Despite the widespread use of cardiac troponins as biomarkers for the diagnosis and quantitation of cardiac injury, the effect of troponin release and a possible autoimmune response to the troponins is unknown. Other investigators reported that programmed cell death – 1 (PD-1) – receptor deficient mice developed severe cardiomyopathy with autoantibodies to troponin I. We found that immunization of genetically susceptible mice with troponin I but not troponin T induced a robust autoimmune response leading to marked inflammation and fibrosis in the myocardium. At later times, antibodies to cardiac myosin were detected in troponin – immunized mice. The severity of inflammation correlated with expression of chemokines RANTES, MIP-2, IP-10 and MCD-1 in the myocardium. Prior immunization with troponin I increased the severity of experimental infarctions, indicating that an autoimmune response to troponin I aggravates acute cardiac damage. Cardiac inflammation, fibrosis and functional impairment were transferred from immunized to naive recipients by CD4+ T cells, and the cytokine profile suggested both a Th2 and Th17 profile in A/J mice. Finally we identified an 18-mer of troponin I containing an immuno-dominant epitope.
The complex of tropomyosin and troponin binds to actin and inhibits activation of myosin ATPase activity and force production of striated muscles at low free Ca2+ concentrations. Ca2+ stimulates ATP activity, and at subsaturating actin concentrations, the binding of NEM-modified S1 to actin–tropomyosin–troponin increases the rate of ATP hydrolysis even further. We show here that the Δ14 mutation of troponin T, associated with familial hypertrophic cardiomyopathy, results in an increase in ATPase rate like that seen with wild-type troponin in the presence of NEM-S1. The enhanced ATPase activity was not due to a decreased incorporation of mutant troponin T with troponin I and troponin C to form an active troponin complex. The activating effect was more prominent with a hybrid troponin (skeletal TnI, TnC, and cardiac TnT) than with all cardiac troponin. Thus it appears that changes in the troponin–troponin contacts that result from mutations or from forming hybrids stabilize a more active state of regulated actin. An analysis of the effect of the Δ14 mutation on the equilibrium binding of S1-ADP to actin was consistent with stabilization of an active state of actin. This change in activation may be important in the development of cardiac disease.
We compared the developmental regulation of the three troponin genes that encode the proteins of the Ca2+ regulatory complex in striated muscles of the Japanese quail. Nuclear run-on transcription and RNA protection analyses showed that the fast skeletal troponin I, the fast skeletal troponin T, and the slow skeletal-cardiac troponin C genes were transcriptionally coactivated and that transcripts rapidly accumulated within 6 to 12 h after the initiation of myoblast differentiation. The fast-isoform mRNAs of troponin I and troponin T were coexpressed at similar levels in different skeletal muscles, whereas the slow-cardiac troponin C mRNA varied independently and was the only one of these genes expressed in embryonic and adult heart. We conclude that these troponin genes are transcriptionally coactivated during skeletal myoblast differentiation, indicating that their transcription is under precise temporal control. However, this troponin C gene is regulated independently is specialized striated muscles.
There are few recommendations about the use of cardiac markers in the investigation and management of atrial fibrillation/flutter. Currently, it is unknown how many patients with atrial fibrillation/flutter undergo troponin testing, and how positive troponin results are managed in the emergency department. We sought to look at the emergency department troponin utilization patterns.
We performed a retrospective chart review of patients with atrial fibrillation/flutter presenting to the emergency department at three centers. Outcome measures included the rates of troponins ordered by emergency doctors, number of positive troponins, and those with positive troponins treated as acute coronary syndrome (ACS) by consulting services.
Four hundred fifty-one charts were reviewed. A total of 388 (86%) of the patients had troponins ordered, 13.7% had positive results, and 4.9% were treated for ACS.
Troponin tests are ordered in a high percentage of patients with atrial fibrillation/flutter presenting to emergency departments. Five percent of our total patient cohort was diagnosed as having acute coronary syndrome by consulting services.
Myocardial infarction (MI) is defined by the presence of myocardial necrosis in combination with clinical evidence of myocardial ischemia. Cardiac troponins are regulatory proteins within the myocardium that are released into the circulation when damage to the myocyte has occurred. Therefore, serum troponin is an exquisitely sensitive marker of myocardial injury and is necessary for establishing the diagnosis of MI. High-sensitivity troponin assays are improving the diagnostic accuracy and rapid detection of myocardial infarction. The early identification of MI is vital for the institution of anti-thrombotic therapy to limit myocardial damage and preserve cardiac function. Troponin has both diagnostic and prognostic significance in the setting of acute coronary syndrome (ACS). Increased troponin levels in the absence of ACS should prompt an evaluation for an alternative, non-thrombotic mechanism of troponin elevation and direct management at the underlying cause. This review describes the role of troponin in the evaluation of patients with suspected myocardial infarction.
myocardial infarction; troponin; high-sensitivity assays
Troponins are regulatory proteins that form the cornerstone of muscle contraction. The amino acid sequences of cardiac troponins differentiate them from that of skeletal muscles, allowing for the development of monoclonal antibody-based assay of troponin I (TnI) and troponin T (TnT). Along with the patient history, physical examination and electrocardiography, the measurement of highly sensitive and specific cardiac troponin has supplanted the former gold standard biomarker (creatine kinase-MB) to detect myocardial damage and estimate the prognosis of patients with ischemic heart disease. The current guidelines for the diagnosis of non-ST segment elevation myocardial infarction are largely based on an elevated troponin level. The implementation of these new guidelines in clinical practice has led to a substantial increase in the frequency of myocardial infarction diagnosis.
Automated assays using cardiac-specific monoclonal antibodies to cardiac TnI and TnT are commercially available. They play a major role in the evaluation of myocardial injury and prediction of cardiovascular outcome in cardiac and non-cardiac causes.
In this review we discuss the clinical applications of cardiac troponins and the interpretation of elevated levels in the context of various clinical settings.
Cardiac troponin; Myocardial injury; Reinfarction; Perioperative infarction
We have cloned and characterized the troponin C gene, pat-10 of the nematode Caenorhabditis elegans. At the amino acid level nematode troponin C is most similar to troponin C of Drosophila (45% identity) and cardiac troponin C of vertebrates. Expression studies demonstrate that this troponin is expressed in body wall muscle throughout the life of the animal. Later, vulval muscles and anal muscles also express this troponin C isoform. The structural gene for this troponin is pat-10 and mutations in this gene lead to animals that arrest as twofold paralyzed embryos late in development. We have sequenced two of the mutations in pat-10 and both had identical two mutations in the gene; one changes D64 to N and the other changes W153 to a termination site. The missense alteration affects a calcium-binding site and eliminates calcium binding, whereas the second mutation eliminates binding to troponin I. These combined biochemical and in vivo studies of mutant animals demonstrate that this troponin is essential for proper muscle function during development.
troponin C; Caenorhabditis elegans; troponin I; muscle gene; gene expression
Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder of the myocardium which is hypertrophied resulting in arrhythmias and heart failure leading to sudden cardiac death (SCD). Several sarcomeric proteins and modifier genes have been implicated in this disease. Troponin I, being a part of the Troponin complex (troponin I, troponin C, troponin T), is an important gene for sarcomeric function. Four mutations (1 novel) were identified in Indian HCM cases, namely, Pro82Ser, Arg98Gln, Arg141Gln and Arg162Gln in Troponin I protein, which are in functionally significant domains. In order to analyse the effect of the mutations on protein stability and protein-protein interactions within the Troponin complex, an in silico study was carried out. The freely available X-ray crystal structure (PDB ID: 1JIE) was used as the template to model the protein followed by loop generation and development of troponin complex for both the troponin I wild type and four mutants (NCBI ID: PRJNA194382). The structural study was carried out to determine the effect of mutation on the structural stability and protein-protein interactions between three subunits in the complex. These mutations, especially the arginine to glutamine substitutions were found to result in local perturbations within the troponin complex by creating/removing inter/intra molecular hydrogen bonds with troponin T and troponin C. This has led to a decrease in the protein stability and loss of important interactions between the three subunits. It could have a significant impact on the disease progression when coupled with allelic heterogeneity which was observed in the cases carrying these mutations. However, this can be further confirmed by functional studies on protein levels in the identified cases.
The cardiac thin filament regulates actomyosin interactions through calcium-dependent alterations in the dynamics of cardiac troponin and tropomyosin. Over the past several decades many details have been discovered regarding the structure and function of the cardiac thin filament and its components. We propose a dynamic, complete model of the thin filament that encompasses known structures of cardiac troponin, tropomyosin and actin and show that it is able to capture key experimental findings. By performing molecular dynamics simulations in two conditions, one with calcium bound and the other without calcium bound to site II of cardiac troponin C (cTnC), we found that subtle changes in structure and protein contacts within cardiac troponin resulted in sweeping changes throughout the complex that alter tropomyosin (Tm) dynamics and cardiac troponin-actin interactions. Significant calcium-dependent changes in dynamics occur throughout the cardiac troponin complex resulting from the combination of: secondary structural changes in the N-lobe of cTnC at and adjacent to sites I and II and the link between them; secondary structural changes of the cardiac troponin I (cTnI) switch peptide, the mobile domain, and in the vicinity of residue 25 of the N-terminus; secondary structural changes in the cardiac troponin T (cTnT) linker and Tm-binding regions; and small changes in cTnC-cTnI and cTnT-Tm contacts. As a result of these changes, we observe large changes in the dynamics of the following regions: the N-lobe of cTnC; the mobile domain of cTnI; the I-T arm; the cTnT linker; and overlapping Tm. Our model demonstrates a comprehensive mechanism for calcium-activation of the cardiac thin filament consistent with previous, independent experimental findings. This model provides a valuable tool for research into the normal physiology of cardiac myofilaments and a template for studying cardiac thin filament mutations that cause human cardiomyopathies.
Cardiac troponin is a specific biomarker for cardiomyocyte necrosis in acute coronary syndromes. Troponin release from the coronary circulation remains to be determined because of the lower sensitivity of the conventional assay. We sought to determine basal and angina-induced troponin release using a highly sensitive troponin assay.
Methods and Results
The cardiac troponin T levels in serum sampled from the peripheral vein (PV), the aortic root (AO), and the coronary sinus (CS) were measured in 105 consecutive stable patients with coronary risk factor(s) and suspected coronary artery disease (CAD) and in 33 patients without CAD who underwent an acetylcholine provocation test. At baseline, there was a significant increase in the troponin levels from AO [9.0 (6.4, 13.1) pg/mL for median (25th, 75th percentiles)] to CS [10.3 (7.3, 15.5) pg/mL, p<0.001] in 96 (91.4%) patients and the difference was 1.1 (0.4, 2.1) pg/mL, which reflected basal transcardiac troponin release (TTR). TTR was positively correlated with PV levels (r = 0.22, p = 0.03). Male sex, left ventricular hypertrophy determined by echocardiography, T-wave inversion, and CAD correlated with elevated TTR defined as above: median, 1.1 pg/mL. A significant increase in TTR was noted in 17 patients with coronary spasms [0.6 (0.2, 1.2) pg/mL, p<0.01] but not in 16 patients without spasms [0.0 (−0.5, 0.9) pg/mL, p = 0.73] after the acetylcholine provocation.
Basal TTR in the coronary circulation was observed in most of the patients with suspected CAD and risk factor(s). This sensitive assay detected myocardial ischemia-induced increases in TTR caused by coronary spasms.
Aims: To establish a practical postnatal reference range for cardiac troponin T in neonates and to investigate concentrations in neonates with respiratory distress.
Methods: Prospective investigation in a tertiary neonatal unit, recruiting infants with and without respiratory distress (sick and healthy infants respectively). Concentrations of cardiac troponin T were compared between sick and healthy infants, accounting for confounding variables.
Results: A total of 162 neonates (113 healthy and 49 sick infants) had samples taken. The median (interquartile range) cardiac troponin T concentration in the healthy infants was 0.025 (0.01–0.062) ng/ml, and the 95th centile was 0.153 ng/ml. There were no significant relations between cardiac troponin T and various variables. The median (interquartile range) cardiac troponin T concentration in the sick infants was 0.159 (0.075–0.308) ng/ml. This was significantly higher (p < 0.0001) than in the healthy infants. In a linear regression model, the use of inotropes and oxygen requirement were significant associations independent of other basic and clinical variables in explaining the variation in cardiac troponin T concentrations.
Conclusions: Cardiac troponin T is detectable in the blood of many healthy neonates, but no relation with important basic and clinical variables was found. Sick infants have significantly higher concentrations than healthy infants. The variations in cardiac troponin T concentration were significantly associated with oxygen requirement or the use of inotropic support in a regression model. Cardiac troponin T may be a useful marker of neonatal and cardiorespiratory morbidity.
Elevations of cardiac enzymes are commonly used to indicate myocardial ischemia, but they can be elevated due to other conditions. Different forms of Troponin (cTnT, sTnT, cTnI), can cause cross-reactivity in the Troponin T assay, leading to false positives. This report describes a patient with polymyositis who had elevated Troponin T, but no cardiac abnormalities. The purpose is to show that Troponin T, which is believed to be solely from cardiac muscle breakdown, can be seen in inflammatory muscle disease, so Troponin I should be used instead.
This is a case report of a 70-year-old woman with a history of diabetes, hypertension, gout and polymyositis, who presented with one-day history of lightheadedness and abdominal pain. To rule out myocardial ischemia, cardiac enzyme testing was ordered which showed elevated CK, CK-MB, and Troponin T. A full cardiac workup was performed which showed no signs of ischemia. Troponin I was <0.05 ng/mL, (normal).
In inflammatory myositis, there are elevations in many cardiac markers due to non-cardiac causes, which could be related to muscle regeneration and gene expression. This is not seen certain isoforms of Troponin I, specifically cardiac Troponin I.
In patients with history of diabetes and other comorbidities, silent myocardial ischemias should be ruled out. Non-cardiac elevations in Troponin T can be seen in patients with inflammatory, so Troponin I should be ordered to get an accurate interpretation. Patients with inflammatory myopathies can have elevations in CK, CK-MB, and Troponin T, but not Troponin I.
false positive Troponin T; Polymyositis; Troponin T; Troponin I
The troponin complex plays an essential role in the thin filament regulation of striated muscle contraction. Of the three subunits of troponin, troponin I (TnI) is the actomyosin ATPase inhibitory subunit and its effect is released upon Ca2+-binding to troponin C. The exon 8-encoded COOH-terminal end segment represented by the last 24 amino acids of cardiac TnI is highly conserved and critical to the inhibitory function of troponin. Here we investigated the function and calcium regulation of the COOH-terminal end segment of TnI. A TnI model molecule was labeled with Alexa fluor 532 at a Cys engineered at the COOH-terminal end and used to reconstitute tertiary troponin complex. A Ca2+-regulated conformational change in the COOH terminus of TnI was shown by a sigmoid-shape fluorescence intensity titration curve similar to that of the circular dichroism calcium titration curve of troponin C. Such corresponding Ca2+-responses are consistent with the function of troponin as a coordinated molecular switch. Reconstituted troponin complex containing a mini-troponin T lacking its two tropomyosin-binding sites showed a saturable binding to tropomyosin at pCa 9 but not at pCa 4. This Ca2+-regulated binding was diminished when the COOH-terminal 19 amino acids of cardiac TnI were removed. These results provided novel evidence for suggesting that the COOH-terminal end segment of TnI participates in the Ca2+-regulation of muscle thin filament through an interaction with tropomyosin.
Troponin I; COOH-terminus; Tropomyosin; Calcium
Familial hypertrophic cardiomyopathy (HCM) can be caused by dominant missense mutations in cardiac troponin T (TnT), alpha-tropomyosin, C-protein, or cardiac myosin heavy chain genes. The myosin mutations are known to impair function, but any functional consequences of the TnT mutations are unknown. This report describes the in vitro function of troponin containing an IIe91Asn mutation in rat cardiac TnT, corresponding to the HCM-causing Ile79Asn mutation in man. Mutant and wild-type TnT cDNAs were expressed in bacteria and the proteins purified and reconstituted with the other troponin subunits, the mutation had no effect on troponin's affinity for tropomyosin, troponin-induced binding of tropomyosin to actin, cooperative binding of myosin subfragment 1 to the thin filament, CA(2+)-sensitive regulation of thin filament-myosin subfragment 1 ATPase activity, or the CA2+ concentration dependence of this regulation. However, the mutation resulted in 50% faster thin filament movement over a surface coated with heavy meromyosin in in vitro motility assays. The increased sliding speed suggests an unexpected role for the amino terminal region of TnT in which this mutation occurs. The relationship between this faster motility and altered cardiac contraction in patients with HCM is discussed.
Mutations in sarcomeric proteins have recently been established as heritable causes of Restrictive Cardiomyopathy (RCM). RCM is clinically characterized as a defect in cardiac diastolic function, such as, impaired ventricular relaxation, reduced diastolic volume and increased end-diastolic pressure. To date, mutations have been identified in the cardiac genes for desmin, α-actin, troponin I and troponin T. Functional studies in skinned muscle fibers reconstituted with troponin mutants have established phenotypes consistent with the clinical findings which include an increase in myofilament Ca2+ sensitivity and basal force. Moreover, when RCM mutants are incorporated into reconstituted myofilaments, the ability to inhibit the ATPase activity is reduced. A majority of the mutations cluster in specific regions of cardiac troponin and appear to be mutational “hot spots”. This paper highlights the functional and clinical characteristics of RCM linked mutations within the troponin complex.
We review development of evidence and current perceptions of the multiple and significant functions of cardiac troponin I in regulation and modulation of cardiac function. Our emphasis is on the unique structure function relations of the cardiac isoform of troponin I, especially regions containing sites of phosphorylation. The data indicate that modifications of specific regions cardiac troponin I by phosphorylations either promote or reduce cardiac contractility. Thus, a homeostatic balance in these phosphorylations is an important aspect of control of cardiac function. A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I.
Cardiac; Sarcomeres; Adrenergic stimulation; Mechanics; Kinases; Phosphatases
Despite the widespread use of cardiac troponins for diagnosis of myocyte injury and risk stratification in acute cardiac disorders, little is known about the long term effects of the released troponins on cardiac function. Recently, we showed that an autoimmune response to cardiac troponin I induces severe inflammation and subsequent fibrosis in the myocardium. This autoimmune disorder predisposes in mice to heart failure and cardiac death.
Methods and Results
To investigate the role of cTnI-specific T-cells, T-cells were isolated from splenocytes of mice immunized with murine cardiac troponin I (mcTnI). WT mice receiving mcTnI-specific T-cells showed high mcTnI-specific antibody titers, increased production of pro-inflammatory cytokines IL-1β and TNF-α, severe inflammation and fibrosis in the myocardium, and reduced fractional shortening. To identify the antigenic determinants of troponin I responsible for the observed inflammation, fibrosis and heart failure, 16 overlapping 16-18mer peptides covering the entire amino acid sequence of mcTnI (211 residues) were synthesized. Only mice immunized with the residues 105-122 of mcTnI developed significant inflammation and fibrosis in the myocardium with increased expression of inflammatory chemokines RANTES, MCP-1, MIP-1α, MIP-1β, MIP-2, TCA-3, eotaxin and chemokine receptors CCR1, CCR2, CCR5. Mice immunized with the corresponding human cTnI residues 104-121 and the mcTnI residues 131-148 developed milder disease.
Transfer of troponin I-specific T-cells can induce inflammation and fibrosis in WT mice leading to deterioration of contractile function. Furthermore, two sequence motifs of cTnI that induce inflammation and fibrosis in the myocardium are characterized.
inflammation; heart failure; myocarditis; immunology
Troponin I isoforms play a key role in determining myofilament Ca2+ sensitivity in cardiac muscle. The goal here was to identify domain clusters and residues that confer troponin I isoform-specific myofilament Ca2+ and pH sensitivities of contraction. Key domains/residues that contribute to troponin I isoform-specific Ca2+ and pH sensitivity were studied using gene transfer of a slow skeletal troponin I (ssTnI) template, with targeted cardiac troponin I (cTnI) residue substitutions. Substitutions in ssTnI with cognate cTnI residues R125Q, H132A, and V134E, studied both independently and together (ssTnIQAE), resulted in efficient stoichiometric replacement of endogenous myofilament cTnI in adult cardiac myocytes. In permeabilized myocytes, the pCa50 of tension ([Ca2+] required for half maximal force), and the acidosis-induced rightward shiftof pCa50 were converted to the cTnI phenotype in myocytes expressing ssTnIQAE or ssTnIH132A, and there was no functionally additive effect of ssTnIQAE versus ssTnIH132A. Interestingly, only the acidosis-induced shift in Ca2+ sensitivity was comparable to cTnI in myocytes expressing ssTnIV134E, while ssTnIR125Q fully retained the ssTnI phenotype. An additional ssTnIN141H substitution, which lies within the same structural region of TnI as V134, produced a shift in myofilament Ca2+ sensitivity comparable to cTnI at physiological pH, while the acidic pH response was similar to the effect of wild-type ssTnI. Analysis of sarcomere shortening in intact adult cardiac myocytes was consistent with the force measurements. Targeted substitutions in the carboxyl portion of TnI produced residue-specific influences on myofilament Ca2+ and pH sensitivity of force and give new molecular insights into the TnI isoform-dependence of myofilament function.
troponin I; heart; myocyte; Ca2+ sensitivity; contractility
Troponin-mediated Ca2+-regulation governs the actin-activated myosin motor function which powers striated (skeletal and cardiac) muscle contraction. This review focuses on the structure-function relationship of troponin T, one of the three protein subunits of the troponin complex. Molecular evolution, gene regulation, alternative RNA splicing, and posttranslational modifications of troponin T isoforms in skeletal and cardiac muscles are summarized with emphases on recent research progresses. The physiological and pathophysiological significances of the structural diversity and regulation of troponin T are discussed for impacts on striated muscle function and adaptation in health and diseases.
troponin T isoform genes; molecular evolution; posttranscriptional modification; striated muscle thin filament; calcium regulation of contraction
This study was to evaluate the predictive value of the cardiac troponins in scorpion sting myocarditis at a tertiary care hospital in Raichur, (Karnataka state) India.
A total of 84 consecutive patients were prospectively studied. The data included the demographics, the time of presentation to the hospital, the clinical features, the cardiac troponin levels and the echocardiographic findings.
12 patients with only local symptoms had troponin levels of less than 0.01μg/L. 12 patients with local and systemic symptoms without an echocardiac evidence of myocarditis had troponin values of 0.01 to 0.11 μg/L. 60 patients with an echocardiographic evidence of myocarditis had troponin levels of above 0.11 μg/L. 6 patients with severe myocarditis who required ventilator support or which led to death had troponin values which were higher than 10 μg/L.
High cardiac troponin levels predict myocarditis in scorpion sting envenomation and they can be a useful tool in guiding the therapy early.
Scorpion; Myocarditis; Envenomation; Echocardiography; Troponins
OBJECTIVE—To compare cardiac troponin T release and lactate metabolism in coronary sinus and arterial blood during uncomplicated coronary grafting on the beating heart with conventional coronary grafting using cardiopulmonary bypass.
DESIGN—A prospective observational study with simultaneous sampling of coronary sinus and arterial blood: before and 1, 4, 10, and 20 minutes after reperfusion for analysis of cardiac troponin T and lactate. Cardiac troponin T was also analysed in venous samples taken 3, 6, 24, 48, and 72 hours after surgery.
SETTING—Cardiac surgical unit in a tertiary referral centre.
PATIENTS—18 patients undergoing coronary grafting on the beating heart (10 single vessel and eight two-vessel grafting) and eight undergoing two-vessel grafting with cardiopulmonary bypass.
RESULTS—Cardiac troponin T was detected in coronary sinus blood in all patients by 20 minutes after beating heart coronary artery surgery before arterial concentrations were consistently increased. Peak arterial and coronary sinus cardiac troponin T values on the beating heart during single (0.03 (0 to 0.05) and 0.09 (0.07 to 0.16 µg/l, respectively) and two-vessel grafting (0.1 (0.07 to 0.11) and 0.19 (0.14 to 0.25) µg/l) were lower than the values obtained during cardiopulmonary bypass (0.64 (0.52 to 0.72) and 1.4 (0.9 to 2.0) µg/l) (p < 0.05). The area under the curve of venous cardiac troponin T over 72 hours for two-vessel grafting on the beating heart was less than with cardiopulmonary bypass (13 (10 to 16) v 68 (26 to 102) µg.h/l) (p < 0.001). Lactate extraction began within one minute of snare release during beating heart coronary surgery while lactate was still being produced 20 minutes after cross clamp release following cardiopulmonary bypass.
CONCLUSIONS—Lower intraoperative and serial venous cardiac troponin T concentrations suggest a lesser degree of myocyte injury during beating heart coronary artery surgery than during cardiopulmonary bypass. Oxidative metabolism also recovers more rapidly with beating heart coronary artery surgery than with conventional coronary grafting. Coronary sinus cardiac troponin T concentrations increased earlier and were greater than arterial concentrations during beating heart surgery, suggesting that this may be a more sensitive method of intraoperative assessment of myocardial injury.
Keywords: beating heart coronary artery surgery; troponin T; cardiopulmonary bypass; intraoperative assessment; myocardial injury
The cardiac troponins are biomarkers used for diagnosis of myocardial injury. They are also powerful prognostic markers in many diseases and settings. Recently introduced high-sensitivity assays indicate that chronic cardiac troponin elevations are common in response to cardiovascular (CV) morbidity. Type 2 diabetes mellitus (T2DM) confers a high risk of CV disease, but little is known about chronic cardiac troponin elevations in diabetic subjects. Accordingly, we aimed to understand the prevalence, determinants, and prognostic implications of cardiac troponin T (cTnT) elevations measured with a high-sensitivity assay in patients with T2DM.
cTnT was measured in stored, frozen serum samples from 124 subjects enrolled in the Asker and Bærum Cardiovascular Diabetes trial at baseline and at 2-year follow-up, if availabe (96 samples available). Results were analyzed in relation to baseline variables, hospitalizations, and group assignment (multifactorial intensive versus conventional diabetes care for lowering CV risk).
One-hundred thirteen (90 %) had detectable cTnT at baseline and of those, 22 (18 % of the total population) subjects had values above the 99th percentile for healthy controls (13.5 ng/L). Levels at baseline were associated with conventional CV risk factors (age, renal function, gender). There was a strong correlation between cTnT levels at the two time-points (r = 0.92, p > 0.001). Risk for hospitalizations during follow-up increased step-wise by quartiles of hscTnT measured at baseline (p = 0.058).
Elevations of cTnT above the 99th percentile measured by a highly sensitive assay were encountered frequently in a population of T2DM patients. cTnT levels appeared to be stable over time and associated with conventional CV risk factors. Although a clear trend was present, no statistically robust associations with adverse outcomes could be found.
The role of the C-domain sites of cardiac troponin C in the modulation of the calcium signal remains unclear. In this study we investigated the effects of hypertrophic cardiomyopathy linked mutations A8V, E134D and D145E in cardiac troponin C on the properties of the C-domain sites. The A8V mutation had essentially no effect on the calcium or magnesium binding properties of the C-domain sites, while E134D mutation moderately decreased calcium and magnesium binding affinities. On the other hand, D145E mutation affected cooperative interactions between sites III and IV, significantly reducing calcium binding affinity of both sites. Binding of the anchoring region of cardiac troponin I (corresponding to residues 34-71) to cardiac troponin C with D145E mutation was not able to recover normal calcium binding to the C-domain. Experiments utilizing the fluorescent hydrophobic probe bis-ANS suggest that D145E mutation dramatically reduced the extent of calcium-induced hydrophobic exposure by the C-domain. At high non-physiological calcium concentration, A8V, E134D and D145E mutations minimally affected the affinity of cardiac troponin C for the regulatory region of cardiac troponin I (corresponding to residues 128-180). In contrast, at lower physiological calcium concentration, D145E mutation led to ~8-fold decrease in the affinity of cardiac troponin C for the regulatory region of cardiac troponin I. Our results suggest that calcium binding properties of the C-domain sites might be important for the proper regulatory function of cardiac troponin C.
Serum cardiac troponin T (cTnT) and CKMB (mass) were analysed in three groups of patients. The first group (n=32) were patients with acute coronary syndromes including myocardial infarction. The second group (n=35)were patients with hypertension. The third group (n=24) were patients who had succumbed to non cardiac diseases. In all 3 groups, cardiac troponin T was elevated when compared with controls (p<0.001). However, CKMB elevation was not significant in all groups. CKMB levels correlated well with troponin T levels only when CKMB was greater than 50 ng/ml (r=1.00). Small elevations of troponin T identifies minimal cardiac necrosis and patients can benefit from early invasive therapy.
Troponin-T; CK-MB (mass); hypertension; acute coronary syndromes
Most neonatal encephalopathic disorders appear to be caused by perinatal events. Persistent myocardial ischemia leads to cellular necrosis and release of troponin from cardiac muscles. Fetal distress during labor may be detected by monitoring the fetal heart rate. However little is known about the relationship, if any, that exists between fetal heart rate abnormalities and the fetal cardiac musculature and its function. The aim of this study was to investigate the relationship, if any, of umbilical cord serum levels of cardiac troponin T with fetal bradycardia or late deceleration.
In this cross sectional study, troponin T level in umbilical cord blood of 80 neonates are measured. There were 23 versus 57 fetuses with and without late deceleration or bradycardia.
Level of cardiac troponin T in umbilical blood of neonates with fetal bradycardia or late deceleration was elevated in comparison to neonates without bradycardia or late deceleration. There was no relation between umbilical troponin T level and mode of delivery.
Infants with fetal bradycardia or late deceleration during labor had significantly higher cord cardiac troponin T levels. If troponin level is normal, the probability of hypoxia will be very low.
Umbilical Cord; Cardiac Troponin T; Fetal bradycardia; Late Deceleration