Cov xwm txheej tam sim no ntawm Neuroprotection hauv Congenital Heart Disease Part 1

Abstract:

Neurological deficits yog ib qho mob hnyav thiab tshwm sim ntawm tus kab mob hauv lub plawv (CHD).Thaum lawv cov txheej txheem hauv qab tsis tau ua tiav, lawv cov kev tshwm sim tau paub zoo thiab nkag siab kom pheej mus txog thaum neeg laus.

Muaj qee qhov kev sib raug zoo ntawm neurological deficits thiab nco, tab sis tsis yog tag nrho cov neurological deficits yuav ua mob nco. Qee tus neeg uas muaj kev puas siab puas ntsws tuaj yeem zam lossis txo cov teeb meem kev nco los ntawm kev daws teeb meem thiab kev kho kom tsim nyog.

Rau qee qhov kev puas hlwb los ntawm kev puas hlwb, xws li Alzheimer's disease, Parkinson's disease, thiab lwm yam, txawm hais tias lawv yuav ua rau muaj kev puas siab puas ntsws loj heev, lawv tseem tuaj yeem rov qab los ntawm qee qhov kev kho mob zoo, kev cob qhia kev txawj ntse, thiab kev kho mob rov qab. Nws tuaj yeem txo cov neeg mob cov tsos mob thiab txhim kho lawv lub neej zoo.

Tsis tas li ntawd, qee qhov kev coj cwj pwm zoo thiab cov hau kev tseem tuaj yeem pab peb txhim kho kev nco, xws li kev pw tsaug zog zoo, noj qab nyob zoo, qoj ib ce, thiab tswj tus cwj pwm zoo. Tag nrho cov no tuaj yeem hloov pauv thiab txhim kho los ntawm koj qhov kev siv zog.

Nyob rau hauv luv luv, txawm hais tias muaj ib qho kev sib raug zoo ntawm neurological deficits thiab nco, tsuav yog peb nquag teb thiab kho kom tsim nyog, thiab txais yuav ib tug zoo txoj kev ua neej, peb muaj peev xwm txhim kho peb lub cim xeeb thiab zoo ntawm lub neej thiab txais tos ib tug zoo yav tom ntej. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola yog cov khoom siv tshuaj hauv Suav teb uas muaj ntau yam teebmeem, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche deserticola los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv los ntawm ntau txoj hauv kev.

Nyem paub txoj hauv kev los txhim kho lub hlwb

Kev txhim kho ntawm kev kho mob los daws lossis tiv thaiv cov kev tsis txaus no yog qhov tseem ceeb kom txo qis kev mob nkeeg yav tom ntej thiab txhim kho lub neej zoo. Hauv qhov kev tshuaj xyuas no, peb tsom los piav qhia txog cov xwm txheej tam sim no ntawm kev kho mob neuroprotective hauv CHD.

Los ntawm kev tshawb nrhiav cov kev tshawb fawb tam sim no hauv kev ua haujlwm ua ntej, kev ua haujlwm hauv kev ua haujlwm, thiab tom qab kev ua haujlwm ntawm kev tswj xyuas tus neeg mob, peb yuav piav qhia txog kev siv tshuaj kho mob thiab lub rooj ntev zaum tam sim no nrog rau kev ua haujlwm tam sim no hauv cheeb tsam kev tshawb fawb no.

Ntsiab lus: congenital mob plawv; neuroprotection; hlwb; plawv anomalies; neurological tsis txaus.

1. Taw qhia

Congenital Heart Disease (CHD) yog qhov ua rau tuag hauv me nyuam mos los ntawm kev paub txog kev yug me nyuam, tshwm sim hauv 8 ntawm 1000 yug nyob [1,2]. Txawm li cas los xij, kev tuag ntawm CHD tau nce qis zuj zus los ntawm kev txhim kho kev kuaj mob, kev phais zoo dua, thiab kev nce qib hauv kev saib xyuas hnyav [3,4].

Tam sim no, feem ntau cov menyuam yaus cuam tshuam los ntawm CHD yuav mus txog rau cov neeg laus uas muaj pov thawj los ntawm ntau dua 50% nce ntawm cov neeg laus muaj feem ntau ntawm xyoo 2000 txog 2010 [3]. Qhov kev nce ntawm cov ciaj sia taus no tau ua rau muaj kev hloov pauv hauv kev tshawb fawb los ntawm kev muaj sia nyob luv luv mus rau lub neej ntev thiab kev ua neej zoo [5,6].

Neurodevelopmental deficits yog ib qho tshwm sim thiab tseem ceeb tshaj plaws hauv cov neeg mob uas muaj CHD, ua rau muaj kev mob ntev ntev uas pib thaum menyuam mos thiab pheej mus rau neeg laus [3,6-10]. Qhov kev nthuav dav thiab qhov hnyav ntawm cov kev tsis txaus siab no cuam tshuam nrog ntau qhov nyuaj ntawm CHD thiab kwv yees kom ncav cuag qhov tshwm sim ntawm kwv yees li 50% cov menyuam mos [6,11].

Tshwj xeeb, qhov tshwm sim ntawm cov teeb meem neurodevelopmental muaj xws li impairedcognition, tag nrho thiab zoo lub cev muaj zog kev txawj ntse, kev sib raug zoo kev sib raug zoo, kev sib txuas lus, thiab kev ua hauj lwm raws li tus cwj pwm impulsive thiab inattention [6,12-14] raws li qhia nyob rau hauv cov kev tshawb fawb nram qab no.

1.1. Boston Circulatory Arrest Trial

Kev tshawb fawb ntev tom qab cov neeg mob nrog CHD thoob plaws hauv menyuam yaus tau xa cov ntaub ntawv tseem ceeb txog kev tsim kho neurodevelopment. Lub Boston Circulatory Arrest Trial yog ib qho kev tshawb fawb ntev uas tau ua raws li cov neeg mob uas muaj kev rov qab los ntawm cov hlab ntsha loj (d-TGA) uas tau ua haujlwm rau kev hloov pauv ntawm cov hlab ntsha (NCT03073122) [10,15,16].

Hauv lawv cov neeg mob thaum yau, Bellinger li al. tau tshaj tawm txog ntau yam kev sib tw nrog rau cov qhab nia qis dua li ib txwm muaj ntawm Bayley Scales of Infant Development thiab cov peev txheej hais lus tsis zoo [17]. Childhoodyears txuas ntxiv cov qauv no ntawm qhov txawv txav ntawm neurodevelopment tshwm sim nyob rau hauv kev soj ntsuam ntawm kev txawj ntse quotient (IQ), kev ua lej thiab kev nyeem ntawv tsis zoo, cov qhab nia tsis nco qab, ua kom pom kev tsis pom kev, ua rau muaj teeb meem kev coj cwj pwm, thiab lub cev tsis muaj zog.

Qhov tseem ceeb tshaj plaws yog qhov kev tshawb pom tias ntau tshaj li ib feem peb ntawm cov pab pawg tau txais kev kho mob hauv tsev kawm ntawv [13,14]. Hnub nyoog 16 kev soj ntsuam pom tau pom zoo sib xws nrog kev pheej hmoo ntawm neuro-deficits thiab kev puas siab puas ntsws, lub cev, thiab kev xav [10,18].

Lwm txoj kev tshawb fawb tau ua hauv Boston Children's Hospital tau pom cov txiaj ntsig zoo sib xws hauv cov neeg mob ntawm 156 tus neeg mob uas tau ua tiav Fontanprocedures rau ib leeg ventricle pathophysiology. Cov qhab nia IQ qis dua, kev ua tiav ntawm tus kheej, kev nco, thiab kev ua haujlwm ua haujlwm nrog rau qhov tshwm sim ntawm kev mloog tsis txaus siab tsis txaus ntseeg (ADHD), kev ntxhov siab, thiab MRI abnormalities piv rau d-TGAcohort qhov kev tshawb pom [19,20].

1.2. Single Ventricle Reconstruction Trial

Cov txiaj ntsig zoo ib yam nrog cov no kuj tau pom nyob rau hauv Kev Sib Tw Ib Lub Ventricle Reconstruction (SVR) (NCT02692443). Tsis ntev los no tau tshaj tawm 6-cov ntaub ntawv tshwm sim xyoo los ntawm SVR trial qhia txog kev puas tsuaj ntawm kev coj tus cwj pwm, kev ua neej zoo, kev ua haujlwm zoo, thiab kev hloov pauv hauv ib pawg ntawm cov menyuam yug tshiab uas muaj txoj cai ventricular anomalies [21,22].

Qhov tshwm sim ntawm cov kev tsis txaus siab no tau dhau los ntawm cov tib neeg ib txwm muaj kev tsis taus me me thiab mob hnyav tshwm sim ntawm 6 thiab 11 npaug ntawm qhov xwm txheej ib txwm muaj raws li qhov sib txawv ntawm cov niam txiv qhia txog kev ua haujlwm tsis zoo tau tshaj tawm txog 4.37 thaum piv rau kev tswj hwm [23 , 24] ib.
Cov ntawv ceeb toom no tau txais kev txhawb nqa los ntawm ntau lwm cov kev tshawb fawb piav txog cov txiaj ntsig zoo sib xws rau kev paub, lub cev muaj zog, thiab kev coj tus cwj pwm ntawm neurodevelopment [25–30]. Qhov tseeb, cov kev tsis txaus siab no muaj ntau thiab tsis yog tshwj xeeb rau asingle CHD subtype.

1.3. Kev pheej hmoo cuam tshuam nrog cov teeb meem tsis txaus ntseeg hauv cov menyuam yaus uas muaj CHD

Qhov ua rau ntawm neurodevelopmental deficits txuam nrog CHD yog cumulative, multifactorial, thiab synergistic (Daim duab 1) [5]. Cov khoom siv caj ces yog qhov tsis txaus ntseeg qhov tseem ceeb hauv kev txhim kho CHD thiab tseem yog ib qho tseem ceeb rau tus neeg mob qhov tsis zoo rau kev raug mob neurologic [5,31,32].

Tsis tas li ntawd nyob rau hauv lub utero theem, mob fetalhypoxia uas tshwm sim los ntawm txawv txav physiology thiab hloov txoj kev tswj yog loj luag hauj lwm rau lub hlwb tsis paub tab [33,34].

Kev tsim kom muaj kev sib txuas ntawm cerebral hypoxia thiab txo lub hlwb ntim nrog rau cov txiaj ntsig tsis zoo hauv cov neeg mob CHD tau yog lub hauv paus tseem ceeb hauv kev thawb los txhim kho kev kho mob ua ntej-neuroprotective txhawm rau hais txog kev xa oxygen tsis txaus rau tus menyuam hauv plab (Daim duab 2) [34, 35] ib.

Kwv yees li ntawm 25% ntawm cov menyuam mos uas muaj CHD yuav xav tau kev kho mob plawv tsis pub dhau lawv thawj xyoo ntawm lub neej thiab yuav muaj kev pheej hmoo rau kev raug mob ntawm lub paj hlwb cuam tshuam nrog kev phais mob tshwj xeeb yog tias yuav tsum tau muaj cardiopulmonary bypass (CPB) [36–38].

CPB ua rau cov kab mob inflammatory teb, ischemia-reperfusion, thiab reoxygenation raug mob nrog rau tom qab microglia-mediated o o thiab txhim kho oxidative kev nyuaj siab, tag nrho cov uas ua rau muaj kev kub ntxhov ntawm cov teeb meem dawb raug mob (WMI) pom inneonates thiab cov me nyuam mos nrog CHD tom qab phais [39 , 40] ib. Txawm hais tias tseem tsis tau hais meej meej, cov txheej txheem tom qab WMI yog lub hom phiaj muaj peev xwm rau kev kho mob neuroprotective.Post-operatively, yam uas ua rau kev txhim kho neurodevelopmental qeeb yog dav dua.

Ib puag ncig, kev lag luam kev noj qab haus huv, thiab kev kis kab mob yog qhov cuam tshuam rau kev loj hlob thiab kev loj hlob ntawm tag nrho cov me nyuam mos, tsis yog cov neeg muaj CHD [5,41-44].Txawm li cas los xij, lawv qhov tseem ceeb hauv cov neeg mob uas twb muaj kev pheej hmoo ntawm kev loj hlob ntawm neurodevelopmental deficits yog nce thiab yuav tsum tau tshawb nrhiav los txiav txim siab txoj hauv kev zoo tshaj plaws los txhawb kev loj hlob.

Lub ntiajteb txawj nqus thiab nthuav dav ntawm neurodevelopmental deficits nyob rau hauv CHD cov pej xeem yuav tsum tau kev kho mob nyob rau txhua theem ntawm tus neeg mob kev tswj kom tiv thaiv neurologicalinjury thiab txhawb neurodevelopment. Ntawm no, peb tshuaj xyuas cov kev tshawb fawb tsis ntev los no uas qhia txog qhov xwm txheej tam sim no ntawm kev kho mob neuroprotective hauv CHD los ntawm kev txheeb xyuas cov tswv yim uas twb muaj lawm nyob rau hauv niam txiv, peri-operative, thiab tom qab kev ua haujlwm ntawm cov neeg mob (Table 1, Daim duab 3).

2. Maternal Neuroprotection-Clinical Studies

2.1. Niam Hyperoxia

Mob hypoxia yog qhov cuam tshuam tseem ceeb ntawm fetal neurodevelopment hauv CHD. Tsis ntev los no, Lawrence et al. elucidated lub luag hauj lwm ntawm mob hypoxia nyob rau hauv neurological raug mob los ntawm employinga fetal yaj qauv.

Lawv tau pom tias mob hypoxia nyob rau hauv lawv lub tsev me nyuam tus qauv txo cov neuronal ntom thiab impaired myelination nyob rau hauv lub fetus zoo li zoo li kev tshawb pom nyob rau hauv neonates nrog CHD [45].

Cov neurological insults tej zaum yuav attenuated los ntawm supplementing cov pa oxygen. Cov kev tshawb fawb yav dhau los tau tshawb xyuas qhov muaj peev xwm nce qib oxygen hauv tus menyuam hauv plab los ntawm leej niam hyperoxygenation thiab tau lees paub tias nws muaj peev xwm los ntawm kev pom qhov tshwm sim tshwm sim hauv fetal oxygenation [46,47].

Ib qho kev tshawb fawb soj ntsuam hauv Canada tsis ntev los no tau pib los tshawb xyuas qhov cuam tshuam ntawm cov pa oxygen ntxiv thaum lub sijhawm 3rd peb lub hlis twg hauv cov niam uas nws cov menyuam tau raug txheeb xyuas tias muaj qee hom CHD (https://clinicaltrials.gov/\protect\leavevmode@ifvmode\kern.5em {}ct2/show/NCT03944837, nkag rau 3 Kaum Ib Hlis 2021). 10 mus rau 15 L / min ntawm cov pa oxygen los ntawm daim npog ntsej muag yog muab luv luv ua kom cov pa oxygen hauv plab me nyuam mus txog rau cov me nyuam mos nrog ua pa ua pa.

Txawm hais tias neurodevelopment tsis yog txhais ncaj qha raws li qhov kawg, qhov kev ntsuas ntawm cerebral oxygen xa, cerebral oxygenconsumption, oximetry ntawm cov hlab ntsha loj, fetal hlwb volumetry, thiab lub hlwb loj yuav muab cov ntaub ntawv muaj txiaj ntsig txog lub cev muaj txiaj ntsig ntawm leej niam hyperoxygenation.

2.2. Progesterone

Txawm hais tias nws cov txheej txheem cellular tseeb tseem tsis tau paub, ntau qhov kev tshawb fawb tsiaj tau qhia tias progesterone thiab nws cov metabolites muaj lub luag haujlwm tiv thaiv neuroprotective hauv lub hlwb [48]. Nyob rau hauv tus qauv mob hypoxia yaj yaj, allopregnanolone, ib qho metabolite ntawm progesterone los ntawm kev ua haujlwm enzymatic ntawm 5 -reductase, tau pom tias muaj kev tswj hwm thiab cuam tshuam nrog kev soj ntsuam cov lus teb neuroprotective tom qab kev qhia txog mob hlwb tsis zoo [49].

Ib qho kev sim cais tau lees paub qhov kev soj ntsuam no los ntawm kev soj ntsuam qhov nce ntxiv ntawm kev raug mob ntawm lub paj hlwb tom qab inhibition ntawm 5 -reductase ntawm finasteride [50]. Tsis tas li ntawd, tib pab pawg kuj tau pom tias tsis muaj kev nce ntxiv hauv cov menyuam yaj hauv lub hlwb allopregnanolone concentration tom qab 20 hnub ntawm mob hypoxia tsim nrog tus qauv ntawm placentalinsufficiency nyob rau hauv cev xeeb tub yaj, qhia tau hais tias muaj txiaj ntsig zoo ntawm allopregnanoloneusage txawm tias nyob hauv lub xeev hypoxic ntev [51].

Kev soj ntsuam ntawm WMI thiab lub hlwb immaturity nyob rau hauv ib tug neonatal nas qauv ntawm mob hypoxia, siv rau mimic cov me nyuam mos nrog cyanotic CHD, tau txais txiaj ntsig zoo ib yam. Qhov tseem ceeb, kev nce hauv lub hlwb qhov hnyav thiab ntau dua lub cev muaj zog thiab kev sib koom ua ke tau pom nyob rau hauv cov pab pawg kho mob progesterone piv rau kev tswj hwm [48]. Tsis tas li ntawd, progesterone tau cuam tshuam rau hauv oligodendrocyte maturation, oligodendrocyte progenitor cell proliferation, thiab kev txhawb nqa myelination los ntawm kev sib cuam tshuam ncaj qha nrog progesterone receptors [52].

Raws li cov teebmeem ntawm progesterone addresscellular mechanisms ntawm neurological raug mob nyob rau hauv CHD, soj ntsuam kev txhais lus ntawm cov kev tshawb fawb no tau nrhiav. Tam sim no, randomized theem 2 mus sib hais nyob rau hauv lub teb chaws USA los soj ntsuam 3rd-trimester Progesterone kev tswj hwm rau leej niam nqa tus me nyuam nrog CHD (https://clinicaltrials.gov/ct2/show/NCT02133573, nkag mus rau 3 Kaum Ib Hlis 2021).

Nrog rau cov ntsiab lus kawg tshwj xeeb kawm cov qhab nias neurodevelopmental thiab lub hlwb kev loj hlob ntawm MRI, kev nkag siab ntau dua ntawm progesterone cov teebmeem ntawm neuroprotection yuav beachieved ntawm nws qhov xaus.

2.3. Topiramate Prophylaxis

Topiramate yog ib qho -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist pom zoo rau kev kho mob ntawm ib feem thiab kev qaug dab peg. Tsis ntev los no nws tau pom tias Topiramate muaj peev xwm Kev kho rau hypoxic-ischemicencephalopathy los ntawm kev txo qis hauv qab-excitatory mechanisms ntawm neural raug mob los ntawm kev ua kom muaj zog gamma butyric acid (GABA) thiab txo glutamate kev ua ub no los daws cov glutamate ntau dhau hauv lub hlwb [53].

Kev sib xyaw cov txiaj ntsig kev tshawb fawb uas tau pom tias nws muaj peev xwm tiv thaiv kab mob neuroprotective thiab muaj peev xwm khaws cia oligodendrocytes hauv kev raug mob hlwb (TBI), mob stroke, mob vwm, thiab periventricular leukomalacia qauv nrog cov lus ceeb toom ntawm kev paub ntev ntev, nco, thiab attenuatedWMI thaum siv nrog kev kho mob hypothermia. propelled Topiramate mus rau qhov chaw kuaj mob theem [54–57].

Filippi et al. Tsis ntev los no tau tshaj tawm cov txiaj ntsig ntawm theem 2multi-center randomized tswj kev sim tshuaj ntsuam xyuas topiramate hauv cov menyuam yaus nrog hypoxic-ischemic encephalopathy (HIE) [58]. Hauv lawv txoj kev tshawb fawb, lawv tau pom qhov tsis tseem ceeb ntawm kev poob qis hauv cov nqi ntawm kev mob vwm hauv cov pab pawg kho mob topiramate piv rau kev tswj hwm tab sis tsis muaj qhov sib txawv tseem ceeb hauv kev tuag thiab mob hnyav neurodevelopmentaldisability.

Txawm li cas los xij, txoj kev tshawb no tau txwv los ntawm nws tus lej me me hauv thawj cohortand qhov txo qis ib feem peb ntawm cov qauv loj vim yog qhov tsis raug randomization.

Ib qho kev tshawb fawb cais ua tiav hauv 2017 kawm txog cov teebmeem ntawm topiramate prophylaxis hauv cov menyuam mos nrog CHD kev phais plawv yuav muab cov ntaub ntawv ntxiv txog kev siv cov topiramate tshwj xeeb hauv CHD nrog rau cov kev taw qhia yav tom ntej ntawm qhov kev cuam tshuam no (https://clinicaltrials.gov/ct2/show /NCT01426542, nkag rau 3 Kaum Ib Hlis 2021).

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