Krvne maščobe, vnetje in hemostaza ter računalniškotomografska (CT) slika koronarne ateroskleroz

Poropat Flerin, Tadeja (avtor), Jug, Borut (mentor)

Uvod Računalniška tomografska koronarografija (CCTA) omogoča natančno neinvazivno oceno prisotnosti, obsega in sestave aterosklerotičnih plakov. Ateroskleroza je kompleksen proces, v katerega so vključeni presnovni, vnetni in hemostatski dejavniki. V zadnjem desetletju se pozornost usmerja na naprednejše biološke označevalce motene presnove krvnih maščob, vnetja in hemostaze, ki lahko omogočijo zgodnje prepoznavanje posameznikov z višjim tveganjem za napredovanje bolezni. Namen doktorske naloge je bil oceniti povezavo med novimi biološkimi označevalci presnove lipidov (HDL2, HDL3, sdLDL), vnetja (hsCRP), oksidativnega statusa (TAS) in hemostaze (OHP, OCP, OFP) ter prisotnostjo, obsegom in sestavo aterosklerotičnih plakov, določenih s CCTA, ter ovrednotiti njihov pomen pri napovedovanju pomembnih srčno-žilnih dogodkov (MACE). Metode V prospektivno kohortno raziskavo smo vključili 181 zaporednih bolnikov z majhno do zmerno pretestno verjetnostjo za koronarno bolezen (povprečna starost 61 let, 50 % žensk). Pri preiskovancih smo opravili CCTA (na 128-rezinskem dvoenergijskem CT-aparatu) ter sočasno določili koncentracije HDL2, HDL3, sdLDL, hsCRP, TAS, CHP, CKP in CFP. Ocenili smo kalcijevo breme (CACS), število prizadetih segmentov (SIS), število zoženih segmentov (SSS) in sestavo plakov (lipidni, fibrotični, kalcificirani del). Bolnike smo spremljali najmanj dve leti za pojavnost MACE (srčna smrt, neusdoni infarkt, nenačrtovana revaskularizacija). Rezultate smo validirali v večji neodvisni retrospektivni kohorti 750 bolnikov (povprečna starost 61 let, 54 % žensk). Rezultati Ocena CACS je bila možna pri 175 bolnikih, CCTA pri 156 bolnikih, analiza plakov pa na 593 segmentih žil, pri čemer so bili plaki prisotni v 116 segmentih. HDL3 je bil dosledno in statistično značilno obratno povezan s CACS (ρ = −0,35, p < 0,001), SIS (ρ = −0,360, p < 0,001) in SSS (ρ = −0,362, p < 0,001) ter z deležem in volumnom kalcificiranih, fibrotičnih in lipidno bogatih plakov (ρ = −0,20 do −0,22, p < 0,001). V regresijskih modelih je bil HDL3 najmočnejši zaščitni napovednik CACS (β = −11,6; p < 0,001) ter obsega in stopnje ateroskleroze (SIS IRR = 0,647; SSS IRR = 0,579; p < 0,001), kar je potrdila tudi ničelno napihnjena negativna binomska regresija (CACS IRR = 0,65; 95 % IZ 0,44–0,96; p = 0,028). Povezave HDL3 so ostale statistično značilne tudi po prilagoditvi za starost, spol in SCORE2 (CACS β = −0,58, p = 0,001; SIS β = −0,250; SSS β = −0,340; p < 0,001). HDL2 je kazal šibkejše negativne povezave s CACS (ρ = −0,18, p = 0,015), SIS (ρ = −0,137, p = 0,087) in SSS (ρ = −0,129, p = 0,109) ter manj dosledno z deležem plakov. V regresijskih modelih je HDL2 pokazal šibkejši zaščitni učinek, statistično značilen le pri obsegu in stopnji ateroskleroze (SIS: IRR = 0,780, p = 0,043; SSS: IRR = 0,725, p = 0,030), medtem ko povezava s CACS po prilagoditvi ni bila značilna. TAS je bil pozitivno povezan s CACS (ρ = 0,35, p < 0,001), SSS (ρ = 0,323, p < 0,001), SIS (ρ = 0,335, p < 0,001) in z vsemi tipi plakov (ρ = 0,17–0,19, p < 0,001). V regresijskih modelih je bil TAS pozitiven za CACS in SSS, vendar po prilagoditvi za starost, spol in SCORE2 ni ostal statistično značilen. Ostali biološki označevalci (sdLDL, hsCRP, CHP, CKP, CFP) niso izkazali statistično značilnih povezav s CACS, SIS, SSS ali sestavo plakov. V prospektivni kohorti je bilo v medianem obdobju 1794 dni zabeleženih 12 MACE (6,6 %). Najmočnejši napovednik dogodkov je bil obseg ateroskleroze (SIS: HR = 1,87, 95 % IZ 1,30–2,67, p < 0,001; SSS: HR = 1,56, 95 % IZ 1,07–2,27, p = 0,021). Med biološkimi označevalci je statistično napovedno vrednost pokazal le sdLDL (HR 1,38, 95 % IZ 1,01–1,89, p = 0,043). V retrospektivni validacijski kohorti so kazalniki obsega in stopnje ateroskleroze na CCTA (SIS, SSS, obstruktivna bolezen) ohranili napovedno vrednost za MACE z zelo dobro diagnostično natančnostjo (AUC 0,77). Zaključki HDL3 je močno in robustno obratno povezan s kalcijevim bremenom, obsegom in sestavo aterosklerotičnih plakov, kar potrjuje njegovo zaščitno vlogo v procesu ateroskleroze. HDL2 je pokazal šibkejše, a podobno usmerjene zaščitne učinke, medtem ko vnetni, koagulacijski in fibrinolitični označevalci ne kažejo značilne povezave z zgodnjo koronarno aterosklerozo, ki jo ocenimo s CCTA. Obseg ateroskleroze (število prizadetih in zoženih segmentov) je najmočnejši neodvisni napovednik srčno-žilnih dogodkov. Naši izsledki poudarjajo pomen kvantitativne ocene koronarne ateroskleroze s CCTA ter izpostavljajo HDL3 kot ključni ateroprotektivni označevalec koronarne ateroskleroze in srčno-žilnega tveganja.

• Jezik: Slovenski jezik
• Ključne besede: ateroskleroza, CCTA, krvne maščobe, vnetje, hemostaza
• Vrsta gradiva: Doktorsko delo/naloga
• Organizacija: MF - Medicinska fakulteta
• Leto izida: 2026
• PID: 20.500.12556/RUL-184944
• Datum objave v RUL: 18.07.2026

Sekundarni jezik

• Jezik: Angleški jezik
• Naslov: Dyslipidemias, inflammation and hemostasis, and computed tomographic (CT) characteristics of coronary atherosclerosis

Izvleček

Introduction Coronary computed tomography angiography (CCTA) provides accurate non-invasive assessment of the presence, extent, and composition of atherosclerotic plaques. Atherosclerosis is a complex process involving metabolic, inflammatory, and hemostatic factors. Recent research has increasingly focused on emerging lipid, inflammation, and hemostatic biomarkers that may identify individuals at higher risk for disease progression. The aim of our doctoral thesis was to evaluate the associations between novel lipid (HDL2, HDL3, sdLDL), inflammation (hsCRP, TAS), and hemostatic biomarkers (OHP, OCP, OFP) with the presence, extent, and composition of atherosclerotic plaques assessed by CCTA, and to determine their prognostic impact on major adverse cardiovascular events (MACE). Methods In a prospective cohort study, we included 181 consecutive patients with low-to-intermediate pre-test probability for coronary artery disease (mean age 61 years, 50 % women). We perforedm CCTA (using a 128-slice dual-energy scanner) and determined levels of HDL2, HDL3, sdLDL, hsCRP, TAS, OHP, OCP, and OFP. We assessed coronary calcium score (CACS), segment involvement score (SIS), segment stenosis score (SSS), and plaque composition (lipid-rich, fibrocalcific, and calcified components). Patients were followed for a minimum of two years for MACE, including cardiac death, nonfatal myocardial infarction, and unplanned revascularization. Results were validated in a larger independent retrospective cohort of 750 patients (mean age 61 years, 54 % women). Results CACS was possible in 175 patients, CCTA in 156, and plaque analysis in 593 vessel segments, with plaques present in 116 segments. HDL3 was consistently and significantly inversely associated with CACS (ρ = −0.35, p < 0.001), SIS (ρ = −0.360, p < 0.001), and SSS (ρ = −0.362, p < 0.001), as well as with the proportion and volume of calcified, fibrocalcific, and lipid-rich plaques (ρ = −0.20 to −0.22, p < 0.001). In regression models, HDL3 was the strongest protective predictor of CACS (β = −11.6; p < 0.001) and of atherosclerosis extent and severity (SIS: IRR = 0.647; SSS: IRR = 0.579; p < 0.001), which was confirmed by zero inflated negative binomial regression models (CACS IRR = 0.65; 95% CI 0.44–0.96; p = 0.028). These associations remained statistically significant after adjustment for age and sex, and for SCORE2 (CACS β = −0.58, p = 0.001; SIS β = −0.250; SSS β = −0.340; p < 0.001). HDL2 demonstrated weaker inverse associations with CACS (ρ = −0.18, p = 0.015), SIS (ρ = −0.137, p = 0.087), and SSS (ρ = −0.129, p = 0.109) and less consistent associations with plaque burden. In regression models, HDL2 showed a modest protective effect, significant only for atherosclerosis extent and severity (SIS IRR = 0.780, p = 0.043; SSS IRR = 0.725, p = 0.030), whereas associations with CACS were no longer significant after adjustment. TAS was positively associated with CACS (ρ = 0.35, p < 0.001), SSS (ρ = 0.323, p < 0.001), SIS (ρ = 0.335, p < 0.001), and all plaque types (ρ = 0.17–0.19, p < 0.001). In regression models, TAS was positively associated with CACS and SSS, but statistical significance was lost after adjustment. Other biomarkers (sdLDL, hsCRP, OHP, OCP, OFP) were not significantly associated with CACS, SIS, SSS, or plaque composition. During a median follow-up of 1794 days in the prospective cohort, 12 MACE occurred (6.6%). The strongest predictor of events was atherosclerosis extent (SIS: HR = 1.87; 95% CI 1.30–2.67; p < 0.001, SSS: HR = 1.56; 95% CI 1.07–2.27; p = 0.021). Among biomarkers, only sdLDL was associated with the risk of MACE (HR 1.38; 95% CI 1.01–1.89; p = 0.043). In the retrospective validation cohort, CCTA-derived measures of atherosclerosis extent and severity (SIS, SSS, obstructive disease) were strong and accurate independent predictors of MACE, with an area under the curve (AUC) of 0.77. Conclusion HDL3 is consistently and robustly inversely associated with coronary calcium, atherosclerosis extent, and plaque composition, confirming its protective role in atherosclerosis. HDL2 demonstrated weaker protective effects, whereas other markers of inflammation and hemostasisy were not associated with early stage atherosclerosis. Atherosclerosis extent (as assessed by SIS and SSS) is the strongest independent predictor of MACE. Our findings underscore the role of quantitative CCTA and highlight HDL3 as a key atheroprotective biomarker, with potential for improved cardiovascular risk assessment.

• Ključne besede: atherosclerosis, CCTA, dyslipidemias, inflammation, hemostasis