Understanding the circulating forms of cardiac troponin: insights for clinical practice
-
Panpan Lv
,
Peng Zhang
and
Junbo Ge
Abstract
Ischemic heart disease remains the leading cause of death globally, with acute coronary syndrome (ACS) being the main reason for emergency hospital admissions and thus representing a significant health care issue worldwide. Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are widely recognized biomarkers of cardiomyocyte injury and the gold-standard biomarkers for diagnosing myocardial infarction (MI). High-sensitivity cardiac troponin (hs-cTn) assays have the ability to accurately detect low cTn concentrations and document minor increases. However, in addition to MI, various other pathophysiological states can trigger elevated cardiac troponin levels, thus creating potential challenges in the diagnostic process. As cTn released into the bloodstream exists in heterogeneous forms, improving our understanding and accurately characterizing these forms across various etiologies might hold clinical significance. In this review, we add to the field by offering an overview of research on possible circulating forms of cTn, the mechanisms of cTn elevation, and the clinical significance of cTn following conditions such as MI, endurance exercise, and chronic kidney disease, thus highlighting the importance and challenge of understanding of the circulating forms of cTn and possible strategies for cTn immunodetection.
Introduction
Despite substantial advances in research on the etiopathogenesis, diagnosis, and treatment of ischemic heart disease, it remains the leading cause of death worldwide (responsible for 16 % of deaths globally) and represents a major global health care issue (World Health Organization. WHO mortality database. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death). Moreover, acute coronary syndrome (ACS), which encompasses a spectrum of conditions ranging from unstable angina (UA) to non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI), is frequently the primary clinical presentation of cardiovascular disease (CVD), and remains the most common cause of emergency hospital admission in Western countries [1], 2].
A safe and rapid diagnosis is paramount for reducing mortality among patients presenting with this life-threatening condition. Accumulating evidence indicates that cardiac troponin T (cTnT) and I (cTnI) serve not only as the biochemical gold standards for diagnosing myocardial infarction (MI) [3], given their superior cardiac specificity and sensitivity compared with other biomarkers that have been routinely used in clinical settings (e.g., creatine kinase, lactate dehydrogenase, and myoglobin) [4], 5] but also as screening and risk stratification tools, particularly when assayed using high-sensitivity cardiac troponin (hs-cTn) assays, for both the general population and selected categories of high-risk patients [6], [7], [8], [9].
In 2018, the expert opinion from the Academy of AACC and Task Force of IFCC [10] established two fundamental criteria for defining high-sensitivity cTnI and cTnT (hs-cTn) methods: (1) the %CV at the 99th percentile URL should be ≤10 %; and (2) measurable cTn concentrations should be attainable at a value at or above the assay’s limit of detection (LoD) for at least 50 % of healthy individuals of both sexes. The hs-cTnI and T assays represent significant advancements, offering substantial benefits for prompt and accurate exclusion and confirmation of MI [2]. Importantly, the 2023 European Society of Cardiology (ESC) Guidelines for the management of ACS [2] recommended the 0 h/1 h algorithm as the preferred approach, with the 0 h/2 h algorithm serving as a secondary option. Both algorithms are designed with stringent diagnostic goals, with rule-out thresholds achieving at least 99 % sensitivity and negative predictive value (NPV), and rule-in thresholds providing a positive predictive value (PPV) of 70 % or higher. In cases where neither the 0 h/1 h nor the 0 h/2 h algorithm is applicable, the earlier 0 h/3 h algorithm remains a viable option. Importantly, the specific cut-off concentrations for these algorithms vary depending on the assay used. For a comprehensive overview of these diagnostic algorithms and their respective cut-off values, the 2023 ESC guidelines serve as an invaluable resource. Hs-cTn assays have further enhanced our understanding by detecting previously undetectable cTn levels across a broad spectrum of acute and chronic diseases [11], 12]. However, the frequent detection of increased cTn concentrations in conditions other than MI poses potential challenges in clinical practice [11], 12]. These limitations create uncertainty in the management of patients with elevated cTn, highlighting the need to investigate new strategies to address this issue.
For nearly three decades, studies have shown that cTn released into the bloodstream exists in heterogeneous forms, including free troponins, troponin complexes, and small cTn fragments [13], [14], [15], [16], [17], [18], [19]. The heterogeneity of these forms complicates their clinical application, as it remains unclear whether they hold distinct clinical relevance or how they impact assay performance. Notably, some forms of cTn in the bloodstream might be disease-specific [20], [21], [22], [23], [24], [25]. Hence, improving our understanding of these forms and accurately characterizing them across various etiologies could hold clinical significance and have implications for the clinical specificity of hs-cTn immunoassays.
This review seeks to consolidate current knowledge on the circulating forms of cTn, focusing on their structure, the specific targets of various commercially available hs-cTn assays, and clinical significance following conditions such as MI, endurance exercise, and chronic kidney disease, and outline potential challenges and future directions.
What is cTn?
In the early 1960s, Professor Ebashi made a groundbreaking discovery by identifying a pivotal protein located within cardiac myocytes essential for cardiac muscle contraction – later universally recognized as troponin [26], [27], [28], which functions as a calcium-sensitive switch in striated muscles [29], 30]. Between 1971 and 1973, Greaser et al. [31], [32], [33], [34] clarified that the cTn complex, an integral part of the myofibrillar apparatus, comprises three distinct proteins: troponin C (TnC, 18 kDa), which binds calcium and modulates thin filament activation, significantly influencing cardiac contraction regulation [35], [36], [37], [38], [39]; troponin I (cTnI, 22.5 kDa), which is involved in the inhibition of actin-activated myosin ATPase activity; and troponin T (cTnT, 37 kDa), which acts as ‘a bridge’, anchoring the troponin complex to tropomyosin [35], 40].
The structure of the core domain of human cTn in its calcium-saturated form was characterized nearly two decades ago [36]. During relaxation, the cTn complex prevents myosin from binding to the actin filament, while cTnI binds to actin, stabilizing the troponin–tropomyosin complex. Following the initiation of an action potential and the subsequent rise in intracellular Ca2+ levels, Ca2+ binds to the N-terminal region of TnC, triggering a conformational change while the central core of the cTn complex remains stable [41]. This conformational shift displaces cTnI, allowing myosin to bind to actin. The activation of thin filaments induces crossbridge cycling, engaging myofibrils, and ultimately, contraction of the heart [42] (Figure 1).
Structure of the cardiac sarcomere (top section) with an expanded panel (bottom section) showing the atomic structure of the troponin core regulatory domain. The troponin core domain structure is shown in Ca2+-saturated form, comprising a trimeric complex of cTnT, cTnI, and TnC. In the sarcomere structure (top right), myosin is depicted in coral pink, actin in amaranth, tropomyosin in purple, the heterotrimeric troponin complex in yellow/purple/green, and exposed myosin binding sites in red.
cTnI expression is restricted to the heart [3], while cTnT isoforms are infrequently detected in diseased skeletal muscle [43]. Following myocardial cell injury, elevated cTn levels in the bloodstream serve as valuable indicators of muscle damage, irrespective of the cause [44], 45]. Multiple factors have been proposed as potential causes of cTn release from the myocardium, such as normal myocardial cell renewal, apoptosis, cellular secretion of cTn degradation fragments, elevated cell wall permeability, the formation and excretion of membranous blebs, and myocyte necrosis [46], [47], [48].
Various forms of cTns in the bloodstream
Due to the presence of various mechanisms of troponin released from myocardial tissue, the cTn fragments released into the bloodstream exhibit diverse compositions. These include free troponins, multiple cTn complexes (such as cTnI-TnC), and small fragments of cTn [13], [14], [15], [16], [17], [18, 21], [49], [50], [51]. Recent research has shown that the composition of cTn undergoes a stepwise transformation following MI, transitioning from the full-size ternary cTnT-cTnI-TnC complex (cTnTIC) to smaller-sized complexes and truncated cTn fragments [15], 52]; however, it has been proposed that the release of free cytoplasmic troponin contributes to the appearance of cTnT and cTnI during the initial phases of injury [49]. Interestingly, despite the robust diagnostic and prognostic capabilities of cTn, there is evidence suggesting a potential association between cTn composition and disease status, with observations indicating links to the ischemic time window [15], 23], 50], 51], 53], 54] and injury severity [16], 55], 56]. Unlike patients with MI, the circulating cTnT forms in patients with end-stage renal disease (ESRD) or after endurance exercise (e.g., marathon running) is predominantly made up of small fragments (<18 kDa) [21], 57] (Figure 2). In view of these findings, the existence of distinct fragmentation patterns may underscore the importance of understanding the cTn forms circulating in an individual’s bloodstream for the development of assays tailored to the differential diagnosis of various forms of cardiac disease. Nonetheless, controversy remains regarding the precise changes in cTn that occur following cellular injury and the exact fragments in the bloodstream during pathological and physiological states [14], 18], 58], 59].
Structure of the cardiac troponin complex and various forms of troponin released during ischemia, necrosis, or conditions like end-stage renal disease and post-vigorous exercise. The troponin complex, located on the thin filament of the cardiomyocyte, consists of three proteins: cTnT, cTnI and TnC. Following ischaemia and necrosis, troponin is released into the bloodstream from both the cytoplasm and the enzymatically cleaved bound complexes. Circulating troponin exists mainly as I:C binary complex, some T:I:C ternary complex, low-molecular weight ternary complex with little free or fragmented cTnI/cTnT. Following other conditions (end-stage renal disease, post-vigorous exercise), circulating cTnT exists mainly as small free fragmented cTnT. The cTnI forms are not depicted here as no studies have investigated the cTnI composition in other pathologies yet, as far as we know.
Current cTnI and cTnT assays
cTnT has emerged as a robust predictor of overall cardiovascular morbidity and mortality, whereas elevated levels of cTnI appear to be more indicative of CAD and ischemic events [60], 61]. These distinctions likely reflect diverse pathways underlying cardiac conditions that lead to troponin release. Nonetheless, the clinical significance of these differences remains unclear. However, the ability to distinguish between the two cTn subtypes could present an opportunity for tailoring personalized cardiac evaluations in the future [62]. The central region of cTnI, spanning residues 30–110, constitutes the Ca2+-dependent TnC binding domain and is recognized as the most stable portion of the molecule [63]. Consequently, it is currently the primary target region for the majority of cTnI assays (The International Federation of Clinical Chemistry and Laboratory Medicine. Biomarkers Reference Tables. https://ifcc.org/ifcc-education-division/emd-committees/committee-on-clinical-applications-of-cardiac-bio-markers-c-cb/biomarkers-reference-tables/) (Figure 3) [64].
Epitope mapping for capture and detection antibodies in various cardiac troponin immunoassays. The molecular structures of (A) cTnI (spanning amino acids 1–210) and (B) cTnT (spanning amino acids 1–288) molecules, with stable central regions highlighted in green. These are antibody binding sites of selected commercial assays (The International Federation of Clinical Chemistry and Laboratory Medicine. Biomarkers Reference Tables. https://ifcc.org/ifcc-education-division/emd-committees/committee-on-clinical-applications-of-cardiac-bio-markers-c-cb/biomarkers-reference-tables/). Antibody binding sites used in the assays are illustrated, with the epitopes for capture antibodies indicated in amaranth and those for detection antibodies in coral pink. Purple refers to the overlap of coral pink and amaranth. △Under research and not available for commercial use.
Unlike cTnI, which can be measured using various commercial immunoassays, cTnT in serum or plasma is limited to a specific commercial immunoassay offered by Roche Diagnostics. This immunoassay targets epitopes located in the central region of the cTnT molecule (amino acid residues 125–131 and 136–147, Figure 3). It employs two monoclonal antibodies, M11.7 and M7, and is calibrated using intact recombinant cTnT [65]. Despite the existence of different complex forms of cTnT in the blood, the current cTnT immunoassay can detect intact, mildly truncated, and heavily truncated short forms of cTnT, including the cTn T-I-C complex and free cTnT, with sizes ranging from intact 40 kDa to 29 kDa and 15–18 kDa. Also known as the total cTnT assay, it maintains consistent analytical specificity across versions [66], while its sensitivity has improved over time. For example, the current 5th generation hs-cTnT immunoassay (Roche Diagnostics) can detect cTnT with concentrations as low as 3 ng/L [67].
The degradation of cTnT is now well established, prompting interest in the detection of degraded cTnT forms, although its clinical implications are still under investigation [66]. Future research should explore the immunoreactivity of these fragments [21] using the current hs-cTnT assay and, more importantly, investigate whether assays targeting specific fragments can improve specificity for diagnosing MI. This proposition has also been recently acknowledged and recommended by other experts in the field [47], 68].
MI
MI is the most important and well-established etiology for elevated cTn levels [2], 3]. The primary cause of MI is insufficient oxygen delivery, resulting in acute ischemia of cardiac tissue [3]. The onset of acute ischemia triggers cardiomyocyte necrosis, leading to cellular membrane and organelle breakdown and subsequent leakage of cellular proteins (e.g., cTn) into the bloodstream [69]. Meanwhile, heterogeneous forms of cTn are believed to be present in the blood of MI patients [15].
cTnI in MI
In 1998, Katrukha et al. [70] demonstrated that proteases rapidly cleaved the N- and C-terminal regions of cTnI, while a fragment spanning residues 30 to 110 exhibited significantly greater stability, possibly due to its shielding by TnC. This was further corroborated in 2018 [18], when the most stable segment of cTnI was identified, approximately delineated by amino acids 34 to 126, which likely plays a crucial role in assay standardization and harmonization efforts [70], [71], [72].
It is widely recognized that cTnI is highly susceptible to degradation [70], predominantly as a heterogeneous mixture of degradation fragments and their complexes with TnC [49]. Later, to study the exact forms of the cTnI composition after myocardial injury, Labugger et al. identified intact cTnI alongside up to 11 fragments in the serum of MI patients by employing Western blot (WB) analysis [73]. Moreover, a spectrum of modified cTnI products (7 degradation products and 3 covalent complexes) was observed in myocardial biopsy samples from bypass patients [74]. Similarly, Madsen et al. demonstrated up to seven cTnI fragments ranging from 12 to 20 kDa in serum samples from STEMI patients [59].
In 2018, Katrukha et al. [18] reported no time-dependent degradation of cTnI. Instead, they found that the ratio of cTnI fragments in sequential samples remained stable during the first 36 h post-MI. Employing antibodies specific to residues 23–40 and/or 140–196 of cTnI could mitigate the adverse effects of protein degradation and interference from autoantibodies, thereby enhancing the accuracy of cTnI measurements. However, the findings of Katrukha et al. [18]differ from those of Madsen et al. [59], who reported a time-dependent degradation of cTnI (e.g., intact cTnI and its primary 20 kDa degradation fragment were detectable as early as 90 min after symptom onset, with further degradation observed by 165 min). This discrepancy might attribute to the sensitivity limitations of detection systems [18], suggesting that early-stage cTnI concentrations might have been too low to detect fragments. Research by Vylegzhanina et al. [15] investigating the forms of cTn complexes circulating in the blood of MI patients, indicated that the ITC complex might degrade over time into the low-molecular-weight ITC complex (LMW-ITC) and IC complex. Additionally, cTnI assays designed to target the 23–126 amino acid residue region of cTnI, might enable the detection of all troponin complexes. Further research revealed that the degradation pattern of cTnI, particularly C-terminal degradation, may be a more accurate indicator of clinically significant MI than total serum troponin levels [16]. Relative to total cTnI concentration, a notable discrepancy was found in the ratio of large cTnT-I-C complexes between early- and late-stage MI patients [52]. Nevertheless, further studies are needed to determine whether the specific quantification of degraded troponin leads to an improved correlation with infarct size. Therefore, it remains to be seen whether these discoveries could lead to the development of a dedicated tool for the diagnosis of acute myocardial injury.
cTnT in MI
cTnT degradation in MI patients has also been reported [49], with studies confirming the substantial degradation of intact cTnT into truncated products [51], 54]. Specifically, Cardinaels ea al [51]. revealed that patients’ sera contained intact cTnT alongside cTnT fragments (predominantly 29 kDa) within the initial hours post-MI. As time progresses (specially, 24 h post-presentation), only secondary fragments (18 kDa) were detectable, highlighting the temporal degradation pattern of cTnT. Notably, similar fragmentation patterns were observed when purified intact cTnT is introduced into the serum of healthy individuals [75], 76]. These findings underscore the progressive breakdown of cTnT in the hours following MI.
Meanwhile, the precise contributing locations of cTnT degradation are worth further investigation. While many studies focus on peripheral blood samples, the recent study conducted by Damen et al. [50] provides additional insight, revealing higher concentrations of the ITC complex, free intact cTnT (40 kDa), and fragments (29 kDa and 15–18 kDa) in coronary venous samples compared to peripheral blood in NSTEMI patients. This finding suggests that cTnT degradation primarily occurs intracellularly. Over time, the proportion of the ITC complex decreases, while the abundance of smaller fragments increases, potentially indicating the time since MI. The distinction between the forms of cTnT in coronary veins and those in the peripheral circulation has been further supported by subsequent research [52].
Additionally, Katrukha et al. [77] examined the fragmentation of cTnT in MI heparin plasma samples and addressed the level and sites of cTnT proteolysis. They identified 23 heterogeneous proteolytic fragments in MI patients (molecular mass of ∼ 8–37 kDa). Notably, the central fragments increase in the first few hours after MI, while the fraction of the C-terminal fragments remained almost unchanged. Accordingly, the cTnT region approximately bordered by aar 69–158 is a promising target for antibodies used for the measurement of total cTnT. These findings collectively provide deeper insights into the progressive degradation of cTnT, offering potential markers for more precise MI diagnostics.
Serum or plasma
To date, most investigations of cTn degradation in MI patients have been carried out using serum samples; however, thrombin, produced during serum collection, has been repeatedly implicated in causing cTnT degradation [13], 14]. Research comparing cTnT from MI heparin plasma and serum samples found that cTnT is primarily present as a full-sized molecule (approximately 35 kDa) in plasma, whereas in serum, it appears mainly as a 29 kDa fragment due to thrombin-induced cleavage [14]. This could suggest that cTnT degradation might appear to be a preanalytical phenomenon rather than an in vivo process [14]. However, this conclusion is debated [50], 78] as evidence indicates that cTnT degradation, including the formation of the 29 kDa fragment, occurs in peripheral blood and is not solely an phenomenon of serum preparation; for example, Cardinaels et al. [51] demonstrated that circulating cTnT undergoes degradation in serum following MI, and the degradation pattern is time-dependent after symptom onset. Furthermore, cTnT is released from cardiomyocytes as a combination of the ITC complex, free intact cTnT, and multiple cTnT fragments, with thrombin being one of several enzymes involved in its degradation [13]. These findings suggest that cTnT degradation is a complex process influenced by both preanalytical and in vivo factors, requiring careful consideration in clinical settings.
To this point, cTn fragmentation in serum vs. plasma has remained a topic of ongoing controversy. Vylegzhanina et al. [15] provided key insights by employing heparin plasma instead of serum. They identified an ITC complex consisting of full-size cTnT (37 kDa) or its 29 kDa fragment, alongside full-size cTnI (29 kDa) or its 27 kDa fragment. Additionally, LMW-ITC, where cTnT is truncated to 14 kDa C-terminal fragments, was observed, as well as a binary cTnI-TnC complex with truncated cTnI (∼14 kDa). As time passed from the onset of MI symptoms, the amount of ITC decreased, while LMW-ITC and short 16- to 20-kDa cTnT central fragments increased. Notably, almost all full-size cTnT and the 29-kDa cTnT fragment in MI plasma samples were components of ITC, with no free full-size cTnT found. Only 16- to 27-kDa central fragments of cTnT were present in a free form in patient blood. Damen et al. [50] demonstrated that compared with serum samples containing only 29 kDa and 15–18 kDa cTnT fragments, plasma samples obtained at the same time exhibited higher concentrations of the ITC complex, free intact cTnT (40 kDa), and the 29 kDa and 15–18 kDa cTnT fragments, indicating potential degradation in the serum.
Collectively [15], 50], we can infer that cTnT may undergo intracellular degradation, while its degradation in serum is potentially caused by thrombin. Distinguishing between intact and degraded troponin forms may be useful for (a) identifying patients with clinically significant infarcts in need of revascularization, (b) monitoring intracellular proteolysis as a possible target for therapeutic intervention, (c) providing an impetus for standardizing the epitopes used in the troponin I assay, and (d) serving as a foundation for the development of a hs-cTnT immunoassay tailored for MI. Hence, further studies to properly characterize these forms are needed.
Chronic kidney disease
The relationship between chronic kidney disease (CKD) and elevated cTn levels has long been an area of sustained interest and ongoing research. Patients with CKD frequently exhibit elevated cTn levels [20], [79], [80], [81], [82], [83], making renal function an important factor to consider when interpreting elevated cTn levels [2], even in the absence of previous CVD [79]. This poses challenges in the emergency department, particularly when CKD or ESRD patients present with chest discomfort and elevated troponin levels, despite the use of rapid troponin algorithms [84]. Higher cutoff concentrations have been recommended for diagnosing myocardial infarction in CKD patients to maintain diagnostic accuracy [81], 85]. In addition, not only have elevated cTnI levels been shown to predict sudden cardiac death, a common cause of mortality in CKD and ESRD patients [86] but also they, along with cTnT, serve as powerful predictors of all-cause mortality in those undergoing hemodialysis or not [86], 87]. Given the increased prevalence of CAD in individuals with CKD [88], such damage may be ascribed to clinically silent microinfarctions [89]. Moreover, left ventricular (LV) hypertrophy and increased LV preload, common in ESRD patients, may lead to elevated cTn release due to myocardial strain and an imbalance between myocardial oxygen supply and demand [90]. Hypertension, also prevalent in CKD patients [88] adds to myocardial strain by increasing LV afterload, providing another mechanism for elevated cTn levels. Other factors contributing to elevated cTn levels include myocardial stunning [91], age, male sex [92], and a higher risk of future cardiovascular events and mortality [93], 94] as well as impaired renal clearance of troponin [87].
The initial investigation that conclusively revealed the existence of only small cTnT fragments (<18 kDa) in the serum of ESRD patients, conducted by Mingels et al. [20], highlighted notable differences compared to the cTnT fragments observed in MI patients. These findings suggest that elevated cTnT levels primarily signify fully degraded cTnT fragments in ESRD patients [95]. This degradation is reported to occur within the intracellular milieu of cardiomyocytes, where the N-terminal region of cTnT is truncated [96], [97], [98], [99]. Furthermore, an immunoassay developed by Airaksinen et al. [21] which targets long forms of cTnT, particularly the long/total cTnT ratio, has demonstrated the ability to effectively distinguish between cTnT elevations in NSTEMI and ESRD patients using a single heparin plasma sample. This novel immunoassay has shown superior accuracy compared to commercially available hs-cTnT assays. Therefore, enhancing the diagnostic specificity of the hs-cTnT immunoassay has been suggested as a potential improvement. External validation of the current findings is essential to enhance their credibility and relevance.
Endurance exercise
The elevation of cTn levels due to endurance exercise (e.g., marathon running) has been well documented. The majority of investigations into the correlation between troponin levels and marathon running have indicated the presence of elevated concentrations in varying proportions of participants [100], [101], [102], [103], [104], [105], [106]. Comparable patterns emerge within the context of a 30-km Swedish race, Lidingoloppet [107], [108], [109], [110], [111], [112]. Interestingly, some post-exercise cTn levels exceed the diagnostic thresholds for MI [57], 100], though the underlying mechanisms remain unclear [113]. Several hypotheses have emerged to explain these increases, (e.g., cardiac damage, release from the cytosolic compartment, increased membrane permeability, cardiac workload, “bleb” formation, and physiologic remodeling) [113]. Oxidative stress and an imbalance between oxygen supply and demand during strenuous exercise are also considered potential triggers for cTn release [114], 115]. Two dominant hypotheses emerged: the physiological hypothesis suggests that exercise-induced cTn release signifies reversible damage to cardiomyocytes, leading to the release of cytosolic cTn, subsequent cardiomyocyte repair, and eventual myocardial hypertrophy [116]. Conversely, the pathological hypothesis posits irreversible damage to cardiomyocytes, followed by myocardial scarring and fibrotic tissue replacement [116]. The physiological hypothesis is supported by the high percentage of individuals exhibiting elevated troponin levels post-exercise, along with low absolute levels and rapid normalization of those values. These patterns are consistent with the release of cytosolic troponin rather than necrosis, which was demonstrated by a comprehensive review involving 145 studies [113]. Typically, there is an initial peak in cTn release during exercise, followed by a second peak 3–6 h after exercise cessation [117]; subsequently, circulating cTn levels decrease markedly within 24–48 h and return to baseline [103], [117], [118], [119], [120]. However, the specific triggers for this release remain to be elucidated [113]. Given the heterogeneity of exercise-induced cTn release, various influencing factors come into play. Investigations have been explored for potential predisposing factors, including exercise modalities (e.g., intensity and duration) and athletes’ characteristics (e.g., age and training experience) [121], 122]. Key factors affecting post-exercise troponin levels may include intensity, age, training experience, timing of sampling, and assay type [113], 123]. These findings provide new insights and potential strategies for understanding and managing exercise-induced cTn release.
Evidence indicates that prolonged endurance exercise in recreational athletes is associated with an acute cardiac function impairment and the release of cTn into the circulation. However, further investigation is needed to determine whether the release of cTn induced by exercise reflects a physiological or pathological process.
Recent studies have further investigated the circulating forms of cTnT in recreational athletes, revealing a predominance of secondary cTnT fragments, characterized by cleavage of both the N-terminal and C-terminal ends of the protein, with molecular weights ranging from 14 to 18 kDa. Interestingly, these fragments closely resemble those observed in patients with ESRD but differ from those observed in patients with MI [22], 57]. However, the specific relationship between endurance exercise and the size of degradation fragments of cTn requires further investigation. Understanding this relationship could shed light on the mechanisms underlying exercise-induced cardiac stress and help with cardiovascular health assessments.
General population
Hs-cTnI and hs-cTnT assays have revolutionized clinical practice by enabling the accurate detection of extremely low concentrations of cTn, even those below the 99th percentile. Consequently, cardiac troponin molecules have been detected in nearly 100 % of healthy individuals [124], [125], [126], [127]. Various biological factors influence cTn release from the healthy myocardium, including sex, age, and circadian rhythm [2], [128], [129], [130], [131], [132], [133], [134]. Specifically, cTn levels in males exhibit 1.2–2.4 times higher than females [135], 136]. Meanwhile, cTn levels decrease after birth, reach its lowest point between the ages of 18 and 30, and then increase with age (particularly notable in individuals older than 60 years) [130], [136], [137], [138]. Additionally, troponin release exhibits circadian variations, with higher levels observed in the morning [134]. These findings suggest multiple potential mechanisms for cTn release [139], 140], including a) regeneration and renewal of myocardial cells, b) apoptosis, c) the formation of membrane vesicles on the surface of myocardial cells, d) intracellular proteolytic degradation of cTn, e) increased membrane permeability, f) subclinical necrosis, and g) noncardiac cells. These mechanisms not only explain the detectable concentrations of cTn in healthy individuals but also indicate that cTn may exhibit substantial accumulation in the context of specific physiological conditions and pathological processes [47], 128], [141], [142], [143], possible showing that irreversible cardiomyocyte damage may not always be the primary cause [144]. The widespread application of hs-cTn testing has extended its use from diagnostics to screening, risk stratification and prognostication both in the general population and selected categories of high-risk patients [6], [7], [8], [9]. Even in the general population, cTn serves as a significant predictor of adverse outcomes [8], 130], [145], [146], [147], which are linked to a heightened risk of experiencing an initial CVD event [147], [148], [149], [150], independent of conventional risk factors [150]. Dai et al. [151] recently demonstrated sex-specific differences in cardiovascular event risk under conditions of psychological stress (women exhibit more pronounced coronary artery inflammation, while men show a greater prevalence of high-risk coronary artery plaques), which addresses the question of whether “cardiac-brain” interactions are influenced by sex. These findings have also prompted new questions regarding whether different degradation fragments exist in these populations, thereby influencing the divergent trajectories of cardiovascular events.
As specific cTn forms represent only subpopulations of the total cTn detected by the current hs-cTn assays, it is challenging to investigate different cTn forms in general population. Even better sensitivities with significantly lower detection limits are required from the detection methods of the specific forms [18]. Nevertheless, investigating troponin forms in general cohorts might offer valuable clinical insights and enhance the utility of troponin testing in a variety of settings. Further investigation is required to elucidate the clinical significance of troponin levels in these nonacute settings [152] and to determine whether different forms of cTn have varying implications for risk assessment in individuals. Moreover, exploring the necessity and feasibility of integrating hs-cTn assays into routine screenings for the general population could yield valuable insights for preventive health care strategies.
Challenges and perspectives
Hs-cTn assays exhibit remarkable utility for triaging patients with suspected ACS in the emergency department. However, the heightened sensitivity of these assays brings forth potential clinical challenges. By detecting cTn at levels within the normal range in the majority of the population, they can also identify minor or transient increases that may not be clinically relevant. While these assays are now exquisitely sensitive to myocardial injury, they lack specificity regarding the underlying cause of the injury [2]. As a result, the theoretical drawbacks may include overdiagnosis, unnecessary noninvasive and invasive procedures, overtreatment, and the subsequent risk of complications, as well as increased hospitalization rates [153]. Furthermore, since the increase in cTn levels is independent of the cause of injury, other pathologies (e.g., cardiac or noncardiac pathologies and even some factors under presumed physiological conditions) might also contribute to the detection of cTn [12], 152], 154], 155], complicating the diagnosis of MI.
Challenges arise from differences in sensitivity and specificity among the numerous commercially available hs-cTn assays. First, the lack of standardization among numerous hs-cTnI assay kits targeting different epitopes hinders comparisons between results [49], 65], [156], [157], [158], [159], with discrepancies in cutoff values and measured concentrations sometimes exceeding 10-fold and even larger variations [49], 70], [160], [161], [162]. Second, the presence of various complex fragments [70] (e.g., degradation structures, proteoforms and physiological phosphorylation structures) further contributes to assay discrepancies. Currently, there are no commercial assays specifically designed to differentiate specific fragments, indicating that the clinical utility of identifying specific fragments is still controversial or under experimental investigation. More prospective studies are needed to confirm the practical clinical value of assays targeting specific fragments. Third, variations in antibody cross-reactivity to different cTnI forms [49] and the potential for cTnT cross-reactivity with skeletal muscle proteins [43] pose additional challenges in interpreting assay results. Moreover, interference from various endogenous antibodies poses a significant challenge to the accuracy of cTn assays, further complicating clinical interpretation. Anti-cTn antibodies could compete with assay antibodies for cTn binding, thereby inhibiting signal detection and causing an underestimation of cTn levels [163]. Likewise, heterophilic antibodies, including human anti-mouse antibodies and rheumatoid factors, might induce crosslinking of assay antibodies independently of cTn binding antibodies, leading to artificially elevated results [164]. Additionally, circulating macrotroponin complexes, formed through the binding of cTn to patient-derived anti-cTn antibodies, have a delayed troponin clearance [164]. These complexes may result in persistently high cTn levels unrelated to acute myocardial injury. Identifying and mitigating these interferences are essential to enhancing the precision of cTn assays and ensuring robust clinical decision-making.
Addressing these challenges requires new strategies, including universal vs. sex-specific cutoffs, age-specific cutoffs, disease-specific cTn forms in blood, variations in antibody recognition of different cTn forms and personalized diagnostic strategies [155].
Conclusions
The significant advancements in cardiac biomarkers, particularly the development of high-sensitivity assays (hs-cTnI and hs-cTnT), have revolutionized clinical practice, yet crucial questions remain about the circulating forms of cTn and their clinical implications. (1) While elevated cTn levels are extremely cardiac specific, they do not always indicate ACS, nor are they always related to clinically significant MI. This ambiguity complicates patient management, especially for those with elevated cTn. (2) The elucidation of the complicated structural forms of cTn is crucial, underscoring that cTn measurement is indeed not a static science. Discrepancies in research findings may arise from factors such as blood collection timing and site (peripheral blood or coronary veins), the interval between symptom onset and blood collection, and the type of blood collection device used, leading to variations on the structure of cTn. (3) There is currently no clinically established method to recognize disease-specific, time point-specific or severity-specific forms of cTn (e.g., in MI or other conditions). Identifying specific degradation fragments of cTn and developing antibodies to enhance the sensitivity and specificity of troponin immunoassays may facilitate the elucidation of whether the appearance or temporary availability of specific troponin structural components correlates with specific cardiovascular conditions, particular time points after MI onset, the severity of infarction or reinfarction, or other physiological factors (e.g., stress).
Such endeavors would aid in the development of specific diagnostic assays targeting different etiologies, which can be integrated into routine clinical practice for the benefit of patients. Hence, further studies to thoroughly characterize these forms are needed, thereby enhancing diagnostic specificity and potentially altering the strategy used for cTn immunodetection.
Funding source: Shanghai Municipal Key Clinicial Specialty
Award Identifier / Grant number: shslczdzk01701
Funding source: the National Key R&D Program of China
Award Identifier / Grant number: 2023YFC2506500
Funding source: Program of Shanghai Academic Research leader
Award Identifier / Grant number: 22XD1423300
Funding source: Science and Technology Innovation Foundation of Zhongshan Hospital
Award Identifier / Grant number: 2023-2ZSCX04
Funding source: Shanghai Municipal Health Commission Special Project on Emerging Interdisciplinary Research
Award Identifier / Grant number: 2022JC012
Funding source: National Natural Science Foundation of China
Award Identifier / Grant number: 82370357
Funding source: Training Program for Outstanding Young Medical and Pharmaceutical Talents of Minhang District Health System
Award Identifier / Grant number: mwyjyx08
Acknowledgments
The Figures were created by BANGTU CULTURE (www.bangtuwh.com). We thank American Journal Experts editorial team (www.aje.com) for language editing service.
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Research ethics: Not applicable.
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Informed consent: Not applicable.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. All authors made a significant contribution to the work reported, whether that is in the conception, manuscript design, execution, and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The authors state no conflict of interest.
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Research funding: This study was support by the National Key R&D Program of China (2023YFC2506500), National Natural Science Foundation of China (82370357), Program of Shanghai Academic Research leader (22XD1423300), Science and Technology Innovation Foundation of Zhongshan Hospital (2023-2ZSCX04), Shanghai Municipal Key Clinicial Specialty (shslczdzk01701), Shanghai Municipal Health Commission Special Project on Emerging Interdisciplinary Research (2022JC012), and Training Program for Outstanding Young Medical and Pharmaceutical Talents of Minhang District Health System (mwyjyx08).
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Data availability: Not applicable.
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© 2025 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Macroprolactinaemia – some progress but still an ongoing problem
- Review
- Understanding the circulating forms of cardiac troponin: insights for clinical practice
- Opinion Papers
- New insights in preanalytical quality
- IFCC recommendations for internal quality control practice: a missed opportunity
- Genetics and Molecular Diagnostics
- Evaluation of error detection and treatment recommendations in nucleic acid test reports using ChatGPT models
- General Clinical Chemistry and Laboratory Medicine
- Pre-analytical phase errors constitute the vast majority of errors in clinical laboratory testing
- Improving the efficiency of quality control in clinical laboratory with an integrated PBRTQC system based on patient risk
- IgA-type macroprolactin among 130 patients with macroprolactinemia
- Prevalence and re-evaluation of macroprolactinemia in hyperprolactinemic patients: a retrospective study in the Turkish population
- Defining dried blood spot diameter: implications for measurement and specimen rejection rates
- Screening primary aldosteronism by plasma aldosterone-to-angiotensin II ratio
- Assessment of serum free light chain measurements in a large Chinese chronic kidney disease cohort: a multicenter real-world study
- Beyond the Hydrashift assay: the utility of isoelectric focusing for therapeutic antibody and paraprotein detection
- Direct screening and quantification of monoclonal immunoglobulins in serum using MALDI-TOF mass spectrometry without antibody enrichment
- Effect of long-term frozen storage on stability of kappa free light chain index
- Impact of renal function impairment on kappa free light chain index
- Standardization challenges in antipsychotic drug monitoring: insights from a national survey in Chinese TDM practices
- Potential coeliac disease in children: a single-center experience
- Vitamin D metabolome in preterm infants: insights into postnatal metabolism
- Candidate Reference Measurement Procedures and Materials
- Development of commutable candidate certified reference materials from protein solutions: concept and application to human insulin
- Reference Values and Biological Variations
- Biological variation of serum cholinesterase activity in healthy subjects
- Hematology and Coagulation
- Diagnostic performance of morphological analysis and red blood cell parameter-based algorithms in the routine laboratory screening of heterozygous haemoglobinopathies
- Cancer Diagnostics
- Promising protein biomarkers for early gastric cancer: clinical performance of combined detection
- Infectious Diseases
- The accuracy of presepsin in diagnosing neonatal late-onset sepsis in critically ill neonates: a prospective study
- Corrigendum
- The Unholy Grail of cancer screening: or is it just about the Benjamins?
- Letters to the Editor
- Analytical validation of hemolysis detection on GEM Premier 7000
- Reconciling reference ranges and clinical decision limits: the case of thyroid stimulating hormone
- Contradictory definitions give rise to demands for a right to unambiguous definitions
- Biomarkers to measure the need and the effectiveness of therapeutic supplementation: a critical issue
Articles in the same Issue
- Frontmatter
- Editorial
- Macroprolactinaemia – some progress but still an ongoing problem
- Review
- Understanding the circulating forms of cardiac troponin: insights for clinical practice
- Opinion Papers
- New insights in preanalytical quality
- IFCC recommendations for internal quality control practice: a missed opportunity
- Genetics and Molecular Diagnostics
- Evaluation of error detection and treatment recommendations in nucleic acid test reports using ChatGPT models
- General Clinical Chemistry and Laboratory Medicine
- Pre-analytical phase errors constitute the vast majority of errors in clinical laboratory testing
- Improving the efficiency of quality control in clinical laboratory with an integrated PBRTQC system based on patient risk
- IgA-type macroprolactin among 130 patients with macroprolactinemia
- Prevalence and re-evaluation of macroprolactinemia in hyperprolactinemic patients: a retrospective study in the Turkish population
- Defining dried blood spot diameter: implications for measurement and specimen rejection rates
- Screening primary aldosteronism by plasma aldosterone-to-angiotensin II ratio
- Assessment of serum free light chain measurements in a large Chinese chronic kidney disease cohort: a multicenter real-world study
- Beyond the Hydrashift assay: the utility of isoelectric focusing for therapeutic antibody and paraprotein detection
- Direct screening and quantification of monoclonal immunoglobulins in serum using MALDI-TOF mass spectrometry without antibody enrichment
- Effect of long-term frozen storage on stability of kappa free light chain index
- Impact of renal function impairment on kappa free light chain index
- Standardization challenges in antipsychotic drug monitoring: insights from a national survey in Chinese TDM practices
- Potential coeliac disease in children: a single-center experience
- Vitamin D metabolome in preterm infants: insights into postnatal metabolism
- Candidate Reference Measurement Procedures and Materials
- Development of commutable candidate certified reference materials from protein solutions: concept and application to human insulin
- Reference Values and Biological Variations
- Biological variation of serum cholinesterase activity in healthy subjects
- Hematology and Coagulation
- Diagnostic performance of morphological analysis and red blood cell parameter-based algorithms in the routine laboratory screening of heterozygous haemoglobinopathies
- Cancer Diagnostics
- Promising protein biomarkers for early gastric cancer: clinical performance of combined detection
- Infectious Diseases
- The accuracy of presepsin in diagnosing neonatal late-onset sepsis in critically ill neonates: a prospective study
- Corrigendum
- The Unholy Grail of cancer screening: or is it just about the Benjamins?
- Letters to the Editor
- Analytical validation of hemolysis detection on GEM Premier 7000
- Reconciling reference ranges and clinical decision limits: the case of thyroid stimulating hormone
- Contradictory definitions give rise to demands for a right to unambiguous definitions
- Biomarkers to measure the need and the effectiveness of therapeutic supplementation: a critical issue
