Jeroen D.E. van Suijlen

Direct comparison of clinical decision limits for cardiac troponin T and I

Objective The 99th percentile upper reference limit of high-sensitivity cardiac troponin (hs-cTn) from a healthy reference population is used for diagnosing acute myocardial infarction (AMI). Accepted current thresholds of hs-cTnT (Roche) and hs-cTnI (Abbott) are 14 and 26 ng/L, respectively. Since thresholds for hs-cTnT and hs-cTnI were derived from different reference cohorts it is unclear whether they are biologically equivalent. We directly assessed sex-specific and age-specific 99th percentile upper reference limits of hs-cTnT and hs-cTnI in a single reference cohort, to investigate whether current divergent thresholds of hs-cTnT and hs-cTnI stem from intrinsic assay differences or reflect cohort variation. Methods A healthy reference population was derived from a population-based cohort (the Maastricht Study: n=3451; age: 40–75 years). Individuals with diabetes mellitus, a history of cardiovascular disease, cardiac ischaemia on ECG, N-terminal pro-brain natriuretic peptide >125 ng/L or estimated glomerular filtration rate <60 mL/min/1.73 m2 were excluded. Non-parametric analyses were performed to assess 99th percentile upper reference limits. Results 1540 individuals were included in the healthy reference population (age 57±8 years, 52.4% women). Overall 99th percentile upper reference limits of hs-cTnT and hs-cTnI were 15 and 13 ng/L, respectively. Upper reference limits were higher in men than women (hs-cTnT: 16 vs 12 ng/L), (hs-cTnI: 20 vs 11 ng/L) and increased with age. Conclusions Direct comparison reveals numerically similar thresholds for hs-cTnT and hs-cTnI assays. This finding is in line with recently reported underdiagnosis of AMI with the current decision limit of 26 ng/L for hs-cTnI, especially among women. Downwards adjustment of the hs-cTnI threshold, differentiated for sex, would equalise clinical decision limits for both assays, and may prevent further underdiagnosis of AMI.

Serum cystatin C-A useful endogenous marker of renal function in intensive care unit patients at risk for or with acute renal failure?

Critically ill patients are at high risk for developing acute renal failure (ARF). The prevention of ARF is of outmost importance in order to improve the increased morbidity and mortality associated with ARF. Unfortunately, there is lack of adequate endogenous markers that can identify renal dysfunction early - this hampers timely application of measures to prevent further renal damage. The use of exogenous markers of renal function is not only time-consuming but also expensive, and therefore can not be used on a regular basis in the intensive care unit. Both the presently used endogenous and exogenous markers are not reliable during continuous renal replacement therapy (CRRT) because these markers are removed by the therapy itself impeding early detection of recovering of renal function. Cystatin C has been proposed as an alternative endogenous marker of renal function for more than 15 years. In this manuscript we review the literature on the role of cystatin C as marker for renal function, focusing on the critically ill patient. Serum cystatin C concentrations have been found to relate to renal impairment and suggest that cystatin C is more sensitive to detect mild decreases in GFR. Cystatin C could be an important tool both to recognize early renal dysfunction and to identify renal recovery while on CRRT in the critically ill patient, however, we are in need of more studies.

Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation

INTRODUCTION Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. OBJECTIVE To determine whether ventilator settings in critically ill patients without acute lung injury (ALI) at onset of mechanical ventilation affect the development of AKI. DESIGN, SETTING, AND PATIENTS Secondary analysis of a randomized controlled trial (N = 150), comparing conventional tidal volume (V(T), 10 mL/kg) with low tidal volume (V(T), 6 mL/kg) mechanical ventilation in critically ill patients without ALI at randomization. During the first 5 days of mechanical ventilation, the RIFLE class was determined daily, whereas neutrophil gelatinase-associated lipocalin and cystatin C levels were measured in plasma collected on days 0, 2, and 4. RESULTS Eighty-six patients had no AKI at inclusion, and 18 patients (21%) subsequently developed AKI, but without significant difference between ventilation strategies. (Cumulative hazard, 0.26 vs 0.23; P = .88.) The courses of neutrophil gelatinase-associated lipocalin and cystatin C plasma levels did not differ significantly between randomization groups. CONCLUSION In the present study in critically patients without ALI at onset of mechanical ventilation, lower tidal volume ventilation did not reduce the development or worsening of AKI compared with conventional tidal volume ventilation.

Recombinant Thromboplastins vs Tissue-Extract Thromboplastins in Patients on Unstable Oral Anticoagulant Therapy

To the Editor: In a previous report in Clinical Chemistry , we described much higher international normalized ratios (INRs)1 with recombinant Neoplastin R (Roche Diagnostics) than with tissue-extract Neoplastin Plus (Roche Diagnostics) in patients initiating oral anticoagulant therapy (1). For patients on stable oral anticoagulation, we observed no significant differences in INRs between the thromboplastins. The increased INR values with Neoplastin R during unstable anticoagulation, such as in the initial phase of oral anticoagulation treatment, could be explained by fluctuations in coagulation factor VII (FVII) concentrations owing to the low half-life of FVII. Recombinant thromboplastin exhibits an increased sensitivity for FVII compared with tissue-derived thromboplastin (2, 3). The difference in sensitivity between Neoplastin R and Neoplastin Plus for FVII could implicate alterations in anticoagulation dosage and time period in obtaining stable anticoagulation. We investigated whether our findings could be extrapolated to other recombinant thromboplastins. We collected and citrate-treated blood samples from 20 patients in the initial phase of …

Strongly Increased International Normalized Ratio with Recombinant Neoplastin R® Compared with Tissue Extract Neoplastin Plus® in Patients Initiating Oral Anticoagulant Therapy: Implications for Anticoagulation Dosage

High-accuracy determination of the international normalized ratio (INR)1 is of importance in controlling treatment of patients with oral anticoagulants. The INR is defined according to a calibration model adopted by the WHO (1) as the normalized prothrombin clotting time (PT/MNPT)ISI, where MNPT is mean normal prothrombin time of 20 healthy individuals. The factor ISI (international sensitivity index) compensates for the differing sensitivities of thromboplastin reagents used to measure prothrombin clotting time. Thromboplastin reagents can vary widely in their sensitivities to clotting factor deficits (induced by coumarin treatment), resulting in INR differences(2). Recombinant thromboplastins have been discussed as being more sensitive to variation in coagulation factor VII (FVII) than tissue extract thromboplastins(2)(3)(4). FVII has a relatively short plasma half-life of 6 h compared to the half-lives of factor X (45 h) and prothrombin (60 h). The increased sensitivity for FVII may be observed during unstable anticoagulation, such as in the initial phase of oral anticoagulant therapy, and may lead to differences in observed INRs that have implications for subsequent oral anticoagulant dosing advice. To …

Clinical Interpretation of Elevated Concentrations of Cardiac Troponin T, but Not Troponin I, in Nursing Home Residents.

OBJECTIVE Cardiac troponins T (cTnT) and I (cTnI) are the preferred biomarkers to detect myocardial damage. The present study explores the value of measuring cardiac troponins (cTn) in nursing home residents, by investigating its relation to heart failure and 1-year mortality using 1 cTnT and 2 cTnI assays that are widely used in clinical practice. DESIGN All participants underwent extensive clinical examinations and echocardiographic assessment for the diagnosis of heart failure. cTn was measured using high-sensitive (hs)- cTnT (Roche), hs-cTnI (Abbott), and sensitive cTnI (Beckman) assays. The glomerular filtration rate was estimated (eGFR) using serum creatinine and cystatin C concentrations. Data on all-cause mortality were collected at 1-year follow-up. PARTICIPANTS AND SETTING Participants were 495 long-term nursing home residents, older than 65 years, of 5 Dutch nursing home organizations. RESULTS Median (IQR) concentrations were 20.6 (17.8-30.6), 6.8 (4.1-12.5), and 4.0 (2.0-8.0) ng/L for hs-cTnT, hs-cTnI, and cTnI, respectively. In total, 79% had elevated hs-cTnT concentrations, whereas only 9% and 5% of hs-cTnI and cTnI concentrations were elevated. Most important and independent determinants for higher hs-cTnT and hs-cTnI concentrations were heart failure and renal dysfunction. Whereas both heart failure (odds ratio [OR] 3.4) and eGFR lower than 60 mL/min/1.73 m(2) (OR 3.6) were equal contributors to higher hs-cTnT concentrations (all P < .001), hs-cTnI and cTnI were less associated with renal dysfunction (OR of, respectively, 1.9 and 2.1; P < .01) in comparison with heart failure (OR 4.3 and 4.7, respectively, P < .001). Furthermore, residents with higher hs-cTnT or hs-cTnI concentrations (fourth quartile) had respectively 4 versus 2 times more risk of 1-year mortality compared with lower concentrations. CONCLUSION Regardless of their cardiac health, hs-cTnT but not hs-cTnI concentrations were elevated in almost all aged nursing home residents, questioning the use of the current diagnostic cutoff in elderly with high comorbidity. Nonetheless, measuring cardiac troponins, especially hs-cTnT, had a promising role in assessing future risk of mortality.

Estimated Glomerular Filtration Rate and Albuminuria Are Associated with Biomarkers of Cardiac Injury in a Population-Based Cohort Study: The Maastricht Study

BACKGROUND Chronic kidney disease (CKD) is associated with an increased cardiovascular disease mortality risk. It is, however, less clear at what point in the course from normal kidney function to CKD the association with cardiovascular disease appears. Studying the associations of estimated glomerular filtration rate (eGFR) and albuminuria with biomarkers of (subclinical) cardiac injury in a population without substantial CKD may clarify this issue. METHODS We examined the cross-sectional associations of eGFR and urinary albumin excretion (UAE) with high-sensitivity cardiac troponin (hs-cTn) T, hs-cTnI, and N-terminal probrain natriuretic-peptide (NT-proBNP) in 3103 individuals from a population-based diabetes-enriched cohort study. RESULTS After adjustment for potential confounders, eGFR and UAE were associated with these biomarkers of cardiac injury, even at levels that do not fulfill the CKD criteria. For example, eGFR 60-<90 mL · min-1 ·(1.73 m2)-1 [vs ≥90 mL · min-1 · (1.73 m2)-1] was associated with a [ratio (95% CI)] 1.21 (1.17-1.26), 1.14 (1.07-1.20), and 1.19 (1.12-1.27) times higher hs-cTnT, hs-cTnI, and NT-proBNP, respectively. The association of eGFR with hs-cTnT was statistically significantly stronger than that with hs-cTnI. In addition, UAE 15-<30 mg/24 h (vs <15 mg/24 h) was associated with a 1.04 (0.98-1.10), 1.08 (1.00-1.18), and 1.07 (0.96-1.18) times higher hs-cTnT, hs-cTnI, and NT-proBNP, respectively. CONCLUSIONS eGFR and albuminuria were already associated with biomarkers of (subclinical) cardiac injury at levels that do not fulfill the CKD criteria. Although reduced renal elimination may partly underlie the associations of eGFR, these findings support the concept that eGFR and albuminuria are, over their entire range, associated with cardiac injury.

The effect of exercise training on the course of cardiac troponin T and I levels: three independent training studies.

With the introduction of high-sensitive assays, cardiac troponins became potential biomarkers for risk stratification and prognostic medicine. Observational studies have reported an inverse association between physical activity and basal cardiac troponin levels. However, causality has never been demonstrated. This study investigated whether basal cardiac troponin concentrations are receptive to lifestyle interventions such as exercise training. Basal high-sensitive cardiac troponin T (cTnT ) and I (cTnI) were monitored in two resistance-type exercise training programs (12-week (study 1) and 24-week (study 2)) in older adults (≥65 years). In addition, a retrospective analysis for high sensitive troponin I in a 24-week exercise controlled trial in (pre)frail older adults was performed (study 3). In total, 91 subjects were included in the final data analyses. There were no significant changes in cardiac troponin levels over time in study 1 and 2 (study 1: cTnT −0.13 (−0.33–+0.08) ng/L/12-weeks, cTnI −0.10 (−0.33–+0.12) ng/L/12-weeks; study 2: cTnT −1.99 (−4.79–+0.81) ng/L/24-weeks, cTnI −1.59 (−5.70–+2.51) ng/L/24-weeks). Neither was there a significant interaction between training and the course of cardiac troponin in study 3 (p = 0.27). In conclusion, this study provides no evidence that prolonged resistance-type exercise training can modulate basal cardiac troponin levels.

Troponin I and T in relation to cardiac injury detected with electrocardiography in a population-based cohort - The Maastricht Study

Interest in high-sensitivity cardiac troponin I(hs-cTnI) and T(hs-cTnT) has expanded from acute cardiac care to cardiovascular disease(CVD) risk stratification. Whether hs-cTnI and hs-cTnT are interchangeable in the ambulant setting is largely unexplored. Cardiac injury is a mechanism that may underlie the associations between troponin levels and mortality in the general population. In the population-based Maastricht Study, we assessed the correlation and concordance between hs-cTnI and hs-cTnT. Multiple regression analyses were conducted to assess the association of hs-cTnI and hs-cTnT with electrocardiographic (ECG) changes indicative of cardiac abnormalities. In 3016 eligible individuals(mean age,60 ± 8years;50.6%,men) we found a modest correlation between hs-cTnI and hs-cTnT(r = 0.585). After multiple adjustment, the association with ECG changes indicative of cardiac abnormalities was similar for both hs-cTn assays(OR,hs-cTnI:1.72,95%CI:1.40-2.10;OR,hs-cTnT:1.60,95%CI:1.22–2.11). The concordance of dichotomized hs-cTnI and hs-cTnT was κ = 0.397(≥sex-specific 75th percentile). Isolated high levels of hs-cTnI were associated with ECG changes indicative of cardiac abnormalities(OR:1.93,95%CI:1.01–3.68), whereas isolated high levels of hs-cTnT were not(OR:1.07,95%CI:0.49–2.31). In conclusion, there is a moderate correlation and limited concordance between hs-cTnI and hs-cTnT under non-acute conditions. These data suggest that associations of hs-cTnI and hs-cTnT with cardiac injury detected by ECG are driven by different mechanisms. This information may benefit future development of CVD risk stratification algorithms.

Twenty-Four-Hour Biological Variation Profiles of Cardiac Troponin I in Individuals with or without Chronic Kidney Disease

To the Editor: The interpretation of cardiac troponin concentrations at presentation and their dynamics over time is a key aspect in the diagnostic workup of acute myocardial infarction in the absence of characteristic electrocardiogram abnormalities. The present biological variation study sought to examine and compare the hour-to-hour biological variation in cardiac troponin I (cTnI) over 24 h in individuals with and without chronic kidney disease (CKD).1 This study was carried out according to the principles of the Declaration of Helsinki and approved by the Institutional Review Board and Ethics Committee of Maastricht University Medical Center (clinicaltrials.gov: NCT02091427 and NCT02210897). All participants provided written informed consent. From 8:30 AM until 9:30 AM the next day, 20 individuals with clinically stable CKD stage 3 or higher (estimated glomerular filtration rate (eGFR) <59 mL · min−1 · 1.73 m−2) and 20 individuals without CKD were restricted to the laboratory environment. All individuals were of Caucasian ethnicity. Every hour during 24 h, …