Introduction
Cardiac troponins (cTns) are well-established biomarkers in diagnosing heart-related injuries, especially myocardial infarction (heart attack). For years, the prevailing belief has been that any increase in cTn levels in the blood is a clear sign of myocardial necrosis-meaning that heart muscle
cells are dying. This assumption has shaped how clinicians interpret cTn levels, influencing decisions from diagnosing heart conditions to determining treatment paths. However, recent research has begun to challenge this long-held view, suggesting that cTn release might not always signal cell death but could also be triggered by other, less severe mechanisms.
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What Are Cardiac Troponins?
Troponins are proteins found in muscle cells that help regulate contraction. In the heart, three types of troponin work together: troponin C, troponin I, and troponin T. These proteins are part of the contractile apparatus, the machinery that allows heart muscle cells, or cardiomyocytes, to contract and pump blood. When heart cells are injured, as in the case of a heart attack, troponins are released into the bloodstream. This makes them excellent biomarkers for detecting heart muscle injury.
The Traditional View: Troponins as Indicators of Necrosis
Historically, the role of cardiac troponins has been relatively straightforward. Elevated levels in the blood have long been used to diagnose myocardial infarction (MI), or heart attack. The conventional understanding was that when heart muscle cells die due to a lack of oxygen, their contents, including troponins, leak into the bloodstream. Thus, a high level of troponins in the blood was interpreted as a sign of significant heart muscle cell death.
This model was supported by numerous studies. For instance, research involving conscious dogs showed that even brief periods of reduced blood flow to the heart led to elevated levels of markers like creatine kinase, suggesting that myocardial necrosis could occur in such conditions. The release of troponins was considered a reliable marker of such cell death, guiding clinical decisions and treatment strategies.
The New Perspective: More Than Just Cell Death?
Recent advancements in troponin testing have challenged the traditional view. The development of high-sensitivity troponin assays has enabled the detection of much lower levels of these proteins in the blood. This newfound sensitivity has revealed that troponin levels can be elevated in scenarios where myocardial necrosis seems unlikely or absent.
Fig. 1 Current concepts of potential cardiac troponin release mechanisms from injured myocardium (Mair J., et al. 2018).
For example, athletes sometimes show elevated troponin levels after intense exercise, despite having no signs of heart muscle damage. Similarly, troponin levels can rise in response to rapid heart rate increases during procedures like atrial pacing, or even after brief periods of myocardial ischemia. These observations have led researchers to question whether troponin release always signifies cell death or if other mechanisms might be involved.
Alternative Mechanisms of cTn Release
One hypothesis is that cTn release could be linked to apoptosis rather than necrosis. Apoptosis, or programmed cell death, is a natural process where cells self-destruct in a controlled manner, without causing inflammation or damage to surrounding tissue. In theory, apoptotic cells could release cTn into the bloodstream without the extensive cell membrane rupture that characterizes necrosis.
Experimental studies support this idea. For example, in a pig model of brief myocardial ischemia, researchers found that cTn levels increased after just 10 minutes of coronary artery occlusion, a duration previously thought too short to cause necrosis. Surprisingly, these cTn increases were delayed rather than immediate, and histological analysis showed evidence of apoptosis but not necrosis. While these findings are intriguing, they also highlight the limitations of current diagnostic techniques-detecting apoptosis in tissue samples is challenging, and more research is needed to confirm these results.
Another potential mechanism involves the release of cTn from viable but stressed cardiomyocytes. Under certain conditions, such as increased mechanical stress or beta-adrenergic stimulation, cardiomyocytes might release cTn through temporary increases in cell membrane permeability or the formation of membrane blebs (small, bubble-like protrusions from the cell surface). This process, known as cell wound repair, allows cells to quickly seal off and repair small membrane disruptions, potentially releasing cTn into the bloodstream without causing permanent cell damage.
Changes in how the body clears cTn from the bloodstream might also play a role. Most proteins, including cTn, are broken down in organs with high metabolic rates, such as the liver, kidneys, and pancreas. In individuals with impaired kidney function, cTn clearance could be slowed, leading to chronically elevated cTn levels even in the absence of ongoing heart damage. This suggests that in some cases, elevated cTn might reflect issues with clearance rather than increased release from the heart.
Implications for Clinical Practice
These new insights into the mechanisms of troponin release have significant implications for clinical practice. As cTn assays become more sensitive, clinicians are increasingly faced with the challenge of interpreting elevated troponin levels in patients who do not fit the typical profile of someone having a heart attack. For example, a patient with chronic kidney disease might have elevated troponin levels due to impaired clearance from the blood, rather than ongoing heart muscle injury. Similarly, a healthy athlete might show elevated troponins after a marathon, even though their heart is not damaged.
This complexity has led some experts to suggest that we need new guidelines for interpreting troponin levels, especially with the advent of "ultra-sensitive" assays. One proposed approach is to consider the kinetics of troponin release-how quickly levels rise and fall-rather than relying solely on a single measurement. For instance, a rapid rise and fall in troponin levels might indicate a temporary, reversible injury, whereas a sustained elevation could suggest ongoing damage.
Conclusion
The emerging evidence that cTn can be released without myocardial necrosis represents a potential paradigm shift in how we understand heart injuries and use cTn as a biomarker. While myocardial necrosis is still the primary cause of cTn elevation in most cases, clinicians and researchers must be open to the possibility that cTn release can occur through other mechanisms, including apoptosis, reversible cell injury, and impaired clearance.
This new perspective calls for a more nuanced approach to interpreting cTn levels in clinical practice, one that takes into account the broader context of the patient's health and the limitations of current diagnostic tools. As research continues to unravel the complexities of cTn release, we may find that the story of this vital biomarker is more intricate and more fascinating than we ever imagined.
References
- Mair J., et al. How is cardiac troponin released from injured myocardium? European Heart Journal: Acute Cardiovascular Care. 2018, 7 (6): 553-60.
- Weil B. R., et al. Brief myocardial ischemia produces cardiac troponin I release and focal myocyte apoptosis in the absence of pathological infarction in swine. Basic to Translational Science. 2017, 2 (2): 105-14.
- Heyndrickx G. R., et al. Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. The Journal of Clinical Investigation. 1975, 56 (4): 978-85.
- Starnberg K., et al. Revision of the troponin T release mechanism from damaged human myocardium. Clinical Chemistry. 2014, 60 (8): 1098-104.
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