Diabetes mellitus (DM) is prevalent in up to 30% of patients with infective endocarditis (IE) and this is associated with more severe outcomes. Current guidelines have no specific recommendations for patients with IE and DM, yet they constitute an important and vulnerable subgroup of patients. The aim of this cohort study was to report clinical characteristics, microbial etiology, and in-hospital mortality for patients with IE by DM status. We used the National Danish Endocarditis Studies (NIDUS) registry. NIDUS is an all-comer Danish nationwide cohort of patients with IE between 2016-2021 with comprehensive clinical data. We included patients with left-sided IE who did not have missing information regarding DM status and had no prior IE. We grouped patients by DM status, and reported who were insulin dependent. We compared their characteristics and in-hospital mortality. We included 2,878 patients with left-sided IE. There were 662 (23.0%) with IE and DM (insulin dependent: 46.7%). A definite diagnosis of IE was recorded similarly between the groups (82.5% vs. 80.5%), the rest had possible IE. Male sex and median age (25th-75th percentile) for patients with IE and DM was 65.6% and 73.1 years (66.2-79.1), and this was 66.8% and 74.4 years (64.7-81.4) in those without DM. Patients with IE and DM presented more often with kidney disease and dialysis (32.2% and 10.1%), compared to those without DM (12.0% and 3.8%). The most predominant microorganism was S. aureus (34.1%) among patients with IE and DM, but this was Streptococcus spp. (33.9%) among patients without DM, see Figure 1. Suspected point-of-entry was available for 66.5% of the patients, and skin was reported more often for patients with IE and DM (19.8% vs. 15.8%, P=0.03). Healthcare acquired IE was reported similarly between the groups (24.5%, vs. 21.5%, P=0.124). The diagnostic echocardiography showed reduced ejection fraction (≤45%) more often for patients with IE and DM compared to those without DM (14.7% vs. 10.5%), and similar proportions of large vegetations ≥10 mm (39.4% vs. 41.4%). IE related to prior prosthetic heart valve (PVE) was also reported with similar rates in both groups (23.0% vs. 23.3%), but patients with IE and DM underwent valve surgery less frequently (17.2% vs. 23.3%). Absolute in-hospital mortality was higher for patients with IE and DM compared to those without DM (23.0% vs. 16.3%, P<0.01). Adjusted in-hospital mortality was higher for patients with IE and DM compared to those without DM (HR=1.28 95% CI: 1.05-1.56). Patients with IE and DM presented with higher proportions of key comorbidities, had a higher proportion of S. aureus, point-of-entry was more often related to skin, and absolute and adjusted in-hospital mortality was higher compared to those without DM. Our findings highlight the need for further research into this clinically important patient group who experience more severe outcomes.

Abstract Background Multivessel coronary artery disease frequently occurs in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS), which is associated with a higher mortality rate. Previous studies have focused on revascularisation during the initial admission. The need for revascularisation after discharge has not yet been well-studied. Purpose To determine the incidence of revascularisation after discharge in patients initially hospitalised with AMICS compared to ST-elevation myocardial infarction (STEMI) patients without CS. Methods Data from a cohort of individually validated AMICS patients admitted to two tertiary cardiac centres in Denmark between 2010 and 2017 - the RETROSHOCK cohort - were included (fig.1). Data were cross-linked with The National Patient Register, containing diagnostic and procedural codes for all hospital contacts for Danish citizens. For comparison, an age- and sex-matched cohort of STEMI patients (4:1 ratio) without CS treated at the same centres and within the same timeframe was established from The National Patient Register. The incidence of revascularisation (percutaneous coronary intervention (PCI) and/or coronary artery bypass grafting (CABG)) was assessed in patients surviving a "blanking period" of 60 days after discharge to take staged elective revascularisation into account and until a maximum follow-up of 5 years. The cumulative incidence function with death as a competing event was used. Gray’s test was used for comparison of incidence functions. Results A total of 1,716 AMICS patients were included, of whom 753 (44%) survived to 60 days after discharge – of those, 538 (71%) patients had STEMI. Revascularisation was performed during follow-up and after the 60-day ‘blanking period’ in 68 patients (9%) – median follow-up time was 3.4 years in the AMICS group and 3.5 years in the control group. Multivessel disease, out-of-hospital cardiac arrest and hyperlipidaemia at index hospitalisation were more prevalent in patients revascularised during the follow-up period (69% vs. 52% p=0.009, 62% vs. 47% p=0.018 and 42% vs. 27% p=0.014) for revascularised vs. not-revascularised). No significant differences in sex or age were present in revascularised vs. not-revascularised patients. The five-year cumulative incidence rate for revascularisation after discharge was 10.0% (95% Confidence Interval (CI) 7.9-12.7%), which was similar compared to the matched STEMI cohort without CS (11.5% 95% (CI) 10.7-12.4%), HR 0.88 95% (CI) 0.68-1.13, p=0.319) (fig.1a). The finding was similar in a subgroup analysis of STEMI-only patients with CS compared to the non-CS cohort. Conclusions The cumulative incidence of revascularisation after discharge for AMICS patients was comparable to STEMI patients without CS during five years follow-up. Multivessel disease, out-of-hospital cardiac arrest and hyperlipidaemia at index admission were more prevalent in patients who were revascularised during follow-up.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by Righospitalets Forskningsfond (07IO) Lundbeck Foundation (R186-2015-2132). Background Inflammation plays an apparent critical role in patients with acute coronary syndrome (ACS) and is associated with mortality. However, the complex process is poorly understood. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel biomarker originating from mature neutrophils and renal tubular cells. It has previously been shown to be associated with mortality and acute kidney injury in ACS patients. In this study we sought to assess the potential additive prognostic value of NGAL and its relation to other markers of inflammation. Methods In 1556 consecutive ST-elevation myocardial infarction (STEMI) patients, NGAL and C-reactive protein (CRP) plasma concentration were measured at hospital admission, before acute coronary angiography. Patients were stratified to plasma concentration of both biomarkers >/< the median concentration into 4 groups (low NGAL/ low CRP (group 1), low NGAL/high CRP (2), high NGAL/low CRP (3), high NGAL/high CRP(4)). Primary outcome was 30-day all-cause mortality. Results In total, 477 (31%), 324 (21%), 316 (20%), and 439 (28%) patients were stratified in group 1-4, respectively. With 0, 1, or 2 biomarker plasma concentration above the median (group 1 – 4), patients were older (61 – 67 years old, p<0.0001), had more comorbidity (hypertension (40 – 53%), p=0.002; previous stroke (4.0 – 9.9%), p=0.007; peripheral arterial disease (PAD) (2.6 – 10%), p<0.0001; chronic kidney dysfunction (CKD) (0.6 – 11%), p<0.0001) and more critical per-infarction circumstances (time from symptom debut to angiography (170 – 229 minutes), p<0.0001; cardiogenic shock (1.3 – 14%), p<0.0001, cardiac arrest (0.8 – 3.4%), p=0.0002) and lower left ventricular ejection fraction (LVEF) (48 – 43%, p<0.0001). Increased NGAL and CRP was associated with 30-day all-cause mortality (Figure A). Only high NGAL/high CRP was independently associated with 30-day mortality in a cox proportional hazard model when adjusting for age, hypertension, previous stroke, CKD, LVEF, and cardiogenic shock (HR (95% CI) 5.19 (1.20 – 22.52), p=0.03). Both CRP and NGAL had significant predictive value of 30-day mortality (AUC ROC 0.67, p<0.0001 and 0.78, p<0.0001, respectively). Combining NGAL and CRP did, however, not increase the predictive value of NGAL alone (AUC ROC 0.77, p=0.86) (Figure B). Conclusion Combined admission NGAL and CRP plasma concentration was independently associated with 30-day all-cause mortality in STEMI patients. Adding CRP to NGAL did, however, not increase the predictive value.Figure AFigure B

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Research Foundation of Rigshospitalet. Background Post-cardiac arrest syndrome (PCAS) following out-of-hospital cardiac arrest (OHCA) is a life-threatening condition, characterized by a cascade of pathological events, including the development of a severe cytokine response. This inflammatory response may be associated with secondary brain injury and multi-organ dysfunction. In the randomized STEROHCA trial, high-dose glucocorticoid was administered immediately following resuscitation in the prehospital setting. The intervention exhibited a significant decrease in interleukin (IL) 6 levels, but its effect on other cytokines has yet to be assessed. Purpose We aimed to investigate the effects of high-dose glucocorticoid treatment in mitigating the cytokine response observed in PCAS after OHCA. Methods The modified intention-to-treat population of the double-blind, randomized STEROHCA trial consisted of 137 OHCA patients, who were randomized to a single prehospital injection of methylprednisolone 250 mg or placebo. Of these, this sub-study included 112 patients who were comatose and admitted to an ICU. Cytokine profiling was performed with a 17-plex assay, including pro- and anti-inflammatory cytokines, which were measured at 0, 24, 48, and 72h after admission. We applied mixed-model analyses to assess the effect of the intervention over time with log-transformed data. To maintain an exploratory approach, we chose not to correct for multiple testing. Results The intervention induced a reduction in the levels of several cytokines, with a significant treatment over time effect for IL-4, IL-8, IL-10, Monocyte Chemoattractant Protein-1 (MCP-1), Macrophage Inflammatory Protein-1 Beta (MIP-1β), and Tumor Necrosis Factor Alpha (TNF-α), all p<0.01. These cytokines, except for IL-10, exhibited lower values in the glucocorticoid group after 24h, Figure 1. Higher levels of IL-10 were observed in the glucocorticoid group at 0h. We found no differences in cytokine levels after 48-, and 72h between the two groups. Conclusion High-dose glucocorticoid treatment administered promptly after resuscitation from OHCA reduced several pro-inflammatory cytokines after 24h. TNF-α has previously been associated with poor outcomes following OHCA, whereas the exact role of the other cytokines following OHCA is unclear.Cytokines at 0-, 24-, 48-, and 72 hours

Abstract Background Transthoracic echocardiography (TTE) offers an immediate non-invasive assessment of cardiac morphology and function that can be performed bedside. Acute TTE in the catheterization laboratory (cath.lab.) may be helpful to identify markers of subsequent development of cardiogenic shock (CS) in patients with ST-elevation myocardial infarction (STEMI) in addition to the previously validated ORBI risk score. This relationship has not been investigated thoroughly previously. Purpose To investigate the association between acute TTE estimates of left ventricular (LV) function prior to primary percutaneous coronary intervention (pPCI) in STEMI patients and pro-B-type natriuretic peptide (proBNP) as a proxy associated with of CS development. Method From September 2023 all non-CS STEMI patients at one tertiary heart center underwent acute bedside TTE in the cath.lab. and ORBI risk score assessing the risk of CS development aiming for inclusion of 500 patients. The 5 minutes TTE-protocol consisted of LV ejection fraction (EF), LV outflow tract velocity time integral (LVOT VTI), mitral inflow (E and E/A), mitral deceleration time, and mitral annular early diastolic velocity é lateral. The primary endpoint was proBNP measured 24 hours (h) after pPCI (12-36h) stratified in quartiles (Q4 vs. Q1-3). The correlation between proBNP and TTE measurements and proBNP and ORBI risk score was examined using univariate linear regression models. Results Until now 153 STEMI patients (mean age 64 years, 25% female) were studied. Anterior STEMI was present in 36%, and median time from cath. lab. arrival to first wire over the culprit lesion was 28 minutes (IQR 24; 37). Patients with high proBNP level (Q4 vs. Q1-3) had significantly higher heart rate (median 84 bpm vs. 72 bpm) and Killip Class>1 (16% vs. 0%) at admission, but similar lactate levels (1.8mM vs. 1.5mM), systolic blood pressure (130 mmHg vs. 137 mmHg), and out-of-hospital cardiac arrest (11% vs. 12%). Patients with high proBNP levels (Q4 vs. Q1-3) had significantly lower LVEF (35% vs. 50%), higher E/é lateral (median 11.4 vs. 7.9), and higher ORBI risk score (median 8 vs. 4). LVEF, LVOT VTI, E/é lateral, and ORBI risk score were significantly associated with proBNP (Figure 1). Two patients developed CS after the pPCI; one with high proBNP level Q4, and one deceased prior to proBNP measurement. Conclusion Acute TTE is an easy tool for assessment of the acute hemodynamic status in STEMI patients bedside in the cath.lab., and it can be without delaying time to revascularization. LVEF, LVOT VTI, E/é lateral, and ORBI were all parameters associated with increased levels of the hemodynamic biomarker proBNP, and may together with the ORBI risk score improve the assessment and risk stratification of STEMI-patients at risk of CS-development.Figure 1.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The BOX trial was supported by a grant (NNF17OC0028706) from the Novo Nordisk Foundation. Dr. Hassager's work is funded by a grant (R186-2015-2132) from the Lundbeck Foundation. Background Lactate levels following out-of-hospital cardiac arrest (OHCA) are associated with arrest duration (time to ROSC) and mortality. However, given the complexity of lactate generation and clearance, lactate levels assessed at hospital arrival represent not only time to ROSC but also the quality of resuscitation, circulatory stability following ROSC, dose of epinephrine administered, kidney, liver, and mitochondrial function in the early post-cardiac arrest phase. Accordingly, we describe the lactate levels at hospital arrival according to time to ROSC and one-year mortality. Method In this sub-study of the randomized clinical BOX trial, blood lactate levels were measured immediately at hospital arrival. Time to ROSC was registered in the medical records. Patients were divided into two groups according to median time to ROSC (≤ 18 min or > 18 min). The primary outcome was one-year mortality. Results The study included 768 (97% of the randomized population) patients of which 386 (50%) patients had ≤ 18 min and 382 (50%) patients had > 18 min to ROSC. The median age (64 (54-73) years) and sex distribution (81% men) was similar in both groups. One-year mortality was 76 (20%) and 199 (52%) in the ≤ 18 min and > 18 min to ROSC groups respectively. Mean lactate levels were 3.8 mmol/L (95%CI: 3.5-4.1) and 5.9 mmol/L (95%CI: 5.4-6.2), respectively. Lactate levels differed significantly between one-year survivors and non-survivors in the patients with ≤ 18 min to ROSC (mean difference: 1.9 mmol/L, 95%CI: 1.0 - 2.8) but not for patients with > 18 min to ROSC (mean difference: 0.6 mmol/L, 95%CI: -0.1-1.3), Figure 1. Further, lactate’s ability to predict one-year mortality was fair in the ≤ 18 min group with an Area Under Receiver Operating Characteristic Curve (AUC) of 0.68 (95%CI: 0.62-0.75) but poor for the > 18 min groups with an AUC of 0.55 (95%CI: 0.50-0.61) (DeLong's test for two ROC curves, p = 0.004), Figure 2. Conclusion Lactate's predictive value for one-year mortality decreases with increasing time to ROSC in OHCA. This highlights the importance of individualized clinical approaches based on lactate dynamics in OHCA patients.Figure 1Figure 2

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Grosserer L. F. Foghts Fond Background Hemodynamic instability is common after resuscitated out-of-hospital cardiac arrest (OHCA). Preventing inadequate oxygen delivery (DO2) to the cells and thus not meeting oxygen demand is crucial to prevent further organ dysfunction. Additionally, oxygen uptake in the cells may be impaired. Oxygen consumption (VO2; the amount of oxygen consumed by the body per minute) could thus also be affected in OHCA. Purpose This study aimed to describe the effect of different mean arterial blood pressure (MAP) and partial arterial oxygen pressure (PaO2) targets on DO2 and VO2. Methods This post-hoc study is based on the BOX trial, a 2x2 factorial design that randomized OHCA patients to a MAP of either 63 mmHg (MAP63) or 77 mmHg (MAP77) and a partial pressure of arterial oxygen of 9 to 10 kPa or a liberal oxygen target of a PaO2 of 13 to 14 kPa at two cardiac centers in Denmark. Pulmonary artery catheters were placed to evaluate cardiac output and collect mixed venous blood samples at prespecified time points. Oxygen blood contents were calculated for arterial (CaO2) and mixed venous blood (CvO2) as Hgb (mg/dl) x 10 x 1.39 x Saturation O2 (proportion) + 0.0225 x PaO2. DO2 = CO x CaO2, and VO2 = CO x (CaO2-CvO2). Results This study included 715 patients (90% of the total cohort with a pulmonary catheter) for analysis. A restrictive or liberal oxygen supplement did not affect DO2 or VO2 during the initial 48 hours. The MAP77 group exhibited on average 11% higher DO2 (95%CI: 6%-15%) and on average a 6% higher VO2 in the first 48 hours (95%CI: 3%-10%) compared to the MAP63 group (see Figure 1). Conclusion Targeting a PaO2 of either 9 to 10 kPa or 13 to 15 kPa resulted in no significant changes in the provision of oxygen to the cells, nor did it increase the consumption of oxygen. In contrast, targeting a MAP of 77 mmHg resulted in an increase in both the provision of oxygen and consumption of oxygen compared to a MAP target of 63 mmHg.Figure 1

Abstract Background Reverse remodeling of the left ventricle (LV) has been proposed as a key mechanism to the cardio-protective effects of sodium-glucose-transporter-2 (SGLT2) inhibitors in patients with heart failure and reduced ejection fraction (HFrEF). Deterioration of the right ventricular (RV) function is associated with poor outcome, whereas improvement in RV dysfunction has been correlated with improved outcomes in HFrEF patients. The impact of SGLT2 inhibitors on the RV remains unclear. Purpose The aim of this post-hoc study of the Empire HF trial was to investigate the effect of Empagliflozin on RV function assessed by echocardiography in patients with HFrEF after 12 weeks of treatment compared to placebo. Methods The Empire HF trial was a double-blind, placebo-controlled, randomized clinical trial, in which 190 stable HFrEF patients with a LV ejection fraction (LVEF) ≤40% were randomized (1:1) to receive Empagliflozin 10 mg once daily or matching placebo for 12 weeks. Echocardiographic images were analysed blinded to treatment allocation. Exploratory outcomes were changes in right ventricular function. Statistical analyses were performed using mixed-effects linear models adjusted for age, sex and baseline variables. Results Baseline characteristics were well balanced between the two groups; mean age 64 (SD±11) years; males: 85%; mean LVEF 29 (SD±8) %, RV free wall strain (RVFWS): -16.7 (SD±6)%, NYHA-functional class II: 78% and ischemic HFrEF etiology: 51%. No significant between-group differences were detected in RV free wall strain (RVFWS), tricuspid annular plane systolic excursion (TAPSE) or S’ RV free wall (all P>0.05), Figure 1. When stratified into baseline tertiles of RVFWS, patients in the lowest tertile showed a significant improvement in the Empagliflozin group compared to placebo (treatment effect: -4.4 % [95% CI: -8.0 to -0.8]; P=0.018), Figure 2. There was no correlation between the effect of Empagliflozin on RVFWS in the lowest RVFWS tertile and other changes such as LVEF (P=0.845), plasma volume (P=0.710) or weight loss (P=0.639). Conclusion In this randomized, short-term trial, Empagliflozin did exert a significant effect on RV function in stable HFrEF patients in the overall study population, but notably improved RVFWS in patients in the lowest tertile of RVFWS at baseline after 12 weeks of treatment. Additional research is required to confirm these explorative findings, and to better understand the impact of SGLT2i on RV function and identify patients who could potentially experience therapeutic and prognostic benefits by RV improvement.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation the Research Foundation of Odense University Hospital & Rigshospitalet. Background The impact of pre-existing mental illness on mortality in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) remains unclear. Purpose This study aims to assess the relation between pharmacologically treated mental disorders at the time of AMICS admission with patient characteristics and mortality. A surrogate marker for mental illness was defined as having at least one reimbursed prescription for psychotropic medication (Anatomical Therapeutic Chemical (ATC) group and subgroups N05, N06) within one year prior to admission with AMICS. Patients were divided into three therapy categories: None, one ATC subgroup, or two or more ATC subgroups. One-year survivors were further stratified by therapy status one year before admission and one year after discharge. Mortality was assessed at 30 days (5 years for one-year survivors). Kaplan-Meier estimates and univariable and multivariable Cox proportional hazards models were used to assess mortality rates stratified by treatment group. Results Of the cohort, 425 patients (25%) received therapy with psychotropic medication within the previous year at the time of presentation with AMICS. Polypharmacy (two or more ATC N05, N06 subgroups) was identified in 132 patients (8%). In these patients, there was a higher prevalence of comorbidities and a greater proportion of females (42% vs. 21%, p<0.001), compared to no treatment. More patients in the polypharmacy group presented with chest pain (60% vs. 52%, p=0.031), they were less often triaged directly to an invasive center (55% vs. 70%, p<0.001), and 30-day mortality was higher (73% vs. 51%, p<0.001). Among the 712 one-year survivors, 121 (17%) were treated with one or more drugs within one year before and after their AMICS admission. 149 (21%) began receiving therapy in the year following their AMICS admission. 422 (59%) never received psychotropic medication. In an unadjusted Cox model, therapy with two or more drugs, compared to no therapy, was associated with higher 30-day mortality (hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.43-2.19, p<0.001). This association remained significant in multivariable analysis (HR 1.66, 95%CI 1.22-2.26, p=0.001). Among one-year survivors, therapy with one or more drugs before and after AMICS was tied to an almost two-fold increase in five-year mortality (adjusted HR 1.95, 95%CI 1.23-3.10, p=0.004). Conclusions AMICS patients with pharmacologically treated mental illnesses were associated with higher mortality rates, as well as less favorable clinical profiles and treatment patterns. This increased risk remains evident among one-year survivors.

Abstract Background The thrifty-substrate hypothesis suggests that Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors increase plasma levels of ketone bodies and create a salutary switch in myocardial fuel metabolism. Purpose We investigated the effect of SGLT2 inhibitor on plasma beta-hydroxybutyrate in patients with heart failure and reduced ejection fraction (HFrEF). Method This is a post hoc analysis of the Empagliflozin in Heart Failure Patients with Reduced Ejection Fraction (Empire HF) trial, an investigator-initiated, double-blind, randomized, placebo-controlled trial which enrolled 190 stable HFrEF patients with a left ventricular ejection fraction (LVEF) of ≤40%. Patients were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo. Analyses were performed in patients with complete data using a linear-mixed effect-model with log-transformed beta-hydroxybutyrate, adjusted for baseline beta-hydroxybutyrate value, age, sex, and type 2 diabetes. Results A total of 188 (99%) patients had available data. The groups were well-matched with respect to baseline characteristics. Mean age was 64 (SD, 11) years; LVEF was 29 (SD, 8) %, 13% had type 2 diabetes, New York Heart Association (NYHA) class II was found in 78%. Median plasma levels of beta-hydroxybutyrate were 0.10 (inter quartile range (IQR) 0.05–0.18) mmol/l at baseline, and 0.11(IQR 0.07–0.2) mmol/l at follow-up in the empagliflozin group. In the placebo group, baseline and at follow-up concentrations were 0.10 (0.06–0.17) mmol/l and 0.09 (0.05–0.15) mmol/l, respectively. Empagliflozin increased plasma levels of beta-hydroxybutyrate compared to placebo (adjusted between-groups treatment effect; Ratio of change 1.45 [95%confidence interval (CI); 1.12–1.87], p = 0.005 (Figure 1). The effect of empagliflozin on beta-hydroxybutyrate outcomes was consistent across multiple subgroups analyses including baseline median age, sex, N-terminal-pro B-type natriuretic peptide (NT-proBNP) cut-off 600 pg/mL, treatment with sacubitril–valsartan or beta-blockers, measured glomerular filtration rate (GFR) level, hemoglobin A1c (HbA1c) level, and concomitant type 2 diabetes (all P interaction>0.05). Conclusion In patients with HFrEF, predominantly without diabetes, short-term treatment with empagliflozin increased the levels of beta-hydroxybutyrate. The absolute changes were modest and the exact contribution of ketone bodies to the cardiovascular benefits of SGLT2 inhibitors requires further clarification.Figure 1Table 1

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Righospitalets Forskningsfond (07IO) Lundbeck Foundation (R186-2015-2132). Background Neurohormonal activation and inflammation is associated with mortality in STEMI patients. We sought to assess, whether AFIB – a known risk factor in MI – also was associated with increased 1-year mortality as well as neurohormonal activation and inflammation in STEMI patients. Methods In 1892 consecutive STEMI patients from two danish tertiary heart centers biomarkers reflecting neurohormonal activation (copeptin, pro-atrial natriuretic peptide (proANP), and mid-regional pro-adrenomedullin (MRproADM)) and inflammation (ST2) was measured. Patients were stratified according to known AFIB or new onset AFIB on admission vs no AFIB. Results In total, 198 (10%, 100 known/98 new onset) patients had AFIB, which was associated with increased 1-year mortality (19% vs. 8.4%, p<0.0001). Patients with AFIB were older (mean (SD) age 70 (13) vs 63 (13) years, p<0.0001), had more comorbidity (e.g. hypertension 61% vs. 43%, p<0.0001; stroke 13% vs 6.4%, p=0.002; heart failure 11% vs 2.3%, p<0.0001), lower left ventricular ejection fraction (LVEF) (mean (SD) 41 (13) vs 45 (13), p<0.0001), were more often comatose after cardiac arrest (12% vs 6%, p=0.001), and in cardiogenic shock (CS) (20% vs 9.1%, p<0.0001). Plasma concentration (median (IQR)) of all four biomarkers were higher in AFIB patients (copeptin 124 (39; 298) vs 66 (21; 170) pmol/L; proANP 1678 (1018; 2439) pmol/L; MRproADM 0.96 (0.76; 1.41) vs 0.70 (0.58; 0.90) nmol/L; ST2 48 (34; 74) vs 39 (29; 55) ng/ml, p<0.0001 for all). When adjusting for age, sex, hypertension, previous stroke, LVEF, CS, and being comatose after cardiac arrest, AFIB remained associated with increased plasma concentration of all four biomarkers (two-fold increase – OR (95% CI): Copeptin 1.21 (1.02-1.23); proANP 2.22 (1.82-2.72); MRproADM 2.01 (1.56-2.60); ST2 1.21 (1.03-1.43)). Conclusion AFIB in STEMI patients is associated with increased admission biomarkers reflecting neurohormonal activation and inflammation and 1-year mortality.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Fonden Background Cardiogenic shock (CS) is seen in up to 10% of patients with ST-elevation myocardial infarction (STEMI) and is associated with a high mortality rate of up to 50%. Approximately 1/3 of STEMI-patients developing CS are not in overt shock at time of hospital admission but will develop hemodynamical instability within the following hours to days. Patients at risk of CS development may be clinically stable but with normal lactate levels (Society for Cardiovascular Angiography and Interventions classification, SCAI A/B). The Observatoire Régional Breton sur l'Infarctus (ORBI) clinical risk score has recently been developed and validated for predicting the risk of in-hospital (late) CS. STEMI-patients with an ORBI score >=10 have a risk of in-hospital CS development of more than 8-10%. NTproBNP is a biomarker released from the myocardium reflecting neurohormonal activation which is strongly correlated with hemodynamic parameters. Neurohormonal activation as well as a systemic inflammatory response are present acutely at hospital admission in STEMI patients developing late CS compared to non-CS patients suggesting an early subclinical hemodynamic deterioration. Dobutamine induces significant positive inotropic- and dose-dependent chronotropic effects and decreases afterload by peripheral vasodilatation, which increases cardiac output and organ perfusion. The interleukin-6 receptor antagonist Tocilizumab has been shown to reduce troponin leakage and increase myocardial salvage in acute MI patients. The effects of Dobutamine and Tocilizumab in a high-risk population have not previously been investigated. Methods DOBERMANN is an investigator-initiated, double blinded randomized clinical trial. Consecutive patients with acute MI admitted for acute coronary angiography and treated with percutaneous coronary intervention are screened with the ORBI risk score in the catheterization laboratory. One hundred adult patients presenting without CS at hospital admission with an intermediate-high risk of CS development (ORBI risk score of >=10) will be randomized 2x2 to receive a continuous intravenous infusion of dobutamine (5 micrograms/kg/minute, 24h) vs. placebo, and a single dose of Tocilizumab (280 mg, 1h) vs. placebo. NTproBNP as a proxy for development of CS and hemodynamic instability will be sampled for primary endpoint analysis. Effects on clinical parameters, mortality, morbidity as well as specific indicators of inflammation, cardiac function, and infarct size will secondarily be assessed noninvasively at 48h and at three months follow-up. Enrollment began in March 2022 and is commencing as planned. Discussion We hypothesize that inflammatory and neurohormonal responses are associated with subclinical hemodynamic instability in patients with AMI with intermediate/high risk of CS. The potentially unstable condition may be targeted pharmacologically as an add-on to existing therapy.

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Anxiety, depression, and post-traumatic stress disorder (PTSD) among out-of-hospital cardiac arrest (OHCA) survivors may impact their long-term recovery and quality of life. Gaining knowledge on sex differences in psychological consequences following cardiac arrest is important to explore strategies aiming to reduce these symptoms. Purpose To explore sex differences in anxiety, depression and PTSD levels after discharge among OHCA survivors hospitalized at a cardiovascular intensive care unit. Methods This was a prospective observational study in OHCA survivors that attended a follow-up after 4 months, (median, IQR 3-8). Presence of symptoms of anxiety and depression was measured using Hospital Anxiety and Depression Scale (HADS), range 0-21. Scores between 8 to 10 suggest the possible presence of a mood disorder whereas scores of 11 and above indicate the probable presence of a mood disorder. Symptoms of PTSD were measured with PTSD Checklist for DSM-5 (PCL-5), a 20-item self-report measure that assesses symptoms of PTSD, range 0-80. Results Between 2016 and 2021, 245 consecutive OHCA survivors admitted in coma (44 women, 18% and 201 men, 82%) completed the survey. Mean values measured on HADS were 2.7 ±3.2 for depression and 4.8±3.9 for anxiety. Depression and anxiety levels were significantly higher in women (3.3±3.4 and 6.1±3.8), respectively, compared to men (2.6±3.2 and 4.5± 3.9), respectively (p<0.0001 for both). Anxiety scores of 8 or more were observed in 43% of women, and 23% of men (p=0.007). Scores of 8 to 10 suggesting the possible presence of anxiety were found in 23% of women and 11% of men (p=0.007), whereas one out of five women scored ≥ 11 (20%) indicating probable anxiety disorder, while one in ten of men(12%), (p=0.02). Further, female sex was significantly associated with higher levels of PTSD (median for women: 33, IQR 24-54, and for men 26, IQR 22-35), (p=<0.0001). Finally, anxiety was significantly correlated to post-traumatic stress symptoms (correlation coefficient 0.81, p=<0.0001). Conclusion Symptoms of anxiety and PTSD are frequent in OHCA survivors and female cardiac arrest survivors report significantly higher symptom levels of anxiety, depression, and PTSD compared to men. These results underline the presence of long-term symptoms in these patients and support further research in sex-specific approaches to alleviating these symptoms in patients surviving OHCA.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Background Patients with pulmonary disease may have altered pulmonary hemodynamic compared to patients without pulmonary disease. We hypothesize that these patients with pre-existing pulmonary disease have significantly elevated pulmonary arterial pressure during the first 48 hours of ICU-stay. Methods The BOX-trial was an investigator-initiated, randomized, controlled study of targeted MAP (63 vs 77 mmHg) and PaO2 (9-10 vs 13-14 kPa) interventions in 789 comatose OHCA (of presumed cardiac origin) patients. Pre-existing, significant pulmonary disease was recorded at baseline. Patients underwent serial hemodynamic assessments with pulmonary artery catheter at time of insertion (0 h), 6 h, 12 h, 24 h, 36 h and 48 h. Among parameters recorded was cardiac output (CO). Pulmonary arterial pressures and central venous pressure were measured continuously. Patient characteristics included age, time to return of spontaneous circulation (ROSC) and initial rhythm. Results Hemodynamic parameters from 730 patients were analysed, of which 89 (12%) had pulmonary disease. Of these, 57 (8%) had COPD, 26 (4%) had asthma and 6 (1%) had non-obstructive pulmonary disease. Patients with pulmonary disease were older (66±12 vs 62±14 years) and had similar time to ROSC (20±14 vs 23±16 minutes). Initial shockable rhythm was present in 73/89 (82%) with pulmonary disease and in 580/641 (90%) without, p=0.015. At 12 hours, mean pulmonary artery pressure (27±5 vs 24±6 p<0.0001, see Figure 1), systolic pulmonary pressure (36±7 vs 33±8 p=0.0004), and diastolic pulmonary pressure (21±5 vs 18±5 p<0.0001) were all significantly higher for patients with pulmonary disease than patients without. This association remain statistically significant, when adjusting for primary rhythm, time to ROSC and age. Also, heart rate (72±21 vs 66±17 bpm, p<0.0056) was significantly higher in patients with pulmonary disease. Cardiac index (cardiac output adjusted for body surface), central mixed venous saturation and CVP was similar between groups. Conclusions Pre-existing pulmonary disease in resuscitated OHCA-patients is associated with significantly elevated pulmonary pressures.

Abstract Funding Acknowledgements Type of funding sources: None. Background Patients who are successfully resuscitated from out-of-hospital cardiac arrest (OHCA) and admitted to the hospital in a comatose stage are in high risk for anoxic brain injury. Multimodal approach for neuroprognostication include measurement of neuron-specific enolase (NSE) as a biomarker for neurological injury. NSE has been intensively studied over the past years and has shown a valid predictive value for neurological outcome. However, there has been no clinical studies comparing NSE analyzed on plasma and serum samples. Purpose To compare NSE at 48 hours obtained from both in serum and plasma samples, and to investigate the performance of both these measuring techniques in predicting all-cause mortality at 365-days among patients resuscitated from out-of-hospital cardiac arrest. Methods This is a post-hoc sub study of the BOX trial in which resuscitated OHCA patients admitted to the hospital in comatose stage were included. NSE was measured 48 hours after admission, both in serum samples used for clinical analysis with no freeze-thaw cycle (NSE-Serum), and plasma samples from biobank (NSE-Plasma). The comparison of NSE-Serum and NSE-Plasma was performed by Spearmans correlation. The area under the receiver operating characteristics curve (AUROC) for predicting all-cause mortality at 365-days for both NSE-Serum and NSE-Plasma were determined. Results 369 patients had NSE values from both serum and plasma at 48 hours available for comparison. In these patients the NSE-Serum was median 21.2 µg/L (IQR 15.7 - 45.5), NSE-Plasma was median 19.3 µg (IQR 11.3 - 40.9), and mortality at 365-days was 32.5%. The correlation between NSE-Serum and NSE-Plasma was r=0.63 P<0.001. AUROC for NSE-Serum and NSE-Plasma were 0.94 and 0.83 respectively (FIGURE), and the differences in AUROC was -0.10 (95% confidence limits: -0.14 to -0.06), p<0.001. Conclusion In this sub study, we found moderate correlation between serum NSE values and plasma NSE values. Moreover, both measuring techniques had good predictive value against 1 year mortality, with clinically measured NSE from serum being slightly superior to NSE from plasma in predicting mortality.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Rigshospitalets and Odense Universitetshospitals common foundation Background Survival after refractory out-of-hospital cardiac arrest (OHCA) is low. Extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly used for selected patients aiming to increase survival after refractory OHCA. However, ECPR is resource heavy and carries risk of poor functional status. Previous studies have shown favorable neurological outcome in the majority of survivors of OHCA managed with ECPR; yet the share of patients able to return to work has not previously been explored. Purpose The purpose of this study is to investigate the fraction of patients returning to work after OHCA managed with ECPR in a national cohort of refractory OHCA-patients. Methods Of about 44,000 OHCAs during the period of 2011-2020, this nationwide registry-based study included 812 refractory OHCA-patients in the working age between 18 years and 65 years (as 65 was the current age of retirement) who were in employment prior to the event. We excluded 113 ECPR-patients and 3,536 refractory OHCA-patients managed with standard advanced cardiac life support (sACLS) due to age or unemployment. We defined refractory OHCA as patients with OHCA brought to hospital with on-going CPR. Information on demographics, OHCA circumstances, status at hospital arrival, and survival were retrieved through the Danish Cardiac Arrest Register. Employment status were retrieved through the Danish Research Institute for Economic Analysis and Modelling database. Maintenance of work was defined as return to work without any sick leave relapse (>4 weeks) during six months of employment. Results Of 812 included refractory OHCA-patients, 137 patients received ECPR while 675 were managed with sACLS. ECPR-patients were slightly younger than sACLS-patients (median 51 vs. 53 years), a higher percentage male sex (84% vs. 79%), and more had favorable OHCA circumstances (witnessed arrest [80% vs. 64%], bystander CPR [75% vs. 67%], and shockable presenting rhythm [59% vs. 37%]). One-year survival was higher for ECPR-patients compared with sACLS-patients (24% vs. 7%, p<0.001). Of one-year survivors, less ECPR-patients were in employment one year after OHCA compared with sACLS-patients (48% vs. 77%, p=0.01). No difference in maintenance of work were found between ECPR- and sACLS-patients after OHCA (88% vs. 79%, p=0.7). Conclusion Survival was higher for refractory OHCA-patients receiving ECPR- compared to sACLS-therapy, which may reflect selection bias. One out of two ECPR patients returned to work and the majority maintained employment for at least six months. More sACLS-survivors returned to work compared with ECPR-survivors likely reflecting survival bias.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Fonden Background In critically ill patients with cardiogenic shock, neurohormonal activation is higher in females compared with males. Whether this is the case in patients resuscitated from out of hospital cardiac arrest (OHCA) is not known and whether sex-based differences relate to achieving mean-arterial-pressure (MAP)-target has not previously been described. Methods This was an investigator-initiated, randomized, controlled study of targeted MAP (63 vs 77 mmHg) and PaO2 (9-10 vs 13-14 kPa) interventions in 789 comatose OHCA (of presumed cardiac origin) patients. Patients underwent serial hemodynamic assessments with pulmonary artery catheter at time of insertion, 6 h, 12 h, 24 h, 36 h and 48 h. Among parameters recorded were heart rate (HR), cardiac output (CO) and central venous pressure (CVP), from which cardiac index (CI) and systemic vascular resistance index (SVRI) were derived. Patient characteristics included sex for stratification, age, time to return of spontaneous circulation (ROSC) and initial electrocardiographic (ECG) rhythm. Results Hemodynamic parameters from 729 patients were analysed, of which 138 (19%) were female and 591 (81%) were male. Both groups had a median age of 64 years, with median time-to-ROSC of 19 minutes in females versus 18 minutes in males. In females versus in males, SVRI and HR were higher (fig.1,2). There were no differences among sexes with regards to CI, MAP, or dose of noradrenaline. At 12 hours, median SVRI in females was 755 dyn·s/cm5·m2 (inter-quartile ratio, IQR 569-931) versus 554 dyn·s/cm5·m2 (IQR 441-684) in males (P<0.0001). At the same point in time, median HR was 71 beats/minute (bpm) in females (IQR 59-82) versus 62 bpm (IQR 54-74) in males (P<0.0001). Lastly, 12-hour median CI was 1.82 L/min/m2 (IQR 1.54-2.40) in females versus 1.95 L/min/m2 (IQR 1.63-2.43) in males (P=0.1303). Conclusions Female comatose OHCA patients had higher SVRI and HR during the first 48 hours of ICU admission, without difference in MAP or vasopressor requirement. Sex specific physiological mechanisms may be involved in maintaining vascular resistance.

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Supported by a grant from the Novo Nordisk Foundation. Background Time to return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA) is closely associated with the likelihood of survival but may also impact hemodynamic stability after ROSC. The aim of this study is to investigate the association between invasive hemodynamics and time to ROSC during the first 48 hours of admission. Methods In this substudy of the BOX trial, adult comatose patients who had been resuscitated after an OHCA with a presumed cardiac cause and had a sustained ROSC were studied. Patients were divided into tertiles according to time to ROSC. Invasive hemodynamic evaluation was performed using a pulmonary artery catheter and invasively measured mean arterial pressure (MAP). Systemic vascular resistant index (SVRI) and cardiac index (CI) were adjusted for body surface area (BSA). Measurements and Main Results We included 714 patients, 243 with ≤13 minutes to ROSC (tertile 1), 235 patients with 14-23 minutes to ROSC (tertile 2), and 236 patients above ≥24 minutes to ROSC (tertile 3). We found no difference in age (p=0.90) or sex (p=0.92) in the three groups. Furthermore, we found no difference in witnessed cardiac arrest (p=0.29) or bystander cardiopulmonary resuscitation (p=0.58) between the tertiles. Upon the first 48 hours of admission, systemic vascular resistant index (SVRI) (p=0.64), cardiac index (p=0.51), and mean arterial pressure (MAP) (p=0.79) were similar in the three groups, while the average heart rate and the use of noradrenaline (NA) were significantly higher (p<0.0001) in patients with prolonged time to ROSC (Figure 1). Conclusions In patients resuscitated after an OHCA, similar central hemodynamics were achieved irrespective of prolonged time to ROSC but at the cost of a higher dose of noradrenaline in the first 48 hours.

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Novo Nordisk Foundation Background Quantitative pupillometry has been implemented in resuscitation guidelines as part of multimodal prognostication in comatose out-of-hospital cardiac arrest (OHCA) patients. Post-resuscitation intensive care allows for different blood-pressure and oxygen targets, but evidence on the implication of these targets on prognostication is limited. Purpose To assess the impact of different blood-pressure and oxygen targets in resuscitated OHCA patients on the prognostic ability of the quantitatively assessed percentage reduction of pupillary size (qPLR, %) and the neurological pupil index (NPi, 0-5). Methods The BOX-trial is a multicenter, double-blind, randomized trial, comparing low (63 mm Hg) versus high (77 mm Hg) mean arterial blood-pressure targets and restrictive (9 to 10 kPa) versus liberal (13 to 14 kPa) partial pressure of arterial oxygen targets in comatose survivors of OHCA. In this predefined, prospective substudy, quantitative pupillometry measurements were obtained from consecutively enrolled patients at 0, 24, 48, 72, 96, and 120 hours after OHCA (t0-t120). The prognostic performance of qPLR and NPi for high and low blood-pressure groups, and liberal and restrictive oxygen target groups were illustrated through the area under the receiver operating characteristic (ROC) curves (AUC). The time point achieving the highest AUC was used for further analyses. AUCs were compared with DeLong’s test. Results The highest AUC for qPLR and NPi were achieved for measurements made 48 hours after OHCA. qPLR produced AUC at 0.79 [95%CI 0.73-0.85] and 0.81 [95%CI 0.75-0.86] for high and low blood-pressure groups, and 0.79 [95%CI 0.73-0.85] and 0.80 [95%CI 0.74-0.86] for liberal and restrictive oxygen target groups, respectively (Fig 1). For NPi AUC were 0.79 [95%CI 0.73-0.85] and 0.78 [95%CI 0.72-0.84] in high and low blood-pressure groups, and 0.77 [95%CI 0.71-0.83] and 0.80 [95%CI 0.75-0.86] in liberal and restrictive oxygen target groups, respectively (Fig 2). No significant difference between any groups, for either blood-pressure or oxygen targets, was found. Conclusion Prognostic value of quantitative pupillometry for predicting outcome in resuscitated OHCA patients was high and consistent across different blood-pressure and oxygen level targets.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Background Previous studies have found lower survival rate and neurological outcomes for female patients with out-of-hospital cardiac arrest (OHCA) compared to males. Recently, the effect of liberal or restrictive oxygenation and lower or higher mean arterial blood-pressures (MAP) on outcome in comatose OHCA patients were investigated; showing no differences between the target groups. Evidence concerning sex differences in outcome after appropriate oxygenation and different MAP levels in comatose OHCA patients is limited. Purpose The aim of this study was to investigate whether female sex was associated with higher rates of unfavourable outcome after treatment with oxygenation and MAP in comatose patients after OHCA related to outcome. Methods Adult comatose OHCA patients (age ≥18 years) of presumed cardiac cause were included in a dual-center, double-blind, randomized trial with a 2-by-2 factorial design. Patients were allocated by a 1:1:1:1 ratio into a MAP target of 63 mm Hg or 77 mm Hg and arterial oxygen concentration during mechanical ventilation of 9–10 kPa (restrictive) or 13–14 kPa (liberal). The primary outcome was a composite of all causes of death within a year or hospital discharge with a cerebral performance category (CPC) of 3 or 4. Results Of the 789 included comatose OHCA patients, 152 (19%) were women. Mean age of women and men were similar, 61±14 years and 63±13 years, respectively. Comorbidities and characteristics of the cardiac arrest were comparable between sexes except for ischemic heart disease, which was more frequent in men (12% women, 24% men) and pulseless electrical activity, which was more frequent in women (8% women, 4% men). CPC 3 or 4 occurred equally in women and men (both 3%). Women had a higher, but non-significant one-year all-cause mortality (women: 42%, men: 35%), Figure 1. In a univariate Cox regression model, the difference in all-cause mortality was not significant (HR: 1.25, CI: 0.95-1.63), but showed significance after adjustment for age (HR: 1.31, CI: 1.004-1.72). Conclusion Men and women in comatose after OHCA had similar unfavourable outcome when treated in the same manner with oxygenation and MAP.