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Aims Morbid obesity is a risk factor for cardiovascular disease. The relative effects of Roux-en-Y gastric bypass surgery (GBS) and intensive lifestyle intervention (ILI) on subclinical myocardial injury, the activity of the cardiac natriuretic system, and systemic inflammation remain unclear. Methods In a 59-week non-randomized clinical trial that included 131 patients with morbid obesity, we compared the effects of GBS and ILI on concentrations of cardiac troponin T (cTnT) and I (cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and C-reactive protein (CRP). Results In the GBS and ILI group, median body mass index (BMI) was reduced by 14.4 kg/m2 versus 3.9 kg/m2, respectively (p value < 0.001). Cardiac troponins decreased after GBS, p = 0.014 (cTnT) and p = 0.065 (cTnI) and increased significantly in those treated with ILI (p values ≤ 0.021) (between-group differences for deltas: p ≤ 0.003). NT-proBNP increased in both groups, but significantly more in the GBS than in the ILI group (between-group differences for deltas: p = 0.008). CRP decreased significantly within the GBS and the ILI group, with this change significantly greater in the GBS group (between-group differences for deltas p < 0.001). The dominating mediator of the biomarker changes was weight loss. Prior coronary artery disease and diabetes were predictive of the magnitude of the changes in cTnI and NT-proBNP, respectively. Conclusion Compared to ILI, GBS was associated with reduced subclinical myocardial injury and systemic inflammation, and enhancement of the cardiac natriuretic peptide system. The biomarker changes were predominantly mediated by weight loss.

Myocardial infarction (MI) is more likely if the heart damage biomarker cardiac troponin T (cTnT) is elevated in a blood sample from a patient with chest pain. There is no conventional method to estimate the risk of MI at a specific cTnT concentration. The purpose of this study was to evaluate the performance of a novel method that converts cTnT concentrations to patient-specific risks of MI.Admission cTnT measurements in 15,425 ED patients from three hospitals with a primary complaint of chest pain, with or without a clinical diagnosis of MI, were Box-Cox-transformed to normality density functions to calculate the percentage with MI among patients with a given cTnT concentration, the parametric predictive value among lookalikes (PALfx). The ability of the PALfx to generate stable risk estimates of MI was examined by bootstrapping and expressed as the coefficient of variation (CV).Four age and sex-specific subgroups above or below 60 years of age with distinct cTnT distributions were identified among patients without MI. The cTnT distributions across subgroups with MI were similar, allowing us to use all admissions with MI to calculate the PALfx in the four subgroups. For instance, at a baseline cTnT concentration of 7 ng/L, a female patient60 years would have a 0.5% risk of MI whereas a male patient60 years would have a 1.9% risk of MI. To assess the stability of the PALfx method we bootstrapped smaller and smaller subsets of the 15,422 ED visits. We found that 1950 patients without MI and 50 patients with MI were sufficient to limit the variation of the PALfx with a CV of 0.8-5.4%, close to the CV using the entire dataset. The MI risk estimates were similar when data from the three hospitals were used separately to derive the PALfx equations.The PALfx can be used to estimate the risk of MI at patient-specific cTnT concentrations with acceptable margins of error. The patient-specific risk of disease using the PALfx could complement decision limits.

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

Background Coronavirus Disease 2019 (COVID-19) has variable clinical presentation, from asymptomatic to severe disease leading to death. Biochemical markers may help with management and prognostication of COVID-19 patients; however, their utility is still under investigation. Methods A retrospective study was conducted to evaluate alanine aminotransferase, C-reactive protein (CRP), ferritin, lactate, and high sensitivity troponin T (TnT) levels in 67 patients who were admitted to a Canadian tertiary care centre for management of COVID-19. Logistic, cause-specific Cox proportional-hazards, and accelerated failure time regression modelling were performed to assess the associations of initial analyte concentrations with in-hospital death and length of stay in hospital; joint modelling was performed to assess the associations of the concentrations over the course of the hospital stay with in-hospital death. Results Initial TnT and CRP concentrations were associated with length of stay in hospital. Eighteen patients died (27%), and the median initial TnT concentration was higher in patients who died (55 ng/L) than those who lived (16 ng/L; P 64 ng/L. While the initial TnT concentration was predictive of death, later measurements were not. Only CRP had prognostic value with both the initial and subsequent measurements: a 20% increase in the initial CRP concentration was associated with a 14% (95% confidence interval (CI): 1–29%) increase in the odds of death, and the hazard of death increased 14% (95% CI: 5–25%) for each 20% increase in the current CRP value. While the initial lactate concentration was not predictive of death, subsequent measurements were. Conclusion CRP, lactate and TnT were associated with poorer outcomes and appear to be useful biochemical markers for monitoring COVID-19 patients.

Background To assess if cardiac troponins can improve diagnostics of acute heart failure (AHF) and provide prognostic information in patients with acute dyspnea. Methods We measured cardiac troponin T with a high-sensitivity assay (hs-cTnT) in 314 patients hospitalized with acute dyspnea. The index diagnosis was adjudicated and AHF patients were stratified into AHF with reduced or preserved ejection fraction (HFrEF/HFpEF). The prognostic and diagnostic merit of hs-cTnT was compared to the merit of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Results In the total population, median age was 73 (quartile [Q] 1–3 63–81) years and 48% were women. One-hundred-forty-three patients were categorized as AHF (46%) and these patients had higher hs-cTnT concentrations than patients with non-AHF-related dyspnea: median 38 (Q1-3 22–75) vs. 13 (4–25) ng/L; p < 0.001. hs-cTnT concentrations were similar between patients with HFrEF and HFpEF (p = 0.80), in contrast to NT-proBNP, which was higher in HFrEF (p < 0.001). C-statistics for discriminating HFpEF from non-AHF-related dyspnea was 0.80 (95% CI 0.73–0.86) for hs-cTnT, 0.79 (0.73–0.86) for NT–proBNP, and 0.83 (0.76–0.89) for hs-cTnT and NT-proBNP in combination. Elevated hs-cTnT remained associated with HFpEF in logistic regression analysis after adjusting for demographics, comorbidities and renal function. During median 27 months of follow-up, 114 (36%) patients died in the total population. Higher hs-cTnT concentrations were associated with increased risk of all-cause mortality after adjustment for clinical variables and NT-proBNP: hazard ratio 1.30 (95% CI 1.07–1.58), p = 0.009. Conclusion hs-cTnT measurements improve diagnostic accuracy for HFpEF and provide independent prognostic information in unselected patients with acute dyspnea.

Background Cardiac troponin (cTn) is a complex of three subunits (T, I, and C), with some studies reporting that ~5–10% is cytosolic and unbound (‘free’). It has been hypothesized that free cTn is released before complex and before or without cell death dependent on the severity of ischemia . In this context, new generation assays that can discriminate free, binary (IC) and ternary (TIC) complex forms may aid to differentiate between type 1 myocardial infarction (MI) and cTn elevations due to different etiologies, e.g. demand ischemia and type 2 MI. Methods Serial plasma samples from six type 1 MI patients and twenty-seven patients with other cTnI elevations, e.g. due to demand ischemia and type 2 MI, were analyzed using high-sensitivity ET Healthcare Pylon assays for total cTnI, complex cTnI (IC and TIC), and cTnTIC. The specificity of the anti-cTnT antibody in the cTnTIC assay was such that only full-size cTnTIC is detected. In vitro stability of different cTnI forms was assessed by spiking free cTnI and cTnTIC in cTnI-free serum, incubating at 4 or 37 °C, and measuring different cTnI forms over 0–182 h. Presence of cytosolic free cTnI was evaluated on fixed rat cardiac tissue using an antibody against free cTnI. Results Pylon assays for total and complex cTnI tracked well over time with each other and gave similar results, both for type 1 MI and non-type 1 MI patients, indicating that the vast majority was complex cTnI. As a minority of complex cTnI was full-size cTnTIC, this indicated that complex cTnI mainly consisted of a degraded form of cTnTIC (low-molecular weight cTnTIC) and/or cTnIC. Full-size cTnTIC was more abundant in early compared to late samples. In vitro studies indicated that free cTnI and cTnTIC are not stable at 37 °C (28% and 11% recovery after 24 h, respectively) and this is also true to some extent for cTnTIC at 4 °C (60% recovery after 24 h). Free cTnI was not readily detected in rat cardiac tissue. Conclusions In agreement with type 1 MI, cTnI in samples of patients with cTnI elevations due to other etiologies is found predominantly as complex cTnI, of which some is full-size cTnTIC. In most cases, assays for total and complex cTnI indicated there was little free cTnI; however, its presence cannot be completely excluded, due to the inability of its direct measurement and limited stability.

As more companies obtain regulatory approval for high-sensitivity cardiac troponin (hs-cTn) assays there is an urgent need for independent analytical and clinical evaluations. To this end, we have evaluated Ortho Clinical Diagnostics' hs-cTnI assay and compared it to their contemporary cTnI-ES assay in emergency department (ED) patients with suspected acute coronary syndrome (ACS).The study cohort consisted of ED patients (n = 906) with symptoms suggestive of ACS who had Ortho hs-cTnI and cTnI-ES results at presentation and 3 h (with calculated delta (0-3 h) defined as the absolute concentration difference between paired results). The primary composite outcome was 7-day myocardial infarction (MI) or cardiovascular death, with secondary analyses performed for 7-day MI and index-MI. Analytical imprecision testing (i.e., coefficient of variation; CV), receiver-operating characteristic (ROC) curve analyses with area under the curve (AUC), and diagnostic parameters (sensitivity/specificity/predictive values) were calculated.The hs-cTnI assay had superior precision compared to the cTnI-ES assay below 5 ng/L in EDTA plasma (hs-cTnI CV ≤ 15% versus cTnI-ES CV ≥ 85%). The AUCs were higher for hs-cTnI as compared to cTnI-ES at 0 h (0.88 vs. 0.85), 3 h (0.94 vs. 0.92), and the delta (0-3 h) value (0.91 vs. 0.85) for the primary composite outcome (p 0.05). At 3 h, the sensitivity/specificity for index-MI was ≥97%/≥82%, for 7-day MI was ≥89%/≥84%, and for the primary composite outcome was ≥90%/≥85% using the manufacturer's sex-specific 99th-percentile cutoffs.The Ortho hs-cTnI assay has superior analytical and clinical performance over their contemporary cTnI-ES assay in evaluating ED patients with symptoms suggestive of ACS.

BACKGROUND: Primary percutaneous coronary intervention (pPCI) is recommended in patients presenting with ST-elevation myocardial infarction (STEMI) within METHOD: Patients older than 18 years with first time STEMI referred to pPCI were eligible. cTnT and copeptin values were measured at admission. A cardiac magnetic resonance scanning (CMR) was done during the index admission for assessment of area at risk (AAR), and later 3 months to assess final infarct size (FIS). Myocardial salvage index (MSI) was calculated based on these measurements.RESULTS: A total of 468 patients were included. The median time from patient-reported onset of symptoms to pPCI was 192 min (IQR 150 min - 290 min). At presentation 416 (89%) patients had hs-cTnT values above the 99th percentile, median hs-cTnT was 53 ng/l (IQR 24 ng/l-146 ng/l) and 318 (68%) patients had copeptin values above the 99th percentile (18.9 pmol/l), median copeptin was 50 pmol/l (IQR 14 pmol/l-131 pmol/l). Symptom duration showed a weak but significant association with AAR (R 2 = 0.02, p = .04), FIS (R 2 = 0.03, p CONCLUSION: Copeptin/troponin-ratio is associated with patient-reported symptom duration, but there was no association with area at risk, final infarct size or myocardial salvage index.

We compared rates of analytical outliers, and percent of emergency department (ED) patients with cardiac troponin (cTn) values above the 99th percentile upper reference limit (URL), for two conventional and one high sensitivity cTn assay.We measured 3008 samples from 1931 ED patients by Roche e411 4th generation Troponin T (cTnT); and Abbott STAT Troponin I (cTnI) and high sensitivity troponin I (hscTnI) on an Architect i2000. Within 24h of initial measurement, samples were aliquoted, re-centrifuged, and repeated in duplicate by all methods. Outliers were defined as one or both replicates exceeding initial value by a critical difference (CD): where CD=z×2×SDanalytical (z=3.29 at a probability of 0.0005), and at least one replicate on a different side of 99th percentile URL compared to initial value. We also assessed percent of ED patients with values99th percentile by all methods (excluding outliers), using both sex-neutral and sex-specific hscTnI URL.The outlier rate for cTnI (3.66%) was significantly higher than the outlier rate for either cTnT (0.33%) or hscTnI (0.47%) (p0.0001). More ED patients (33%) had elevated cTnT values compared to either cTnI (25%) or hscTnI (29%). Application of sex-specific URL did not change the percent of ED patients with99th percentile hscTnI values.Abbott STAT cTnI had more analytic outliers than Roche cTnT or Abbott hscTnI. Compared to cTnT, use of hscTnI will significantly decrease the percent of ED patients with elevated cTn values without increasing analytical outliers.

Our purpose was to determine a) overall and sex-specific 99th percentile upper reference limits (URL) and b) influences of statistical methods and comorbidities on the URLs.Heparin plasma from 838 normal subjects (423 men, 415 women) were obtained from the AACC (Universal Sample Bank). The cobas e602 measured cTnT (Roche Gen 5 assay); limit of detection (LoD), 3ng/L. Hemoglobin A1c (URL 6.5%), NT-proBNP (URL 125ng/L) and eGFR (60mL/min/1.73m355 men and 339 women remained after exclusions. Overall50% of subjects had measureable concentrations ≥ LoD: 45.6% no exclusion, 43.5% after exclusion; compared to men: 68.1% no exclusion, 65.1% post exclusion; women: 22.7% no exclusion, 20.9% post exclusion. The statistical method used influenced URLs as follows: pre/post exclusion overall, NP 16/16ng/L, HDE 17/17ng/L, R not available; men NP 18/16ng/L, HDE 21/19ng/L, R 16/11ng/L; women NP 13/10ng/L, HDE 14/14ng/L, R not available.We demonstrated that a) the Gen 5 cTnT assay does not meet the IFCC guideline for high-sensitivity assays, b) surrogate biomarkers significantly lowers the URLs and c) statistical methods used impact URLs. Our data suggest lower sex-specific cTnT 99th percentiles than reported in the FDA approved package insert. We emphasize the importance of detailing the criteria used to include and exclude subjects for defining a healthy population and the statistical method used to calculate 99th percentiles and identify outliers.

Objective The extent of kidney-dependent clearance of the cardiac damage biomarker cardiac troponin T (cTnT) is not known. Methods and results We examined clearance of cTnT after injection of heart extracts in rats with or without clamped kidney vessels. The extent of degradation of cTnT to fragments able to pass the glomerular membrane and the kidney extraction index of cTnT was examined in human subjects. After a bolus injection of rat cardiac extract, simulating a large myocardial infarction, there was no significant difference in clearance of cTnT with or without kidney function. However, a slower clearance was observed late in the clearance process, when cTnT levels were low. When low levels of rat cardiac extract were infused at a constant rate to steady state, clamping of the renal vessels resulted in significant 2-fold reduction in clearance of cTnT. Over 60% of the measured cTnT in human subjects had a molecular weight below 17 kDa, expected to have a relatively free passage over the glomerular membrane. The extraction index of cTnT in three heart failure patients undergoing renal vein catheterization was 8–19%. Kidney function adjusted cTnT levels increased the area under the ROC curve for diagnosis of myocardial infarction of the cTnT analysis in an emergency room cohort. Conclusions At high concentrations, often found after a large myocardial infarction, extrarenal clearance of cTnT dominates. At low levels of cTnT, often found in patients with stable cTnT elevations, renal clearance also contribute to the clearance of cTnT. This potentially explains why stable cTnT levels tend to be higher in patients with low kidney function.

Objectives Cardiac troponins are specific for the heart, but not for the acute coronary syndrome. We wanted to assess how common elevated cardiac troponin concentrations were, in a population with significant non-cardiac disease. Design & Methods We measured both hs-cTnT and hs-cTnI on all samples submitted to the laboratory during one 24 h period, and assessed the magnitude of the cTn concentration with the location and severity of disease of the patient. Results Community patients and patients from the maternity ward had the lowest cTn concentrations with results above the 99th percentile being only 0–2% of the total. As expected, the highest proportion of results > 99th percentile came from Coronary Care and Intensive Care. However, substantial numbers of persons on Medical and Surgical wards, without a primary diagnosis of cardiac disease, also had cTn > 99th percentile. Particularly for cTnT, there was a highly significant odds ratio predicting mortality when results above and below the 99th percentile were compared. Conclusions Significant illnesses apart from the acute coronary syndrome are important causes of a rise in cTn to above the 99th percentile, and appear to reflect the total body burden of disease. Even when the high hs-cTn concentration is not due to the acute coronary syndrome, there is a significant association with all-cause mortality.

Objective To determine gender-specific reference limits of high-sensitivity (hs) cardiac troponins (cTn) and validity of hs assay designation for both genders. Methods After screening with a questionnaire, 827 presumably healthy individuals were further selected based on clinical criteria (n = 740), clinical criteria plus cardiac imaging including stress magnetic resonance imaging or stress echocardiography (n = 726), and extended cardio-pulmonary parameters (n = 626). Blood samples were measured with hs-cTnT (Roche Diagnostics) on a cobas e602 analyzer as well as hs-cTnI (Abbott Diagnostics) on an ARCHITECTi2000SR. The impact of health definition, statistical methods, instrument selection and limit of detection (LoD) on overall and gender-specific 99th percentiles was assessed. Results Median age was 56 years (50.9% female) for the total study cohort. 99th percentiles for females and males ranged between 13.1 and 13.3 ng/L and 16.8–19.9 ng/L for hs-cTnT as well as 10.3–12.5 ng/L and 27.4–29.7 ng/L for hs-cTnI depending on health definition. Utilization of stricter health definition criteria reduced the difference of the gender-specific 99th percentiles between males and females for hs-cTnT to 3.7 ng/L (males 16.8 ng/L, females 13.1 ng/L), whereas the difference rather increased for hs-cTnI to 19.4 ng/L (males 29.7 ng/L, females 10.3 ng/L). Values > LoD could be measured in the majority of males and females using hs-TnT (81.4–83.3% and 96.5–96.9%, respectively). In contrast, values > LoD could not be observed in the majority of females using hs-cTnI (38.4–41.1%). Conclusions In a well-phenotyped healthy cohort, reference values for hs-cTnT were slightly higher, whereas hs-cTnI cut-offs were considerably lower than previously observed. Gender differences were more pronounced in hs-cTnI than in hs-cTnT and were further reduced for hs-cTnT by application of stricter health definition criteria. Contrary to hs-cTnI, hs-cTnT fulfilled criteria for hs designation for both genders.

Background Myocardial infarction is more likely if the heart damage biomarker cardiac troponin T (cTnT) is elevated in a blood sample, indicating that cardiac damage has occurred. No method allows the clinician to estimate the risk of myocardial infarction at a specific cTnT level in a given patient. Methods Predictive value among lookalikes (PAL) uses pre-test prevalence, sensitivity and specificity at adjacent cTnT limits based on percentiles. PAL is the pre-test prevalence-adjusted probability of disease between two adjacent cTnT limits. If a chest pain patient's cTnT level is between these limits, the risk of myocardial infarction can be estimated. Results The PAL based on percentiles had an acceptable sampling error when using 100 bootstrapped data of 18 different biomarkers from 38,945 authentic lab measurements. A PAL analysis of an emergency room cohort (n = 11,020) revealed that the diagnostic precision of a high-sensitive cTnT assay was similar among chest pain patients at different ages. The higher incidence of false positive results due to non-specific increases in cTnT in the high-age group was counterbalanced by a higher pre-test prevalence of myocardial infarction among older patients, a finding that was missed when using a conventional ROC plot analysis. Conclusions The PAL was able to calculate the risk of myocardial infarction at specific cTnT levels and could complement decision limits.

Objectives To study the relationship between cardiovascular risk factors and detectable cardiac troponin-T using a highly sensitive assay (hs-cTnT) among persons without a history of cardiovascular disease. Design and methods We examined the cross-sectional associations between cardiovascular risk factors and hs-cTnT in 9593 participants (mean age 65.6 (SD, 5.6), 41% female, 22% black) free of cardiovascular disease in a community-based cohort, through the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to characterize the association between cardiovascular risk factors and detectable (≥ 3.0 to 13.9 ng/L) and elevated (≥ 14.0 ng/L) hs-cTnT. Results hs-cTnT was detectable in 59% and elevated in 7% of the study population. Among persons with ideal cardiovascular health, hs-cTnT was detectable in 44%. In models adjusting for significant determinants of hs-cTnT concentration, detectable hs-cTnT was more frequent among males, blacks and persons with diabetes and hypertension and less frequent among statin users, current smokers and drinkers. Other risk factors associated with detectable hs-cTnT were older age, lower kidney function and higher body mass index. These risk factors were associated with elevated hs-cTnT in a similar pattern. Conclusion In a community-based sample without cardiovascular disease hs-cTnT is detectable in most adults, even among those with ideal cardiovascular health. Although most traditional cardiovascular risk factors were significant determinants of detectable and elevated hs-cTnT, the associations were particularly robust for sex, age, race, hypertension and diabetes.

It is unknown, whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the detection of exercise-induced myocardial ischemia.We investigated patients with suspected myocardial ischemia referred for exercise or pharmacological rest/stress myocardial perfusion single-photon emission computed tomography (SPECT) to directly compare the diagnostic accuracy of high-sensitivity cTnI (hs-cTnI) and hs-cTnT. Diagnostic performance was analyzed separately according to stress modality. Hs-cTnI and hs-cTnT were measured before, immediately after, as well as 2h and 4h after maximal exercise in a blinded fashion. Further, all clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: once prior and once after stress-testing. The presence of stress-induced myocardial ischemia was adjudicated using SPECT combined with coronary angiography findings.A total of 403 consecutive patients were enrolled in our study, of which 229 underwent exercise stress and 174 patients pharmacological stress. Exercise-stress-induced myocardial ischemia was detected in 90 patients (39.3% of 229). Levels of hs-cTnI and hs-cTnT were both significantly higher at all time-points examined in patients with exercise-induced myocardial ischemia as compared to patients without myocardial ischemia (all p0.001). Correlation of hs-cTnI and hs-cTnT was high in direct comparison of time-points (Spearman's rho all ≥0.7). The AUCs for baseline/peak/2h/4h for hs-cTnI and hs-cTnT were 0.71/0.71/0.72/0.69 vs. 0.74/0.73/0.71/0.72, respectively (all p=ns for hs-cTnI versus hs-cTnT). In patients undergoing pharmacological stress, the AUCs for baseline/peak/2h/4h for hs-cTnI and hs-cTnT were 0.66/0.66/0.68/0.67 and 0.61/0.62/0.64/0.59, respectively (all p=ns for hs-cTnI versus hs-cTnT). Also the combinations including clinical judgment or changes during serial sampling were similar for hs-cTnI and hs-cTnT (all p=ns).Hs-cTnI and hs-cTnT provide comparable diagnostic information regarding exercise-induced myocardial ischemia. Overall, their diagnostic accuracy seems moderate.NCT01838148.

Objective To evaluate the long term biological variation of high-sensitivity cardiac troponin T (hs-cTnT) in stable outpatients with cardiovascular disease (CVD). Methods After applying 8 exclusion criteria to 965 patients, hs-cTnT was measured at index visit and at a 12-month interval in 169 stable outpatients presenting for routine follow-up visits for any CVD. Stability was defined as absence of any endpoint within the follow-up period. Reference change values (RCVs) and minimal important differences (MIDs) were determined to assess biological variation of hs-cTnT. Results MID and RCV for the 12 months interval in patients were 3.8 ng/L or 44.2%, respectively. MID and transformed MID values were lower than the corresponding RCV with a value of 5.1 ng/L for the transformed RCV and 28.1% for the transformed MID. Similar patterns were shown in different subgroups as sex, age, and renal function . We observed a baseline hs-cTnT value dependent change of MID and RCV with increasing values for MID and decreasing values for RCV which converge to stable values between a baseline hs-cTNT value of 11 to 25 ng/L. Conclusions Biological variation of hs-cTnT over 12 months in stable outpatients depends on the concentration at index visit, and is consistent among important prespecified subgroups. MID shows a low biovariability over 12 months. Clinical Trials Identifier: NCT01954303

Introduction Exercise (ESE) and dobutamine stress echocardiography (DSE) have high sensitivity and specificity to detect inducible myocardial ischemia in patients with significant coronary artery disease (CAD). High-sensitivity cardiac troponin (hs-cTn) assays detect troponin concentrations in the ng/L range. The aim of this study was to determine the kinetics of hs-cTnT in patients undergoing ESE and DSE and possible association of hs-cTnT with inducible myocardial ischemia. Methods In this prospective study adult patients undergoing ESE/DSE were enrolled. Peripheral blood samples were obtained before, and 30 min, 1, 2, and 4–6 h after completion of ESE/DSE. Hs-cTnT was measured on a Roche Diagnostics Elecsys 2010 analyzer. Results We enrolled 48 patients (33 ESE and 15 DSE); 11 patients (23%) had elevated baseline hs-cTnT concentrations >14 ng/L (99th percentile URL); 31/48 (65%) developed an hs-cTnT increase after ESE/DSE (peak 4–6 h post stress test), but only three patients (all in ESE group) had a positive stress test. Absolute and relative hs-cTnT increases were higher after DSE (median Δhs-cTnT +9.7 ng/L [IQR 4.5, 27.2]; +123% [IQR 49, 271]) compared to ESE (median Δhs-cTnT +2.3 ng/L [IQR 1, 4.9]; +37% [IQR 9.1, 221]). Conclusions One in four patients undergoing ESE/DSE had increased hs-cTnT values prior to stress testing. Hs-cTnT increased above the upper limit of normal occurred commonly after ESE/DSE but was more pronounced after DSE. Increases in hs-cTn did not appear to be associated with inducible myocardial ischemia. These findings may have important implications for the clinical use of hs-cTnT within 6 h after ESE/DSE.

Objectives We hypothesized significant gaps remained for cardiac troponin (cTn) utilization in the United States, despite an emerging evidence base and guideline recommendations. We tested this hypothesis and investigated differences and trends between the use of cTn in adult versus pediatric hospitals. Design and methods Individuals were identified by a targeted distribution through personal contact and professional society email lists. Participants completed an online survey (Qualtrics) from 07/15/13 to 07/26/13. The 31-item questionnaire used skipped logic and collected data about the respondent and their institutional cTn clinical practices. Data tabulation and analysis were conducted using Qualtrics and Microsoft Excel. Results A total of 159 unique laboratories responded to the survey, representing primarily adult (81%) versus pediatric (19%) institutions. 59% of laboratories utilize the guideline recommended 99th percentile as the upper reference limit (URL) for cTn, with large variability in reporting practices among users of the same assay. 73% of laboratories reported simultaneous ordering of other cardiac biomarkers with cTn, a majority which included CK-MB. Interpretive comments were used with cTn in 71 laboratories with a significant amount of heterogeneity. Pediatric hospitals reported a lower frequency of cTn orders and were less likely to consider elevated cTn a critical value. Conclusions Gaps in current utilization and reporting of cTn exist, along with practices inconsistent with clinical guideline recommendations. Implementation of the 99th percentile and serial sampling protocols will be critical to adoption of high-sensitivity cTn assays. Differences in chest pain etiology are the most likely reason for the notable differences between cTn use in adults versus pediatric hospitals.

Cardiac troponins (cTn) I and T are organ-specific, but not disease specific biomarkers. Although acute myocardial infarction (AMI) is the most important cause of cTn elevation, other cardiac disorders as well as primarily noncardiac disorders with cardiac involvement often are also associated with cardiomyocyte injury. Levels of cTn should be interpreted as quantitative markers of cardiomyocyte injury with the likelihood of AMI increasing with the level of cTn. Similar to the level of cTn at presentation, acute changes in cTn help to differentiate chronic disorders, which show no change, from acute conditions, which usually show a rise from presentation to the second measurement at 1-3h in the emergency department. Thereby, changes in cTn help to overcome some of the challenges posed by cTn elevations in non-AMI patients. Absolute changes in cTn provide a higher diagnostic accuracy for AMI as compared to relative changes. Again, the higher the absolute change, the higher the likelihood for AMI. Two caveats apply to the diagnostic use of cTn changes. First, patients with AMI may show no or only a minimal change when assessed around the peak of cTn release. Second, in addition to AMI, several other acute cardiac conditions including tachyarrhythmias, myocarditis, hypertensive crisis, and Takotsubo cardiomyopathy also may present with substantial cTn changes.

Objectives This article is a systematic review of the effectiveness of four practices (assay selection, decision point cardiac troponin (cTn) threshold selection, serial testing, and point of care testing) for improving the diagnostic accuracy Non-ST-Segment Elevation Myocardial Infarction (NSTEMI) in the Emergency Department. Design and methods The CDC-funded Laboratory Medicine Best Practices (LMBP) Initiative systematic review method for quality improvement practices was used. Results The current ACC/AHA guidelines recommend using cardiac troponin assays with a 99th percentile upper reference limit (URL) diagnostic threshold to diagnose NSTEMI. The evidence in this systematic review indicates that contemporary sensitive cTn assays meet the assay profile requirements (sensitivity, specificity, PPV, and NPV) to more accurately diagnose NSTEMI than alternate tests. Additional biomarkers did not increase diagnostic effectiveness of cTn assays. Sensitivity, specificity, and NPV were consistently high and low PPV improved with serial sampling. Evidence for use of point of care cTn testing was insufficient to make recommendation, though some evidence suggests that use may result in reduction to patient length of stay and costs. Conclusions Based on the review of and the LMBP(TM) A-6 Method criteria, we recommend the use of cardiac troponin assays without additional biomarkers using the 99th percentile URL as the clinical diagnostic threshold for the diagnosis of NSTEMI. We recommend serial sampling with one sample at presentation and at least one additional second sample taken at least 6 h later to identify a rise or fall in the troponin level. No recommendation is made either for or against the use of point of care tests. Disclaimer The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry (CDC/ATSDR).

Whereas elevated cardiac troponin (cTn) concentrations i.e. above the 99th percentile of healthy reference population (recommended cutoff for the diagnosis of myocardial infarction) are well-documented in healthy individuals after prolonged and/or intensive exercises such as marathons, data on less-strenuous sports are scarce. Therefore, our aim was to investigate cTnI and cTnT release in response to recreational resistance training, here a single-bout of 1-h kettlebell workout.Serum samples were collected from 11 apparently healthy volunteers the previous day (pre-exercise), three hours after the kettlebell class (post-exercise), the next day and three days later. The aliquoted samples were analyzed with Abbott Laboratories' Architect high-sensitivity (hs)-cTnI assay (limit of detection, LoD = 2 ng/L), our 3+1-type cTnI assay free from cTn-specific autoantibody interference (LoD = 3 ng/L) and Roche Diagnostics' hs-cTnT assay (LoD = 5 ng/L).The post-exercise cTn concentrations were significantly higher than the pre-exercise values (median 5.5-9.6 ng/L vs.LoD, P0.05 for all) and they correlated strongly between the three assays (Spearman r = 0.881-0.960, P0.001 for all). Furthermore, a few post-exercise concentrations even exceeded the 99th percentile of Architect hs-cTnI (26 ng/L, n = 2) and/or hs-cTnT (14 ng/L, n = 4). The cTn concentrations returned to baseline during the three days of follow-up.Our study demonstrates abnormally elevated cTns with well-validated sensitive cTn assays after resistance training. This confirms that different kinds of recreational physical activity are yet another confounder that may affect the determination and use of 99th percentile reference values. Therefore, exercise-associated changes should be carefully addressed as part of the evaluation what is "normal cTn".

Objectives To determine the impact of long distance rowing (160 km, nonstop) on standard biological parameters and to study the relation between inflammation, myocardial necrosis , lipid profile , heart rate and energy expenditure. Methods Electrolytes, lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), procalcitonin (PCT), high-sensitive troponin T (hs-cTnT), and N-terminal pro-brain natriuretic peptide (NT-proBNP), were measured on non-fasting venous blood samples collected 8 h before and after the rowing race on five healthy competitors. Heart rate and energy expenditure were measured using sporting self-measurement devices. Results After 16.5 h of race, significant increases in median CRP (+ 25.2 mg/l; p = 0.04), IL-6 (+ 1.85 pg/ml; p = 0.04), TNF-α (+ 1.2 pg/ml; p = 0.04) and NT-proBNP levels (+ 88.8 pg/ml; p = 0.04) were observed, and a close to significant elevation for hs-cTnT(+ 6 ng/l; p = 0.06) and PCT (+ 0.14 μg/l; p = 0.07). On the other hand, significant decrease in median total cholesterol (− 0.5 mmol/l; p = 0.04), triglycerides (− 0.7 mmol/l; p = 0.04) were observed. Furthermore, significant correlations between the maximal heart rate reached during the race and CRP (r = 0.90; p = 0.03), IL-6 (r = 0.90; p = 0.03), and NT-proBNP (r = 0.90; p = 0.03) were observed, whereas no such associations were retrieved with median heart rate, the percentage of time passed over 70% of maximal heart rate or energy expenditure during the race. There was no association between PCT, NT-proBNP, hs-cTnT, inflammatory biomarkers, lipid profile or heart rate parameters. Conclusions Long distance rowing induces inflammation and myocardial strain related to the maximal effort generated during the race, but has a favourable effect on lipid profile.

Objective To externally validate a clinical decision rule incorporating heart fatty acid binding protein (h-FABP), high-sensitivity troponin (hs-cTn) and electrocardiogram (ECG) for the detection of acute myocardial infarction (AMI) on presentation to the Emergency Department. We also investigated whether this clinical decision rule improved identification of AMI over algorithms incorporating hs-cTn and ECG only. Design and methods This study included data from 789 patients from the Brisbane ADAPT cohort and 441 patients from the Christchurch TIMI RCT cohort. The primary outcome was index AMI. Sensitivity, specificity, positive predictive value and negative predictive value were used to assess the diagnostic accuracy of the algorithms. Results 1230 patients were recruited, including 112 (9.1%) with AMI. The algorithm including h-FABP and hs-cTnT had 100% sensitivity and 32.4% specificity. The algorithm utilising h-FABP and hs-cTnI had similar sensitivity (99.1%) and higher specificity (43.4%). The hs-cTnI and hs-cTnT algorithms without h-FABP both had a sensitivity of 98.2%; a result that was not significantly different from either algorithm incorporating h-FABP. Specificity was higher for the hs-cTnI algorithm (68.1%) compared to the hs-cTnT algorithm (33.0%). The specificity of the algorithm incorporating hs-cTnI alone was also significantly higher than both of the algorithms incorporating h-FABP ( p Conclusion For patients presenting to the Emergency Department with chest pain, an algorithm incorporating h-FABP, hs-cTn and ECG has high accuracy and can rule out up to 40% of patients. An algorithm incorporating only hs-cTn and ECG has similar sensitivity and may rule out a higher proportion of patients. Each of the algorithms can be used to safely identify patients as low risk for AMI on presentation to the Emergency Department.

Background It is unclear if cardiac troponin values are stable in patients prior to undergoing non-cardiac surgery, or if they tend to rise towards the day of surgery. Methods In this small pilot study (n = 18) among patients with cardiac risk undergoing non-cardiac surgery, we determined if high-sensitivity cardiac troponin I (hscTnI) changes between the preoperative clinic visit and the day of surgery. HscTnI was measured on an Abbott Architect STAT (Abbott Laboratories, USA) platform. Results The mean duration between preoperative clinic visit and day of surgery was 8.7 ± 2.8 (SD) days. Median hscTnI was 3.4 ng/L [2.0–4.8, IQR] at the preoperative visit and 2.8 ng/L [2.3–4.4] on the day of surgery (mean difference − 0.24 ng/L, 95% CI - 0.73 to 0.24 ng/L, p = 0.30). Only one patient had a large change (> 50%) along with symptoms. Discussion Evidence from this small study suggests that cardiac troponin values are stable in most high-risk patients, absent clinical events, within 10 days prior to non-cardiac surgery.

Using objective laboratory and clinical criteria to more accurately determine the 99th percentile values for cardiac troponin I and T.We measured cardiac troponin T and cardiac troponin I with high-sensitivity assays in a large cohort of apparently healthy community subjects and calculated 99th percentiles for different sexes and ages. Subjects with possible subclinical disease were eliminated based on objective laboratory criteria, eGFR and NT-proBNP, and clinical criteria, history and examination and echocardiogram.For men and women of all ages, separately, more than 50% of subjects were excluded using these criteria, with a lesser proportion of younger subjects being excluded. In men aged75 years, the 99th percentile for cTnI decreased by more than 50% from 22.9 ng/L to 10.3 ng/L. In other age groups and for cTnT the decrease was smaller (%) but still considerable.For establishing cardiac troponin 99th percentiles, simply using self-reporting of health is insufficient. Objective laboratory measures and clinical and echocardiographic assessments are essential to define a healthy population, especially in older persons.

Objective Chronic Chagas disease afflicts millions of patients in Latin America of which 70% remain asymptomatic but 30% develop fatal heart injury. To evaluate the impact of laboratory medicine for diagnosis and guiding of patients with Chagas' heart disease, we measured N-terminal B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT). Design and methods NT-proBNP and cTnT using the highly sensitive assay (hs-cTnT) were measured in 48 asymptomatic Chagas' patients (control group; (−) CM), and in symptomatic patients who suffered from mild/moderate (group (+/++) CM, n = 62) or severe cardiomyopathy (group (+++) CM, n = 27). Results Both markers were higher in (+/++) CM and (+++) CM vs. (−) CM and increased in the cardiomyopathy severity. Values of 3 ng/L cTnT and 160 ng/L NT-proBNP were calculated as optimal cut-offs to distinguish (−) CM vs. CM. The NT-proBNP cut-off of 125 ng/L, as recommended by international guidelines, was additionally incorporated in the analysis. Cardiomyopathy was most successfully predicted by dual positivity of both markers (positive predictive value = 1.0). Negativity of both markers effectively excluded cardiomyopathy (negative predictive value of 0.85). Positivity for at least one of the markers is the best for overall correct classification. Conclusions Combined measurement of hs-cTnT and NT-proBNP can be used for diagnosis and monitoring of cardiomyopathy in chronic Chagas' patients. In this way, laboratory medicine increases the pre-test probability of the cardiologic diagnostics, which would reduce its time, cost, and logistical problems.

Objectives: Parathyroid hormone (PTH) is a major systemic calcium-regulating hormone. Recent evidence has suggested that measurement of PTH might provide complementary information for the diagnosis and risk stratification of patients with heart failure (HF). The aim of our study was to compare intact and bioactive PTH assays in patients with severe heart failure. Design and methods: The following measurements were carried out in blood samples from 73 patients with severe heart failure: bioactive PTH (1-84) assay, intact PTH assay, non-PTH (1-84), 25-hydroxyvitamin D, B-type natriuretic peptide (BNP), N-terminal proBNP (Nt-proBNP), Galectin-3 and high sensitive troponin T (hsTnT). Results: The correlation between intact and bioactive PTH assays was very high in HF patients. However, the bioactive PTH concentrations were lower than those measured with the intact assay. Intact and bioactive PTH as well as non-PTH (1-84) was significantly and positively correlated to BNP, Nt-proBNP, and galectin-3 but not to hsTnT. The strongest relationships with these cardiac biomarkers and with cardiovascular death were observed with the bioactive PTH assay. Conclusions: The PTH concentrations obtained with intact and bioactive assays are not comparable in patients with severe HF. The specificity of PTH assays might therefore impact on the potential diagnosis and prognosis values of PTH testing in patients with heart failur

Previous work on high-sensitivity troponin I (hs-cTnI) has demonstrated that it may identify patients with stable cardiovascular disease (CVD) at risk for future myocardial infarction (MI). In this study, we assessed if hs-cTnT concentrations could also identify those stable CVD patients at high risk for future MI and other ischemic cardiac outcomes.hs-cTnT (lot:153-401) was measured in specimens obtained at randomisation in the Heart Outcomes Prevention Evaluation (HOPE) study (n=2941 stable CVD patients, 4.5 years follow-up). The primary outcome for the HOPE study (MI, stroke, or cardiovascular death) was used to identify cutoffs by receiver operating characteristic (ROC) curve analysis and was used in conjunction with the 95th and 99th percentile upper limits to construct different concentration ranges, which were assessed using log-rank tests and multivariable Cox proportional hazard models. These different concentration ranges were then assessed for the components of the primary outcome and for heart failure (HF).The ROC derived hs-cTnT cutoff was 8 ng/L for the primary outcome. Subjects with hs-cTnT either below (8 to14 ng/L) or slightly above the published 99th from a healthy population (14 to 21 ng/L) had similar probability for the primary outcome. Those with hs-cTnT concentrations31 ng/L had the highest probability and greatest risk for future MI, HF, and cardiovascular death as compared to those with hs-cTnT concentrations8 ng/L.In patients with stable CVD disease hs-cTnT measurement identifies those at risk for MI as well as HF and cardiovascular death.

Background Anemia is common in patients with chronic heart failure (CHF) and is associated with a worse prognosis. This study aims to identify the biological mechanisms which reflect evolutionary changes in the hemoglobin concentrations in heart failure patients who are still not anaemic. Methods Fifty-nine patients (54 ± 14 years, 83% males) with CHF (LVEF 28 ± 10%), who did not have anemia, and had not received any previous transfusions, were included. The parameters studied were: iron metabolism (ferritin, iron, transferrin, soluble transferrin receptor (sTfR), hepcidin); inflammation (C-reactive protein, soluble TNFα receptor I (sTNFRI), interleukin 6); and myocardial stress (NT-proBNP, high sensitivity TnT, growth differentiation factor 15). All parameters were measured on inclusion and 1 year after inclusion. Results Baseline hemoglobin (g/dL) was 14.7 ± 1.5 and at 1 year of follow-up it showed a significant decrease of − 0.4 (RIC: − 0.7 to − 0.06) ( p = 0.02). At baseline, only the sTNFRI was a predictor of a decrease in hemoglobin 1 year later ( p = 0.007). During follow-up, the increase in sTNFRI ( p = 0.002, r = − 0.39) and hepcidin ( p = 0.006, r = − 0.35) were both associated with a decrease in hemoglobin. Similarly, the patients who became anemic (13%) had higher levels of hepcidin ( p = 0.001) and sTNFRI ( p = 0.008). The remaining parameters did not show any relationship with the evolution in the hemoglobin. Conclusions In CHF patients without anemia, the increase in the inflammatory state (sTNFRI) and the following deterioration in the iron metabolism (hepcidin) were the main determinants of a decrease in hemoglobin and the appearance of anemia in the long term follow-up period.