Hyperadrenergic State Research Articles

Abstract 10850: Investigating the Role of a Cardiac Enhancer in the Development of Heart Failure

Introduction: Alpha actinin-2 (ACTN2) is a major cytoskeletal protein that plays a critical role in maintaining the structural and functional integrity of the sarcomere. ACTN2 mutations, although rare, have been shown to be associated with various types of cardiomyopathy. Using genome-wide association and multi-omic approaches, we recently identified non-coding variants that showed a strong association with heart failure (HF). Two of the variants are within an evolutionary conserved transcriptional enhancer region that regulates the ACTN2 gene in human stem cell derived cardiomyocytes (hPSC-CMs). However, the role of cardiac enhancers in the development of HF remains unknown, therefore we used engineered heart tissues (EHT) from hPSC-CMs to investigate the effects of the ACTN2 enhancer. Methods: We used hPSC-CMs and performed morphologic and functional analyses by immunostaining, calcium transient measurements and quantitative assays such as western blotting, proteomics, qPCR and single cell transcriptomics. Next, we utilized CRISPR interference (CRISPRi) and chromatin immunoprecipitation (ChIP) to analyze the transcriptional regulation of the ACTN2 enhancer. Finally, we measured force generation using EHTs. Results: We first engineered hPSC-CMs carrying an ACTN2 enhancer deletion. This resulted in decreased ACTN2 gene and protein expression, and cardiomyocytes developed myofibrillar disarray, hypertrophy, lower beating rates and suppressed calcium transients. Moreover, EHTs demonstrated reduced mechanical force. Using CRISPRi and ChIP we found that the transcription factor MEF2c binds a short DNA sequence containing an enhancer variant to regulate ACTN2 expression. Single cell RNA-Seq analysis of hPSC-CMs treated with isoproterenol to model the hyperadrenergic state observed in HF, revealed the induction of pathways involved in protein quality control, actin fragmentation and apoptosis. We have also recently developed a mouse model to address the effect of the enhancer in vivo . Conclusions: Our study confirms that a conserved and clinically relevant enhancer region can effectively regulate ACTN2 , and variants within that region can have detrimental consequences on CMs which can contribute to HF.

52-Year-Old Woman With Palpitations, Abdominal Distension, and Severe Abdominal Pain

52-Year-Old Woman With Palpitations, Abdominal Distension, and Severe Abdominal Pain

β2-Adrenergic receptor agonist induced hepatic steatosis in mice: modeling nonalcoholic fatty liver disease in hyperadrenergic states.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders ranging from hepatic steatosis [excessive accumulation of triglycerides (TG)] to nonalcoholic steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The molecular pathogenesis of steatosis and progression to more severe NAFLD remains unclear. Obesity and aging, two principal risk factors for NAFLD, are associated with a hyperadrenergic state. β-Adrenergic responsiveness in liver increases in animal models of obesity and aging, and in both is linked to increased hepatic expression of β2-adrenergic receptors (β2-ARs). We previously showed that in aging rodents intracellular signaling from elevated hepatic levels of β2-ARs may contribute to liver steatosis. In this study we demonstrate that injection of formoterol, a highly selective β2-AR agonist, to mice acutely results in hepatic TG accumulation. Further, we have sought to define the intrahepatic mechanisms underlying β2-AR mediated steatosis by investigating changes in hepatic expression and cellular localization of enzymes, transcription factors, and coactivators involved in processes of lipid accrual and disposition-and also functional aspects thereof-in livers of formoterol-treated animals. Our results suggest that β2-AR activation by formoterol leads to increased hepatic TG synthesis and de novo lipogenesis, increased but incomplete β-oxidation of fatty acids with accumulation of potentially toxic long-chain acylcarnitine intermediates, and reduced TG secretion-all previously invoked as contributors to fatty liver disease. Experiments are ongoing to determine whether sustained activation of hepatic β2-AR signaling by formoterol might be utilized to model fatty liver changes occurring in hyperadrenergic states of obesity and aging, and thereby identify novel molecular targets for the prevention or treatment of NAFLD.NEW & NOTEWORTHY Results of our study suggest that β2-adrenergic receptor (β2-AR) activation by agonist formoterol leads to increased hepatic TG synthesis and de novo lipogenesis, incomplete β-oxidation of fatty acids with accumulation of long-chain acylcarnitine intermediates, and reduced TG secretion. These findings may, for the first time, implicate a role for β2-AR responsive dysregulation of hepatic lipid metabolism in the pathogenetic processes underlying NAFLD in hyperadrenergic states such as obesity and aging.

Thyrotoxic Periodic Paralysis in Young Caucasian Male

Abstract Background: Thyrotoxic periodic paralysis (TPP) can be a medical emergency as delay in diagnosis can lead to life-threatening arrhythmia. Periodic paralysis is more prevalent in the Asian population. We report a case of thyrotoxic periodic paralysis in a young Caucasian male. Case: A 24-year-old male with a past history of Graves’ disease, hypertension, and asthma was brought to the hospital due to leg weakness and fall. He was initially diagnosed with Graves’ disease 2 years ago. The patient could not take methimazole or metoprolol due to the affordability issue for the last 18 months. On presentation, he fell on the floor while attempting to stand up from the couch. He could not stand up or pick his cell phone. He remained on the floor for 2-3 hrs. A review of the system was positive for palpitation and fatigue and negative for diarrhea, weight loss, anxiety, sleep problem, and dry eyes. On arrival, he had a pulse of 100/min, BP of 157/85 mmHg with rest of vitals signs normal. Motor strength on bilateral lower extremities were 2/5. Upper extremity strength was normal. No thyromegaly or thyroid bruit was noted in the exam. The rest of the physical exam was normal. Labs showed Potassium 1.9 with a normal reference range (RR) of 3.5 - 5.1 mmol/l. His TSH was < 0.01 (RR 0.35 - 5.00 MCU/ML), Free T4 was 5.0 (RR 0.6- 1.6 NG/DL), Total T3 was 425 (RR 87 - 180 NG/DL) and CK was 70 (RR 35- 232 U/L). EKG showed sinus rhythm at 90 bpm with no PR, T/ST, or QT abnormalities. He was given IV potassium and was also started on methimazole 10mg TID and metoprolol. His weakness and tachycardia were improved the next day. We discussed with him the options of medical management vs. surgery. He underwent a total thyroidectomy. Biopsy showed nodular hyperplasia consistent with graves’ disease. Discussion: Thyrotoxic periodic paralysis (TPP) is characterized by hypokalemia and episode of acute muscle weakness in lower extremities in the setting of hyperthyroidism. The pathophysiology of TPP remains uncertain. Hyperthyroidism is a hyperadrenergic state in which beta-2-adrenergic stimulation in muscle cells directly induces cellular K+ uptake by increasing cAMP, leading to activation of Na/K ATPase. The increase in the influx of intracellular K+ leads to hypokalemia and skeletal muscle weakness. Some studies show pathophysiology can be different in Caucasians compared to the Asian population that there could be abnormalities in Na and K channels other than Na/K ATPase. Potassium replacement should be done with caution as hypokalemia is due to intracellular shift and rebound hyperkalemia is common during the management. Beta-blocker may reverse adrenergic overstimulation of Na/K ATPase. It can help rapidly improve paralytic symptoms.

A nationwide observational cohort study of the relationship between beta-blockade and survival after hip fracture surgery

PurposeDespite advances in the care of hip fractures, this area of surgery is associated with high postoperative mortality. Downregulating circulating catecholamines, released as a response to traumatic injury and surgical trauma, is believed to reduce the risk of death in noncardiac surgical patients. This effect has not been studied in hip fractures. This study aims to assess whether survival benefits are gained by reducing the effects of the hyper-adrenergic state with beta-blocker therapy in patients undergoing emergency hip fracture surgery.MethodsThis is a retrospective nationwide observational cohort study. All adults ge 18 years were identified from the prospectively collected national quality register for hip fractures in Sweden during a 10-year period. Pathological fractures were excluded. The cohort was subdivided into beta-blocker users and non-users. Poisson regression with robust standard errors and adjustments for confounders was used to evaluate 30-day mortality.Results134,915 patients were included of whom 38.9% had ongoing beta-blocker therapy at the time of surgery. Beta-blocker users were significantly older and less fit for surgery. Crude 30-day all-cause mortality was significantly increased in non-users (10.0% versus 3.7%, p < 0.001). Beta-blocker therapy resulted in a 72% relative risk reduction in 30-day all-cause mortality (incidence rate ratio 0.28, 95% CI 0.26–0.29, p < 0.001) and was independently associated with a reduction in deaths of cardiovascular, respiratory, and cerebrovascular origin and deaths due to sepsis or multiorgan failure.ConclusionsBeta-blockers are associated with significant survival benefits when undergoing emergency hip fracture surgery. Outlined results strongly encourage an interventional design to validate the observed relationship.

NON-ST-Segment Elevation Myocardial Infarction Associated with Inadvertent Thyroid Hormone Overdose.

Thyroid hormone has a major role in cardiovascular function and cardiac hemodynamics. A slight change in thyroid affects ventricular function, serum cholesterol levels, increases the risk of coronary artery disease as well as cardiovascular mortality. In this report, we present a 62-year-old female with history significant for ischemic heart disease who was admitted for acute coronary syndrome (ACS) with persistent tachycardia, requiring urgent cardiac catheterization. Complete cardiac workup revealed that the patient had most likely suffered from vasospastic angina secondary to inadvertent overdose of her prescribed levothyroxine. This report emphasizes the significant cardiac complications caused by a deluged hyperadrenergic state secondary to overt hyperthyroidism. We conclude that thyrotoxicosis is a significant risk factor for cardiovascular disease and should be considered as a cause of life-threatening myocardial ischemia, especially in patients with known ischemic heart disease and thyroid disorders.

Pre-operative beta-blocker therapy does not affect short-term mortality after esophageal resection for cancer

BackgroundIt has been postulated that the hyperadrenergic state caused by surgical trauma is associated with worse outcomes and that β-blockade may improve overall outcome by downregulation of adrenergic activity. Esophageal resection is a surgical procedure with substantial risk for postoperative mortality. There is insufficient data to extrapolate the existing association between preoperative β-blockade and postoperative mortality to esophageal cancer surgery. This study assessed whether preoperative β-blocker therapy affects short-term postoperative mortality for patients undergoing esophageal cancer surgery.MethodsAll patients with an esophageal cancer diagnosis that underwent surgical resection with curative intent from 2007 to 2017 were retrospectively identified from the Swedish National Register for Esophagus and Gastric Cancers (NREV). Patients were subdivided into β-blocker exposed and unexposed groups. Propensity score matching was carried out in a 1:1 ratio. The outcome of interest was 90-day postoperative mortality.ResultsA total of 1466 patients met inclusion criteria, of whom 35% (n = 513) were on regular preoperative β-blocker therapy. Patients on β-blockers were significantly older, more comorbid and less fit for surgery based on their ASA score. After propensity score matching, 513 matched pairs were available for analysis. No difference in 90-day mortality was detected between β-blocker exposed and unexposed patients (6.0% vs. 6.6%, p = 0.798).ConclusionPreoperative β-blocker therapy is not associated with better short-term survival in patients subjected to curative esophageal tumor resection.

Reviewing stress in COVID-19 times

Covid-19 pandemic, apart from being a serious multi organ virus infectious disease, is a facilitator and also causal etiology of psychological and psychiatric manifestations. Much has been written on depression but manifestations of other behavioral problems appear either together or after its clinical course occurrence, being stress one of the most prevalent of all. Stress raises responses in the body from practically all of the organs such as tachycardia, dyspineia, anxiety and suffering emotions. This is a defense mechanism learnt since primordial times by mammals in occasions of fear of attack. Pathophysiologically it causes a hyper adrenergic state that triggers the symptoms that accompany it. Many metabolic changes occur in parallel and not only the health professional but the population itself must be aware of its potential occurrence and effects so that therapeutic and preventive measures may be installed. The excessive mechanisms of adaptation are responsible for adaptation diseases such as hypertension, infarction, ulcer, etc. The organism is therefore harmed by its own defense mechanisms, a fact that calls for clinical attention and intervention.

A BRIDGE INTO TROUBLED MYOCARDIUM

SESSION TITLE: Medical Student/Resident Cardiovascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Myocardial bridging refers to the anomalous intra-myocardial course of a segment of a major coronary artery. Though usually benign, it may manifest in peculiar situations. CASE PRESENTATION: A 47-year-old male with a history of moderate persistent asthma presented with a severe acute exacerbation. On arrival to the emergency department, there was a witnessed cardiopulmonary arrest requiring intubation and advanced cardiac life support for an initial rhythm of pulseless electrical activity. Sustained return of spontaneous circulation was achieved after the administration of 1mg of intravenous epinephrine. Subsequent 12 lead electrocardiogram (ECG) demonstrated 3mm ST-segment elevations in leads aVR and V1, with widespread ST-segment depressions (figure 1a). An emergent left heart catheterization revealed hyper-dynamic contractility and a rhythmic occlusion of the proximal left anterior descending with near total occlusion during systole (figure 2b) that became non-obstructed during diastole (figure 2a). On ECG thirty minutes later, at a notably slower heart rate, there was resolution of the ST segment abnormalities (figure 1b). DISCUSSION: The myocardial bridge of an epicardial coronary artery is usually an incidental finding on autopsy. However, scant observational data have revealed potential clinical manifestations including dysrhythmias, acute coronary syndromes and sudden cardiac death.[1] The hemodynamic implications of this phenomenon may depend on certain aspects of the intra-myocardial course such as the depth, length and orientation of fibers. Physiologic stressors have been shown to unmask an otherwise clinically irrelevant bridge by reducing coronary blood flow during both phases of the cardiac cycle; tachycardia results in shortened diastolic filling time, and hyper-contractility augments the dynamic compression of the bridged segment during systole. Ostensibly, exogenous epinephrine may exaggerate these mechanisms resulting in potentially catastrophic consequences, as seen in our case.[2] Therapeutic strategies are primarily aimed at reduction in the hemodynamic disturbance of the bridge. Despite a paucity of randomized clinical trials, beta blockers and calcium channel blockers have proven beneficial. Per contra, pure vasodilators such as nitrates have been shown to worsen the pressure gradient across the bridge leading to poorer clinical outcomes. Stenting, myotomy and bypass grafting may also be considered in refractory cases.[1] CONCLUSIONS: In critically ill patients, especially those in hyper-adrenergic states, fluctuating myocardial ischemia may be a sign of myocardial bridging. Reference #1: Corban MT, Hung OY, Eshtehardi P, Rasoul-Arzrumly E, McDaniel M, Mekonnen G, Timmins LH, Lutz J, Guyton RA, Samady H. Myocardial Bridging. J Am Coll Cardiol. 2014 Jun, 63 (22) 2346-2355. Reference #2: Ge J, Jeremias A, Rupp A, et al. New signs characteristic of myocardial bridging demonstrated by intracoronary ultrasound and Doppler. Eur Heart J. 1995;20:1707–16. Reference #3: Ripa C, Melatini MC, Olivieri F, Antonicelli R. Myocardial bridging: A 'forgotten’ cause of acute coronary syndrome - a case report. Int J Angiol. 2007;16(3):115–118. doi:10.1055/s-0031-1278262. DISCLOSURES: No relevant relationships by William Kogler, source=Web Response No relevant relationships by Michael Omar, source=Web Response No relevant relationships by Pujan Patel, source=Web Response No relevant relationships by Patrisha Shelley, source=Web Response

Sympathetic Overactivation in Patients With Essential Hypertension and Hepatic Iron Overload.

Iron overload has been recently shown to be associated with a hyperadrenergic state in genetic hemochromatosis. Whether this is also the case in essential hypertension, characterized by sympathetic activation and frequently by body iron overload, is unknown. In 17 healthy normotensive controls (age 52.3±3.2 years, mean±SE), in 21 age-matched patients with hypertension with iron overload (HT+), defined by serum ferritin levels, and in 28 hypertensives without this condition, we measured efferent postganglionic muscle sympathetic nerve traffic (microneurography), heart rate and blood pressure variability (power spectral analysis), serum ferritin, and metabolic variables. Muscle sympathetic nerve traffic was significantly (P<0.02 at least) greater in HT+ than in patients with hypertension without iron overload and normotensive subjects both when expressed as bursts incidence over time (41.8±1.4 versus 31.5±1.4 and 23.6±0.9 bursts/min) and as bursts corrected for heart rate (55.3±1.8 versus 42.3±1.2 and 31.7±1.2 bursts/100 heartbeats). In HT+, low-frequency systolic blood pressure variability was significantly reduced. In HT+, but not in the other 2 groups, muscle sympathetic nerve traffic was significantly related to serum ferritin (r=0.51, P<0.03), transferrin saturation (r=0.47, P<0.03), and hepatic iron load (r=0.76, P<0.0001, magnetic resonance imaging), as well as to homeostatic model assessment index values (r=0.46, P<0.05). These data provide the first evidence that in HT+ elevated serum ferritin is associated with a hyperadrenergic state of greater magnitude than the one seen in patients with hypertension without iron overload. They also show that the potentiation of the sympathetic activation detected in HT+ is related to elevated serum ferritin and to the associated metabolic alterations, possibly participating in the increased cardiovascular risk characterizing iron overload.

Sympathetic function and markers of inflammation in well-controlled HIV

PurposeHIV-associated autonomic neuropathy (HIV-AN) is common and may be associated with both sympathetic and parasympathetic dysfunction. Sympathetic nervous system (SNS) dysfunction occurs on a continuum of hyper-to hypo-adrenergic function, and may be a mediator between psychological stress and chronic inflammation. We sought to describe patterns of SNS dysfunction in people living with HIV, and to determine whether SNS dysfunction is associated with markers of systemic inflammation (focusing on IL-6 and TNF-α) and pain and anxiety. MethodsForty-seven people with well-controlled HIV and without confounding medical conditions or medications completed the Medical Outcomes Survey (MOS-HIV), quantification of a panel of 41 plasma cytokines/chemokines, and a standardized, non-invasive autonomic reflex screen (ARS). Adrenergic baroreflex sensitivity (BRSA) was calculated from the ARS as a measure of SNS function. ResultsPain (46%) and anxiety (52%) were commonly reported on the MOS-HIV. BRSA was reduced in 30% of participants and elevated in 9% with the latter occurring only in participants with normal to mild HIV-AN. BRSA was significantly associated with IL-6, but not with TNF-α, pain or anxiety. Exploratory analyses also revealed positive associations of BRSA with numerous other cytokines with no significant inverse associations. ConclusionHigher BRSA, indicative of a more hyperadrenergic state, can be part of the spectrum of early HIV-AN, and may be associated with elevations in multiple cytokines including IL-6. These associations do not appear to be driven by stressors such as pain or anxiety.

Sustained stimulation? Characteristics of modified release and immediate release stimulant exposures reported to the national poison data system

Objective We sought to examine ADHD modified release (MR) and immediate release (IR) stimulant ingestion exposures reported to the National Poison Data System (NPDS) to characterize the nature of the exposures and the outcomes associated with them. Methods The NPDS was queried for all single-substance exposures to MR and IR ADHD preparations between January 1, 2007 and December 31, 2017. MR and IR preparations were identified by a generic code of “amphetamine and related compounds” or “methylphenidate” and specific product name containing XR, CD, ER, LA, and SR. Results A total of 15,796 MR ingestions and 23,418 IR ingestions were identified and followed to known outcome. The majority of ingestions occurred in male patients and in own residence. More serious outcomes (moderate, major, or death) were more common in adult IR and MR ingestions as compared to pediatric; rates of serious outcome increased with age amongst pediatric ingestions. Unintentional ingestions were more common in both MR and IR pediatric cases while intentional ingestions occurred more frequently in adult cases. Symptoms consistent with a hyperadrenergic state were experienced in adult and pediatric patients for both MR and IR ingestions. Supportive care including benzodiazepine administration was more common in IR than MR ingestions. Decontamination with whole bowel irrigation was infrequent. Conclusion Rates of more serious outcome were similar between IR and MR ADHD stimulant ingestions. More serious outcomes were associated with advancing age and intentional ingestions. Similar rates of agitation, tachycardia, and hypertension were experienced by pediatric IR and MR ingestions while more common in adult IR as compared to MR ingestions. Rates of decontamination with whole bowel irrigation were overall low.

Sleep apnea: before and after heart transplant.

Sleep disorder breathing is a highly prevalent public health problem and is common among patients with cardio and cerebrovascular diseases. Respiratory events are associated with numerous consequences, such as the hyperadrenergic state, known as a predictor of premature mortality in patients with heart failure. On the other hand, reduced stroke volume is associated with fluid retention in patients with heart failure, leading to changes in the upper airflow dynamics. Whether and how to treat sleep disorder breathing enables chronic cardiovascular consequences to be reversed is not fully established. Few cases are known where sleep disordered breathing diagnosis was made several years before heart transplantation. To better understand how does sleep apnea evolve and to ponder about what is the best treatment approach in this context, is the objective with this case presentation.

Impact of Injury Severity on the Inflammatory State and Severe Anemia

BackgroundSevere traumatic injury is a major cause of morbidity and mortality. Our goal was to analyze blunt traumatic injury by injury severity score (ISS) and compare with elective hip repair, as a transient injury, and healthy control with the hypothesis that more severe injury would lead to an increase in neuroendocrine activation, systemic inflammation, and worse anemia. Materials and methodsA prospective observational cohort study was performed at a level 1 trauma center, comparing blunt trauma patients (n = 37), elective hip replacement patients (n = 26), and healthy controls (n = 8). Bone marrow and plasma were assessed for hyperadrenergic state, erythropoiesis, and systemic inflammation. Trauma patient's ISS ranged from 4 to 41 and were broken down into quartiles for analysis. The ISS quartiles were 4-13, 14-20, 21-26, and 27-41. ResultsPlasma norepinephrine, interleukin-6, tumor necrosis factor-alpha, and hepcidin increased progressively as ISS increased. Hemoglobin significantly decreased as ISS increased and packed red blood cell (pRBC) transfusion increased as ISS increased. Elective hip replacement patients had an appropriate increase in the bone marrow expression of erythropoietin and the erythropoietin receptor, which was absent in all trauma patient groups. ConclusionsIncreased neuroendocrine activation, systemic inflammation, and anemia correlated with worsening injury severity, lower age, and increased pRBC transfusions. Elective hip replacement patients have only minimal systemic inflammation with an appropriate bone marrow response to anemia. This study demonstrates a link between injury severity, neuroendocrine activation, systemic inflammation, and the bone marrow response to anemia.

Cerebrovascular and cardiovascular diseases caused by drugs of abuse.

Drugs such as stimulants, sedatives, sleeping pills, and narcotics are associated with drug abuse and are therefore regulated by law. Physical dependence on these drugs is sometimes difficult to control despite an awareness of the problems they cause in daily life and the harm they can cause to the body. Drug dependence is a social problem worldwide, and the physical implications are serious. Many of these drugs cause cerebrovascular and cardiovascular diseases, which often require emergency medical treatment. Differential diagnosis is essential because of the likelihood of life-threatening events, especially among young people who exhibit cerebrovascular and cardiovascular diseases without any of the typical risk factors. Drugs of abuse, especially stimulants, induce a hyperadrenergic state that evokes vasoconstriction and tachycardia, as well as subsequent ischemic and hemorrhagic stroke, acute coronary syndrome, arrhythmias, and aortic dissection. Chronic drug abuse can also cause cardiac hypertrophy and left ventricular dysfunction. As a treatment for these conditions, sedative drugs can be effective but the use of vasodilators may also be required. There are concerns that the use of both alpha- and beta-adrenergic receptor blockers may cause tachycardia and increased blood pressure. Therefore, careful differential diagnosis and selection of therapeutic agents is required.

Acute inferior ST-elevation myocardial infarction due to delirium tremens: a case report

BackgroundDelirium tremens is a severe form of alcohol withdrawal syndrome. Literature documenting acute coronary events in the setting of alcohol withdrawal remains scarce. An accepted hypothesis for the underlying process is focused on the hyperadrenergic state that leads to coronary vasospasm and increased myocardial oxygen demand.Case presentationA 47-year-old Caucasian man with a past medical history of tobacco and alcohol abuse, hypertension, and anxiety presented to the emergency department for crampy epigastric abdominal pain with intractable nausea and vomiting for the past 2 days. His reported last alcoholic intake was about 10 days prior; however, outpatient records indicated otherwise. He was admitted for electrolyte replacement and fluid resuscitation secondary to gastrointestinal losses from presumed early alcohol withdrawal syndrome. The following night, he developed acute substernal chest pain with elevated cardiac enzymes. Electrocardiography showed an acute inferoposterior infarct with reciprocal changes in leads V1–V4. The patient was taken for emergent catheterization, and a drug-eluting stent was placed in the middle of the left anterior descending artery. Postcatheterization electrocardiography showed sustained inferolateral ST elevations consistent with acute injury pattern. The patient had not required any benzodiazepines until this point. On the morning of catheterization, the patient’s Clinical Institute Withdrawal Assessment for Alcohol–Revised score was 19 with a high of 25, and he was actively hallucinating. He was treated for delirium tremens and an acute coronary event along with an incidental pneumonia. He did not require any benzodiazepines during the last 4 days of admission, and he made a full recovery.ConclusionsThe prevalence of alcohol dependence in hospitalized patients is substantial. Although our patient was being treated with the standard protocols for alcohol withdrawal, he rapidly developed delirium tremens, which led to an acute inferior ST-elevation myocardial infarction in the setting of nonoccluded coronary vessels. This case report adds to the sparse literature documenting acute coronary events in the setting of alcohol withdrawal and suggests that our patient’s ST-elevation myocardial infarction is not fully explained by the current coronary vasospasm hypothesis, but rather was in part the result of direct catecholamine-associated myocardial injury. Further research should be conducted on prophylactic agents such as β-blockers and calcium channel blockers.

THE SCN5A VARIANT C683R RESULTS IN A GAIN-OF-FUNCTION OF THE CARDIAC SODIUM CURRENT (NAV1.5) WITH ADRENERGIC MODULATION

Congenital Long QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged cardiac repolarization that may result in torsades de pointes and sudden cardiac death. Gain-of-function variants of the SCN5A gene, encoding the cardiac sodium channel Nav1.5; INa, underlie nearly 10% of LQTS and cause LQT3. In LQT3 patients, bradycardia and low sympathetic tone (associated with sleep and rest) have been considered to trigger the arrhythmias. Recently, a novel SCN5A variant (C683R) was identified in two unrelated patients with personal/family history of prolonged QT and sudden cardiac arrest. Paradoxically, C683R-associated arrhythmias in these two patients have only been observed during hyperadrenergic states. We therefore conducted a functional study to characterize the electrophysiological effects of the SCN5A C683R variant on Nav1.5 current in a cellular model. The C683R SCN5A variant was engineered into the pcDNA1 vector by using site-directed mutagenesis. Wild-Type (WT) or C683R SCN5A cDNA was transfected into tsA201 cells, along with the human Nav1.5 channel ß1-subunit. Electrophysiological characterization of the C683R variant was performed using the whole cell patch-clamp technique. The selective protein kinase A (PKA) activator 8-CPT-cAMP 50 μM was used in the pipette solution to mimic the effect of epinephrine on either WT or C683R Nav1.5 currents. The C683R variant did not generate any persistent (late) Nav1.5 current when compared to WT. It did not cause any significant change on recovery from inactivation vs WT nor on both steady-state and slow inactivation. However, the C683R variant increased maximal Nav1.5 current density from 341±64 to 766±103 pA/pF when compared to WT (p < 0.05, n≥9) and the midpoint of activation voltage (V½) was negatively shifted from -57.18±1.24 to -63.63±1.40 mV (p < 0.001 vs WT). Moreover, when exposed to the PKA activator 8-CPT-cAMP 50 μM, the C683R variant showed a greater maximal Nav1.5 current density than WT; 993±100 vs 645±137 pA/pF (p < 0.05, n≥6). Our observations suggest a gain-of-function of the Nav1.5 current in the C683R variant compared to the WT protein. This gain of function may be further enhanced upon stimulation with catecholamines. The C683R variant of SCN5A results in a significant gain of function of the Nav1.5 current with increased responsiveness to adrenergic stimulation. Our observations provide a likely explanation for the unusual phenotype in carriers of the C683R variant that is characterized by epinephrine-triggered ventricular arrhythmias. The electrophysiological properties are different from conventional LQT3 and may represent a distinct inherited arrhythmia syndrome.

SEIZING THE DAY: A CASE OF POST-ICTAL NEUROGENIC PULMONARY EDEMA

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Neurogenic pulmonary edema may present due to complex hemodynamic disturbances secondary to a central nervous system insult. It occurs rarely after generalized tonic-clonic seizures. We present a case of a young patient with recurrent generalized tonic-clonic seizures complicated by bilateral pulmonary edema requiring mechanical ventilation. CASE PRESENTATION: A 29-year-old African American man with a history of seizure disorder, cannabis use, and anxiety presented to the emergency department for decreased responsiveness after a seizure episode with a duration of 90 seconds. He had his first seizure 5 months ago and a concussion with loss of consciousness 2 months prior. He was not taking any anti-epileptic medications. On arrival, the patient had a respiratory rate of 41/min and was intubated for acute hypoxemic respiratory failure. Arterial blood gas prior to intubation showed a pH of 7.16, pCO2 of 41.5 mmHg, pO2 of 74.5 mmHg, and HCO3 of 14.4 mmol/L with a lactate of 5.84 mmol/L on FiO2 100%. Physical exam was remarkable for frothy blood in the mouth and chest auscultation revealed diffuse crackles bilaterally. Approximately 300 cc of pink frothy fluid was suctioned from the endotracheal tube. Chest x-ray (CXR) revealed bilateral pulmonary edema (Figure 1) and computed tomography (CT) chest showed dense central bilateral ground glass infiltrates with minimal sparing of periphery (Figure 2). CT head and electroencephalogram were unremarkable. Transthoracic echocardiogram estimated an ejection fraction of 50-55%. Bronchoscopy showed clearing pink secretions throughout the tracheobronchial tree. Seven days later, he was extubated and eventually discharged. DISCUSSION: The majority of neurogenic pulmonary edema is secondary to intracranial hemorrhage and less than two percent are caused by seizures. Other causes include spinal cord injury, stroke, and intracranial trauma. Post-ictal pulmonary edema can present within minutes to hours after a seizure resolving within days (1,2). Pathophysiology is hypothesized to be due to an intense hyperadrenergic state causing pulmonary and systemic vasoconstriction leading to increased capillary hydrostatic pressure and permeability (2). Postictal laryngospasm with deep inspiratory effort against a closed glottis increases negative intrathoracic pressure is another possible mechanism. This causes hydrostatic fluid shifts which further worsen the pulmonary edema (3). Treatment is supportive and centered on managing the underlying neurological disorder. CONCLUSIONS: Post-ictal pulmonary edema is an uncommon cause of neurogenic pulmonary edema. It is important to recognize this as a potential contributor to acute hypoxemic respiratory failure in patients with epilepsy and other central nervous system disorders. Reference #1: Izumida H, Homma K, Sasaki J, Hori S. Pulmonary edema following tonic–clonic seizure. Acute Med Surg. 2016 Dec 9;4(2):221-222. Reference #2: Romero Osorio OM, Abaunza Camacho JF, Sandoval Briceño D, Lasalvia P, Narino Gonzalez D. Postictal neurogenic pulmonary edema: Case report and brief literature review. Epilepsy Behav Case Rep. 2017 Sep 28;9:49-50. Reference #3: Kennedy JD, Hardin KA, Parikh P, Li CS, Seyal M. Pulmonary edema following generalized tonic clonic seizures is directly associated with seizure duration. Seizure. 2015 Apr;27:19-24. DISCLOSURES: No relevant relationships by Sarah Jaroudi, source=Web Response No relevant relationships by David Sotello Aviles, source=Web Response No relevant relationships by Victor Test, source=Web Response

Adrenergic Autoantibody-Induced Postural Tachycardia Syndrome in Rabbits.

BackgroundPrevious studies have demonstrated that functional autoantibodies to adrenergic receptors may be involved in the pathogenesis of postural tachycardia syndrome. The objective of this study was to examine the impact of these autoantibodies on cardiovascular responses to postural changes and adrenergic orthosteric ligand infusions in immunized rabbits.Methods and ResultsEight New Zealand white rabbits were coimmunized with peptides from the α1‐adrenergic receptor and β1‐adrenergic receptor (β1AR). Tilt test and separate adrenergic agonist infusion studies were performed on conscious animals before and after immunization and subsequent treatment with epitope‐mimetic peptide inhibitors. At 6 weeks after immunization, there was a greater percent increase in heart rate upon tilting compared with preimmune baseline. No significant difference in blood pressure response to tilting was observed. The heart rate response to infusion of the β‐adrenoceptor agonist isoproterenol was significantly enhanced in immunized animals, suggesting a positive allosteric effect of β1AR antibodies. In contrast, the blood pressure response to infusion of the α1‐adrenergic receptor agonist phenylephrine was attenuated in immunized animals, indicating a negative allosteric effect of α1‐adrenergic receptor antibodies. Injections of antibody‐neutralizing peptides suppressed the postural tachycardia and reversed the altered heart rate and blood pressure responses to orthosteric ligand infusions in immunized animals at 6 and 30 weeks. Antibody production and suppression were confirmed with in vitro bioassays.ConclusionsThe differential allosteric effect of α1‐adrenergic receptor and β1AR autoantibodies would lead to a hyperadrenergic state and overstimulation of cardiac β1AR. These data support evidence for an autoimmune basis for postural tachycardia syndrome.

Beta-blocker Therapy is Associated with Decreased 1-year Mortality After Emergency Laparotomy in Geriatric Patients.

Emergency laparotomy is associated with a great risk of mortality in the elderly. The hyperadrenergic state induced by surgical trauma may play an important role in the pathophysiology of this increased risk. Studies have shown that beta-blocker exposure may be associated with decreased morbidity and mortality in the perioperative period. We aimed to study the effect of beta-blocker on mortality in geriatric patients undergoing emergency laparotomy. This is a retrospective study of patients who underwent emergency laparotomy between 1 January 2015 and 31 December 2016 at a single institution. The outcomes of interest were the association between post-operative complications and in-hospital and 1-year mortality in patients on beta-blocker therapy (BB(+)) and those who were not (BB(-)). The Poisson regression analysis was used to evaluate the association. A total of 192 patients were included of whom 62 (32.2%) had pre-operative beta-blocker therapy with continued exposure during their hospital stay. The in-hospital mortality was 17.7% in the BB(+) and 23.8% in the BB(-) cohorts (p = 0.441). One-year mortality was significantly lower in the BB(+) group compared to the BB(-) group (30.6% versus 47.7%; p = 0.038). After adjusting for confounders, the incidence of deaths during 1 year post-operatively decreased by 35% in the BB(+) group (incidence rate ratio = 0.65, p = 0.004). No significant differences in the incidence of post-operative complications between the two groups could be measured. Beta-blocker therapy may be associated with reduced 1-year mortality following emergency laparotomy in geriatric patients.