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We have previously demonstrated associations between- and negative predictive values of high circulating catecholamines and endothelial damage in trauma, sepsis and ST segment elevation myocardial infarction patients. However, no studies have previously investigated the association between circulating catecholamines, endothelial damage and outcome in cardiac arrest patients. The objective of the present study was to investigate the association between sympathoadrenal activation, endothelial damage and outcome in OHCA patients, hypothesizing that excessive sympathoadrenal activation and endothelial damage would be associated and linked to poor outcome. We had access to previously collected plasma samples from OHCA patients included at a single site in The Targeted Temperature Management at 33 degrees C versus 36 degrees C after Cardiac Arrest trial. The main TTM study reported similar outcomes with targeting 33 versus 36 degrees. The TTM protocol was approved by the ethics committees in each participating country and institution and the Danish Data Protection Agency) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from a legal surrogate and from all patients who regained mental capacity. Participant consent was documented as a signed consent form that was kept according to Danish Legislation. The procedure for obtaining written informed consent was approved by the ethics committee. The TTM inclusion criteria were patients _18 years of age who were unconscious <8) on admission to the hospital after OHCA of presumed cardiac cause, irrespective of the initial rhythm. Eligible patients had more than 20 consecutive minutes of spontaneous circulation after resuscitation. The main exclusion criteria were an interval from the ROSC to screening of more than 240 minutes, unwitnessed arrest with asystole as the initial rhythm, suspected or known acute intracranial hemorrhage or stroke and a body temperature of less than 30°C. Eligible patients for the present study were patients included at Rigshospitalet, Copenhagen University Hospital, Denmark. Furthermore, to be included, an adequate volume of stored plasma and serum should be available from the pre-intervention admission blood sample to allow for investigation of the planned biomarkers. The present study is based on these 163 patients. We had access to the following data as part of the TTM trial protocol: Demography, medical history, characteristics of the cardiac arrest, patient characteristics at admission and outcome and modified Rankin scale ; all surviving patients were followed until 180 days after the enrollment of the last patient). In the present study, OHCA patients presented with high and inter-correlated levels of circulating catecholamines and biomarkers of excessive endothelial damage. Increased time from OHCA to ROSC, lower pH and STEMI were independently associated with higher syndecan-1 levels, a marker of glycocalyx damage, whereas lower pH, higher age and higher sVE-cadherin were independently associated with higher thrombomodulin levels, a marker of endothelial cell injury. By Cox proportional-hazards analyses, high thrombomodulin levels independently predicted 30-day and 180-day mortality. Acute critical illness is accompanied by excessive sympathoadrenal activation that induces widespread, dose-dependent effects on the vascular system, including the endothelium. We have proposed that endogenously released catecholamines ensure oxygen supply to vital organs in acute critical illness by balancing the clotting ability of the circulating blood according to the degree of endothelial anti-/procoagulation in the microcirculation. Hereby, progressive endothelial damage in the microcirculation is balanced by increasing hypocoagulability in the circulating blood. Given this, the evolutionary rational for the coagulopathy observed in many acute critically ill patients, may be that evolution has prioritized tissue oxygenation above hemostasis. We have reported of associations between- and negative predictive values of high circulating catecholamines and endothelial damage in trauma, sepsis and STEMI patients. In line with this, the present study found that circulating levels of adrenaline and noradrenaline correlated positively with syndecan-1 and thrombomodulin levels, biomarkers of endothelial glycocalyx and cell damage, respectively. Furthermore, high circulating thrombomodulin was an independent predictor of mortality. The present study thus supports the notion that different “injurious” hits can mount a similar, universal response, characterized by excessive sympathoadrenal activation, endothelial damage and coagulopathy. Gando et al suggested years ago that the endothelial damage observed in OHCA patients could in part be attributed to both exogenous administered and endogenously released catecholamines. As the precursor sequence does not align with any of the previously-reported gene superfamilies, this peptide represents a first-in-class compound ). Total chemical synthesis was carried out to enable pharmacological and structural characterization of this novel toxin. The peptide acts as an antagonist of nicotinic acetylcholine receptors, with greatest potency at the a9a10 nAChR, a subtype expressed in a variety of tissues ranging from immune cells to sperm. Conotoxins are a highly specialized set of disulfide-bonded peptides that are structurally and functionally diverse. Despite this diversity, toxins identified to date may be grouped into approximately 17 gene superfamilies based on conservation of the signal sequence. Within these gene superfamilies, the mature peptides adopt one of 23 patterns of arrangement of cysteine residues. Pharmacological targets within a gene superfamily may differ. For example, in the A superfamily, there are both paralytic and excitotoxic peptides. Although cone snails hunt fish, molluscs and worms, worms are the most common prey. The nAChR subunits from these polychaete marine worms have not been cloned; however, it is of note that aB-VxXXIVA preferentially targets the a9a10 subtype of nAChR. The a9 subunit is a member of the nAChR family although it is more distantly related; indeed it appears to be the closest subunit to the ancestor that gave rise to the nAChR family. Thus, it is tempting to speculate that, among Conus, the worm-hunting species may be particularly likely to produce toxins that target a9 receptors. The a9 subunit is also of increasing interest in biomedicine. Conotoxins that target the a9 nAChR have been shown to be analgesic and to accelerate the recovery of function after nerve injury, possibly through immune-mediated mechanisms. In addition, small molecule antagonists of a9a10 nAChRs are analgesic in models of neuropathic pain. The a9a10 receptor is present in keratinocytes and is implicated in the pathophysiology of wound healing. Recently it has been shown that the a9 subunit is overexpressed in breast cancer tissue. a9 antagonists reduce tumour growth. Moreover, variants of the a9 subunit affect transformation and proliferation of bronchial cells. Thus, novel antagonists of the a9a10 nAChR are not only of value to structure/function analysis of this receptor subtype but may also help inform development of novel therapeutics. Palmitoylethanolamide is an endogenous fatty acid ethanolamide expressed in many mammalian tissues. It has demonstrated anti-inflammatory and analgesia effects through the activation of nuclear receptor peroxisome proliferator-activated receptor-alpha. The endogenous levels of PEA in animal tissues are controlled by enzymes responsible for its formation and degradation. PEA is synthesized from a phospholipid precursor of N-palmitoylphosphatidylethanolamine catalyzed by NAPE-specific phospholipase D and degraded to palmitic acid by the deactivation enzymes, i.e., Nacylethanolamine- hydrolyzing acid amidase and fatty acid amide hydrolase. FAAH is a membrane-bound protein responsible for fatty acid ethanolamide hydrolysis. FAAH inhibitors have been extensively studied and they have exhibited broad pharmacological properties. In contrast to FAAH, NAAA is a subcellular protein located in lysosome and its bioactivity is optimal at pH of 4.5-5.0. Though both FAAH and NAAA can hydrolyze various FAEs, their molecular homologues show no similarity and the substrate preferences are quite different as well. NAAA shows high reactivity to PEA, while FAAH prefers anandamide. NAAA is a N-terminal nucleophile hydrolase that catalyzes the degradation of several non-peptide C-N bonds. The N-terminal self cleavage is a critical action during the enzyme activation, and cysteine 131 is suggested to be nucleophile residue that forms the catalytic pocket with other amino acids, such as Aspartic acid, Tyrosine and Asparagine. NAAA is wildly expressed in many tissues, especially those associated with immune responses, e.g., lung, spleen and small intestine, and exhibits significant antiinflammatory properties. Microcirculatory failure is a hallmark of acute critical illness: It is caused by numerous injurious hits on the vascular system, including the endothelium, and it is a driver of organ failure and thereby closely linked to outcome. One of the hits encountered by the vascular system and endothelium in acute critical illness, including cardiac arrest, is a toxic high level of catecholamines, either endogenously released following excessive sympathoadrenal activation and/or exogenously administered as vasopressor/inotropic therapy.</p>

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