Use and misuse of cardiac troponins in clinical practice

Cardiac troponins are very sensitive and specific markers of myocardial injury. Elevated troponin levels in the setting of acute coronary syndrome are diagnostic of acute myocardial infarction and provide guidance to clinicians with regard to appropriate use of intensive medical and revascularization therapies. However, elevated troponin levels are commonly seen in several noncoronary ischemia presentations and create considerable confusion among clinicians in these settings. In this review article, we discuss the utility of troponins in various clinical settings and present a "common sense" approach to interpreting troponin elevation outside the setting of acute coronary syndrome.     

Novel biomarkers in cardiovascular disease: update 2010

The rapid evaluation of patients presenting with symptoms suggestive of an acute coronary syndrome is of great clinical relevance. Biomarkers have become increasingly important in this setting to supplement electrocardiographic findings and patient history because one or both can be misleading. Today, cardiac troponin is still the only marker used routinely in this setting due to its myocardial tissue specificity and sensitivity, as well as its established usefulness for therapeutic decision making. However, even current generation troponin assays have certain limitations such as insufficient sensitivity for diagnosing unstable angina. Novel high-sensitivity assays for cardiac troponin have the potential to overcome these limitations. Further studies are needed to answer some critical questions regarding the best cutoffs for diagnosis and risk assessment and the optimal work-up for rule-out of acute myocardial infarction. Other nonmyocardial tissue-specific markers might help in this setting. Myeloperoxidase, copeptin, and growth differentiation factor 15 reflect different aspects of the development of atherosclerosis or acute ischemia. Each has demonstrated impact in risk stratification of acute coronary syndromes. Limited data also show that copeptin may, when used together with cardiac troponin, improve the sensitivity for diagnosing acute myocardial infarction, and growth differentiation factor 15 may help in selection of patients that benefit from invasive therapy. Further evaluation is needed before these markers can be adopted routinely in clinical practice.     

超敏肌钙蛋白在急性冠状动脉综合征中的临床应用

急性心肌梗死的早期诊断和及时进行再灌注治疗为降低死亡率的关键,故对因急性胸痛就诊的患者进行快速、正确的评估以及危险分层尤为重要;而评估心肌坏死的特异性生化标记物为急性心肌梗死诊断、监测病程与评价预后的主要指标之一。近期发展的超敏肌钙蛋白(hsTn)的检测技术可更精确地测定肌钙蛋白(cTn)的浓度并可检测99%健康人群以上的异常值,其不仅可提高急性心肌梗死的诊断率,亦可进一步进行危险分层,可用于急性冠状动脉综合征患者的长期风险评估。     

Troponins in acute coronary syndromes

Delivering superior clinical specificity and sensitivity for myocardial necrosis, cardiac troponin has replaced creatine kinase-MB as the preferred biomarker for establishing the diagnosis of myocardial infarction. On the basis of expert recommendations, present convention sets the diagnostic decision-limit for each assay at the 99th percentile of troponin levels in an apparently healthy reference population. Owing to a lack of standardization between different assays, this level, corresponding to the 99th percentile, will vary depending upon the manufacturer. Among patients presenting with an acute coronary syndrome (ACS), even low-level elevations of cardiac troponin T or I are associated with higher risk of death and recurrent ischemic events compared with patients with a troponin level below the appropriate decision limit. Renal failure does not appear to diminish the prognostic value of troponins among patients with a high clinical probability of ACS. In addition, patients with elevated levels of troponin appear to gain the most benefit from more aggressive medical therapy with antithrombin and antiplatelet medications as well as an early invasive management strategy. Cardiac troponins offer extremely high tissue specificity but do not discriminate between ischemic and nonischemic mechanisms of myocardial injury; thus, presently the clinician must assess whether a patient's presenting symptoms are consistent with ACS. It is possible that future generations of troponin assays will detect specific post-translational modifications of troponins that may increase the analytic sensitivity for myocardial damage and offer insight into the timing and mechanism of myocardial injury.     

Troponins in acute coronary syndromes

Cardiac troponins have replaced creatine kinase-MB as the preferred biomarker for establishing the diagnosis of myocardial infarction (MI). Expert recommendations set the diagnostic decision-limit for each assay at the 99th percentile of troponin levels in an apparently healthy reference population, which due to a lack of standardization, will vary depending upon the manufacturer. Among patients presenting with an acute coronary syndrome (ACS), even low-level elevations of cardiac troponin T or I correlate with higher risk of death and recurrent ischemic events compared to patients with levels of troponin below the decision limit. Renal failure does not appear to diminish the prognostic value of troponins among patients with a high clinical probability of ACS. Moreover, patients with elevated levels of troponin derive the most benefit from more intense medical therapy with antithrombin and antiplatelet medications, as well as an early invasive management strategy. Whereas cardiac troponins are extremely specific for myocardial necrosis, they do not discriminate between ischemic and non-ischemic etiologies of myocardial injury. Clinicians must, therefore, determine whether a patient's presenting symptoms are consistent with ACS. Combining troponin with other cardiac biomarkers may offer complimentary information on the underlying pathobiology and prognosis in an individual patient. Future generations of troponin assays may detect specific posttranslational modifications of troponins that may increase the analytic sensitivity for myocardial damage and offer insight into the timing and mechanism of myocardial injury.     

Biomarkers of myocardial ischemia in the emergency room: cardiospecific troponin and beyond

A timely and efficient diagnosis is critical in patients with chest pain, to optimize the efficacy of myocardial revascularization in those with an acute coronary syndrome, and offset the increasing overcrowding in the emergency room by early discharge of subjects without myocardial ischemia. Although cardiospecific troponins remain the biochemical gold standards for diagnosing an acute coronary syndrome, several additional biomarkers have been proposed. As a general rule, there are important issues that should be addressed when combining an innovative diagnostic test with troponin, including a benchmark evaluation of diagnostic performance, the impact on throughput and turnaround time, along with the analytical features of the assay and the cost to benefit ratio of a multi-marker approach. Despite a considerable amount of data has been published, there is insufficient analytical and clinical evidence to support the use of most of these novel biomarkers as surrogates or in combination with troponin for diagnosing ischemic heart disease, especially when the latter is assessed with the novel highly-sensitive immunoassays.     

Outcomes of hospitalized patients with non-acute coronary syndrome and elevated cardiac troponin level

Objective

Cardiac troponin levels help risk-stratify patients presenting with an acute coronary syndrome. Although cardiac troponin levels may be elevated in patients presenting with non-acute coronary syndrome conditions, specific diagnoses and long-term outcomes within that cohort are unclear.

Methods

By using the Veterans Affairs centralized databases, we identified all hospitalized patients in 2006 who had a troponin assay obtained during their initial reference hospitalization. On the basis of the diagnostic codes of the International Classification of Diseases, 9th Revision, primary diagnoses were categorized as acute coronary syndrome or non-acute coronary syndrome conditions.

Results

Of a total of 21,668 patients with an elevated troponin level who were discharged from the hospital, 12,400 (57.2%) had a non-acute coronary syndrome condition. Among that cohort, the most common diagnostic category involved the cardiovascular system, and congestive heart failure (N = 1661) and chronic coronary artery disease (N = 1648) accounted for the major classifications. At 1 year after hospital discharge, mortality in patients with a non-acute coronary syndrome condition was 22.8% and was higher than in the acute coronary syndrome cohort (odds ratio 1.39; 95% confidence interval, 1.30-1.49). Despite the high prevalence of cardiovascular diseases in patients with a non-acute coronary syndrome diagnosis, use of cardiac imaging within 90 days of hospitalization was low compared with that in patients with acute coronary syndrome (odds ratio 0.25; 95% confidence interval, 0.23-0.27).

Conclusions

Hospitalized patients with an elevated troponin level more often have a primary diagnosis that is not an acute coronary syndrome. Their long-term survival is poor and justifies novel diagnostic or therapeutic strategy-based studies to target the highest risk subsets before hospital discharge.     

血小板膜糖蛋白Ⅵ：一种新的急性冠状动脉综合征生物学指标

目前研究认为,血小板膜糖蛋白Ⅵ在动脉血栓形成方面发挥关键作用。用流式细胞技术测定血小板活性标志蛋白如血小板选择素（P-selectin）、血小板膜GPIbα（CD42b）和血小板膜糖蛋白Ⅵ的表达,发现患有急性冠状动脉综合征的患者,其血小板膜糖蛋白Ⅵ表达比稳定型心绞痛患者和健康人有明显的提高,且其表达量与P-selectin正相关。血小板膜糖蛋白Ⅵ高表达水平往往与急性冠状动脉综合征的心肌坏死因子如肌钙蛋白和肌酸激酶相关。同时发现,在急性冠状动脉综合征的患者中,血小板膜糖蛋白Ⅵ的表达比肌钙蛋白和肌酸激酶这些心肌受损的指标提早数小时。因此认为,血小板膜糖蛋白Ⅵ可作为心肌梗死患者的潜在性危险程度指标。     

La troponine et les autres marqueurs de souffrance myocardique,quelle signification en médecine interne ?

PURPOSE: Troponin is now the gold standard for the diagnosis of myocardial infarction. Aiming at improving the management of a patient suspect of an acute coronary syndrome, this article will point the interpretation of troponin dosages according to the clinical presentation and concomitant diseases. ACTUALITIES: First, the interest of troponin dosage as compared with other markers of myocardial ischemia will be underlined. Then, the literature available about troponin in cardiovascular diseases but also in extracardiac diseases will be analysed. Finally, the difficulties of assay will be discussed. PERSPECTIVES: The availability of a sensitive and specific marker such as troponin is definitively a progress in the management of patients with an acute coronary syndromes. But it remains a biological contribution to the global management of the patient. It is important to know the causes susceptible to increase the levels of troponin to avoid a wrong interpretation of the dosage, leading to diagnostic but also therapeutic mistakes.     

Detection of reperfusion after thrombolytic therapy by the analysis of released biochemical markers

Although the advent of thrombolytic therapy for acute coronary occlusion has substantially reduced the mortality of acute myocardial infarction (AMI), the best available thrombolytic regimens only achieve adequate reperfusion in a little over half the patients who are treated. The ability to detect failure of reperfusion by non-invasive means would permit further therapy in this patient group who currently have a high mortality. As coronary reperfusion causes a rapid release of many myocardial proteins into the blood stream, analysis of the rate of release of markers such as myoglobin, troponin, and creatine kinase (CK) during the first 90 minutes after thrombolytic therapy can identify about 80% of the patients in whom thrombolytic therapy has been ineffective. An ideal marker of reperfusion would be rapidly released after reperfusion, rapidly cleared from the circulation, highly myocardial specific, and amenable to rapid quantitative assay to permit 'real time' determination of coronary patency status. At present myoglobin and cardiac troponins appear most promising for detection of reperfusion, but other markers such as CK isoforms may prove useful if reliable rapid assays become available.     

A rapid troponin I assay is not optimal for determination of troponin status and prediction of subsequent cardiac events at suspicion of unstable coronary syndromes

BACKGROUND: Troponin is a specific marker of myocardial damage. For early prediction of coronary events in patients with suspicion of acute coronary syndromes the assay also needs to be highly sensitive. METHODS AND RESULTS: A rapid troponin I assay was performed prior to inclusion in 4447 acute coronary syndrome patients in the GUSTO-IV trial. A quantitative troponin T analysis was later performed on blood samples obtained at randomization by a central laboratory. There was an agreement between the rapid troponin I assay and troponin T (< or =/>0.1 microg/l) in 3596 (80.9%) patients. A positive rapid troponin I was identifying any elevation of troponin T (>0.01 microg/l) in 1990 patients (90.4%) whereas a negative rapid troponin I was corresponding to negative troponin T (< or =0.01 microg/l) in only 1217 patients (54.2%). Patients with a positive versus negative rapid troponin I had an increased risk of death or myocardial infarction at 30 days (9.3 vs. 5.9%; odds ratio, O.R. 1.64; 95% confidence interval, 1.31-2.06). Troponin T elevation (>0.1 microg/l) provided a better (10.5 v. 4.9%, O.R. 2.26; C.I. 1.79-2.85) risk stratification. Regardless of a positive or a negative rapid troponin I, the troponin T result (>0.1 vs. < or =0.1 microg/l) stratified the patients into high and low risk of events at 30 days, (10.3 vs. 5.7%, P=0.002) and (11.5 vs. 4.8%, P<0.001), respectively. CONCLUSION: In a population with non-ST elevation acute coronary syndrome a positive rapid troponin I assay is a specific indicator of troponin elevation and a predictor of early outcome. However, a negative rapid troponin I is not a reliable indicator of the absence of myocardial damage and does not indicate a low risk of subsequent cardiac events. A rapid troponin I assay was performed prior to inclusion in 4447 acute coronary syndrome patients in the GUSTO-IV trial and related to a centrally analyzed quantitative troponin T test. A positive rapid troponin I was well corresponding to any elevation of troponin T (>0.01 microg/l) and predicted an unfavorable outcome at 30 days. However, a negative rapid troponin I was corresponding to troponin T < or =0.01 microg/l in only half of the patients. Troponin T >0.1 microg/l vs. < or =0.1 microg/l provided a better risk stratification than the rapid troponin I result. For patients with troponin T elevation (>0.1 microg/l) the 30 day event rate was high regardless of the rapid troponin I result.     

Acute coronary syndrome: biochemical strategies in the troponin era

New biomarkers, such as cardiac troponins, have a major role to play for cost-effective management of individuals with acute chest pain and suspected coronary syndrome, and the laboratory is now poised to assume a vital role in assessing damage and determining prognosis. The redefined biochemical criterion proposed to classify acute coronary syndrome patients presenting with ischemic symptoms as patients with myocardial infarction is heavily predicated on an increased troponin concentration in blood. In an era of evidence-based medicine, we can no longer overlook the diagnostic and prognostic benefits provided by the measurement of these highly sensitive and specific proteins.     

Cardiovascular outcome in hospitalized patients with minimal troponin I elevation and normal creatine phosphokinase

BACKGROUND: Among patients with acute coronary syndrome, elevated cardiac troponin and creatine phosphokinase MB fraction levels have both prognostic and diagnostic values. However, in hospitalized patients, cardiac biomarkers are measured in a variety of clinical situations including but not limited to acute coronary syndrome. Moreover, these patients may have elevated troponin levels with no increase in creatine phosphokinase MB fraction levels. OBJECTIVE: To evaluate the cardiovascular outcome of acutely ill, hospitalized patients with minimal troponin I increase with normal creatine phosphokinase MB fraction. METHODS: We identified 64 patients retrospectively from our database with minimal troponin I increase and normal creatine phosphokinase MB fraction hospitalized between November 1998 and April 2000. Discharged patients were questioned about re-hospitalization for myocardial infarction, unstable coronary syndrome, congestive heart failure and percutaneous coronary intervention by means of a structured questionnaire. For those patients who died during hospitalization, data were collected from hospital records. For patients who died at home or at a different institution, a surviving relative completed the questionnaire. Primary outcomes were death, myocardial infarction and the need for revascularization or re-hospitalization. RESULTS: Composite endpoint of death, myocardial infarction, percutaneous coronary intervention or coronary artery bypass grafting and re-hospitalization for cardiac cause occurred in 35.95% of patients within 1 year. CONCLUSIONS: There is a significant composite event rate of death, myocardial infarction or re-hospitalization for cardiac causes in acutely ill, hospitalized patients with normal creatine phosphokinase MB fraction and minimally elevated troponin I, regardless of the cause for hospitalization.     

Elevated troponin I levels in acute liver failure: is myocardial injury an integral part of acute liver failure?

Although rare instances of cardiac injury or arrhythmias have been reported in acute liver failure (ALF), overall, the heart is considered to be spared in this condition. Troponin I, a sensitive and specific marker of myocardial injury, may be elevated in patients with sepsis and acute stroke without underlying acute coronary syndrome, indicating unrecognized cardiac injury in these settings. We sought to determine whether subclinical cardiac injury might also occur in acute liver failure. Serum troponin I levels were measured in 187 patients enrolled in the US Acute Liver Failure Study Group registry, and correlated with clinical variables and outcomes. Diagnoses were representative of the larger group of >1000 patients thus far enrolled and included 80 with acetaminophen-related injury, 26 with viral hepatitis, 19 with ischemic injury, and 62 others. Overall, 74% of patients had elevated troponin I levels (>0.1 ng/ml). Patients with elevated troponin I levels were more likely to have advanced hepatic coma (grades III or IV) or to die (for troponin I levels >0.1 ng/ml, odds ratio 3.88 and 4.69 for advanced coma or death, respectively). CONCLUSION: In acute liver failure, subclinical myocardial injury appears to occur more commonly than has been recognized, and its pathogenesis in the context of acute liver failure is unclear. Elevated troponin levels are associated with a significant increase in morbidity and mortality. Measurement of troponin I levels may be helpful in patients with acute liver failure, to detect unrecognized myocardial damage and as a marker of unfavorable outcome.     

新型心肌损伤标志物在胸痛患者早期诊断中的应用

急性冠状动脉综合征是一类心脏突发缺血性综合征。目前临床广泛使用的传统心肌损伤标志物如肌钙蛋白等在特异性、灵敏度以及信号时效性等方面存在局限性,致使急性胸痛患者误诊、漏诊或延误治疗而错过最佳抢救治疗时机。为此,研究人员近年来研究发现一些针对急性冠状动脉综合征患者具有早期诊断预测价值的新型心肌损伤标志物。本文将针对这些新型心肌损伤标志物在急性冠状动脉综合征患者早期诊断应用中的研究进展进行综述。     

Prevalence,Determinants, and Clinical Associations of High-Sensitivity Cardiac Troponin in Patients Attending Emergency Departments

Background

High-sensitivity cardiac troponin assays may improve the diagnosis of myocardial infarction but increase the detection of elevated cardiac troponin in patients without acute coronary syndrome.

Cardiac troponins in renal insufficiency: review and clinical implications

Patients with renal insufficiency may have increased serum troponins even in the absence of clinically suspected acute myocardial ischemia. While cardiovascular disease is the most common cause of death in patients with renal failure, we are just beginning to understand the clinical meaning of serum troponin elevations. Serum troponin T is increased more frequently than troponin I in patients with renal failure, leading clinicians to question its specificity for the diagnosis of myocardial infarction. Many large-scale trials demonstrating the utility of serum troponins in predicting adverse events and in guiding therapy and intervention in acute coronary syndromes have excluded patients with renal failure. Despite persistent uncertainty about the mechanism of elevated serum troponins in patients with reduced renal function, data from smaller groups of renal failure patients have suggested that troponin elevations are associated with added risk, including an increase in mortality. It is possible that increases in serum troponin from baseline in patients with renal insufficiency admitted to hospital with acute coronary syndrome may signify myocardial necrosis. Further studies are needed to clarify this hypothesis.     

Stress testing and troponin in unstable coronary syndromes: the status trial-clinical outcomes and resource use

Cardiac troponins are markers used to diagnose acute myocardial infarction, but their value in guiding management in low- to intermediate-risk patients is not well established. Using a randomized design, the authors compared a strategy using stress testing with blinded troponins vs a troponin I-guided strategy for risk stratification and management of 241 patients with intermediate-risk unstable angina. Fewer stress-tested patients required coronary care unit admission and repeat hospitalization for acute coronary syndrome, at a lower cost. There was no significant difference in rates of death and myocardial infarction due to acute coronary syndrome at 6 months' follow-up. For patients with intermediate-risk acute coronary syndrome, stress testing is as safe as, and more cost-effective than, a troponin I-guided strategy. Patients with marginal troponin I elevations can safely undergo stress testing. Further studies combining stress testing and a troponin I-guided strategy are warranted.     

New features of troponin testing in different clinical settings

Abstract. Omland T. (Institute of Clinical Medicine, University of Oslo, Oslo and Division of Medicine, Akershus University Hospital, Lørenskog, Norway) New features of troponin testing in different clinical settings (Review). J Intern Med 2010; 268 : 207–217. Cardiac troponin levels are routinely measured for diagnosing acute myocardial infarction. Cardiac troponin measurements also provide information concerning prognosis and the effect of early intervention in patients with acute coronary syndromes. The recent development of highly sensitive cardiac troponin assays permits detection of very low circulating levels. Use of sensitive troponin assays improves overall diagnostic accuracy in patients with suspected acute coronary syndromes, and these assays provide strong prognostic information in stable coronary artery disease and chronic heart failure. However, increased sensitivity comes with a cost of decreased specificity, and serial testing, as well as clinical context and judgment, is likely to become increasingly important in the interpretation of troponin assay results.     

Clinical performance of three cardiac troponin assays in patients with unstable coronary artery disease (a FRISC II substudy)

The assay of cardiac-specific troponins (cTroponins) is a sensitive and specific means to diagnose myocardial injury. Several assays for the measurement of cardiac-specific troponin I (cTnI), but only 1 for the assay of cardiac specific troponin T (cTnT), are commercially available. The aim of this study was to compare 3 of these assays (i.e., Access AccuTnI [cTnI], AxSym [cTnI], and Elecsys 3(rd) generation [cTnI]) and their clinical performances in a group of patients (n = 1,763) with unstable coronary artery disease (Fragmin and fast Revascularisation during InStability in Coronary artery disease [FRISC II] trial). Clinical events after 1-year follow-up, such as death and death and/or acute myocardial infarction, were recorded and the effects of invasive or noninvasive treatment evaluated in relation to cTroponin levels. Overall the 2 cTnI methods showed good correlation (r(s) = 0.96), whereas correlations to the cTnT assay were somewhat lower (r(s) = 0.93). Patients with nonelevated levels, as measured with any of the 3 biomarkers, had a significantly better prognosis than patients with elevated levels (p <0.001). A cohort of 10% to 12.4% of patients with a poor prognosis was identified only by the Access AccuTnI assay. Invasive treatment reduced clinical events only in the group of patients with elevated cTroponin levels. We conclude that stratification of patients with unstable coronary artery disease by means of cTroponin measurements is important in clinical management. It is also apparent that assays with superior sensitivity, such as the Access AccuTnI, identify more patients with poor prognosis who are candidates for early invasive procedures.