Exercise-induced cardiac troponin release in athletes with versus without coronary atherosclerosis.

The magnitude of exercise-induced cardiac troponin (cTn) elevations is dependent on cardiovascular health status, and previous studies have shown that occult coronary atherosclerosis is highly prevalent among amateur athletes. We tested the hypothesis that middle-aged and older athletes with coronary atherosclerosis demonstrate greater cTn elevations following a controlled endurance exercise test compared with healthy peers. We included 59 male athletes from the Measuring Athletes' Risk of Cardiovascular events 2 (MARC-2) study and stratified them as controls [coronary artery calcium score (CACS) = 0, n = 20], high CACS [≥300 Agatston units or ≥75th Multi-Ethnic Study of Atherosclerosis (MESA) percentile, n = 20] or significant stenosis (≥50% in any coronary artery, n = 19). Participants performed a cycling test with incremental workload until volitional exhaustion. Serial high-sensitivity cTn (hs-cTn) T and I concentrations were measured (baseline, after 30-min warm-up, and 0, 30, 60, 120, and 180 min postexercise). There were 58 participants (61 [58-69] yr) who completed the exercise test (76 ± 14 min) with a peak heart rate of 97.7 [94.8-101.8]% of their estimated maximum. Exercise duration and workload did not differ across groups. High-sensitivity cardiac troponin T (Hs-cTnT) and high-sensitivity cardiac troponin I (hs-cTnI) concentrations significantly increased (1.55 [1.33-2.14]-fold and 2.76 [1.89-3.86]-fold, respectively) over time, but patterns of cTn changes and the incidence of concentrations >99th percentile did not differ across groups. Serial sampling of hs-cTnT and hs-cTnI concentrations during and following an exhaustive endurance exercise test did not reveal differences in exercise-induced cTn release between athletes with versus without coronary atherosclerosis. These findings suggest that a high CACS or a >50% stenosis in any coronary artery does not aggravate exercise-induced cTn release in middle-aged and older athletes.NEW & NOTEWORTHY Exercise-induced cardiac troponin (cTn) release is considered to be dependent on cardiovascular health status. We tested whether athletes with coronary atherosclerosis demonstrate greater exercise-induced cTn release compared with healthy peers. Athletes with coronary atherosclerosis did not differ in cTn release following exercise compared with healthy peers. Our findings suggest that a high CACS or a >50% stenosis in any coronary artery does not aggravate exercise-induced cTn release in middle-aged and older athletes.

Cardiac troponin release following coronary artery bypass grafting: mechanisms and clinical implications.

The use of biomarkers is undisputed in the diagnosis of primary myocardial infarction (MI), but their value for identifying MI is less well studied in the postoperative phase following coronary artery bypass grafting (CABG). To identify patients with periprocedural MI (PMI), several conflicting definitions of PMI have been proposed, relying either on cardiac troponin (cTn) or the MB isoenzyme of creatine kinase, with or without supporting evidence of ischaemia. However, CABG inherently induces the release of cardiac biomarkers, as reflected by significant cTn concentrations in patients with uncomplicated postoperative courses. Still, the underlying (patho)physiological release mechanisms of cTn are incompletely understood, complicating adequate interpretation of postoperative increases in cTn concentrations. Therefore, the aim of the current review is to present these potential underlying mechanisms of cTn release in general, and following CABG in particular (Graphical Abstract). Based on these mechanisms, dissimilarities in the release of cTnI and cTnT are discussed, with potentially important implications for clinical practice. Consequently, currently proposed cTn biomarker cut-offs by the prevailing definitions of PMI might warrant re-assessment, with differentiation in cut-offs for the separate available assays and surgical strategies. To resolve these issues, future prospective studies are warranted to determine the prognostic influence of biomarker release in general and PMI in particular.

Exercise-Induced Cardiac Troponin Elevations: From Underlying Mechanisms to Clinical Relevance.

Serological assessment of cardiac troponins (cTn) is the gold standard to assess myocardial injury in clinical practice. A greater magnitude of acutely or chronically elevated cTn concentrations is associated with lower event-free survival in patients and the general population. Exercise training is known to improve cardiovascular function and promote longevity, but exercise can produce an acute rise in cTn concentrations, which may exceed the upper reference limit in a substantial number of individuals. Whether exercise-induced cTn elevations are attributable to a physiological or pathological response and if they are clinically relevant has been debated for decades. Thus far, exercise-induced cTn elevations have been viewed as the only benign form of cTn elevations. However, recent studies report intriguing findings that shed new light on the underlying mechanisms and clinical relevance of exercise-induced cTn elevations. We will review the biochemical characteristics of cTn assays, key factors determining the magnitude of postexercise cTn concentrations, the release kinetics, underlying mechanisms causing and contributing to exercise-induced cTn release, and the clinical relevance of exercise-induced cTn elevations. We will also explain the association with cardiac function, correlates with (subclinical) cardiovascular diseases and exercise-induced cTn elevations predictive value for future cardiovascular events. Last, we will provide recommendations for interpretation of these findings and provide direction for future research in this field.

Protein Alterations in Cardiac Ischemia/Reperfusion Revealed by Spatial-Omics.

Myocardial infarction is the most common cause of death worldwide. An understanding of the alterations in protein pathways is needed in order to develop strategies that minimize myocardial damage. To identify the protein signature of cardiac ischemia/reperfusion (I/R) injury in rats, we combined, for the first time, protein matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and label-free proteomics on the same tissue section placed on a conductive slide. Wistar rats were subjected to I/R surgery and sacrificed after 24 h. Protein MALDI-MSI data revealed ischemia specific regions, and distinct profiles for the infarct core and border. Firstly, the infarct core, compared to histologically unaffected tissue, showed a significant downregulation of cardiac biomarkers, while an upregulation was seen for coagulation and immune response proteins. Interestingly, within the infarct tissue, alterations in the cytoskeleton reorganization and inflammation were found. This work demonstrates that a single tissue section can be used for protein-based spatial-omics, combining MALDI-MSI and label-free proteomics. Our workflow offers a new methodology to investigate the mechanisms of cardiac I/R injury at the protein level for new strategies to minimize damage after MI.

Mass Spectrometry Spatial-Omics on a Single Conductive Slide.

Mass spectrometry imaging (MSI) can analyze the spatial distribution of hundreds of different molecules directly from tissue sections usually placed on conductive glass slides to provide conductivity on the sample surface. Additional experiments are often required for molecular identification using consecutive sections on membrane slides compatible with laser capture microdissection (LMD). In this work, we demonstrate for the first time the use of a single conductive slide for both matrix-assisted laser desorption ionization (MALDI)-MSI and direct proteomics. In this workflow, regions of interest can be directly ablated with LMD while preserving protein integrity. These results offer an alternative for MSI-based multimodal spatial-omics.

Cardiovascular magnetic resonance accurately detects obstructive coronary artery disease in suspected non-ST elevation myocardial infarction: a sub-analysis of the CARMENTA Trial.

BACKGROUND: Invasive coronary angiography (ICA) is still the reference test in suspected non-ST elevation myocardial infarction (NSTEMI), although a substantial number of patients do not have obstructive coronary artery disease (CAD). Early cardiovascular magnetic resonance (CMR) may be a useful gatekeeper for ICA in this setting. The main objective was to investigate the accuracy of CMR to detect obstructive CAD in NSTEMI. METHODS: This study is a sub-analysis of a randomized controlled trial investigating whether a non-invasive imaging-first strategy safely reduced the number of ICA compared to routine clinical care in suspected NSTEMI (acute chest pain, non-diagnostic electrocardiogram, high sensitivity troponin T > 14 ng/L), and included 51 patients who underwent CMR prior to ICA. A stepwise approach was used to assess the diagnostic accuracy of CMR to detect (1) obstructive CAD (diameter stenosis ≥ 70% by ICA) and (2) an adjudicated final diagnosis of acute coronary syndrome (ACS). First, in all patients the combination of cine, T2-weighted and late gadolinium enhancement (LGE) imaging was evaluated for the presence of abnormalities consistent with a coronary etiology in any sequence. Hereafter and only when the scan was normal or equivocal, adenosine stress-perfusion CMR was added. RESULTS: Of 51 patients included (63 ± 10 years, 51% male), 34 (67%) had obstructive CAD by ICA. The sensitivity, specificity and overall accuracy of the first step to diagnose obstructive CAD were 79%, 71% and 77%, respectively. Additional vasodilator stress-perfusion CMR was performed in 19 patients and combined with step one resulted in an overall sensitivity of 97%, specificity of 65% and accuracy of 86%. Of the remaining 17 patients with non-obstructive CAD, 4 (24%) had evidence for a myocardial infarction on LGE, explaining the modest specificity. The sensitivity, specificity and overall accuracy to diagnose ACS (n = 43) were 88%, 88% and 88%, respectively. CONCLUSION: CMR accurately detects obstructive CAD and ACS in suspected NSTEMI. Non-obstructive CAD is common with CMR still identifying an infarction in almost one-quarter of patients. CMR should be considered as an early diagnostic approach in suspected NSTEMI. TRIAL REGISTRATION: The CARMENTA trial has been registered at ClinicalTrials.gov with identifier NCT01559467.

Cardiac Troponin T: The Impact of Posttranslational Modifications on Analytical Immunoreactivity in Blood up to the Excretion in Urine.

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.

TSH suppression aggravates arterial inflammation - an 18F-FDG PET study in thyroid carcinoma patients.

PURPOSE: We aimed to investigate the influence of both hypothyroidism and thyroid-stimulating hormone (TSH) suppression on vascular inflammation, as assessed with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT). METHODS: Ten thyroid carcinoma patients underwent an 18F-FDG PET/CT during post-thyroidectomy hypothyroidism and during thyrotropin (TSH) suppression after 131I (radioiodine) ablation therapy. We analysed the 18F-FDG uptake in the carotids, aortic arch, ascending, descending, and abdominal aorta to investigate the effects of thyroid hormone status on arterial inflammation. Target-to-background ratios (TBRs) corrected for blood pool activity were established for all arterial territories. Results were further compared to euthyroid historic control subjects. RESULTS: In general, there was a trend towards higher vascular TBRs during TSH suppression than during hypothyroidism (TBRmax all vessels = 1.6 and 1.8, respectively, p = 0.058), suggesting a higher degree of arterial inflammation. In concurrence with this, we found increased C-reactive protein (CRP) levels after levothyroxine treatment (CRP = 2.9 mg/l and 4.8 mg/l, p = 0.005). An exploratory comparison with euthyroid controls showed significant higher TBRs during TSH suppression for the carotids, aortic arch, thoracic descending aorta, and when all vascular territories were combined (TBRmaxp = 0.013, p = 0.016, p = 0.030 and p = 0.018 respectively). CONCLUSIONS: Arterial inflammation is increased during TSH suppression. This finding sheds new light on the underlying mechanism of the suspected increased risk of cardiovascular disease in patients with TSH suppression.

Trends in mass spectrometry imaging for cardiovascular diseases.

Mass spectrometry imaging (MSI) is a widely established technology; however, in the cardiovascular research field, its use is still emerging. The technique has the advantage of analyzing multiple molecules without prior knowledge while maintaining the relation with tissue morphology. Particularly, MALDI-based approaches have been applied to obtain in-depth knowledge of cardiac (dys)function. Here, we discuss the different aspects of the MSI protocols, from sample handling to instrumentation used in cardiovascular research, and critically evaluate these methods. The trend towards structural lipid analysis, identification, and "top-down" protein MSI shows the potential for implementation in (pre)clinical research and complementing the diagnostic tests. Moreover, new insights into disease progression are expected and thereby contribute to the understanding of underlying mechanisms related to cardiovascular diseases.

Sex-Related Aspects of Biomarkers in Cardiac Disease.

Biomarkers play an important role in the clinical management of cardiac care. In particular, cardiac troponins (cTn) and natriuretic peptides are the cornerstones for the diagnosis of acute myocardial infarction (AMI) and for the diagnosis of heart failure (HF), respectively. Current guidelines do not make a distinction between women and men. However, the commonly used "one size fits all" algorithms are topic of debate to improve assessment of prognosis, particularly in women. Due to the high-sensitivity assays (hs-cTn), lower cTn levels (and 99th percentile upper reference limits) were observed in women as compared with men. Sex-specific diagnostic thresholds may improve the diagnosis of AMI in women, though clinical relevance remains controversial and more trials are needed. Also other diagnostic aspects are under investigation, like combined biomarkers approach and rapid measurement strategies. For the natriuretic peptides, previous studies observed higher concentrations in women than in men, especially in premenopausal women who might benefit from the cardioprotective actions. Contrary to hs-cTn, natriuretic peptides are particularly incorporated in the ruling-out algorithms for the diagnosis of HF and not ruling-in. Clinical relevance of sex differences here seems marginal, as clinical research has shown that negative predictive values for ruling-out HF were hardly effected when applying a universal diagnostic threshold that is independent from sex or other risk factors. Apart from the diagnostic issues of AMI in women, we believe that in the future most sex-specific benefits of cardiac biomarkers can be obtained in patient follow-up (guiding therapy) and prognostic applications, fitting modern ideas on preventive and personalized medicine.

Cardiac Troponin T: Smaller Molecules in Patients with End-Stage Renal Disease than after Onset of Acute Myocardial Infarction.

BACKGROUND: We have found previously that in acute myocardial infarction (AMI), cardiac troponin T (cTnT) is degraded in a time-dependent pattern. We investigated whether cTnT forms differed in patients with chronic cTnT increases, as seen with renal dysfunction, from those in the acute phase of myocardial infarction. METHODS: We separated cTnT forms by gel filtration chromatography (GFC) in end-stage renal disease (ESRD) patients: prehemodialysis (pre-HD) and post-HD (n = 10) and 2 months follow-up (n = 6). Purified (cTnT) standards, quality control materials of the clinical cTnT immunoassay (Roche), and AMI patients' sera also were analyzed. Immunoprecipitation and Western blotting were performed with the original cTnT antibodies from the clinical assay and antibodies against the N- and C-terminal end of cTnT. RESULTS: GFC analysis revealed the retention of purified cTnT at 27.5 mL, identical to that for cTnT in quality controls. For all ESRD patients, one cTnT peak was found at 45 mL, pre- and post-HD, and stable over time. Western blotting illustrated that this peak corresponded to cTnT fragments <18 kDa missing the N- and C-terminal ends. AMI patients' sera revealed cTnT peaks at 27.5 and 45 mL, respectively, corresponding to N-terminal truncated cTnT of 29 kDa and N- and C-terminal truncated fragments of <18 kDa, respectively. CONCLUSIONS: We found that cTnT forms in ESRD patients are small (<18 kDa) and different from forms seen in AMI patients. These insights may prove useful for development of a more specific cTnT immunoassay, especially for the acute and diagnostic phase of myocardial infarction.

Acute chest pain in the high-sensitivity cardiac troponin era: A changing role for noninvasive imaging?

Management of patients with acute chest pain remains challenging. Cardiac biomarker testing reduces the likelihood of erroneously discharging patients with acute myocardial infarction (AMI). Despite normal contemporary troponins, physicians have still been reluctant to discharge patients without additional testing. Nowadays, the extremely high negative predictive value of current high-sensitivity cardiac troponin (hs-cTn) assays challenges this need. However, the decreased specificity of hs-cTn assays to diagnose AMI poses a new problem as noncoronary diseases (eg, pulmonary embolism, myocarditis, cardiomyopathies, hypertension, renal failure, etc) may also cause elevated hs-cTn levels. Subjecting patients with noncoronary diseases to unnecessary pharmacological therapy or invasive procedures must be prevented. Attempts to improve the positive predictive value to diagnose AMI by defining higher initial cutoff values or dynamic changes over time inherently lower the sensitivity of troponin assays. In this review, we anticipate a potential changing role of noninvasive imaging from ruling out myocardial disease when troponin values are normal toward characterizing myocardial disease when hs-cTn values are (mildly) abnormal.

Modeling creatine-kinase MB concentrations following coronary artery bypass grafting.

OBJECTIVES: An increase in cardiac biomarkers is a prerequisite to diagnose periprocedural myocardial infarction (PMI) after coronary artery bypass grafting (CABG). Early-phase risk detection may be aided by modeling time-dependent serum creatine kinase-MB (CK-MB) concentrations. This study aimed to model the kinetics of CK-MB, while identifying its influencing factors. METHODS: Patients who underwent elective CABG and had CK-MB measurements within 72 hours postoperatively were included. The primary outcome was the modeled post-hoc kinetics of CK-MB in patients without potential PMI. These patients were defined as having no potential PMI in case of absence of: ischemic electrocardiographic abnormalities, imaging abnormalities, in-hospital cardiac arrest, mortality, or postoperative unplanned catheterization. A web-based application was created using mixed-effect modeling to provide an interactive and individualized result. RESULTS: 635 patients underwent elective isolated CABG, resulting in 1589 CK-MB measurements. Of these, 609 patients (96%) had no potential PMI, while 26 (4%) had potential PMI. Male sex, aortic cross-clamp time, and cardioplegia type significantly impacted CK-MB concentrations. The diagnostic accuracy of the model had an area under the ROC curve of 82.8% (72.6-90.2%). A threshold of 7 µg/L yielded a sensitivity of 94% and a specificity of 80% (positive predictive value, 17%; negative predictive value, 99%) for excluding potential PMI in our own study population. CONCLUSION: CK-MB release after CABG depends on the timing of measurement, sex, aortic cross-clamp time, and cardioplegia type. The model at https://www.cardiomarker.com/ckmb can be validated, reproduced, refined, and applied to other biomarkers.

Cardiac troponin concentrations following exercise and the association with cardiovascular disease and outcomes: rationale and design of the prospective TREAT cohort study.

Exercise can produce transient elevations of cardiac troponin (cTn) concentrations, which may resemble the cTn release profile of myocardial infarction. Consequently, clinical interpretation of postexercise cTn elevations (ie, values above the 99th percentile upper reference limit) remains challenging and may cause clinical confusion. Therefore, insight into the physiological versus pathological nature of postexercise cTn concentrations is warranted. We aim to (1) establish resting and postexercise reference values for recreational athletes engaged in walking, cycling or running exercise; (2) compare the prevalence of (sub)clinical coronary artery disease in athletes with high versus low postexercise cTn concentrations and (3) determine the association between postexercise cTn concentrations and the incidence of major adverse cardiovascular events (MACE) and mortality during long-term follow-up. For this purpose, the prospective TRoponin concentrations following Exercise and the Association with cardiovascular ouTcomes (TREAT) observational cohort study was designed to recruit 1500 recreational athletes aged ≥40 to <70 years who will participate in Dutch walking, cycling and running events. Baseline and postexercise high-sensitivity cTnT and cTnI concentrations will be determined. The prevalence and magnitude of coronary atherosclerosis on computed tomography (eg, coronary artery calcium score, plaque type, stenosis degree and CT-derived fractional flow reserve) will be compared between n=100 athletes with high postexercise cTn concentrations vs n=50 age-matched, sex-matched and sport type-matched athletes with low postexercise cTn concentrations. The incidence of MACE and mortality will be assessed in the entire cohort up to 20 years follow-up. The TREAT study will advance our understanding of the clinical significance of exercise-induced cTn elevations in middle-aged and older recreational athletes. Trial registration number NCT06295081.

The association between coronary artery calcification and vectorcardiography in mechanically ventilated COVID-19 patients: the Maastricht Intensive Care COVID cohort.

BACKGROUND: Coronary artery calcification (CAC) is associated with poor outcome in critically ill patients. A deterioration in cardiac conduction and loss of myocardial tissue could be an underlying cause. Vectorcardiography (VCG) and cardiac biomarkers provide insight into these underlying causes. The aim of this study was to investigate whether a high degree of CAC is associated with VCG-derived variables and biomarkers, including high-sensitivity troponin-T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). METHODS: Mechanically ventilated coronavirus-19 (COVID-19) patients with an available chest computed tomography (CT) and 12-lead electrocardiogram (ECG) were studied. CAC scores were determined using chest CT scans. Patients were categorized into 3 sex-specific tertiles: low, intermediate, and high CAC. Daily 12 leads-ECGs were converted to VCGs. Daily hs-cTnT and NT-proBNP levels were determined. Linear mixed-effects regression models examined the associations between CAC tertiles and VCG variables, and between CAC tertiles and hs-cTnT or NT-proBNP levels. RESULTS: In this study, 205 patients (73.2% men, median age 65 years [IQR 57.0; 71.0]) were included. Compared to the lowest CAC tertile, the highest CAC tertile had a larger QRS area at baseline (6.65 µVs larger [1.50; 11.81], p = 0.012), which decreased during admission (- 0.27 µVs per day [- 0.43; - 0.11], p = 0.001). Patients with the highest CAC tertile also had a longer QRS duration (12.02 ms longer [4.74; 19.30], p = 0.001), higher levels of log hs-cTnT (0.79 ng/L higher [0.40; 1.19], p < 0.001) and log NT-proBNP (0.83 pmol/L higher [0.30; 1.37], p = 0.002). CONCLUSION: Patients with a high degree of CAC had the largest QRS area and higher QRS amplitude, which decreased more over time when compared to patients with a low degree of CAC. These results suggest that CAC might contribute to loss of myocardial tissue during critical illness. These insights could improve risk stratification and prognostication of patients with critical illness.

Differences in Cardiac Troponin T Composition in Myocardial Infarction and End-Stage Renal Disease Patients: A Blood Tube Effect?

BACKGROUND: Cardiac troponin T (cTnT) is key in diagnosing myocardial infarction (MI) but is also elevated in end-stage renal disease (ESRD) patients. Specific larger cTnT proteoforms were identified for the acute phase of MI, while in serum of ESRD patients solely small cTnT fragments were found. However, others allocated this to a pre-analytic effect due to abundant thrombin generation in serum. Therefore, we investigated the effect of various anticoagulation methods on cTnT composition and concentration and compared the cTnT composition of MI and ESRD patients. METHODS: The agreement of cTnT concentrations between simultaneously collected serum, lithium-heparin (LH) plasma, and ethylenediaminetetraacetic acid (EDTA) plasma was studied using the high-sensitivity (hs-)cTnT immunoassay. cTnT proteoform composition was investigated in a standardized time-dependent manner through spike experiments and in simultaneously collected blood matrixes of MI and ESRD patients. RESULTS: Excellent hs-cTnT concentration agreements were observed across all blood matrixes (slopes > 0.98; 95% CI, 0.96-1.04). Time-dependent degradation (40 kDa intact:29 kDa fragment:15 to 18 kDa fragments) was found in LH plasma and EDTA plasma, and serum in ratios (%) of 90:10:0, 0:5:95, and 0:0:100, respectively (48 h after blood collection). Moreover, gel filtration chromatography (GFC) profiles illustrated mainly larger cTnT proteoforms in MI patients, while in ESRD patients mainly 15 to 18 kDa fragments were found for all matrices. CONCLUSIONS: The extent of cTnT degradation in vitro is dependent on the (anti)coagulation method, without impacting hs-cTnT concentrations. Furthermore, mainly larger cTnT proteoforms were present in MI patients, while in ESRD patients mainly small 15 to 18 kDa cTnT fragments were found. These insights are essential when developing a novel hs-cTnT assay targeting larger cTnT proteoforms.

The role of cardiovascular magnetic resonance imaging and computed tomography angiography in suspected non-ST-elevation myocardial infarction patients: design and rationale of the CARdiovascular Magnetic rEsoNance imaging and computed Tomography Angiography (CARMENTA) trial.

BACKGROUND: Although high-sensitivity cardiac troponin (hs-cTn) substantially improves the early detection of myocardial injury, it lacks specificity for acute myocardial infarction (MI). In suspected non-ST-elevation MI, invasive coronary angiography (ICA) remains necessary to distinguish between acute MI and noncoronary myocardial disease (eg, myocarditis), unnecessarily subjecting the latter to ICA and associated complications. This trial investigates whether implementing cardiovascular magnetic resonance (CMR) or computed tomography angiography (CTA) early in the diagnostic process may help to differentiate between coronary and noncoronary myocardial disease, thereby preventing unnecessary ICA. STUDY DESIGN: In this prospective, single-center, randomized controlled clinical trial, 321 consecutive patients with acute chest pain, elevated hs-cTnT, and nondiagnostic electrocardiogram are randomized to 1 of 3 strategies: (1) CMR, or (2) CTA early in the diagnostic process, or (3) routine clinical management. In the 2 investigational arms of the study, results of CMR or CTA will guide further clinical management. It is expected that noncoronary myocardial disease is detected more frequently after early noninvasive imaging as compared with routine clinical management, and unnecessary ICA will be prevented. The primary end point is the total number of patients undergoing ICA during initial admission. Secondary end points are 30-day and 1-year clinical outcome (major adverse cardiac events and major procedure-related complications), time to final diagnosis, quality of life, and cost-effectiveness. CONCLUSION: The CARMENTA trial investigates whether implementing CTA or CMR early in the diagnostic process in suspected non-ST-elevation MI based on elevated hs-cTnT can prevent unnecessary ICA as compared with routine clinical management, with no detrimental effect on clinical outcome.

Time-dependent degradation pattern of cardiac troponin T following myocardial infarction.

BACKGROUND: Cardiac troponin T (cTnT) is widely used for the diagnosis of acute myocardial infarction (AMI). However, it is still unclear whether degraded cTnT forms circulate in the patient's blood. We therefore aimed to elucidate which cTnT forms are detected by the clinical assay. METHODS: Separation of cTnT forms by gel filtration chromatography (GFC) was performed in sera from 13 AMI patients to examine cTnT degradation. The GFC eluates were subjected to Western blot analysis with the original antibodies from the Roche immunoassay used to mimic the clinical cTnT assay. To investigate the degradation pattern with time, standardized serum samples of 18 AMI patients collected 0-72 h after admission were analyzed by Western blot analysis. RESULTS: GFC analysis of AMI patients' sera revealed 2 cTnT peaks with retention volumes of 5 and 21 mL. Western blot analysis identified these peaks as cTnT fragments of 29 and 14-18 kDa, respectively. Furthermore, the performance of direct Western blots on standardized serum samples demonstrated a time-dependent degradation pattern of cTnT, with fragments ranging between 14 and 40 kDa. Intact cTnT (40 kDa) was present in only 3 patients within the first 8 h after hospital admission. CONCLUSIONS: These results demonstrate that the Roche cTnT immunoassay detects intact as well as degraded cTnT forms in AMI patients' sera during the period of diagnostic testing. Moreover, following AMI, cTnT is degraded in a time-dependent pattern.

A comprehensive review of upper reference limits reported for (high-)sensitivity cardiac troponin assays: the challenges that lie ahead.

Cardiac troponins (cTn) are the preferred markers for the diagnosis of acute myocardial infarction (AMI). The guidelines recommend the use of the 99th percentile upper reference concentration of a healthy population as the diagnostic cut-off for AMI. However, a broad range of upper reference limits is still employed, complicating the diagnosis of AMI. This overview is meant to assist laboratory specialists to define an appropriate cut-off value for the diagnosis of AMI. Therefore, we provide an overview of the analytical performance and upper reference limits of seven (high-)sensitivity cTn assays: Roche high-sensitivity cTnT and ADVIA Centaur, Stratus CS, Dimension Vista, Vitros ECi, Access and Architect cTnI assays. It is shown that none of the reference populations completely met the guidelines, including those in package inserts. Forty percent of the studies collected less than the advised minimum of 300 subjects. Many studies (50%) did not report their inclusion criteria, while lower 99th percentile limits were observed when more stringent selection criteria were applied. Higher troponin cut-offs were found in men and elderly subjects, suggesting sex- and age-specific cut-offs would be considered. Therefore, there is still need for a large, rigorously screened reference population to more accurately establish cTn upper reference limits.

Resveratrol treatment does not reduce arterial inflammation in males at risk of type 2 diabetes: a randomized crossover trial.

PURPOSE: Resveratrol has shown promising anti-inflammatory effects in in vitro and animal studies. We aimed to investigate this effect on arterial inflammation in vivo. METHODS: This was an additional analysis of a double-blind randomized crossover trial which included eight male subjects with decreased insulin sensitivity who underwent an 18F-fluoroxyglucose (18F-FDG) PET/CT after 34 days of placebo and resveratrol treatment (150 mg/day). 18F-FDG uptake was analyzed in the carotid arteries and the aorta, adipose tissue regions, spleen, and bone marrow as measures for arterial and systemic inflammation. Maximum target-to-background ratios (TBRmax) were compared between resveratrol and placebo treatment with the non-parametric Wilcoxon signed-rank test. Median values are shown with their interquartile range. RESULTS: Arterial 18F-FDG uptake was non-significantly higher after resveratrol treatment (TBRmax all vessels 1.7 (1.6-1.7)) in comparison to placebo treatment (1.5 (1.4-1.6); p=0.050). Only in visceral adipose tissue, the increase in 18F-FDG uptake after resveratrol reached statistical significance (p=0.024). Furthermore, CRP-levels were not significantly affected by resveratrol treatment (p=0.091). CONCLUSIONS: Resveratrol failed to attenuate arterial or systemic inflammation as measured with 18F-FDG PET in subjects at risk of developing type 2 diabetes. However, validation of these findings in larger human studies is needed.