Title Prognostički značaj određivanja monocitnog kemotaksijskog proteina - 1 i interleukina - 18 u bolesnika sa stenozom karotidnih arterija : doktorski rad Author Ines Strenja-Linić Mentor Zlatko Trobonjača (mentor)Mentor Miljenko Kovačević (sumentor)Committee member Gordana Laškarin (predsjednik povjerenstva)Committee member Zlatko Trkanjec (član povjerenstva)Committee member Alen Ružić (član povjerenstva)Committee member Zlatko Trobonjača (član povjerenstva)Committee member Miljenko Kovačević (član povjerenstva)Granter University of Rijeka Defense date and country 2013-01-01, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 616 - Pathology. Clinical medicine Abstract Uvod: Rani probir bolesnika sa stenozom karotidnih arterija kao i poslijeoperacijsko praćenje uĉinaka lijeĉenja trombendarekterektomijom (CEA od engl. carotid endarterectomy) ili endovaskularnim lijeĉenjem (CAS od engl. carotid artery stenting) poradi rane detekcije restenoza karotidnih arterija od kljuĉne je vaţnosti u primarnoj i sekundarnoj prevenciji moţdanog udara. Endotelna disfunkcija (ED) je neizostavna, prodromalna faza u zaĉecima razvoja aterosklerotskog procesa. Ateroskleroza je prema većini današnjih teorija degenerativna bolest s upalnom sastavnicom, koja je etiopatogenetski obiljeţena s jedne strane imunosnim mehanizmima a s druge strane disfunkcionalnošću endotela. Brojni dokazi podupiru hipotezu da razliĉiti medijatori, poput adhezijskih molekula, citokina i kemokina jesu ukljuĉeni u zapoĉimanje i napredovanje aterosklerotske lezije. U ovim procesima velik znaĉaj ima monocitni kemotaksijski protein (MCP-1) i njegov receptor CCR2, stoga MCP-1 moţemo smatrati jednim od najranijih pokazatelja endotelne disfunkcije. Isto tako brojna istraţivanja na ţivotinjskim modelima dokazala su proaterosklerotska svojstva interleukina-18 (IL-18). Proliferacija krvoţilnih glatkih mišićnih stanica (SMC od engl. smooth muscle cells) uzrokom je restenoza, a novije studije istiĉu vaţnost uloge IL-18 u migraciji SMC u aterosklerotskoj leziji. Cilj istraživanja: Osnovni cilj bio je utvrditi prognostiĉku vrijednost odreĊivanja MCP-1 i IL-18 u sistemskoj cirkulaciji te izraţaj MCP-1 na aterosklertoskim plakovima koji su dobiveni tijekom CEA, s ciljem ranog probira bolesnika s povećanim rizikom za razvoj rane restenoze karotidnih arterija. Ispitanici i metode: Ukljuĉili smo ukupno 75 bolesnika sa stenozom karotidne arterije koji su prema kliniĉkim simptomima podijeljeni u dvije podgrupe i to u asimptomatske bolesnike (45 bolesnika) i simptomatske bolesnike (30 bolesnika). Bolesnici su po uĉinjenoj CEA stenozirane karotidne arterije ultrazvuĉno praćeni po algoritmu 7 dana, 30 dana i 90 dana radi ranog utvrĊivanja razvoja restenoze karotidne arterije. Koncentracija MCP-1 i IL-18 u serumu bolesnika odreĊena je ELISA metodom (KIT Quantikine, Invitrogen,CA), a postupak je proveden prema zadanom protokolu 0. dan (prijeoperacijski), 2. dan i 90. dan od CEA. Izraţaj MCP-1 na aterosklerotskim plakovima utvrĊivao se imunohistokemijskom metodom te semikvantitativno procjenjivan s obzirom na intenzitet obojenja. Rezultati: Prijeoperacijska koncentracija MCP-1 u serumu bolesnika sa stenozama karotida i u bolesnika s restenozom karotida statistiĉki su znaĉajano više od koncentracija izmjerenih u serumu kontrolne skupine zdravih osoba. UtvrĊena je statistiĉki znaĉajna razlika izmeĊu skupina bolesnika sa stenozom i restenozom podijeljenih u skupine s urednim i povišenim vrijednostima MCP-1 u plazmi koji je odreĊivan 0 dana (prijeoperacijski) te 90-tog dana od CEA. U bolesnika sa stenozama karotidnih arterija MCP-1 je u pozitivnoj korelaciji s omjerom obujma stuka i bokova, koncentracijom glukoze u plazmi, kolesterola i triglicerida što ukazuje na pozitivan meĊuodnos parametara metaboliĉkog sindroma. Izraţaj MCP-1 na endotelnim i upalnim stanicama plaka u asimptomatskih i simptomatskih bolesnika nije bio statistiĉki znaĉajno razliĉit. MeĊutim, analiza plakova skupine bolesnika sa stenozom karotida u odnosu na bolesnike s restenozom pokazala je statistiĉki znaĉajnu razliku u izraţaju MCP-1. Razina IL-18 nije se statistiĉki znaĉajno razlikovala izmeĊu bolesnika sa stenozom i onih u kontrolnoj zdravoj skupini. U našim rezultatima statistiĉki znaĉajno bila je povišena serumska razina IL-18 samo prijeoperacijski u odnosu na one koji su razvili restenozu. Pored visine i teţine ispitanika IL-18 je u pozitivnoj korelaciji s brojem monocita i limfocita u krvi bolesnika sa stenozom karotidnih arterija što govori u prilog prirode IL-18 kao proupalnog biljega. Zaključak: Ovi rezultati jasno su pokazali prognostiĉku vrijednost odreĊivanja razine MCP-1 i IL-18 u serumu kao i izraţaja MCP-1 na aterosklerotskim plakovima u bolesnika sa stenozom karotida budući da se već prijeoperacijski te po uĉinjenoj CEA moţe sa velikom sigurnošću prepoznati bolesnike u kojih je potrebno intenzivnije praćenje ultrazvukom radi ranog probira onih s prijetnjom razvoja restenoze.
Abstract (english) Introduction: Early screening of patients with carotid artery stenosis as well as postoperative follow up of thrombendarterectomy (CEA) and endovascular (CAS) treatment is instrumental in primary and secondary prevention of stroke. Endothel dysfunction (ED) is an obligatory, prodromal stage in atherosclerosis development. Atherosclerosis is, according to most modern theories, a chronic inflamatory disease ethiopathogenetically marked both by immune response and a dysfunctional arterial endothel. There is much evidence to support a hypothesis that various mediators, such as adhesion molecules, cytokines and chemokines are included in the initiation and progression of atherosclerotic lesions. Monocyte chemotactic protein (MCP-1) as well as his receptor CCR2 are of great significance in this process therefore we can put MCP-1 as one of the earliest signs of endothel dysfunction. Furthermore, research done on animal models have proven significant proatherosclerotic characteristics of Interleukin 18 (IL-18). Smooth muscle cell proliferation (SMC) is a marker of restenosis and newer studies point out the importance of IL-18 in smooth muscle cells migrating into the atherosclerotic lesion. Research aim: We attmpted to ascertain the prognostic value of determinig MCP-1 and IL-18 levels in system circulation as well as measure MCP-1 expression on aherosclerotic plaque (gained through CEA) aimed at early screening and discovery of patients with a high risk of carotid restenosis. Patients and methods: In our study we included 75 patients with carotid artery stenosis that were divided into two groups according to clinical manifestations, asymptomatic (45 patients) and sympotmatic (30 patients). After stenosis of carotid artery has been diagnosed and CEA peroformed we organized a ultrasonographic follow up according to a 7, 30 and 90 day after CEA alghoritm in order to early discover developing carotid artery restenosis. MCP-1 and IL-18 serum levels have been determined using the ELISA method (KIT Quantikine, Invitrogen,CA) and procedure where we implemented follow up according to a 0, 2 and 90 day after CEA alghoritm. Atherosclerotic plaque MCP-1 expression was determined immunohistochemically and was semiquantitatively ascertained depending on staining. Results: Preoperative MCP-1 values in stenosis and restenosis groups was found to be higher with statistical significance when compared to healthy control group serum concentrations. The groups were divides into subgroups according to MCP-1 plasma levels determined on day 0 (before CEA) and on day 90 after CEA. In patients with carotid artery stenosis, MCP-1 is in positive correlation when compared to waist/hip ratio, plasma glucose values, cholesterol and triglicerides which indicates a positive interrelation of metabolic syndrome parameters. Although MCP-1 endothel and plaque inflammatory cell expression in has not shown a statistically significant difference between asymptomatic and symptomatic patients, plaque analysis between stenosis and restenosis patients shows a significant difference in MCP-1 expression. IL-18 levels have shown no statistical significance between stenosis patients when compared to control. Aside from height and weight, IL-18 is in positive correlation with the number of blood monocytes and lymphocytes in patients with carotid artery stenosis which further indicates the proinflammatory nature of IL-18. Conclusion: These results clearly show a great prognostic value in determining MCP-1 and IL-18 serum levels as well as MCP-1 plaque expression because we can now recognize potential for restenosis in patients with carotid artery stenosis and implement intensive follow up both before and after CEA.
Keywords
ateroskleroza
endotelna disfunkcija
interleukin – 18
monocitni kemotaksijski protein–1
stenoza karotidnih arterija
trombarterektomija.
Keywords (english)
atherosclerosis
carotid artery stenosis
endothelial dysfunction
interleukin-18
monocyte chemoattractant protein-1
thrombendarterectomy
Language croatian URN:NBN urn:nbn:hr:188:670976 Study programme Title: Biomedicine Postgraduate (doctoral) study programme Catalog URL https://libraries.uniri.hr/cgi-bin/unilib.cgi?form=D1130218001 Type of resource Text Extent 176 str; 30 cm File origin Born digital Access conditions Closed access Terms of use Created on 2017-01-19 18:20:34
