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Title: Inflammatory and Non-Inflammatory Risk Factors in Acquired Aortic Valve Stenosis. Doctoral Thesis
Other Titles: Iekaisīgie un neiekaisīgie riska faktori iegūtas aortas vārstuļa stenozes gadījumā. Promocijas darbs
Authors: Mackēvičs, Vitolds
Tretjakovs, Pēteris
Hofmanis, Juris
Keywords: Medicine, Specialty – Internal Medicine;Doctoral Thesis
Issue Date: 2019
Publisher: Rīga Stradiņš University
Citation: Hofmanis, J. 2019. Inflammatory and Non-Inflammatory Risk Factors in Acquired Aortic Valve Stenosis: Doctoral Thesis: Specialty – Internal Medicine. Riga: Rīga Stradiņš University.
Abstract: Calcific stenosis of the aortic valve (AVS) manifests with fibro-calcific remodelation (transformation) of the aortic valve (AV), which is a slow process of chronic inflammation and calcification with completely unexplored and ambiguous etiology and pathogenesis. Currently, there is no medical treatment to stop or delay the progression of the disease. The only treatment available is a surgical replacement of AV or transcathether aortic valve implantation. With increasing people’s survival the number of patients with clinically relevant AVS is increasing. Almost in 25% of people after the age of 65 echocardiographically AV sclerosis is found and about 17% of these people further develop AVS. The time between diagnosis of AV sclerosis and development of severe AVS is on average 6–8 years. The aim of the research work is to analyze and find out which factors involved in the inflammation and calcification process, cell-produced regulatory molecules (cytokines) affect AVS development in all three AVS severity degrees and to what extent. As a result, some biomarkers could be isolated to predict the rate of progression of AVS. Cell-produced regulatory molecules (cytokines) were detected in blood serum and plasma (thioredoxin reductase-1, mieloperoxidase). The interaction of oxidative stress and inflammation in all three AVS severity degrees was analyzed during the research work. The direct and indirect effects of total cholesterol and its fractions on the development of AVS were also re-evaluated. The conducted clinical-analytical study is a prospective case-control study of mixed type. 102 patients were selected voluntarily according to inclusion and exclusion criteria and divided into two basic groups: the control group and the AVS group. Individuals in the control group were included according to an echocardiographically approved healthy aortic valve between the age of 50 to 80 years, which corresponds to the AVS patients' age at the 2012 European Society of Cardiology and the European Association for Cardio-Thoracic Surgery Guidelines for the management of valvular heart disease. Patients of the AVS group were divided into three subgroups according to the degree of the AV stenosis, based on the 2012 European Society of Cardiology and the European Association for Cardio–Thoracic Surgery Guidelines for the Management of Valvular Heart Disease. In the study for the first time in the Latvia population, inflammatory and noninflammatory factors, cell-produced regulatory molecules (cytokines) in blood serum and plasma were analyzed. The obtained results were compared between the control group and all three AVS grades. Knowing recent studies on etiopathogenesis of the calcific AVS, inflammatory and noninflammatory factors (chemerin, FGF-21, TrxR1 and MPO) that have not been studied in AVS patients so far were identified. The obtained results provide more complete information on the pathogenesis of AVS and the correlation between the analyzed inflammatory and non-inflammatory factors. The relationship between chemerin and TrxR1 shows that inflammation and oxidative stress are already present in the mild AVS grade. The results obtained in the study allow to suggest that chemerin in AVS patients promotes inflammation. Chemerin can be used AVS a good diagnostic marker for the mild AVS. Hereafter, a follow-up program for the AV sclerosis patients should be developed and chemerin should be determined in dynamics to find out whether this biomarker can predict the development of AVS. Analyzing level of FGF-21 in AVS severity grades and its correlation with other factors, it can be concluded that it has anti-inflammatory activity at the beginning of AVS development. FGF-21 role in the subsequent AVS severity grades cannot be unequivocally define AVS it may be associated with both progressive calcification process and counteraction to myocardial hypertrophy. When analyzing MMP and TIMP, we obtained the result of MMP-1 that suggests the role of genetic polymorphism in the progression process of AVS. In the future, it would be useful to study MMP-1 polymorphism to clarify whether 1G allele carriers have slower AVS progression. Analysis of the MPO level and its association with HDL-C shows that HDL-C is indirectly associated with the AVS process, AVS ox-LDL-C levels increase under oxidative stress conditions, resulting in HDL-C dysfunction and formation of ox-HDL-C. The results of MPO and TrxR1 suggest that oxidative stress and progressive calcification are prevalent in moderate to severe AVS. The conducted study shows that AVS is an active process in all degrees of severity regulated by inflammation, oxidative stress, and extracellular remodeling and progressive calcification which depends on them. The results of the study suggest that special attention should be paid to the patients with AV sclerosis and mild AVS, their dynamic monitoring (echocardiography, analysis) should be done to find other biomarkers that can predict disease progression.
Description: The Doctoral Thesis was carried out Rīga Stradiņš University. Defence: at the public session of the Doctoral Council of Medicine on 12 september 2019 at 12.00 in Hippocrates Lecture Theatre, 16 Dzirciema Street, Rīga Stradiņš University.
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Appears in Collections:2015.–2019. gadā aizstāvētie promocijas darbi un kopsavilkumi

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