Biochemical, functional and structural profiling of arterial damage in atherosclerosis

Abstract

Arterite jäikus iseloomustab arterite laienemisvõimet vererõhu tõusu mõjul. Jäigenenud arterid tõstavad vasaku vatsakese järelkoormust, mis omakorda põhjustab vasaku vatsakese hüpertroofiat ja suurendab müokardi hapnikuvajadust. Lisaks langetab arterite jäigenemine diastoolset vererõhku ja vähendab veelgi koronaarperfusiooni, mis viib circulus vitiosus’e tekkeni. Aordi suurenenud jäikus ennustab iseseisvalt üld- ja kardiovaskulaarset suremust kõrge riskiga patsientidel ja üldrahvastikus. Arterite kaltsifikatsioonil on oluline roll ateroskleroosi patogeneesis. Nii eksperimentaalsete kui kliiniliste uuringute tulemused viitavad sellele, et kaltsiumi ladestumine aordi seinas on reguleeritud mitmete kaltsifikatsiooni aktivaatorite ja inhibiitoritega. Osteoprotegeriin on kaltsifikatsiooni inhibiitor, mis kuulub tuumornekroosi-faktori retseptorite perekonda. Loomkatsetega on näidatud osteoprotegeriini protektiivset rolli ateroskleroosi korral. Osteopontiin kuulub samuti kaltsifikatsiooni inhibiitorite hulka ja osaleb põletiku poolt vahendatud aterosklerootilises protsessis. Vitamiin D on oluline lüli luu ainevahetuse ning südame- ja veresoonkonnahaiguste vahel. Kuid vitamiin D roll arterite kaltsifikatsiooni patogeneesis on vastuoluline - nii vitamiin D defitsiit kui liigsus on seotud arterite väljendunud kaltsifikatsiooniga. Süsteemne krooniline põletik ja tugev kestev oksüdatiivne stress on keskses rollis ateroskleroosi patogeneesis. β2-mikroglobuliin on glükoproteiin, mis osaleb põletikulise protsessi regulatsioonis. β2-mikroglobuliini sisaldus seerumis on suurenenud infektsioonide, autoimmuunhaiguste ja ateroskleroosi korral ning on üldsuremuse riski sõltumatuks teguriks. Oksüdeeritud madala tihedusega lipoproteiin on oksüdatiivse stressi marker, mis omab tugevat proaterogeenset toimet ja ennustab kardiovaskulaarseid tüsistusi ja suremust. Alajäsemete arterite ateroskleroos on levinud haigus, mis avaldub vahelduva lonkamise ja rahuolekuvaludena, kuid võib raskematel juhtudel tüsistuda gangreeniga. Samuti on nendel haigetel oluliselt suurenenud ka müokardi- ja ajuinfarkti tekke risk. Varasemate uuringute tulemused viitavad sellele, et süsteemne krooniline põletik, tugev oksüdatiivne stress ja arterite kaltsifikatsioon ning jäigenemine võivad mõjutada alajäseme arterite ateroskleroosi kliinilist kulgu. Ometi on vähe andmeid nende tegurite vaheliste seoste kohta alajäseme arterite ateroskleroosi korral. Käesolevas uurimustöös leidsime, et alajäsemete arterite ateroskleroosiga patsientidel oli suurenenud aordi jäikus ja kaltsifikatsioon, tõusnud osteoprotegeriini, osteopontiini, β2-mikroglobuliini ning oksüdeeritud madala tihedusega lipoproteiini seerumi tase, kuid vähenenud vitamiin D sisaldus seerumis. Nii osteoprotegeriini, osteopontiini kui ka oksüdeeritud madala tihedusega lipoproteiini seerumi tase oli sõltumatult seotud aordi jäikusega nii ateroskleroosiga patsientidel kui ka kliiniliselt tervetel uuritavatel. β2-mikroglobuliini tase oli iseseisvalt seotud aordi jäikusega ateroskleroosiga patsientidel. Aordi kaltsifikatsioon oli sõltumatult seotud aordi jäikusega nii ateroskleroosiga haigetel kui ka kontrollrühma uuritavatel. Aordi kaltsifikatsioon oli seotud vitamiin D taseme suurenemisega ateroskleroosiga haigetel, kuid vitamiin D taseme vähenemisega tervetel inimestel. Lisaks oli aordi jäikus seotud aterosklerootilise kahjustuse ulatuse ja raskusastmega alajäsemete arterite ateroskleroosiga haigetel.

Arterial stiffness describes the rigidity of arterial wall and is one of the earliest detectable manifestations of adverse structural and functional changes within vessel wall. Arterial stiffening increases the left ventricular afterload and promotes development of left ventricular hypertrophy. Moreover, arterial stiffening leads to reduction in diastolic blood pressure, thus diminishing coronary perfusion and causes unbalanced myocardial demand/coronary perfusion pre¬disposing to ischaemia. Aortic stiffness has an independent predictive value for cardiovascular events and all-cause mortality in high-risk patients and in general population. Vascular calcification is another important factor in pathogenesis of atherosclerosis. Experimental and clinical evidence indicate that vascular calcification is an actively regulated process that involves a complex interplay between the promoters and inhibitors of calcification. Osteoprotegerin is an inhibitor of calcification, which is a member of the tumour necrosis factor receptor superfamily. Animal models indicate that osteoprotegerin has a protective role in the arterial system. Osteopontin is also an inhibitor of vascular calcification. It has been shown that osteopontin stimulates inflammatory response and is implicated in the patho¬genesis of atherosclerosis. Vitamin D is another important link between bone metabolism and cardiovascular disease. However, the role of vitamin D in vascular calcification remains controversial. Previous research suggests that both excess and deficiency of vitamin D are pro-moting the development of vascular calcification. Systemic chronic inflammation and high-grade oxidative stress play a key role in development and progression of athero¬sclerosis. The β2-microglobulin has recently emerged as a novel marker of inflammation. Plasma β2-microglobulin is increased in patients with autoimmune diseases, infections and atherosclerosis. A recent population-based study has demonstrated that β2-microglobulin is an independent predictor of all-cause mortality in elderly subjects. Oxidized low-density lipoprotein is a marker of oxidative stress, which exerts strong pro-atherogenic effects and predicts cardiovascular events and mortality. Peripheral arterial disease is a highly prevalent public health problem. The main symptoms of peripheral arterial disease include intermittent claudication, ischaemic rest pain, ulceration and gangrene. Furthermore, patients with the diagnosis of peripheral arterial disease are at high risk of myocardial infarction and stroke. Calcified atherosclerotic arteries, increased arterial stiffness, high-grade oxidative stress and chronic inflammation might influence the clinical course of peripheral arterial disease. However, data about the association between these parameters in patients with peripheral arterial disease are limited. The results of the present study indicate that the patients with peripheral arterial disease had significantly higher aortic stiffness and calcification as well as increased serum levels of osteoprotegerin, osteopontin, β2-microglobulin and oxidized low-density lipoprotein but lower vitamin D levels compared with the controls. Serum osteoprotegerin, osteopontin and oxidized low-density lipoprotein levels were significantly associated with aortic stiffness in the patients with peripheral arterial disease as well as in the healthy subjects. The β2-microglobulin levels were independently associated with aortic stiffness in the patients with symptomatic peripheral arterial disease. Aortic calcification was independently associated with increased aortic stiffness in the patients with peripheral arterial disease and in the clinically healthy subjects. Aortic calcification showed positive correlation with vitamin D levels in the patient group and negative correlation among the control subjects. Finally, aortic stiffness was related to the distribution and severity of atherosclerotic lesions in the lower extremity arteries in patients with peripheral arterial disease.