Search

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been linked to thrombotic complications and endothelial dysfunction. We assessed the prognostic implications of endothelial activation through measurement of endothelin-I precursor peptide (proET-1), the stable precursor protein of Endothelin-1, in a well-defined cohort of patients hospitalized with COVID-19.MethodsWe measured proET-1 in 74 consecutively admitted adult patients with confirmed COVID-19 and compared its prognostic accuracy to that of patients with community-acquired pneumonia (n = 876) and viral bronchitis (n = 371) from a previous study by means of logistic regression analysis. The primary endpoint was all-cause 30-day mortality.ResultsOverall, median admission proET-1 levels were lower in COVID-19 patients compared to those with pneumonia and exacerbated bronchitis, respectively (57.0 pmol/l vs. 113.0 pmol/l vs. 96.0 pmol/l, p ConclusionsCompared to other types of pulmonary infection, COVID-19 shows only a mild activation of the endothelium as assessed through measurement of proET-1. Therefore, the high mortality associated with COVID-19 may not be attributed to endothelial dysfunction by the surrogate marker proET-1.

Objectives Midregional pro-adrenomedullin (MR-proADM) is a vasoactive peptide with key roles in reducing vascular hyperpermeability and thereby improving endothelial stability during infection. While MR-proADM is useful for risk stratification in patients with sepsis, clinical data about prediction accuracy in patients with severe acute respiratory syndrome coronavirus 2 disease (COVID-19) is currently missing. Methods We included consecutively adult patients hospitalized for confirmed COVID-19 at a tertiary care center in Switzerland between February and April 2020. We investigated the association of MR-proADM levels with in-hospital mortality in logistic regression and discrimination analyses. Results Of 89 included COVID-19 patients, 19% (n=17) died while in the hospital. Median admission MR-proADM levels (nmol/L) were increased almost 1.5-fold increased in non-survivors compared to survivors (1.3 [interquartile range IQR 1.1–2.3]) vs. 0.8 [IQR 0.7–1.1]) and showed good discrimination (area under the curve 0.78). An increase of 1 nmol/L of admission MR-proADM was independently associated with a more than fivefold increase in in-hospital mortality (adjusted odds ratio of 5.5, 95% confidence interval 1.4–21.4, p=0.015). An admission MR-proADM threshold of 0.93 nmol/L showed the best prognostic accuracy for in-hospital mortality with a sensitivity of 93%, a specificity of 60% and a negative predictive value of 97%. Kinetics of follow-up MR-proADM provided further prognostic information for in-hospital treatment. Conclusions Increased levels of MR-proADM on admission and during hospital stay were independently associated with in-hospital mortality and may allow a better risk stratification, and particularly rule-out of fatal outcome, in COVID-19 patients.

Background The European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) initiated the CArdiac MARker Guidelines Uptake in Europe (CAMARGUE) Study to survey if current biomarker testing for heart failure (HF) in Europe is in accordance with up-dated guidelines. Methods A web-based questionnaire was distributed to clinical laboratories via European biochemical societies in 2019. Questions covered the type of natriuretic peptide (NP) assays performed, decision limits for HF, and opinion concerning requirement of different thresholds in patients with renal failure or obesity. Results There were 347 participating laboratories mostly from European countries with 266 offering NP testing. NP testing was increased from 67% to 77% between 2013 and 2019. NT-proBNP remained the preferred biomarker. Recommended decision limits were implemented for BNP (85%) and better focused for NT-proBNP (40%) than in the previous survey. The survey revealed that laboratorians are willing to support the translation of adjusted cut-off values for age, gender and for patients with conditions like renal insufficiency. Conclusion Guidelines stimulate clinical laboratories to offer NP testing with high value for the diagnosis and management of HF, and to present adjusted medical decision limits. Future guidelines should encourage the use of personalized cut-offs for some confounding factors.

AimsMajor adverse cardiac events (MACE) triggered by non-cardiac surgery are prognostically important perioperative complications. However, due to often asymptomatic presentation, the incidence and timing of postoperative MACE are incompletely understood.Methods and resultsWe conducted a prospective observational study implementing a perioperative screening for postoperative MACE [cardiovascular death (CVD), acute heart failure (AHF), haemodynamically relevant arrhythmias, spontaneous myocardial infarction (MI), and perioperative myocardial infarction/injury (PMI)] in patients at increased cardiovascular risk (≥65 years OR ≥45 years with history of cardiovascular disease) undergoing non-cardiac surgery at a tertiary hospital. All patients received serial measurements of cardiac troponin to detect asymptomatic MACE. Among 2265 patients (mean age 73 years, 43.4% women), the incidence of MACE was 15.2% within 30 days, and 20.6% within 365 days. CVD occurred in 1.2% [95% confidence interval (CI) 0.9–1.8] and in 3.7% (95% CI 3.0–4.5), haemodynamically relevant arrhythmias in 1.2% (95% CI 0.9–1.8) and in 2.1% (95% CI 1.6–2.8), AHF in 1.6% (95% CI 1.2–2.2) and in 4.2% (95% CI 3.4–5.1), spontaneous MI in 0.5% (95% CI 0.3–0.9) and in 1.6% (95% CI 1.2–2.2), and PMI in 13.2% (95% CI 11.9–14.7) and in 14.8% (95% CI 13.4–16.4) within 30 days and within 365 days, respectively. The MACE-incidence was increased above presumed baseline rate until Day 135 (95% CI 104–163), indicating a vulnerable period of 3–5 months.ConclusionOne out of five high-risk patients undergoing non-cardiac surgery will develop one or more MACE within 365 days. The risk for MACE remains increased for about 5 months after non-cardiac surgery.Trial registrationhttps://www.clinicaltrials.gov. Unique identifier: NCT02573532.

Background The CArdiac MARker Guidelines Uptake in Europe Study (CAMARGUE) initiated by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) aims to survey the current use of evidence-based guidelines for dyslipidemia testing in Europe. Methods In 2019 a web-based questionnaire was distributed via EFLM National Societies to clinical laboratories in Europe. Questions covered pre-analytics, analytical methods, measurement units, flagging of decision thresholds, and use of decision-enhancing comments. Results Returns were obtained from 452 laboratories from 28 countries. Most laboratories always use nonfasting blood samples for lipid assays (66%). Lipid profiles are reported in mmol/L by 59% of the laboratories, mainly from 14 countries promoting the use of SI units. Important differences in flagging of decision thresholds were observed, with less than half of the laboratories applying the guideline-recommended LDL cholesterol threshold. Only 17% of the laboratories add an alert comment when familial hypercholesterolemia is suspected and 23% when risk of pancreatitis from hypertriglyceridemia is high. Conclusions There are marked differences among laboratories in Europe in terms of pre-analytical, analytical, and post-analytical lipid management that could have an important clinical impact. This relates to different availability of assays or different laboratory practices on reporting and flagging of lipid profiles.

Peri-operative myocardial infarction/injury (PMI) has been identified as an unexpectedly common complication following noncardiac surgery associated with post-operative mortality ([1][1],[2][2]). PMI is not a homogenous disease, but is a heterogenous syndrome with multiple different underlying

BackgroundActivation of the vasopressin system plays a key role for the maintenance of osmotic, cardiovascular, and stress hormone homeostasis during disease. We investigated levels of copeptin, the C-terminal segment of the vasopressin prohormone, that mirrors the production rate of vasopressin in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).MethodsWe measured levels of copeptin on admission and after days 3/4, 5/6, and 7/8 in 74 consecutive hospitalized adult COVID-19 patients and compared its prognostic accuracy to that of patients with community-acquired pneumonia (n = 876) and acute or chronic bronchitis (n = 371) from a previous study by means of logistic regression analysis. The primary endpoint was all-cause 30-day mortality.ResultsMedian admission copeptin levels in COVID-19 patients were almost 4-fold higher in nonsurvivors compared with survivors (49.4 pmol/L [iterquartile range (IQR) 24.9–68.9 pmol/L] vs 13.5 pmol/L [IQR 7.0–26.7 pmol/L]), resulting in an age- and gender-adjusted odds ratio of 7.0 (95% confidence interval [CI] 1.2–40.3), p < 0.03 for mortality. Higher copeptin levels in nonsurvivors persisted during the short-term follow-up. Compared with the control group patients with acute/chronic bronchitis and pneumonia, COVID-19 patients did not have higher admission copeptin levels.ConclusionsA pronounced activation of the vasopressin system in COVID-19 patients is associated with an adverse clinical course in COVID-19 patients. This finding, however, is not unique to COVID-19 but similar to other types of respiratory infections.

Background Perioperative myocardial infarction/injury (PMI) diagnosed by high-sensitivity troponin (hs-cTn) T is frequent and a prognostically important complication of non-cardiac surgery. We aimed to evaluate the incidence and outcome of PMI diagnosed using hs-cTnI, and compare it to PMI diagnosed using hs-cTnT. Methods We prospectively included 2455 patients at high cardiovascular risk undergoing 3111 non-cardiac surgeries, for whom hs-cTnI and hs-cTnT concentrations were measured before surgery and on postoperative days 1 and 2. PMI was defined as a composite of perioperative myocardial infarction (PMIInfarct) and perioperative myocardial injury (PMIInjury), according to the Fourth Universal Definition of Myocardial Infarction. All-cause mortality was the primary endpoint. Results Using hs-cTnI, the incidence of overall PMI was 9% (95% confidence interval [CI] 8–10%), including PMIInfarct 2.6% (95% CI 2.0–3.2) and PMIInjury 6.1% (95% CI 5.3–6.9%), which was lower versus using hs-cTnT: overall PMI 15% (95% CI 14–16%), PMIInfarct 3.7% (95% CI 3.0–4.4) and PMIInjury 11.3% (95% CI 10.2–12.4%). All-cause mortality occurred in 52 (2%) patients within 30 days and 217 (9%) within 1 year. Using hs-cTnI, both PMIInfarct and PMIInjury were independent predictors of 30-day all-cause mortality (adjusted hazard ratio [aHR] 2.5 [95% CI 1.1–6.0], and aHR 2.8 [95% CI 1.4–5.5], respectively) and, 1-year all-cause mortality (aHR 2.0 [95% CI 1.2–3.3], and aHR 1.8 [95% CI 1.2–2.7], respectively). Overall, the prognostic impact of PMI diagnosed by hs-cTnI was comparable to the prognostic impact of PMI using hs-cTnT. Conclusions Using hs-cTnI, PMI is less common versus using hs-cTnT. Using hs-cTnI, both PMIInfarct and PMIInjury remain independent predictors of 30-day and 1-year mortality. Graphic abstract

Background European Society of Cardiology/European Society of Anaesthesiology (ESC/ESA) guidelines inform cardiac workup before noncardiac surgery based on an algorithm. Our primary hypotheses were that there would be associations between (i) the groups stratified according to the algorithms and major adverse cardiac events (MACE), and (ii) over- and underuse of cardiac testing and MACE. Methods This is a secondary analysis of a multicentre prospective cohort. Major adverse cardiac events were a composite of cardiac death, myocardial infarction, acute heart failure, and life-threatening arrhythmia at 30 days. For each cardiac test, pathological findings were defined a priori. We used multivariable logistic regression to measure associations. Results We registered 359 MACE at 30 days amongst 6976 patients; classification in a higher-risk group using the ESC/ESA algorithm was associated with 30-day MACE; however, discrimination of the ESC/ESA algorithms for 30-day MACE was modest; area under the curve 0.64 (95% confidence interval: 0.61–0.67). After adjustment for sex, age, and ASA physical status, discrimination was 0.72 (0.70–0.75). Overuse or underuse of cardiac tests were not consistently associated with MACE. There was no independent association between test recommendation class and pathological findings (P=0.14 for stress imaging; P=0.35 for transthoracic echocardiography; P=0.52 for coronary angiography). Conclusions Discrimination for MACE using the ESC/ESA guidelines algorithms was limited. Overuse or underuse of cardiac tests was not consistently associated with cardiovascular events. The recommendation class of preoperative cardiac tests did not influence their yield. Clinical trial registration NCT02573532.

Background The high molecular complexity of variably O-glycosylated and degraded pro B-type natriuretic peptide (proBNP) derived molecular forms challenges current immunoassays. Antibodies used show pronounced differences in cross-reactivities with these circulating fragments, which still need to be better characterized on a molecular level. To pave the way for advanced quantitative assays in the future, it is critical to fully understand these circulating forms. Methods Plasma samples were collected from 8 heart failure (HF) patients and 2 healthy controls. NT-proBNP and proBNP were purified by immunoprecipitation and analyzed by nano-flow liquid chromatography coupled to high-resolution mass spectrometry. Fragments formed during proteolysis in solution digestion were distinguished from naturally occurring peptides by using an 18O stable isotope labeling strategy. Results We detected 16 previously unknown circulating fragments of proBNP peptides (9 of which are located in the N-terminal and 7 in the C-terminal region), revealing a more advanced state of degradation than previously known. Two of these fragments are indicative of either unidentified processing modes or a far-reaching C-terminal degradation (or a combination thereof) of the precursor proBNP. Conclusions Our results further restrict ideal target epitopes for immunoassay antibodies and expand the current thinking of diversity, degradation, and processing of proBNP, as well as the distribution of circulating forms.

The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), LDL cholesterol (LDLC), and calculated non-HDLC (=total – HDLC) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDLC is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDLC shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a) [Lp(a)]-cholesterol is part of measured or calculated LDLC and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDLC declines poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDLC or apolipoprotein B (apoB), especially in patients with mild-to-moderate hypertriglyceridemia (2–10 mmol/L). Non-HDLC includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apoB measurement can detect elevated LDL particle (LDLP) numbers often unidentified on the basis of LDLC alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20–100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds.

AIM OF THE STUDY To compare admission characteristics, predictors and outcomes of patients with confirmed coronavirus disease 2019 (COVID-19) hospitalised in a tertiary care hospital in Switzerland during the first and second waves of the pandemic. METHODS This retrospective observational analysis included adult patients with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection confirmed by a real-time reverse transcriptase polymerase chain reaction (RT-PCR) or rapid antigen test and hospitalised at the Cantonal Hospital Aarau from 26 February to 30 April 2020 (first wave) and from 1 October to 31 December 2020 (second wave). The primary endpoint was all-cause in-hospital mortality. The secondary endpoints were transfer to the intensive care unit (ICU) and length of hospital stay (LOS). RESULTS Overall, 486 patients (mean age 65.9 years ± 14.7 SD, 65% male) were included. Ninety-two patients (19%) died during the hospital stay and 92 patients (19%) were transferred to the ICU. Admission characteristics, including comorbidities and frailty, were similar for patients of the first (n = 100) and second wave (n = 386). However, during the second wave the median time from symptom onset to presentation to the emergency department (ED) was shorter (7 days, interquartile range [IQR] 4–9 vs 8 days, IQR 4–11; p = 0.02). In the second wave, most patients received high-dose glucocorticoid treatment (0% vs 76%, p

We validated a clinical prediction rule for Legionella based on clinical parameters (dry cough, fever) and laboratory findings (C-reactive protein, lactate dehydrogenase, sodium, platelet counts) in 713 consecutive patients with community-acquired pneumonia. The Legionella Score performed well in estimating the likelihood for Legionella infection and thus may help to direct diagnostic and therapeutic decisions.

Cardiac arrhythmias are associated with substantial morbidity and mortality. Recent advances in the pathophysiological understanding of cardiac arrhythmia indicate that inflammation, fibrosis, and even autoimmune mechanisms could facilitate the development of arrhythmias by interfering either with fibroblast activation-related electrical remodeling or with the function of different cardiac ion channels, leading to the emerging concepts of autoimmune and inflammatory channelopathies. In this descriptive review, we considered recent data of the literature focusing on biomarkers reflecting the degree of inflammation, myocardial stretch, fibrosis and sustained B-cell activation as potential additional diagnostic, risk stratification tools and potential therapeutic targets in cardiac arrhythmia.

Background Discriminating Mycoplasma pneumoniae (MP) from Streptococcus pneumoniae (SP) and viral etiologies of community-acquired pneumonia (CAP) is challenging but has important implications regarding empiric antibiotic therapy. We investigated patient parameters upon hospital admission to predict MP infection. Methods All patients hospitalized in a tertiary care hospital between 2013 and 2017 for CAP with a confirmed etiology were analyzed using logistic regression analyses and area under the receiver operator characteristics (ROC) curves (AUC) for associations between demographic, clinical and laboratory features and the causative pathogen. Results We analyzed 568 patients with CAP, including 47 (8%) with MP; 152 (27%) with SP and 369 (65%) with influenza or other viruses. Comparing MP and SP by multivariate logistic regression analysis, younger age (odds ration [OR] 0.56 per 10 years, 95% CI 0.42–0.73), a lower neutrophil/lymphocyte ratio (OR 0.9, 0.82–0.99) and an elevated C-reactive protein/procalcitonin (CRP/PCT) ratio (OR 15.04 [5.23–43.26] for a 400 mg/μg cut-off) independently predicted MP. With a ROC curve AUC of 0.91 (0.80 for the >400 mg/μg cutoff), the CRP/PCT ratio was the strongest predictor of MP vs. SP. The discriminatory value resulted from significantly lower PCT values (p 400 mg/μg cutoff, 2.26–13.64). Conclusions In patients hospitalized with CAP, a high admission CRP/PCT ratio predicts M. pneumoniae infection and may improve empiric management.

Background The prevalence of pulmonary embolism (PE) in patients presenting with syncope to the emergency department (ED) is largely unknown. This information, however, is necessary to balance the potential medical benefit or harm of systematic PE screening in patients presenting with syncope to the ED. Objectives This study sought to determine the prevalence of PE in patients with syncope. Methods Unselected patients presenting with syncope to the ED were prospectively enrolled in a diagnostic multicenter study. Pre-test clinical probability for PE was assessed using the 2-level Wells score and the results of D-dimer testing using age-adapted cutoffs. Presence of PE was evaluated by imaging modalities, when ordered as part of the clinical assessment by the treating ED physician or by long-term follow-up data. Results Long-term follow-up was complete in 1,380 patients (99%) at 360 days and 1,156 patients (83%) at 720 days. Among 1,397 patients presenting with syncope to the ED, PE was detected at presentation in 19 patients (1.4%; 95% confidence interval [CI]: 0.87% to 2.11%). The incidence of new PEs or cardiovascular death during 2-year follow-up was 0.9% (95% CI: 0.5% to 1.5%). In the subgroup of patients hospitalized (47%), PE was detected at presentation in 15 patients (2.3%; 95% CI: 1.4% to 3.7%). The incidence of new PEs or cardiovascular death during 2-year follow-up was 0.9% (95% CI: 0.4% to 2.0%). Conclusions PE seems to be a rather uncommon cause of syncope among patients presenting to the ED. Therefore, systematic PE-screening in all patients with syncope does not seem warranted. (BAsel Syncope EvaLuation Study [BASEL IX]; NCT01548352)

This article summarises insights and discussion points from the first meeting of the Swiss working group on cardiovascular bio­markers.

ObjectiveRecently, daytime variation in perioperative myocardial injury (PMI) has been observed in patients undergoing cardiac surgery. We aim at investigating whether daytime variation also occurs in patients undergoing non-cardiac surgery.MethodsIn a prospective diagnostic study, we evaluated the presence of daytime variation in PMI in patients at increased cardiovascular risk undergoing non-cardiac surgery, as well as its possible impact on the incidence of acute myocardial infarction (AMI), and death during 1-year follow-up in a propensity score–matched cohort. PMI was defined as an absolute increase in high-sensitivity cardiac troponin T (hs-cTnT) concentration of ≥14 ng/L from preoperative to postoperative measurements.ResultsOf 1641 patients, propensity score matching defined 630 with similar baseline characteristics, half undergoing non-cardiac surgery in the morning (starting from 8:00 to 11:00) and half in the afternoon (starting from 14:00 to 17:00). There was no difference in PMI incidence between both groups (morning: 50, 15.8% (95% CI 12.3 to 20.3); afternoon: 52, 16.4% (95% CI 12.7 to 20.9), p=0.94), nor if analysing hs-cTnT release as a quantitative variable (median morning group: 3 ng/L (95% CI 1 to 7 ng/L); median afternoon group: 2 ng/L (95% CI 0 to 7 ng/L; p=0.16). During 1-year follow-up, the incidence of AMI was 1.2% (95% CI 0.4% to 3.2%) among morning surgeries versus 4.1% (95% CI 2.3% to 6.9%) among the afternoon surgeries (corrected HR for afternoon surgery 3.44, bootstrapped 95% CI 1.33 to 10.49, p log-rank=0.03), whereas no difference in mortality emerged (p=0.70).ConclusionsAlthough there is no daytime variation in PMI in patients undergoing non-cardiac surgery, the incidence of AMI during follow-up is increased in afternoon surgeries and requires further study.Clinical trial registrationNCT02573532;Results.

BACKGROUND We undertook an assessment of current use of evidence-based guidelines for the use of cardiac biomarkers in Europe (EU) and North America (NA). METHODS In 2013–2014 a web-based questionnaire was distributed via NA and EU biochemical societies. Questions covered cardiac biomarkers measured, analytical methods used, decision thresholds, and use of decision-making protocols. Results were collated using a central database and analyzed using comparative and descriptive nonparametric statistics. RESULTS In EU, returns were obtained from 442 hospitals, 50% central or university hospitals, and 39% from local hospitals from 35 countries with 395/442 (89%) provided an acute service. In NA there were 91 responses (63.7% central or university hospitals, 19.8% community hospitals) with 76/91 (83.5%) providing an acute service. Cardiac troponin was the preferred cardiac biomarker in 99.5% (EU) and 98.7% (NA), and the first line marker in 97.7% (EU) and 97.4% (NA). There were important differences in the choice of decision limits and their derivations. The origin of the information was also significantly different, with EU vs NA as follows: package insert, 61.9% vs 40%; publications, 17.1% vs 15.0%; local clinical or analytical validation choice, 21.0% vs 45.0%; P = 0.0003. CONCLUSIONS There are significant differences between EU and NA use of cardiac biomarkers. This probably relates to different availability of assays between EU and NA (such as high-sensitivity troponin assays) and different laboratory practices on assay introduction (greater local evaluation of assay performance occurred in NA).

We aimed to directly compare preoperative high-sensitivity cardiac troponin (hs-cTn) I and T concentration for the prediction of major cardiac complications after non-cardiac surgery.We measured hs-cTnI and hs-cTnT preoperatively in a blinded fashion in 1022 patients undergoing non-cardiac surgery. The primary endpoint was a composite of major cardiac complications including cardiac death, cardiac arrest, myocardial infarction, clinically relevant arrhythmias, and acute heart failure within 30 days. We hypothesized that the type of surgery may impact on the predictive accuracy of hs-cTnI/T and stratified all analyses according to the type of surgery.Major cardiac complications occurred in 108 (11%) patients, 58/243 (24%) patients undergoing vascular surgery and 50/779 (6%, P .001) patients undergoing non-vascular surgery. Using regulatory-approved 99th percentile cut-off concentrations, preoperative hs-cTnI elevations were less than one-fifth as common as preoperative hs-cTnT elevations (P .001). Among patients undergoing vascular surgery, preoperative hs-cTnI concentrations, but not hs-cTnT, was an independent predictor of cardiac complications (adjusted odds ratio (aOR) 1.5, 95% confidence interval (95% CI) 1.0-2.1). The area under the receiver-operating characteristics curve (AUC) was 0.67 (95% CI, 0.59-0.75) for hs-cTnI versus 0.59 (95% CI 0.51-0.67, P = .012) for hs-cTnT. In contrast, among patients undergoing non-vascular surgery both preoperative hs-cTnI and hs-cTnT were independent predictors of the primary endpoint (aOR 1.6, 95% CI 1.3-2.0, and aOR 3.0, 95% CI 2.0-4.6, respectively) and showed higher predictive accuracy (AUC 0.77, 95% CI, 0.71-0.83, and 0.79, 95% CI 0.73-0.85, P = ns).Preoperative hs-cTnI and hs-cTnT concentrations predict major cardiac complications after non-vascular surgery, while, in patients undergoing vascular surgery, hs-cTnI may have better accuracy.

Background The aim of this survey was to investigate how well heart failure (HF) guidelines for use of natriuretic peptides (NPs) have been implemented in laboratory practice in Europe and North America. Methods In 2013 and 2014, a web-based questionnaire was distributed via North American and European biochemical societies. Questions covered assay performed, reason for method choice, decision limits for HF, and laboratory accreditation status. Results There were 442 European Union and 91 North American participating laboratories with response rates of 50% and 64% from major or university hospitals, respectively. NP measurements were offered in 67% of European Union and 58% of North American respondents. N-terminal pro–B-type natriuretic peptide (NT-proBNP) was most widely used in Europe (68%) and B-type natriuretic peptide (BNP) was more commonly used (58%) in North America. The most frequent reason for use of a specific assay was the availability of instruments that measure either NT-proBNP (51%) or BNP (67%). For diagnosis of acute HF, NT-proBNP decision limits were diverse; age-dependent limits based on the 2012 European Society of Cardiology (ESC) recommendations were used in only 17% of European sites and 26% of North American sites. For BNP, the guideline-recommended acute HF decision limit of 100 ng/L was better adhered to in Europe (48%) and North America (57%). Surprisingly, similar decision limits were stated for acute and chronic HF by >50% of respondents. Conclusions NP measurement for HF diagnosis was available in >50% of responding laboratories. However, guideline recommended cutoff values for both acute and chronic HF were still implemented in

To analyze the influence of aspirin (ASA) intake on PSA values and prostate cancer (PCa) development in a prospective screening study cohort. 4314 men from the Swiss section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were included. A transrectal prostate biopsy was performed in men with a PSA level ≥ 3 ng/ml. Mortality data were obtained through registry linkages. PCa incidence and grade, total PSA, free-to-total PSA and overall survival were compared between ASA users and non-users. Median follow-up time was 9.6 years. In 789 men (18.3%) using aspirin [ASA +], the overall PCa incidence was significantly lower (6.8% vs. 9.6%, p = 0.015), but the multivariate Cox regression analysis showed no significant decrease in risk of PCa diagnosis (HR 0.84, p = 0.297). Total PSA values were significantly lower in ASA users for both baseline (1.6 vs. 1.8 ng/ml, p = 0.007) and follow-up visits (1.75 vs. 2.1 ng/ml, p

Objective To investigate the relationship between circulating plasma copeptin values and infarct size as well as myocardial function at baseline and 4 months after mechanical reperfusion for ST segment elevation myocardial infarction (STEMI). Design Prospective observational cohort study. Setting University Hospital of Innsbruck. Patients 54 patients with acute STEMI. Main outcome measures Correlation of plasma copeptin with infarct size as well as left ventricular ejection fraction (LVEF) and remodelling. Methods Participants underwent contrast enhanced cardiac MRI at baseline and 4 months thereafter. Blood samples were drawn 2 days after the onset of symptoms. Copeptin values were determined by an immunofluorescent assay. Results Copeptin concentrations (median 10.4 pmol/l, IQR 6.0–14.4) were associated with early and chronic infarct size (r=0.388, p=0.004 at baseline; r=0.385, p=0.011 at follow-up) and inversely related to LVEF at both times (r=−0.484, p Conclusions Increased copeptin values 2 days after STEMI are associated with larger acute and chronic infarct sizes. Moreover, elevated copeptin concentrations at baseline were associated with myocardial function and remodelling 4 months post-STEMI. These findings strengthen the role of copeptin as a biomarker of adverse outcome after STEMI.

Summary Introduction The cardio-neuro-endocrine axis seems to be involved in the cascade of postictal events in children. The aim of this study was to assess the relationship between childhood epilepsy and cerebrospinal fluid (CSF) or serum concentrations of the N-terminal pro B-type natriuretic peptide (NT-proBNP) interictally. Methods A total of seventy-four children agreed to participate in the study. Twenty-two children with epilepsy and mild developmental delay (mean±SD [median] age 5.8±4.9 [4.3] years), 15 children with newly diagnosed multiple sclerosis (MS) (15.1±1.4 [15.3] years) and 37 children with cryptogenic mild developmental delay (8.0±4.6 [7.4] years), serving as controls, were eligible. Results In children with epilepsy, interictal CSF NT-proBNP concentrations were greater when compared to the MS group and to controls (mean±SD [median] 193.0±78.1 [176.0]ng/L vs. 147.8±60.2 [138.0]ng/L vs. 140.4±36.5 [134.0]ng/L; p =0.014 and p =0.009). In contrast, serum NT-proBNP concentrations and the CSF/serum NT-proBNP ratio did not differ between groups. Discussion Greater CSF NT-proBNP concentrations in children with epilepsy may reflect an unspecific activation of the cardio-neuro-endocrine system involving endocrinological stress–response mechanisms interictally. The relationship between epilepsy and the cardio-neuro-endocrine axis may further the understanding of seizure susceptibility in children as well as influences of epilepsy on central modulation of autonomic cardiovascular control.

Aim. Increased aortic stiffness might adversely affect cardiac structure, function, and perfusion. Release of biomarkers of hemodynamic stress is thought to be enhanced by these alterations. We aimed to evaluate the association between biomarkers of hemodynamic stress and aortic stiffness assessed at a chronic stage after ST-segment elevation myocardial infarction (STEMI).Methods. Fifty-four patients four months after STEMI were enrolled in this cross-sectional, single-center study. N-terminal pro–B-type natriuretic peptide (NT-proBNP), mid-regional pro–A-type natriuretic peptide (MR-proANP), and mid-regional proadrenomedullin (MR-proADM) levels were measured by established assays. Aortic stiffness was assessed by the measurement of pulse wave velocity using phase-contrast cardiovascular magnetic resonance.Results. NT-proBNP, MR-proANP, and MR-proADM concentrations were all correlated with aortic stiffness in univariate analysis (r=0.378,r=0.425, andr=0.532; allP<0.005, resp.). In multiple linear regression analysis, NT-proBNP (β=0.316,P=0.005) and MR-proADM (β=0.284,P<0.020) levels were associated with increased aortic stiffness independently of age, blood pressure, and renal function. NT-proBNP was the strongest predictor for high aortic stiffness (area under the curve: 0.82, 95% CI 0.67–0.96).Conclusion. At a chronic stage after STEMI, concentrations of biomarkers for hemodynamic stress, especially NT-proBNP, are positively correlated with aortic stiffness. These biomarkers might also be useful as predictors of high aortic stiffness after STEMI.

Background: Previous studies comparing children with cardiac disease with children with lung disease or healthy children indicated that natriuretic peptides are promising markers in pediatric patients. The aim of this study was to further clarify the diagnostic usefulness of N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements in a less preselected population of children younger than 3 years, a population in which clinical symptoms are frequently unspecific. Methods: NT-proBNP concentrations (Roche Diagnostics) were measured in sera of 142 pediatric patients (age range, 33–1070 days) presenting at the Gynaecologic and Pediatric Hospital (Linz, Austria) between January 2003 and January 2004. ROC curve analysis for the diagnostic performance of NT-proBNP, the Mann–Whitney U-test for group comparison, and linear regression analysis for influencing factors were performed. Results: NT-proBNP concentrations were significantly increased in infants with cardiac diseases [median (25th–75th percentile), 3681 (1045–13557) ng/L; n = 23] compared with infants with other diseases [241 (116–542) ng/L; n = 119], and ROC analysis revealed good performance for NT-proBNP in differentiating between infants with and without cardiac diseases [mean area under the curve (AUC) with 95% confidence interval (CI), 0.87 (0.76–0.94)]. A subgroup analysis of exactly age- and sex-matched infants was performed, which revealed results comparable to those for the whole study population [mean (95% CI) AUC, 0.84 (0.68–0.93)]. Conclusion: In a heterogeneous group of pediatric patients

Among all natriuretic peptides and neurohormones, B-type natriuretic peptide (BNP) and its Nterminal prohormone fragment (NT-proBNP) have been shown to be the best and most powerful markers to identify patients with acute and chronic heart failure (HF). The fully automated BNP and NT-proBNP assays require only 15-20 min to achieve a test result so that a turn-around time of less than 60 min is possible, as requested by the guidelines of the cardiological societies. The in-vitro stabilities of BNP and NT-proBNP are sufficient for routine use. Most of the commercially available assays, except if they are sublicensed, use different antibodies. This may explain that in general, BNP and NT-proBNP assays show close correlations, but do not agree in absolute values. The assays have not been standardized so far and the application of various calibration materials may contribute to different results. Thus, reference ranges are dependent on the assay used, and reference ranges have to be determined for each assay separately. The increasing values with age may be related to the increasing frequency of subclinical renal or cardiac dysfunction in the elderly. Estrogens stimulate the natriuretic peptide production in females, and reference ranges depend on sex from adolescence to menopause. Immediately after birth, BNP and NTproBNP levels are substantially higher in neonates than in their mothers. The high biological variation of natriuretic peptides must be considered when interpreting serial BNP and NT-proBNP results. Therefore, only marked BNP or NT-proBNP changes during follow-up are related to changes in the clinical HF status. A conclusion of all major studies is that in patients with chronic HF BNP and NT-proBNP are rather rule-out than rule-in markers because of limited cardiac specificities. Patients with acute HF usually show higher BNP and NT-proBNP levels than patients with chronic HF. The greatest efficiency of BNP and NT-proBNP testing was demonstrated in patients presenting to the emergency department with acute dyspnoea or in outpatients with symptoms suggesting chronic HF. Many studies indicate that short- and long-term prognosis in HF can be assessed by BNP or NT-proBNP determination. These hormones are independent predictors of death or HF hospitalizations. Natriuretic peptides are increased in all diseases affecting the cardiac or renal function and fluid balance. BNP and NT-proBNP are markers of cardiac dysfunction in patients with renal failure as well, but higher decision limits have to be used. Decreased BNP and NT-proBNP concentrations in obesity are not fully understood and controversial reports are found in the literature. In summary, BNP or NT-proBNP determination is a powerful test for ruling out HF. Furthermore, these markers are a useful addition to the standard clinical investigations of patients with suspected ventricular dysfunction.

Zusammenfassung: Die Fruhdiagnose einer Myokardischamie wird immer noch anhand des Elektrokardiogramms gestellt, da die konventionellen kardialen Marker in den ersten 4 Stunden nach Symptombeginn nicht sensitiv genug sind. Auserdem sind nur die kardialen Troponine herzspezifisch, die deshalb von den kardiologischen Gesellschaften als der neue „Goldene Standard” zur Labordiagnose von Myokardschadigung vorgeschlagen wurden. Kardiale Troponine sind jedoch erst 10 – 12 Stunden nach Symptombeginn verlassliche Ausschlussparameter einer Myokardnekrose. Fruhe, sensitive und spezifische Laborparameter, die innerhalb von 4 Stunden ansteigen und Patienten mit Angina pectoris-Symptomatik korrekt identifizieren, waren hilfreich, um rechtzeitig durch geeignete therapeutische Masnahmen grosere Nekrosen zu verhindern. Ein neuer Ischamiemarker, Ischamie-modifiziertes Albumin (IMA), scheint dabei vielversprechend zu sein. Durch Ischamie wird das N-terminale Ende von Albumin innerhalb von kurzer Zeit so modifiziert, dass das Ubergangsmetall Kobalt nicht mehr binden kann. IMA erreicht bei akuten Koronarsyndrom-Patienten nach 3 – 4 Stunden eine hohe Sensitivitat von uber 0,80. Ein weiterer aussichtsreicher Kandidat mit ahnlicher Sensitivitat (0,77) wie IMA ist die Glykogenphosphorylase BB (GPBB), die durch Ischamie aus ihrem unloslichen Komplex gelost wird. Allerdings muss die Membranpermeabilitat erhoht sein, damit die GPBB in die Blutzirkulation gelangen kann, sodass die GPBB keinen reinen Ischamiemarker darstellt. B-Typ natriuretisches Peptid (BNP) ist ebenfalls ein Parameter, der fruh nach akutem Myokardinfarkt signifikant ansteigt. Die Abgrenzung zwischen kardialer Ischamie und Ventrikeldysfunktion ist bei diesem Marker jedoch schwierig, da die kardiale Ischamie haufig eine ventrikulare Dysfunktion verursacht und BNP je nach Schweregrad einer Herzinsuffizienz aus dem Myokard ausgeschuttet wird. IMA, GPBB und BNP sind drei vielversprechende Marker, die zu einer fruhzeitigen und kosteneffizienten Diagnosefindung bei Patienten mit kardialen ischamischen Geschehen beitragen konnen. Summary: The early diagnosis of myocardial ischaemia is still performed by the electrocardiogram, because the conventional cardiac markers are not sensitive enough during the first 4 h after symptom onset. Only cardiac troponins are heart specific and were therefore proposed by the cardiological societies as new criterion standards for the laboratory diagnosis of myocardial necrosis. However, cardiac troponins can reliably exclude myocardial necrosis only 10 – 12 h after symptom onset. Early, sensitive and specific laboratory parameters that increase rapidly during the first 4 h would be helpful for initiating therapeutic interventions in time to prevent more extended myocardial necrosis. A new parameter for ischaemia, ischaemia-modified albumin (IMA), seems to be promising. Ischaemia causes a very rapid modification of the N-terminus of albumin. As a consequence, the transition metal cobalt is no longer able to bind. In acute coronary syndrome patients, IMA reaches a sensitivity of 0.80 within 3 – 4 h. A further candidate with similar sensitivity (0,77) to IMA is glycogen phosphorylase BB (GPBB), which is detached from its insoluble complex by ischaemia. However, GPBB can only reach the blood circulation when the cell membrane permeability is increased; therefore, GPBB is not a pure marker of ischaemia. B-type natriuretic peptide (BNP) is another parameter that increases very early after acute myocardial infarction. The differentiation between cardiac ischaemia and left ventricular dysfunction is difficult, because cardiac ischaemia causes ventricular dysfunction and BNP is released from the myocardium in relation to the severity of heart failure. IMA, GPBB and BNP are three promising markers that can help to identify patients with cardiac ischaemia very early and cost efficiently.

Introduction: Antithrombin (AT) is well known as an important inhibitor of the coagulation system. An interesting new hypothesis is that antithrombin exerts specific anti-inflammatory effects by stimulating the production of prostacyclin in endothelial cells. Recent studies report beneficial influence on ischemia/reperfusion injury in several organs. These effects are independent of the coagulation system. We investigated the influence of antithrombin on ischemia/reperfusion injury and prostacyclin release in the isolated rat heart. Since the perfusion of the hearts was without blood, the used model essentially describes effects of antithrombin on endothelial cells. Material and methods: Experiments were performed using the temperature-controlled and pressure-constant Langendorff apparatus. The hearts of 32 male Sprague–Dawley rats were subjected to 20 min of global ischemia followed by 30 min of reperfusion. Antithrombin was administered in three different concentrations (1, 4 and 8 U/ml) 15 min prior to global ischemia. Cardiac contractility parameters and biochemical parameters were measured. Results: Treatment with antithrombin did not increase the release of prostacyclin significantly after ischemia. Antithrombin at a concentration of 8 U/ml led to a significant increase in creatine kinase (CK; p

Objective: The aim of the present study was to evaluate the attitude of cardiac surgery patients towards gene therapeutic approaches to heart disease. Methods: One hundred and fifty patients having undergone coronary artery bypass grafting ðn ¼ 97Þ, valvular operations ðn ¼ 40Þ or combined procedures ðn ¼ 13Þ were personally interviewed prior to discharge using a self designed questionnaire. Results: Seventeen percent of the surveyed patients were unable to complete the interview because of total non-understanding of the topic. Of the remaining patients, 33% could basically define the term ‘gene’. After explanation of gene therapy principles 70% believed that gene therapy protocols had already been started clinically. Fifty-two percent would accept enrollment in a clinical trial (85% in cases of otherwise incurable disease). If clinical gene transfer would be carried out 73% of patients would accept adenovirus as a vector, 94 and 80%, respectively, would accept catheter-based intervention or surgery for performance of gene therapy. Fifty-four percent would agree to a prophylactic gene therapy protocol. Conclusions: We conclude that the general attitude of heart surgery patients regarding gene therapy is positive. A considerable number of patients are unable to understand the basic principles of gene therapy. These data can be useful for planning of clinical gene therapy trials and show potential difficulties in obtaining informed consent. q 2002 Elsevier Science B.V. All rights reserved.

Individuals with an impaired ventricular function have a poor prognosis due to underlying heart failure and higher mortality rates. Patients with peripheral arterial disease (PAD) represent a high-risk population for left ventricular systolic dysfunction (LVSD).The left ventricular ejection fraction (LVEF) was measured in a subset of the CAVASIC Study, consisting of 180 male patients with intermittent claudication and 226 controls. The patients were prospectively followed for a median time of 7 years. The association of LVEF with PAD and prevalent cardiovascular disease (CVD) as well as with incident CVD and survival rates during follow-up was analyzed.The prevalence of LVSD (LVEF55%) was 30% among PAD patients and 7% among controls (p0.001). The adjusted logistic regression analysis showed that a decrease of LVEF by one standard deviation (SD) and an LVEF below 55% was associated with PAD (OR = 1.72, 95%CI 1.30-2.28 and OR = 5.71, 95%CI 2.52-12.95, both p0.001). Similar results were found for prevalent CVD (n = 50) in PAD patients: LVEF per SD: OR 1.60; LVEF55%: OR 2.81, both p ≤ 0.008. The adjustment for ln-NT-proBNP or hs-cTnT resulted in a borderline significant association. In the adjusted Cox regression analysis a decrease of LVEF by one SD showed a trend for association with all-cause mortality (n = 32) (HR 1.27, p = 0.08). An impaired LVEF significantly increased the risk for incident major CVD events (n = 52): HR 1.56, p0.01.Patients with PAD have significantly lower LVEF values compared to controls. The LVEF can serve as a risk predictor for subsequent cardiovascular disease among this high-risk population.

Aortic pulse wave velocity (PWV) was linked to LV-geometry and -function in patients with kidney disease and non-ischemic cardiomyopathy. The role of aortic compliance after acute STEMI is so far unknown. In the present study, we prospectively investigated the relationship of increased aortic stiffness with biomarkers of myocardial wall stress 4 months after STEMI.48 STEMI patients who were reperfused by primary coronary angioplasty underwent cardiovascular magnetic resonance (CMR) at baseline and at 4-month follow-up. The CMR protocol comprised cine-CMR as well as gadolinium contrast-enhanced CMR. Aortic PWV was determined by velocity-encoded, phase-contrast CMR. Blood samples were routinely drawn at baseline and follow-up to determine N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a subgroup of patients, mid-regional pro-adrenomedullin (MR-proADM) and mid-regional pro-A-type natriuretic peptide (MR-proANP) levels were determined.Patients with a PWV above median (7.0m/s) had significantly higher NT-proBNP, MR-proADM and MR-proANP concentrations at 4-month follow-up than patients with a PWV below median (all p0.02). PWV showed moderate to good correlation with NT-proBNP, MR-proAMD and MR-proANP levels 4 months after STEMI (all p0.05). Multivariate analysis revealed PWV, beside myocardial infarct size, as an independent predictor of 4-month NT-proBNP levels after correction for age, creatinine and LV ejection fraction (model r: 0.781, p0.001).Aortic stiffness is directly associated with biomarkers of myocardial wall stress 4 months after reperfused STEMI, suggesting a role for aortic stiffness in chronic LV-remodelling.

Brain natriuretic peptide (BNP), NT-proBNP and NT-pro-atrial natriuretic peptide (NT-proANP) were measured in blood samples from 57 patients using immunoassays and immunoradiometric assays to evaluate the usefulness as diagnostic markers for the detection of heart failure. For the detection of impaired left ventricular ejection fraction (LVEF), receiver operating characteristic curves showed that BNP had the best diagnostic performance with an area under curve (AUC) of 0.75+/-0.06. However, NT-proBNP (AUC: 0.67+/-0.07) and NT-proANP (AUC: 0.69+/-0.08) showed no significant difference to BNP. In a further analysis for the detection of resting LVEF

Background: Because of controversial earlier studies, the purpose of this study was to provide novel experimental and additional clinical data regarding the possible reexpression of cardiac troponin T (cTnT) in regenerating skeletal muscle in Duchenne muscular dystrophy (DMD).Methods: Plasma from 14 patients (mean age, 7.5 years; range, 5.7–19.4 years) with DMD was investigated for creatine kinase (CK), the CK MB isoenzyme (CKMB), cTnT and cardiac troponin I (cTnI), and myoglobin. cTnT concentrations were measured by an ELISA (second-generation assay; Roche) using the ES 300 Analyzer. cTnI, myoglobin, and CKMB were measured by an ELISA using the ACCESS System (Beckman Diagnostics). Troponin isoform expression was studied by Western blot analysis in remnants of skeletal muscle biopsies of three patients with DMD and in an animal model of DMD (mdx mice; n = 6).Results: There was no relation of cTnT and cTnI to clinical evidence for cardiac failure. cTnI concentrations remained below the upper reference limit in all patients. cTnT was increased (median, 0.11 μg/L; range, 0.06–0.16 μg/L) in 50% of patients. The only significant correlation was found for CK (median, 3938 U/L; range, 2763–5030 U/L) with age (median, 7.5 years; range, 6.8–10.9 years; r = −0.762; P = 0.042). Western blot analysis of human or mouse homogenized muscle specimens showed no evidence for cardiac TnT and cTnI expression, despite strong signals for skeletal muscle troponin isoforms.Conclusions: We found no evidence for cTnT reexpression in human early-stage DMD and in mdx mouse skeletal muscle biopsies. Discrepancies of cTnT and cTnI in plasma samples of DMD patients were found, but neither cTnT nor cTnI plasma concentrations were related with other clinical evidence for cardiac involvement.

We studied the influence of a 3-week hiking vacation at moderate altitude on cardiac pump and endocrine function. 18 males (mean age: 55 years, range 36-60) with metabolic syndrome participated in a 3-week structured guided hiking vacation program (4 times per week at 55-65% of maximal heart rate, total exercise time 29 h). Echocardiography, B-type natriuretic peptide (BNP), NT-proBNP, and endothelin-1 measurements were performed at baseline in Innsbruck (576 m a.s.l., Austria), on the first day at moderate altitude (Obertauern, 1700 m a.s.l., Austria), after 3 weeks in Obertauern, and at follow-up in Innsbruck. We found no adverse cardiovascular effects and no significant changes in echocardiographic measures of systolic or diastolic function, estimated systolic pulmonary artery pressure, exercise capacities, BNP and NT-proBNP, or endothelin-1 concentrations. The blood pressure at rest significantly decreased from baseline to follow-up.

Objective To test the performance of N-terminal pro B-type natriuretic peptide to distinguish from cardiac and non-cardiac disease in the pediatric patient population. Method NT-proBNP concentrations were retrospectively analysed in 102 pediatric patients (median age: 5.96 years; 0–18 years) with cardiac diseases comprising left-to-right-shunt lesions ( n =42), left heart lesions ( n =47) and right heart lesions ( n =13) and in 65 pediatric patients (median age: 3.37 years; 0.03–18 years) with acute infection, minor trauma or neurological disorder. Results NT-proBNP levels between patients without heart disease and patients with heart disease differed significantly with a median NT-proBNP value of 224.9 ng/l, 108.7 ng/l–945.6 ng/l (25th–75th percentile) versus 76.7 ng/l, 35.0 ng/l–122.4 ng/l, p p Conclusions NT-proBNP measurement is a helpful addition to identify pediatric patients with heart disease.

Natriuretic peptides are well-established markers in adult heart failure patients (1) and may also be useful for identifying neonates or children with cardiac diseases. Recent studies demonstrated high N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations in healthy neonates with a subsequent rapid decrease within several days (2)(3). However, in the transition from fetal to neonatal life, the physiologic role of natriuretic peptides is not fully understood. Furthermore, it is currently not known whether natriuretic peptides in the fetal circulation derive from the fetus itself or whether there is a placental exchange of maternal natriuretic peptides. The aim of this study, therefore, was to determine the NT-proBNP concentrations in healthy neonates and to compare their concentrations with the values for their respective mothers to indirectly demonstrate a possible placental NT-proBNP exchange. From 100 neonates delivered consecutively between November 2003 and February 2004 (Gynaecologic and Paediatric Hospital Linz), we compared …

Cognitive performance and alertness are two determinants for work efficiency, varying throughout the day and depending on bright light. We conducted a prospective crossover study evaluating the impacts of exposure to an intense, early morning illumination on sustained attention, alertness, mood, and serum melatonin levels in 33 healthy individuals. Compared with a dim illumination, the intense illumination negatively impacted performance requiring sustained attention; however, it positively impacted subjective alertness and mood and had no impact on serum melatonin levels. These results suggest that brief exposure to bright light in the morning hours can improve subjective measures of mood and alertness, but can also have detrimental effects on mental performance as a result of visual distraction. Therefore, it is important that adequate lighting should correspond to both non-visual and visual demands.

Background: Natriuretic peptides (NP) are well-established markers of heart failure (HF). During the past 5 years, analytical and clinical recommendations for measurement of these biomarkers have been published in guidelines. The aim of this follow-up survey was to investigate how well these guidelines for measurement of NP have been implemented in laboratory practice in Europe. Methods: Member societies of the European Federation of Clinical Chemistry and Laboratory Medicine were invited in 2009 to participate in a web-based audit questionnaire. The questionnaire requested information on type of tests performed, decision limits for HF, turn-around time and frequency of testing. Results: There was a moderate increase (12%) of laboratories measuring NP compared to the initial survey in 2006. The most frequently used HF decision limits for B-type NP (BNP) and N-terminal BNP (NT-proBNP) were, respectively, 100 ng/L and 125 ng/L, derived from the package inserts in 55%. Fifty laboratories used a second decision limit. Age or gender dependent decision limits were applied in 10% (8.5% in 2006). The vast majority of laboratories (80%) did not have any criteria regarding frequency of testing, compared to 33% in 2006. Conclusions: The implementation of NP measurement for HF management was a slow process between 2006 and 2009 at a time when guidelines had just been established. The decision limits were derived from package insert information and literature. There was great uncertainty concerning frequency of testing which may reflect the debate about the biological variability which was not published for most of the assays in 2009.

Background We compared high‐sensitivity cardiac troponin T (hs‐cTnT) and standard cTnT for acute myocardial infarction ( AMI ) diagnosis in everyday clinical practice of an emergency department ( ED ). Methods and Results cTnT was measured in 2384 consecutive patients (60±21 years, 52% female) on ED admission. Readmissions to the ED (n=720) and mortality (n=101) were followed for an average period of 239±49 days. There were 53 AMI s (delay, 1 to 96 hours; median, 3 hours), 440 chest pain patients, 286 dyspnea patients, 785 acute or chronic cardiac diseases, and 540 neurological diseases, with the remaining having various internal diseases. The diagnostic performances of hs‐ and standard cTnT were comparable for AMI diagnosis (area under receiver operating characteristics curves [ ROC AUC ], 0.91±0.02 versus 0.90±0.03; P =0.31). Using the 99th‐percentile cutoff, the sensitivities and specificities for AMI in the whole population were 91% and 74% for hs‐cTnT and 89% and 80% for standard cTnT. hs‐cTnT detected significantly more patients with cardiac diseases ( ROC AUC , 0.77±0.01 versus 0.67±0.01; P ED readmissions but not of mortality, but both were not independent predictors of ED readmissions or the combined end point of readmission or mortality in binary logistic regression analysis. Conclusions In unselected ED patients the diagnostic performances of hs‐cTnT and standard cTnT for AMI diagnosis did not differ significantly. hs‐cTnT detected significantly more cardiac diseases. hs‐cTnT and standard cTnT were not independent predictors of ED readmissions and mortality from all causes.

The laboratory examination of hematologic diseases has made great progress in the last 30 years and is now based on a fourfold strategy: cytomorphology, flow cytometry, cytogenetics, and molecular genetics. Cytomorphology is still the crucial first step, and then it usually followed by flow cytometric immunophenotyping of relevant cell population. Both investigations require a highly expert laboratory team and, often, an exchange of information among the clinicians. It is a challenge for small specialized laboratories to reach quality standards and economic efficiency nowadays, even with highly specialized personnel. One solution is the collaboration among institutes of clinical pathology (usually a central laboratory), smaller laboratories specialized in hematology, and usually residents in departments of hematologic diseases, as is the practice in the Interdiscipline Hematologic Competence Center (IHK) of Innsbruck since 2008. Thus, in Innsbruck, this competence center concentrates the whole expertise in the hematology laboratory of the hospital based on cytomorphology and flow cytometry. Besides the clarification of already identified hematologic diseases, the IHK has optimal conditions not only for the specific and prompt first-time diagnosis of hematologic diseases (e.g., additional diagnostic findings) but also for the screening of blood samples, from tertiary care hospitals, that require further diagnostic workup for specific disease clarification based on numeric and morphologic abnormalities. For the further progression of the IHK, the integration of cytogenetic and molecular genetic diagnostics is essential. The interdisciplinary collaboration of clinical pathologists, hematology clinicians, and cytogenetic and molecular genetics experts improves the knowledge transfer and expertise of all members and enhances the efficiency and quality level of such a collaborating laboratory division. Further advantages can be achieved in important laboratory development processes (e.g., laboratory accreditation, implementation of expensive laboratory equipment, such as ten-color flow cytometers, introduction of modern laboratory information systems, or image-archiving systems), with a high potential of synergetic effects stemming from the collaboration. The establishment of interdisciplinary competence centers for hematologic diagnostics is therefore a milestone in modern laboratory diagnostics.

Background: Cardiac troponin T (cTnT) has been reported to be a predictor of stroke outcome. We hypothesized that the high-sensitivity cTnT (hs-cTnT) assay is superior to its previous assay generation for stroke outcome prediction. Methods: cTnT was measured on emergency department admission in 60 consecutive patients (35 males, age 69.4±13.9 years) with ischemic stroke. Adverse 90-day clinical outcome was defined as death or dependence (modified Rankin scale ≥3 or Barthel index Results: Stroke aetiology was microangiopathy in three, macroangiopathy in 17, cardiac embolism in 26, dissection in one and unknown in 13 patients. At 90-day follow-up 16 (27%) patients had an adverse outcome. Receiver operating characteristics (ROC) curve analysis yielded a significantly better performance of hs-cTnT vs. cTnT (area under ROC curve: 0.80 [95% CI 0.68–0.89] vs. 0.70 [95% CI 0.57–0.82], p=0.017). The optimal discriminator values according to ROC analysis were 5.1 ng/L (hs-cTnT assay) and 11 ng/L (4th generation cTnT assay) with: sensitivities 94% vs. 56%, specificities 57% vs. 84%, positive predictive values 44% vs. 56%, and negative predictive values 96% vs. 84%. Conclusions: Improvements in cTnT assay sensitivity and precision at the low measuring range resulted in a more accurate prediction of ischemic stroke outcome, particularly for ruling out worse outcome.

Guidelines on preferred cardiac marker strategies for investigation of patients with acute coronary syndromes (ACS) are available from the laboratory medicine and cardiology communities. Therefore, implementation of these guidelines into daily clinical practice should be a joint effort of laboratory specialists and clinicians. This was investigated in this survey.: A pilot study was performed sponsored by the European Federation of Clinical Chemistry and Laboratory Medicine. A link to an online questionnaire was e-mailed to 990 laboratories from eight European countries in May 2006. The requested information included tests performed, clinical protocol development, and reference limits.: We obtained a total of 220 responses. Out of these, 208 responses (95%) were from hospitals that provide 24-h admission of patients. The suggested turn-around-time (88% for cardiac troponin T/I and for CK-MB mass. The majority of the laboratories derive their decision limits from kit inserts provided by the manufacturers. The results revealed a worrying fact that external quality assessments are not used in all testing.: Our survey demonstrated that cardiac troponin is the preferred biomarker for the diagnosis of ACS. Half of the participants had written protocols, mostly as a result of collaboration between laboratorians and clinicians.Clin Chem Lab Med 2009;47:227–34.

Background: Ischemia-modified albumin (IMA) is an emerging marker of ischemia. To investigate the applicability of IMA for the diagnosis of skeletal muscle ischemia, we examined IMA changes as measured by the albumin-cobalt binding test, in a group of healthy volunteers after standardized exercise-induced calf muscle ischemia. Methods: A total of 12 healthy volunteers underwent standardized exercise on a plantar flexion pedal. Ischemic conditions were achieved by inflating a femoral blood pressure cuff at incremental pressures of 0, 60, 90, 120 and 150 mm Hg. Calf muscle ischemia was identified by synchronous 31 P magnetic resonance spectroscopy, measuring intracellular concentrations of phosphocreatine (PCr) and inorganic phosphate (Pi). In addition, IMA, serum albumin, lactate, troponin T (TnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and at 5, 10, 30, 360 and 720 min after cuff release. Results: Magnetic resonance spectroscopy showed calf muscle ischemia in all participants upon exercise and cuff inflation. Circulating IMA concentrations increased significantly after cuff release (p=0.03) and returned to baseline within 30 min. While we found a significant negative correlation with albumin, there was no association of IMA levels with lactate or intracellular levels of PCr or Pi in samples obtained at baseline and post-ischemia. TnT and NT-proBNP remained within the normal range throughout the observation period in all participants. Conclusions: IMA may represent a clinical marker for skeletal muscle ischemia, although its lack of specificity requires careful clinical interpretation of data. The short period of IMA elevation after ischemic exercise requires standardized conditions for use as a diagnostic tool and hints at IMA applicability as a marker of prolonged or chronic ischemia.

We examined whether B-type natriuretic peptide (BNP) and its precursor fragment, N-terminal proBNP (NT-proBNP), can serve as non-invasive markers of hemodynamic response to treatment in acute heart failure in a prospective observational study.29 unselected, consecutive patients (mean age: 61.6, 39-83 years; 25 males, 4 females) in urgent need for positive inotropic support and invasive hemodynamic monitoring by a Swan-Ganz catheter. Positive hemodynamic response to treatment was defined asor =25% decrease in pulmonary artery occlusion pressure after 24 h. Hemodynamics were recorded simultaneously with blood sampling for BNP and NT-proBNP testing before and 24 h after initiation of inotropic support. BNP (Bayer Diagnostics) and NT-proBNP (Roche Diagnostics) were measured by commercial immunoassays.Both markers were markedly elevated. However, there were no close correlations (r0.43, p0.05) of BNP or NT-proBNP with hemodynamic parameters at baseline or 24 h thereafter. Only BNP showed a significant (p=0.023) decrease compared to baseline values in hemodynamic responders. The area under receiver operating characteristics curve for relative changes of BNP for the prediction of hemodynamic response was 0.76.Our preliminary results indicate that BNP is more sensitive to acute hemodynamic changes than NT-proBNP. This study also highlights limitations of both markers as surrogates of hemodynamics in critically ill acute heart failure patients.

SUMMARY 1 Preconditioning has been demonstrated to ameliorate ischaemia/reperfusion injury in several cells and tissues. Therefore, in the present study we investigated whether preconditioning of human bypass grafts, internal mammary artery (IMA) and saphenous vein (SV) induces heat shock protein (Hsp) expression and reduces apoptosis in response to subsequent hypoxia/re-oxygenation damage in both vessels. 2 Internal mammary artery and SV rings, obtained from 30 patients (median age 66.5 years) undergoing coronary artery bypass grafting, were either incubated for 30 min at 42°C (preconditioned) or kept in a standard incubator at 37°C (not preconditioned). Six hours later, graft segments were exposed to 90 min hypoxia followed by a 30 min re-oxygenation period. Western blot, real-time quantative polymerase chain reaction analysis and apoptosis detection by the Terminal deoxyribonucleotidyl transferase-mediated dUTP–digoxigenin nick end-labelling method were performed. 3 Heat-preconditioned IMA showed significantly increased protein expression of Hsp72 after hypoxia/re-oxygenation treatment compared with controls (median 9.1 vs 5.0 µg/mg total protein; P = 0.048). Expression of Hsp73 was weak and Hsp60 was not detectable in the IMA. 4 In the SV, neither protein nor mRNA expression of Hsp were significantly different between preconditioned and not preconditioned veins. 5 There were significantly fewer apoptotic cells in the intima of the preconditioned compared with not preconditioned IMA (P = 0.041) after hypoxia/re-oxygenation injury, whereas in the SV apoptosis was not significantly prevented by preconditioning. 6 Mild heat preconditioning before hypoxia/re-oxygenation injury is a stimulus for Hsp72 protein expression and a reduction in apoptosis in the human IMA.

Neointimal hyperplasia in aortocoronary vein grafts represents a significant problem that, by itself or by development of vein graft atherosclerosis, leads to the return of symptoms and to major adverse cardiac events after coronary artery bypass grafting. The main causes of neointimal hyperplasia are surgical trauma, intraoperative ischemia reperfusion injury, and implantation of a vein into the arterial circulation. All these pathogenetic factors cause a loss of protective endothelial mediators. The initiating steps lead to the induction of a significant inflammatory response and to the production of mitogenic factors in the vascular wall. DNA synthesis in vascular smooth muscle cells is markedly up-regulated, and intracellular signal transduction leads to transcription of immediate early genes, which causes an intense proliferative response. Vascular smooth muscle cells proliferate, migrate through the internal elastic lamina with the support of proteases, and transform from contractile-type into secretory-type cells. A thick layer of neointima is formed. The prevention of neointimal hyperplasia includes meticulous surgical technique, the choice of a large target vessel, and adequate intraoperative storage of the vein graft. Local intraoperative therapy of the implanted graft has been successfully tested in the experimental setting with a variety of substances that tackle different steps in the pathologic mechanism. Systemic pharmacologic therapy in clinical use primarily consists of the use of platelet inhibitors and anticoagulants. The transfer of experimental knowledge to bedside application has been slow. Gene therapy represents a promising field for the improved management of vein graft neointimal hyperplasia.

Background: Cardiac troponins replaced creatine kinase and lactate dehydrogenase isoenzymes as criterion standards for the laboratory diagnosis of myocardial damage. However, there are only few publications on correlations of cardiac troponin T (cTnT) with pathologically determined infarct size which are flawed by insufficient sample size. Methods: In 38 anesthetized wildtype mice, the chest and pericardium were opened and the left descending artery was ligated. After sham operation, all mice recovered. Twenty-four hours after surgical induction of acute myocardial infarction heparinized blood samples were collected, the animals sacrificed and hearts harvested. Plasma cTnT was measured by a quantitative rapid assay using the Cardiac Reader (Roche Diagnostics). The hearts were cut into four transverse sections which were stained with 1.5% triphenyltetrazolium chloride for evaluation of necrosis by computerized planimetry. Pearson correlation coefficients were calculated between histological infarct size and cardiac markers. Results: Infarct sizes ranged from 14% to 55% of left ventricle and cTnT concentrations from 3.9 to 14.1 μg/l. cTnT correlated closely with histological infarct size (r=0.84, p