Role of biochemical markers in diagnosis of myocardial infarction

An ideal cardiac biochemical marker should have not only high sensitivity but also high specificity to myocardial infarction. The creatine kinase-MB, a relatively specific cardiac marker, could be elevated in situations other than acute myocardial infarction, such as renal failure, muscular injury, and myopathy. Although these are more specific than creatine kinase-MB, cardiac troponins have also been reported to be elevated in conditions other than acute myocardial infarction, such as chronic renal failure, acute myocarditis, cardiomyopathy, congestive heart failure, pulmonary embolism, rhabdomyolysis, sepsis, and left ventricular hypertrophy. With the ongoing research in this field, future holds hopes of finding an ideally specific marker of myocardial infarction, but until then biochemical markers should be used in conjunction with clinical assessment and electrocardiography in making the diagnosis of myocardial infarction, and the patients should not be treated merely on the basis of elevated serum levels of cardiac biochemical markers.     

Troponins in patients with acute coronary syndromes: biologic,diagnostic, and therapeutic implications

The cardiac troponins have expanded the spectrum of detectable myocardial injury and enhanced the clinician's ability to identify patients with acute coronary syndromes who are at higher risk for death or recurrent ischemic events. Based on available data, it appears most likely that any reliably detected troponin elevation results from myocyte necrosis. This notion has served as the basis for the recent revision of diagnostic criteria for acute myocardial infarction based on cardiac troponin. Nevertheless, further research is necessary to conclusively refute the possibility that the release of cardiac troponins may also occur in the setting of reversible myocyte injury resulting from cellular ischemia. Such an investigation establishing biologic correlates of troponin elevation is likely to prove valuable in guiding diagnostic terminology as well as in therapy. For example, clinical research finding cardiac troponin elevation to be predictive of intracoronary throumbus and distal microvascular obstruction has been important to the evaluation of troponis for targeting powerful antiplatelet and antithrombin therapies. Whether related to irreversible or reversible injury, the cardiac troponins have blurred the traditional boundaries between unstable angina and myocardial infarction and have evolved as powerful tools for risk stratification and therapeutic decision-making.     

Troponin for the estimation of infarct size: what have we learned?

In acute myocardial infarction (AMI), the extent of myocardial damage is closely linked to prognosis. Early determination of infarct size is therefore key to assessing the future risk of patients and instructive for optimization of therapeutic strategies. The cardiac troponins, by allowing the physician to track the extent of injury suffered by the myocardium, provide a window into the heart. This article addresses the relationship between the cardiac troponins and the infarct size in AMI. Taken together, the data suggest that the cardiac troponins provide very useful information in this respect and especially in patients with ST elevation myocardial infarction. More studies are needed to understand how cardiac troponin-estimated infarct size may be integrated with other prognostic assessments and employed systematically in risk stratification. Early data are promising and indicate that cardiac troponins could provide useful information for early risk assessment that is complementary to the determination of cardiac function and volumes.     

Mécanismes d'augmentation et rôle diagnostique des troponines hautement sensibles dans l'hypertension artérielle

Improvement in immunochemical methods for the determination of key biomarkers of acute myocardial infarction has led not only to an improvement in the early diagnosis of acute myocardial infarction, but also to a change in many of our ideas about the biology and diagnostic role of cardiac troponins. Modern (highly and ultrasensitive) laboratory methods for the determination of cardiac troponin molecules in human biological fluids are highly sensitive, which makes it possible to detect even the smallest damage to cardiomyocytes that occur at the early stages of many pathologies of cardiac (coronary heart disease, arterial hypertension, etc.) and extracardiac etiology (renal failure, sepsis, chronic obstructive pulmonary disease and others), as well as under the influence of a number of physiological conditions, including the influence of physical exercises, psychoemotional stress, gender characteristics (higher levels of cardiac troponins in men, compared with women), age characteristics (an increase in the concentration of cardiac troponins with age) and circadian characterisics (prevalence of morning values of cardiac troponins concentration over evening ones). In this regard, the diagnostic capabilities of the use of highly sensitive cardiac troponins have been significantly expanded. One of the promising areas for the use of highly sensitive cardiac troponins includes the assessment of the risk of adverse cardiovascular events both in healthy patients and in patients with various risk factors for their development, one of which can be considered arterial hypertension. This article systematizes the results of clinical studies evaluating the diagnostic role of highly sensitive cardiac troponins in biological fluids (blood serum and urine) in hypertension and discusses in detail the mechanisms of increasing the levels of highly sensitive troponins in this pathological condition.     

Risk stratification in acute coronary syndrome

BACKGROUND: The spectrum of symptoms of patients with active ischemic heart disease ranges from silent ischemia to acute myocardial infarction and the extent of myocardial damage from reversible myocardial injury to extensive necrosis. The term "acute coronary syndrome" comprises this continuum. In particular the evaluation of patients without ST-segment elevation is difficult, for clinical symptoms, ECG criteria and CK-MB measurements appear insufficient for appropriate risk stratification. TROPONIN MEASUREMENT: Serial measurements of either troponin T or I reliably detect minor myocardial damage in those patients, who are known to be at a higher risk for adverse cardiac events comparable to the risk of patients with acute myocardial infarction. Hence determination of troponins allow superior risk stratification contributing to early triage and therapeutic decision making. Without elevation of troponins the cardiac risk for death or myocardial infarction will not exceed 1%. CONCLUSION: Patients with elevated troponins should be early hospitalized and further evaluated in order to begin efficacious therapy as soon as possible. These patients represent a high-risk subgroup of patients clinically classified as unstable angina, who might benefit from potential antithrombotic treatment such as low-molecular weight heparin or glycoprotein IIb/IIIa antagonists without or with revascularization strategies.     

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.     

Temporal pattern of cardiac troponin I after thoracotomy and lung surgery

BACKGROUND: Several studies have shown that patients with perioperative myocardial infarction (MI) are at higher risk for subsequent cardiac events and the identification of these patients is important. However, the diagnosis of perioperative MI can be difficult in many cases. The cardiac troponins are biomarkers with high cardiospecificity, and the aim of this study was to assess cTnI and cTnT among other cardiac biomarkers after thoracotomy and lung surgery. METHODS: 24 consecutive patients were included in the final analysis. Venous blood samples were drawn prior to the procedure, 1-3, 4-6, 16-18 and 30-32 h after surgery. Thoracotomy was performed as a standard posterolateral incision on the left or right side under general anesthesia. RESULTS: Both cTnI and cTnT were completely unaffected by the thoracotomy and the lung surgery. Furthermore, no single value of the troponins was above the 99th percentile at any time. In contrast, CK-MB was elevated in nearly half the patients, although the mean values complied well with the reference limit. CK and myoglobin were both considerably elevated and did not discriminate between acute myocardial infarction and release of the markers due to extracardiac injury. CONCLUSIONS: Only the troponins were unaffected by extracardiac surgery and were, thus, reliable markers of myocardial injury in patients who underwent thoracotomy and lung surgery. If the troponins are unavailable, CK-MB mass combined with the CK-MB/CK percentage should be preferred.     

Cardiac troponin T in ST-segment elevation acute myocardial infarction revisited

Cardiac troponins not only allow for risk stratification and guidance of therapy in unstable angina and non-Q-wave acute myocardial infarction but also may be useful in the diagnostic workup and monitoring of patients with ST-segment elevation myocardial infarction. In clinical practice, troponins are used for confirmation and monitoring of myocardial infarction, noninvasive prediction of reperfusion success after thrombolytic therapy, and noninvasive estimation of infarct size. Accumulating evidence suggests that the measurement of cardiac troponins on admission may represent a relatively novel application that is useful for early risk stratification and prediction of reperfusion success after thrombolysis or primary percutaneous coronary interventions. Potential mechanisms of the predictive power of cardiac troponins are discussed.     

Role and importance of biochemical markers in clinical cardiology.

This paper reviews the current contribution of the biochemical marker determination to clinical cardiology and discusses some important developments in this field. Biochemical markers play a pivotal role in the diagnosis and management of patients with acute coronary syndrome (ACS), as witnessed by the incorporation of cardiac troponins into new international guidelines for patients with ACS and in the re-definition of myocardial infarction. Despite the success of cardiac troponins, there is still a need for the development of early markers that can reliably rule out ACS from the emergency room at presentation and also detect myocardial ischaemia in the absence of irreversible myocyte injury. Under investigation are two classes of indicators: markers of early injury/ischaemia and markers of inflammation and coronary plaque instability and disruption. Finally, with the characterisation of the cardiac natriuretic peptides, Laboratory Medicine is also assuming a role in the assessment of cardiac function.     

循环微小RNA与急性心肌梗死早期诊断的研究进展

急性心肌梗死是常见的心血管急症,是造成急性死亡的主要原因.心肌损伤标志物可以反映心肌坏死程度,为急性心肌梗死的诊断和预后判断提供重要信息.肌钙蛋白敏感性和特异性高,是目前临床中应用最广泛的心肌损伤标志物.然而肌钙蛋白起峰偏晚,不利于急性心肌梗死极早期的诊断.寻找敏感性准确性更高、起峰更快的新型心肌损伤标志物是冠心病领域研究的热点.最近的研究发现,急性心肌梗死时循环血中心肌特异性的微小RNA升高,可能作为心肌梗死新的生化指标,现对此做简要综述.     

Redefinition des Herzinfarkts – Bedeutung von Biomarkern

Myocardial infarction (MI) as an acute and life-threatening complication of coronary heart disease is one of the most frequent causes of death in Germany. Therefore, diagnosis, risk stratification and treatment of acute MI are of great clinical relevance. Specific recommendations concerning diagnosis of acute MI can be found in current guidelines of the European Society of Cardiology (ESC) and the German Cardiac Society, as well as in a consensus document "Universal definition of myocardial infarction", which has been published at the end of 2007. Here, cardiac markers, namely cardiac troponins, play a central role as a criterion for the diagnosis of myocardial infarction. Moreover, cardiac troponins provide prognostic information and are of great value for risk stratification of patients. Measurement of creatine kinase CK-MB is an alternative to troponin measurement, but is only recommended, if troponins are not available. As a cutoff value for cardiac biomarkers the 99th percentile of a healthy reference population has been defined. However, assays that are used for routine testing require adequate precision.Besides established biomarkers, several novel markers have been evaluated in clinical studies in recent years. Especially B-type natriuretic peptides (BNP and NT-proBNP) and C-reactive protein (CRP) have gained great interest and sufficient data has been gathered, justifying clinical application of these novel markers. As a consequence, BNP/NT-proBNP and CRP are mentioned in the current guidelines of the ESC as appropriate biomarkers for risk stratification. The clinical relevance of other novel biomarkers remains uncertain and necessitates further studies.     

Cardiac troponins in renal insufficiency and other non-ischemic cardiac conditions

The emergence of cardiac troponins has been an interesting step in the diagnosis of ACS. It has clearly helped us to better triage patients toward a more aggressive posture in performing early cardiac catheterization, and in some cases, early use of adjunctive Gp IIb/IIIa antagonists and percutaneous or surgical myocardial revascularization. However, with this step forward has come uncertainty and many cardiology consults regarding positive cardiac troponins in patients without ACS or myocardial infarction. In general, increased cardiac troponins imply a worse prognosis. This is clearly true of patients with ESRD and advanced heart failure. It is also true of patients with severe, noncardiac illnesses. In other situations, such as acute pericarditis and cardiac surgery, slightly elevated cardiac troponins do not seem to predict a worse prognosis, and can probably be disregarded. The elevation of cardiac troponins after successful percutaneous coronary interventions is not unexpected, and the level of cardiac troponin release seems to predict problems, but lively controversy persists. Last, monitoring cardiac troponins in cardiac transplant recipients and those receiving certain cardiotoxic chemotherapies may be of some diagnostic value, but clearly more experience and clinical research are needed.     

Elevated cardiac troponin levels in patients with submassive pulmonary embolism.

BACKGROUND: Cardiac troponins are reliable markers of myocardial injury that are being used increasingly in patients presenting with undifferentiated chest pain or dyspnea to diagnose an acute coronary syndrome. If elevated cardiac troponin levels also occur in patients with pulmonary embolism because of right ventricular dilation and myocardial injury, such patients could be misdiagnosed. We performed a prospective cohort study to determine the prevalence of elevated cardiac troponin I (cTnI) levels in patients with submassive pulmonary embolism. METHODS: Consecutive patients with objectively confirmed submassive pulmonary embolism and no previous history of ischemic heart disease, other cardiac disease, or renal insufficiency were included. Creatine kinase and cTnI levels were measured within 24 hours of clinical presentation on 2 occasions 8 to 12 hours apart. RESULTS: Of 24 patients with submassive pulmonary embolism, 5 (20.8%) had elevated cTnI levels of 0.4 microg/L or higher (95% confidence interval, 7.1-42.2%). One of these patients had a cTnI level higher than 2.3 microg/L that was suggestive of myocardial infarction. CONCLUSION: Pulmonary embolism should be considered in the differential diagnosis of patients presenting with undifferentiated chest pain or dyspnea and an elevated cardiac troponin level.     

Physical activity,exercise and cardiac troponins: Clinical implications

Cardiac troponins constitute essential components of the cardiac contractile apparatus and are released into the bloodstream following cardiomyocyte injury. Because of their cardiac specificity, cardiac troponin I or T are the recommended biomarkers for diagnosing acute myocardial infarction. However, cardiac troponin concentrations also frequently increase acutely after strenuous prolonged exercise, making the interpretation of cardiac troponin test results in patients presenting with acute chest pain challenging. This acute troponin response following exercise is commonly considered to be physiological and without adverse long-term consequences, but the possibility of exercise-induced, minor myocardial injury that may become clinically relevant if repeated over decades, has not been ruled out. Attempts to biochemically differentiate between physiological cardiac troponin release versus release after acute ischemic myocardial injury has so far proved largely unsuccessful, but future measurement of specific troponin fragments could be promising. Cardiac troponins also provide strong prognostic information across the spectrum of cardiovascular (CV) disease (CVD). In the chronic setting, low-level elevation of cardiac troponins has been associated with adverse outcome, and concentrations even within the normal range provide independent information concerning risk of developing heart failure (HF) and CVD death. Exercise exerts many beneficial effects on the CV system, and longitudinal observational data from epidemiological studies suggest that higher physical activity (PA) is associated with lower concentrations of cardiac troponins. Conversely, a sedentary life-style has been associated with higher cardiac troponin concentrations and a parallel increase in the risk of HF. Serial measurement of cardiac troponins using high sensitivity assays for monitoring the effect of life-style intervention, including PA appears promising.     

An Update on Cardiac Troponins as Circulating Biomarkers in Heart Failure

Circulating troponins and natriuretic peptides are the only biomarkers specifically released from cardiac myocytes that can be determined with robust and sensitive analytical methods, even in healthy subjects. These intracellular proteins are released from reversibly or irreversibly damaged cardiac myocytes into the bloodstream by mechanisms that are not entirely clear. The recent introduction of a new generation of highly sensitive assays of cardiac troponin I or T has not only improved the early diagnosis of acute myocardial infarction but also suggested that there are several causes for troponin release other than acute coronary syndromes. Circulating troponins are elevated in patients with acute or chronic heart failure and are strongly associated with outcome, independently of natriuretic peptides, the benchmark biomarkers in heart failure. In the absence of further experimental evidences, the pathophysiologic basis for the elevation of circulating cardiac troponins in patients with stable chronic heart failure remains speculative.     

The clinical significance of cardiac troponins in medical practice

Troponins are regulatory proteins that form the cornerstone of muscle contraction. The amino acid sequences of cardiac troponins differentiate them from that of skeletal muscles, allowing for the development of monoclonal antibody-based assay of troponin I (TnI) and troponin T (TnT). Along with the patient history, physical examination and electrocardiography, the measurement of highly sensitive and specific cardiac troponin has supplanted the former gold standard biomarker (creatine kinase-MB) to detect myocardial damage and estimate the prognosis of patients with ischemic heart disease. The current guidelines for the diagnosis of non-ST segment elevation myocardial infarction are largely based on an elevated troponin level. The implementation of these new guidelines in clinical practice has led to a substantial increase in the frequency of myocardial infarction diagnosis.Automated assays using cardiac-specific monoclonal antibodies to cardiac TnI and TnT are commercially available. They play a major role in the evaluation of myocardial injury and prediction of cardiovascular outcome in cardiac and non-cardiac causes.In this review we discuss the clinical applications of cardiac troponins and the interpretation of elevated levels in the context of various clinical settings.     

Degradation of troponin I in serum or plasma: mechanisms, and analytical and clinical implications

A prolonged myocardial ischemia, which results from a total deprivation of blood supply to an area of cardiac muscle for an appreciable period of time, is the leading mechanism responsible for acute myocardial infarction (AMI). The irreversible injury of myocardiocytes and the subsequent release of a variety of intracellular components into blood is the cornerstone of the diagnosis of AMI. Cardiac troponins are advocated as the biochemical gold standards among the various biomarkers of plaque instability, plaque rupture, ischemia, reversible cellular injury, and early and late necrosis (i.e., irreversible injury). The assessment of cardiac troponins in the diagnostic approach of patients with chest pain presents, however, some specific challenges due to the complex mechanisms of release from the injured myocardium, as well as to the enzymatic degradation by cardiac and extracardiac proteases (i.e., calpains, caspases, cathepsin L, and gelatinase A) that might alter the immunoreactivity (and thus laboratory detection) of the molecules. These two aspects will be discussed in this article, with specific focus on cardiac troponin I, as a variety of immunoassays based on antibodies which recognize different epitopes on the molecule is available for the measurement of this important cardiac biomarker.     

Clinical implications of high‐sensitivity cardiac troponins

Cardiac troponin assays have become more sensitive over the years leading to the clinical introduction of high‐sensitivity cardiac troponin assays in 2010. Their use has revolutionized the assessment of patients with chest pain in the emergency department by allowing earlier rule‐in and rule‐out of myocardial infarction leading to shorter stays in the emergency department and reduced admissions for chest pain. The incidence of myocardial infarction has increased slightly, and patients with myocardial infarction diagnosed with high‐sensitivity cardiac troponins have been found to have a reduced risk of reinfarction, though without an impact on survival. High‐sensitivity cardiac troponins are powerful predictors of long‐term mortality and cardiovascular disease in the general population as well as in patients with chest pain with or without cardiovascular disease. The increase in risk for death and cardiovascular disease associated with high‐sensitivity cardiac troponins is graded and starts already at detectable levels, well below the upper normal level. The aim of this review was to describe the clinical use and consequences of the introduction of high‐sensitivity cardiac troponins. In addition, the importance of persistently elevated troponin levels for prognosis and what investigations may be appropriate to perform in patients with stable troponin elevations are discussed.     

Cardiac markers in the diagnosis of acute coronary syndromes

Evolution of the role of cardiac markers has ranged from the diagnosis of acute myocardial infarction in patients with nondiagnostic electrocardiograms to prognostic risk stratification and to guide therapy. The technology to provide rapid, real time measurements by immunoassay has provided the laboratory and clinician with a range of test options. The principal changes have been the use of rapid serial marker measurements of well-recognized cardiac markers, and the development of immunoassays for the cardiac structural proteins. Measurement of cardiac troponins has generated a new diagnostic paradigm in patients with suspected acute coronary syndromes. There is now a new gold standard biochemical test for myocardial infarction. A range of interventions can be guided by troponin measurement. The use of troponin measurements is central to management of patients with suspected acute coronary syndromes. Future developments in this field will focus on the role of existing and novel markers of inflammation and ischemia.     

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.