While treating Acute Coronary Syndrome (ACS), biomarkers become important to help improve diagnostic accuracy of the disease, as treatments are not without risk. Furthermore, biomarkers also provide prognostic information about the disease, which then aids clinicians in deciding how aggressively they need to treat the disease. Here, Dr. Sundeep Mishra covers the various new biomarkers and their importance in the diagnosis of ACS.

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Acute coronary syndrome (ACS) is the most dreaded complication of coronary artery disease (CAD), usually caused by decreased coronary artery perfusion due to stenosis or distal embolisation of the thrombus and/or sudden total occlusion of a coronary artery by thrombosis. It presents as acute retro-sternal chest pain along with persistent ST-segment elevation in an electrocardiogram (ECG) and elevation of cardiac enzymes reflective of myocardial injury/necrosis. However, this classic triad may not be present in all and some patients indeed present without obvious symptoms or changes in the ECG.

The measurement of several cardiac biomarkers is the main diagnostic modality in these cases. Furthermore, development of ECG changes may take some time and any other non-ECG markers of myocardial infarction if present can aid in early diagnosis, risk stratification and even management of ACS.

Classically, biomarkers such as cardiac troponin has been found to be associated with ACS and thus may play an important role in routine clinical practice. The pre-requisite for an ideal biomarker for detecting myocardial injury is that it needs to be expressed at relatively high levels within cardiac tissue, with high clinical sensitivity and specificity that is detectable in the blood early after the onset of symptoms, such as chest pain. As a matter of fact, there are numerous cardiac biomarkers, which can be classified based on various pathophysiologic groups, such as myocardial ischaemia/necrosis, inflammation, haemodynamics, angiogenesis, atherosclerosis, or plaque instability. However, the one which is most useful in this setting is the one marking for cardiac ischaemia/injury/necrosis.

Classically, cardiac troponin (cTn), expressed as three similar isoforms (I, C, and T), is the biomarker of choice for the diagnosis of myocardial necrosis because it is the most sensitive and specific biochemical marker of myocardial ischaemia/necrosis readily available. However, it has been demonstrated that plasma cTn content is elevated in many cardiovascular diseases besides ACS/acute myocardial infarction (AMI); acute or chronic heart failure, aortic dissection, myocarditis, Takotsubo cardiomyopathy, atrial fibrillation, and even stroke.

The mechanisms underlying the release of cTn into the bloodstream are believed to include cell turnover, myocyte apoptosis, necrosis and reversible injury, increased cell membrane permeability, and release of cardiac troponin degeneration products. Moreover, some studies have revealed that membranous blebs enable the release of cardiac troponin in response to ischaemia without necrosis.

Among the isoforms, the most specific markers for acute coronary syndromes are cardiac troponin I (cTnI) and cardiac troponin T (cTnT), particularly their high-sensitivity components hs-cTnT and hs-cTnl, the elevations of which have become a predominant indicator for AMI and practically the “gold standard” in AMI diagnosis.

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Cardiac Troponin

As discussed hs-cTn estimation has become the standard of care for early diagnosis of ACDS. However, ‘early’ is only a relative term because this biomarker becomes elevated only after 1 hour of AMI. Among the 2 troponin biomarkers, hs-cTnT has been used more frequently but recent evidence suggests that while hs-cTnT and hs-cTnI seem to have comparable diagnostic accuracies, hs-cTnI has a greater early diagnostic accuracy. That suggests that hs-cTnI can be examined separately to rule-in or rule-out patients in time, if possible, in the advanced analytical technique. Additionally, another study showed that the hs-cTnT blood concentration exhibited a diurnal rhythm, and therefore suggested relatively less accurate diagnosis if based on this marker. In any case, both markers take at least an hour to become clinically useful and therefore there is an ongoing search for even early markers. The below table shows the utility of various markers in context of ACS/AMI.

Biomarkers for acute myocardial infarction and acute coronary syndrome

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C-Reactive Protein

C-reactive Protein (CRP) is a useful prognostic indicator in patients with ACS, as elevated CRP levels are independent predictors of cardiac death, AMI, and congestive heart failure. However, it is more widely used as an inflammatory marker in routine clinical practice rather than in early diagnosis of ACS. This is because CRP is a less specific and sensitive biomarker of cardiac injury compared to hs-cTn.

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Copeptin

Copeptin, is the c-terminal part of the vasopressin pro-hormone that is released together with arginine vasopressin (AVP) within 0 to 4 hours after symptom onset of ACS. Thus, used in conjunction with troponins it can improve baseline cTn sensitivity and its effectiveness and safety of cTnT or cTnI for early rule-out of AMI without serial testing in comparison to cTn alone. However, on its own it is a non-specific prognostic marker of ACS and other conditions could also influence the level of copeptin, such as renal disease and lower respiratory tract infections.

Interestingly, the 2015 European Society of Cardiology guidelines for NSTE-AC recommend copeptin as a routine clinical examination to clinicians in the patients suspected of having myocardial infarction in the ED (emergency department).

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cMyC

cMyC is the cardiac isoform of myosin-binding protein C expressed in the cardiac tissue (other 2 isoforms being expressed in the skeletal muscle). Following cardiomyocyte necrosis, cMyC appears in the circulation earlier compared to hs-cTn. Notably, the cMyC has a higher efficacy for ruling out (safe) and ruling in patients than hs-cTn, while the diagnostic accuracy is similar. Furthermore, cMyC has discriminatory power which is equal to hs-cTn and thus may be useful early on in predicting AMI.

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Heart-Type Fatty Acid Binding Protein (hFABP)

Heart-Type Fatty Acid Binding Protein (hFABP) is released from injured myocardium and may serve as a potential biomarker for AMI. The assessment of HFABP at the ED admission adds an incremental value to the initial hs-cTnT. As a matter of fact, the increase in the sensitivity and negative predictive value for patients with chest pain with equivocal ECG could potentially allow safe and early rule-out of AMI even without serial troponin testing.

In the patients presenting to the ED with chest pain and no cTnI elevations, hFABP has shown a higher sensitivity in the diagnosis of AMI with a positive rate of 55% (and thus its usefulness in this situation). Thus, hFABP may be a better biomarker (as compared to troponins) for early diagnosis of AMI in ED setting. Moreover, the addition of hFABP to hs-cTn may increase accuracy and accelerate the clinical diagnostic decisions by identifying the patients at low risk for AMI.

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Endothelial cell related biomarkers

Endothelial cell-specific molecule 1 (ESM-1), also known as endocan, is a biomarker for endothelial dysfunction and may serve as a novel evaluation method for risk stratification of patients with AMI. Furthermore, high endocan level at presentation is an independent predictor for adverse cardiac events. However, while an important prognosticator, its usefulness in early diagnosis of ACS is limited.

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Platelet related biomarkers

Mean platelet volume (MPV) and beta-thromboglobulin (beta-TG) are two important platelet biomarkers that may increase during platelet activation and have a higher expression in patients with CAD in context of ACS. High MPV value also correlates with an increased incidence of long-term adverse events, especially all-cause mortality in NSTEMI patients undergoing PCI and MPV to platelet count ratio (MPV/P ratio) has a good prognostic performance in predicting the outcomes of patients with AMI which may be similar to that provided by GRACE score. Moreover, MPV/P ratio is easier to calculate.

The MPV/P ratio has superior performance compared to MPV alone in predicting adverse outcomes in patients with NSTEMI undergoing PCI primarily. Regarding use of platelet microRNA-126 as a novel early biomarker for diagnosis of AMI; however, the low correlation between its expression and platelet activity limits its diagnostic utility.

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Suppression of Tumorigenicity 2 (ST2)

ST2 is a member of IL-1 receptor family with two forms, namely, transmembrane (ST2L) and soluble (sST2) isoforms. sST2 has been shown to have high expression in patients with AMI, accompanied by the elevation of GDF-15, HFABP, and suPAR, and downregulation of Fetuin A. Elevated ST2 concentration is a predictor of major adverse cardiac events in ACS patients, however, it has no role in early diagnosis of AMI.

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Triggering Receptor Expressed on Myeloid Cells (TREML)

TREMLs are important effectors of the innate immune system and TREML4 are upregulated in the early stage of the ACS and thus may serve as a biomarker in the early stage of ACS and to monitor the recovery of early myocardial ischaemia. TREML1 expression is also upregulated in ischaemic myocardium its blood concentration is co-relative of death in AMI its genetic or pharmacological inhibition may dampen myocardial inflammation and improve left ventricular function and survival.

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Pregnancy-Associated Plasma Protein-A (PAPP-A)

PAPP-A is a high molecular weight and zinc-binding metalloproteinase, a sensitive, specific, and early marker for ACS diagnosis. In the early stages of STEMI, the sensitivity of PAPP-A is superior to that of CK-MB and troponin T. Furthermore, elevated PAPP-A can be used as an independent predictor of adverse outcomes in context of ACS even in cTnI-negative patients. Meta-analysis has revealed that PAPP-A is also an independent risk factor for all-cause mortality/cardiovascular events.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Sundeep Mishra is a Professor of Cardiology.