Plasma Catecholamine Levels Research Articles

Characterization of pathological remodeling in the chronic atrioventricular block cynomolgus monkey heart.

We studied time course of pathological remodeling occurring in the cynomolgus monkey hearts against persistent atrioventricular block condition (n = 10). The atrioventricular block induced the ventricular and atrial dilation followed by the ventricular hypertrophy. Interstitial fibrosis in the ventricle was also observed along with gradual increases in the plasma angiotensin II and aldosterone concentrations. These adaptations were associated with the changes in gene expression profiling reflecting fibrosis and hypertrophy. Atrioventricular block reduced the ventricular rate and cardiac output, but the ejection fraction and stroke volume increased, whereas the cardiac output was gradually restored to its basal level. Systolic/diastolic blood pressure after the atrioventricular block was kept equal to or lower than that before the block, according with lack of increase in the plasma catecholamine levels. Chronic atrioventricular block gradually prolonged the QRS width and JT interval, leading to the QT interval prolongation in conscious state. 10mg/kg of dl-sotalol hydrochloride induced torsade de pointes (TdP) in 6 out of 10 animals by 15months. Animals showing longer QTcF under anesthesia after the atrioventricular block developed dl-sotalol-induced TdP earlier. No marked difference was observed in pharmacokinetics of dl-sotalol between 1 and 7months after the atrioventricular block. Each TdP spontaneously terminated, reflecting a monkey's relatively small "effective size of the heart (=∛(left ventricular weight)/wavelength of reentry)". These fundamental knowledge will help better utilize the chronic atrioventricular block monkeys as an in vivo proarrhythmia model for detecting drug-induced TdP.

The Effect of Antioxidants and Cardiovascular Drugs in the Treatment of Cardiac Diseases

Abstract: Background: Reactive oxygen species mediate oxidative stress, is one of the major causes of the athero-thrombotic process involved in the etiology of peripheral arterial disease, ischemic strokes, and heart attack. Angiotensin-1 receptor blockers, betablockers, angiotensin-converting enzyme inhibitors, diuretics, calcium channel blockers are traditional cardio-protective drugs. But the problem associated with these medications is, a person diagnosed with high blood pressure in younger age, has to take these drugs for lifelong, which may lead to develop harmful drug-induced diseases on long-term use like Alzheimer’s disease, Raynaud’s phenomenon, decreased levels of plasma catecholamines, etc. Materials and Methods: Among all anti-hypertensive agents, angiotensin-1 receptor blockers are safer as they have minimal long-term health hazards. Many pieces of the literature suggest that, intake of foods rich in anti-oxidant reduces the chance of cardiovascular disease, as they consume free radicals formed by various endogenous systems, pathological states or exposure to different physiochemical conditions, and improper oxidation of lipids. We can focus on synergistic benefit of both anti-hypertensive drug and antioxidants. Conclusion: Hence, we can assume that, intake of antioxidant as an active pharmaceutical ingredient may positively benefit in the treatment of cardiovascular diseases. Co-administration of existing cardiovascular drug and a suitable antioxidant(s) may produce a better result. Keywords: Cardiovascular diseases, Oxidative stress, Reactive oxygen species, Antioxidants, AT1 receptor blocker.

Determination of Catecholamines in a Small Volume (25μL) of Plasma from Conscious Mouse Tail Vein.

The determination of plasma catecholamine levels is commonly used as a measure of the sympathetic nervous system's response to stress and is highly important for diagnosis, therapy, and prognosis of cardiovascular diseases, catecholamine-secreting tumors arising from the chromaffin cells of the sympathoadrenal system, and affective disorders. Diseases in which catecholamines are significantly elevated include pheochromocytoma, Parkinson's disease, Alzheimer's disease, neuroblastoma, ganglioneuroblastoma, von Hippel-Lindau disease, baroreflex failure, chemodectina (nonchromaffin paraganglioma), and multiple endocrine neoplasia. Plasma norepinephrine levels provide a guide to prognosis in patients with stable, chronic, and congestive heart diseases. The method described here for the determination of plasma catecholamines is based on the principle that plasma catecholamines are selectively adsorbed on acid-washed alumina at pH 8.7 and then eluted at a pH between 1.0 and 2.0. Upon injection, catecholamines in elutes were separated by a reversed phase C-18 column. After separation, the catecholamines present within the mobile phase enter the electrochemical detector. Electrochemical detection occurs because electroactive compounds oxidize at a certain potential and thereby liberate electrons that create measurable current. Catecholamines readily form quinones under these conditions, get oxidized, release two electrons, and create current. The electrochemical detector detects this electrical current that linearly correlates to the catecholamine concentration loaded into the ultra-performance liquid chromatography instrument. A 15-min mixing time during the adsorption and desorption steps was found to be optimal. If the washing step was omitted, the catecholamines could not be eluted from the acid-washed alumina. To prevent dilution, the alumina had to be centrifuged and not aspirated to dryness after the washing step. We report here that by changing the range in the electrochemical detector, plasma catecholamines were measured with only 12.5μL of plasma and more reliably with 25μL of plasma. The detection limit was 1ng/mL. This assay method is very useful as blood can be collected from the tail vein in a conscious mouse and the same mouse can be used for time-dependent or age-dependent studies.

Effects of inspiratory muscle training on blood pressure- and sleep-related outcomes in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials.

Obstructive sleep apnea (OSA) is frequently accompanied by hypertension, resulting in cardiovascular comorbidities. Continuous positive airway pressure is a standard therapy for OSA but has poor adherence. Inspiratory muscle training (IMT) may reduce airway collapsibility and sympathetic output, which may decrease OSA severity and blood pressure. In this meta-analysis of randomized controlled trials (RCTs), we evaluated the efficacy of IMT in patients with OSA. We searched PubMed, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov databases for relevant RCTs published before November 2022. Seven RCTs with a total of 160 patients with OSA were included. Compared with the control group, the IMT group exhibited significantly lower systolic and diastolic blood pressure (mean difference [MD]: - 10.77 and - 4.58mmHg, respectively), plasma catecholamine levels (MD: - 128.64pg/mL), Pittsburgh Sleep Quality Index (MD: - 3.06), and Epworth Sleepiness Scale score (MD: - 4.37). No significant between-group differences were observed in the apnea-hypopnea index, forced vital capacity (FVC), ratio of forced expiratory volume in 1s to FVC, or adverse effects. The data indicate comprehensive evidence regarding the efficacy of IMT for OSA. However, the level of certainty (LOC) remains low. IMT improved blood pressure- and sleep-related outcomes without causing adverse effects and may thus be a reasonable option for lowering blood pressure in patients with OSA. However, additional studies with larger sample sizes and rigorous study designs are warranted to increase the LOC.

Profiling the Adrenergic System in Breast Cancer and the Development of Metastasis.

Epidemiological studies and preclinical models suggest that chronic stress might accelerate breast cancer (BC) growth and the development of metastasis via sympathetic neural mechanisms. Nevertheless, the role of each adrenergic pathway (α1, α2, and β) in human samples remains poorly depicted. Herein, we propose to characterize the profile of the sympathetic system (e.g., release of catecholamines, expression of catecholamine metabolic enzymes and adrenoreceptors) in BC patients, and ascertain its relevance in the development of distant metastasis. Our results demonstrated that BC patients exhibited increased plasma levels of catecholamines when compared with healthy donors, and this increase was more evident in BC patients with distant metastasis. Our analysis using the BC-TCGA database revealed that the genes coding the most expressed adrenoreceptors in breast tissues (ADRA2A, ADRA2C, and ADRB2, by order of expression) as well as the catecholamine synthesizing (PNMT) and degrading enzyme (MAO-A and MAO-B) genes were downregulated in BC tissues. Importantly, the expression of ADRA2A, ADRA2C, and ADRB2 was correlated with metastatic BC and BC subtypes, and thus the prognosis of the disease. Overall, we gathered evidence that under stressful conditions, both the α2- and β2-signaling pathways might work on a synergetic matter, thus paving the way for the development of new therapeutic approaches.

OR14-3 Disrupted circadian rhythm in catecholamines in youth-onset Type 2 Diabetes

Abstract Objectives In healthy, normal - weight adults there is a circadian rhythm in blood pressure (BP) and plasma catecholamines (epinephrine and norepinephrine): BP and the levels of norepinephrine and epinephrine decline during sleep, followed by a rapid increase during the early morning hours. Studies in adults with Type 2 diabetes (T2D) show blunted reductions in BP and plasma catecholamine levels during sleep that are associated with increased risks for heart failure, stroke, myocardial infarction, and sudden death. In this study, we explored if the circadian rhythm in catecholamines is disrupted in youth-onset T2D. We hypothesized that increased sympatho-adrenal activity during sleep differentiates youth with T2D from non-diabetic overweight/obese and lean youth of comparable age, pubertal status, and ethnicity. To that end, we measured urine catecholamines in fasting – morning-spot urines and 24-hour urine samples. Methods 56 non-diabetic adolescents with overweight/obesity ("obese"), 42 adolescents with T2D ("T2D"), and 43 normal-weight controls ("lean"); aged 12-21 years, were studied. None was diagnosed with hypertension, and none was on antihypertensive treatment. Weight, height, BMI, BMI%, and BP were extracted from medical charts. Body fat percent (BF%) was measured by TANITA. Stress levels were assessed using PHQ-2 and PHQ-9 questionnaires. Fractionated free urine catecholamines (epinephrine, norepinephrine, and dopamine) were analyzed by liquid chromatography/tandem mass spectrometry (LC/MS-MS) in both spot and 24-hour urines, normalized to urinary creatinine. The ratio of fasting morning urine catecholamines to 24-hour urine catecholamines was calculated to assess circadian variation in catecholamines. Group differences were assessed by Kruskal-Wallis or ANOVA. Results Groups were comparable for age (obese 14.8 +/- 1.9; T2D 15.7 +/- 2.1 and lean 14.9 +/- 1.9-yr), pubertal status, and ethnicity. Obese youth with and without T2D were predominantly female (T2D, 28 F, 14 M; obese 33 F, 23 M; lean, 17 F, 26 M); those with T2D had highest BF% (obese 37.3 +/- 9.5; T2D 42.9 +/- 9.9; lean 20.1 +/- 6.3%; p=2.58e-22) and systolic blood pressure (obese 115.36 +/- 11.54; T2D 127.83 +/- 12.08 and lean 111.65 +/- 9.13 mmHg; p=5.49e-10). Fractionated free urine catecholamines (epinephrine, norepinephrine and dopamine) were comparable across groups in 24-hour urines. However, fasting morning epinephrine levels and the ratio of fasting morning/24-hour epinephrine were higher in T2D (p=0.0035, and p=0.035, respectively) than in either lean or nondiabetic youth with obesity. There were no differences in morning urine catecholamines between lean controls and non-diabetic youth with obesity. Conclusions Our results suggest a disrupted circadian rhythm in catecholamines in youth-onset T2D, with a blunted overnight fall in epinephrine levels. Higher levels of epinephrine levels at night in youth with T2D might be associated with, or predispose to, hypertension and long-term cardiovascular complications. Presentation: Sunday, June 12, 2022 11:30 a.m. - 11:45 a.m.

PMON85 Co-occurrence of Carotid Body Tumor, Meningioma and Schwannoma in a Symptomatic Patient, Incidental Findings Vs Genetic Syndrome: A Case Report

Abstract Carotid body tumors, also known as chemodectomas/paraganglionomas; are rare neuroendocrine tumors that arise from parasympathetic ganglionic cells. They are usually benign with incidence of malignancy is <10%. In majority of cases, tumors are asymptomatic and found incidentally on clinical exam or radiological imagining. Their association with other non-neuroendocrine tumors as seen in present case; has not been well documented in literature. Case presentation 43 y/o female with PMH of GERD, obesity, asthma and anxiety disorder who came to endocrine clinic for left middle thyroid lobe nodule(0.9×0.6×0.6cm) evaluation; incidentally noted to have a multilobulated heterogeneous hypo echoic and iso-echoic mildly vascularized solid nodular mass (3.46×1.83×1.93 cm) in the left carotid bifurcation area; splaying the common and the internal carotid arteries on US. Review of systems was positive for left sided neck pain, intermittent palpitations, headaches, anxiety, and sleep disturbances. Clinical exam was remarkable for thyromegaly and a palpable non-tender 3cm left neck mass with no cervical lymphadenopathy. Initial labs were notable for mild elevation of chromogranin A (108.4 ng/ml) with normal levels of TSH, free T3, free T4, plasma metanephrines and 24-hour urinary metanephrines. Considering patient's persistent symptoms; plasma catecholamines levels were done and were negative. MRI soft tissue neck confirmed 2.8 cm lobular mass suggestive of paraganglioma. Metastatic work up was negative. Patient was referred for genetic testing considering young age and to rule out hereditary disorders. Interim, patient presented to the ED with complain of sudden onset lumbar backache without sphincteric involvement; neurological exam was unrevealing but on MRI lumbar spine found to have a 5.7×4.8×4cm lobulated well-circumscribed homogeneous soft tissue mass suggestive of schwannoma. Cervical and thoracic spine imaging was unremarkable. MRI brain showed a 1.1cm enhancing mass in right Meckel cave suggestive of meningioma. PET-DOTATATE scan was performed that revealed left neck mass as intensely avid, Right petrous apex mass as moderately avid and lumbar mass as not avid at all, consistent with the diagnosis of paraganglionoma, meningioma and schwannoma respectively. No evidence of DOTATATE avid nodal/ distant metastatic disease was found. Initially a hereditary etiology was suspected but genetic testing including (VHL, NF1/2, SDHD, SDHB) came back negative. Case was discussed with multidisciplinary teams; Neurosurgery service recommends conservative management of both meningioma and schwannoma at the moment considering benign course. Regarding paraganglioma, as tumor is non-secretory on repeated work up; sympathetic blockade is not warranted and patient is scheduled for pre-op embolization and surgical resection by Head and Neck surgery. Conclusion Paraganglionomas are generally benign non-secretory tumors that usually occur with other neuroendocrine tumors both as hereditary syndromes and sporadic cases. But their association with non-neuroendocrine tumors is mere incidental or has a genetic causation; is still unclear and warrants further research. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON85 Co-occurrence of Carotid Body Tumor, Meningioma and Schwannoma in a Symptomatic Patient, Incidental Findings Vs Genetic Syndrome; a case report.

Abstract Carotid body tumors, also known as chemodectomas/paraganglionomas; are rare neuroendocrine tumors that arise from parasympathetic ganglionic cells. They are usually benign with incidence of malignancy is <10%. In majority of cases, tumors are asymptomatic and found incidentally on clinical exam or radiological imagining. Their association with other non-neuroendocrine tumors as seen in present case; has not been well documented in literature. Case presentation 43 y/o female with PMH of GERD, obesity, asthma and anxiety disorder who came to endocrine clinic for left middle thyroid lobe nodule(0.9×0.6×0.6cm) evaluation; incidentally noted to have a multilobulated heterogeneous hypo echoic and iso-echoic mildly vascularized solid nodular mass (3.46×1.83×1.93 cm) in the left carotid bifurcation area; splaying the common and the internal carotid arteries on US. Review of systems was positive for left sided neck pain, intermittent palpitations, headaches, anxiety, and sleep disturbances. Clinical exam was remarkable for thyromegaly and a palpable non-tender 3cm left neck mass with no cervical lymphadenopathy. Initial labs were notable for mild elevation of chromogranin A (108.4 ng/ml) with normal levels of TSH, free T3, free T4, plasma metanephrines and 24-hour urinary metanephrines. Considering patient's persistent symptoms; plasma catecholamines levels were done and were negative. MRI soft tissue neck confirmed 2.8 cm lobular mass suggestive of paraganglioma. Metastatic work up was negative. Patient was referred for genetic testing considering young age and to rule out hereditary disorders. Interim, patient presented to the ED with complain of sudden onset lumbar backache without sphincteric involvement; neurological exam was unrevealing but on MRI lumbar spine found to have a 5.7×4.8×4cm lobulated well-circumscribed homogeneous soft tissue mass suggestive of schwannoma. Cervical and thoracic spine imaging was unremarkable. MRI brain showed a 1.1cm enhancing mass in right Meckel cave suggestive of meningioma.PET-DOTATATE scan was performed that revealed left neck mass as intensely avid, Right petrous apex mass as moderately avid and lumbar mass as not avid at all, consistent with the diagnosis of paraganglionoma, meningioma and schwannoma respectively. No evidence of DOTATATE avid nodal/ distant metastatic disease was found. Initially a hereditary etiology was suspected but genetic testing including (VHL, NF1/2, SDHD, SDHB) came back negative. Case was discussed with multidisciplinary teams; Neurosurgery service recommends conservative management of both meningioma and schwannoma at the moment considering benign course. Regarding paraganglioma, as tumor is non-secretory on repeated work up; sympathetic blockade is not warranted and patient is scheduled for pre-op embolization and surgical resection by Head and Neck surgery. Conclusion Paraganglionomas are generally benign non-secretory tumors that usually occur with other neuroendocrine tumors both as hereditary syndromes and sporadic cases. But their association with non-neuroendocrine tumors is mere incidental or has a genetic causation; is still unclear and warrants further research. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Atrial Fibrillation Detected After Acute Ischemic Stroke

Atrial fibrillation (AF) increases 4-5 times incidence of cardiac embolic stroke. In contrast, as many as 70% of AF cases can be detected in stroke within three days of onset, and this can affect the patient's prognosis. This case report describes the causal pathophysiology of AF and acute stroke and identifies the associated risk factors. Case 1 is a 44-year-old woman, acute stroke with acute decrease level of consciousness. The patient came with status epilepticus and a hypertensive emergency. Obtained a history of stroke, uncontrolled hypertension, and myocardial infarction. Initial Score National Institutes of Health Stroke Scale (NIHSS) was 33 and CHA2DS2-VASc was 5. Investigation non-contrast head Computed Tomography (CT) scan showed no bleeding and echocardiography (ECG) showed AF with rapid ventricular response. The patient died after 3 days of treatment. Case 2 is an 83-year-old woman, acute stroke with acute decrease level of consciousness and right motor lateralization. There was a history of hypertension and stroke with left hemiparesis. The initial NIHSS was 28 and CHA2DS2-VASc was 6. Investigations non-contrast head CT scan showed no bleeding and ECG showed AF with normal ventricular response. The patient was discharged from the hospital after being treated for 22 days with NIHSS of 20. Several risk factors for post-stroke AF are elderly, hypertension, subtype of ischemic stroke, prior stroke, and comorbidities such as DM and hypertension. Post-stroke AF can occur because of changes in heart rhythm through autonomic disorders, increased plasma catecholamine levels, and inflammatory reactions. Early Recognition of risk factors, focusing on patients at higher risk of AF detected after stroke becomes important for comprehensive management of stroke with AF.
 Keywords: acute ischemic stroke, atrial fibrillation, CHA2DS2-VASc score, risk factors.

The music therapy effectiveness in hypertensive patients with acute myocardial infarction after previous coronary artery bypass surgery; 18-year experience of the MUSIC study

Abstract Patients who have clinical evidence of hypertension (HT) after coronary artery bypass surgery (CABS) have a poor prognosis in expression of acute myocardial infarction (AMI), as one of the MACE. Unrelieved anxiety can produce an increase in sympathetic nervous system activity leading to an increase in cardiac workload. The purpose of this study was to evaluate the effectiveness of music therapy on prognosis of patients with HT and AMI, after CABS. Methods 314 patients (males 78.4%, mean age 59.8±1.2 yrs) with AMI after previous CABS have been selected from the patients consecutively submitted from January 2003 to January 2019. HT was registered in 166 (53.0%) pts with AMI after previous CABS. All patients with HT were randomized and divided in 2 groups: Study group of 83 patients treated with music therapy and Control group of 83 patients with no music therapy. Each patient in study group underwent two sessions of medical therapy (12 minutes) in a day. Both groups were similar in baselines, post-AMI characteristics and post-AMI medical therapy. The plasma cytokine and catecholamine were measured in both groups. Results In the Study group, heart rate was significantly decreased by music therapy (p=0.0196). In the Control group, there were no significant changes in heart rate. Among cytokines (p=0.0160), plasma interleukin-6 (IL-6) (p=0.0179) in the Study group was significantly lower than those in the Control group, as well as plasma adrenaline (p=0.0162) and noradrenalin (p=0.0218) levels. Conclusion This study provides support for the use of musical therapy in patients with HT and AMI after previous CABS. The positive effects of music therapy, in these patients, are probably because of enhanced of parasympathetic activities and reduction of plasma cytokine and catecholamine levels. Funding Acknowledgement Type of funding sources: None.

Impact of left bundle branch block in Takotsubo Syndrome.

BackgroundLeft bundle branch block (LBBB) causes left ventricular dyssynchrony, and its presence with concomitant left ventricular dysfunction has been proven to play a synergistic role, worsening ventricular function. Our study seeks to further explore the association between LBBB and various in-hospital outcomes in patients with takotsubo syndrome (TTS).MethodsThe national inpatient sample was queried from 2016 to 2019 to identify all admissions with a primary diagnosis of TTS. International classification of diseases, tenth revision codes were used to divide patients based on the presence or absence of LBBB. Multivariate regression analysis was performed to assess the effect of LBBB among all the pre-specified outcomes.ResultsA total of 26,615 admissions were included in the analysis. Admissions with LBBB were more likely to be older (72.2 vs. 66.2 years) and have a higher burden of comorbidities. The presence of a LBBB was associated with ventricular arrhythmias (OR = 1.97, 95% CI 1.08–3.61, p = 0.028) but not with sudden cardiac arrest (SCA), acute heart failure, cardiogenic shock, and all-cause intra-hospital mortality.ConclusionsIntraventricular dyssynchrony appears to play a significant role in ventricular arrhythmogenesis and SCA, as several trials have demonstrated that cardiac resynchronization therapy alone without defibrillator function reduces the rate of ventricular arrhythmias and SCA in patients with heart failure with systolic dysfunction and a widened QRS complex. The most likely mechanism of arrhythmia development in TTS is related to the elevated plasma levels of catecholamines and their proarrhythmic effects in the ventricular myocardium.

Water-soluble tomato concentrate modulates shear-induced platelet aggregation and blood flow in vitro and in vivo.

Water-soluble tomato concentrate (WSTC), extracted from mature tomatoes, is the first health product in Europe that has been approved “to help maintain normal platelet activity to maintain healthy blood flow.” We hypothesized that WSTC might exert an influence on blood flow shear stress-induced platelet aggregation (SIPA) and in turn maintains healthy blood flow. We used a microfluidic system to measure the effects of WSTC on SIPA in vitro. We also used the strenuous exercise rat model and the κ-carrageenan-induced rat tail thrombosis model to demonstrate the effects of WSTC on blood flow. WSTC significantly inhibited platelet aggregation at pathological high shear rate of 4,000 s–1 and 8,000 s–1 in vitro (P < 0.05 or P < 0.01). WSTC reduced the platelet adhesion rate and increased the rolling speed of platelets by inhibiting binding to Von Willebrand Factor (vWF) (P < 0.05 or P < 0.01). The oral administration of WSTC for 4 weeks in strenuous exercise rats alleviated hyper-reactivity of the platelets and led to a significant reduction in the plasma levels of catecholamine and IL-6. WSTC treatment also led to a reduction in black tail length, reduced blood flow pulse index (PI) and vascular resistance index (RI), and ameliorated local microcirculation perfusion in a rat model of thrombosis. WSTC exerted obvious inhibitory effects on the platelet aggregation induced by shear flow and alleviated the blood flow and microcirculation abnormities induced by an inflammatory reaction.

Importance of catecholamine signaling in the development of platelet exhaustion after traumatic injury

BackgroundImpaired ex vivo platelet aggregation is common in trauma patients. The mechanisms driving these impairments remain incompletely understood, but functional platelet exhaustion due to excessive in vivo activation is implicated. Given platelet adrenoreceptors and known catecholamine surges after injury, impaired ex vivo platelet aggregation in trauma patients may be linked to catecholamine‐induced functional platelet exhaustion. ObjectiveTo determine the relationship of catecholamines with platelet‐dependent hemostasis after injury and to model catecholamine‐induced functional platelet exhaustion in healthy donor platelets. Patients/MethodsWhole blood was collected from 67 trauma patients as part of a prospective cohort study. Platelet aggregometry and rotational thromboelastometry were performed, and plasma epinephrine (EPI) and norepinephrine (NE) concentrations were measured. The effect of catecholamines on healthy donor platelets was examined in a microfluidic model, with platelet aggregometry, and by flow cytometry examining surface markers of platelet activation. ResultsIn trauma patients, EPI and NE were associated with impaired platelet aggregation (both p < 0.05), and EPI was additionally associated with decreased viscoelastic clot strength, increased fibrinolysis, and mortality (all p < 0.05). In healthy donors, short duration incubation with EPI enhanced platelet aggregation, platelet adhesion under flow, and increased glycoprotein IIb/IIIa activation, while weaker effects were observed with NE. Compared with short incubation, longer incubation with EPI resulted in decreased platelet adhesion, platelet aggregation, and surface expression of glycoprotein IIb/IIIa. ConclusionsThese findings suggest sympathoadrenal activation in trauma patients contributes to impaired ex vivo platelet aggregation, which mechanistically may be explained by a functionally exhausted platelet phenotype under prolonged exposure to high plasma catecholamine levels.

Dexmedetomidine to reduce vasopressor resistance in refractory septic shock: Protocol for a double-blind randomized controlled pilot trial (ADRESS Pilot study).

IntroductionRefractory septic shock (RSS) is characterized by high vasopressor requirements, as a consequence of vasopressor resistance, which may be caused or enhanced by sympathetic hyperactivation. Experimental models and clinical trials show a reduction in vasopressor requirements and improved microcirculation compared to conventional sedation. Dexmedetomidine did not reduce mortality in clinical trials, but few septic shock patients were enrolled. This pilot trial aims to evaluate vasopressor re-sensitization with dexmedetomidine and assess the effect size, in order to design a larger trial.MethodsThis is an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial, comparing dexmedetomidine versus placebo in RSS patients with norepinephrine dose ≥0.5μg/kg/min. The primary outcome is blood pressure response to phenylephrine challenge, 6 hours after completion of a first challenge, after study treatment initiation. Secondary outcomes include feasibility and safety outcomes (bradycardia), mortality, vasopressor requirements, heart rate variability, plasma and urine catecholamines levels. The sample size is estimated at 32 patients to show a 20% improvement in blood pressure response to phenylephrine. Randomization (1:1) will be stratified by center, sedation type and presence of liver cirrhosis. Blood pressure and ECG will be continuously recorded for the first 24 h, enabling high-quality data collection for the primary and secondary endpoints. The study was approved by the ethics committee “Sud-Est VI” (2019-000726-22) and patients will be included after informed consent.DiscussionThe present study will be the first randomized trial to specifically address the hemodynamic effects of dexmedetomidine in patients with septic shock. We implement a high-quality process for data acquisition and recording in the first 24 h, ensuring maximal quality for the evaluation of both efficacy and safety outcomes, as well as transparency of results. The results of the study will be used to elaborate a full-scale randomized controlled trial with mortality as primary outcome in RSS patients.Trial registrationRegistered with ClinicalTrials.gov (NCT03953677). Registered 16 May 2019, https://clinicaltrials.gov/ct2/show/NCT03953677.

A Real Pandora's Box in Pandemic Times: A Narrative Review on the Acute Cardiac Injury Due to COVID-19.

The intricate relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the cardiovascular system is an extensively studied pandemic topic, as there is an ever-increasing amount of evidence that reports a high prevalence of acute cardiac injury in the context of viral infection. In patients with Coronavirus disease 2019, COVID-19, a significant increase in serum levels of cardiac troponin or other various biomarkers was observed, suggesting acute cardiac injury, thus predicting both a severe course of the disease and a poor outcome. Pathogenesis of acute cardiac injury is not yet completely elucidated, though several mechanisms are allegedly involved, such as a direct cardiomyocyte injury, oxygen supply-demand inequity caused by hypoxia, several active myocardial depressant factors during sepsis, and endothelial dysfunction due to the hyperinflammatory status. Moreover, the increased levels of plasma cytokines and catecholamines and a significantly enhanced prothrombotic environment may lead to the destabilization and rupture of atheroma plaques, subsequently triggering an acute coronary syndrome. In the present review, we focus on describing the epidemiology, pathogenesis, and role of biomarkers in the diagnosis and prognosis of patients with acute cardiac injury in the setting of the COVID-19 pandemic. We also explore some novel therapeutic strategies involving immunomodulatory therapy, as well as their role in preventing a severe form of the disease, with both the short-term outcome and the long-term cardiovascular sequelae being equally important in patients with SARS-CoV-2 induced acute cardiac injury.

Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome.

Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion on standing in 28 patients with postural tachycardia syndrome (31 ± 12 years old, 25 females) and 21 matched controls. We found that patients had higher somatic vigilance (P = 0.0167) and more anxiety (P < 0.0001). They also had a more pronounced anticipatory tachycardia right before assuming the upright position in a tilt-table test (P = 0.015), a physiological indicator of fear conditioning to orthostasis. While standing, patients had faster heart rate (P < 0.001), higher plasma catecholamine levels (P = 0.020), lower end-tidal CO2 (P = 0.005) and reduced middle cerebral artery blood flow velocity (P = 0.002). Multi-linear logistic regression modelling showed that both epinephrine secretion and excessive somatic vigilance predicted the magnitude of the tachycardia and the hyperventilation. These findings suggest that the postural tachycardia syndrome is a functional disorder in which standing may acquire a frightful quality, so that even when experienced alone it may elicit a fearful conditioned response. Heightened somatic anxiety is associated with and may predispose to a fear-conditioned hyperadrenergic state when standing. Our results have therapeutic implications.

Early donepezil monotherapy or combination with metoprolol significantly prevents subsequent chronic heart failure in rats with reperfused myocardial infarction

Despite the presence of clinical guidelines recommending that β-blocker treatment be initiated early after reperfused myocardial infarction (RMI), acute myocardial infarction remains a leading cause of chronic heart failure (CHF). In this study, we compared the effects of donepezil, metoprolol, and their combination on the progression of cardiac remodeling in rats with RMI. The animals were randomly assigned to untreated (UT), donepezil-treated (DT), metoprolol-treated (MT), and a combination of donepezil and metoprolol (DMT) groups. On day 8 after surgery, compared to the UT, the DT and DMT significantly improved myocardial salvage, owing to the suppression of macrophage infiltration and apoptosis. After the 10-week treatment, the DT and DMT exhibited decreased heart rate, reduced myocardial infarct size, attenuated cardiac dysfunction, and decreased plasma levels of brain natriuretic peptide and catecholamine, thereby preventing subsequent CHF. These results suggest that donepezil monotherapy or combined therapy with β-blocker may be an alternative pharmacotherapy post-RMI.

Differential Expression of Secretogranins II and III in Canine Adrenal Chromaffin Cells and Pheochromocytomas.

Secretogranin II (SgII) and III (SgIII) function within peptide hormone-producing cells and are involved in secretory granule formation. However, their function in active amine-producing cells is not fully understood. In this study, we analyzed the expression profiles of SgII and SgIII in canine adrenal medulla and pheochromocytomas by immunohistochemical staining. In normal adrenal tissues, the intensity of coexpression of these two secretogranins (Sgs) differed from each chromaffin cell, although a complete match was not observed. The coexpression of vesicular monoamine transporter 2 (VMAT2) with SgIII was similar to that with chromogranin A, but there was a subpopulation of VMAT2-expressing cells that were negative or hardly detectable for SgII. These results are the first to indicate that there are distinct expression patterns for SgII and SgIII in adrenal chromaffin cells. Furthermore, the expression of these two Sgs varied in intensity among pheochromocytomas and did not necessarily correlate with clinical plasma catecholamine levels in patients. However, compared with SgIII, the expression of SgII was shown to be strong at the single-cell level in some tumor tissues. These findings provide a fundamental understanding of the expression differences between SgII and SgIII in normal adrenal chromaffin cells and pheochromocytomas.

Undifferentiated pleomorphic sarcoma of the retroperitoneum mimicking a cortisol‐ and catecholamine‐secreting adrenal tumor

IntroductionRetroperitoneal tumors with endocrine abnormalities are suspected to be functional adrenal tumors. Retroperitoneal soft tissue sarcomas are rare tumors, without endocrine potential.Case presentationA 60‐year‐old male was referred for a 15 cm mass in the left suprarenal space. His plasma cortisol and catecholamine levels were elevated. He underwent open left adrenalectomy with radical nephrectomy and his endocrinological abnormalities were improved. Pathological findings suggested that it had originated from the retroperitoneal fat tissue, and a diagnosis of undifferentiated pleomorphic sarcoma was made based on the results of immunohistochemical analysis and fluorescence in situ hybridization. Interestingly, neither cortisol nor catecholamine was elevated when, 6 months after surgery, local recurrence developed.ConclusionThis is the first reported case of undifferentiated pleomorphic sarcoma accompanied by high levels of cortisol and catecholamine. We should keep in mind the possibility of tumors like retroperitoneal soft tissue sarcomas inducing endocrine abnormalities.

Plasma and Urinary Levels of Nerve Growth Factor Are Elevated in Primary Hypertension.

Nerve growth factor (NGF) is the main neurotrophic factor that can control sympathetic nerve innervation and sympathetic neural activity in cardiovascular organs. Although NGF overproduction and its influences on the sympathetic nervous system have been shown in hypertensive animals, NGF status and its association with sympathetic nerve activity have not yet been explored in human hypertension. In the present study, therefore, plasma and urinary levels of NGF and those of catecholamines (i.e., indices for NGF status and sympathoadrenal activity, respectively) were compared between 83 untreated primary hypertensives without apparent cardiovascular damages and 81 healthy normotensive subjects. Plasma and urinary levels of NGF were significantly greater in the hypertensive group (311 ± 158 pg/mL and 72.7 ± 54.0 ng/g of Cr) than in the normotensive group (168 ± 188 pg/mL and 54.5 ± 38.8 ng/g of Cr) (p < 0.05 for each measurement), even if the baseline differences of age and gender between the groups were adjusted. Similarly, plasma and urinary levels of catecholamines were significantly higher in the hypertensive group than in the normotensive group except for plasma noradrenaline. In addition, despite no significant correlations between plasma levels of NGF and catecholamines in both groups, urinary NGF significantly correlated positively with both urinary noradrenaline and urinary adrenaline in the hypertensive group (r = 0.259, p=0.018 and r = 0.232, p=0.035), but not in the normotensive group (r = 0.115, p=0.307 and r = −0.018, p=0.871). On the contrary, plasma and urinary levels of NGF as well as those of catecholamines did not associate with any systemic hemodynamic indices such as blood pressure and pulse rate in either group. Thus, primary hypertension was characterized by the enhancements of both NGF status and sympathoadrenal activity and the positive relationship between them. Our data indicate that enhanced NGF status and subsequent NGF-induced sympathoadrenal overactivity could occur in primary hypertension.