+

WO2009093077A1 - Prédiction d'une fibrillation auriculaire postopératoire - Google Patents

Prédiction d'une fibrillation auriculaire postopératoire Download PDF

Info

Publication number
WO2009093077A1
WO2009093077A1 PCT/GB2009/050060 GB2009050060W WO2009093077A1 WO 2009093077 A1 WO2009093077 A1 WO 2009093077A1 GB 2009050060 W GB2009050060 W GB 2009050060W WO 2009093077 A1 WO2009093077 A1 WO 2009093077A1
Authority
WO
WIPO (PCT)
Prior art keywords
cardiac
metabolite
metabolites
surgery
tissue sample
Prior art date
Application number
PCT/GB2009/050060
Other languages
English (en)
Inventor
Manuel Mayr
Shamil Yusuf
Original Assignee
St. George's Hospital Medical School
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by St. George's Hospital Medical School filed Critical St. George's Hospital Medical School
Publication of WO2009093077A1 publication Critical patent/WO2009093077A1/fr

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6806—Determination of free amino acids
    • G01N33/6812—Assays for specific amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/326—Arrhythmias, e.g. ventricular fibrillation, tachycardia, atrioventricular block, torsade de pointes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease

Definitions

  • the present invention relates to determining susceptibility to and /or time of onset of cardiac arrhythmia, especially atrial fibrillation, in a human patient following cardiac surgery by relying on determining metabolite alterations in a cardiac tissue sample taken from the patient during surgery.
  • this tissue sample may be an atrial sample commonly resected during atrial cannulation for bypass but normally discarded.
  • the levels of metabolites in such a sample associated with glycolytic and lipid metabolism especially for example the ratio of glucose to acetate.
  • Post-operative arrhythmia is a frequent complication of human cardiac surgery.
  • the ability to distinguish susceptibility to arrhythmia ahead of on-set would enable better management of such patients with consequent reduction in patient stay and benefit in surgical success rate.
  • the most common type of arrhythmia is atrial fibrillation (AF) occurring in up to 30% of patients.
  • AF atrial fibrillation
  • AF is a self-perpetuating arrhythmia, i.e. the longer it is present the more persistent it becomes leading to the notion that 'AF begets AF' (Wijffels et al. (1995) Circulation 92, 1954-1968).
  • AF leads to several different forms of re-modelling within atria - electrical, contractile and structural. Electrical and contractile re-modelling appear to be closely related through a down regulation of the L-type Ca 2+ current and are fully reversed within a few days of sinus rhythm being restored. Structural re-modelling on the other hand encompasses a plethora of potentially irreversible intra- and extra-cellular processes. While electrical, structural and contractile remodelling processes are well-recognised contributors to the self-perpetuating nature of AF, the impact of cardiac metabolism upon the initiation of AF has not been explored.
  • the present invention provides a method for determining susceptibility to postoperative cardiac arrhythmia such as atrial fibrillation (AF) in a human patient following cardiac surgery, said method comprising comparing a first metabolic profile of at least two metabolites in a cardiac tissue sample, e.g. an atrial tissue sample, taken from said patient during surgery with a control metabolic profile to be expected in an identical tissue sample but from a cardiac patient who remains in post-operative sinus rhythm, wherein said first metabolic profile is obtained by assessing the levels of metabolites including metabolites of both glycolytic and lipid metabolism, such as the glucose to acetate ratio, but not necessarily excluding other metabolites of cardiac metabolism, and difference between said first metabolic profile and said control metabolic profile is indicative of risk of onset of post-operative arrhythmia.
  • a cardiac tissue sample e.g. an atrial tissue sample
  • a control metabolic profile to be expected in an identical tissue sample but from a cardiac patient who remains in post-operative sinus rhythm
  • said first metabolic profile is obtained by assessing the levels of metabol
  • metabolic interrogation of cardiac tissue samples for the purpose of diagnosis according to the invention may, for example, employ proton NMR, preferably with determination of ratios of principal spectral components as illustrated by the exemplification, more conveniently specific metabolite assays may be employed to target metabolites of interest. Mass spectrometry may also be employed using for example multiple reaction monitoring.
  • the targeted metabolites will include at least one metabolite of glycolytic metabolism, such as glucose, alanine and lactate, and at least one metabolite of lipid metabolism, such as the end product acetate.
  • targeting of other metabolites of cardiac metabolism is not excluded.
  • Targeted metabolites of lipid metabolism in addition or alternatively to acetate might include fatty acids or ketone bodies.
  • a ratio of metabolite levels including or consisting of at least one metabolite of glycolytic metabolism and at least one metabolite of lipid metabolism will be determined, most preferably as indicated above the glucose to acetate ratio and /or the ratio of alanine and lactate to acetate.
  • such ratios can be expected to be reduced in cardiac, e.g. atrial tissue samples, from cardiac surgery patients (e.g. CABG or valve surgery patients) who go on to develop post- operative arrhythmia compared to that to be expected if SR is maintained (determined from control samples).
  • the degree of reduction may be usefully further used to predict time of onset of arrhythmia, e.g. atrial fibrillation, as illustrated by Figure 4B.
  • Assays that might be employed include many widely employed enzymic assays and hence the invention might be conveniently and routinely used to supplement and improve cardiac surgery without any impact on the surgery itself.
  • Figure 1 Representative NMR spectra of atrial appendages.
  • Figure 2 A representation of enzyme and metabolic changes in persistent in AF.
  • the illustration shows the TCA cycle, oxidative phosphorylation and protein and metabolite changes observed in patients with persistent AF.
  • the probability for 3 metabolites to be associated with 3 enzymes out of the 17 differentially expressed proteins by chance was estimated at less than 5%, after running 1 million simulations on Matlab (Mathworks). Each simulation consisted in randomly selecting 3 metabolites out of 24 measured, generating 1500 proteins, randomly associating 300 of them with pairs of metabolites (based on the fact that about 20% of spots on 2D gel maps from human hearts are metabolic enzymes) and randomly selecting 17 of the 1500 proteins. A success was defined as having the 3 selected metabolites associated with at least 3 proteins among the 17 selected.
  • PCA principal component analysis
  • Figure 4 Metabolite ratios. Reduction of the glucose to acetate ratio in patients susceptible to post-operative AF irrespective of the underlying cardiac pathology (A). Positive correlation between the ratio of glycolytic endproducts (alanine, lactate) to endproducts of lipid metabolism (acetate) and the onset of post-operative AF in patients with coronary artery disease (B). Examples
  • Atrial appendages were obtained as surgical specimens from patients undergoing cardiac surgery by use of established procedures as approved by the Local Regional Ethics Committee Board. Informed consent was obtained from all patients recruited into the study. All subjects in the persistent AF cohort had severe non- rheumatic valvular disease as the principle underlying pathology for surgery. Patients in the post-operative AF cohort had undergone either CABG or valve surgery. For comparison, matched patients who remained in sinus rhythm (SR) were screened to ensure they had never experienced AF by direct questioning of symptoms suggestive of such and by the retrospective analysis of all 12 lead electrocardiograms during their entire pre-operative review period. No patients in the SR cohort had ever been or were on any anti-arrhythmic drugs other than beta-blockers or calcium channel blockers.
  • SR sinus rhythm
  • AV nodal blocking agents in the postoperative AF cohort included beta-blockers, calcium channel blockers and digoxin and no subjects in AF were on other anti-arrhythmic drugs at the time of surgery. Tissue was harvested during cannulation of the right atrium for bypass and specimens were immediately snap-frozen and stored in liquid nitrogen.
  • Proteomic analysis was performed as described previously by two-dimensional gel electrophoresis (2-DE) using a broad pH gradient (Marchr et al. (2004) Circ. Res. 94. e87-96; Mayr et al. (2004) Am. J. Phsiol. Heart Circ. Physiol. 287. H937-H945 & H946-H956). Frozen heart samples were pulverized under liquid nitrogen into a fine powder. The resulting powder was homogenized in lysis buffer (9.5 M urea, 2% w/v CHAPS.
  • a protein load of 100 ⁇ g and 400 ⁇ g was applied to each IPG strip using an in-gel re-hydration method.
  • Samples were diluted in re-hydration solution (8 M urea, 0.5% w/v CHAPS, 0.2% w/v DTT, and 0.2 % w/v Pharmalyte pH 3- 10) and re-hydrated overnight in a re-swelling tray.
  • Strips were focused at 0.05 mA/IPG strip for 60 kVh at 20°C.
  • the strips were equilibrated in 6M urea containing 30% v/v glycerol, 2% w/v SDS and 0.01 % w/v Bromophenol blue, with addition of 1 % w/v DTT for 15 min, followed by the same buffer without DTT but with the addition of 4.8% w/v iodoacetamide for 15 min.
  • SDS-PAGE was performed using 12% T (total acrylamide concentration), 2.6% C (degree of cross-linking) polyacrylamide gels without a stacking gel, using the Ettan DALT system. The second dimension was carried out at 10°C and was terminated when the Bromophenol dye front had migrated of the lower end to the gels.
  • MS Mass spectrometry
  • Alpha-cyano-4-hydroxy-cinnaminic acid was applied as matrix. Spectra were internally calibrated using trypsin autolysis products. The resulting peptide masses were searched against databases using the MASCOT program (Perkins et al. (1999) 20, 3551-3567). One missed cleavage per peptide was allowed and carbamidomethylation of cysteine as well as partial oxidation of methionine were assumed.
  • the column was coupled to an electrospray source and spectra were collected from an ion-trap mass analyzer (LCQ Deca XP Plus, Thermo Electron Corporation) using full ion scan mode over the mass-to-charge ⁇ m/z) range 300-1800.
  • MS/MS was performed on the top three ions in each MS scan using the data-dependent acquisition mode with dynamic exclusion enabled.
  • Database search was performed using the TurboSEQUEST software (Bioworks 3.2, Thermo Finnigan). Assignments were accepted when Xcorr score > 1.5 for singly charged ions, > 2.0 for doubly charged ions, and > 2.5 for triply charged ions, along with deltaCN values ⁇ 0.1.
  • PA0001 1 :100, Lab Frontier
  • SOD-1 FL-154, 1 :100, Santa Cruz
  • C-reactive protein, interleukin-6 and tumour necrosis factor- alpha were measured using commercially available assays (Euro/DPC Ltd, Gwynedd, UK) with an Immulite® automated analyser (Euro/DPC Ltd).
  • Pattern recognition Proton NMR spectroscopy metabolic profiles from 1.0 ppm to 4.0 ppm with positive intensities scaled to total intensity in the spectrum were used for generating bucket tables, producing signals of 600 data points. Principal Component Analysis (PCA) reduced the data dimensionality to 10 variables, enough to accurately represent more than 96% of the original data. Linear Discriminant Analysis (LDA), a classification method, was then applied on the new representation of the data. LDA constructs a separating hyperplane from an optimal projection, which maximises the distances between groups while minimizing the distances within the groups. The classification results obtained were validated through a leave-one-out scheme, in which the classifier was trained and tested n times, respectively on n-1 and 1 sample, in order to reduce selection bias.
  • PCA Principal Component Analysis
  • LDA Linear Discriminant Analysis
  • Protein changes in persistent AF To provide insight into the consequences of persistent AF on protein expression, comparison was made of the proteome of atrial appendages from patients in SR and persistent AF. Protein extracts were separated by 2-DE using a broad range pH gradient as described above. 2-DE gels comprised approximately 1500 protein features. Differentially expressed spots were numbered, excised and subject to in-gel tryptic digestion. Protein identifications were made by MALDI-MS.
  • triose phosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase two glycolytic enzymes known to be up- regulated as part of the reprogramming of the human atrial transcriptome in permanent atrial fibrillation (Barth et al. ibid), 3-oxoacid transferase, the key enzyme in the extrahepatic utilization of ketone bodies, and NADH dehydrogenase and ubiquinol cytochrome C reductase, complex I and III of the respiratory chain, both of which are linked via the redox span of the coenzyme Q couple (see Figure 2).
  • Lactate 5 .266 ( ⁇ 1.650) 1 .334 ( ⁇ 0.380) 0.059
  • Tyrosine 0 .015 ( ⁇ 0.004) 0 .012 ( ⁇ 0.009) 0.131
  • PCA proton NMR principal component analysis
  • NS denotes "not significant”
  • ACEI indicates Angiotensin Converting Enzyme Inhibitor
  • AIIR indicates Angiotensin Il Receptor blocker.
  • Lactate 5.266 ( ⁇ 1.650) 1.334 ( ⁇ 0.380) 5. .198 ( ⁇ 0.521 ) 5.224 ( ⁇ 1.856) 0.158 0.084 0.064
  • Glycocholic acid 0.634 ( ⁇ 0.066) 0.61 1 ( ⁇ 0.066) 0 .591 ( ⁇ 0.086) 0.852 ( ⁇ 0.203) 0.400 0.370 0.343
  • Tyrosine 0 .015 ( ⁇ 0.004) 0 .012 ( ⁇ 0 .009) 0 .01 1 ( ⁇ 0 .004) 0 .017 ( ⁇ 0 .007) 0.979 0.842 0.918
  • the ratio of glycolytic endproducts (alanine, lactate) to endproducts of lipid metabolism (acetate) correlated positively to the time of onset of postoperative AF in the CABG group; the lower the ratio of glycolytic endproducts to endproducts of lipid metabolism in human atrial tissue, the earlier the onset of the arrhythmia ( Figure 4B).
  • the higher incidence of postoperative AF in the valve surgery cohort meant that it was excluded from the time of onset analysis.
  • the findings support that metabolite alterations are associated with the onset of arrhythmia post cardiac surgery and that metabolic profiling of cardiac tissue, e.g. atrial tissue obtained during cardiac surgery as result of atrial cannulation, provides a convenient means of assessing susceptibility to post-operative arrhythmia, especially for example atrial fibrillation (AF). While determination of absolute metabolite levels associated with glycolytic and lipid metabolism is of value in such tissue samples, the data now presented supports that metabolite ratios of one or more metabolites of glycolytic metabolism to one or more metabolites of lipid metabolism, e.g. the glucose to acetate ratio, provides a preferred indicator for post-operative arrhythmia irrespective of the underlying pathology.
  • metabolite ratios of one or more metabolites of glycolytic metabolism to one or more metabolites of lipid metabolism e.g. the glucose to acetate ratio
  • Hydrogen peroxide reacts with reduced O-dianisidine in the presence of peroxidase to form a coloured product.
  • Oxidized o-dianisidine reacts with sulfuric acid to form a more stable coloured product.
  • the intensity of the colour measured at 540 nm is proportional to the original glucose concentration.
  • Non-esterified fatty acids when treated with acyl-CoA synthetase (ACS) in the presence of adenosine triphosphate (ATP), magnesium cations and CoA, form the thiol esters of CoA known as acyl-CoA as well as the byproducts adenosine monophosphate (AMP) and pyrophosphate (PPi).
  • ACS acyl-CoA synthetase
  • ATP adenosine triphosphate
  • AMP adenosine monophosphate
  • PPi pyrophosphate
  • the acyl-CoA is oxidized by added acyl-CoA oxidase (ACOD) to produce hydrogen peroxide which in the presence of added peroxidase (POD) allows the oxidative condensation of 3-methyl-N-ethyl-N-(beta-hydroxy- ethyl) -aniline (MEHA) with 4- aminoanti pyrine to form a purple coloured adduct with an absorption maximum at 550 nm.
  • the amount of NEFA in the sample can be determined from the optical density measured at 550 nm.
  • Ascorbic acid (vitamin C) existing in the sample would be expected to cause significant interference due to its biological role as an antioxidant and known ability to react with hydrogen peroxide. Therefore, ascorbate oxidase (AOD) is added to the reaction mixture at the outset to conveniently and completely remove all ascorbic acid from the sample.
  • AOD ascorbate oxidase
  • ketone bodies (Autokit total ketone bodies, Wako, Germany): Acetoacetate and 3-hydroxybutyrate in the sample are converted to 3-hydroxybutyrate and acetoacetate, respectively, in the presence of 3-hydroxybutyrate dehydrogenase, NADH and Thio-NAD. 3-hydroxybutyrate and acetoacetate produced in the enzymatic reactions are, then, converted to acetoacetate and 3-hydroxybutyrate, respectively. During these cyclic reactions, NAD and Thio-NADH are produced. By measuring the rate of Thio-NADH production spectrophotometrically, the concentration of total ketone bodies in the sample is determined.
  • metabolite profiling in cardiac tissue specimens could be performed by mass spectrometry using for example multiple reaction monitoring.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Pathology (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • General Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Food Science & Technology (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne la détermination d'une prédisposition à une arythmie cardiaque postopératoire, telle que la fibrillation auriculaire, chez un patient humain, après une opération chirurgicale cardiaque, reposant sur la détermination de niveaux de métabolites dans un échantillon de tissu cardiaque prélevé chez le patient durant l'opération chirurgicale, par exemple un échantillon de tissu auriculaire venant d'une canulation de l'oreillette. Les métabolites d'intérêt comprennent des métabolites du métabolisme glycolytique et du métabolisme lipidique. Par exemple, il s'est avéré que le rapport glucose à acétate et le rapport alanine et lactate à acétate fournissaient des informations.
PCT/GB2009/050060 2008-01-23 2009-01-23 Prédiction d'une fibrillation auriculaire postopératoire WO2009093077A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0801203.1 2008-01-23
GB0801203A GB0801203D0 (en) 2008-01-23 2008-01-23 Prediction of post-operative atrial fibrillation

Publications (1)

Publication Number Publication Date
WO2009093077A1 true WO2009093077A1 (fr) 2009-07-30

Family

ID=39166213

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2009/050060 WO2009093077A1 (fr) 2008-01-23 2009-01-23 Prédiction d'une fibrillation auriculaire postopératoire

Country Status (2)

Country Link
GB (1) GB0801203D0 (fr)
WO (1) WO2009093077A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008019060A2 (fr) * 2006-08-03 2008-02-14 U.S. Department Of Veterans Affairs Office Of General Counsel-Psg Iv (024) Procédé de prédiction de l'apparition et du risque d'une fibrillation auriculaire (fa)

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008019060A2 (fr) * 2006-08-03 2008-02-14 U.S. Department Of Veterans Affairs Office Of General Counsel-Psg Iv (024) Procédé de prédiction de l'apparition et du risque d'une fibrillation auriculaire (fa)

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BARTH ANDREAS S ET AL: "Reprogramming of the human atrial transcriptome in permanent atrial fibrillation - Expression of a ventricular-like genomic signature", CIRCULATION RESEARCH, vol. 96, no. 9, May 2005 (2005-05-01), pages 1022 - 1029, XP002520834, ISSN: 0009-7330 *
MAYR ET AL: "Combined Metabolomic and Proteomic Analysis of Human Atrial Fibrillation", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, ELSEVIER, NEW YORK, NY, US, vol. 51, no. 5, 29 January 2008 (2008-01-29), pages 585 - 594, XP022437306, ISSN: 0735-1097 *
MAYR ET AL: "Proteomics and Metabolomics Combined in Cardiovascular Research", TRENDS IN CARDIOVASCULAR MEDICINE, ELSEVIER SCIENCE, NEW YORK, NY, US, vol. 17, no. 2, 7 February 2007 (2007-02-07), pages 43 - 48, XP005878221, ISSN: 1050-1738 *
MAYR MANUEL ET AL: "Loss of PKC-delta alters cardiac metabolism.", AMERICAN JOURNAL OF PHYSIOLOGY. HEART AND CIRCULATORY PHYSIOLOGY AUG 2004, vol. 287, no. 2, August 2004 (2004-08-01), pages H937 - H945, XP002520833, ISSN: 0363-6135 *
MAYR U ET AL: "Integrated proteomic and metabolomic analysis reveals metabolic remodelling in human persistent atrial fibrillation", MOLECULAR & CELLULAR PROTEOMICS, vol. 4, no. 8, Suppl. 1, August 2005 (2005-08-01), & 4TH ANNUAL WORLD CONGRESS OF THE HUMAN-PROTEOME-ORGANISATION (HUPO); MUNICH, GERMANY; AUGUST 28 -SEPTEMBER 01, 2005, pages S174, XP009114362, ISSN: 1535-9476 *
NEUMAN ROBERT B ET AL: "Oxidative stress markers are associated with persistent atrial fibrillation", CLINICAL CHEMISTRY, vol. 53, no. 9, September 2007 (2007-09-01), pages 1652 - 1657, XP002520832, ISSN: 0009-9147 *

Also Published As

Publication number Publication date
GB0801203D0 (en) 2008-02-27

Similar Documents

Publication Publication Date Title
Tang et al. Reference intervals for serum 24, 25-dihydroxyvitamin D and the ratio with 25-hydroxyvitamin D established using a newly developed LC–MS/MS method
Shankaran et al. Circulating protein synthesis rates reveal skeletal muscle proteome dynamics
Meller et al. Integration of tissue metabolomics, transcriptomics and immunohistochemistry reveals ERG-and gleason score-specific metabolomic alterations in prostate cancer
Burniston Adaptation of the rat cardiac proteome in response to intensity‐controlled endurance exercise
Moriggi et al. Long term bed rest with and without vibration exercise countermeasures: effects on human muscle protein dysregulation
Choksi et al. Age-related alterations in oxidatively damaged proteins of mouse skeletal muscle mitochondrial electron transport chain complexes
Aye et al. Proteome-wide protein concentrations in the human heart
US10768183B2 (en) Metabolite panel for improved screening and diagnostic testing of cystic fibrosis
Epperson et al. Seasonal proteomic changes reveal molecular adaptations to preserve and replenish liver proteins during ground squirrel hibernation
EP2780700B1 (fr) 2-hydroxyglutarate comme biomarqueur de l'hypoxie chronique
Wang et al. Metabolic characterization of hypertrophic cardiomyopathy in human heart
Pienkowski et al. Proteomics and metabolomics approach in adult and pediatric glioma diagnostics
Viganò et al. Protein modulation in mouse heart under acute and chronic hypoxia
Alagaratnam et al. Serum protein profiling in mice: identification of Factor XIIIa as a potential biomarker for muscular dystrophy
Fujimura et al. Mass spectrometry-based metabolic profiling of gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells
Cao et al. Metabolic alterations of Qinghai–Tibet Plateau pikas in adaptation to high altitude
Buszewska-Forajta et al. New approach in determination of urinary diagnostic markers for prostate cancer by MALDI-TOF/MS
Zhou et al. Proteomics analysis of tumor microenvironment: Implications of metabolic and oxidative stresses in tumorigenesis
Kasakin et al. Changes in amino acid and acylcarnitine plasma profiles for distinguishing patients with multiple sclerosis from healthy controls
Shi et al. Aging-related markers in rat urine revealed by dynamic metabolic profiling using machine learning
Wang et al. Exploration of potential lipid biomarkers for premature canities by UPLC‐QTOF‐MS analyses of hair follicle roots
Li et al. Time course label-free quantitative analysis of cardiac muscles of rats after myocardial infarction
WO2009093077A1 (fr) Prédiction d'une fibrillation auriculaire postopératoire
CN105044240B (zh) 一种适合于食管鳞状细胞癌早期诊断的诊断标记物
Caussé et al. Serum allantoin and aminothiols as biomarkers of chronic heart failure

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09704150

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09704150

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载