Prolonged Door-to-Balloon time leads to glycocalyx damage and endothelial dysfunction in patients with ST-Elevation Myocardial Infarction and cardiogenic shock

Prolonged Door-to-Balloon time leads to glycocalyx damage and endothelial dysfunction in patients with ST-Elevation Myocardial Infarction and cardiogenic shock | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prolonged Door-to-Balloon time leads to glycocalyx damage and endothelial dysfunction in patients with ST-Elevation Myocardial Infarction and cardiogenic shock Carl Vahldieck, Benedikt Fels, Samuel Löning, Laura Nickel, Joachim Weil, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3234193/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Damage to the endothelial glycocalyx (eGC) and endothelial dysfunction have been reported to develop during cardiac ischemia-and-reperfusion injury (IRI), such as ST-elevation myocardial infarction (STEMI). For patients with acute ischemic syndromes and cardiogenic shock a door-to-balloon time (D2B) < 60 min with rapid revascularization was shown to reduce both mortality and nonfatal complications. Here, we hypothesize that prolonged D2B is associated with an unfavorable outcome for the eGC of patients with STEMI. Methods Data of 126 individuals were analyzed in this study. Sixty-three STEMI patients with cardiogenic shock in the event of STEMI were included. All received revascularization through primary percutaneous coronary intervention (PCI). 63 age- and sex-matched healthy volunteers served as controls. After stimulating endothelial cells with patient sera, the nanomechanical properties of the eGC were analyzed using the atomic force microscopy-based nanoindentation technique. Serum levels of eGC components as well as complement anaphylatoxins and angiopoetin-2 were measured via ELISA. Nitric oxide (NO) levels were determined chemiluminescence-based. Results eGC height and stiffness (both, p < 0.001) as well as NO concentration (p < 0.001) were reduced after STEMI. Longer D2B led to significantly higher amounts of eGC components (syndecan-1: 35.5 vs. 136.7 ng/ml; p < 0.001 / heparan sulfate: 4.6 vs. 10.8 ng/ml; p < 0.001 / hyaluronic acid: 116.7 vs. 182.9 µg/ml; p < 0.0001) and troponin-t (p 60 min led to pronounced loss of eGC height and stiffness (both, p < 0.001), activated the complement system (p < 0.001), and prolonged the hospital stay (p < 0.01) compared to D2B ≤ 60 min. Conclusion Increased D2B led to severe eGC shedding and endothelial dysfunction in a temporal context. In addition, levels of syndecan-1 and proinflammatory mediators correlated with prolonged D2B, indicating a time-dependent immune reaction during cardiogenic shock with increased IRI to the eGC and prolonged hospitalization. D2B therefore appears to be a crucial factor for endothelial IRI in the case of STEMI with cardiogenic shock. Combining the clinical evaluation of the eGC condition with levels of biomarkers such as syndecan-1 might serve as important predictor for eGC impairment of STEMI patients with cardiogenic shock in the future. Endothelial glycocalyx Endothelial dysfunction ST-elevation myocardial infarction (STEMI) Cardiogenic shock Door-to-balloon time Nitric oxide Figures Figure 1 Figure 2 Figure 3 Introduction The endothelial glycocalyx (eGC) and the cellular cortex (CTX) of endothelial cells (EC) provide a protective barrier on top of these cells. Thus, changes in their mechanical properties might induce endothelial dysfunction. 1 A possible cause of such alterations of the endothelial surface is ischemia-reperfusion (I/R) injury (IRI), a protracted, but reversible interruption in blood supply and tissue oxygenation leading to organ damage. 2,3 IRI causes rapid dismantling of the microvascular eGC in all tissues and its degradation might be the earliest form of structural damage in I/R. 2 Furthermore, cardiac IRI contributes to up to 50% of the final infarct size, thus playing a significant role in the development of cardiogenic shock. 4 eGC damage in the context of cardiac IRI has been demonstrated in the setting of acute myocardial infarction with cardiogenic shock followed by cardiac interventions, both in experimental and clinical settings. 5,6 In ST-elevation myocardial infarction (STEMI), rapid revascularization was shown to reduce in-hospital and long-term mortality as well as decrease the number of nonfatal complications in numerous studies. 7,8 The time interval between a patient entering the medical system and revascularization to open the occluded, culprit vessel is termed “Door-to-Balloon”-time (D2B). The preferred mode of revascularization is primary percutaneous coronary intervention (PCI) and, as recommended by the European Society of Cardiology (ESC), the gold standard time from hospital entry to PCI (D2B) is ≤ 60 min for PCI-capable hospitals to prevent ischemic cardiogenic shock from progressing further. 9,10 Our group previously reported damage to the eGC in the case of STEMI with syndecan-1 as a biomarker for IRI. 11 The eGC component syndecan-1 (Syn-1; CD138), a transmembrane proteoglycan that builds the structural backbone of the eGC, is damaged during STEMI. Syndecan-1 acts as a core unit for other eGC components such as heparan sulfate and hyaluronic acid and transmits extracellular signals to the intracellular environment of endothelial cells through its transmembrane domain, which is directly associated with the actin cytoskeleton of the endothelial cell cortex. 11,12 Furthermore, syndecan-1 can be used as a biomarker of eGC damage after revascularization as it is independently associated with 6-month mortality after STEMI 13 and represents an independent predictor of 30-day mortality in cardiogenic shock 14 .Time-to-revascularization as well as levels of eGC components are important predictors in the development of cardiogenic shock. By implementing direct access to catheterization laboratories and bypassing the emergency department, the time from first medical contact to PCI has been reduced over the past few years and there is general consensus that a shorter D2B is associated with a better prognosis. 9,10 However, up to now, the relationship between D2B duration and eGC damage/endothelial dysfunction is unknown. The purpose of this study therefore was to investigate whether a prolonged D2B had an impact on eGC damage in cardiogenic shock or whether it is associated with unfavorable outcomes for endothelial function in STEMI patients. Methods Study population In this study, 63 consecutive patients with a first onset of STEMI were included at the University of Luebeck in cooperation with the intensive care unit (ICU) of the Department of Cardiology and Angiology of the Sana-Kliniken-Luebeck-hospital, Germany, in accordance with the Declaration of Helsinki and approved by the Local Ethics Committee (Case: 19–310). Informed consent was obtained from each patient. All patients received emergency coronary angiography and PCI as first-line therapy with subsequent treatment in the ICU after STEMI was diagnosed. The diagnosis of STEMI was based on the criteria of the Guidelines on Management of Acute Myocardial Infarction in Patients Presenting with ST-Segment Elevation of the ESC. 10 Cardiogenic shock was evaluated by the attending physician according to clinical signs (e.g. cyanotic extremities, signs of cerebral hypoperfusion with somnolence/confusion) as well as hemodynamic signs (e.g. systolic blood pressure < 90 mmHg, administration of catecholamines) based on the German-Austrian S3-Guideline “Cardiogenic Shock Due to Myocardial Infarction”. 15 Blood samples were collected during emergency PCI (hereafter termed STEMI group). Sixty-three age- and sex-matched volunteers without cardiovascular comorbidities served as controls (hereafter termed CTR group). Patients undergoing cardiopulmonary resuscitation or patients after gaining a return of spontaneous circulation (ROSC) were excluded, as were patients who died during or after PCI. Patients requiring extracorporeal membrane oxygenation/extracorporeal life support (ECMO/ECLS) were also excluded. Further exclusion criteria were age below 18 years or pregnancy. Serum samples from patients and controls were immediately treated according to the manufacturer’s information (S-Monovette®, Sarstedt, Nümbrecht, Germany). Therefore, samples were kept on ice and centrifuged at 4°C within 60 min after collection. Afterwards the samples were snap-frozen and stored at -80°C. For D2B analysis, patients were retrospectively divided into two groups: i) D2B ≤ 60 min; ii) D2B > 60 min. The D2B was defined as the time interval between the STEMI patient entering the emergency room and the time of the first balloon dilatation in the catheter laboratory. The cut-off of 60 min was chosen in accordance with the recommendations of the ESC guidelines for PCI-capable hospitals. 9 Cell isolation and culture Primary human umbilical vein endothelial cells (HUVEC) were isolated (approved by the local ethical committee; Case: 18–325) and cultured as described previously 11,16 . Cells were cultured in HUVEC culture medium (Gibco Medium 199) + 10% fetal calf serum (Gibco, Carlsbad, CA) + penicillin/streptomycin 1% (Gibco, Carlsbad, CA; 100 U/ml; 100 mg/ml) + heparin 5000 U/ml (Biochrom, Schaffhausen, Switzerland) + large-vessel endothelial supplement 1% (Gibco, Carlsbad, CA, USA). Cell culture flasks were coated with 0.5% gelatin (Sigma-Aldrich, St. Louis, MO, USA) 1 h before seeding and cultivated at 37°C, 21% O 2 , and 5% CO 2 . For experiments HUVEC were cultivated on fibronectin-coated glass coverslips to confluence for at least 4 days under standard cell culture conditions and stimulated with 10% STEMI or CTR sera for 24 h prior to the experiment. Atomic force microscopy The thickness and stiffness of the eGC were determined by using the AFM nanoindentation technique, as described previously 11 . Indentation measurements were performed on living confluent HUVEC at 37°C using a Nanoscope Multimode-8 AFM (Bruker Nano GmbH, Berlin, Germany). Briefly, a laser beam was aligned on the back of a gold-coated triangular cantilever (Novascan Technologies, Boone, North Carolina, United States) with a mounted spherical tip (diameter 10 µm) and a nominal spring constant of 10 pN/nm. The cantilever indents the endothelial cell surface with a loading force of 0.5 nN. The reflection of a laser beam is used to quantify the cantilever deflection. The height of the eGC can be calculated by knowing the cantilever force, the piezo displacement, and the deflection sensitivity. For each patient and control serum a total of two repetitions with 25–30 cells were measured. For each cell 6–8 force distance curves (FDC) were generated and averaged, resulting in n = 600 to 960 FDC per individual. FDC data were collected with the Research NanoScope version 9.20 (64 bit; Bruker Nano GmbH). The stiffness and thickness of the eGC were calculated using the protein unfolding and nanoindentation analysis software Punias 3D (Version 1.0; Release 2.3; Copyright 2009). Enzyme-linked immunosorbent assay In addition to the standard clinical laboratory examinations of the patient's blood, additional parameters in the serum of the patients were determined via enzyme-linked immunosorbent assay (ELISA). To determine the dissolved glycocalyx constituents, syndecan-1, heparan sulfate, and hyaluronic acid (hyaluronan) concentrations were measured. ( syndecan-1 : Human CD138 ELISA kit, Diaclone Research, Cedex, France; catalog: 950.640.192 / heparan sulfate : Human Heparan sulfate Proteoglycan (HSPG) ELISA Kit, MBS, San Diego, California, USA; catalog: MBS2023323 / hyaluronan : Hyaluronan Quantikine ELISA Kit, R&D Systems, Minneapolis, Minnesota, USA; catalog: DHYAL0). Angiopoetin-2 was quantified using a Human Angiopoietin-2 Quantikine ELISA Kit (R&D Systems, Minneapolis, Minnesota, USA; catalog: DANG20). Activation of the complement system was measured by quantifying the anaphylatoxins C3a and C5a (Thermo Fisher Scientific, Hamburg, Germany; C3a, catalog: BMS2089; C5a, catalog: BMS2088). Nitric oxide product measurements For measuring total nitrate and nitrite in the STEMI and CTR sera, the chemiluminescence detector Sievers Nitric Oxide Analyzer (NOA-280i; GE Water & Process Technologies, Analytic Instruments; Boulder, Colorado, USA) was used. Subsequent procedures were performed according to the operation and maintenance manual (Firmware Version 3.00 and later) provided by the manufacturer. The assay is based on the reduction of all nitrates and nitrites into nitric oxide (NO) by vanadium (III) chloride. NO reacts with ozone inside the NOA-280i to produce nitrogen dioxide (NO 2 ), which is sensitively detected by virtue of its chemiluminescence. NO products (NO x ) of the STEMI and CTR sera were analyzed by injecting 50 µL of each serum sample into a purge vessel containing a solution of vanadium (III) chloride (50 mmol/L; Sigma-Aldrich, Germany) in hydrochloric acid (HCl) (1 mol/L; Sigma-Aldrich, Germany) at 95°C, continuously purged with a stream of nitrogen gas, connected to the NOA-280i. A gas bubbler between the purge vessel and the NOA-280i was filled with 15 mL of 1 M aqueous NaOH solution (Sigma-Aldrich, Germany) to prevent HCl vapors from entering the NOA-280i. Concentrations were calculated using the manufacturer’s NOAnalysis Software for Liquid (Version 3.21/Liquid, GE Water & Process Technologies, Analytic Instruments; Boulder, Colorado, USA). Statistical Analysis Data were analyzed using IBM SPSS Statistics for Windows (IBM Corp. Released 2020, Version 28.0.1 Armonk, New York, USA) and the 2D graphic and biostatistics software GraphPad PRISM (Version 8.4.2, GraphPad Software Inc., California, USA). GraphPad PRISM was also used to prepare the figures. Gaussian distribution was determined by D'Agostino & Pearson omnibus normality test and presented graphically via quantile-quantile plot (Q-Q Plot). Data with no proven linearity were plotted, and the curves were fitted to determine the interrelationships of the function. The best-fit model was implemented. Data were tested for outliers before applying statistical tests using the ROUT outlier test based on the false discovery rate (FDR; Q value = 1%). Outliers were omitted from further analysis. Differences between two groups were analyzed using Student’s t-test for parametric values. For nonparametric values, the Mann-Whitney test (for unpaired data) or the Wilcoxon matched-pairs signed-rank test (paired data) was applied. Group differences at the nominal scale level were measured using Cramer-V. Categorical variables were compared by using the chi-squared test. Correlations at ordinal scale level were measured using Spearman, at metric scale level using Pearson correlations (with Rho (r); coefficient of determination (R²)). With a sample size of n = 63, a statistical power of 0.8. and a significance level of α = 0.05, a correlation of r = 0.344 was needed for a significant result. Patients were retrospectively divided into cohorts: a) D2B ≤ 60 vs. >60 min in accordance with the recommendations of the European Society of Cardiology guidelines (ESC) for PCI-capable hospitals 9 ; b) syndecan-1 levels ≤ 120 vs. >120 ng/ml in accordance to the findings of Wernly et al. 13 . Killip classification was determined on admission and carried out according to Kilipp and Kimball (1967). 17 Differences were considered statistically significant when p-values were < 0.05 (*: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001). Confidence level was set at 95%. Data are presented as absolute values of mean ± standard deviation (m ± SD). Boxplots show first quartile, mean, and third quartile; whiskers show minimum and maximum values. Results Characteristics of STEMI group The patients in the STEMI group (see Table 1 ) were 64 (± 13) years old on average and predominantly male (76%). All of them presented with at least one cardiovascular risk factor (CVRF: male sex, hypertension, diabetes, obesity, a positive family history of myocardial infarction, hyperlipidemia, uremia, or active smoking), and 65% had more than 3 CVRF. The average D2B was 55.5 (± 27.2) min, whereby D2B was less than 60 min in 66% and more than 90 min in 14%. In 69% a Killip classification of III or IV was calculated on admission, with 38% of the patients having a preserved left-ventricular ejection fraction (LVEF) of over 50%. Reduced LVEF was diagnosed in 16%. The average systolic blood pressure was 85.4 (± 14.7) mmHg. Cardiac markers (troponin-t, creatine kinase (CK), lactate dehydrogenase (LDH), pro-brain natriuretic peptide II (pro-BNP II)) as well as creatinine levels determined in laboratory examinations of the STEMI group showed elevated levels overall compared to the laboratory reference values (Table 1 ). Markers for inflammatory processes such as C-reactive protein (CRP), leukocyte count, eGC components, and complement activation were increased in the STEMI group compared to healthy controls. On average, patients were hospitalized for 8 (± 3) days before being discharged from the hospital. Table 1 Characteristics of STEMI group STEMI group (n = 63) Age (years) 64 (13) Male sex (%) 76.2 Hypertension (%) 79.0 Diabetes (%) 65.5 BMI (kg/m²) 27.4 (4.5) pos. family history (%) 86.7 Hyperlipidemia (%) 88.9 Smoking (%) 62.3 Number of cardiovascular risk factors (%) 1–2 34.9 3–4 57.2 > 4 7.9 Door-to-Balloon time (min) 55.5 (27.2) Door-to-Needle (min) 11.7 (7.8) Puncture-to-Balloon (min) 31.3 (16.3) Door-to-Balloon time (%) ≤ 60 min 66.7 > 60 min 33.3 > 90 min 14.3 Killip class (%) I-II 30.2 III-IV 69.9 heart rate (1/min) 102.6 (15.3) RR systolic (mmHg) 85.4 (14.7) RR diastolic (mmHg) 54.3 (14.5) Anterior infarction (%) 65.1 LV EF (%) 48.71 LV EF (goups) 50% 37.8 Days until discharge 8.4 (3.7) Troponin max. (pg/ml) [Ref.: 0–14] 3053.0 (2653) CK max. (U/l) [Ref.: 20–200] 1100.8 (1464) LDH max. (U/l) [Ref.: 135–225] 446.6 (318.9) Pro BNP II (pg/ml) [Ref.: 0-121] 1972.7 (2614) Creatinine (mg/dl) [Ref.: 0.7–1.2] 2.19 (0.9) inflammatory markers CRP max. (mg/l) [Ref.: 0–5] 45.4 (48.0) Leukocytes (Gpt/l) [Re.: 4–9] 17.41 (4.6) eGC height (nm) 125.9 (32.8) eGC stiffness (pN/nm) 0.34 (0.05) Syndecan-1 (ng/ml) 136.72 (69.3) Heparan sulfate (ng/ml) 10.82 (8.6) Hyaluronic acid (µg/ml) 182.9 (85.9) Nitric Oxide (mM) 6.39 (2.3) Angiopoetin-2 (ng/ml) 18.5 (8.7) C3a (ng/ml) 676.0 (343.4) C5a (ng/ml) 36.2 (27.0) STEMI: ST-elevation myocardial infarction; BMI: body mass index; Pos. family history: positive family history of myocardial infarction; RR: (Riva-Rocci) Blood pressure; LV EF: left ventricular ejection fraction; CK: creatine kinase; LDH: lactate dehydrogenase; BNP: brain natriuretic peptide; CRP: c-reactive protein C3a: Complement factor C3a; C5a: Complement factor C5a; eGC: endothelial glycocalyx. Data in mean ± standard deviation (m ± SD); categorical data in percentage (%). Ref.: laboratory reference values Please insert Table 1 here STEMI leads to eGC damage and endothelial dysfunction The nanomechanical properties (height and stiffness) of the eGC were quantified using the AFM nanoindentation technique. Height of eGC was 38% lower in the STEMI group than in the CTR group (p < 0.001; Fig. 1 A). eGC stiffness was reduced by 17% in the STEMI group compared to CTR (p < 0.001; Fig. 1 B). Overall, the levels of shedded glycocalyx constituents measured via ELISA were elevated in the STEMI group: mean syndecan-1 levels in the CTR group were 35.5 ng/ml (± 10.4 ng/ml) whereas the STEMI mean levels were about four times higher (136.72 ± 69.3 ng/ml; p < 0.0001; Fig. 1 C). Mean heparan sulfate levels were 4.6 ng/ml (± 3.6 ng/ml) in the CTR group, with the amount of detected heparan sulfate being twice as high in the STEMI group (10.82 ± 8.6 ng/ml; p < 0.001; Fig. 1 D). Additionally, the measured levels of hyaluronic acid (hyaluronan) were elevated by 44% in the STEMI group compared to healthy CTR (p < 0.0001; Fig. 1 E). NO x were measured using the NOAnalyzer-280i. Levels of NO x were lower in the STEMI group than in the CTR group by about 34% (6.4 vs. 9.7; p < 0.001; Fig. 1 F). Correlations between the individual parameters were determined with the help of regression analyses. eGC height was positively associated with eGC stiffness (r = .918, p < 0.001; Fig. 1 G). Days until discharge from hospital were negatively correlated to both eGC height (r = .572; p < 0.001; Fig. 1 H) and eGC stiffness (r = .674; p 60 min leads to eGC damage and prolonged hospitalization Patients were divided into two cohorts according to their D2B time (≤ 60 vs. > 60 min). In order to maintain a better overview, the group with a D2B time ≤ 60 min will be referred to as BELOW in the following, the group with a D2B time > 60 minutes as the ABOVE group. In all, 34% of the STEMI group had a D2B of > 60 min (Table 2 ). There was no statistically significant difference between the two groups in terms of age, sex, or CVRF. There was a nonsignificant trend towards higher rates of Killip class III and IV (28.6% vs 71.4%; p = 0.066) between the BELOW and the ABOVE group (Table 2 ). eGC height was reduced by 16% in the ABOVE compared to the BELOW group (124.9 vs. 106.8 nm; p < 0.001; Fig. 2 A). Stiffness of eGC was higher in the BELOW than in the ABOVE group (0.35 vs. 0.3 pN/nm; p < 0.001; Fig. 2 B). Levels of syndecan-1 were elevated by 53% (p = 0.02; Fig. 2 C) and troponin levels were twice as high (p < 0.01; Fig. 2 D) in the ABOVE group. Door-to-needle time at 9.8 (± 11.9) min as well as puncture-to-balloon time at 25.1 (± 21.6) min were shorter in the BELOW than in the ABOVE group (Table 2 ). D2B negatively correlated with both eGC height (r = .516; p < 0.001; Fig. 2 E) and eGC stiffness (r = .586; p < 0.001; Fig. 2 F). Positive correlations could be shown between the D2B and syndecan-1 levels (r = .637; Fig. 2 G) as well as with number of days until discharge from hospital (r = .426; Fig. 2 H). Table 2 Characteristics of patients with Door-to-Balloon Time ≤ 60 min vs > 60 min. D2B ≤ 60 min (n = 42) D2B > 60 min (n = 21) p-value Age (years) 66 (11) 63 (12) .422 Male sex (%) 71.4 78.6 .530 Hypertension (%) 70.0 83.3 .228 Diabetes (%) 29.4 36.8 .287 BMI (kg/m²) 25.9 (5.3) 28.0 (3.9) .087 pos. family history (%) 80.9 90.4 .591 Hyperlipidemia (%) 85.7 90.5 .321 Smoking (%) 63.2 61.9 .925 Door-to-Balloon time (min) 39.2 (21.7) 88.0 (8.4) < 0.001 Door-to-Needle (min) 9.8 (11.9) 17.0 (4.6) < 0.01 Puncture-to-Balloon (min) 25.1 (21.6) 43.7 (7.4) < 0.001 Killip class I-II 31.0 28.6 .066 III-IV 69.0 71.4 heart rate (1/min) 100.7 (16.0) 106.1 (13.5) .183 RR systolic (mmHg) 86.1 (14.4) 83.9 (15.5) .581 RR diastolic (mmHg) 54.1 (14.4) 54.6 (15.1) .904 LV EF (%) 49.32 47.36 .619 LV EF (goups) 50% 35.7 37.8 Days until discharge 7.9 (3.4) 9.3 (3.8) .162 Troponin max. (ng/ml) 1.7 (2.2) 3.5 (2.7) < 0.01 CK max. (U/l) 800.5 0(1350) 1250.9 (1511) .253 LDH max. (U/l) 413.9 (275.4) 462.5 (340.1) .580 Pro BNP II (pg/ml) 1752.7 (2993) 2440.3 (1611) .551 Creatinine (mg/dl) 2.08 (1.4) 2.39 (0.5) .237 inflammatory markers CRP max. (mg/l) 40.9 (58.3) 54.4 (42.1) .296 Leukocytes (Gpt/l) 11.54 (4.0) 12.37 (5.7) .634 eGC height (nm) 124.9 (16.9) 106.8 (34.9) < 0.001 eGC stiffness (pN/nm) 0.35 (0.04) 0.30 (0.05) < 0.001 Syndecan-1 (ng/ml) 118.11 (88.1) 173.95 (49.0) 0.02 Heparan sulfate (ng/ml) 7.99 (3.2) 12.24 (10.1) .065 Hyaluronic acid (µg/ml) 174.9 (90.8) 198.9 (83.3) .300 Nitric Oxide (mM) 6.12 (2.6) 6.88 (2.1) .253 Angiopoetin-2 (ng/ml) 17.7 (9.6) 20.1 (8.3) .302 C3a (ng/ml) 643.0 (385.3) 972.2 (262.5) < 0.001 C5a (ng/ml) 38.3 (28.7) 61.4 (22.7) < 0.001 D2B: Door-to-Balloon time; BMI: body mass index; Pos. family history: positive family history of myocardial infarction; RR: (Riva-Rocci) Blood pressure; LV EF: left ventricular ejection fraction; CK: creatine kinase; LDH: lactate dehydrogenase; BNP: brain natriuretic peptide; CRP: c-reactive protein C3a: Complement factor C3a; C5a: Complement factor C5a; eGC: endothelial glycocalyx. Data in mean ± standard deviation (m ± SD); categorical data in percentage (%). P-values are shown in bold for variables with p < 0.05. In addition to markers for vascular inflammation such as eGC height and stiffness further inflammatory markers such as CRP and leukocyte count showed elevated levels compared to the laboratory reference values (Table 2 ), although there were no significant differences between ABOVE and BELOW. Prolonged D2B, however, led to significant activation of the complement system in the ABOVE group with elevated levels of C3a (972.2 ± 262.5 ng/ml, p < 0.001) and C5a (61.4 ± 22.7 ng/ml, p < 0.001) (Table 2 ). Please insert Table 2 here High syndecan-1 levels are associated with unfavorable outcomes for eGC and patients Patients were divided into two cohorts according to their syndecan-1 levels according to the findings of Wernly et al. (2019) 13 . In the further course of this report, the group with syndecan-1 levels ≤ 120 ng/ml will be referred to as LOW and the group with syndecan-1 levels > 120 ng/ml as HIGH. In the STEMI group, 54% had syndecan-1 levels > 120 ng/ml (Table 3 ). Comparisons between the LOW and HIGH group showed no statistically significant differences in terms of age, sex, CVRF, Killip classification, or LVEF (Table 3 ). There were, however, nonsignificant trends towards higher levels of ProBNP II (p = 0.069), creatinine (p = 0.067), and CRP (p = 0.08) in the HIGH compared to the LOW group (Table 3 ). eGC height and stiffness were reduced in the HIGH compared to the LOW group: eGC height by 32% (151.3 vs. 104.4 nm; p < 0.001; Fig. 3 A) and eGC stiffness by 24% (0.38 vs. 0.29 pN/nm; p < 0.001; Fig. 3 B). In addition to the D2B time (63.9 ± 31.3 minutes; p = 0.006; Fig. 3 C) also door-to-needle time (13.9 ± 9.7 minutes, p = 0.033; Table 3 ) of the HIGH group was longer than times of the LOW group. Patients with syndecan-1 levels > 120ng/ml stayed in the hospital longer than those in the LOW group (10 vs. 6 days until discharge from hospital; p < 0.001; Fig. 3 D). eGC height (r = .924; p < 0.001; Fig. 3 E) and eGC stiffness (r = .811; p < 0.001; Fig. 3 F) correlated significantly with syndecan-1 levels. Furthermore, there was a linear relationship between the syndecan-1 levels and the days until discharge of r = .709 (p 120 ng/ml Syn-1 ≤ 120 ng/ml (n = 29) Syn-1 > 120 ng/ml (n = 34) p-value Age (years) 66 (13) 63 (12) .306 Male sex (%) 79.3 73.5 .591 Hypertension (%) 79.3 78.8 .960 Diabetes (%) 53.8 75.9 .086 BMI (kg/m²) 27.9 (4.0) 26.9 (4.9) .396 pos. family history (%) 85.7 87.5 .919 Hyperlipidemia (%) 93.1 85.3 .326 Smoking (%) 58.6 65.6 .573 Door-to-Balloon (min) 45.5 (17.1) 63.9 (31.3) < 0.01 Door-to-Needle (min) 9.5 (4.7) 13.9 (9.7) 0.033 Puncture-to-Balloon (min) 30.2 (11.5) 32.3 (19.6) .627 Killip class I-II 31.0 29.4 .290 III-IV 69.0 70.6 heart rate (1/min) 101.1 (16.2) 103.8 (14.6) .480 RR systolic (mmHg) 86.6 (14.1) 84.4 (15.4) .574 RR diastolic (mmHg) 51.8 (12.1) 56.3 (14.5) .230 LV EF (%) 49.41 48.04 .708 LV EF (goups) 50% 36.4 39.1 Days until discharge 6.3 10.2 < 0.001 Troponin max. (ng/ml) 2.8 (3.0) 3.3 (2.4) .467 CK max. (U/l) 239.0 (861.9) 759.1 (1767) < 0.01 LDH max. (U/l) 386.4 (265.1) 497.7 (354.3) .176 Pro BNP II (pg/ml) 986.8 (1279) 2882.9 (3210) .069 Creatinine (mg/dl) 2.43 (1.4) 1.98 (0.2) .067 inflammatory markers CRP max. (mg/l) 43.8 (39.7) 46.8 (54.7) .080 Leukocytes (Gpt/l) 11.16 (3.7) 12.24 (5.2) .357 eGC height (nm) 151.3 (32.0) 104.4 (10.5) < 0.001 eGC stiffness (pN/nm) 0.38 (0.03) 0.29 (0.02) < 0.001 Syndecan-1 (ng/ml) 88.93 (28.3) 177.49 (67.9) < 0.001 Heparan sulfate (ng/ml) 6.88 (10.8) 11.67 (2.5) < 0.001 Hyaluronic acid (µg/ml) 198.4 (107.2) 169.7 (60.8) .188 Nitric Oxide (mM) 6.14 (2.2) 6.60 (2.3) .468 Angiopoetin-2 (ng/ml) 20.1 (9.1) 17.2 (8.4) .183 C3a (ng/ml) 505.5 (144.6) 963.6 (322.9) < 0.001 C5a (ng/ml) 30.5 (11.6) 59.1 (29.5) < 0.001 Syn-1: Syndecan-1; BMI: body mass index; Pos. family history: positive family history of myocardial infarction; RR: (Riva-Rocci) Blood pressure; LV EF: left ventricular ejection fraction; CK: creatine kinase; LDH: lactate dehydrogenase; BNP: brain natriuretic peptide; CRP: c-reactive protein C3a: Complement factor C3a; C5a: Complement factor C5a; eGC: endothelial glycocalyx. Data in mean ± standard deviation (m ± SD); categorical data in percentage (%). P-values are shown in bold for variables with p < 0.05. Levels of heparan sulfate (11.67 ± 2.5 ng/ml; p < 0.001; Table 3 ) and CK (759.1 ± 1767 U/l; p < 0.01; Table 3 ) were elevated in the HIGH group compared to the LOW group. There was a significant elevation of inflammatory markers in the HIGH group compared to the laboratory reference values. Furthermore, the HIGH group showed an activation of the complement system with elevated levels of C3a (963.6 ± 322.9 ng/ml, p < 0.001) and C5a (59.1 ± 29.5 ng/ml, p < 0.001) (Table 3 ). Please insert Table 3 here Discussion The current study aimed to investigate the relationship between a prolonged D2B time and eGC damage in the case of cardiogenic shock during STEMI. Particular attention was paid to the relationships between eGC damage and endothelial dysfunction with regard to the D2B. Multiple studies have demonstrated the importance of the shortest possible period of time between the first medical contact and revascularization in acute myocardial infarction 9,18 , but to our knowledge there is no published data showing a temporal link between myocardial infarction and endothelial injury. Acute ischemic syndromes such as STEMI ultimately lead to cardiogenic shock with advancing time. 19 A cut-off of < 60 min D2B time was used in accordance with the current guidelines and an overall association of a D2B over 60 min with higher morbidity and mortality. 20,21 Using AFM for quantifying the nanomechanical properties (height/stiffness) of the eGC, our data shows that the endothelial surface is injured during STEMI, causing deterioration of the eGC. For the first time we could demonstrate that a shorter D2B time is associated both with fewer changes in the nanomechanical properties of the eGC (r = .516) and lower concentrations of syndecan-1 (r = .637), indicating less damage to the eGC. The eGC damage and loss of endothelial function was significantly lower in the group of patients with a D2B of under 60 min. Furthermore, shorter D2B resulted in a shorter hospitalization. Although it has been shown that cardiac I/R severely damages the eGC, which can be detected by increased circulating levels of its principal constituents 13,22 , until now there were no published data that have demonstrated a temporal relationship between eGC components and the D2B. A prolonged D2B may thus cause more severe damage to the eGC, which might be the “stumbling block” to severe cardiac IRI ultimately leading to cardiogenic shock. A reduction in eGC height and stiffness indicates eGC shedding 23 . Shedding of eGC is known to be caused by different factors that are elevated and activated during cardiac IRI and cardiogenic shock 24 . Those factors are associated with cardiac mechanical stress, generalized vascular trauma, and an increased inflammatory response 11,25 , as indicated by proinflammatory mediators such as interleukins 26 , catecholamines 27 , angiopoetin-2 28 , CRP 29 , leukocytes 25 , matrix metalloproteinases (MMP) 26 , or the complement system. 30 This inflammation-mediated response results in cell death of the ischemic tissue and subsequent long-term consequences such as postinfarction heart failure with the hallmarks of cardiac fibrosis and heart dysfunction. 31 In the present study, the strong correlations between eGC impairment and the elevated levels of CRP, leukocyte count, and elevation of the complement anaphylatoxins indicate a proinflammatory response. The process of eGC shedding is further underpinned by elevated levels of the eGC components (syndecan-1, heparan sulfate, and hyaluronic acid) measured in the STEMI sera, indicating elevated levels of MMPs, and by the strong correlation between eGC height and stiffness (r = .918). High syndecan-1 levels have been found to be an independent predictor for outcome in patients with STEMI independent of the infarct-related myocardial injury 13 and are an independent predictor of mortality in cardiogenic shock. 32 Compared to healthy individuals, syndecan-1 concentrations were significantly higher in STEMI patients. This effect is mostly explained by the activation of MMPs, which have been shown to be commonly upregulated in cardiac IRI triggering glycocalyx damage. 33 The exact physiological and pathophysiological role of syndecan-1 in cardiac IRI are beyond the scope of this paper; however, this matter was dealt with in detail in previous work of our group. 11 In this context, it can be hypothesized that increased syndecan-1 indicates eGC shedding after STEMI, impairing eGC and vascular function and leading to adverse outcomes. The same applies to increased levels of other eGC components such as heparan sulfate or hyaluronic acid. Syndecan-1 levels > 120 ng/ml have been shown to be independently associated with higher 6-month mortality after STEMI 13 . In our cohort 54% of the STEMI patients showed an elevation of this magnitude. Without analyzing mortality as an endpoint in this study, a prolonged hospital stay suggests that patients with an elevated syndecan-1 level > 120ng/ml were significantly more severely ill than patients with lower syndecan-1 levels. Likewise, there was a strong interaction between nanomechanical properties of the eGC and syndecan-1 levels, which further correlated with a prolonged D2B time, indicating a time dependency of the eGC damage during STEMI. This time dependency of eGC damage could be explained by an overall prolonged inflammatory response in the phase of chronic inflammation after myocardial ischemia. 34 The deterioration of the eGC also correlated with the degree of NO release - the hallmark for endothelial dysfunction. 35 In a functional endothelium NO is released by the endothelial cells themselves and diffuses to adjacent vascular smooth muscle cells (VSMC) where it triggers vasodilation via cyclic guanosine monophosphate (cGMP)-dependent pathways. 36 Here, the reduction in NO production demonstrates the link between the altered nanomechanical properties of the eGC and the beginning of endothelial dysfunction during STEMI. The disruption in eGC integrity in cardiac IRI has been documented in the meantime 2 , but, to date, no satisfactory cardioprotective therapy against IRI is available for daily clinical practice 37 . Here, protecting the eGC in the case of STEMI and cardiogenic shock leads to less eGC damage, resulting in turn in less cardiac IRI, which has previously been demonstrated by using a recombinant syndecans-1 as an eGC recovering agent. 11 Our study has established the basis for further investigations to illustrate the important role that the eGC plays in the development of cardiac IRI. Despite all previous knowledge, the eGC still represents an underestimated factor in the development of cardiac IRI. On the one hand, this is due to the complex and multi-layered cell biological background and mechanisms of eGC damage in cardiac IRI 3 , but, on the other, also to the limited translatability from basic research to clinical practice, both for diagnostic options and pharmacological approaches to managing IRI. 37 Our AFM-based methodology is time consuming and sophisticated, which precludes analyzing considerably larger, random sets of samples; however, there are approaches for meaningful analysis of the eGC status that can be probed in everyday clinical practice: For example, by visualizing the sublingual microcirculation the integrity of the glycocalyx could be assessed indirectly and could represent an important diagnostic tool to measure eGC integrity in the future and further predict the outcome of STEMI patients. 38 The association between sublingual microcirculation parameters and eGC dimensions has already been demonstrated for critically ill patients. 39 It is now known that the study of microcirculation parameters and eGC dimensions is an important part of the assessment of septic patients. 40 So far, however, this need has not been demonstrated for patients in cardiogenic shock. Here, we establish the basis for further investigations and illustrate the important role the eGC condition plays in the development of cardiac IRI in the event of STEMI. Conclusion In our study, we could show that eGC shedding and the D2B are associated in a time-dependent manner after STEMI. In addition, levels of syndecan-1 and proinflammatory mediators correlated with prolonged D2B, eGC damage, and endothelial dysfunction and could therefore be important factors for risk stratification of cardiac IRI. A combination of clinical evaluation of the eGC condition and levels of biomarkers such as syndecan-1 might serve as important predictor for eGC impairment of STEMI patients with cardiogenic shock in the future. Future clinical studies should evaluate the prognostic value of eGC protection or restoration in the case of cardiogenic shock due to myocardial infarction. Limitations of the Study There are potential limitations of our interpretation: the number of patients and therefore serum samples used for the in vitro studies are limited. This relates to the fact that the AFM nanoindentation technique is time consuming and sophisticated, which precludes analysis of considerably larger random sets of samples. The present experimental design ignores the potential influence of hemodynamics (e.g., circulating fluid, shear stress, etc.). Abbreviations ABOVE group with a D2B time > 60 minutes AFM atomic force microscope BELOW group with a D2B time ≤ 60 minutes BMI body-mass-index C3a complement factor C3a C5a complement factor C5a cGMP cyclic guanosine monophosphate CK creatine kinase CRP c-reactive protein CTR control CVRF cardiovascular risk-factor D2B Door-to-Balloon time ECLS extracorporeal life support ECMO extracorporeal membrane oxygenation eGC endothelial Glycocalyx ELISA Enzyme-Linked Immunosorbent Assay ESC European Society of Cardiology FDC force distance curve HCl hydrochloric acid HIGH group with syndecan-1 levels ≤ 120 ng/ml HUVEC human umbilical vein endothelial cells I/R ischemia-reperfusion ICU intensive care unit IRI ischemia-reperfusion injury LDH lactate dehydrogenase LOW group with syndecan-1 levels ≤ 120 ng/ml LVEF left-ventricular ejection-fraction MMP matrix metalloproteinases NO nitric oxide PCI percutaneous coronary intervention Pro-BNP II Pro-brain natriuretic peptide II ROSC return of spontaneous circulation RR Riva-Rocci, blood pressure SD Standart deviation STEMI ST-elevation myocardial infarction Syn-1 syndecan-1 VSMC vascular smooth muscle cells Declarations Ethics approval and consent to participate Ethics approval and approval was given by the local ethics committee of the University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany. Blood samples and patient data: Case 19-310; Extraction and use of primary human umbilical vein endothelial cells: Case 18-325 Consent for publication Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests Funding This work was supported by a research grant of the German Cardiac Society to CV; grants from the Deutsche Forschungsgemeinschaft (KU1496/7-1, KU1496/7-3, INST392/141-1) to KKV. Authors' contributions All authors contributed to the manuscript. Conceptualization: CV, BF and KK-V; methodology: CV, BF, SL and LN; software: CV, BF and SL; analysis: CV and SL; investigation: CV, LN and JW; writing - original draft preparation: CV; writing - review and editing: CV, BF, SL, LN, JW and KK-V; visualization: CV and BF; supervision: KK-V and JW; project administration: CV and KK-V; funding acquisition: CV and KK-V. All authors have read and agreed to the published version of the manuscript. Acknowledgements We would like to thank all involved laboratory technicians of the University of Luebeck, as well as all involved clinicians of the Sana Kliniken Luebeck (intensive care unit; catheter laboratory) for their support of this study. We thank Univ.-Prof. Dr. rer. biol. hum. Inke R. König for statistical consultation. The authors gratefully acknowledge Sherryl Sundell for language editing. References Cosgun ZC, Fels B, Kusche-Vihrog K. Nanomechanics of the Endothelial Glycocalyx: From Structure to Function. Am J Pathol. 2020;190(4):732–741. doi: 10.1016/j.ajpath.2019.07.021 Abassi Z, Armaly Z, Heyman SN. Glycocalyx Degradation in Ischemia-Reperfusion Injury. Am J Pathol. 2020;190(4):752–767. doi: 10.1016/j.ajpath.2019.08.019 Ferdinandy P, Andreadou I, Baxter GF, Bøtker HE, Davidson SM, Dobrev D, Gersh BJ, Heusch G, Lecour S, Ruiz-Meana M, Zuurbier CJ, Hausenloy DJ, Schulz R. Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning. Pharmacol Rev. 2023;75(1):159–216. doi: 10.1124/pharmrev.121.000348 Simonis G, Strasser RH, Ebner B. Reperfusion injury in acute myocardial infarction. Crit Care. 2012;16(2):A22. doi: 10.1186/cc11280 Lee SJ, Lee CK, Kang S, Park I, Kim YH, Kim SK, Hong SP, Bae H, He Y, Kubota Y, Koh GY. Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction. J Clin Invest. 2018;128(11):5018–5033. doi: 10.1172/JCI99659 Rehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, Chappell D, Stoeckelhuber M, Welsch U, Reichart B, Peter K, Becker BF. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation. 2007;116(17):1896–1906. doi: 10.1161/CIRCULATIONAHA.106.684852 Jaffe R, Karkabi B, Goldenberg I, Shlomo N, Vorobeichik D, Zafrir B, Shiran A, Adawi S, Iakobishvili Z, Beigel R, Rubinshtein R, Flugelman MY. Avoidance of Coronary Angiography in High-Risk Patients With Acute Coronary Syndromes: The ACSIS Registry Findings. Cardiovasc Revascularization Med Mol Interv. 2020;21(10):1230–1236. doi: 10.1016/j.carrev.2019.12.021 Pedersen S, Galatius S, Mogelvang R, Davidsen U, Galloe A, Abildstrom SZ, Abildgaard U, Hansen PR, Bech J, Iversen A, Jorgensen E, Kelbaek H, Saunamaki K, Madsen JK, Jensen JS. Long-term prognosis in an ST-segment elevation myocardial infarction population treated with routine primary percutaneous coronary intervention: from clinical trial to real-life experience. Circ Cardiovasc Interv. 2009;2(5):392–400. doi: 10.1161/CIRCINTERVENTIONS.108.845636 Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimský P, ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–177. doi: 10.1093/eurheartj/ehx393 Thiele H, Desch S, de Waha S. Akuter Myokardinfarkt bei Patienten mit ST-Strecken-Hebungs-Infarkt. Herz. 2017;42(8):728–738. doi: 10.1007/s00059-017-4641-7 Vahldieck C, Cianflone E, Fels B, Löning S, Depelmann P, Sabatino J, Salerno N, Karsten CM, Torella D, Weil J, Sun D, Goligorsky MS, Kusche-Vihrog K. Endothelial Glycocalyx and Cardiomyocyte Damage Is Prevented by Recombinant Syndecan-1 in Acute Myocardial Infarction. Am J Pathol. 2023;193(4):474–492. doi: 10.1016/j.ajpath.2022.12.009 Tkachenko E, Rhodes JM, Simons M. Syndecans: new kids on the signaling block. Circ Res. 2005;96(5):488–500. doi: 10.1161/01.RES.0000159708.71142.c8 Wernly B, Fuernau G, Masyuk M, Muessig JM, Pfeiler S, Bruno RR, Desch S, Muench P, Lichtenauer M, Kelm M, Adams V, Thiele H, Eitel I, Jung C. Syndecan-1 Predicts Outcome in Patients with ST-Segment Elevation Infarction Independent from Infarct-related Myocardial Injury. Sci Rep. 2019;9(1):18367. doi: 10.1038/s41598-019-54937-x Jung C, Fuernau G, Muench P, Desch S, Eitel I, Schuler G, Adams V, Figulla HR, Thiele H. Impairment of the endothelial glycocalyx in cardiogenic shock and its prognostic relevance. Shock Augusta Ga. 2015;43(5):450–455. doi: 10.1097/SHK.0000000000000329 Pilarczyk K, Werdan K, Russ M, Thiele H, Michels G, Boeken U, Thielmann M. The German-Austrian S3 Guideline “Cardiogenic Shock Due to Myocardial Infarction: Diagnosis, Monitoring, and Treatment.” Thorac Cardiovasc Surg. 2021;69(8):684–692. doi: 10.1055/s-0040-1719155 Fels B, Acharya S, Vahldieck C, Graf T, Käding N, Rupp J, Kusche-Vihrog K. Mineralocorticoid receptor-antagonism prevents COVID-19-dependent glycocalyx damage. Pflugers Arch. 2022;474(10):1069–1076. doi: 10.1007/s00424-022-02726-3 Killip T, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol. 1967;20(4):457–464. doi: 10.1016/0002-9149(67)90023-9 Wong GC, Welsford M, Ainsworth C, Abuzeid W, Fordyce CB, Greene J, Huynh T, Lambert L, Le May M, Lutchmedial S, Mehta SR, Natarajan M, Norris CM, Overgaard CB, Perry Arnesen M, Quraishi A, Tanguay JF, Traboulsi M, van Diepen S, Welsh R, Wood DA, Cantor WJ, members of the Secondary Panel. 2019 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Guidelines on the Acute Management of ST-Elevation Myocardial Infarction: Focused Update on Regionalization and Reperfusion. Can J Cardiol. 2019;35(2):107–132. doi: 10.1016/j.cjca.2018.11.031 Holmes DR, Berger PB, Hochman JS, Granger CB, Thompson TD, Califf RM, Vahanian A, Bates ER, Topol EJ. Cardiogenic Shock in Patients With Acute Ischemic Syndromes With and Without ST-Segment Elevation. Circulation. 1999;100(20):2067–2073. doi: 10.1161/01.CIR.100.20.2067 Hudson MP, Armstrong PW, O’Neil WW, Stebbins AL, Weaver WD, Widimsky P, Aylward PE, Ruzyllo W, Holmes D, Mahaffey KW, Granger CB. Mortality implications of primary percutaneous coronary intervention treatment delays: insights from the Assessment of Pexelizumab in Acute Myocardial Infarction trial. Circ Cardiovasc Qual Outcomes. 2011;4(2):183–192. doi: 10.1161/CIRCOUTCOMES.110.945311 Karkabi B, Meir G, Zafrir B, Jaffe R, Adawi S, Lavi I, Flugelman MY, Shiran A. Door-to-balloon time and mortality in patients with ST-elevation myocardial infarction undergoing primary angioplasty. Eur Heart J - Qual Care Clin Outcomes. 2021;7(4):422–426. doi: 10.1093/ehjqcco/qcaa037 Bruegger D, Brettner F, Rossberg I, Nussbaum C, Kowalski C, Januszewska K, Becker BF, Chappell D. Acute degradation of the endothelial glycocalyx in infants undergoing cardiac surgical procedures. Ann Thorac Surg. 2015;99(3):926–931. doi: 10.1016/j.athoracsur.2014.10.013 Fels J, Kusche-Vihrog K. Endothelial Nanomechanics in the Context of Endothelial (Dys)function and Inflammation. Antioxid Redox Signal. 2019;30(7):945–959. doi: 10.1089/ars.2017.7327 Lassus J, Tarvasmäki T, Tolppanen H. Biomarkers in cardiogenic shock. Adv Clin Chem. 2022;109:31–73. doi: 10.1016/bs.acc.2022.03.002 Seropian IM, Sonnino C, Van Tassell BW, Biasucci LM, Abbate A. Inflammatory markers in ST-elevation acute myocardial infarction. Eur Heart J Acute Cardiovasc Care. 2016;5(4):382–395. doi: 10.1177/2048872615568965 Wu Y, Pan N, An Y, Xu M, Tan L, Zhang L. Diagnostic and Prognostic Biomarkers for Myocardial Infarction. Front Cardiovasc Med. 2021;7:617277. doi: 10.3389/fcvm.2020.617277 Ostrowski SR, Pedersen SH, Jensen JS, Mogelvang R, Johansson PI. Acute myocardial infarction is associated with endothelial glycocalyx and cell damage and a parallel increase in circulating catecholamines. Crit Care Lond Engl. 2013;17(1):R32. doi: 10.1186/cc12532 Pöss J, Fuernau G, Denks D, Desch S, Eitel I, de Waha S, Link A, Schuler G, Adams V, Böhm M, Thiele H. Angiopoietin-2 in acute myocardial infarction complicated by cardiogenic shock–a biomarker substudy of the IABP-SHOCK II-Trial. Eur J Heart Fail. 2015;17(11):1152–1160. doi: 10.1002/ejhf.342 Kusche-Vihrog K, Urbanova K, Blanqué A, Wilhelmi M, Schillers H, Kliche K, Pavenstädt H, Brand E, Oberleithner H. C-reactive protein makes human endothelium stiff and tight. Hypertens Dallas Tex 1979. 2011;57(2):231–237. doi: 10.1161/HYPERTENSIONAHA.110.163444 Bavia L, Lidani KCF, Andrade FA, Sobrinho MIAH, Nisihara RM, de Messias-Reason IJ. Complement activation in acute myocardial infarction: An early marker of inflammation and tissue injury? Immunol Lett. 2018;200:18–25. doi: 10.1016/j.imlet.2018.06.006 Fang Z, Li X, Liu J, Lee H, Salciccioli L, Lazar J, Zhang M. The role of complement C3 in the outcome of regional myocardial infarction. Biochem Biophys Rep. 2023;33:101434. doi: 10.1016/j.bbrep.2023.101434 Jung C, Fuernau G, Muench P, Desch S, Eitel I, Schuler G, Adams V, Figulla HR, Thiele H. Impairment of the endothelial glycocalyx in cardiogenic shock and its prognostic relevance. Shock Augusta Ga. 2015;43(5):450–455. doi: 10.1097/SHK.0000000000000329 Serraino GF, Jiritano F, Costa D, Ielapi N, Battaglia D, Bracale UM, Mastroroberto P, Andreucci M, Serra R. Metalloproteinases in Cardiac Surgery: A Systematic Review. Biomolecules. 2023;13(1):113. doi: 10.3390/biom13010113 Riehle C, Bauersachs J. Key inflammatory mechanisms underlying heart failure. Herz. 2019;44(2):96–106. doi: 10.1007/s00059-019-4785-8 Fels J, Callies C, Kusche-Vihrog K, Oberleithner H. Nitric oxide release follows endothelial nanomechanics and not vice versa. Pflugers Arch. 2010;460(5):915–923. doi: 10.1007/s00424-010-0871-8 Fels B, Kusche-Vihrog K. It takes more than two to tango: mechanosignaling of the endothelial surface. Pflugers Arch. 2020;472(4):419–433. doi: 10.1007/s00424-020-02369-2 Wang Q, Zuurbier CJ, Huhn R, Torregroza C, Hollmann MW, Preckel B, van den Brom CE, Weber NC. Pharmacological Cardioprotection against Ischemia Reperfusion Injury-The Search for a Clinical Effective Therapy. Cells. 2023;12(10):1432. doi: 10.3390/cells12101432 Duranteau J, De Backer D, Donadello K, Shapiro NI, Hutchings SD, Rovas A, Legrand M, Harrois A, Ince C. The future of intensive care: the study of the microcirculation will help to guide our therapies. Crit Care Lond Engl. 2023;27(1):190. doi: 10.1186/s13054-023-04474-x Rovas A, Lukasz AH, Vink H, Urban M, Sackarnd J, Pavenstädt H, Kümpers P. Bedside analysis of the sublingual microvascular glycocalyx in the emergency room and intensive care unit - the GlycoNurse study. Scand J Trauma Resusc Emerg Med. 2018;26(1):16. doi: 10.1186/s13049-018-0483-4 Rovas A, Sackarnd J, Rossaint J, Kampmeier S, Pavenstädt H, Vink H, Kümpers P. Identification of novel sublingual parameters to analyze and diagnose microvascular dysfunction in sepsis: the NOSTRADAMUS study. Crit Care Lond Engl. 2021;25(1):112. doi: 10.1186/s13054-021-03520-w Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3234193","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":224491105,"identity":"7fc88b6f-8e06-46d6-982f-86d9b2fc391e","order_by":0,"name":"Carl Vahldieck","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYHACxgNAIoGPIbGBgeGADYMEAw8DCOEFYC1sEC1pJGlJADEPE9bC3372wQHGNrs8Nvbkxgc/zpxPnNl/9gDDmwrcWiTOpBsAtSQXs/E8bDbsuXE7cbZEXgLjnDO4tRgwpAEddoY5sU0isU2a4cPtxHkSPAbMvG14tPA/A2mpB2lp/83w4VziPP4zQC3/8GiRANlScRhsCzPDjQOJsxlygFoa8PjlBtCWhIrjiW1Av0j2nEk2njkjx+DgnGO4tfD3pzE++GBQndjPnv7ww49jdrIzzp8xfPCmBrcWMEhAFzhAQMMoGAWjYBSMAgIAAKD8V9tsmgRPAAAAAElFTkSuQmCC","orcid":"","institution":"University Medical Centre Schleswig-Holstein Campus Luebeck","correspondingAuthor":true,"prefix":"","firstName":"Carl","middleName":"","lastName":"Vahldieck","suffix":""},{"id":224491106,"identity":"b8ea31f6-df94-4db4-b228-d2b964d033c0","order_by":1,"name":"Benedikt Fels","email":"","orcid":"","institution":"University of Luebeck","correspondingAuthor":false,"prefix":"","firstName":"Benedikt","middleName":"","lastName":"Fels","suffix":""},{"id":224491107,"identity":"f423c6ad-4b02-4a65-b56f-3f00dadaf7d9","order_by":2,"name":"Samuel Löning","email":"","orcid":"","institution":"University of Luebeck","correspondingAuthor":false,"prefix":"","firstName":"Samuel","middleName":"","lastName":"Löning","suffix":""},{"id":224491108,"identity":"1d9055bf-bac7-4b85-85bb-57ab468ba9d5","order_by":3,"name":"Laura Nickel","email":"","orcid":"","institution":"Medizinische Klinik II, Sana Kliniken Luebeck","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Nickel","suffix":""},{"id":224491109,"identity":"11cba989-461b-4ce1-a5cb-6c40162a248a","order_by":4,"name":"Joachim Weil","email":"","orcid":"","institution":"Medizinische Klinik II, Sana Kliniken Luebeck","correspondingAuthor":false,"prefix":"","firstName":"Joachim","middleName":"","lastName":"Weil","suffix":""},{"id":224491110,"identity":"8f6794b9-b312-4bb4-93cc-d9b0319f7853","order_by":5,"name":"Kristina Kusche-Vihrog","email":"","orcid":"","institution":"University of Luebeck","correspondingAuthor":false,"prefix":"","firstName":"Kristina","middleName":"","lastName":"Kusche-Vihrog","suffix":""}],"badges":[],"createdAt":"2023-08-04 09:44:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3234193/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3234193/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":41380405,"identity":"b43a4990-3b11-4589-a1ef-58a77ba7e186","added_by":"auto","created_at":"2023-08-10 15:21:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":239297,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eST-elevation myocardial infarction (STEMI) leads to endothelial glycocalyx (eGC) damage and endothelial dysfunction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEndothelial glycocalyx (eGC) height (\u003cstrong\u003eA\u003c/strong\u003e) and eGC stiffness (\u003cstrong\u003eB\u003c/strong\u003e) measured via AFM nanoindentation technique. Each dot representing one patient/healthy control (n = 126; each dot showing a mean of 50-60 cells per patient). Serum levels of syndecan-1 (\u003cstrong\u003eC\u003c/strong\u003e), heparan sulfate (\u003cstrong\u003eD\u003c/strong\u003e) and hyaluronic acid (hyaluronan) (\u003cstrong\u003eE\u003c/strong\u003e) were measured via ELISA. Nitric oxide (NO) products (\u003cstrong\u003eF\u003c/strong\u003e) were quantified via NO-Analyzer-280i. \u003cstrong\u003eA-F\u003c/strong\u003e: data showing mean ± SD.\u003c/p\u003e\n\u003cp\u003eCorrelation of eGC height vs. eGC stiffness (\u003cstrong\u003eG\u003c/strong\u003e) and days until discharge from hospital (\u003cstrong\u003eH\u003c/strong\u003e). Correlation of eGC stiffness vs. days until discharge from hospital (\u003cstrong\u003eI\u003c/strong\u003e). Direct comparison of individual eGC height of STEMI patients and age and sex matched controls (\u003cstrong\u003eJ\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGroups:\u003c/strong\u003e \u003cstrong\u003eCTR\u003c/strong\u003e (control) stimulation with cell culture media + 10 % serum of healthy controls; \u003cstrong\u003eSTEMI\u003c/strong\u003e (ST-elevation myocardial infarction) stimulation with media + 10 % serum of STEMI patients.\u003c/p\u003e\n\u003cp\u003eP-values: ****: p \u0026lt; 0.0001; ***: p \u0026lt; 0.001. Rho (r), p-values (p), coefficient of determination (R²) and curve-fit model shown for correlations.\u003c/p\u003e","description":"","filename":"FiguresDoorToBalloonVahldieck2308041.png","url":"https://assets-eu.researchsquare.com/files/rs-3234193/v1/610ddfb9328e188794a4df27.png"},{"id":41381345,"identity":"b56b629e-7938-44ff-ac5f-6f7a13467492","added_by":"auto","created_at":"2023-08-10 15:29:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":176421,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDoor to Balloon (D2B) time \u0026gt;60 minutes leads to endothelial glycocalyx (eGC) damage and prolonged hospitalization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSTEMI (ST-elevation myocardial infarction) patients were divided into cohorts: a) Door-to-Balloon time (D2B) ≤60 min; b) D2B \u0026gt;60 min. Endothelial glycocalyx (eGC) height (\u003cstrong\u003eA\u003c/strong\u003e) and eGC stiffness (\u003cstrong\u003eB\u003c/strong\u003e) measured via AFM nanoindentation technique. Each dot representing one patient/healthy control (n = 63; each dot showing a mean of 50-60 cells per patient). Quantification of syndecan-1 (\u003cstrong\u003eC\u003c/strong\u003e), and troponin-t (\u003cstrong\u003eD\u003c/strong\u003e) serum levels.\u003c/p\u003e\n\u003cp\u003eCorrelation of D2B vs. eGC height (\u003cstrong\u003eE\u003c/strong\u003e), eGC stiffness (\u003cstrong\u003eF\u003c/strong\u003e), syndecan-1 levels (\u003cstrong\u003eG\u003c/strong\u003e) and days until discharge from hospital (\u003cstrong\u003eH\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eP-values: *; p \u0026lt; 0.05; **: p \u0026lt; 0.01; ***: p \u0026lt; 0.001. Rho (r), p-values (p), coefficient of determination (R²) and curve-fit model shown for correlations.\u003c/p\u003e","description":"","filename":"FiguresDoorToBalloonVahldieck2308042.png","url":"https://assets-eu.researchsquare.com/files/rs-3234193/v1/5330af0d9763cfe4ef6a79df.png"},{"id":41380406,"identity":"5a20babf-7c75-43ba-b00b-8a4c8c99cc77","added_by":"auto","created_at":"2023-08-10 15:21:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":164565,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHigh Syndecan-1 is associated with unfavorable outcomes for endothelial glycocalyx (eGC) and patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSTEMI (ST-elevation myocardial infarction) patients were divided into cohorts: a) syndecan-1 levels ≤120 ng /ml; b) syndecan-1 levels \u0026gt;120 ng/ml. Endothelial glycocalyx (eGC) height (\u003cstrong\u003eA\u003c/strong\u003e) and eGC stiffness (\u003cstrong\u003eB\u003c/strong\u003e) measured via AFM nanoindentation technique. Each dot representing one patient/healthy control (n = 63; each dot showing a mean of 50-60 cells per patient). Group differences between a) vs. b) concerning Door-to-balloon (D2B) time (\u003cstrong\u003eC\u003c/strong\u003e) and days until discharge from hospital (\u003cstrong\u003eD\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eCorrelation of syndecan-1 levels vs. eGC height (\u003cstrong\u003eE\u003c/strong\u003e), eGC stiffness (\u003cstrong\u003eF\u003c/strong\u003e) and days until discharge from hospital (\u003cstrong\u003eG\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eP-values: **: p \u0026lt; 0.01; ***: p \u0026lt; 0.001. Rho (r), p-values (p), coefficient of determination (R²) and curve-fit model shown for correlations.\u003c/p\u003e","description":"","filename":"FiguresDoorToBalloonVahldieck2308043.png","url":"https://assets-eu.researchsquare.com/files/rs-3234193/v1/f2909018478647c18fa16166.png"},{"id":41574293,"identity":"1139eed0-fdc2-46a5-b845-a3bf2e75e9a7","added_by":"auto","created_at":"2023-08-15 10:07:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1369240,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3234193/v1/6991efc3-7c22-4828-8013-7cdbdabf98a5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prolonged Door-to-Balloon time leads to glycocalyx damage and endothelial dysfunction in patients with ST-Elevation Myocardial Infarction and cardiogenic shock","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe endothelial glycocalyx (eGC) and the cellular cortex (CTX) of endothelial cells (EC) provide a protective barrier on top of these cells. Thus, changes in their mechanical properties might induce endothelial dysfunction.\u003csup\u003e1\u003c/sup\u003e A possible cause of such alterations of the endothelial surface is ischemia-reperfusion (I/R) injury (IRI), a protracted, but reversible interruption in blood supply and tissue oxygenation leading to organ damage.\u003csup\u003e2,3\u003c/sup\u003e IRI causes rapid dismantling of the microvascular eGC in all tissues and its degradation might be the earliest form of structural damage in I/R.\u003csup\u003e2\u003c/sup\u003e Furthermore, cardiac IRI contributes to up to 50% of the final infarct size, thus playing a significant role in the development of cardiogenic shock.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eeGC damage in the context of cardiac IRI has been demonstrated in the setting of acute myocardial infarction with cardiogenic shock followed by cardiac interventions, both in experimental and clinical settings.\u003csup\u003e5,6\u003c/sup\u003e In ST-elevation myocardial infarction (STEMI), rapid revascularization was shown to reduce in-hospital and long-term mortality as well as decrease the number of nonfatal complications in numerous studies.\u003csup\u003e7,8\u003c/sup\u003e The time interval between a patient entering the medical system and revascularization to open the occluded, culprit vessel is termed \u0026ldquo;Door-to-Balloon\u0026rdquo;-time (D2B). The preferred mode of revascularization is primary percutaneous coronary intervention (PCI) and, as recommended by the European Society of Cardiology (ESC), the gold standard time from hospital entry to PCI (D2B) is \u0026le;\u0026thinsp;60 min for PCI-capable hospitals to prevent ischemic cardiogenic shock from progressing further.\u003csup\u003e9,10\u003c/sup\u003e Our group previously reported damage to the eGC in the case of STEMI with syndecan-1 as a biomarker for IRI.\u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe eGC component syndecan-1 (Syn-1; CD138), a transmembrane proteoglycan that builds the structural backbone of the eGC, is damaged during STEMI. Syndecan-1 acts as a core unit for other eGC components such as heparan sulfate and hyaluronic acid and transmits extracellular signals to the intracellular environment of endothelial cells through its transmembrane domain, which is directly associated with the actin cytoskeleton of the endothelial cell cortex.\u003csup\u003e11,12\u003c/sup\u003e Furthermore, syndecan-1 can be used as a biomarker of eGC damage after revascularization as it is independently associated with 6-month mortality after STEMI\u003csup\u003e13\u003c/sup\u003e and represents an independent predictor of 30-day mortality in cardiogenic shock\u003csup\u003e14\u003c/sup\u003e.Time-to-revascularization as well as levels of eGC components are important predictors in the development of cardiogenic shock. By implementing direct access to catheterization laboratories and bypassing the emergency department, the time from first medical contact to PCI has been reduced over the past few years and there is general consensus that a shorter D2B is associated with a better prognosis.\u003csup\u003e9,10\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, up to now, the relationship between D2B duration and eGC damage/endothelial dysfunction is unknown. The purpose of this study therefore was to investigate whether a prolonged D2B had an impact on eGC damage in cardiogenic shock or whether it is associated with unfavorable outcomes for endothelial function in STEMI patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003e In this study, 63 consecutive patients with a first onset of STEMI were included at the University of Luebeck in cooperation with the intensive care unit (ICU) of the Department of Cardiology and Angiology of the Sana-Kliniken-Luebeck-hospital, Germany, in accordance with the Declaration of Helsinki and approved by the Local Ethics Committee (Case: 19\u0026ndash;310). Informed consent was obtained from each patient.\u003c/p\u003e \u003cp\u003eAll patients received emergency coronary angiography and PCI as first-line therapy with subsequent treatment in the ICU after STEMI was diagnosed. The diagnosis of STEMI was based on the criteria of the Guidelines on Management of Acute Myocardial Infarction in Patients Presenting with ST-Segment Elevation of the ESC.\u003csup\u003e10\u003c/sup\u003e Cardiogenic shock was evaluated by the attending physician according to clinical signs (e.g. cyanotic extremities, signs of cerebral hypoperfusion with somnolence/confusion) as well as hemodynamic signs (e.g. systolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;90 mmHg, administration of catecholamines) based on the German-Austrian S3-Guideline \u0026ldquo;Cardiogenic Shock Due to Myocardial Infarction\u0026rdquo;.\u003csup\u003e15\u003c/sup\u003e Blood samples were collected during emergency PCI (hereafter termed STEMI group). Sixty-three age- and sex-matched volunteers without cardiovascular comorbidities served as controls (hereafter termed CTR group).\u003c/p\u003e \u003cp\u003ePatients undergoing cardiopulmonary resuscitation or patients after gaining a return of spontaneous circulation (ROSC) were excluded, as were patients who died during or after PCI. Patients requiring extracorporeal membrane oxygenation/extracorporeal life support (ECMO/ECLS) were also excluded. Further exclusion criteria were age below 18 years or pregnancy.\u003c/p\u003e \u003cp\u003eSerum samples from patients and controls were immediately treated according to the manufacturer\u0026rsquo;s information (S-Monovette\u0026reg;, Sarstedt, N\u0026uuml;mbrecht, Germany). Therefore, samples were kept on ice and centrifuged at 4\u0026deg;C within 60 min after collection. Afterwards the samples were snap-frozen and stored at -80\u0026deg;C.\u003c/p\u003e \u003cp\u003eFor D2B analysis, patients were retrospectively divided into two groups: i) D2B\u0026thinsp;\u0026le;\u0026thinsp;60 min; ii) D2B\u0026thinsp;\u0026gt;\u0026thinsp;60 min. The D2B was defined as the time interval between the STEMI patient entering the emergency room and the time of the first balloon dilatation in the catheter laboratory. The cut-off of 60 min was chosen in accordance with the recommendations of the ESC guidelines for PCI-capable hospitals.\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eCell isolation and culture\u003c/h2\u003e \u003cp\u003ePrimary human umbilical vein endothelial cells (HUVEC) were isolated (approved by the local ethical committee; Case: 18\u0026ndash;325) and cultured as described previously\u003csup\u003e11,16\u003c/sup\u003e. Cells were cultured in HUVEC culture medium (Gibco Medium 199)\u0026thinsp;+\u0026thinsp;10% fetal calf serum (Gibco, Carlsbad, CA)\u0026thinsp;+\u0026thinsp;penicillin/streptomycin 1% (Gibco, Carlsbad, CA; 100 U/ml; 100 mg/ml)\u0026thinsp;+\u0026thinsp;heparin 5000 U/ml (Biochrom, Schaffhausen, Switzerland)\u0026thinsp;+\u0026thinsp;large-vessel endothelial supplement 1% (Gibco, Carlsbad, CA, USA). Cell culture flasks were coated with 0.5% gelatin (Sigma-Aldrich, St. Louis, MO, USA) 1 h before seeding and cultivated at 37\u0026deg;C, 21% O\u003csub\u003e2\u003c/sub\u003e, and 5% CO\u003csub\u003e2\u003c/sub\u003e. For experiments HUVEC were cultivated on fibronectin-coated glass coverslips to confluence for at least 4 days under standard cell culture conditions and stimulated with 10% STEMI or CTR sera for 24 h prior to the experiment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAtomic force microscopy\u003c/h2\u003e \u003cp\u003eThe thickness and stiffness of the eGC were determined by using the AFM nanoindentation technique, as described previously\u003csup\u003e11\u003c/sup\u003e. Indentation measurements were performed on living confluent HUVEC at 37\u0026deg;C using a Nanoscope Multimode-8 AFM (Bruker Nano GmbH, Berlin, Germany).\u003c/p\u003e \u003cp\u003eBriefly, a laser beam was aligned on the back of a gold-coated triangular cantilever (Novascan Technologies, Boone, North Carolina, United States) with a mounted spherical tip (diameter 10 \u0026micro;m) and a nominal spring constant of 10 pN/nm. The cantilever indents the endothelial cell surface with a loading force of 0.5 nN. The reflection of a laser beam is used to quantify the cantilever deflection. The height of the eGC can be calculated by knowing the cantilever force, the piezo displacement, and the deflection sensitivity. For each patient and control serum a total of two repetitions with 25\u0026ndash;30 cells were measured. For each cell 6\u0026ndash;8 force distance curves (FDC) were generated and averaged, resulting in n\u0026thinsp;=\u0026thinsp;600 to 960 FDC per individual. FDC data were collected with the Research NanoScope version 9.20 (64 bit; Bruker Nano GmbH). The stiffness and thickness of the eGC were calculated using the protein unfolding and nanoindentation analysis software Punias 3D (Version 1.0; Release 2.3; Copyright 2009).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEnzyme-linked immunosorbent assay\u003c/h2\u003e \u003cp\u003eIn addition to the standard clinical laboratory examinations of the patient's blood, additional parameters in the serum of the patients were determined via enzyme-linked immunosorbent assay (ELISA).\u003c/p\u003e \u003cp\u003eTo determine the dissolved glycocalyx constituents, syndecan-1, heparan sulfate, and hyaluronic acid (hyaluronan) concentrations were measured. (\u003cem\u003esyndecan-1\u003c/em\u003e: Human CD138 ELISA kit, Diaclone Research, Cedex, France; catalog: 950.640.192 / \u003cem\u003eheparan sulfate\u003c/em\u003e: Human Heparan sulfate Proteoglycan (HSPG) ELISA Kit, MBS, San Diego, California, USA; catalog: MBS2023323 / \u003cem\u003ehyaluronan\u003c/em\u003e: Hyaluronan Quantikine ELISA Kit, R\u0026amp;D Systems, Minneapolis, Minnesota, USA; catalog: DHYAL0). Angiopoetin-2 was quantified using a Human Angiopoietin-2 Quantikine ELISA Kit (R\u0026amp;D Systems, Minneapolis, Minnesota, USA; catalog: DANG20). Activation of the complement system was measured by quantifying the anaphylatoxins C3a and C5a (Thermo Fisher Scientific, Hamburg, Germany; C3a, catalog: BMS2089; C5a, catalog: BMS2088).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eNitric oxide product measurements\u003c/h2\u003e \u003cp\u003eFor measuring total nitrate and nitrite in the STEMI and CTR sera, the chemiluminescence detector Sievers Nitric Oxide Analyzer (NOA-280i; GE Water \u0026amp; Process Technologies, Analytic Instruments; Boulder, Colorado, USA) was used. Subsequent procedures were performed according to the operation and maintenance manual (Firmware Version 3.00 and later) provided by the manufacturer. The assay is based on the reduction of all nitrates and nitrites into nitric oxide (NO) by vanadium (III) chloride. NO reacts with ozone inside the NOA-280i to produce nitrogen dioxide (NO\u003csub\u003e2\u003c/sub\u003e), which is sensitively detected by virtue of its chemiluminescence.\u003c/p\u003e \u003cp\u003eNO products (NO\u003csub\u003ex\u003c/sub\u003e) of the STEMI and CTR sera were analyzed by injecting 50 \u0026micro;L of each serum sample into a purge vessel containing a solution of vanadium (III) chloride (50 mmol/L; Sigma-Aldrich, Germany) in hydrochloric acid (HCl) (1 mol/L; Sigma-Aldrich, Germany) at 95\u0026deg;C, continuously purged with a stream of nitrogen gas, connected to the NOA-280i. A gas bubbler between the purge vessel and the NOA-280i was filled with 15 mL of 1 M aqueous NaOH solution (Sigma-Aldrich, Germany) to prevent HCl vapors from entering the NOA-280i. Concentrations were calculated using the manufacturer\u0026rsquo;s NOAnalysis Software for Liquid (Version 3.21/Liquid, GE Water \u0026amp; Process Technologies, Analytic Instruments; Boulder, Colorado, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using IBM SPSS Statistics for Windows (IBM Corp. Released 2020, Version 28.0.1 Armonk, New York, USA) and the 2D graphic and biostatistics software GraphPad PRISM (Version 8.4.2, GraphPad Software Inc., California, USA). GraphPad PRISM was also used to prepare the figures. Gaussian distribution was determined by D'Agostino \u0026amp; Pearson omnibus normality test and presented graphically via quantile-quantile plot (Q-Q Plot). Data with no proven linearity were plotted, and the curves were fitted to determine the interrelationships of the function. The best-fit model was implemented. Data were tested for outliers before applying statistical tests using the ROUT outlier test based on the false discovery rate (FDR; Q value\u0026thinsp;=\u0026thinsp;1%). Outliers were omitted from further analysis.\u003c/p\u003e \u003cp\u003eDifferences between two groups were analyzed using Student\u0026rsquo;s t-test for parametric values. For nonparametric values, the Mann-Whitney test (for unpaired data) or the Wilcoxon matched-pairs signed-rank test (paired data) was applied. Group differences at the nominal scale level were measured using Cramer-V. Categorical variables were compared by using the chi-squared test. Correlations at ordinal scale level were measured using Spearman, at metric scale level using Pearson correlations (with Rho (r); coefficient of determination (R\u0026sup2;)). With a sample size of n\u0026thinsp;=\u0026thinsp;63, a statistical power of 0.8. and a significance level of α\u0026thinsp;=\u0026thinsp;0.05, a correlation of r\u0026thinsp;=\u0026thinsp;0.344 was needed for a significant result.\u003c/p\u003e \u003cp\u003ePatients were retrospectively divided into cohorts: a) D2B\u0026thinsp;\u0026le;\u0026thinsp;60 vs. \u0026gt;60 min in accordance with the recommendations of the European Society of Cardiology guidelines (ESC) for PCI-capable hospitals\u003csup\u003e9\u003c/sup\u003e; b) syndecan-1 levels\u0026thinsp;\u0026le;\u0026thinsp;120 vs. \u0026gt;120 ng/ml in accordance to the findings of Wernly et al.\u003csup\u003e13\u003c/sup\u003e. Killip classification was determined on admission and carried out according to Kilipp and Kimball (1967).\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDifferences were considered statistically significant when p-values were \u0026lt;\u0026thinsp;0.05 (*: p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; **: p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; ***: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; ****: p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Confidence level was set at 95%. Data are presented as absolute values of mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (m\u0026thinsp;\u0026plusmn;\u0026thinsp;SD). Boxplots show first quartile, mean, and third quartile; whiskers show minimum and maximum values.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of STEMI group\u003c/h2\u003e \u003cp\u003eThe patients in the STEMI group (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) were 64 (\u0026plusmn;\u0026thinsp;13) years old on average and predominantly male (76%). All of them presented with at least one cardiovascular risk factor (CVRF: male sex, hypertension, diabetes, obesity, a positive family history of myocardial infarction, hyperlipidemia, uremia, or active smoking), and 65% had more than 3 CVRF. The average D2B was 55.5 (\u0026plusmn;\u0026thinsp;27.2) min, whereby D2B was less than 60 min in 66% and more than 90 min in 14%. In 69% a Killip classification of III or IV was calculated on admission, with 38% of the patients having a preserved left-ventricular ejection fraction (LVEF) of over 50%. Reduced LVEF was diagnosed in 16%. The average systolic blood pressure was 85.4 (\u0026plusmn;\u0026thinsp;14.7) mmHg. Cardiac markers (troponin-t, creatine kinase (CK), lactate dehydrogenase (LDH), pro-brain natriuretic peptide II (pro-BNP II)) as well as creatinine levels determined in laboratory examinations of the STEMI group showed elevated levels overall compared to the laboratory reference values (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Markers for inflammatory processes such as C-reactive protein (CRP), leukocyte count, eGC components, and complement activation were increased in the STEMI group compared to healthy controls. On average, patients were hospitalized for 8 (\u0026plusmn;\u0026thinsp;3) days before being discharged from the hospital.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of STEMI group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSTEMI group (n\u0026thinsp;=\u0026thinsp;63)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale sex (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypertension (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiabetes (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI (kg/m\u0026sup2;)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.4 (4.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003epos. family history (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHyperlipidemia (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eNumber of cardiovascular risk factors (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1\u0026ndash;2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3\u0026ndash;4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDoor-to-Balloon time (min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.5 (27.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDoor-to-Needle (min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.7 (7.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePuncture-to-Balloon (min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.3 (16.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eDoor-to-Balloon time (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;\u003cb\u003e60 min\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;60 min\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;90 min\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eKillip class (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eI-II\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIII-IV\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eheart rate (1/min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e102.6 (15.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRR systolic (mmHg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85.4 (14.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRR diastolic (mmHg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.3 (14.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnterior infarction (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLV EF (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eLV EF (goups)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;40%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e40\u0026ndash;50%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;50%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDays until discharge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.4 (3.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTroponin max. (pg/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e[Ref.: 0\u0026ndash;14]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3053.0 (2653)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCK max. (U/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e[Ref.: 20\u0026ndash;200]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1100.8 (1464)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH max. (U/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e[Ref.: 135\u0026ndash;225]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e446.6 (318.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePro BNP II (pg/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e[Ref.: 0-121]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1972.7 (2614)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCreatinine (mg/dl)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e[Ref.: 0.7\u0026ndash;1.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.19 (0.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003einflammatory markers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRP max. (mg/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e[Ref.: 0\u0026ndash;5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45.4 (48.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLeukocytes (Gpt/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e[Re.: 4\u0026ndash;9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.41 (4.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eeGC height (nm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125.9 (32.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eeGC stiffness (pN/nm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.34 (0.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSyndecan-1 (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e136.72 (69.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeparan sulfate (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.82 (8.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHyaluronic acid (\u0026micro;g/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e182.9 (85.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNitric Oxide (mM)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.39 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAngiopoetin-2 (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.5 (8.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC3a (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e676.0 (343.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC5a (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.2 (27.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eSTEMI: ST-elevation myocardial infarction; BMI: body mass index; Pos. family history: positive family history of myocardial infarction; RR: (Riva-Rocci) Blood pressure; LV EF: left ventricular ejection fraction; CK: creatine kinase; LDH: lactate dehydrogenase; BNP: brain natriuretic peptide; CRP: c-reactive protein C3a: Complement factor C3a; C5a: Complement factor C5a; eGC: endothelial glycocalyx. Data in mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (m\u0026thinsp;\u0026plusmn;\u0026thinsp;SD); categorical data in percentage (%). Ref.: laboratory reference values\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003ePlease insert\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003ehere\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSTEMI leads to eGC damage and endothelial dysfunction\u003c/h2\u003e \u003cp\u003eThe nanomechanical properties (height and stiffness) of the eGC were quantified using the AFM nanoindentation technique. Height of eGC was 38% lower in the STEMI group than in the CTR group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). eGC stiffness was reduced by 17% in the STEMI group compared to CTR (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOverall, the levels of shedded glycocalyx constituents measured via ELISA were elevated in the STEMI group: mean syndecan-1 levels in the CTR group were 35.5 ng/ml (\u0026plusmn;\u0026thinsp;10.4 ng/ml) whereas the STEMI mean levels were about four times higher (136.72\u0026thinsp;\u0026plusmn;\u0026thinsp;69.3 ng/ml; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Mean heparan sulfate levels were 4.6 ng/ml (\u0026plusmn;\u0026thinsp;3.6 ng/ml) in the CTR group, with the amount of detected heparan sulfate being twice as high in the STEMI group (10.82\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6 ng/ml; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). Additionally, the measured levels of hyaluronic acid (hyaluronan) were elevated by 44% in the STEMI group compared to healthy CTR (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). NO\u003csub\u003ex\u003c/sub\u003e were measured using the NOAnalyzer-280i. Levels of NO\u003csub\u003ex\u003c/sub\u003e were lower in the STEMI group than in the CTR group by about 34% (6.4 vs. 9.7; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). Correlations between the individual parameters were determined with the help of regression analyses. eGC height was positively associated with eGC stiffness (r\u0026thinsp;=\u0026thinsp;.918, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG). Days until discharge from hospital were negatively correlated to both eGC height (r\u0026thinsp;=\u0026thinsp;.572; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eH) and eGC stiffness (r\u0026thinsp;=\u0026thinsp;.674; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI). eGC height of the STEMI group was lower in 97% of the cases in direct comparison to the individual patient\u0026rsquo;s age- and sex-matched controls (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eJ).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eD2B time\u0026thinsp;\u0026gt;\u0026thinsp;60 min leads to eGC damage and prolonged hospitalization\u003c/h2\u003e \u003cp\u003ePatients were divided into two cohorts according to their D2B time (\u0026le;\u0026thinsp;60 vs. \u0026gt; 60 min). In order to maintain a better overview, the group with a D2B time\u0026thinsp;\u0026le;\u0026thinsp;60 min will be referred to as BELOW in the following, the group with a D2B time\u0026thinsp;\u0026gt;\u0026thinsp;60 minutes as the ABOVE group.\u003c/p\u003e \u003cp\u003eIn all, 34% of the STEMI group had a D2B of \u0026gt;\u0026thinsp;60 min (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was no statistically significant difference between the two groups in terms of age, sex, or CVRF. There was a nonsignificant trend towards higher rates of Killip class III and IV (28.6% vs 71.4%; p\u0026thinsp;=\u0026thinsp;0.066) between the BELOW and the ABOVE group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). eGC height was reduced by 16% in the ABOVE compared to the BELOW group (124.9 vs. 106.8 nm; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Stiffness of eGC was higher in the BELOW than in the ABOVE group (0.35 vs. 0.3 pN/nm; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Levels of syndecan-1 were elevated by 53% (p\u0026thinsp;=\u0026thinsp;0.02; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC) and troponin levels were twice as high (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD) in the ABOVE group. Door-to-needle time at 9.8 (\u0026plusmn;\u0026thinsp;11.9) min as well as puncture-to-balloon time at 25.1 (\u0026plusmn;\u0026thinsp;21.6) min were shorter in the BELOW than in the ABOVE group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). D2B negatively correlated with both eGC height (r\u0026thinsp;=\u0026thinsp;.516; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE) and eGC stiffness (r\u0026thinsp;=\u0026thinsp;.586; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF). Positive correlations could be shown between the D2B and syndecan-1 levels (r\u0026thinsp;=\u0026thinsp;.637; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG) as well as with number of days until discharge from hospital (r\u0026thinsp;=\u0026thinsp;.426; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eH).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients with Door-to-Balloon Time\u0026thinsp;\u0026le;\u0026thinsp;60 min vs\u0026thinsp;\u0026gt;\u0026thinsp;60 min.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eD2B\u0026thinsp;\u0026le;\u0026thinsp;60 min (n\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eD2B\u0026thinsp;\u0026gt;\u0026thinsp;60 min (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.422\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale sex (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.530\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypertension (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.228\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiabetes (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.287\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI (kg/m\u0026sup2;)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.9 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.0 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003epos. family history (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.591\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHyperlipidemia (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.321\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.925\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDoor-to-Balloon time (min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.2 (21.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88.0 (8.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDoor-to-Needle (min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.8 (11.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.0 (4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePuncture-to-Balloon (min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.1 (21.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43.7 (7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eKillip class\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eI-II\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.066\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIII-IV\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eheart rate (1/min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100.7 (16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e106.1 (13.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.183\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRR systolic (mmHg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86.1 (14.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83.9 (15.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.581\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRR diastolic (mmHg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.1 (14.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54.6 (15.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.904\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLV EF (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.619\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eLV EF (goups)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;40%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e.817\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e40\u0026ndash;50%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;50%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDays until discharge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.9 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.3 (3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.162\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTroponin max. (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.7 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.5 (2.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCK max. (U/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e800.5 0(1350)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1250.9 (1511)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.253\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH max. (U/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e413.9 (275.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e462.5 (340.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.580\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePro BNP II (pg/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1752.7 (2993)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2440.3 (1611)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.551\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCreatinine (mg/dl)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.08 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.39 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.237\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003einflammatory markers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRP max. (mg/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.9 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54.4 (42.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.296\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLeukocytes (Gpt/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.54 (4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.37 (5.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.634\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eeGC height (nm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124.9 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e106.8 (34.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eeGC stiffness (pN/nm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.35 (0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30 (0.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSyndecan-1 (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118.11 (88.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e173.95 (49.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.02\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeparan sulfate (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.99 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.24 (10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.065\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHyaluronic acid (\u0026micro;g/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e174.9 (90.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e198.9 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.300\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNitric Oxide (mM)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.12 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.88 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.253\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAngiopoetin-2 (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.7 (9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20.1 (8.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.302\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC3a (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e643.0 (385.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e972.2 (262.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC5a (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.3 (28.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61.4 (22.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eD2B: Door-to-Balloon time; BMI: body mass index; Pos. family history: positive family history of myocardial infarction; RR: (Riva-Rocci) Blood pressure; LV EF: left ventricular ejection fraction; CK: creatine kinase; LDH: lactate dehydrogenase; BNP: brain natriuretic peptide; CRP: c-reactive protein C3a: Complement factor C3a; C5a: Complement factor C5a; eGC: endothelial glycocalyx. Data in mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (m\u0026thinsp;\u0026plusmn;\u0026thinsp;SD); categorical data in percentage (%). P-values are shown in bold for variables with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn addition to markers for vascular inflammation such as eGC height and stiffness further inflammatory markers such as CRP and leukocyte count showed elevated levels compared to the laboratory reference values (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), although there were no significant differences between ABOVE and BELOW. Prolonged D2B, however, led to significant activation of the complement system in the ABOVE group with elevated levels of C3a (972.2\u0026thinsp;\u0026plusmn;\u0026thinsp;262.5 ng/ml, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and C5a (61.4\u0026thinsp;\u0026plusmn;\u0026thinsp;22.7 ng/ml, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003ePlease insert\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cb\u003ehere\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eHigh syndecan-1 levels are associated with unfavorable outcomes for eGC and patients\u003c/h2\u003e \u003cp\u003ePatients were divided into two cohorts according to their syndecan-1 levels according to the findings of Wernly et al. (2019)\u003csup\u003e13\u003c/sup\u003e. In the further course of this report, the group with syndecan-1 levels\u0026thinsp;\u0026le;\u0026thinsp;120 ng/ml will be referred to as LOW and the group with syndecan-1 levels\u0026thinsp;\u0026gt;\u0026thinsp;120 ng/ml as HIGH.\u003c/p\u003e \u003cp\u003eIn the STEMI group, 54% had syndecan-1 levels\u0026thinsp;\u0026gt;\u0026thinsp;120 ng/ml (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Comparisons between the LOW and HIGH group showed no statistically significant differences in terms of age, sex, CVRF, Killip classification, or LVEF (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). There were, however, nonsignificant trends towards higher levels of ProBNP II (p\u0026thinsp;=\u0026thinsp;0.069), creatinine (p\u0026thinsp;=\u0026thinsp;0.067), and CRP (p\u0026thinsp;=\u0026thinsp;0.08) in the HIGH compared to the LOW group (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). eGC height and stiffness were reduced in the HIGH compared to the LOW group: eGC height by 32% (151.3 vs. 104.4 nm; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA) and eGC stiffness by 24% (0.38 vs. 0.29 pN/nm; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). In addition to the D2B time (63.9\u0026thinsp;\u0026plusmn;\u0026thinsp;31.3 minutes; p\u0026thinsp;=\u0026thinsp;0.006; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC) also door-to-needle time (13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7 minutes, p\u0026thinsp;=\u0026thinsp;0.033; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) of the HIGH group was longer than times of the LOW group. Patients with syndecan-1 levels\u0026thinsp;\u0026gt;\u0026thinsp;120ng/ml stayed in the hospital longer than those in the LOW group (10 vs. 6 days until discharge from hospital; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). eGC height (r\u0026thinsp;=\u0026thinsp;.924; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE) and eGC stiffness (r\u0026thinsp;=\u0026thinsp;.811; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eF) correlated significantly with syndecan-1 levels. Furthermore, there was a linear relationship between the syndecan-1 levels and the days until discharge of r\u0026thinsp;=\u0026thinsp;.709 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eG).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of patients with Syndecan-1 levels\u0026thinsp;\u0026le;\u0026thinsp;120 ng/ml vs\u0026thinsp;\u0026gt;\u0026thinsp;120 ng/ml\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSyn-1\u0026thinsp;\u0026le;\u0026thinsp;120 ng/ml (n\u0026thinsp;=\u0026thinsp;29)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSyn-1\u0026thinsp;\u0026gt;\u0026thinsp;120 ng/ml (n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 (13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.306\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale sex (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.591\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypertension (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.960\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiabetes (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.086\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI (kg/m\u0026sup2;)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.9 (4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.9 (4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.396\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003epos. family history (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.919\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHyperlipidemia (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e85.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.326\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.573\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDoor-to-Balloon (min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45.5 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63.9 (31.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDoor-to-Needle (min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.5 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.9 (9.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.033\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePuncture-to-Balloon (min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.2 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.3 (19.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.627\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKillip class\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eI-II\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e.290\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eIII-IV\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eheart rate (1/min)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e101.1 (16.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e103.8 (14.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.480\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRR systolic (mmHg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86.6 (14.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84.4 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.574\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRR diastolic (mmHg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.8 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56.3 (14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.230\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLV EF (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.708\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLV EF (goups)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;40%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e.758\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e40\u0026ndash;50%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;50%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDays until discharge\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTroponin max. (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.8 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.3 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.467\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCK max. (U/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e239.0 (861.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e759.1 (1767)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH max. (U/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e386.4 (265.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e497.7 (354.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.176\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePro BNP II (pg/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e986.8 (1279)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2882.9 (3210)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCreatinine (mg/dl)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.43 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.98 (0.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.067\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003einflammatory markers\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRP max. (mg/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.8 (39.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46.8 (54.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.080\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLeukocytes (Gpt/l)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.16 (3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12.24 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.357\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eeGC height (nm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e151.3 (32.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e104.4 (10.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eeGC stiffness (pN/nm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.38 (0.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.29 (0.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSyndecan-1 (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.93 (28.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e177.49 (67.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeparan sulfate (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.88 (10.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.67 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHyaluronic acid (\u0026micro;g/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e198.4 (107.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e169.7 (60.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.188\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNitric Oxide (mM)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.14 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.60 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.468\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAngiopoetin-2 (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.1 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.2 (8.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e.183\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC3a (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e505.5 (144.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e963.6 (322.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC5a (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.5 (11.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59.1 (29.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eSyn-1: Syndecan-1; BMI: body mass index; Pos. family history: positive family history of myocardial infarction; RR: (Riva-Rocci) Blood pressure; LV EF: left ventricular ejection fraction; CK: creatine kinase; LDH: lactate dehydrogenase; BNP: brain natriuretic peptide; CRP: c-reactive protein C3a: Complement factor C3a; C5a: Complement factor C5a; eGC: endothelial glycocalyx. Data in mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (m\u0026thinsp;\u0026plusmn;\u0026thinsp;SD); categorical data in percentage (%). P-values are shown in bold for variables with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eLevels of heparan sulfate (11.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5 ng/ml; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) and CK (759.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1767 U/l; p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) were elevated in the HIGH group compared to the LOW group. There was a significant elevation of inflammatory markers in the HIGH group compared to the laboratory reference values. Furthermore, the HIGH group showed an activation of the complement system with elevated levels of C3a (963.6\u0026thinsp;\u0026plusmn;\u0026thinsp;322.9 ng/ml, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and C5a (59.1\u0026thinsp;\u0026plusmn;\u0026thinsp;29.5 ng/ml, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003ePlease insert\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e \u003cb\u003ehere\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe current study aimed to investigate the relationship between a prolonged D2B time and eGC damage in the case of cardiogenic shock during STEMI. Particular attention was paid to the relationships between eGC damage and endothelial dysfunction with regard to the D2B. Multiple studies have demonstrated the importance of the shortest possible period of time between the first medical contact and revascularization in acute myocardial infarction\u003csup\u003e9,18\u003c/sup\u003e, but to our knowledge there is no published data showing a temporal link between myocardial infarction and endothelial injury. Acute ischemic syndromes such as STEMI ultimately lead to cardiogenic shock with advancing time.\u003csup\u003e19\u003c/sup\u003e A cut-off of \u0026lt;\u0026thinsp;60 min D2B time was used in accordance with the current guidelines and an overall association of a D2B over 60 min with higher morbidity and mortality.\u003csup\u003e20,21\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eUsing AFM for quantifying the nanomechanical properties (height/stiffness) of the eGC, our data shows that the endothelial surface is injured during STEMI, causing deterioration of the eGC. For the first time we could demonstrate that a shorter D2B time is associated both with fewer changes in the nanomechanical properties of the eGC (r\u0026thinsp;=\u0026thinsp;.516) and lower concentrations of syndecan-1 (r\u0026thinsp;=\u0026thinsp;.637), indicating less damage to the eGC. The eGC damage and loss of endothelial function was significantly lower in the group of patients with a D2B of under 60 min. Furthermore, shorter D2B resulted in a shorter hospitalization. Although it has been shown that cardiac I/R severely damages the eGC, which can be detected by increased circulating levels of its principal constituents\u003csup\u003e13,22\u003c/sup\u003e, until now there were no published data that have demonstrated a temporal relationship between eGC components and the D2B. A prolonged D2B may thus cause more severe damage to the eGC, which might be the \u0026ldquo;stumbling block\u0026rdquo; to severe cardiac IRI ultimately leading to cardiogenic shock.\u003c/p\u003e \u003cp\u003eA reduction in eGC height and stiffness indicates eGC shedding \u003csup\u003e23\u003c/sup\u003e. Shedding of eGC is known to be caused by different factors that are elevated and activated during cardiac IRI and cardiogenic shock\u003csup\u003e24\u003c/sup\u003e. Those factors are associated with cardiac mechanical stress, generalized vascular trauma, and an increased inflammatory response\u003csup\u003e11,25\u003c/sup\u003e, as indicated by proinflammatory mediators such as interleukins\u003csup\u003e26\u003c/sup\u003e, catecholamines\u003csup\u003e27\u003c/sup\u003e, angiopoetin-2\u003csup\u003e28\u003c/sup\u003e, CRP\u003csup\u003e29\u003c/sup\u003e, leukocytes\u003csup\u003e25\u003c/sup\u003e, matrix metalloproteinases (MMP)\u003csup\u003e26\u003c/sup\u003e, or the complement system.\u003csup\u003e30\u003c/sup\u003e This inflammation-mediated response results in cell death of the ischemic tissue and subsequent long-term consequences such as postinfarction heart failure with the hallmarks of cardiac fibrosis and heart dysfunction.\u003csup\u003e31\u003c/sup\u003e In the present study, the strong correlations between eGC impairment and the elevated levels of CRP, leukocyte count, and elevation of the complement anaphylatoxins indicate a proinflammatory response. The process of eGC shedding is further underpinned by elevated levels of the eGC components (syndecan-1, heparan sulfate, and hyaluronic acid) measured in the STEMI sera, indicating elevated levels of MMPs, and by the strong correlation between eGC height and stiffness (r\u0026thinsp;=\u0026thinsp;.918).\u003c/p\u003e \u003cp\u003eHigh syndecan-1 levels have been found to be an independent predictor for outcome in patients with STEMI independent of the infarct-related myocardial injury\u003csup\u003e13\u003c/sup\u003e and are an independent predictor of mortality in cardiogenic shock.\u003csup\u003e32\u003c/sup\u003e Compared to healthy individuals, syndecan-1 concentrations were significantly higher in STEMI patients. This effect is mostly explained by the activation of MMPs, which have been shown to be commonly upregulated in cardiac IRI triggering glycocalyx damage.\u003csup\u003e33\u003c/sup\u003e The exact physiological and pathophysiological role of syndecan-1 in cardiac IRI are beyond the scope of this paper; however, this matter was dealt with in detail in previous work of our group.\u003csup\u003e11\u003c/sup\u003e In this context, it can be hypothesized that increased syndecan-1 indicates eGC shedding after STEMI, impairing eGC and vascular function and leading to adverse outcomes. The same applies to increased levels of other eGC components such as heparan sulfate or hyaluronic acid. Syndecan-1 levels\u0026thinsp;\u0026gt;\u0026thinsp;120 ng/ml have been shown to be independently associated with higher 6-month mortality after STEMI\u003csup\u003e13\u003c/sup\u003e. In our cohort 54% of the STEMI patients showed an elevation of this magnitude. Without analyzing mortality as an endpoint in this study, a prolonged hospital stay suggests that patients with an elevated syndecan-1 level\u0026thinsp;\u0026gt;\u0026thinsp;120ng/ml were significantly more severely ill than patients with lower syndecan-1 levels. Likewise, there was a strong interaction between nanomechanical properties of the eGC and syndecan-1 levels, which further correlated with a prolonged D2B time, indicating a time dependency of the eGC damage during STEMI. This time dependency of eGC damage could be explained by an overall prolonged inflammatory response in the phase of chronic inflammation after myocardial ischemia.\u003csup\u003e34\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe deterioration of the eGC also correlated with the degree of NO release - the hallmark for endothelial dysfunction.\u003csup\u003e35\u003c/sup\u003e In a functional endothelium NO is released by the endothelial cells themselves and diffuses to adjacent vascular smooth muscle cells (VSMC) where it triggers vasodilation via cyclic guanosine monophosphate (cGMP)-dependent pathways.\u003csup\u003e36\u003c/sup\u003e Here, the reduction in NO production demonstrates the link between the altered nanomechanical properties of the eGC and the beginning of endothelial dysfunction during STEMI.\u003c/p\u003e \u003cp\u003eThe disruption in eGC integrity in cardiac IRI has been documented in the meantime\u003csup\u003e2\u003c/sup\u003e, but, to date, no satisfactory cardioprotective therapy against IRI is available for daily clinical practice\u003csup\u003e37\u003c/sup\u003e. Here, protecting the eGC in the case of STEMI and cardiogenic shock leads to less eGC damage, resulting in turn in less cardiac IRI, which has previously been demonstrated by using a recombinant syndecans-1 as an eGC recovering agent.\u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur study has established the basis for further investigations to illustrate the important role that the eGC plays in the development of cardiac IRI. Despite all previous knowledge, the eGC still represents an underestimated factor in the development of cardiac IRI. On the one hand, this is due to the complex and multi-layered cell biological background and mechanisms of eGC damage in cardiac IRI\u003csup\u003e3\u003c/sup\u003e, but, on the other, also to the limited translatability from basic research to clinical practice, both for diagnostic options and pharmacological approaches to managing IRI.\u003csup\u003e37\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur AFM-based methodology is time consuming and sophisticated, which precludes analyzing considerably larger, random sets of samples; however, there are approaches for meaningful analysis of the eGC status that can be probed in everyday clinical practice: For example, by visualizing the sublingual microcirculation the integrity of the glycocalyx could be assessed indirectly and could represent an important diagnostic tool to measure eGC integrity in the future and further predict the outcome of STEMI patients.\u003csup\u003e38\u003c/sup\u003e The association between sublingual microcirculation parameters and eGC dimensions has already been demonstrated for critically ill patients.\u003csup\u003e39\u003c/sup\u003e It is now known that the study of microcirculation parameters and eGC dimensions is an important part of the assessment of septic patients.\u003csup\u003e40\u003c/sup\u003e So far, however, this need has not been demonstrated for patients in cardiogenic shock. Here, we establish the basis for further investigations and illustrate the important role the eGC condition plays in the development of cardiac IRI in the event of STEMI.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn our study, we could show that eGC shedding and the D2B are associated in a time-dependent manner after STEMI. In addition, levels of syndecan-1 and proinflammatory mediators correlated with prolonged D2B, eGC damage, and endothelial dysfunction and could therefore be important factors for risk stratification of cardiac IRI. A combination of clinical evaluation of the eGC condition and levels of biomarkers such as syndecan-1 might serve as important predictor for eGC impairment of STEMI patients with cardiogenic shock in the future. Future clinical studies should evaluate the prognostic value of eGC protection or restoration in the case of cardiogenic shock due to myocardial infarction.\u003c/p\u003e "},{"header":"Limitations of the Study","content":"\u003cp\u003eThere are potential limitations of our interpretation: the number of patients and therefore serum samples used for the \u003cem\u003ein vitro\u003c/em\u003e studies are limited. This relates to the fact that the AFM nanoindentation technique is time consuming and sophisticated, which precludes analysis of considerably larger random sets of samples. The present experimental design ignores the potential influence of hemodynamics (e.g., circulating fluid, shear stress, etc.).\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eABOVE\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;group with a D2B time \u0026gt; 60 minutes\u003c/p\u003e\n\u003cp\u003eAFM\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;atomic force microscope\u003c/p\u003e\n\u003cp\u003eBELOW\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;group with a D2B time \u0026le; 60 minutes\u003c/p\u003e\n\u003cp\u003eBMI\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;body-mass-index\u003c/p\u003e\n\u003cp\u003eC3a\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;complement factor C3a\u003c/p\u003e\n\u003cp\u003eC5a\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;complement factor C5a\u003c/p\u003e\n\u003cp\u003ecGMP\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;cyclic guanosine monophosphate\u003c/p\u003e\n\u003cp\u003eCK\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;creatine kinase\u003c/p\u003e\n\u003cp\u003eCRP\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;c-reactive protein\u003c/p\u003e\n\u003cp\u003eCTR\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;control\u003c/p\u003e\n\u003cp\u003eCVRF\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;cardiovascular risk-factor\u003c/p\u003e\n\u003cp\u003eD2B\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Door-to-Balloon time\u003c/p\u003e\n\u003cp\u003eECLS\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;extracorporeal life support\u003c/p\u003e\n\u003cp\u003eECMO\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;extracorporeal membrane oxygenation\u003c/p\u003e\n\u003cp\u003eeGC\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;endothelial Glycocalyx\u003c/p\u003e\n\u003cp\u003eELISA\u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Enzyme-Linked Immunosorbent Assay\u003c/p\u003e\n\u003cp\u003eESC\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;European Society of Cardiology\u003c/p\u003e\n\u003cp\u003eFDC\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;force distance curve\u003c/p\u003e\n\u003cp\u003eHCl\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;hydrochloric acid\u003c/p\u003e\n\u003cp\u003eHIGH\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;group with syndecan-1 levels \u0026le; 120 ng/ml\u003c/p\u003e\n\u003cp\u003eHUVEC\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;human umbilical vein endothelial cells\u003c/p\u003e\n\u003cp\u003eI/R\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;ischemia-reperfusion\u003c/p\u003e\n\u003cp\u003eICU\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;intensive care unit\u003c/p\u003e\n\u003cp\u003eIRI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;ischemia-reperfusion injury\u003c/p\u003e\n\u003cp\u003eLDH\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;lactate dehydrogenase\u003c/p\u003e\n\u003cp\u003eLOW\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;group with syndecan-1 levels \u0026le; 120 ng/ml\u003c/p\u003e\n\u003cp\u003eLVEF\u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;left-ventricular ejection-fraction\u003c/p\u003e\n\u003cp\u003eMMP\u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;matrix metalloproteinases\u003c/p\u003e\n\u003cp\u003eNO\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;nitric oxide\u003c/p\u003e\n\u003cp\u003ePCI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;percutaneous coronary intervention\u003c/p\u003e\n\u003cp\u003ePro-BNP II\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Pro-brain natriuretic peptide II\u003c/p\u003e\n\u003cp\u003eROSC\u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;return of spontaneous circulation\u003c/p\u003e\n\u003cp\u003eRR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Riva-Rocci, blood pressure\u003c/p\u003e\n\u003cp\u003eSD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Standart deviation\u003c/p\u003e\n\u003cp\u003eSTEMI\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;ST-elevation myocardial infarction\u003c/p\u003e\n\u003cp\u003eSyn-1\u0026nbsp; \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;syndecan-1\u003c/p\u003e\n\u003cp\u003eVSMC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;vascular smooth muscle cells\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval and approval was given by the local ethics committee of the University of Luebeck, Ratzeburger Allee 160, 23562 Luebeck, Germany.\u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u003c/strong\u003eBlood samples and patient data: Case 19-310; Extraction and use of primary human umbilical vein endothelial cells: Case 18-325\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by a research grant of the German Cardiac Society to CV; grants from the Deutsche Forschungsgemeinschaft (KU1496/7-1, KU1496/7-3, INST392/141-1) to KKV.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the manuscript. Conceptualization: CV, BF and KK-V; methodology: CV, BF, SL and LN; software: CV, BF and SL; analysis: CV and SL; investigation: CV, LN and JW; writing - original draft preparation: CV; writing - review and editing: CV, BF, SL, LN, JW and KK-V; visualization: CV and BF; supervision: KK-V and JW; project administration: CV and KK-V; funding acquisition: CV and KK-V. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank all involved laboratory technicians of the University of Luebeck, as well as all involved clinicians of the Sana Kliniken Luebeck (intensive care unit; catheter laboratory) for their support of this study. We thank Univ.-Prof. Dr. rer. biol. hum. Inke R. K\u0026ouml;nig for statistical consultation. The authors gratefully acknowledge Sherryl Sundell for language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCosgun ZC, Fels B, Kusche-Vihrog K. Nanomechanics of the Endothelial Glycocalyx: From Structure to Function. Am J Pathol. 2020;190(4):732\u0026ndash;741. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajpath.2019.07.021\u003c/span\u003e\u003cspan address=\"10.1016/j.ajpath.2019.07.021\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbassi Z, Armaly Z, Heyman SN. Glycocalyx Degradation in Ischemia-Reperfusion Injury. Am J Pathol. 2020;190(4):752\u0026ndash;767. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajpath.2019.08.019\u003c/span\u003e\u003cspan address=\"10.1016/j.ajpath.2019.08.019\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFerdinandy P, Andreadou I, Baxter GF, B\u0026oslash;tker HE, Davidson SM, Dobrev D, Gersh BJ, Heusch G, Lecour S, Ruiz-Meana M, Zuurbier CJ, Hausenloy DJ, Schulz R. Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning. Pharmacol Rev. 2023;75(1):159\u0026ndash;216. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1124/pharmrev.121.000348\u003c/span\u003e\u003cspan address=\"10.1124/pharmrev.121.000348\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSimonis G, Strasser RH, Ebner B. Reperfusion injury in acute myocardial infarction. Crit Care. 2012;16(2):A22. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/cc11280\u003c/span\u003e\u003cspan address=\"10.1186/cc11280\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee SJ, Lee CK, Kang S, Park I, Kim YH, Kim SK, Hong SP, Bae H, He Y, Kubota Y, Koh GY. Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction. J Clin Invest. 2018;128(11):5018\u0026ndash;5033. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1172/JCI99659\u003c/span\u003e\u003cspan address=\"10.1172/JCI99659\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRehm M, Bruegger D, Christ F, Conzen P, Thiel M, Jacob M, Chappell D, Stoeckelhuber M, Welsch U, Reichart B, Peter K, Becker BF. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation. 2007;116(17):1896\u0026ndash;1906. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCULATIONAHA.106.684852\u003c/span\u003e\u003cspan address=\"10.1161/CIRCULATIONAHA.106.684852\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJaffe R, Karkabi B, Goldenberg I, Shlomo N, Vorobeichik D, Zafrir B, Shiran A, Adawi S, Iakobishvili Z, Beigel R, Rubinshtein R, Flugelman MY. Avoidance of Coronary Angiography in High-Risk Patients With Acute Coronary Syndromes: The ACSIS Registry Findings. Cardiovasc Revascularization Med Mol Interv. 2020;21(10):1230\u0026ndash;1236. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.carrev.2019.12.021\u003c/span\u003e\u003cspan address=\"10.1016/j.carrev.2019.12.021\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePedersen S, Galatius S, Mogelvang R, Davidsen U, Galloe A, Abildstrom SZ, Abildgaard U, Hansen PR, Bech J, Iversen A, Jorgensen E, Kelbaek H, Saunamaki K, Madsen JK, Jensen JS. Long-term prognosis in an ST-segment elevation myocardial infarction population treated with routine primary percutaneous coronary intervention: from clinical trial to real-life experience. Circ Cardiovasc Interv. 2009;2(5):392\u0026ndash;400. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCINTERVENTIONS.108.845636\u003c/span\u003e\u003cspan address=\"10.1161/CIRCINTERVENTIONS.108.845636\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIbanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsk\u0026yacute; P, ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119\u0026ndash;177. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/eurheartj/ehx393\u003c/span\u003e\u003cspan address=\"10.1093/eurheartj/ehx393\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThiele H, Desch S, de Waha S. Akuter Myokardinfarkt bei Patienten mit ST-Strecken-Hebungs-Infarkt. Herz. 2017;42(8):728\u0026ndash;738. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00059-017-4641-7\u003c/span\u003e\u003cspan address=\"10.1007/s00059-017-4641-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVahldieck C, Cianflone E, Fels B, L\u0026ouml;ning S, Depelmann P, Sabatino J, Salerno N, Karsten CM, Torella D, Weil J, Sun D, Goligorsky MS, Kusche-Vihrog K. Endothelial Glycocalyx and Cardiomyocyte Damage Is Prevented by Recombinant Syndecan-1 in Acute Myocardial Infarction. Am J Pathol. 2023;193(4):474\u0026ndash;492. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajpath.2022.12.009\u003c/span\u003e\u003cspan address=\"10.1016/j.ajpath.2022.12.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTkachenko E, Rhodes JM, Simons M. Syndecans: new kids on the signaling block. Circ Res. 2005;96(5):488\u0026ndash;500. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/01.RES.0000159708.71142.c8\u003c/span\u003e\u003cspan address=\"10.1161/01.RES.0000159708.71142.c8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWernly B, Fuernau G, Masyuk M, Muessig JM, Pfeiler S, Bruno RR, Desch S, Muench P, Lichtenauer M, Kelm M, Adams V, Thiele H, Eitel I, Jung C. Syndecan-1 Predicts Outcome in Patients with ST-Segment Elevation Infarction Independent from Infarct-related Myocardial Injury. Sci Rep. 2019;9(1):18367. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41598-019-54937-x\u003c/span\u003e\u003cspan address=\"10.1038/s41598-019-54937-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJung C, Fuernau G, Muench P, Desch S, Eitel I, Schuler G, Adams V, Figulla HR, Thiele H. Impairment of the endothelial glycocalyx in cardiogenic shock and its prognostic relevance. Shock Augusta Ga. 2015;43(5):450\u0026ndash;455. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/SHK.0000000000000329\u003c/span\u003e\u003cspan address=\"10.1097/SHK.0000000000000329\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePilarczyk K, Werdan K, Russ M, Thiele H, Michels G, Boeken U, Thielmann M. The German-Austrian S3 Guideline \u0026ldquo;Cardiogenic Shock Due to Myocardial Infarction: Diagnosis, Monitoring, and Treatment.\u0026rdquo; Thorac Cardiovasc Surg. 2021;69(8):684\u0026ndash;692. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1055/s-0040-1719155\u003c/span\u003e\u003cspan address=\"10.1055/s-0040-1719155\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFels B, Acharya S, Vahldieck C, Graf T, K\u0026auml;ding N, Rupp J, Kusche-Vihrog K. Mineralocorticoid receptor-antagonism prevents COVID-19-dependent glycocalyx damage. Pflugers Arch. 2022;474(10):1069\u0026ndash;1076. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00424-022-02726-3\u003c/span\u003e\u003cspan address=\"10.1007/s00424-022-02726-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKillip T, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol. 1967;20(4):457\u0026ndash;464. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/0002-9149(67)90023-9\u003c/span\u003e\u003cspan address=\"10.1016/0002-9149(67)90023-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWong GC, Welsford M, Ainsworth C, Abuzeid W, Fordyce CB, Greene J, Huynh T, Lambert L, Le May M, Lutchmedial S, Mehta SR, Natarajan M, Norris CM, Overgaard CB, Perry Arnesen M, Quraishi A, Tanguay JF, Traboulsi M, van Diepen S, Welsh R, Wood DA, Cantor WJ, members of the Secondary Panel. 2019 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Guidelines on the Acute Management of ST-Elevation Myocardial Infarction: Focused Update on Regionalization and Reperfusion. Can J Cardiol. 2019;35(2):107\u0026ndash;132. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.cjca.2018.11.031\u003c/span\u003e\u003cspan address=\"10.1016/j.cjca.2018.11.031\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolmes DR, Berger PB, Hochman JS, Granger CB, Thompson TD, Califf RM, Vahanian A, Bates ER, Topol EJ. Cardiogenic Shock in Patients With Acute Ischemic Syndromes With and Without ST-Segment Elevation. Circulation. 1999;100(20):2067\u0026ndash;2073. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/01.CIR.100.20.2067\u003c/span\u003e\u003cspan address=\"10.1161/01.CIR.100.20.2067\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHudson MP, Armstrong PW, O\u0026rsquo;Neil WW, Stebbins AL, Weaver WD, Widimsky P, Aylward PE, Ruzyllo W, Holmes D, Mahaffey KW, Granger CB. Mortality implications of primary percutaneous coronary intervention treatment delays: insights from the Assessment of Pexelizumab in Acute Myocardial Infarction trial. Circ Cardiovasc Qual Outcomes. 2011;4(2):183\u0026ndash;192. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/CIRCOUTCOMES.110.945311\u003c/span\u003e\u003cspan address=\"10.1161/CIRCOUTCOMES.110.945311\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarkabi B, Meir G, Zafrir B, Jaffe R, Adawi S, Lavi I, Flugelman MY, Shiran A. Door-to-balloon time and mortality in patients with ST-elevation myocardial infarction undergoing primary angioplasty. Eur Heart J - Qual Care Clin Outcomes. 2021;7(4):422\u0026ndash;426. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ehjqcco/qcaa037\u003c/span\u003e\u003cspan address=\"10.1093/ehjqcco/qcaa037\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBruegger D, Brettner F, Rossberg I, Nussbaum C, Kowalski C, Januszewska K, Becker BF, Chappell D. Acute degradation of the endothelial glycocalyx in infants undergoing cardiac surgical procedures. Ann Thorac Surg. 2015;99(3):926\u0026ndash;931. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.athoracsur.2014.10.013\u003c/span\u003e\u003cspan address=\"10.1016/j.athoracsur.2014.10.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFels J, Kusche-Vihrog K. Endothelial Nanomechanics in the Context of Endothelial (Dys)function and Inflammation. Antioxid Redox Signal. 2019;30(7):945\u0026ndash;959. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1089/ars.2017.7327\u003c/span\u003e\u003cspan address=\"10.1089/ars.2017.7327\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLassus J, Tarvasm\u0026auml;ki T, Tolppanen H. Biomarkers in cardiogenic shock. Adv Clin Chem. 2022;109:31\u0026ndash;73. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/bs.acc.2022.03.002\u003c/span\u003e\u003cspan address=\"10.1016/bs.acc.2022.03.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeropian IM, Sonnino C, Van Tassell BW, Biasucci LM, Abbate A. Inflammatory markers in ST-elevation acute myocardial infarction. Eur Heart J Acute Cardiovasc Care. 2016;5(4):382\u0026ndash;395. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/2048872615568965\u003c/span\u003e\u003cspan address=\"10.1177/2048872615568965\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Y, Pan N, An Y, Xu M, Tan L, Zhang L. Diagnostic and Prognostic Biomarkers for Myocardial Infarction. Front Cardiovasc Med. 2021;7:617277. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fcvm.2020.617277\u003c/span\u003e\u003cspan address=\"10.3389/fcvm.2020.617277\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOstrowski SR, Pedersen SH, Jensen JS, Mogelvang R, Johansson PI. Acute myocardial infarction is associated with endothelial glycocalyx and cell damage and a parallel increase in circulating catecholamines. Crit Care Lond Engl. 2013;17(1):R32. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/cc12532\u003c/span\u003e\u003cspan address=\"10.1186/cc12532\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eP\u0026ouml;ss J, Fuernau G, Denks D, Desch S, Eitel I, de Waha S, Link A, Schuler G, Adams V, B\u0026ouml;hm M, Thiele H. Angiopoietin-2 in acute myocardial infarction complicated by cardiogenic shock\u0026ndash;a biomarker substudy of the IABP-SHOCK II-Trial. Eur J Heart Fail. 2015;17(11):1152\u0026ndash;1160. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ejhf.342\u003c/span\u003e\u003cspan address=\"10.1002/ejhf.342\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKusche-Vihrog K, Urbanova K, Blanqu\u0026eacute; A, Wilhelmi M, Schillers H, Kliche K, Pavenst\u0026auml;dt H, Brand E, Oberleithner H. C-reactive protein makes human endothelium stiff and tight. Hypertens Dallas Tex 1979. 2011;57(2):231\u0026ndash;237. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/HYPERTENSIONAHA.110.163444\u003c/span\u003e\u003cspan address=\"10.1161/HYPERTENSIONAHA.110.163444\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBavia L, Lidani KCF, Andrade FA, Sobrinho MIAH, Nisihara RM, de Messias-Reason IJ. Complement activation in acute myocardial infarction: An early marker of inflammation and tissue injury? Immunol Lett. 2018;200:18\u0026ndash;25. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.imlet.2018.06.006\u003c/span\u003e\u003cspan address=\"10.1016/j.imlet.2018.06.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFang Z, Li X, Liu J, Lee H, Salciccioli L, Lazar J, Zhang M. The role of complement C3 in the outcome of regional myocardial infarction. Biochem Biophys Rep. 2023;33:101434. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.bbrep.2023.101434\u003c/span\u003e\u003cspan address=\"10.1016/j.bbrep.2023.101434\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJung C, Fuernau G, Muench P, Desch S, Eitel I, Schuler G, Adams V, Figulla HR, Thiele H. Impairment of the endothelial glycocalyx in cardiogenic shock and its prognostic relevance. Shock Augusta Ga. 2015;43(5):450\u0026ndash;455. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/SHK.0000000000000329\u003c/span\u003e\u003cspan address=\"10.1097/SHK.0000000000000329\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerraino GF, Jiritano F, Costa D, Ielapi N, Battaglia D, Bracale UM, Mastroroberto P, Andreucci M, Serra R. Metalloproteinases in Cardiac Surgery: A Systematic Review. Biomolecules. 2023;13(1):113. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/biom13010113\u003c/span\u003e\u003cspan address=\"10.3390/biom13010113\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiehle C, Bauersachs J. Key inflammatory mechanisms underlying heart failure. Herz. 2019;44(2):96\u0026ndash;106. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00059-019-4785-8\u003c/span\u003e\u003cspan address=\"10.1007/s00059-019-4785-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFels J, Callies C, Kusche-Vihrog K, Oberleithner H. Nitric oxide release follows endothelial nanomechanics and not vice versa. Pflugers Arch. 2010;460(5):915\u0026ndash;923. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00424-010-0871-8\u003c/span\u003e\u003cspan address=\"10.1007/s00424-010-0871-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFels B, Kusche-Vihrog K. It takes more than two to tango: mechanosignaling of the endothelial surface. Pflugers Arch. 2020;472(4):419\u0026ndash;433. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00424-020-02369-2\u003c/span\u003e\u003cspan address=\"10.1007/s00424-020-02369-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Q, Zuurbier CJ, Huhn R, Torregroza C, Hollmann MW, Preckel B, van den Brom CE, Weber NC. Pharmacological Cardioprotection against Ischemia Reperfusion Injury-The Search for a Clinical Effective Therapy. Cells. 2023;12(10):1432. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cells12101432\u003c/span\u003e\u003cspan address=\"10.3390/cells12101432\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuranteau J, De Backer D, Donadello K, Shapiro NI, Hutchings SD, Rovas A, Legrand M, Harrois A, Ince C. The future of intensive care: the study of the microcirculation will help to guide our therapies. Crit Care Lond Engl. 2023;27(1):190. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13054-023-04474-x\u003c/span\u003e\u003cspan address=\"10.1186/s13054-023-04474-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRovas A, Lukasz AH, Vink H, Urban M, Sackarnd J, Pavenst\u0026auml;dt H, K\u0026uuml;mpers P. Bedside analysis of the sublingual microvascular glycocalyx in the emergency room and intensive care unit - the GlycoNurse study. Scand J Trauma Resusc Emerg Med. 2018;26(1):16. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13049-018-0483-4\u003c/span\u003e\u003cspan address=\"10.1186/s13049-018-0483-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRovas A, Sackarnd J, Rossaint J, Kampmeier S, Pavenst\u0026auml;dt H, Vink H, K\u0026uuml;mpers P. Identification of novel sublingual parameters to analyze and diagnose microvascular dysfunction in sepsis: the NOSTRADAMUS study. Crit Care Lond Engl. 2021;25(1):112. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13054-021-03520-w\u003c/span\u003e\u003cspan address=\"10.1186/s13054-021-03520-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Endothelial glycocalyx, Endothelial dysfunction, ST-elevation myocardial infarction (STEMI), Cardiogenic shock, Door-to-balloon time, Nitric oxide","lastPublishedDoi":"10.21203/rs.3.rs-3234193/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3234193/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDamage to the endothelial glycocalyx (eGC) and endothelial dysfunction have been reported to develop during cardiac ischemia-and-reperfusion injury (IRI), such as ST-elevation myocardial infarction (STEMI). For patients with acute ischemic syndromes and cardiogenic shock a door-to-balloon time (D2B)\u0026thinsp;\u0026lt;\u0026thinsp;60 min with rapid revascularization was shown to reduce both mortality and nonfatal complications. Here, we hypothesize that prolonged D2B is associated with an unfavorable outcome for the eGC of patients with STEMI.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eData of 126 individuals were analyzed in this study. Sixty-three STEMI patients with cardiogenic shock in the event of STEMI were included. All received revascularization through primary percutaneous coronary intervention (PCI). 63 age- and sex-matched healthy volunteers served as controls. After stimulating endothelial cells with patient sera, the nanomechanical properties of the eGC were analyzed using the atomic force microscopy-based nanoindentation technique. Serum levels of eGC components as well as complement anaphylatoxins and angiopoetin-2 were measured via ELISA. Nitric oxide (NO) levels were determined chemiluminescence-based.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eeGC height and stiffness (both, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) as well as NO concentration (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were reduced after STEMI. Longer D2B led to significantly higher amounts of eGC components (syndecan-1: 35.5 vs. 136.7 ng/ml; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 / heparan sulfate: 4.6 vs. 10.8 ng/ml; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 / hyaluronic acid: 116.7 vs. 182.9 \u0026micro;g/ml; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and troponin-t (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) in the patient sera. Notably, D2B had a strong impact on patient outcome. D2B\u0026thinsp;\u0026gt;\u0026thinsp;60 min led to pronounced loss of eGC height and stiffness (both, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), activated the complement system (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and prolonged the hospital stay (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) compared to D2B\u0026thinsp;\u0026le;\u0026thinsp;60 min.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIncreased D2B led to severe eGC shedding and endothelial dysfunction in a temporal context. In addition, levels of syndecan-1 and proinflammatory mediators correlated with prolonged D2B, indicating a time-dependent immune reaction during cardiogenic shock with increased IRI to the eGC and prolonged hospitalization. D2B therefore appears to be a crucial factor for endothelial IRI in the case of STEMI with cardiogenic shock. Combining the clinical evaluation of the eGC condition with levels of biomarkers such as syndecan-1 might serve as important predictor for eGC impairment of STEMI patients with cardiogenic shock in the future.\u003c/p\u003e","manuscriptTitle":"Prolonged Door-to-Balloon time leads to glycocalyx damage and endothelial dysfunction in patients with ST-Elevation Myocardial Infarction and cardiogenic shock","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-08-10 15:21:38","doi":"10.21203/rs.3.rs-3234193/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6681c859-145f-4c65-92c9-dbc6c206cb5a","owner":[],"postedDate":"August 10th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-08-23T07:29:06+00:00","versionOfRecord":[],"versionCreatedAt":"2023-08-10 15:21:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3234193","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3234193","identity":"rs-3234193","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}