Evolution of Myocardial Infarction and its Biomarkers: A Historical Perspective

INTRODUCTION

One hundred fifty (150) years ago, Rudolph Virchow (1821–1902) described the cellular basis of venothrombosis in pulmonary embolism.[1] Several scientific historians have synthesized these concepts as thrombogenesis. These concepts are known today as Virchow's Triad:[2]stasis, endothelial injury or vessel wall injury and hypercoagulabilty. Virchow did not propose the triad but consensus was reached proposing that thrombosis is the result of alterations in blood flow, vascular endothelial injury or alterations in the constitution of blood.[3] These theories were very similar to the description provided by Virchow of the pathophysiology of pulmonary embolism. We can assess and appreciate the applicability of these perceptions to current medicine, especially in cardiology.

It took a long time for cardiologists to understand the pathogenesis of myocardial infarction, requiring publication of a definition of infarction that was revised three times (1971, 2000, 2012) to help physicians identify the illness rapidly since early treatment is crucial in its prognosis. This article will focus on a brief historical sketch of the disease, including the important biomarkers CK-MB and troponin.

ACUTE CORONARY SYNDROME AND ACUTE MYOCARDIAL INFARCTION

The conventional wisdom is that coronary artery disease is thought to be a disease of modern human beings and related to contemporary lifestyles but a recent study in the Lancet[4] has shown us that the disease has been present since 4000 years. The authors studied whole body CT scans of 137 mummies from four geographical regions spanning more than 4000 years: ancient Egypt, ancient Peru, the Ancestral Puebloans of southwest America and the Unangan of the Aleutian Islands. Atherosclerosis was considered definite if a calcified plaque was seen in the wall of an artery and probable if calcifications were seen along the expected course of an artery. They found probable or definite atherosclerosis in 47/137 (34%) mummies. The authors concluded that atherosclerosis was common in premodern human beings, and raises the possibility of a basic predisposition to the disease. The study opens up a whole area of research.

For many years the pathogenesis of coronary artery disease and myocardial infarction were unknown. In 1879, the pathologist Ludvig Hektoen[3] (1863 – 1951) concluded that myocardial infarction is caused by coronary thrombosis. The clinicopathologic process linking coronary thrombosis, myocardial necrosis, and the clinical syndrome now recognized as acute coronary syndromes (ACS) which include unstable angina and non-ST segment and ST segment elevation acute myocardial infarction (AMI), was not elucidated until the beginning of this century. The processes described in Virchow's Triad are implicated in myocardial ischemia. We now understand that acute coronary syndrome is due to thrombosis of the coronary arteries. The pathophysiology of this clinical entity is characterized by coronary plaque disruption with superimposed thrombus formation, leading to myocardial ischemia and hence, myocardial damage.

Initially, the disease was thought to be fatal but in the beginning of the 20^th century, it was established that coronary thrombosis was not always fatal and physicians focused on treatment. James Herrick in 1912 established the importance of bed rest[5] and rest and supportive treatment were the only therapy for many years until the advent of the CCU in 1961. Modern therapy has included antiarrhythmic, pharmacological intervention, limitation of infarct size, antiplatelet/anticoagulant therapy, surgery (CABG) and reperfusion (PTCA). All of these treatment modalities lowered mortality.

We have come a long way in the treatment of ACS and AMI but physicians want more accuracy in identifying patients with AMI in the emergency room. AMI is still a major cause of mortality and morbidity. The highest risk of death occurs within the initial hours of onset of AMI.

The diagnosis of myocardial infarction has conventionally relied on the presence of chest pain or typical ST-segment and T-wave abnormalities on the 12-lead-electrocardiogram (ECG) and a rise in the serum concentrations of cardiac muscle enzymes. Most patients with ST-segment elevation have high cardiac muscle enzyme values indicating myocardial damage and will be admitted to a coronary care unit (CCU). However, a large number of patients with less specific ST-segment changes may not have increased cardiac muscle enzymes (in which case, it was called stable angina or non-cardiac chest pain in the past). It is in such subset of patients that the emergency room (ER) cardiologist need to decide whether to keep the patient in the hospital for observation or send home reasonably safely. Improper diagnosis of patients with chest pain often leads to inappropriate admission of patients without AMI and vice versa, hence, a highly sensitive and specific test for AMI that is relatively quick and easy to perform has been earnestly pursued. Such test became available to physicians and is known to us as cardiac biomarkers: substances that are released into the blood when the heart is damaged or stressed and are measured by immunoassay in patients suspected of ACS and AMI.

It is important to accurately and reproducibly define myocardial infarction since early recognition and institution of appropriate treatment is crucial to influencing the prognosis of the disease. The WHO, in 1971, published the first standardized definition of AMI. At that time, the WHO definition did not include biomarkers of cardiac necrosis because of their lack of specificity and reproducibility.[6]

In 1999, the Joint European Society of Cardiology (ESC) and the American College of Cardiology (ACC) Committee jointly proposed and published in 2000 the new definition for myocardial infarction, emphasizing the importance of sensitive serological biomarkers for the diagnosis of acute myocardial infarction (AMI). Both cardiac societies introduced cardiac troponins (cTn) as the gold standard.[7] The newer concept of diagnosis of AMI emphasized the importance of the 12-lead ECG and the assessment of early cardiac biomarkers since ECG by itself is often inadequate to diagnose AMI. Rapid identification of AMI is mandatory to initiate effective treatment for better prognosis.

The definition of AMI was again revised in 2012 because of important discoveries and developments in the diagnosis of cardiac necrosis, particularly in the settings of critical illnesses and post-revascularization, with consequent publication of the Third Universal Definition of Myocardial Infarction.[7] The American College of Cardiology (ACC) Foundation published in 2012 in the Journal of the American College of Cardiology (JACC) an expert consensus document on the practical clinical considerations in the interpretation of troponin elevations.[8]

Through the years, the most important cardiac biomarkers have been CK-MB and the troponins. We will consider their history and their future uses in ACS and acute myocardial infarction.

CK-MB

In the 1970s and 1980s, CK-MB was the standard for the diagnosis and quantitative assessment of myocardial infarction.

In high school biology we were taught that the muscles of the body function through the use of ATP, or adenosine triphosphate, to power contractions. Creatine kinase (CK) is an enzyme chiefly found in the brain, skeletal muscles, and heart. The heart, a muscle that continually contracts without a break, has a high energy requirement. Thus, when the heart muscle dies during myocardial infarction, it releases many molecules into the bloodstream, one of the more abundant being CK. There are three types of CK called isoenzymes: CK-MM, found in skeletal muscle and heart; CK-MB, found in the heart and rises when heart muscle is damaged; and CK-BB, found mostly in the brain.[6,7]

In 1966, Van der Ween and Willebrands showed that CK-MB is a highly specific marker of myocardial infarction.[6,7] Elegant animal studies showed that myocardial damage in AMI occurred over several hours and that mortality and morbidity was dependent on the extent of damage to the myocardium. It was recognized that by determining the total amount of CK released in the blood, it was possible to determine the extent of myocardial damage.[5] Total CK however, was deemed as non-specific.

In 1974, the first quantitative assay for CK-MB was published[7] in the American Journal of Cardiology. Since that time, the detection and quantification of CK-MB would dominate and motivate countless research projects and these corpus was published in mainstream cardiology journals.

The diagnosis of AMI by use of CK-MB required only 12-24 hours and the traditional 3 days in the CCU for those without infarction was reduced to one day. At that time, elevations of CK-MB was the most specific, accurate, and cost-effective means of detecting cardiac injury, hence CK-MB became the marker of choice for cardiac injury.

However, with reperfusion therapy it was imperative to identify patients with acute myocardial infarction earlier.[6] Separating patients with myocardial infarction in those with chest pain and non-Q-wave on ECG was difficult. Rapid assay of the subforms of CK-MB offered the potential to screen patients with ACS and to separate the group with infarction (necrosis) from those with ischemia only. Research has shown that CKMB subforms can diagnose AMI within six hours after the onset of symptoms, and more than 60% of infarctions were detectable within the first hour of arriving in the emergency room.[9]

The development of rapid, automated, and accurate laboratory testing for CK-MB revolutionized the treatment of patients with acute cardiac events in the 70s and 80s.[10] Elevations in CK-MB, in the context of a clinical diagnosis and ECG findings of ACS rapidly became the gold standard for identifying cardiac injury then. CK-MB allowed earlier diagnosis of AMI and detection of reinfarction, and the degree of elevation could be measured for estimation of infarct size. The assay of CK-MB subforms reliably detected myocardial infarction within the first six hours after the onset of symptoms, and its use could reduce admission to the coronary care unit by 50 to 70 percent, thereby reducing costs.[11]

However, it soon became apparent that its use was not sensitive and specific as it could be elevated also in other diseases. For example, in renal failure, up to 20% “false-positive” have been reported; this elevation is thought to be due to skeletal muscle injury. The medical literature reported other conditions that could increase CK-MB in the absence of cardiac injury: non-cardiac surgery, chest trauma, asthma, pulmonary embolism, chronic and acute muscle disease, head trauma, hyperventilation, and hypothyroidism. If the physician did not believe that the clinical presentation fits ACS, then assay elevation of CK-MB could be considered false positive.[10] Therefore, a cardiac biomarker with better specificity and sensitivity was needed.

Although the subforms of CK-MB are highly specific for acute myocardial infarction within the first 4-6 hours, it is not widely used but it could possibly be used to detect non-Q-wave myocardial infarction before reperfusion therapy. It can also be used in excluding AMI in individuals who come to the emergency room with chest pain and non-ST elevation ECG since it has a 99% negative predictive value.[5] Savings could be considerable.

Fortunately, as many cardiologists argue that it is time to stop using CK-MB for detecting myocardial infarction, troponin biomarker is gaining more enthusiasm to be the gold standard for the diagnosis of AMI.

TROPONIN

Troponins are regulatory proteins found in skeletal and cardiac muscle that is integral to muscle contraction. Cardiac troponins T (cTnT) and I (cTnI) control the calcium mediated interaction between actin and myosin.[11] Numerous research has proved its high sensitivity and specificity in the identification of cardiac muscle damage, and some institutions have stopped using CK-MB to save costs because use of both markers only increased costs.[10]

Troponin T was discovered by the German physician Hugo A. Katus in the University of Hedelberg in Germany. He also developed the troponin T assay. Troponins are crucial in the early diagnosis of ACS so that a consensus document was published on the proper interpretation of troponin elevation.[12] The upper limit of troponin T for normal individuals is <0.15 ng/ml.

Laboratory assay of troponin filled the need for a highly sensitive and specific marker of cardiac injury. The ability to measure cardiac specific markers has brought about or should bring about a change in the way we do and think about the management of ACS. Effective treatment of acute myocardial infarction requires swift decision that it is AMI we are dealing with so that appropriate treatment can be initiated promptly and improve prognosis. The ECG by itself is often inadequate to diagnose AMI. Important discoveries and development in the diagnosis of cardiac necrosis particularly in the context of critical illnesses and post-revascularization prompted re-evaluation of ACS and AMI and eventual publication of the Third Universal Definition of Myocardial Infarction[8] in the journal Circulation in 2012.

The cardiac troponins have become the cardiac markers of choice for patients with ACS. The ESC and ACC guidelines recommend that cardiac biomarkers should be measured at presentation in patients with suspected MI, and that the only biomarker that is recommended to be used for the diagnosis of AMI at this time is cardiac troponin due to its superior sensitivity and accuracy.[13,14] CK-MB assay is felt to be redundant as its assay does not add any additional information or enlightenment as to the correct management of the patient.

According to the ESC/ACC Foundation/AHA/World Heart Federation (WHF) guidelines, “AMI refers specifically to myocardial necrosis due to myocardial ischemia. However, although elevations in the serum levels of TnI, TnT, and CK-MB indicate the presence of injury-associated necrosis of myocardial cells, such elevations do not point to the underlying mechanism of the necrosis. While elevated troponin due to myocardial necrosis occurs in AMI, it can also be a product of predominantly nonischemic myocardial injury, as occurs in association with heart failure, arrhythmia, myocarditis, renal failure, pulmonary embolism, and percutaneous or surgical coronary procedures”.[8]

Assays for cTn, namely cTnI and cardiac troponin T (cTnT), are the preferred diagnostic tests for ACS, in particular non–ST-segment–elevation myocardial infarction, because of the tissue-specific expression of cTnI and cTnT in the myocardium. The results of cTn testing often guide the decision for coronary intervention.[15] There are many different commercially available troponin assays but their sensitivity, specificity, and precision vary considerably due to lack of standardization and other factors.[16]

There is a lot of confusion among clinicians concerning the proper interpretation of a raised serum cTn, and hence, many still order CK-MB measurement in conjunction with troponins. For example, patients with elevated troponin levels but negative CK-MB values who were formerly diagnosed with unstable angina or minor myocardial injury are now reclassified as non–ST-segment elevation MI (NSTEMI), even in the absence of diagnostic electrocardiogram (ECG) changes. Up to 80% of patients with acute MI will have an elevated troponin level within 2-3 hours of emergency department (ED) arrival, versus 6-9 hours or more with CK-MB and other cardiac markers. Therefore, some have advocated relying solely on troponin and discontinuing the use of CK-MB.[11] Nevertheless, CK-MB and other markers continue to be used in some hospitals to rule out MI and to monitor for additional cardiac muscle injury over time.

Cardiac troponins may not be detected in the serum for up to four hours after the onset of an acute coronary event, therefore the guidelines recommend that troponin be repeated after 12 hours if the troponin concentration on admission is not raised in an individual presenting with chest pain. Troponin T is measured using a single assay, and generally a cutoff value of 0.1 μg/litre is indicative of myocardial damage. In contrast, there are several cTnI assays with differing sensitivities and cutoff values. The ESC and ACC consensus document recommends that each laboratory should determine its cutoffs for each test at the 99^th percentile of normal with ≤10% coefficient of variation[11] Using these criteria, serum cTnI values indicative of myocyte necrosis/myocardial damage range from 0.1 to 2 μg/litre.[17]

Raised cardiac troponin concentrations are now accepted as the standard biochemical marker for the diagnosis of myocardial infarction.[18,19] However, cardiac markers are not necessary for the diagnosis of patients who present with ischemic chest pain and diagnostic ECGs with ST-segment elevation. These patients may be candidates for thrombolytic therapy or primary angioplasty. Treatment should not be delayed to wait for cardiac marker results, especially since the sensitivity is low in the first 6 hours after symptom onset. ACC/AHA guidelines recommend immediate reperfusion therapy for qualifying patients with ST-segment elevation MI (STEMI), without waiting for cardiac marker results.[20,21]

It is now clear that minor cardiac injury occurs in many situations, and in most circumstances, the associated increases in troponin values correlate with adverse short- and long-term outcomes[11], highlighting the fact that cardiac injury is a component of many non-ischemic syndromes and the physician must be familiar with these syndromes. The clinician, confronted with an elevated or raised troponin, must determine whether the raised troponin value is due to cardiac injury or not. Many clinicians still feel that CK-MB has a role in the diagnosis of an infarction, reinfarction, post procedure MI (CABG and PTCA), estimation of an infarct size and chronic troponin elevations.

The recent ACC/AHA/ESC Task Force for the Redefinition of Myocardial Infarction[8] recommended the use of troponin over CK-MB for this purpose. If used for reinfarction, a 20% change in troponin values is required for diagnosis (roughly 3 SD of the variability of the method once values are greater than the 99^th percentile). For reinfarction, changes in troponin values must correlate with the clinical status of the patient because an occasional patient will have a secondary rise in troponin (especially with cardiac troponin T) after ST-segment elevation myocardial infarction in the absence of symptoms.

Most of the marked elevations of CK-MB and/or troponin after intervention[22] are related to elevations of troponin at baseline and are missed by the less sensitive marker, CK-MB. When the baseline value is rising, distinguishing the troponin elevation related to the procedure from those that are due to the original presenting symptoms can be problematic. Key to this analysis is use of the 99^th percentile cutoff value because concentrations greater than the 99th percentile have prognostic significance.[23,24] Hence, the recent AHA/ACC/ESC Task Force for the Redefinition of Myocardial Infarction[8] suggested that post–percutaneous coronary intervention values are of use only if the baseline troponin value is within the normal range or remains unchanged over time.

Many clinicians still believe that CK-MB assist in evaluating subsets of patients who have chronic troponin elevations such as those that occur in renal failure patients, the critically ill, and those who exercise.[25,26] Although CK-MB is frequently elevated in patients with renal failure, CK-MB has not been reported to help distinguish patients at risk from those who are not. In such group of patients, a changing pattern of troponin serves to identify those with acute versus chronic disease. Troponin is elevated in patients who are critically ill and identifies patients at risk for future cardiac events.[27] It is recognized that after vigorous exercise CK-MB rises and this is due to release from skeletal muscle. Troponin rises transiently after 24 hours but are not of short term consequence.[10]

CONCLUSION

We have considered the evolution in the pathogenesis of cardiac injury, and the diagnostic usefulness of the biomarkers CK-MB and the troponins. The definition of myocardial infarction has been revised to help clinicians manage their patients better. We have briefly touched on the relative merits of each biomarker in our quest for a sensitive and specific test to assist clinicians in identifying those suffering from a myocardial infarction. Prompt and early recognition and institution of appropriate therapy is crucial to prognosis.

No laboratory test could replace the physician's clinical insight. The guidelines advocate that clinicians incorporate the patient symptoms, ECG changes, and the highly sensitive cardiac troponin to guide clinicians in managing patients. Does CK-MB still have a role to play? Some institutions have done away with this test, claiming that it does not add information to the more sensitive troponin test; it only adds to the cost. There is also confusion among clinicians as to how to properly interpret an elevated troponin value. Among the many advantages of a troponin test is that increase in troponin is associated with patient prognosis.

It may be time for our old and glorified historical friend CK-MB who carried the flag of myocardial infarction for so many years to retire and rest in peace.

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Nil.

Conflicts of interest

There are no conflicts of interest.