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BY 4.0 license Open Access Published by De Gruyter November 28, 2022

Differences between high-sensitivity cardiac troponin T and I in stable populations: underlying causes and clinical implications

  • Kai M. Eggers ORCID logo EMAIL logo , Ola Hammarsten and Bertil Lindahl

Abstract

Objectives

Measurement of high-sensitivity (hs) cardiac troponin (cTn) T and I is widely studied for cardiac assessment of stable populations. Recent data suggest clinical and prognostic discrepancies between both hs-cTn. We aimed at reviewing published studies with respect to underlying causes and clinical implications.

Content

We summarized current evidence on release and clearance mechanisms of cTnT and I, and on preanalytical and assay-related issues potentially portending to differences in measured concentrations. We also performed a systematic review of outcome studies comparing both hs-cTn in the general population, patients with congestive heart failure, stable coronary artery disease and atrial fibrillation.

Summary and outlook

For the interpretation of concentrations of hs-cTnT, stronger association with renal dysfunction compared to hs-cTnI should be considered. Hs-cTnT also appears to be a stronger indicator of general cardiovascular morbidity and all-cause mortality. Hs-cTnI concentrations tend to be more sensitive to coronary artery disease and ischemic outcomes. These findings apparently reflect variations in the mechanisms of cardiac affections resulting in cTn release. Whether these differences are of clinically relevance remains to be elucidated. However, having the option of choosing between either hs-cTn might represent an option for framing individualized cardiac assessment in the future.

Introduction

Measurement of cardiac troponin (cTn) T or I concentrations is a cornerstone in the diagnosis of myocardial infarction [1]. With the introduction of high-sensitivity (hs) assays, it has become clear that cTn concentrations also can be detected in other populations including subjects from the community [2], [3], [4], [5], [6]. In general, hs-cTn is associated with cardiovascular (CV) risk factors, structural and functional myocardial abnormalities, and coronary artery disease (CAD) [4], [5], [6]. Elevated hs-cTn concentrations have consistently emerged as strong predictors of adverse outcome [26]. However, despite the expression of cTnT and cTnI as an obligate 1:1 complex in cardiac tissue [7] and the reasonably well calibration of cTn assays such as those from Roche and Abbott [8], the correlation of concentrations of cTnT and I using these assays is often surprisingly low. Moreover, current evidence suggests the presence of subtle differences in the associations of both cTn with CV conditions and outcomes [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19].

These issues are important for an improved understanding of the clinical information conveyed by either hs-cTnT or I. Here, we describe pathophysiological issues, preanalytical and assay-related factors contributing to differences in the concentrations of both cTn, and variations in their prognostic value.

Methods

In this review, we summarize the evidence on biochemical differences between hs-cTnT and hs-cTnI together with assay-related issues affecting measured concentrations. We also conducted a comprehensive review of outcome studies using “high-sensitivity cardiac troponin T” AND “high-sensitivity cardiac troponin I” AND (“outcome” OR “prognosis”) as search terms on PubMed. Additionally, we screened the reference lists of relevant articles to identify papers of potential interest. We considered only publications that reported prognostic estimates for both hs-cTn. We refrained from reporting data on composite endpoints since an understanding of the mechanisms linking hs-cTn concentrations with poor prognosis depends on their associations with single outcomes. We focused on clinically stable populations. Patients presenting with acute conditions were not considered since concentrations of hs-cTnT or hs-cTnI in such settings rather reflect the amount of acute myocardial injury than intrinsic differences between both molecules.

Cardiac troponin biochemistry

cTn is a regulatory protein that is structurally bound to tropomyosin which is part of the cardiomyocyte sarcomere. The cTn complex consists of cTnT, cTnI and cTnC, a cluster of three subunits that work in concert with tropomyosin and filamentous actin in order to control cardiac muscle contraction.

In case of cardiomyocyte injury, the cTn are released into the circulation as free proteins or complexed forms [20]. Hs-cTnI concentrations increase faster compared to hs-cTnT in both reversible ischemia [21] and myocardial infarction (MI), often reach ten-times higher peak concentrations and decrease more quickly [8, 22], [23], [24]. These kinetic differences appear to be caused by a faster proteolytic degradation of cTnI in necrotic tissue resulting in the release of cTnI fragments that are detectable with immunoassays [20]. cTnT in contrast, mostly remains bound to tropomyosin with a greater degree of degradation occurring locally by phagocytes so that only a small proportion of cTnT reaches the circulation [8]. This contributes to less pronounced increases of cTnT in acute situations [8, 2224]. Notably, cTn release may also occur in conditions not associated with acute cardiomyocyte necrosis, e.g. reversible cell damage or apoptosis [25].

cTnT and cTnI are detectable in the circulation in different forms. These include the ternary cTnT:I:C complex, the binary cTnI:C complex, free cTnT and cTnI, and smaller immunoreactive fragments [20]. In particular cTnI is subject to extensive proteolytic degradation which results in a large heterogeneity of detectable forms [20].

Under physiological conditions, cTnT and cTnI are predominantly cleared by the kidneys at similar rates [8]. Still, hs-cTn concentrations tend to be higher in subjects with renal dysfunction. The current view is that hs-cTn elevation in this setting primarily reflects underlying cardiac disease and increased cardiac work load. Notably, renal failure is more apt to result in increases of cTnT compared to cTnI [26, 27]. The cause of this discrepancy is incompletely understood. Possible explanations include an increased degree of cTnI degradation in a uremic environment, accumulation of immunoreactive cTnT fragments or cTnT expression in skeletal muscle tissue [28].

Preanalytical issues

Interferences may affect the results of all immunoassays. They are caused by compounds that cross-react with the analyte itself or with the capture and detection antibodies of immunoassays. Interferences are rarely a matter of concern but may sometimes be the cause of confounding results for hs-cTnT or I [29].

cTn auto-antibodies bind and delay the clearance of cTn and can induce marked increases in measured concentrations. Auto-antibodies may also cause false-negative hs-cTn results due to their capacity to block the binding of the assays capture and/or detection antibodies. Heterophilic antibodies can bind to both antibodies of immunoassays, thereby simulating the presence of cTn which generates a false-positive result. The degree of these interferences differs among cTn assays but appears to be more common for hs-cTnI [29]. Hemolysis (>1 g hemoglobin/L) may cause false-negative (hs-cTnT) and occasionally false-positive (hs-cTnI) results. Even daily consumption of biotin has been shown to falsely lower hs-cTnT results [29].

Discrepant results for hs-cTnT and hs-cTnI can also occur in patients with myopathies. This may be due to skeletal muscle expression of cTnT [30, 31] or cross-reaction of skeletal muscle troponin T isoforms with cTnT immonoassays [31]. However, current evidence and the potential clinical implications of this issue are debated [32].

Cardiac biomarker concentrations may moreover, be affected by their biological variability. However, both hs-cTnT and I have a low index of individuality (<0.35). This indicates stable concentrations within an individual over time [33]. Interestingly, a diurnal variation has been described for hs-cTnT but not for hs-cTnI [34]. However, these data need to be interpreted with some caution due to the small size of that investigation (n=17).

Assay-related issues

A closer look at the analytical characteristics of hs-cTn assays is essential for a better understanding of the differences between hs-cTnT and hs-cTnI. Currently used assays vary in several aspects, e.g. analytical sensitivity, imprecision, recognized epitopes on the targeted molecules and preanalytical interferences. Owing to previous patent restrictions, the vast majority of hs-cTnT measurements is performed using the Roche assay. For cTnI, various hs-assays with different analytical characteristics are marketed. Table 1 provides an overview of selected methods. A more detailed summary of available assays together with information on their analytical performance can be found at [35].

Table 1:

Analytical characteristics of selected hs-cTnT and hs-cTnI assays.

Assay/platform Analyte Limit of blank Overall 99th percentile Sex-specific 99th percentilesa 10% CV concentration Detection rates in normals
ET Healthcare Pylon cTnT 0.8 ng/L 13.0 ng/L 13.0/14.0 ng/L 10.0 ng/L 91%
Roche cobas e601, e602, E170 cTnT 2.3 ng/L 14.0 ng/L 9.0/16.0 ng/L 5.0 ng/L 59%
Roche cobas e411 cTnT 2.6 ng/L 14.0 ng/L 9.0/16.0 ng/L 5.0 ng/L 59%
Abbott Alinity cTnI 1.0 ng/L 26.2 ng/L 15.6/34.2 ng/L 4.7 ng/L 85%
Abbott ARCHITECT cTnI 0.7–1.3 ng/L 26.2 ng/L 15.6/34.2 ng/L 4.7 ng/L 85%
Beckman Coulter Access 2 cTnI 0.0–1.7 ng/L 17.5 ng/L 11.6/19.8 ng/L 5.6 ng/L >50%
Beckman Coulter Access cTnI 0.0–0.8 ng/L 17.9 ng/L 14.9/19.8 ng/L 5.6 ng/L >50%
bioMérieux VIDAS cTnI 1.9 ng/L 19.0 ng/L 11.0/25.0 ng/L Not provided Not provided
LSO Medience PATHFAST cTnI Not provided 15.5 ng/L 16.9/11.5 ng/L 3.1 ng/L 78%
Ortho VITROS cTnI 0.1–0.5 ng/L 11.0 ng/L 9.0/12.0 ng/L 2.0 ng/L >50%
Siemens ATELLICA cTnI 0.5 ng/L 45.4 ng/L 38.6/53.5 ng/L <6.0 ng/L 75%
Siemens ADVIA Centaur cTnI 0.5 ng/L 46.5 ng/L 39.6/58.0 ng/L <6.0 ng/L 72%
Siemens Dimension VISTA cTnI 1.1 ng/L 58.9 ng/L 53.7/78.5 ng/L 10.0 ng/L 82%
Singulex Clarity cTnI 0.02 ng/L 8.7 ng/L 8.8/9.2 ng/L 0.5 ng/L 99%
  1. aConcentrations in men and women, respectively. Data from [35].

hs-cTnI assays are often able to measure lower concentrations than the Roche hs-cTnT assay (Table 1). For example, the ratios between the reported median concentration and the limit of blank were 1.6 and 1.1 for hs-cTnI (Abbott) and T (Roche), respectively, in a large cohort of community-dwelling subjects (n=19,501) from the GS:SFH study [36]. This contributes to variations in detection rates for hs-cTnT and I in populations with low hs-cTn concentrations, e.g. subjects from the community (Table 2). Differences in assay calibration or analytical imprecision may contribute to these variations. These issues may impact on direct comparisons of both cTn because of different proportions of subjects being censored from such analyses due concentrations deemed as undetectable [37].

Table 2:

Results from studies comparing hs-cTnT and hs-cTnI in stable populations.

n Assay Median concentration Detectable concentration Correlation hs-cTnT/hs-cTnI Outcome Follow-up duration HR (95% CI)
General population

Dallmeier [38] 1,422 hs-cTnT 3 (3–10) ng/L 55% r=0.46 D 4 years 2.2 (1.6–2.9)
hs-cTnI (Abbott) 6 (4–9) ng/L 100% 1.9 (1.5–2.3)
Welsh [11] 19,501 hs-cTnT 3 (2–6) ng/La 53% r=0.44 D 7.8 years 1.4 (1.3–1.6)
hs-cTnI (Abbott) 2 (1–3) ng/La 75% 1.3 (1.2–1.4)
hs-cTnT See above See above See above CVD See above 1.5 (1.3–1.8)
hs-cTnI (Abbott) 1.6 (1.4–1.8)
hs-cTnT See above See above See above Non-CVD See above 1.4 (1.2–1.5)
hs-cTnI (Abbott) 1.0 (0.9–1.2)
hs-cTnT See above See above See above MI See above 0.9 (0.8–1.1)
hs-cTnI (Abbott) 1.2 (1.0–1.4)
hs-cTnT See above See above See above HF See above 1.7 (1.4–2.0)
hs-cTnI (Abbott) 1.9 (1.7–2.1)

Heart failure

Gohar [39] 1,096 hs-cTnT n.a. n.a. r=0.76 D/HF 1.1 years 1.5 (1.3–1.6)
hs-cTnI (Abbott) n.a. n.a. 1.4 (1.2–1.5)

Stable coronary artery disease

Omland [17] 3,623 hs-cTnT 6/5 ng/Lbc 98%c r=0.44 CVD/HF 5.2 years 1.5 (1.2–2.0)d
hs-cTnI (Abbott) 5/4 ng/Lb 96% 1.2 (1.0–1.4)d
hs-cTnT See above See above See above MI See above 1.0 (0.8–1.1)d
hs-cTnI (Abbott) 1.2 (1.0–1.4)d
Jansen [40] 1,068 hs-cTnT 14 (9–21) ng/L n.a. r=0.67 D 13 years 1.2 (1.0–1.5)
hs-cTnI (Abbott) 14 (9–24) ng/L n.a. 1.2 (1.1–1.4)
hs-cTnT See above See above See above CVD See above 1.6 (1.2–2.1)
hs-cTnI (Abbott) 1.4 (1.2–1.7)
Bay [16] 1,478 hs-cTnT 17 (10–34) ng/L n.a. n.a. D 4.4 years 2.0 (1.6–2.6)e
hs-cTnI (Abbott) 9 (4–23) ng/L n.a. 1.5 (1.2–1.8)e

Atrial fibrillation

Røsjø [19] 14,980 hs-cTnT 12 (8–18)/10 (7–14) ng/Lb 34% r=0.70/0.69b D 1.9 years 2.2 (1.9–2.5)
hs-cTnI (Abbott) 6 (3–11)/5 (3–9) ng/Lb 9% 2.5 (2.1–2.8)
hs-cTnT See above See above See above CVD See above 2.9 (2.3–3.6)
hs-cTnI (Abbott) 3.5 (2.7–4.4)
hs-cTnT See above See above See above MI See above 2.6 (1.7–4.0)
hs-cTnI (Abbott) 2.5 (1.7–3.7)
hs-cTnT See above See above See above Stroke/SEE See above 1.6 (1.3–1.9)
hs-cTnI (Abbott) 1.5 (1.3–1.8)
  1. D, all-cause death; CVD, cardiovascular death; MI, myocardial infarction; HF, incident heart failure; SEE, stroke/systemic embolic event; HR, hazard ratio; n.a., not applicable. Median hs-cTn concentrations are presented with interquartile ranges, if available. Hazard ratios refer to models applying hs-cTn as a continuous variable if not stated otherwise, and adjusting for cardiovascular risk factors and comorbidities. aData from [36]. bData refer to results in men and women, respectively. cData from [41]; n=3,679. The level of detection for hs-cTnT was given as 1 ng/L. dAdditionally adjusted for NT-proBNP, CRP and hs-cTnT or hs-cTnI, respectively. eAdditionally adjusted for NT-proBNP and CRP. Hazard ratios refer to models comparing highest vs. lowest hs-cTn quartiles.

Hs-cTnT and hs-cTnI concentrations in selected populations

Community-dwelling subjects

Hs-cTn concentrations are often detectable in community-dwelling subjects [3]. Detection rates vary greatly depending on the applied assay and the characteristics of the investigated cohort. Hs-cTn concentrations do not reflect acute ischemic cardiomyocyte necrosis in these subjects but rather chronic processes affecting cell integrity that lead to subsequent diffuse cardiac fibrosis, hypertrophy and dysfunction [25]. Hs-cTn concentrations have consistently been shown to be associated with estimates of subclinical or manifest cardiac disease including CAD. However, some variations appear to exist in the pattern of entities associated with hs-cTnT or hs-cTnI. Hs-cTnT concentrations often exhibit stronger associations with diabetes and renal dysfunction [9], [10], [11], [12]. For hs-cTnI in contrast, stronger associations with male sex, hypertension, CAD, myocardial hypertrophy and strain have been reported [9], [10], [11], [12], [13].

Both hs-cTn are strongly associated with mortality with hs-cTnT appearing to be a somewhat stronger predictor. The pooled hazard ratios (HR) for hs-cTnT and hs-cTnI were 1.31 and 1.14, respectively regarding all-cause mortality and 1.37 and 1.21, respectively regarding CV mortality in a recent meta-analysis based on 65,019 subjects from 11 cohorts. The difference in risk estimates for CV mortality was statistically significant [14]. Similarly, another meta-analysis (n=203,202; 23 cohorts) demonstrated significant discrepancies between hs-cTnT and hs-cTnI with pooled HR of 1.63 and 1.26, respectively regarding CV events, and of 1.57 and 1.47, respectively regarding HF hospitalizations [15]. In this context, it should however, be emphasized that HR from these meta-analyses were derived from continuous hs-cTn concentrations. In other words: they reflect risk gradients but do not reveal whether prognostic discrepancies exist in the lower or in the higher range of measured concentrations.

There are only two studies that compared hs-cTnT and I concentrations in a head-to-head manner (Table 2). Overall, these studies suggested similar prognostic value of both hs-cTn regarding all-cause mortality [11, 38]. Interestingly, data from the large GS:SFH study (n=19,501) demonstrated that hs-cTnI was more predictive of CV mortality and future MI whereas hs-cTnT exhibited stronger associations with non-CV mortality [11]. These associations persisted in models adjusting for both hs-cTn indicating that their prognostic value with respect to different outcomes is independent of each other. In support of these variations, another study from the ARIC cohort (n=8,121) demonstrated incremental value of both hs-cTn to each other regarding the prediction of the composite of atherosclerotic CV disease [10].

Patients with stable congestive heart failure

Elevation of hs-cTn concentrations is commonly observed in patients with congestive heart failure (HF) [4]. Hs-cTn elevation in HF patients is not necessarily associated with symptomatic decompensation, but indicates the presence of a more deleterious phenotype with a greater tendency towards myocardial remodeling [4].

Hs-cTn concentrations are strong predictors of poor prognosis in stable HF. According to a meta-analysis investigating 67,063 patients from 16 cohorts, the pooled HR regarding incident HF were 2.11 and 2.09 for highest vs. lowest tertiles of hs-cTnT and hs-cTnI, respectively [42]. Importantly, the overall association of hs-cTn with incident HF was independent of B-type natriuretic peptide concentrations. Another meta-analysis (n=6,888; 12 cohorts) demonstrated pooled HR of 2.92 and 2.64 for cTnT and cTnI respectively, regarding the prediction of all-cause mortality [43]. This analysis however, considered both conventional and hs-cTn assays with heterogeneous thresholds why these results should be interpreted with caution.

There is only one study that directly compared hs-cTnT and hs-cTnI in patients with stable HF. In the investigation from Gohar et al. (n=1,096), risk estimates for both hs-cTn were similar regarding the composite endpoint of all-cause mortality or HF hospitalization (Table 2) [39].

Patients with stable coronary artery disease

The use of hs-cTn measurement in the work-up of patients with suspected or known CAD is a matter of increasing interest since hs-cTn concentrations might serve as a marker of a lowered ischemic threshold or of subclinical ischemia [5]. In a recent study investigating 1,829 subjects referred for invasive coronary angiography, both hs-cTn were independently associated with the presence of CAD [16]. However, similarly as seen in community-dwelling subjects, hs-cTnI exhibited somewhat stronger associations with CAD extent and severity, expressed by SYNTAX- and GENSINI scores.

Hs-cTn concentrations are strong risk predictors in patients with stable CAD. Significant relationships exist between higher hs-cTn concentrations and various prognostic outcomes, as demonstrated in a meta-analysis based on 34,854 patients from 16 cohorts [44]. However, this analysis did not differentiate between hs-cTnT and hs-cTnI.

The prognostic value of both hs-cTn was largely similar in studies that performed comparative analyses in CAD patients [16, 17, 40] (Table 2). In the PEACE study (n=3,623) however, hs-cTnI concentrations emerged as stronger predictors of future MI and exhibited stronger associations with previous manifestations of CAD [17].

Patients with atrial fibrillation

Atrial fibrillation (AF) is often associated with elevated hs-cTn concentrations [6]. The underlying mechanisms are probably multifactorial, similar as in other populations with stable cardiac disease. Hs-cTn predicts various adverse outcomes in AF, interestingly including stroke/systemic embolism [18, 19, 45]. Hs-cTn concentrations have been shown to correlate with the presence of spontaneous echocardiographic contrast and thrombi in the atria [46] which might represent a mechanistic link.

The prognostic value of cTnT and cTnI has been investigated in a meta-analysis studying 22,697 AF patients from six cohorts. The pooled HR were 2.49 and 1.91, respectively regarding all-cause mortality [47]. However, this investigation included studies using both conventional and hs-cTn assays which limits the interpretation of these data.

hs-cTnT and hs-cTnI have been compared directly in two investigations from the ARISTOTLE trial (n=14,806) [18, 19]. While risk estimates for both hs-cTn differed only marginally regarding all-cause mortality and stroke/systemic embolism, hs-cTnI appeared to be a stronger predictor of cardiac mortality and MI (Table 2). Patients with isolated hs-cTnI elevation (above median) were reported to have 66% higher annual cardiac mortality rates and 32% higher annual MI rates compared to patients with isolated hs-cTnT elevation [18]. In this context, it is noteworthy that AF patients with isolated hs-cTnI elevation were characterized by higher prevalence of CV disease (e.g. HF, persistent/permanent AF, vascular disease) whereas those with isolated hs-cTnT elevation more often had other risk factors (e.g. higher age, diabetes).

Summary, knowledge gaps and future directions

Our review of the literature emphasizes that differences between hs-cTnT and hs-cTnI exist in several aspects. This is illustrated both by the often surprisingly low correlation between both hs-cTn (Table 2) and by variations in their distribution pattern with narrower ranges of hs-cTnI compared to hs-cTnT [17, 18]. Analytical issues or preanalytical interferences appear only to a minor degree to explain these discrepancies. It is thus, conceivable that they rather signify variations in the mechanisms of cardiac affections resulting in hs-cTn elevation, and of differences in cTn release and clearance patterns.

cTnT is tighter bound to tropomyosin [8] and thus, released into the circulation at a slower rate compared to cTnI in case of cardiomyocyte injury [8, 21], [22], [23], [24]. cTnT moreover, is to a stronger degree affected by renal dysfunction but even diabetes [9], [10], [11], [12, 18, 26, 27], i.e. entities reflecting general morbidity. Along this line, hs-cTnT appears to be a stronger predictor of mortality, in particular of non-CV mortality as demonstrated by the results from the GS:SFH study [11]. cTnI in contrast, appears to be more sensitive to myocardial ischemia [9], [10], [11], [12], [13, 16], [17], [18]. It is however, hard to believe that higher hs-cTnI elevations reflect acute subclinical cardiac insults. The consequence would be a substantial loss of viable cardiomoycytes over time in patients with moderately raised concentrations, not observed in clinical studies. As to whether other mechanisms, e.g. cellular aging or increased cellular stress, might contribute to differences in release patterns and prognostic implications of both cTn remains to be elucidated.

The causes of the discrepancies between concentrations of hs-cTnT and hs-cTnI are multifactorial, and we just have started to understand the underlying cellular mechanisms [8]. Further preclinical studies are clearly needed. Even longitudinal investigations on the associations of temporal concentration changes for either hs-cTn with ischemic or non-ischemic outcomes, respectively would be of interest. This also applies to studies on the impact of directed medical interventions on changes of either hs-cTnT or hs-cTnI concentrations. Finally, as only the Roche and Abbott hs-assays have been used in the comparison studies, it needs to be established whether differences between both hs-cTn are generalizable to other assays.

To summarize, the preference regarding the use of either hs-cTnT or hs-cTnI for assessment of stable populations depends ultimately on the objective for testing. The current accumulated evidence suggests that hs-cTnT rather is an indicator of general CV illness whereas hs-cTnI is a stronger predictor of CAD and ischemic risk. However, the predictive differences between both hs-cTn are not tremendous and probably of minor importance when it comes to real-life clinical applications. Combination testing for both hs-cTn might be an option to improve risk prediction in stable populations but will inevitably increase the complexity of result interpretation and is for this reason not recommended. This is at difference to acutely diseased patients in whom the hs-cTnI/T ratio appears to carry some information on underlying disease mechanisms [48, 49]. The choice regarding the use of hs-cTnT or hs-cTnI needs also to be embedded in each respective clinical environment. The used hardware at the central laboratory needs to be considered in this context together with established pathways for patient management. Nonetheless, having the possibility to choose between either hs-cTnT or I might be an option for framing individualized CV assessment in the future.


Corresponding author: Kai M. Eggers, MD, PhD, Department of Medical Sciences, Cardiology, Uppsala University, 751 85 Uppsala, Sweden, Phone: +46-18-611 00 00, Fax: +46-18-50 66 38, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Dr Eggers has received consulting honoraria from Roche Diagnostics. The other authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

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Received: 2022-08-09
Accepted: 2022-11-09
Published Online: 2022-11-28
Published in Print: 2023-02-23

© 2022 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

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