Publications by authors named "Otto Bekers"

97 Publications

Meta-Analysis Evaluating High-Sensitivity Cardiac Troponin T Kinetics after Coronary Artery Bypass Grafting in Relation to the Current Definitions of Myocardial Infarction.

Am J Cardiol 2022 01 8;163:25-31. Epub 2021 Nov 8.

Department of Central Diagnostic Laboratory; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.

Various definitions of myocardial infarction type 5 after coronary artery bypass grafting (CABG) have been proposed (myocardial infarction [MI-5], also known as peri-procedural MI), using different biomarkers and different and arbitrary cut-off values. This meta-analysis aims to determine the expected release of high-sensitivity cardiac troponin T (hs-cTnT) after CABG in general and after uncomplicated surgery and off-pump CABG in particular. A systematic search was applied to 3 databases. Studies on CABG as a single intervention and reporting on postoperative hs-cTnT concentrations on at least 2 different time points were included. All data on hs-cTnT concentrations were extracted, and mean concentrations at various points in time were stratified. Eventually, 15 studies were included, encompassing 2,646 patients. Preoperative hs-cTnT was 17 ng/L (95% confidence interval [CI] 13 to 20 ng/L). Hs-cTnT peaked at 6 to 8 hours postoperatively (628 ng/L, 95% CI 400 to 856 ng/L; 45x upper reference limit [URL]) and was still increased after 48 hours. In addition, peak hs-cTnT concentration was 614 ng/L (95% CI 282 to 947 ng/L) in patients with a definite uncomplicated postoperative course (i.e., without MI). For patients after off-pump CABG compared to on-pump CABG, the mean peak hs-cTnT concentration was 186 ng/L (95% CI 172 to 200 ng/L, 13 × URL) versus 629 ng/L (95% CI 529 to 726 ng/L, 45 × URL), respectively. In conclusion, postoperative hs-cTnT concentrations surpass most of the currently defined cut-off values for MI-5, even in perceived uncomplicated surgery, suggesting thorough reassessment. Hs-cTnT release differences following on-pump CABG versus off-pump CABG were observed, implying the need for different cut-off values for different surgical strategies.
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http://dx.doi.org/10.1016/j.amjcard.2021.09.049DOI Listing
January 2022

Role of Drug-Gene Interactions and Pharmacogenetics in Simvastatin-Associated Pulmonary Toxicity.

Drug Saf 2021 Nov 4;44(11):1179-1191. Epub 2021 Oct 4.

ILD Care Foundation Research Team, Ede, The Netherlands.

Introduction: Simvastatin has previously been associated with drug-induced interstitial lung disease. In this retrospective observational study, cases with non-specific interstitial pneumonia (NSIP) or idiopathic pulmonary fibrosis (IPF) with simvastatin-associated pulmonary toxicity (n = 34) were evaluated.

Objective: To identify whether variations in genes encoding cytochrome P450 (CYP) enzymes or in the SLCO1B1 gene (Solute Carrier Organic anion transporting polypeptide 1B1 gene, encoding the organic anion transporting polypeptide 1B1 [OATP1B1] drug transporter enzyme), and/or characteristics of concomitantly used drugs, predispose patients to simvastatin-associated pulmonary toxicity.

Methods: Characteristics of concomitantly used drugs and/or variations in the CYP or SLCO1B1 genes and drug-gene interactions were assessed. The outcome after withdrawal of simvastatin and/or switch to another statin was assessed after 6 months.

Results: Multiple drug use involving either substrates and/or inhibitors of CYP3A4 and/or three or more drugs with the potential to cause acidosis explained the simvastatin-associated toxicity in 70.5% (n = 24) of cases. Cases did not differ significantly from controls regarding CYP3A4, CYP2C9, or OATP1B1 phenotypes, and genetic variation explained only 20.6% (n = 7) of cases. Withdrawal of simvastatin without switching to another statin or with a switch to a hydrophilic statin led to improvement or stabilization in all NSIP cases, whereas all cases who were switched to the lipophilic atorvastatin progressed.

Conclusion: Simvastatin-associated pulmonary toxicity is multifactorial. For patients with this drug-induced pulmonary toxicity who need to continue taking a statin, switching to a hydrophilic statin should be considered. CLINICALTRIALS.

Gov Identifier: NCT00267800, registered in 2005.
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http://dx.doi.org/10.1007/s40264-021-01105-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553720PMC
November 2021

Differential Impact of Cytochrome 2C19 Allelic Variants on Three Different Platelet Function Tests in Clopidogrel-Treated Patients.

J Clin Med 2021 Sep 3;10(17). Epub 2021 Sep 3.

Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The Netherlands.

On-treatment platelet reactivity in clopidogrel-treated patients can be measured with several platelet function tests (PFTs). However, the agreement between different PFTs is only slight to moderate. Polymorphisms of the gene have an impact on the metabolization of clopidogrel and, thereby, have an impact on on-treatment platelet reactivity. The aim of the current study is to evaluate the differential effects of the genotype on three different PFTs.

Methods: From a prospective cohort study, we included patients treated with clopidogrel following percutaneous coronary intervention (PCI). One month after PCI, we simultaneously performed three different PFTs; light transmission aggregometry (LTA), VerifyNow P2Y12, and Multiplate. In whole EDTA blood, genotyping of the polymorphisms was performed.

Results: We included 308 patients treated with clopidogrel in combination with aspirin (69.5%) and/or anticoagulants (33.8%) and, based on genotyping, classified them as either extensive (36.4%), rapid (34.7%), intermediate (26.0%), or poor metabolizers (2.9%). On-treatment platelet reactivity as measured by LTA and VerifyNow is significantly affected by metabolizer status ( < 0.01); as metabolizer status changes from rapid, via extensive and intermediate, to poor, the mean platelet reactivity increases accordingly ( < 0.01). On the contrary, for Multiplate, no such ordering of metabolizer groups was found ( = 0.10).

Conclusions: For VerifyNow and LTA, the on-treatment platelet reactivity in clopidogrel-treated patients correlates well with the underlying polymorphism. For Multiplate, no major effect of genetic background could be shown, and effects of other (patient-related) variables prevail. Thus, besides differences in test principles and the influence of patient-related factors, the disagreement between PFTs is partly explained by differential effects of the genotype.
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http://dx.doi.org/10.3390/jcm10173992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432532PMC
September 2021

Machine learning-based glucose prediction with use of continuous glucose and physical activity monitoring data: The Maastricht Study.

PLoS One 2021 24;16(6):e0253125. Epub 2021 Jun 24.

CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.

Background: Closed-loop insulin delivery systems, which integrate continuous glucose monitoring (CGM) and algorithms that continuously guide insulin dosing, have been shown to improve glycaemic control. The ability to predict future glucose values can further optimize such devices. In this study, we used machine learning to train models in predicting future glucose levels based on prior CGM and accelerometry data.

Methods: We used data from The Maastricht Study, an observational population-based cohort that comprises individuals with normal glucose metabolism, prediabetes, or type 2 diabetes. We included individuals who underwent >48h of CGM (n = 851), most of whom (n = 540) simultaneously wore an accelerometer to assess physical activity. A random subset of individuals was used to train models in predicting glucose levels at 15- and 60-minute intervals based on either CGM data or both CGM and accelerometer data. In the remaining individuals, model performance was evaluated with root-mean-square error (RMSE), Spearman's correlation coefficient (rho) and surveillance error grid. For a proof-of-concept translation, CGM-based prediction models were optimized and validated with the use of data from individuals with type 1 diabetes (OhioT1DM Dataset, n = 6).

Results: Models trained with CGM data were able to accurately predict glucose values at 15 (RMSE: 0.19mmol/L; rho: 0.96) and 60 minutes (RMSE: 0.59mmol/L, rho: 0.72). Model performance was comparable in individuals with type 2 diabetes. Incorporation of accelerometer data only slightly improved prediction. The error grid results indicated that model predictions were clinically safe (15 min: >99%, 60 min >98%). Our prediction models translated well to individuals with type 1 diabetes, which is reflected by high accuracy (RMSEs for 15 and 60 minutes of 0.43 and 1.73 mmol/L, respectively) and clinical safety (15 min: >99%, 60 min: >91%).

Conclusions: Machine learning-based models are able to accurately and safely predict glucose values at 15- and 60-minute intervals based on CGM data only. Future research should further optimize the models for implementation in closed-loop insulin delivery systems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253125PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224858PMC
November 2021

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

Adv Exp Med Biol 2021 ;1306:41-59

Unit of Clinical Chemistry, Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.

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.
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http://dx.doi.org/10.1007/978-3-030-63908-2_4DOI Listing
May 2021

A comparison of machine learning models versus clinical evaluation for mortality prediction in patients with sepsis.

PLoS One 2021 19;16(1):e0245157. Epub 2021 Jan 19.

Department of Clinical Chemistry, Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands.

Introduction: Patients with sepsis who present to an emergency department (ED) have highly variable underlying disease severity, and can be categorized from low to high risk. Development of a risk stratification tool for these patients is important for appropriate triage and early treatment. The aim of this study was to develop machine learning models predicting 31-day mortality in patients presenting to the ED with sepsis and to compare these to internal medicine physicians and clinical risk scores.

Methods: A single-center, retrospective cohort study was conducted amongst 1,344 emergency department patients fulfilling sepsis criteria. Laboratory and clinical data that was available in the first two hours of presentation from these patients were randomly partitioned into a development (n = 1,244) and validation dataset (n = 100). Machine learning models were trained and evaluated on the development dataset and compared to internal medicine physicians and risk scores in the independent validation dataset. The primary outcome was 31-day mortality.

Results: A number of 1,344 patients were included of whom 174 (13.0%) died. Machine learning models trained with laboratory or a combination of laboratory + clinical data achieved an area-under-the ROC curve of 0.82 (95% CI: 0.80-0.84) and 0.84 (95% CI: 0.81-0.87) for predicting 31-day mortality, respectively. In the validation set, models outperformed internal medicine physicians and clinical risk scores in sensitivity (92% vs. 72% vs. 78%;p<0.001,all comparisons) while retaining comparable specificity (78% vs. 74% vs. 72%;p>0.02). The model had higher diagnostic accuracy with an area-under-the-ROC curve of 0.85 (95%CI: 0.78-0.92) compared to abbMEDS (0.63,0.54-0.73), mREMS (0.63,0.54-0.72) and internal medicine physicians (0.74,0.65-0.82).

Conclusion: Machine learning models outperformed internal medicine physicians and clinical risk scores in predicting 31-day mortality. These models are a promising tool to aid in risk stratification of patients presenting to the ED with sepsis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245157PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815112PMC
May 2021

Mass Spectrometry Spatial-Omics on a Single Conductive Slide.

Anal Chem 2021 02 7;93(4):2527-2533. Epub 2021 Jan 7.

Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.

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.
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http://dx.doi.org/10.1021/acs.analchem.0c04572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859928PMC
February 2021

Serial measurements in COVID-19-induced acute respiratory disease to unravel heterogeneity of the disease course: design of the Maastricht Intensive Care COVID cohort (MaastrICCht).

BMJ Open 2020 09 29;10(9):e040175. Epub 2020 Sep 29.

Department of Intensive Care, Maastricht University Medical Center+, Maastricht, The Netherlands.

Introduction: The course of the disease in SARS-CoV-2 infection in mechanically ventilated patients is unknown. To unravel the clinical heterogeneity of the SARS-CoV-2 infection in these patients, we designed the prospective observational Maastricht Intensive Care COVID cohort (MaastrICCht). We incorporated serial measurements that harbour aetiological, diagnostic and predictive information. The study aims to investigate the heterogeneity of the natural course of critically ill patients with a SARS-CoV-2 infection.

Methods And Analysis: Mechanically ventilated patients admitted to the intensive care with a SARS-CoV-2 infection will be included. We will collect clinical variables, vital parameters, laboratory variables, mechanical ventilator settings, chest electrical impedance tomography, ECGs, echocardiography as well as other imaging modalities to assess heterogeneity of the course of a SARS-CoV-2 infection in critically ill patients. The MaastrICCht is also designed to foster various other studies and registries and intends to create an open-source database for investigators. Therefore, a major part of the data collection is aligned with an existing national intensive care data registry and two international COVID-19 data collection initiatives. Additionally, we create a flexible design, so that additional measures can be added during the ongoing study based on new knowledge obtained from the rapidly growing body of evidence. The spread of the COVID-19 pandemic requires the swift implementation of observational research to unravel heterogeneity of the natural course of the disease of SARS-CoV-2 infection in mechanically ventilated patients. Our study design is expected to enhance aetiological, diagnostic and prognostic understanding of the disease. This paper describes the design of the MaastrICCht.

Ethics And Dissemination: Ethical approval has been obtained from the medical ethics committee (Medisch Ethische Toetsingscommissie 2020-1565/3 00 523) of the Maastricht University Medical Centre+ (Maastricht UMC+), which will be performed based on the Declaration of Helsinki. During the pandemic, the board of directors of Maastricht UMC+ adopted a policy to inform patients and ask their consent to use the collected data and to store serum samples for COVID-19 research purposes. All study documentation will be stored securely for fifteen years after recruitment of the last patient. The results will be published in peer-reviewed academic journals, with a preference for open access journals, while particularly considering deposition of the manuscripts on a preprint server early.

Trial Registration Number: The Netherlands Trial Register (NL8613).
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http://dx.doi.org/10.1136/bmjopen-2020-040175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526030PMC
September 2020

Sex-specific effects of implementing a high-sensitivity troponin I assay in patients with suspected acute coronary syndrome: results from SWEDEHEART registry.

Sci Rep 2020 09 17;10(1):15227. Epub 2020 Sep 17.

Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.

Using high-sensitivity cardiac troponin (hs-cTn) assays with sex-specific 99th percentiles may improve management of patients with suspected acute myocardial infarction (AMI). We investigated the impact of transitioning from a conventional troponin I assay to a high-sensitivity assay with sex-specific thresholds, in patients with suspected acute coronary syndrome admitted to Swedish coronary care units. Based on data from SWEDEHEART registry (females, n = 4,819/males, n = 7,670), we compared periods before and after implementation of hs-cTnI assay (Abbott) using sex-specific 99th percentiles. We investigated differences on discharge diagnosis, in-hospital examinations, treatments, and clinical outcome. Upon implementation of the hs-cTnI assay, proportion of patients with troponin levels above diagnostic AMI threshold increased in women and men by 24.3% versus 14.8%, respectively. Similarly, incidence of AMI increased by 11.5% and 9.8%. Diagnostic interventions and treatments increased regardless of sex. However, these associations did not persist following multivariable adjustment, probably due to the effect of temporal management trends during the observation period. Overall, no risk reduction on major adverse cardiovascular events was observed (HR: 0.91 [95% CI 0.80-1.03], P = 0.126). The implementation of hs-cTnI assay together with sex-specific 99th percentiles was associated with an increase in incidence of AMI regardless of sex, but had no major impact on clinical management and prognosis.
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http://dx.doi.org/10.1038/s41598-020-72204-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499170PMC
September 2020

Influence of CYP3A5 Genetic Polymorphism on Long-Term Renal Function in Chinese Kidney Transplant Recipients Using Limited Sampling Strategy and Abbreviated Area Under the Curve for Tacrolimus Monitoring.

Prog Transplant 2020 09 17;30(3):249-253. Epub 2020 Jun 17.

Department of Internal Medicine, 199236Maastricht University Medical Centre, Maastricht, the Netherlands.

Introduction: Although the association between CYP3A5 gene polymorphism and tacrolimus dosing requirements was well established, the impact on how CYP3A5 genotype affects the acute rejection and long-term renal function in patients who received kidney transplants and were treated with tacrolimus remained controversial.

Design: Sixty-seven Chinese patients with kidney transplants receiving de novo tacrolimus-based immunosuppressive therapy with known CYP3A5 genotype were divided into 2 groups. Those with at least 1 CYP3A5*1 allele were CYP3A5 expressers while homozygotes for the mutant allele CYP3A5*3 were nonexpressers. Instead of trough level, our center used abbreviated area under the curve for tacrolimus monitoring. Primary outcome was the long-term renal function between both groups while secondary outcomes included the weight-adjusted daily tacrolimus dose, graft survival, incidence of biopsy-proven acute rejection (BPAR), opportunistic infection, and cancer.

Results: Thirty-five (52.2%) patients were CYP3A5 expressers while 32 were nonexpressers. Mean daily tacrolimus dose in the CYP3A5 expressers and nonexpressers was 0.08 (0.03) and 0.05 (0.02) mg/kg, respectively ( < .01). Starting from 1-month posttransplant, the renal function was comparable between both groups, which persisted up to 10-year. Ten patients experienced BPAR rejection and there was no significant difference in the rejection-free survival between both groups ( = .87). There was also no significant difference in the death-censored graft survival between both groups ( = .86). Finally, the incidence of opportunistic infection and posttransplant cancer was similar between them.

Discussion: There was no significant difference in renal function, graft survival, and acute rejection between CYP3A5 expressers and nonexpressers.
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http://dx.doi.org/10.1177/1526924820933823DOI Listing
September 2020

Associations of 24-Hour Urinary Sodium and Potassium Excretion with Cardiac Biomarkers: The Maastricht Study.

J Nutr 2020 06;150(6):1413-1424

Division of Nephrology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, Netherlands.

Background: It is a matter of debate whether sodium and potassium intake are associated with heart disease. Further, the mechanisms underlying associations of sodium and potassium intake with cardiac events, if any, are not fully understood.

Objectives: We examined cross-sectional associations of 24-h urinary sodium excretion (UNaE) and potassium excretion (UKE), as estimates of their intakes, with high-sensitivity cardiac troponins T (hs-cTnT) and I (hs-cTnI), and N-terminal pro-B-type natriuretic peptide (NT-proBNP), which are markers of cardiomyocyte injury and cardiac dysfunction.

Methods: We included 2961 participants from the population-based Maastricht Study (mean ± SD age 59.8 ± 8.2 y, 51.9% men), who completed the baseline survey between November 2010 and September 2013. Associations were examined with restricted cubic spline linear regression analyses and ordinary linear regression analyses, adjusted for demographics, lifestyle, and cardiovascular disease (CVD) risk factors.

Results: Median [IQR] 24-h UNaE and UKE were 3.7 [2.8-4.7] g/24 h and 3.0 [2.4-3.6] g/24 h, respectively. After adjustment for potential confounders, 24-h UNaE was not associated with hs-cTnT, hs-cTnI, and NT-proBNP concentrations. In contrast, after adjustment for potential confounders, lower 24-h UKE was nonlinearly associated with higher hs-cTnT and NT-proBNP. For example, as compared with the third/median quintile of 24-h UKE (range: 2.8-3.2 g/24 h), participants in the first quintile (range: 0.5-2.3 g/24 h) had 1.05 (95% CI: 0.99, 1.11) times higher hs-cTnT and 1.14 (95% CI: 1.03, 1.26) times higher NT-proBNP. Associations were similar after further adjustment for estimated glomerular filtration rate, albuminuria, blood pressure, and serum potassium.

Conclusions: Twenty-four-hour UNaE was not associated with the studied cardiac biomarkers. In contrast, lower 24-h UKE was nonlinearly associated with higher hs-cTnT and NT-proBNP. This finding supports recommendations to increase potassium intake in the general population. In addition, it suggests that cardiac dysfunction and/or cardiomyocyte injury may underlie previously reported associations of lower potassium intake with CVD mortality.
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http://dx.doi.org/10.1093/jn/nxaa080DOI Listing
June 2020

Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers.

Int J Mol Sci 2020 Apr 16;21(8). Epub 2020 Apr 16.

ild Care Foundation Research Team, 6711 NR Ede, The Netherlands.

Drugs are serious but underestimated causative agents of interstitial lung disease (ILD). Both cytotoxic and immune mechanisms may be involved in drug-induced ILD (DI-ILD). We aimed to investigate whether polymorphisms of relevant CYP enzymes involved in the metabolization of tamsulosin might explain the pathologic mechanism of the DI-ILD in the cases with suspected tamsulosin DI-ILD. We collected 22 tamsulosin-associated DI-ILD cases at two ILD Expertise Centers in the Netherlands between 2009 and 2020. CYP2D6, CYP2C9, CYP2C19, CYP3A4, and CYP3A5 single nucleotide polymorphisms were genotyped and compared with a control group of 78 healthy Caucasian male volunteers. Nine cases were phenotyped as CYP2D6 poor metabolizers and 13 as CYP2D6 intermediate metabolizers. The phenotypes of the cases differed significantly from those of the healthy controls, with more poor metabolizers. After withdrawal of tamsulosin, the pulmonary condition of three cases had improved, six patients had stabilized, and one patient stabilized after reducing the tamsulosin dose. The described 22 cases suggest that an association between the presence of CYP2D6 allelic variants and tamsulosin-associated ILD is highly likely. These cases highlight the importance of both clinical and genetic risk stratification aimed to achieve a more accurate prevention of DI-ILD in the future and enhance the quality of life of patients.
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http://dx.doi.org/10.3390/ijms21082770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215842PMC
April 2020

Biotin interference in high-sensitivity cardiac troponin T testing: a real-world evaluation in acute cardiac care.

Cardiovasc Res 2019 Dec;115(14):1950-1951

Central Diagnostic Laboratory, Department of Clinical Chemistry, Maastricht University Medical Center, Maastricht, The Netherlands.

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http://dx.doi.org/10.1093/cvr/cvz277DOI Listing
December 2019

Cardiac Troponin T: Only Small Molecules in Recreational Runners After Marathon Completion.

J Appl Lab Med 2019 03 6;3(5):909-911. Epub 2018 Sep 6.

Central Diagnostic Laboratory Maastricht University Medical Center Maastricht, the Netherlands

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http://dx.doi.org/10.1373/jalm.2018.027144DOI Listing
March 2019

Longitudinal changes in placental biomarkers in women with early versus late placental dysfunction.

Hypertens Pregnancy 2019 Nov 27;38(4):268-277. Epub 2019 Sep 27.

Department of Obstetrics & Gynecology, Maastricht University Medical Centre (MUMC+) , Maastricht , The Netherlands.

: To evaluate longitudinal changes of angiogenic biomarkers in early- (EO-PD) versus late-onset (LO-PD) placental dysfunction. : Serum PlGF and sFlt-1 measured at different intervals in EO-PD (n= 43), LO-PD (n= 31) and controls (n = 133). : sFlt-1/PlGF ratio was higher at 16 weeks (30.6 vs 17.5), 20 weeks (29.3 vs 8.9) and 30 weeks (16.6 vs 6.7) in EO-PD vs controls (all p< 0.05), but not in LO-PD. Longitudinal changes for all intervals had higher AUC than single measurements. : Longitudinal biomarker change between 12 and 30 weeks could improve prediction of EO-PD compared to single measurements.
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http://dx.doi.org/10.1080/10641955.2019.1668948DOI Listing
November 2019

Drug-induced interstitial lung disease: role of pharmacogenetics in predicting cytotoxic mechanisms and risks of side effects.

Curr Opin Pulm Med 2019 09;25(5):468-477

ILD Care Foundation Research Team, Ede, The Netherlands.

Purpose Of Review: The diagnosis of drug-induced interstitial lung disease (DI-ILD) is challenging and mainly made by exclusion of other possible causes. Toxicity can occur as a cause of drug(s) or drug-drug interactions. In this review, we summarize the possible role of pharmacogenetics of metabolizing enzymes in DI-ILD.

Recent Findings: Knowledge of the genetic predispositions of enzymes involved in drug metabolization and their relation with proposed cytotoxic mechanisms of DI-ILD, in particular direct cell toxicity and free oxygen radical production is increasing. The cytochrome P450 enzyme family and other enzymes play an important role in the metabolism of all sorts of ingested, injected, or inhaled xenobiotic substances. The liver is the major site for metabolism. Metabolic cytotoxic mechanisms have however also been detected in lung tissue. Polymorphisms in genes coding for enzymes that influence metabolic activity may lead to localized (toxic) reactions and tissue damage. This knowledge may be helpful in preventing the risk of DI-ILD.

Summary: Drug toxicity can be the consequence of absence or very poor enzyme activity, especially if no other metabolic route is available. In the case of reduced enzyme activity, it is recommended to reduce the dose or to prescribe an alternative drug, which is metabolized by a different, unaffected enzyme system to prevent toxic side effects. However, enhanced enzyme activity may lead to excessive formation of toxic and sometimes reactive metabolites. Therefore, knowing a patient's drug-metabolizing profile before drug prescription is a promising way to prevent or explain DI-ILD.
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http://dx.doi.org/10.1097/MCP.0000000000000590DOI Listing
September 2019

Multi-Site Coronary Vein Sampling Study on Cardiac Troponin T Degradation in Non-ST-Segment-Elevation Myocardial Infarction: Toward a More Specific Cardiac Troponin T Assay.

J Am Heart Assoc 2019 07 4;8(14):e012602. Epub 2019 Jul 4.

2 Central Diagnostic Laboratory Maastricht University Medical Center Maastricht The Netherlands.

Background Cardiac troponin T ( cTnT ) is seen in many other conditions besides myocardial infarction, and recent studies demonstrated distinct forms of cTnT . At present, the in vivo formation of these different cTnT forms is incompletely understood. We therefore performed a study on the composition of cTnT during the course of myocardial infarction, including coronary venous system sampling, close to its site of release. Methods and Results Baseline samples were obtained from multiple coronary venous system locations, and a peripheral artery and vein in 71 non- ST -segment-elevation myocardial infarction patients. Additionally, peripheral blood was drawn at 6- and 12-hours postcatheterization. cTnT concentrations were measured using the high-sensitivity- cTnT immunoassay. The cTnT composition was determined via gel filtration chromatography and Western blotting in an early and late presenting patient. High-sensitivity - cTnT concentrations were 28% higher in the coronary venous system than peripherally (n=71, P<0.001). Coronary venous system samples demonstrated cT n T-I-C complex, free intact cTnT , and 29 kD a and 15 to 18 kD a cTnT fragments, all in higher concentrations than in simultaneously obtained peripheral samples. While cT n T-I-C complex proportionally decreased, and disappeared over time, 15 to 18 kD a cTnT fragments increased. Moreover, cT n T-I-C complex was more prominent in the early than in the late presenting patient. Conclusions This explorative study in non- ST -segment-elevation myocardial infarction shows that cTnT is released from cardiomyocytes as a combination of cT n T-I-C complex, free intact cTnT , and multiple cTnT fragments indicating intracellular cTnT degradation. Over time, the cT n T-I-C complex disappeared because of in vivo degradation. These insights might serve as a stepping stone toward a high-sensitivity- cTnT immunoassay more specific for myocardial infarction.
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http://dx.doi.org/10.1161/JAHA.119.012602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662151PMC
July 2019

Impact of CYP3A5 Genetic Polymorphism on Intrapatient Variability of Tacrolimus Exposure in Chinese Kidney Transplant Recipients.

Transplant Proc 2019 Jul - Aug;51(6):1754-1757. Epub 2019 Jun 27.

Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: Although high tacrolimus (FK) intrapatient variability (IPV) was shown to be associated with poor graft outcome in kidney transplant recipients (KTRs), it is uncertain whether there is any association between the CYP3A5 genotype and IPV of FK concentrations. Instead of trough level, we use calculated abbreviated AUC to investigate the impact of CYP3A5 genetic polymorphism on IPV of FK pharmacokinetics.

Methods: We conducted a retrospective, single-center study of 86 adult Chinese KTRs with known CYP3A5 genotype. Coefficient of variation (CV) was used for the quantification of FK IPV. CV of dose-normalized FK AUC was calculated and was compared between the CYP3A5 expresser group and nonexpresser group.

Results: Forty-one patients (47.7%) were classified as CYP3A5 expressers while 45 were nonexpressers. No significant differences in the baseline characteristics were found between expressers and nonexpressers. CYP3A5 expressers required 1.8 times higher FK dose compared with the nonexpressers. There was no significant difference in the FK CV between CYP3A5 expressers (18.2 ± 7.5%) and nonexpressers (16.7 ± 5.7%) (P = .31).

Conclusion: The IPV of FK exposure was not associated with CYP3A5 genotype in stable KTRs. Further studies should focus on other factors such as medication nonadherence, which may explain FK IPV.
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http://dx.doi.org/10.1016/j.transproceed.2019.04.019DOI Listing
November 2019

Can Fetal Growth Velocity and First Trimester Maternal Biomarkers Improve the Prediction of Small-for-Gestational Age and Adverse Neonatal Outcome?

Fetal Diagn Ther 2019 8;46(4):274-284. Epub 2019 May 8.

Department of Obstetrics and Gynecology, GROW School of Oncology and Developmental Biology, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands.

Background And Objectives: The aim of this study was to evaluate the value of adding fetal growth velocity and first trimester maternal biomarkers to baseline screening, for the prediction of small-for-gestational age (SGA) and adverse neonatal outcomes.

Method: A retrospective cohort study was conducted of singleton pregnancies in the Maastricht University Medical Centre between 2012 and 2016. The biomarkers PAPP-A, β-hCG, PlGF, and sFlt-1 were measured at 11-13 weeks of gestational age (GA) and two fetal growth scans were performed (18-22 and 30-34 weeks of GA). Differences in biomarkers and growth velocities were compared between appropriate-for-gestational age (AGA; birth weight percentile 10-90) and SGA (birth weight percentile <10). Combinations of the biomarkers and fetal growth velocity were added to baseline screening for the prediction of SGA and adverse neonatal outcome.

Results: We included 296 singleton pregnancies. Compared to AGA (n = 251), SGA neonates (n = 45) had significantly lower growth velocities in the abdominal circumference (mm/week): 10.1 ± 0.98 versus 10.8 ± 0.98, p = 0.001. Compared with AGA, the SGA neonates had higher sFlt-1 multiples of the median (MoM): 0.89 (0.55) versus 0.76 (0.44), p = 0.023, and a higher sFlt-1/PlGF MoM ratio: 1.09 (1.03) versus 0.90 (0.64), p = 0.027. For a 15% false-positive rate, the prediction of SGA neonates increased from 44.8% for the baseline screening model to 56.5% after the addition of fetal growth velocities, and to 73.9% after the further addition of maternal biomarkers (PPV 9.6%, NPV 82.4%). The corresponding AUC for the three models were 0.722, 0.804, and 0.839, respectively. In addition, AGA neonates with reduced fetal growth velocity had more adverse neonatal outcomes compared to the AGA reference group (12.4 vs. 3.9%, p = 0.013).

Conclusions: Combining fetal growth velocity with first trimester biomarkers resulted in a better prediction of SGA compared to baseline screening parameters alone. This approach could possibly result in reduced adverse neonatal outcomes in neonates, who are at a potential risk due to late mild placental dysfunction.
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http://dx.doi.org/10.1159/000499580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878734PMC
March 2020

Trends in mass spectrometry imaging for cardiovascular diseases.

Anal Bioanal Chem 2019 Jul 12;411(17):3709-3720. Epub 2019 Apr 12.

Maastricht MultiModal Molecular Imaging (M4I) Institute, Division of Imaging Mass Spectrometry, Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.

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.
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http://dx.doi.org/10.1007/s00216-019-01780-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594994PMC
July 2019

and Polymorphisms: A Case Report in a Dutch Family with Pulmonary Fibrosis.

Int J Mol Sci 2019 Mar 7;20(5). Epub 2019 Mar 7.

ILD Care Foundation Research Team, 6711 NR Ede, The Netherlands.

Here, we describe a Dutch family with idiopathic pulmonary fibrosis (IPF). We hypothesized that there might be an association between the presence of Vitamin K epoxide reductase complex 1 () and/or cytochrome P450 variant alleles and the early onset of IPF in the members of this family. (rs9923231 and rs9934438) and (rs1799853 and rs1057910) were genotyped in this family, which includes a significant number of pulmonary fibrosis patients. In all family members, at least one of the variant alleles tested was present. The presence of the variant alleles in all of the IPF cases and variants in all but one, which likely leads to a phenotype that is characterized by the early onset and progressive course of IPF. Our findings indicate a role of these allelic variants in (familial) IPF. Therefore, we suggest that the presence of these variants, in association with other pathogenic mutations, should be evaluated during genetic counselling. Our findings might have consequences for the lifestyle of patients with familial IPF in order to prevent the disease from becoming manifest.
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http://dx.doi.org/10.3390/ijms20051160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429271PMC
March 2019

Cross-Sectional Associations Between Cardiac Biomarkers, Cognitive Performance, and Structural Brain Changes Are Modified by Age.

Arterioscler Thromb Vasc Biol 2018 08;38(8):1948-1958

From the Department of Internal Medicine (M.G.J.V., R.M.A.H., M.T.S., M.J.M.v.A., C.J.H.v.d.K., S.J.S.S., A.A.K., C.D.A.S.).

Objective- NT-proBNP (N-terminal pro-B-type natriuretic peptide) and cardiac troponin T (cTNT) are associated with cognitive performance. Whether this extends to individuals <60 years of age is unclear. We investigated whether age modified the associations between NT-proBNP and cTNT and cognitive performance and structural brain changes. Approach and Results- In 3011 individuals (60±8 years; 49% women), NT-proBNP and cTNT, memory, information processing speed and executive functioning, grey matter (GM) and white matter, and white matter hyperintensity (WMH) volumes were determined. We used regression, adjusted for educational level, cardiovascular factors, and lifestyle factors, to test whether cross-sectional associations between biomarkers and cognitive performance and structural brain changes were modified by age (<60 versus ≥60 years). ≥60 years, higher NT-proBNP was associated with lower memory (β [SD] per 10-fold higher level [95% confidence interval (CI)], -0.11 [-0.22 to -0.00]), information processing speed (-0.12 [95% CI, -0.21 to -0.03]), executive functioning (-0.12 [95% CI, -0.22 to -0.03]), and smaller GM (β [mL] per 10-fold higher level, -6.89 [95% CI, -11.58 to -2.20]). Additionally, higher cTNT was associated with lower memory (-0.33 [95% CI, -0.53 to -0.12]) and information processing speed (-0.17 [95% CI, -0.3 to -0.01]); with smaller GM (-16.07 [95% CI, -24.90 to -7.24]) and greater WMH (10 WMH per 10-fold higher level, 0.31 [95% CI, 0.10-0.52]). <60 years, NT-proBNP and cTNT were not associated with cognitive performance ( P, <0.10). In contrast, higher NT-proBNP was associated with smaller GM (-7.43 [95% CI, -11.70 to -3.16]) and greater WMH (0.13 [95% CI, 0.01-0.25]; P,>0.10). Higher cTNT was associated with greater WMH (0.18 [95% CI, -0.01 to 0.37]; P,>0.10) but not with GM (0.07 [95% CI, -6.87 to 7.02]; P, <0.10). Conclusions- Biomarkers of cardiac injury are continuously associated with structural brain changes in both older and younger individuals but with poorer cognitive performance only in older individuals. These findings stress the continuous nature of the heart-brain axis in the development of cognitive impairment.
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http://dx.doi.org/10.1161/ATVBAHA.118.311082DOI Listing
August 2018

Sex-Specific Versus Overall Clinical Decision Limits for Cardiac Troponin I and T for the Diagnosis of Acute Myocardial Infarction: A Systematic Review.

Clin Chem 2018 07 29;64(7):1034-1043. Epub 2018 May 29.

Department of Central Diagnostic Laboratory, Clinical Chemistry, Maastricht University Medical Center, Maastricht, the Netherlands;

Background: The overall clinical decision limits of high-sensitivity cardiac troponin I (hs-cTnI; 26 ng/L) and T (hs-cTnT; 14 ng/L) may contribute to underdiagnosis of acute myocardial infarction in women. We performed a systematic review to investigate sex-specific and overall 99th percentiles of hs-cTnI and hs-cTnT derived from healthy reference populations.

Content: We searched in PubMed and EMBASE for original studies, and by screening reference lists. Reference populations designed to establish 99th percentiles of hs-cTnI (Abbott) and/or hs-cTnT (Roche), published between January 2009 and October 2017, were included. Sex-specific and overall 99th percentile values of hs-cTnI and hs-cTnT were compared with overall clinical decision ranges (hs-cTnI, 23-30 ng/L; hs-cTnT, 13-25 ng/L). Twenty-eight studies were included in the systematic review. Of 16 hs-cTnI and 18 hs-cTnT studies, 14 (87.5%) and 11 (61.1%) studies reported lower female-specific hs-cTn cutoffs than overall clinical decision ranges, respectively. Conversely, male-specific thresholds of both hs-cTnI and hs-cTnT were in line with currently used overall thresholds, particularly hs-cTnT (90% concordance). The variation of estimated overall 99th percentiles was much higher for hs-cTnI than hs-cTnT (29.4% vs 80.0% of hs-cTnI and hs-cTnT studies reported values within the current overall clinical decision range, respectively).

Summary: Our data show substantially lower female-specific upper reference limits of hs-cTnI and hs-cTnT than overall clinical decision limits of 26 ng/L and 14 ng/L, respectively. The statistical approach strongly affects the hs-cTnI threshold. Downward adjustment of hs-cTn thresholds in women may be warranted to reduce underdiagnosis of acute myocardial infarction in women.
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http://dx.doi.org/10.1373/clinchem.2018.286781DOI Listing
July 2018

Increase in tacrolimus exposure after steroid tapering is influenced by CYP3A5 and pregnane X receptor genetic polymorphisms in renal transplant recipients.

Nephrol Dial Transplant 2018 09;33(9):1668-1675

Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: Tacrolimus, a drug for prevention of rejection after kidney transplantation, has a narrow therapeutic window and is metabolized by the cytochrome P540 3A (CYP3A) system. Tacrolimus exposure increases after steroid tapering in many patients. The pregnane X receptor (PXR)-a mediator for CYP3A-has a steroid receptor and might regulate CYP3A5 activity depending on single nucleotide polymorphisms (SNPs) of CYP3A5 or PXR. This may contribute to differences in tacrolimus exposure after steroid tapering.

Methods: In a cohort of renal transplant recipients, the influence of CYP3A5 and PXR SNPs (A7635G, C8055T and C25385T) on the dose-normalized Tacrolimus trough concentration (DnC0) and their potential interaction with each other after steroid taper were analysed by linear regression. Eligible were all 83 outpatient renal transplant patients on tacrolimus and steroids in a pharmacokinetic steady state at least 6 weeks after transplantation and whose blood was available for genetic analysis.

Results: Compared with the CYP3A5*1/*3 genotype, the CYP3A5*3/*3 SNP showed a significantly stronger increase in DnC0 after steroid taper (+0.29 µg/L/mg; P = 0.002). Of the tested PXR SNPs, PXR G7635G individuals had a significantly stronger increase in DnC0 (compared with A7635A, +0.31 µg/L/mg; P = 0.02), with a weaker increase in A7635G heterozygotes (+0.17 µg/L/mg; P = 0.124). There was neither interaction nor association between CYP3A5 and PXR SNPs.

Conclusions: The magnitude of the DnC0 increase due to steroid taper after renal transplantation is related to CYP3A5 SNPs. Independently, the PXR G7635G SNP is related to this increase, proving the role of PXR in tacrolimus metabolism.
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http://dx.doi.org/10.1093/ndt/gfy096DOI Listing
September 2018

Mass Spectrometric Identification of Cardiac Troponin T in Urine of Patients Suffering from Acute Myocardial Infarction.

J Appl Lab Med 2018 May;2(6):857-867

Department of Clinical Chemistry, Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, the Netherlands.

Background: Because of its high cardiospecificity, cardiac troponin T (cTnT) is one of the first-choice biomarkers to diagnose acute myocardial infarction (AMI). cTnT is extensively fragmented in serum of patients suffering from AMI. However, it is currently unknown whether all cTnT is completely degraded in the body or whether some cTnT fragments can leave the body via urine. The aim of the present study is to develop a method for the detection of cTnT in urine and to examine whether cTnT is detectable in patient urine.

Methods: Proteins in urine samples of 20 patients were precipitated using a cTnT-specific immunoprecipitation technique and a nonspecific acetonitrile protein precipitation. After in-solution digestion of the precipitated proteins, the resulting peptides were separated and analyzed using HPLC and mass spectrometry with a targeted selected ion monitoring assay with data-dependent tandem mass spectrometry (t-SIM/dd-MS2).

Results: The t-SIM/dd-MS2 assay was validated using a synthetic peptide standard containing 10 specific cTnT peptides of interest and with purified human intact cTnT spiked in urine from healthy individuals. Using this assay, 6 different cTnT-specific peptides were identified in urine samples from 3 different patients, all suffering from AMI.

Conclusions: We show here for the first time that cTnT can be present in the urine of AMI patients using a targeted LC-MS/MS assay. Whether the presence of cTnT in urine reflects a physiological or pathophysiological process still needs to be elucidated.
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http://dx.doi.org/10.1373/jalm.2017.024224DOI Listing
May 2018

Combining High-Sensitivity Cardiac Troponin I and Cardiac Troponin T in the Early Diagnosis of Acute Myocardial Infarction.

Circulation 2018 09;138(10):989-999

2nd Department of Cardiology and School of Medicine with the Division of Dentistry, Zabrze, Medical University of Katowice, Katowice, Poland (B.M., D.K.).

Background: Combining 2 signals of cardiomyocyte injury, cardiac troponin I (cTnI) and T (cTnT), might overcome some individual pathophysiological and analytical limitations and thereby increase diagnostic accuracy for acute myocardial infarction with a single blood draw. We aimed to evaluate the diagnostic performance of combinations of high-sensitivity (hs) cTnI and hs-cTnT for the early diagnosis of acute myocardial infarction.

Methods: The diagnostic performance of combining hs-cTnI (Architect, Abbott) and hs-cTnT (Elecsys, Roche) concentrations (sum, product, ratio, and a combination algorithm) obtained at the time of presentation was evaluated in a large multicenter diagnostic study of patients with suspected acute myocardial infarction. The optimal rule-out and rule-in thresholds were externally validated in a second large multicenter diagnostic study. The proportion of patients eligible for early rule-out was compared with the European Society of Cardiology 0/1 and 0/3 hour algorithms.

Results: Combining hs-cTnI and hs-cTnT concentrations did not consistently increase overall diagnostic accuracy as compared with the individual isoforms. However, the combination improved the proportion of patients meeting criteria for very early rule-out. With the European Society of Cardiology 2015 guideline recommended algorithms and cut-offs, the proportion meeting rule-out criteria after the baseline blood sampling was limited (6% to 24%) and assay dependent. Application of optimized cut-off values using the sum (9 ng/L) and product (18 ng/L) of hs-cTnI and hs-cTnT concentrations led to an increase in the proportion ruled-out after a single blood draw to 34% to 41% in the original (sum: negative predictive value [NPV] 100% [95% confidence interval (CI), 99.5% to 100%]; product: NPV 100% [95% CI, 99.5% to 100%]) and in the validation cohort (sum: NPV 99.6% [95% CI, 99.0-99.9%]; product: NPV 99.4% [95% CI, 98.8-99.8%]). The use of a combination algorithm (hs-cTnI <4 ng/L and hs-cTnT <9 ng/L) showed comparable results for rule-out (40% to 43% ruled out; NPV original cohort 99.9% [95% CI, 99.2-100%]; NPV validation cohort 99.5% [95% CI, 98.9-99.8%]) and rule-in (positive predictive value [PPV] original cohort 74.4% [95% Cl, 69.6-78.8%]; PPV validation cohort 84.0% [95% Cl, 79.7-87.6%]).

Conclusions: New strategies combining hs-cTnI and hs-cTnT concentrations may significantly increase the number of patients eligible for very early and safe rule-out, but do not seem helpful for the rule-in of acute myocardial infarction.

Clinical Trial Registration: URL (APACE): https://www.clinicaltrial.gov . Unique identifier: NCT00470587. URL (ADAPT): www.anzctr.org.au . Unique identifier: ACTRN12611001069943.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032003DOI Listing
September 2018

Increased circulating desmosine and age-dependent elastinolysis in idiopathic pulmonary fibrosis.

Respir Res 2018 03 20;19(1):45. Epub 2018 Mar 20.

Department of Pulmonary Medicine, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532, SZ, Nijmegen, The Netherlands.

Although chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) seem to be opposite entities from a clinical perspective, common initial pathogenic steps have been suggested in both lung diseases. Emphysema is caused by an elastase/anti-elastase imbalance leading to accelerated elastin degradation. Elastinolysis is however, also accelerated in the IPF patients' lungs. The amino acids desmosine and isodesmosine (DES) are unique to elastin. During the degradation process, elastases liberate DES from elastin fibers. Blood DES levels consequently reflect the rate of systemic elastinolysis and are increased in COPD. This is the first report describing elevated DES levels in IPF patients. We also demonstrated that the age-related increment of DES concentrations is enhanced in IPF. Our current study suggests that elastinolysis is a shared pathogenic step in both COPD and IPF. Further investigation is required to establish the relevance of accelerated elastin degradation in IPF and to determine whether decelerating this process leads to slower progression of lung fibrosis and better survival for patients with IPF.
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http://dx.doi.org/10.1186/s12931-018-0747-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859529PMC
March 2018

Biological Variation of Creatinine, Cystatin C, and eGFR over 24 Hours.

Clin Chem 2018 05 26;64(5):851-860. Epub 2018 Feb 26.

Department of Clinical Chemistry, Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, the Netherlands;

Background: Estimated glomerular filtration rate (eGFR) is widely used in clinical practice. This study assessed the within-subject biological variation (CV) of different eGFR equations in people with chronic kidney disease (CKD) and people without CKD. The aims of this study were () to determine the 24-h biological variation profiles of creatinine, cystatin C, and eGFR and () to determine whether CV of creatinine, cystatin C, and eGFR changes on deterioration of glomerular filtration.

Methods: Hourly blood samples were analyzed from 37 individuals (17 without CKD, 20 with CKD) during 24 h. Creatinine (enzymatic method) and cystatin C were measured using a Cobas 8000 (Roche Diagnostics). eGFR was estimated using the Modification of Diet in Renal Disease and the Chronic Kidney Disease Epidemiology Collaboration based on creatinine and/or cystatin C. Plasma samples were stored at -80 °C before analysis. Outlier and homogeneity analyses were checked before performing a nested ANOVA to determine biological variation.

Results: CV of creatinine was higher in people without CKD than in those with CKD (6.4% vs 2.5%) owing primarily to the more profound effect of meat consumption on creatinine variability in individuals with lower baseline creatinine concentrations. Unlike creatinine, cystatin C concentrations were unaffected by meat consumption. Cystatin C showed some diurnal rhythmic variation and less in people with CKD. Reference change values (RCVs) of all eGFR equations were within 13% to 20% in both study groups.

Conclusions: Despite differences in CV of creatinine, the CV and RCV of the eGFR equations were relatively similar for people with or without CKD.
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http://dx.doi.org/10.1373/clinchem.2017.282517DOI Listing
May 2018

The effects of vitamin E or lipoic acid supplementation on oxyphytosterols in subjects with elevated oxidative stress: a randomized trial.

Sci Rep 2017 11 10;7(1):15288. Epub 2017 Nov 10.

Department of Human Biology, NUTRIM school of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.

Despite increased serum plant sterol concentrations after consumption of plant sterol enriched margarines, plasma oxyphytosterol concentrations were not increased in healthy subjects. Here, we assessed plasma oxyphytosterol concentrations and whether they are affected by antioxidants in subjects with elevated oxidative stress. Twenty subjects with impaired glucose tolerance (IGT) or type 2 diabetes (DM2) consumed for 4 weeks placebo, vitamin E (804 mg/d) or lipoic acid capsules (600 mg/d). Plasma and blood cell oxyphytosterol and oxycholesterol concentrations were determined in butylated hydroxytoluene-enriched EDTA plasma via GC-MS. Also, markers reflecting oxidative stress and antioxidant capacity were measured. Plasma oxycampesterol and oxysitosterol concentrations were 122% and 83% higher in IGT or DM2 subjects than in healthy subjects, as determined in an earlier study. Vitamin E or lipoic acid supplementation did not reduce plasma oxyphytosterol and oxycholesterol concentrations, or other markers reflecting oxidative stress or antioxidative capacity. Concentrations of different oxyphytosterols correlated within plasma, and within red blood cells and platelets. However, plasma and blood cell oxyphytosterol levels did not correlate. Although plasma oxyphytosterol concentrations are higher in IGT or DM2 subjects than in healthy subjects, 4-weeks vitamin E or lipoic acid supplementation does not lower plasma oxycholesterol or oxyphytosterol concentrations.
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http://dx.doi.org/10.1038/s41598-017-15615-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681676PMC
November 2017
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