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Cardiac troponins and adverse outcomes in European patients with atrial fibrillation: A report from the ESC-EHRA EORP atrial fibrillation general long-term registry

  • Marco Vitolo
    Footnotes
    Affiliations
    Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Via del Pozzo, 71, Modena 41124, Italy

    Liverpool Center for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom

    Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy
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  • Vincenzo L. Malavasi
    Footnotes
    Affiliations
    Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Via del Pozzo, 71, Modena 41124, Italy
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  • Marco Proietti
    Affiliations
    Liverpool Center for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom

    Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    Geriatric Unit, IRCCS Istituti Clinici Scientifici Maugeri, Milan, Italy
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  • Igor Diemberger
    Affiliations
    Department of Experimental, Diagnostic and Specialty Medicine, Institute of Cardiology, University of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy
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  • Laurent Fauchier
    Affiliations
    Service de Cardiologie, Center Hospitalier Universitaire Trousseau, Tours, France
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  • Francisco Marin
    Affiliations
    Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, University of Murcia, CIBERCV, Murcia, Spain
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  • Michael Nabauer
    Affiliations
    Department of Cardiology, Ludwig-Maximilians-University, Munich, Germany
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  • Tatjana S. Potpara
    Affiliations
    School of Medicine, University of Belgrade, Belgrade, Serbia

    Intensive Arrhythmia Care, Cardiology Clinic, Clinical Center of Serbia, Belgrade, Serbia
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  • Gheorghe-Andrei Dan
    Affiliations
    Carol Davila' University of Medicine, Colentina University Hospital, Bucharest, Romania
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  • Zbigniew Kalarus
    Affiliations
    Department of Cardiology, SMDZ in Zabrze, Silesian Center for Heart Diseases, Medical University of Silesia, Zabrze, Katowice, Poland
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  • Luigi Tavazzi
    Affiliations
    Maria Cecilia Hospital, GVM Care and Research, Cotignola, Italy
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  • Aldo Pietro Maggioni
    Affiliations
    ANMCO Research Center, Firenze, Italy
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  • Deirdre A. Lane
    Affiliations
    Liverpool Center for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom

    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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  • Author Footnotes
    2 Gregory YH Lip and Giuseppe Boriani are joint senior authors.
    Gregory Y.H. Lip
    Footnotes
    2 Gregory YH Lip and Giuseppe Boriani are joint senior authors.
    Affiliations
    Liverpool Center for Cardiovascular Science, University of Liverpool and Liverpool Heart and Chest Hospital, Liverpool, United Kingdom

    Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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  • Author Footnotes
    2 Gregory YH Lip and Giuseppe Boriani are joint senior authors.
    Giuseppe Boriani
    Correspondence
    Corresponding author.
    Footnotes
    2 Gregory YH Lip and Giuseppe Boriani are joint senior authors.
    Affiliations
    Cardiology Division, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Policlinico di Modena, Via del Pozzo, 71, Modena 41124, Italy
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  • on behalf of theESC-EHRA EORP-AF Long-Term General Registry Investigators
    3
  • Author Footnotes
    1 Marco Vitolo and Vincenzo L. Malavasi contributed equally to this paper.
    2 Gregory YH Lip and Giuseppe Boriani are joint senior authors.
    3 Listed in Appendix.
Published:February 14, 2022DOI:https://doi.org/10.1016/j.ejim.2022.01.025

      Highlights

      • Elevated levels of cTn were independently associated with an increased risk adverse cardiovascular events, even in AF patients without coronary artery disease.
      • A reasonable application of cardiac troponins in AF patients may support clinical-decision making and also integrate outcome prediction and risk stratification.
      • Future studies are needed to investigate the mechanisms of cardiac troponins elevation in AF patients independently of cardiac ischemia.

      Abstract

      Background

      Cardiac troponins (cTn) have been reported to be predictors for adverse outcomes in atrial fibrillation (AF), patients, but their actual use is still unclear.

      Aim

      To assess the factors associated with cTn testing in routine practice and evaluate the association with outcomes.

      Methods

      Patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry were stratified into 3 groups according to cTn levels as (i) cTn not tested, (ii) cTn in range (≤99th percentile), (iii) cTn elevated (>99th percentile). The composite outcome of any thromboembolism /any acute coronary syndrome/cardiovascular (CV) death, defined as Major Adverse Cardiovascular Events (MACE) and all-cause death were the main endpoints.

      Results

      Among 10 445 AF patients (median age 71 years, 40.3% females) cTn were tested in 2834 (27.1%). cTn was elevated in 904/2834 (31.9%) and in-range in 1930/2834 (68.1%) patients. Female sex, in-hospital enrollment, first-detected AF, CV risk factors, history of coronary artery disease, and atypical AF symptoms were independently associated with cTn testing. Elevated cTn were independently associated with a higher risk for MACE (Model 1, hazard ratio [HR] 1.74, 95% confidence interval [CI] 1.40–2.16, Model 2, HR 1.62, 95% CI 1.28–2.05; Model 3 HR 1.76, 95% CI 1.37–2.26) and all-cause death (Model 1, HR 1.45, 95% CI 1.21–1.74; Model 2, HR 1.36, 95% CI 1.12–1.66; Model 3, HR 1.38, 95% CI 1.12–1.71).

      Conclusions

      Elevated cTn levels were associated with an increased risk of all-cause mortality and adverse CV events. Clinical factors that might enhance the need to rule out CAD were associated with cTn testing.

      Graphical abstract

      Keywords

      Abbreviations:

      ACS (acute coronary syndrome), AF (atrial fibrillation), CAD (coronary artery disease), CKD (chronic kidney disease), CI (confidence interval), cTn (cardiac troponins), CV (cardiovascular), EHRA (European Heart Rhythm Association), EORP (EurObservational Research Programme), ESC (European Society of Cardiology), HF (heart failure), HR (hazard ratio), IQR (interquartile range), MACE (major adverse cardiovascular events), MI (myocardial infarction), OR (odds ratio), RCTs (randomized controlled trials), SE (systemic embolisms), TE (thromboembolic events)

      1. Introduction

      Cardiac troponins (cTn) are the preferred biomarkers for the detection of myocardial injury and the diagnosis of myocardial infarction (MI) [
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      ]. However, with the advent of high-sensitivity (hs)-cTn assays, elevated levels of cTn may be a common finding in daily clinical practice even in several non-ischaemic, acute or chronic conditions, such as heart failure (HF), chronic kidney disease (CKD), sepsis, inflammatory diseases, etc. [
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      High-sensitivity cardiac troponin T is associated with cognitive decline in older adults at high cardiovascular risk.
      ].
      In the last decades, several biomarkers have emerged as significant predictors for adverse outcomes in atrial fibrillation (AF) patients [
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      The significance of troponin elevation in atrial fibrillation.
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      Optimizing indices of AF susceptibility and burden to evaluate AF severity, risk and outcomes.
      ]. As for the other clinical conditions reported above, independent of the specific assay used, cTn elevations may be detected in AF patients with or without overt coronary artery disease (CAD) [
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      Cardiac troponin and adverse outcomes in atrial fibrillation: a meta-analysis.
      ]. Additionally, elevated levels of cTn have been found to be independent predictors of AF in the general population [
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      High-sensitivity cardiac troponin T and the risk of incident atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study.
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      High-sensitive troponin T is associated with atrial fibrillation in a general population.
      ]. Despite the increasing number of studies investigating biomarkers in AF, including cTn, their value in daily clinical practice and routine risk prediction is still debated [
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      ]. Since most of the studies available were based on a highly selected populations from randomized controlled trials (RCTs), [
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      High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin.
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      Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial.
      ] data on real-world AF patients are limited.
      Accordingly, the aim of this study was to assess the factors associated with cTn testing in routine clinical practice and evaluate the association of elevated levels of cTn with adverse outcomes in a large contemporary cohort of AF patients from the European Society of Cardiology (ESC) EURObservational Research Programme (EORP) Atrial Fibrillation General Long-Term Registry.

      2. Methods

      2.1 Study design and cohort

      The EORP-AF Long-Term General Registry is a prospective, observational, large-scale multicenter registry on AF patients in current cardiology practice held by the ESC and endorsed by the European Heart Rhythm Association (EHRA). A detailed description of the study design, baseline characteristics and 1-year follow-up results have been previously reported [
      • Boriani G.
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      Contemporary stroke prevention strategies in 11096 European patients with atrial fibrillation: a report from the EURObservational research programme on atrial fibrillation (EORP-AF) long-term general registry.
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      The euro heart survey and EURObservational research programme (EORP) in atrial fibrillation registries: contribution to epidemiology, clinical management and therapy of atrial fibrillation patients over the last 20 years.
      ].
      Briefly, the registry consecutively enrolled both in- and out- AF patients in 250 centers from 27 participating ESC countries when presenting with AF as a primary or secondary diagnosis from October 2013 to September 2016. All patients were ≥ 18 years old and provided written informed consent. The qualifying AF event had to be recorded by a 12-lead ECG, 24 h ECG Holter, or other electrocardiographic documentation within the 12 months before enrolment. Exclusion criteria were: (i) no objective proof of AF; (ii) being previously enrolled in the EORP-AF Pilot Registry; or (iii) being or planned to be enrolled in a pharmacological interventional clinical trial. Institutional review board approved the study protocol for every institution. The study was performed according to the EU Note for Guidance on Good Clinical Practice CPMP/ECH/135/95 and the Declaration of Helsinki.
      All data regarding baseline clinical characteristics, previous clinical history, history of previous interventional procedures and specific diagnostic procedures and interventional procedures performed during the admission/consultation were collected at the moment of enrolment by any investigator/sub-investigator using clinical notes and electronic clinical data archives, where available.
      Thromboembolic risk was defined according to CHA2DS2-VASc score. ‘Low risk’ was defined as a CHA2DS2-VASc 0 in males and 1 in females; ‘moderate risk’ was defined for a CHA2DS2-VASc 1 in males; ‘high risk’ was defined as CHA2DS2-VASc ≥ 2. Bleeding risk was defined according to HAS-BLED score. ‘Low risk’ was defined as HAS-BLED 0–2, while ‘high risk’ was defined as HAS-BLED ≥ 3. Symptomatic status was defined according to EHRA score.
      Participating countries were grouped in European regions as follows: (i) Northern Europe—Denmark, Estonia, Latvia, Norway, UK; (ii) Western Europe—Belgium, France, Germany, Netherlands, Switzerland; (iii) Eastern Europe—Bulgaria, Czech Republic, Georgia, Kazakhstan, Kyrgyzstan, Poland, Romania, Russia; and (iv) Southern Europe—Albania, FYR Macedonia, Italy, Malta, Montenegro, Portugal, Serbia, Spain, Turkey.
      For the purpose of this analysis, all AF patients with available data on cTn testing and follow-up data were included. Elevated levels of cTn were defined when plasma levels of cTn (either troponin T or troponin I) were increased above the 99th percentile upper reference limit according to manufacturer indications and specific assay (conventional or high-sensitivity) available in each enrolling center. Patients were stratified into three groups according to cTn measurement (according to the reference values of every site) as (i) cTn not tested, (ii) cTn tested in range (i.e. at or below the 99th percentile) and (iii) cTn elevated (i.e above the 99th percentile).

      2.2 Follow-up and adverse outcomes

      All follow-up was performed at 1 and 2 years after the enrolment. All of the following incident major adverse clinical events were recorded: (i) all cause death; (ii) any hemorrhagic events (i.e. intracranial bleeding, major bleeding or clinically relevant non-major bleeding; (iii) any thromboembolism (TE) (including stroke, transient ischaemic attack [TIA], and any peripheral embolism); (iv) any ACS; (v) CV-death and (vi) any myocardial revascularization (including percutaneous coronary intervention [PCI] and coronary artery bypass grafting [CABG]). The composite outcome of any TE/any ACS/CV death, defined as Major Adverse Cardiovascular Events (MACE) and all-cause death were the main endpoints of the study.
      All data about hospital admissions (any admission, AF-related, CV-related and non CV-related) were also recorded. Investigators reported all available details about incident major adverse clinical events on the centralized electronic case report form. Events are reported according to the three groups (cTn not tested, cTn in range, and cTn elevated).
      To further explore the possible association between cTn levels and adverse outcomes in “non-ischaemic” AF patients, we performed a secondary analysis excluding all the patients with a previous history of CAD and those who had a diagnosis at discharge/consultation of ACS, who underwent PCI and/CABG during the admission and/or were treated with oral anticoagulant (OAC) plus antiplatelet therapy.

      2.3 Statistical analysis

      All continuous variables were reported as median and interquartile range (IQR). Among-group comparisons were made using non-parametric tests, Mann-Whitney U or Kruskal–Wallis test where appropriate. Categorical variables were reported as counts and percentages. Among-group comparisons were made using a χ2 test or Fisher's exact test (if any expected cell count was less than five).
      Univariate logistic regression analysis was performed to identify baseline characteristics associated with the measurement of cTn during admission or consultation. All variables with p < 0.10 in the univariate analysis were used in the multivariable model to identify independent variables associated with cTn testing.
      Plots of Kaplan–Meier curves for time to MACE and all-cause death according to cTn measurements were performed. Survival distributions were compared using the log-rank test. To identify which particular group had different survival distributions we performed a pairwise comparisons with a Bonferroni correction adjusting the level of significance by the number of comparisons (statistical significance accepted at the p < 0.0167 level).
      We built three different Cox regression models to establish the relationship between cTn measurements and the risk of the primary endpoints of the study (MACE and all-cause death). Model 1 was adjusted for adjusted for CHA2DS2VASc score, site of inclusion (hospital vs outpatient clinic), use of OAC, presence of atypical AF-related symptoms (chest pain, dyspnea or syncope), CKD (i.e. creatinine clearance <60 ml/min calculated with Cockcroft-Gault equation), malignancy and type of AF; Model 2 was adjusted for the individual components of the CHA2DS2VASc score in addition to the other covariates of Model 1; Model 3 was adjusted for the variables that were statistically different between patients without cTn tested and cTn tested at the univariate analysis. For the other outcomes (any TE, any ACS, any CV death and any PCI/CABG) a multivariable Cox regression analysis adjusted for CHA2DS2VASc score, site of inclusion (hospital vs outpatient clinic), use of OAC, presence of atypical AF-related symptoms (chest pain, dyspnea or syncope), CKD malignancy and type of AF was used. The proportional hazard assumption for Cox models was checked through visual procedures and by Schoenfeld residuals. Results were expressed as hazard ratio (HR) and 95% confidence interval (CI).
      For the remaining outcomes of interest, time-to-event data was not available, therefore we built a multivariable logistic regression model to establish the relationship with the occurrence of any hemorrhagic events, any admission, including admission AF-, CV- and non CV-related according to cTn measurement. Adjustment for CHA2DS2VASc score, site of inclusion (hospital vs outpatient clinic), use of OAC, presence of atypical AF-related symptoms (chest pain, dyspnea or syncope), CKD, malignancy and type of AF were undertaken for every outcome except for hemorrhagic events, which adjusted for the HASBLED score, sex, site of inclusion (hospital vs outpatient clinic), use of OAC, presence of atypical AF-related symptoms, malignancy and type of AF were used. Results were expressed as odds ratio (OR) and 95% confidence interval (CI)
      A two-sided P-value <0.05 was considered statistically significant, expect for the pairwise comparisons of survival distributions with the Bonferroni correction where the statistical significance was accepted as p < 0.0167.
      All analyses were performed using SPSS statistical software (version 26.0, Statistical Package for the Social Sciences, SPSS, IBM, Chicago, Illinois).

      3. Results

      Among the 11,096 AF patients originally enrolled into the ESC-EHRA EORP Atrial Fibrillation General Long-Term Registry, a total of 10,445 (94.1%) patients with available data on cTn measurement and follow-up status at 2-years were included in this analysis. Cardiac troponins were tested in 2834 (27.1%) being elevated in 904/2834 (31.9%) and in-range in 1930/2834 (68.1%) patients
      Median (IQR) age was 71 (63–77) years, 40.3% were female and overall, the median (IQR) CHA2DS2VASc and HASBLED score were 3 (2–4) and 1 (1–2), respectively. Baseline characteristics according to cTn testing are shown in Tables 1 and S1 (Supplementary materials).
      Table 1Baseline characteristics of study population according to cTn assessment.
      TotalcTn not testedcTn in rangecTn elevatedp
      (N = 10,445)(n = 7611, 72.9%)(n = 1930, 18.5%)(n = 904, 8.7%)
      Age (years), median (IQR)71 (63–77)71 (63–78)68 (60–76)73 (65–79)<0.001⁎⁎
      Female, n (%)4214/10445 (40.3)3014/7611 (39.6)849/1930 (44.0)351/904 (38.8)0.001*
      BMI (kg/m2), median (IQR)27.5 (24.8–31.1)27.5 (24.8–31.1)27.6 (24.7–31.2)27.7 (24.8–31.2)0.86⁎⁎
      Site of inclusion, n (%)<0.001*
      Hospital5321/10,445 (50.9)2939/7611 (38.6)1559/1930 (80.8)823/904 (91.0)
      Outpatient or office based5214/10,445 (49.1)4672/7611 (61.4)371/1930 (19.2)81/904 (9.0)
      Region of enrolment§, n (%)<0.001*
      Western Europe3368/10,445 (32.2)2598/7611 (34.1)529/1930 (27.4)241/904 (26.7)
      Southern Europe3812/10,445 (36.5)2621/7611 (34.4)832/1930 (43.1)359/904 (39.7)
      Northern Europe1380/10,445 (13.2)965/7611 (12.7)273/1930 (14.1)142/904 (15.7)
      Eastern Europe1885/10,445 (18.0)1427/7611 (18.7)296/1930 (15.3)162/904 (17.9)
      AF type, n (%)<0.001*
      First diagnosed1611/10,264 (15.7)841/7481 (11.2)492/1898 (25.9)278/885 (31.4)
      Paroxysmal2690/10,264 (26.2)1880/7481 (25.1)589/1898 (31.0)221/885 (25.0)
      persistent2024/10,264 (19.7)1562/7481 (20.9)349/1898 (18.4)113/885 (12.8)
      longstanding persistent456/10,264 (4.4)369/7481 (4.9)65/1898 (3.4)22/885 (2.5)
      Permanent3483/10,264 (33.9)2829/7481 (37.8)403/1898 (21.2)251/885 (28.4)
      Hypertension, n (%)6433/10,354 (62.1)4817/7556 (63.8)1107/1905 (58.1)509/893 (57.0)<0.001*
      Diabetes mellitus, n (%)2393/10,378 (23.1)1686/7572 (22.3)418/1909 (21.9)289/897 (32.2)<0.001*
      Smoking (current), n (%)909/9687 (9.4)562/6985 (8.0)239/1832 (13.0)108/870 (12.4)<0.001*
      No physical activity, n (%)3798/8973 (42.3)2600/6453 (40.3)764/1706 (44.8)434/814 (53.3)<0.001*
      Lipid disorder, n (%)4139/9990 (41.4)3067/7273 (42.2)690/1842 (37.5)382/875 (43.7)<0.001*
      Heart failure, n (%)4039/10,357 (39.0)2856/7553 (37.8)722/1908 (37.8)461/896 (51.5)<0.001*
      NYHA III/IV, n (%)1421/4033 (35.2)912/2852 (32.0)293/721 (40.6)216/460 (47.0)<0.001*
      Dilated CMP, n (%)908/10,322 (8.8)610/7533 (8.1)208/1899 (11.0)90/890 (10.1)<0.001*
      Hypertrophic CMP, n (%)320/10,315 (3.1)233/7531 (3.1)52/1894 (2.7)35/890 (3.9)0.24*
      Pulmonary arterial hypertension, n (%)721/10,266 (7.0)533/7501 (7.1)134/1878 (7.1)54/887 (6.1)0.52*
      LVEF (%), median (IQR)55 (45–62)56 (48–63)55 (45–60)50 (35–58)<0.001⁎⁎
      Bundle Branch Block, n (%)<0.001*
      No8207/9670 (84.9)6049/7100 (85.2)1549/1773 (87.4)609/797 (76.4)
      LBBB816/9670 (8.4)583/7100 (8.2)129/1773 (7.3)104/797 (13.0)
      RBBB647/9670 (6.7)468/7100 (6.6)95/1773 (5.4)84/797 (10.5)
      Coronary artery disease, n (%)2856/9851 (29.0)1877/7207 (26.0)506/1771 (28.6)473/873 (54.2)<0.001*
      Previous MI1263/2856 (44.2)744/1877 (39.6)196/506 (38.7)323/473 (68.3)<0.001*
      Previous PCI1173/2856 (41.1)776/1877 (41.3)185/506 (36.6)212/473 (44.8)0.03*
      Previous CABG541/2856 (18.9)396/1877 (21.1)74/506 (14.6)71/473 (15.0)<0.001*
      Previous angina930/2856 (32.6)590/1877 (31.4)208/506 (41.1)132/473 (27.9)<0.001*
      Valvular alterations, n (%)5149/10,234 (50.3)3913/7463 (52.4)797/1882 (42.3)439/889 (49.4)<0.001*
      Previous TE events, n (%)1200/10,348 (11.6)871/7542 (11.5)206/1911 (10.8)123/895 (13.7)0.07*
      Previous ischaemic stroke, n(%)632/10,347 (6.1)461/7541 (6.1)102/1911 (5.3)69/895 (7.7)0.05*
      Previous TIA, n(%)322/10,347 (3.1)236/7541 (3.1)52/1911 (2.7)34/895 (3.8)0.31*
      Previous EP/DVT, n(%)224/10,347 (2.2)156/7541 (2.1)51/1911 (2.7)17/895 (1.9)0.23*
      Previous hemorrhagic events, n(%)550/10,342 (5.3)397/7541 (5.3)84/1902 (4.4)69/899 (7.7)0.001*
      Peripheral vascular disease, n(%)813/10,230 (7.9)603/7484 (8.1)108/1872 (5.8)102/874 (11.7)<0.001*
      Liver disease, n(%)283/10,387 (2.7)204/7568 (2.7)46/1922 (2.4)33/897 (3.7)0.14*
      COPD, n(%)923/10,367 (8.9)666/7553 (8.8)168/1913 (8.8)89/901 (9.9)0.56*
      dementia, n(%)134/10,404 (1.3)95/7585 (1.3)25/1921 (1.3)14/898 (1.6)0.74*
      anemia, n(%)560/10,412 (5.4)358/7587 (4.7)102/1922 (5.3)100/903 (11.1)<0.001*
      Malignancy (current+prior), n(%)785/10,375 (7.6)557/7561 (7.4)128/1918 (6.7)100/896 (11.2)<0.001*
      Hyperthyroidism, n(%)470/10,216 (4.6)339/7442 (4.6)96/1887 (5.1)35/887 (3.9)0.38*
      Hypothyroidism, n(%)974/10,232 (9.5)741/7448 (9.9)154/1894 (8.1)79/890 (8.9)0.04*
      CKD, n(%)1283/10,365 (12.4)893/7541 (11.8)196/1923 (10.2)194/901 (21.5)<0.001*
      CrCl (C-G) (ml/min), median (IQR)75 (55–97)75 (56–97)78 (57–103)63 (46–86)<0.001⁎⁎
      CHA2DS2VASc, median (IQR)3 (2–4)3 (2–4)3 (2–4)4 (2–5)<0.001⁎⁎
      Truly low-risk#957/10,438 (9.2)670/7610 (8.8)246/1925 (12.8)41/903 (4.5)<0.001*
      HASBLED, median (IQR)1 (1–2)1 (1–2)1 (1–2)2 (1–3)<0.001⁎⁎
      EHRA score, median (IQR)2 (1–2)1 (1–2)2 (1–3)2 (1–3)<0.001⁎⁎
      Chest pain, dyspnea and/or syncope, n(%)3789/10,445 (36.3)2446/7611 (32.1)935/1930 (48.4)408/904 (45.1)<0.001*
      Multimorbidity, n(%)6750/8578 (78.7)4995/6307 (79.2)1094/1512 (72.4)661/759 (87.1)<0.001⁎⁎
      Legend: AF= atrial fibrillation; BMI= body mass index; CABG= coronary artery bypass grafting; CAD= coronary artery disease; CKD= chronic kidney disease; CMP= cardiomyopathy; COPD=chronic obstructive pulmonary disease; cTn= cardiac troponin; CV= cardiovascular; EHRA= European Heart Rate Association; DVT= deep vein thrombosis; CrCl C-G=creatinine clearance according to Cockroft-Gault formula; IQR, interquartile range; LBBB= left bundle branch block; LVEF, left ventricular ejection fraction; NYHA=New York Heart Association PCI= percutaneous coronary intervention; PE= pulmonary embolism; RBBB= right bundle branch block; TE= thromboembolic; TIA= transient ischaemic attack. §Regions of enrolment. Northern Europe: Denmark, Estonia, Latvia, Norway, UK; Western Europe: Belgium, France, Germany, Netherlands, Switzerland; Eastern Europe: Bulgaria, Czech Republic, Georgia, Kazakhstan, Kyrgyzstan, Poland, Romania, Russia; Southern Europe: Albania, FYR Macedonia, Italy, Malta, Montenegro, Portugal, Serbia, Spain, Turkey. #Truly low-risk patients were defined as CHA2DS2-VASc 0 in males or score of 1 in females. *p-values for among-group comparisons are from Pearson's χ2 test; **p-values for among-group comparisons are from Kruskal–Wallis test.
      Patients in whom cTn was elevated tended to be older (p < 0.001), more frequently enrolled in a hospital setting (p <0.001) with significantly higher baseline CHA2DS2VASc and HASBLED scores (p < 0.001) (Table 1).
      There was a significant association between the measurement of cTn and symptomatic status at admission/consultation. EHRA score was higher in patients in those where cTn was tested (median 2 (1-2) vs 2 (1–3), p < 0.001) as well as the presence of atypical AF-related symptoms (i.e. chest pain, dyspnea or syncope) (Tables 1 and S1). Diabetes mellitus, current smoking and physical inactivity were reported less frequently in patients without a cTn assessment (all p < 0.001). Heart failure, previous CAD, peripheral vascular disease, anemia, CKD and malignancy were more prevalent in patients with elevated cTn (Table 1). AF was the main reason for admission or consultation in two-thirds (66.6%). Other reasons for admission or consultation included HF (10%), valvular heart disease (2.8%), hypertension (2.1%) and others CV and non-CV reasons in the remaining cases. Only 3.4% had a suspected ACS at admission/consultation, whereas a diagnosis of ACS was confirmed in 215 patients (2.1%) at discharge.
      Pharmacological treatments, including antithrombotic patterns, and cardiac interventions performed during the admission/consultation are shown in Table S2. Overall, non-vitamin K antagonist OACs (NOACs) were prescribed in 3340 (32.0%) while 4303 (41.2%) patients received vitamin K antagonists (VKA). Patients with cTn tested were more frequently treated with OAC with concomitant antiplatelet(s) (p < 0.001) (Table S2).
      Overall, myocardial revascularization (either PCI or CABG) were performed in 245/10,445 (2.3%) patients with a significant higher occurrence in patients with elevated cTn compared with patients without cTn testing or those with cTn in range (12.2% vs 1.0% vs 3.0%, p < 0.001) (Table S2).

      3.1 Factors associated with cardiac troponin assessment and regional differences

      Univariate logistic regression analysis for factors associated with cTn assessment during admission or consultation in the whole cohort is presented in the Supplementary materials (Table S3).
      On multivariable analysis (Table 2), female sex, site of inclusion (hospital vs outpatient clinic/office based), first detected AF, smoking, no physical activity, lipid disorder, history of CAD and presence of atypical AF-related symptoms were independently associated with cTn testing. Conversely, hypertension, hypothyroidism and valvular heart disease were inversely associated with cTn measurement (Table 2).
      Table 2Multivariable logistic regression analysis for factors associated with cardiac troponins testing during admission or consultation.
      Multivariable Analysis
      Odds Ratio95% CIp value
      Age1.000.99–1.000.48
      Female sex1.231.08–1.400.001
      Site of inclusion (hospital)7.696.70–8.83<0.001
      Region of enrolment
      Western Europe (reference)---
      Southern Europe0.830.71–0.96<0.01
      Northern Europe0.910.74–1.120.39
      Eastern Europe0.510.42–0.62<0.001
      First detected AF2.141.84–2.48<0.001
      Hypertension0.820.72–0.930.002
      Diabetes mellitus1.010.88–1.170.84
      Smoking1.431.17–1.74<0.001
      No physical activity1.281.14–1.45<0.001
      Lipid disorder1.211.061.360.003
      Heart failure0.890.78–1.020.10
      Dilated cardiomyopathy1.140.92–1.410.23
      Coronary artery disease1.781.56–2.04<0.001
      Valvular alterations0.600.53–0.68<0.001
      copd0.950.77–1.170.65
      anemia1.070.84–1.370.55
      Hypothyroidism0.760.62–0.930.008
      CKD1.130.94–1.350.17
      Chest pain, dyspnea or syncope1.461.30–1.65<0.001
      Legend: CI=confidence interval, for other abbreviations see Table 1.
      We also performed additional sub-analyses by stratifying the population according to the site of inclusion (hospital vs outpatient clinic/office based) and by regions of enrolment (Supplementary materials, Tables S4–S8). There was a relatively higher frequency in cTn testing both in South and North European countries in the outpatient clinic setting (12.9% and 11.3% compared to 5.2% in Western and 7.3% in Easter Europe, p < 0.001) (Table S4). On multivariable logistic regression analysis, only Southern European countries were independently associated with cTn testing as out-patients (OR 2.91, 95% CI 2.08–4.06) (Table S6). Conversely, when stratifying the analysis in hospitalized patients, Southern and Eastern regions were inversely associated with cTn testing in this setting (OR 0.65, 95% CI 0.52–0.83 and OR 0.48, 95% CI 0.37–0.63, respectively) (Table S8).

      3.2 Follow-up and survival analysis

      Crude rates of adverse events during the follow-up according to cTn levels are shown in Table 3. After a median (IQR) follow-up of 730 (692–749) days, there were 957 (9.7%) MACE and 994 (9.5%) deaths; additionally, 405 (4.1%) hemorrhagic events were recorded. Patients with elevated cTn levels had significantly higher rates of almost all of the adverse outcomes (all p < 0.001), when compared with the other groups (Table 3), with the exception of any TE (p = 0.07) and stroke/TIA (p = 0.77). Patients with elevated levels of cTn also reported higher crude rates of any hospital readmission, including any CV-, any non-CV- and any CV non-AF related (all p < 0.001) (Table 3).
      Table 3Major adverse events during follow-up according to cTn assessment.
      Total (N = 10,445)cTn not tested (n = 7611, 72.9%)cTn in range (n = 1930, 18.5%)cTn elevated (n = 904, 8.7%)p
      MACE, n(%)957/9818 (9.7)499/7210 (6.9)205/1734 (11.8)253/874 (28.9)<0.001*
      All cause death, n(%)994/10,445 (9.5)636/7611 (8.4)177/1930 (9.2)181/904 (20.0)<0.001*
      Hemorrhagic events, n(%)405/9756 (4.1)261/7188 (3.6)66/1726 (3.8)78/851 (9.2)<0.001*
      Any TE, n(%)228/9766 (2.3)153/7190 (2.1)52/1742 (3.0)23/852 (2.7)0.07*
      Stroke/TIA, n(%)171/10,445 (1.6)121/7611 (1.6)33/1930 (1.7)17/904 (1.9)0.77*
      Any ACS, n(%)422/9782 (4.3)154(7192 (2.1)88/1727 (5.1)180/863 (20.9)<0.001*
      CV death, n(%)377/9805 (3.8)217/7209 (3.0)77/1730 (4.5)83/866 (9.6)<0.001*
      Any PCI/CABG, n(%)263/10,445 (2.5)148/7611 (1.9)54/1930 (2.8)61/904 (6.7)<0.001*
      Any readmission, n(%)3794/9762 (38.9)2539/7189 (35.3)798/1723 (46.3)457/850 (53.8)<0.001*
      Any CV readmission, n(%)2450/9762 (25.1)1625/7189 (22.6)517/1723 (30.0)308/850 (36.2)<0.001*
      Any AF readmission, n(%)1294/9762 (13.3)824/7189 (11.5)320/1723 (18.6)150/850 (17.6)<0.001*
      Any non-CV readmission, n(%)1133/9762 (11.6)787/7189 (10.9)217/1723 (12.6)129/850 (15.2)<0.001*
      Any CV non-AF readmission, n(%)1600/9762 (16.4)1077/7189 (15.0)296/1723 (17.2)227/850 (26.7)<0.001*
      Legend: MACE= Any TE/ACS/CV death; *p-values for among-group comparisons are from Pearson's χ2 test. For abbreviations see Table 1.
      Kaplan–Meier analysis showed a lower cumulative survival for MACE and all-cause death in patients with elevated cTn levels (Fig. 1A, B) (Log Rank tests, p < 0.001). The multivariable adjusted Cox regression analyses (Tables 4 and S9) showed that patients with elevated levels of cTn had an independent higher risk for the main outcomes (Model 1: HR 1.74, 95% CI 1.40–2.16; Model 2: HR 1.62, 95% CI 1.28–2.05; Model 3: HR 1.76, 95% CI 1.37–2.26 for MACE; Model:1 HR 1.45, 95% CI 1.21–1.74; Model 2: 1.36, 95%CI 1.12–1.66; Model 3: HR 1.38, 95% CI 1.12–1.71, for all-cause death). Additionally, elevated levels of cTn were significantly associated with a higher risk of any ACS, CV death and any PCI/CABG (Table 5).
      Fig. 1
      Fig. 1Kaplan–Meier curves for main study outcomes according to cTn assessment
      Panel A. MACE (Any TE/ACS/CV death); Panel B. All-cause death
      Legend: ACS= acute coronary syndrome; cTn= cardiac troponins; CV= cardiovascular; MACE= major adverse cardiovascular events; TE= thromboembolic events.
      *= statistical significance is accepted at the p < 0.0167 level with Bonferroni correction.
      Fig. 1
      Fig. 1Kaplan–Meier curves for main study outcomes according to cTn assessment
      Panel A. MACE (Any TE/ACS/CV death); Panel B. All-cause death
      Legend: ACS= acute coronary syndrome; cTn= cardiac troponins; CV= cardiovascular; MACE= major adverse cardiovascular events; TE= thromboembolic events.
      *= statistical significance is accepted at the p < 0.0167 level with Bonferroni correction.
      Table 4Multivariable Cox regression analysis for cTn levels and the main outcomes.
      Multivariable Cox Regression Analysis
      MACEModel 1Model 2Model 3
      HR[95% CI]p valueHR[95% CI]p valueHR[95% CI]p value
      cTn not tested (ref)---------
      cTn in range1.20[0.99–1.46]0.071.06[0.85–1.33]0.601.13[0.89–1.43]0.30
      cTn elevated1.741.40–2.16<0.0011.62[1.28–2.05]<0.0011.76[1.37–2.26]<0.001
      All-cause deathModel 1Model 2Model 3
      HR[95% CI]p valueHR[95% CI]p valueHR[95% CI]p value
      cTn not tested (ref)---------
      cTn in range0.940.79–1.130.540.860.71–1.060.160.860.69–1.070.18
      cTn elevated1.451.21–1.74<0.0011.361.12–1.660.0021.381.12–1.710.002
      Legend: HR, hazard ratio; CI confidence interval. For other abbreviations see Table 1.
      MACE= composite of any TE/ACS/CV death. Model 1 was adjusted for CHA2DS2VASc score, site of inclusion (hospital vs outpatient clinic), use of OAC, presence of atypical AF-related symptoms (chest pain, dyspnea or syncope), CKD (i.e. creatinine clearance <60 ml/min calculated with Cockcroft-Gault equation), malignancy and type of AF; Model 2 was adjusted for the individual components of the CHA2DS2VASc score in addition to the other covariates of Model 1; Model 3 was adjusted for the variables that were statistically different between patients without cTn tested and cTn tested at the univariate analysis. The full Cox models are reported in the Supplementary materials (Table S9).
      Table 5Multivariable Cox regression analysis for cTn levels and adverse outcomes.
      Multivariable Cox Regression Analysis
      HR [95 % CI]p value
      Any TE
      cTn not tested (ref)--
      cTn in range1.24 [0.86–1.79]0.24
      cTn elevated1.01 [0.61–1.65]0.98
      Any ACS
      cTn not tested (ref)--
      cTn in range1.34 [0.96–1.87]0.09
      cTn elevated2.56 [1.79–3.65]<0.001
      CV death
      cTn not tested (ref)--
      cTn in range1.07 [0.81–1.41]0.65
      cTn elevated1.66 [1.26–2.18]<0.001
      Any PCI/CABG
      cTn not tested (ref)--
      cTn in range1.18 [0.84–1.67]0.30
      cTn elevated2.58 [1.82–3.63]<0.001
      HR, hazard ratio; CI confidence interval. For other abbreviations see Table 1.
      MACE= composite of any TE/ACS/CV death
      Adjusted analysis for CHA2DS2VASc score, site of inclusion (hospital vs outpatient), use of OAC, presence of symptoms [chest pain, dyspnea or syncope], CKD, malignancy and type of AF.
      On multivariable logistic regression analysis, adjusted for HASBLED score, sex, site of inclusion (hospital vs outpatient), use of OAC, presence of atypical symptoms, malignancy and type of AF, elevated levels of cTn were independently associated with the occurrence of hemorrhagic events (OR 2.00, 95% CI 1.49–2.69) (Table S10). Other events, such as any readmission, including any CV readmission, any AF-, any CV non-AF related, were also significantly associated with elevated cTn levels (Table S10).
      Similar results were found when excluding patients with history of CAD, diagnosis of ACS at discharge, those who underwent a PCI or CABG during the admission and/or who were treated with OAC plus antiplatelet therapy. In particular, elevated levels of cTn were independently associated with a higher occurrence of MACE, all-cause death, any ACS, CV death, hemorrhagic events and hospital readmission (Tables S11, S12).
      Finally, restricting the analysis to truly low-risk AF patients (i.e. CHA2DS2-VASc 0 (males), or score of 1 (females)]) we found higher crude rates of MACE in patients with elevated levels of cTn compared to patients with no cTn elevations (12.5% vs 2.6%, p = 0.007). On Cox regression analysis adjusted for the site of inclusion (hospital vs outpatient), use of OAC, presence of symptoms [chest pain, dyspnea or syncope], CKD, malignancy and type of AF, these results were suggestive of a 3 fold risk but this was not statistically significant, given the small numbers and wide 95%CIs (HR 3.06, 95% CI 0.83–11.40, p = 0.09).

      4. Discussion

      The principal findings of this analysis based on the EORP-AF General Long-Term Registry are: (i) cTn was assessed in more than a quarter of AF patients enrolled; (ii) overall, clinical factors that might enhance the need to rule out an underlying ACS, such as presence of atypical AF-related symptoms, previous history of CAD and first detected AF were independently associated with cTn measurement in daily clinical practice; and (iii) AF patients with elevated cTn levels had a significant independent increased risk for CV adverse events, all-cause mortality, hemorrhagic events and hospital readmissions, even after the exclusion of patients with CAD or history of CAD.
      To the best of our knowledge, the present study represents one of the largest analysis assessing the current use, as well as the prognostic implications, of cTn measurement in unselected AF patients and had the advantage of exploring AF management in the “real world”. The present analysis offers a “real-world” snapshot on unselected AF patients showing that cTn testing is common in daily clinical practice and provides new insights in the possible diagnostic and predictive implications of cTn measurement in such patients. Indeed, a reasonable application of biomarkers, according to clinical judgment and patient profile, appears to support clinical-decision making at first patient assessment, but may also integrate outcome prediction and clinical risk stratification. However, cTn should be considered only in selected AF patients since inappropriate use or interpretation of cTn, could results in unnecessary and even harmful procedures, and a waste of healthcare resources.
      It is noteworthy that at the time of data collection (2013–2016) no specific indications for measuring cTn were included in the guidelines for the management of AF [
      • Camm A.J.
      • Kirchhof P.
      • Lip G.Y.
      • Schotten U.
      • Savelieva I.
      • Ernst S.
      • et al.
      Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC).
      ]. Even later, the role of cTn has remained undefined, with some indications for improving risk stratification for stroke and bleeding, apart the expected (and more established) role of ruling out cardiac ischemia [
      • Kirchhof P.
      • Benussi S.
      • Kotecha D.
      • Ahlsson A.
      • Atar D.
      • Casadei B.
      • et al.
      2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
      ,
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • Chiang C.E.
      • Fargo R.
      • Freedman B.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      ,
      • Hindricks G.
      • Potpara T.
      • Dagres N.
      • Arbelo E.
      • Bax J.J.
      • Blomström-Lundqvist C.
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS).
      ]. Our analysis highlights that the practice of use of cTn is variable, with a wider use in some geographical regions and contexts. In interpreting this heterogeneity, both the variability in local protocols and habits, as well as regional differences in patient characteristics, and management options, should be considered, as previously suggested by other analysis from the EORP-AF Pilot registry [
      • Lip G.Y.
      • Laroche C.
      • Boriani G.
      • Dan G.A.
      • Santini M.
      • Kalarus Z.
      • et al.
      Regional differences in presentation and treatment of patients with atrial fibrillation in Europe: a report from the EURObservational Research Programme Atrial Fibrillation (EORP-AF) pilot general registry.
      ].
      In the literature, the use of cTn is variable, even in the context of assessment of patients presenting with chest pain [
      • Shin Y.S.
      • Ahn S.
      • Kim Y.J.
      • Ryoo S.M.
      • Sohn C.H.
      • Kim W.Y.
      Risk stratification of patients with chest pain or anginal equivalents in the emergency department.
      ]. This variability may involve patients presenting with AF, especially patients presenting at emergency departments (ED), where the use of cTn evaluation may differ among countries in quantitative terms, as well as in terms of clinical guidance [
      • Shah A.S.V.
      • Sandoval Y.
      • Noaman A.
      • Sexter A.
      • Vaswani A.
      • Smith S.W.
      • et al.
      Patient selection for high sensitivity cardiac troponin testing and diagnosis of myocardial infarction: prospective cohort study.
      ,
      • Martellini A.
      • di MC.
      High-sensitivity troponin allows accurate rapid diagnosis and discharge but it is not a substitute for a comprehensive patient evaluation.
      ]. In view of the variable positive predictive accuracy for cardiac ischemia according to patient selection, it appears appropriate, according to our findings, to better define the indications for using cTn, either in terms of diagnostic testing and separately, to risk stratify patient outcomes.
      The first part on our analysis focused on describing how frequently cTn was tested in general AF patients and which clinical variables could drive the clinician to proceed with such measurements.
      As expected, most of the cTn assessments were performed in hospitalized AF patients. Nevertheless, since our registry enrolled both in and out-patients, it was quite surprising that 16% of cTn tests were performed during regular out-patient clinic consultations and theoretically, in stable AF patients, with significant differences among European countries that could reflect differences in habits, protocols or characteristics of healthcare systems [
      • Lip G.Y.
      • Laroche C.
      • Boriani G.
      • Dan G.A.
      • Santini M.
      • Kalarus Z.
      • et al.
      Regional differences in presentation and treatment of patients with atrial fibrillation in Europe: a report from the EURObservational Research Programme Atrial Fibrillation (EORP-AF) pilot general registry.
      ,
      • Holstenson E.
      • Ringborg A.
      • Lindgren P.
      • Coste F.
      • Diamand F.
      • Nieuwlaat R.
      • et al.
      Predictors of costs related to cardiovascular disease among patients with atrial fibrillation in five European countries.
      ]. In the “real world”, cTn testing may be frequent even in the absence of symptoms or clinical presentation suggestive of CAD or ACS [
      • Jaakkola S.
      • Paana T.
      • Nuotio I.
      • Kiviniemi T.O.
      • Pouru J.P.
      • Porela P.
      • et al.
      Etiology of minor troponin elevations in patients with atrial fibrillation at emergency department-tropo-AF study.
      ,
      • Shah A.S.V.
      • Sandoval Y.
      • Noaman A.
      • Sexter A.
      • Vaswani A.
      • Smith S.W.
      • et al.
      Patient selection for high sensitivity cardiac troponin testing and diagnosis of myocardial infarction: prospective cohort study.
      ,
      • Makam A.N.
      • Nguyen OK.
      Use of cardiac biomarker testing in the emergency department.
      ] and in this setting the most recent guidelines take into consideration a potential role in refining risk stratification for stroke or bleeding [
      • Lip G.Y.H.
      • Banerjee A.
      • Boriani G.
      • Chiang C.E.
      • Fargo R.
      • Freedman B.
      • et al.
      Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report.
      ,
      • Hindricks G.
      • Potpara T.
      • Dagres N.
      • Arbelo E.
      • Bax J.J.
      • Blomström-Lundqvist C.
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS).
      ].
      In a large retrospective study of emergency department (ED) visits from the National Hospital Ambulatory Medical Care Survey in the United States, cardiac biomarkers were tested in 8.2% (95% CI, 7.1–9.5%) of visits in the absence of ACS-related symptoms [
      • Makam A.N.
      • Nguyen OK.
      Use of cardiac biomarker testing in the emergency department.
      ]. Of note, more than a quarter of all visits with cardiac biomarker testing did not have an electrocardiogram recorded which should be one of the first diagnostic tests in patients with suspected ACS [
      • Makam A.N.
      • Nguyen OK.
      Use of cardiac biomarker testing in the emergency department.
      ,
      • Boriani G.
      • Vitolo M.
      The 12-lead ECG: a continuous reference for the cardiologist.
      ]. These data further confirm that in some settings cTn may be widely used in the ED, as a first line routine assessment, even before a full clinical evaluation [
      • Gardezi SA.
      Troponin: think before you request one.
      ].
      We also investigated the factors associated with troponin testing. The main reasons why clinicians performed cTn testing in AF patients were mostly related to a suspicion of underlying ACS, both in hospitalized and outpatient clinic setting. Indeed, atypical AF-related symptoms (such as chest pain, dyspnea or syncope), first detected AF, history of CAD or CV risk factors such as smoking or physical inactivity, were independent predictors of cTn testing. The findings that atypical AF-related symptoms were significantly associated with cTn testing may be justified either by the need to rule-out cardiac ischemia, or by the fact that atypical AF clinical presentation seems to be associated with less favourable outcome. As reported, AF patients presenting with atypical symptoms had higher rates of cerebrovascular events and mortality compared to patients with typical presentation even after adjustment for the CHA2DS2-VASc score, comorbidities, and OAC therapy [
      • Siontis K.C.
      • Gersh B.J.
      • Killian J.M.
      • Noseworthy P.A.
      • McCabe P.
      • Weston S.A.
      • et al.
      Typical, atypical, and asymptomatic presentations of new-onset atrial fibrillation in the community: characteristics and prognostic implications.
      ].
      In the recent years, it has been discussion over whether elevated levels of cTn in AF patients, either symptomatic or asymptomatic, could indicate the presence of masked CAD, cardiac ischemia or myocardial injury. In daily clinical practice, cardiac biomarkers are often tested in patients with AF presenting to the hospital, especially in patients with new onset AF, to rule out an underlying ACS. However, the use of cTn in this setting and its predictive value to detected significant CAD, are not well established [
      • Costabel J.P.
      • Burgos L.M.
      • Trivi M.
      The significance of troponin elevation in atrial fibrillation.
      ,
      • Alghamry A.
      • Hanna J.
      • Pelecanos A.
      • Kyranis S.
      • Khelgi V.
      • O'Rourke P.
      • et al.
      Predictors of significant coronary artery disease in atrial fibrillation: are cardiac troponins a useful measure.
      ,
      • Conti A.
      • Angeli E.
      • Scorpiniti M.
      • Alesi A.
      • Trausi F.
      • Lazzeretti D.
      • et al.
      Coronary atherosclerosis and adverse outcomes in patients with recent-onset atrial fibrillation and troponin rise.
      ]. Recent results from the Troponins in Atrial Fibrillation study (The Tropo-AF Study) found that AF patients presenting to the ED had often minor cTn elevation related to non-ischaemic causes (such as infections, cerebrovascular events, HF, bone fractures, chronic kidney disease etc) [
      • Jaakkola S.
      • Paana T.
      • Nuotio I.
      • Kiviniemi T.O.
      • Pouru J.P.
      • Porela P.
      • et al.
      Etiology of minor troponin elevations in patients with atrial fibrillation at emergency department-tropo-AF study.
      ]. Different mechanisms have been proposed to explain the release of cTn during AF. Indeed, masked CAD may be just one of the cause of cTn elevation in AF patients, since AF itself, as any other supraventricular tachycardia, may cause cTn elevation in the absence of significant underlying heart disease due only to the high ventricular heart rate. A recent retrospective Finnish study, investigated the association of heart rate with hs-cTnT levels in patients admitted to the ED for AF, finding that high ventricular heart rate was significantly related with troponin release with a nonlinear association that became evident only above the heart rate threshold of 125 bpm [
      • Pouru J.P.
      • Jaakkola S.
      • Biancari F.
      • Kiviniemi T.O.
      • Nuotio I.
      • Airaksinen KEJ.
      Association of heart rate with troponin levels among patients with symptomatic atrial fibrillation.
      ].
      In support of these results, the Rate Control in Atrial Fibrillation (RATAF) trial found that cTn was detectable even in stable patients with permanent AF, preserved left ventricular ejection fraction and without ischemic heart disease or HF and a moderate reduction of heart rate by beta-blockers and calcium channel blockers, was significantly associated with lower cTn levels [
      • Ulimoen S.R.
      • Enger S.
      • Norseth J.
      • Pripp A.H.
      • Abdelnoor M.
      • Arnesen H.
      • et al.
      Improved rate control reduces cardiac troponin T levels in permanent atrial fibrillation.
      ]. Other known mechanisms of cTn release in AF patients, include high atrial rates, reduced ventricular perfusion during AF, cell injury, apoptosis, myocardial strain, inflammation, and acute or chronic renal impairment [
      • Giannitsis E.
      • Katus H.A.
      Cardiac troponin level elevations not related to acute coronary syndromes.
      ,
      • Agewall S.
      • Giannitsis E.
      • Jernberg T.
      • Katus H.
      Troponin elevation in coronary vs. non-coronary disease.
      ,
      • Turer A.T.
      • Addo T.A.
      • Martin J.L.
      • Sabatine M.S.
      • Lewis G.D.
      • Gerszten R.E.
      • et al.
      Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay: insights from a coronary sinus sampling study.
      ,
      • Logeart D.
      • Beyne P.
      • Cusson C.
      • Tokmakova M.
      • Leban M.
      • Guiti C.
      • et al.
      Evidence of cardiac myolysis in severe nonischemic heart failure and the potential role of increased wall strain.
      ,
      • Jeremias A.
      • Gibson CM.
      Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded.
      ].
      In our cohort, AF patients with elevated cTn levels had a significant independent higher risk of all cause-death and MACE. These findings integrate and extend to the “real-world” setting the results of different sub-analyses focused on cardiac biomarkers of the pivotal RCTs on NOACs, performed in highly selected patients [
      • Hijazi Z.
      • Oldgren J.
      • Andersson U.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Hohnloser S.H.
      • et al.
      Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a randomized evaluation of long-term anticoagulation therapy (RE-LY) substudy.
      ,
      • Hijazi Z.
      • Wallentin L.
      • Siegbahn A.
      • Andersson U.
      • Alexander J.H.
      • Atar D.
      • et al.
      High-sensitivity troponin T and risk stratification in patients with atrial fibrillation during treatment with apixaban or warfarin.
      ,
      • Oyama K.
      • Giugliano R.P.
      • Berg D.D.
      • Ruff C.T.
      • Jarolim P.
      • Tang M.
      • et al.
      Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial.
      ,
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • Murphy S.A.
      • Brown K.
      • Jarolim P.
      • et al.
      Cardiovascular biomarker score and clinical outcomes in patients with atrial fibrillation: a subanalysis of the ENGAGE AF-TIMI 48 randomized clinical trial.
      ]. Our analysis actually expands the implications for the outcomes of elevated cTn levels highlighted by these studies performed in selected trial populations. It is noteworthy that we found similar results even after excluding those AF patients with various form of CAD, thus empathizing the negative prognostic impact of elevated levels of cTn, independent of a known history of CAD.
      Although the present analyses were adjusted for CHA2DS2-VASc score and presence of comorbidities, the association between AF and coronary events could also be justified by the similar risk factors and pathophysiological processes such as inflammation, prothrombotic state, endothelial dysfunction etc., shared by AF and CAD patients [
      • Steensig K.
      • Olesen K.K.W.
      • Thim T.
      • Nielsen J.C.
      • Jensen S.E.
      • Jensen L.O.
      • et al.
      Should the presence or extent of coronary artery disease be quantified in the CHA2DS2-VASc score in atrial fibrillation? A report from the Western Denmark heart registry.
      ,
      • Vitolo M.
      • Javed S.
      • Capodanno D.
      • Rubboli A.
      • Boriani G.
      • Lip GYH.
      Antithrombotic treatment in atrial fibrillation patients undergoing percutaneous coronary interventions: focus on stent thrombosis.
      ]. In a study by Conti et al., the relationship between of coronary atherosclerosis and adverse outcomes was analyzed using troponin levels rises in more than 3500 recent-onset AF patients without severe comorbidities [
      • Conti A.
      • Angeli E.
      • Scorpiniti M.
      • Alesi A.
      • Trausi F.
      • Lazzeretti D.
      • et al.
      Coronary atherosclerosis and adverse outcomes in patients with recent-onset atrial fibrillation and troponin rise.
      ]. Patients with a recent-onset AF and a troponin rise had significantly increased risk of adverse coronary events when compared with patients without troponin rise (19% vs 1%) and during a 5-year follow-up almost 50% of the patients with a troponin rise underwent coronary revascularization [
      • Conti A.
      • Angeli E.
      • Scorpiniti M.
      • Alesi A.
      • Trausi F.
      • Lazzeretti D.
      • et al.
      Coronary atherosclerosis and adverse outcomes in patients with recent-onset atrial fibrillation and troponin rise.
      ].
      In consideration of the observational nature of our study and available data, we were able to simply stratify our cohort between patients with normal or elevated plasma cTn levels, but we were not able to investigate differences in outcome across specific ranges of elevated cTn values. Serial troponins were not tested in some patients and in some cases our results were based on a single cTn determination. We could not determinate a “rise and fall” or temporal pattern of cTn release that is used to rule out ACS. However, our aim was to evaluate if even one cTn assessment could have prognostic implications independently from the diagnosis of myocardial infarction in a general AF population. It has been reported that any abnormally elevated cTn at any level were associated with adverse outcomes [
      • Jeremias A.
      • Gibson CM.
      Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded.
      ,
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • Murphy S.A.
      • Brown K.
      • Jarolim P.
      • et al.
      Cardiovascular biomarker score and clinical outcomes in patients with atrial fibrillation: a subanalysis of the ENGAGE AF-TIMI 48 randomized clinical trial.
      ,
      • Hamm C.W.
      • Giannitsis E.
      • Katus HA.
      Cardiac troponin elevations in patients without acute coronary syndrome.
      ]. Even a single elevated cTn value at presentation indicates an increased risk of adverse clinical outcomes (e.g. all-cause or cardiovascular death) in different patient populations (including those without acute ischemic conditions) [
      • Giannitsis E.
      • Katus H.A.
      Cardiac troponin level elevations not related to acute coronary syndromes.
      ]. This was confirmed by the additional subanalysis that we performed excluding patients with ACS or CAD in whom elevated cTn were still significantly associated with adverse outcomes. Of note, our study actually reflects what frequently occurs in clinical practice where troponin levels are often dichotomized into “positive” (i.e. >99th percentile of the upper limit of normal for the cTn assay) or “negative”.
      Finally our study also showed that patients with cTn tested in range were associated with higher occurrence of adverse events during follow-up. Given the observational nature of the study, our findings have to be interpreted in terms of associations, and may be affected by confounding. We can hypothesize that the patient clinical profile that let physicians to test for cTn may imply some additional risk of bleeding or hospital re-admission, to explain the associations found.

      4.1 Limitations

      The main limitation of our study is related to its observational nature, since cTn assessment was not predefined. Additionally, the data presented do not imply causality, but simply report associations. Second, some patients were lost at follow-up, notwithstanding similar proportion of losses were reported by other registries. Another limitation is related to the study setting, based exclusively on cardiology practices. Lastly, a specific limitation of this analysis was the analytic accuracy of the prognostic value of troponin, given the different assays used at each center. We could not discriminate between hs-cTn and conventional cTn since each center used his own cTn assay. We could only stratify our cohort as normal or elevated plasma cTn and we were not able to investigate differences in outcome across specific ranges of elevated cTn values. Nevertheless, as found by a recent meta-analysis on more than 20,000 AF patients, the prognostic value of cTn seems to be independent of the method of determination and type of troponin measured [
      • Fan Y.
      • Zhao X.
      • Li X.
      • Li N.
      • Hu X.
      Cardiac troponin and adverse outcomes in atrial fibrillation: a meta-analysis.
      ].

      5. Conclusions

      In this large contemporary cohort of European AF patients a clinical presentation or baseline characteristics that might enhance the need to rule out an underlying ACS, such as presence of atypical AF-related symptoms, previous history of CAD and first detected AF were independently associated with cTn measurement in daily clinical practice. Elevated levels of cTn were independently associated with an increased risk of all-cause mortality and adverse CV events, including hospital readmissions, even after exclusion of patients with CAD or history of CAD.

      Funding

      Since the start of EORP, the following companies have supported the program: Abbott Vascular Int. (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2016), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2011–2017), Edwards (2016–2019), Gedeon Richter Plc. (2014–2017), Menarini Int. Op. (2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2010–2021), and Vifor (2019–2022).

      Data availability

      The data underlying this article were provided by the European Society of Cardiology by permission. Data will be shared on request to the corresponding author with permission of ESC Editorial is also expected but not yet confirmed.

      Declaration of Competing Interest

      GB: small speaker fee from Medtronic, Boston, Boehringer Ingelheim and Bayer. LF: Consultant or speaker for Bayer, BMS/Pfizer, Boehringer Ingelheim, Medtronic, Novartis and XO. FM: Advisor fees Boehringer-Ingelheim, Research Grants Ferrer, Speaker fees Boehringer-Ingelheim, Astra-Zeneca, Pfizer and Bayer; TP: Consultant for Bayer and Pfizer (no fees). GAD: Small speaker fees from Boehringer-Ingelheim, Pfizer, Bayer, Sanofi and Zentiva; LT is committee member for Servier and CVIE Therapeutics and speaker for Servier. DAL has received an investigator-initiated educational grant from Bristol-Myers Squibb (BMS); has been a speaker for Boehringer Ingelheim and BMS/Pfizer; and has consulted for BMS, Boehringer Ingelheim, and Daiichi-Sankyo. GYHL: Consultant and speaker for Bayer/Janssen, BMS/Pfizer, Boehringer Ingelheim, and Daiichi-Sankyo (No fees are directly received personally). All the disclosures occurred outside the submitted work. Other authors have no disclosures to declare.

      Acknowledgments

      EORP Oversight Committee, Executive and Steering Committees (National Coordinators) of the EURObservational Research Program (EORP)—Atrial Fibrillation General Long-Term (EORP- AFGen LT) Registry of the European Society of Cardiology (ESC). Data collection was conducted by the EORP department by Patti- Ann McNeill as Project Officer, Viviane Missiamenou as Data Manager. Overall activities were coordinated and supervised by Doctor Aldo P. Maggioni (EORP Scientific Coordinator).

      Appendix B. Supplementary materials

      Appendix

      EURObservational Research Programme Atrial Fibrillation (EORP-AF) Long-Term General Registry Committees and Investigators
      Executive committee: G.Boriani (Chair), G.Y.H. Lip, L. Tavazzi, A. P. Maggioni, G-A. Dan, T. Potpara, M. Nabauer, F. Marin, Z. Kalarus, L. Fauchier.
      Steering Committee (National Coordinators): A. Goda, University Hospital Center "Mother Tereza", Tirana, Albania; G. Mairesse, Cliniques du Sud-Luxembourg, Arlon, Belgium; T. Shalganov, National Heart Hospital, Sofia, Bulgaria; L. Antoniades, Nicosia General Hospital, Latsia, Cyprus; M. Taborsky, University Hospital Olomouc, Olomouc, Czech Republic; S. Riahi, Aalborg University Hospital, Aalborg, Denmark; P. Muda, University of Tartu, Tartu, Estonia; I. García Bolao, Navarra Institute for Health Research, Pamplona, Spain; O. Piot, Center Cardiologique du Nord, Saint-Denis, France; M. Nabauer, Ludwig-Maximilians-University, Munich, Germany; K. Etsadashvili, G. Chapidze Emergency Cardiology Center, Tbilisi, Georgia; EN. Simantirakis, University Hospital of Heraklion, School of Medicine, University of Crete, Heraklion, Crete, Greece; M. Haim, Soroka Medical Center, Beer Sheva, Israel; A. Azhari, J. Najafian, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran; M. Santini, San Filippo Neri Hospital, Rome, Italy; E. Mirrakhimov, National Center of Cardiology and Internal Medicine, Bishkek, Kyrgyzstan; K. Kulzida, Scientific-Research Institute of Cardiology and Internal Diseases, Almaty, Republic of Kazakhstan; A. Erglis, Pauls Stradins Clinical University Hospital University of Latvia Riga Latvia; L. Poposka, University Clinic of Cardiology, Faculty of Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia; MR. Burg, Mater Dei Hospital, Triq Dun Karm Psaila, Malta; H. Crijns, Ö. Erküner, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands; D. Atar, Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Oslo, Norway; R. Lenarczyk, Silesian Center for Heart Disease, Zabrze, Poland; M. Martins Oliveira, Hospital Santa Marta, Lisbon, Portugal; D. Shah, Department of Medicine Specialities, University Hospital Geneva, Geneva, Switzerland; G-A. Dan, Colentina University Hospital, Bucharest, Romania; E. Serdechnaya, Northern State Medical University, Arkhangelsk, Russia; T. Potpara, Cardiology Clinic, Clinical Center of Serbia, Belgrade, Serbia; E. Diker, Başakşehir Çam and Sakura City Hospital, Istanbul, Turkey; G.Y.H. Lip, D. Lane; City Hospital, University of Birmingham, Birmingham, United Kingdom.
      Participants: ALBANIA Durrës: E. Zëra, Tirana: U. Ekmekçiu, V. Paparisto, M. Tase, Tirana: H. Gjergo, J. Dragoti, A. Goda, BELGIUM Bastogne: M. Ciutea, N. Ahadi, Z. el Husseini, M. Raepers, Gilly: J. Leroy, P. Haushan, A. Jourdan, Haine Saint Paul: C. Lepiece, Hasselt: L. Desteghe, J. Vijgen, P. Koopman, G. Van Genechten, H. Heidbuchel, Kortrijk: T. Boussy, M. De Coninck, H. Van Eeckhoutte, N. Bouckaert, La Louviere: A. Friart, J. Boreux, C. Arend, Liege: P. Evrard, Liège: L. Stefan, E. Hoffer, J. Herzet, M. Massoz, Liège: C. Celentano, M. Sprynger, L. Pierard, Liège: P. Melon, Overpelt: B. Van Hauwaert, C. Kuppens, D. Faes, D. Van Lier, A. Van Dorpe, Waremme: A. Gerardy, Yvoir: O. Deceuninck, O. Xhaet, F. Dormal, E. Ballant, D. Blommaert, BULGARIA Pleven: D. Yakova, M. Hristov, T. Yncheva, N. Stancheva, S. Tisheva, Plovdiv: M. Tokmakova, F. Nikolov, D. Gencheva, Sofia: T. Shalganov, B. Kunev, M. Stoyanov, Sofia: D. Marchov, V. Gelev, V. Traykov, Varna: A. Kisheva, H. Tsvyatkov, R. Shtereva, S. Bakalska-Georgieva, S. Slavcheva, Y. Yotov, CZECH REPUBLIC Ústí nad Labem: M. Kubíčková, DENMARK Aalborg: A. Marni Joensen, A. Gammelmark, L. Hvilsted Rasmussen, P. Dinesen, S. Riahi, S. Krogh Venø, B. Sorensen, A. Korsgaard, K. Andersen, C. Fragtrup Hellum, Esbjerg: A. Svenningsen, O. Nyvad, P. Wiggers, Herning: O. May, A. Aarup, B. Graversen, L. Jensen, M. Andersen, M. Svejgaard, S. Vester, S. Hansen, V. Lynggaard, Madrid: M. Ciudad, Tallinn: R. Vettus, Tartu: P. Muda, ESTONIA Elche, Alicante: A. Maestre, Toledo: S. Castaño, FRANCE Abbeville: S. Cheggour, Abbeville: J. Poulard, V. Mouquet, S. Leparrée, Aix-en-Provence: J. Bouet, J. Taieb, Amiens: A. Doucy, H. Duquenne, Angers: A. Furber, J. Dupuis, J. Rautureau, Aurillac: M. Font, P. Damiano, Avignon Cedex: M. Lacrimini, Brest: J. Abalea, S. Boismal, T. Menez, J. Mansourati, Chartres: G. Range, H. Gorka, C. Laure, C. Vassalière, Creteil: N. Elbaz, N. Lellouche, K. Djouadi, Montpellier: F. Roubille, D. Dietz, J. Davy, Nimes: M. Granier, P. Winum, C. Leperchois-Jacquey, Paris: H. Kassim, E. Marijon, J. Le Heuzey, Paris: J. Fedida, C. Maupain, C. Himbert, E. Gandjbakhch, F. Hidden-Lucet, G. Duthoit, N. Badenco, T. Chastre, X. Waintraub, M. Oudihat, J. Lacoste, C. Stephan, Pau: H. Bader, N. Delarche, L. Giry, Pessac: D. Arnaud, C. Lopez, F. Boury, I. Brunello, M. Lefèvre, R. Mingam, M. Haissaguerre, Rennes: M. Le Bidan, D. Pavin, V. Le Moal, C. Leclercq, Saint Denis: O. Piot, T. Beitar, Saint Etienne: I. Martel, A. Schmid, N. Sadki, C. Romeyer-Bouchard, A. Da Costa, Tours: I. Arnault, M. Boyer, C. Piat, L. Fauchier, FYR MACEDONIA Bitola: N. Lozance, S. Nastevska, Ohrid: A. Doneva, B. Fortomaroska Milevska, B. Sheshoski, K. Petroska, N. Taneska, N. Bakrecheski, Skopje: K. Lazarovska, S. Jovevska, V. Ristovski, A. Antovski, Skopje: E. Lazarova, I. Kotlar, J. Taleski, L. Poposka, S. Kedev, Skopje: N. Zlatanovik, Štip: S. Jordanova, T. Bajraktarova Proseva, S. Doncovska, GEORGIA Tbilisi: D. Maisuradze, A. Esakia, E. Sagirashvili, K. Lartsuliani, N. Natelashvili, N. Gumberidze, R. Gvenetadze, Tbilisi: K. Etsadashvili, N. Gotonelia, N. Kuridze, Tbilisi: G. Papiashvili, I. Menabde, GERMANY Aachen: S. Glöggler, A. Napp, C. Lebherz, H. Romero, K. Schmitz, M. Berger, M. Zink, S. Köster, J. Sachse, E. Vonderhagen, G. Soiron, K. Mischke, Bad Reichenhall: R. Reith, M. Schneider, Berlin: W. Rieker, Biberach: D. Boscher, A. Taschareck, A. Beer, Boppard: D. Oster, Brandenburg: O. Ritter, J. Adamczewski, S. Walter, Chemnitz: A. Frommhold, E. Luckner, J. Richter, M. Schellner, S. Landgraf, S. Bartholome, Chemnitz: R. Naumann, J. Schoeler, Dachau: D. Westermeier, F. William, K. Wilhelm, M. Maerkl, Detmold: R. Oekinghaus, M. Denart, M. Kriete, U. Tebbe, Ebersbach: T. Scheibner, Erlangen: M. Gruber, A. Gerlach, C. Beckendorf, L. Anneken, M. Arnold, S. Lengerer, Z. Bal, C. Uecker, H. Förtsch, S. Fechner, V. Mages, Friedberg: E. Martens, H. Methe, Göttingen: T. Schmidt, Hamburg: B. Schaeffer, B. Hoffmann, J. Moser, K. Heitmann, S. Willems, S. Willems, Hartmannsdorf: C. Klaus, I. Lange, Heidelberg: M. Durak, E. Esen, Itzehoe: F. Mibach, H. Mibach, Kassel: A. Utech, Kirchzarten: M. Gabelmann, R. Stumm, V. Ländle, Koblenz: C. Gartner, C. Goerg, N. Kaul, S. Messer, D. Burkhardt, C. Sander, R. Orthen, S. Kaes, Köln: A. Baumer, F. Dodos, Königsbrück: A. Barth, G. Schaeffer, Leisnig: J. Gaertner, J. Winkler, Leverkusen: A. Fahrig, J. Aring, I. Wenzel, Limburg: S. Steiner, A. Kliesch, E. Kratz, K. Winter, P. Schneider, Ludwigsburg: A. Haag, I. Mutscher, R. Bosch, Markkleeberg: J. Taggeselle, S. Meixner, Meissen: A. Schnabel, Meppen: A. Shamalla, H. Hötz, A. Korinth, Merzig: C. Rheinert, Moosburg: G. Mehltretter, Mühldorf: B. Schön, N. Schön, A. Starflinger, E. Englmann, Munich: G. Baytok, T. Laschinger, G. Ritscher, Munich: A. Gerth, Münster: D. Dechering, L. Eckardt, Nienburg: M. Kuhlmann, N. Proskynitopoulos, Paderborn: J. Brunn, K. Foth, Pirna: C. Axthelm, H. Hohensee, K. Eberhard, S. Turbanisch, Plauen: N. Hassler, A. Koestler, Riesa: G. Stenzel, Riesa: D. Kschiwan, M. Schwefer, S. Neiner, S. Hettwer, Rotenburg a.d. Fulda: M. Haeussler-Schuchardt, R. Degenhardt, S. Sennhenn, S. Steiner, Starnberg: M. Brendel, Westerstede: A. Stoehr, W. Widjaja, S. Loehndorf, A. Logemann, J. Hoskamp, J. Grundt, Zorneding: M. Block, Zwiesel: R. Ulrych, A. Reithmeier, V. Panagopoulos, ITALY Bologna: C. Martignani, D. Bernucci, E. Fantecchi, I. Diemberger, M. Ziacchi, M. Biffi, P. Cimaglia, J. Frisoni, G. Boriani, Firenze: I. Giannini, S. Boni, S. Fumagalli, S. Pupo, A. Di Chiara, P. Mirone, Modena: E. Fantecchi, G. Boriani, F. Pesce, C. Zoccali, V.L.Malavasi, KAZAKHSTAN Almaty: A. Mussagaliyeva, B. Ahyt, Z. Salihova, K. Koshum-Bayeva, KYRGYZSTAN Bishkek: A. Kerimkulova, A. Bairamukova, E. Mirrakhimov, LATVIA Riga: B. Lurina, R. Zuzans, S. Jegere, I. Mintale, K. Kupics, K. Jubele, A. Erglis, O. 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      Linked Article

      • Atrial fibrillation and troponin elevation: It's time to give up the chase to diagnosis and step forward with prognosis
        European Journal of Internal MedicineVol. 99
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          Atrial fibrillation (AF) is the most common sustained arrhythmia with an estimated prevalence in adults as high as 4%. AF negatively affects the quality of life and it is associated with incident adverse cardiovascular events and two-fold higher mortality. Lifetime risk of AF increases with age but many other risk factors such as diabetes, chronic kidney disease, hypertension and obesity may promote its development. Owing to the shared risk factors, AF and coronary artery disease (CAD) can both be found in the same patient at some point in life [1].
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