Piero Marin Živković

Ime i prezime: dr. sc. PIERO MARIN ŽIVKOVIĆ, dr. med.
 
Naslov disertacije: „KATESTATIN I POKAZATELJI ELASTIČNOSTI ARTERIJSKE STIJENKE U BOLESNIKA S UPALNIM BOLESTIMA CRIJEVA“
 
Mentor: izv. prof. dr. sc. JOŠKO BOŽIĆ
 
Datum obrane: 2. studenoga 2022.
 
Poveznnica: 
https://repozitorij.mefst.unist.hr/islandora/object/mefst:1693/datastream/PDF/view
Kvalifikacijski znanstveni radovi za doktorsku disertaciju:
Zivkovic PM, Matetic A, Tadin Hadjina I, Rusic D, Vilovic M, Supe-Domic D, Borovac JA, Mudnic I, Tonkic A, Bozic J. Serum Catestatin Levels and Arterial Stiffness Parameters Are Increased in Patients with Inflammatory Bowel Disease. J Clin Med. 2020;9(3):628.
doi: 10.3390/jcm9030628.
SAŽETAK:
Uvod: Katestatin je važan peptid u patofiziologiji kroničnih upalnih stanja. Pacijenti s upalnim bolestima crijeva (IBD) imaju povišen kardiovaskularni rizik (CV) u odnosu na opću populaciju, usprkos nižoj prevalenciji tipičnih rizika za KV bolesti. U upalnim bolestima crijeva nedostaje kliničkih studija vezanih uz katestatin kao i analize parametara arterijske krutosti u odnosu na razinu katestatina.
Cilj: Glavni ciljevi ove studije su bili utvrditi potencijalnu razliku u razini katestatina i pokazateljima elastičnosti arterijske stijenke između bolesnika s upalnim bolestima crijeva u odnosu na kontrolnu skupinu ispitanika. Sporedni ciljevi istraživanja su bili ispitati postoji li razlika u razinama katestatina te parametara elastičnosti arterijske stijenke između skupina ispitanika s ulceroznim kolitisom (UC) i Crohnovom bolesti (CD) te između ispitanika na biološkoj terapiji i onih liječenih drugom terapijom. Također kao jedan od sporednih ciljeva je bio ispitati postoji li povezanost razina katestatina s određenim antropometrijskim, kliničkim, laboratorijskim parametrima aktivnosti upalnih bolesti crijeva te s pokazateljima elastičnosti arterijske stijenke.
Metode: Nakon primjene predefiniranih uključnih i isključnih kriterija, uključeno je ukupno 80 ispitanika (od kojih 45 ispitanika s Crohnovom bolesti te 35 ispitanika s ulceroznim kolitisom) te 75 zdravih kontrolnih ispitanika. Svim bolesnicima je uzeta anamneza, izvršen fizikalni pregled uz antropomentrijska mjerenja, uzorkovana krv za laboratorijske analize. Serumska koncentracija katestatina (Phoenix Pharmaceuticals Inc., Burlingame, CA, SAD) je određena dvostrukim enzim-imunoadsorpcijskim testom (engl. enzyme-linked immunosorbent assay, ELISA) po uputstvima proizvođača. Za procjenu arterijske krutosti korištena je aplanacijska tonometrija (AT), neinvazivna metoda kojom se određuje brzina pulsnog vala (engl. pulse wave velocity, PWV), koja ima snažnu korelaciju s invazivnim metodama. Procjena aktivnosti bolesti u ispitanika s IBD-em je urađena od strane dva iskusna specijalista gastroenterologije koji su procjenjivali neovisno. Korišteni su standardni klinički i endoskopski zbirovi.
Rezultati: Razine katestatina bile su statistički značajno više u ispitanika s IBD-om u usporedbi s kontrolnim ispitanicima (11.29 ± 9.14 vs. 7.13 ± 6.08 ng/mL; p = 0.001). Ispitanici s UC su imali statistički značajno višu razinu katestatina u usporedbi s CD ispitanicima (13.50 ± 9.58 vs. 9.03 ± 6.92 ng/mL; p = 0.021), koja je perzistirala statistički značajnom nakon ANCOVA analize. IBD ispitanicima su izmjerene statistički značajno više vrijednosti cAIx (16.36 ± 9.95 vs. 10.31 ± 8.19 %; p < 0.001), cAIx-75 (14.88 ± 10.59 vs. 6.87 ± 9.50 %; p < 0.001), PWV (8.06 ± 3.23 vs. 6.43 ± 1.47 m/s; p < 0.001) i frekvencije pulsa (72.04 ± 12.21 vs. 68.13 ± 9.14 otkucaja/min; p = 0.027) u odnosu na kontrolnu skupinu ispitanika, razlika navedenih parametara arterijske krutosti među ispitivanim skupinama perzistirala i nakon prilagodbe za dob i BMI (p < 0.05). IBD skupina je imala statistički značajno više ispitanika s oštećenjem ciljnog organa, definiranu kao PWV>10 m/s (17.5%, N=14 vs. 2.7%, N=1; p = 0.002), a skupina ispitanika s pozitivnim kriterijima PWV za ciljno oštećenje organa (PWV>10 m/s) je imala statistički značajno višu razinu katestatina (20.7-23 vs. 7,4-11 ng/mL; p = 0.001). Multipla linearna regresijska analiza utvrdila je kako je PWV neovisni prediktor razine katestatina (β = 1.20; p < 0.001). Binomijalna logistička regresija utvrdila je kako su katestatin (1.089 (1.022-1.161), p = 0.009), PWV (1.515 (1.166-1968), p = 0.002) i cAIx-75 (1.060 (1.024-1.097), p = 0.001) statistički značajni prediktori pozitivnog IBD statusa.
Zaključak: Ispitanici s upalnim bolestima crijeva imaju statistički značajno višu razinu katestatina te veću arterijsku krutost u usporedbi sa zdravim ispitanicima. Katestatin i brzina pulsnog vala su dokazani kao neovisni prediktori prisutnosti upalne bolesti crijeva. Povišen katestatin i brzina pulsnog vala u ispitanika s upalnim bolestima crijeva bi mogli upućivati na povišen kardiovaskularni rizik u ovoj populaciji, neovisno o klasičnim čimbenicima rizika za kardiovaskularne bolesti. Konačno, u budućnosti su potrebne nove pretkliničke i translacijske studije koje bi istražile kompleksnu patofiziologiju kardiovaskularnih bolesti u upalnim bolesticma crijeva.
 
SUMMARY:
Background: Catestatin is an important peptide in the pathophysiology of chronic inflammatory conditions. Patients with inflammatory bowel diseases (IBD) have an increased cardiovascular (CV) risk compared to the general population, despite the lower prevalence of typical CV disease risks. In IBD, there is a lack of clinical studies related to catestatin, as well as analyzes of arterial stiffness parameters in relation to catestatin levels.
Aims of the study: The main objectives of this study were to determine the potential difference in the level of catestatin and indicators of arterial wall elasticity between patients with inflammatory bowel diseases compared to the control group of subjects. The secondary objectives of the study were to examine whether there is a difference in catestatin levels and arterial wall elasticity parameters between groups of subjects with ulcerative colitis (UC) and Crohn's disease (CD), and between subjects on biological therapy and those treated with other therapy. Also, as secondary goals, were to examine whether there is a connection between catestatin levels and certain anthropometric, clinical, and laboratory parameters of inflammatory bowel disease activity and with indicators of the elasticity of the arterial wall.
Participants and Methods: A total of 80 IBD subjects were included (of which 45 subjects with Crohn's disease and 35 subjects with ulcerative colitis) and 75 healthy control subjects, after applying predefined inclusion and exclusion criteria. Anamnesis was taken from all patients, a physical examination was performed with anthropometric measurements and blood was sampled for laboratory analysis. The serum concentration of catestatin (Phoenix Pharmaceuticals Inc., Burlingame, CA, USA) was determined by a double enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions. Applanation tonometry (AT), a non-invasive method for determining pulse wave velocity (PWV), which has a strong correlation with invasive methods, was used to assess arterial stiffness. Assessment of disease activity in subjects with IBD was performed by two experienced gastroenterology specialists who assessed disease activity parameters independently. Standard clinical and endoscopic collections were used.
Results: Catestatin levels were in significantly positive corelation in subjects with IBD compared to control subjects (11.29 ± 9.14 vs. 7.13 ± 6.08 ng/mL; p = 0.001). Subjects with UC had a statistically significant higher level of catestatin compared to CD subjects (13.50 ± 9.58 vs. 9.03 ± 6.92 ng/mL; p = 0.021), this corelation remained significant after ANCOVA analysis. Subjects with IBD had statistically significant higher values of cAIx (16.36 ± 9.95 vs. 10.31 ± 8.19 %; p < 0.001), cAIx-75 (14.88 ± 10.59 vs. 6.87 ± 9.50 %; p < 0.001), PWV (8.06 ± 3.23 vs. 6.43 ± 1.47 m/s; p < 0.001) and pulse frequency (72.04 ± 12.21 vs. 68.13 ± 9.14 beats/min; p = 0.027) compared to the control group of subjects, the difference in the mentioned parameters of arterial stiffness among the studied groups persisted even after adjustments for age and BMI (p < 0.05). The IBD group had statistically significant more subjects with target organ damage, defined as PWV>10 m/s (17.5%, N=14 vs. 2.7%, N=1; p = 0.002), and the group of subjects with positive PWV criteria for target organ damage (PWV>10 m/s) had a statistically significant higher catestatin level (20.7-23 vs. 7.4-11 ng/mL; p = 0.001). Multiple linear regression analysis determined that PWV is an independent predictor of catestatin level (β = 1.20; p < 0.001). Binomial logistic regression found that catestatin (1.089 (1.022-1.161), p = 0.009), PWV (1.515 (1.166-1968), p = 0.002) and cAIx-75 (1.060 (1.024-1.097), p = 0.001) statistically significant predictors of positive IBD status.
Conclusions: Subjects with IBD have a statistically significant higher level of catestatin and greater arterial stiffness compared to healthy subjects. Catestatin and pulse wave velocity have been shown to be independent predictors of the presence of inflammatory bowel disease. Elevated catestatin and pulse wave velocity in subjects with inflammatory bowel disease could indicate an increased cardiovascular risk in this population, independent of classical risk factors for cardiovascular disease. Finally, new preclinical and translational studies are needed in the future to investigate the complex pathophysiology of cardiovascular diseases in inflammatory bowel diseases. Ispiši stranicu