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Abstract Background The PFD1235w Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) antigen is associated with severe malaria in children and can be expressed on the surface of infected erythrocytes (IE) adhering to ICAM1. However, the exact three-dimensional structure of this PfEMP1 and its surface-exposed epitopes are unknown. An insect cell and Escherichia coli based system was used to express single and double domains encoded by the pfd1235w var gene. The resulting recombinant proteins have been evaluated for yield and purity and their ability to induce rat antibodies, which react with the native PFD1235w PfEMP1 antigen expressed on 3D7PFD1235w-IE. Their recognition by human anti-malaria antibodies from previously infected Tanzanian donors was also analysed. Methods The recombinant proteins were run on SDS-PAGE and Western blots for quantification and size estimation. Insect cell and E. coli-produced recombinant proteins were coupled to a bead-based Luminex assay to measure the plasma antibody reactivity of 180 samples collected from Tanzanian individuals. The recombinant proteins used for immunization of rats and antisera were also tested by flow cytometry for their ability to surface label 3D7PFD1235w-IE. Results All seven pAcGP67A constructs were successfully expressed as recombinant protein in baculovirus-infected insect cells and subsequently produced to a purity of 60-97% and a yield of 2-15 mg/L. By comparison, only three of seven pET101/D-TOPO constructs expressed in the E. coli system could be produced at all with purity and yield ranging from 3-95% and 6-11 mg/L. All seven insect cell, but only two of the E. coli produced proteins induced antibodies reactive with native PFD1235w expressed on 3D7PFD1235w-IE. The recombinant proteins were recognized in an age- and transmission intensity-dependent manner by antibodies from 180 Tanzanian individuals in a bead-based Luminex assay. Conclusions The baculovirus based insect cell system was distinctly superior to the E. coli expression system in producing a larger number of different recombinant PFD1235w protein domains and these were significantly easier to purify at a useful yield. However, proteins produced in both systems were able to induce antibodies in rats, which can recognize the native PFD1235w on the surface of IE.

Abstract Background Malaria caused by Plasmodium falciparum can result in several different syndromes with severe clinical consequences for the about 200 million individuals infected each year. During pregnancy, women living in endemic areas become susceptible to malaria due to lack of antibodies against a unique P. falciparum membrane protein, named VAR2CSA. This antigen is not expressed in childhood infections, since it binds chondroitin sulphate A (CSA) expressed on the intervillous space in the placenta. A vaccine appears possible because women acquire protective antibodies hindering sequestration in the placenta as a function of parity. A challenge for vaccine development is to design small constructs of this large antigen, which can induce broadly protective antibodies. It has previously been shown that one domain of VAR2CSA, DBL4-FCR3, induces parasite adhesion-blocking antibodies. In this study, it is demonstrated that other domains of VAR2CSA also can induce antibodies with inhibitory activity. Methods All VAR2CSA domains from the 3D7 and HB3 parasites were produced in Baculovirus-transfected insect cells. Groups of three rats per protein were immunized and anti-sera were tested for surface reactivity against infected erythrocytes expressing FCR3 VAR2CSA and for the ability to inhibit FCR3CSA parasite adhesion to CSA. The fine specificity of the immune sera was analysed by VAR2CSA peptide arrays. Results Inhibitory antibodies were induced by immunization with DBL3-HB3 T1 and DBL1-3D7. However, unlike the previously characterised DBL4-FCR3 response the inhibitory response against DBL1-3D7 and DBL3-HB3 T1 was poorly reproduced in the second rounds of immunizations. Conclusion It is possible to induce parasite adhesion-blocking antibodies when immunizing with a number of different VAR2CSA domains. This indicates that the CSA binding site in VAR2CSA is comprised of epitopes from different domains.

Objective: On the basis of the role of activin A in inflammation, atherogenesis, and glucose homeostasis, we investigated whether activin A could be related to glucometabolic abnormalities in patients with acute myocardial infarction (MI).Research Design and Methods: Activin A measurement and oral glucose tolerance tests (OGTTs) were performed in patients (n = 115) with acute MI, without previously known diabetes, and repeated after 3 months. Release of activin A and potential anti-inflammatory effects of activin A were measured in human endothelial cells. Activin A effects on insulin secretion and inflammation were tested in human pancreatic islet cells.Results: 1) In patients with acute MI, serum levels of activin A were significantly higher in those with abnormal glucose regulation (AGR) compared with those with normal glucose regulation. Activin A levels were associated with the presence of AGR 3 months later (adjusted odds ratio 5.1 [95% CI 1.73-15.17], P = 0.003). 2) In endothelial cells, glucose enhanced the release of activin A, whereas activin A attenuated the release of interleukin (IL)-8 and enhanced the mRNA levels of the antioxidant metallothionein. 3) In islet cells, activin A attenuated the suppressive effect of inflammatory cytokines on insulin release, counteracted the ability of these inflammatory cytokines to induce mRNA expression of IL-8, and induced the expression of transforming growth factor-β.Conclusions: We found a significant association between activin A and newly detected AGR in patients with acute MI. Our in vitro findings suggest that this association represents a counteracting mechanism to protect against inflammation, hyperglycemia, and oxidative stress. [ABSTRACT FROM AUTHOR]

Aim: To assess short- and long-term outcomes of acute myocardial infarction (AMI) complicated by out-of-hospital cardiac arrest (OHCA) or in-hospital cardiac arrest (IHCA) in a nationwide cohort., Methods: Cohort study of AMI patients admitted to hospitals in Norway 2013-2022 registered in the Norwegian Myocardial Infarction Registry. Outcomes were in-hospital and long-term mortality. Cumulative mortality was assessed with the Kaplan-Meier and the Life-table methods. Cox regression was used for risk comparisons., Results: Among 105,439 AMI patients (35% women), we identified 3,638 (3.5%) patients with OHCA and 2,559 (2.4%) with IHCA. The mean age was 65.7 (13.2), 70.9 (12.6) and 70.7 (13.6) years for OHCA, IHCA, and AMI without cardiac arrest (CA), respectively. The median follow-up time was 3.3 (25th, 75th percentile; 1.1, 6.3) years. In-hospital mortality was 28%, 49% and 5%, in OHCA, IHCA and AMI without CA, and estimated 5-year cumulative mortality was 48% (95% CI 46-50%), 69% (95% CI 67-71%), and 35% (95% CI 34-35%), respectively. Among patients surviving to hospital discharge, no significant difference in mortality during follow-up was found between OHCA and AMI without CA (adjusted Hazard Ratio (HR) 1.04, 95% CI 0.96-1.13), while the long-term mortality of AMI patients with IHCA was higher (age-adjusted HR 1.31, 95% CI 1.19-1.45)., Conclusion: In this large, contemporary cohort of AMI patients, in-hospital mortality of patients with OHCA or IHCA was still high. Among patients surviving to hospital discharge, long-term mortality was comparable between OHCA and AMI without CA, while the outcome of patients with IHCA was significantly worse., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: In acute heart failure (HF), reduced cardiac output, vasoconstriction and congestion may damage the intestinal mucosa and disrupt its barrier function. This could facilitate the leakage of bacterial products into circulation and contribute to inflammation and adverse cardiac remodelling. We aimed to investigate gut leakage markers and their associations with inflammation, infarct size and cardiac function., Methods: We examined 61 ST-elevation myocardial infarction (STEMI) patients who developed acute HF within 48 hours of successful percutaneous coronary intervention (PCI). Serial blood samples were taken to measure lipopolysaccharide (LPS), LPS-binding protein (LBP), soluble cluster of differentiation 14 (sCD14) and intestinal fatty acid binding protein (I-FABP). Cumulative areas under the curve (AUCs) from baseline to day 5 were calculated. Serial echocardiography was performed to assess left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and wall motion score index (WMSI). Single-photon emission CT (SPECT) was performed at 6 weeks to determine infarct size and LVEF., Results: I-FABP AUC correlated positively with infarct size (r s =0.45, p=0.002), GLS (r s =0.32, p=0.035) and WMSI (r s =0.45, p=0.002) and negatively with LVEF measured by SPECT (r s =-0.40, p=0.007) and echocardiography (r s =-0.33, p=0.021) at 6 weeks. LPS AUC , LBP AUC and sCD14 AUC did not correlate to any cardiac function marker or infarct size. Patients, who at 6 weeks had above median GLS and WMSI, and below-median LVEF measured by SPECT, were more likely to have above median I-FABP AUC during admission (adjusted OR (aOR) 5.22, 95% CI 1.21 to 22.44; aOR 5.05, 95% CI 1.25 to 20.43; aOR 5.67, 95% CI 1.42 to 22.59, respectively). The same was observed for patients in the lowest quartile of LVEF measured by echocardiography (aOR 9.99, 95% CI 1.79 to 55.83) and three upper quartiles of infarct size (aOR 20.34, 95% CI 1.56 to 264.65)., Conclusions: In primary PCI-treated STEMI patients with acute HF, I-FABP, a marker of intestinal epithelial damage, was associated with larger infarct size and worse cardiac function after 6 weeks., Competing Interests: Competing interests: The Department of Cardiology, Oslo University Hospital Ullevaal received an unrestricted educational grant from the manufacturer of levosimendan, Orion Pharma in 2005. Orion Pharma did not, however, provide study medication or participate in the design, monitoring or analyses of the present study. The authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI) patients when administered before percutaneous coronary intervention (PCI). The mechanisms underlying ischemia-reperfusion injury remain unclear. In this sub-study, we investigated whether endothelial and platelet-derived CXC chemokines are involved, as they represent inflammatory mediators from two cell types relevant to myocardial infarction. Associations between these chemokines and neutrophils, C-reactive protein (CRP), troponin T (TnT), myocardial salvage index (MSI), microvascular obstruction (MVO), and infarct size., Methods: This is a sub-study of the ASSAIL-MI trial, a double-blind clinical trial that randomized 199 STEMI patients to receive either 280 mg tocilizumab (n = 101) or placebo (n = 98) intravenously before PCI. Blood samples were collected prior to infusion, at day 1-2, 3-7, and at 3 and 6 months. Heparin was administered before baseline in 150 patients, while 49 received it after. We measured CXC-chemokines CXCL4, CXCL5, CXCL6, CXCL7, and CXCL12 using immunoassays. Cardiac MRI was performed in the first week and at 6 months., Results: Tocilizumab did not significantly affect CXC-chemokines levels. Although some correlations were observed between chemokine levels and neutrophil counts and CRP, none of the CXC chemokines were associated with infarct size, MSI, MVO, or TnT levels. Notably, CXCL 12 levels increased in patients who received heparin before baseline, while other CXC-chemokines decreased significantly., Conclusion: This study suggests that the beneficial effects of tocilizumab in STEMI patients are not due to changes in circulating endothelial or platelet-derived CXC-chemokines, compared to placebo. However, heparin significantly influences the levels of these chemokines., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Circular (circ) RNAs are non-coding RNAs with important functions in the nervous system, cardiovascular system, and cancer. Their role in atherosclerosis and myocardial infarction (MI) remains poorly described. We aim to investigate the potential circRNAs in immune cells during atherogenesis and examine the most regulated during MI and the modulation by interleukin (IL)-6 receptor inhibition by tocilizumab. Wild-type (WT) and ApoE -/- mice were fed an atherogenic diet for 10 weeks, and the circRNA profile was analyzed by circRNA microarray. Whole blood from patients with ST-elevated MI (STEMI) and randomized to tocilizumab ( n = 21) or placebo ( n = 19) was collected at admission, 3-7 days, and at 6 months, in addition to samples from healthy controls ( n = 13). Primers for human circRNA were designed, and circRNA levels were measured using RT-qPCR. mRNA regulation of predicted circRNA targets was investigated by RNA sequencing. The expression of 867 circRNAs differed between atherogenic and WT mice. In STEMI patients, circUBAC2 was significantly lower than in healthy controls. CircANKRD42 and circUBAC2 levels were inversely correlated with troponin T, and for circUBAC2, an inverse correlation was also seen with final infarct size at 6 months. The predicted mRNA targets for circUBAC2 and circANKRD42 were investigated and altered levels of transcripts involved in the regulation of inflammatory/immune cells, apoptosis, and mitochondrial function were found. Finally, tocilizumab induced an up-regulation of circANKRD42 and circUBAC2 3-7 days after percutaneous coronary intervention. CircRNA levels were dysregulated in STEMI, potentially influencing the immune system, apoptosis, and mitochondrial function.

Background: Interleukin-6-receptor inhibition with tocilizumab improves myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). Reduced levels of neutrophil extracellular traps (NETs), which consist of nuclear material studded with proteins released upon neutrophil activation, might contribute to this effect., Objectives: The purpose of this study was to evaluate the effect of tocilizumab on NETs and investigate the association between NETs and myocardial injury in patients with STEMI., Methods: In the ASSAIL-MI study, 199 patients with STEMI were randomized to tocilizumab or placebo during percutaneous coronary intervention. In this substudy, we analyzed blood levels of the NET markers double-stranded deoxyribonucleic acid (dsDNA), myeloperoxidase-DNA, and citrullinated histone 3 (H3Cit) at admission and after 24 hours and 3 to 7 days. In a subgroup of patients, we assessed regulation of transcripts related to the formation of NETs. We also investigated associations between NET markers and the myocardial salvage index (MSI)., Results: All NET markers were lower in the tocilizumab group than in the placebo group at 3 to 7 days (all P  < 0.04). Several NET-related pathways were downregulated in the tocilizumab group. The beneficial effect of tocilizumab on the MSI seemed to be partly dependent on reduction of NETs (structural equation modeling: 0.05, P  = 0.001 [dsDNA] and 0.02, P  = 0.055 [H3Cit]). Patients with NETs in the 3 lowest quartiles had higher MSI than patients in quartile 4 (10.9 [95% CI: 4.0-15.0] [dsDNA] and 8.9 [95% CI: 2.0-15.9] [H3Cit], both P  = 0.01)., Conclusions: NETs were reduced by tocilizumab and associated with myocardial injury. The effect of tocilizumab on MSI might be mediated through reduced NETs. (ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial [ASSAIL-MI]; NCT03004703)., Competing Interests: This work was supported by the 10.13039/501100006095South-Eastern Norway Regional Health Authority. Roche provided the investigational medicinal products and an unrestricted grant for the ASSAIL-MI study. Dr Broch has received lecture and consultant fees from Amgen, AstraZeneca, Bohringer Ingelheim, Merck, MSD, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, and Vifor Pharma. Dr Gullestad has received lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Amgen; and has been a member of local advisory board in AstraZeneca and Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Purpose: Mild hypercapnia did not improve neurological outcomes for resuscitated out-of-hospital cardiac arrest (OHCA) patients in the Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial. However, the effects of hypercapnic acidosis on myocardial injury in patients with cardiac arrest is unexplored. We investigated whether mild hypercapnia compared to normocapnia, following emergency coronary intervention, increased myocardial injury in comatose OHCA-patients with AMI., Methods: Single-centre, prospective, pre-planned sub-study of the TAME trial. Patients were randomised to targeted mild hypercapnia (PaCO 2  = 6.7-7.3 kPa) or normocapnia (PaCO 2  = 4.7-6.0 kPa) for 24 h. Myocardial injury was assessed with high-sensitive cardiac troponin T (hs-cTnT) measured at baseline, 24, 48 and 72 h. Haemodynamics were assessed with right heart catheterisation and blood-gas analyses every 4th hour for 48 h., Results: We included 125 OHCA-patients. 57 (46%) had an AMI, with 31 and 26 patients randomised to hypercapnia and normocapnia, respectively. Median peak hs-cTnT in AMI-patients was 58% lower in the hypercapnia-group: 2136 (IQR: 861-4462) versus 5165 ng/L (IQR: 2773-7519), p = 0.007. Lower average area under the hs-cTnT curve was observed in the hypercapnia-group: 2353 (95% CI 1388-3319) versus 4953 ng/L (95% CI 3566-6341), P-group = 0.002. Hypercapnia was associated with increased cardiac power output (CPO) and lower lactate levels in patients with AMI (P-group < 0.05). hs-cTnT, lactate and CPO were not significantly different between intervention groups in OHCA-patients without AMI (p > 0.05)., Conclusions: Mild hypercapnia was not associated with increased myocardial injury in resuscitated OHCA-patients. In AMI-patients, mild hypercapnia was associated with lower hs-cTnT and lactate, and improved cardiac performance., Trial Registration Number: NCT03114033., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: “Theresa Olasveengen reports a relationship with Laerdal Foundation For Acute Medicine that includes: board membership. Kjetil Sunde and Theresa Olasveengen are part of the Resuscitation Editorial Board.”, (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: We aimed to determine whether serum levels of proteins related to changes in cardiac extracellular matrix (ECM) were associated with ischemic injury assessed by cardiac magnetic resonance (CMR) and mortality in patients with ST-elevation myocardial infarction (STEMI)., Methods: The concentrations of six ECM-related proteins (periostin, osteopontin, syndecan-1, syndecan-4, bone morphogenetic protein 7, and growth differentiation factor (GDF)-15) were measured in serum samples from patients on Day 1 and Month 4 after STEMI (n = 239). Ischemic injury was assessed by myocardial salvage index, microvascular obstruction, infarct size, and left ventricular function measured by CMR conducted during the initial admission (median 2 days after admission) and after 4 months. All-cause mortality was recorded after a median follow-up time of 70 months., Results: Levels of periostin increased from Day 1 to Month 4 after hospitalization, while the levels of GDF-15, osteopontin, syndecan-1, and syndecan-4 declined. At both time points, high levels of syndecan-1 were associated with microvascular obstruction, large infarct size, and reduced left ventricular ejection fraction, whereas high levels of syndecan-4 at Month 4 were associated with a higher myocardial salvage index and less dilatation of the left ventricle. Higher mortality rates were associated with periostin levels at both time points, low syndecan-4 levels at Month 4, or high GDF-15 levels at Month 4., Conclusions: In patients with STEMI, we found an association between serum levels of ECM biomarkers and ischemic injury and mortality. The results provide new insight into the role ECM components play in ischemic injury following STEMI and suggests a potential for these biomarkers in prognostication after STEMI., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: A patent application filed by the University of Oslo covering the use of ECM enzyme inhibitor in cardiac remodelling and heart failure (WO2015004209A1) is granted in Europe (EP3756667A1) and granted in the United States (US10744155B2), where MV is among the inventors. Related to this patent, the University of Oslo has a licence agreement with the pharmaceutical company Paradigm Biopharma for the development of pentosane polysulfate in the treatment of cardiac remodelling and heart failure, and MV has performed consulting services for Paradigm to support this development. MV has participated in advisory boards for Pharmacosmos and AstraZeneca, on the topics iron supplementation and the use of sodium-glucose cotransporter 2 inhibitors in heart failure. The authors declare no other conflicts of interest related to the content of this manuscript., (Copyright: © 2024 Andrup et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Prognosis after out-of-hospital cardiac arrest (OHCA) is presumed poorer in patients with non-shockable than shockable rhythms, frequently leading to treatment withdrawal. Multimodal outcome prediction is recommended 72 h post-arrest in still comatose patients, not considering initial rhythms. We investigated accuracy of outcome predictors in all comatose OHCA survivors, with a particular focus on shockable vs. non-shockable rhythms., Methods: In this observational NORCAST sub-study, patients still comatose 72 h post-arrest were stratified by shockable vs. non-shockable rhythms for outcome prediction analyzes. Good outcome was defined as cerebral performance category 1-2 within 6 months. False positive rate (FPR) was used for poor and sensitivity for good outcome prediction accuracy., Results: Overall, 72/128 (56%) patients with shockable and 12/50 (24%) with non-shockable rhythms had good outcome (p < .001). For poor outcome prediction, absent pupillary light reflexes (PLR) and corneal reflexes (clinical predictors) 72 h after sedation withdrawal, PLR 96 h post-arrest, and somatosensory evoked potentials (SSEP), all had FPR <0.1% in both groups. Unreactive EEG and neuron-specific enolase (NSE) >60 μg/L 24-72 h post-arrest had better precision in shockable patients. For good outcome, the clinical predictors, SSEP and CT, had 86%-100% sensitivity in both groups. For NSE, sensitivity varied from 22% to 69% 24-72 h post-arrest. The outcome predictors indicated severe brain injury proportionally more often in patients with non-shockable than with shockable rhythms. For all patients, clinical predictors, CT, and SSEP, predicted poor and good outcome with high accuracy., Conclusion: Outcome prediction accuracy was comparable for shockable and non-shockable rhythms. PLR and corneal reflexes had best precision 72 h after sedation withdrawal and 96 h post-arrest., (© 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Aim: Hypercapnia may elicit detrimental haemodynamic effects in critically ill patients. We aimed to investigate the consequences of targeted mild hypercapnia versus targeted normocapnia on pulmonary vascular resistance and right ventricular function in patients resuscitated from out-of-hospital cardiac arrest (OHCA)., Methods: Pre-planned, single-centre, prospective, sub-study of the Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial. Patients were randomised to mild hypercapnia (PaCO 2  = 6.7-7.3 kPa) or normocapnia (PaCO 2  = 4.7-6.0 kPa) for 24 hours. Haemodynamic assessment was performed with right heart catheterisation and serial blood-gas analyses every4th hour for 48 hours., Results: We studied 84 patients. Mean pH was 7.24 (95% CI 7.22-7.30) and 7.32 (95% CI 7.31-7.34) with hypercapnia and normocapnia, respectively (P-group < 0.001). Pulmonary vascular resistance index (PVRI), pulmonary artery pulsatility index, and right atrial pressure did not differ between groups (P-group > 0.05). Mean cardiac index was higher with mild hypercapnia (P-group < 0.001): 2.0 (95% CI 1.85-2.1) vs 1.6 (95% CI 1.52-1.76) L/min/m 2 . Systemic vascular resistance index was 2579 dyne-sec/cm-5/ m 2 (95% CI 2356-2830) with hypercapnia, and 3249 dyne-sec/cm-5/ m 2 (95% CI 2930-3368) with normocapnia (P-group < 0.001). Stroke volumes (P-group = 0.013) and mixed venous oxygen saturation (P-group < 0.001) were higher in the hypercapnic group., Conclusion: In resuscitated OHCA patients, targeting mild hypercapnia did not increase PVRI or worsen right ventricular function compared to normocapnia. Mild hypercapnia comparatively improved cardiac performance and mixed venous oxygen saturation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Theresa Olasveengen reports a relationship with Laerdal Foundation For Acute Medicine that includes: board membership. Kjetil Sunde and Theresa Olasveengen are part of the Resuscitation Editorial Board., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Early prediction of outcomes in comatose patients after out-of-hospital cardiac arrest is challenging. Prognostication tools include clinical examination, biomarkers, and neuroradiological and neurophysiological tests. We studied the association between transcranial Doppler (TCD) and the outcome., Methods: This was a pre-defined sub-study of the prospective observational Norwegian Cardiorespiratory Arrest Study. Patients underwent standardized post-resuscitation care, including target temperature management (TTM) to 33°C for 24 h. TCD was performed at days 1, 3, and 5-7. The primary endpoint was cerebral performance category (CPC) at 6 months, dichotomized into good (CPC 1-2) and poor (CPC 3-5) outcomes. We used linear mixed modeling time-series analysis., Results: Of 139 TCD-examined patients, 81 (58%) had good outcomes. Peak systolic velocity in the middle cerebral artery (PSV) was low during TTM (Day 1) and elevated after rewarming (Day 3). Thereafter, it continued to rise in patients with poor, but normalized in patients with good, outcomes. At days 5-7, PSV was 1.0 m/s (95% CI 0.9; 1.0) in patients with good outcomes and 1.3 m/s (95% CI 1.1; 1.4) in patients with poor outcomes (p < 0.001)., Conclusion: Elevated PSV at days 5-7 indicated poor outcomes. Our findings suggest that serial TCD examinations during the first week after cardiorespiratory arrest may improve our understanding of serious brain injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Reichenbach, Alteheld, Henriksen, Nakstad, Andersen, Sunde, Šaltytė Benth and Lundqvist.)

Background: Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size., Methods: STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24-36, 72-168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months., Results: Repeated measures analysis of variance showed significant (p<0.001) between-group difference in changes for IL-6, IL-8 and IL-1ra due to an increase in the tocilizumab group during hospitalisation. IL-6 and IL-8 correlated to neutrophils in the placebo group (r=0.73, 0.68, respectively), which was attenuated in the tocilizumab group (r=0.28, 0.27, respectively). A similar pattern was seen for MSI and IL-6 and IL-8 in the placebo group (r=-0.29, -0.25, respectively) in patients presenting ≤3 hours from symptom onset, which was attenuated in the tocilizumab group (r=-0.09,-0.14, respectively)., Conclusions: Tocilizumab increases IL-6, IL-8 and IL-1ra in STEMI. IL-6 and IL-8 show correlations to neutrophils/CRP and markers of cardiac injury in the placebo group that was attenuated in the tocilizumab group. This may suggest a beneficial effect of tocilizumab on the ischaemia-reperfusion injury in STEMI patients., Trial Registration Number: NCT03004703., Competing Interests: Competing interests: Roche provided the investigational medicinal products and an unrestricted grant for the ASSAIL-MI study., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes., Methods: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco 2 ], 50 to 55 mm Hg) or normocapnia (target Paco 2 , 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months., Results: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups., Conclusions: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.)., (Copyright © 2023 Massachusetts Medical Society.)

Acute myocardial infarction (AMI) is accompanied by a systemic trauma response that impacts the whole body, including blood. This study addresses whether macrophages, key players in trauma repair, sense and respond to these changes. For this, healthy human monocyte-derived macrophages are exposed to 20% human AMI (n = 50) or control (n = 20) serum and analyzed by transcriptional and multiparameter functional screening followed by network-guided data interpretation and drug repurposing. Results are validated in an independent cohort at functional level (n = 47 AMI, n = 25 control) and in a public dataset. AMI serum exposure results in an overt AMI signature, enriched in debris cleaning, mitosis, and immune pathways. Moreover, gene networks associated with AMI and with poor clinical prognosis in AMI are identified. Network-guided drug screening on the latter unveils prostaglandin E2 (PGE2) signaling as target for clinical intervention in detrimental macrophage imprinting during AMI trauma healing. The results demonstrate pronounced context-induced macrophage reprogramming by the AMI systemic environment, to a degree decisive for patient prognosis. This offers new opportunities for targeted intervention and optimized cardiovascular disease risk management., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Brain injury in out-of-hospital cardiac arrest (OHCA) survivors affects health status and health-related quality of life (HRQoL). It is unknown how HRQoL evolves over time, and assessments at different time points may lead to different results., Methods: In a NORCAST sub study, OHCA survivors eligible for health status (EQ-5D-3L) and HRQoL (SF-36) assessments were examinated six months and five years after OHCA. At five-year follow-up, survivors also retrospectively assessed their health status for each consecutive year following OHCA. The next of kin independently assessed health status and HRQoL of their respective OHCA survivors., Results: Among 138 survivors alive after six months and 117 after five years, 80 (88% male) completed both follow-ups. Health status and HRQoL remained stable over time, except for increasing SF-36 mental summary score and decreasing physical functioning and physical component score. Anxiety and depression levels were generally low, although younger survivors stated more anxiety than older survivors. Retrospective assessment showed reduced health status for the first two years, which increased only from the third year. Explorative analyses revealed that younger age, longer time to return of spontaneous circulation (tROSC) and late awakening affected health status, particularly in the first two years post-arrest., Conclusions: OHCA survivors showed stable health status and HRQoL with only minor differences between six months and five years. Younger survivors with long tROSC, late awakening, and more anxiety and depression symptoms at six months, had reduced health status the first two years with significant improvements towards the fourth year., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The complement system and neutrophil extracellular traps (NETs) might contribute to ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI). We aimed to estimate associations between complement activation and NETs in STEMI, and their prognostic value on clinical endpoints., Methods: In this cohort study, 864 patients admitted for PCI during STEMI were included. Complement activation was analyzed by the terminal complement complex (TCC), while NETs were analyzed by myeloperoxidase-DNA, citrullinated histone 3 (CitH3) and dsDNA. The composite endpoint was reinfarction, unscheduled revascularization, stroke, hospitalization due to heart failure, or death, and the secondary endpoint was total mortality. The association between TCC and clinical endpoints was assessed by Cox regression and ROC curve analysis., Results: TCC was weakly correlated to dsDNA ( r  = 0.127, p  < 0.001) and CitH3 ( r  = 0.102, p  = 0.003). After a median follow-up time of 4.6 years, 184 (21.3 %) patients had reached a clinical endpoint. TCC was not associated with the composite endpoint, but with total mortality (HR: 1.673, 95 % CI: [1.014, 2.761], p  = 0.044). The significant association was lost when adjusting for CRP, NT-proBNP, LVEF and time from symptoms to PCI. In ROC curve analysis of total mortality, the AUC for TCC alone was 0.549 (95 % CI: [0.472, 0.625]), AUC for dsDNA alone was 0.653 (95 % CI: [0.579, 0.720]), while AUC for TCC and dsDNA combined was 0.660 (95 % CI: [0.590, 0.730])., Conclusions: In this STEMI cohort, TCC was not associated with the composite endpoint, but somewhat with total mortality. Combining TCC and dsDNA did not increase the prognostic value compared to dsDNA alone., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Study Design: Systematic Review., Objective: To evaluate the efficacy of available treatment options for patients with persistent coccydynia through a systematic review., Methods: Original peer-reviewed publications on treatment for coccydynia were identified using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines by performing a literature search of relevant databases, from their inception to January 17, 2020, combined with other sources. Data on extracted treatment outcome was pooled based on treatment categories to allow for meta-analysis. All outcomes relevant to the treatment efficacy of coccydynia were extracted. No single measure of outcome was consistently present among the included studies. Numeric Rating Scale, (NRS, 0-10) for pain was used as the primary outcome measure. Studies with treatment outcome on adult patients with chronic primary coccydynia were considered eligible., Results: A total of 1980 patients across 64 studies were identified: five randomized controlled trials, one experimental study, one quasi-experimental study, 11 prospective observational studies, 45 retrospective studies and unpublished data from the DaneSpine registry. The greatest improvement in pain was achieved by patients who underwent radiofrequency therapy (RFT, mean Visual Analog Scale (VAS) decreased by 5.11 cm). A similar mean improvement was achieved from Extracorporeal Shockwave Therapy (ESWT, 5.06), Coccygectomy (4.86) and Injection (4.22). Although improved, the mean change was less for those who received Ganglion block (2.98), Stretching/Manipulation (2.19) and Conservative/Usual Care (1.69)., Conclusion: This study highlights the progressive nature of treatment for coccydynia, starting with noninvasive methods before considering coccygectomy. Non-surgical management provides pain relief for many patients. Coccygectomy is by far the most thoroughly investigated treatment option and may be beneficial for refractory cases. Future randomized controlled trials should be conducted with an aim to compare the efficacy of interventional therapies amongst each other and to coccygectomy.

Background: We recently showed that interleukin (IL)-6 inhibition by tocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect are not clear., Methods: In this exploratory sub-study of the ASSAIL-MI trial, we examined leukocyte differential counts and their relation to myocardial salvage and peak troponin T (TnT) in STEMI patients randomised to tocilizumab (n = 101) or placebo (n = 98). We performed RNA-sequencing on whole blood (n = 40) and T cells (n = 20). B and T cell subpopulations were examined by flow cytometry (n = 69)., Findings: (i) STEMI patients had higher neutrophil counts at hospitalisation compared with stable angina patients. (ii) After percutaneous coronary intervention there was a gradual decline in neutrophils, which was significantly more pronounced in the tocilizumab group. (iii) The decrease in neutrophils in the tocilizumab group was associated with improved myocardial salvage and lower peak TnT. (iv) RNA-sequencing suggested that neutrophil function was also attenuated by tocilizumab. (v) B and T cell sub-populations changed only minimally after STEMI with minor effects of tocilizumab, supported as well by RNA-sequencing analyses of T cells. (vi) However, a low CD8 + count was associated with improved myocardial salvage in patients admitted to the hospital > 3 h after symptom onset., Interpretation: Tocilizumab induced a rapid reduction in neutrophils and seemed to attenuate neutrophil function in STEMI patients potentially related to the beneficial effects of tocilizumab on myocardial salvage., Funding: South-Eastern Norway Regional Health Authority (Nos. 2019067, 2017084), the Central Norway Regional Health Authority and Norwegian Research Council (No. 283867)., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Complement activation plays an important pathogenic role in numerous diseases. The ratio between an activation product and its parent protein is suggested to be more sensitive to detect complement activation than the activation product itself. In the present study we explored whether the ratio between the activation product and the parent protein for C3 (C3bc/C3) and for C5 (sC5b-9/C5) increased the sensitivity to detect complement activation in acute clinical settings compared to the activation product alone., Materials and Methods: Samples from patients with acute heart failure following ST-elevated myocardial infarction (STEMI) and from patients with out-of-hospital cardiac arrest (OHCA) were used. C3, C3bc and C5, sC5b-9 were analysed in 629 and 672 patient samples, respectively. Healthy controls (n = 20) served to determine reference cut-off values for activation products and ratios, defined as two SD above the mean., Results: Increased C3bc/C3- and sC5b-9/C5 ratios were vastly dependent on C3bc and sC5b-9. Thus, 99.5 % and 98.1 % of the increased C3bc/C3- and sC5b-9/C5 ratios were solely dependent on increased C3bc and sC5b-9, respectively. Significantly decreased C3 and C5 caused increased ratios in only 3/600 (0.5 %) and 4/319 (1.3 %) samples, respectively. Strong correlations between C3bc and C3bc/C3-ratio and between sC5b-9 and sC5b-9/C5-ratio were found in the STEMI- (r = 0.926 and r = 0.786, respectively) and the OHCA-population (r = 0.908 and r = 0.843, respectively; p < 0.0001 for all). Importantly, sC5b-9 identified worse outcome groups better than sC5b-9/C5-ratio., Conclusion: C3bc and sC5b-9 were sensitive markers of complement activation. The ratios of C3bc/C3 and sC5b-9/C5 did not improve detection of complement activation systemically., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Inflammation has emerged as a new treatment target in patients with coronary artery disease and inflammation seems to play an important role in ischaemia/reperfusion injury that follows ST-elevation myocardial infarction (STEMI). We aimed to explore the role of acute and sustained interleukin 6 (IL-6) signalling, including soluble IL-6 receptor (IL-6R), with regard to infarct size, adverse remodelling and future cardiovascular events in patients with STEMI., Methods: We included 269 patients with first-time STEMI, symptom duration <6 hours and treated with percutaneous coronary intervention. Blood sampling and cardiac MRI were performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12-month and 70-month follow-up, respectively., Results: IL-6 levels above median at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF). IL-6 levels in the highest quartile were at all sampling points associated with an increased risk of having an adverse clinical event during the first 12 months and with long-term all-cause mortality. IL-6R was not associated with infarct size, LVEF, myocardial salvage or long-term all-cause mortality., Conclusion: Acute and sustained elevation of IL-6 measured 4 months after STEMI were associated with larger infarct size, reduced LVEF and adverse clinical events including all-cause mortality. The results add important information to the sustained role of inflammation in patients with STEMI and IL-6 as a potential target for long-term intervention., Trial Registration Number: NCT00922675., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Cardiopulmonary resuscitation after cardiac arrest initiates a whole-body ischemia-reperfusion injury, which may activate the innate immune system, including the complement system. We hypothesized that complement activation and subsequent release of soluble endothelial activation markers were associated with cerebral outcome including death., Methods: Outcome was assessed at six months and defined by cerebral performance category scale (1-2; good outcome, 3-5; poor outcome including death) in 232 resuscitated out-of-hospital cardiac arrest patients. Plasma samples obtained at admission and day three were analysed for complement activation products C3bc, the soluble terminal complement complex (sC5b-9), and soluble CD14. Endothelial cell activation was measured by soluble markers syndecan-1, sE-selectin, thrombomodulin, and vascular cell adhesion molecule., Results: Forty-nine percent of the patients had good outcome. C3bc and sC5b-9 were significantly higher at admission compared to day three (p < 0.001 for both) and in patients with poor compared to good outcome (p = 0.03 and p < 0.001, respectively). Unadjusted, higher sC5b-9 at admission was associated with poor outcome (odds ratio 1.08 (95% CI 1.01-1.14), p = 0.024). Adjusted, sC5b-9 was still associated with outcome, but the association became non-significant when time to return-of-spontaneous-circulation above 25 min was included as a covariate. Endothelial cell activation markers increased from admission to day three, but only sE-selectin and thrombomodulin were significantly higher in patients with poor versus good outcome (p = 0.004 and p = 0.03, respectively) and correlated to sCD14 and sC5b-9/C3bc, respectively., Conclusion: Complement system activation, reflected by sC5b-9 at admission, leading to subsequent endothelial cell activation, was associated with poor outcome in out-of-hospital cardiac arrest patients., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: The aim of this study was to identify factors associated with poor outcome following coccygectomy on patients with chronic coccydynia and instability of the coccyx., Methods: From the Danish National Spine Registry, DaneSpine, 134 consecutive patients were identified from a single centre who had coccygectomy from 2011 to 2019. Patient demographic data and patient-reported outcomes, including pain measured on a visual analogue scale (VAS), Oswestry Disability Index (ODI), EuroQol five-dimension five-level questionnaire, and 36-Item Short-Form Health Survey questionnaire (SF-36) were obtained at baseline and at one-year follow-up. Patient satisfaction was obtained at follow-up. Regression analysis, including age, sex, smoking status, BMI, duration of symptoms, work status, welfare payment, preoperative VAS, ODI, and SF-36 was performed to identify factors associated with dissatisfaction with results at one-year follow-up., Results: A minimum of one year follow-up was available in 112 patients (84%). Mean age was 41.9 years (15 to 78) and 97 of the patients were female (87%). Regression showed no statistically significant association between the investigated prognostic factors and a poor outcome following coccygectomy. The satisfied group showed a statistically significant improvement in patient-reported outcomes at one-year follow-up from baseline, whereas the dissatisfied group did not show a significant improvement., Conclusion: We did not identify factors associated with poor outcome following coccygectomy. This suggests that neither of the included parameters should be considered contraindications for coccygectomy in patients with chronic coccydynia and instability of the coccyx. Cite this article: Bone Jt Open  2021;2(7):540-544.

Background: Health-related quality of life (HRQoL) is affected after out-of-hospital cardiac arrest (OHCA), but data several years after the arrest are lacking. We assessed long-term HRQoL in OHCA survivors and how known outcome predictors impact HRQoL., Methods: In adult OHCA survivors, HRQoL was assessed five years post arrest using Short-form 36 (SF-36), EQ-5D-3 L (EQ-5D) and Hospital Anxiety and Depression Scale (HADS) among others. Results were compared to the next of kins' estimates and to a Norwegian reference population., Results: Altogether 96 survivors were included mean 5.3 (range 3.6-7.2) years after OHCA. HRQoL compared well to the reference population, except for lower score for general health with 67.2 (95%CI (62.1; 72.3) vs. 72.9 (71.9; 74.0)), p = 0.03. Younger (≤58 years) vs. older survivors scored lower for general health with mean (SD) of 62.1 (27.5) vs. 73.0 (19.5), p = 0.03, vitality (55.2 (20.5) vs. 64.6 (17.3), p = 0.02, social functioning (75.3 (28.7) vs. 94.1 (13.5), p < 0.001 and mental component summary (49.0 (9.9) vs. 55.8 (6.7), p < 0.001. They scored higher for HADS-anxiety (4.8 (3.6 vs. 2.7 (2.5), p = 0.001, and had lower EQ-5D index (0.72 (0.34) vs. 0.84 (0.19), p = 0.04. Early vs. late awakeners had higher EQ-5D index (0.82 (0.23) vs. 0.71 (0.35), p = 0.04 and lower HADS-depression scores (2.5 (2.9) vs. 3.8 (2.3), p = 0.04. Next of kin estimated HRQoL similar to the survivors' own estimates., Conclusions: HRQoL five years after OHCA was good and mainly comparable to a matched reference population. Stratified analyses revealed impaired HRQoL among younger survivors and those awakening late, mainly for mental domains., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To compare the outcomes in patients with refractory out-of-hospital cardiac arrest (OHCA) fulfilling the criteria for extracorporeal cardiopulmonary resuscitation (ECPR) before and after implementation of an ECPR protocol, whether the patient received ECPR or not., Methods: We compared cardiac arrest registry data before (2014-2015) and after (2016-2019) implementation of the ECPR protocol. The ECPR criteria were presumed cardiac origin, witnessed arrest with ventricular fibrillation, bystander CPR, age 18-65, advanced life support (ALS) within 15 min and ALS > 10 min without return of spontaneous circulation (ROSC). The primary outcome was 30-day survival; the secondary outcomes were sustained ROSC, neurological outcome and the proportion of patients transported with ongoing ALS., Results: There were 1086 and 3135 patients in the pre- and post-implementation sample; 48 (4%) and 100 (3%) met the ECPR criteria, respectively. Of these, 21 (44%) vs. 37 (37%) were alive after 30 days, p = 0.4, and 30 (63%) vs. 50 (50%) achieved sustained ROSC, p = 0.2. All survivors in the pre-implementation sample had cerebral performance category 1-2 vs. 30 (81%) in the post-implementation sample, p = 0.03. Of the patients fulfilling the ECPR criteria, 7 (15%) and 26 (26%), p = 0.1, were transported with ongoing ALS in the pre- and post-implementation sample, respectively., Conclusions: There were no differences in 30-day survival or prehospital ROSC in patients with refractory OHCA before and after initiation of an ECPR protocol., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response., Objectives: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI., Methods: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days., Results: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups., Conclusions: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703)., Competing Interests: Funding Support and Author Disclosures This work was supported by the South-Eastern Norway Regional Health Authority, the Central Norway Regional Health Authority, and Roche. Roche provided the investigational medicinal products and an unrestricted grant. Trial registration number: ClinicalTrials.gov (NCT03004703NCT3004703). Dr. Gullestad has received lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Amgen; and has been a member of the local advisory board in AstraZeneca and Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The clinical impact of chronic substance abuse of alcohol and drugs-referred to as substance use disorders (SUD)-is often overlooked in the intensive care (ICU) setting. The aims of the present study were to identify patients with SUD-regardless of cause of admission-in a mixed Norwegian ICU-population, and to compare patients with and without SUD with regard to clinical characteristics and mortality., Methods: Cross-sectional prospective study of a mixed medical and surgical ICU-population aged ≥18 years in Oslo, Norway. Data were collected consecutively, using a questionnaire including the AUDIT-C test, medical records and toxicology results. Patients classified with SUD were divided into the subgroups alcohol use disorders (AUD) and drug use disorders (DUD)., Results: Overall, 222 (26%) of the 861 patients included were classified with SUD; 137 (16%) with AUD and 85 (10%) with DUD. 130/222 (59%) of the SUD-patients had substance abuse-related cause of ICU-admission. Compared to non-SUD patients, DUD-patients were younger (median age 42 vs 65 years) and had lower SAPS II scores (41 vs 46), while AUD-patients had higher SOFA scores (8.0 vs 7.3). Overall, age-adjusted logistic regression analysis showed similar hospital mortality for SUD-patients and non-SUD patients, but AUD was associated with increased mortality among medical patients and in patients with sepsis (OR 1.7 (95% CI 1.0-2.8), and OR 2.6 (95% CI 1.1-6.2))., Conclusion: One in four ICU-patients had SUD regardless of cause of admission. Alcohol use disorder was associated with increased mortality in medical patients and in patients with sepsis., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Aims: The aim of this study was to investigate the efficacy of coccygectomy in patients with persistent coccydynia and coccygeal instability., Methods: The Danish National Spine Registry, DaneSpine, was used to identify 134 consecutive patients who underwent surgery, performed by a single surgeon between 2011 and 2019. Routine demographic data, surgical variables, and patient-reported outcomes, including a visual analogue scale (VAS) (0 to 100) for pain, Oswestry Disability Index (ODI), EuroQol five-dimension questionnaire (EQ-5D), and the Physical Component Score (PCS) and Mental Component Score (MCS) of the 36-Item Short-Form Health Survey questionnaire (SF-36) were collected at baseline and one-year postoperatively., Results: A total of 112 (84%) patients with a minimum follow-up of one year had data available for analysis. Their mean age was 41.9 years, and 15 (13%) were males. At 12 months postoperatively, there were statistically significant improvements (p < 0.001) from baseline for the mean VAS for pain (70.99 to 35.34), EQ-5D (0.52 to 0.75), ODI (31.84 to 18.00), and SF-36 PCS (38.17 to 44.74). A total of 78 patients (70%) were satisfied with the outcome of treatment., Conclusion: Patients with persistent coccydynia and coccygeal instability resistant to nonoperative treatment may benefit from coccygectomy. Cite this article: Bone Joint J  2021;103-B(3):542-546.

We compared the ST elevation myocardial infarction (STEMI) incidence during COVID-19 pandemic (March 2020) to January-February 2020 and to same time period in earlier years 2017-2019 in five Nordic-Baltic tertiary centers. During 2017-2019, there were no marked differences in STEMI incidence between January, February and March. During 2020, there was an average drop of 32% in STEMI incidence in March. The isolation measures may decrease the risk for respiratory virus infection and contribute to the lower STEMI incidence and that we might benefit from firmer suggestions on hand hygiene and social distancing during flu season at least among high-risk individuals.

Objective: The role of neutrophil extracellular traps (NETs) in acute heart failure is unknown. We recently showed that interleukin 8, a putative NETs stimulator, was associated with myocardial recovery in acute heart failure complicating ST-elevation myocardial infarction (STEMI). In this exploratory post-hoc study, we aimed to investigate the role of NETs components in relation to myocardial function and interleukin 8 in STEMI patients with symptomatic acute heart failure., Methods: In 61 STEMI patients developing acute heart failure within 48 hours of successful revascularization, wall motion score index (WMSI), global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography at baseline and on day 5. Blood drawn at baseline and days 1, 2 and 5 was used to quantify double-stranded DNA (dsDNA), myeloperoxidase-DNA complexes (MPO-DNA) and citrullinated histone 3 (CitH3). The area under the curve (AUC) of each NETs marker and interleukin 8 was approximated for the first 5 days., Results: dsDNAAUC and MPO-DNAAUC correlated significantly with change in WMSI from baseline to day 5 (rs = 0.28 for both, p≤0.05), whereas NETs AUCs did not correlate with changes in GLS and LVEF. dsDNAAUC was significantly correlated with interleukin 8AUC (r = 0.40, p = 0.003). However, mixed model regression could not identify a significant effect of the NETs components on myocardial function parameters., Conclusions: In this cohort with acute heart failure complicating STEMI, NETs components were partly correlated with myocardial function and interleukin 8 levels, yet no causal relationship between NETs components and myocardial recovery could be established., Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT00324766., Competing Interests: The authors have declared that no competing interests exist.

Background: During atherogenesis, cholesterol precipitates into cholesterol crystals (CC) in the vessel wall, which trigger plaque inflammation by activating the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome. We investigated the relationship between CC, complement and NLRP3 in patients with cardiovascular disease., Methods: We analysed plasma, peripheral blood mononuclear cells (PBMC) and carotid plaques from patients with advanced atherosclerosis applying ELISAs, multiplex cytokine assay, qPCR, immunohistochemistry, and gene profiling., Findings: Transcripts of interleukin (IL)-1beta(β) and NLRP3 were increased and correlated in PBMC from patients with acute coronary syndrome (ACS). Priming of these cells with complement factor 5a (C5a) and tumour necrosis factor (TNF) before incubation with CC resulted in increased IL-1β protein when compared to healthy controls. As opposed to healthy controls, systemic complement was significantly increased in patients with stable angina pectoris or ACS. In carotid plaques, complement C1q and C5b-9 complex accumulated around CC-clefts, and complement receptors C5aR1, C5aR2 and C3aR1 were higher in carotid plaques compared to control arteries. Priming human carotid plaques with C5a followed by CC incubation resulted in pronounced release of IL-1β, IL-18 and IL-1α. Additionally, mRNA profiling demonstrated that C5a and TNF priming followed by CC incubation upregulated plaque expression of NLRP3 inflammasome components., Interpretation: We demonstrate that CC are important local- and systemic complement activators, and we reveal that the interaction between CC and complement could exert its effect by activating the NLRP3 inflammasome, thus promoting the progression of atherosclerosis., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Outcome prediction after out-of-hospital cardiac arrest (OHCA) may lead to withdrawal of life-sustaining therapy if the prognosis is perceived negative. Single use of uncertain prognostic tools may lead to self-fulfilling prophecies and death. We evaluated prognostic tests, blinded to clinicians and without calls for hasty outcome prediction, in a prospective study., Methods: Comatose, sedated TTM 33-treated OHCA patients of all causes were included. Clinical-neurological/-neurophysiological/-biochemical predictors were registered. Patients were dichotomized into good/poor outcome using cerebral performance category (CPC) six months and > four years post-arrest. Prognostic tools were evaluated using false positive rates (FPR)., Results: We included 259 patients; 49 % and 42 % had good outcome (CPC 1-2) after median six months and 5.1 years. Unwitnessed arrest, non-shockable rhythms, and no-bystander-CPR predicted poor outcome with FPR (CI) 0.05 (0.02-0.10), 0.13 (0.08-0.21), and 0.13 (0.07-0.20), respectively. Time to awakening was median 6 (0-25) days in good outcome patients. Among patients alive with sedation withdrawal >72 h, 49 % were unconscious, of whom 32 % still obtained good outcome. Only absence of pupillary light reflexes (PLR) -and N20-responses in somato-sensory evoked potentials (SSEP), as well as increased neuron-specific enolase (NSE) later than 24 h to >80 μg/L, had FPR 0. Malignant EEG (burst suppression/epileptic activity/flat) differentiated poor/good outcome with FPR 0.05 (0.01-0.15)., Conclusion: Time to awakening was over six days in good outcome patients. Most clinical parameters had too high FPRs for prognostication, except for absent PLR and SSEP-responses >72 h after sedation withdrawal, and increased NSE later than 24 h to >80 μg/L., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Neutrophil extracellular traps (NETs) have been implicated in atherothrombosis; however, their potential role as markers of risk is unclear. We investigated whether circulating NETs-related components associated with clinical outcome and hypercoagulability in ST-elevation myocardial infarction (STEMI). In this observational cohort study, STEMI patients admitted for PCI (n = 956) were followed for median 4.6 years, recording 190 events (reinfarction, unscheduled revascularization, stroke, heart failure hospitalization, or death). Serum drawn median 18 hours post-PCI was used to quantify double-stranded DNA (dsDNA) and the more specific NETs markers myeloperoxidase-DNA and citrullinated histone 3. Levels of the NETs markers did not differ significantly between groups with/without a primary composite endpoint. However, patients who died (n = 76) had higher dsDNA compared to survivors (p < 0.001). Above-median dsDNA was associated with an increased number of deaths (54 vs. 22, p < 0.001). dsDNA in the upper quartiles (Q) was associated with increased mortality (Q3 vs. Q1 + 2 adjusted HR: 1.89 [95% CI 1.03 to 3.49], p = 0.041 and Q4 vs. Q1 + 2 adjusted HR: 2.28 [95% CI 1.19 to 4.36], p = 0.013). dsDNA was weakly correlated with D-dimer (r s  = 0.17, p < 0.001). dsDNA levels associated with increased all-cause mortality, yet weakly with hypercoagulability in STEMI patients. The prognostic significance of potentially NETs-related markers requires further exploration.

Background and Aims: We have previously found increased levels of the cysteine protease legumain in plasma and plaques from patients with carotid atherosclerosis. This study further investigated legumain during acute cardiovascular events., Methods: Circulating levels of legumain from patients and legumain released from platelets were assessed by enzyme-linked-immunosorbent assay. Quantitative PCR and immunoblotting were used to study expression, while localization was visualized by immunohistochemistry., Results: In the SUMMIT Malmö cohort (n = 339 with or without type 2 diabetes and/or cardiovascular disease [CVD], and 64 healthy controls), the levels of circulating legumain were associated with the presence of CVD in non-diabetics, with no relation to outcome. In symptomatic carotid plaques and in samples from both coronary and intracerebral thrombi obtained during acute cardiovascular events, legumain was co-localized with macrophages in the same regions as platelets. In vitro, legumain was shown to be present in and released from platelets upon activation. In addition, THP-1 macrophages exposed to releasate from activated platelets showed increased legumain expression. Interestingly, primary peripheral blood mononuclear cells stimulated with recombinant legumain promoted anti-inflammatory responses. Finally, in a STEMI population (POSTEMI; n = 272), patients had significantly higher circulating legumain before and immediately after percutaneous coronary intervention compared with healthy controls (n = 67), and high levels were associated with improved outcome., Conclusions: Our data demonstrate for the first time that legumain is upregulated during acute cardiovascular events and is associated with improved outcome., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Host-microbiota interactions involving inflammatory and metabolic pathways have been linked to the pathogenesis of multiple immune-mediated diseases and metabolic conditions like diabetes and obesity. Accumulating evidence suggests that alterations in the gut microbiome could play a role in cardiovascular disease. This review focuses on recent advances in our understanding of the interplay between diet, gut microbiota and cardiovascular disease, with emphasis on heart failure and coronary artery disease. Whereas much of the literature has focused on the circulating levels of the diet- and microbiota-dependent metabolite trimethylamine-N-oxide (TMAO), several recent sequencing-based studies have demonstrated compositional and functional alterations in the gut microbiomes in both diseases. Some microbiota characteristics are consistent across several study cohorts, such as a decreased abundance of microbes with capacity for producing butyrate. However, the published gut microbiota studies generally lack essential covariates like diet and clinical data, are too small to capture the substantial variation in the gut microbiome, and lack parallel plasma samples, limiting the ability to translate the functional capacity of the gut microbiomes to actual function reflected by circulating microbiota-related metabolites. This review attempts to give directions for future studies in order to demonstrate clinical utility of the gut-heart axis., Competing Interests: Declaration of Competing Interest Dr. Trøseid, Dr Broch and Dr Andersen declare no conflict of interest. Dr. Hov has received funding from Biogen, personal fees from Novartis, and personal fees from Orkla Health., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The effectiveness of adrenaline during resuscitation continues to be debated despite being recommended in international guidelines. There is evidence that the β-adrenergic receptor (AR) effects of adrenaline are harmful due to increased myocardial oxygen consumption, post-defibrillation ventricular arrhythmias and increased severity of post-arrest myocardial dysfunction. Esmolol may counteract these unfavourable β-AR effects and thus preserve post-arrest myocardial function. We evaluated whether a single dose of esmolol administered prior to adrenaline preserves post-arrest cardiac output among successfully resuscitated animals in a novel, ischaemic cardiac arrest porcine model., Methods: Myocardial infarction was induced in 20 anaesthetized pigs by inflating a percutaneous coronary intervention (PCI) balloon in the circumflex artery 15 min prior to induction of ventricular fibrillation. After 10 min of untreated VF, resuscitation with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated and the animals were randomized to receive an injection of either 1 mg/kg esmolol or 9 mg/ml NaCl, prior to adrenaline. Investigators were blinded to allocation. Successful defibrillation was followed by a 1-h high-flow VA-ECMO before weaning and an additional 1-h stabilization period. The PCI-balloon was deflated 40 min after inflation. Cardiac function pre- and post-arrest (including cardiac output) was assessed by magnetic resonance imaging (MRI) and invasive pressure measurements. Myocardial injury was estimated with MRI, triphenyl tetrazolium chloride (TTC) staining and serum concentrations of cardiac troponin T., Results: Only seven esmolol and five placebo-treated pigs were successfully resuscitated and available for post-arrest measurements (p = 0.7). MRI revealed severe but similar reductions in post-arrest cardiac function with cardiac output 3.5 (3.3, 3.7) and 3.3 (3.2, 3.9) l/min for esmolol and control (placebo) groups, respectively (p = 0.7). The control group had larger left ventricular end-systolic and end-diastolic ventricular volumes compared to the esmolol group (75 (65, 100) vs. 62 (53, 70) ml, p = 0.03 and 103 (86, 124) vs. 87 (72, 91) ml, p = 0.03 for control and esmolol groups, respectively). There were no other significant differences in MRI characteristics, myocardial infarct size or other haemodynamic measurements between the two groups., Conclusions: We observed similar post-arrest cardiac output with and without a single dose of esmolol prior to adrenaline administration during low-flow VA-ECMO in an ischaemic cardiac arrest pig model.

Background: The relevance of neutrophil extracellular traps (NETs) in acute ST-elevation myocardial infarction (STEMI) is unclear. We explored the temporal profile of circulating NET markers and their associations to myocardial injury and function and to adverse clinical events in STEMI patients., Methods and Results: In 259 patients, blood samples were drawn before and after PCI, on day 1, and after 4 months. Double-stranded deoxyribonucleic acid (dsDNA) and myeloperoxidase-DNA (MPO-DNA) were measured in serum by a nucleic acid stain and ELISA. Cardiac magnetic resonance imaging assessed microvascular obstruction (MVO), area at risk, infarct size, myocardial salvage index, left ventricular ejection fraction (LVEF), and change in indexed left ventricular end-diastolic volume (LVEDVi). Clinical events were registered after 12 months. dsDNA and MPO-DNA levels were highest before PCI, with reduced levels thereafter (all p ≤ 0.02). Patients with high vs. low day 1 dsDNA levels (>median; 366 ng/ml) more frequently had MVO, larger area at risk, larger infarct size acutely and after 4 months, and lower myocardial salvage index (all p < 0.03). Moreover, they had lower LVEF acutely and after 4 months, and larger change in LVEDVi (all p ≤ 0.014). High day 1 dsDNA levels also associated with risk of having a large infarct size (>75th percentile) and low LVEF (≤49%) after 4 months when adjusted for gender, time from symptoms to PCI, and infarct localization (OR 2.3 and 3.0, both p < 0.021), and patients with high day 1 dsDNA levels were more likely to experience an adverse clinical event, also when adjusting for peak troponin T (hazard ratio 5.1, p = 0.012). No such observations were encountered for MPO-DNA., Conclusions: High day 1 dsDNA levels after STEMI were associated with myocardial infarct size, adverse left ventricular remodeling, and clinical outcome. Although the origin of dsDNA could be discussed, these observations indicate a potential role for dsDNA in acute myocardial ischemia. This trial is registered with S-08421d, 2008/10614 (Regional Committee for Medical Research Ethics in South-East Norway (2008))., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2019 Ragnhild Helseth et al.)

Introduction: Interleukin-6 (IL-6) may be involved in ischaemia-reperfusion injury and myocardial remodelling after myocardial infarction (MI). We have recently shown that IL-6 inhibition by tocilizumab attenuates systemic inflammation and troponin T-release in patients with acute non-ST elevation MI (NSTEMI). Experimental studies suggest that IL-6 inhibition can limit infarct size through anti-inflammatory mechanisms, but this has not been tested in clinical studies. With the ASS essing the effect of A nti- IL -6 treatment in MI (ASSAIL-MI) trial, we aim to examine whether a single administration of the IL-6 receptor antagonist tocilizumab can increase myocardial salvage in patients with acute ST-elevation MI (STEMI)., Methods and Analysis: The ASSAIL-MI trial is a randomised, double blind, placebo-controlled trial, conducted at three high-volume percutaneous coronary intervention (PCI) centres in Norway. 200 patients with first-time STEMI presenting within 6 hours of the onset of chest pain will be randomised to receive tocilizumab or matching placebo prior to PCI. The patients are followed-up for 6 months. The primary endpoint is the myocardial salvage index measured by cardiac MRI (CMR) 3-7 days after the intervention. Secondary endpoints include final infarct size measured by CMR and plasma markers of myocardial necrosis. Efficacy and safety assessments during follow-up include blood sampling, echocardiography and CMR., Ethics and Dissemination: Based on previous experience the study is considered feasible and safe. If tocilizumab increases myocardial salvage, further endpoint-driven multicentre trials may be initiated. The ASSAIL-MI trial has the potential to change clinical practice in patients with STEMI., Registration: Clinicaltrials.gov, identifier NCT03004703., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Neutrophil extracellular traps (NETs) have recently been identified as mediators in atherothrombosis. Although NETosis in general has been suggested to be glucose dependent, the transferability to patients with acute ST-elevation myocardial infarction (STEMI) is unclear. We assessed whether the NETs markers double-stranded deoxyribonucleid acid (dsDNA) and myeloperoxidase-DNA (MPO-DNA) associated with plasma glucose and the glucometabolic status in the acute phase and 3 months after a STEMI. We also explored whether an acute glucose load resulted in upregulated NETosis by assessment of peptidylarginine deiminase 4 (PAD4) gene expression., Methods: In total, 224 STEMI patients were prospectively enrolled and underwent blood sampling acutely (median 16.5 h after PCI) and after 3 months. Glucometabolic status was defined based on the results of an oral glucose tolerance test (OGTT) as normal glucose regulation (NGR), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or type 2 diabetes (T2DM). dsDNA and MPO-DNA were measured in serum, while PAD4 mRNA was measured in circulating leukocytes by RT-PCR., Results: dsDNA levels were significantly correlated to plasma glucose both acutely and after 3 months (r = 0.12 and r = 0.17, both p < 0.02), whereas MPO-DNA was not. No associations with the glucometabolic status were encountered for dsDNA and MPO-DNA acutely, but after 3 months dsDNA levels were elevated in patients with IFG and T2DM vs. NGR (428 vs. 371 ng/ml and 408 vs. 371 ng/ml, both p < 0.045). During the acute glucose load after 3 months, dsDNA and MPO-DNA remained unchanged while PAD4 mRNA increased significantly (RQ 0.836 vs. 0.920, p = 0.02)., Conclusions: In this cohort of STEMI patients, levels of dsDNA associated with plasma glucose both in the acute and stable condition. The glucometabolic status was not substantially related to the selected NETs markers, however, an acute glucose load by OGTT performed after 3 months resulted in increased PAD4 expression, suggestive of enhanced NETosis in the aftermath of STEMI., Trial Registration: www.clinicaltrials.gov, NCT00926133 . Registered June 23, 2009.

Purpose: Studies have reported an association between low levels of natural immunoglobulin M antibodies against phosphorylcholine(IgM anti-PC) and worse prognosis in patients with coronary artery disease (CAD). The aims of the present study were, in patients with ST-elevation myocardial infarction (STEMI); 1) to compare serum levels of IgM anti-PC measured acutely and after 3 months; 2) to study an association between levels of IgM anti-PC and the severity ofCAD, and; 3) to investigate whether IgM anti-PC levels are associated with long-term clinical outcome., Methods: A total of 213 patients without known diabetes (median age 59 years) with a PCI treated STEMI were enrolled. IgM anti-PC was measured in-hospital and after 3 months. Median follow-up time was 6.5 years (all-cause mortality, non-fatal myocardial re-infarction, recurrent ischemia causing hospital admission, heart failure and stroke). The severity of CAD was evaluated by coronary angiograms and patients were classified as having single- or multi-vessel disease and by SYNTAX score (SXscore)., Results: IgM anti-PC levels were stable over time when measured acutely and after 3 months. Patients with multi-vessel disease and high SXscore had significantly lower levels of IgM anti-PC in the acute phase of STEMI. Low levels of IgM anti-PC (the 25 percentile) measured acutely were associated with a 2-fold increase in the odds of having multi-vessel disease (adjusted OR 2.28 (95% CI 1.17, 4.44), p = 0.016), but not with high SXscore (Crude OR 2.20 (95% CI 0.96, 5.07), p = 0.06). Fifty-three patients experienced a new clinical event during long-term follow-up. Low levels of IgM anti PC were not associated with worse prognosis, (crude HR 1.54 (0.87-2.76), p = 0.14)., Conclusion: STEMI patients with multi-vessel disease or high SXscore had significantly lower levels of IgM anti-PC in the acute phase and low levels were associated with multi-vessel disease, but not with worse clinical outcome during long-term follow-up., Competing Interests: The authors have declared that no competing interests exist.

Aims: Regional heterogeneities in contraction contribute to heart failure with reduced ejection fraction (HFrEF). We aimed to determine whether regional changes in myocardial relaxation similarly contribute to diastolic dysfunction in post-infarction HFrEF, and to elucidate the underlying mechanisms., Methods and Results: Using the magnetic resonance imaging phase-contrast technique, we examined local diastolic function in a rat model of post-infarction HFrEF. In comparison with sham-operated animals, post-infarction HFrEF rats exhibited reduced diastolic strain rate adjacent to the scar, but not in remote regions of the myocardium. Removal of Ca2+ within cardiomyocytes governs relaxation, and we indeed found that Ca2+ transients declined more slowly in cells isolated from the adjacent region. Resting Ca2+ levels in adjacent zone myocytes were also markedly elevated at high pacing rates. Impaired Ca2+ removal was attributed to a reduced rate of Ca2+ sequestration into the sarcoplasmic reticulum (SR), due to decreased local expression of the SR Ca2+ ATPase (SERCA). Wall stress was elevated in the adjacent region. Using ex vivo experiments with loaded papillary muscles, we demonstrated that high mechanical stress is directly linked to SERCA down-regulation and slowing of relaxation. Finally, we confirmed that regional diastolic dysfunction is also present in human HFrEF patients. Using echocardiographic speckle-tracking of patients enrolled in the LEAF trial, we found that in comparison with controls, post-infarction HFrEF subjects exhibited reduced diastolic train rate adjacent to the scar, but not in remote regions of the myocardium., Conclusion: Our data indicate that relaxation varies across the heart in post-infarction HFrEF. Regional diastolic dysfunction in this condition is linked to elevated wall stress adjacent to the infarction, resulting in down-regulation of SERCA, disrupted diastolic Ca2+ handling, and local slowing of relaxation., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: The aim of this study was to investigate the association between TIMI myocardial perfusion (TMP) grading acute and cardiac magnetic resonance (CMR) first-pass perfusion early and at 4 months in patients with ST-segment-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI)., Material and Methods: One hundred ninety-eight STEMI patients were recruited from the POSTEMI study. TMP grade was assessed after PCI; CMR was performed at day 2 and after 4 months. Signal intensity was measured on first-pass perfusion images, and a maximum contrast enhancement index (MCE) was calculated., Results: Patients with TMP grade 2-3 (n = 108) after PCI had significantly better EF (59 ± 10 vs. 51 ± 13, p < 0.001) and smaller infarct volume (12 ± 8 vs. 19 ± 12 %, p < 0.001) at 4 months compared with patients with TMP grade 0-1 (n = 81). MCE in the infarcted (MCEi) and remote myocardium (MCEr) improved from early to follow-up CMR, MCEi from 94 ± 56 to 126 ± 59, p < 0.001, and MCEr from 112 ± 51 to 127 ± 50, p < 0.001. In patients with the lowest CMR perfusion early, perfusion at 4 months remained decreased compared with the other groups, MCEi 108 ± 75 vs. 133 ± 51, p = 0.01, and MCEr 115 ± 41 vs. 131 ± 52, p = 0.047., Conclusion: TMP grade and early CMR first-pass perfusion were associated with CMR outcomes at 4 months. First-pass perfusion improved after 4 months in the infarcted and remote myocardium. However, in patients with the lowest CMR perfusion early, perfusion was still reduced after 4 months., Key Points: • Cardiac magnetic resonance myocardial first-pass perfusion and TMP grading after successful PCI helps to assess risk in patients with ST elevation myocardial infarction. • Cardiac magnetic resonance myocardial first-pass perfusion shows that microvascular perfusion after ST elevation myocardial infarction can be impaired in both infarcted and non-infarcted myocardium. • Microvascular perfusion improves over time in patients with ST elevation myocardial infarction treated with primary PCI.

Background: The optimal management of elderly patients with non-ST-segment elevation myocardial infarction (NSTEMI) is still discussed. We aimed to study short- and long-term survival in NSTEMI patients ≥75 years managed with an invasive or a conservative strategy., Methods: NSTEMI patients admitted to Oslo University Hospital Ulleval during 2005-2011 were included consecutively in a prospective registry. Vital status until December 31, 2013, was obtained from the Norwegian Cause of Death Registry. Patients ≥75 years were identified, and 30-day and 7-year survival were analyzed. Logistic- and Cox regression was used to estimate OR and hazard ratio (HR) for death in the invasive versus conservative group, adjusting for registered confounders., Results: There were 2,064 NSTEMI patients ≥75 years (48.2% women); 1,200 (58.1%) were treated with an invasive strategy, and were younger, more likely to be male and previously revascularized compared to 864 (41.9%) patients treated conservatively (p < 0.0001 for all). Survival at 30-day was 94.9% in the invasive and 76.6% in the conservative group. For 30-day survivors, 7-year survival was 47.4% (95% CI 42.9-51.8) and 11.6% (95% CI 8.3-15.6), respectively. After multivariate adjustment, an invasive strategy was associated with lower long-term risk (adjusted HR [aHR] 0.49 [95% CI 0.41-0.59]). Actual revascularization was associated with lower risk of long-term mortality compared to angiography only (aHRPCI 0.73 [95% CI 0.59-0.90], aHRCABG 0.43 [95% CI 0.28-0.65])., Conclusion: In this real-life cohort of NSTEMI patients ≥75 years, 30-day survival was 95%, and 7-year survival was 47% with an invasive strategy. Revascularized patients had a superior long-term prognosis. With a conservative strategy, short- and long-term survival was lower, probably due to selection bias and unmeasured confounding., (The Author(s). Published by S. Karger AG, Basel.)

Objectives: The aim of the study was to evaluate CMR myocardial first-pass perfusion in the injured region as well as the non-infarcted area in ST-elevation myocardial infarction (STEMI) patients few days after successful primary percutaneous coronary intervention (PCI)., Materials and Methods: 220 patients with first time STEMI successfully treated with PCI (with or without postconditioning) were recruited from the Postconditioning in STEMI study. Contrast enhanced CMR was performed at a 1.5 T scanner 2 (1-5) days after PCI. On myocardial first-pass perfusion imaging signal intensity (SI) was measured in the injured area and in the remote myocardium and maximum contrast enhancement index (MCE) was calculated. MCE = (peak SI after contrast-SI at baseline) / SI at baseline x 100., Results: There were no significant differences in first-pass perfusion between patients treated with standard PCI and patients treated with additional postconditioning. The injured myocardium showed a significantly lower MCE compared to remote myocardium (94 ± 55 vs. 113 ± 49; p < 0.001). When patients were divided into four quartiles of MCE in the injured myocardium (MCE injured myocardium), patients with low MCE injured myocardium had: significantly lower ejection fraction (EF) than patients with high MCE injured myocardium, larger infarct size and area at risk, smaller myocardial salvage and more frequent occurrence of microvascular obstruction on late gadolinium enhancement. MCE in the remote myocardium revealed that patients with larger infarction also had significantly decreased MCE in the non-infarcted, remote area., Conclusion: CMR first-pass perfusion can be impaired in both injured and remote myocardium in STEMI patients treated with primary PCI. These findings indicate that CMR first-pass perfusion may be a feasible method to evaluate myocardial injury after STEMI in addition to conventional CMR parameters., Competing Interests: The authors have declared that no competing interests exist.

Targeted temperature management is part of the standardized treatment for patients in cardiac arrest. Hypothermia decreases cerebral oxygen consumption and induces bradycardia; thus, increasing the heart rate may be considered to maintain cardiac output. We hypothesized that increasing heart rate during hypothermia would impair diastolic function. Human left ventricular trabeculae obtained from explanted hearts of patients with terminal heart failure were stimulated at 0.5 Hz, and contraction-relaxation cycles were recorded. Maximal developed force (F max ), maximal rate of development of force [(dF/d t) max ], time to peak force (TPF), time to 80% relaxation (TR80), and relaxation time (RT = TR80 - TPF) were measured at 37, 33, 31, and 29°C. At these temperatures, stimulation frequency was increased from 0.5 to 1.0 and to 1.5 Hz. At 1.5 Hz, concentration-response curves for the β-adrenergic receptor (β-AR) agonist isoproterenol were performed. F max , TPF, and RT increased when temperature was lowered, whereas (dF/d t) max decreased. At all temperatures, increasing stimulation frequency increased F max and (dF/d t) max , whereas TPF and RT decreased. At 31 and 29°C, resting tension increased at 1.5 Hz, which was ameliorated by β-AR stimulation. At all temperatures, maximal β-AR stimulation increased F max , (dF/d t) max , and maximal systolic force, whereas resting tension decreased progressively with lowering temperature. β-AR stimulation reduced TPF and RT to the same extent at all temperatures, despite the more elongated contraction-relaxation cycle at lower temperatures. Diastolic dysfunction during hypothermia results from an elongation of the contraction-relaxation cycle, which decreases the time for ventricular filling. Hypothermic bradycardia protects the heart from diastolic dysfunction and increasing the heart rate during hypothermia should be avoided. NEW & NOTEWORTHY Decreasing temperature increases the duration of the contraction-relaxation cycle in the human ventricular myocardium, significantly reducing the time for ventricular filling during diastole. During hypothermia, increasing heart rate further reduces the time for ventricular filling and in some situations increases resting tension further impairing diastolic function. Modest β-adrenergic receptor stimulation can ameliorate these potentially detrimental changes during diastole while improving contractile force generation during targeted temperature management.