In medicine, as in all human communication, it is essential to define the entities being discussed clearly. The history of medicine is replete with examples of communication failure resulting from poor definition of a particular disease entity. In clinical practice, as well as in clinical science, a clear definition of the disease diagnosed or studied is the first step in achieving effective control of that illness. Accurate, clear, and easily interpreted definitions of a disease entity allow physicians to communicate with each other, study the disease, and ultimately explain to patients the implications of the specific condition from which the patient suffers. A clinical scientist’s diagnostic criteria must be accurate and reproducible, so that similar patients with the disease being studied can be entered into clinical trials. Eventually, the results of clinical trials involving patients with clearly defined diagnoses can be generalized for the management of other patients who satisfy the same disease criteria. Results from one clinical trial can be compared with the results of others, as long as the same disease definition and criteria are used.
Given the worldwide importance of morbidity and mortality related to cardiovascular disease, considerable scientific effort has been placed on identifying tools for defining the various syndromes of acute ischemic heart disease accurately. Biomarkers are adjunctive tests used with clinical findings to aid the physician in making an accurate clinical diagnosis of a specific disease entity, as well as in predicting its prognosis. Various biomarkers have been used for decades in patients with acute ischemic heart disease; however, the advent of highly specific troponin assays has resulted in a substantially improved ability to identify patients with acute ischemic heart disease and to gauge the level of risk of morbidity and mortality associated with these syndromes. Other biomarkers have been used in the past to detect myocardial necrosis; however, their use has been markedly attenuated with the advent of routine troponin determinations in daily clinical practice and clinical investigation.
What is a Biomarker?
The term was introduced in 1989 to mean a measurable and quantifiable biologic parameter (e.g., a concentration of a specific biologic substance) obtained from an individual. Its concentration implies certain pathophysiologic consequences. A variety of such biomarkers have been identified in a vast array of diseases. Most often, biomarkers are measured from blood samples. However, biomarkers from other body fluids or tissues are also of clinical and research significance.
The goal of cardiovascular biomarker determination is to enable clinicians to manage patients with heart and vascular disease optimally by defining the presence of a specific pathophysiologic process and by obtaining prognostic information about the disease that is present. A biomarker is valuable only if it can be accurately and reproducibly determined in clinical chemistry laboratories worldwide. The biomarker determination must be made under standardized conditions and associated with a high degree of sensitivity and specificity. Finally, the determination of specific biomarker levels must contribute to the overall management of the patient with the disease entity under evaluation if they are to be deemed cost-effective. Meticulous laboratory techniques must be used in collecting, processing, and measuring biomarkers if the values obtained are to be accurate and reproducible. Inadequate attention paid to the accuracy and reproducibility of the biomarker used can and will lead to confusion in the clinical setting, with possible associated medical error.
Biomarkers imply a variety of features about an individual’s state of health or disease. Thus, biomarkers are seen to be indicators of the presence or absence of a disease or disease trait. The use of troponin blood assays to define various syndromes of acute ischemic heart disease has gained worldwide use. Specifically, in the appropriate clinical setting, an elevated blood troponin level is used today as the gold standard for identifying acute ischemic myocardial necrosis—that is, acute myocardial infarction (MI).
The clinical definition of acute MI was one of the earliest disease entities for which biomarker diagnostic support was sought. Unfortunately, and until recently, the ideal of a universally understood and applied definition involving biomarker determination did not exist for MI. Over many decades, different definitions of MI have been used and, consequently, confusion has existed about the exact definition of MI. In the arena of public health statistics, similar problems have existed with different studies using varying definitions of MI. Statistics based on hospital discharge diagnosis of MI are also often inaccurate because the definitions of MI used vary from one physician to another.
As recently as 40 years ago, the biomarkers used for the diagnosis of acute MI were nonspecific, and often the assays were not highly reproducible from one laboratory to another. This led to intense scientific efforts to develop a highly reproducible, sensitive, and specific biomarker to identify myocardial necrosis to create a clearly defined algorithm for the definition of MI in its acute phase.
More than 30 years ago, the World Health Organization (WHO) sought to define MI accurately. The criteria used, however, were often nonspecific or open to important interpretation bias. Thus, a patient’s clinical chest discomfort or an equivalent symptom, for example, sudden onset of unexplained dyspnea, might be interpreted differently by different observers. Similarly, a reading of the same electrocardiogram (ECG) might vary among different expert electrocardiographers. Early biomarkers were nonspecific and assays were not highly reproducible. Consequently, biomarker measurement was not an important component of the original WHO definition of acute MI.
In an attempt to improve the accuracy of the diagnosis of MI for clinicians, and to make it easier to compare results from various clinical trials, a multinational task force met in 1999 under the auspices of the European Society of Cardiology and the American College of Cardiology. The task force sought to develop a simple, clinically oriented, universal definition for MI that could be used in daily clinical practice and in clinical investigation. The task force was successful in creating this definition, which was published simultaneously in the European Heart Journal and the Journal of the American College of Cardiology .
Central to this new definition of MI was the use of highly sensitive and specific biomarkers determined from serial blood samples. The particular biomarker that has gained almost universal use in the diagnosis of MI is troponin ( Fig. 12-1 ). This biomarker enables clinicians and clinical scientists to identify even small quantities of necrotic myocardium in the clinical setting. Given specific clinical settings and associated findings, such as ischemic changes in the ECG, the report of the task force in 2000 set criteria for both acute and established MI. Recently, the definition was revised, based on scientific advances that have occurred since 2000.
The global definition of MI from the 2000 and 2007 reports , is based on troponin analysis and identify infarcts that may be too small to be seen with the naked eye during a routine pathologic examination. Biomarker diagnosis in patients with acute ischemic heart disease has become an essential component of the their diagnostic evaluation and care. The use of troponin level determinations in the routine management of patients with acute ischemic heart disease aids clinicians and clinical scientists more than merely making the diagnosis of myocardial necrosis more accurate. The presence and degree of elevation of blood troponin levels in a patient with an acute ischemic syndrome has important prognostic and therapeutic implications (see later).
Since the publication of the European Society of Cardiology (ESC)–American College of Cardiology (ACC) report in 2000, which emphasized the use of newer, highly sensitive and specific biomarkers of myocardial cell necrosis in the diagnosis of MI, many investigators have explored the implications of the revised definition of MI as compared with older, more traditional (and less specific) diagnostic criteria. These studies have demonstrated that the modern troponin-based definition of MI has resulted in an increased number of patients identified as having had an MI. This finding is not surprising, because troponin is considerably more sensitive when compared with earlier biomarkers, such as creatine kinase MB (CK-MB). Because troponin identifies smaller infarcts than CK-MB, the acute or short-term prognosis for patients with troponin-positive, CK-MB–negative infarcts is better than that for patients with elevated troponin and CK-MB values.
This increase in the number of patients labeled with the disease entity, myocardial infarction, presents clinical and investigative cardiologists with a number of problems. For example, a patient who formerly would have been diagnosed as a case of angina pectoris or even unstable angina now falls under the diagnostic rubric of MI. The latter diagnosis carries important psychological and social implications for the patient. Depending on the patient’s employment, certain careers may be interdicted by a diagnosis of MI and the specter of disability may be raised by the patient, family members, and/or employer. The personal and societal implications of the troponin-based definition of acute MI are discussed more fully later.
Given the importance of myocardial infarction seen from a clinical and societal perspective, the prospective investigation of Roger and colleagues is of considerable scientific and clinical impact. These investigators used several standardized definitions of MI, including the one suggested by the first task force for the revision of the definition. This comparison involved almost 2000 patients with the following discharge diagnoses—acute and old MI, unstable angina, coronary heart disease, angina pectoris, and other forms of ischemic heart disease. All patients had at least one, and often serial, determinations of blood troponin, creatine kinase (CK), and MB fraction of CK levels. The biochemical data were correlated with clinical information and short-term (30-day) outcome.
As expected, the new (troponin) definition of MI identified substantially more patients with ischemic myocardial necrosis than CK alone or CK combined with CK-MB. Depending on the level of troponin selected as the cutoff point beyond which MI was diagnosed, as well as on the number of samples taken, the percentage increase in the number of infarcts diagnosed by troponin alone ranged from 35% to 112%. Equally interesting was a much smaller but noticeable group of patients who were diagnosed as having had an MI by their elevated CK-MB level, despite having a normal troponin value. Clearly, this small but clinically important group of patients was falsely diagnosed by the CK-MB criterion as substantiated by their excellent prognosis, both in the study by Roger and associates and in others. However, the prognosis of those patients with smaller infarctions diagnosed solely by abnormal troponin values was better at 30 days (5% mortality) as compared with patients with larger infarctions who had both elevated troponin and positive CK or CK-MB (11% mortality) levels. These observations underscore the fact that troponin analysis increases sensitivity and specificity of infarct diagnosis.
Diagnostic Application of Biomarkers in the Universal Definition of Myocardial Infarction
There have been considerable advances in the diagnosis and management of myocardial infarction since the original redefinition document was published. Consequently, together with the World Heart Federation (WHF), the ESC, ACC, and American Heart Association (AHA) convened a global task force to update the 2000 consensus document. As with the previous consensus committee, the global task force was composed of a number of working groups to refine as precisely as possible the original ESC-ACC criteria for the diagnosis of MI from various perspectives. With this goal in mind, the working groups were composed of experts in the fields of biomarkers, electrocardiography, imaging, interventional cardiology, clinical investigation, and global perspectives and implications. During several task force meetings, the recommendations of the working groups were co-coordinated, resulting in an updated consensus document.
Myocardial infarction is defined by pathology as myocardial cell death caused by prolonged ischemia. In a clinical setting, these conditions are met if the following criteria are present:
- 1
Detection of increase and/or decrease of cardiac biomarker levels
- 2
At least one value above the 99th percentile of the upper reference limit (URL), together with evidence of myocardial ischemia, as recognized by at least one of the following:
- •
Symptoms of ischemia
- •
ECG changes of new ischemia or development of pathologic Q waves,
- •
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
- •
Cardiac troponins I and T are the preferred markers for the diagnosis of myocardial injury because the troponins have almost absolute myocardial tissue specificity, as well as high sensitivity, thereby reflecting even microscopic zones of myocardial necrosis. An increased value for cardiac troponin is defined as a measurement exceeding the 99th percentile of the URL. Detection of an increase and/or fall of the measurements is essential for the diagnosis of acute myocardial infarction (AMI), and optimal precision at the 99th percentile URL for each assay should be defined as a coefficient of variation (CV) ≤10%. , If troponin assays are not available, the best alternative is the MB fraction of CK as measured by mass assay. As with troponin, an increased CK-MB mass value is defined as a measurement above the 99th percentile URL using gender-appropriate normal ranges.
The increased sensitivity and specificity of the troponin biomarker depend not only on measuring the presence of the troponin molecule, but also on the ability of the assay to provide the necessary information. Some assays, including most of those developed for point of care use, are not nearly as sensitive as those performed on the larger pieces of equipment used in central laboratories. One needs to be cautious in using point of care assays to avoid underidentification of patients at risk. There are also other problems that must be considered. Fibrin interference can occur and cause an occasional high troponin value. If a value appears to be out of proportion to other values, it is suggested that the sample be respun and reassayed, especially if serum samples are being used. Uncommonly, there can be cross-reacting antibodies or antibodies to the proteins used to make the antibodies for troponin detection. , In general, this artifact is easy to detect. It should be suspected when values are elevated and stay reasonably constant over time.
As troponin assays have become more sensitive, it has become increasingly clear that a changing pattern of values is the key to distinguishing acute problems from more chronic ones. The ability to detect changes is heavily dependent on the precision of the assay. In general, there has been an advocacy for a 10% coefficient of variability at the 99th percentile of a normal population. , This standard has rarely been met with current assays, in which variability is substantially higher. For a while, this led some to advocate the use of a cutoff value equivalent to the 10% CV value to protect against false-positive results caused by imprecision. This turns out to be unnecessary because it is now clear that true normal values are far lower than those that can be measured with contemporary assays. However, assay imprecision makes it much more difficult to detect when a true increase occurs. Thus, assays that are very imprecise will require very large values to show differences, whereas those that are more precise will require lower values. Usually, once values are significantly elevated, all assays yield fairly good results, with relatively low levels of imprecision. In that situation, a 20% change, or roughly an approximately 5% to 7% CV, can be assumed.
If one uses sensitive assays and the 99th percentile URL, the troponin level will be seen to increase more rapidly than the CK-MB level (see Fig. 12-1 ); the use of biomarkers such as myoglobin and other putatively rapidly increasing markers is thus no longer necessary to establish the diagnosis of AMI. This value also maximizes the sensitivity and specificity of troponin values in patients with MI ( Fig. 12-2 ). In addition, the diagnosis of AMI can be made in as many as 80% of patients within 3 hours of presentation, even if one selects a cohort that presents early (all within 4 hours) to evaluate. Late detection is also facilitated. This is because the rate of increase of the troponin level allows one to detect these values at an earlier point in time. The use of the rate of increase and the association with the 99th percentile URL facilitates the rapidity and accuracy of diagnosis.
Both cardiac troponin I (cTnI) and cardiac troponin T (cTnT), assuming good assays and appropriate cutoff values, perform comparably in terms of their diagnostic proficiency. The one difference occurs in renal failure patients, in whom there are many more elevations of cTnT than cTnI levels. Pathologic studies have suggested that these elevations denote cardiac abnormalities and are highly prognostic. Thus, patients who have elevated levels of cTnT require evaluation, but they may not have acute myocardial disease. When these patients present with MI, their subsequent cTn values increase from the elevated baseline. A rising pattern of cTn values distinguishes those who have acute disease from those with chronic elevations. Patients with troponin level elevations and MI are a particularly high-risk group.
The prognostic significance of troponin seems to exist across heterogeneous clinical situations. Once the diagnosis of acute coronary syndrome is confirmed, the prognostic significance of an elevated troponin level is clear. In patients who have ST-segment elevation MI (STEMI), those with elevated troponin levels are at increased risk for subsequent adverse events. , This is partially related to the fact that it takes time for the troponin level to increase. However, when analyses have been done attempting to correct for the time from the onset of symptoms to presentation, the effect is still noted. In studies with primary angioplasty, the procedural success rate is lower if the troponin level is elevated at the time of presentation than if it is not. With non-STEMI (NSTEMI), the finding of an elevated troponin level presages an adverse short-term outcome and usually indicates the need for aggressive anticoagulant therapy and early interventional therapy. However, there can be a heterogeneity of causes for myocardial infarction ( Table 12-1 ). MI can be a spontaneous event related to plaque rupture or fissuring, dissection of an atherosclerotic plaque or, as recently described, nodular plaque rupture, a type 1 MI. Alternatively, MI can be caused by increased myocardial oxygen demand when the ability of the heart to increase coronary supply is incommensurate with that demand. This could be the result of anemia, arrhythmia, hypertension or hypotension, vasoconstriction, or arterial spasm causing a marked reduction in the degree of myocardial blood flow, known as a type 2 MI. In addition, elevations of troponin levels associated with percutaneous coronary intervention (PCI; type 4a MI) should also be designated AMI because they are caused by ischemia. Another subtype of type 4 MI is type 4b, which is the result of stent thrombosis. Finally, elevations of troponin levels can be used to assist in the diagnosis of a type 5 MI (i.e., an infarct associated with coronary artery bypass grafting [CABG]). The one circumstance in which biomarkers are not of value is when the patient with a typical presentation for myocardial ischemia or MI dies before it is possible to detect blood biomarker elevation, either because the test sample was not obtained or measured before the patient succumbed. Such patients are designated as having a type 3 MI.
| Type | Features |
|---|---|
| 1 | Spontaneous myocardial infarction related to ischemia caused by a primary coronary event (e.g., plaque erosion or rupture, fissuring, dissection) |
| 2 | Myocardial infarction secondary to ischemia caused by imbalance between oxygen demand and supply (e.g., coronary spasm, anemia, hypotension) |
| 3 | Sudden cardiac death, with symptoms of ischemia, accompanied by new ST elevation or left bundle branch block, or verified coronary thrombus by angiography or autopsy, but death occurring before blood samples could be obtained |
| 4a | MI associated with PCI |
| 4b | MI associated with verified stent thrombosis |
| 5 | MI associated with CABG |
Once elevations of biomarkers are present, as in these patients, attempting to differentiate the effects of the NSTEMI on the troponin levels from those associated with the PCI itself is impossible, which is why a normal baseline value is essential if a diagnosis of post-PCI AMI is to be made. The prognostic significance of an elevated troponin value is related to the magnitude of the elevation. As smaller and smaller degrees of cardiac injury can be detected, prognosis of those patients with lower values is slightly less adverse than in those who present with higher values. Troponin measurement is also helpful in the management of patients with acute coronary syndromes and in the post-PCI setting, as noted, as well as in the diagnosis of reinfarction when patients have recurrent chest discomfort. Recent data have suggested that the troponin measurement is as accurate as the determination of CK-MB for identifying reinfarction ( Fig. 12-3 ). , Given the increased sensitivity and specificity of troponin, one would suspect that if a trial were performed comparing troponin with CK-MB for the identification of reinfarction, the former biomarker would actually be superior (see Fig. 12-3 ).
Effect of the New Troponin-Based Definition of Myocardial Infarction
The ESC and ACC redefined the criteria for the diagnosis of MI in 2000. , The diagnosis was changed from one based on epidemiology to a definition based on elevation of the troponin level in the clinical setting of myocardial ischemia. This change dramatically increased the frequency of the diagnosis of MI and affected epidemiologic studies and clinical practice, with the prognosis for MI being improved. Employment, health insurance, and evaluation of health care delivery have also been affected.
In a small study of 401 patients admitted with suspected cardiac chest pain, implementation of the redefinition criteria increased the numbers of patients with an MI by 26.1% as compared with the WHO classification. It is notable that the WHO criteria resulted in false-positive rates of MI diagnosis of approximately 5%. Most of the additional patients with the diagnosis of MI were previously diagnosed as having unstable angina but 33% were previously diagnosed as having other cardiac or noncardiac diagnoses.
In a prospective U.S. community study of 1851 patients presenting with cardiac pain, the use of contemporary cut points for troponin T assays (with an increase or decrease >0.03 µg/mL for the diagnosis of MI), there was a 74% increase over CK and a 41% increase over CK-MB criteria for MI. If a criterion of an increase in only one troponin level was used, the increase in diagnosis over the CK criterion was 112%. The increase was particularly robust in women. Patients diagnosed with troponin-only criteria were at increased risk but at less risk than those who also had elevated CK-MB levels.
General Implications of Redefining Myocardial Infarction
Evolution of the definition of a specific diagnosis such as AMI has a number of implications for individuals, as well as for society at large. The process of assigning a specific diagnosis to a patient should be associated with a specific value for that patient. The resources spent on recording and tracking a particular diagnosis must also have a specific value to society to justify the effort. A tentative or final diagnosis is the basis for advice about further diagnostic testing, treatment, lifestyle changes, and prognosis for the patient. The aggregate of patients with a particular diagnosis is the basis for health care planning and policy and resource allocation.
One of the goals of good clinical practice is to reach a definitive and specific diagnosis, supported by current scientific knowledge. The currently revised approach to the definition of MI meets this goal. Thus, the current diagnosis of AMI is a clinical diagnosis based on patient symptoms, ECG changes, and highly sensitive biochemical markers, as well as information gleaned from various imaging techniques. However, it is important to characterize the extent of the infarct, residual left ventricular function, and severity of associated coronary artery disease, as opposed merely to diagnosing MI. The information conveyed about the patient’s prognosis and ability to return to work requires more than just the statement that the patient has suffered an infarct. The other factors noted are also required so that appropriate social, family, and employment decisions can be made. A number of risk scores have been developed for predicting postinfarction prognosis. The classification of the various other prognostic entities associated with myocardial necrosis should lead to a reconsideration of the clinical coding entities currently used for patients with the myriad conditions that can lead to myocardial necrosis, with consequent elevation of biomarker levels.
The change in the definition of MI will have a substantial impact on the identification, prevention, and treatment of cardiovascular disease globally. The new definition will affect epidemiologic data from developing countries relating to prevalence and incidence. Cultural, financial, structural, and organizational problems relating to diagnosis and therapy of AMI will require ongoing investigation. It is essential that the gap between therapeutic and diagnostic advances be addressed in this expanding area of cardiovascular disease.
Case Studies of Correct Interpretation of Blood Troponin Results
The high sensitivity and specificity of abnormal blood troponin levels for the detection of myocardial cell necrosis represents a potential aid and possible hazard for the clinician. On the one hand, this highly sensitive biomarker can be used to demonstrate that a patient has suffered a small but potentially dangerous MI. This information should lead the clinician to follow an aggressive medical and often concomitant interventional therapeutic strategy. On the other hand, an elevated troponin level in a patient with multisystem disease involving pathologic states such as respiratory and renal failure usually signifies collateral myocardial necrosis secondary to the underlying medical conditions. The latter situation is not an ischemic MI and should not be treated as such. The section of this chapter dealing with troponin measurement and its implications has listed a number of clinical entities in addition to MI that could lead to abnormally elevated blood troponin levels. When elevated troponin levels are found in such patients, this invariably implies a worsened prognosis for the patient, even though an ischemic myocardial infarction has not occurred. The following three case studies will demonstrate the points just made.
Case 1
A 60-year-old man awakens in the early morning hours with a progressively severe episode of central chest discomfort. The patient has had stable angina pectoris for several years, treated medically. His physician has informed him about symptoms that might occur with an AMI and the patient dissolves first one and then a second nitroglycerin tablet beneath his tongue. The discomfort gradually fades after approximately 1 hour. His wife is awakened by her husband’s restlessness and insists that they drive immediately to the emergency department. On arrival at the hospital, an ECG demonstrates 1.5 mm of new ST-segment depression in leads V3 to V6. A blood troponin level obtained on admission to the emergency department is elevated. The patient is treated with additional aspirin, clopidogrel, low-molecular-weight heparin, and intravenous beta blockade. His discomfort has now completely resolved, and he is admitted to the hospital where later that morning he undergoes a cardiac catheterization. This demonstrates an ulcerated plaque with overlying thrombus almost totally occluding the mid–left anterior descending artery. The patient has this lesion treated with a stent. The patient is then started on an intravenous glycoprotein (GP) IIb/IIIa inhibitor in the catheterization laboratory, and later in the day statin and angiotensin-converting enzyme inhibitor therapy is initiated following the interventional cardiac procedure. His recovery is uneventful. A subsequent transthoracic echocardiogram a month later demonstrates mild to moderate hypokinesis of the anterior wall of the left ventricle.
C omment : This patient’s clinical scenario (symptoms and ECG abnormalities), taken together with an elevated blood troponin level, demonstrate that an AMI of the non–ST-segment elevation variety had occurred because of plaque rupture. This would be a type 1 AMI. The patient was managed appropriately with modern, evidence-based, medical and interventional therapy. His recovery was aided by establishing the correct diagnosis with the assistance of blood troponin measurement.
Case 2
A 50-year-old woman with chronic renal failure secondary to interstitial nephritis treated with chronic dialysis develops extensive bronchopneumonia. She is brought to the emergency department by her family, where hypoxemia and hypotension are documented. She is markedly tachypneic and requires intubation shortly after arriving in the emergency room. She is admitted to the medical intensive care unit (MICU) and has a stormy 3-week course there, which includes sepsis, delirium, and adult respiratory distress syndrome, complicated by recurrent bouts of severe hypoxemia and hypotension. Repeated ECGs demonstrate only modest nonspecific ST-T wave changes that are not noted to be labile. Several times during her protracted MICU admission, elevated blood troponin values are demonstrated. A transthoracic echocardiogram demonstrates mild, diffuse left ventricular dysfunction, with a global left ventricular ejection fraction of 48%. The patient is treated with assisted ventilation, frequent dialysis, intravenous antibiotics, and intravenous pressors. She gradually recovers. She does not undergo cardiac catheterization during her admission. Two months later, a repeat transthoracic echocardiogram demonstrates normal left ventricular function, with a global ejection fraction of 67%.
C omment : This patient had myocyte necrosis as a result of severe multisystem illness. The myocardial injury was correctly presumed to be the result of a combination of factors, including hypoxemia, hypotension, and markedly elevated blood values of various inflammatory cytokines. All these factors led to her modest myocardial injury. At no time during her hospitalization did her ECG or clinical course suggest acute ischemia. It is possible, however, that if atherosclerotic disease were present in this patient, that some of the myocyte necrosis detected by troponin could have been caused by myocardial ischemia secondary to presumably fixed atherosclerotic coronary artery disease. Her subsequently normal echocardiogram supports the diagnosis, made in the MICU, of myocyte necrosis secondary to the patient’s severe multisystem illness. Her myocardial injury subsequently resolved and her left ventricular ejection fraction normalized following her recovery.
Case 3
A 35-year-old man with known familial dilated cardiomyopathy and moderately symptomatic (New York Heart Association [NYHA] Class II) chronic congestive heart failure is managed as an outpatient with an extensive oral medical regimen consisting of carvedilol, lisinopril, furosemide, spironolactone, digoxin, aspirin, and isosorbide mononitrate. He is followed closely by his internist and cardiologist. He participates in a supervised cardiac rehabilitation exercise program, which includes a component of moderate weight training. On a routine office visit to the internist, the patient complains of right chest discomfort the day after upper extremity weight exercises. On physical examination, the physician notes moderate right pectoral muscle tenderness. Blood troponin and brain natriuretic peptide (BNP) levels are ordered. The results for both blood biomarkers are moderately elevated. The BNP value has been elevated in the past, but this is the first time that a troponin level has been measured. The patient does not have a family history of atherosclerotic heart disease or diabetes mellitus and his systolic blood pressure readings measured in the physician’s office and at home have always been below 110 mm Hg. A recent lipid panel was normal, with total cholesterol of 145 mg/dL and a low-density lipoprotein (LDL) cholesterol value of 68 mg/dL. His physicians discuss the laboratory and clinical findings and decide that the elevated troponin level is caused by his dilated cardiomyopathy and not by ischemic heart disease. The dosages of his medications are increased serially over several weeks. His BNP level returns to normal with increased medical therapy, but troponin levels remain mildly and persistently elevated. His chest discomfort resolves with local heat and rest. He reports that his effort dyspnea is improved with the increased intensity of medical therapy.
C omment : This patient’s elevated troponin value denotes ongoing myocyte necrosis secondary to his underlying familial dilated cardiomyopathy. It is possible that he has endothelial dysfunction or supply demand imbalance in the subendocardium and thus, in one sense, has some ischemic injury to his myocardium, but this is not the result of plaque rupture or atherosclerotic coronary heart disease. The elevated blood troponin value is not the result of atherosclerotic ischemic injury to his myocardium, and hence is not indicative of an acute AMI. However, a persistently elevated troponin level in a patient with chronic heart failure implies a poorer prognosis for this patient than would be the case if the blood troponin level had been normal.
These three scenarios are examples of elevated troponin blood levels in three patients with different causes for this abnormal laboratory result. In the first patient, the elevated troponin value together with supportive clinical information led to the diagnosis of AMI, with the institution of appropriate, evidence-based therapy. In the second case, the patient developed myocardial necrosis secondary to a life-threatening multisystem illness. This patient’s myocardium recovered once the patient’s severe illness resolved. In the third example, blood troponin levels were elevated secondary to a chronic pathologic process involving the patient’s myocardium. Atherosclerotic ischemic heart disease with plaque rupture and coronary arterial thrombosis was not present in either of the latter two patients.
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