Biochemical cardiac markers: present and future.
Patients with active myocardial ischemia are at substantial risk of experiencing adverse cardiac events in the future. As the next century approaches, it is reasonable to predict that cardiac markers will take on an increasingly important role for diagnosis and to guide preventive therapy for myocardial infarction and ischemia.
Acute myocardial ischemia represents a spectrum of disease called the acute coronary syndromes, which range from angina, or attacks of thoracic pain, through Q-wave myocardial infarction. These syndromes are a pathological continuum involving erosion and rupture of coronary artery plaques, activation of platelets, and typically mural thrombus. This continuum reflects the physiologic process of acute myocardial ischemia as well as the progression of damage that begins with plaque rupture in a coronary artery and ends with MI [ILLUSTRATION FOR FIGURE 1 OMITTED], and most importantly from a clinical standpoint, reflects a continuum of progressive patient risk.
For the past several decades, myocardial ischemia was largely regarded as a binary phenomenon - it either brought on an infarction or it did not. The World Health Organization criteria for diagnosing myocardial infarction are that the patient presents with at least 2 out of the following 3 criteria: clinical symptoms suggestive of myocardial ischemia, characteristic changes on the electrocardiogram (ECG), and a rise and fall in biochemical markers.
As the WHO recommends, careful assessment of clinical symptoms is essential, but these symptoms can be nonspecific for up to one-third of patients, particularly for those with diabetes and for the elderly who most frequently present with atypical symptoms of ischemia. The second criterion, monitoring the ECG, is also important and should begin quickly after presentation because patients with diagnostic changes are candidates for immediate reperfusion therapy. However, the ECG is not a perfect evaluation tool because its clinical sensitivity for MI is only about 50%.
The third WHO criterion, monitoring changes in cardiac markers, is considered the benchmark for the diagnosis of MI.(4) For symptomatic patients presenting with diagnostic ECG changes, the role of biochemical markers is limited to confirmation of an MI; however, these markers are essential to assess patients who present with nonspecific symptoms and a nondiagnostic ECG. The latter description is characteristic of approximately 55% of individuals eventually diagnosed as having an MI. It is also important to note that the diagnosis is missed in 4-8% of patients with an MI, and that mortality is high in this group. In addition, misdiagnosis of MI represents the highest outlay of malpractice dollars among emergency medicine physicians. To cope with this high-prevalence disease and its substantial associated costs, many institutions have initiated Chest Pain Evaluation Centers (CPECs), which are specific protocol-driven treatment areas intended for systematic and cost-effective care. Rapid, real-time availability of cardiac markers has become an integral part of most CPEC protocols, which have cut the rate of missed MI from 4.2% to 0.4%.
This article reviews:
* current cardiac markers and strategies for diagnosing MI
* potential use of biochemical markers to (1) indicate adverse outcomes and (2) identify a patient's status in the continuum of acute coronary syndromes
* progress and possibilities for using cardiac markers to guide therapeutic intervention in patients with acute coronary syndromes
Markers of myocardial infarction
Characteristics of the traditional biochemical markers listed in Figure 1 are well known, and assays to test for the existence of some of these markers are available (see Table 1). However, only the cardiac markers of MI (see Table 1, bottom) are currently used routinely to assess the acute coronary syndromes. To appropriately use all of the current markers, proper timing of specimen collection is essential. Guidelines for the utilization of MI markers have recently been proposed.
Creatine kinase-MB. Based on more than 2 decades of experience, creatine kinase (CK)-MB is a benchmark for other markers of acute coronary syndromes. Cytoplasmic CK is composed of M and/or B subunits that associate to form CK-MM, CK-MB, and CK-BB isoenzymes. For patients having significant myocardial disease, the CK-MB isoenzyme makes up approximately 20% of the total CK in myocardial tissue, On the other hand, skeletal muscle is composed of only 0-3 % CK-MB. Although CK-MB is a sensitive marker for myocardial injury, skeletal muscle has both higher total CK activity per gram of tissue and may be composed of up to 3% CK-MB. Because there are multiple sources of CK isoenzyme, it is a nonspecific marker of cardiac damage, especially in patients with concomitant myocardial and skeletal muscle injury. To confer greater cardiac specificity on CK-MB measurements, a CK-MB "relative index" is frequently calculated according to the following equation:
100% x CK-MB/total CK
Some authors suggest that CK-MB relative index values higher than 2.5% are associated with a myocardial source of the MB isoenzyme. However, a recent review shows that the relative index for CK-MB from a myocardial source is reportedly as low as 2% and as high as 5%, depending on the variability of both the numerator and denominator terms.
When patients experience an MI, the first rise in CK-MB occurs within 4-6 hours after the onset of symptoms; but for diagnosis with high sensitivity and specificity, serial sampling over a period of 8-12 hours is required. Immuno. assays for CK-MB, also known as mass assays, were examined [TABULAR DATA FOR TABLE 1 OMITTED] in a meta-analysis for retrospective diagnosis of MI within 12-48 hours after the onset of symptoms or admission. This analysis showed that CK-MB had a clinical sensitivity of 96.8% [95% confidence interval (CI): 95-98%] and a clinical specificity of 89.6% (CI: 87-92%) when assayed from samples obtained 12-48 hours after the onset of symptoms or admission. Also, the National Heart Attack Alert Program (NHAAP) evaluated cardiac marker utilization, focusing on the emergency medicine environment. When performed on multiple samples, CK-MB testing was listed as very accurate for the diagnosis of MI and has a large clinical impact. Despite this excellent clinical performance, CK-MB is not an ideal marker, because it is not tissue specific, and its increase requires 8-12 hours after the onset of symptoms to be diagnostically useful.
Myoglobin. Of the routinely available biochemical markers used to assess acute coronary syndromes, myoglobin appears earliest in the blood after myocardial injury. The characteristic early rise of myoglobin is mainly because of its relatively small molecular size, high concentration in tissue, and renal clearance mechanism. Its amino acid sequence is the same in both cardiac and skeletal muscle; thus, this marker has lower clinical specificity because of false-positive results in populations having renal insufficiency or skeletal muscle injury. Consequently, testing guidelines suggest using myoglobin as an early preliminary cardiac marker, because results are rapidly available and highly sensitive. 
A number of studies have examined the negative predictive value (NPV) of myoglobin, finding satisfactory high values with onset of acute chest pain.[15-21] based on these data for high NPV, testing strategies at many medical centers include myoglobin in combination with markers more specific for myocardial damage. Conversely, other institutions believe that myoglobin adds little information, and the NHAAP report rated the clinical impact of myoglobin as indicating only modest accuracy and small clinical impact.
In summary, myoglobin has a high NPV in the early hours after MI. Optimal clinical utilization requires serial sampling performed at the time of presentation and between 2-6 hours later. However, not all clinicians are convinced that myoglobin measurements contribute significantly to the assessment of patients with acute coronary syndromes. To be useful in the early assessment of patients, myoglobin results must be available in real time, i.e., with a turnaround time of approximately 30 minutes to 1 hour.
Cardiac troponins T and I. Along with troponin C, troponin T and troponin I are structural proteins that are essential components in the contractile apparatus of striated muscle. In contrast to troponin C, there are cardiac-specific forms of troponin T and troponin I. Immunoassays directed at troponins T and I allow for specific assessment of myocardial ischemia. Cardiac troponins T and I (cTnT, cTnI, respectively) can be used (1) for the diagnosis of acute MI, (2) for the late diagnosis of MI, and (3) for risk stratification of patients. However, the issues surrounding these markers are complicated because troponin I assays are numerous, and several generations of troponin T assays have been available for the past few years. In addition, the troponin complex is composed of a troponin C/troponin T/troponin I structural troika, and strong evidence suggests that troponin I is released as a troponin I/troponin C complex after cardiac injury. Reagents containing antibodies against troponin I reveal different reactivity to various complexed forms, which complicates interpretation of results. Assay standardization is needed because results for troponin I may vary 20-fold among the different assays, and the American Association for Clinical Chemistry has formed a committee to address this need.
Cardiac troponin I for MI diagnosis. A research version of a troponin I assay (Stratus, Dade Behring, Miami, FL) was evaluated in 188 patients, 89 of whom were diagnosed as having MI. Using samples collected 12 hours or longer after admission, this study demonstrated high sensitivity and specificity for troponin I compared with the benchmark CK-MB mass. The troponin I method available on the Access instrument (Beckman Coulter, Brea, CA) was also evaluated for diagnosis of MI and compared with both CK-MB mass in 208 patients and the Stratus troponin I method in 201 patients. The Stratus troponin I comparison showed 93% overall concordance, with agreement for MI diagnosis in 34 of 36 MI patients. There were no statistically significant differences in clinical sensitivity and specificity between either of the cTnI assays or CK-MB.
Data from the package insert for the Stratus troponin cTnI procedure define the expected clinical sensitivity for diagnosis of MI (see Table 2). These data clearly illustrate that the timing of sample collection is critically important for cTnI utilization, because there was a significant difference between cTnI and CK-MB mass assay in clinical sensitivity at both 0-4 hours (P = 0.012) and 5-11 hours (P = 0.021) after the onset of symptoms. However, in the time period after 12 hours, there was no difference in clinical sensitivity between these markers.
To further illustrate the importance of sample timing, an emergency medicine study revealed a temporal difference in clinical sensitivity between cTnI and CK-MB mass (see Table 3). Use of a troponin I decision point of 1.5 ng/mL showed significantly lower clinical sensitivity compared with CK-MB mass at both 2 hours (P = 0.0001) and at 6 hours (P = 0.00016) after presentation. Further, Table 3 indicates that even use of a more sensitive cutoff of 0.6 ng/mL also showed statistically significant differences between cTnI and CK-MB at 2 hours (P [less than] 0.0238) and 6 hours (P = 0.025). No difference in clinical sensitivities was noted at 12-24 hours after onset of symptoms. Clinical specificity for MI diagnosis exceeded 97% for cTnI in all time frames examined.
For diagnosis of MI, serial sampling is necessary unless results of the first measurement exceed the decision point. To optimize clinical sensitivity for MI diagnosis, the data above and overall indicate that troponin I samples must be collected for 12 hours after onset of symptoms.
Cardiac troponin T for MI diagnosis. A meta-analysis found that at 12 hours after onset of symptoms, cTnT had a clinical sensitivity of 98.2% (CI: 97-99%) for diagnosis of MI. However, clinical specificity for cTnT was 68.8% (CI: 66-72%), which was significantly lower than CK-MB mass (P [less than] 0.001). The most likely explanation for this difference was attributed to positive cTnT results from the inclusion of patients with minor myocardial injury associated with unstable angina. As will be presented later, these positive cTnT results are important, because they identify unstable angina patients at increased risk for adverse cardiac events. Also, since this metaanalysis was performed, even more cardiac-specific second- and third-generation versions of the cTnT assay have become available.
Clinical sensitivity for cTnT is also time dependent (see Table 3). For optimal clinical sensitivity when using cTnT to diagnose MI, samples must be collected 8-12 hours after the onset of symptoms.
Cardiac troponins T and I for risk stratification. For patients with acute coronary syndrome, measurement of troponins T or I has been shown to identify patients at increased risk for adverse events (MI and death) in both the short term (presentation to about 40 days later), and long term (greater than 6 months after the index event). This use of cardiac markers to stratify risk is an area of great potential for a positive impact on healthcare.
Use of troponin I for risk stratification was demonstrated in a study that measured this marker at enrollment for 1,404 patients. Of this total population, 845 patients presented more than 6 hours after onset of clinical symptoms suggestive of acute coronary syndrome; these later-presenting patients were the focus for much of the analysis. The troponin I decision point used in this study was 0.4 ng/mL, which was the minimum detectable concentration of the assay used. This study showed that for each increase of 1.0 ng/mL in troponin I, the risk of 42-day mortality was significant after correction for baseline variables of age and ST-segment [TABULAR DATA FOR TABLE 2 OMITTED] depression. Troponin I measurement at enrollment was an independent risk factor for 42-day mortality, and timing of troponin I measurement was important. Another important finding was that among patients presenting more than 6 hours after onset of symptoms suggestive of acute coronary syndrome, troponin I measurement was prognostic when the CK-MB mass was within the reference interval, presumably because CK-MB has insufficient sensitivity and specificity for microinfarction.
Troponin T measurements at enrollment were examined for use in risk stratification in a GUSTO IIa substudy, using an outcome of 30-day mortality for 801 patients with acute coronary syndromes. For these patients, troponin T measurement was an independent risk factor that demonstrated a larger contribution for predicting 30-day mortality than either ECG category or CK-MB mass result. Further, this study used logistic regression analysis to demonstrate that after adjusting for ECG category and baseline CK-MB mass concentration, troponin T's contribution to prediction of 30-day mortality was highly significant (P = 0.027). However, after adjustment for troponin T and ECG category, CK-MB results did not add significantly to the ability of the model to predict 30-day mortality (P = 0.717). Thus, CK-MB mass results are not useful to stratify risk when troponin T measurements are available, as was also found for troponin I.
The two aforementioned troponin studies included only enrollment or "baseline" samples. The contribution of later troponin T measurements, (at 8 hours and 16 hours after onset of symptoms) for improving mortality predictions at 30 days and 1 year was reported in the GUSTO IIa population. The 8-hour troponin T measurement added significantly to baseline measurements (P = 0.0015) in a logistic regression model for predicting 1-year mortality. The 16-hour troponin T measurement significantly improved the predictive ability of the model for both 30-day (P = 0.0382) and 1-year mortality (P = 0.0004). Data also indicate that it is not necessary to collect both 8-hour and 16-hour samples because together they do not add significant information to the predictive ability of cTnT. This study showed that serial sampling at baseline and then at 8 hours or (preferably) 16 hours is useful for evaluating the risk of serious cardiac events.
Are troponins T and I equivalent for risk stratification? The answer has several components, among which is the timing of specimen collection and differences in methods among troponin I assays. These issues were evaluated by using the GUSTO IIa cohort to examine performance of troponins T and I in baseline samples and their ability to predict risk of 30-day mortality. In a combined logistic regression analysis where 30-day mortality was the outcome, quantitative results from both troponins T and I were considered continuous variables along with the ECG. For a model developed with the ECG and troponin T, predictive ability was not improved significantly (P = 0.675) when troponin I was added. However, prediction of 30-day mortality was significantly improved (P = 0.045) when troponin T was added to a model containing ECG category and troponin I.
It is noteworthy that when later samples (collected at 8 and 16 hours after onset of symptoms) are included, troponin I's ability to predict mortality seemed to approach that of the combination model involving troponin T and the ECG. Preliminary analysis of GUSTO IIa data indicates that after adding the 8-hour or 16-hour samples, there was no difference between the ability of troponins T and I to predict 30-day mortality. To underscore this point, a meta-analysis was conducted comparing troponins T and I to evaluate risk stratification in unstable angina patients. The studies included in the meta-analysis used results from specimens collected within 12-24 hours of presentation or chest pain. This meta-analysis revealed no significant difference between troponins T and I for predicting nonfatal MI and death.
Both troponin T and I can be assayed at the point of care, and the potential contribution from these technologies was examined in a strategy that evaluated results for qualitative troponins T and I in 773 patients with acute chest pain to determine risk of nonfatal MI and mortality in the 30 days after the index event. Patients with ST-segment elevation were excluded from the study, and sampling was performed at presentation and then at 6 or more hours after symptoms onset. The risk of nonfatal MI or cardiac death in patients with negative test results was extremely low, as only 1.1% of the patients with negative results for troponin T and 0.3% of the patients with negative results for troponin I had these outcomes within the 30-day follow-up period. It should be noted that the troponin T qualitative device used in this study is no longer available because a more sensitive qualitative troponin T device has replaced it. The study supported the need for serial sampling to assess risk and concluded that, while qualitative results for troponins T or I cannot replace clinical evaluation, qualitative troponin results should be available for emergency medicine caregivers and chest-pain units.
Other potential markers
The WHO criteria that define cardiac ischemia as binary may soon be archaic, because this ischemia is part of the disease continuum for acute coronary syndromes [ILLUSTRATION FOR FIGURE 1 OMITTED]. Identifying each patient's status in the continuum has biologic implications for reversibility of injury, quantity of ischemic cell injury, and the patient's relative risk for an adverse outcome.
As stated earlier, much of the focus for biochemical markers has included markers of necrosis. However, other substances (see Table 1) can be used as markers, because they are released or activated at some point during the periods of plaque rupture through ischemia that may precede necrosis. These markers would then have an important role in identifying risk for the patient with acute coronary syndrome. The acute phase proteins, such as C-reactive protein (CRP) and serum amyloid A (SAA), are nonspecific, but their increase may help identify patients with unstable coronary plaques and may be prognostic in patients with unstable angina. As the plaques are disrupted, cytokines are released from activated monocytes and macrophages at the disrupted site. A possible component of the observed association between acute phase proteins and increased risk is that these proteins may reflect infectious disease within the coronary vessels. Aspirin or other nonsteroidal anti-inflammatory agents may reduce risk for patients with coronary artery disease (CAD), presumably by inhibiting the inflammatory process.
Platelet activation is important in the mechanism of thrombus formation and the progression of acute coronary syndromes. Indicators of platelet activation may help assess a patient's tendency for intracoronary thrombosis. Tests for platelet activation must be performed within 3 hours of blood collection. Examples of indicators include platelet aggregation studies or assays for levels of P-selectin, an adhesion molecule expressed on the surface of [TABULAR DATA FOR TABLE 3 OMITTED] activated platelets. Expression of P-selectin may indicate risk for acute coronary events. Platelet activation can result from contact with exposed collagen, thrombin, and/or other agonists induced by plaque disruption. Markers of activated platelets may indicate their tendency to adhere to leukocytes, causing platelet accumulation and consequent thrombotic complications.
Thrombus formation is fundamental to occlusion of the infarct-related artery, and thus markers of thrombosis, including soluble fibrin and fibrin degradation products, may reveal a recent thrombotic process or risk of an impending event. Although not sensitive or specific enough to diagnose MI, soluble fibrin and cross-linked fibrin degradation products are increased in patients who are at higher risk for complications. Soluble fibrin is a marker for precoagulant fibrinolytic products that may predict patients at a higher risk for MI-related complications.
A biochemical marker of myocardial ischemia that occurs in the absense of or before infarction would also help locate a patient's position on the continuum of acute coronary syndrome. Glycogen phosphorylase-BB (GP-BB) is reportedly increased in association with ischemia without necrosis and may be a potential marker of ischemia. Release of GP-BB is linked to the sudden burst of glycogenolysis that occurs in the injured myocardium after acute ischemia.
In the future, the markers of plaque rupture, indicators of activated platelets and/or intracoronary thrombosis and myocardial ischemia, and markers of necrosis may be combined with clinical indicators, the ECG, echocardiogram, and imaging studies in an integrated approach for assessing patient risk.
Guidance of therapy
Strong evidence supports troponins T and I as indicators of increased risk for patients with acute coronary syndrome, and efforts are underway to determine whether therapeutic intervention can reduce this risk. These activities are confluent with efforts from the therapeutics industry, because many drugs for patients with acute coronary syndrome are expensive, and definitive benefit is difficult to demonstrate. This combination of high costs and minimal outcomes-based evidence forces healthcare institutions to seek ways to minimize use of therapy for all patients who only exhibit physical symptoms of MI. Exciting future strategies to minimize overuse of cardiac therapeutics could include biochemical markers to identify patients at increased risk who would likely benefit from therapies. To gain insight into the future role of cardiac markers, and indeed other in vitro diagnostics as well, it is important to monitor the direction and evidence base of therapeutics and therapeutic trials. Two examples of the potential role for cardiac markers in the guidance of intervention are presented below.
The FRISC study examined the potential of using troponin T assays to identify patients with unstable CAD who might benefit from therapeutic intervention. This issue was investigated by measuring serum troponin T levels from 971 patients who received either placebo or low-molecular-weight heparin (LMWH) in short-term (6-day) or long-term (5-week) regimens. Among patients having troponin T levels below a cutoff of less than 0.1 [[micro]gram]/L, short-term treatment showed no significant decrease in the incidence of death and/or MI. However, for patients with levels of troponin T greater than or equal to 0.1 [[micro]gram]/L, differences in the incidence of death and MI were significant (P [less than] 0.05), as the event rate was 6.0% in the placebo group versus 2.5% for short-term treatment. Long-term treatment with LMWH revealed more dramatic results. For patients with troponin T levels greater than or equal to 0.1 [[micro]gram]/L, death and/or MI occurred at a rate nearly double in the placebo group compared with the group receiving LMWH (14.2% vs. 7.4%; P [less than] 0.01). Conversely, troponin T levels less than 0.1 [[micro]gram]/L identified a low-risk group in whom death and MI showed no difference between the LMWH-treated and placebo groups. This study indicated that elevated troponin T concentrations could potentially identify patients who would benefit from long-term treatment with LMWH.
An important focus in cardiovascular therapeutics has been development of antagonists of the platelet glycoprotein (GP) IIb/IIIa receptor, for which conformational changes are the final step in platelet activation. These antagonists prevent platelets from becoming activated and contributing to the potential of thrombosis. The CAPTURE study included unstable angina patients who were randomized to receive either a GP IIb/IIIa receptor inhibitor or a placebo [ILLUSTRATION FOR FIGURE 2 OMITTED]. Before randomization, troponin T levels were measured for each patient, who was then classified as either positive or negative and received either placebo or GP IIb/IIIa receptor inhibitor. In the 24-36 hours after receiving either therapy, cardiac catheterization was performed with angioplasty if necessary. The patients for whom the troponin T was below the cutoff used in the study showed a low incidence of death or MI while awaiting cardiac catheterization [ILLUSTRATION FOR FIGURE 2 OMITTED]. Likewise, the patients with positive troponin T results who received the GP IIb/IIIa inhibitor had a similarly low rate of death or MI. However, if they were receiving the placebo and were positive for troponin T, patients had a significantly higher event rate of 4.1% (P = 0.03) compared with the troponin T group who received the platelet inhibitor [ILLUSTRATION FOR FIGURE 2 OMITTED]. Thus, in the CAPTURE trial, troponin T measurements identified a group that benefited from administration of the GP IIb/IIIa inhibitor. Troponin T measurement may help identify those patients with acute coronary syndrome who could benefit from these antagonists.
The acute coronary syndromes are a continuum of myocardial ischemia ranging from angina, indicating reversible tissue injury, through frank MI with extensive tissue necrosis. A new generation of biochemical markers for indicating plaque disruption, platelet reactivity, and early MI offers promise for better assessment of patient risk so that clinicians may intervene to avoid adverse outcomes. Although historically CK-MB has been a useful marker for the diagnosis of MI according to WHO criteria, troponins T and I have emerged as sensitive, more cardiac-specific clinical indicators that are useful for MI diagnosis and even for risk stratification. Other biochemical markers, including the acute phase reactants CRP and SAA, markers of platelet reactivity (P-selectin), and markers of thrombosis, may become useful for identifying a patient's location on the spectrum of acute coronary syndrome and thus the risk of adverse events.
Biochemical markers will continue to play a traditional role in the work-up for MI patients. However, along with the ECG and clinical judgment, these markers are also becoming an important adjunct for patient decision-making. Some studies have also indicated that troponin T or I can be used to guide therapeutic intervention. Heart disease is the biggest killer in the Western world, and this is unlikely to change in the future. The importance of cardiac marker assays will increase in the future, particularly as the knowledge accumulates regarding use of these markers to guide treatment.
To earn CEUs, see test on page 40.
1. Explain the concept and milestones of the spectrum of acute coronary syndromes.
2. Compare and contrast the usefulness of any 3 biochemical markers in locating a patient's position on the acute coronary syndromes continuum.
3. Discuss 1 example of how a cardiac marker may be useful in guiding therapeutic intervention.
CE test published through an educational grant from
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Robert H. Christenson is director of clinical chemistry and rapid response laboratories at the University of Maryland Medical Center and professor of pathology and medical and research technology at the University of Maryland School of Medicine in Baltimore.
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|Title Annotation:||Cardiac Markers|
|Author:||Christenson, Robert H.|
|Publication:||Medical Laboratory Observer|
|Date:||Sep 1, 1999|
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