Arterite jäikuse metaboloomiline profiil ja varajase neerukahjustuse biomarkerid ateroskleroosi korral

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Ateroskleroos on krooniline põletikuline haigus, mis põhjustab arterite ahenemist ja/või sulgumist ning sellest tingituna eluohtlikku organite verevarustuse puudulikkust (nt. infarkt, insult, gangreen). Ateroskleroosi täpsem varajaste riskitegurite ja patofüsioloogiliste tekkemehhanismide tuvastamine on kriitilise tähtsusega, sest arterikahjustustest tingitud südame- ja veresoonkonna haigused on paljudes riikides, sealhulgas Eestis, surmapõhjustena esikohal. Enamasti kaasub ateroskleroosiga ka arterite jäigenemine (s.o. arterite vähenenud võime laieneda vererõhu tõusu mõjul). Aordi suurenenud jäikus ennustab sõltumatult üld- ja kardiovaskulaarset suremust nii erinevates haigusgruppides kui ka üldrahvastikus. Kuna arterite jäigenemine ei ole isoleeritud patoloogiline protsess, vaid on seotud mitmete süsteemsete hemodünaamiliste ja biokeemiliste muutustega, võib just nende seoste detailsem tuvastamine ja analüüs viia sügavama arusaamani veresoonte funktsiooni languse põhjustest. Meie töö eesmärgiks oli tuvastada nii subkliinilise neerukahjustuse kui ka madalmolekulaarsete ühendite profiili (sh lipiidid, aminohapped, süsivesikud) potentsiaalsed seosed arterite jäikusega sümptomaatilise stabiilse südame isheemiatõve ja sümptomaatilise alajäsemete arterite ateroskleroosiga haigetel. Varasemalt on näidatud, et krooniline neerupuudulikkus on seotud arterite funktsiooni häirumisega. Antud töös leidsime, et suurenenud arterite jäikus on sõltumatult seotud uute varajase neerukahjustuse biomarkerite kõrgema tasemega ka nendel ateroskleroosiga haigetel, kellel kliiniliselt väljendunud neeruhaigus puudub. Seega võivad muutused arterite funktsioonis olla seotud neerukahjustusega juba enne kliiniliselt olulise neerufunktsiooni languse väljakujunemist. Samuti leidsime uudsed sõltumatud seosed lipiidide ainevahetuse ühendite (atsüülkarnitiinid, fosfatidüülkoliinid, lüsofosfatidüülkoliinid), aordi jäikuse, endoteeli düsfunktsiooni ning teatud hemodünaamiliste näitajate vahel. Tuvastatud arterite kahjustusega seotud madalmolekulaarsed ühendid võivad tulevikus klassikaliste lipiidide ainevahetuse markerite (üldkolesterool, kõrge ja madala tihedusega lipoproteiinid, triglütseriidid) kõrval rakendust leida uudsete südame- ja veresoonkonna haiguste indikaatoritena, riski täpsema hindamise vahenditena, aga miks mitte ka ravi sihtmärkidena.Atherosclerosis is a chronic inflammatory disorder where the arteries become narrowed and/or occluded and the blood supply to vital organs is restricted leading to potentially fatal complications (e.g. myocardial infarction, stroke, gangrene). A more precise determination of risk factors and pathophysiological mechanisms of atherosclerosis is of critical importance since cardiovascular disease is the leading global cause of death. Atherosclerosis is generally accompanied by increased arterial stiffness (defined as the reduced capability of arteries to expand in response to rising blood pressure). Increased aortic stiffness is an independent predictor of cardiovascular and all-cause mortality in many different patient groups and in the general population. Since arterial stiffening is not an isolated pathological process, but is associated with systemic hemodynamic and biochemical alterations, a more detailed insight into these associations can lead to deeper understanding of the mechanisms contributing to vascular dysfunction. In our study, we aimed to determine whether sublinical renal damage and serum low molecular weight metabolites (e.g. lipids, amino acids, carbohydrates) associate with arterial stiffness, hemodynamical parameters and inflammation in patients with symptomatic coronary artery disease and in patients with symptomatic peripheral arterial disease. Findings from previous studies indicate that chronic renal disease is associated with arterial dysfunction. We found independent relationships between novel early biomarkers of renal damage and aortic stiffness in atherosclerotic patients without clinically significant renal disease. Thus, our results suggest that arterial stiffness is an early contributor of renal damage. We also determined novel independent associations between intermediates of lipid metabolism (acylcarnitines, phosphatidylcholines, lysophosphatidylcholines), aortic stiffness, endothelial dysfunction and certain hemodynamic parameters. Apart from the classical lipid biomarkers (total cholesterol, low-density and high-density lipoproteins, triglycerides) that have long been used in everyday clinical practice, the arterial damage-related low molecular weight lipids identified in our study may prove to be useful in the early detection and risk stratification of cardiovascular disease in the future, possibly even becoming sufficient therapeutic targets

Alkaptonuuriast põhjustatud aordiklapi kitsenemus, südame pärgarteri haigus, teisene osteoartroos ja nende kirurgiline ravi

Alkaptonuuria on haruldane, progresseeruv ja pöördumatu geneetiline ainevahetushaigus. Klassikalise kliinilise triaadina esinevad selle korral homogentisiinhappe eritus uriiniga, sidekoe (eriti kõhrkoe) pigmentatsioon ning degeneratiivne liigesepõletik. Aordiklapi kitsenemus on alkaptonuuriast põhjustatud enam levinud südamehaigus, mille kaugelearenenud faasis võib olla vajalik kirurgiline ravi. Vahel võib klapirikkele lisanduda ka pärgarterite stenoseeriv kahjustus ja teisene osteoartroos. Eesti Arst 2013; 92(7):399–40

Viie aasta elulemus pärast plaanilist aordi aneurüsmi ravi avatud ja endovaskulaarsel meetodil

Eesti Arst 2023; 102(6–7):35

Five-year survival after elective open and endovascular aortic aneurysm repair

Background and objective: Current evidence suggests short-term survival benefit from endovascular aneurysm repair (EVAR) versus open surgical repair (OSR) in elective abdominal aortic aneurysm (AAA) procedures, but this benefit is lost during long-term follow-up. The aim of this study was to compare short- and mid-term all-cause mortality in patients with non-ruptured aneurysm treated by OSR and EVAR; and to assess the rate of complications and reinterventions, as well as to evaluate their impact on survival. Methods: The medical records of the non-ruptured AAA patients undergoing OSR or EVAR between 1 January 2011 and 31 December 2019 at Tartu University Hospital, Estonia, were retrospectively reviewed. We gathered survival data from the national registry (mean follow-up period was 3.7 +/- 2.3 years). Results: A total of 225 non-ruptured AAA patients were treated operatively out of whom 95 (42.2%) were EVAR and 130 (57.8%) were OSR procedures. The difference in estimated all-cause mortality between the OSR and EVAR groups at day 30 was statistically irrelevant (2.3% vs 0%; p = 0.140), but OSR patients showed statistically significantly higher 5 year survival compared with EVAR patients (75.3% vs 50.0%, p = 0.002). Complication and reintervention rates for the EVAR and OSR groups did not differ statistically (26.3% vs 16.9%, p = 0.122; 10.5% vs 11.5%, p = 0.981, respectively). Multivariate analysis revealed that greater aneurysm diameter (p = 0.012), EVAR procedure (p = 0.016), male gender (p = 0.023), and cerebrovascular diseases (p = 0.028) were independently positively associated with 5-year mortality. Conclusions: Thirty-day mortality, and complication and reintervention rates for EVAR and OSR after elective AAA repair were similar. Although the EVAR procedure is an independent risk factor for 5-year mortality, higher age and greater proportion of comorbidities among EVAR patients may influence not only the choice of treatment modality, but also prognosis.Peer reviewe

Effect of kidney donation on bone mineral metabolism.

Kidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age (53±10 vs 50±14 years, p = 0.33), BMI (26.3±2.89 vs 25.9±3.65, p = 0.59), systolic BP (128±13 vs 130±6 mmHg, p = 0.59), diastolic BP (80±9 vs 81±9 mmHg, p = 0.68) and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m2, p = 0.89). eGFR reduced from 84.4±20.2 to 52.3±17.5 ml/min/1.73m2 (p<0.001) by day 1 with incomplete recovery by 12 months (67.7±22.6; p = 0.002). Phosphate increased by day 1 (1.1(0.9-1.2) to 1.3(1.1-1.4) mmol/L, p <0.001) but declined to 0.8(0.8-1.0) mmol/L (p<0.001) before normalizing by 6 weeks. Calcium declined on day 1 (p = 0.003) but recovered at 6 weeks or 12 months. PTH and FGF-23 remained unchanged, but α-Klotho reduced by day 1 (p = 0.001) and remained low at 6 weeks (p = 0.02) and 1 year (p = 0.04). In this study, we conclude that kidney donation results in acute disturbances in mineral metabolism characterised by a reduced phosphate and circulating α-Klotho concentration without acute changes in the phosphaturic hormones FGF23 and PTH

Metabolomics of Arterial Stiffness

Arterial stiffness (AS) is one of the earliest detectable signs of structural and functional alterations of the vessel wall and an independent predictor of cardiovascular events and death. The emerging field of metabolomics can be utilized to detect a wide spectrum of intermediates and products of metabolism in body fluids that can be involved in the pathogenesis of AS. Research over the past decade has reinforced this idea by linking AS to circulating acylcarnitines, glycerophospholipids, sphingolipids, and amino acids, among other metabolite species. Some of these metabolites influence AS through traditional cardiovascular risk factors (e.g., high blood pressure, high blood cholesterol, diabetes, smoking), while others seem to act independently through both known and unknown pathophysiological mechanisms. We propose the term &lsquo;arteriometabolomics&rsquo; to indicate the research that applies metabolomics methods to study AS. The &lsquo;arteriometabolomics&rsquo; approach has the potential to allow more personalized cardiovascular risk stratification, disease monitoring, and treatment selection. One of its major goals is to uncover the causal metabolic pathways of AS. Such pathways could represent valuable treatment targets in vascular ageing

Severity of Osteoarthritis Is Associated with Increased Arterial Stiffness

Objective. Osteoarthritis (OA) is associated with increased cardiovascular comorbidity and mortality. Evidence is lacking about whether arterial stiffness is involved in OA. The objective of our study was to find out associations between OA, arterial stiffness, and adipokines. Design. Seventy end-stage knee and hip OA patients (age 62±7 years) and 70 asymptomatic controls (age 60±7 years) were investigated using the applanation tonometry to determine their parameters of arterial stiffness. Serum adiponectin, leptin, and matrix metalloproteinase 3 (MMP-3) levels were determined using the ELISA method. Correlation between variables was determined using Spearman’s rho. Multiple regression analysis with a stepwise selection procedure was employed. Results. Radiographic OA grade was positively associated with increased carotid-femoral pulse wave velocity (cf-PWV) (r=0.272, p=0.023). We found that OA grade was also associated with leptin and MMP-3 levels (rho=-0.246, p=0.040 and rho=0.235, p=0.050, resp.). In addition, serum adiponectin level was positively associated with augmentation index and inversely with large artery elasticity index (rho=0.293, p=0.006 and rho=-0.249, p=0.003, resp.). Conclusions. Our results suggest that OA severity is independently associated with increased arterial stiffness and is correlated with expression of adipokines. Thus, increased arterial stiffness and adipokines might play an important role in elevated cardiovascular risk in end-stage OA

Early Biomarkers of Renal Damage in Relation to Arterial Stiffness and Inflammation in Male Coronary Artery Disease Patients

Background/Aims: Plasma neutrophil gelatinase-associated lipocalin (NGAL), urinary liver-type fatty acid-binding protein (L-FABP) and urinary kidney injury molecule-1 (KIM-1) have emerged as promising biomarkers for both acute and chronic kidney injury that also provide prognostic value for cardiovascular morbidity and mortality. Our aim was to evaluate their relationships with arterial stiffness and inflammation in coronary artery disease (CAD) patients and in clinically healthy controls. Methods: We studied 52 patients with CAD (age 63.2 ± 9.2 years) and 41 healthy controls (age 60.1 ± 7.2 years). Urinary L-FABP and KIM-1 as well as serum NGAL, adiponectin and resistin levels were measured using the enzyme-linked immunosorbent assay method. The technique of applanation tonometry was used for non-invasive pulse wave analysis and pulse wave velocity assessments. Results: Urinary L-FABP and KIM-1 were independent determinants of cf-PWV for the CAD patients (R2=0.584, Pr=0.31, P=0.028) only for the patients, while NGAL correlated with WBC count (rho=0.29, P=0.038; r=0.35, P=0.029) and resistin (rho=0.60, PConclusion: Our findings suggest that urinary L-FABP and KIM-1 may be independently associated with aortic stiffness in individuals with CAD

Metabolomic profiles of lipid metabolism, arterial stiffness and hemodynamics in male coronary artery disease patients

Background/objectives: Metabolomic profiling allows to take a detailed look at lipid metabolism and to study the levels and roles of its numerous intermediates and products in the pathogenesis of cardiovascular disease (CVD). This study aimed to investigate the relationship between the metabolic profiles of lipid metabolism, arterial stiffness and hemodynamics in patients with coronary artery disease (CAD) and for healthy controls. Methods: Serum levels of 186 metabolites were determined with the AbsoluteIDQ™ p180 kit (BIOCRATES Life Sciences AG, Innsbruck, Austria). The technique of applanation tonometry was used for non-invasive pulse wave analysis and carotid-femoral pulse wave velocity (cf-PWV) assessments. Principal component analysis (PCA) was carried out in order to reduce the large number of correlated metabolites to fewer uncorrelated factors. Results: Elevated levels of C16:1, C18:1, C3-DC(C4-OH), PC aa C40:6, Met-SO/Met, and reduced levels of lysoPC a C18:2 were observed in the CAD group compared to the healthy controls. The cf-PWV showed positive correlations with C14, C16:1, (C2 + C3) / C0, C2 / C0 and the CPT-1 ratio for the CAD group. Moreover, PCA-derived factor 3 (medium- and long-chain acylcarnitines) proved to be an independent determinant of cf-PWV for these patients. Conclusions: We demonstrated an independent association between the serum medium- and long-chain acylcarnitine profile and aortic stiffness for the CAD patients. In addition to the lipid-related classical CVD risk markers, the intermediates of lipid metabolism may serve as novel indicators for altered vascular function