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Troponin structure and function: a view of recent progress.
Marston, S, Zamora, JE
Journal of muscle research and cell motility. 2020;(1):71-89
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Abstract
The molecular mechanism by which Ca2+ binding and phosphorylation regulate muscle contraction through Troponin is not yet fully understood. Revealing the differences between the relaxed and active structure of cTn, as well as the conformational changes that follow phosphorylation has remained a challenge for structural biologists over the years. Here we review the current understanding of how Ca2+, phosphorylation and disease-causing mutations affect the structure and dynamics of troponin to regulate the thin filament based on electron microscopy, X-ray diffraction, NMR and molecular dynamics methodologies.
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Prognostic Value of Troponins in Patients With or Without Coronary Heart Disease: Is it Dependent on Structure and Biology?
Lippi, G, Cervellin, G, Sanchis-Gomar, F
Heart, lung & circulation. 2020;(3):324-330
Abstract
Convincing evidence has emerged that cardiac troponins (cTns) T and I are the biochemical gold standard for diagnosing cardiac injury, and may also be used as efficient screening and risk stratification tools, especially when measured with the new high-sensitivity (hs-) immunoassays. In this narrative review, we aim to explore and critically discuss the results of recent epidemiological studies that have attempted to characterise the prognostic value of cTns in patients with or without cardiovascular disease, and then interpret this information according to cTn biology. Overall, all recent studies agree that higher blood levels of cTns reflect the larger risk of cardiovascular events and/or death, both in the general population and in patients with cardiovascular disease. Additional evidence has shown that the clinical information provided by assessment of both cTns molecules is greater compared to that of either protein alone, and this is mostly due to differential metabolism and clearance of cTnI and cTnT after release in the bloodstream. Although it seems likely that the prognostic value of these biomarkers may be higher than that of other conventional cardiovascular risk factors such as cholesterol or C reactive protein, large and reliable cost-effectiveness investigations are needed to define whether cTns-based population screening may be biologically plausible, clinically effective and economically sustainable.
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Evidence of direct cardiac damage following high-intensity exercise in chronic energy restriction: A case report and literature review.
Baird, MF, Grace, F, Sculthorpe, N, Graham, SM, Fleming, A, Baker, JS
Medicine. 2017;(27):e7030
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Abstract
RATIONALE Following prolonged endurance events such as marathons, elevated levels of cardiospecific biomarkers are commonly reported. Although transiently raised levels are generally not considered to indicate clinical myocardial damage, comprehension of this phenomenon remains incomplete. The popularity of high-intensity interval training highlights a paucity of research measuring cardiac biomarker response to this type of exercise. This a posteriori case report discusses the elevation of cardiac troponins (cTn) associated with short interval, high-intensity exercise. PATIENT CONCERNS In this case report, an apparently healthy 29-year-old recreationally active female presented clinically raised cardiac troponin I (cTnI) levels (>0.04 ng/mL), after performing high-intensity cycle ergometer sprints. As creatine kinase (CK) is expressed by multiple organs (e.g., skeletal muscle, brain, and myocardium), cTnI assays were performed to determine any changes in total serum CK levels not originating from skeletal muscle damage. DIAGNOSIS A posteriori the individual's daily energy expenditure indicated chronically low-energy availability. Psychometric testing suggested that the individual scored positive for disordered eating, highly for fatigue levels, and low in mental health components. OUTCOMES The current case report provides novel evidence of elevated cTnI occurring as a result of performing short duration, high intensity, cycle ergometer exercise in an individual with self-reported chronically depleted energy balance. A schematic to identify potentially "at risk" individuals is presented. LESSONS Considering this as a case report, results cannot be generalized; however, the main findings suggest that individuals who habitually restrict their calorie intake below their bodies' daily energy requirements, may have elevated biomarkers of exercise induced myocardial stress from performing high-intensity exercise.
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Cardiac troponin after percutaneous coronary intervention and 1-year mortality in non-ST-segment elevation acute coronary syndrome using systematic evaluation of biomarker trends.
Tricoci, P, Leonardi, S, White, J, White, HD, Armstrong, PW, Montalescot, G, Giugliano, RP, Gibson, CM, Van de Werf, F, Califf, RM, et al
Journal of the American College of Cardiology. 2013;(3):242-251
Abstract
OBJECTIVES This study sought to review cardiac troponin (cTn) trends during non-ST-segment elevation acute coronary syndrome (NSTE ACS) in patients undergoing percutaneous coronary intervention (PCI) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndromes) and SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) studies and to study the relationship between post-PCI cTn and mortality. BACKGROUND The prognostic value of cTn post-PCI is controversial. In patients with NSTE ACS, it is especially difficult to distinguish between cTn elevations due to PCI or index myocardial infarction (MI). METHODS Time and cTn (indexed by upper limit of normal [ULN]) data pairs were plotted for 10,199 patients and independently reviewed by 2 physicians to identify patients in whom post-PCI cTn elevation could be distinguished from that of index MI. Post-PCI cTn peak was identified for each plot, and its relationship with 1-year mortality was evaluated using Cox modeling, correcting for 15 clinical variables from the EARLY ACS 1-year mortality model (including baseline cTn). We used an identical methodology to assess the association between creatine kinase-myocardial band and 1-year mortality. RESULTS Patients with cTn (re-)elevation post-PCI not evaluable were identified and excluded from further analysis (4,198 [41%] with cTn rising prior to PCI; 229 [2%] with missing cTn). Among the remainder (n = 5,772 [57%]), in the multivariable model, peak cTn post-PCI was associated with a 7% increase in mortality (hazard ratio [HR] for 10 × ULN increase: 1.07, 95% confidence interval [CI]: 1.02 to 1.11; p = 0.0038). Peak post-PCI creatine kinase-myocardial band was significantly associated with 1-year mortality (HR for 1 × ULN increase: 1.13, 95% CI: 1.05 to 1.21; p = 0.0013). CONCLUSIONS We used a methodology that differentiated post-PCI cTn (re-)elevation from that of presenting MI in more than one-half of patients with NSTE ACS undergoing PCI. This identified a highly significant relationship between post-PCI cTn and 1-year mortality, with implications for both incorporating a cTn post-PCI MI definition and preventing PCI-related myonecrosis.
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Significance of elevated cardiac troponin I in patients with diabetic ketoacidosis.
Abdo, AS, Geraci, SA
Journal of the Mississippi State Medical Association. 2013;(5):127-30
Abstract
BACKGROUND Cardiac troponin I displays significant prognostic value in acute coronary syndromes and in other non-coronary conditions and systemic illnesses. Elevated levels of this biomarker in the setting of diabetic ketoacidosis may also provide useful prognostic information regarding outcome. METHODS A systematic review of the English language medical literature was performed using PubMed. Articles reporting original data on major clinical outcomes on cohorts of patients were included. RESULTS Three reports examining the relationship between cardiac troponin I and clinical outcomes in patients with diabetic ketoacidosis qualified for review. A spectrum of electrolyte and cardiac abnormalities were observed in the studied populations which were more frequent in those with troponin elevations. Short- and long-term outcomes appeared worse for patients with elevated troponin levels, but small study populations and other experimental issues including concurrent diseases which could have confounded the apparent relationship between troponin concentrations and outcome reduced the confidence of the findings. CONCLUSIONS The available literature suggests an association between elevated cardiac-specific troponin I serum concentrations and clinical outcomes among diabetic patients with ketoacidosis, but data are insufficient to draw conclusions at this time. Large prospective observational studies which exclude or control for other conditions which could contribute to troponin release will be needed before the predictive value of this biomarker in ketoacidosis can be reliably defined.
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Current trends in diagnostic biomarkers of acute coronary syndrome.
Moe, KT, Wong, P
Annals of the Academy of Medicine, Singapore. 2010;(3):210-5
Abstract
The diagnosis and management of patients with acute coronary syndrome (ACS) have evolved dramatically over the past decade. Biomarkers play an important role in the diagnosis of ACS, especially in unstable angina and non-ST-segment elevation myocardial infarction. Among these, cardiac troponin and creatine kinase appear to be the most sensitive and specific markers of myocardial injury. Recent studies have revealed several novel biomarkers. Elevated levels of C-reactive protein and interleukin-6 are strong independent markers of increased mortality among patients with ACS. However, the ideal biomarkers that offer early detection, risk stratification, selection of therapy, monitoring disease progression, and treatment efficacy remain to be elucidated. This review assesses limitations and contemporary needs for biomarkers in the context of diagnosis of ACS. It also discusses the newly developing technologies for novel biomarkers or novel biomarker protein signatures discovery, and importance of point-of-care testing for future management.
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[The use of cardiac troponins (T or I) measurement in cardiology and various clinical settings].
Berroëta, C, Provenchère, S, Mongredien, A, Lasocki, S, Benessiano, J, Dehoux, M, Philip, I
Annales francaises d'anesthesie et de reanimation. 2006;(10):1053-63
Abstract
Measurement of cardiac troponin I or T in serum (highly specific for the myocardium) have replaced classical markers, such as creatine kinase MB. Cardiac troponins are preferred markers because of their high specificity and sensitivity. This had led to modifications of the original World Health Organization criteria for acute myocardial infarction. Furthermore, the place of the troponins as superior markers of subsequent cardiac risk in acute coronary syndrome has now become firmly established, for both diagnostic and risk stratification purposes. The use of C-reactive protein and/or other inflammatory biomarkers may add independent information in this context. After non cardiac surgery, the total cardiospecificity of cardiac troponins explains why other biomarkers of necrosis should no longer be used. Recent studies suggest that any elevation of troponin in the postoperative period is indicative of increased risk of long-term cardiac complications. This prognostic value has been previously demonstrated in other clinical settings such as invasive coronary intervention (surgical myocardial revascularization and percutaneous coronary intervention) and after heart valve surgery. Increases of troponin indicate cardiac damage, whatever the mechanism (ischemic or not). Other causes of cardiac injury include: pulmonary embolism, myocarditis, pericarditis, congestive heart failure, septic shock, myocardial contusion. In most cases, elevation of troponins has been shown to be associated with a bad outcome.
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Myocardial regulatory proteins and heart failure.
Adamcová, M, Stĕrba, M, Simůnek, T, Potácová, A, Popelová, O, Gersl, V
European journal of heart failure. 2006;(4):333-42
Abstract
Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are considered to be the most specific and sensitive biochemical markers of myocardial damage. Troponins have been studied in a wide range of clinical settings, including heart failure; however, there are few data on the role of regulatory proteins in the pathogenesis of heart failure, although a few interesting hypotheses have been proposed. A considerable body of evidence favours the view that alteration of the myocardial thin filament is the primary event leading to defective contractility of the failing myocardium, while the changes in Ca(2+) handling are a compensatory response. A better understanding of the role of regulatory proteins under different physiological and pathological conditions could lead to new therapeutic approaches in heart failure. Recently, calcium sensitisation has been proposed as a novel method by which cardiac performance may be enhanced via an increase in the affinity of troponin C for calcium but without affecting intracellular calcium concentration. To date, the only calcium sensitizer used in clinical practice is levosimendan.
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Cardiac enzymes, renal failure and renal transplantation.
Bozbas, H, Yildirir, A, Muderrisoglu, H
Clinical medicine & research. 2006;(1):79-84
Abstract
Diagnostic accuracy of the currently available serum markers of cardiac injury, such as myoglobin, creatine kinase and its myocardial isoform, are altered in patients with renal failure. It is shown that cardiac troponins have decreased diagnostic sensitivity and specificity in patients receiving renal replacement therapy. Data regarding serum levels of these cardiac biomarkers, especially those of the cardiac troponins, in patients with a transplanted kidney are limited. Current data show that levels of cardiac troponin I are unaltered in patients who have undergone renal transplantation, while levels of cardiac troponin T may be elevated.We believe that cardiac troponin I should be the biomarker of choice for diagnosis of myocardial injury in these patients. However, further trials are required for conclusive results.
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Common scenarios to clarify the interpretation of cardiac markers.
Ross, GE, Bever, FN, Uddin, Z, Devireddy, L, Gardin, JM
The Journal of the American Osteopathic Association. 2004;(4):165-76
Abstract
The authors present a practical approach for physicians in clinical practice to use cardiac troponins in the interpretation of heart disease and myocardial damage. Laboratory results that fall within the intermediate area of facility-specific cutoff reference values for elevated troponin levels confer lower risks to patients than do higher levels of cardiac troponin. Perhaps not surprisingly, the actual anatomy of the vessels at cardiac catheterization does not correlate well with the troponin level. In the six cases presented here, the patients' low levels of troponin release are discussed using the new term minimal myocardial infarction, which is synonymous with conditions that would previously have been diagnosed as unstable angina. Elevated levels of cardiac troponin provide a very sensitive measure for clinicians diagnosing patients with myocardial necrosis, but such measures are also useful in defining a broad spectrum of disease. Whenever the troponin levels are elevated (barring laboratory error), the patient has a poorer prognosis. The greatest challenge for physicians is in determining which patients with cardiac troponin elevation will best benefit from heart catheterization and percutaneous intervention.