Search

Various definitions of myocardial infarction type 5 after coronary artery bypass grafting (CABG) have been proposed (myocardial infarction [MI-5], also known as peri-procedural MI), using different biomarkers and different and arbitrary cut-off values. This meta-analysis aims to determine the expected release of high-sensitivity cardiac troponin T (hs-cTnT) after CABG in general and after uncomplicated surgery and off-pump CABG in particular. A systematic search was applied to 3 databases. Studies on CABG as a single intervention and reporting on postoperative hs-cTnT concentrations on at least 2 different time points were included. All data on hs-cTnT concentrations were extracted, and mean concentrations at various points in time were stratified. Eventually, 15 studies were included, encompassing 2,646 patients. Preoperative hs-cTnT was 17 ng/L (95% confidence interval [CI] 13 to 20 ng/L). Hs-cTnT peaked at 6 to 8 hours postoperatively (628 ng/L, 95% CI 400 to 856 ng/L; 45x upper reference limit [URL]) and was still increased after 48 hours. In addition, peak hs-cTnT concentration was 614 ng/L (95% CI 282 to 947 ng/L) in patients with a definite uncomplicated postoperative course (i.e., without MI). For patients after off-pump CABG compared to on-pump CABG, the mean peak hs-cTnT concentration was 186 ng/L (95% CI 172 to 200 ng/L, 13 x URL) versus 629 ng/L (95% CI 529 to 726 ng/L, 45 x URL), respectively. In conclusion, postoperative hs-cTnT concentrations surpass most of the currently defined cut-off values for MI-5, even in perceived uncomplicated surgery, suggesting thorough reassessment. Hs-cTnT release differences following on-pump CABG versus off-pump CABG were observed, implying the need for different cut-off values for different surgical strategies. (C) 2021 The Author(s). Published by Elsevier Inc.

Cardiac troponin T (cTnT) is a sensitive and specific biomarker for detecting cardiac muscle injury. Its concentration in blood can be significantly elevated outside the normal reference range under several pathophysiological conditions. The classical analytical method in routine clinical analysis to detect cTnT in serum or plasma is a single commercial immunoassay, which is designed to quantify the intact cTnT molecule. The targeted epitopes are located in the central region of the cTnT molecule. However, in blood cTnT exists in different biomolecular complexes and proteoforms: bound (to cardiac troponin subunits or to immunoglobulins) or unbound (as intact protein or as proteolytic proteoforms). While proteolysis is a principal posttranslational modification (PTM), other confirmed PTMs of the proteoforms include N-terminal initiator methionine removal, N-acetylation, O-phosphorylation, O-(N-acetyl)-glucosaminylation, N(ɛ)-(carboxymethyl)lysine modification and citrullination. The immunoassay probably detects several of those cTnT biomolecular complexes and proteoforms, as long as they have the centrally targeted epitopes in common. While analytical cTnT immunoreactivity has been studied predominantly in blood, it can also be detected in urine, although it is unclear in which proteoform cTnT immunoreactivity is present in urine. This review presents an overview of the current knowledge on the pathophysiological lifecycle of cTnT. It provides insight into the impact of PTMs, not only on the analytical immunoreactivity, but also on the excretion of cTnT in urine as one of the waste routes in that lifecycle. Accordingly, and after isolating the proteoforms from urine of patients suffering from proteinuria and acute myocardial infarction, the structures of some possible cTnT proteoforms are reconstructed using mass spectrometry and presented.

Background Cardiac troponins are the preferred biomarkers for the diagnosis of myocardial infarction (MI) and play an important role in coronary artery bypass grafting (CABG) related MI (type 5 MI). Different cut-off values, as defined by multiples of the 99th percentile upper reference limit (URL) for isolated and non-isolated troponin elevations have been proposed. Also, these definitions are based on arbitrarily chosen and varying values (3rd and 4th Universal definition: 10xURL, Society for Cardiovascular Angiography and Interventions (SCAI): 35 and 70xURL) and electrocardiographical or imaging findings. In addition to the controversy in MI definitions, the introduction of high-sensitivity cardiac troponin (hs-cTn) assays and their subsequent lower thresholds warrant a thorough re-assessment of hs-cTn dynamics after CABG. Purpose To evaluate the rise and fall of hs-cTn after CABG in relation to the definitions of myocardial infarction. Methods Studies published between 2008 and 2020 reporting hs-cTn concentrations in relation to CABG were searched through Pubmed and reviewed by 2 independent screeners. The search terms were “coronary artery bypass” AND “high-sensitivity cardiac troponin”, including alternative names and abbreviations. Inclusion criteria were the use of a hs-cTn assay in the postoperative phase, either for cardiac troponin T or I. This study was performed in agreement with the PRISMA guidelines. Results Out of 37 screened studies, 15 studies were included (2860 patients). The overall preoperative hs-cTnT concentration (median, 25th-75th percentile) was 43.5 (16.3–57.9) ng/L. Subsequently, in >80% of CABG patients, preoperative hs-cTnT was elevated >14 ng/L. Hs-cTnT was highly variable over time, with a peak of 408.7 (14.9–717.2) ng/L 6–8 h after CABG. Postoperative peak hs-cTnT concentrations rose >10xURL (Universal definition) in 100% of CABG patients. Peak hs-cTnT >35xURL and ±20% >70xURL (SCAI definition) during the first 48 h was 30% and ∼20%, respectively (estimated from data depicted in Figure 1). Electrocardiographic and imaging findings were available for only 1 study (554 patients). Overall 30-day mortality was 1.7 (0.8–4.0)%, reported by 7 studies (2291 patients). Data regarding the association of hs-cTnT and clinical outcome was reported by 1 study. As only 4 studies (217 patients) reported on the results of hs-cTnI, using assays from different vendors, a meta-analysis for hs-cTnI could not be performed. Conclusion The different definitions of type 5 MI propose arbitrarily chosen cTn cut-off values, varying enormously between the definitions. The current thresholds may not apply to the majority of CABG patients, since >80% had elevated preoperative hs-cTnT. Furthermore, hs-cTnT obtained within 48 h after CABG is highly variable over time. Therefore, further research is needed to establish clinically relevant hs-cTn thresholds and timing of sampling for a more accurate diagnosis of CABG procedure related MI. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): ZonMw Veni grant

To the Editor: Vigorous endurance-type exercise causes cardiac troponin T (cTnT)1 elevations that often exceed the diagnostic cutoff value for acute myocardial infarction (AMI) (1). It remains to be investigated whether exercise-induced cTnT release reflects a physiological or pathological process. Our recent studies utilizing multiple protein analysis techniques allowed determination of circulating cTnT forms, and it appeared that these are different in acute vs chronic pathologies (2, 3). In sera of AMI patients, cTnT is degraded from its intact form (estimated molecular weight by SDS-PAGE; MW est, 40 kDa) to primary ( MW est, 29 kDa) and subsequent secondary ( MW est, 14–18 kDa) fragments in a time-dependent manner (2). Only …

We read with interest the paper by Schmid et al. [(1)][1], who described elevated cardiac troponin T (cTnT) concentrations in patients with skeletal myopathies in which they suggested cross-reaction of the high-sensitivity (hs-)cTnT immunoassay with skeletal muscle troponin T (skTnT) isoforms as

Background High-sensitivity cardiac troponin (hs-cTn) assays have reduced specificity for myocardial infarction (MI). In conditions other than MI, cardiac troponin T (cTnT) elevations have been attributed to small cTnT fragments. In search of improved cTnT assay specificity for MI, determination of the in-vivo molecular appearance of cTnT during MI is pivotal. Purpose To determine cTnT composition close to its site of release and during the course of MI by multi-site coronary venous system (CVS) and peripheral sampling. Methods Lithium-heparinized (LH) plasma and serum samples were obtained from multiple CVS locations in NSTEMI patients. Additionally, samples were drawn from a peripheral artery and vein followed by collections at 6- and 12 hours post-catheterization. cTnT concentrations were measured using the hs-cTnT immunoassay (Roche). The molecular cTnT composition was determined by gel filtration chromatography and Western blotting in an early and late presenting patient. Results CVS hs-cTnT concentrations were 28% higher than in the peripheral artery sample (n=71, p Central illustration Conclusions In NSTEMI, cTnT is released as a combination of cTn T-I-C complex, free intact cTnT and multiple cTnT fragments. Over time, the composition of observed cTnT forms changes due to in-vivo degradation. These findings serve as a stepping stone to improve diagnostic accuracy of the hs-cTnT assay for MI.

Background Cardiac troponin T ( cTnT ) is seen in many other conditions besides myocardial infarction, and recent studies demonstrated distinct forms of cTnT . At present, the in vivo formation of these different cTnT forms is incompletely understood. We therefore performed a study on the composition of cTnT during the course of myocardial infarction, including coronary venous system sampling, close to its site of release. Methods and Results Baseline samples were obtained from multiple coronary venous system locations, and a peripheral artery and vein in 71 non– ST ‐segment–elevation myocardial infarction patients. Additionally, peripheral blood was drawn at 6‐ and 12‐hours postcatheterization. cTnT concentrations were measured using the high‐sensitivity‐ cTnT immunoassay. The cTnT composition was determined via gel filtration chromatography and Western blotting in an early and late presenting patient. High‐sensitivity ‐ cTnT concentrations were 28% higher in the coronary venous system than peripherally (n=71, P cT n T‐I‐C complex, free intact cTnT , and 29 kD a and 15 to 18 kD a cTnT fragments, all in higher concentrations than in simultaneously obtained peripheral samples. While cT n T‐I‐C complex proportionally decreased, and disappeared over time, 15 to 18 kD a cTnT fragments increased. Moreover, cT n T‐I‐C complex was more prominent in the early than in the late presenting patient. Conclusions This explorative study in non– ST ‐segment–elevation myocardial infarction shows that cTnT is released from cardiomyocytes as a combination of cT n T‐I‐C complex, free intact cTnT , and multiple cTnT fragments indicating intracellular cTnT degradation. Over time, the cT n T‐I‐C complex disappeared because of in vivo degradation. These insights might serve as a stepping stone toward a high‐sensitivity‐ cTnT immunoassay more specific for myocardial infarction.

Background and aims: Inflammation has become a key element in cardiovascular disease, and recently, new anti-inflammatory interventions have shown promising results. In this context, CRP levels have been thoroughly studied in vitro and in animals, but studies in humans are scarce and insights into its release, site(s) of production and uptake are not uniform.Methods: We performed a biomarker study with multi-site sampling in the coronary circulation, in non-ST elevation MI (NSTEMI) patients with coronary angiography and right-sided catheterisation. Trans-lesional gradients were obtained by sampling distal to the culprit lesion, in patients with a suitable anatomy. To asses trans-cardiac gradients, blood was sampled from the systemic circulation, coronary sinus (CS) and great cardiac vein. Concentrations of CRP were measured with a high-sensitivity assay.Results: In 42 patients, a median systemic venous CRP concentration of 4.97 mg/L was observed. There was no evidence of a trans-lesional gradient (4.59 mg/L versus 4.56 mg/L, p = 0.278; n = 14). A significant decrease in CRP concentration was observed between systemic arterial and CS samples (4.88 mg/L versus 4.44 mg/L; p Conclusions: In the context of NSTEMI, we observed a trans-cardiac decrease in CRP, which may indicate the first human in vivo proof of a net CRP uptake by the myocardium, with a role for CRP both in the injured and adjacent myocardium.

Background: ITPA polymorphisms have been associated with protection against ribavirin-induced anemia in chronic hepatitis C (HCV) patients. Here we determined the association of inosine triphosphate pyrophosphohydrolase (inosine triphosphatase or ITPase) enzyme -activity with ITPA genotype in predicting ribavirin-induced anemia. Methods: In a cohort of 106 HCV patients, hemoglobin (Hb) values were evaluated after 4 weeks (T 4) and at the time of lowest Hb value (T nadir). ITPase activity was measured and ITPA genotype determined. Single-nucleotide polymorphisms (SNPs) tested were c.124+21A>C and c.94C>A. ITPase activity = 1.11 mU/mol Hb was considered as normal. Results: After 4 weeks of treatment, 78% of the patients with normal ITPase activity were anemic and 21% of the patients with low ITPase activity (pC 46% (p=0.068), and wt/c.94C>A 29% (p=0.021). At T nadir, virtually all patients with normal ITPase activity were anemic, compared to only 64% of the patients with low activity (p=0.02). Thirteen patients had wt/c.124+241A>C genotype. Within this group all five patients with normal ITPase activity and only four of eight with decreased activity developed anemia. Presence of HCV RNA did not influence ITPase activity. Conclusions: This study is the first to report that ITPase activity predicts the development of anemia during ribavirin treatment. ITPase activity and ITPA genotype have high positive predictive values for development of ribavirin-induced anemia at any time during treatment, but ITPase activity predicts ribavirin-induced anemia more accurately.

To the Editor: We read with interest the recent article by Katrukha et al. concerning thrombin-mediated degradation of human cardiac troponin T (cTnT) in serum (1). In their study, Katrukha and coworkers confirmed the finding of Streng et al. that human coagulation factor II (thrombin) is a strong mediator of cTnT degradation (2). They compared cTnT degradation in serum and heparin plasma collected simultaneously from the same patients with acute myocardial infarction (AMI), revealing substantial differences in cTnT fragment composition. They also performed in vitro experiments in which troponin T, thrombin, and hirudin were supplemented in various combinations. In addition, the cleavage site in cTnT was localized by use of mass spectrometry and probing of different proteolytic fragments with the use of various antibodies. Their main conclusion was that the primary 29-kDa cTnT fragment was mainly formed because of thrombin activation during serum preparation. We believe that the evidence for thrombin as one of the main proteases for cTnT degradation is convincing. However, we disagree with their final conclusion because there is published evidence suggesting …

The aim of this study was to assess inosine triphosphate (ITPase) expression in the different leukocyte populations present in peripheral blood samples of a nonimmune compromised control group. For this purpose, a multiparameter flow cytometric assay was developed and performed to study ITPase expression in peripheral leukocyte subpopulations of healthy volunteers (n = 20). Qualitative ITPase expression was assessed by determining the percentage of ITPase-positive cells. Quantitative data were obtained by measuring the median fluorescent intensity (MFI). Subcellular localization of ITPase was analyzed using immunocytochemistry. Immunocytochemistry showed that ITPase is present in all leukocytes and localized intracellular. Based on this finding, a multiparameter flow cytometric assay was developed using a Fix & Perm strategy. Qualitative and quantitative ITPase expression remained stable (variation

The role of cardiac troponins (cTn) have become increasingly important in diagnosing myocardial infarction (MI), especially in patients without electrocardiogram abnormalities (1).