Determination of Tissue Iron and Ferritin in Liver Pathology. Comparison of Histochemical and Biochemical Results

Peer Reviewe

Circulating Cardiac Troponin T Exhibits a Diurnal Rhythm

ObjectivesThe goal of this study was to test the unverified assumption that chronically elevated cardiac troponin T (cTnT) levels fluctuate randomly around a homeostatic set point.BackgroundThe introduction of high-sensitivity cardiac troponin (cTn) assays has improved sensitivity for acute myocardial infarction (AMI). However, many patients with a single positive cTn test result do not have AMI. Therefore, the diagnosis of AMI relies strongly on serial testing and interpretation of cTn kinetics. Essential in this regard is a profound understanding of the biological variation of cTn.MethodsTwo studies were conducted to assess biological cTnT variation and to investigate the presence of a diurnal rhythm of cTnT. Study 1 comprised 23 male subjects with type 2 diabetes, with no acute cardiovascular disease. Serial venous blood samples were drawn over an 11-h period (8:30 am to 7:30 pm). In study 2, the presence of a diurnal cTnT rhythm was investigated by hourly sampling of 7 subjects from study 1 over 25 h.ResultsIn study 1, we observed a gradual decrease in cTnT concentrations during the day (24 ± 2%). This decrease was present in all participants and was most prominent in subjects with the highest baseline cTnT values (Pearson’s R 0.93). Diurnal variation of cTnT, as assessed in study 2, was characterized by peak concentrations during morning hours (8:30 am, 17.1 ± 2.9 ng/l), gradually decreasing values during daytime (8:30 pm, 11.9 ± 1.6 ng/l), and rising concentrations during nighttime (8:30 am the next day, 16.9 ± 2.8 ng/l).ConclusionsA diurnal cTnT rhythm substantiates the recommendation that all dynamic changes in cTnT should be interpreted in relation to the clinical presentation. Epidemiological studies and risk-stratification protocols with the use of cTnT may benefit from standardized sampling times. (Exercise and Glycemic Control in Type 2 Diabetes; NCT00945165

Potential biomarkers for diagnosis of sarcoidosis using proteomics in serum

SummaryBackgroundSarcoidosis is a multi-systemic inflammatory disorder, which affects the lungs in 90% of the cases. The main pathologic feature is chronic inflammation resulting in non-caseating granuloma formation. Until now there is no satisfying biomarker for diagnosis or prognosis of sarcoidosis. This study is focused on the detection of potential biomarkers in serum for the diagnosis of sarcoidosis using surface-enhanced laser desorption ionization-time of flight-mass spectrometry (SELDI-TOF-MS).MethodsFor detection of potential biomarkers, protein profiles of anion exchange fractionated serum of 35 sarcoidosis patients and 35 healthy controls were compared using SELDI-TOF-MS. Sensitivities and specificities of the potential biomarkers obtained with SELDI-TOF-MS, generated with decision tree algorithm, were compared to the conventional markers angiotensin converting enzyme (ACE) and soluble interleukin-2 receptor (sIL-2R).ResultsOptimal classification was achieved with metal affinity binding arrays. A single marker with a mass-to-charge (m/z) value of 11,955 resulted in a sensitivity and specificity of 86% and 63%, respectively. A multimarker approach of two peaks, m/z values of 11,734 and 17,377, resulted in a sensitivity and specificity of 74% and 71%, respectively. These sensitivities and specificities were higher compared to measurements of ACE and sIL-2R. Identification of the peak at m/z 17,377 resulted in the α-2chain of haptoglobin.ConclusionsThis study acts as a proof-of-principle for the use of SELDI-TOF-MS in the detection of new biomarkers for sarcoidosis. The peak of the multimarker at m/z 17,377 was identified as the α-2chain of haptoglobin

Prognostic value of basal high-sensitive cardiac troponin levels on mortality in the general population

Interest in the use of cardiac troponin T (cTnT) and cardiac troponin I (cTnI) has expanded from diagnosis of acute myocardial infarction to risk assessment for morbidity and mortality. Although cTnT and cTnI were shown to have equivalent diagnostic performance in the setting of suspected acute myocardial infarction, potential prognostic differences are largely unexplored. The aim of this study is to quantify and compare the relationship between cTnT and cTnI, and cardiovascular and all-cause mortality in the general population. Medline, Embase, and the Cochrane Library (from inception through October 2016) were searched for prospective observational cohort studies reporting on the prognostic value of basal high-sensitive cTnT and/or cTnI levels on cardiovascular and all-cause mortality in the general population. Data on study characteristics, participants' characteristics, outcome parameters, and quality [according to the Effective Public Health Practice Project (EPHPP) "Quality Assessment Tool For Quantitative Studies] were retrieved. Hazard ratios per standard deviation increase in basal cardiac troponin level (HR per 1-SD; retrieved from the included articles or estimated) were pooled using a random-effects model. On a total of 2585 reviewed citations, 11 studies, with data on 65,019 participants, were included in the meta-analysis. Random effects pooling showed significant associations between basal cardiac troponin levels and HR for cardiovascular and all-cause mortality [HR per 1-SD 1.29 (95% confidence interval, 95% CI, 1.20-1.38) and HR per 1-SD 1.18 (95% CI, 1.11-1.26), respectively]. Stratified analyses showed higher HRs for cTnT than cTnI [cardiovascular mortality: cTnT HR per 1-SD 1.37 (95% CI, 1.23-1.52); and cTnI HR per 1-SD 1.21 (95% CI, 1.16-1.26); all-cause mortality: cTnT HR per 1-SD 1.31 (955 CI, 1.13-1.53); and cTnI HR per 1-SD 1.14 (95% CI, 1.06-1.22)]. These differences were significant (P < 0.01) in meta-regression analyses for cardiovascular mortality but did not reach statistical significance for all-cause mortality. Elevated, basal cTnT, and cTnI show robust associations with an increased risk of cardiovascular and all-cause mortality during follow-up in the general population

Circulating cardiac troponin T exhibits a diurnal rhythm

Objectives The goal of this study was to test the unverified assumption that chronically elevated cardiac troponin T (cTnT) levels fluctuate randomly around a homeostatic set point. Background The introduction of high-sensitivity cardiac troponin (cTn) assays has improved sensitivity for acute myocardial infarction (AMI). However, many patients with a single positive cTn test result do not have AMI. Therefore, the diagnosis of AMI relies strongly on serial testing and interpretation of cTn kinetics. Essential in this regard is a profound understanding of the biological variation of cTn. Methods Two studies were conducted to assess biological cTnT variation and to investigate the presence of a diurnal rhythm of cTnT. Study 1 comprised 23 male subjects with type 2 diabetes, with no acute cardiovascular disease. Serial venous blood samples were drawn over an 11-h period (8:30 AM to 7:30 PM). In study 2, the presence of a diurnal cTnT rhythm was investigated by hourly sampling of 7 subjects from study 1 over 25 h. Results In study 1, we observed a gradual decrease in cTnT concentrations during the day (24 2%). This decrease was present in all participants and was most prominent in subjects with the highest baseline cTnT values (Pearson’s R 0.93). Diurnal variation of cTnT, as assessed in study 2, was characterized by peak concentrations during morning hours (8:30 AM, 17.1 2.9 ng/l), gradually decreasing values during daytime (8:30 PM, 11.9 1.6 ng/l), and rising concentrations during nighttime (8:30 AM the next day, 16.9 2.8 ng/l). Conclusions A diurnal cTnT rhythm substantiates the recommendation that all dynamic changes in cTnT should be interpreted in relation to the clinical presentation. Epidemiological studies and risk-stratification protocols with the use of cTnT may benefit from standardized sampling times. (Exercise and Glycemic Control in Type 2 Diabetes; NCT00945165) (J Am Coll Cardiol 2014;63:1788–95) ª 2014 by the American College of Cardiology Foundation C

Validation, optimisation, and application data in support of the development of a targeted selected ion monitoring assay for degraded cardiac troponin T

AbstractCardiac troponin T (cTnT) fragmentation in human serum was investigated using a newly developed targeted selected ion monitoring assay, as described in the accompanying article: “Development of a targeted selected ion monitoring assay for the elucidation of protease induced structural changes in cardiac troponin T” [1]. This article presents data describing aspects of the validation and optimisation of this assay. The data consists of several figures, an excel file containing the results of a sequence identity search, and a description of the raw mass spectrometry (MS) data files, deposited in the ProteomeXchange repository with id PRIDE: PXD003187

High-sensitive Troponin T assay for the diagnosis of acute myocardial infarction: An economic evaluation

__Abstract__ Background: Delayed diagnosis and treatment of Acute Myocardial Infarction (AMI) has a major adverse impact on prognosis in terms of both morbidity and mortality. Since conventional cardiac Troponin assays have a low sensitivity for diagnosing AMI in the first hours after myocardial necrosis, high-sensitive assays have been developed. The aim of this study was to assess the cost effectiveness of a high-sensitive Troponin T assay (hsTnT), alone or combined with the heart-type fatty acid-binding protein (H-FABP) assay in comparison with the conventional cardiac Troponin (cTnT) assay for the diagnosis of AMI in patients presenting to the hospital with chest pain.Methods: We performed a cost-utility analysis (quality adjusted life years-QALYs) and a cost effectiveness analysis (life years gained-LYGs) based on a decision analytic model, using a health care perspective in the Dutch context and a life time time-horizon. The robustness of model predictions was explored using one-way and probabilistic sensitivity analyses.Results: For a life time incremental cost of 30.70 Euros, use of hsTnT over conventional cTnT results in gain of 0.006 Life Years and 0.004 QALY. It should be noted here that hsTnT is a diagnostic intervention which costs only 4.39 Euros/test more than the cTnT test. The ICER generated with the use of hsTnT based diagnostic strategy comparing with the use of a cTnT-based strategy, is 4945 Euros per LYG and 7370 Euros per QALY. The hsTnT strategy has the highest probability of being cost effective at thresholds between 8000 and 20000 Euros per QALY. The combination of hsTnT and h-FABP strategy's probability of being cost effective remains lower than hsTnT at all willingness to pay thresholds.Conclusion: Our analysis suggests that hsTnT assay is a very cost effective diagnostic tool relative to conventional TnT assay. Combination of hsTnT and H-FABP does not offer any additional economic and health benefit over hsTnT test alone

The effect of exercise training on the course of cardiac troponin T and i levels: Three independent training studies

With the introduction of high-sensitive assays, cardiac troponins became potential biomarkers for risk stratification and prognostic medicine. Observational studies have reported an inverse association between physical activity and basal cardiac troponin levels. However, causality has never been demonstrated. This study investigated whether basal cardiac troponin concentrations are receptive to lifestyle interventions such as exercise training. Basal high-sensitive cardiac troponin T ( cTnT ) and I ( cTnI ) were monitored in two resistance-type exercise training programs ( 12-week ( study 1 ) and 24-week ( study 2 ) ) in older adults ( ≥65 years ). In addition, a retrospective analysis for high sensitive troponin I in a 24-week exercise controlled trial in ( pre )frail older adults was performed ( study 3 ). In total, 91 subjects were included in the final data analyses. There were no significant changes in cardiac troponin levels over time in study 1 and 2 ( study 1: cTnT −0.13 ( −0.33–+0.08 ) ng/L/12-weeks, cTnI −0.10 ( −0.33–+0.12 ) ng/L/12-weeks; study 2: cTnT −1.99 ( −4.79–+0.81 ) ng/L/24-weeks, cTnI −1.59 ( −5.70–+2.51 ) ng/L/24-weeks ). Neither was there a significant interaction between training and the course of cardiac troponin in study 3 ( p = 0.27 ). In conclusion, this study provides no evidence that prolonged resistance-type exercise training can modulate basal cardiac troponin levels

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

BackgroundAlthough 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 DesignIn 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.ConclusionThe 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