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Troponin complex is a component of skeletal and cardiac muscle thin filaments. It consists of three subunits — troponin I, T, and C, and it plays a crucial role in muscle activity, connecting changes in intracellular Ca 2+ concentration with generation of contraction. In spite of more than 40 years of studies, many aspects of troponin functioning are still not completely understood, and several models describing the mechanism of muscle contraction exist. Being a key factor in the regulation of cardiac muscle contraction, troponin complex is utilized in medicine as a target for some cardiotonic drugs used in the treatment of heart failure. A number of mutations in troponin subunits are associated with development of different types of cardiomyopathy. Moreover, for the last 25 years cardiac isoforms of troponin I and T have been widely used for immunochemical diagnostics of pathologies associated with cardiomyocyte death (myocardial infarction, myocardial trauma, and others). This review summarizes the existing evidence on the structure and function of troponin complex subunits, their role in the regulation of cardiac muscle contraction, and their clinical applications.

Abstract Background Many studies have assessed the biological variation (BV) of cardiac-specific troponins (cTn), reporting widely varying within-subject BV (CVI) estimates. The aim of this study was to provide meta-analysis-derived BV estimates for troponin I (cTnI) and troponin T (cTnT) for different sampling intervals and states of health. Methods Relevant studies were identified by a systematic literature search. Studies were classified according to their methodological quality by the Biological Variation Data Critical Appraisal Checklist (BIVAC). Meta-analyses of BIVAC-compliant studies were performed after stratification by cTn isoform, exclusion of results below the limit of detection, states of health, and sampling interval to deliver reference change values (RCV), index of individuality (II) and analytical performance specifications (APS) for these settings. Results Sixteen and 15 studies were identified for cTnI and cTnT, respectively, out of which 6 received a BIVAC grade A. Five studies had applied contemporary cTnI assays, but none contemporary cTnT. High-sensitivity (hs-) cTnI and cTnT delivered similar estimates in all settings. Long-term CVI estimates (15.1; 11.3%) derived from healthy individuals were higher than short-term (4.3%; 5.3%) for hs-cTnI and hs-cTnT, respectively, although confidence intervals overlapped. Estimates derived from diseased subjects were similar to estimates in healthy individuals for all settings. Conclusions This study provides robust estimates for hs-cTnI and hs-cTnT applicable for different clinical settings and states of health, allowing for the use of RCV both to aid in the diagnosis of myocardial injury and for prognosis. BV-based APS appear too strict for some currently available technologies.

Point-of-care (POC) cardiac troponin-I (cTnI) measurement methods often involve immunoassays, which can provide a momentary view of cTnI levels but the current modality highly restricts access to and frequency of testing in a sports and exercise medicine setting due to the requirement of a blood draw. This study aimed to compare cTnI concentrations in saliva and serum in athletes before (T1), early (T2), 4 h (T3), and 24 h (T4) after exercise. 82 male runners (age: 26.82 ± 2.49 years) were recruited and then randomly assigned to two groups using computer-generated permuted blocks with a 2:1 ratio via sequentially numbered opaque envelopes. 54 participants (group 1) completed a 5-km time-trial, while 28 participants (group 2) did not undergo this exercise. POC testing device was used to quantify salivary and serum concentrations of cTnI in both groups at T1, T2, T3, and T4. In group 1, salivary and serum concentrations of cTnI increased at T2 (0.41 ± 0.06 ng/mL and 0.48 ± 0.06 ng/mL) compared to T1 (0.18 ± 0.04 ng/mL and 0.22 ± 0.04 ng/mL), reaching the highest values at T3 (0.62 ± 0.05 ng/mL and 0.76 ± 0.05 ng/mL) with the subsequent return to baseline values at T4 (0.16 ± 0.03 ng/mL and 0.22 ± 0.03 ng/mL). In group 2, there were no time-dependent changes in cTnI levels in both saliva (T1: 0.17 ± 0.04 ng/mL, T2: 0.16 ± 0.03 ng/mL, T3: 0.16 ± 0.04 ng/mL, T4: 0.16 ± 0.04 ng/mL) and serum (T1: 0.22 ± 0.04 ng/mL, T2: 0.22 ± 0.04 ng/mL, T3: 0.21 ± 0.03 ng/mL, T4: 0.21 ± 0.04 ng/mL). Salivary and serum concentrations of cTnI were significantly lower in group 2 compared to group 1 at T2 and T3; there was no difference between groups at T1 and T4. Deming regression and Passing–Bablok regression revealed that there was differential bias (at T3), but proportional agreement (at T1, T2, T3, T4) between salivary and serum levels of cTnI in both groups. The Bland–Altman method indicated that there was a negative differential bias but no proportional bias in the data. Recalibration of the new measurement approach (measurement of cTnI levels in saliva) by using the MethodCompare R package was effective in removing existing bias, as evidenced by its similar precision to the reference method (measurement of cTnI levels in serum), particularly at T2, T3, and T4. In athletic settings, quantification of cTnI levels in saliva utilizing the POC-cTnI-Getein1100 assay may be a useful non-invasive tool in evaluating whether exercise-induced increases in cTnI levels are transient or there are acutely or chronically elevated cTnI concentrations.

Troponin I (TnI), together with troponin T (TnT) and troponin C (TnC), forms the troponin complex, a thin filament protein of the striated muscle that plays a key role in regulation of muscle contraction. In humans, TnI is represented by three isoforms: cardiac, which is synthesized only in myocardium, and fast and slow skeletal, which are synthesized in fast- and slow-twitch muscle fibers, respectively. Skeletal TnI isoforms could be used as biomarkers of skeletal muscle damage of various etiologies, including mechanical trauma, myopathies, muscle atrophy (sarcopenia), and rhabdomyolysis. Unlike classical markers of muscle damage, such as creatine kinase or myoglobin, which are also present in other tissues, skeletal TnIs are specific for skeletal muscle. In this study, we developed a panel of monoclonal antibodies for immunochemical detection of skeletal TnI isoforms using Western blotting (sensitivity: 0.01-1 ng per lane), immunohistochemical assays, and fluorescence immunoassays. Some of the designed fluorescence immunoassays enable quantification of fast skeletal (limit of detection [LOD] = 0.07 ng/mL) and slow skeletal (LOD = 0.1 ng/mL) TnI isoforms or both isoforms (LOD = 0.1 ng/ml). Others allow differential detection of binary (with TnC) or ternary (with TnT and TnC) complexes, revealing composition of troponin forms in the human blood.

The metabolic processes of endo- and exogenous compounds play an important role in diagnosing and treating patients since many metabolites are laboratory biomarkers and/or targets for therapeutic agents. Cardiac troponins are one of the most critical biomarkers to diagnose cardiovascular diseases, including acute myocardial infarction. The study of troponin metabolism is of great interest as it opens up new possibilities for optimizing laboratory diagnostics. This article discusses in detail the key stages of the cardiac troponins metabolism, in particular the mechanisms of release from a healthy myocardium, mechanisms of circulation in the bloodstream, possible mechanisms of troponin penetration into other biological fluids (oral fluid, cerebrospinal fluid, pericardial and amniotic fluids), mechanisms of elimination of cardiac troponins from the blood, and daily changes in the levels of troponins in the blood. Considering these aspects of cardiac troponin metabolism, attention is focused on the potential value for clinical practice.

Data from 15 international cohorts of patients with suspected acute MI were used to create and validate a risk-assessment tool integrating high-sensitivity troponin I or T at presentation, the change during serial sampling, and the time between samples to estimate the probability of MI on ED presentation and 30-day outcomes.

Increasing numbers of patients are presenting worldwide to emergency departments with suspected myocardial infarction. The use of point-of-care troponin assays might enable faster decision-making in this high-risk population and reduce the burden on emergency facilities. Here, we evaluate the diagnostic performance of a point-of-care high-sensitivity troponin I assay. We conducted a prospective cohort study including patients presenting to the emergency department with suspected myocardial infarction from July 2013 to July 2016. A diagnostic algorithm for a high-sensitivity troponin I point-of-care assay was developed in a derivation data set with 669 patients and validated in an additional 610 patients. The derived 0/1 h algorithm for the point-of-care assay consisted of an admission troponin I <4 ng/L and a δ from 0 h to 1 h <3 ng/L for rule out and an admission troponin I ≥90 ng/L or a δ from 0 h to 1 h ≥20 ng/L for rule in of non-ST-elevation myocardial infarction. Application to the validation cohort showed a negative predictive value of 99.7% (95% CI, 98.1%-100.0%) and 48.0% of patients ruled out, whereas 14.6% were ruled in with a positive predictive value of 86.5% (95% CI, 77.6%-92.8%). The diagnostic performance of the point-of-care high-sensitivity assay was highly comparable to guideline-recommended use of a laboratory-based high-sensitivity troponin assay. The clinical application of a 0/1 h diagnostic algorithm based on a high-sensitivity troponin I point-of-care assay is safe, and diagnostic performance is comparable to a laboratory-based high-sensitivity troponin I assay.

Although cardiac troponin I (cTnI) and troponin T (cTnT) form a complex in the human myocardium and bind to thin filaments in the sarcomere, cTnI often reaches higher concentrations and returns to normal concentrations faster than cTnT in patients with acute myocardial infarction (MI). We compared the overall clearance of cTnT and cTnI in rats and in patients with heart failure and examined the release of cTnT and cTnI from damaged human cardiac tissue in vitro. Ground rat heart tissue was injected into the quadriceps muscle in rats to simulate myocardial damage with a defined onset. cTnT and cTnI peaked at the same time after injection. cTnI returned to baseline concentrations after 54 h, compared with 168 h for cTnT. There was no difference in the rate of clearance of solubilized cTnT or cTnI after intravenous or intramuscular injection. Renal clearance of cTnT and cTnI was similar in 7 heart failure patients. cTnI was degraded and released faster and reached higher concentrations than cTnT when human cardiac tissue was incubated in 37°C plasma. Once cTnI and cTnT are released to the circulation, there seems to be no difference in clearance. However, cTnI is degraded and released faster than cTnT from necrotic cardiac tissue. Faster degradation and release may be the main reason why cTnI reaches higher peak concentrations and returns to normal concentrations faster in patients with MI.

Cardiac troponins (cTn) T and I are biochemical markers of myocardial injury. In this review article, we aim to summarize the mechanisms and significance of cardiac troponin (cTn) elevation unrelated to acute myocardial infarction (AMI) in the most frequently occurring non-cardiac conditions, where the accurate interpretation of elevated cTn levels is often challenging. Different mechanisms in non-cardiac conditions can cause non-ischemic myocardial injury. Understanding the pathophysiology of cTn release is an essential precondition for minimizing unnecessary, costly, and potentially risky (cardiac) interventions and for providing timely and appropriate medical care. Elevated cTn in critically ill patients and in patients with chronic disease/conditions is an independent predictor (risk factor) of cardiovascular and overall mortality. Treatment of underlying conditions is of primary importance, and close monitoring for the occurrence of cardiovascular complications during hospitalizations should be considered in these patients. Also, when the patient recovers from the underlying disease, clinical judgement should be employed to decide whether and to what extent further cardiological evaluation is indicated.

Troponin is essential in Ca(2+) regulation of skeletal and cardiac muscle contraction. It consists of three subunits (TnT, TnC and TnI) and, together with tropomyosin, is located on the actin filament. Here we present crystal structures of the core domains (relative molecular mass of 46,000 and 52,000) of human cardiac troponin in the Ca(2+)-saturated form. Analysis of the four-molecule structures reveals that the core domain is further divided into structurally distinct subdomains that are connected by flexible linkers, making the entire molecule highly flexible. The alpha-helical coiled-coil formed between TnT and TnI is integrated in a rigid and asymmetric structure (about 80 angstrom long), the IT arm, which bridges putative tropomyosin-anchoring regions. The structures of the troponin ternary complex imply that Ca(2+) binding to the regulatory site of TnC removes the carboxy-terminal portion of TnI from actin, thereby altering the mobility and/or flexibility of troponin and tropomyosin on the actin filament.