Coronary Angiography After Out-of-Hospital Cardiac Arrest Without ST-Segment Elevation: One-Year Outcomes of a Randomized Clinical Trial.

Importance: Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest (OHCA). The long-term effect of early coronary angiography on patients with OHCA with possible coronary trigger but no ST-segment elevation remains unclear. Objective: To compare the clinical outcomes of early unselective angiography with the clinical outcomes of a delayed or selective approach for successfully resuscitated patients with OHCA of presumed cardiac origin without ST-segment elevation at 1-year follow-up. Design, Setting, and Participants: The TOMAHAWK trial was a multicenter, international (Germany and Denmark), investigator-initiated, open-label, randomized clinical trial enrolling 554 patients between November 23, 2016, to September 20, 2019. Patients with stable return of spontaneous circulation after OHCA of presumed cardiac origin but without ST-segment elevation on the postresuscitation electrocardiogram were eligible for inclusion. A total of 554 patients were randomized to either immediate coronary angiography after hospital admission or an initial intensive care assessment with delayed or selective angiography after a minimum of 24 hours. All 554 patients were included in survival analyses during the follow-up period of 1 year. Secondary clinical outcomes were assessed only for participants alive at 1 year to account for the competing risk of death. Interventions: Early vs delayed or selective coronary angiography and revascularization if indicated. Main Outcomes and Measures: Evaluations in this secondary analysis included all-cause mortality after 1 year, as well as severe neurologic deficit, myocardial infarction, and rehospitalization for congestive heart failure in survivors at 1 year. Results: A total of 281 patients were randomized to the immediate angiography group and 273 to the delayed or selective group, with a median age of 70 years (IQR, 60-78 years). A total of 369 of 530 patients (69.6%) were male, and 268 of 483 patients (55.5%) had a shockable arrest rhythm. At 1 year, all-cause mortality was 60.8% (161 of 265) in the immediate angiography group and 54.3% (144 of 265) in the delayed or selective angiography group without significant difference between the treatment strategies, trending toward an increase in mortality with immediate angiography (hazard ratio, 1.25; 95% CI, 0.99-1.57; P = .05). For patients surviving until 1 year, the rates of severe neurologic deficit, myocardial infarction, and rehospitalization for congestive heart failure were similar between the groups. Conclusions and Relevance: This study found that a strategy of immediate coronary angiography does not provide clinical benefit compared with a delayed or selective invasive approach for patients 1 year after resuscitated OHCA of presumed coronary cause and without ST-segment elevation. Trial Registration: ClinicalTrials.gov Identifier: NCT02750462.

Early versus delayed coronary angiography in patients with out-of-hospital cardiac arrest and no ST-segment elevation: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Recent randomized controlled trials did not show benefit of early/immediate coronary angiography (CAG) over a delayed/selective strategy in patients with out-of-hospital cardiac arrest (OHCA) and no ST-segment elevation. However, whether selected subgroups, specifically those with a high pretest probability of coronary artery disease may benefit from early CAG remains unclear. METHODS: We included all randomized controlled trials that compared a strategy of early/immediate versus delayed/selective CAG in OHCA patients and no ST elevation and had a follow-up of at least 30 days. The primary outcome of interest was all-cause death. Odds ratios (OR) were calculated and pooled across trials. Interaction testing was used to assess for heterogeneity of treatment effects. RESULTS: In total, 1512 patients (67 years, 26% female, 23% prior myocardial infarction) were included from 5 randomized controlled trials. Early/immediate versus delayed/selective CAG was not associated with a statistically significant difference in odds of death (OR 1.12, 95%-CI 0.91-1.38), with similar findings for the composite outcome of all-cause death or neurological deficit (OR 1.10, 95%-CI 0.89-1.36). There was no effect modification for death by age, presence of a shockable initial cardiac rhythm, history of coronary artery disease, presence of an ischemic event as the presumed cause of arrest, or time to return of spontaneous circulation (all P-interaction > 0.10). However, early/immediate CAG tended to be associated with higher odds of death in women (OR 1.52, 95%-CI 1.00-2.31, P = 0.050) than in men (OR 1.04, 95%-CI 0.82-1.33, P = 0.74; P-interaction 0.097). CONCLUSION: In OHCA patients without ST-segment elevation, a strategy of early/immediate versus delayed/selective CAG did not reduce all-cause mortality across major subgroups. However, women tended to have higher odds of death with early CAG.

Mid-regional pro-adrenomedullin and lactate levels for risk stratification in patients with out-of-hospital cardiac arrest.

AIMS: Adrenomedullin (ADM) is a free-circulating peptide that regulates endothelial barrier function and vascular tone. Here, we sought to study the relationship of ADM in combination with lactate and the risk of death in patients with out-of-hospital cardiac arrest (OHCA). METHODS AND RESULTS: Mid-regional pro-adrenomedullin (MR-proADM) and lactate concentrations were measured in patients with OHCA who survived at least 24 h after the return of spontaneous circulation. The outcome of interest was all-cause death. Patients were characterized by the quartiles (Q) of MR-proADM and lactate concentrations. Cox models were adjusted for age, sex, shockable rhythm, bystander resuscitation, simplified acute physiology score II (SAPS II), and estimated glomerular filtration rate (eGFR). A total of 232 patients were included in the present study (28% women, 67 years, SAPS II 80). The median MR-proADM and lactate levels at 24 h were 1.4 nmol/L [interquartile range (IQR) 0.8-2.8 nmol/L] and 1.8 mmol/L (IQR 1.3-3.4 mmol/L), respectively. Mid-regional pro-adrenomedullin concentrations correlated weakly with lactate levels (r = 0.36, P < 0.001). High (Q4) vs. low (Q1-Q3) MR-proADM concentrations were significantly associated with an increased rate of death at 28 days (75.9 vs. 45.4%; P < 0.001). After multivariable adjustment (including lactate levels at 24 h), higher MR-proADM levels were significantly associated with an increased risk of death [Q4 vs. Q1-Q3: adjusted hazard ratio (adj-HR) 1.67, 95% confidence interval (CI) 1.12-2.50; adj-HR for a 1-unit increase in a standardized biomarker 1.44, 95% CI 1.19-1.73]. This relationship remained significant even after further adjustment for baseline NT-proBNP and high-sensitivity troponin T levels. The combination of high MR-proADM and high lactate (Q4) concentrations identified patients at a particularly elevated risk (adj-HR 3.50; 95% CI 1.92-6.39). CONCLUSION: Higher MR-proADM concentrations are associated with an increased risk of death in patients with OHCA, and the combination of high MR-proADM and lactate levels identifies patients at a distinctly elevated risk.

Effect of SARS-CoV-2 mRNA-Vaccine on the Induction of Myocarditis in Different Murine Animal Models.

In the course of the SARS-CoV-2 pandemic, vaccination safety and risk factors of SARS-CoV-2 mRNA-vaccines were under consideration after case reports of vaccine-related side effects, such as myocarditis, which were mostly described in young men. However, there is almost no data on the risk and safety of vaccination, especially in patients who are already diagnosed with acute/chronic (autoimmune) myocarditis from other causes, such as viral infections, or as a side effect of medication and treatment. Thus, the risk and safety of these vaccines, in combination with other therapies that could induce myocarditis (e.g., immune checkpoint inhibitor (ICI) therapy), are still poorly assessable. Therefore, vaccine safety, with respect to worsening myocardial inflammation and myocardial function, was studied in an animal model of experimentally induced autoimmune myocarditis. Furthermore, it is known that ICI treatment (e.g., antibodies (abs) against PD-1, PD-L1, and CTLA-4, or a combination of those) plays an important role in the treatment of oncological patients. However, it is also known that treatment with ICIs can induce severe, life-threatening myocarditis in some patients. Genetically different A/J (most susceptible strain) and C57BL/6 (resistant strain) mice, with diverse susceptibilities for induction of experimental autoimmune myocarditis (EAM) at various age and gender, were vaccinated twice with SARS-CoV-2 mRNA-vaccine. In an additional A/J group, an autoimmune myocarditis was induced. In regard to ICIs, we tested the safety of SARS-CoV-2 vaccination in PD-1-/- mice alone, and in combination with CTLA-4 abs. Our results showed no adverse effects related to inflammation and heart function after mRNA-vaccination, independent of age, gender, and in different mouse strains susceptible for induction of experimental myocarditis. Moreover, there was no worsening effect on inflammation and cardiac function when EAM in susceptible mice was induced. However, in the experiments with vaccination and ICI treatment, we observed, in some mice, low elevation of cardiac troponins in sera, and low scores of myocardial inflammation. In sum, mRNA-vaccines are safe in a model of experimentally induced autoimmune myocarditis, but patients undergoing ICI therapy should be closely monitored when vaccinated.

Non-Invasive Ventilation as a Therapy Option for Acute Exacerbations of Chronic Obstructive Pulmonary Disease and Acute Cardiopulmonary Oedema in Emergency Medical Services.

In this observational prospective multicenter study conducted between October 2016 and October 2018, we tested the hypothesis that the use of prehospital non-invasive ventilation (phNIV) to treat patients with acute respiratory insufficiency (ARI) caused by severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and acute cardiopulmonary oedema (ACPE) is effective, time-efficient and safe. The data were collected at four different physician response units and three admitting hospitals in a German EMS system. Patients with respiratory failure due to acute exacerbation of chronic obstructive pulmonary disease and acute cardiopulmonary oedema were enrolled. A total of 545 patients were eligible for the final analysis. Patients were treated with oxygen supplementation, non-invasive ventilation or invasive mechanical ventilation. The primary outcomes were defined as changes in the clinical parameters and the in-hospital course. The secondary outcomes included time efficiency, peri-interventional complications, treatment failure rate, and side-effects. Oxygenation under phNIV improved equally to endotracheal intubation (ETI), and more effectively in comparison to standard oxygen therapy (SOT) (paO2 SOT vs. non-invasive ventilation (NIV) vs. ETI: 82 mmHg vs. 125 mmHg vs. 135 mmHg, p-value SOT vs. NIV < 0.0001). In a matched subgroup analysis phNIV was accompanied by a reduced time of mechanical ventilation (phNIV: 1.8 d vs. ETI: 4.2 d) and a shortened length of stay at the intensive care unit (3.4 d vs. 5.8 d). The data support the hypothesis that the treatment of severe AECOPD/ACPE-induced ARI using prehospital NIV is effective, time efficient and safe. Compared to ETI, a matched comparison supports the hypothesis that prehospital implementation of NIV may provide benefits for an in-hospital course.

Angiography after Out-of-Hospital Cardiac Arrest without ST-Segment Elevation.

BACKGROUND: Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest. However, the benefits of early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation are unclear. METHODS: In this multicenter trial, we randomly assigned 554 patients with successfully resuscitated out-of-hospital cardiac arrest of possible coronary origin to undergo either immediate coronary angiography (immediate-angiography group) or initial intensive care assessment with delayed or selective angiography (delayed-angiography group). All the patients had no evidence of ST-segment elevation on postresuscitation electrocardiography. The primary end point was death from any cause at 30 days. Secondary end points included a composite of death from any cause or severe neurologic deficit at 30 days. RESULTS: A total of 530 of 554 patients (95.7%) were included in the primary analysis. At 30 days, 143 of 265 patients (54.0%) in the immediate-angiography group and 122 of 265 patients (46.0%) in the delayed-angiography group had died (hazard ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.63; P = 0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (in 164 of 255 patients [64.3%]) than in the delayed-angiography group (in 138 of 248 patients [55.6%]), for a relative risk of 1.16 (95% CI, 1.00 to 1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in the two groups. CONCLUSIONS: Among patients with resuscitated out-of-hospital cardiac arrest without ST-segment elevation, a strategy of performing immediate angiography provided no benefit over a delayed or selective strategy with respect to the 30-day risk of death from any cause. (Funded by the German Center for Cardiovascular Research; TOMAHAWK ClinicalTrials.gov number, NCT02750462.).

Relationship between markers of inflammation and hemodynamic stress and death in patients with out-of-hospital cardiac arrest.

Biomarkers that reflect hemodynamic stress, inflammation, extracellular matrix remodeling, angiogenesis, and endothelial dysfunction may improve risk stratification and add valuable pathobiological insight in patients with out-of-hospital cardiac arrest (OHCA). In total, 120 patients with OHCA who survived at least 48 h after return of spontaneous circulation were consecutively included in the present analysis. Concentrations of 30 biomarkers were measured simultaneously using a multi-panel biomarker assay. Cox regression models were adjusted for age, sex, estimated glomerular filtration rate, lactate concentration, bystander resuscitation, initial cardiac rhythm, and type of targeted temperature management. Overall, 57 patients (47.5%) had a favorable neurological outcome (Cerebral Performance Category ≤ 2) at 30 days, while palliative care was initiated in 49 patients (40.8%), and 52 patients (43.3%) died. After correction for multiple testing with Bonferroni-Holm, 8 biomarkers (including Angiopoietin-2, Procalcitonin, Resistin, IL-4Rα, MMP-8, TNFα, Renin, and IL-1α) were significantly associated with all-cause death. After multivariable adjustment, only angiopoietin-2 (Adjusted (Adj) hazard ratio (HR) per 1-unit increase in standardized biomarker concentrations 1.52 (95% CI 1.16-1.99)) and renin (Adj HR 1.32 (95% CI 1.06-1.65) remained independently associated with an increased risk of death. The discriminatory performance indicated good performance for angiopoietin-2 (area under the curve (AUC): 0.75 (95% CI 0.66-0.75) and was significantly higher (P = 0.011) as compared with renin (AUC: 0.60, 95% CI 0.50-0.60). In conclusion, angiopoietin-2 was significantly associated with all-cause mortality in patients with OHCA who survived the first 48 h and may prove to be useful for risk stratification of these patients.

Validation of two severity scores as predictors for outcome in Coronavirus Disease 2019 (COVID-19).

BACKGROUND: An established objective and standardized reporting of clinical severity and disease progression in COVID-19 is still not established. We validated and compared the usefulness of two classification systems reported earlier-a severity grading proposed by Siddiqi and a system from the National Australian COVID-19 guideline. Both had not been validated externally and were now tested for their ability to predict complications. METHODS: In this retrospective, single-centre observational study, patients hospitalized with confirmed COVID-19 across all severity stages were enrolled. The clinical severity was graded at admission and during hospitalization. Multivariate Cox regression was used to identify independent risk factors for mortality, a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation), a secondary endpoint (mortality, incident acute myocardial injury, incident venous thrombosis, pulmonary embolism or stroke) and progression of severity grades. RESULTS: Of 109 patients 17 died, 31 and 48 developed the primary and secondary endpoint, respectively. Worsening of the severity grade by at least one stage occurred in 27 and 28 patients, respectively. Siddiqi and Australian classification were identified as independent predictors for the primary endpoint (adjusted hazard ratio (aHR) 2.30, p<0.001 and aHR 2.08, p<0.001), for the secondary endpoint (aHR 2.12, p<0.001 and aHR 1.79, p<0.001) and mortality (aHR 2.30, p = 0.071 and aHR 1.98, p = 0.017). Both classification systems showed very good agreement regarding initial grading and good agreement regarding progression of severity stages. CONCLUSIONS: Standardized and objective severity grading is useful to unequivocally stratify patients presenting with COVID-19 for their individual risk of complications.

Feasibility of CardioSecur®, a Mobile 4-Electrode/22-Lead ECG Device, in the Prehospital Emergency Setting.

Background: This study explores the application of CardioSecur® (CS-ECG), a hand-held 4-electrode/22-lead ECG-device, in comparison with conventional 12-lead electrocardiogram (c12L-ECG) in patients with acute chest pain in the prehospital emergency setting. Methods: CS-ECG systems were provided for two physician-staffed emergency ambulances and parallel recordings of c12L-ECG and CS-ECG were obtained from all patients with acute chest pain. Treating emergency physicians were asked to evaluate the CS-ECG system with a standardized questionnaire. Following study completion, acquired ECGs were analyzed separately by two independent cardiologists blinded to all other medical records. Results: Over a period of 20 months a total of 203 patients were included in our study. According to a standardized questionnaire, 79% of emergency medical professionals preferred application of CS-ECG, with 87% of teams judging CS-ECG to be beneficial for patients. Morover, 79% of physicians reported a reduction in time to definitive diagnosis with implementation of CS-ECG. The majority of professional users attested user-friendliness and feasibility of CS-ECG in terms of easy general handling (94%), application (93%), and placement of electrodes (98%). During prehospital triage, both c12L-ECG and CS-ECG correctly identified 31 (91%) patients with ST-elevation myocardial infarction (STEMI). Conclusion: In this first pilot study, implementation of the CardioSecur®-ECG system in the prehospital emergency setting demonstrated feasibility and user-friendliness so that emergency teams generally preferred CS-ECG to c12L-ECG. Diagnostic yield of CS-ECG was similar to c12L-ECG recordings.

[Recommendations for emergency management of patients with permanent mechanical circulatory support : Consensus statement of DGTHG, DIVI, DGIIN, DGAI, DGINA, DGfK and DGK]. / Empfehlungen zum Notfallmanagement von Patienten mit permanenten Herzunterstützungssystemen : Konsensuspapier der DGTHG, DIVI, DGIIN, DGAI, DGINA, DGfK und DGK.

The prevalence of patients living with long-term mechanical circulatory support (MCS) is rapidly increasing due to improved technology, improved survival, reduced adverse event profiles, greater reliability and mechanical durability, and limited numbers of organs available for donation. Patients with long-term MCS are very likely to require emergency medical support due to MCS-associated complications (e.g., right heart failure, left ventricular assist device malfunction, hemorrhage and pump thrombosis) but also due to non-MCS-associated conditions. Because of the unique characteristics of mechanical support, management of these patients is complicated and there is very little literature on emergency care for these patients. The purpose of this national scientific statement is to present consensus-based recommendations for the initial evaluation and resuscitation of adult patients with long-term MCS.

[Recommendations for emergency management of patients with permanent mechanical circulatory support : Consensus statement of DGTHG, DIVI, DGIIN, DGAI, DGINA, DGfK and DGK]. / Empfehlungen zum Notfallmanagement von Patienten mit permanenten Herzunterstützungssystemen : Konsensuspapier der DGTHG, DIVI, DGIIN, DGAI, DGINA, DGfK und DGK.

The prevalence of patients living with long-term mechanical circulatory support (MCS) is rapidly increasing due to improved technology, improved survival, reduced adverse event profiles, greater reliability and mechanical durability, and limited numbers of organs available for donation. Patients with long-term MCS are very likely to require emergency medical support due to MCS-associated complications (e.g., right heart failure, left ventricular assist device malfunction, hemorrhage and pump thrombosis) but also due to non-MCS-associated conditions. Because of the unique characteristics of mechanical support, management of these patients is complicated and there is very little literature on emergency care for these patients. The purpose of this national scientific statement is to present consensus-based recommendations for the initial evaluation and resuscitation of adult patients with long-term MCS.

Serum neprilysin and the risk of death in patients with out-of-hospital cardiac arrest of non-traumatic origin.

BACKGROUND: Early risk stratification remains an unmet clinical need in patients with in out-of-hospital cardiac arrest. We hypothesised that soluble neprilysin may represent a promising biomarker in patients with out-of-hospital cardiac arrest of non-traumatic origin and provide new pathobiological insight. METHODS: This pilot study was a biomarker analysis from the Heidelberg Resuscitation Registry. Serum soluble neprilysin levels on admission were measured in 144 patients with successful return of spontaneous circulation after out-of-hospital cardiac arrest of non-traumatic origin. The primary endpoint was time to all-cause mortality. KM Event Rates are reported. Cox models were adjusted for age, bystander resuscitation, initial ECG rhythm, baseline estimated glomerular filtration rate, baseline lactate, left ventricular function at baseline, and targeted temperature management. RESULTS: In total, 90 (62.5%) patients died over a follow-up of at least 30 days. Soluble neprilysin correlated weakly with high-sensitivity troponin T (r=0.18, P=0.032) but did not correlate significantly with estimated glomerular filtration rate (r=-0.12) or lactate (r=0.11). Patients with elevated soluble neprilysin levels on admission were at significantly higher risk of all-cause mortality (Q4 69.1% vs. Q1 48.4%). After multivariable adjustment, soluble neprilysin in the top quartile (Q4) was significantly associated with all-cause mortality (Q4 vs. Q1: adjusted hazard ratio 2.48 (1.20-5.12)). In an adjusted multimarker model including high-sensitivity troponin T and high-sensitivity C-reactive protein, soluble neprilysin and high-sensitivity troponin T remained independently associated with all-cause mortality (soluble neprilysin: adjusted hazard ratio 2.27 (1.08-4.78); high-sensitivity troponin T: adjusted hazard ratio 3.40 (1.63-7.09)). CONCLUSION: Soluble neprilysin, measured as early as on hospital admission, was independently associated with all-cause mortality in patients with out-of-hospital cardiac arrest of non-traumatic origin and may prove to be useful in the estimation of risk in these patients.

Ticagrelor promotes atherosclerotic plaque stability in a mouse model of advanced atherosclerosis.

OBJECTIVE: There is increasing evidence supporting the role of platelets in atherosclerotic vascular disease. The G-protein-coupled receptor P2Y12 is a central mediator of platelet activation and aggregation but has also been linked to platelet-independent vascular disease. Ticagrelor is an oral P2Y12 antagonist that is used as a standard treatment in patients after acute myocardial infarction. However, the effects of ticagrelor on advanced atherosclerosis have not been investigated. MATERIALS AND METHODS: Twenty-week-old apolipoprotein-E-deficient mice received standard chow or standard chow supplemented with 0.15% ticagrelor (approximately 270 mg/kg/day) for 25 weeks. The lesion area was evaluated in the aortic sinus by Movat's pentachrome staining and lesion composition, thickness of the fibrous cap, and size of the necrotic core evaluated by morphometry. RAW 264.7 macrophages were serum starved and treated with ticagrelor in vitro for the detection and quantification of apoptosis. In addition, oxLDL uptake in RAW 264.7 macrophages was evaluated. RESULTS: A trend toward the reduction of total lesion size was detected. However, data did not reach the levels of significance (control, n=11, 565,881 µm(2) [interquartile range {IQR} 454,778-603,925 µm(2)] versus ticagrelor, n=13, 462,595 µm(2) [IQR 379,740-546,037 µm(2)]; P=0.1). A significant reduction in the relative area of the necrotic core (control, n=11, 0.46 [IQR 0.4-0.51] versus ticagrelor, n=13, 0.34 [IQR 0.31-0.39]; P=0.008), and a significant increase in fibrous caps thickness (control, n=11, 3.7 µm [IQR 3.4-4.2 µm] versus ticagrelor, n=13, 4.7 [IQR 4.3-5.5 µm], P=0.04) were seen in ticagrelor-treated mice. In vitro studies demonstrated a reduction in apoptotic RAW 264.7 macrophages (control 0.07±0.03 versus ticagrelor 0.03±0.03; P=0.0002) when incubated with ticagrelor. Uptake of oxLDL in RAW 264.7 was significantly reduced when treated with ticagrelor (control 9.2 [IQR 5.3-12.9] versus ticagrelor 6.4 [IQR 2.5-9.5], P=0.02). CONCLUSION: The present study demonstrates for the first time a plaque-stabilizing effect of ticagrelor in a model of advanced vascular disease, potentially induced by a reduction of oxLDL uptake or an inhibition of apoptosis as seen in vitro.

Fibroblast growth factor 23 (FGF-23) is an early predictor of mortality in patients with cardiac arrest.

BACKGROUND: Post-cardiac arrest management has seen significant advances with profound improvements in survival and neurologic outcome. However, early prognostication after return of spontaneous circulation remains most challenging. Biomarkers have evolved as helpful tools in identifying patients who are at increased risk of adverse outcome. While fibroblast growth factor 23 (FGF-23) has recently emerged as a promising predictor of mortality in patients with cardiogenic shock, its role in risk stratification in post-resuscitation management remains unresolved. METHODS: This study included 90 patients who had been resuscitated and transferred to the ICU of the University Hospital Heidelberg. Survivors and non-survivors were retrospectively analyzed for known prognostic biomarkers as well as FGF-23 serum levels 24h and 72 h post cardiac arrest (CA). RESULTS: FGF-23 levels were significantly elevated in non-survivors compared to survivors. ROC analysis of FGF-23 levels at 24h and 72 h post CA yielded an AUC of 0.759 and 0.726, respectively, for prediction of overall survival after 6 months. FGF-23 levels remained as significant prognosticators after adjusting for age, renal function, and initial cardiac rhythm. FGF-23 levels did not show significant differences in patient outcome after stratification for cardiac origin of CA or left ventricular dysfunction. Furthermore, FGF-23 levels were moderately predictive of poor neurologic outcome in ROC analysis on day 1 and day 3 post CA with an AUC of 0.738 and 0.687, respectively. CONCLUSION: This study demonstrates elevated FGF-23 serum levels to be potentially helpful in prediction of mortality and poor neurological outcome as early as 24h post cardiac arrest.

Dabigatran etexilate retards the initiation and progression of atherosclerotic lesions and inhibits the expression of oncostatin M in apolipoprotein E-deficient mice.

OBJECTIVE: Thrombin has multiple proatherogenic effects including platelet activation and the induction of inflammatory processes. Recently, the cytokine oncostatin M has been shown to have proinflammatory effects. This study was designed to investigate the effects of thrombin inhibition on the initiation and progression of atherosclerosis and on the expression of oncostatin M. METHODS: Apolipoprotein E-deficient mice at different ages were fed the thrombin inhibitor dabigatran etexilate. The mean lesion area was measured in the aortic sinus and in the innominate artery. CD45-positive cells within the aortic tissue were measured by flow cytometry. Oncostatin M expression was measured in the tissue sections by immunocytochemistry. RESULTS: Treatment with dabigatran etexilate resulted in a significant reduction of the mean area of atherosclerotic lesions in the aortic sinus in both the young mice (11,176±1,500 µm(2) (control) versus 3,822±836 µm(2) (dabigatran etexilate), P<0.05) and selectively in the older mice at 28 weeks (234,099±13,500 µm(2) (control) versus 175,226±16,132 µm(2) (dabigatran etexilate), P<0.05). There were also fewer CD45-positive cells within the aortas of the dabigatran-treated mice and enhanced NO production in endothelial cells pretreated with dabigatran. In addition, the expression of oncostatin M was reduced in the lesions of dabigatran etexilate-treated mice. CONCLUSION: Inhibition of thrombin by dabigatran retards the development of early lesions and the progression of some established lesions in ApoE-/- mice. It improves endothelial function and retards macrophage accumulation within the vascular wall. Dabigatran also inhibits the expression of oncostatin M, and this suggests that oncostatin M may play a role in the initiation and progression of atherosclerosis.

Combined treatment with olmesartan medoxomil and amlodipine besylate attenuates atherosclerotic lesion progression in a model of advanced atherosclerosis.

INTRODUCTION: Besides their blood pressure-lowering effects, olmesartan medoxomil and amlodipine besylate exhibit additional anti-inflammatory mechanisms in atherosclerosic disease. Most of the studies investigating the effects of atherosclerosis focused on early atherosclerotic lesions, whereas lesions in human disease, at the time when medical treatment is started, are already well established. Therefore, we set up a model of advanced atherosclerosis and investigated the effects of olmesartan medoxomil, amlodipine besylate, and the combination of both on atherosclerotic lesion size and lesion composition. MATERIALS AND METHODS: Olmesartan medoxomil (1 mg/kg/day), amlodipine besylate (1.5 mg/kg/day), and the combination of both was added to chow and was fed to apolipoprotein E-deficient (ApoE(-/-)) mice at 25 weeks of age. Mice were sacrificed after 25 weeks of drug administration and perfused with formalin. Innominate arteries were dissected out and paraffin embedded. Serial sections were generated, and lesion sizes and their composition - such as minimal thickness of the fibrous cap, size of the necrotic core, and presence of calcification - were analyzed. Electrophoretic mobility shift assays were used to detect DNA-binding activity of the transcription factor nuclear factor-kappa B (NF-κB) in aortic tissue. RESULTS: Treatment with the combination of olmesartan medoxomil and amlodipine besylate led to a significant reduction in atherosclerotic lesion size in ApoE(-/-) mice (olmesartan medoxomil/amlodipine besylate: 122,277±6,795 µm(2), number [n]=14; versus control: 177,502±10,814 µm(2), n=9; P<0.001). Treatment with amlodipine besylate (n=5) alone did not reach significance. However, a trend toward a decrease in lesion size in the amlodipine besylate-treated animals could be observed. In the histological analysis of atherosclerotic lesion composition, significantly thicker fibrous caps were found in treatment with amlodipine besylate (amlodipine: 5.12±0.26 µm, n=6; versus control: 3.98±0.18 µm, n=10; P<0.01). Furthermore, all sections revealed morphological signs of calcification, but no difference could be detected. Treatment with the combination of olmesartan medoxomil and amlodipine besylate showed no effect on lesion composition. Electrophoretic mobility shift assays of nuclear extracts demonstrated reduced activity of the transcription factor NF-κB when treated with olmesartan medoxomil, amlodipine besylate, or their combination, as compared to controls. CONCLUSION: Combined treatment with olmesartan medoxomil and amlodipine besylate attenuated atherosclerotic lesion progression, possibly due to anti-inflammatory mechanisms. Our data support the hypothesis that even in advanced atherosclerosis anti-inflammatory treatment, using angiotensin II type 1 receptor blockers and calcium channel antagonists of the dihydropyridine type can attenuate atherosclerotic lesion progression.