Excessive Catecholamine Release Research Articles

Methamphetamine-induced cardiotoxicity: in search of protective transcriptional mechanisms.

Crystalline methamphetamine hydrochloride is an illegal drug with ahigh addictive potential, better known by its colloquial name "ice" or "crystal meth". The abuse of this drug has led to significant health problems worldwide. Like other amphetamine-type stimulants, chronic consumption of methamphetamine leads to direct toxic effects on the central nervous system, causing cognitive impairment, depressive behavior, and other severe neurological or psychiatric symptoms. Besides its neurotoxicity, the drug exhibits numerous deleterious effects on the cardiovascular system, including hypertension, accelerated atherosclerosis, vasospasm-induced acute coronary syndromes, sudden cardiac death, and dilated cardiomyopathy with congestive heart failure and left ventricular dysfunction. The excessive release of catecholamines upon methamphetamine exposure causes vasoconstriction and vasospasm, which ultimately lead to hypertension, tachycardia, endothelial dysfunction, and cardiotoxicity. While numerous studies have focused on transcription factors expressed in the brain that cause the neurotoxic effects of the drug, much less is known about transcription factors involved in the development of methamphetamine-induced heart failure. In this article, we provide an overview of the Janus kinase-signal transducer and activator of transcription3 (JAK-STAT3) pathway involved in ischemia/reperfusion injury in the myocardium, which may be activated by the vasospasm-inducing action of the drug. However, much more work is needed to decipher the precise role of STAT protein family members, including the potentially cardioprotective STAT3, in the pathogenesis of methamphetamine-induced cardiotoxicity.

8204 Rare Asymptomatic Presentation Of A Large Pheochromocytoma

Abstract Disclosure: A. Lorin: None. C.K. Persaud: None. M.H. Kemm: None. Background: Pheochromocytoma is a rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla. It is associated with excessive release of catecholamines causing symptoms of hypertension, palpitations, diaphoresis, and headaches. These symptoms are particularly prominent with larger pheochromocytomas. We present the case of a large 13 cm pheochromocytoma (PCC) without the typical associated symptoms. Clinical Case: A 45-year-old male with medical history of osteoarthritis and gastroesophageal reflux presented to his primary care doctor with 2 months of intermittent right upper quadrant abdominal pain associated with nausea. Work up with CT abdomen/pelvis found a 9.3 cm heterogeneous right adrenal mass with mass effect on the right liver lobe, superior pole of the right kidney, duodenum, and pancreatic head. Hormonal testing was notable for plasma metanephrine 257.8 pg/mL (0-88), plasma normetanephrine 12063.7 pg/mL (0.0-218.9), 24 hr urine metanephrine 159 mcg/24 hr (58-276), 24 hr urine normetanephrine 22575 mcg/24 hr (156-729), and chromogranin A 5387 mg/mL (0-101.8). Given lab evaluation, diagnosis was made of pheochromocytoma, and patient was initiated on alpha blockade with doxazosin. Patient’s blood pressure and heart rate were at goal prior to doxazosin initiation and patient needed to be decreased from 1 mg daily to 0.5 mg daily due to side effects of low blood pressure and orthostatic hypotension. Patient had an uncomplicated open right adrenalectomy with pathology showing a 13 cm pheochromocytoma with invasion through the capsule into the periadrenal adipose tissue. Genetic testing revealed no known mutation variants associated with PCC. Labs drawn two weeks postoperatively showed resolution of elevated plasma metanephrine, normetanephrine, and chromogranin A. Conclusion: While the patient had an elevated plasma metanephrine, the normetanephrine was predominantly elevated. Such a hormone profile is more common in extra-adrenal PCCs, consistent with cluster 1 associated genes. This noradrenergic phenotype is likely a reason the patient did not have typical symptoms, despite the size of his pheochromocytoma. A proposed pathophysiologic mechanism for this is the dissociation of renal medulla from the cortex given the large size of the tumor. This would lead to lower local availability of corticosteroid to potentiate the conversion of norepinephrine to epinephrine, thus decreasing likelihood of classical PCC symptoms. Despite lack of expected symptoms and an imaging initially concerning for adrenocortical carcinoma, we should recognize the potential for a large adrenal tumor to represent PCC and evaluate accordingly. Presentation: 6/1/2024

6661 Critical Limb Ischemia - An Unusual Presentation Of A Pheochromocytoma

Abstract Disclosure: S. Hassan: None. Background: Pheochromocytomas can lead to vasoconstriction and its various clinical manifestations due to excess catecholamine release. Critical limb ischemia as a clinical manifestation of pheochromocytoma has been reported sparsely. Clinical Case: A 43 year old female with a past medical history of type 2 diabetes mellitus, Turner syndrome, and hypertension presented to the emergency department with acute on chronic left leg pain. She underwent workup with a CT angiography of the abdomen with runoff for evaluation of her vessels, which revealed an occlusion of her left superficial femoral artery with chronic stenosis of the right femoral system. Multiple unsuccessful attempts were made at revascularization of her left lower extremity, including femoropopliteal bypass, with eventual left above knee amputation, multiple fasciotomies, and angiogram and stenting of multiple vessels. The patient was on a combined OCP (norethindrone-ethinyl estradiol) for hormone replacement for Turner syndrome for the past 30 years, and did not have a personal or family history of clotting disorders. She underwent a hypercoagulable workup which was negative. Echocardiogram was negative for thrombi and was otherwise unremarkable. Incidentally discovered on her initial CT angiography was a heterogeneously enhancing right adrenal mass, which was further delineated on a dedicated CT of the adrenals, which showed a 3.7 cm right adrenal mass with pre-contrast Hounsfield units measuring 46. Biochemical workup revealed a normal plasma renin activity and aldosterone, plasma metanephrine elevated to 5.20 nmol/L (range 0.00 – 0.49 nmol/L), plasma normetanephrine elevated to 4.95 nmol/L (range 0.00 – 0.89 nmol/L), 24 hour urine metanephrine elevated to 3830 ug/d (range 36-229 ug/d), and 24 hour urine normetanephrine 1733 ug/d (range 95 – 650 ug/d). She reports a diagnosis of hypertension at age 36, with no secondary workup pursued; she had suboptimal control on three separate medications, lisinopril, metoprolol, and hydrochlorothiazide. Her blood pressure and heart rate were noted to be labile during her aforementioned surgery. Alpha blockade with doxazosin was started based on her significantly elevated plasma and urine metanephrines and normetanephrines, with improvement in her blood pressure control. She was not found to have a definitive cause of her critical limb ischemia; she was noted to have atherosclerosis in the vessels of her lower extremities, and her chronic oral contraceptive use may also have played a role. However, OCPs are often reported to cause venous rather than arterial thrombi. Therefore, it can be inferred that the catecholamine excess from her presumed pheochromocytoma caused vasoconstriction which may have played a role in the development of her critical limb ischemia. Conclusion: Catecholamine excess that is resultant from a pheochromocytoma may manifest as critical limb ischemia. Presentation: 6/1/2024

Diabetes and obesity: the role of stress in the development of cancer.

Diabesity is a condition where an individual has both diabetes and obesity, which can lead to severe complications including cardiovascular disease, a leading cause of mortality. Recently, cancer has become a leading cause of excess hospitalizations, and both diabetes and obesity are associated with a higher risk of developing several types of cancer. In this review, we propose that chronic stress significantly increases this association. Managing diabetes and obesity is challenging as they both cause significant distress. The relationship between stress and cancer is interconnected, with anxiety and depression being common in cancer patients. Cancer diagnosis and treatment can cause lasting changes in the body's neuroendocrine system, with stress causing an excessive release of catecholamines and prostaglandins in patients undergoing cancer surgery, which promotes the spread of cancer to other parts of the body. Furthermore, stress could significantly increase the risk of cancer in patients with diabetes, obesity, or both.

“A BROKEN TRANSPLANTED HEART”: A CASE OF TAKOTSUBO SYNDROME IN A HEART TRANSPLANT RECIPIENT

Abstract 75–year–old female patient went to the emergency department for oppressive chest pain radiating to the left arm and dyspnea, developed after an argument with family members. The patient underwent heart transplant in 2010 because of chronic ischemic heart disease. In history: systemic arterial hypertension, former smoking, dyslipidemia, and chronic renal failure. At blood tests: TnIHS 78.4 ng/L (<29 ng/L), CK–MB 1.9 microg/L, PROBNP–NT 43,000 pg/ml, creatinine 2 mg/dL. ECG showed inverted T waves in DI, AVL and V4 to V6 (fig 1). Transthoracic echocardiography was remarkable for a moderate reduction in systolic function (EF 38%), akinesia of apical portion, mid–segment of the IVS and mid–segment of posterior wall. Coronarography showed epicardial coronaries free of angiographically significant lesions. We decided to not perform ventriculography to avoid worsening renal function. At clinical stabilization, the patient underwent cardiac MRI with evidence of hypokinesia of the mid–ventricular segments with preserved global systolic function and hypo/akinesia of right ventricular apex with endocavitary thrombosis. Tissue characterization images were compatible with the presence of diffuse phlogistic involvement of the left ventricular myocardium (most evident at the mid–ventricular segments), in the absence of areas of myocardial necrosis. On pre–dimission echocardiogram, global left ventricular systolic function appeared markedly improved (auto EF 52%). DISCUSSION Our case is a rare case of Takotsubo syndrome (TS) in a transplanted heart. While TS accounts for 1–2% of all ACS in the general population, there is no precise data on its prevalence in heart transplant recipients. Although the pathophysiological mechanism underlying TS is still debated, there is evidence of hyperactivation of the sympathetic system with excessive catecholamine release. What is particular in our clinical case is that transplanted heart is denervated (because of resection of the post–ganglionic neural axons), although in some patients there is progressive reinnervation starting around the second year. Myocardial scintigraphy with iodine–123 meta iodobenzylguanidine can be used to study reinnervation. In our case, the presence of typical angor may be a clinical indicator of reinnervation, as many transplant patients present with CAV in the absence of chest pain.

Amphetamine increases vascular permeability by modulating endothelial actin cytoskeleton and NO synthase via PAR-1 and VEGF-R

Abuse of amphetamine-type stimulants is linked to cardiovascular adverse effects like arrhythmias, accelerated atherosclerosis, acute coronary syndromes and sudden cardiac death. Excessive catecholamine release following amphetamine use causes vasoconstriction and vasospasms, over time leading to hypertension, endothelial dysfunction or even cardiotoxicity. However, immediate vascular pathomechanisms related to amphetamine exposure, especially endothelial function, remain incompletely understood and were analyzed in this study. Pharmaco-pathological effects of acute d-amphetamine-sulfate (DAM) were investigated ex vivo using contraction–force measurements of rat carotid artery rings and in vitro using label-free, real-time electrochemical impedance spectroscopy (EIS) on endothelial and smooth muscle cells. Specific receptor and target blocking was used to identify molecular targets and to characterize intracellular signaling. DAM induced vasodilation represented by 29.3±2.5% decrease in vascular tone (p<0.001) involving vascular endothelial growth factor receptor (VEGF-R) and protease activated receptor 1 (PAR-1). EIS revealed that DAM induces endothelial barrier disruption (−75.9±1.1% of initial cellular impedance, p<0.001) also involving VEGF-R and PAR-1. Further, in response to DAM, Rho-associated protein kinase (ROCK) mediated reversible contraction of actin cytoskeleton resulting in endothelial barrier disruption. Dephosphorylation of Serine1177 (−50.8±3.7%, p<0.001) and Threonine495 (−44.8±6.5%, p=0.0103) of the endothelial NO synthase (eNOS) were also observed. Blocking of VEGF-R and PAR-1 restored baseline eNOS Threonine495 phosphorylation. DAM induced vasodilation, enhanced vascular permeability and actin cytoskeleton contraction and induced eNOS hypophosphorylation involving VEGF-R, PAR-1 and ROCK. These results may contribute to a better understanding of severe adverse cardiovascular effects in amphetamine abuse.

Successful treatment of cardiogenic shock due to Takotsubo syndrome with implantation of a temporary microaxial left ventricular assist device in transaxillary approach

ObjectivesCardiogenic shock (CS) can occur in patients with Takotsubo syndrome (TTS). As TTS has received increasing attention and has been more closely researched, several aspects of the pathogenesis have been identified, particularly that an excessive release of catecholamines plays an important role. Nevertheless, evidence on specific therapy concepts is still lacking. As a result, TTS with severe hemodynamic instability and low cardiac output creates unique challenges, and mechanical circulatory support is needed with as few inotropic drugs as possible.MethodsWe present a 77-year-old female patient who underwent minimally invasive surgical mitral valve replacement. After an uneventful course, the patient developed acute heart failure eleven days after surgery. Transthoracic echocardiography (TTE) revealed a new onset of TTS. The patient needed left ventricular venting and full haemodynamic flow. We successfully implanted a microaxial left ventricular assist device (Impella 5.5) using the transaxillary approach. The haemodynamic situation stabilised immediately. The patient was weaned and the Impella 5.5 was explanted after five days.ConclusionWe present the first-in-man implantation of a transaxillary Impella 5.5 in a patient with TTS. The patient benefitted from Impella 5.5 therapy with full haemodynamic support and venting of the left ventricle.

OTHER-11 DEMENTIA AND EPILEPSY REVERSED SUCCESSFULLY THROUGH STAGED EMBOLISATION OF A SYMPTOMATIC HYPERVASCULAR PARAGANGLIOMA : A CASE REPORT

Abstract INTRODUCTION Paragangliomas (PGs) are rare neuroendocrine tumours that can arise from parasympathetic glossopharyngeal and vagus nerves. Atypical presentations involving seizures and dementia can occur due to excessive catecholamine release. Physiological intracranial arteriovenous fistulae (AVF) can occur concurrently due to increased vascularity, especially in the cavernous and sigmoid sinuses. METHODS We present a case of a patient who developed a highly vascular AVF from an ipsilateral glomus jugulare PG, presenting with rapidly progressive but reversible dementia and epilepsy. CASE: A 64-year-old lady presented on several occasions with new-onset stereotyped episodes of confusional dysphasia suggestive of seizures, confirmed on electroencephalography. Further history revealed two years of progressive deafness and imbalance, and one year of increasing forgetfulness and executive dysfunction, which had deteriorated rapidly in the period of the patient's current presentations. Montreal cognitive assessment (MoCA) score was 21/30 at baseline (normal score &amp;gt;25/30), and she had no lateralising signs. Serial brain magnetic resonance imaging (MRI) revealed progressively worsening vasculopathic white matter hyper-intensities (WMHs). Eventual MR angiography showed a 14x22×23mm right glomus jugulotympanicum PG with numerous feeding arteries, and associated multiple AVFs (Cognard grade III). She was initially managed with anti-seizure medications and then discussed in our multidisciplinary neurosciences meeting. The patient underwent staged right glomus jugulare embolization over several weeks. Her cognitive function gradually improved, and at three months she had fully returned to normal functioning with a MoCA of 30/30 and no residual neurological deficit. The WMHs disappeared on follow-up MRI scans. CONCLUSION Our case highlights a rare clinical presentation of dementia and seizures from a right glomus jugulare PG with associated AVF. Multidisciplinary involvement was key in excluding other causes, and definitive treatment of the PG led to complete reversal of the patient’s dementia.

PD-L1 Expression is Linked to Tumor-Infiltrating T-Cell Exhaustion and Adverse Pathological Behavior in Pheochromocytoma/Paraganglioma

Pheochromocytoma/paraganglioma (PPGL) is an endocrine-related tumor associated with excessive catecholamine release and has limited treatment options once metastasis occurs. Although recent phase 2 clinical trials of immune checkpoint inhibitors in the treatment of PPGL have preliminarily shown promising results, the fundamentals of immunotherapy for PPGL have not yet been established. In the early research, using bulk RNA sequencing of tumor samples from 7 PPGL patients, we found that PPGL tumor tissues exhibited high PD-L1 mRNA expression compared with adjacent normal adrenal medulla tissues, and this was related to T-cell exhaustion biomarkers. To further validate the association, in this study (n = 60), we first stratified all PPGL samples according to PD-L1 expression as determined by immunohistochemical staining, and then subjected 23 fresh PPGL tumor samples from the cohort to a quantitative polymerase chain reaction (n = 16), flow cytometry (n = 7), and multiplex-immunofluorescence staining. Subsequently, we evaluated the pathological manifestations of all 60 PPGL tumor samples and analyzed the correlation among PD-L1 expression, adverse pathological behavior, various clinicopathological data, and genotypes in PPGL. The results showed that PD-L1-positive expression correlated with the exhaustion of tumor-infiltrating T cells, preoperative abnormal elevation of plasma norepinephrine, high Ki67 index, and adverse pathological behavior in PPGL but not with genetic mutation or metastatic disease, possibly due to the limitation of the small number of patients with metastatic disease (n = 4) in the study cohort. In conclusion, our findings reveal that PD-L1 expression is associated with T-cell exhaustion and adverse pathological behavior in PPGL. These results are expected to provide a new theoretical basis and clinical guidance for the treatment of PPGL.

Hypoglycemia In Non-Diabetic Patient: Report of Two Cases of Insulinoma

Background: Insulinoma is a B-cell tumor of the islets of the pancreas with an incidence of 4 per 1 million people per year, which produces excess insulin and can cause symptoms related to hypoglycemia at the level of the central nervous system or symptoms related to excess release of catecholamines. The presence of hypoglycemia, elevated insulin, proinsulin, and c-peptide levels suggest endogenous hyperinsulinism, which together with imaging findings suggestive of neuroendocrine tumor, allow establishing the diagnostic impression of Insulinoma. Case Report: Patients with neuroglycopenic symptoms, biochemical profile of hypoglycemia, endogenous hyperinsulinemia and radiological finding compatible with insulinoma are reported, who were treated by surgical resection of the tumor, with complete resolution of the initial symptoms. Conclusion: The clinical presentation, diagnosis and treatment of insulinoma represents a clinical challenge, since it is a rare pathology and the delay in diagnosis can have catastrophic consequences for the patient such as permanent brain damage and death.

The Hemodynamic-Stabilizing Properties of Dexmedetomidine on Adrenalectomy For Pheochromocytoma: A Case Report

Pheochromocytoma is a catecholamine-secreting neuroendocrine tumor and represents a challenge to the anesthesiologist. Without adequate preoperative preparation, excessive catecholamine release can result in life-threatening cardiovascular complications. To control blood pressure during the surgery, an infusion of sodium nitroprusside and dexmedetomidine was administered. Dexmedetomidine helps prevent hemodynamic instability during the tumor resection and was a way of interrupting the catecholamine release. This report attempts to address the preoperative and intraoperative issues in managing these challenging tumors with an emphasis on other therapeutic options to control the adrenergic crisis during the surgery.

Abstract 15304: Apical Ballooning Syndrome in the Setting of Severe Chronic Obstructive Pulmonary Disease Exacerbation

Apical ballooning syndrome (ABS), also known as Takotsubo cardiomyopathy, is a form of acute dilated cardiomyopathy associated with excessive catecholamine release. A 74-year-old female, chronic smoker with previously diagnosis of obstructive lung disease presented in the emergency department with severe shortness of breath and increase sputum production for the last 24hr. The patient was diagnosed with severe COPD exacerbation and received multiple doses of albuterol, methylprednisolone, ipratropium bromide/albuterol, and azithromycin. Despite this, the patient remained tachypneic and tachycardic with signs of impending respiratory failure. She was transferred to the ICU and intubated. After intubation, the patient received a continuous albuterol nebulizer, methylprednisolone, and ceftriaxone. A few hours later, the patient complained of chest pain, and EKG was done showing T wave inversion in lateral leads, troponin levels were 1.08 ng/mL (ULN 0.12ng/mL), and 2D Echo showed EF 50-55%, apical ballooning with dyskinesia, and inferior wall hypokinesis. Left heart catheterization showed non-obstructive coronary artery disease with 50% stenosis on the left anterior descending artery and distal ostial artery. Based on the previously recommended criteria, the diagnosis of the ABS was made. The patient had resolution of symptoms and echocardiogram findings after follow up. Although albuterol acts mainly on beta-2 receptors, cross-activation of beta-1 receptors can potentially lead to tachycardia. Previous case reports also support that excessive albuterol use in cases of asthma and COPD exacerbation may lead to ABS. This case may raise awareness that the extensive use of albuterol could have dramatic effects. Early switch to beta-2 agonist with higher specificity such as levalbuterol could be a reasonable approach in patients with severe COPD exacerbation.

PSAT123 Pheochromocytoma Resection and Coronary Artery Bypass Surgery: Chicken or the Egg??? - A Case Report

Abstract Introduction Pheochromocytoma (PCC) is a rare catecholamine-secreting neuroendocrine tumor with an incidence of 8 per million person-years. Advanced Coronary artery disease (CAD) and PCC may coexist secondary to chronic sympathetic activation, resulting in irreversible vascular wall growth and accelerated vascular atherosclerosis. The hemodynamic management of this association often represents a challenging dilemma due to the dramatic consequences of the hypertensive crisis caused by excessive catecholamine release. here we present a case of concomitant triple vessel disease and PCC to shed a light on our sequence of management to help guide providers as currently due to the rarity of the disease and the association, the available data regarding the sequence of management is controversial and is decided on a case by case basis. Case presentation a 55-year-old male with a history of uncontrolled hypertension, Chronic headaches, and kidney disease presented due to abrupt onset of crushing chest pain and was admitted for further evaluation of hypertensive emergency and NSTEMI with a blood pressure of 260/170 and Troponin of 3.8 ng/L. Coronary Angiography showed significant triple-vessel disease. Due to persistent hypertension and high suspicion of PCC, Serum metanephrine and normetanephrine, and fractioned catecholamines were ordered and showed significant elevation. CT of the abdomen and pelvis showed a 1.5 cm heterogeneous left adrenal mass. Nuclear medicine scan showed increased uptake of radiotracer in the left adrenal gland suggestive of PCC. Discussion PCC presents a high risk of morbidity and mortality, especially during surgical procedures if left untreated. The management of concomitant advanced CAD and PCC poses a unique challenge in terms of appropriate sequence and time interval between the two procedures. After a multidisciplinary team discussion including cardiology, cardiothoracic surgery, and endocrinology we decided to perform CABG first with preoperative preparation including Alpha-adrenoreceptor blockage for 1 week prior to surgery, followed by PCC resection at a later stage. The patient underwent coronary revascularization with grafting of three vessels. The perioperative course was uneventful. After three weeks the patient underwent successful PCC resection, with successful gradual down titration of alpha locate therapy. Conclusion A two-stage approach of CABG was PCC the section at a later stage under optimal preoperative preparation appears to be a safe and feasible modality in patients with advanced CAD and PCC. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

0800 Dozing off is a problem, as is a toe falling off - Methylphenidate induced Raynaud’s phenomenon

Abstract Introduction Narcolepsy is a clinical syndrome characterized by a constellation of symptoms including excessive daytime sleepiness, cataplexy, sleep paralysis and sleep hallucinations. Stimulants are commonly used to treat hypersomolence associated with narcolepsy. Common adverse reactions reviewed with patients prior to initiation of amphetamines include decreased appetite, nausea, xerostomia, headache, insomnia, tachycardia and hypertension. A relatively rare concern with stimulants is development of peripheral vasculopathy including Raynaud’s phenomenon. Report of Cases: A 25-year-old female with past medical history of anxiety, depression and obstructive sleep apnea in childhood was treated with tonsillectomy and adenoidectomy. Over the years, she continued to have persistent hypersomnolence, auditory hypnogogic hallucinations with no symptoms of sleep paralysis or cataplexy. She had a polysomnography (PSG) along with multiple sleep latency test (MSLT). PSG did not show evidence of sleep apnea with an AHI of 0.96 per hour. MSLT confirmed the diagnosis of Narcolepsy, Type 2, with a mean sleep onset latency of 3.6 minutes and five sleep-onset REM periods (SOREMPs). She was started on 400mg daily of Modafinil and 20mg daily of Methylphenidate. After a month of using methylphenidate, she noticed purplish discoloration of her digits, sometimes with exposure to cold, other times with no obvious triggers, consistent with development of Raynaud’s phenomenon. The proposed mechanism is that use of methylphenidate causes excessive release of catecholamines due to inhibition of the reuptake of dopamine and norepinephrine, leading to peripheral vasoconstriction. As the patient’s hypersomnolence persisted, she was started on sodium oxybate and the dosage of methylphenidate was decreased to 10mg daily and eventually discontinued. With reduction in the dosage and discontinuation of methylphenidate, symptoms of Raynaud’s phenomenon improved. Conclusion Dose-related peripheral vasculopathy including Raynaud’s phenomenon has been reported in several case reports with the use of methylphenidate. Awareness of this relatively rare adverse effect is imperative among sleep physicians as it could cause significant delay in the diagnosis, management of Raynaud’s phenomenon and its complications including critical digital ischemia and gangrene. Dose adjustments and discontinuation of methylphenidate should be considered in the treatment course of the patients with such concern. Support (If Any)

Neurogenic stunned myocardium resulting from surgical brainstem handling during resection of paediatric recurrent medulloblastoma—a possible brain heart interaction

Neurogenic stunned myocardium (NSM) is characterised by an acute onset cardiac dysfunction following an acute neurological insult which mimics acute coronary syndrome. A 12-year-old male child was admitted to the neuro-intensive care unit (NICU) following midline suboccipital craniotomy and resection of recurrent medulloblastoma. Postoperatively, in NICU, he developed tachycardia and hypotension, which was unresponsive to fluid challenge requiring norepinephrine infusion. Intraoperatively, during tumour resection from the dorsal medulla, episodes of hypertension and bradycardia were observed. Intraoperative blood loss was adequately managed with a stable hemodynamic profile without postoperative anaemia. An electrocardiogram showed sinus tachycardia with T wave inversion, and blood investigation revealed elevated cardiac troponin T levels. Point of care ultrasound (POCUS) of heart and lung showed features of NSM. Infusion dobutamine was added to achieve a target mean arterial pressure of 65mm Hg with concomitant furosemide infusion and fluid restriction. Daily POCUS assessment of cardiac contractility and volume status was done. The patient was weaned from vasoactive drugs and ventilator following improvement of cardiac function and was discharged from NICU after 17days. NSM results from the excessive release of catecholamines following stimulation of trigger zones in the brain. To date, a handful of cases of pediatric NSM following primary brain tumour are reported where hydrocephalus resulted in trigger zone activation. In this presented case, direct brain stem stimulation during tumour resection might have triggered NSM. Irrespective of the cause, timely diagnosis and execution of supportive management in our patient resulted in a positive outcome.

Hypoglycemia in Non-Diabetic Patient: Report of Two Cases of Insulinoma

Background: Insulinoma is a B-cell tumor of the islets of the pancreas with an incidence of 4 per 1 million people per year, which produces excess insulin and can cause symptoms related to hypoglycemia at the level of the central nervous system or symptoms related to excess release of compensatory catecholamines. The presence of hypoglycemia, elevated insulin, proinsulin, and c-peptide levels suggest endogenous hyperinsulinism, which together with imaging findings suggestive of neuroendocrine tumor, allow establishing the diagnostic impression of Insulinoma. Cases report: Patients with neuroglycopenic symptoms, biochemical profile of hypoglycemia, endogenous hyperinsulinemia and radiological finding compatible with insulinoma are reported, who were treated by surgical resection of the tumor, with complete resolution of the initial symptoms. Conclusion: The clinical presentation, diagnosis and treatment of insulinoma represents a clinical challenge, since it is a rare pathology and the delay in diagnosis can have catastrophic consequences for the patient, stories such as permanent brain damage and death.

The role of β2 adrenergic receptor on infection development after ischaemic stroke

Mechanisms underlying post-stroke immune impairments and subsequent development of fatal lung infection have been suggested to involve multiple pathways, including hyperactivation of the sympathetic nervous system (SNS), which results in the excessive release of catecholamines and activation of β-adrenergic receptors (βARs). Indeed, previous reports from experimental studies demonstrated that post-stroke infection can be inhibited with treatment of β-blockers. However, the effectiveness of β-blockers in reducing post-stroke infection has yielded mixed results in retrospective clinical trials and its use remain controversial. In this study, we performed mid-cerebral artery occlusion in mice either genetically deficient in β2-adrenergic receptor (β2AR) or treated with non-selective and selective βAR antagonists to explore the contributions of the SNS in the development of post-stroke lung infection. Stroke induced a systemic activation of the SNS as indicated by elevated levels of plasma catecholamines and UCP-1 activity. However, β2AR deficient mice showed similar degrees of post-stroke immune impairment and infection rate compared to wildtype counterparts, potentially due to compensatory mechanisms common in transgenic animals. To overcome this, we treated post-stroke wildtype mice with pharmacological inhibitors of the βARs, including the non-selective antagonist propranolol (PPL) and selective β2AR antagonist ICI-118551. Both pharmacological strategies to block the action of SNS signalling were unable to reduce infection in mice that underwent ischaemic stroke. Overall, our data suggests that other mechanisms independent or in combination with β2AR activation contribute to the development of post-stroke infection.

Segmental Arterial Mediolysis: A Multiguised Vasospastic Arteriopathy with Collateral Mesangial Cell Hyperplasia and Cardiac Toxicity Generated by Norepinephrine and Hyperdense Adrenoceptors Alone or by Crosstalk with Other Pressor Agents.

Segmental arterial mediolysis (SAM), an uncommon vasospastic arteriopathy occurring in the muscular arteries innervated by the peripheral sympathetic nervous system, usually presents with catastrophic abdominal and retroperitoneal hemorrhages in elderly patients. SAM is initiated by the coupling of norepinephrine to plastically derived hyperdense foci of alpha-1 adrenergic receptors on the sarcolemma of arterial muscle. This ligand is created by stimuli signaled by iatrogenic sympathomimetic agonists, some beta-2 agonists, or an excessive release of adrenal catecholamines. Coupling of this ligand with cytoplasmic heterotrimeric Gq protein excessively signals a cascade of biochemical events generating two principal lesions of injurious-phase SAM—the shearing of the outer media from the adventitia and an overload of cytoplasmic calcium ions toxic to mitochondria causing mediolysis and/or apoptosis. The massive hemorrhages are caused by ruptured gap aneurysms created by the transmedial loss of the medial muscle. A norepinephrine-directed reparative response rapidly develops either resolving angiographic injurious lesions or creating a body of vascular disorders, the new guises of SAM with ischemic clinical profiles. These present in the epicardial, vertebral, intestinal, and retroperitoneal arteries, often in younger females as fibromuscular dysplasia, dissecting hematomas, and persistent aneurysms. Norepinephrine can crosstalk with other pressor agents to create SAM lesions—serotonin with idiopathic pulmonary hypertension and persistent pulmonary hypertension in the newborn, histamine in spontaneous coronary artery dissections with eosinophilia, and endothelin-1 in a field effect generated by SAM that creates venous fibromuscular dysplasia. Norepinephrine also participates in the collateral development of mesangial hyperplasia with focal segmental glomerulosclerosis and myocardial mediolysis and apoptosis in subjects with markedly elevated heart rates. Conclusion. Norepinephrine coupling with plastically elevated alpha-1 adrenoceptor or other pressor agents generates SAM, a histologically recognizable vasospastic arteriopathy, that with repair is transformed into several different standardized arterial diseases that alter SAM's clinical profile from a hemorrhagic to an ischemic disorder.

Catestatin in patients with essential hypertension of different cardiovascular risk

Abstract Maximum association of arterial hypertension is found with sympathetic overactivity which is involved in different mechanisms including RAAS, OSA, obesity, etc. It is not overt sympathetic activity but disturbed basal sympathetic tone. However, the factors that indicate the beginning of the regulation system impairment in hypertensive patients haven't been studied enough. Catestatin is considered by some studies as a part of the “catecholamines-catestatin buffer system” because of its inhibitory effect on excess catecholamine release. The purpose of the study was to assess the concentrations of catestatin and to analyze its relationships with cardiovascular continuum in patients with essential hypertension (EH) of different cardiovascular risk (CVR). The methods of the research. The study included 180 men in age from 30 to 50 years old, the patients were divided into groups: group 1 (n=28) – EH of moderate CVR, group 2 (n=76) – EH of high CVR, group 3 (n=31) – EH of very high CVR. The control group (n=45) included almost healthy men with optimal and normal blood pressure (BP). All included in the study were examined, anamnesis and complaints were collected, daily monitoring of BP and ECG, TTE were performed, carotid intima–media thickness (IMT) was measured. Catestatin (ng/ml) was determined by the ELISA method using RayBiotech kits. Results Patients with moderate and very high CVR and a history of inherited EH had statistically significantly higher (p&amp;lt;0,05) catestatin concentrations compared to those in the control group who has a family history of EH. Catestatin correlations with a history of inherited EH were revealed in groups of patients with EH of moderate (r=0,555; p=0,049) and high (r=−0,285; p=0,027) CVR. The participation of catestatin in cardiovascular remodeling mediated by hypertension was proved: in a group of patients with EH of high CVR catestatin correlations with carotid IMT were received (r=−0,246; p=0,040). The relationships between catestatin concentrations and left ventricular posterior wall thickness (r=−0,523; p=0,045) and the interventricular septum (r=−0,523, p=0,045) in group 2 in diastole were discovered. Catestatin concentrations in patients with normal heart geometry were higher (p=0,04) comparing to the patients with cardiac remodeling (9,05±5,12 vs 7,49±3,62 ng/ml respectively). Catestatin concentrations correlated with indicators characterizing the CVR: diastolic BP variability in all included in the study patients with EH (r=0,218; p=0,022), group 2 (r=0,326; p=0,006), and the value of the morning surge (r=−0,745; p=0,002). Conclusion Catestatin concentrations change at all stages of the cardiovascular continuum of arterial hypertension, which is proved by the obtained correlations, so all of the above allows us to consider catestatin as a new factor in the regulation of blood pressure in patients with essential hypertension of different cardiovascular risk. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Samara Region Provincial Grant

The Synergy of ADAM17-Induced Myocardial Inflammation and Metabolic Lipids Dysregulation During Acute Stress: New Pathophysiologic Insights Into Takotsubo Cardiomyopathy.

Due to its reversible nature, Takotsubo cardiomyopathy (TTC) is considered an intriguing and fascinating cardiovascular disease characterized by a transient wall motion abnormality of the left ventricle, affecting more than one coronary artery territory, often in a circumferential apical distribution. Takotsubo cardiomyopathy was discovered by a Japanese cardiovascular expert and classified as acquired primary cardiomyopathy by the American Heart Association (AHA) in 1990 and 2006, respectively. Regardless of the extensive research efforts, its pathophysiology is still unclear; therefore, there are no well-established guidelines specifically for treating and managing TTC patients. Increasing evidence suggests that sympatho-adrenergic stimulation is strongly associated with the pathogenesis of this disease. Under acute stressful conditions, the hyperstimulation of beta-adrenergic receptors (β-ARs) resulting from excessive release of catecholamines induces intracellular kinases capable of phosphorylating and activating “A Disintegrin and Metalloprotease 17” (ADAM17), a type-I transmembrane protease that plays a central role in acute myocardial inflammation and metabolic lipids dysregulation which are the main hallmarks of TTC. However, our understanding of this is limited; hence this concise review provides a comprehensive insight into the key role of ADAM17 in acute myocardial inflammation and metabolic lipids dysregulation during acute stress. Also, how the synergy of ADAM17-induced acute inflammation and lipids dysregulation causes TTC is explained. Finally, potential therapeutic targets for TTC are also discussed.