High-Sensitivity Cardiac Troponin I and T Kinetics after Non-ST-Segment Elevation Myocardial Infarction

To the Editor: Diagnosis of non-ST-segment elevation myocardial infarction (NSTEMI)1 strongly relies on serial cardiac troponin (cTn) measurements and interpretation of kinetic changes (1). The current evidence suggests distinct kinetic changes for troponin I and T with a monophasic release curve of cTnI and biphasic, prolonged, release pattern of cTnT (2). These observations stem from the era of conventional assays, and it is unclear whether this is representative for today's high-sensitivity (hs) assays. Another unexplored aspect is the troponin kinetics in patients with NSTEMI. Indeed, previous studies were solely conducted in STEMI (2, 3), and it is conceivable that NSTEMI is characterized by distinct kinetics. The objective of this study was to assess hs-troponin I and T kinetics in patients with NSTEMI. Patients who consented to the CARMENTA trial (NCT01559467) were used for this study (4). Briefly, CARMENTA enrolled patients between 2012 and 2016 who presented to the cardiac emergency unit with clinical symptoms suggestive of NSTEMI, normal or inconclusive electrocardiogram, and increased hs-cTnT levels (>14 ng/L at presentation or 3 h later). The study was approved by the Ethical Committee (11–2-077) and complied with the Declaration of Helsinki. Standardized serum sampling was done at presentation and 3, 6, 24, and 48 h after presentation. Furthermore, all additional serum samples taken at the discretion of the attending physician for routine clinical care during hospitalization were collected. This analysis included patients with an adjudicated NSTEMI diagnosis of whom ≥3 serum samples were available (n = 61). Four patients with a suspected reinfarction during hospitalization were excluded. Troponin concentrations were assessed using the hs-cTnI (Abbott) and hs-cTnT (Roche) immunoassays. The hs-cTnI and hs-cTnT assay have a limit of blank of 0.7 to 1.3 and 2.26 ng/L, limit of detection of 1.1 to 1.9 and 2.85 ng/L, and limit of quantification (10% CV) of 4.7 and 5.03 ng/L, respectively. The measuring ranges are 4.7 to 50000 ng/L for hs-cTnI and 5.03 to 10000 ng/L for hs-cTnT. Time-course of hs-cTnI and hs-cTnT kinetics were modeled using local regression, a nonparametric regression method combining multiple regression models in a k-nearest-neighbors-based metamodel. Data are presented as median (interquartile range). Statistical analyses were performed with R (3.3.1) and package ggplot2 (3.0.0). The average number of samples per patient was 5.1 ± 1.4. Presenting levels of hs-cTnI were substantially higher than hs-cTnT [173 ng/L (61–540 ng/L) vs 62 ng/L (26–144 ng/L); P < 0.001]. These levels increased to peak concentrations of 645 ng/L (251–2101 ng/L) and 157 ng/L (74–288 ng/L) (P < 0.001), respectively. Peak concentrations were measured 8.3 h (6.3–15.7 h) after emergency department presentation for hs-cTnI and 11.2 h (6.3–30.9 h) for hs-cTnT (P = 0.01). Modeling of hs-cTn kinetic curves revealed a monophasic release pattern for hs-cTnI, whereas a shoulder-like release pattern was observed for hs-cTnT (Fig. 1). These patterns were identical when troponin measurements postrevascularization were excluded (data not shown). Pseudo-R2 of modeled kinetic curves was 0.41 and 0.22 for hs-cTnI and hs-cTnT, respectively. Despite substantial unexplained variation in the regression model, the progressively decreasing elimination rate for hs-cTnT is consistent with the current notion of a biphasic release curve for hs-cTnT (2, 3). Quantification of the elimination rate showed that hs-cTnI elimination from the circulation was significantly faster than hs-cTnT: 50% reduction of the maximum concentration was observed after 44.6 vs 115.9 h (P < 0.001). Individual data points are depicted as open dots (hs-cTnI) and closed dots (hs-cTnT). CIs (95%) are shown as shaded areas surrounding both curves. This study is the first to model hs-cTnI and hs-cTnT kinetics in NSTEMI patients. We report 2 major findings. First, presenting and peak concentrations of hs-cTnI were 3- to 4-fold higher than hs-cTnT. Because cTnI and cTnT are different molecules, such numerical differences are not surprising. Intriguingly, however, the hs-cTnI/hs-cTnT ratio in these patients is opposite to the ratio observed in patients with chronic hs-cTn elevations, for whom hs-cTnI is generally lower than hs-cTnT (5). Second, modeled hs-cTn kinetic curves reveal fast monophasic elimination of hs-cTnI and a relatively slow, progressively decreasing elimination rate of hs-cTnT. These data confirm and extend the troponin kinetics in patients with STEMI, assessed by conventional and hs assays (2, 3). Multiple hypotheses exist for the difference in kinetics, including cytosolic fraction vs myofibril-bound fraction differences, immunoreactivity, and different kidney-clearing pathways (3). However, these are highly suggestive and warrant further investigation. Two limitations of this study merit attention. First, this study is limited, as time of pain onset was not obtained. However, our sampling window comprised both the rise and fall of hs-cTnI and hs-cTnT, including peak concentrations. These are the most important reference points to assess kinetic differences of troponin I and T. Second, data density was limited >60 h. Nevertheless, the increasing CIs do not overlap confirming the difference in kinetics. In conclusion, using hs-cTn assays we show that cTnI and cTnT exhibit distinct kinetics in patients with NSTEMI: fast monophasic elimination of hs-cTnI and relatively slow progressively decreasing elimination of hs-cTnT. non-ST-segment elevation myocardial infarction cardiac troponin high sensitivity. Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Employment or Leadership: None declared. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: M.W. Smulders, Netherlands Heart Foundation (2014T051); S.J.R. Meex, Abbott Diagnostics. Abbott Diagnostics provided high-sensitivity troponin I assays. Expert Testimony: None declared. Patents: None declared. The authors thank Abbott Diagnostics for providing high-sensitivity troponin I assays.