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Calcific aortic valve disease (CAVD) is associated with increased presence of myofibroblasts, osteoblastic cells and, occasionally, adipocytes and chondrocytes in lesions. The ectopic cell types in diseased valves may be elaborated by an unidentified multipotent progenitor subpopulation within the valve interstitial cells (VICs) that populate the valve interstitium. Notably, lesions form preferentially in the fibrosa layer, the stiffer layer of the valve leaflet. It has been shown that differentiation of VICs to myofibroblasts and osteoblasts is modulated by matrix stiffness. However, the molecular mechanisms involved in mediating stiffness-dependent mechanotransduction remain obscure. The objectives of this thesis were: (1) to determine whether VICs contain a subpopulation of multipotent mesenchymal progenitor cells and to measure the frequencies of the mesenchymal progenitors and osteoprogenitors; (2) to determine the role of β-catenin and matrix stiffness in transforming growth factor-β1 (TGF-β1)-induced myofibroblast differentiation of VICs; and (3) to preliminarily investigate the involvement of four and a half LIM domains protein 2 (FHL2) in CAVD and stiffness-dependent mechanotransduction downstream of RhoA in VICs. Firstly, VICs were found to contain a subpopulation of mesenchymal progenitors that are inducible to osteogenic, myofibroblastic, adipogenic, and chondrogenic lineages. The frequencies of mesenchymal progenitors and osteoprogenitors were significantly higher than other reported sources. Secondly, it was demonstrated that β-catenin is required in TGF-β1-induced, matrix stiffness-regulated myofibroblast differentiation. Notably, TGF-β1 was only able to induce β-catenin nuclear translocation and myofibroblast differentiation on matrices with fibrosa-like stiffness, but not on matrices with ventricularis-like stiffness. Thirdly, FHL2 was found to be upregulated and colocalized with runt-related transcriptional factor 2 (Runx2) in lesions in the fibrosa layer of diseased valves, suggesting its role in osteogenic processes in CAVD. Notably, increasing matrix stiffness increased FHL2 nuclear translocation and RhoA activity in VICs. Preliminary data showed that matrix stiffness regulates FHL2 nuclear translocation via RhoA activity. These results suggest that differentiation of the rich valve progenitor subpopulation, regulated by both mechanical and biochemical cues, may contribute to the preferential occurrence of ectopic cell types in the fibrosa in CAVD. More broadly, these results highlight the critical role of mechanical environment in modulating cellular biochemical signaling.

In der Literatur wird bei kleineren Patientenkohorten über eine erhöhte Prävalenz des linkskoronaren Versorgungstyps bei Patienten mit valvulärer Aortenklappenstenose berichet. Es wird auch postuliert, dass dies nur Patienten mit Aortenklappenstenose und bikuspider Aortenklappe betrifft. Die funktionelle Konsequenz der Kombination aus einem linksdominanten koronaren Versorgungstyp und valvulärer Aortenklappenstenose ist bisher nicht klar. Ziel der vorliegenden Arbeit war es, die Prävalenz des Linksversorgungstyps in einer großen Kohorte von Patienten mit diagnostizierter relevanter Aortenklappenstenose im Vergleich zu einer Kontrollkohorte ohne Aortenklappenstenose zu analysieren. Es galt ferner zu prüfen, ob sich eine etwaig höhere Prävalenz des koronaren Linksversorgungstyps auf Patienten mit bikuspider Aortenklappe beschränkt, ob der koronare Linksversorgungstyp ein unabhängiger Risikofaktor für die Progression einer Aortenklappenstenose ist und ob die koronare Linksdominanz Relevanz für das postoperative beziehungsweise postinterventionelle Outcome nach Aortenklappenersatz hat. Über eine Datenbankabfrage wurden alle Patienten identifiziert, die vom 01.01.2007 bis 31.12.2008 in der Klinik für Innere Medizin und Kardiologie im Herzzentrum der Universität Leipzig aufgenommen wurden. Zwei Subkohorten wurden extrahiert. Kohorte 1 umfasste alle Patienten mit einer bekannten oder neu diagnostizierten, symptomatischen und isolierten Stenose der nativen Aortenklappe. Kohorte 2 umfasste alle Patienten, welche einer invasiven Koronarangiographie unterzogen wurden und keine beginnende oder fortgeschrittene Aortenklappenstenose zeigten sowie ≥70 Jahre waren. Kohorte 1 umfasste 721, Kohorte 2 6990 Patienten. Der linkskoronare Versorgungstyp zeigte sich bei Patienten mit Aortenklappenstenose signifikant häufiger als bei Kontrollpatienten ohne Aortenklappenstenose (13.2% versus 10.2%, p=0.003). Eine signifikant niedrigere Prävalenz des rechtskoronaren Versorgungstypen fand sich bei Patienten mit einer Aortenklappenstenose (66.9% versus 71.6%, p=0.008). Beide Prävalenzen waren unabhängig vom Vorliegen einer bi- oder trikuspiden Klappenarchitektur. Es bestand lediglich ein geringer Trend zu einer höheren Prävalenz der linkskoronaren Dominanz bei Patienten mit bikuspider Klappe im Vergleich zu Patienten mit trikuspider Klappe (15 [20.8%] versus 60 [13.9%], p=0.12). Keine Unterschiede zeigten sich indessen für die intrahospitale Mortalität und Auftreten eines akuten Myokardinfarktes zwischen den koronaren Versorgungstypen. Die linkskoronare Dominanz ist kein Risikofaktor für eine Progression der Aortenklappenstenose.

Abdominal Aortic Aneurysms (AAA) are amongst the top ten most common cause of death in those over 55 years of age. The disease is usually asymptomatic, often being diagnosed incidentally. Once diagnosed, elective repair of an AAA results in excellent long-term survival with a 3-5% operative mortality. However, up to one half of patients present with ruptured aneurysms, a complication that carries an 80% mortality in the community, and of those reaching hospital, a 50% mortality. Clearly early diagnosis and treatment results in improved survival. Screening for AAA, with ultrasound, would detect aneurysms early, prior to rupture. However, debate continues over the cost effectiveness of population based screening programmes. The identification of a sub-population at a higher risk of developing AAA would increase the yield of a screening prograrmne. A number of populations have been examined, none of which have received international acceptance. About 20% of patients with an AAA have a family history of an aneurysm. The disease is also considered to be a disease of Caucasians, both facts suggesting a strong genetic component to the disease. Perhaps a genetically identified sub-population at a high risk of developing an AAA would prove to be an ideal population for screening. This thesis examines the incidence of aneurysms and the family histories of patients with AAA in the Otago region of New Zealand. Almost twenty percent of the population has a family history of AAA. DNA was collected from each of these patients for genetic analysis. The population was divided into familial AAA and non-familial AAA for the purpose of genetic analysis and compared to a control population. AAA is believed to be a disease of Caucasians; a non-Caucasian population with a low incidence of AAA may prove to be a good control population for genetic studies. A literature review demonstrated a higher incidence of AAA in Caucasians than other ethnic groups and within Caucasians a higher incidence in patients of Northern European origin. The incidence was low in Asian communities, even in studies involving of migrant Asian populations. The New Zealand Maori are believed to have originated from South East Asia, therefore could be expected to have a low incidence of AAA and would make an ideal control population for genetic studies. A pilot study was undertaken to examine the incidence of AAA in the New Zealand Maori. The age standardised incidence of AAA proved to be at least equal in Maori to non-Maori, with a more aggressive form of the disease in Maori, manifesting with a younger age at presentation and a higher incidence of ruptured aneurysms at diagnosis. It is well known that at the time of surgery, an AAA is at the end stage in its life. At this time, inflammation and matrix metalloproteinases (MMP) enzymes are prevalent within the aneurysm wall and have destroyed the wall of the aorta. One of the most important genetic pathways regulating these enzymes is the plasminogen activator inhibiter 1-Tissue plasminogen activator-plasmin pathway. Genetic analysis of this pathway demonstrated an association of the 4G5G polymorphism in the promoter of the PAl-1 gene with familial AAA. In this insertion:deletion polymorphism, the 5G variant binds an activator and repressor, resulting in reduced PAI-1 expression and ultimately increased MMP activation. This allele was associated with familial aneurysms, 47% versus 62% non-familial AAA and 61% controls (p=0.024). A polymorphism within the tissue plasminogen activator gene was also examined and no association was found with AAA. Another way the MMPs expression could be increased is from mutations or polymorphisms in their own genetic structure. Stromelysin 3 is itself a MMP capable of destroying the aortic wall and it has a role in activating other MMPs. A 5A6A insertion:deletion polymorphism exists in the promoter of this gene. The 5A allele variant results in increased stromelysin expression and is associated with AAA 46% versus 33% in controls p=0. 0006. The actions of the MMPs are themselves inhibited by the tissue inhibitors of matrix metalloproteinases. The TIMP genes have been sequenced; two polymorphisms have been identified in the non-coding promoter area of the TIMP 1 gene. Further studies are necessary to examine the effect of these polymorphisms. Inflammation has been implicated in aneurysm progression. One of the roles of the inflammatory cells found in an aneurysm is to deliver the MMP�s to the AAA. The HLA system is integral in controlling this inflammation and was therefore examined. From this series of studies it is concluded that there is a genetic component to AAA. This thesis presents the first genetic polymorphism associated with familial AAA and explores the role of a genetic pathway in the formation of AAA.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 5 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2008. / Härtill 4 uppsatser.

Thesis (M.S.)--Rochester Institute of Technology, 2009. / Typescript. Includes bibliographical references (leaves 67-69).

Thesis (Ph. D.)--Ohio State University, 2009. / Title from first page of PDF file. Includes vita. Includes bibliographical references (p. 113-121).

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.