDI model. Pharmacological blockade or genetic ablation of the alpha 2 adrenergic receptor ameliorates intestinal inflammation, disease severity, and mortality rate. These results underscore the role of the SNS and the alpha 2 adrenergic receptor in CDI pathogenesis and suggest that targeting neural systems could be a promising approach to therapy in severe disease.