Combining anatomical and biochemical markers in the detection and risk stratification of coronary artery disease.

AIM: We aimed to test the hypothesis if combining coronary artery calcium score (Ca-score) as a quantitative anatomical marker of coronary atherosclerosis with high-sensitive cardiac troponin as a quantitative biochemical marker of myocardial injury provided incremental value in the detection of functional relevant CAD (fCAD) and risk stratification. METHODS AND RESULTS: Consecutive patients undergoing myocardial perfusion SPECT (MPS) without prior CAD were enrolled. The diagnosis of fCAD was based on the presence of ischemia on MPS and coronary angiography- fCAD was centrally adjudicated in the diagnostic and prognostic domain. Diagnostic accuracy was evaluated using the area under receiver-operating characteristic curve. The composite of cardiovascular death and non-fatal acute myocardial infarction (AMI) within 730 days were the primary prognostic endpoints.Among 1715 patients eligible for the diagnostic analysis, 399 patients had fCAD. The combination of Ca-Score and hs-cTnT had good diagnostic accuracy for the diagnosis of fCAD, AUC 0.79 (95 % CI 0.77-0.81), but no incremental value compared to the Ca-score alone (AUC 0.79 (95%CI 0.77-0.81, p=0.965). Similar results were observed using hs-cTnI (AUC 0.80, 95%CI 0.77-0.82) instead of hs-cTnT.Among 1709 patients (99.7%) with available follow-up, 59 patients (3.5%) suffered the composite primary prognostic endpoint (nonfatal AMI n=34, CV death n=28).Both, Ca-score and hs-cTnT had independent prognostic value. Increased risk was restricted to patients with elevation in both markers. CONCLUSION: The combination of the Ca-score with hs-cTnT increases the prognostic accuracy for future events defining fCAD, but does not provide incremental value versus the Ca-Score alone for the diagnosis of fCAD.

Comparing the utility of clinical risk scores and integrated clinical judgement in patients with suspected acute coronary syndrome.

AIMS: The utility of clinical risk scores regarding the prediction of major adverse cardiac events (MACE) is uncertain. We aimed to directly compare the prognostic performance of five established clinical risk scores as well as an unstructured integrated clinical judgement (ICJ) of the treating emergency department (ED) physician. METHODS AND RESULTS: Thirty-day MACE including all-cause death, life-threatening arrhythmia, cardiogenic shock, acute myocardial infarction (including the index event), and unstable angina requiring urgent coronary revascularization were centrally adjudicated by two independent cardiologists in patients presenting to the ED with acute chest discomfort in an international multicentre study. We compared the prognostic performance of the HEART score, GRACE score, T-MACS, TIMI score, and EDACS, as well as the unstructured ICJ of the treating ED physician (visual analogue scale to estimate the probability of acute coronary syndrome, ranging from 0 to 100). Among 4551 eligible patients, 1110/4551 patients (24.4%) had at least one MACE within 30 days. Prognostic accuracy was high and comparable for the HEART score, GRACE score, T-MACS, and ICJ [area under the receiver operating characteristic curve (AUC) 0.85-0.87] but significantly lower and only moderate for the TIMI score (AUC 0.79, P < 0.001) and EDACS (AUC 0.74, P < 0.001), resulting in sensitivities for the rule-out of 30-day MACE of 93-96, 87 (P < 0.001), and 72% (P < 0.001), respectively. CONCLUSION: The HEART score, GRACE score, T-MACS, and unstructured ICJ of the treating physician, not the TIMI score or EDACS, performed well for the prediction of 30-day MACE and may be considered for routine clinical use. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00470587.

Association of accompanying dyspnoea with diagnosis and outcome of patients presenting with acute chest discomfort.

AIMS: The presence of accompanying dyspnoea is routinely assessed and common in patients presenting with acute chest pain/discomfort to the emergency department (ED). We aimed to assess the association of accompanying dyspnoea with differential diagnoses, diagnostic work-up, and outcome. METHODS AND RESULTS: We enrolled patients presenting to the ED with chest pain/discomfort. Final diagnoses were adjudicated by independent cardiologists using all information including cardiac imaging. The primary diagnostic endpoint was the final diagnosis. The secondary diagnostic endpoint was the performance of high-sensitivity cardiac troponin (hs-cTn) and the European Society of Cardiology (ESC) 0/1h-algorithms for the diagnosis of myocardial infarction (MI). The prognostic endpoints were cardiovascular and all-cause mortality at two years. Among 6045 patients, 2892/6045 (48%) had accompanying dyspnoea. The prevalence of acute coronary syndrome (ACS) in patients with vs. without dyspnoea was comparable (MI 22.4% vs. 21.9%, P = 0.60, unstable angina 8.7% vs. 7.9%, P = 0.29). In contrast, patients with dyspnoea more often had cardiac, non-coronary disease (15.3% vs. 10.2%, P < 0.001). Diagnostic accuracy of hs-cTnT/I concentrations was not affected by the presence of dyspnoea (area under the curve 0.89-0.91 in both groups), and the safety of the ESC 0/1h-algorithms was maintained with negative predictive values >99.4%. Accompanying dyspnoea was an independent predictor for cardiovascular and all-cause death at two years [hazard ratio 1.813 (95% confidence intervals, 1.453-2.261, P < 0.01)]. CONCLUSION: Accompanying dyspnoea was not associated with a higher prevalence of ACS but with cardiac, non-coronary disease. While the safety of the diagnostic work-up was not affected, accompanying dyspnoea was an independent predictor for cardiovascular and all-cause death. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00470587, number NCT00470587.

Hyperacute T Wave in the Early Diagnosis of Acute Myocardial Infarction.

STUDY OBJECTIVE: The diagnostic performance of T-wave amplitudes for the detection of myocardial infarction is largely unknown. We aimed to address this knowledge gap. METHODS: T-wave amplitudes were automatically measured in 12-lead ECGs of patients presenting with acute chest discomfort to the emergency department within a prospective diagnostic multicenter study. The final diagnosis was centrally adjudicated by 2 independent cardiologists. Patients with left ventricular hypertrophy, complete left bundle branch block, or paced ventricular depolarization were excluded. The performance for lead-specific 95th-percentile thresholds were reported as likelihood ratios (lr), specificity, and sensitivity. RESULTS: Myocardial infarction was the final diagnosis in 445 (18%) of 2457 patients. In most leads, T-wave amplitudes tended to be greater in patients without myocardial infarction than those with myocardial infarction, and T-wave amplitude exceeding the 95th percentile had positive and negative lr close to 1 or with confidence intervals (CIs) crossing 1. The exceptions were leads III, aVR, and V1, which had positive lrs of 3.8 (95% CI, 2.7 to 5.3), 4.3 (95% CI, 3.1 to 6.0) and 2.0 (95% CI, 1.4 to 2.9), respectively. These leads normally have inverted T waves, so T-wave amplitude exceeding the 95th percentile reflects upright rather than increased-amplitude hyperacute T waves. CONCLUSION: Hyperacute T waves, when defined as increased T-wave amplitude exceeding the 95th percentile, did not provide useful information in diagnosing myocardial infarction in this sample.

Serum neurofilament light chain in functionally relevant coronary artery disease and adverse cardiovascular outcomes.

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.

Diagnostic discrimination of a novel high-sensitivity cardiac troponin I assay and derivation/validation of an assay-specific 0/1h-algorithm.

BACKGROUND: We aimed to assess the diagnostic utility of the Dimension EXL LOCI High-Sensitivity Troponin I (hs-cTnI-EXL) assay. METHODS: This multicenter study included patients with chest discomfort presenting to the emergency department. Diagnoses were centrally and independently adjudicated by two cardiologists using all available clinical information. Adjudication was performed twice including serial measurements of high-sensitivity cardiac troponin (hs-cTn) I-Architect (primary analysis) and serial measurements of hs-cTnT-Elecsys (secondary analysis) in addition to the clinically used (hs)-cTn. The primary objective was to assess and compare the discriminatory performance of hs-cTnI-EXL, hs-cTnI-Architect and hs-cTnT-Elecsys for acute myocardial infarction (MI). Furthermore, we derived and validated a hs-cTnI-EXL-specific 0/1h-algorithm. RESULTS: Adjudicated MI was the diagnosis in 204/1454 (14%) patients. The area under the receiver operating characteristics curve for hs-cTnI-EXL was 0.94 (95%CI, 0.93-0.96), and comparable to hs-cTnI-Architect (0.95; 95%CI, 0.93-0.96) and hs-cTnT-Elecsys (0.93; 95%CI, 0.91-0.95). In the derivation cohort (n = 813), optimal criteria for rule-out of MI were <9ng/L at presentation (if chest pain onset >3h) or <9ng/L and 0h-1h-change <5ng/L, and for rule-in ≥160ng/L at presentation or 0h-1h-change ≥100ng/L. In the validation cohort (n = 345), these cut-offs ruled-out 56% of patients (negative predictive value 99.5% (95%CI, 97.1-99.9), sensitivity 97.8% (95%CI, 88.7-99.6)), and ruled-in 9% (positive predictive value 83.3% (95%CI, 66.4-92.7), specificity 98.3% (95%CI, 96.1-99.3)). Secondary analyses using adjudication based on hs-cTnT measurements confirmed the findings. CONCLUSIONS: The overall performance of the hs-cTnI-EXL was comparable to best-validated hs-cTnT/I assays and an assay-specific 0/1h-algorithm safely rules out and accurately rules in acute MI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00470587.

Clinical effect of obesity on N-terminal pro-B-type natriuretic peptide cut-off concentrations for the diagnosis of acute heart failure.

AIMS: Obese patients have lower natriuretic peptide concentrations. We hypothesized that adjusting the concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) for obesity could further increase its clinical utility in the early diagnosis of acute heart failure (AHF). METHODS AND RESULTS: This hypothesis was tested in a prospective diagnostic study enrolling unselected patients presenting to the emergency department with acute dyspnoea. Two independent cardiologists/internists centrally adjudicated the final diagnosis using all individual patient information including cardiac imaging. NT-proBNP plasma concentrations were applied: first, using currently recommended cut-offs; second, using cut-offs lowered by 33% with body mass index (BMI) of 30-34.9 kg/m2 and by 50% with BMI ≥ 35 kg/m2 . Among 2038 patients, 509 (25%) were obese, of which 271 (53%) had AHF. The diagnostic accuracy of NT-proBNP as quantified by the area under the receiver-operating characteristic curve was lower in obese versus non-obese patients (0.890 vs. 0.938). For rapid AHF rule-out in obese patients, the currently recommended cut-off of 300 pg/ml achieved a sensitivity of 96.7% (95% confidence interval [CI] 93.8-98.2%), ruling out 29% of patients and missing 9 AHF patients. For rapid AHF rule-in, the age-dependent cut-off concentrations (age <50 years: 450 pg/ml; age 50-75 years: 900 pg/ml; age >75 years: 1800 pg/ml) achieved a specificity of 84.9% (95% CI 79.8-88.9%). Proportionally lowering the currently recommended cut-offs by BMI increased sensitivity to 98.2% (95% CI 95.8-99.2%), missing 5 AHF patients; reduced the proportion of AHF patients remaining in the 'gray zone' (48% vs. 26%; p = 0.002), achieving a specificity of 76.5% (95% CI 70.7-81.4%). CONCLUSIONS: Adjusting NT-proBNP concentrations for obesity seems to further increase its clinical utility in the early diagnosis of AHF.

Performance of the American Heart Association/American College of Cardiology/Heart Rhythm Society versus European Society of Cardiology guideline criteria for hospital admission of patients with syncope.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Diurnal Variations in Natriuretic Peptide Levels: Clinical Implications for the Diagnosis of Acute Heart Failure.

BACKGROUND: Current guidelines recommend interpreting concentrations of NPs (natriuretic peptides) irrespective of the time of presentation to the emergency department. We hypothesized that diurnal variations in NP concentration may affect their diagnostic accuracy for acute heart failure. METHODS: In a secondary analysis of a multicenter diagnostic study enrolling patients presenting with acute dyspnea to the emergency department and using central adjudication of the final diagnosis by 2 independent cardiologists, the diagnostic accuracy for acute heart failure of BNP (B-type NP), NT-proBNP (N-terminal pro-B-type NP), and MR-proANP (midregional pro-atrial NP) was compared among 1577 daytime presenters versus 908 evening/nighttime presenters. In a validation study, the presence of a diurnal rhythm in BNP and NT-proBNP concentrations was examined by hourly measurements in 44 stable individuals. RESULTS: Among patients adjudicated to have acute heart failure, BNP, NT-proBNP, and MR-proANP concentrations were comparable among daytime versus evening/nighttime presenters (all P=nonsignificant). Contrastingly, among patients adjudicated to have other causes of dyspnea, evening/nighttime presenters had lower BNP (median, 44 [18-110] versus 74 [27-168] ng/L; P<0.01) and NT-proBNP (median, 212 [72-581] versus 297 [102-902] ng/L; P<0.01) concentrations versus daytime presenters. This resulted in higher diagnostic accuracy as quantified by the area under the curve of BNP and NT-proBNP among evening/nighttime presenters (0.97 [95% CI, 0.95-0.98] and 0.95 [95% CI, 0.93-0.96] versus 0.94 [95% CI, 0.92-0.95] and 0.91 [95% CI, 0.90-0.93]) among daytime presenters (both P<0.01). These differences were not observed for MR-proANP. Diurnal variation of BNP and NT-proBNP with lower evening/nighttime concentration was confirmed in 44 stable individuals (P<0.01). CONCLUSIONS: BNP and NT-proBNP, but not MR-proANP, exhibit a diurnal rhythm that results in even higher diagnostic accuracy among evening/nighttime presenters versus daytime presenters. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT01831115, NCT02091427, and NCT02210897.

International Validation of the Canadian Syncope Risk Score : A Cohort Study.

BACKGROUND: The Canadian Syncope Risk Score (CSRS) was developed to predict 30-day serious outcomes not evident during emergency department (ED) evaluation. OBJECTIVE: To externally validate the CSRS and compare it with another validated score, the Osservatorio Epidemiologico della Sincope nel Lazio (OESIL) score. DESIGN: Prospective cohort study. SETTING: Large, international, multicenter study recruiting patients in EDs in 8 countries on 3 continents. PARTICIPANTS: Patients with syncope aged 40 years or older presenting to the ED within 12 hours of syncope. MEASUREMENTS: Composite outcome of serious clinical plus procedural events (primary outcome) and the primary composite outcome excluding procedural interventions (secondary outcome). RESULTS: Among 2283 patients with a mean age of 68 years, the primary composite outcome occurred in 7.2%, and the composite outcome excluding procedural interventions occurred in 3.1% at 30 days. Prognostic performance of the CSRS was good for both 30-day composite outcomes and better compared with the OESIL score (area under the receiver-operating characteristic curve [AUC], 0.85 [95% CI, 0.83 to 0.88] vs. 0.74 [CI, 0.71 to 0.78] and 0.80 [CI, 0.75 to 0.84] vs. 0.69 [CI, 0.64 to 0.75], respectively). Safety of triage, as measured by the frequency of the primary composite outcome in the low-risk group, was higher using the CSRS (19 of 1388 [0.6%]) versus the OESIL score (17 of 1104 [1.5%]). A simplified model including only the clinician classification of syncope (cardiac syncope, vasovagal syncope, or other) variable at ED discharge-a component of the CSRS-achieved similar discrimination as the CSRS (AUC, 0.83 [CI, 0.80 to 0.87] for the primary composite outcome). LIMITATION: Unable to disentangle the influence of other CSRS components on clinician classification of syncope at ED discharge. CONCLUSION: This international external validation of the CSRS showed good performance in identifying patients at low risk for serious outcomes outside of Canada and superior performance compared with the OESIL score. However, clinician classification of syncope at ED discharge seems to explain much of the performance of the CSRS in this study. The clinical utility of the CSRS remains uncertain. PRIMARY FUNDING SOURCE: Swiss National Science Foundation & Swiss Heart Foundation.

Soluble urokinase plasminogen activator receptor and functionally relevant coronary artery disease: a prospective cohort study.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker associated with anatomical CAD burden and cardiovascular outcomes including myocardial infarction (MI) and death. We aimed to validate previous findings of the prognostic value of suPAR and to evaluate its diagnostic potential for functional relevant CAD (fCAD). METHODS: Consecutive patients with suspected fCAD were enrolled. Adjudication of fCAD was performed blinded to suPAR concentrations by myocardial perfusion single-photon emission tomography (MPI-SPECT) and coronary angiography. Prognostic outcome measures included all-cause death, cardiovascular death, and incident MI during 2-year follow-up. RESULTS: Among consecutive 968 patients, suPAR concentrations were higher in patients with fCAD compared to those without (3.45 vs. 3.20 ng/mL, p = 0.007), but did not provide acceptable diagnostic accuracy (area under the curve [AUC]: 0.56, 95%CI 0.52-0.60). SuPAR correlated with high-sensitivity cardiac-troponin T (Spearman's rho (ρ) 0.393, p < 0.001), NT-proBNP (ρ = 0.327, p < 0.001), age (ρ = 0.364, p < 0.001) and very weakly with coronary atherosclerosis (ρ = 0.123, p < 0.001). Prognostic discrimination of suPAR was moderate for cardiovascular death (AUC = 0.72, 95%CI 0.62-0.81) and all-cause death (AUC = 0.72, 95%CI 0.65-0.79) at 2-years. SuPAR remained a significant predictor for all-cause death in multivariable Cox regression (HR = 1.96, p = 0.001). CONCLUSIONS: SuPAR was an independent predictor of all-cause death, without diagnostic utility for fCAD. CLINICAL TRIAL REGISTRATION: NCT01838148.

Gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and cardiovascular risk in patients with suspected functionally relevant coronary artery disease (fCAD).

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 < 0.001); however, diagnostic accuracy was low (TMAO area under the receiver operating curve [AUC]: 0.56, 95% CI [0.53-0.59], p < 0.001). In prognostic analyses, TMAO, choline and carnitine above the median were associated with significantly (p < 0.001 for all) higher cumulative events for death and CVD during 5-years follow-up. TMAO remained a significant predictor for death and CVD even in full models adjusted for renal function (HR = 1.58 (1.16, 2.14), 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.

Patient- and procedure-related factors in the pathophysiology of perioperative myocardial infarction/injury.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Activity of the adrenomedullin system to personalise post-discharge diuretic treatment in acute heart failure.

BACKGROUND: Quantifying the activity of the adrenomedullin system might help to monitor and guide treatment in acute heart failure (AHF) patients. The aims were to (1) identify AHF patients with marked benefit or harm from specific treatments at hospital discharge and (2) predict mortality by quantifying the adrenomedullin system activity. METHODS: This was a prospective multicentre study. AHF diagnosis and phenotype were centrally adjudicated by two independent cardiologists among patients presenting to the emergency department with acute dyspnoea. Adrenomedullin system activity was quantified using the biologically active component, bioactive adrenomedullin (bio-ADM), and a prohormone fragment, midregional proadrenomedullin (MR-proADM). Bio-ADM and MR-proADM concentrations were measured in a blinded fashion at presentation and at discharge. Interaction with specific treatments at discharge and the utility of these biomarkers on predicting outcomes during 365-day follow-up were assessed. RESULTS: Among 1886 patients with adjudicated AHF, 514 patients (27.3%) died during 365-day follow-up. After adjusting for age, creatinine, and treatment at discharge, patients with bio-ADM plasma concentrations above the median (> 44.6 pg/mL) derived disproportional benefit if treated with diuretics (interaction p values < 0.001). These findings were confirmed when quantifying adrenomedullin system activity using MR-proADM (n = 764) (interaction p values < 0.001). Patients with bio-ADM plasma concentrations above the median were at increased risk of death (hazard ratio 1.87, 95% CI 1.57-2.24; p < 0.001). For predicting 365-day all-cause mortality, both biomarkers performed well, with MR-proADM presenting an even higher predictive accuracy compared to bio-ADM (p < 0.001). CONCLUSIONS: Quantifying the adrenomedullin's system activity may help to personalise post-discharge diuretic treatment and enable accurate risk-prediction in AHF.

Direct comparison of high-sensitivity cardiac troponin T and I in the early differentiation of type 1 vs. type 2 myocardial infarction.

AIMS: To directly compare the diagnostic accuracy of high-sensitivity cardiac troponin (hs-cTn) T vs. hs-cTnI in the early non-invasive differentiation of Type 1 myocardial infarction (T1MI) due to plaque rupture and atherothrombosis from Type 2 myocardial infarction (T2MI) due to supply-demand mismatch. METHODS AND RESULTS: In a prospective multicentre diagnostic study, two independent cardiologists centrally adjudicated the final diagnosis of T1MI vs. T2MI according to the fourth universal definition of myocardial infarction (MI), using all available clinical information including cardiac imaging in patients presenting with acute chest pain. Diagnostic accuracy was quantified by the area under the receiver operating characteristics curve (AUC). The most extensively validated hs-cTnT-Elecsys and hs-cTnI-Architect assays were measured at presentation, 1 h, and 2 h. Among 5887 patients, 1106 (19%) had a final diagnosis of MI, including 860 (78%) T1MI and 246 (22%) T2MI. The AUC of hs-cTnT-Elecsys to differentiate T1MI from T2MI was moderate and comparable to that provided by hs-cTnI-Architect: hs-cTnT-Elecsys AUC-presentation 0.67 [95% confidence interval (CI) 0.64-0.71], AUC-1 h 0.70 (95% CI 0.66-0.74), and AUC-2 h 0.71 (95% CI 0.66-0.75) vs. hs-cTnI-Architect AUC-presentation 0.71 (95% CI 0.67-0.74), AUC-1 h 0.72 (95% CI 0.68-0.76), and AUC-2 h 0.74 (95% CI 0.69-0.78), all P = not significant (NS). Similarly, the AUC of absolute changes was moderate and comparable for hs-cTnT-Elecsys and hs-cTnI-Architect (all P = NS). Cut-off concentrations achieving at least 90% specificity for the differentiation of T1MI vs. T2MI were >114 ng/L for hs-cTnT-Elecsys [odds ratio (OR) 4.2, 95% CI 2.7-6.6] and >371 ng/L for hs-cTnI-Architect (OR 4.0, 95% CI 2.6-6.2). CONCLUSION: hs-cTnT-Elecsys and hs-cTnI-Architect provided comparable, albeit only moderate, diagnostic accuracy for the early differentiation of T1MI vs. T2MI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00470587, https://clinicaltrials.gov/ct2/show/NCT00470587.

Incidence, clinical presentation, management, and outcome of acute pericarditis and myopericarditis.

AIMS: Little is known about the epidemiology, clinical presentation, management, and outcome of acute pericarditis and myopericarditis. METHODS AND RESULTS: The final diagnoses of acute pericarditis, myopericarditis, and non-ST-segment elevation myocardial infarction (NSTEMI) of patients presenting to seven emergency departments in Switzerland with acute chest pain were centrally adjudicated by two independent cardiologists using all information including serial measurements of high-sensitivity cardiac troponin T. The overall incidence of pericarditis and myopericarditis was estimated relative to the established incidence of NSTEMI. Current management and long-term outcome of both conditions were also assessed. Among 2533 chest pain patients, the incidence of pericarditis, myopericarditis, and NSTEMI were 1.9% (n = 48), 1.1% (n = 29), and 21.6% (n = 548), respectively. Accordingly, the estimated incidence of pericarditis and myopericarditis in Switzerland was 10.1 [95% confidence interval (95% CI) 9.3-10.9] and 6.1 (95% CI 5.6-6.7) cases per 100 000 population per year, respectively, vs. 115.0 (95% CI 112.3-117.6) cases per 100 000 population per year for NSTEMI. Pericarditis (85% male, median age 46 years) and myopericarditis (62% male, median age 56 years) had male predominance, and commonly (50% and 97%, respectively) resulted in hospitalization. No patient with pericarditis or myopericarditis died or had life-threatening arrhythmias within 30 days [incidence 0% (95% CI 0.0-4.8%)]. Compared with NSTEMI, the 2-year all-cause mortality adjusted hazard ratio of pericarditis and myopericarditis was 0.40 (95% CI 0.05-2.96), being 0.59 (95% CI 0.40-0.88) for non-cardiac causes of chest pain. CONCLUSION: Pericarditis and myopericarditis are substantially less common than NSTEMI and have an excellent short- and long-term outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov, number NCT00470587, https://clinicaltrials.gov/ct2/show/NCT00470587.

Mimics and chameleons of COVID-19: patient presentation and accuracy of triage during the first wave.

STUDY AIMS: To quantify mimics and chameleons of coronavirus disease 2019 (COVID-19), to analyse the diagnostic accuracy of the triage protocol, and to describe the resulting groups of mimics and chameleons - including their presenting symptoms and final diagnoses. METHODS: Diagnostic accuracy study including all adult patients tested for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) at the emergency department of the University Hospital Basel, Switzerland during the first wave of pandemic in spring 2020. Diagnostic accuracy of triage was determined by calculating sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratio. Triage to the group of suspected (+) and not suspected (-) COVID-19 was considered the index test, whereas a SARS-CoV-2 polymerase chain reaction test result was used as reference standard. Mimics were defined as false positives and chameleons as false negatives. RESULTS: Of 2898 patients included in the analysis, 191 were true positives, 895 were false positives (mimics), 9 were false negatives (chameleons) and 1803 were true negatives. This resulted in a sensitivity of 0.95 (95% confidence interval [CI] 0.92-0.98) and a specificity of 0.67 (95% CI 0.65-0.69) for standardised triage. Among mimics, the main categories of final diagnoses were other infections (n = 513, 57.3%), cardiovascular diseases (excluding cerebrovascular) (n = 125, 14%), and non-infectious diseases of the respiratory system (n = 84, 9.4%). Fever (n = 357, 39.9% vs n = 104, 54.5%), cough (n = 466, 52.1% vs n = 126 66%), and smell or taste dysfunction (n = 60, 6.7% vs n = 24, 12.6%) were less frequently observed in mimics than in COVID-19 patients. Eight of nine COVID-19 chameleons presented with either nonspecific complaints (weakness and/or fatigue) or gastrointestinal symptoms. CONCLUSION: The quantitative assessment of COVID-19 mimics and chameleons showed a high prevalence of mimics. Clinical differentiation between true positives and false positives is not feasible due to largely overlapping symptoms. Prevalence of chameleons was very low.

Influence of renin-angiotensin-aldosterone system inhibitors on plasma levels of angiotensin-converting enzyme 2.

AIMS: Concern has been raised that treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the expression of angiotensin-converting enzyme 2 (ACE2), which acts as the entry receptor for SARS-CoV-2, and lead to an increased risk of death from SARS-CoV-2. We aimed to address this concern by evaluating the in vivo relationship of treatment with ACE inhibitors and angiotensin receptor blockers (ARB) with circulating plasma concentrations of ACE2 in a large cohort of patients with established cardiovascular disease (n = 1864) or cardiovascular risk factors (n = 2144) but without a history of heart failure. METHODS AND RESULTS: Angiotensin-converting enzyme 2 was measured in 4008 patients (median age 68, 33% women, 31% on ACE-inhibitors, 31% on ARB) using the SOMAscan proteomic platform (SomaLogic Inc, Colorado, USA). Plasma concentration of ACE2 was comparable in 1250 patients on ACE inhibitors (mean 5.99) versus patients without ACE inhibitors (mean 5.98, P = 0.54). Similarly, plasma concentration of ACE2 was comparable in 1260 patients on ARB (mean 5.99) versus patients without ARB (mean 5.98, P = 0.50). Plasma concentration of ACE2 was comparable in 2474 patients on either ACE inhibitors or ARB (mean 5.99) versus patients without ACE inhibitors or ARB (mean 5.98, P = 0.31). Multivariable quantile regression model analysis confirmed the lack of association between treatment with ACE inhibitors or ARB and ACE2 concentrations. Body mass index showed the only positive association with ACE2 plasma concentration (effect 0.015, 95% confidence interval 0.002 to 0.028, P = 0.024). CONCLUSIONS: In a large cohort of patients with established cardiovascular disease or cardiovascular risk factors but without heart failure, ACE inhibitors and ARB were not associated with higher plasma concentrations of ACE2.