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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 108 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 109 studije koje bi istražile kompleksnu patofiziologiju kardiovaskularnih bolesti u upalnim bolesticma crijeva., 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 112 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 113 future to investigate the complex pathophysiology of cardiovascular diseases in inflammatory bowel diseases.

Uvod: Zatajivanje srca (ZS) je kompleksan klinički sindrom koji nastaje kao posljedica strukturnog i/ili funkcionalnog poremećaja miokarda čime se onemogućava adekvatno punjenje i/ili pražnjenje krvi iz klijetki za vrijeme srčanog ciklusa. Uz etablirane biljege koji se rutinski mjere u kontekstu ZSa, postoji potreba za novim molekularnim biljezima koji bi mogli pružiti uvid u neki od brojnih patofizioloških mehanizama koji se aktiviraju u ZS-u, čime bi se mogli otvoriti putevi ka novim modalitetima liječenja ili bi se mogla facilitirati prognoza u zatajivanju srca. Tako su katestatin, kao moćan supresor adrenergičke aktivacije te solubilni supresor tumorigeneze 2 (sST2), kao medijator upalnih signalnih puteva i patološke remodelacije miokarda, dva među mnogim novootkrivenim proteinima čija se uloga u posljednje vrijeme istražuje u kontekstu kompleksne patofiziologije ZS-a. Ciljevi istraživanja: Glavni ciljevi ove studije su bili utvrditi potencijalnu razliku u serumskim koncentracijama katestatina i sST2 između ispitanika s ishemijskom u odnosu na neishemijsku etiologiju ZS-a te između podskupina ispitanika stratificiranih s obzirom na očuvanost istisne frakcije lijeve klijetke (LVEF), a koji su bili podijeljeni na 3 klinička fenotipa: ispitanici sa sniženom LVEF (HFrEF), graničnom LVEF (HFmrEF) i očuvanom LVEF (HFpEF). Također je jedan od glavnih ciljeva bio ispitati međusoban odnos između serumskih koncentracija katestatina i sST2 te utvrditi potencijalni odnos navedenih biljega sa stupnjem funkcionalne težine ZS-a izmjerenom posredstvom NYHA funkcionalne klasifikacije. Sporedni ciljevi istraživanja su bili ispitati odnos serumskih koncentracija katestatina i sST2 s relevantnim ehokardiografskim, laboratorijskim i antropometrijskim parametrima ispitanika s akutnim pogoršanjem ZS-a. Ispitanici i metode: Nakon primjene predefiniranih uključnih i isključnih kriterija, uključeno je ukupno 90 ispitanika koji su imali znakove i simptome akutnog pogoršanja ZS-a, a bili su hospitalizirani na Klinici za bolesti srca i krvnih žila KBC-a Split u razdoblju od siječnja 2018. do veljače 2019. godine. Svim bolesnicima je uzeta anamneza, izvršen fizikalni pregled, uzorkovana krv za laboratorijske analize, snimljen 12-kanalni EKG te odrađen ultrazvučni pregled srca. Rezultati: Prosječna dob ispitanika iznosila je 70,3 ± 10,2 godina, a 52,2% su bile žene. Nešto više od polovice ispitanika (56,0%) je imalo neishemijsku etiologiju ZS-a, a velika većina (78,9%) je imalo NYHA funkcionalni stupanj ZS-a od III ili više. Relativna većina ispitanika je imala sniženu LVEF (43,4%) nakon čega je slijedila očuvana LVEF sa 34,4% ispitanika, a 22,2% ispitanika je imalo graničnu LVEF. Podskupina ispitanika s ishemijskom etiologijom ZS-a je imala značajno više serumske koncentracije katestatina u odnosu na podskupinu s neishemijskom etiologijom ZS-a (8,94 ± 6,39 vs. 4,90 ± 2,74 ng/mL, P=0,001), dok se navedene podskupine nisu značajno razlikovale u serumskim koncentracijama sST2 (41,98 ± 32,16 vs. 46,15 ± 38,86 ng/mL, P=0,596). Nije utvrđena statistički značajna razlika u serumskim koncentracijama katestatina među podskupinama ispitanika 142 stratificiranih u 3 klinička fenotipa s obzirom na vrijednost LVEF (7,74 ± 5,64 ng/mL za HFrEF, 5,75 ± 4,19 ng/mL za HFmrEF te 5,35 ± 2,77 ng/mL za HFpEF, P=0,143). Također, nije utvrđena značajna razlika među navedenim skupinama u smislu prosječnih serumskih koncentracija sST2 (47,89 ± 37,74 ng/mL za HFrEF, 34,02 ± 35m89 ng/mL za HFmrEF te 45,01 ± 32,10 ng/mL za HFpEF, P=0,410). U modelu multiple linearne regresije, prilagođene za zbunjujuće faktore, serumske koncentracije katestatina i sST2 su neovisno, pozitivno i značajno korelirale sa stupnjem zatajivanja srca po NYHA funkcionalnoj klasifikaciji (β=0,491, P, Background: Heart failure (HF) is a complex clinical syndrome that is the consequence of the structural and/or functional disorders of the heart which impair adequate filling and/or emptying of blood from the ventricles during the cardiac cycle. Along with established biomarkers that are routinely used in the context of HF, there exists a research interest for new molecular biomarkers that could provide insights in some of the pathophysiological mechanisms that are activated in HF thus opening an avenue toward new treatment modalities and facilitation of prognosis in HF. Such novel biomarkers that are contemporarily being investigated in a context of HF pathophysiology are catestatin (CST), a potent suppressor of adrenergic system and soluble suppressor of tumorigenicity 2 (sST2), a mediator of proinflammatory pathways and adverse ventricular remodeling. Aims of the study: Principal goals of the current study were to determine a potential difference in serum concentrations of CST and sST2 between patients with ischemic vs. non-ischemic etiology of HF and to determine potential difference in concentrations of these biomarkers among patient subgroups stratified in three clinical phenotypes according to the left-ventricular ejection fraction (LVEF): heart failure with reduced LVEF (HFrEF), midrange LVEF (HFmrEF) and preserved LVEF (HFpEF). Additionally, we examined the relationship of CST and sST2 concentrations and their association with the functional disease severity as assessed by the NYHA classification. Secondary goals were to determine potential associations of CST and sST2 concentrations with relevant echocardiographic, laboratory and anthropometric parameters among enrolled patients. Participants and Methods: After applying predefined inclusion and exclusion criteria, a total of 90 participants that had signs and symptoms consistent with the acute worsening of HF and were hospitalized at the Clinic for Cardiovascular Diseases of UHC Split from January 2018 until February 2019, were included in the final analysis. All participants have undergone detailed physical examination and history taking along with anthropometric measurements, peripheral blood sampling, 12-lead ECG recording and a standard transthoracic echocardiography examination. Results: The mean age of participants was 70.3 ± 10.2 years and 52.2% were women. A slightly more than half of participants (56.0%) had non-ishemic etiology of the disease while vast majority (78.9%) were in NYHA III or IV functional class of HF. The relative majority of participants had reduced LVEF (43.4%), followed by the preserved LVEF in 34.4% participants, and a midrange LVEF in 22.2% of participants. A subgroup of participants with ischemic etiology of HF had significantly higher serum CST concentrations compared with a subgroup with non-ischemic etiology of HF (8.94 ± 6.39 vs. 4.90 ± 2.74 ng/mL, P=0.001) while both of these groups did not significantly differ in terms of serum sST2 concentrations (41.98 ± 32.16 vs. 46.15 ± 38.86 ng/mL, P=0.596). There was no significant difference in serum concentrations of CST among subgroups stratified in three clinical 145 phenotypes based on the LVEF values (7.74 ± 5.64 ng/mL for HFrEF, 5.75 ± 4.19 ng/mL for HFmrEF, and 5.35 ± 2.77 ng/mL for HFpEF, P=0.143). Similarly, there was no significant difference among these groups in respect to mean sST2 concentrations (47.89 ± 37.74 ng/mL for HFrEF, 34.02 ± 35.89 ng/mL for HFmrEF, and 45.01 ± 32.10 ng/mL for HFpEF, P=0.410). In the multiple linear regression model, adjusted for confounding variables, concentrations of both CST and sST2 exhibited independent and significant positive correlation with the degree of functional disease burden as assessed by the NYHA classification (β=0.491, P