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Current American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) and European Society of Cardiology (ESC) guidelines recommend different strategies to avoid low-yield admissions in patients with syncope.The purpose of this study was to directly compare the safety and efficacy of applying admission criteria of both guidelines to patients presenting with syncope to the emergency department in 2 multicenter studies.The international BASEL IX (BAsel Syncope EvaLuation) study (median age 71 years) and the U.S. SRS (Improving Syncope Risk Stratification in Older Adults) study (median age 72 years) were investigated. Primary endpoints were sensitivity/specificity for the adjudicated diagnosis of cardiac syncope (BASEL IX only) and 30-day major adverse cardiovascular events (30d-MACE).Among 2560 patients in the BASEL IX and 2085 in SRS studies, ACC/AHA/HRS and ESC criteria recommended admission for a comparable number of patients in BASEL IX (27% vs 28%), but ACC/AHA/HRS criteria less often in SRS (19% vs 32%; P.01). Recommendations were discordant in ∼25% of patients. In BASEL IX, sensitivity for cardiac syncope and 30d-MACE among patients without admission criteria was comparable for ACC/AHA/HRS and ESC criteria (64% vs 65%, P = .86; and 67% vs 71%, P = .15, respectively). In SRS, sensitivity for 30d-MACE was lower with ACC/AHA/HRS (54%) vs ESC criteria (88%; P.001). Similarly, specificity for cardiac syncope and 30d-MACE in BASEL IX was comparable for both guidelines, but in SRS the ACC/AHA/HRS guidelines showed a higher specificity for 30d-MACE than the ESC guidelines.ACC/AHA/HRS and ESC guidelines showed disagreement regarding admission for 1 in 4 patients and had only modest sensitivity, all indicating possible opportunities for improvements.

Background: Functionally relevant coronary artery disease (fCAD), causing symptoms of myocardial ischemia, can currently only be reliably detected with advanced cardiac imaging. Serum neurofilament light chain (sNfL) is a biomarker for neuro-axonal injury known to be elevated by cardiovascular (CV) risk factors and cerebrovascular small-vessel diseases. Due to their pathophysiological similarities with fCAD and the link to CV risk factors, we hypothesised that sNfL may have diagnostic and prognostic value for fCAD and adverse cardiovascular outcomes. Methods: Of the large prospective Basel VIII study (NCT01838148), 4’016 consecutive patients undergoing cardiac work-up for suspected fCAD were included (median age 68 years, 32.5% women, 46.9% with history of CAD). The presence of fCAD was adjudicated using myocardial perfusion imaging single-photon emission tomography (MPI-SPECT) and coronary angiography. sNfL was measured using a high-sensitive single-molecule array assay. All-cause and cardiovascular death, myocardial infarction (MI), and stroke/transient ischaemic attack (TIA) during 5-year follow-up were the prognostic endpoints. Results: The diagnostic accuracy of sNfL for fCAD as quantified by the area under the curve (AUC) was low (0.58, 95%CI 0.56–0.60). sNfL was strongly associated with age, renal dysfunction, and body mass index and was a strong and independent predictor of all-cause death, cardiovascular death, and stroke/TIA but not MI. Time-dependent AUC for cardiovascular-death at 1-year was 0.85, 95%CI 0.80–0.89, and 0.81, 95%CI 0.77–0.86 at 2-years. Conclusion: While sNfL concentrations did not show a diagnostic role for fCAD, in contrast, sNfL was a strong and independent predictor of cardiovascular outcomes, including all-cause death, cardiovascular death and stroke/TIA.

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c -statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a “universal” surrogate end point for cardiovascular risk.

Background Combining high-sensitivity cardiac troponin (hs-cTn) with estimated glomerular filtration rate and glucose within the Clinical Chemistry Score (CCS) could help in the assessment of patients with suspected acute myocardial infarction (AMI). Methods In patients presenting with suspected AMI to the emergency department, we aimed to externally validate the performance of the CCS in a prospective international multicenter study and to directly compare the diagnostic and prognostic performance of the CCS with hs-cTnT and hs-cTnI baseline levels alone using a single cut-off approach. The diagnostic endpoint was diagnostic accuracy for AMI as centrally adjudicated by two independent cardiologists including cardiac imaging and serial hs-cTnT/I measurements. The prognostic endpoint was 30-day AMI or death. Results AMI was the final diagnosis in 620/3827 patients (16.2%) adjudicated with hs-cTnT and 599 patients (15.7%) adjudicated with hs-cTnI. The CCS resulted in high diagnostic accuracy for AMI and prognostic accuracy for 30-days AMI/death as quantified by the area under the receiver-operating characteristic curve (AUC), using hs-cTnT 0.90 (95%CI 0.89–0.91) and 0.89 (95%CI 0.88–0.90), using hs-cTnI 0.91 (95%Cl 0.90–0.92) and 0.90 (95%CI 0.89–0.91) respectively. E.g. a CCS of 0 points resulted in a sensitivity of 99.8% (95%CI 99.1–100%) for rule-out of index AMI and 99.5% (95%CI 98.5–100%) for AMI/death at 30 days for hs-cTnT and 99.8% (95%CI 98.9–100%) and 99.6% (95%CI 98.6–100%) using hs-cTnI. Overall, the single hs-cTnT/I measurement approach provided comparable diagnostic (sensitivity 99.5–99.7%) and prognostic (sensitivity 98.9–99.5%) performance versus the CCS. Interpretation The CCS provided high diagnostic and prognostic performance also in this independent large validation cohort. A single hs-cTnT/I measurement approach for rule-out MI yielded similar estimates.

Aim: Exercise stress testing is used to detect myocardial ischaemia, but is limited by low sensitivity and specificity. The authors investigated the value of the analysis of high-frequency QRS components as a marker of abnormal depolarization in addition to standard ST-deviations as a marker of abnormal repolarization to improve the diagnostic accuracy. Methods and results: Consecutive patients undergoing bicycle exercise stress nuclear myocardial perfusion imaging were prospectively enrolled. Presence of myocardial ischaemia, the primary diagnostic endpoint, was adjudicated using MPI and coronary angiography. Automated high-frequency QRS analysis was performed in a blinded fashion. The prognostic endpoint was major adverse cardiac events (MACEs) during two years of follow-up. Exercise-induced ischaemia was detected in 147/662 patients (22%). The sensitivity of high-frequency QRS was similar to ST-deviations (46% vs. 43%, p=0.59), while the specificity was lower (75% vs. 87%, p Conclusion: The use of high-frequency QRS analysis in addition to ST-deviation analysis improves the diagnostic accuracy during exercise stress testing and adds independent prognostic information.

Objective: To evaluate associations of high-sensitivity cardiac troponin-T (cTnT) with cardiovascular disease (CVD), heart failure (HF), and mortality in community-dwelling women and men. Participants and Methods: A total of 8226 adults from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort (1997–1998) were enrolled in a prospective observational study (mean age: 49 years; 50.2% women). Sex-specific associations of cTnT levels with future clinical outcomes were evaluated using adjusted Cox-regression models. Results: Measurable cTnT levels (≥3 ng/L) were detected in 1102 women (26.7%) and in 2396 men (58.5%). Baseline cTnT levels were associated with a greater risk of developing CVD in women than men [Hazard ratio (HRwomen), 1.48 per unit increase in log2-cTnT; 95% CI, 1.21 to 1.81 vs HRmen, 1.20; 95% CI, 1.07 to 1.35; Pinteractioninteraction= .005) and mortality (Pinteraction= .008). Further, compared with referent category (cTnT

The impact of obesity on the incidence of perioperative myocardial infarction/injury (PMI) and mortality following non-cardiac surgery is not well understood. We performed a prospective diagnostic study enrolling consecutive patients undergoing non-cardiac surgery, who were considered at increased cardiovascular risk. All patients were screened for PMI, defined as an absolute increase from preoperative to postoperative sensitive/high-sensitivity cardiac troponin T (hs-cTnT) concentrations. The body mass index (BMI) was classified according to the WHO classification (underweight 40 kg/m2). The incidence of PMI and all-cause mortality at 365 days, both stratified according to BMI. We enrolled 4277 patients who had undergone 5413 surgeries. The median BMI was 26 kg/m2 (interquartile range 23–30 kg/m2). Incidence of PMI showed a non-linear relationship with BMI and ranged from 12% (95% CI 9–14%) in obesity class I to 19% (95% CI 17–42%) in the underweight group. This was confirmed in multivariable analysis with obesity class I. showing the lowest risk (adjusted OR 0.64; 95% CI 0.49–0.83) for developing PMI. Mortality at 365 days was lower in all obesity groups compared to patients with normal body weight (e.g., unadjusted OR 0.54 (95% CI 0.39–0.73) and adjusted OR 0.52 (95% CI 0.38–0.71) in obesity class I). Obesity class I was associated with a lower incidence of PMI, and obesity in general was associated with a lower all-cause mortality at 365 days.

Perioperative myocardial infarction/injury (PMI) is a frequent, often missed and incompletely understood complication of noncardiac surgery. The aim of this study was to evaluate whether patient- or procedure-related factors are more strongly associated to the development of PMI in patients undergoing repeated noncardiac surgery.In this prospective observational study, patient- and procedure-related factors were evaluated for contribution to PMI using: 1) logistic regression modelling with PMI as primary endpoint, 2) evaluation of concordance of PMI occurrence in the first and the second noncardiac surgery (surgery 1 and 2). and 3) the correlation of the extent of cardiomyocyte injury quantified by high-sensitivity cardiac troponin T between surgery 1 and 2. The secondary endpoint was all-cause mortality associated with PMI reoccurrence in surgery 2.Among 784 patients undergoing repeated noncardiac surgery (in total 1'923 surgical procedures), 116 patients (14.8%) experienced PMI during surgery 1. Among these, PMI occurred again in surgery 2 in 35/116 (30.2%) patients. However, the vast majority of patients developing PMI during surgery 2 (96/131, 73.3%) had not developed PMI during surgery 1 (phi-coefficient 0.150, p 0.001). The correlation between the extent of cardiomyocyte injury occurring during surgery 1 and 2 was 0.153. All-cause mortality following a second PMI in surgery 2 was dependent on time since surgery (adjusted hazard ratio 5.6 within 30 days and 2.4 within 360 days).In high-risk patients, procedural factors are more strongly associated with occurrence of PMI than patient factors, but patient factors are also contributors to the occurrence of PMI.

Background Especially in patients with acute heart failure (AHF) the NYHA classification remains of uncertain representation of patients' actual health state. Alternatively, patient's subjective well-being, in terms of health-related quality of life (HRQL), showed to have an excellent prognostic ability in out clinic patients with chronic heart failure. Objectives It is unknown whether HRQL instruments can assess a more reliable prognostication in patients hospitalized due to AHF than the NYHA classification. Methods Goal Directed Afterload Reduction in Acute Congestive Cardiac Decompensation Study (GALACTIC) was a multicenter, randomized, open-label blinded-end-point trial that emphasized early intensive and sustained vasodilation in adult patients hospitalized due to AHF with NYHA functional class III/IV, however provided neutral findings. HRQL was assessed by the generic EQ-5D-3L which is a 3-leveled 5-item instrument and the disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ). Unadjusted and adjusted Cox regression models were performed after patients were grouped into low (EQ-5D −0.074 Results 781 patients were enrolled in 10 centres in 5 countries over 2 continents among which 536 (69%) patientshad completed theEQ-5D and 419 (54%) the KCCQ shortly after admission. Within 180 days of follow-up69 (13%) and 54 (13%) patients died and 151 (28%) and 122 (29%) died or were rehospitalized due to AHF, respectively. Cumulative incidence as well as HRs in patients grouped according to NYHA (n=536) indicated a comparable or significantly lower risk in patients with NYHA IV: e.g. for the combined outcome HR 1.07 (95% CI 0.777–1.473) and aHR 0.463 (95% CI 0.245–0.875). Whereas HRs in patients grouped according to both, EQ-5D (n=536) and KCCQ (n=419), increased from the group with highest to the group with the lowest HRQL: e.g. aHR for moderately high 1.11 (95% CI 0.718–1.715), for moderately low 1.721 (95% CI 1.102–2.688) and for low EQ-5D index 1.891 (95% CI 1.136–3.149) referenced to high HRQL (EQ-5D index 0.75–1.0). Conclusions These findings corroborate and extend previous work suggesting that NYHA classification poorly discriminates AHF patients' prognosis and challenge its' extensive application. HRQL might be a possible alternative to easily assess these patients' heath state. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation, the Swiss Heart Foundation A. 180-day mortality; B. composite outcome

Background: The non–ST-segment–elevation myocardial infarction (NSTEMI) guidelines of the European Society of Cardiology (ESC) recommend a 3h cardiac troponin determination in patients triaged to the observe-zone of the ESC 0/1h-algorithm; however, no specific cutoff for further triage is endorsed. Recently, a specific cutoff for 0/3h high-sensitivity cardiac troponin T (hs-cTnT) change (7 ng/L) was proposed, warranting external validation. Methods: Patients presenting with acute chest discomfort to the emergency department were prospectively enrolled into an international multicenter diagnostic study. Final diagnoses were centrally adjudicated by 2 independent cardiologists applying the fourth universal definition of myocardial infarction, on the basis of complete cardiac workup, cardiac imaging, and serial hs-cTnT. Hs-cTnT concentrations were measured at presentation, after 1 hour, and after 3 hours. The objective was to externally validate the proposed cutoff, and if necessary, derive and internally as well as externally validate novel 0/3h-criteria for the observe-zone of the ESC 0/1h-hs-cTnT-algorithm in an independent multicenter cohort. Results: Among 2076 eligible patients, application of the ESC 0/1h-hs-cTnT-algorithm triaged 1512 patients (72.8%) to either rule out or rule in NSTEMI, leaving 564 patients (27.2%) in the observe-zone (adjudicated NSTEMI prevalence, 120/564 patients, 21.3%). The suggested 0/3h-hs-cTnT-change of Conclusions: A combination of a 3h-hs-cTnT concentration ( Registration: URL: https://clinicaltrials.gov ; Unique identifier: NCT00470587.

Contains fulltext : 219680.pdf (Publisher’s version ) (Open Access) BACKGROUND: There are limited data from randomized trials regarding whether volume-based, low-dose computed tomographic (CT) screening can reduce lung-cancer mortality among male former and current smokers. METHODS: A total of 13,195 men (primary analysis) and 2594 women (subgroup analyses) between the ages of 50 and 74 were randomly assigned to undergo CT screening at T0 (baseline), year 1, year 3, and year 5.5 or no screening. We obtained data on cancer diagnosis and the date and cause of death through linkages with national registries in the Netherlands and Belgium, and a review committee confirmed lung cancer as the cause of death when possible. A minimum follow-up of 10 years until December 31, 2015, was completed for all participants. RESULTS: Among men, the average adherence to CT screening was 90.0%. On average, 9.2% of the screened participants underwent at least one additional CT scan (initially indeterminate). The overall referral rate for suspicious nodules was 2.1%. At 10 years of follow-up, the incidence of lung cancer was 5.58 cases per 1000 person-years in the screening group and 4.91 cases per 1000 person-years in the control group; lung-cancer mortality was 2.50 deaths per 1000 person-years and 3.30 deaths per 1000 person-years, respectively. The cumulative rate ratio for death from lung cancer at 10 years was 0.76 (95% confidence interval [CI], 0.61 to 0.94; P = 0.01) in the screening group as compared with the control group, similar to the values at years 8 and 9. Among women, the rate ratio was 0.67 (95% CI, 0.38 to 1.14) at 10 years of follow-up, with values of 0.41 to 0.52 in years 7 through 9. CONCLUSIONS: In this trial involving high-risk persons, lung-cancer mortality was significantly lower among those who underwent volume CT screening than among those who underwent no screening. There were low rates of follow-up procedures for results suggestive of lung cancer. (Funded by the Netherlands Organization of Health Research and Development and others; NELSON Netherlands Trial Register number, NL580.).

BACKGROUND The clinical utility of procalcitonin in the diagnosis and management of pneumonia remains controversial. METHODS We assessed the clinical utility of procalcitonin in 2 prospective studies: first, a multicenter diagnostic study in patients presenting to the emergency department with acute dyspnea to directly compare the diagnostic accuracy of procalcitonin with that of interleukin 6 and C-reactive protein (CRP) in the diagnosis of pneumonia; second, a randomized management study of procalcitonin guidance in patients with acute heart failure and suspected pneumonia. Diagnostic accuracy for pneumonia as centrally adjudicated by 2 independent experts was quantified with the area under the ROC curve (AUC). RESULTS Among 690 patients in the diagnostic study, 178 (25.8%) had an adjudicated final diagnosis of pneumonia. Procalcitonin, interleukin 6, and CRP were significantly higher in patients with pneumonia than in those without. When compared to procalcitonin (AUC = 0.75; 95% CI, 0.71–0.78), interleukin 6 (AUC = 0.80; 95% CI, 0.77–0.83) and CRP (AUC = 0.82; 95% CI, 0.79–0.85) had significantly higher diagnostic accuracy (P = 0.010 and P < 0.001, respectively). The management study was stopped early owing to the unexpectedly low AUC of procalcitonin in the diagnostic study. Among 45 randomized patients, the number of days on antibiotic therapy and the length of hospital stay were similar (both P = 0.39) in patients randomized to the procalcitonin-guided group (n = 25) and usual-care group (n = 20). CONCLUSIONS In patients presenting with dyspnea, diagnostic accuracy of procalcitonin for pneumonia is only moderate and lower than that of interleukin 6 and CRP. The clinical utility of procalcitonin was lower than expected. SUMMARY Pneumonia has diverse and often unspecific symptoms. As the role of biomarkers in the diagnosis of pneumonia remains controversial, it is often difficult to distinguish pneumonia from other illnesses causing shortness of breath. The current study prospectively enrolled unselected patients presenting with acute dyspnea and directly compared the diagnostic accuracy of procalcitonin, interleukin 6, and CRP for the diagnosis of pneumonia. In this setting, diagnostic accuracy of procalcitonin for pneumonia was lower as compared to interleukin 6 and CRP. The clinical utility of procalcitonin was lower than expected. ClinicalTrials.gov Identifier NCT01831115.

Background To assess the prognostic performance of Growth differentiation factor-15 (GDF-15) concentrations in unselected patients presenting with suspected acute myocardial infarction (AMI) and adjudication based on high-sensitivity cardiac troponin (hs-cTn). Methods and results In an ongoing prospective multicenter diagnostic study, consecutive patients presenting with suspected AMI to the emergency department and available GDF-15 and hs-cTnT concentrations were included. Adjudication of AMI was performed central by two independent cardiologists using all available clinical information including cardiac imaging and serial hs-cTn concentrations. Overall, 718 patients were included, with 23% (162/718) having an adjudicated diagnosis of AMI. The cumulative incidence of death within 2 years was 19% in patients with AMI (30 deaths in 162 patients) versus 5% in patients without AMI (25 deaths in 556 patients; P Conclusions GDF-15 concentrations at emergency department presentation have a high predictive accuracy for all-cause death in patients with suspected AMI and allow the identification of a large proportion of AMI patients with very low mortality risk.

Background The clinical availability of high-sensitivity cardiac troponin (hs-cTn) has enabled the development of several innovative strategies for the rapid rule-out of acute myocardial infarction (AMI). Due to the lack of direct comparisons, selection of the best strategy for clinical practice is challenging. Methods In a prospective international multicenter diagnostic study enrolling 3696 patients presenting with suspected AMI to the emergency department, we compared the safety and efficacy of 14 different hs-cTn-based strategies: hs-cTn concentrations below the limit of detection (LoD), dual-marker combining hs-cTn with copeptin, ESC 0 h/1 h-algorithm, 0 h/2 h-algorithm, 2 h-ADP-algorithm, NICE-algorithm, and ESC 0 h/3 h-algorithm, each using either hs-cTnT or hs-cTnI. The final diagnosis of AMI was adjudicated by two independent cardiologists using all available clinical information including cardiac imaging and serial hs-cTn concentrations. Results AMI was the final diagnosis in 16% of patients. Using hs-cTnT, safety quantified by the negative predictive value (NPV) and sensitivity was very high (99.8–100% and 99.5–100%) and comparable for all strategies, except the dual-marker approach (NPV 98.7%, sensitivity 96.7%). Similarly, using hs-cTnI, safety quantified by the NPV and sensitivity was very high (99.7–100% and 98.9–100%) and comparable for all strategies, except the dual-marker approach (NPV 96.9%, sensitivity 90.4%) and the NICE-algorithm (NPV 99.1%, sensitivity 94.7%). Efficacy, quantified by the percentage of patients eligible for rule-out, differed markedly, and was lowest for LoD-algorithm (15.7–26.8%). Conclusion All rapid rule-out algorithms, except the dual-marker strategy and the NICE-algorithm using hs-cTnI, favorably combine safety and efficacy, and can be considered for routine clinical practice. Clinical trial registration NCT00470587, http://clinicaltrials.gov/show/NCT00470587.

Background Trimethylamine N-oxide (TMAO) has been associated with cardiovascular outcomes. However, the diagnostic value of TMAO and its precursors have not been assessed for functionally relevant coronary artery disease (fCAD) and its prognostic potential in this setting needs to be evaluated. Methods Among 1726 patients with suspected fCAD serum TMAO, and its precursors betaine, choline and carnitine, were quantified using liquid chromatography tandem mass spectrometry. Diagnosis of fCAD was performed by myocardial perfusion single photon emission tomography (MPI-SPECT) and coronary angiography blinded to marker concentrations. Incident all-cause death, cardiovascular death (CVD) and myocardial infarction (MI) were assessed during 5-years follow-up. Results Concentrations of TMAO, betaine, choline and carnitine were significantly higher in patients with fCAD versus those without (TMAO 5.33 μM vs 4.66 μM, p p p p = 0.003; HR = 1.66 [1.07, 2.59], p = 0.025). Prognostic discriminative accuracy for TMAO was good and robust for death and CVD (2-years AUC for CVD 0.73, 95% CI [0.65–0.80]). Conclusion TMAO and its precursors, betaine, choline and carnitine were significantly associated with fCAD, but with limited diagnostic value. TMAO was a strong predictor for incident death and CVD in patients with suspected fCAD. Clinical trial registration NCT01838148. Graphical abstract

The nasal mucosa constitutes the primary entry site for respiratory viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the imbalanced innate immune response of end-stage coronavirus disease 2019 (COVID-19) has been extensively studied, the earliest stages of SARS-CoV-2 infection at the mucosal entry site have remained unexplored. Here, we employed SARS-CoV-2 and influenza virus infection in native multi-cell-type human nasal turbinate and lung tissues ex vivo, coupled with genome-wide transcriptional analysis, to investigate viral susceptibility and early patterns of local mucosal innate immune response in the authentic milieu of the human respiratory tract. SARS-CoV-2 productively infected the nasal turbinate tissues, predominantly targeting respiratory epithelial cells, with a rapid increase in tissue-associated viral subgenomic mRNA and secretion of infectious viral progeny. Importantly, SARS-CoV-2 infection triggered robust antiviral and inflammatory innate immune responses in the nasal mucosa. The upregulation of interferon-stimulated genes, cytokines, and chemokines, related to interferon signaling and immune-cell activation pathways, was broader than that triggered by influenza virus infection. Conversely, lung tissues exhibited a restricted innate immune response to SARS-CoV-2, with a conspicuous lack of type I and III interferon upregulation, contrasting with their vigorous innate immune response to influenza virus. Our findings reveal differential tissue-specific innate immune responses in the upper and lower respiratory tracts that are specific to SARS-CoV-2. The studies shed light on the role of the nasal mucosa in active viral transmission and immune defense, implying a window of opportunity for early interventions, whereas the restricted innate immune response in early-SARS-CoV-2-infected lung tissues could underlie the unique uncontrolled late-phase lung damage of advanced COVID-19. IMPORTANCE In order to reduce the late-phase morbidity and mortality of COVID-19, there is a need to better understand and target the earliest stages of SARS-CoV-2 infection in the human respiratory tract. Here, we have studied the initial steps of SARS-CoV-2 infection and the consequent innate immune responses within the natural multicellular complexity of human nasal mucosal and lung tissues. Comparing the global innate response patterns of nasal and lung tissues infected in parallel with SARS-CoV-2 and influenza virus, we found distinct virus-host interactions in the upper and lower respiratory tract, which could determine the outcome and unique pathogenesis of SARS-CoV-2 infection. Studies in the nasal mucosal infection model can be employed to assess the impact of viral evolutionary changes and evaluate new therapeutic and preventive measures against SARS-CoV-2 and other human respiratory pathogens.

BACKGROUND The diagnosis of cardiac syncope remains a challenge in the emergency department (ED). OBJECTIVE Assessing the diagnostic accuracy of the early standardized clinical judgement (ESCJ) including a standardized syncope-specific case report form (CRF) in comparison with a recommended multivariable diagnostic score. METHODS In a prospective international observational multicentre study, diagnostic accuracy for cardiac syncope of ESCJ by the ED physician amongst patients ≥ 40 years presenting with syncope to the ED was directly compared with that of the Evaluation of Guidelines in Syncope Study (EGSYS) diagnostic score. Cardiac syncope was centrally adjudicated independently of the ESCJ or conducted workup by two ED specialists based on all information available up to 1-year follow-up. Secondary aims included direct comparison with high-sensitivity cardiac troponin I (hs-cTnI) and B-type natriuretic peptide (BNP) concentrations and a Lasso regression to identify variables contributing most to ESCJ. RESULTS Cardiac syncope was adjudicated in 252/1494 patients (15.2%). The diagnostic accuracy of ESCJ for cardiac syncope as quantified by the area under the curve (AUC) was 0.87 (95% CI: 0.84-0.89), and higher compared with the EGSYS diagnostic score (0.73 (95% CI: 0.70-0.76)), hs-cTnI (0.77 (95% CI: 0.73-0.80)) and BNP (0.77 (95% CI: 0.74-0.80)), all P

Aims Diagnosis of acute myocardial infarction (AMI) can be challenging in patients with prior coronary artery bypass grafting (CABG). Methods and results Final diagnoses were adjudicated by two independent cardiologists using the universal definition of AMI among patients presenting to the emergency department (ED) with suspected AMI. Diagnostic accuracy of 34 chest pain characteristics (CPCs) and four electrocardiogram (ECG) signatures stratified according to the presence or absence of prior CABG were prospectively quantified. Among 4015 patients (no prior CABG: n = 3686; prior CABG: n = 329), prevalence of AMI and unstable angina were higher in patients with prior CABG (35% vs. 18%; 26% vs. 8%; both P Conclusions Patients with prior CABG presenting with suspected AMI have a high prevalence of AMI and unstable angina and lower diagnostic accuracy of CPCs and the ECG, possibly justifying liberal use of early coronary angiography in these vulnerable patients. ClinicalTrials.gov registry Number NCT00470587.

Background The incidence, characteristics, determinants, and prognostic impact of recurrent syncope are largely unknown, causing uncertainty for both patients and physicians. Methods We characterized recurrent syncope including sex-specific aspects and its impact on death and major adverse cardiovascular events (MACE) in a large prospective international multicenter study enrolling patients ≥40 years presenting with syncope to the emergency department (ED). Syncope etiology was centrally adjudicated by two independent and blinded cardiologists using all information becoming available during syncope work-up and 12-month follow-up. MACE were defined as a composite of all-cause death, acute myocardial infarction, surgical or percutaneous coronary intervention, life-threatening arrhythmia including cardiac arrest, pacemaker or implantable cardioverter defibrillator implantation, valve intervention, heart-failure, gastrointestinal bleeding or other bleeding requiring transfusion, intracranial hemorrhage, ischemic stroke or transient ischemic attack, sepsis and pulmonary embolism. Results Incidence of recurrent syncope among 1790 patients was 20% (95%-confidence interval (CI) 18% to 22%) within 24 months. Patients with an adjudicated final diagnosis of cardiac syncope (hazard ratio (HR) 1.50, 95%-CI 1.11 to 2.01) or syncope of unknown etiology even after central adjudication (HR 2.11, 95%-CI 1.54 to 2.89) had an increased risk for syncope recurrence (Figure). LASSO regression fit on all patient information available early in the ED identified more than three previous episodes of syncope as the only independent predictor for recurrent syncope (HR 2.13, 95%-CI 1.64 to 2.75). Recurrent syncope within the first 12 months after the index event carried an increased risk for all-cause death (HR 1.59, 95%-CI 1.06 to 2.38) and MACE (HR 2.24, 95%-CI 1.67 to 3.01), whereas recurrences after 12 months did not have a significant impact on outcome measures. Conclusion Recurrence rates of syncope are substantial and vary depending on syncope etiology. There seem to be no reliable patient characteristics available early on the ED that allow for the prediction of recurrent syncope with only a history of more than three previous syncope being associated with a higher risk for future recurrences. Importantly, recurrent syncope within the first 12 months carries an increased risk for death and MACE. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation, Swiss Heart Foundation

Background Management and risk stratification of patients with syncope in the emergency department (ED) is often challenging. In an effort to support ED physicians in disposition decisions, the Canadian Syncope Risk Score (CSRS) was developed to predict 30-day serious outcomes. Methods The CSRS was developed in a Canadian multicenter study and contains nine predictors: predisposition to vasovagal syncope, heart disease, systolic pressure 180mmHg in the ED, troponin level >99th percentile, abnormal QRS axis, QRS duration >130ms, QTc interval >480ms and an ED diagnosis of vasovagal or cardiac syncope. Patients can achieve a CSRS score between −3 and +11 points. We validated the CSRS in a large prospective international multicenter study recruiting patients 40 years or older presenting to the ED with a syncopal event within the last 12 hours. Recruitment centers contained smaller provincial hospitals, as well as big University Hospitals in eight countries on three continents. Primary outcome measure were 30-day serious arrhythmic and non-arrhythmic adverse events, as defined by the authors of the original score. Results 1581 patients were eligible for this analysis. The population in this validation cohort was older (mean age 68 vs 54 years) and had a considerably higher rate of serious outcomes compared to the derivation cohort (n=186 (11.8%) vs n=147 (3.6%)). The area under the receiver operating characteristic curve (AUC) for the CSRS was 0.88 (95% confidence interval (CI) 0.86–0.91) and significantly higher compared to the validated OESIL score (AUC 0.75, 95% CI 0.71–0.78, p Conclusion This is the first validation of the Canadian Syncope Risk Score in a large international syncope cohort. The prognostic discrimination of the CSRS for 30-day serious outcomes was very good in our validation cohort and comparable to that of the Canadian derivation study. Despite suboptimal calibration, prognostic analysis showed a high rate of serious outcomes in the CSRS (very) high risk group and a low rate of serious outcomes in the very low risk group. Allowing the clinical judgement of the ED physician in the form of suspected syncope etiology to be a part of the score seems to largely contribute to the high performance of the CSRS. Additional validation studies might be needed to further increase the accuracy of the CSRS in different patient populations with a different incidence of outcomes in settings outside of Canada. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation; Swiss Heart Foundation

Background Recurrence of acute chest pain after percutaneous coronary intervention (PCI) is common. The early detection of acute myocardial infarction (AMI) as a possible cause of acute chest pain can be challenging in patients with a history of PCI due to e.g. pre-existing electrocardiographic abnormalities. It is unknown, whether high-sensitivity cardiac troponin T (hs-cTnT) concentrations and hs-cTnT-based rapid algorithms perform equally well in patients with a history of PCI. Purpose To investigate the impact of prior PCI on the diagnostic performance of hs-cTnT concentrations for early rule-out and rule-in of AMI. Methods In an ongoing multicentre international study, we prospectively enrolled unselected patients presenting to the emergency department (ED) with symptoms suggestive of AMI. Final diagnoses were centrally adjudicated by two independent cardiologists using all available medical records obtained during clinical care including 90 day follow-up information and cardiac imaging. High-sensitivity cTnT concentrations at presentation and after 1h were compared against the adjudicated final diagnosis. Patients were stratified according to the presence or absence of previous PCI. Results Among 5536 patients (1313 with and 4223 without previous PCI), incidence of AMI was significantly higher in patients with previous PCI (26.3% versus 21.4%; p Conclusions History of PCI impacts on the diagnostic performance of hs-cTnT. Although the ESC 0/1h-algorithm still performs very safe when applied to patients with a history of PCI, its efficacy is significantly reduced. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the Stiftung für kardiovaskuläre Forschung Basel the University of Basel and the University Hospital Basel

Background Syncope in the ED is linked with high diagnostic and prognostic uncertainty, leading to an extremely high rate of admissions. These often inappropriate admissions are costly and expose patients to unnecessary testing. The recent ESC and AHA guidelines aim at reducing these admissions by stratifying patients in high- and low-risk groups. Methods The BASEL IX Syncope study is a large prospective international multicenter study recruiting patients 40 years presenting to the ED with syncope within the last 12 hours in eight countries on three continents. Cardiac syncope was centrally adjudicated by two physicians using all data collected up to 1-y follow-up. We classified patients as requiring admission or being judged safe for discharge according to the ESC and AHA guidelines criteria and compared these with the physician's decision regarding hospitalization. We assessed the consequence of these decisions on 30-day serious cardiac events and mortality. We validated our findings in a large American cohort recruiting syncope patients >60 years in 11 EDs. Results 1977 patients were eligible for this analysis. 215 (10.8%) experienced 30-day Major Adverse Cardiovascular Events (MACE). The ESC and AHA guidelines would have admitted a largely different number of patients (75.9% vs 29.6%) and provided different safety regarding adverse events and death at 30 days (Figure). The validation in the US cohort provided similar results, however US ED physicians decided to admit more patients (84%) as compared with the international derivation cohort (46.6%). Conclusion The AHA and ESC syncope guidelines recommend admission based on very different criteria and for a largely different number of patients. While the most recent ESC guidelines were written with the aim to limit the number of patients admitted, they still classify a large majority of an ED syncope cohort as high risk and warranting admission. The large discrepancy between the two guidelines is based on the criteria used for the classification: While the ESC guidelines consider risk factors, previous cardiac history, physical examination and ECG criteria, the AHA guidelines focus on serious conditions previously known or diagnosed in the ED. Figure: Percentage of the overall cohort admitted (green) or discharged (red) according to the AHA and ESC guidelines and to the decision of the physician in the BASEL-IX cohort. Patients experiencing a cardiac syncope, a 30-day MACE or death are represented for both the discharged and admitted groups. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): University hospital Basel

Background The European Society of Cardiology (ESC) high sensitivity cardiac troponin T 0/1h-algorithm has substantially improved the management of patients with suspected acute myocardial infarction (AMI) by triaging about 75% of patients to rapid rule-out and/or rapid rule-in. However, about 25% of patients remain in the “observe-zone”, and the optimal management of these patients is unknown. Recently, a pilot single center study with a low prevalence of AMI suggested that an absolute change of less than 7ng/L between the 0h and 3h hs-cTnT concentration would allow to help in the evaluation of patients in the observe-zone and allow triage towards rule-out with very high negative predictive value [NPV]. Purpose To externally validate this suggested modification of the ESC 0/1h-algorithm for early rule out of AMI. Methods In an ongoing multicentre international study, we prospectively enrolled unselected patients presenting to the emergency department with symptoms suggestive of MI. Final diagnoses were centrally adjudicated by two independent cardiologists using all available medical records obtained during clinical care including 90 day follow-up information and cardiac imaging. High sensitivity-cTnT (Elecsys) concentrations were measured at presentation and after 1 and 3 hours. The primary outcome was safety, quantified by the sensitivity and NPV for early rule out of NSTEMI. Results Among 1633 enrolled patients with available 0, 1 and 3h hs-cTnT concentrations, NSTEMI was the adjudicated final diagnosis in 337 (20.6%) patients. The ESC 0/1h-algorithm ruled out 918 (56.2%) patients, with a sensitivity of 98.8% (95% confidence interval [CI], 97.0–99.5) and a NPV of 99.6% (95% CI, 98.9–99.8). A total of 428 patients (26.2%) remained in the observe zone. After applying the suggested 0–3 hour absolute change cut-off criteria of 7ng/L, 393 (92.0%) additional patients from the observe zone were triaged towards ruled out. However, the safety of this triage step was poor with 62 patients with NSTEMI missed, resulting in a sensitivity of 33.3% and a NPV of 84.2% for rule-out. Conclusions The suggested 0/3h absolute change cut-off of 7ng/L for patients remaining in the observe zone of the ESC 0/1h-algorithm does NOT allow safe rule-out of AMI and should therefore NOT be implemented into routine clinical care. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation, the Swiss Heart Foundation, the Stiftung für kardiovaskuläre Forschung Basel, the University of Basel and the University Hospital Basel

Background Guidelines recommend evaluating the risk/benefit ratio of novel therapies individually in women and men, as the pathophysiology and the response to treatment may differ between women and men. Among patients with acute heart failure (AHF), a strategy of intensive vasodilation, compared with usual care, overall did provide comparable outcomes. Purpose To evaluate the effect of a strategy that emphasized early intensive and sustained vasodilation in women with AHF. Methods In a randomized, open-label blinded-end-point trial patients hospitalized for AHF were enrolled in 10 hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Inclusion criteria were AHF expressed by acute dyspnea and increased plasma concentrations of natriuretic peptides, systolic blood pressure ≥100mmHg, and a plan for treatment in a general ward. Patients were randomized 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization or usual care. The primary end point was a composite of all-cause mortality or rehospitalization for AHF at 180 days. Results Among 788 patients randomized, 781 completed the trial and were eligible for the primary end point analysis. Of these 288 (36.9%) were women. The primary end point, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 53 female patients (37.9%) in the intervention group (including 28 deaths [20.0%]) and in 34 female patients (23.0%) in the usual care group (including 22 deaths [14.9%]) (absolute difference for the primary end point, 14.9%; adjusted hazard ratio, 1.67 [95% CI: 1.08–2.59]; P=0.02). Clinically significant adverse events with early intensive and sustained vasodilation vs usual care included hypotension (8% vs 2%). Conclusion Among women with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, had a detrimental effect on a composite outcome of all-cause mortality and AHF rehospitalization at 180 days. Cox Proportional Hazard Curve Funding Acknowledgement Type of funding source: None

Background Previous studies have shown the prognostic value of health-related quality of life (HRQL) in stable and ambulatory chronic heart failure patients. However, it is unknown whether HRQL can predict all-cause mortality in patients presenting to the emergency department (ED) after acute onset of symptoms. In order to address this unmet need, the aim of this study was to assess the prognostic value of HRQL in patients with acute dyspnea caused by acute heart failure (AHF) and other dyspnea aetiologies for 360-day mortality. Purpose To assess prognostic value of HRQL using the generic EQ-5D and visual analogue scale (EQ VAS) in patients with acute dyspnea. Methods Basics in Acute Shortness of Breath EvaLuation (BASEL V) is a prospective, multicenter, diagnostic study enrolling adult patients presenting with acute dyspnea to the ED. For this analysis, only patients with a complete set of variables necessary for calculation of EQ-5D (range 0–10; with higher score indicating worse HRQL) and EQ VAS (range 0–100; with 100 being the best imaginable health state) at baseline were included. The endpoint was the prognostic value of EQ-5D and EQ VAS at 360 days of follow-up regarding all-cause death. Prognostic accuracy was calculated using c-statistics. In a cox regression analysis EQ-5D was treated as both, a continuous and categorical variable. Adjustments were made for clinically relevant covariates (age, sex, orthopnoea, edema, level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) at presentation, history of coronary artery disease and chronic obstructive pulmonary disease, diuretics, β-blockers and ACE-inhibitors at discharge). Results Among 2605 patients enrolled, 1141 (43,8%) had a complete set of variables allowing the calculation of EQ-5D and EQ VAS. Of these patients 594 (52.1%) had an adjudicated final diagnosis of AHF. 211 (18.5%) patients died within 360 days of follow-up. Median EQ-5D was 3 (interquartile range (IQR) 1.5–5) and median EQ VAS was 50 (IQR 40–70). The prognostic accuracy for 360-day mortality was 0.65 (95% confidence interval ((CI) 0.61–0.69) and 0.58 (95% CI 0.54–0.62) for EQ-5D and EQ VAS, respectively (p=0.002). After combining EQ-5D and EQ VAS in a logistic regression model c-statistics regarding all-cause mortality within 360 days did not improve. The prognostic accuracy of EQ-5D was comparable to that of NT-proBNP (c-statistics 0.69, p=0.385). In an adjusted cox regression analysis the hazard ratio for patients with EQ-5D >4 was 2.2 (95% CI 1.7–2.9; p Conclusions In patients presenting with acute dyspnea HRQL is a strong prognostic instrument. Independently of the aetiology of the dyspnea the prognostic value of the generic EQ-5D for 360-day mortality is comparable to NT-proBNP. Patients with an EQ-5D >4 are at significantly higher risk for mortality within 360 days. Figure 1. Prognostic value of HRQL Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation, Swiss Heart Foundation

Background Risk stratification of older patients presenting to the Emergency Department (ED) with syncope remains an unmet clinical need. The FAINT Score was derived in a large American cohort in an attempt to predict 30-day serious cardiac outcomes in patients >60y.o. While a FAINT score of 0 showed high sensitivity to exclude death and serious outcomes at 30 days in the derivation cohort, it remains unvalidated. Methods We validated the FAINT score (History of heart failure, history of arrhythmia, initial ECG result abnormal, elevate NT-proBNP, elevated hs-troponin T) in a large prospective international multicenter study recruiting patients 40 years presenting to the ED with syncope within the last 12 hours in eight countries on three continents. Main outcome measure was 30-day serious cardiac events or mortality. We assessed the performance and calibration of the FAINT score for validation and compared it to the OESIL score (Age >64y, cardiovascular disease history, syncope without prodromes, abnormal ECG). Results 1885 patients were eligible for this validation analysis. 169 (8.9%) patients experienced 30-day serious adverse events. A FAINT score of 0 was present for 378 patients (20% of the cohort) and allowed for a sensitivity of 0.97 to rule out adverse events and death at 30-days. A FAINT score of 0 or 1 was present for 626 patients (33% of the cohort) and allowed for a sensitivity of 0.92. The area under the receiver operating characteristic curve (AUC) for the FAINT score was 0.75 (95%, Confidence Interval (CI) 0.72–0.79), which was comparable to the performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) or high-sensitivity Troponin T (hs-cTnT) alone, which are two biomarkers used in the FAINT score. The score did not outperform the OESIL score. A calibration curve showed that the score was extremely well calibrated for low-risk patients. Conclusion This is the first validation of the FAINT score in a large international syncope cohort. The safety of a FAINT score of 0 or 1 was good and comparable to the results obtained in the derivation cohort. While the score is suitable to highlight low-risk patients and calibrates well in an external cohort, its discrimination for higher risk patients is not better than biomarkers alone or an older, less complex risk score. Figure 1. Area under the Receiver Operating Curve (ROC) for the FAINT score and for NT-proBNP and hs-cTnT as continuous markers as well as for the OESIL score. CI = Confidence Interval. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): University Hospital Basel, Switzerland

Background The early diagnosis of cardiac syncope is often challenging. We therefore developed an ECG-based risk calculator as an aid for rapid rule-out or rule-in of cardiac syncope and aimed to validate this decision tool. Methods In a prospective diagnostic international multicenter study (derivation cohort), 2007 patients, 40 years or older, presenting with syncope to the emergency department were recruited. The primary diagnostic outcome, cardiac syncope, was centrally adjudicated by two independent cardiologists using all clinical information obtained during syncope work-up including 12-month follow up. 12-lead ECG was recorded at presentation and read by residents blinded to clinical information. Significant ECG predictors of cardiac syncope were identified using penalized backward selection. Findings were validated in an independent US multicenter cohort with 2'269 syncope patients. Results In the derivation cohort (median age 71 years, 40% women), centrally adjudicated cardiac syncope was present in 267 patients (16%). Seven ECG criteria (rhythm, heart rate, corrected QT-interval, ST-segment depression, atrioventricular-block, bundle-branch-block and ventricular extrasystole/non-sustained ventricular tachycardia) were identified as significant predictors for cardiac syncope and combined into the bAseL Ecg Risk calculaTor for Cardiac Syncope (ALERT-CS). Diagnostic accuracy of ALERT-CS for cardiac syncope, as quantified by the area under the receiver-operating characteristics curve (AUC), was high (0.80, 95%-confidence interval (CI) 0.77–0.83) and significantly higher compared to the EGSYS score (0.73, 95% CI 0.70–0.76, p A predicted probability for cardiac syncope below 5.5% by ALERT-CS identified 138 patients (8%) eligible for triage towards rapid rule-out of cardiac syncope with a sensitivity of 99%. A predicted probability above 37.5% identified 181 patients (11%) eligible for triage towards rapid rule-in of cardiac syncope with a specificity of 95%. Prognostic verification for 30-day major adverse cardiac events (MACE) showed a high rate of MACE in the rule-in group and a very low rate of MACE in the rule-out group (Figure). External validation (median age 72 years, 48% women) showed similar diagnostic accuracy (AUC 0.76, 95% CI 0.73–0.79) and prognostic results. Conclusion Combining seven ECG criteria within the simple ALERT-CS may aid ED physicians in the early rule-out or rule-in of cardiac syncope. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation, Swiss Heart Foundation

Diagnosing stable ischemic heart disease (IHD) is challenging, especially in females. Currently, no blood test is available. Plasma extracellular vesicles (EV) are emerging as potential biomarker source. We therefore aimed to identify stress induced ischemia due to stable IHD with plasma extracellular vesicle protein levels in chest pain patients. We analyzed 450 patients suspected for stable IHD who were referred for 82Rb PET/CT in the outpatient clinic. Blood samples were collected before PET/CT and plasma EVs were isolated in 3 plasma subfractions named: TEX, HDL, LDL. In total 6 proteins were quantified in each of these subfractions using immuno-bead assays. CD14 and CystatinC protein levels were independent significant predictors of stress-induced ischemia in the LDL and the HDL subfraction and SerpinC1 and SerpinG1 protein levels in the HDL fraction. Subgroup-analysis on sex revealed that these associations were completely attributed to the associations in women. None of the significant EV proteins remained significant in men. Plasma EV proteins levels are associated with the presence of stable IHD in females presenting with chest pain. This finding, if confirmed in larger cohort studies could be a crucial step in improving diagnostic assessment of women with suspected IHD.

BackgroundThe US guidelines recommend low-dose CT (LDCT) lung cancer screening for high-risk individuals. New solid nodules after baseline screening are common and have a high lung cancer probability. Currently, no evidence exists concerning the risk stratification of non-resolving new solid nodules at first LDCT screening after initial detection.MethodsIn the Dutch-Belgian Randomized Lung Cancer Screening (NELSON) trial, 7295 participants underwent the second and 6922 participants the third screening round. We included participants with solid nodules that were registered as new or 3).ResultsOverall, 680 participants with 1020 low-risk and intermediate-risk new solid nodules were included. A total of 562 (55%) new solid nodules were resolving, leaving 356 (52%) participants with a non-resolving new solid nodule, of whom 25 (7%) were diagnosed with lung cancer. At first screening after initial detection, volume doubling time (VDT), volume, and VDT combined with a predefined ≥200 mm3 volume cut-off had high discrimination for lung cancer (VDT, area under the curve (AUC): 0.913; volume, AUC: 0.875; VDT and ≥200 mm3 combination, AUC: 0.939). Classifying a new solid nodule with either ≤590 days VDT or ≥200 mm3 volume positive provided 100% sensitivity, 84% specificity and 27% positive predictive value for lung cancer.ConclusionsMore than half of new low-risk and intermediate-risk solid nodules in LDCT lung cancer screening resolve. At follow-up, growth assessment potentially combined with a volume limit can be used for risk stratification.Trial registration numberISRCTN63545820; pre-results.

microRNAs (miRNAs) have shown promise as potential new biomarkers for myocardial injury and myocardial ischemia. New digital polymerase chain reaction (PCR) techniques allow for highly precise and reliable absolute direct quantification.In this pilot study we used droplet digital PCR (ddPCR) to assess if miRNAs might be released into circulation in patients with functionally relevant coronary artery disease (CAD). Blood samples for measurement of high-sensitivity cardiac troponin I (hs-cTnI) and miRNAs were obtained before, immediately after peak stress, and 2 h after stress testing in a blinded manner in consecutive patients referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT/CT). ddPCR was used to directly quantify the serum concentrations of miR-21, miR-208a, and miR-499 as potential markers of myocardial injury/ischemia. Functionally relevant CAD was determined by expert interpretation of MPI-SPECT/CT, coronary angiography and fractional flow reserve, if performed.Overall, 200 patients were included and functionally relevant CAD was detected in 85 of them (42%). Neither miR-21, miR-208a, nor miR-499 concentrations differed at rest, stress, or 2-h after stress when comparing patients with versus without functionally relevant CAD, while hs-cTnI concentrations were significantly higher in patients with functionally relevant CAD (P 0.001). Exercise-induced changes in miRNA or hs-cTnI concentrations did not have diagnostic utility and were similar in patients with versus without functionally relevant CAD.miR-208a, miR-21 and miR-499 concentrations at rest, after exercise and exercise-induced changes do not provide additional clinical value regarding the detection of functionally relevant CAD.

Aims The aim of this study is to characterize recurrent syncope, including sex-specific aspects, and its impact on death and major adverse cardiovascular events (MACE). Methods and results We characterized recurrent syncope in a large international multicentre study, enrolling patients ≥40 years presenting to the emergency department (ED) with a syncopal event within the last 12 h. Syncope aetiology was centrally adjudicated by two independent cardiologists using all information becoming available during syncope work-up and long-term follow-up. Overall, 1790 patients were eligible for this analysis. Incidence of recurrent syncope was 20% [95% confidence interval (CI) 18–22%] within the first 24 months. Patients with an adjudicated final diagnosis of cardiac syncope (hazard ratio (HR) 1.50, 95% CI 1.11–2.01) or syncope with an unknown aetiology even after central adjudication (HR 2.11, 95% CI 1.54–2.89) had an increased risk for syncope recurrence. Least Absolute Shrinkage and Selection Operator regression fit on all patient information available early in the ED identified >3 previous episodes of syncope as the only independent predictor for recurrent syncope (HR 2.13, 95% CI 1.64–2.75). Recurrent syncope carried an increased risk for death (HR 1.87, 95% CI 1.26–2.77) and MACE (HR 2.69, 95% CI 2.02–3.59) over 24 months of follow-up, however, with a time-dependent effect. These findings were confirmed in a sensitivity analysis excluding patients with syncope recurrence or MACE before or during ED evaluation. Conclusion Recurrence rates of syncope are substantial and vary depending on syncope aetiology. Importantly, recurrent syncope carries a time-dependent increased risk for death and MACE. Trial registration BAsel Syncope EvaLuation (BASEL IX, ClinicalTrials.gov registry number NCT01548352).

BACKGROUND We aimed to directly compare high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) in the detection of functionally relevant coronary artery disease (fCAD). METHODS Consecutive patients referred with clinical suspicion of fCAD and no structural heart disease other than coronary artery disease were included. The presence of fCAD was based on rest/stress myocardial perfusion single-photon emission computed tomography/computed tomography and coronary angiography. hs-cTnI and hs-cTnT concentrations were measured in a blinded fashion. Diagnostic accuracy was quantified using the area under the ROC curve (AUC) and evaluated both for uniform use in all patients and for sex-specific use in women and men separately. The prognostic end point was major adverse cardiac events (MACEs; cardiovascular death or myocardial infarction) within 2 years. For the prognostic performance, we used a multivariable model comparison with the Akaike information criterion (AIC). RESULTS fCAD was detected in 613 of 2062 patients (29.7%) overall, 112 of 664 of women (16.9%), and 501 of 1398 of men (35.8%). hs-cTnI and hs-cTnT had comparable diagnostic accuracy when assessed for uniform use in all patients (AUC, 0.68 vs 0.66; P = 0.107) and separately in women (AUC, 0.68 vs 0.63; P = 0.068) and men (AUC, 0.65 vs 0.64; P = 0.475). However, women required lower rule-out cutoffs to achieve high sensitivity, and men needed higher rule-in cutoffs to achieve high specificity. hs-cTnI and hs-cTnT were strongly and independently associated with MACE within 2 years (P < 0.001), with comparable prognostic accuracies by the AIC. CONCLUSIONS hs-cTnI and hs-cTnT provide moderate and comparable diagnostic accuracy. Sex-specific cutoffs may be preferred. The prognostic utility of both troponins is comparable.

Background : Various scores have been derived for the assessment of syncope patients in the emergency department (ED) but stay inconsistently validated. We aim to compare their performance to the one of a common, easy-to-use CHADS 2 score. Methods : We prospectively enrolled patients ≥ 40 years old presenting with syncope to the ED in a multicenter study. Early clinical judgment (ECJ) of the treating ED-physician regarding the probability of cardiac syncope was quantified. Two independent physicians adjudicated the final diagnosis after 1-year follow-up. Major cardiovascular events (MACE) and death were recorded during 2 years of follow-up. Nine scores were compared by their area under the receiver-operator characteristics curve (AUC) for death, MACE or the diagnosis of cardiac syncope. Results : 1490 patients were available for score validation. The CHADS 2 -score presented a higher or equally high accuracy for death in the long- and short-term follow-up than other syncope-specific risk scores. This score also performed well for the prediction of MACE in the long- and short-term evaluation and stratified patients with accuracy comparative to OESIL, one of the best performing syncope-specific risk score. All scores performed poorly for diagnosing cardiac syncope when compared to the ECJ. Conclusions : The CHADS 2 -score performed comparably to more complicated syncope-specific risk scores in the prediction of death and MACE in ED syncope patients. While better tools incorporating biochemical and electrocardiographic markers are needed, this study suggests that the CHADS 2 -score is currently a good option to stratify risk in syncope patients in the ED. Trial registration: NCT01548352

PurposeNew nodules after baseline are regularly found in low-dose CT lung cancer screening and have a high lung cancer probability. It is unknown whether morphological and location characteristics can improve new nodule risk stratification by size.MethodsSolid non-calcified nodules detected during incidence screening rounds of the randomised controlled Dutch-Belgian lung cancer screening (NELSON) trial and registered as new or previously below detection limit (15 mm3) were included. A multivariate logistic regression analysis with lung cancer as outcome was performed, including previously established volume cut-offs (3, 30–3 and ≥200 mm3) and nodule characteristics (location, distribution, shape, margin and visibility 3 in retrospect).ResultsOverall, 1280 new nodules were included with 73 (6%) being lung cancer. Of nodules ≥30 mm3 at detection and visible 3 in retrospect, 22% (6/27) were lung cancer. Discrimination based on volume cut-offs (area under the receiver operating characteristic curve (AUC): 0.80, 95% CI 0.75 to 0.84) and continuous volume (AUC: 0.82, 95% CI 0.77 to 0.87) was similar. After adjustment for volume cut-offs, only location in the right upper lobe (OR 2.0, P=0.012), central distribution (OR 2.4, P=0.001) and visibility 3 in retrospect (OR 4.7, P=0.003) remained significant predictors for lung cancer. The Hosmer-Lemeshow test (P=0.75) and assessment of bootstrap calibration curves indicated adequate model fit. Discrimination based on the continuous model probability (AUC: 0.85, 95% CI 0.81 to 0.89) was superior to volume cut-offs alone, but when stratified into three risk groups (AUC: 0.82, 95% CI 0.78 to 0.86), discrimination was similar.ConclusionContrary to morphological nodule characteristics, growth-independent characteristics may further improve volume-based new nodule lung cancer prediction, but in a three-category stratification approach, this is limited.Trial registration numberISRCTN63545820; pre-results.

BACKGROUND This study aimed to prospectively advance a rule-out strategy for functionally significant coronary artery disease (CAD) by use of high-sensitivity cardiac troponin I (hs-cTnI) from bench to bedside, by application of a 3-step approach: validation in serum, correlation in plasma, and application on a clinical platform. METHODS Patients without known CAD referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT/CT) were assigned to 3 consecutive cohorts: validation, correlation, and application. Functionally relevant CAD was adjudicated with the use of expert interpretation of MPI-SPECT/CT and, if available, coronary angiography. In the validation cohort resting hs-cTnI was measured in serum before stress testing with the research Erenna system, in serum and plasma in the correlation cohort with the research Erenna system, and in plasma in the application cohort with the clinical Clarity system. RESULTS Overall, functionally relevant CAD was adjudicated in 21% (304/1478) of patients. In the validation cohort (n = 613), hs-cTnI concentrations were significantly higher in patients with functionally relevant CAD (median 2.8 ng/L vs 1.9 ng/L, P < 0.001) as compared to patients without functionally relevant CAD and allowed a rule out with 95% sensitivity in 14% of patients. In the correlation cohort (n = 606), hs-cTnI concentrations in serum and plasma strongly correlated (Spearman r = 0.921) and had similar diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (0.686 vs 0.678, P = 0.425). In the application cohort (n = 555), very low hs-cTnI plasma concentrations (< 0.5 ng/L) ruled out functionally relevant CAD with 95% sensitivity in 10% of patients. CONCLUSIONS A single resting plasma hs-cTnI measurement can safely rule out functionally relevant CAD in around 10% of patients without known CAD.

BACKGROUND: New nodules are regularly found after the baseline round of low-dose computed tomography (LDCT) lung cancer screening. The relationship between a participant's number of new nodules and lung cancer probability is unknown. METHODS: Participants of the ongoing Dutch-Belgian Randomized Lung Cancer Screening (NELSON) Trial with (sub)solid nodules detected after baseline and registered as new by the NELSON radiologists were included. The correlation between a participant's new nodule count and the largest new nodule size was assessed using Spearman's rank correlation. To evaluate the new nodule count as predictor for new nodule lung cancer together with largest new nodule size, a multivariable logistic regression analysis was performed. RESULTS: In total, 705 participants with 964 new nodules were included. In 48% (336/705) of participants no nodule had been found previously during baseline screening and in 22% (154/705) of participants >1 new nodule was detected (range 1-12 new nodules). Eventually, 9% (65/705) of the participants had lung cancer in a new nodule. In 100% (65/65) of participants with new nodule lung cancer, the lung cancer was the largest or only new nodule at initial detection. The new nodule lung cancer probability did not differ significantly between participants with 1 (10% [56/551], 95%CI 8-13%) or >1 new nodule (6% [9/154], 95%CI 3-11%, P = .116). An increased number of new nodules positively correlated with a participant's largest nodule size (P

Introduction: Low-dose computed tomography (LDCT) lung cancer screening is recommended in the United States. While new solid nodules after baseline screening have a high lung cancer probability at small size and require lower size cutoff values than baseline nodules, there only is limited evidence on management of new subsolid nodules.Methods: Within the Dutch-Belgian randomized controlled LDCT lung cancer screening trial (NELSON), 7557 participants underwent baseline screening between April 2004 and December 2006. Participants with new subsolid nodules detected after the baseline screening round were included.Results: In the three incidence screening rounds, 60 new subsolid nodules (43 [72%] part-solid, 17 [28%] nonsolid) not visible in retrospect were detected in 51 participants, representing 0.7% (51 of 7295) of participants with at least one incidence screening. Eventually, 6% (3 of 51) of participants with a new subsolid nodule were diagnosed with (pre-)malignancy in such a nodule. All (pre-) malignancies were adenocarcinoma (in situ) and diagnostic workup (referral 950, 364, and 366 days after first detection, respectively) showed favorable staging (stage I). Overall, 67% (33 of 49) of subsolid nodules with an additional follow-up screening were resolving.Conclusions: Less than 1% of participants in LDCT lung cancer screening presents with a new subsolid nodule after baseline. Contrary to new solid nodules, data suggest that new subsolid nodules may not require a more aggressive follow-up. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Background Debate about the optimal lung cancer screening strategy is ongoing. In this study, previous screening history of the Dutch-Belgian Lung Cancer Screening trial (NELSON) is investigated on if it predicts the screening outcome (test result and lung cancer risk) of the final screening round. Methods 15â €..792 participants were randomised (1:1) of which 7900 randomised into a screening group. CT screening took place at baseline, and after 1, 2 and 2.5â €..years. Initially, three screening outcomes were possible: negative, indeterminate or positive scan result. Probability for screening outcome in the fourth round was calculated for subgroups of participants. Results Based on results of the first three rounds, three subgroups were identified: (1) those with exclusively negative results (n=3856; 73.0%); (2) those with ≥1 indeterminate result, but never a positive result (n=1342; 25.5%); and (3) with ≥1 positive result (n=81; 1.5%). Group 1 had the highest probability for having a negative scan result in round 4 (97.2% vs 94.8% and 90.1%, respectively, p

INTRODUCTION: In incidence lung cancer screening rounds, new pulmonary nodules are regular findings. They have a higher lung cancer probability than baseline nodules. Previous studies have shown that baseline perifissural nodules (PFNs) represent benign lesions. Whether this is also the case for incident PFNs is unknown. This study evaluated newly detected nodules in the Dutch-Belgian randomized-controlled NELSON study with respect to incidence of fissure-attached nodules, their classification, and lung cancer probability. METHODS: Within the NELSON trial, 7557 participants underwent baseline screening between April 2004 and December 2006. Participants with new nodules detected after baseline were included. Nodules were classified based on location and attachment. Fissure-attached nodules were re-evaluated to be classified as typical, atypical, or non-PFN by two radiologists without knowledge of participant lung cancer status. RESULTS: One thousand four hundred eighty-four new nodules were detected in 949 participants (77.4% male, median age 59 years [interquartile range: 55-63 years]) in the second, third, and final NELSON screening round. Based on 2-year follow-up or pathology, 1393 nodules (93.8%) were benign. In total, 97 (6.5%) were fissure-attached, including 10 malignant nodules. None of the new fissure-attached malignant nodules was classified as typical or atypical PFN. CONCLUSIONS: In the NELSON study, 6.5% of incident lung nodules were fissure-attached. None of the lung cancers that originated from a new fissure-attached nodule in the incidence lung cancer screening rounds was classified as a typical or atypical PFN. Our results suggest that also in the case of a new PFN, it is highly unlikely that these PFNs will be diagnosed as lung cancer. ispartof: JOURNAL OF THORACIC ONCOLOGY vol:15 issue:1 pages:125-129 ispartof: location:United States status: published

Background The optimal noninvasive method for surveillance in symptomatic patients with stable coronary artery disease (CAD) is unknown. Objective To apply a novel approach using very low concentrations of high-sensitivity cardiac troponin I (hs-cTnI) for exclusion of inducible myocardial ischemia in symptomatic patients with CAD. Design Prospective diagnostic cohort study. (ClinicalTrials.gov: NCT01838148). Setting University hospital. Patients 1896 consecutive patients with CAD referred with symptoms possibly related to inducible myocardial ischemia. Measurements Presence of inducible myocardial ischemia was adjudicated using myocardial perfusion imaging with single-photon emission computed tomography, as well as coronary angiography and fractional flow reserve measurements where available. Staff blinded to adjudication measured circulating hs-cTn concentrations. An hs-cTnI cutoff of 2.5 ng/L, derived previously in mostly asymptomatic patients with CAD, was assessed. Predefined target performance criteria were at least 90% negative predictive value (NPV) and at least 90% sensitivity for exclusion of inducible myocardial ischemia. Sensitivity analyses were based on measurements with an hs-cTnT assay and an alternative hs-cTnI assay with even higher analytic sensitivity (limit of detection, 0.1 ng/L). Results Overall, 865 patients (46%) had inducible myocardial ischemia. The hs-cTnI cutoff of 2.5 ng/L provided an NPV of 70% (95% CI, 64% to 75%) and a sensitivity of 90% (CI, 88% to 92%) for exclusion of inducible myocardial ischemia. No hs-cTnI cutoff reached both performance characteristics predefined as targets. Similarly, using the alternative assays for hs-cTnI or hs-cTnT, no cutoff achieved the target performance: hs-cTnT concentrations less than 5 ng/L yielded an NPV of 66% (CI, 59% to 72%), and hs-cTnI concentrations less than 2 ng/L yielded an NPV of 68% (CI, 62% to 74%). Limitation Data were generated in a large single-center diagnostic study using central adjudication. Conclusion In symptomatic patients with CAD, very low hs-cTn concentrations, including hs-cTnI concentrations less than 2.5 ng/L, do not generally allow users to safely exclude inducible myocardial ischemia. Primary funding source European Union, Swiss National Science Foundation, Kommission fur Technologie und Innovation (Innosuisse), Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University of Basel, University Hospital Basel, Roche, Abbott, and Singulex.

We studied 2240 indeterminate solid nodules (volume 50–500mm3) to determine the correlation of diameter and semi-automated volume measurements for pulmonary nodule size estimation. Intra-nodular diameter variation, defined as maximum minus minimum diameter through the nodule’s center, varied by 2.8 mm (median, IQR:2.2–3.7 mm), so above the 1.5 mm cutoff for nodule growth used in Lung CT Screening Reporting and Data System (Lung-RADS). Using mean or maximum axial diameter to assess nodule volume led to a substantial mean overestimation of nodule volume of 47.2% and 85.1%, respectively, compared to semi-automated volume. Thus, size of indeterminate nodules is poorly represented by diameter.Trial registration numberPre-results, ISRCTN63545820.

Until now, high-sensitivity cardiac troponin (hs-cTn) assays were mainly developed for large central laboratory platforms.This study aimed to assess the clinical performance of a point-of-care (POC)-hs-cTnI assay in patients with suspected myocardial infarction (MI).This study enrolled patients presenting to the emergency department with symptoms suggestive of MI. Two cardiologists centrally adjudicated the final diagnosis using all clinical data including cardiac imaging. The primary objective was to directly compare diagnostic accuracy of POC-hs-cTnI-TriageTrue versus best-validated central laboratory assays. Secondary objectives included the derivation and validation of a POC-hs-cTnI-TriageTrue-specific 0/1-h algorithm.MI was the adjudicated final diagnosis in 178 of 1,261 patients (14%). The area under the curve (AUC) for POC-hs-cTnI-TriageTrue at presentation was 0.95 (95% confidence interval [CI]: 0.93 to 0.96) and was at least comparable to hs-cTnT-Elecsys (AUC: 0.94; 95% CI: 0.93 to 0.96; p = 0.213) and hs-cTnI-Architect (AUC: 0.92; 95% CI: 0.90 to 0.93; p 0.001). A single cutoff concentration 3 ng/l at presentation identified 45% of patients at low risk with a negative predictive value (NPV) of 100% (95% CI: 99.4% to 100%). A single cutoff concentration60 ng/l identified patients at high risk with a positive predictive value (PPV) of 76.8% (95% CI: 68.9% to 83.6%). The 0/1-h algorithm ruled out 55% of patients (NPV: 100%; 95% CI: 98.8% to 100%), and ruled in 18% of patients (PPV: 76.8%; 95% CI: 67.2% to 84.7%). Ruled-out patients had cumulative event rates of 0% at 30 days and 1.6% at 2 years. This study confirmed these findings in a secondary analysis including hs-cTnI-Architect for central adjudication.The POC-hs-cTnI-TriageTrue assay provides high diagnostic accuracy in patients with suspected MI with a clinical performance that is at least comparable to that of best-validated central laboratory assays. (Advantageous Predictors of Acute Coronary Syndromes Evaluation Study [APACE]; NCT00470587).

Background The clinical significance of prominent T-waves, also referred as hyperacute T-waves, in the early diagnosis of acute myocardial infarction (AMI) is unknown. Purpose To evaluate the clinical utility of hyperacute T-waves in the early diagnosis of AMI. Methods In a prospective diagnostic study enrolling patients presenting to the emergency department (ED) with symptoms suggestive of AMI, final diagnoses were adjudicated by two independent cardiologists based on clinical information including cardiac imaging. Electronic electrocardiogram data were available in 2946 consecutive patients. Patients with left ventricular hypertrophy, complete left bundle branch block or pacemaker were excluded from further analysis. In the remaining 2382 patients, the T-wave amplitude was automatically derived from the standard 10 seconds 12-lead ECG recorded at presentation to the ED using an established algorithm. Results Median (IQR) time from chest pain onset (CPO) to ED presentation was 5 (IQR [2.5, 12.2]) hours. A total of 219 patients (9%) presented to the ED within 1h or less from CPO. AMI was the final diagnosis in 18% (NSTEMI in 15%, STEMI in 3%) of patients. High T-wave amplitude in leads AVF, III and V1 were associated with AMI. Optimal cut-offs were derived to achieve a predefined positive predictive value (PPV) of at least 75%. These criteria were 473mV, 357mV and 483mV for AVF, III and V1, respectively. With these cut-offs 1.4%, 4.2% and 0.9% of all patients with AMI were detected and specificity was 99.9% (95% CI [99.7%, 100%]), 99.7% (95% CI [99.4%, 99.9%]) and 99.9% (95% CI [99.8%, 100%]). However, majority of the patients with AMI correctly identified by the hyperacute T-wave had also significant ST-element elevations (AVF: 5 out of 6; [83.3%]; III: 10 out of 18 [56%]; V1:1 out of 4; [25%]). Conclusion In patients presenting to the ED with symptoms suggestive of AMI, only leads AVF, III and V1 showed hyperacute T-waves with high PPV. However, incidence of this finding is very low. In addition, majority of the cases correctly identified by hyperacute T-waves also had concomitant ST-segment elevations. Therefore, hyperacute T-waves have only very limited utility in the early diagnosis of AMI in the ED. Acknowledgement/Funding Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union,the Stiftung für kardiovaskuläre Forschung Basel

Background The MEESSI-acute heart failure (AHF) risk score has high accuracy in the prediction of 30-day mortality in patients presenting with AHF and may be considered the current gold standard for this indication. Purpose As the original MEESSI model does not include measurements of inflammatory biomarkers, the impact of interleukin-6 or C-reactive protein (CRP) on the model's goodness of fit is unknown. Methods In a prospective multicenter diagnostic study the presence of AHF was centrally adjudicated by two independent cardiologists among patients presenting with acute dyspnea to the ED. The MEESSI-AHF risk score was calculated using a recalibrated model containing 12 independent risk factors. The incremental value of interleukin-6 and CRP was examined by the use of logistic regression analysis and enter method variable selection with an entry criterion of p Results In 1247 patients with adjudicated AHF, the MEESSI-AHF risk score was calculated. Of these, 1113 patients (89.3%) had available measurements of interleukin-6 and CRP. In the logistic regression analysis both biomarkers had a highly significant impact on the MEESSI model (p Discrimination original_updated Conclusion There is significant incremental value of interleukin-6 and CRP to the MEESSI score as indicated by the improved goodness of fit compared to the original model. Acknowledgement/Funding European Union, the Swiss National Science Foundation, the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel

Background Better characterization of the different pathophysiological mechanisms involved in normotensive and hypertensive acute heart failure (AHF) might help to develop novel individualized treatment strategies. Methods The extent of hemodynamic cardiac stress and cardiomyocyte injury was quantified by measuring B-type natriuretic peptide (BNP) as well as high-sensitive cardiac troponin T (hs-cTnT) in 1,152 unselected patients presenting with AHF to the emergency department (derivation cohort). Systolic blood pressure (SBP) of 90 - 140 mmHg at presentation was used to define normotensive AHF. Findings regarding hemodynamic cardiac stress and cardiomyocyte injury were validated in a second independent AHF cohort (validation cohort; n=324). Results In the derivation cohort 667 (58%) patients had hypertensive AHF. Hemodynamic cardiac stress, as quantified by BNP levels, was significantly higher in normotensive AHF as compared to hypertensive AHF (1,105 pg/mL versus 827 pg/mL, p Table 1. Cardiac stress and myocardial necrosis as quantified by BNP and hs-cTnT plasma concentrations Overall Hypertensive AHF Normotensive AHF p-value BNP in pg/ml, median (IQR) 974 (536–1,712) 827 (448–1,419) 1,105 (611–1,956) Figure 1 Conclusion Biomarker profiling revealed that the extent of hemodynamic stress and cardiomyocyte injury is different in patients with normotensive and hypertensive AHF. This characterization could help to understand AHF phenotypes better, which in turn may lead to more specific management in future, thus improving the dismal prognosis in these patients. Acknowledgement/Funding European Union, Swiss National Science Foundation, Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University of Basel

Background Cardiac myosin-binding protein C (cMyC) is a novel biomarker quantifying cardiac injury. Its utility for the diagnosis, prognosis, and therapy guidance in acute heart failure (AHF) is unclear. Methods In a prospective diagnostic multicentre study, unselected patients presenting with acute dyspnoea to the emergency department were enrolled. cMyC, high-sensitive cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations were measured. Two independent cardiologists/internists centrally adjudicated the final diagnosis using all individual patient's information. Co-primary outcome measures were cMyC's: diagnostic safety and efficacy; prognostic accuracy. Results Among 1,330 recruited patients, 247 from an AHF substudy were not included in the diagnostic analysis. Accordingly, 548 patients (51%) in this analysis had an adjudicated diagnosis of AHF. For the rapid rule-out of AHF, the cMyC cut-off concentration at 16 ng/L achieved a sensitivity of 95% (95% CI, 93–97%), a negative predictive value of 88% (95% CI, 84–92%), and allowed to rule-out 21% of the patients. Correspondingly, cMyC's efficacy and safety in the triage of AHF were slightly lower than NT-proBNP's. Of the 790 AHF patients in the prognostic analysis, 222 (28%) died during the 360 days' follow-up. Patients with cMyC plasma concentrations above the median had significantly shorter mean time to death (274 versus 320 days, p=0.001). Compared to hs-cTnT and discharge NT-proBNP, cMyC showed non-inferior prognostic accuracy. No significant interactions between cMyC and cardiac medical therapies at discharge in predicting 360 days survival were present. Conclusion cMyC performs well in the rapid triage and prognosis of AHF. Acknowledgement/Funding European Union, Swiss National Science Foundation, Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University Hospital of Basel

Background The novel high-sensitivity cardiac troponin I (hs-cTnI)-Vitros assay was developed recently. Before its possible implementation into routine clinical care for triage of chest pain patients, its performance needs clinical validation. Purpose To clinically validate hs-cTnI-Vitros and to derive and validate an assay-specific 0/1h-algorithm following the European Society of Cardiology (ESC) recommendations. Methods In a prospective international multicentre study (12 centres in 5 European countries) we enrolled patients presenting to the emergency department with symptoms suggestive of acute myocardial infarction (AMI). Final diagnoses were centrally adjudicated by two independent cardiologists including all clinical information including cardiac imaging twice: first, using serial hs-cTnT (Elecsys, primary analysis) and second, using hs-cTnI (Architect, secondary analysis) measurements in addition to the clinically used (hs)-cTn. Hs-cTnI-Vitros was measured at presentation and at 1h in a blinded fashion. Primary objective was direct comparison of diagnostic accuracy as quantified by the area under the receiver-operating-characteristic curve (AUC) of hs-cTnI-Vitros versus the two established hs-cTn assays (hs-cTnT-Elecsys, hs-cTnI-Architect). Secondary objectives included the derivation and validation of a hs-cTnI-Vitros specific 0/1h-algorithm. Results AMI was the adjudicated final diagnosis in 158/1231 (13%) patients. The AUC at presentation for hs-cTnI-Vitros was 0.95 (95% CI, 0.93–0.96), and significantly higher as hs-cTnT-Elecsys (0.94 [95% CI, 0.92–0.95; p=0.01]) and hs-cTnI-Architect (0.92 [95% CI, 0.90–0.94; p ROC Curves for the 3 hs-cTn assays at 0h Conclusions The novel hs-cTnI-Vitros assay has even higher diagnostic accuracy as the current gold-standards hs-cTnT and hs-cTnI. The hs-cTnI-Vitros specific 0/1h-algorithms allows a safe rule-out and accurate rule-in of AMI in about 70% of patients within 1h after presentation to the ED. Acknowledgement/Funding Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union, the Stiftung für kardiovaskuläre Forschung Basel