Hyperadrenergic State Research Articles

Pediatric postural orthostatic tachycardia syndrome: From mechanisms to individualized management

AbstractPostural orthostatic tachycardia syndrome (POTS) represents chronic orthostatic intolerance. Patients usually suffer from presyncopal symptoms, such as lightheadedness, headache, blurred vision, and fatigue. Central hypovolemia, peripheral vascular dysfunction, and a hyperadrenergic state may contribute to the pathogenesis of POTS. It is necessary to comprehensively assess the clinical characteristics, physiological changes, and biochemical markers to select an appropriate therapy. Since the introduction of the concept of individualized treatment for POTS, great progress has been made in the field.

The impact of intravenous metoprolol tartrate on mortality rates in patients with septic shock due to ventilator-associated pneumonia: A randomized clinical trial

Background: Septic shock, particularly due to ventilator-associated pneumonia (VAP), is a significant cause of mortality in critically ill patients. Traditional treatments include antimicrobial therapy, fluid resuscitation, and vasopressors. However, recent interest has emerged in using β-blockers to modulate the hyperadrenergic state seen in sepsis. β-blockers, like metoprolol, may improve cardiac efficiency, reduce myocardial oxygen demand, and ultimately enhance patient outcomes. Objective: This study aimed to assess the impact of administering intravenous metoprolol tartrate on the mortality rates of patients with septic shock due to VAP. Methods: This study employed a randomized clinical trial design within the Intensive Care Units of Alexandria Main University Hospital. A cohort of 100 patients diagnosed with septic shock due to ventilator-associated pneumonia (VAP) participated in the trial. Upon achieving hemodynamic stabilization, participants were randomly assigned to either receive standard care alone or standard care supplemented with intravenous metoprolol. Variables of interest included assessing 28-day mortality rates, duration of ICU stay and mechanical ventilation, reliance on intravenous fluids and vasopressors, acid-base balance, lactate levels, inflammatory markers, and mean arterial pressure (MAP). This comprehensive approach aimed to evaluate the impact of metoprolol on critical outcomes in this patient population. Results: The administration of intravenous metoprolol tartrate resulted in significant clinical benefits, including lower 28-day mortality rates (P = 0.013), shortened durations of ICU stay (P < 0.001), and reduced mechanical ventilation periods (P < 0.001). These outcomes were explained by the observed decreased reliance on intravenous fluids and vasopressors (P < 0.001), improved acid-base balance and lactate levels. The rapid reduction of inflammatory markers (P < 0.001) and the sustained improvement of MAP in the metoprolol group compared to the control group further contributed to the explication of these findings. Conclusion: Intravenous metoprolol tartrate effectively controlled inflammation, optimized hemodynamics, and improved patient outcomes compared to standard care, suggesting it as a beneficial adjunct in the management of septic shock. Trial registration: PACTR202404531355476. Keywords: Metoprolol; septic shock; ventilator-associated pneumonia; beta-blockers; mortality.

Glycyrrhizic acid induced acquired apparent mineralocorticoid excess syndrome with a hyperadrenergic state: a case report

BackgroundSyndrome of apparent mineralocorticoid excess (AME) is characterized by excessive MR stimulation despite low levels of aldosterone. 11Beta-hydroxysteroid dehydrogenase-2 (11βDSH-2) inactivates cortisol to cortisone, preventing cortisol-induced MR activation. Genetic defects in 11βDSH-2 cause AME through accumulation of cortisol in the distal nephron, leading to MR activation induced hypertension, hypokalemia and metabolic alkalosis. Acquired AME can occur due to the ingestion of glycyrrhizic acid, found in licorice root, which inhibits 11βDSH-2 and has additional effects on cortisol homeostasis through inhibition of 11βDSH-1.Case reportWe present a case of acquired AME with a hyperadrenergic symptoms induced by ingestion of Advanced Liver Support, a nutritional supplement produced by Advanced BioNutritionals(R), in a 65-year-old Caucasian female who presented with accelerated hypertension, hypokalemia, metabolic alkalosis and adrenergic symptoms. Cessation of the licorice-containing supplement resulted in complete resolution of the patient's hypertension, symptoms and abnormal lab values. To our knowledge this is the first reported case of AME from this supplement, and the first to describe accompanying hyperadrenergic symptoms.ConclusionsGlycyrrhizic acid is increasingly being found in unregulated nutritional supplements and has the potential to induce a reversable syndrome of AME. Acquired AME should be suspected in individuals who present with hypertension along with hypokalemia, metabolic alkalosis and low plasma renin and serum aldosterone levels.

Plasma epinephrine and norepinephrine responses to extreme heat exposures in young and older adults.

Hyperthermia is known as a hyperadrenergic state, yet there is a lack of data on the sympathetic responses to ambient heat stress in humans. Therefore, we investigated the plasma epinephrine and norepinephrine concentrations of healthy young and older adults exposed to 3 h of very hot and dry, as well as hot and humid, heat, both with accompanying activities of daily living. We hypothesized that older adults, compared with young adults, would have augmented increases in epinephrine and norepinephrine concentrations secondary to increased thermal strain. Young (n = 20) and older (n = 18) participants underwent two 3-h heat exposures on different days: very hot and dry [47°C and 15% relative humidity (RH)] and hot and humid (41°C and 40% RH). To mimic heat generation comparable to activities of daily living, participants performed seven 5-min bouts of light cycling (approximately 3 METS) dispersed throughout the heat exposure. We measured plasma concentrations of epinephrine and norepinephrine at baseline, end, and 2-h postheat exposure. There was a group-wide increase in epinephrine from baseline to the end of the heat exposure (Δ19 ± 27 pg/mL; P < 0.001) in the hot and humid condition, but not in the very hot and dry condition (Δ6 ± 19 pg/mL; P = 0.10). There were group-wide decreases in norepinephrine concentrations from baseline to the end of the heat exposure in both the very hot and dry (Δ-131 ± 169 pg/mL; P < 0.001) and the hot and humid (Δ-138 ± 157 pg/mL; P < 0.001) conditions, with both returning to near baseline at 2-h postexposure. These data suggest that ambient heating with accompanying bouts of light intermittent exercise may lead to decreases in circulating concentrations of norepinephrine.NEW & NOTEWORTHY Herein we present plasma epinephrine and norepinephrine concentrations to 3 h of very hot and dry, as well as hot and humid, heat exposures with accompanying activities of daily living in young and older participants. We found 1) increased plasma concentrations of epinephrine in young and older adults following the hot and humid, but not the very hot and dry exposures and 2) decreased concentrations of norepinephrine in both groups following exposure to both conditions.

Increased β2-adrenergic signaling promotes fracture healing through callus neovascularization in mice.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the β2-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene-related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

Propranolol Alleviates Cardiac Injury After Acute Catecholamine Infusion Through p38-MAPK Pathways.

Hypercatecholaminergic conditions are known to cause heart failure and cardiac fibrosis when severe. Although previous investigations have studied the effects of beta-blockade in experimental models of catecholaminergic states, the detailed benefits of beta-blockade in more realistic models of hyper-adrenergic states were less clear. In this study, we examined acute cardiac changes in rats with hyperacute catecholamine-induced heart failure with and without propranolol treatment. Male Sprague-Dawley rats (n = 12) underwent a 6-hour infusion of epinephrine and norepinephrine alone, with an additional propranolol bolus (1 mg/kg) at hour 1 (n = 6). Cardiac tissues were examined after 6 hours. Cardiac immunohistochemistry revealed significantly decreased expression of phosphorylated p-38 (left ventricle, P = 0.021; right ventricle, P = 0.021), with upregulation of reactive oxidative species and other profibrosis proteins, after catecholamine infusion alone. After 1 propranolol 1 mg/kg bolus, the levels of phosphorylated-p38 returned to levels comparable with sham (left ventricle, P = 0.021; right ventricle, P = 0.043), with additional findings including downregulation of the apoptotic pathway and profibrotic proteins. We conclude that catecholamine-induced heart failure exerts damage through the p-38 mitogen-activated protein kinase pathway and demonstrates profibrotic changes mediated by matrix metalloproteinase 9, alpha-smooth muscle actin, and fibroblast growth factor 23. Changes in these pathways attenuated acute catecholamine-induced heart failure after propranolol bolus 1 mg/kg. We conclude that propranolol bolus at 1 mg/kg is able to mediate the effects of catecholamine excess through the p-38 mitogen-activated protein kinase pathway, profibrosis, and extrinsic apoptosis pathway.

Physiological effects of ivabradine in heart failure and beyond.

Ivabradine is a pharmacologic agent that inhibits the funny current responsible for determining heart rate in the sinoatrial node. Ivabradine's clinical potential has been investigated in the context of heart failure since it is associated with reduced myocardial oxygen demand, enhanced diastolic filling, stroke volume, and coronary perfusion time; however, it is yet to demonstrate definitive mortality benefit. Alternative effects of ivabradine include modulation of the renin-angiotensin-aldosterone system, sympathetic activation, and endothelial function. Here, we review key clinical trials informing the clinical use of ivabradine and explore opportunities for leveraging its potential pleiotropic effects in other diseases, including treatment of hyperadrenergic states and mitigating complications of COVID-19 infection.

A HYPERADRENERGIC STATE IN HYPERTENSION IS ASSOCIATED WITH MOOD DISTURBANCE AND IMPAIRED STRESS-MODULATED VASOMOTOR RESPONSES

Objective: Increasing evidence suggests a high prevalence of affective disorders in hypertension, however, the physiological associations remain unclear. Noradrenergic activation in the central and peripheral nervous systems is a putative mechanism that may explain the link between both conditions. Here, we investigate whether these stress-sensitive co-morbidities may be dependent on basal noradrenergic activity and whether vascular responses to centrally acting stimuli vary according to noradrenergic activity. Design and method: We examined the relation of affective disorders and stress-mediated vascular responses to plasma concentrations of normetanephrine (NMN), a measure of noradrenergic activity, in subjects with primary hypertension. Subjects on antidepressant medication, alpha- and beta-blockers were excluded. The Patient Health Questionnaire (PHQ-9), the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR-16), and Generalised Anxiety Disorder-7 (GAD-7) questionnaires were used for the evaluation of symptoms of depression and anxiety. Forearm blood flow (strain gauge plethysmography) was used to assess vascular responses to mental stress (Stroop colour-word test) and slow breathing (by biofeedback), interventions that respectively increase or decrease noradrenergic activity in the pre-frontal cortex and locus coeruleus. Results: 100 subjects (53% male) with (mean ± SD) age 43.4 ± 10.9 years were recruited. 88% of subjects were treated with anti-hypertensive medications and 4% had type 2 diabetes. 31% and 34% of the study population scored moderate to severe depression for PHQ-9 and QIDSSR-16 respectively indicating significant mood disturbance. Scores representing low mood and high anxiety were 2-3-fold higher for hypertensive subjects in the highest compared to lowest NMN tertiles (PHQ-9: 9.2 ± 5.8 vs 3.8 ± 2.7, P &lt; 0.001; QIDSSR-16: 12.3 ± 4.9 vs 4.5 ± 3.5, P = 0.003; GAD-7: 9.0 ± 5.5 vs 4.6 ± 3.8, P = 0.003). Forearm vasodilator responses to mental stress and vasoconstrictor responses to slow breathing were attenuated in those with high compared to low NMN (28.3 ± 21% vs. 47.1 ± 30% increases for mental stress and 3.7 ± 21% vs. 18.6 ± 15% decreases for slow breathing for highest vs. lowest tertiles of NMN, both P &lt; 0.01). Conclusions: A hyperadrenergic state in hypertension is associated with mood disturbance and impaired stress-modulated vasomotor responses. This association may be mediated by chronic stress impinging on pathways regulating central arousal and peripheral sympathetic nerve activity.

Anabolic–androgenic steroid abuse: psychiatric manifestations and treatment

IntroductionAnabolic-androgenic steroids (AAS) are synthetic derivatives of steroids which are frequently utilized in order to increase muscle mass and strength. Estimates of AAS abuse vary according to different studies. However, a global lifetime prevalence of 3.3% has been reported. The increasing illicit use of AAS over the years has raised serious public health concerns.ObjectivesTo report a clinical case of AAS abuse and review the psychopathology associated with AAS abuse and its treatment.MethodsThe authors report a clinical case and conducted a non-systematic review on the Pubmed database with the terms “anabolic-androgenic steroids”, “abuse” and “psychiatric manifestations”.ResultsA 25-year-old male patient with history of body dysmorphic disorder was admitted to the emergency services following severe psychomotor agitation and verbal and physical aggression towards his family members. He explained he had begun using AAS years prior in order to improve his physical appearance. Recently he had been administering AAS injections on a more regular basis and restricting his food and water intake. His sleep-wake cycle was disrupted and he began experiencing increasing anxiety and persecutory ideation. Additionally, increased aggression was reported and numerous conflicts with his family members took place in the weeks previous to his psychiatric observation. AAS abuse has been associated with psychiatric symptoms such as aggression and violence, mania and less commonly psychosis and suicidal ideation. Moreover, its prolonged abuse can lead to symptoms of dependence and withdrawal following suspension. A biphasic model of steroid dependence has been described. First there is a brief hyperadrenergic state with opoid-like withdrawal symptoms which is then followed by a prolonged period of depression and craving. During this phase symptoms such as fatigue, muscle and joint pain, insomnia, anxiety and depression may occur. There are no established guidelines for treatment. Acute care of agitation should follow a similar course as the one utilized in other forms of substance induced-agitation: firstly, the least invasive interventions should be implemented. If medication is required, haloperidol has been reported to be effective, although evidence is scarce. Benzodiazepines may be considered, although its use with AAS has not been reported. In regards to long term care, AAS discontinuation is vital in conjunction with proper management of withdrawal symptoms. If a patient presents symptoms of opioid-like withdrawal, treatment with clonidine may be initiated. The use of medically prescribed steroids has been suggested in order to alleviate withdrawal symptoms. Other treatment options such as human chorionic gonadotrophin and clomiphene have also been proposed.ConclusionsAAS abuse is a serious public health concern. Clinicians should be aware of its serious psychiatric effects and possible treatment courses.Disclosure of InterestNone Declared

Administration of botulinum toxin a and vascular endhotelial growth factor reduce norepinephrine levels and increase viability of modified mcfarlane flap in wistar rat

Local hyperadrenergic states after a random flap elevation mediated by humoral vasoconstrictors can lead to flap necrosis. This study aimed to evaluate the effect of Botulinum Toxin A (BoNT-A) on reducing levels of Norepinephrine (NE) as the main humoral vasoactive substance, as well as its additive effect with Vascular Endothelial Growth Factor (VEGF) in increasing the viability of random flap. 28 Wistar Rats with Caudally Based Modified McFarlane Flap were divided into four groups. Group I received BoNT-A 3 days before flap elevation, group II received VEGF immediately after flap elevation, group III received a combination of BoNT-A and VEGF, group IV was a control group. Result in this study NE levels lowest was found in the BoNT-A+VEGF combination group (94.63 ± 5 .25 ng/ml, p&lt;0.05 in group I, p&lt;0.01 in groups II and IV). The highest value of FVR was shown in the BoNT-A+VEGF combination group (93.37 ± 2.19 %, p &lt; 0.05 in group I, p &lt; 0.01 in groups II and IV). Meanwhile, the increase in flap viability in the VEGF group was not statistically significant. So Conclusion administration of BoNT-A in combination with VEGF can increase the viability of random flaps by decreasing NE levels.

ODP583 Screening for Pheochromocytoma in a Cohort of Patients with Takotsubo Cardiomyopathy: New insights on Prevalence and Screening Tests Reliability Surrounding the Acute Cardiac Event

Abstract Background According to Takotsubo cardiomyopathy (TCM) diagnostic criteria, pheochromocytoma and paraganglioma (PPGL) should be excluded as secondary causes. However, it is unclear whether PPGL screening in the setting of acute TCM is reliable. We aimed to assess the prevalence of PPGL and the reliability of PPGL screening in a cohort of patients with TCM. Method: We retrospectively reviewed data from patients admitted in a tertiary hospital between August 2012 and January 2021 with a diagnosis of TCM proven by typical echocardiography findings and no acute occlusion on coronarography, who were screened for PPGL by plasma metanephrines/normetanephrines (M/NM). If the first screening was positive, a second plasma M/NM sample was used for confirmation. Time between TCM diagnosis and PPGL screening was collected. Results Among 64 patients identified with TCM, 42 underwent plasma M/NM screening. 81. 0% were female, and the mean age was 67.4 ± 9.9 years old. Ten patients (23.8%) had a positive result. Of those, 8 patients had a weakly positive result (1-2×upper limit of normal [ULN]) and 2 had a strongly positive result (&amp;gt;2×ULN). Of those 10 patients, 6 underwent a second screening: 5 had a normal result and 1 had a weakly positive result (plasma NM 1. 06×ULN). This patient underwent a third screening that was negative. In addition, an abdominal CT showed normal adrenal glands, and their chromogranin A levels were normal. Four patients had a positive initial PPGL screening, but they did not undergo a second screening: 3 died of causes unrelated to TCM before a second plasma M/NM sample was taken and one patient was lost to follow-up (his plasma NM was weakly positive at 1.29×ULN). They all had an abdominal CT that showed normal adrenal glands. Average time between TCM diagnosis and PPGL screening in all patients and in patients with a positive initial screening was 4.57 ± 3.91 and 3.38 ± 2.12 days, respectively. A linear regression model suggested an inverse relationship between plasma M/NM and time between TCM diagnosis and screening, with R2 = 0.2275. Conclusion TCM occurring as the initial presentation of PPGL is rare. All patients with a positive screening ended up being false positives in our study. The ratio of false positive results when screening for PPGL in the setting of acute TCM seems to be higher than in the general population, which could be explained by a hyperadrenergic state. It is unclear whether a shorter delay between TCM diagnosis and PPGL screening may be associated with more false positives. More research is needed to determine what is the optimal timing for PPGL screening in acute TCM and if higher cut-offs should be used to minimize false positive results. Presentation: No date and time listed

ODP655 Apathetic Hyperthyroidism

Abstract Introduction Apathetic hyperthyroidism is a rare presentation of hyperthyroidism described in the elderly population. It is insidious in onset and symptoms are depression, lethargy, and weight loss. The adrenergic symptoms of hyperthyroidism are often absent. Furthermore, orbital disease associated apathetic hyperthyroidism has not been reported widely in literature. We present a clinical scenario of apathetic hyperthyroidism associated with orbitopathy. A 64-year-old lady presented with acute onset bilateral periorbital swelling that developed over 2 days. About 3 weeks prior, she began experiencing symptoms of brain fog, lethargy, intermittent nausea, anorexia, and headache. She experienced palpitations with exertion. Review of other systems was negative. Clinical exam: HR 70. Thyroid gland was enlarged, symmetric with no nodules and nontender, bilateral periorbital puffiness and mild conjunctival redness was noted. Lab data was significant for TSH at 0. 03 uIU/mL, elevated FT4 2.5ng/dL, total T3 of 222ng/dL, TSI 4.2 and sed rate of 10. Her thyroid ultrasound indicated hypervascular and heterogenous gland. Our patient was diagnosed with apathetic hyperthyroidism and thyroid eye disease. She was started on propranolol 60mg ER one tablet a day and methimazole 10mg a day. CT scan of the orbit indicated symmetric enlargement of extraocular muscles. Evaluation by the ophthalmologist confirmed the presence of thyroid eye disease with a clinical activity score of 6 out of 7 indicating severe thyroid eye disease and she was a candidate for treatment with teprotumumab. Discussion Apathetic hyperthyroidism was first described by Lahey in 1931, as a state of non-activated hyperthyroidism. It is manifested with gradual onset of apathy, depressed mood, lethargy, nausea, lack of appetite, weight loss, proximal muscle weakness, goiter, atrial fibrillation, and congestive heart failure. It lacks the typical presentation of a hyperadrenergic state of hyperthyroidism which include palpitations, anxiety, tremor, heat intolerance, and diaphoresis. Due to the lack of typical presentation of hyperthyroidism, timely diagnosis and treatment may be challenging. Concomitant occurrence of occult malignancy and hyperglycemia have been reported in case reports. Patients can also transition from apathetic state to hyperadrenergic state of hyperthyroidism and vice versa. Lahey emphasized the risk of unexpected death following surgery in apathetic hyperthyroidism. The absence of adrenergic symptoms could be supported by the theory that these patients are in a relative state of catecholamine deficiency or have a state of end organ catecholamine resistance. Significant orbital involvement in apathetic hyperthyroidism is not widely reported in the literature. Blepharoptosis has been mentioned in association with this form of hyperthyroidism. Our patient presented with acute onset eye symptoms which prompted testing of thyroid function. Further review of symptoms led to a diagnosis of apathetic hyperthyroidism with thyroid eye disease.

Exercise-induced ventricular arrythmia in asymptomatic patients with Mitral Valve Prolapse

Abstract Introduction Mitral Valve Prolapse (MVP) is associated with complex ventricular arrythmia (VA) and sudden cardiac death but risk stratification remains unclear. Exercise induces an hyperadrenergic state and could trigger VA, however, data on exercise-induced VA (EIVA) in MVP patients are scarce. Objective To describe EIVA prevalence, origin, characteristics and associated features in MVP patients. Methods In this observational prospective study, 64 MVP asymptomatic patients (58±14 years, 41 men) with mild to severe mitral regurgitation (MR) and without left ventricular (LV) dysfunction, underwent echocardiography and symptom-limited exercise testing. Continuous 12-lead ECG monitoring was performed throughout testing. Severe EIVA was defined as ventricular triplets, sustained or non-sustained ventricular tachycardia (NSVT) or ventricular fibrillation. Results All patients exercised at maximal intensity until exhaustion. EIVA was observed in 54 (84%) subjects including 12 (19%) patients with severe EIVA (7 triplets, 5 NSVT). Severe EIVA originated mainly from the mitral apparatus (all but one) and occurred at high exercise intensity (median 90% of predicted workload) or during early recovery phase. Compared to the rest of the cohort the patients with severe EIVA had similar resting ECG characteristics, similar LV dimension and function, similar degree of MR and mitral apparatus morphology. Finally, severe EIVA was not associated with an alteration of exercise tolerance. Conclusion Exercise frequently unmasks ventricular arrythmia in patients with MVP. EIVA appears not linked to MVP features nor to exercise tolerance and seems to provide additional phenotyping information that could be linked to prognosis. Funding Acknowledgement Type of funding sources: None.

Trauma center admission risk conditions and the probability for developing alcohol withdrawal syndrome: A retrospective study

BackgroundBecause the proportion of trauma patients developing alcohol withdrawal syndrome (AWS) is low, AWS risk conditions have not been precisely delineated. We aimed to create multifactor screening strategies to assess probabilities for the likelihood of developing AWS. MethodsWe performed a retrospective chart review of 1,011 trauma patients admitted to a Level I trauma center to investigate the associations between AWS and probable AWS risk conditions. Included patients were adults who met trauma registry inclusion criteria and had blood alcohol concentration (BAC) testing performed. Patients were excluded if they had a traumatic brain injury with a Glasgow Coma Score (GCS) ≤ 8, or no BAC testing performed. We defined heavy drinking as daily drinking or >7 per week. ResultsAWS had univariate associations with heavy drinking history, Injury Severity Score (ISS) ≥15, psychiatric disorders, liver disease, smoking history, in-hospital bronchodilator administration, age ≥45, male sex, Intensive Care Unit (ICU) admission, serum aspartate aminotransferase (AST) ≥40 U/L, and cognitive preservation (GCS ≥13 with BAC ≥100 mg/dL) (all, p < 0.05). ICU admission, AST ≥40 U/L, cognitive preservation, male sex, and age ≥45 had associations with ISS ≥15 or alcohol misuse (all, p < 0.0001). For patients with age ≥45 and heavy drinking history or age <45 and heavy drinking history with ISS ≥15 and ICU admission, the AWS proportion (15.3%) was greater in comparison to other patients (0.3%). The AWS risk score was the sum of the following nine conditions, assigned a zero when the condition was absent and one when present (range 0–9): ISS ≥15, psychiatric disorders, liver disease, smoking history, in-hospital bronchodilator administration, age ≥45, male sex, AST ≥40 U/L, and cognitive preservation. The AWS proportion was greater with a risk score of 5–9 (16.8%) than of 0–4 (1.2%; p < 0.0001). ConclusionsAWS in the setting of traumatic injury is associated with multiple risk conditions. The presence of multiple risk conditions might have additive effects that could contribute toward a clinical manifestation of AWS. The identified risk conditions may be associated with a hyperadrenergic state.

Epileptic seizures and Epilepsy Monitoring Unit admission disclose latent cardiac electrical instability

BackgroundSudden cardiac arrest results from cardiac electrical instability and is 3-fold more frequent in patients with chronic epilepsy than in the general population. We hypothesized that focal to bilateral tonic-clonic seizures (FTBTCS) would acutely impact T-wave alternans (TWA), a marker of cardiac electrical instability linked to an elevated risk for sudden cardiac death, more than focal seizures (FS) [focal aware seizures (FAS) and focal with impaired awareness seizures (FIAS)], due to their greater sympathetic stimulation of the heart. Since stress has been shown to cause significant TWA elevations in patients with heart disease, we also hypothesized that the early days of an inpatient admission to an epilepsy monitoring unit (EMU) would be associated with higher TWA levels compared to later hospital days in patients with chronic epilepsy, presumably due to stress. Design/MethodsWe analyzed the acute effects of seizures [FAS, FIAS, FTBTCS, and nonepileptic seizures (NES)] and day of hospital stay on TWA in 18 patients admitted to the EMU using high-resolution wireless electrocardiographic (ECG) patch monitors. ResultsA total of 5 patients had FTBTCS, 7 patients had FS (2 FAS, 5 FIAS), and 3 patients had NES only during the index hospital stay. Four patients did not have any electroclinical seizures or NES. FTBTCS resulted in marked acute increases in ictal TWA from baseline (2 ± 0.3 µV) to ictal maximum (70 ± 6.1 µV, p < 0.0001), the latter exceeding the 60 µV cut point defined as severely abnormal. By comparison, while FAS and FIAS also provoked significant increases in TWA (from 2 ± 0.5 µV to 30 ± 3.3 µV, p < 0.0001), maximum ictal TWA levels did not reach the 47 µV cut point defined as abnormal. Heart rate increases during FTBTCS from baseline (62 ± 5.8 beats/min) to ictal maximum (134 ± 8.6 beats/min, an increase of 72 ± 7.2 beats/min, p < 0.02) were also greater (p = 0.014) than heart rate increases during FS (from 70 ± 5.2 beats/min to 118 ± 6.2 beats/min, an increase of 48 ± 2.6 beats/min, p < 0.03). In 3 patients with NES, TWA rose mildly during the patients’ typical episodes (from 2 ± 0.6 µV to 14 ± 2.6 µV, p < 0.0004), well below the cut point of abnormality, while heart rate increases were observed (from 75 ± 1.3 to 112 ± 8.7 beats/min, an increase of 37 ± 8.9 beats/min, p = 0.03). Patients with EEG-confirmed electroclinical seizures recorded while in the EMU exhibited significantly elevated interictal TWA maxima (61 ± 3.4 µV) on EMU admission day which were similar in magnitude to ictal maxima seen during FTBTCS (70 ± 6.1 µV, p = 0.21). During subsequent days of hospitalization, daily interictal TWA maxima showed gradual habituation in patients with both FS and FTBTCS but not in patients with NES only. ConclusionsThis is the first study to our knowledge demonstrating that FTBTCS acutely provoke highly significant increases in TWA to levels that have been associated with heightened risk for sudden cardiac death in other patient populations. We speculate that mortality temporally associated with FTBTCS may, in some cases, be due to sudden cardiac death rather than respiratory failure. In patients with EEG-confirmed epilepsy, hospital admission is associated with interictal TWA maxima that approach those seen during FTBTCS, presumably related to stress during the early phase of hospitalization compared to later in the hospitalization, indicating cardiac electrical instability and potential vulnerability to sudden cardiac death related to stress independent of temporal relationships to seizures. The elevated heart rates observed acutely with seizures and on hospital Day 1 are consistent with a hyperadrenergic state and the effect of elevated sympathetic output on a vulnerable cardiac substrate, a phenomenon termed “the Epileptic Heart.”

Hemodynamic stress‐induced cardiac remodelling is not modulated by ablation of phosphodiesterase 4D interacting protein

Adrenergic stimulation in the heart activates the protein kinase A (PKA), which phosphorylates key proteins involved in intracellular Ca2+ handling. PKA is held in proximity to its substrates by protein scaffolds, the A kinase anchoring proteins (AKAPs). We have previously identified the transcript of phosphodiesterase 4D interacting protein (Pde4dip; also known as myomegalin), one of the sarcomeric AKAPs, as being differentially expressed following hemodynamic overload, a condition inducing hyperadrenergic state in the heart. Here, we addressed whether PDE4DIP is involved in the adverse cardiac remodelling following hemodynamic stress. Homozygous Pde4dip knockout (KO) mice, generated by CRISPR‐Cas9 technology, and wild‐type (WT) littermates were exposed to aortocaval shunt (shunt) or transthoracic aortic constriction (TAC) to induce hemodynamic volume overload (VO) or pressure overload (PO), respectively. The mortality, cardiac structure, function and pathological cardiac remodelling were followed up after hemodynamic injuries. The PDE4DIP protein level was markedly downregulated in volume‐overloaded‐ but upregulated in pressure‐overloaded‐WT hearts. Following shunt or TAC, mortality rates were comparably increased in both genotypes. Twelve weeks after shunt or TAC, Pde4dip‐KO animals showed a similar degree of cardiac hypertrophy, dilatation and dysfunction as WT mice. Cardiomyocyte hypertrophy, myocardial fibrosis, reactivation of cardiac stress genes and downregulation of ATPase, Ca2+ transporting, cardiac muscle, slow twitch 2 transcript did not differ between WT and Pde4dip‐KO hearts following shunt or TAC. In summary, despite a differential expression of PDE4DIP protein in remodelled WT hearts, Pde4dip deficiency does not modulate adverse cardiac remodelling after hemodynamic VO or PO.

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.

Low-Dose Propranolol Prevents Functional Decline in Catecholamine-Induced Acute Heart Failure in Rats.

Severe hyper-catecholaminergic states likely cause heart failure and cardiac fibrosis. While previous studies demonstrated the effects of beta-blockade in experimental models of single-catecholamine excess states, the detailed benefits of beta-blockade in more realistic models of hyper-adrenergic states are less clearly understood. In this study, we examined different therapeutic dosages and the effects of propranolol in rats with hyper-acute catecholamine-induced heart failure, and subsequent cardiopulmonary changes. Rats (n = 41) underwent a 6 h infusion of epinephrine and norepinephrine alone, with additional low-dose (1 mg/kg) or high-dose propranolol (10 mg/kg) at hour 1. Cardiac and pulmonary tissues were examined after 6 h. Catecholamine-only groups had the lowest survival rate. Higher doses of propranolol (15 mg/kg) caused similarly low survival rates and were not further analyzed. All low-dose propranolol rats survived, with a modest survival improvement in the high-dose propranolol groups. Left ventricular (LV) systolic pressure and LV end-diastolic pressure improved maximally with low-dose propranolol. Cardiac immunohistochemistry revealed an LV upregulation of FGF-23 in the catecholamine groups, and this improved in low-dose propranolol groups. These results suggest catecholamine-induced heart failure initiates early pre-fibrotic pathways through FGF-23 upregulation. Low-dose propranolol exerted cardio-preventative effects through FGF-23 downregulation and hemodynamic-parameter improvement in our model of hyper-acute catecholamine-induced heart failure.

The Connection Between Opioid Withdrawal and Takotsubo Cardiomyopathy: Case Reports of ‘Opioid Octopus Heart’

Introduction Takotsubo Cardiomyopathy (TCM) is an incompletely understood diagnosis. The leading hypothesis of its pathogenesis is that a hyperadrenergic state leads to cardiotoxicity, which is supported by case findings. Withdrawal from opioids is one potential etiology of an excessive adrenergic response and, therefore, may precipitate TCM. Case Presentations Here, we present 2 cases of TCM in patients who chronically used opioids, both at the same institution within 1 month of each other. The first patient is a 68-year-old man who presented with a chronic obstructive pulmonary disease exacerbation and did not disclose his long-standing opioid use disorder. One day after admission, he was found to be in opioid withdrawal and, soon after, developed TCM. He was originally treated for non-ST elevation myocardial infarction and opioid withdrawal but decompensated. He was sent to the intensive care unit (ICU) to receive pressors and fluid resuscitation. He soon recovered and his cardiac function returned to baseline. The second patient is a 33-year-old woman with opioid use disorder taking methadone who presented with lower extremity weakness, edema, and pain. She was diagnosed with infective endocarditis. While awaiting surgery and receiving antibiotics, she developed respiratory failure and was upgraded to the ICU. There was a lapse in her opioid treatment, and she subsequently developed TCM. She was treated with pressors and fluids in the ICU, and eventually recovered with reduced cardiac function at the time of discharge. Conclusions While clinical evidence indicated opioid withdrawal as the likely provoking factor for development of TCM in the first case, the second patient’s symptoms from other clinical complications confounded the cause of her TCM. Twelve similar cases have been reported in the literature, suggesting that opioid withdrawal may be associated with development of TCM. Further quantitative research is required to establish this relationship. Our findings contribute to the theoretical pathophysiology of TCM and offer important considerations for clinical management of opioid withdrawal.

Beta blockade in TBI: Dose-dependent reductions in BBB leukocyte mobilization and permeability in vivo.

Traumatic brain injury (TBI) is accompanied by a hyperadrenergic catecholamine state that can cause penumbral neuroinflammation. Prospective human studies demonstrate improved TBI survival with beta blockade (bb), although mechanisms remain unclear. We hypothesized that deranged post-TBI penumbral blood brain barrier (BBB) leukocyte mobilization and permeability are improved by bb. CD1 male mice (n = 64) were randomly assigned to severe TBI-controlled cortical impact: 6 m/s velocity, 1 mm depth, 3 mm diameter-or sham craniotomy, and IP injection of either saline or propranolol (1, 2, or 4 mg/kg) every 12 hours for 2 days. At 48 hours, in vivo pial intravital microscopy visualized live endothelial-leukocyte (LEU) interactions and BBB microvascular leakage. Twice daily clinical recovery was assessed by regaining of lost body weight and the Garcia Neurological Test (motor, sensory, reflex, balance assessments). Brain edema was determined by hemispheric wet-to-dry ratios. Propranolol after TBI reduced both in vivo LEU rolling and BBB permeability in a dose-dependent fashion compared with no treatment (p < 0.001). Propranolol reduced cerebral edema (p < 0.001) and hastened recovery of lost body weight at 48 hours (p < 0.01). Compared with no treatment (14.9 ± 0.2), 24-hour Garcia Neurologic Test scores were improved with 2 (15.8 ± 0.2, p = 0.02) and 4 (16.1 ± 0.1, p = 0.001) but not with 1 mg/kg propranolol. Propranolol administration reduces post-TBI LEU mobilization and microvascular permeability in the murine penumbral neurovasculature and leads to reduced cerebral edema. This is associated with hastened recovery of post-TBI weight loss and neurologic function with bb treatment. Dose-dependent effects frame a mechanistic relationship between bb and improved human outcomes after TBI.