Gus Koerbin

Cardiac troponin may be released by ischemia alone, without necrosis.

Whilst it is formally stated that cardiac troponin is only released when cardiac myocytes undergo necrosis, there are a number of clinical situations where troponin is present in the circulation, without any apparent cardiac injury. In these cases, troponin half-life in the circulation is usually substantially shorter than that seen when troponin is released following myocardial infarction with frank necrosis. A mechanism has been described in liver, where large cytoplasmic molecules can pass from the intra- to extra-cellular space without cellular necrosis occurring. This occurs by the formation of membranous blebs which bud off from the plasma membrane of the cell. Blebs develop during cellular ischemia. If the ischemia is limited and re-oxygenation occurs, the blebs may be released into the circulation without rupture of the plasma membrane, resulting in a one-off release of cytoplasmic contents including macromolecules. Evidence from cardiac studies is presented supporting the presence of membranous blebs in cardiac myocytes, enabling troponin to be released from cardiac cells due to ischemia alone, without necrosis.

Characterisation of a highly sensitive troponin I assay and its application to a cardio-healthy population.

Abstract Background: Abbott Diagnostics have developed a new highly sensitive troponin I (hs-TnI) assay. We have assessed its analytical characteristics and applied the assay to a population of apparently cardio-healthy persons. Methods: We assessed imprecision, bias compared to the previous generation assay, matrix effects, and interferences and applied the assay to an apparently healthy population, deriving the 99th percentile limit of the distribution of values in reference populations for men and women separately. Results: The dynamic range of the assay was ranged from 0.5–50,000 ng/L (pg/mL). The 10% CV was at a concentration of 3.9 ng/L, and the 20% CV was at a concentration of 1.8 ng/L. The new and current version of the TnI assay were highly correlated [slope: 0.98 (95%CI:0.88–1.07), y-intercept:1.20 (95%CI:-2.35–4.75) r2=0.99]. The 99th percentile limit of the distribution of values in a reference population was different for males and females: for males 14.0 ng/L and for females 11.1 ng/L and at these concentrations the assay CV was 5.0%. TnI was detectable in nearly all patient samples from the healthy reference population (98.6%). Conclusions: This new hs-TnI assay is able to measure to an order of magnitude lower than the current generation TnI assay from the same manufacturer. With TnI being detectable in nearly all apparently healthy subject samples this suggests that TnI presence does not always indicate cardiomyocyte necrosis.

Effect of population selection on 99th percentile values for a high sensitivity cardiac troponin I and T assays.

OBJECTIVE Using objective laboratory and clinical criteria to more accurately determine the 99th percentile values for cardiac troponin I and T. DESIGN AND METHODS 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. RESULTS 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 aged <75 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. CONCLUSIONS 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.

Over time, high-sensitivity TnT replaces NT-proBNP as the most powerful predictor of death in patients with dialysis-dependent chronic renal failure

BACKGROUND Cardiac biomarkers are emerging as a potentially powerful prognostic tool for renal-dialysis patients. The optimal biomarker and/or combination of biomarkers for predicting mortality remain uncertain. This study evaluates the prognostic value of the new high-sensitivity troponin T (TnT) assay compared to established biomarkers. METHODS All patients had blood sampled for prospective assessment of the prognostic value of traditional risk markers including albumin and CRP, and cardiac biomarkers BNP, NT-proBNP, TnT and TnI. Patients were closely monitored clinically. Mortality and morbidity outcomes were documented for a national morbidity and mortality database. Stored samples were subsequently used to measure TnT with a new high-sensitivity assay. RESULTS After a median of 30 months from blood collection, NT-proBNP was the most powerful predictor of all-cause mortality, along with albumin. After a median of 46.7 months the new high-sensitive TnT assay was the only cardiac biomarker predictive of all-cause mortality. TnT was detectable in all dialysis patients using the high-sensitive TnT assay with a cut-point of 24.15 ng/L below which all patients survived. CONCLUSIONS The new hs-TnT is the most powerful biomarker for prognostic classification for all-cause mortality of all the commonly used biomarkers for our renal-dialysis population. Our study also suggests that cardiac biomarkers have a different prognostic ability for different time frames with NT-proBNP being a better predictor for early mortality and troponin for later mortality.

Prognostic efficacy of cardiac biomarkers for mortality in dialysis patients

Background: The high prevalence of cardiovascular mortality in the end‐stage renal disease population is well established. The aim of this current study was to document the relative prognostic significance of established cardiac biomarkers troponin T (TnT), troponin I (TnI), B‐type natriuretic peptide (BNP) and N‐terminal pro‐BNP (NT‐pro‐BNP) in this population.

Newer cardiac troponin I assays have similar performance to troponin T in patients with end-stage renal disease

Background: Troponin T is present in the blood of a majority of patients with endstage renal disease (ESRD) undergoing regular dialysis and presence of troponin T is a predictor of adverse outcome in these patients. With several new formulations of troponin I assays available, this study was performed to see whether these newer assays were able to detect troponin I in these patients more effectively than the older assays. Methods: One hundred and forty-three patients undergoing regular haemodialysis or peritoneal dialysis had plasma collected and troponin T and troponin I measured by a variety of assays. Results: The newer troponin I assays (Abbott Architect, Bayer Centaur and Beckman Accu-TnI) were able to detect troponin I (>75% of samples) as effectively as the Roche assay was able to detect troponin T, while other troponin I assays had a much lower rate of detection of troponin - DPC Immulite 2000 16% and Abbott AxSYM 35%. However, the troponin T assay had more samples detected at concentrations corresponding to an assay CV of 10% (59% of samples) than did the newer troponin I assays (highest on the Bayer Centaur at 37%). Conclusions: Newer assays demonstrate that troponin I is present in a similar number of samples as is troponin T, in the blood of patients with dialysis-dependent renal failure, and these newer troponin I assays identify patients at risk of experiencing a cardiac event.

Longitudinal Studies of Cardiac Troponin I in a Large Cohort of Healthy Children

BACKGROUND There is little information available on cardiac troponin concentrations in healthy young children. METHODS Using a precommercial high-sensitivity assay from Abbott Diagnostics, we measured cardiac troponin I (cTnI) in longitudinal blood samples collected at ages 8, 10, and 12 years from a cohort of healthy, community-dwelling children. The 99th percentile values were calculated and estimates of the long-term biological variation were made. RESULTS cTnI concentrations were above the limit of detection in 87%, 90%, and 98% of the children at ages 8, 10, and 12 years. The 99th percentiles were lower compared to a healthy adult population in both male and female children at all ages studied. At the 3 periods of study assessment, different children had cTnI concentrations above the 99th percentile. The calculated 99th percentile varied markedly depending upon whether the lowest or highest cTnI measurement for an individual child was included in the calculation. Biological variation varied markedly between 0% and 136%, the index of individuality was low at 0.36, and the reference change value was an increase of 147% or a decrease of 59%. CONCLUSIONS In this longitudinal study of cTnI concentrations in healthy children as determined by a high-sensitivity assay, different children had concentrations of cTnI above the 99th percentile at the 3 episodes of assessment. These results suggest that in children the 99th percentile may not be a reliable index of silent cardiac disease, but rather may be indicating low-grade intercurrent illness.

Use of Observed Within-Person Variation of Cardiac Troponin in Emergency Department Patients for Determination of Biological Variation and Percentage and Absolute Reference Change Values

BACKGROUND Many patients presenting to the emergency department (ED) for assessment of possible acute coronary syndrome (ACS) have low cardiac troponin concentrations that change very little on repeat blood draw. It is unclear if a lack of change in cardiac troponin concentration can be used to identify acutely presenting patients at low risk of ACS. METHODS We used the hs-cTnI assay from Abbott Diagnostics, which can detect cTnI in the blood of nearly all people. We identified a population of ED patients being assessed for ACS with repeat cTnI measurement who ultimately were proven to have no acute cardiac disease at the time of presentation. We used data from the repeat sampling to calculate total within-person CV (CV(T)) and, knowing the assay analytical CV (CV(A)), we could calculate within-person biological variation (CV(i)), reference change values (RCVs), and absolute RCV delta cTnI concentrations. RESULTS We had data sets on 283 patients. Men and women had similar CV(i) values of approximately 14%, which was similar at all concentrations <40 ng/L. The biological variation was not dependent on the time interval between sample collections (t = 1.5-17 h). The absolute delta critical reference change value was similar no matter what the initial cTnI concentration was. More than 90% of subjects had a critical reference change value <5 ng/L, and 97% had values of <10 ng/L. CONCLUSIONS With this hs-cTnI assay, delta cTnI seems to be a useful tool for rapidly identifying ED patients at low risk for possible ACS.

Evidence-based approach to harmonised reference intervals.

Although we are in the era of evidence-based medicine, there is still a substantial gap between theory and current practice with the application of reference intervals as decision making tools. Different laboratories may have different reference intervals for the same tests using the same analytical methods and platforms. These differences have the potential to confuse physicians making the assessment and monitoring of patients more difficult by providing discordant information. This paper attempts to demonstrate how to use evidence-based approach for harmonising reference intervals. In order to consider harmonisation we must first have an appreciation of the various factors that influence the determination of that reference interval such as the choice of individuals within the population studied, biological variability of the analyte studied, partitioning, sample collection, analytical aspects such as bias and statistical models. An a priori approach for determining reference intervals, whilst recommended, may be beyond the scope of most laboratories and consideration should be given to the use of a validated indirect a posteriori approach. Regardless of method used, the continuing application of an evidence-based approach in harmonised reference intervals to meet the quality expectations of physicians should be pursued.

Is It Time to Do Away With the 99th Percentile for Cardiac Troponin in the Diagnosis of Acute Coronary Syndrome and the Assessment of Cardiac Risk

Is It Time to Do Away With the 99th Percentile for Cardiac Troponin in the Diagnosis of Acute Coronary Syndrome and the Assessment of Cardiac Risk?