Acute coronary syndromes (ACS) is an umbrella term comprising a spectrum of clinical conditions ranging from unstable angina to non-ST elevation myocardial infarction and ST elevation myocardial infarction. ACS begins when an atherosclerotic plaque ruptures or erodes and a platelet-fibrin clot obstructs coronary blood flow. These critical disorders are a major cause of emergency medical care and hospitalization in the US, and coronary heart disease is the principal cause of mortality and morbidity in the western world.
Despite these facts, there has been little recent progress in the diagnosis of ACS, so it remains one of the most difficult medical challenges facing physicians. There are several cardiac biomarkers that individually can assist in the evaluation of patients with ACS, however the application of a multi-marker strategy provides the most effective option for future of clinical practice.
The Historical Approach to ACS Diagnosis
ACS are divided into those with and without ST-segment elevation. ST segment elevation MI is a unique category in which a coronary artery is completely occluded and there is an immediate mandate for reperfusion therapy. Traditionally, a diagnosis is based entirely using results from a standard 12-lead electrocardiogram (ECG).
The larger group of patients with acute coronary syndromes present without ST elevation on the ECG and this proportion increases every year. The culprit lesion in non-ST elevation ACS is characterized by plaque rupture, thrombus formation, and distal embolization to the coronary microcirculation; some blood flow usually persists in the artery, albeit at a reduced rate. Diagnosing non ST elevation ACS is much more challenging than ST elevation MI, and an ECG alone is usually insufficient. Firstly, if a patient has a classic history and evidence of myocardial necrosis with Creatine Kinase-MB (CK-MB) or troponin elevation, the diagnosis of a non-ST elevation infarct is made. Conversely, if a patient has a clinical history consistent with unstable angina but there is no evidence of necrosis, the diagnosis of unstable angina is made using clinical judgement alone. Thus, the diagnosis of unstable angina is imperfect and overly subjective.
Novel Cardiac Biomarkers in ACS
The use of novel cardiac biomarkers can be divided into two categories, diagnosis and risk stratification (i.e. trying to estimate prognosis following chest pain syndromes or confirmed ACS). From a diagnostic standpoint, the aim is to try and develop biomarkers that identify patients with ACS even when there is no evidence of myocyte necrosis. This diagnostic aim is still in its infancy. The biomarker that has been best studied is Ischemia-Modified Albumin (IMA). Under conditions of ischemia, albumin undergoes a conformational change, so that it can no longer bind to transitional metals such as copper or cobalt. Using the albumin cobalt binding test, the proportion of albumin modified by ischemia can be estimated and this may serve as an index of ischemia. The commercially available IMA test appears to be relatively sensitive for identifying unstable angina. However, the test's specificity is relatively poor. While it may be a useful test in the emergency department (ED) to rule out ischemia, it is not useful at this stage to confirm (i.e. "rule in") ischemia.
Another biomarker that has been proposed in this area and is is Myeloperoxidase (MPO), a leukocyte enzyme that circulates in the coronary circulation, and plays an important role in LDL oxidation and coronary inflammation. It also appears to elevate early after ACS and does appear to identify patients with ACS earlier than traditional biomarkers like troponin and CK-MB.1 Most importantly, it also appears to provide risk stratification information for patients who are troponin negative. For example, for patients who present to the ED with chest pain and negative troponin levels are at increased risk for readmission and other adverse cardiac end points if MPO is elevated. The data for MPO are emerging but it is unclear as yet whether this marker should be routinely used in clinical practice.
Biomarkers for the Prognosis of ACS
Evidence for use of biomarkers for risk stratification is more robust than that for diagnosis of ACS. The incorporation of panels of biomarkers that reflect different components of underlying pathobiology can facilitate risk stratification, better than just using the ECG and cardiac troponin. The markers that have been best researched are natriuretic peptides (B-type natriuretic peptide (BNP) and N-terminal Pro BNP), which index the hemodynamic and neurohormonal responses to ischemia. There are now over 15 studies in patients with ACS, including both ST-elevation MI and non ST-elevation ACS, that show very powerful ability to predict the risk of death and heart failure following ACS with BNP or NT-pro BNP.
The risk stratification information contained in the natriuretic peptides is very robust and very reproducible. Thus, patients with elevated BNP or NT-Pro BNP are at significantly increased risk for subsequently developing heart failure and death, regardless of whether troponin positive or negative, even if there is no evidence to suggest the presence of heart failure.2
Patients with BNP or NT-proBNP elevation during ACS warrant more aggressive treatment. Clinicians may, for example, may adopt a more aggressive approach to coronary angiography and revascularization among patients with BNP elevation than they would if both BNP and troponin were normal. Studies have shown that BNP tracks with a number of high risk features in ACS, such as more severe underlying atherosclerosis, left ventricular (LV) dysfunction, LV hypertrophy, and the burden of the ischemic insult.3 Although ischemia itself might trigger the release of BNP, this should not be misinterpreted to suggest that BNP will work as a diagnostic marker for ACS. In patients with ACS, the higher the BNP, the more severe the ischemic insult, and the worse the prognosis.
Troponin and BNP are the dominant risk stratification biomarkers today, and the data are extremely robust for both. The data for troponin are particularly robust, even with the very lowest levels of elevation. Even minor troponin elevations in the appropriate clinical context (high certainty that the troponin is due to the ACS) identify high risk underlying coronary morphology, which result in patients having high-risk lesions with plaque rupture, an abundance of thrombus and distal embolization.4 Such patients clearly benefit from aggressive anti platelet, anti thrombotic and interventional strategies.5
In addition to troponins, natriuretic peptides index a different component of biology: hemodynamic stress and neurohormonal activation. In light of this, one question still remains, whether it is possible to go beyond the troponins and naturetic peptides to other pathophysiologic constructs like inflammation. Seemingly the answer is yes. For instance, C-reactive protein (CRP) in addition to BNP and troponin does appear to provide some incremental value;6 however, the value is not as strong as that which is seen with troponin and BNP in ACS. This raises the question, in the early period after ACS, might other inflammatory markers beyond CRP that are more specific to the pathophysiology of ACS be used? CRP is a very non-specific inflammatory marker that is released by the liver in response to the acute phase injury response that happens after ACS. Thus, several markers, more specific to the pathophysiology of ACS have been investigated, including MPO, which was described above.
Another proposed marker is monocyte chemo attractive protein (MCP)-1, a chemokine signal that recruits monocytes to sites of inflammation. A series of studies has shown that MCP-1 does appear to identify patients with a greater proportion of cardiac risk factors and a higher risk of adverse outcomes after ACS.7 Others have investigated placental growth factor, an angiogenic factor in the vascular endothelial growth factor (VEGF) family. It appears to identify increased risk, as does its receptor, soluble fms-related tyrosine kinase 1 (FLT1).
Other markers that might index different properties include soluble CD40 ligand, a pro-inflammatory marker, that seems to be mostly a marker of platelet activation. The data for soluble CD40 ligand are not uniformly consistent, but overall there is some suggestion that patients with higher levels of soluble CD40 ligand do appear to be at increased risk for recurrent ischemic events. In particular, the CAPTURE investigators suggest that patients with elevated soluble CD40 ligand (a marker of platelet activation) might derive particularly robust benefit from aggressive anti-platelet therapies.8 This is one example of how biomarkers might be used as a means indvidualizing therapy. However, as yet the data for soluble CD40 ligand are not overly robust.
The Multi-marker Approach
Risk Stratification
The multi-marker approach for risk assessment operates under the principle that if biomarkers that reflect different components of pathophysiology are combined together into panels, risk stratification can be improved. An initial study combined troponin (a necrosis marker), BNP (a marker of hemodynamic stress) and CRP (as an inflammatory marker). When a greater number of these biomarkers was elevated, the patient had a higher likelihood of death, heart failure or recurrent myocardial infarction. These clinical results were robust across several trials and across multiple different end points, and clearly provided information over and above what can be ascertained during a bedside examination with historical information and the ECG.6 This multi-marker approach apepars to be more powerful than measuring any of the individual markers alone. The next step for multi-markers is to use this information to define a pathophysiological profile to enable individualized therapy. Individuals with ACS are a heterogeneous group and eventually profiles of these patients will be created based on panels of markers. For example, some patients may have an inflammatory profileand eventually be targeted for very aggressive anti-inflammatory therapies.
Others may have a profile that might suggests that hemodynamic stress and neurohormonal activation have occurred and they might be targeted for very aggressive antagonism of those pathways with beta blockade and ACE inhibition. Conversely, a third group of patients might have evidence of coronary thrombus and might be targeted for aggressive anti thrombotic therapies. The potential of these types of studies is limitless, although this promise of multi-marker strategy is unlikely to be realized for many years.
Diagnosis
These tools will also aid physicians in the emergency department. Multi-marker panels can be constructed that include diagnostics for multiple diseases that might present in the same fashion. For example, if a patient presents at the emergency room with atypical chest pain and shortness of breath, it is often unclear to the physician exactly what the problem might be. The patient might be having a heart attack, suffering a pulmonary embolism, or have an exacerbation of lung disease or even an aortic dissection. A multi-marker diagnostic approach will allow for all these eventualities to be examined. For example this might include markers of cardiac necrosis and markers of cardiac ischemia such as MPO or IMA to evaluate ACS. In addition, markers that identify smooth muscle injury might be included to evaluate aortic dissection and d-dimer included to evaluate pulmonary embolism. In a rapid manner at the patient's bedside in the emergency room, the physician might be able to narrow the differential diagnosis.
Therapeutic Implications of Multi-Marker Strategies
This is the area where the most work needs to be done. The only biomarker for which there is a clear therapeutic mandate at this time is troponin. Troponin elevation in patients with suspected ACS would indicate that more aggressive anti-platelet and anti-thrombotic regimens should be applied, and the use of coronary revascularisation should be more aggressively used because those patients are at very high risk for ischemic events. The data for BNP are less robust but do support a more aggressive approach to cardiac catherization. At this time, there is no clinical data available for CRP, MPO, IMA or any of the other biomarkers in terms of therapeutic implications. Although this research is difficult to carry out, more is still needed in this area. Partnerships between academics, the diagnostics industry and large pharmaceutical companies are required.
The Cost-effectiveness of the Multi-marker Approach
Although this is a new area, troponin testing in the emergency room is clearly cost-effective because it can allow a physician to decide who to admit to hospital, and who to release. It can streamline the process of therapeutic decision-making and allow restrictions of the most expensive therapies to the patients who would derive the most benefit. Whether BNP is cost effective in ACS is not yet known, because the main issue is that because it does not have a clear therapeutic mandate, it may not directly inform clinical decisions. In selected patients it is likely to be cost-effective because a physician is able to identify patients at very high risk for very important adverse outcomes, allowing targeted intervention and more intensive follow-up.
The area that has the potential for the most cost savings is diagnostics, both the multi-marker panels for differential diagnosis, as well as the development of ischemia markers to facilitate the diagnosis of ACS. In the US enormous resources are wasted by over-hospitalising and over-testing patients with low probability of ACS who present with chest pain. If diagnostic tools were available that accurately excluded ACS, unnecessary admissions and testing could be minimized. Additionally, if a physician was sure an individual would not suffer a heart attack, it would also reduce medical/legal liability for emergency department physicians, an area of tremendous concern.
New Risk Stratification Models for ACS
There are several new risk stratification models for ACS but these have only included limited biomarker data, because they were derived from clinical trials and registries that largely measured older biomarkers such as CKMB. The TIMI risk score is a simple integer useful for selecting between therapies, but does suffer from the fact that it was derived in a clinical trial population, and is missing some factors that are commonly associated with risk. There are more complicated, comprehensive models such as the PURSUIT model, which was developed in a clinical trial. However, it is difficult to calculate at the bedside and requires computerized calculations. The GRACE model, derived from a 'real-world' registry, appears to better characterize risk than the TIMI and PURSUIT scores. It is very likely that CT angiography and bedside echocardiography will be incorporated into risk stratification algorithms along with the multiple marker panels, as cost decreases and availability increase. The future includes iterative risk stratification with clinical variables, ECG, early measurement of biomarkers and, in selected patients more advanced imaging modalities such as CT angiography and echocardiography.
The Future for Cardiac Biomarkers
As the number and complexity of options to treat patients with cardiovascular disease continues to expand, the idea that every patient with ACS should be treated in the same way becomes more and more obsolete. It is clear that patients are heterogeneous and that the pathophysiology underlying ACS is not the same in every patient. Tools should be designed that allow a cardiologist to understand individual differences, and allow for the choosing of the right drug for the right patient. Genetics and biomarkers are a large part of how this goal of personalized medicine will be achieved. Although it will be a long and hard pathway to reach this destination, it is a noble goal, and the correct direction for the future of cardiac medicine.