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Background: Sex- and population-specific 99th percentiles of high-sensitivity cardiac troponin (hs-cTn) are recommended in guidelines although the evidence for a clinical utility is sparse. The DANSPOT trial will investigate the clinical effect of sex- and population-specific 99th percentiles of cTn. We report the 99th percentiles derived from this trial and their dependency on kidney function., Methods: We used samples from healthy Danish blood donors and measured hemoglobin A1c, N-terminal pro-brain natriuretic peptide and creatinine, and calculated an estimated glomerular filtration rate (eGFR). We compared 2 cutoffs for the eGFR of healthy participants (60 vs 90 mL/min/1.73 m2). The cTn assays investigated were Siemens Atellica and Dimension Vista hs-cTnI, Abbott hs-cTnI, and Roche hs-cTnT., Results: A total of 2287 participants were sampled, of which 71 (3.1%) were excluded due to a history of heart disease (n = 4), insufficient material (n = 7), or a screening biomarker (n = 60). Of the remaining 2216 participants, 1325 (59.8%) had an eGFR ≥90 mL/min/1.73 m2. Compared to a cutoff of 60 mL/min/1.73 m2 for eGFR, using 90 mL/min/1.73 m2 resulted in lower 99th percentiles for females; Siemens Vista (46 vs 70 ng/L), Abbott (14 vs 18 ng/L), and Roche cTnT (10 vs 13 ng/L), and decreased the number of measurements above the manufacturers' 99th percentiles for all assays., Conclusions: We present reference values for 4 cTn assays for eGFR cutoffs of 60 and 90 mL/min/1.73 m2. These cutoffs differ based on the eGFR threshold for inclusion indicating that any chosen cutoff is also valuable with moderately reduced kidney function., (© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Cardiac troponins are the preferred biomarkers for the diagnosis of acute myocardial infarction. Although sex-specific 99th percentile thresholds of troponins are recommended in international guidelines, the clinical effect of their use is poorly investigated. The DANSPOT Study (The Danish Study of Sex- and Population-Specific 99th percentile upper reference limits of Troponin) aims to evaluate the clinical effect of a prospective implementation of population- and sex-specific diagnostic thresholds of troponins into clinical practice., Methods: This study is a nationwide, multicenter, stepped-wedge cluster-randomized trial of the implementation of population- and sex-specific thresholds of troponins in 22 of 23 clinical centers in Denmark. We established sex-specific thresholds for 5 different troponin assays based on troponin levels in a healthy Danish reference population. Centers will sequentially cross over from current uniform manufacturer-derived thresholds to the new population- and sex-specific thresholds. The primary cohort is defined as patients with symptoms suggestive of acute coronary syndrome having at least 1 troponin measurement performed within 24 hours of arrival with a peak troponin value between the current uniform threshold and the new sex-specific female and male thresholds. The study will compare the occurrence of the primary outcome, defined as a composite of nonfatal myocardial infarction, unplanned revascularization, and all-cause mortality within 1 year, separately for men and women before and after the implementation of the new sex-specific thresholds., Conclusions: The DANSPOT Study is expected to show the clinical effects on diagnostics, treatment, and clinical outcomes in patients with myocardial infarction of implementing sex-specific diagnostic thresholds for troponin based on a national Danish reference population., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05336435.

Background: Amino-terminal-pro-B-type-natriuretic-peptide (NT-proBNP) is a diagnostic biomarker for heart failure (HF), but plasma concentrations are influenced by numerous factors. Mid-regional-pro-atrial-natriuretic-peptide (MR-proANP) have comparable diagnostic value in acute HF. However, data are lacking in the non-acute setting. This study sought to assess the diagnostic utility of MR-proANP in outpatients with a high risk of HF. Methods: This prospective study included 399 outpatients. Inclusion criteria were: age ≥ 60 years, ≥1 risk factor for HF (diabetes, chronic kidney disease, vascular disease, atrial fibrillation, hypertension), without known or suspected HF. Unrecognized HF was diagnosed based on clinical signs, patient-reported symptoms and echocardiography. Plasma concentrations of MR-proANP and NT-proBNP were analysed. Results: In total, 65 patients were diagnosed with HF or asymptomatic left ventricular systolic dysfunction ( N  = 12 LVEF ≤ 40%, N  = 7 LVEF > 40% to ≤50%, N  = 46 LVEF > 50%). Both MR-proANP (odds-ratio: 1.77; 95% CI:1.16-2.72; p  = 0.009) and NT-proBNP (odds-ratio: 1.49; 95% CI:1.22-1.82; p  < 0.001) were associated with HF. Area under receiver-operator characteristics curve (AUC) for the diagnosis of HF or asymptomatic left ventricular systolic dysfunction was higher for MR-proANP (AUC = 0.886; p  < 0.001) and NT-proBNP (AUC = 0.910; p  < 0.001) compared to patient-reported symptoms of HF (AUC = 0.830), but NT-proBNP added more diagnostic information compared to MR-proANP ( p  = 0.022). Conclusions: Both NT-proBNP and MR-proANP are useful biomarkers in the diagnosis of HF or asymptomatic left ventricular systolic dysfunction in a non-acute setting. However, NT-proBNP added more diagnostic information compared to MR-proANP.

Background: Cardiac-specific troponin T (cTnT) and troponin I (cTnI) are considered diagnostically equal in patients with acute coronary syndrome (ACS). The aim of this systematic review was to compare the prevalence and prognostic strength of elevations of cTnT and cTnI in patients with other conditions than ACS., Methods: A systemic review was conducted in concordance with the PRISMA guidelines. The studies were identified by searching PubMed, EMBASE and Cochrane Central Register, from May to August 2016. Studies measuring both cTnT and cTnI in populations without ACS were eligible., Results: Twenty-nine studies were included (n = 25,859). Seventeen studies reported on prognostic information with follow-up time ranging for 30 d-5 years. Elevation above the 99th percentile (reference value for a healthy population) in non-ACS population was reported to be 0-39% for cTnI and 40-100% for cTnT. Elevation of cTnT tends to be a superior predictor for all-cause mortality and elevation of cTnI tends to be a superior predictor for cardiovascular related mortality., Discussion: In the absence of ACS, elevation of cTnT is more frequent than elevation of cTnI., Conclusion: Both cTnT and cTnI elevations have important prognostic information regarding morbidity, cardiac mortality and all-cause mortality.

Objective: Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker associated with presence and progression of disease and with increased risk of mortality. We aimed to evaluate the unspecific biomarker suPAR as a prognostic marker in patients admitted to acute care., Methods: This registry-based retrospective cohort study included 4343 consecutively admitted patients from the Acute Medical Unit at a large Danish university hospital. Time to readmission and death were analysed by multiple Cox regression. Results were reported as HRs for 30-day and 90-day follow-up., Results: During 30-day follow-up, 782 patients (18.0%) were readmitted and 224 patients (5.2%) died. Comparing 30-day readmission and mortality between patients in the highest and lowest suPAR quartiles yielded HRs of 2.11 (95% CI 1.70 to 2.62) and 4.11 (95% CI 2.46 to 6.85), respectively, when adjusting for age, sex, Charlson score and C reactive protein. Area under the curve for receiver operating characteristics curve analysis of suPAR for 30-day mortality was 0.84 (95% CI 0.81 to 0.86). Furthermore, in the entire cohort, women had slightly higher suPAR compared with men, and suPAR was associated with age, admission time, admission to intensive care unit and Charlson score., Conclusions: In this large unselected population of acute medical patients, suPAR is strongly associated with disease severity, readmission and mortality after adjusting for all other risk factors, indicating that suPAR adds information to established prognostic indicators. While patients with low suPAR levels have low risk of readmission and mortality, patients with high suPAR levels have a high risk of adverse events., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Several biomarkers have shown to carry prognostic value beyond current triage algorithms and may aid in initial risk stratification of patients in the emergency department (ED). It has yet to be established if information provided by biomarkers can be used to prevent serious complications or deaths. Our aim is to determine whether measurement of the blood level of the biomarker soluble urokinase plasminogen activator receptor (suPAR) can enhance early risk stratification leading to reduced mortality, lower rate of complications, and improved patient flow in acutely admitted adult patients at the ED. The main hypothesis is that the availability of suPAR can reduce all-cause mortality, assessed at least 10 months after admission, by drawing attention towards patients with an unrecognized high risk, leading to improved diagnostics and treatment., Methods: The study is designed as a cross-over cluster randomized interventional trial. SuPAR is measured within 2 h after admission and immediately reported to the treating physicians in the ED. All ED physicians are educated in the prognostic capabilities of suPAR prior to the inclusion period. The inclusion period began January 11(th) 2016 and ends June 6(th) 2016. The study aims to include 10.000 patients in both the interventional and control arm. The results will be presented in 2017., Discussion: The present article aims to describe the design and rationale of the TRIAGE III study that will investigate whether the availability of prognostic information can improve outcome in acutely admitted patients. This might have an impact on health care organization and decision-making., Trial Registration: The trial is registered at clinicaltrials.gov (ID NCT02643459 , November 13, 2015) and at the Danish Data Protection agency (ID HGH-2015-042 I-Suite no. 04087).

Background: The European Society of Cardiology (ESC) guideline on non-ST-elevation acute coronary syndrome (N-STE ACS) proposed a new ACS rule-out protocol., Objectives: To evaluate this new tool, which uses diagnostic levels of high-sensitivity troponin T (hs-TnT; > 14 ng/L) in a slightly modified version and compare this to a recently proposed approach using undetectable levels of hs-TnT to rule out patients., Methods: There were 534 consecutive patients with suspected ACS included. Protocol 1: symptom duration, hs-TnT at 0 and 6-9 h, Global Registry of Acute Coronary Events (GRACE) score, and symptom status at 6-9 h. Protocol 2: a single blood sample of hs-TnT. The primary endpoint was a discharge diagnosis of ACS by blinded adjudication. Secondary endpoints were ACS re-admission < 30 days and 1-year mortality., Results: Protocol 1 classified 434/534 (81%) patients, with 27.9% being ruled out. All myocardial infarctions were correctly ruled in, but 15 cases of unstable angina were missed, resulting in a sensitivity and negative predictive value of 87.3% (79.6-92.5%) and 87.6% (80.4-92.9%), respectively. Protocol 2 ruled out 17.5% of the population, yielding a sensitivity and negative predictive value of 94.1% (88.2-97.6%) and 90.8% (81.9-96.2%), respectively. Both protocols correctly ruled in 2/3 patients with ACS re-admission < 30 days and 55/56 1-year fatalities., Conclusion: The present study confirms the diagnostic value of a modified version of the ESC rule-out protocol (Protocol 1) in N-STE ACS patients, but also suggests that a simpler protocol using undetectable levels of hs-TnT (Protocol 2) could provide a similar or even superior sensitivity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Patient crowding in emergency departments (ED) is a common challenge and associated with worsened outcome for the patients. Previous studies on biomarkers in the ED setting has focused on identification of high risk patients, and and the ability to use biomarkers to identify low-risk patients has only been sparsely examined. The broader aims of the TRIAGE study are to develop methods to identify low-risk patients appropriate for early ED discharge by combining information from a wide range of new inflammatory biomarkers and vital signs, the present baseline article aims to describe the formation of the TRIAGE database and characteristize the included patients., Methods: We included consecutive patients ≥ 17 years admitted to hospital after triage staging in the ED. Blood samples for a biobank were collected and plasma stored in a freezer (-80 °C). Triage was done by a trained nurse using the Danish Emergency Proces Triage (DEPT) which categorizes patients as green (not urgent), yellow (urgent), orange (emergent) or red (rescusitation). Presenting complaints, admission diagnoses, comorbidities, length of stay, and 'events' during admission (any of 20 predefined definitive treatments that necessitates in-hospital care), vital signs and routine laboratory tests taken in the ED were aslo included in the database., Results: Between September 5(th) 2013 and December 6(th) 2013, 6005 patients were included in the database and the biobank (94.1 % of all admissions). Of these, 1978 (32.9 %) were categorized as green, 2386 (39.7 %) yellow, 1616 (26.9 %) orange and 25 (0.4 %) red. Median age was 62 years (IQR 46-76), 49.8 % were male and median length of stay was 1 day (IQR 0-4). No events were found in 2658 (44.2 %) and 158 (2.6 %) were admitted to intensive or intermediate-intensive care unit and 219 (3.6 %) died within 30 days. A higher triage acuity level was associated with numerous events, including acute surgery, endovascular intervention, i.v. treatment, cardiac arrest, stroke, admission to intensive care, hospital transfer, and mortality within 30 days (p < 0.001)., Conclusion: The TRIAGE database has been completed and includes data and blood samples from 6005 unselected consecutive hospitalized patients. More than 40 % experienced no events and were therefore potentially unnecessary hospital admissions.

For more than a decade, pregnancy-associated plasma protein-A (PAPP-A) has been examined for its relation to acute coronary syndrome (ACS) and the vulnerable plaque. This review summarizes the current knowledge of plasma PAPP-A in relation to nonpregnant individuals focusing on patients with ACS, discusses its use as a possible biomarker for diagnosis and prognosis in ACS, briefly describes the challenges in different assay technologies and describes the effect of heparin administration on PAPP-A concentrations in plasma.

Background: Predicting mortality in emergency departments (EDs) using machine learning models presents challenges, particularly in balancing simplicity with performance. This study aims to develop models that are both simple and effective for predicting short- and long-term mortality in ED patients. Our approach uses a minimal set of variables derived from one single blood sample obtained at admission. Methods: Data from three cohorts at two large Danish university hospitals were analyzed, including one retrospective and two prospective cohorts where prognostic models were applied to predict individual mortality risk, spanning the years 2013–2022. Routine biochemistry analyzed in blood samples collected at admission was the primary data source for the prediction models. The outcomes were mortality at 10, 30, 90, and 365 days after admission to the ED. The models were developed using Light Gradient Boosting Machines. The evaluation of mortality predictions involved metrics such as Area Under the Receiver Operating Characteristic Curve (AUC), sensitivity, specificity, negative predictive values, positive predictive values, and Matthews correlation coefficient (MCC). Results: A total of 43,648 unique patients with 65,484 admissions were analyzed. The models showed high accuracy, with very good to excellent AUC values between 0.87 and 0.93 across different time intervals. Conclusions: This study demonstrates that a single assessment of routine clinical biochemistry upon admission can serve as a powerful predictor for both short-term and long-term mortality in ED admissions. [ABSTRACT FROM AUTHOR]

End-stage renal disease is associated with a high risk of cardiovascular disease. We compared the concentration and prognostic ability of high sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) and cardiac myosin-binding protein C (cMyC) among stable hemodialysis patients. Patients were sampled before and after hemodialysis. We measured hs-cTnI, hs-cTnT and cMyC and used Cox regressions to assess the association between quartiles of concentrations and all-cause mortality and a combination of cardiovascular events and all-cause mortality during follow-up. A total of 307 patients were included, 204 males, mean age 66 years (SD 14). Before dialysis, 299 (99 %) had a hs-cTnT concentration above the 99th percentile, compared to 188 (66 %) for cMyC and 35 (11 %) for hs-cTnI. Hs-cTnT (23 %, p<0.001) and hs-cTnI (15 %, p=0.049) but not cMyC (4 %, p=0.256) decreased during dialysis. Follow-up was a median of 924 days (492–957 days); patients in the 3rd and 4th quartiles of hs-cTnT (3rd:HR 3.0, 95 % CI 1.5–5.8, 4th:5.2, 2.7–9.8) and the 4th quartile of hs-cTnI (HR 3.8, 2.2–6.8) had an increased risk of mortality. Both were associated with an increased risk of the combined endpoint for patients in the 3rd and 4th quartiles. cMyC concentrations were not associated with risk of mortality or cardiovascular event. Hs-cTnT was above the 99th percentile in almost all patients. This was less frequent for hs-cTnI and cMyC. High cTn levels were associated with a 3-5-fold higher mortality. This association was not present for cMyC. These findings are important for management of hemodialysis patients. [ABSTRACT FROM AUTHOR]

Introduction: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep venous thrombosis (DVT). Biomarkers are potentially valuable clinical tools for handling PTS. The purpose of this review was to examine which biomarkers are associated with the development of PTS in adults with lower extremity DVT. Methods: We performed a systematic review of all English language prospective studies of biomarkers and PTS published in PubMed and EMBASE. Studies were included if diagnosing DVT by diagnostic imaging and assessing PTS by clinical scales, for example, the Villalta scale. Biomarkers of thrombophilia and pathological clot properties were not assessed. Data was reported qualitatively. Results: 15 prospective studies were included. Studies varied widely in study design and methods of data analysis. Forty-six different biomarkers were examined, with seven being measured in two or more studies. The most frequently studied biomarkers were D-dimer, CRP, and IL-6. Associations between PTS and D-dimer were predominantly significant, while results on CRP and IL-6 were inconsistent. ICAM-1 was consistently associated with PTS in all studies and at all timepoints. IL-10 was significantly related to PTS development in the largest study and at all time points. Adiponectin, tPA, HRG and TAFI, MMP-1 and -8, and TIMP-1 and -2 were significantly associated with PTS in single studies. Conclusion: (1) Further research on biomarkers and PTS is clearly warranted. (2) Significant differences in study designs made it difficult to draw reliable conclusions regarding individual biomarkers. We suggest the implementation of a standardized framework for the study of biomarkers and PTS, to make comparison of future studies more feasible. (3) D-dimer, ICAM-1, IL-10, MMP-1 and 8, TIMP-1, TIMP-2, and adiponectin are clinical biomarkers of particular interest to include in future studies of PTS. Large scale systemic quantitative proteomic analyses of DVT patients could help identify novel biomarkers of interest in PTS-patients. [ABSTRACT FROM AUTHOR]

Keywords: acute coronary syndrome; biomarkers; cardiovascular disease; troponin EN acute coronary syndrome biomarkers cardiovascular disease troponin 921 929 9 05/12/22 20220501 NES 220501 Introduction Cardiac troponin (cTn) is the gold standard for the diagnosis of myocardial infarction (MI) [[1]]. Of these, concentration at peak was higher for cTnI-U than hs-cTnI in 54 (91.5%) cases, and 54 (91.5%) cases had acute myocardial injury using cTnI-U while the remaining 5 (8.5%) had acute myocardial injury using hs-cTnI. Notably, of the 15 patients with MI using cTnI-U but not hs-cTnI, 9 (60%) did have myocardial injury using hs-cTnI but did not have a significant rise or fall. (B) Bland-Altmann plot of cTnI-U and hs-cTnI (n=2,649 of 4,378, 61%) and highlighted (red) measurements where either cTnI-U or hs-cTnI was 5 times higher than the other with at least one measurement >40 ng/L. The black line indicates the mean difference (23%), and the red dashed lines indicate the limits of agreement (-52 and 213%). [Extracted from the article]

Background: Prioritization of acutely ill patients in the Emergency Department remains a challenge. We aimed to evaluate whether routine blood tests can predict mortality in unselected patients in an emergency department and to compare risk prediction with a formalized triage algorithm. Methods: A prospective observational cohort study of 12,661 consecutive admissions to the Emergency Department of Nordsjælland University Hospital during two separate periods in 2010 (primary cohort, n = 6279) and 2013 (validation cohort, n = 6383). Patients were triaged in five categories by a formalized triage algorithm. All patients with a full routine biochemical screening (albumin, creatinine, c-reactive protein, haemoglobin, lactate dehydrogenase, leukocyte count, potassium, and sodium) taken at triage were included. Information about vital status was collected from the Danish Central Office of Civil registration. Multiple logistic regressions were used to predict 30-day mortality. Validation was performed by applying the regression models on the 2013 validation cohort. Results: Thirty-day mortality was 5.3%. The routine blood tests had a significantly stronger discriminative value on 30-day mortality compared to the formalized triage (AUC 88.1 [85.7;90.5] vs. 63.4 [59.1;67.5], p < 0.01). Risk stratification by routine blood tests was able to identify a larger number of low risk patients (n = 2100, 30-day mortality 0.1% [95% CI 0.0;0.3%]) compared to formalized triage (n = 1591, 2.8% [95% CI 2.0;3.6%]), p < 0.01. Conclusions: Routine blood tests were strongly associated with 30-day mortality in acutely ill patients and discriminatory ability was significantly higher than with a formalized triage algorithm. Thus routine blood tests allowed an improved risk stratification of patients presenting in an emergency department. [ABSTRACT FROM AUTHOR]

Background Rapid risk stratification is a core task in emergency medicine. Identifying patients at high and low risk shortly after admission could help clinical decision-making regarding treatment, level of observation, allocation of resources and post discharge follow-up. The purpose of the present study was to determine short-, mid- and long-term mortality by plasma measurement of copeptin in unselected admitted patients. Method Consecutive patients >40-years-old admitted to an inner-city hospital were included. Within the first 24 hours after admission, a structured medical interview was conducted and self- reported medical history was recorded. All patients underwent a clinical examination, an echocardiographic evaluation and collection of blood for later measurement of risk markers. Results Plasma for copeptin measurement was available from 1,320 patients (average age 70.5 years, 59.4% women). Median follow-up time was 11.5 years (range 11.0 to 12.0 years). Copeptin was elevated (that is, above the 97.5 percentile in healthy individuals). Mortality within the first week was 2.7% (17/627) for patients with elevated copeptin (above the 97.5 percentile, that is, ≤11.3 pmol/L) compared to 0.1% (1/693) for patients with normal copeptin concentrations (that is, =11.3 pmol/L) (P <0.01). Three-month mortality was 14.5% (91/627) for patients with elevated copeptin compared to 3.2% (22/693) for patients with normal copeptin. Similar figures for one-year mortality and for the entire observation period were 27.6% (173/627) versus 8.7% (60/693) and 82.9% (520/527) versus 57.5% (398/693) (P <0.01 for both), respectively. Using multivariable Cox regression analyses shows that elevated copeptin was significantly and independently related to short-, mid- and long-term mortality. Adjusted hazard ratios were 2.4 for three-month mortality, 1.9 for one-year mortality and 1.4 for mortality in the entire observation period. Conclusions In patients admitted to an inner-city hospital, copeptin was strongly associated with short-, mid- and long-term mortality. The results suggest that rapid copeptin measurement could be a useful tool for both disposition in an emergency department and for mid- and long-term risk assessment. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate if pregnancy associated plasma protein-A (PAPP-A) was present in the vulnerable plaque, and if not, to find alternative hypothesis for the release of PAPP-A. Design and methods: Vulnerable plaques and control tissues were examined by immunohistochemistry. Volunteers and patients with non-atherosclerotic disease were examined for release of PAPP-A during ischemia and medical treatment. Non-atherosclerotic tissue samples were examined after incubation with heparins. Results: We were not able to detect PAPP-A in vulnerable plaques. Patients and volunteers experiencing ischemic events without atherosclerotic lesions only had elevated PAPP-A when treated with heparin. When tissue from normal artery wall was incubated with heparin, PAPP-A was eluted. This was not the case for non-arterial tissue samples. Conclusion: Elevation of PAPP-A in patients with acute coronary syndromes seems to be caused by heparin induced release of PAPP-A from the arterial wall and not due to excretion from vulnerable plaques. [Copyright &y& Elsevier]

Abstract: Objective: Pregnancy associated plasma protein-A (PAPP-A) is a potential new marker for vulnerable plaques in the coronary arteries only examined in stable coronary disease (CAD) in patients undergoing coronary angiography. Here we address the prognostic value of serum PAPP-A in unselected stable CAD patients. Method: Blood samples were drawn at study entry. Serum PAPP-A values ≥4mIU/L were considered elevated. Mortality and non-fatal myocardial infarction was prospectively registered. The primary outcome was the composite outcome of myocardial infarction and all-cause mortality, secondary outcomes were all-cause mortality and myocardial infarction. Results: Patients (n =4243) were followed for a median of 2.8 years. In a Cox analysis, elevated PAPP-A was significantly related to the composite outcome of myocardial infarction and death (HR 1.99, 95% CI 1.62–2.45, p <0.0005), all-cause mortality (HR 2.42, 1.92–3.06, p <0.0005), and myocardial infarction (HR 1.40, 1.01–1.94, p =0.046). After Holm''s correction, the latter significance disappeared. After adjustment for risk factors and medication at entry, elevated PAPP-A remained significantly related to the composite outcome (HR 1.51, 1.22–1.86, p <0.0005) and all-cause mortality (HR 1.68, 1.32–2.13, p <0.0005). Conclusion: In patients with stable CAD elevated serum PAPP-A seems promising as aid in identifying patients at high risk for death. [Copyright &y& Elsevier]

Abstract: Objectives: To examine if pregnancy-associated plasma protein-A (PAPP-A) in patients with chest pain, could identify patients at risk for death or myocardial infarction. Design and methods: Patients admitted with chest pain and both normal ECG and normal biomarkers were evaluated by serial measurement of PAPP-A. Main outcome measures were mortality and non-fatal myocardial infarction. Results: Median age of patients included (415) was 67years and 43% were women. The risk of death or non-fatal myocardial infarction after 3 months was 15% in the highest quartile of circulating PAPP-A compared with 3% in the lowest quartile (relative risk 3.7, p <0.01). Corresponding numbers after 1 year were 24% and 10% (relative risk 2.4, p =0.01). Conclusion: In patients admitted with chest pain and both normal ECG and normal biomarkers PAPP-A seems to be valuable for predicting patients at high risk of death or non-fatal myocardial infarction. [Copyright &y& Elsevier]

To investigate whether pregnancy-associated plasma protein-A (PAPP-A) is a prognostic marker in patients admitted with high-risk acute coronary syndrome. In patients admitted with high-risk non–ST-segment elevation acute coronary syndrome (NSTE-ACS) and ST-segment elevation myocardial infarction (STEMI), risk stratification is primarily determined by the markers of myocardial necrosis and known demographic risk profiles. However, it has recently been proposed that the presence and extent of vulnerable plaques might influence the prognosis significantly. A marker for the vulnerable plaque could identify patients at high risk who would potentially benefit from intensive treatment and surveillance. Two populations of consecutive patients admitted with high-risk NSTE-ACS (n = 123) and STEMI (n = 314) were evaluated with serial measurements of PAPP-A. The incidence of mortality and nonfatal myocardial infarction was prospectively registered for 2.66 to 3.47 years. In the patients with high-risk NSTE-ACS, PAPP-A was related to the risk of nonfatal myocardial infarction (p = 0.02) and death (p = 0.03). This result was consistent on multivariate analysis of the combination of mortality or nonfatal myocardial infarction (odds ratio 2.65, 95% confidence interval 1.40 to 5.03) but not for mortality alone (p = NS). In patients with STEMI, PAPP-A was related to the risk of death (p = 0.01) but not the composite outcome of myocardial infarction and death. This was also true after adjustment for other univariate predictors of death (odds ratio 2.19, 95% confidence interval 1.16 to 4.16). In conclusion, PAPP-A seems to be valuable in predicting the outcomes of patients admitted with high-risk NSTE-ACS or STEMI. [Copyright &y& Elsevier]

Abstract: Objectives: To describe the presence and time-related pattern of circulating pregnancy associated plasma protein A (PAPP-A) levels in patients with non ST-segment elevation acute coronary syndrome (NSTE-ACS). Design and methods: Consecutively admitted patients (N =573) with clinical signs of NSTE-ACS were included. Blood samples for analysis of PAPP-A were drawn at admission and every 6–8 h until levels of biomarkers of myocardial necrosis showed a consistent decrease. Results: High-risk NSTE-ACS was diagnosed in 123 patients (23%). Significantly more patients with high-risk NSTE-ACS (63%) had detectable PAPP-A than did those with low-risk NSTE-ACS (49%) (P <0.001). PAPP-A concentrations were significantly associated with typical angina at admission, significant ST-depressions on the ECG, multivessel disease and presence of high-risk NSTE-ACS. Conclusion: PAPP-A seems to be a marker ischaemia both in patients with low- and high-risk NSTE-ACS, possibly due to the release of PAPP-A from the vulnerable plaque. [Copyright &y& Elsevier]

Traditional biomarkers in acute coronary syndromes reflect myocardial necrosis but not the underlying arteriosclerotic disease. Pregnancy-associated plasma protein A (PAPP-A) is a new biomarker in acute coronary syndromes that detects vulnerable plaques in arteriosclerotic disease and identifies acute coronary syndromes earlier than traditionally used biomarkers. Information regarding circulating PAPP-A levels in patients with ST elevation myocardial infarctions (STEMIs) is limited and contradictory. The aim of the present study was to describe the presence and time-related pattern of circulating PAPP-A levels in patients with STEMIs. Consecutive patients (n = 354) referred for primary percutaneous intervention because of STEMI were included in the study. Blood samples for the analysis of PAPP-A, creatine kinase-MB (CKMB), and troponin T were drawn at admission and every 6 to 8 hours until biomarkers of myocardial necrosis were consistently decreasing. PAPP-A was measured using a newly developed sandwich enzyme-linked immunosorbent assay technique based on 2 monoclonal antibodies. In total, 1,091 PAPP-A, 1,049 troponin T, and 1,016 CKMB samples were analyzed. Mean PAPP-A values at admission were significantly higher in patients with STEMIs than in those with non–ST elevation myocardial infarctions or unstable angina pectoris (27.6 vs 12.2 mIU/L, p <0.01). In samples drawn <2 hours after admission, the sensitivity of PAPP-A was superior (93%) to that of CKMB (60%) and troponin T (61%). In conclusion, PAPP-A levels are elevated in >90% of patients presenting with STEMIs if measured <6 hours after the onset of symptoms or <2 hours of primary percutaneous coronary intervention. In the early stages of STEMI, PAPP-A seems to be a more sensitive marker of myocardial infarction than CKMB and troponin T. [Copyright &y& Elsevier]

Elevated pregnancy-associated plasma protein A (PAPP-A) is associated with mortality in acute coronary syndromes. Few studies have assessed PAPP-A in stable coronary artery disease (CAD) and results are conflicting. We assessed the 10-year prognostic relevance of PAPP-A levels in stable CAD. The CLARICOR trial was a randomized controlled clinical trial including outpatients with stable CAD, randomized to clarithromycin versus placebo. The placebo group constituted our discovery cohort (n = 1.996) and the clarithromycin group the replication cohort (n = 1.975). The composite primary outcome was first occurrence of cardiovascular event or death. In the discovery cohort, incidence rates (IR) for the composite outcome were higher in those with elevated PAPP-A (IR 12.72, 95% Confidence Interval (CI) 11.0–14.7 events/100 years) compared to lower PAPP-A (IR 8.78, 8.25–9.34), with comparable results in the replication cohort. Elevated PAPP-A was associated with increased risk of the composite outcome in both cohorts (discovery Hazard Ratio (HR) 1.45, 95% CI 1.24–1.70; replication HR 1.29, 95% CI 1.10–1.52). In models adjusted for established risk factors, these trends were attenuated. Elevated PAPP-A was associated with higher all-cause mortality in both cohorts. We conclude that elevated PAPP-A levels are associated with increased long-term mortality in stable CAD, but do not improve long-term prediction of death or cardiovascular events when added to established predictors. [ABSTRACT FROM AUTHOR]

Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a strong prognostic biomarker in cardiovascular disease but there is limited data for its use among patients undergoing dialysis. This was a cohort study of patients receiving maintenance hemodialysis from two Danish centers. Blood sampling and echocardiography were performed before and after a dialysis session. We calculated the area under the curve (AUC) for the receiver operating characteristics for diagnosing heart failure and Cox regressions for cardiovascular events and all-cause mortality. Of the 306 patients, 284 (93%) had MR-proANP measurements both before and after dialysis. Median concentration was 642 pmol/L (IQR 419–858) before and 351 pmol/L (IQR 197–537) after dialysis, a mean decrease of 330 pmol/L (43%, CI 296–364, P < 0.001). MR-proANP concentration both before and after dialysis was negatively correlated to left ventricular ejection fraction with no difference in predictive ability for heart failure, AUC before and after dialysis were 0.60 (CI 0.50–0.70) and 0.61 (CI 0.51–0.71) (P = 0.40). Median follow-up was 32 months (IQR 31–33), during which 99 patients (32%) had a cardiovascular event and 110 (36%) died. A doubling of MR-proANP concentration was associated with a hazard ratio (HR) of 1.6 (CI 1.3–1.9) before and 1.7 (CI 1.4–2.0) after dialysis for mortality and a HR of 1.5 (CI 1.2–1.9) before and 1.4 (CI 1.2–1.7) after dialysis for cardiovascular events (all P < 0.001). The MR-proANP concentration is elevated among patients undergoing hemodialysis and decreases during dialysis. MR-proANP concentration both before, after and intra-dialysis change strongly predicted cardiovascular events and all-cause mortality. [ABSTRACT FROM AUTHOR]

Background Both iron deficiency (ID) and cardiovascular biomarkers are associated with a poor outcome in heart failure (HF). The relationship between different cardiovascular biomarkers and ID is unknown, and the true prevalence of ID in an outpatient HF clinic is probably overlooked. Objectives To identify the prevalence of ID in a HF clinic and evaluate whether ID is associated with increased plasma concentrations of different cardiovascular biomarkers that carry a poor prognosis. Methods We prospectively included 149 patients with systolic HF referred to an outpatients HF clinic. ID was defined as ferritin < 100 μg/L or ferritin 100-300 μg/L and Tranferin-saturation < 0.20. Five different cardiovascular biomarkers were analyzed on frozen plasma. Results The patients had a median age of 70 (Interquartile range: 64-75) years, 25% were females, 29% were in functional class III-IV and LVEF was 32 (27-39) %. The prevalence of ID was 45% (95%-confidence interval (CI): 37-53%). In multivariate analyses, ID was not associated with plasma concentrations of troponin I, NT-proBNP, MR-proANP, chromogranin A or copeptin (P > 0.05 for all) but with plasma concentrations of hs-CRP (odds ratio: 2.03, 95%-CI: 1.02-4.02, P = 0.043). Conclusion ID is frequent in an outpatient HF clinic. ID is not associated with cardiovascular biomarkers after adjustment for traditional confounders. Inflammation, but not neurohormonal activation is associated with ID in systolic HF. Further studies are needed to understand iron metabolism in elderly HF patients [ABSTRACT FROM AUTHOR]

Background: Renal dysfunction (RD) is associated with poor outcome in systolic heart failure (HF). Left ventricular ejection fraction (LVEF) is not depressed to a greater extent in patients with RD compared to patients with normal renal function, but it is relatively unknown whether other measures of myocardial function are impaired by RD. The objective of the present study is to evaluate whether RD in systolic HF is associated with excessive impairment of myocardial function, evaluated by strain analysis and cardiac biomarkers. Methods: Patients with LVEF < 0.45% were enrolled from an outpatient HF clinic. The patients underwent advanced echocardiography. Glomerular filtration rate was estimated by the CKD-EPI equation (eGFR) and patients grouped by eGFR: eGFRgroup-I, ≥ 90 ml/min/1.73 m²; eGFRgroup-II, 60–89 ml/min/1.73m²; and eGFRgroup-III, ≤ 59 ml/min/1.73 m². Multivariate regression models were developed to evaluate the associations between eGFR groups, echocardiographic measures and cardiac biomarkers. Results: A total of 149 patients participated in the study. Median age was 69 years, 26% were female; LVEF was 33%. Patients with a low eGFR were older (P < 0.001), but there were no differences in frequency of atrial fibrillation, hypertension, diabetes and ischemic heart disease between eGFR groups (P > 0.05 for all). RD was associated with impaired global longitudinal strain (P = 0.018), increased E/e′ (P = 0.032), larger left atria (P = 0.038) and increased levels of proANP (P < 0.001), NT-proBNP (P < 0.001) and troponin I (P = 0.019) after adjustment for traditional confounders. Conclusions: Echocardiographic measures and biomarkers reflecting different aspects of myocardial function are impaired in systolic HF patients with RD and the increased mortality risk in these patients may partly be explained by a depressed cardiac function. [ABSTRACT FROM AUTHOR]

The plasma level of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is an independent predictor of cardiovascular disease and all-cause mortality in healthy subjects. The prognostic capability of suPAR, its temporal course, and its relation to plasma C-reactive protein (CRP) in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous intervention (PCI) is unknown. Therefore, the plasma suPAR and CRP levels were measured in 296 consecutive patients with ST-segment elevation myocardial infarction admitted for primary PCI at baseline and every 6 to 8 hours thereafter until the cardiac biomarker levels had peaked. The end points were all-cause mortality and fatal or nonfatal recurrent myocardial infarction (MI). During a median follow-up period of 5.75 years, 69 deaths and 48 nonfatal and 14 fatal recurrent MIs occurred. All-cause mortality increased significantly from 8.1% to 41.5% across increasing quartiles of suPAR levels at the end of follow-up (log-rank p <0.0001). After adjustment for other independent prognostic factors, a highly significant increase was seen in all-cause mortality (hazard ratio 1.45, 95% confidence interval, 1.19 to 1.76; p <0.001) and recurrent MI (hazard ratio 1.53, 95% confidence interval 1.16 to 2.01; p <0.01) for each standard deviation increment of suPAR levels). In contrast to plasma CRP, the suPAR levels remained stable after primary PCI. Furthermore, CRP did not predict mortality or reinfarction after adjustment for age and gender (p = 0.34). In conclusion, suPAR is a stable plasma biomarker after ST-segment elevation myocardial infarction treated with primary PCI that predicts all-cause mortality and recurrent MI. [ABSTRACT FROM AUTHOR]