Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis.

Transcriptional coactivators regulate the rate of gene expression in the nucleus. Nuclear receptor coactivator 6 (NCOA6), a coactivator, has been implicated in embryonic development, metabolism, and cancer pathogenesis, but its role in innate immunity and inflammatory diseases remains unclear. Here, we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions. Unexpectedly, nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC, forming cytoplasmic specks. Mechanistically, NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3, promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1ß and active caspase-1. Of note, Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3R258W gain-of-function mutation in macrophages. Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases, folic-induced acute tubular necrosis and crystal-induced arthritis, in mice. Consistent with these findings, NCOA6 was highly expressed in macrophages derived from gout patients, and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results. Conclusively, NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases, including gout.

Proposition of Adaptive Read Bias: A Solution to Overcome Power and Scaling Limitations in Ferroelectric-Based Neuromorphic System.

Hardware neuromorphic systems are crucial for the energy-efficient processing of massive amounts of data. Among various candidates, hafnium oxide ferroelectric tunnel junctions (FTJs) are highly promising for artificial synaptic devices. However, FTJs exhibit non-ideal characteristics that introduce variations in synaptic weights, presenting a considerable challenge in achieving high-performance neuromorphic systems. The primary objective of this study is to analyze the origin and impact of these variations in neuromorphic systems. The analysis reveals that the major bottleneck in achieving a high-performance neuromorphic system is the dynamic variation, primarily caused by the intrinsic 1/f noise of the device. As the device area is reduced and the read bias (VRead ) is lowered, the intrinsic noise of the FTJs increases, presenting an inherent limitation for implementing area- and power-efficient neuromorphic systems. To overcome this limitation, an adaptive read-biasing (ARB) scheme is proposed that applies a different VRead to each layer of the neuromorphic system. By exploiting the different noise sensitivities of each layer, the ARB method demonstrates significant power savings of 61.3% and a scaling effect of 91.9% compared with conventional biasing methods. These findings contribute significantly to the development of more accurate, efficient, and scalable neuromorphic systems.

Regulation of Dihydropyrimidinase-like 3 Gene Expression by MicroRNAs in PC12 Cells with Induced Ischaemia and Hypothermia.

Although hypothermic treatment has been reported to have some beneficial effects on ischaemia at the clinical level, the mechanism of ischaemia suppression by hypothermia remains unclear due to a lack of mechanism understanding and insufficient data. The aim of this study was to isolate and characterize microRNAs specifically expressed in ischaemia-hypothermia for the dihydropyrimidinase-like 3 (Dpysl3) gene. PC12 cells were induced with CoCl2 for chemical ischaemia and incubated at 32 ℃ for hypothermia. In ischaemia-hypothermia, four types of microRNAs (miR-106b-5p, miR-194-5p, miR-326-5p, and miR-497-5p) were highly related to the Dpysl3 gene based on exosomal microRNA analysis. Dpysl3 gene expression was up-regulated by miR-497-5p but down-regulated by miR-106b-5p, miR-194-5p and miR-326-5p. Our results suggest that these four microRNAs are involved in the regulation of Dpysl3 gene expression. These findings provide valuable clues that exosomal microRNAs could be used as therapeutic targets for effective treatment of ischaemia.

Cr-catalysed ethylene dimerization in an ionic liquid-organic solvent biphasic system with perfect 1-butene selectivity.

Cr-catalyzed ionic liquid-organic biphasic ethylene dimerization was realized with 100% 1-butene selectivity. The perfect α-olefin selectivity can be rationalized in terms of the poor solubility of the oligomerized long-chain olefins in ionic liquids, and enables the establishment of a dimerization process without any complicated and energy-intensive catalyst and byproduct separation processes.

Regulation of Hepatic Gluconeogenesis by Nuclear Receptor Coactivator 6.

Nuclear receptor coactivator 6 (NCOA6) is a transcriptional coactivator of nuclear receptors and other transcription factors. A general Ncoa6 knockout mouse was previously shown to be embryonic lethal, but we here generated liver-specific Ncoa6 knockout (Ncoa6 LKO) mice to investigate the metabolic function of NCOA6 in the liver. These Ncoa6 LKO mice exhibited similar blood glucose and insulin levels to wild type but showed improvements in glucose tolerance, insulin sensitivity, and pyruvate tolerance. The decrease in glucose production from pyruvate in these LKO mice was consistent with the abrogation of the fasting-stimulated induction of gluconeogenic genes, phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose-6-phosphatase (G6pc). The forskolin-stimulated inductions of Pck1 and G6pc were also dramatically reduced in primary hepatocytes isolated from Ncoa6 LKO mice, whereas the expression levels of other gluconeogenic gene regulators, including cAMP response element binding protein (Creb), forkhead box protein O1 and peroxisome proliferator-activated receptor γ coactivator 1α, were unaltered in the LKO mouse livers. CREB phosphorylation via fasting or forskolin stimulation was normal in the livers and primary hepatocytes of the LKO mice. Notably, it was observed that CREB interacts with NCOA6. The transcriptional activity of CREB was found to be enhanced by NCOA6 in the context of Pck1 and G6pc promoters. NCOA6-dependent augmentation was abolished in cAMP response element (CRE) mutant promoters of the Pck1 and G6pc genes. Our present results suggest that NCOA6 regulates hepatic gluconeogenesis by modulating glucagon/cAMP-dependent gluconeogenic gene transcription through an interaction with CREB.

Induction of apoptosis through the up-regulation of endoplasmic reticulum stress sensors by 5-hydroxy-7- (4"-hydroxy-3"-methoxyphenyl)-1-phenyl-3-heptanone.

The diarylheptanoid, 5-hydroxy-7-(4"-hydroxy-3"-metho-xyphenyl)-1-phenyl-3-heptanone (HPH), is isolated from rhizomes of Alpinia officinarum. There is no reported biological function for this compound other than the inhibition of pancreatic lipase. Cell viability, the expression of endoplasmic reticulum (ER) stress genes, the activation of ER stress sensors, and the induction of apoptosis and autophagy were confirmed following HPH treatment of PC12 cells. No cytotoxicity was observed when the cells were treated with 50 µg/ml HPH, but 40% cell death was observed using MTT assays with 100 µg/ml HPH. Although HPH did not change the expression of the ER chaperones PDI, binding BiP, and calnexin, it upregulated the expression of genes for the ER stress sensors ATF6, eIF2α, and PERK. HPH also induced apoptosis via the activation of ATF6 fragmentation, the phosphorylation of eIF2α, and XBP1 mRNA splicing. Eventually, the results of this study demonstrated that HPH induces apoptosis through upregulation of gene expression of ER stress sensors, which may provide a basis for the development of new drugs using HPH.

Impact of Endoplasmic Reticulum Stress Sensors on Pectolinarin Induced Apoptosis.

Pectolinarin, [5,7-Dihydroxy 4',6-dimethoxyflavone 7-rutinoside, 7-[[6-O-(6-Deoxy-α-L-mannopyranosyl)-ß-D-glucopyranosyl] oxy]-5-hydroxy-6-methoxy-2-(4-ethoxyphenyl)-4H-1-benzopyran-4-one], has been stated one of the major compounds in Cirsium nipponicum (Maxim.) Makino. It is characterized by biological functions of hepatoprotective, anti-inflammatory and antiobesity activities. In this research, it was explained that pectolinarin causes apoptosis in PC12 cells conducted by DNA fragmentation and formation on apoptotic bodies through the activation of ER stress sensors (ATF6 fragmentation and eIF2α phosphorylation). The result of treating the PC12 cells with 50 µM pectolinarin for 24 h has come to increase ATF6 mRNA expression up to 1.6 times, PERK expression up to 1.7 times and IRE1 expression up to 1.4 times, respectively, compared to those of the control. ATF6 fragmentation by pectolinarin treatment was increased about 2 times compared with its control, and phosphorylation of eIF2α was increased 2.5 times. The results proposed that the perception of the molecular mechanisms underlying pectolinarin-caused apoptosis may be useful in new natural medicinal products and health supplements for the apoptosis-related diseases.

Regulation of adipocyte differentiation by clusterin-mediated Krüppel-like factor 5 stabilization.

Clusterin (CLU) is a heterodimeric glycoprotein involved in a range of biological processes. We investigated the function of CLU as a novel regulator of adipogenesis. CLU expression increased during 3T3-L1 preadipocyte differentiation. CLU overexpression promoted adipogenic differentiation of preadipocytes and increased the mRNA levels of adipogenic markers including peroxisome proliferator-activated receptor γ (Pparg) and CCAAT enhancer-binding protein α (Cebpa). Conversely, knockdown of CLU attenuated adipogenesis and reduced transcript levels of Pparg and Cebpa. However, the promoter activities of both the Pparg and the Cebpa gene were not affected by alteration of CLU expression on its own. Additionally, the protein level of Krüppel-like factor 5 (KLF5), an upstream transcription factor of Pparg and Cebpa involved in adipogenic differentiation, was upregulated by CLU overexpression, although the mRNA level of Klf5 was not altered by changes in the expression level of CLU. Cycloheximide chase assay showed that the increased level of KLF5 by CLU overexpression was due to decreased degradation of KLF5 protein. Interestingly, CLU increased the stability of KLF5 by decreasing KLF5 ubiquitination. CLU inhibited the interaction between KLF5 and F-box/WD repeat-containing protein 7, which is an E3 ubiquitin ligase that targets KLF5. The adipogenic role of CLU was also addressed in mesenchymal stem cells (MSCs) and Clu-/- mouse embryonic fibroblasts (MEFs). Furthermore, CLU enhanced KLF5-mediated transcriptional activation of both the Cebpa and the Pparg promoter. Taken together, these results suggest that CLU is a novel regulator of adipocyte differentiation by modulating the protein stability of the adipogenic transcription factor KLF5.

Cerebrospinal fluid lactate dehydrogenase as a potential predictor of neurologic outcomes in cardiac arrest survivors who underwent target temperature management.

PURPOSE: Cerebrospinal fluid (CSF) lactate dehydrogenase (LDH) levels increase in patients with brain injury. We investigated neurologic outcomes associated with CSF LDH levels in out-of-hospital cardiac arrest (OHCA) survivors who underwent target temperature management (TTM). MATERIALS AND METHODS: This was a prospective single-centre observational study from April 2018 to May 2019 on a cohort of 41 patients. CSF and serum LDH samples were obtained immediately (LDH0) and at 24 (LDH24), 48 (LDH48), and 72 h (LDH72) after return of spontaneous circulation (ROSC). Neurologic outcomes were assessed at 3 months after ROSC using the Cerebral Performance Category scale. RESULTS: Twenty-one patients had a poor neurologic outcome. CSF LDH levels were significantly higher in the poor neurologic outcome group at each time point. The area under the curve (AUC) of CSF LDH48 was 0.941 (95% confidence interval [CI], 0.806-0.992). With a cut off value of 250 U/L, CSF LDH48 had a high sensitivity (94.1%; 95% CI, 71.3-99.9) at 100% specificity. CONCLUSIONS: CSF LDH level at 48 h was a highly specific and sensitive marker for 3-month poor neurologic outcome. This may constitute a useful predictive marker for neurologic outcome in OHCA survivors treated with TTM.

Liver Donation After Brain Death Following Intentional Ingestion of 99% E-Cigarette Liquid Nicotine 10 mL.

Incidences of brain death due to nicotine overdose by e-cigarettes have been increasing. In such cases, liver donation has been not reported because of the secondary damage to the liver due to metabolism of large amounts of nicotine. However, kidneys have been considered acceptable for transplant. Here, we present a successful case of liver transplant from a brain-dead donor due to intentional nicotine ingestion who did not have extensive steatosis. To the best of our knowledge, this is the first report of such a case.

The usefulness of neuron-specific enolase in cerebrospinal fluid to predict neurological prognosis in cardiac arrest survivors who underwent target temperature management: A prospective observational study.

AIM: Cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels increase ahead of serum NSE levels in patients with severe brain injury. We examined the prognostic performance between CSF NSE and serum NSE levels in out-of-cardiac arrest (OHCA) survivors who had undergone target temperature management (TTM). METHODS: This single-centre prospective observational study included OHCA patients who had undergone TTM. NSE levels were assessed in blood and CSF samples obtained immediately (Day 0), and at 24 h (Day 1), 48 h (Day 2), and 72 h (Day 3) after return of spontaneous circulation (ROSC). The primary outcome was the 6-month neurological outcome. RESULTS: We enrolled 34 patients (males, 24; 70.6%), and 16 (47.1%) had a poor neurologic outcome. CSF NSE and serum NSE values were significantly higher in the poor outcome group compared to the good outcome group at each time point, except for serum Day 0. CSF NSE and serum NSE had an area under curve (AUC) of 0.819-0.972 and 0.648-0.920, respectively. CSF NSE prognostic performances were significantly higher than serum NSE levels at Day 1 and showed excellent AUC values (0.969; 95% confidence interval [CI] 0.844-0.999) and high sensitivity (93.8%; 95% CI 69.8-99.8) at 100% specificity. CONCLUSION: We found CSF NSE values were highly predictive and sensitive markers of 6-month poor neurological outcome in OHCA survivors treated with TTM at Day 1 after ROSC. Therefore, CSF NSE levels at day 1 after ROSC can be a useful early prognosticator in OHCA survivors.

Relationship between time related serum albumin concentration, optic nerve sheath diameter, cerebrospinal fluid pressure, and neurological prognosis in cardiac arrest survivors.

AIM: The optimal time to measure serum albumin concentration (SAC) to predict prognosis in cardiac arrest (CA) survivors has not been elucidated. We aimed to compare the relationships between time-related SAC, optic nerve sheath diameter (ONSD), intracranial pressure (ICP), and neurological prognosis in CA survivors. METHODS: We undertook a retrospective study examining CA patients treated with target temperature management (TTM). ICP was measured using cerebrospinal fluid (CSF) pressure and ONSD was obtained before TTM. SAC was measured repeatedly at 4-6 h intervals from the hospital arrival time. We analysed CSF pressure, ONSD, and minimum SAC (MSAC) separately, or in combination, to predict poor neurological outcome. RESULTS: Of 83 patients enrolled, the good outcome group comprised 25 (34%) patients. MSAC at 24 h (MSAC24) had a higher area under the receiver operating characteristic curve (AUC) (0.687; 95% confidence interval (CI), 0.668-0.926) than other time points. CSF pressure showed a higher AUC (0.973; 95% CI, 0.911-0.996) than MSAC24 and ONSD (0.677; 95% CI, 0.565-0.776). In contrast to using MSAC24 and ONSD separately, the combination of both modalities resulted in a better AUC, thus improving the prediction of the neurological outcome (0.734; 95% CI, 0.626-0.825) and ICP (0.758; 95% CI, 0.651-0.845) after return of spontaneous circulation (ROSC) from CA. CONCLUSION: A higher ICP was strongly associated with and seemed predictive of poor outcome. Furthermore, the MSAC24/ONSD combination may be a useful predictor of high ICP and poor neurological outcome. Prospective studies should be conducted to confirm these results.

Comparison of right and left ventricular enhancement times using a microbubble contrast agent between proximal humeral intraosseous access and brachial intravenous access during cardiopulmonary resuscitation in adults.

AIM: The present study aimed to compare the ventricular enhancement time between humeral intraosseous access (HIO) and brachial intravenous access (BIV) during cardiopulmonary resuscitation (CPR) in adult humans. To our knowledge, this is the first such study during CPR in adult humans. METHODS: This prospective single-centre observational cohort study assessed the medical records of patients who underwent CPR between January 2018 and March 2018. The primary endpoints were the left and right ventricular enhancement (LVE and RVE, respectively) times after administration of a microbubble contrast agent via HIO or BIV. Continuous variables are reported as means and standard deviations depending on normal distribution, while categorical variables are reported as frequencies and percentages. The paired t-test and analysis of variance were used to compare HIO and BIV. Differences were considered significant at a P-value <0.05. RESULTS: The study included 10 patients. The HIO time (15.60 ±â€¯6.45 s) was significantly lower than the BIV time (20.80 ±â€¯7.05 s; P = 0.009). The RVE time was significantly lower with HIO (5.60 ±â€¯1.71 s) than with BIV (15.40 ±â€¯3.24 s; P < 0.001). Additionally, the LVE time was significantly lower with HIO (120.20 ±â€¯4.18 s) than with BIV (132.00 ±â€¯3.09 s; P < 0.001). CONCLUSION: Our results indicated that the arrival times of a drug at the right and left ventricles are significantly lower with HIO than with BIV in an adult cardiac arrest model.

Osteoclast-secreted SLIT3 coordinates bone resorption and formation.

Coupling is the process that links bone resorption to bone formation in a temporally and spatially coordinated manner within the remodeling cycle. Several lines of evidence point to the critical roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, we used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating ß-catenin. SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in Slit3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption. Mice lacking Slit3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific Slit3 deletion or osteoblast-specific Slit3 deletion had normal bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism. In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after an ovariectomy. Thus, these results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases.

Luteolin-induced apoptosis through activation of endoplasmic reticulum stress sensors in pheochromocytoma cells.

Luteolin [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone] is an active flavonoid compound from Lonicera japonica (Caprifoliaceae). Luteolin inhibits tumor cell proliferation, inflammatory and oxidative stress better, when compared with other flavonoids. In the present study, it was demonstrated that luteolin induces typical apoptosis in PC12 cells (derived from a pheochromocytoma of the rat adrenal medulla) accompanied by DNA fragmentation and formation of apoptotic bodies. In addition, luteolin regulates expression of the endoplasmic reticulum (ER) chaperone binding immunoglobulin protein, activating ER stress sensors (eukaryotic initiation factor 2α phosphorylation and X­box binding protein 1 mRNA splicing) and induced autophagy. The results indicated that luteolin induces the upregulation of the unfolded protein response pathway through the ER stress sensors, which helps as an influential regulator for the apoptosis pathway in PC12 cells. The results suggested that the understanding of the molecular mechanisms underlying luteolin­induced apoptosis may be useful in cancer therapeutics, chemoprevention and neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease.

Regulation of Nampt expression by transcriptional coactivator NCOA6 in pancreatic ß-cells.

Nuclear receptor coactivator 6 (NCOA6) is a transcriptional coactivator and crucial for insulin secretion and glucose metabolism in pancreatic ß-cells. However, the regulatory mechanism of ß-cell function by NCOA6 is largely unknown. In this study, we found that the transcript levels of nicotinamide phosphoribosyltransferase (Nampt) were decreased in islets of NCOA6+/- mice compared with NCOA6+/+ mice. Moreover, NCOA6 overexpression increased the levels of Nampt transcripts in the mouse pancreatic ß-cell line NIT-1. Promoter analyses showed that transcriptional activity of the Nampt promoter was stimulated by cooperation of sterol regulatory element binding protein-1c (SREBP-1c) and NCOA6. Additional studies using mutant promoters demonstrated that SREBP-1c activates Nampt promoter through the sterol regulatory element (SRE), but not through the E-box. Using chromatin immunoprecipitation assay, NCOA6 was also shown to be directly recruited to the SRE region of the Nampt promoter. Furthermore, treatment with nicotinamide mononucleotide (NMN), a product of the Nampt reaction and a key NAD+ intermediate, ameliorates glucose-stimulated insulin secretion from NCOA6+/- islets. These results suggest that NCOA6 stimulates insulin secretion, at least partially, by modulating Nampt expression in pancreatic ß-cells.

Angiopoietin-like peptide 4 regulates insulin secretion and islet morphology.

Insulin secretion from pancreatic islet ß-cells is primarily regulated by the blood glucose level, and also modulated by a number of biological factors produced inside the islets or released from remote organs. Previous studies have shown that angiopoietin-like protein 4 (Angptl4) controls glucose and lipid metabolism through its actions in the liver, adipose tissue, and skeletal muscles. In this present study, we investigated the possible role of Angptl4 in the regulation of insulin secretion from pancreatic islets. Angptl4 was found to be highly expressed in the α-cells but not ß-cells of rodent islets. Moreover, treatment of rodent islets with Angptl4 peptide potentiated glucose-stimulated insulin secretion through a protein kinase A-dependent mechanism. Consistently, Angptl4 knockout mice showed impaired glucose tolerance. In the cultured islets from Angptl4 knockout mice, glucose-stimulated insulin secretion was significantly lower than in islets from wild type mice. Angptl4 peptide replacement partially reversed this reduction. Moreover, Angptl4 knockout mice had dysmorphic islets with abnormally distributed α-cells. In contrast, the ß-cell mass and distribution were not significantly altered in these knockout mice. Our current data collectively suggest that Angptl4 may play a critical role in the regulation of insulin secretion and islet morphogenesis.

Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice.

Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)-containing plasmalogens, expression of glyceronephosphate O-acyltransferase (Gnpat; the rate-limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin-induced depletion of FC transactivated Δ-6 desaturase by increasing sterol regulatory element-binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ-6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator-activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA-containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα-dependent increase in fatty acid oxidation. Gnpat+/- mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. CONCLUSION: Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416-431).

Vasopressor requirement during targeted temperature management for out-of-hospital cardiac arrest caused by acute myocardial infarction without cardiogenic shock.

OBJECTIVE: We investigated whether patients with out-of-hospital cardiac arrest (OHCA) due to an acute myocardial infarction without cardiogenic shock required higher doses of vasopressors with low targeted temperature management (TTM) after return of spontaneous circulation. METHODS: We included consecutive comatose patients resuscitated from OHCA between January 2011 and December 2013. Patients with return of spontaneous circulation, regional wall motion abnormality on echocardiography, and coronary artery stenosis of ≥70% on percutaneous coronary artery angiography were enrolled. These patients received 36°C TTM or 33°C TTM following approval of TTM by patients' next-of-kin (36°C and 33°C TTM groups, respectively). The cumulative vasopressor index was compared between groups. RESULTS: During induction phase, dose of vasopressors did not differ between groups. In the maintenance phase, the norepinephrine dose was 0.37±0.57 and 0.26±0.91 µg·kg-1·min-1 in the 33°C and 36°C TTM groups, respectively (P<0.01). During the rewarming phase, the norepinephrine and dopamine doses were 0.49±0.60 and 9.67±9.60 mcg·kg-1·min-1 in the 33°C TTM group and 0.14±0.46 and 3.13±7.19 mcg·kg-1·min-1 in the 36°C TTM group, respectively (P<0.01). The median cumulative vasopressor index was 8 (interquartile range, 3 to 8) and 4 (interquartile range, 0 to 8) in the 33°C and 36°C TTM groups, respectively (P=0.03). CONCLUSION: In this study, patients with OHCA due to acute myocardial infarction without cardiogenic shock had an elevated vasopressor requirement with 33°C TTM compared to 36°C TTM during the maintenance and rewarming phases.