Sensitive cTn Research Articles

Why all the struggle about CK-MB and PCI?

Cardiovascular medicine has, in general, enthusiastically embraced new technologies and used them per appropriate guidelines. However, one area in which this has not been as much the case has been with cardiac troponin (cTn). There has been reluctance to use cTn at the suggested 99th percentile of the upper reference range (URL).1 Part of this reluctance reflects a lack of comfort with the large number of increases seen with such a sensitive probe that challenge clinicians.2 However, the reluctance to utilize cTn properly has distorted the utility of cTn in many areas,1,2 but perhaps it has caused the greatest confusion in the area of post-PCI biomarker increases as attested to by recent articles.3–5 In this area, the reluctance to give up the paradigms of the past and to use cTn per guidelines has led to confusion and inaccurate conclusions in articles published even in our most prestigious journals. This editorial from a group of researchers knowledgeable in this area attempts to articulate some of the difficulties with the interpretations thus far posed and suggest how proper use of cTn can achieve a better understanding in this important area. It does not and cannot answer all of the questions going forward but progress is only possible if we understand and properly interpret the data that presently exist. A recent article in this area published in JACC3 is an excellent example of the problems in this area. It was followed by an editorial that misconstrues most of the important concepts.4 The article utilized MR imaging post-PCI to visualize areas of cardiac injury putatively related to the procedure. Because they used a good and sensitive cTn assay and the recommended cut-off values, they found that more increases in CK-MB were associated findings of …

Early diagnosis of acute myocardial infarction in patients with pre-existing coronary artery disease using more sensitive cardiac troponin assays

We sought to examine the diagnostic and prognostic utility of sensitive cardiac troponin (cTn) assays in patients with pre-existing coronary artery disease (CAD). We conducted a multicentre study to examine the diagnostic accuracy of one high-sensitive and two sensitive cTn assays in 1098 consecutive patients presenting with symptoms suggestive of acute myocardial infarction (AMI), of whom 401 (37%) had pre-existing CAD. Measurements of Roche high-sensitive cTnT (hs-cTnT), Siemens cTnI-Ultra, Abbott-Architect cTnI and the standard assay (Roche cTnT) were performed in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. Acute myocardial infarction was the final diagnosis in 19% of CAD patients. Among patients with diagnoses other than AMI, baseline cTn levels were elevated above the 99th percentile with Roche hs-cTnT in 40%, with Siemens TnI-Ultra in 15%, and Abbott-Architect cTnI in 13% of them. In patients with pre-existing CAD, the diagnostic accuracy at presentation, quantified by the area under the receiver operator characteristic curve (AUC), was significantly greater for the sensitive cTn assays compared with the standard assay (AUC for Roche hs-cTnT, 0.92; Siemens cTnI-Ultra, 0.94; and Abbott-Architect cTnI, 0.93 vs. AUC for the standard assay, 0.87; P < 0.01 for all comparisons). Elevated levels of cTn measured with the sensitive assays predicted mortality irrespective of pre-existing CAD, age, sex, and cardiovascular risk factors. Sensitive cTn assays have high-diagnostic accuracy also in CAD patients. Mild elevations are common in non-AMI patients and test-specific optimal cut-off levels tend to be higher in CAD patients than in patients without history of CAD. Sensitive cTn assays also retain prognostic value. (ClinicalTrials.gov number, NCT00470587).

Early diagnosis of acute myocardial infarction in the elderly using more sensitive cardiac troponin assays

To examine the diagnostic accuracy of sensitive cardiac troponin (cTn) assays in elderly patients, since elevated levels with sensitive cTn assays were reported in 20% of elderly patients without acute myocardial infarction (AMI). In this multi-centre study, we included 1098 consecutive patients presenting with symptoms suggestive of AMI, 406 (37%) were >70 years old. Measurement of three investigational sensitive cTn assays [Roche high-sensitive cTnT (hs-cTnT), Siemens cTnI-Ultra, and Abbott-Architect cTnI) and the standard assay (Roche cTnT) was performed in a blinded fashion. The final diagnosis was adjudicated by two independent cardiologists. Acute myocardial infarction was the adjudicated final diagnosis in 24% of elderly patients. Among elderly patients without AMI, baseline cTn levels were elevated above the 99th percentile in 51% with Roche hs-cTnT, in 17% with Siemens TnI-Ultra, and 13% with Abbott-Architect cTnI. The diagnostic accuracy as quantified by the area under the receiver operating characteristic (ROC) curve (AUC) was significantly greater for the sensitive cTn assays compared with the standard assay (AUC for Roche hs-cTnT, 0.94; Siemens cTnI-Ultra, 0.95; and Abbott-Architect cTnI, 0.95 vs. AUC for the standard assay, 0.90; P < 0.05 for comparisons). The best cut-offs for the sensitive cTn-assays determined by the ROC-curve in elderly patients differed clearly from those in younger patients. Furthermore, the prognostic value regarding 90-day mortality varied among the sensitive cTn assays. Sensitive cTn assays have high diagnostic accuracy also in the elderly. Mild elevations are common in elderly non-AMI patients, therefore the optimal cut-off levels are substantially higher in elderly as compared with younger patients. Furthermore, sensitive cTn assays yielded different prognostic value.

High-sensitivity troponin assays in the evaluation of patients with acute chest pain in the emergency department

Evaluating patients with acute chest pain presenting to the emergency department remains an ongoing challenge. The spectrum of etiologies in acute chest pain ranges from minor disease entities to life-threatening diseases, such as pulmonary embolism, acute aortic dissection or acute myocardial infarction (MI). The diagnosis of acute MI is usually made integrating the triad of patient history and clinical presentation, readings of 12-lead ECG and measurement of cardiac troponins (cTn). Introduction of high-sensitivity cTn assays substantially increases sensitivity to identify patients with acute MI even at the time of presentation to the emergency department at the cost of specificity. However, the proportion of patients presenting with cTn positive, non-vascular cardiac chest pain triples with the implementation of new sensitive cTn assays increasing the difficulty for the emergency physician to identify those patients who are at need for invasive diagnostics. The main objectives of this mini-review are 1) to discuss elements of disposition decision made by the emergency physician for the evaluation of chest pain patients, 2) to summarize recent advances in assay technology and relate these findings into the clinical context, and 3) to discuss possible consequences for the clinical work and suggest an algorithm for the clinical evaluation of chest pain patients in the emergency department.

Diagnostic and Prognostic Information Provided by a High Sensitivity Assay for Cardiac Troponin T

Diagnostic and Prognostic Information Provided by a High Sensitivity Assay for Cardiac Troponin TCardiac troponins (cTns) are the preferred biomarkers for the diagnosis of acute myocardial infarction, assessment of risk and prognosis, and for determination of antithrombotic and revascularization strategy in patients with acute coronary syndromes. The implementation of high sensitivity cTn assays into the clinical routine has increased the number of patients diagnosed with myocardial infarction. In addition, the number of patients with elevated cTn levels that cannot be explained by acute ischemic injury was increased, which is observed in patients with chronic heart disease and other nonischemic cardiac injury or in patients with impaired renal function. The new definition of myocardial infarction provides support for the interpretation of elevated cTn measured with high sensitivity cTn assays in patients with suspected acute coronary syndrome. This review will summarize clinical studies with the recently introduced high sensitivity cTnT assay (TnT hs) with reference to recent experience with high sensitivity cTn assays in general.

Sensitive Cardiac Troponin Assays: Myth and Magic or a Practical Way Forward?

Sensitive Cardiac Troponin Assays: Myth and Magic or a Practical Way Forward?Cardiac troponins (cTn) are considered to be the ‘gold standard’ biomarkers for the diagnosis of acute coronary syndrome (ACS) a pathological spectrum which includes cardiac ischemia, angina, myocardial infarction and ultimately cardiac failure. The growing evidence base for the diagnostic and prognostic use of cTn in ACS has resulted in a universal redefinition of acute myocardial infarction (AMI). A diagnosis of AMI includes the detection of an elevated cTn (or CK-MB) with at least one measurement within 24 hours of the cardiac episode being &gt;upper 99th percentile of a reference population, in conjunction with evidence of myocardial ischemia. A number of high sensitivity immunoassays with claims of superior imprecision and a definable 99th percentile have been produced. Clinically, these have two important impacts. First, there is a drive to change the values into whole numbers by the application of a unit change which carries the scope for confusion. Secondly, the near-normal Gaussian distribution of sensitive cTn in healthy subjects will increase the frequency of cTn positivity in the non-ACS population. The problem is to decipher if such minor elevations in cTn are of clinical concern. What is certain is that AMI remains a clinical not a biochemical diagnosis and the interpretation of cTn concentrations should be made according to the clinical context.

Troponin as a Biomarker of Cardiac Toxicity

Cardiac troponin (cTn) is a sensitive and specific biomarker for assessing cardiac damage and should be utilized in drug safety assessment. Lactate dehydrogenase and creatine kinase isoenzyme analyses have historically been used in pre-clinical toxicity testing to assess cardiac injury, but since these assays are less sensitive and specific than cTn, isoenzyme analyses, as determined by the manual electrophoretic technique, are no longer warranted. Commercial cTn assays developed for humans do not have the same immunoreactivity and functional sensitivity in the common pre-clinical testing species, so it is important to show that the assay that is chosen is appropriate for the pre-clinical species being assessed. The kinetics of the cTn response depends on the dose and frequency of test article administration as well as the mechanism of the cardiac injury induced by the test article. Cardiac troponin should be used in the assessment of classes of compound that have previously been shown to induce cardiac necrosis or if cardiac necrosis is identified histologically with a novel compound. Next generation high sensitivity cTn assays are being developed and the low levels of cTn detected with these assays may be an early sign of possibly reversible damage to the heart.

Clinical Application of Sensitive Cardiac Troponin Assays: Potential and Limitations

Acute myocardial infarction (AMI) is the major cause of death worldwide. Cardiac troponins (cTns) are structural proteins, unique to the heart, that currently form the cornerstone of the AMI diagnosis. The major limitation of standard cTn assays is a sensitivity deficit at presentation caused by a delayed increase of circulating levels. Recent multicenter studies have demonstrated that novel, more sensitive and precise cTn assays improve the early diagnosis of AMI. cTn has to be interpreted as a quantitative variable. The term 'troponin positive' should, therefore, be avoided. 'Detectable' levels will become the norm and have to be clearly differentiated from 'elevated' levels. The differential diagnosis of a small amount of myocardial injury and, therefore, mild elevation of cTn is broad, and includes acute and chronic disorders. The differential diagnosis of a large amount of myocardial injury and, therefore, substantial elevation of cTn is much smaller and largely restricted to AMI, myocarditis and takotsubo cardiomyopathy. The aim of this article is to guide clinicians in the use of sensitive cTn.

Troponins and High-Sensitivity Troponins as Markers of Necrosis in CAD and Heart Failure

For years, cardiac troponins (cTn) have been regarded as the preferred biomarkers for the diagnosis of myocardial infarction and for the risk stratification of patients with acute coronary syndromes, as well as for the selection of patients who need an early invasive strategy, and for the guidance of adjunctive pharmacological therapy. In addition, measurement of cTn has been found useful for detection of myocardial necrosis in conditions unrelated to myocardial ischemia including acute pulmonary embolism, myocarditis, heart failure, sepsis, and end-stage renal disease. In these conditions, an unfavorable prognosis is unequivocally associated with detectable concentrations of cTn.A major limitation of most currently available cTn assays is the lack of adequate precision, i.e., to measure cTn concentrations at the 99th percentile value with a coefficient of variation < 10%. As a consequence, many manufacturers have developed more sensitive cTn assays that now comply with precision criteria required by the Joint European Society of Cardiology/ American College of Cardiology/American Heart Association/World Heart Federation Task Force for the Redefinition of Acute Myocardial Infarction.Using assays with higher analytic sensitivity more patients will be seen in clinical practice with the high-sensitivity cardiac troponin T (TnThs) above the 99th percentile discriminator. The causes of these elevations may be due to acute, subacute and chronic cardiac disease such as heart failure or cardiomyopathies.

PAPP-A as a marker of increased long-term risk in patients with chest pain

Objectives Long-term risk stratification in patients presenting with acute coronary syndromes (ACS) is possible by measuring cardiac troponin (cTn). The present study examined whether PAPP-A measured in an emergency department (ED) chest pain population in association with conventional and novel high sensitivity cTn (hs-cTnI) assays can predict long-term mortality. Methods In 320 patients with cTn measurements the earliest heparinized plasma PAPP-A concentration after presentation was used for risk stratification for death by Kaplan–Meier and Cox analyses. Subgroup analyses using the earliest PAPP-A concentrations were also performed in a cohort of subjects with presentation cTnI ≤ 99th percentile but with significantly changing cardiac troponin concentrations as measured by the AccuTnI assay and the hs-cTnI assay ( n = 45 and 120 subjects, respectively). Results Subjects with PAPP-A concentrations in the highest tertile were at higher risk for death (HR > 2.00; p ≤ 0.05 at 2 years) even after adjusting for cTnI at presentation. In the cohort with cTnI ≤ 99th percentile but with changing hs-cTnI concentrations, subjects in the top PAPP-A tertile had a higher probability for death ( p = 0.02). Conclusion Early measurement of PAPP-A may identify chest pain patients at higher risk for long-term death. Additional prospective ACS studies are required to fully elucidate PAPP-A's role.

Reference Population and Marathon Runner Sera Assessed by Highly Sensitive Cardiac Troponin T and Commercial Cardiac Troponin T and I Assays

Endurance exercise can increase cardiac troponin (cTn) concentrations as high as those seen in cases of minor myocardial infarction. The inability of most cTn assays to reliably quantify cTn at very low concentrations complicates a thorough data analysis, and the clinical implications of such increases remain unclear. The application of recently developed highly sensitive cTn immunoassays may help resolve these problems. We evaluated the precommercial highly sensitive cardiac troponin T (hs-cTnT) assay from Roche Diagnostics and the Architect cardiac troponin I (cTnI-Architect) assay from Abbott Diagnostics by testing samples from a reference population of 546 individuals and a cohort of 85 marathon runners. We also measured the samples with the current commercial cTnT assay for comparison. Although the hs-cTnT and cTnI-Architect assays were capable of measuring cTn concentrations at low concentrations (<0.01 microg/L), only the hs-cTnT assay demonstrated a CV of <10% at the 99th percentile of the reference population and a near-gaussian distribution of the measurements. After a marathon, 86% of the runners had cTnT concentrations greater than the 99th percentile with the hs-cTnT assay, whereas only 45% of the runners showed increased concentrations with the current cTnT assay. cTn concentrations remained significantly increased the day after the marathon. A multiple regression analysis demonstrated marathon experience and age to be significant predictors of postmarathon cTn concentrations (P < 0.05). The hs-cTnT assay was the only assay tested with a performance capability sufficient to detect cTn concentrations in healthy individuals. The number of runners with increased cTn concentrations after a marathon depends highly on an assay's limit of detection (LOD). The assay with the lowest LOD, the hs-cTnT assay, showed that almost all runners had increased cTn concentrations. The clinical implications of these findings require further investigation.

Higher sensitivity troponin assays: Quo vadis?

Central to the universal definition of myocardial infarction (MI) is the recommendation that cardiac troponin (cTn; I or T) is the biomarker of choice for detection of myocardial necrosis because of its high clinical sensitivity and almost absolute myocardial tissue specificity.1 The guidelines are based on the assays presently available for clinical use. However, predicated on data suggesting that there is additional information below the levels that are presently being measured, manufacturers have begun to develop much more sensitive cTn assays that allow measurement of concentrations in the range of pg/ml rather than ng/ml. These assays should permit accurate measurement of most if not all normal subjects with an optimal level of analytical imprecision (coefficient of variation ≤10%). Preliminary observations using levels now measurable and based on values below the present 99th percentile of the current assays suggest that more sensitive assays will result in an increased diagnosis of MI and that these patients are at substantial risk post-infarction.2 Recent data indicate that these previously undetectable levels are also associated with worse outcomes in patients with an acute coronary syndrome,2 especially if these low level elevations continue post-event,3 in those with heart failure,4 and stable angina pectoris,5 and even elderly apparently healthy population cohorts.6,7 These concentrations have also been found to be associated with cardiovascular high-risk features, higher carotid artery plaque burden, and … *Corresponding author. Tel: +45 89497614, Fax: +45 89497619, Email: Kristian.Thygesen{at}as.aaa.dk; or kthygesen{at}oncable.dk

Implementation of a highly sensitive cardiac troponin I assay: Test volumes, positivity rates and interpretation of results

Background While more sensitive cardiac troponin (cTn) assays may overcome current limitations in diagnosing acute coronary syndrome (ACS), clinicians and laboratorians are concerned about the clinical impact of higher rates of cTn positivity. Methods We collected statistics on test volume and positivity rates before and after the implementation of a more sensitive assay. We divided patients into 6 groups based on their cardiac troponin I (cTnI) results and utilized additional laboratory test results to determine the impact of the new assay. In addition, we assessed the clinical significance of low-positive cTnI results (0.05–0.10 µg/l). Results Lowering the diagnostic cutoff from 0.10 to 0.04 µg/l increased the number of positive test results by 44.2% hospital-wide and 114.4% in the emergency department without significantly changing test volume. In some patients, low-positive results were part of the typical rise and fall of cTnI consistent with myocardial damage. Diagnosis was more challenging in patients with consistently low-positive results. Patients in this group were significantly more likely to have impaired renal function than those with cTnI elevations > 0.10 µg/l. Conclusions More sensitive cTn assays will increase the number of positive results and allow for earlier detection of cardiac injury while also detecting non-ACS related pathologies.

Troponin revisited 2008: assay performance

Troponin quality specifications describing the pre-analytical, analytical and post-analytical performance of cardiac troponin (cTn) assays are important for both manufacturers of cTn assays and laboratories that routinely test for cTn. Pre-analytical requirements refer not only to acceptable sample type for analysis and the stability of cTn but also to the proper handling of specimens prior to analysis to avoid pre-analytical false positive results. Analytical issues that may contribute to differences between cTn assays include analytical sensitivity and imprecision at low cTn concentration, antibody specificity and immunoreactivity of plasma cTn forms, assay specificity and the presence of falsely positive and negative interferences, and for cTnI the lack of standardised measurement, all which may impact on patient cTn results. Current second generation cTnI and fourth generation cTnT assays generally have an imprecision of around 20% coefficient of variation (CV) at the 99th percentile of the reference population, which is greater than the recommended imprecision of 10% CV. As the next generation of more analytically sensitive cTn assays are developed it can be anticipated that cTn upper reference limits will decrease by approximately 10-fold. Monitoring assay imprecision at ultra low cTn concentrations will require that the laboratory uses a quality control close to this level and a negative control to monitor baseline drift. Establishment of cTn reference ranges will require reference populations to be cardio-healthy to enable differentiation from community populations who are at increased cardiovascular risk. Close collaboration between the laboratory and local clinicians is required to ensure adequate clinical validation of more sensitive cTn assays.