THE ROLE OF VALVE INTERSTITIAL CELLS IN THE PATHOGENESIS OF CALCIFIC AORTIC VALVE DISEASE
Tesi di Dottorato
Data di Pubblicazione:
2014
Citazione:
THE ROLE OF VALVE INTERSTITIAL CELLS IN THE PATHOGENESIS OF CALCIFIC AORTIC VALVE DISEASE / P. Poggio ; tutor: E. Tremoli ; correlatore: G. Ferrari ; coordinatore: A. E. Panerai. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2014 Jan 16. 26. ciclo, Anno Accademico 2013. [10.13130/poggio-paolo_phd2014-01-16].
Abstract:
Calcific aortic valve disease (CAVD) is the most common etiology of acquired aortic valve disease. The early stage is characterized by thickening of the leaflets and none or marginal effect on the
mechanical properties of the valve, while the end stage disease is associated with impaired leaflet motion and resistances to blood flow. These conditions are known as aortic valve sclerosis (AVSc) and calcific aortic valve stenosis (AVS), respectively. AVSc is present in 25–30% of patients over 65 years of age and
in up to 40% of those over 75 years of age. Moreover, since AVSc hemodynamics are comparable to healthy controls, the presentation of the
disease is largely asymptomatic and almost 10% of these patients will progress to AVS within 10 years from the
diagnosis. Patients with severe AVS have a life expectancy of less than 10 years if untreated. Currently the main indication for AVS is aortic valve replacement (AVR).
Over the last decade several clinical trials have been performed to halt the progression of CAVD with contradictory results. The early enthusiastic findings documenting a reduction in the progression of CAVD have been questioned by later randomized studies, which show substantial equivalence between treatments and placebo. It has been proposed that CAVD therapy may have been initiated too late in the course of the disease to have the desired effect. In conclusion, there is currently no definitive therapy supported by prospective and randomized studies to halt or delay the progression of CAVD, leaving AVR the treatment of choice. Therefore, the identification of high-risk patients at early stages of degeneration will open new perspectives for the appropriate timing of therapeutic intervention on future clinical trials.
We implemented in vitro and ex vivo experiments to better characterize the early asymptomatic stage of CAVD and to evaluate osteopontin (OPN) as a potential biomarker in the progression of this degenerative disease. Moreover, we focused on OPN role in valve endothelial cells (VEC) migration, as well as valve interstitial cells (VIC) osteoblastic-like activation and biomineralization. Our results supported the correlation between CAVD progression and increased OPN levels in aortic valve tissue and blood. Interestingly, in advance stages of calcification, we demonstrated that the overexpressed OPN had different post-translational modification compared to healthy controls. Moreover, we analyzed bone morphogenetic protein 4 (BMP4) pathway and mechanical tensile stretch as cause of VIC osteogenic-like transdifferentiation and calcium accumulation.
Tipologia IRIS:
Tesi di dottorato
Keywords:
Calcific aortic valve disease ; valve endothelial cells ; valve interstitial cells ; aortic stenosis ; aortic sclerosis
Elenco autori:
P. Poggio
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