Design, Rationale and Initial Findings From HERA-FIB on 10 222 Patients With Atrial Fibrillation Presenting to an Emergency Department Over An 11-Year Period.

BACKGROUND: For the majority of patients with atrial fibrillation (AF), disease management has improved in recent years. However, there are still populations underrepresented or excluded in current registries and randomized controlled trials. HERA-FIB (Heidelberg Registry of Atrial Fibrillation) was planned to assess real-world evidence for the prevalence, demographic characteristics and management of patients with the diagnosis of AF presenting consecutively to a chest pain unit. METHODS AND RESULTS: HERA-FIB is a retrospective, observational, single-center study on patients with a diagnosis of AF presenting to a chest pain unit from June 2009 until March 2020. This article describes the structure, governance, outcome assessment, quality and data collection processes of the registry. Additionally, characteristics of populations of special interest are described. The study consecutively enrolled 10 222 patients presenting with AF to the chest pain unit of the University Hospital of Heidelberg. Clinical parameters and patient characteristics were assessed retrospectively. Outcome parameters included rates for all-cause death, stroke, myocardial infarction and major bleedings. We were able to investigate patient cohorts of special interest such as advanced chronic kidney disease, octogenarians, and those with acute coronary syndrome who are often underrepresented in current studies and randomized controlled trials. CONCLUSIONS: HERA-FIB is one of the largest real-world single-center retrospective registries on patients with AF, which captures the era of transition from vitamin K antagonists to non-vitamin K oral anticoagulation regimens in clinical practice and offers the possibility to investigate patient populations usually underrepresented or excluded in current available randomized controlled trials and registries. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT05995561.

Comparison of the clinical chemistry score to other biomarker algorithms for rapid rule-out of acute myocardial infarction and risk stratification in patients with suspected acute coronary syndrome.

BACKGROUND: The clinical chemistry score (CCS) comprising high-sensitivity cardiac troponins (hs-cTn), glucose and estimated glomerular filtration rate has been previously validated with superior accuracy for detection and risk stratification of acute myocardial infarction (AMI) compared to hs-cTn alone. METHODS: The CCS was compared to other biomarker-based algorithms for rapid rule-out and prognostication of AMI including the hs-cTnT limit-of-blank (LOB, <3 ng/L) or limit-of-detection (LOD, <5 ng/L) and a dual marker strategy (DMS) (copeptin <10 pmol/L and hs-cTnT ≤14 ng/L) in 1506 emergency department (ED) patients with symptoms suggestive of acute coronary syndrome. Negative predictive values (NPV) and sensitivities for AMI rule-out, and 12-month combined endpoint rates encompassing mortality, myocardial re-infarction, as well as stroke were assessed. RESULTS: NPVs of 100% (95% CI: 98.3-100%) were observed for CCS = 0, hs-cTnT LoB and hs-cTnT LoD with rule-out efficacies of 11.1%, 7.6% and 18.3% as well as specificities of 13.0% (95% CI: 9.9-16.6%), 8.8% (95% CI: 7.3-10.5%) and 21.4% (95% CI: 19.2-23.8%), respectively. A CCS ≤ 1 achieved a rule-out in 32.2% of all patients with a NPV of 99.6% (95% CI: 98.4-99.9%) and specificity of 37.4% (95% CI: 34.2-40.5%) compared to a rule-out efficacy of 51.2%, NPV of 99.0 (95% CI: 98.0-99.5) and specificity of 59.7% (95% CI: 57.0-62.4%) for the DMS. Rates of the combined end-point of death/AMI within 30 days ranged between 0.0% and 0.7% for all fast-rule-out protocols. CONCLUSIONS: The CCS ensures reliable AMI rule-out with low short and long-term outcome rates for a specific ED patient subset. However, compared to a single or dual biomarker strategy, the CCS displays reduced efficacy and specificity, limiting its clinical utility.

Absence of visible infarction on cardiac magnetic resonance imaging despite the established diagnosis of myocardial infarction by 4th Universal Definition of Myocardial Infarction.

AIMS: Myocardial scarring due to acute myocardial infarction (AMI) can be visualized by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. However, a recent study revealed a group of Type 1 AMI patients with undetectable myocardial injury on LGE. This study aims to describe these cases in detail and explore possible explanations for this new phenomenon. METHODS AND RESULTS: A total of 137 patients diagnosed with either ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (non-STEMI) diagnosed according to the 4th Universal Definition of Myocardial Infarction underwent LGE-CMR after invasive coronary angiography. Fourteen of them (10.2%) showed no LGE and were included in the final study population. Most patients presented with acute chest pain, 3 patients were diagnosed as STEMI, and 11 as non-STEMI. Peak high-sensitive cardiac troponin T ranged from 45 to 1173 ng/L. A culprit lesion was identified in 12 patients. Severe coronary stenoses were found in five patients, while seven patients had subtotal to total coronary artery occlusion. Percutaneous coronary intervention was performed in 10 patients, while 2 patients required coronary artery bypass grafting and no intervention was required in 2 patients. Cardiac magnetic resonance was performed 30 (4-140) days after the initial presentation. Most patients showed preserved left ventricular ejection fraction on CMR. No alternative reasons for the rise/fall of high-sensitive cardiac troponin T were found. CONCLUSION: The absence of LGE on CMR in patients with Type 1 AMI is a new finding. While insufficient spatial resolution of LGE imaging, delayed CMR performance, spontaneous reperfusion, and coronary collaterals may provide some explanations, further investigations are required to fully understand this phenomenon.

Real-World Evidence on Disparities on the Initiation of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome.

Background Management of patients with non-ST-segment-elevation acute coronary syndrome (NSTE-ACS) is based on 2020 European Society of Cardiology guidelines, which recommend the preferential use of prasugrel over ticagrelor. Because the selection of the respective P2Y12 inhibitor has to consider label restrictions, we sought to evaluate the proportion of patients qualifying for either ticagrelor or prasugrel and reasons for noneligibility in an unselected cohort of patients with acute coronary syndrome. Methods and Results In this retrospective observational study, patients with ST-segment-elevation myocardial infarction (STEMI) or NSTE-ACS presenting consecutively during a 24-month period were enrolled. The eligibility of patients for a dual antiplatelet therapy option was assessed retrospectively. A total of 1502 patients had confirmed acute coronary syndrome (287 STEMI and 1215 NSTE-ACS). Eligibility for ticagrelor and full-dose prasugrel differed significantly for STEMI and NSTE-ACS (93% versus 51%, P<0.0001 versus 80% versus 31%, P<0.0001). Eligibility remained significantly lower (STEMI 78% versus NSTE-ACS 52%) if low-dose prasugrel was considered. Patients eligible for full-dose prasugrel had lower ischemic risk per GRACE (Global Registry of Acute Coronary Events) score (109 points [90-129 points] versus 121 points [98-146 points], P<0.0001) and lower bleeding risk (14 points [13-15 points] versus 20 points [12-29 points], P<0.0001) per PRECISE-DAPT (Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy) score. Conclusions In real life, eligibility for prasugrel in patients requiring dual antiplatelet therapy is considerably lower than for ticagrelor, even in a cohort with high rates of coronary angiography and percutaneous coronary interventions. The recommended use of prasugrel over ticagrelor in current acute coronary syndrome guidelines contrasts with our observations of a substantial disparity on the eligibility. This important aspect has not received appropriate attention yet. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT05774431.

Modification of the GRACE Risk Score for Risk Prediction in Patients With Acute Coronary Syndromes.

Importance: The Global Registry of Acute Coronary Events (GRACE) risk score, a guideline-recommended risk stratification tool for patients presenting with acute coronary syndromes (ACS), does not consider the extent of myocardial injury. Objective: To assess the incremental predictive value of a modified GRACE score incorporating high-sensitivity cardiac troponin (hs-cTn) T at presentation, a surrogate of the extent of myocardial injury. Design, Setting, and Participants: This retrospectively designed longitudinal cohort study examined 3 independent cohorts of 9803 patients with ACS enrolled from September 2009 to December 2017; 2 ACS derivation cohorts (Heidelberg ACS cohort and Newcastle STEMI cohort) and an ACS validation cohort (SPUM-ACS study). The Heidelberg ACS cohort included 2535 and the SPUM-ACS study 4288 consecutive patients presenting with a working diagnosis of ACS. The Newcastle STEMI cohort included 2980 consecutive patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Data were analyzed from March to June 2023. Exposures: In-hospital, 30-day, and 1-year mortality risk estimates derived from an updated risk score that incorporates continuous hs-cTn T at presentation (modified GRACE). Main Outcomes and Measures: The predictive value of continuous hs-cTn T and modified GRACE risk score compared with the original GRACE risk score. Study end points were all-cause mortality during hospitalization and at 30 days and 1 year after the index event. Results: Of 9450 included patients, 7313 (77.4%) were male, and the mean (SD) age at presentation was 64.2 (12.6) years. Using continuous rather than binary hs-cTn T conferred improved discrimination and reclassification compared with the original GRACE score (in-hospital mortality: area under the receiver operating characteristic curve [AUC], 0.835 vs 0.741; continuous net reclassification improvement [NRI], 0.208; 30-day mortality: AUC, 0.828 vs 0.740; NRI, 0.312; 1-year mortality: AUC, 0.785 vs 0.778; NRI, 0.078) in the derivation cohort. These findings were confirmed in the validation cohort. In the pooled population of 9450 patients, modified GRACE risk score showed superior performance compared with the original GRACE risk score in terms of reclassification and discrimination for in-hospital mortality end point (AUC, 0.878 vs 0.780; NRI, 0.097), 30-day mortality end point (AUC, 0.858 vs 0.771; NRI, 0.08), and 1-year mortality end point (AUC, 0.813 vs 0.797; NRI, 0.056). Conclusions and Relevance: In this study, using continuous rather than binary hs-cTn T at presentation, a proxy of the extent of myocardial injury, in the GRACE risk score improved the mortality risk prediction in patients with ACS.

Effector T cell chemokine IP-10 predicts cardiac recovery and clinical outcomes post-myocardial infarction.

Background and aims: Preclinical data suggest that activation of the adaptive immune system is critical for myocardial repair processes in acute myocardial infarction. The aim of the present study was to determine the clinical value of baseline effector T cell chemokine IP-10 blood levels in the acute phase of ST-segment elevation myocardial infarction (STEMI) for the prediction of the left ventricular function changes and cardiovascular outcomes after STEMI. Methods: Serum IP-10 levels were retrospectively quantified in two independent cohorts of STEMI patients undergoing primary percutaneous coronary intervention. Results: We report a biphasic response of the effector T cell trafficking chemokine IP-10 characterized by an initial increase of its serum levels in the acute phase of STEMI followed by a rapid reduction at 90min post reperfusion. Patients at the highest IP-10 tertile presented also with more CD4 effector memory T cells (CD4 TEM cells), but not other T cell subtypes, in blood. In the Newcastle cohort (n=47), patients in the highest IP-10 tertile or CD4 TEM cells at admission exhibited an improved cardiac systolic function 12 weeks after STEMI compared to patients in the lowest IP-10 tertile. In the Heidelberg cohort (n=331), STEMI patients were followed for a median of 540 days for major adverse cardiovascular events (MACE). Patients presenting with higher serum IP-10 levels at admission had a lower risk for MACE after adjustment for traditional risk factors, CRP and high-sensitivity troponin-T levels (highest vs. rest quarters: HR [95% CI]=0.420 [0.218-0.808]). Conclusion: Increased serum levels of IP-10 in the acute phase of STEMI predict a better recovery in cardiac systolic function and less adverse events in patients after STEMI.

Correlation of serial high-sensitivity cardiac Troponin T values to infarct mass determined by cardiac magnetic resonance imaging: a validation study.

AIM: To validate correlations between contrast-enhanced magnetic resonance imaging (CE-MRI) infarct mass and high-sensitivity cardiac Troponin T (hs-cTnT) values at different time points in patients with confirmed acute myocardial infarction (AMI). METHODS AND RESULTS: Patients presenting with AMI and with available CE-MRI between 1 January 2018 and 31 December 2020 were included. Correlation coefficients between hs-cTnT on admission, after 24, 48, 72, and 96 h, and peak hs-cTnT values and CE-MRI infarct mass were calculated. Correlations between hs-cTnT and CE-MRI infarct mass were compared with those of a third generation cTnT assay from a previously published study of our group. A total of 137 patients were included for the present analysis. Median CE-MRI infarct mass was 12,5 g [95% confidence interval (CI): 9.8-16.2 g]. Hs-cTnT values and infarct mass correlated well at all time points including admission (r = 0.474, 95% CI: 0.331-0.560, P < 0.0001), 24 h (r = 0.508, 95% CI: 0.370-0.625, P < 0.0001), 48 h (r = 0.547, 95% CI: 0.404-0.664, P < 0.0001), 72 h (r = 0.489, 95% CI: 0.320-0.628, P < 0.0001), 96 h (r = 0.509, 95% CI: 0.330-0.653, P < 0.001) including peak hs-cTnT values (r = 0.547, 95% CI: 0.416-0.656, P < 0.0001), and maximum absolute delta changes within 96 h (r = 0.507, 95% CI: 0.369-0.622, P < 0.001). Correlations of the third generation assay could be confirmed for hs-cTnT at all time points. A superior correlation with CE-MRI infarct mass was observed for hs-cTnT values on admission. CONCLUSION: Hs-cTnT values at different time points correlate well with CE-MRI infarct mass. Correlations of admission hs-cTnT values are superior to those of a third generation assay.

Cathepsin S Levels and Survival Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes.

BACKGROUND: Patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are at high residual risk for long-term cardiovascular (CV) mortality. Cathepsin S (CTSS) is a lysosomal cysteine protease with elastolytic and collagenolytic activity that has been involved in atherosclerotic plaque rupture. OBJECTIVES: The purpose of this study was to determine the following: 1) the prognostic value of circulating CTSS measured at patient admission for long-term mortality in NSTE-ACS; and 2) its additive value over the GRACE (Global Registry of Acute Coronary Events) risk score. METHODS: This was a single-center cohort study, consecutively recruiting patients with adjudicated NSTE-ACS (n = 1,112) from the emergency department of an academic hospital. CTSS was measured in serum using enzyme-linked immunosorbent assay. All-cause mortality at 8 years was the primary endpoint. CV death was the secondary endpoint. RESULTS: In total, 367 (33.0%) deaths were recorded. CTSS was associated with increased risk of all-cause mortality (HR for highest vs lowest quarter of CTSS: 1.89; 95% CI: 1.34-2.66; P < 0.001) and CV death (HR: 2.58; 95% CI: 1.15-5.77; P = 0.021) after adjusting for traditional CV risk factors, high-sensitivity C-reactive protein, left ventricular ejection fraction, high-sensitivity troponin-T, revascularization and index diagnosis (unstable angina/ non-ST-segment elevation myocardial infarction). When CTSS was added to the GRACE score, it conferred significant discrimination and reclassification value for all-cause mortality (Delta Harrell's C: 0.03; 95% CI: 0.012-0.047; P = 0.001; and net reclassification improvement = 0.202; P = 0.003) and CV death (AUC: 0.056; 95% CI: 0.017-0.095; P = 0.005; and net reclassification improvement = 0.390; P = 0.001) even after additionally considering high-sensitivity troponin-T and left ventricular ejection fraction. CONCLUSIONS: Circulating CTSS is a predictor of long-term mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score.

Prognostic value of circulating microRNAs compared to high-sensitivity troponin T in patients presenting with suspected acute coronary syndrome to the emergency department.

BACKGROUND: To evaluate the prognostic value of eleven microRNAs (miRNAs) compared to high-sensitivity Troponin T (hs-cTnT) in patients presenting with suspected acute coronary syndrome (ACS) to the emergency department (ED). METHODS: 1,042 patients presenting between August 2014 and April 2017 were included. Expression levels of eleven microRNAs (miR-21-5p, miR-22-3p, miR-29a-3p, miR-92a-3p, miR-122-5p, miR-126-3p, miR-132-3p, miR-133a-3p, miR-134-5p, miR-191-3p, and miR-423-5p) were determined using RT-qPCR. All-cause mortality (ACM) and a composite of ACM, acute myocardial infarction (AMI) and stroke were defined as endpoints. RESULTS: During a median follow-up of 399 (P25-P75: 381-525) days 58 patients (5.6%) died. The composite endpoint occurred in 86 patients (8.3%). Different expression levels of miR-21-5p (median, P25-P75: 5.28 [5.14-5.51] vs. 5.16 [4.97-5.35], p = 0.0033) and miR-122-5p (median, P25-P75: 5.17 [4.81-5.49] vs. 5.35 [5.01-5.69], p = 0.0184) were observed in patients who died compared to survivors. ROC-optimized cutoff of miR-21-5p (HR, P25-P75: 3.3 [1.2-9.4], p = 0.0239), but not miR-122-5p (HR, P25-P75: 0.4 [0.2-0.8], p = 0.0116), was predictive for all-cause mortality, even after adjustment in a multivariate model. Nevertheless, addition of miR-21-5p and miR-122-5p decreased prognostic accuracy of hs-cTnT for all-cause mortality (△AUC: 0.112, p = 0.0159). Hs-cTnT admission values had a high prognostic value for ACM (AUC [95%CI] = 0.794 [0.751-0.837]) and the composite of ACM, AMI and stroke (AUC [95%CI] = 0.745 [0.695-0.794]). CONCLUSIONS: Despite a different expression depending on outcomes miR-21-5p and miR-122-5p do not add prognostic information to hs-cTnT in patients presenting with suspected ACS to the ED.

Prognostic value of changes in high-sensitivity cardiac troponin T beyond biological variation in stable outpatients with cardiovascular disease: a validation study.

OBJECTIVE: To evaluate the prognostic implications of longitudinal long-term changes beyond the biological variation of high-sensitivity cardiac troponin T (hs-cTnT) in outpatients with stable or asymptomatic cardiovascular disease (CV) and to assess possible differences in the prognostic value while using reference change value (RCV) and minimal important differences (MID) as metric for biological variation. METHODS: Hs-cTnT was measured at index visit and after 12 months in outpatients presenting for routine follow-up. The prognostic relevance of a concentration change of hs-cTnT values exceeding the biological variation defined by RCV and MID of a healthy population within the next 12 months following the stable initial period was determined regarding three endpoints: all-cause mortality (EP1), a composite of all-cause mortality, non-fatal myocardial infarction and stroke (EP2), and a composite of all-cause mortality, non-fatal myocardial infarction, stroke, hospitalization for acute coronary syndrome (ACS) or decompensated heart failure, and planned and unplanned percutaneous coronary interventions (PCI, EP3). RESULTS: Change in hs-cTnT values exceeding the biovariability defined by MID but not by RCV discriminated a group with a higher cardiovascular risk profile. Changes within MID were associated with uneventful course (NPV 91.6-99.7%) while changes exceeding MID were associated with a higher occurrence of all endpoints within the next 365 days indicating a 5.5-fold increased risk for EP 1 (p = 0.041) a 2.4-fold increased risk for EP 2 (p = 0.049) and a 1.9-fold increased risk for EP 3 (p < 0.0001). CONCLUSIONS: In stable outpatients MID calculated from hs-cTnT changes measured 365 ± 120 days apart are helpful to predict an uneventful clinical course. CLINICAL TRIALS IDENTIFIER: NCT01954303.

Low-Level Elevations of Procalcitonin Are Associated with Increased Mortality in Acute Heart Failure Patients, Independent of Concomitant Infection.

We aimed to evaluate the prognostic value of procalcitonin (PCT) in acute heart failure (AHF) patients, especially in those without underlying infection. We enrolled patients presenting with acute dyspnea to the emergency department (ED) of Heidelberg University Hospital and studied the prognostic role of PCT on all-cause death. Of 312 patients, AHF was diagnosed in 139 patients. Of these, 125 patients had AHF without signs of infection, and 14 had AHF complicated by respiratory or other infection. The optimal prognostic PCT cutoff value for mortality prediction was calculated by a receiver operating characteristics curve. In patients with AHF, the prognostic PCT cutoff value was 0.08 ng/mL. The Kaplan-Meier survival analysis showed that AHF patients with PCT values > 0.08 ng/mL had a higher all-cause mortality at 120 days than those with PCT values ≤ 0.08 ng/mL (log-rank p = 0.0123). Similar results could be obtained after subdivision into AHF patients with and without signs of overt infection. In both cases, mortality was higher in patients with PCT levels above the prognostic PCT cutoff than in those with values ranging below this threshold. Moreover, we show that the prognostic PCT cutoff values for mortality prediction ranged below the established PCT cutoff for the guidance of antibiotic therapy. In conclusion, the data of our study revealed that low-level elevations of PCT were associated with an increased mortality in patients with AHF, irrespective of concomitant respiratory or other infection. PCT should thus be further used as a marker in the risk stratification of AHF.

Comparison of the analytical performance of the PATHFAST high sensitivity cardiac troponin I using fresh whole blood vs. fresh plasma samples.

OBJECTIVES: The PATHFAST hs-cTnI (high-sensitivity cardiac troponin) assay is the first point-of-care assay with a high-sensitivity designation that received FDA approval for diagnosis of myocardial infarction (MI). Testing from whole blood does not need centrifugation and therefore is faster and more convenient in the emergency room instead of plasma. However, there is sparse evidence whether point-of-care testing of Tn from whole blood is as reliable as from plasma samples. METHODS: We investigated the agreement between plasma and whole blood hs-cTnI by using the PATHFAST hs-cTnI assay. Hs-cTnT measured on Cobas 602 in the central laboratory and compared to a final diagnosis of NSTEMI using serial hs-cTnT served as reference. We assessed biases, limits of agreement (±1.96 SD) and coefficients of correlation, and tested the discriminatory ability of the baseline sample of plasma and whole blood hs-cTnI and plasma hs-cTnT to discriminate non-ST-segment elevation myocardial infarction (NSTEMI). RESULTS: A total of 224 paired fresh samples were collected simultaneously from 191 patients presenting with suspected acute coronary syndrome. There was an excellent correlation between plasma and whole blood hs-cTnI (r=0.99), and a very good inter-rater agreement (k=0.93) between elevated and normal plasma and whole blood results. Precision evaluation according to CLSI ep 15 revealed comparable coefficients of variation (CV) in whole blood and plasma. The discriminatory ability of baseline hs-cTnT, plasma and whole blood hs-cTnI was excellent (AUC 0.967, AUC 0.954 and AUC 0.953) without significant difference. CONCLUSIONS: Whole blood can be used interchangeably with plasma for more convenient and less time and labor-consuming testing of hs-cTnI on the PATHFAST instrument.

Interpretation of myocardial injury subtypes in COVID-19 disease per fourth version of Universal Definition of Myocardial Infarction.

BACKGROUND: Application of the 4th version of Universal Definition of Myocardial Infarction (UDMI) to characterize rates and prognostic relevance of myocardial injury in COVID-19 disease. METHODS: This retrospective, single-centre observational study enrolled 104 patients hospitalized with SARS-CoV-2 infection. Kaplan-Meier analysis and multivariate Cox regression were used to identify influence of acute or chronic myocardial injury on a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation) and secondary endpoint (mortality, incident acute myocardial injury during hospitalization, incident venous thrombosis, pulmonary embolism or stroke). RESULTS: A total of 27 (26.0%) patients presented with chronic myocardial injury, and 19 (18.3%) with acute myocardial injury. 42 patients(40.4%) developed an incident myocardial injury during hospitalization. The presence of acute or chronic myocardial injury on admission and incident myocardial injury during hospitalization were associated with higher rates of endpoints. Independent predictors for the primary endpoint were higher severity stages according to Siddiqi et al. classification system and history of dyslipidaemia. Maximal hs-cTnT and D-dimer concentrations during hospitalization showed an association (r = 0.61). CONCLUSIONS: Objective description of myocardial injury according to the 4th UDMI in the current COVID-19 pandemic is crucial in order to discriminate patients with acute myocardial infarction and acute, chronic or incident myocardial injury.

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.

Diagnostic value of circulating microRNAs compared to high-sensitivity troponin T for the detection of non-ST-segment elevation myocardial infarction.

AIMS: To assess the diagnostic value of microRNAs (miRNAs) for the detection of non-ST-segment elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: A total of 1042 patients presenting between August 2014 and April 2017 to the emergency department with the suspected acute coronary syndrome were included. Non-ST-segment elevation myocardial infarction was diagnosed per criteria of the fourth Universal definition of myocardial infarction (UDMI) using high-sensitivity troponin T (hs-cTnT). Expression levels of eleven microRNAs (miR-21, miR-22, miR-29a, miR-92a, miR-122, miR-126, miR-132, miR-133, miR-134, miR-191, and miR-423) were determined using RT-qPCR. Discrimination of NSTEMI was assessed for individual and a panel of miRNAs compared to the hs-cTnT reference using C-statistics and reclassification analysis. NSTEMI was diagnosed in 137 (13.1%) patients. The area under the curve (AUC) of the hs-cTnT based reference was 0.937. In a multivariate model, three miRNAs (miR-122, miR-133, and miR-134) were found to be associated with NSTEMI with AUCs between 0.506 and 0.656. A panel consisting of these miRNAs revealed an AUC of 0.662 for the diagnosis of NSTEMI. The AUC of the combination of the miRNA panel and troponin reference was significantly lower than the reference standard (AUC: 0.897 vs. 0.937, P = 0.006). Despite a significant improvement of NSTEMI reclassification measured by IDI and NRI, miRNAs did not improve the specificity of hs-cTnT kinetic changes for the diagnosis of NSTEMI (ΔAUC: 0.04). CONCLUSION: Although single miRNAs are significantly associated with the diagnosis of NSTEMI a miRNA panel does not add diagnostic accuracy to the hs-cTnT reference considering baseline values and kinetic changes as recommended by the fourth version of UDMI. CLINICAL TRIALS IDENTIFIER: NCT02116153.

Peptide YY (PYY) Is Associated with Cardiovascular Risk in Patients with Acute Myocardial Infarction.

AIMS: Recent studies have found circulating concentrations of the gastrointestinal hormone GLP-1 to be an excellent predictor of cardiovascular risk in patients with myocardial infarction. This illustrates a yet not appreciated crosstalk between the gastrointestinal and cardiovascular systems, which requires further investigation. The gut-derived hormone Peptide YY (PYY) is secreted from the same intestinal L-cells as GLP-1. Relevance of PYY in the context of cardiovascular disease has not been explored. In this study, we aimed to investigate PYY serum concentrations in patients with acute myocardial infarction and to evaluate their association with cardiovascular events. MATERIAL AND METHODS: PYY levels were assessed in 834 patients presenting with acute myocardial infarction (553 Non-ST-Elevation Myocardial Infarction (NSTEMI) and 281 ST-Elevation Myocardial Infarction (STEMI)) at the time of hospital admission. The composite outcomes of first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke (3-P-MACE), and all-cause mortality were assessed with a median follow-up of 338 days. RESULTS: PYY levels were significantly associated with age and cardiovascular risk factors, including hypertension, diabetes, and kidney function in addition to biomarkers of heart failure (NT-pro BNP) and inflammation (hs-CRP). Further, PYY was significantly associated with 3-P-MACE (HR: 1.7; 95% CI: 1-2.97; p = 0.0495) and all-cause mortality (HR: 2.69; 95% CI: 1.61-4.47; p = 0.0001) by univariable Cox regression analyses, which was however lost after adjusting for multiple confounders. CONCLUSIONS: PYY levels are associated with parameters of cardiovascular risk as well as cardiovascular events and mortality in patients presenting with acute myocardial infarction. However, this significant association is lost after adjustment for further confounders.

Prognostic Value of Elevated Copeptin and High-Sensitivity Cardiac Troponin T in Patients with and without Acute Coronary Syndrome: The ConTrACS Study.

AIMS: We aimed to assess the prognostic role of copeptin in patients presenting to the emergency department with acute symptoms and increased high-sensitivity cardiac troponin T. METHODS: A total of 3890 patients presenting with acute symptoms to the emergency department of Heidelberg University Hospital were assessed for increased hs-cTnT (>14 ng/L) from three cohorts: the Heidelberg Acute Coronary Syndrome (ACS) Registry (n = 2477), the BIOPS Registry (n = 320), and the ACS OMICS Registry (n = 1093). In a pooled analysis, 1956 patients remained, comprising of 1600 patients with ACS and 356 patients with non-ACS. RESULTS: Median follow-up was 1468 days in the ACS cohort and 709 days in the non-ACS cohort. Elevated copeptin levels (>10 pmol/L) were found in 1174 patients (60.0%) in the entire cohort (58.1% in ACS and 68.5% in non-ACS, respectively) and mortality rates were significantly higher than in patients with normal copeptin levels (29.0% vs. 10.7%, p < 0.001). In a multivariate Cox regression, elevated copeptin was independently associated with all-cause death in the ACS (HR = 1.7, 1.3-2.3, p = 0.002) and non-ACS cohort (HR = 2.7, 1.4-5.0, p = 0.0018). CONCLUSION: Copeptin may aid in identifying patients at risk for adverse outcomes in patients with increased levels of hs-cTnT in ACS patients and in non-ACS conditions.

Effects of crowding in the emergency department on the diagnosis and management of suspected acute coronary syndrome using rapid algorithms: an observational study.

OBJECTIVES: Fast diagnostic algorithms using high-sensitivity troponin (hsTn) in suspected acute coronary syndrome (ACS) are regarded as beneficial to expedite diagnosis and safe discharge of patients in crowded emergency departments (ED). This study investigates the effects of crowding on process times related to the diagnostic protocol itself or other time delays, and outcomes. DESIGN: Prospective single-centre observational study. SETTING: ED (Germany). PARTICIPANTS: Final study population of 2525 consecutive patients with suspected ACS within 12 months, after exclusion of patients with ST-elevation myocardial infarction, missing blood samples, referral from other hospitals or repeated visits. INTERVENTIONS: Use of fast algorithms as per 2015 European Society of Cardiology guidelines. MAIN OUTCOME MEASURES: Crowding was defined as mismatch between patient numbers and monitoring capacities, or mean physician time per case, categorised as normal, high and very high crowding. Outcome measures were length of ED stay, direct discharge from ED, laboratory turn around times (TAT), utilisation of fast algorithms, absolute and relative non-laboratory time, as well as mortality. RESULTS: Crowding was associated with increased length of ED stay (3.75-4.89 hours, p<0.001). While median TAT of the first hsTnT increased (53-57 min, p<0.001), total TAT of serial hsTnT did not increase significantly with higher crowding (p=0.170). Lower utilisation of fast algorithms (p=0.009) and increase of additional hsTnT measurements after diagnosis (p=0.001) were observed in higher crowding. Most importantly, crowding was significantly associated with prolonged absolute (p<0.001), and particularly relative non-laboratory time (63.3%-71.3%, p<0.001). However, there was no significant effect of crowding on mortality, even after adjustment for relevant clinical variables. CONCLUSIONS: Process times, and particularly non-laboratory times, are prolonged in a crowded ED diminishing some positive effects of fast diagnostic algorithms in suspected ACS. Higher crowding levels were not significantly associated with higher all-cause mortality rates. TRIAL REGISTRATION NUMBER: NCT03111862.

Diagnostic performance of D-dimer in predicting venous thromboembolism and acute aortic dissection.

BACKGROUND: D-dimer is elevated in a variety of conditions. The purpose of this study was to assess the positive predictive value of D-dimer to rule in patients with confirmed pulmonary embolism, deep vein thrombosis, acute aortic dissection or thrombosis of the upper extremity in comparison to patients with elevated D-dimer for other reasons. METHODS AND RESULTS: We studied 1334 patients presenting to the emergency department with pulmonary embolism (n=193), deep vein thrombosis (n=73), acute aortic dissection (n=22), thrombosis of the upper extremity (n=8) and 1038 controls. The positive predictive value was increased with higher D-dimer concentrations improving the ability to identify diseases with high thrombus burden. Patients with venous thromboembolism, acute aortic dissection and thrombosis of the upper extremity showed a maximum positive predictive value of 85.2% at a D-dimer level of 7.8 mg/L (95% confidence interval (CI) 78.1 to 90.4). The maximum positive predictive value was lower in cancer patients with venous thromboembolism, acute aortic dissection and thrombosis of the upper extremity, reaching 68.9% at a D-dimer level of 7.5 mg/L (95% CI 57.4 to 78.4). The positive likelihood ratio was very consistent with the positive predictive value. Using a cut-off level of 0.5 mg/L, D-dimer showed a high sensitivity of at least 93%, but a very low specificity of nearly 0%. Conversely, an optimised cut-off value of 4.6 mg/L increased specificity to 95% for the detection of life-threatening venous thromboembolism, acute aortic dissection or thrombosis of the upper extremity at the costs of moderate sensitivities (58% for pulmonary embolism, 41% for deep vein thrombosis, 65% for pulmonary embolism with co-existent deep vein thrombosis, 50% for acute aortic dissection and 13% for thrombosis of the upper extremity). Using the same cut-off in cancer patients, higher values were observed for sensitivity at a specificity level of more than 95%. The area under the curve for the discrimination of venous thromboembolism/acute aortic dissection/thrombosis of the upper extremity from controls was significantly higher in cancer versus non-cancer patients (area under the curve 0.905 in cancer patients, 95% CI 0.89 to 0.92, vs. area under the curve 0.857 in non-cancer patients, 95% CI 0.84 to 0.88; P=0.0349). CONCLUSION: D-dimers are useful not only to rule out but also to rule in venous thromboembolism and acute aortic dissection with an at least moderate discriminatory ability, both in patients with and without cancer.