Thesis defence in the University of Oulu

Doctoral Candidate

Licenciate in medicine, specialist in pathology, neuropathologist Juha Näpänkangas

Faculty and research unit

University of Oulu Graduate School, Faculty of Medicine, Cancer and translational medicine research unit

Field of study

Pathology

Date and time of the thesis defence

18.10.2019 12:00

Place of the thesis defence

Auditorium F202 of the Faculty of Medicine (Aapistie 5 B, Oulu)

Topic of the dissertation

Pathogenesis of calcific aortic valve disease

Opponent

Professor Johanna Kuusisto, University of Eastern Finland and Kuopio university hospital

Custos

Associate professor Jaana Rysä, University of Eastern Finland

Pathogenesis of calcific aortic valve disease

The study was aimed to identify differentially expressed transcripts and molecular markers, many of them associated also with atherosclerosis, taking part in the pathophysiology behind calcific aortic valve disease (CAVD). The aortic valves used in the study were obtained during years 2007-2011 in the Oulu university hospital. It was demonstrated that these molecules are expressed in aortic valves and dysregulated in calcified valves. These results can help to clarify the mechanisms driving CAVD, thus being potential targets for pharmacological therapy. Furthermore, the studied molecules may reflect the stage and possible subgroups of CAVD.

CAVD represents a disease spectrum, ranging from mild aortic valve sclerosis to severe obstructive aortic stenosis (AS), associated with a high risk of myocardial infarction and cardiovascular death. It is a common disease in the Western countries, particularly in older age groups. Thus, with the aging populations, its prevalence is likely to increase. The most important risk factors for CAVD, along with old age, are the other risk factors for atherosclerosis (e.g. male sex, hypertension, smoking, and disturbances in lipid metabolism), as well as developmental disorders of the aortic valve. The most common and the most important developmental disorder is bicuspid aortic valve, which results in the calcification of the valve at a younger age when compared with the individuals with a normal tricuspid valve.

Today, CAVD is recognized as an actively regulated disease. Mechanical stress and injury of the endothelial cells covering the valve are the initiating factors, followed by lipid accumulation and oxidation, leading to inflammation, fibrosis and calcification. Ultimately, the progressive calcification hinders the normal valvular function and obstructs the flow of blood through the valve. The only effective treatment for symptomatic AS is aortic valve replacement. The trials with pharmacological treatments, mainly with anti-atherosclerotic drugs, have not been successful in slowing the progression of the disease. Thus, the only known means to prevent CAVD is to lead a healthy lifestyle.

The results showed that the renin-angiotensin system, also present in atherosclerosis, is active in CAVD and that the expression of the factors associated with it and regulating it (e.g. apelin-APJ axis, renin, prorenin, and (pro)renin receptor) is changed. This favors the profibrotic branch of renin-angiotensin system and leads to disease progression. There are many steps in the renin-angiotensin system that could be modulated with drug therapies, thus slowing down the disease progression. In addition, the expressions of granzymes and perforin were found to be enhanced, which increases inflammation and the cytotoxic reactions related to it. These factors are also potential targets for medication. Furthermore, an increased expression of podoplanin was found to be associated with calcifications, probably reflecting the differentiation of stromal cells into cells forming calcifications and even bone. While calcification, once started, is a self-promoting and progressive process, these cells may provide a target for pharmacological therapies even during the later stages of CAVD. The calcified tricuspid aortic valves express more podoplanin than the bicuspid ones, which may be a result of the differences in the disease process of the valves with developmental disorders in comparison with normal tricuspid valves.

 

Dissertation

Last updated: 10.10.2019