ES2627019T3 - Medios y procedimientos para diagnosticar y vigilar la insuficiencia cardiaca en un sujeto - Google Patents

Medios y procedimientos para diagnosticar y vigilar la insuficiencia cardiaca en un sujeto Download PDF

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ES2627019T3
ES2627019T3 ES12745444.5T ES12745444T ES2627019T3 ES 2627019 T3 ES2627019 T3 ES 2627019T3 ES 12745444 T ES12745444 T ES 12745444T ES 2627019 T3 ES2627019 T3 ES 2627019T3
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until
acid
positive
sphingomyelin
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Regina Reszka
Jens Fuhrmann
Jürgen KASTLER
Bianca Bethan
Martin Kluttig
Hugo Katus
Norbert Frey
Johanna Wolf
Tanja Weis
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Universitaet Heidelberg
BASF Metabolome Solutions GmbH
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Universitaet Heidelberg
Metanomics GmbH
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Abstract

Un procedimiento para diagnosticar la insuficiencia cardiaca en un sujeto, que comprende las etapas de: a) determinar, en una muestra de un sujeto que se sospecha que padece insuficiencia cardiaca, la cantidad de al menos un biomarcador seleccionado entre los biomarcadores relacionados en la Tabla 1A1, 1A2, 1B1, 1B2, 2A1, 2A2, 2B1, 2B2, 3A1, 3A2, 3B1, 3B2, 4A1, 4A2, 4B1, 4B2, 5A1, 5A2, 5B1, 5B2, 6A1, 6A2, 6B1, 6B2, 7A1, 7A2, 7B1, 7B2, 8A1, 8A2, 8B1 o 8B2; en el que uno de dicho al menos un biomarcador es colesterilester C18:0; b) comparar la cantidad de dicho al menos un biomarcador con una referencia, mediante lo cual se va a diagnosticar la insuficiencia cardiaca.

Description

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Tabla 2A.2: Metabolitos que están significativamente disminuidos en plasma (valor p < 0,05) entre pacientes de CHF (DCMP) asintomáticos con NYHA I y controles
METABOLITO Biliverdina eritro-C16-Esfingosina treo-Esfingosina (*1) 5-O-Metilesfiingosina (*1) CE-Colesterilester C16:0
relación
regulación valor p
0,562
hasta 0,027
0,8592
hasta 0,029152
0,8906
hasta 0,013527
0,8943
hasta 0,047886
0,9077
hasta 0,043609
Tabla 3A.1: Metabolitos que están significativamente aumentados en plasma (valor p < 0,05) entre pacientes de CHF (ICMP) asintomáticos con NYHA I y controles
METABOLITO Ácido 4-Hidroxi-3-metoximandélico TAG (C16:0,C18:1,C18:2) TAG (C18:1,C18:2) TAG (C16:O,C16:1) TAG (C18:2,C18:2) ácido 15-hidroxieicosatetraenoico (C20:cis[5,8,11,13]4) TAG (C18:2,C18:3) TAG (C16:0,C18:1,C18:3) ácido 8-hidroxieicosatetraenoico (C20:[5] trans[9,11,14]4) (8-HETE) Ácido 14,15-Dihidroxieicosatrienoico (C20:cis[5,8,11]3) DAG (C18:1,C18:2) Piruvato trans-4-Hidroxiprolina SM_Esfingomielina (d18:0,C18:0) Ácido oleico (C18:cis[9]1) Alanina Prolina CER_Ceramida (d18:1,C18:0) Fosfatidilcolina (C18:0,C20:4) Fosfatidilcolina (C16:0,C18:2)
relación
regulación valor p
1,6392
hasta 0,011879
1,572
hasta 4,23E-05
1,5059
hasta 2,41 E-05
1,4663
hasta 0,00067
1,4275
hasta 0,000482
1,3706
hasta 0,002652
1,3664
hasta 0,020521
1,3518
hasta 0,003772
1,3335
hasta 0,004867
1,332
hasta 0,000468
1,3115
hasta 0,001439
1,2874
hasta 0,005757
1,2253
hasta 0,029368
1,187
hasta 0,021168
1,1837
hasta 0,035226
1,1628
hasta 0,001332
1,1575
hasta 0,013187
1,1554
hasta 0,020581
1,0451
hasta 0,001529
1,0142
hasta 0,017665
Tabla 3A.2: Metabolitos que están significativamente disminuidos en plasma (valor p < 0,05) entre pacientes de CHF (ICMP) asintomáticos con NYHA I y controles
METABOLITO CE_Colesterilester C12:0 CE_Colesterilester C20:1 CE_Colesterilester C18:0 Esfingosina-1-fosfato (d17:1) eritro-C16-Esfingosina SM_Esfingomielina (d18:2,C23:1) 5-O-Metilesfiingosina (*1) CE_Colesterilester C20:2 Esfingadienina-1-fosfato (d18:2) 3-O-Metilesfiingosina (*1) Esfingosina-1-fosfato (d18:1) treo-Esfingosina (*1) SM_Esfingomielina (d18:2,C24:2) SM_Esfingomielina (d18:2,C14:0) SM-Esfingomielina (d18:1,C23:1) eritro-Esfingosina (*1) SM_Esfingomielina (d18:1,C24:2) Esfinganina-1-fosfato (d18:0) Fitoesfingosina, total SM_Esfingomielina (d18:1,C16:0) SM-Esfingomielina (d16:1,C24:1) SM_Esfingomielina (d16:1,C16:0) CE_Colesterilester C16:0 Lisofosfatidiletanolamina (C22:5) SM_Esfingomielina (d18:2,C21:0) FS_Colesterol, libre SM_Esfingomielina (d18:2,C24:1)
relación
regulación valor p
0,6027
hasta 0,00105
0,7369
hasta 0,00017
0,7737
hasta 0,00143
0,803
hasta 0,00025
0,8147
hasta 0,00311
0,8247
hasta 0,00017
0,8249
hasta 0,00065
0,8323
hasta 0,00076
0,8333
hasta 0,00026
0,8364
hasta 0,00203
0,8409
hasta 0,00118
0,8433
hasta 0,00014
0,8439
hasta 0,00035
0,8444
hasta 0,00223
0,8516
hasta 0,00045
0,8604
hasta 0,0016
0,8659
hasta 0,00206
0,8684
hasta 0,01946
0,8783
hasta 0,01206
0,8816
hasta 0,00039
0,8836
hasta 0,01867
0,8877
hasta 0,01607
0,8917
hasta 0,01189
0,8927
hasta 0,02336
0,8977
hasta 0,0347
0,8988
hasta 0,02029
0,9026
hasta 0,04993
20
imagen19
imagen20
imagen21
imagen22
(continuación)
METABOLITO
relación regulación valor p
ácido 8-hidroxieicosatetraenoico (C20:[5] trans[9,11,14]4) 1,2893
hasta 0,01092
(8-HETE) TAG (C18:2,C18:2) TAG (C16:0,C18:1,C18:3) N,N-Dimetilarginina (ADMA) Ácido ribónico Esfingosina (d18:1) Carnitina CER_Ceramida (d18:1,C18:0) trans-4-Hidroxiprolina Eritrol Ácido úrico Ácido 14,15-Dihidroxieicosatrienoico (C20:cis[5,8,11]3) DAG (C18:1,C18:2) Ácido 13-hidroxioctadecadienoico (13-HODE) (C18:cis[9] trans[11]2) Creatina Ácido 5-Hidroxi-3-indolacético (5-HIAA) Cistina Ornitina Pseudouridina Homoserina CER_Ceramida (d18:1,C20:0) CER_Ceramida (d18:1,C16:0) Glicerol-3-fosfato, fracción polar Prolina Pentosas mio-Inositol Tirosina Citrato Isoleucina Hexadecanol 5-Oxoprolina CER_Ceramida (d18:1,C24:1) Fenilalanina Sarcosina Fumarato Fosfatidilcolina (C18:0,C18:2)
1,2887
hasta 0,015905
1,279
hasta 0,022255
1,275
hasta 0,003233
1,2754
hasta 7,31E-05
1,2619
hasta 0,04417
1,256
hasta 0,030164
1,2549
hasta 0,000174
1,2455
hasta 0,015447
1,2236
hasta 0,000267
1,2131
hasta 6,69E-05
1,2078
hasta 0,017081
1,2042
hasta 0,034391
1,1878
hasta 0,035187
1,1854
hasta 0,030902
1,1786
hasta 0,025837
1,1522
hasta 0,026543
1,1476
hasta 0,001497
1,1458
hasta 0,000741
1,1422
hasta 0,021709
1,1392
hasta 0,02812
1,1368
hasta 0,001467
1,1367
hasta 0,047191
1,1351
hasta 0,026886
1,1339
hasta 0,017548
1,1268
hasta 0,006009
1,114
hasta 0,010745
1,1116
hasta 0,028918
1,1112
hasta 0,0105
1,1103
hasta 0,046868
1,1092
hasta 0,000298
1,1009
hasta 0,046187
1,0919
hasta 0,005826
1,0863
hasta 0,009006
1,0795
hasta 0,004964
1,011
hasta 0,033217
Tabla 6A.2: Metabolitos que están significativamente disminuidos en plasma (valor p < 0,05) en pacientes de DCPM sintomáticos con NYHA II o NYHA III frente a controles
METABOLITO Sulfato de deshidroepiandrosterona SM_Esfingomielina (d17:1,C23:0) SM_Esfingomielina (d16:1,C24:0) CE_Colesterilester C20:5 Ácido hipúrico SM_Esfingomielina (d16:1,C23:0) CE_Colesterilester C15:0 CE_Colesterilester C14:1 SM_Esfingomielina (d17:1,C24:0) eritro-C16-Esfingosina Colesterilester C18:2 CER_Ceramida (d17:1,C23:0) 1-Hidroxi-2-amino-(cis,trans)-3,5-octadecadieno (*1) SM_Esfingomielina (d16:1,C22:0) Ácido eicosapentaenoico (C20:cis[5,8,11,14,17]5) CE_Colesterilester C12:0 CER_Ceramida (d16:1,C23:0) CER_Ceramida (d17:1,C24:0) CER_Ceramida (d16:1,C24:0) SM_Esfingomielina (d17:1,C22:0) Ácido tricosanoico (C23:0)
relación
regulación valor p
0,5178
hasta 6,03E-05
0,5651
hasta 5,24E-13
0,603
hasta 4,96E-10
0,6079
hasta 6,3E-06
0,6092
hasta 0,004051
0,6162
hasta 4,31 E-14
0,6334
hasta 3,38E-10
0,6428
hasta 0,00125
0,6433
hasta 5,96E-16
0,6456
hasta 2,33E-10
0,6644
hasta 1,01E-09
0,6651
hasta 2,96E-07
0,6659
hasta 9,04E-12
0,6678
hasta 1,17E-11
0,6684
hasta 0,000223
0,6723
hasta 0,007976
0,6728
hasta 3,18E-06
0,6742
hasta 7,34E-08
0,6754
hasta 1,48E-06
0,6766
hasta 6,68E-14
0,6836
hasta 5,19E-12
25
imagen23
imagen24
imagen25
imagen26
Tabla 8A.1: Metabolitos que están significativamente aumentados en plasma (valor p < 0,05) en pacientes de HCMP
sintomáticos con NYHA II o NYHA III frente a controles
METABOLITO Maltosa Sacarosa ácido 12-hidroxieicosatetraenoico (C20:cis[5,8,10,14]4) Sorbitol Esfingadienina (d18:2) Glicerol, fracción lipídica Ácido láurico (C12:0) Fructosa Piruvato Ácido palmitoleico (C16:cis[9]1) Esfingosina (d16:1) SM_Esfingomielina (d18:0,C18:0) TAG (C16:0,C16:1) Ácido oleico (C18:cis[9]1) Noradrenalina (norepinefrina) Ácido heptadecenoico (C17:cis[10]1) Taurina Cistina Ácido palmítico (C16:0) TAG (C16:0,C18:2) CER_Ceramida (d18:1,C18:0) Ácido úrico Ácido eicosenoico (C20:cis[11]1) N,N-Dimetilarginina (ADMA) 2-Hidroxibutirato Ácido esteárico (C18:0) CER_Ceramida (d18:2,C18:0) ácido araquidónico (C20:cis[5,8,11,14]4) SM_Esfingomielina (d18:1,C24:1) eritro-Dihidroesfingosina Glicerolfosfato, fracción lipídica Ácido ribónico Ácido --dihomo-gamma-linoleico (C20:cis[8,11,14]3) isocitrato Eritrol Cisteína Urea CER_Ceramida (d18:1,C24:1) Ácido nervónico (C24:cis[15]1) Arginina CER_Ceramida (d18:1,C16:0) SM_Esfingomielina (d18:1,C18:0) SM_Esfingomielina (d18:2,C18:0) Glucosa-1-fosfato Pseudouridina SM_Esfingomielina (d18:2,C16:0) Glucosa Fosfatidilcolina (C18:0,C20:3) Fosfatidilcolina (C18:0,C20:4)
relación
regulación valor p
1,9048
hasta 4,63E-06
1,6319
hasta 0,005063
1,4659
hasta 0,045714
1,449
hasta 0,018141
1,4046
hasta 0,003857
1,4021
hasta 0,005953
1,4008
hasta 0,046554
1,3913
hasta 0,024517
1,3862
hasta 0,001018
1,3808
hasta 0,004711
1,3506
hasta 0,002776
1,3198
hasta 0,00064
1,2688
hasta 0,04947
1,265
hasta 0,006908
1,2552
hasta 0,01379
1,2412
hasta 0,009838
1,2387
hasta 0,002057
1,2339
hasta 0,003384
1,2333
hasta 0,008969
1,2318
hasta 0,025907
1,2204
hasta 0,003156
1,2023
hasta 0,000657
1,2003
hasta 0,031408
1,193
hasta 0,034953
1,1838
hasta 0,042946
1,1822
hasta 0,010717
1,1778
hasta 0,029595
1,175
hasta 0,006487
1,1695
hasta 0,02742
1,1688
hasta 0,028152
1,1537
hasta 0,044528
1,1534
hasta 0,036068
1,1508
hasta 0,04874
1,1491
hasta 0,010786
1,1465
hasta 0,026373
1,1423
hasta 0,000431
1,1413
hasta 0,045112
1,1373
hasta 0,017432
1,1302
hasta 0,023448
1,1292
hasta 0,03428
1,1208
hasta 0,011296
1,1186
hasta 0,022073
1,117
hasta 0,033572
1,1138
hasta 0,035621
1,1109
hasta 0,019312
1,0871
hasta 0,036787
1,0724
hasta 0,03724
1,0644
hasta 0,021365
1,0411
hasta 0,007723
Tabla 8A.2: Metabolitos que están significativamente disminuidos en plasma (valor p < 0,05) en pacientes de HCPM sintomáticos con NYHA II o NYHA III frente a controles
METABOLITO Biliverdina ácido 12-Hidroxiheptadecatrienoico (C17:[5,8,10]3) Ácido hipúrico Hipoxantina Beta-caroteno Criptoxantina Colesterilester C18:2
relación
regulación valor p
0,460
hasta 0,024536
0,5252
hasta 0,023105
0,6822
hasta 0,033329
0,7217
hasta 0,012505
0,7326
hasta 0,008399
0,7535
hasta 0,031981
0,7662
hasta 0,000292
30
imagen27
imagen28
imagen29
imagen30
imagen31
imagen32
imagen33
imagen34
imagen35
imagen36
imagen37
imagen38
imagen39
imagen40
imagen41
imagen42
imagen43
imagen44
imagen45
imagen46
imagen47
imagen48
imagen49
imagen50
imagen51
imagen52
imagen53
Tabla 13B.1: Metabolitos que muestran una correlación significativamente positiva (p < 0,05) con LVEF en plasma de pacientes de CHF y controles
METABOLITO estimación correlación valor p
Ácido hipúrico 1,529516 positivo 2.68E-06
Androstenodiona 1,487558 positivo 3.76E-06
Ácido 7-Metilúrico 1,401171 positivo 8.24E-05
Ácido indol-3-láctico 1,382959 positivo 0,000475
Histidina 1,322863 positivo 1.62E-07
7-Metilxantina 1,322406 positivo 0,000124
O-Acetilcarnitina 1,274541 positivo 0,003596
Carnitina 1,272619 positivo 0,000514
Ácido 1-Metilúrico 1,231272 positivo 0,002592
3,4-Dihidroxifenilalanina (DOPA) 1,205536 positivo 7,71 E-07
Glicina 1,205223 positivo 4.08E-06
Citrato 1,197805 positivo 0,00045
Ácido úrico 1,196162 positivo 0,001527
Ácido pantoténico 1,188484 positivo 0,000115
Metixantina 1,171143 positivo 0,006775
Treonina 1,162344 positivo 8.37E-06
Lisina 1,161343 positivo 0,003507
Ácido 3-hidroxiisovalérico 1,159363 positivo 8.58E-05
Uracilo 1,156814 positivo 1,63E-06
21-Hidroxiprogesterona (11-
Desoxicorticoesterona) 1,1557 positivo 0,007924
Tabla 13B.2: Metabolitos que muestran una correlación significativamente negativa (p < 0,05) con LVEF en plasma de pacientes de CHF y controles
METABOLITO estimación correlación valor p
Furoilglicina Ácido trans-ferúlico
0,687448 0,76225 negativo negativo 0,000503 0,000699
Sacarosa
0,762679 negativo 9.07E-07
Monofosfato
de guanosina cí clico
(GMPc)
0,797882 negativo 1.47E-10
Fructosa
0,840587 negativo 0,002537
Glicerol-3-fosfato, fracción polar
0,850218 negativo 7.94E-05
Normetanefrina
0,866303 negativo 4.53E-08

Tabla 14: Propiedades químicas/físicas de los analitos seleccionados. Estos biomarcadores se caracterizan en el presente documento por las propiedades químicas y físicas.
Metabolito
Modelo de fragmentación (GC-MS) y descripción
Glicerolfosfato, fracción lipídica
Glicerolfosfato, la fracción lipídica representa el parámetro sumatorio de metabolitos que contienen un resto glicerol-2-fosfato o un resto glicerol-3-fosfato y que están presentes en la fracción lipídica tras la extracción y separación del extracto en una fracción polar y una fracción lipídica.
3-O-Metilesfingosina
3-O-Metilesfingosina presenta los siguientes fragmentos iónicos característicos si se detecta con GC/MS, aplicando la espectrometría de masas mediante ionización por impacto de electrones (EI), tras la metanolisis ácida y la derivatización con clorhidrato de O-metilhidroxilamina al 2% en piridina y posteriormente con N-metil-Ntrimetilsililtrifluoracetamida: MS (EI, 70 eV): m/z (%): 204 (100), 73 (18), 205 (16), 206 (7), 354 (4), 442 (1).
5-O-Metilesfingosina
5-O-Metilesfingosina presenta los siguientes fragmentos iónicos característicos si se detecta con GC/MS, aplicando la espectrometría de masas mediante ionización por impacto de electrones (EI), tras la metanolisis ácida y la derivatización con clorhidrato de O-metilhidroxilamina al 2% en piridina y posteriormente con N-metil-Ntrimetilsililtrifluoracetamida: MS (EI, 70 eV): m/z (%): 250 (100), 73 (34), 251 (19), 354 (14), 355 (4), 442 (1).
Deshidroepiandrosterona sulfato
Sulfato de deshidroepiandrosterona representa el parámetro sumatorio de los sulfatos esteroides. Presenta las siguientes especies características cuando se detecta con LC/MS, aplicando espectrometría de masas mediante ionización por electropulverización (ESI): la relación masa a carga (m/z) de las especies iónicas cargadas negativamente es 367,4 (+/-0,5).
58
(continuación)
Metabolito
Modelo de fragmentación (GC-MS) y descripción
Fosfatidilcolina N.º 02
Fosfatidilcolina N.º 02 representa el parámetro sumatorio de las fosfatidilcolinas. Presenta las siguientes especies características cuando se detecta con LC/MS, aplicando espectrometría de masas mediante ionización por electropulverización (ESI): la relación masa a carga (m/z) de las especies iónicas cargadas positivamente es 808,4 (+/-0,5).
TAG (C16:0,C16:1)
TAG (C16:0,C16:1) representa el parámetro sumatorio de los triacilglicéridos que contienen la combinación de una unidad de ácido graso C16:0 y una unidad de ácido graso C16:1. Presenta las siguientes especies características cuando se detecta con LC/MS, aplicando espectrometría de masas mediante ionización por electropulverización (ESI): la relación masa a carga (m/z) de las especies iónicas cargadas positivamente es 549,6 (+/-0,5).
TAG (C16:0,C18:2)
TAG (C16:0,C18:2) representa el parámetro sumatorio de los triacilglicéridos que contienen la combinación de una unidad de ácido graso C16:0 y una unidad de ácido graso C18:2. Presenta las siguientes especies características cuando se detecta con LC/MS, aplicando espectrometría de masas mediante ionización por electropulverización (ESI): la relación masa a carga (m/z) de las especies iónicas cargadas positivamente es 575,6 (+/-0,5).
TAG (C18:1,C18:2)
TAG (C18:1,C18:2) representa el parámetro sumatorio de los triacilglicéridos que contienen la combinación de una unidad de ácido graso C18:1 y una unidad de ácido graso C18:2. Presenta las siguientes especies características cuando se detecta con LC/MS, aplicando espectrometría de masas mediante ionización por electropulverización (ESI): la relación masa a carga (m/z) de las especies iónicas cargadas positivamente es 601,6 (+/-0,5).
TAG (C18:2,C18:2)
TAG (C18:2,C18:2) representa el parámetro sumatorio de los triacilglicéridos que contienen la combinación de dos unidades de ácido graso C18:2. Presenta las siguientes especies características cuando se detecta con LC/MS, aplicando espectrometría de masas mediante ionización por electropulverización (ESI): la relación masa a carga (m/z) de las especies iónicas cargadas positivamente es 599,6 (+/-0,5).
TAG (C18:2, C18:3)
TAG (C18:2,C18:3) representa el parámetro sumatorio de los triacilglicéridos que contienen la combinación de una unidad de ácido graso C18:2 y una unidad de ácido graso C18:3. Presenta las siguientes especies características cuando se detecta con LC/MS, aplicando espectrometría de masas mediante ionización por electropulverización (ESI): la relación masa a carga (m/z) de las especies iónicas cargadas positivamente es 597,6 (+/-0,5).
59

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