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Review: Clinical significance of high-sensitivity troponin elevation.
What does elevated troponin mean? The first choice must be acute myocardial infarction (AMI)! There was no problem with this answer a few years ago, but now it is not accurate because of the appearance of "highly sensitive troponin". Professor Wu Yonglun, a famous expert, quoted a photo of "the scene of a three-car rear-end accident" in a lecture slide in June, 20 13, which vividly described the current situation of high-sensitivity troponin detection.

The key to the above results is insufficient communication. Clinicians don't know enough about learning high-sensitivity troponin; It is not enough for the clinical laboratory to take the initiative to enter the clinic for publicity and communication. In addition, there are some quality problems in the laboratory, which can not always guarantee the accuracy and controllability of the results.

These problems appeared in Europe as early as a few years ago, and the US Food and Drug Administration (FDA) will soon approve its clinical application, and will also encounter these problems. However, Americans did a lot of work before the official use and formed some "consensus". The main purpose is to let clinicians know how to use it best and explain the results scientifically and reasonably.

In China, many hospitals have used high-sensitivity troponin detection reagents for 4 years, and more and more problems have been encountered. How to avoid some problems and how to unify our understanding? We believe that laboratories and clinics should strengthen learning and communication, learn from European and American experiences, avoid detours or turning back, and reach a consensus as soon as possible.

First of all, it should be clear that "high sensitivity troponin" is a reflection of experimental characteristics (that is, the improvement of detection sensitivity), rather than a new form of cardiac troponin. Most "highly sensitive" reagents are optimized and improved only in increasing the detection amount of samples, increasing the detection concentration of labeled antibodies, reducing the background signal of buffer and prolonging the reaction time.

The result of the improvement is that the detection sensitivity is increased by 10 times, and the release of 6%-8% free troponin in cytoplasm can be detected. Because the reagent calibrator is a recombinant of human cTnT from Escherichia coli, and the 5th generation reagent calibrator of cTnT is not exactly the same as the 4th generation, the detection results of the same sample will be different, for example, the critical value of the 4th generation hs-cTnT is 30ng/L, while the critical value of the 5th generation cTnT is 50 ng/L. Although the standardization of cTnl is improved by 10 times, the consistency is improved.

The problem of false positive analysis should be considered when the increase of cTn has nothing to do with clinical situation and/or its increase does not change with time. The most common problem is fibrin interference, which should be centrifuged again. Some interfering antibodies can cause false positives and false negatives, which can be easily solved by using blocking antibodies (which should be equipped in the kit) in the laboratory. In addition, interfering substances can also be identified by dilution. For hs-cTn, sample pretreatment and attention to the above problems are more important.

First of all, we must achieve several unifications. First, the naming is unified. There are "high performance", "high sensitivity", "high sensitivity", "super sensitivity", "new high sensitivity", "sensitivity" and "high sensitivity" in English literature. Apple and others suggested that "high sensitivity" should be used uniformly in the journal of Clinical Chemistry and all scientific documents.

Similarly, there are many names in China, such as "high sensitivity", "high sensitivity", "hypersensitivity", "enhancement" and "ultra-hypersensitivity". It is suggested to call it "high sensitivity troponin (hs-cTn)". Second, a unified definition requires two conditions: First, the coefficient of variation (CV) of the 99th percentile is ≤10%. Secondly, in healthy people, the detection rate below the 99th percentile is more than 50% (the best state is more than 95%).

At present, there are five kinds of hs-cTnl and 1 hs-cTnT reagents that can meet the above standards, but only Roche's hs-cTnT detection is used worldwide (except the United States, which has not been approved by FDA so far), and several other hs-cTnl reagents will be registered and approved in China in 20 14 and put into clinical application. Finally, the unification of units can avoid confusion, and it is suggested that ng/L or pg/ml be used instead of mg/ml or ug/L, which are commonly used at present.

Although the third edition of the 20 12 global definition of myocardial infarction once again puts forward the 99th percentile as the cut-off value for diagnosing MI, it is clearly required in the document that the discriminating ability of the 99th percentile for diagnosing MI must be determined by the specific reagents used and the quality control situation in the laboratory.

Reagent suppliers should provide the 99th percentile values of their respective reagents according to the actual situation of users, and repeatedly emphasize that the results of different detection reagents in the same sample will be different, and the 99th percentile values of different reagents will also be different. But in practical application, it is found that the consistency of these data is poor. So far, there is no clear standard for the statistical analysis and calculation of the 99th percentile.

What is the definition of a healthy person is still a hot topic of debate. Apple and Collinson think that there are several points to consider in judging healthy people: (1) Ask personal medication history, such as the history of statin use in patients with hyperlipidemia; (2) Complications that easily lead to cardiovascular diseases, such as nephropathy or diabetes history; (3) The clinician determines it through physical examination, or electrocardiogram and echocardiography.

According to the distribution of patients with heart disease, they are divided into young people (< 30 years old) and middle-aged and elderly people (> 30, with a median of 60-65 years old, representing the age of high incidence of heart disease). They choose healthy people, ask about their past medical history, judge the potential disease state, detect BNP/Nt-proBNP, and exclude those with cardiac insufficiency. Gender balance and race and ethnicity should be considered when grouping.

Some articles require higher revision, that is, the determination of reference range should refer to demographic characteristics, including blood pressure, blood sugar, serum creatinine and BNP within the normal range, not taking cardiac drugs, and no structural heart disease was found through cardiac ultrasound and cardiac MRI/CT examination. Meeting these conditions is a great challenge, especially for the elderly.

CLSI's suggestion is that each group should have at least 120 people, but it is only applicable to the establishment of 95%(2.5% and 97.5%) reference intervals of nonparametric estimation methods of normal distribution, and it is not applicable to the establishment of the 99th percentile. It is suggested that 300-500 people are more appropriate.

It is unrealistic to consider biological variation in clinic by using the previous generation reagents, because these reagents can not reliably detect cTn in healthy people, and the detection rate of most reagents in healthy people is less than 15%. Apple studied the biological variation of the above five highly sensitive reagents, and found that the individual variation was cTnl2.2ng/L and ctnt 4.9 ng/l; The reference range is 32.0%-69.3%.

According to the definition of global myocardial infarction in 2007 and 20 12, there are two conditions for the detection of troponin, namely ≥99% percentile value and ≤ 10% CV value. If these two requirements are met, significant changes can be found in a series of tests.

Although the cv value of the 99th percentile ≤20% will not lead to misjudgment of diagnosis and risk stratification, it is still very helpful for laboratories and clinicians if the cv value there is ≤ 10%, because it can make them believe the test report and the value changing with time, which is not caused by the analysis of "noise".

The third edition of 20 12 "Global Definition of Diagnosis of Myocardial Infarction" emphasizes once again the increase and/or decrease of cardiovascular markers (preferably troponin), and at least the measured value of 1 exceeds the 99th percentile, accompanied by at least one of the following: ischemic symptoms; ECC change; Image evidence. Detection of troponin is the first choice and necessary condition for diagnosis of myocardial infarction.

However, we should know that troponin is a laboratory test of myocardial necrosis/injury, while MI is a clinical diagnosis. The interpretation of any laboratory test results can not be divorced from the clinical background. Don't forget: the main challenge of hs-cTn in clinical application is improper detection and incorrect interpretation of the results, not the markers themselves.

The cornerstone of diagnosing ACS is still a complete and detailed medical history, and the combination of ECG and cTn is the core of current diagnosis. In a word, "clinical background is the key". If used well, it will be "comfortable" in solving blasphemy, diagnosis, risk stratification and patient management.

With the continuous progress of medicine, the markers of myocardial infarction or injury are constantly changing and developing. From "traditional myocardial enzyme spectrum" to "gold standard" CK-MB, and then to the most specific marker of myocardial injury/necrosis-troponin T/I; From the previous "markers of myocardial infarction" to "markers of myocardial injury"; From simple diagnosis of myocardial infarction to acute coronary syndrome (ACS) and risk stratification.

All these reflect the rapid development and continuous progress of laboratory medicine in the cardiovascular field, and the key is to benefit patients. In recent years, the minimum detection limit of troponin has been decreasing, the detection accuracy has been improving, and "high-sensitivity troponin" has been introduced, which has greatly changed the diagnostic range of myocardial injury. However, we should know that the detection of troponin can specifically reflect the injury/necrosis of myocardial cells, but it cannot reflect the specific injury mechanism.

In other words, at present, it is "only concerned with the consequences, regardless of the process." Therefore, our inertia thinking should also be changed. Now we should know that the reasons for the increase of high-sensitivity troponin are attributed to four aspects: 1 type MI or type 2 MI; Non-ACS acute disease; Or chronic acute coronary syndrome.

Since the above four conditions exist, it is inevitable that "high-sensitivity troponin" will be criticized in specific clinical applications. But you can't back down or even go back because of criticism/incomprehension.

Because:

1. Taking the 99th percentile as the cut-off value for the diagnosis of MI, people who were previously clinically diagnosed with unstable angina pectoris are now more diagnosed with non-ST-segment elevation acute myocardial infarction, which is conducive to taking more active treatment measures in clinic and benefiting patients. This is one of the main values of clinical application of high-sensitivity troponin.

Second, no matter what the reason, the increase of troponin means that the prognosis of patients is not good, and it is necessary to actively find out the reasons and actively treat them, which has reached a consensus. Although some doctors in Europe and America complain that the increase of troponin has nothing to do with ACS in many cases, which is called "troponemia" or "tropodystrophy", they do not evade the existing problems, but actively face them.

1. Fully understand the pathophysiological significance of high-sensitivity troponin: You should know that a considerable part of the so-called "normal population" (more than 50%-95%) can be detected; We should know that the detection time window of high-sensitivity troponin blood will be 2-3 hours earlier than the previous generation products; You should know that it is helpful for the detection of myocardial injury;

To know that troponin is a highly individualized detection index (individual index is low), we should consider biological variation, that is, the influence of individual variation on the judgment of continuous results, and the individual variation of hsTnT(CVi, 48%), hsTnl(CVi, 9.7%) and similar people.

2. The laboratory results should be accurate and controllable: the analysis variation is ≤20%, preferably < 10% (cv value of the 99th percentile > 10%, which cannot be called "high sensitivity"); Quick report, TAT time < < 60 minutes (preferably < 50 minutes); The equipment should be turned on 24 hours a day, do a good job in low-concentration indoor quality control, and participate in high-quality inter-room quality control; Strengthen equipment maintenance and keep the equipment in the best condition.

3. Clinicians should know whether the elevation of troponin is acute or chronic as soon as possible: even if it is acute, there are AMI and non-myocardial ischemic acute myocardial injury (NAMI).

Non-myocardial ischemic acute myocardial injury has the following conditions:

(1) Direct myocardial injury: CHF, infection (viral myocarditis, infective endocarditis), inflammation, myocarditis, pericarditis, malignant tumor, tumor chemotherapy, trauma, electric shock, radiofrequency ablation, invasive disease, left ventricular apical balloon syndrome of stress cardiomyopathy;

(2) Other causes such as pulmonary embolism, septicemia, renal failure, cerebrovascular accident, subarachnoid hemorrhage, etc.

* * V. Is it necessary to continuously improve the sensitivity of troponin detection * *

Several "high-sensitivity troponin detection systems" published in AACC News in 2065438+01February, such as ABC Access HS-CTNL [LOD 0.0021ug/L, 99t%% 0.0086ug/L,1L. Nanosphere HS-CTNL (LOD 0.0002 ug/L, 99% 0.0028 ug/L, 10%CV 0.0005ug/L, 75%-95% lower than the detection value of 99%);

Roche-hs-cTnT(LOD 0.002ug/L, 00th% 0.0 13ug/L, 10%CV 0.0 12ug/L, lower than 99% detection value ≥ 95%); Single molecule CTNL (LOD 0.0002 ug/L, 99% 0.009 ug/L, 10%CV 0.0009ug/L, lower than 99% detection value ≥95%) has several LOD < 1 pg/mL or more.

At present, it is necessary to continue to improve the sensitivity in clinic. I think it is necessary! Because the final judgment of cardiac troponin on myocardial "organ-specific, not disease-specific" damage should be solved by deeply studying the different mechanisms of myocardial cell-related damage protein modification and improving the detection sensitivity.

Omland et al. used Abbott's new generation hs-cTnl detection reagent to study patients with stable coronary heart disease, and found that in chronic phase, the release concentration correlation between hs-cTnT and hs-cTnl was moderate, suggesting that their release mechanism and potential degradation mode may be different. In addition, hs-cTnl rather than hs-cTnT is an important and independent predictor of previous and subsequent AMI.

It was found that before AMl, hs-cTnl was more important than hs-cTnT in blood circulation. Each cTn subunit plays an independent function, and different fragments may have different biological activities (different biological characteristics and transcription characteristics), reflecting different causes of subtle heart injury and clearance mechanism from blood. Whether there are different diagnostic and predictive characteristics is still unclear.

Another study found that hs-cTnT can be used as a diagnostic tool, that is, immediately exclude AMI. They used Roche's 5th generation cTnT detection reagent (LOD < 3 ng/L, 99th percentile 14ng/L) to follow up 703 emergency patients suspected of AMI due to chest pain for 6 months.

It was found that among those whose HS-CTNT > 14 ng/L, 1 1 was AMI and11was non-AMl;. Among the patients with hs-cTnT3- 14ng/L, 19 cases were AMI and 277 cases were non-AMI. Of particular concern are 195 patients with HS-CTNT < 3 ng/L, and none of them was finally diagnosed as AMI within half a year.

Their research well confirmed that above the 99th percentile, not all patients are AMI;; If it is lower than the 99th percentile, AMI cannot be ruled out immediately. If Lod is lower than, AMI can be ruled out immediately. Therefore, peacock, an emergency doctor at Cleveland Heart Center, wrote a critical article for this study: Negative Value.

Although only 27.5% of patients with chest pain ruled out AMI through this single experiment, the clinical relevance of this figure may be too small, but the benefits of applying this strategy to specific practice are enormous, which means accurately ruling out AMI. Therefore, if hs-cTn does not increase 6-9 hours after symptoms appear, MI should not be considered.

Regarding the cardiotoxicity of drugs, experts agree that hs-cTn is the best biomarker to detect drug-related myocardial injury. Now pharmaceutical companies have begun to use hs-cTn to evaluate potential cardiotoxic components. These studies may reveal new and potentially important pathophysiological significance, but these are guaranteed by high-sensitivity detection.

Detecting such a low level of cTn will challenge the interpretation of the results, but it will open a new era, that is, screening subclinical population and improving the speed of disease surveillance. Therefore, Jaffe said at the end of the article: This is an exciting moment, because the increase of troponin can reveal some new pathophysiological problems, which will benefit patients.

The high negative predictive value and low false negative rate of hs-cTn are clear, but the positive predictive value also brings "trouble" to clinic. Although repeatedly stressed: we should focus on what it means to increase cTn, rather than lowering the diagnostic threshold of MI. Elevated cTn means poor prognosis, but improper treatment caused by elevated cTn is also dangerous. In order to overcome these problems, people are trying various detection methods.

Although the reduction of cut-off value will lead to the double-edged sword problem of improving diagnostic sensitivity and reducing specificity, it is meaningless to "raise the threshold" and "high sensitivity", and their value will be greatly reduced, which will definitely "miss diagnosis/cover up" many problems, which is not conducive to timely intervention and treatment of patients.

The global definitions of myocardial infarction in 2007 and 20 12 mentioned the "increase and decrease" mode of troponin, that is, continuous monitoring and dynamic observation. In practical clinical application, dynamic observation is valuable only when the concentration of troponin is very low (of course, dynamic observation will improve the specificity of diagnosing acute injury, but at the expense of sensitivity).

NACB suggests that the difference between the two results is 20% (based on the baseline), but this value is only empirical because it has exceeded the analysis of variance (the minimum requirement of analysis of variance). With the emergence of hs-cTn, some patients do not have myocardial ischemia/infarction, but have a situation of "large relative value but small absolute value", but these "small absolute value increases" are not MI in the end. Therefore, some researchers have proposed to judge by the concentration.

Hs-cTnT≤53ng/L, the variation value is 50%, and when it is higher than 53ng/L, the variation value is 20%. The Norwegian laboratory suggests not to use the 99th percentile, but to choose 0.03ng/ml as the cutoff value of MI, so as to avoid over-diagnosis of MI (especially the cTnT in the blood circulation of the elderly will be higher than 0.0 14ng/ml, age) At present, there is no large-scale research on hs-cTnl, and a specific scheme is put forward.

In view of the above four cases (1 type MI or type 2 mi; Non-ACS acute condition or non-ACS chronic condition), expert consensus on clinical interpretation of elevated troponin in ACCF 20 12 lists the diagnosis flow chart for clinical reference.

When chest pain occurs in patients with hs-cTn > 99%, two situations should be considered:

1. Chronic increase (hs-cTn increased, but did not increase or decrease after continuous monitoring), structural heart disease and chronic kidney disease may be considered, and echocardiography is recommended for diagnosis.

2. Acute elevation (increased or decreased after continuous monitoring), combined with [clinical history]

] (/index/search? Msg _ KEY =% E4% B8% B4% E5% BA% 8A% E7% 97% 85% E5% 8F% B2), ECG or cardiac imaging were performed to determine whether there is a mechanism of cardiac ischemia. If there is no possibility of myocardial ischemia, non-ischemic acute myocardial injury, such as pulmonary embolism and acute heart failure, should be considered in clinical treatment of primary disease, but CTT should be considered.

If the mechanism of myocardial ischemic injury is considered in clinical judgment, this situation can be divided into two possibilities. First, if the clinical manifestations are considered to be caused by the rupture of atherosclerotic plaque, it is diagnosed as 1 type MI, and AMI will be treated according to the guidelines. Secondly, if we consider other sudden non-coronary artery diseases, such as anemia, tachyarrhythmia, severe hypertension and so on. These conditions are diagnosed as type 2 MI, so we should consider correcting the sudden changes and using aspirin and β -blockers in clinic.

The purpose of this process is to improve the specificity and positive predictive value and shorten the observation time. How effective is this process in clinical application? It must be clinically verified. So far, no guidance document has been formed.

Finally, we should clearly realize that hs-cTn detection is of great benefit to patients, and clinicians will still face "numerous challenges" in clinic, because it is a symbol of "agnosticism" and there are still many unsolved mysteries!