The ongoing evolution of cardiac biomarkers for myocardial infarction

Chest pain is one of the leading reasons people visit hospital emergency departments in the United States.¹ Early identification of people at risk of having a myocardial infarction (MI) or heart attack is critical, as they will benefit most from early and appropriate treatment. While the time it takes to diagnose certain types of heart attacks has decreased significantly and positively impacted outcomes, there is still room for improvement.

Cardiac biomarkers are crucial

Today the preferred biomarkers used to identify suspected MI are cardiac troponins, which are regulatory proteins found in the heart muscle that can detect injury to the heart.² Cardiac troponin I (cTnI) was first described as a biomarker specific for MI in 1987,³ and troponin T (cTnT) was first described in 1989.⁴ It was many years before cardiac troponin (cTn) was incorporated into guidelines and recommendations as a preferred marker for use in the diagnosis of MI.⁵ This transition from the historical markers of cardiac injury, myoglobin (MB), creatine kinase (CK), and lactate dehydrogenase (LD), required many studies that would show the benefits of cTn over the standard of care of the time. This led to the initial improvements in the time to diagnosis which cTn brought. Thus the expectations are high for studies and research that would be required to show improvements over the current standard of care that utilizes cTn.

New criteria for diagnoses

In addition to cardiac troponins being used in the diagnosis of MI, these diagnostics are helping clinicians redefine some of these diagnoses and their criteria. For many years, the diagnosis of acute MI relied on the revised criteria established by the World Health Organization (WHO) task force in 1979.⁶ These criteria were epidemiological and aimed at specificity. A joint European Society of Cardiology (ESC) and American College of Cardiology (ACC) committee proposed a more clinically based definition of an acute, evolving, or recent MI in 2000.⁷ In 2007 the Joint Task Force of the European Society of Cardiology, American College of Cardiology Foundation, the American Heart Association, and the World Health Federation (ESC/ACCF/AHA/WHF) refined the 2000 criteria and defined acute MI as a clinical event consequent to the death of cardiac myocytes (myocardial necrosis) that is caused by ischemia (as opposed to other etiologies such as myocarditis or trauma).⁵

This definition was not fundamentally changed in the third universal definition of MI released in 2012 by the ESC/ACCF/AHA/WHF² and includes the following criteria for the diagnosis of MI: detection of a rise and/or fall of cardiac biomarker values (preferably cTn with at least one value above the 99^th percentile upper reference limit [URL]) and with at least one of the following:

• Symptoms of ischemia
• Development of pathologic Q waves in the ECG
• New or presumed new significant ST-segment-T wave (ST-T) changes or new left bundle branch block (LBBB)
• Identification of an intracoronary thrombus by angiography or autopsy
• Imaging evidence of new loss of viable myocardium or a new regional wall motion abnormality.

Troponin values in healthy populations

The consensus recommendation for the use of the 99^th percentile URL, or normal range, is of great importance. With most troponin assays presently in use (also referred to as contemporary assays), young, healthy individuals without pathologic myocardial cell stress or damage have little or no measurable troponin in their blood. As troponin assays have become more sensitive it appears that more healthy individuals do have measurable levels of troponin. With more sensitive assays, individuals with increased values above the 99^th percentile URL are seen as being at increased cardiovascular risk. Some values even slightly below the 99^th percentile value seem to suggest risk, but contemporary assays are not capable of defining these values very well due to marked imprecision, especially at low concentrations.

High sensitivity assays and patient care

Recently, new cTn assays have been developed to improve cardiac biomarkers and address their imprecision at low levels. These new assays are referred to as high sensitivity (hs) assays. They follow a proposed definition for hs assays that states that the number of normal subjects they are capable of detecting be >50% as well as imprecision of <10% at the 99^th percentile.⁸ Some of these hsTn assays detect nearly 100% of normal subjects depending on the population.⁹ These improvements include the early rule out of MI.

In an hsTnI study performed in Germany in which a total of 1,818 patients with suspected acute coronary syndrome presented in the emergency department, use of the 99^th percentile cutoff provided a negative predictive value (NPV) greater than 99%, potentially allowing a safe rule out of MI. Another advancement hs assays have led to is the 99^th percentile differences between men and women; this supports the use of gender specific 99^th percentiles,⁹ which may aid physicians to diagnose heart attacks in women especially in cases of early presentation with atypical signs and symptoms. High sensitive troponin I and troponin T assays from major manufacturers have been released for use in most of the world. They have not yet been approved for use in the United States.

The newer assays have tremendous potential for clinical medicine. For instance, they are likely to increase the rapidity and accuracy of diagnosis of MI or to identify patients at high risk of events with cardiovascular disease.^10,11 Furthermore, they may be of value in patients with stable disease and eventually for more chronic screening, including during stress testing and in patients with heart failure.^10-13

Current considerations and perspectives

Today, the diagnosis of an acute myocardial infarction depends on observation of a rise and/or fall of blood biomarkers, with at least one value above the 99^th percentile, in addition to clinical information or electrocardiographic changes. The more sensitive the assay, the more important it is to determine a change for confirmation. This need is particularly important with highly sensitive assays. There is still disagreement on the level of change or whether that is a relative change or an absolute change.

With high sensitivity assays, values that are elevated above the 99^th percentile URL define a high-risk group. However, even for subjects within the normal range of these highly sensitive assays, it appears that the higher the value, the greater the risk.^11,12 This suggests that each individual has his/her own normal baseline and that elevations above that baseline occur as cardiac disease ensues and thus defines increased risk.

High sensitivity assays provide improvements to the analytical performance of troponin. It will be interesting to see where they will lead us next in the guidelines and the diagnosis and/or prognosis of MI. It will also be exciting to see if there will be new guidelines that include the recommendation for gender-specific 99^th percentiles or new algorithms based on hscTn assays.