The Pathophysiology of Cardiac Troponin Release and the Various Circulating Cardiac Troponin Forms-Potential Clinical Implications

Abstract

Current routine high-sensitivity cardiac troponin assays are the criterion standard for the laboratory diagnosis of myocardial injury due to their high analytical sensitivity and specificity. However, in daily clinical practice, unexpectedly elevated cardiac troponin test results without an obvious clinical correlate are becoming more frequent compared with previous cardiac troponin assay generations. In these patients, myocardial injury may sometimes be undetected by imaging techniques, including cardiac magnetic resonance imaging. This has led to an increased interest in the pathophysiology of cardiac troponin release, particularly with regard to whether troponin can be released in the absence of myocardial necrosis and thereby resulting in an increase in cardiac troponin in the systemic circulation. Although there is in vitro evidence that cardiac biomarkers are released from reversibly injured cultured cardiomyocytes, there is still a lack of evidence for cardiac troponin release apart from different forms of cell death (i.e., apoptosis or necrosis) in animal experiments. Conversely, various circulating cardiac troponin forms have been identified in human blood samples using different analytical methods, raising the question of whether the cause of myocardial injury can be reliably determined by measuring specific circulating cardiac troponin forms. Preliminary clinical data suggests that testing for specific circulating troponin forms could increase the specificity of cardiac troponin for diagnosing acute myocardial infarctions caused by an acute coronary syndrome. This review aims to provide an up-to-date overview of these current cardiac troponin research topics with their potential clinical implications. Typical clinical cases illustrate how to interpret cTn in the individual patient and how to derive a correct diagnosis.

Keywords: acute myocardial infarction; cardiac troponin; circulating troponin forms; myocardial injury; pathophysiology; release.

Figure 1

Potential mechanisms of cardiac troponin release from reversibly injured cardiomyocytes. Degraded and dissociated cTn is released into the supernatant via cell wounds, cytoplasmic blebbing, and the formation of extracellular vesicles through a temporarily leaky plasma membrane. Abbreviations: cardiac troponin (cTn).

Figure 2

Potential cardiac troponin release mechanisms from injured myocardium. Cardiomyocyte necrosis is the only generally accepted cause of a cTn increase into the systemic circulation in humans. In animal experiments, cardiomyocyte apoptosis was associated with cTn increases into the systemic circulation.

Figure 3

Cardiac biomarker release in a patient undergoing uncomplicated bifurcation percutaneous transluminal coronary intervention for unstable angina. This case clearly demonstrates the importance of specifying exactly when a proposed cTn decision limit should be used to diagnose peri-interventional AMI after elective PCI. A 55-year-old male with a history of CAD was admitted with symptoms of unstable angina. He underwent PCI of the left circumflex coronary artery 11 years ago. Serial ECGs before and after PCI showed no signs of acute myocardial ischemia. Serial hs-cTnT testing in the emergency department before PCI revealed concentrations within the normal range without a significant change. The criteria for AMI were not met. Urgent coronary angiography revealed a subtotal in-stent restenosis at the distal end of the stent involving the distal circumflex artery bifurcation (see (A), marked with a circle). There was no other significant stenosis. PCI was performed with an excellent primary result without any complications (see (B), marked with circle). The biomarker time courses are listed in (C). hs-cTnT showed no significant increase within 4 h after PCI, but increased significantly above the upper reference limit of 14 ng/L the following morning. Creatine kinase activities remained within the reference limit even showing a constant decline; the patient was a tunnel-building construction worker with physically demanding work. Abbreviations: high-sensitivity troponin T (hs-cTnT), percutaneous coronary intervention (PCI), circumflex artery (RCX), coronary artery disease (CAD), acute myocardial infarction (AMI).