Marfan Syndrome leads to the weakening of the thoracic aorta and ultimate rupture causing death of the patient. Current monitoring method involves measuring the diameter of the aorta near the heart. Our approach is to develop a new technology that will provide clinicians the ability to evaluate the size, shape and motion of the entire thoracic aorta using four-dimensional cardiac MRI. This project alters the existing research algorithms to provides an integrated application for processing the images and provides novel measurements about the aorta from a data set of 32 normal subjects and 38 patients with serial scans.

Atherosclerosis is accepted to be a chronic inflammatory disease of the arterial vessel wall. Several cellular subsets of the immune system are involved in its initiation and progression, such as monocytes, macrophages, T and B cells. Recent research has demonstrated that dendritic cells (DCs) contribute to atherosclerosis, too. DCs are defined by their ability to sense and phagocyte antigens, to migrate and to prime other immune cells, such as T cells. Although all DCs share these functional characteristics, they are heterogeneous with respect to phenotype and origin. Several markers have been used to describe DCs in different lymphoid and non-lymphoid organs; however, none of them has proven to be unambiguous. The expression of surface molecules is highly variable depending on the state of activation and the surrounding tissue. Furthermore, DCs in the aorta or the atherosclerotic plaque can be derived from designated precursor cells or from monocytes. In addition, DCs share both their marker expression and their functional characteristics with other myeloid cells like monocytes and macrophages. The repertoire of aortic DCs in healthy and atherosclerotic mice has just recently started to be explored, but yet there is no systemic study available, which describes the aortic DC compartment. Because it is conceivable that distinct aortic DC subsets exert dedicated functions, a detailed description of vascular DCs is required. The first part of this thesis characterizes DC subsets in healthy and atherosclerotic mice. It describes a previously unrecognized DC subset and also sheds light on the origin of vascular DCs. In recent years, microRNAs (miRNAs) have been demonstrated to regulate several cellular functions, such as apoptosis, differentiation, development or proliferation. Although several cell types have been characterized extensively with regard to the miRNAs involved in their regulation, only few studies are available that focus on the role of miRNAs in DCs. Because an improved understanding of the regulation of DC functions would allow for new therapeutic options, research on miRNAs in DCs is required. The second part of this thesis focuses on the role of the miRNA cluster miR- 17~92 in DCs by exploring its functions in healthy and atherosclerotic mice. This thesis clearly demonstrates for the first time an anti-inflammatory and atheroprotective role for the miR17-92 cluster. A model for its mechanism is suggested. / Atherosklerose ist eine chronisch-entzündliche Erkrankung der arteriellen Gefäßwand und zahlreiche Zellen des Immunsystems, wie zum Beispiel Monozyten, Makrophagen, T und B Zellen sind an der Entstehung und Entwicklung beteiligt. Aktuelle Forschungsergebnisse haben gezeigt, dass auch dendritische Zellen (DCs) zur Atherosklerose beitragen. DCs sind durch ihre Fähigkeit gekennzeichnet, Antigene zu erkennen, aufzunehmen, zu migrieren und andere Immunzellen, wie zum Beispiel T Zellen, zu aktivieren. Auch wenn alle DCs diese funktionellen Merkmale teilen, so sind sie in Bezug auf ihren Phänotyp oder Ursprung eine eher heterogene Gruppe. Zahlreiche Oberflächenmoleküle wurden in der Vergangenheit genutzt, um DCs in lymphatischen und nicht-lymphatischen Geweben zu beschreiben. Allerdings hat sich keines dieser Moleküle als spezifisch und unverwechselbar erwiesen. Die Expression von Oberflächenmolekülen ist sehr variabel und hängt nicht nur vom Aktivierungszustand der DCs, sondern auch vom umliegenden Gewebe ab. Dazu kommt, dass DCs in der Aorta, beziehungsweise im atherosklerotischen Plaque, von designierten Vorläuferzellen, aber auch von Monozyten abstammen können und DCs das Profil ihrer Oberflächenmoleküle, sowie ihre funktionellen Eigenschaften, mit anderen myeloiden Zellen wie Monozyten und Makrophagen teilen. Neuere Arbeiten haben damit begonnen das Repertoire an DCs in der Aorta von gesunden und atherosklerotischen Mäusen zu untersuchen. Da es naheliegt, dass verschiedene DC Untergruppen ganz bestimmte Funktionen ausüben, wird eine detaillierte Beschreibung vaskulärer DCs in der Forschung benötigt. Weil es hierzu allerdings bislang kaum Studien gibt, untersucht der erste Teil dieser Arbeit zum ersten Mal systematisch die in gesunden und atherosklerotischen Mäusen vorkommenden Gruppen an DCs. Sie beschreibt außerdem eine zuvor nicht beachtete DC-Untergruppe und gibt Aufschluss über den Ursprung vaskulärer DCs. In den letzten Jahren wurde gezeigt, dass microRNAs (mirRNAs) zahlreiche zelluläre Vorgänge wie Apoptose, Differenzierung, Entwicklung und Proliferation regulieren. Obwohl viele Zelltypen in Bezug auf die in ihrer Regulation eingebundenen mirRNAs charakterisiert wurden, gibt es nur wenige Studien, die sich mit der Rolle von mirRNAs in DCs beschäftigen. Der zweite Teil dieser Arbeit konzentriert sich auf die Rolle der miRNA Gruppe miR-17~92 in DCs und untersucht deren Rolle in gesunden und atherosklerotischen Mäusen. Diese Arbeit zeigt erstmals eine deutliche anti-inflammatorische und protektive Rolle dieser miRNA und schlägt ein Modell für die entdeckten Mechanismen vor.

Vascular reactivity to vasopressin and phenylephrine is potentiated by constrictor prostanoids (CP) in normotensive female (F) but not male (M) rat aorta and CP function is estrogen-dependent. This study investigated the effects of estrogen on CP function and arterial blood pressure (MAP) during development of aortic coarctation-induced hypertension (HT). M and F rats, (15-18 wks.) in four groups: normotensive (NT), hypertensive (HT), ovariectomized (OVX), and OVX estrogen-replaced (OE), underwent abdominal aortic coarctation or sham surgery (NT). At 14 days, SQ 29,548 (SQ, Thromboxane A2 (TXA2) receptor antagonist) was given i.v. to the groups. In another experiment, rats received Ridogrel (TXA2 receptor antagonist+TXA2 synthase (TXS) inhibitor) or vehicle (methyl cellulose) daily, for 14 days. Thoracic aortae were analyzed for morphology, incubated in Kreb’s Henseleit Buffer (KHB) ± angiotensin II (ANG II), or underwent continuous pulsatile flow and pressure experiments (PFP) with KHB ± ANG II. Perfusate was analyzed for thromboxane B2 (TXB2) and prostaglandin F1α (PGF1α). RT-PCR and immunohistochemistry were performed for TXS. MAP was higher in F-HT than in M-HT after 14 days. SQ infusion reduced MAP substantially more in F-HT and OE-HT than in others. Ridogrel prevented increases in MAP in F/OE-HT rats, but not M/OVX-HT. Basal release of TXB2 and PGF1α increased to a greater extent in F-HT than in M-HT relative to their controls. ANG II-stimulated TXB2 and PGF1α release increased to a greater extent in F-HT than in M-HT. With or without ANG II, TXB2 production in HT during PFP increased with estrogen. PGF1α increased during PFP with estrogen, however not with ANG II. Pressurization resulted in less diameter change in F and OE-HT than in OVX-HT. Elastin increased with HT (inhibited by Ridogrel) in all but M. Collagen increased in HT with estrogen (inhibited by Ridogrel). Neither OVX-HT nor Ridogrel had any effect on morphology. Estrogen increased TXS with HT. Estrogen enhanced vascular CP and MAP in F-HT by increased expression of TXS and collagen density in the vasculature indicating that in aortic coarctation-induced HT, CP are upregulated by estrogen. Specific forms of HT in human beings may involve estrogen-induced vascular CP upregulation.

Vascular reactivity to vasopressin and phenylephrine is potentiated by constrictor prostanoids (CP) in normotensive female (F) but not male (M) rat aorta and CP function is estrogen-dependent. This study investigated the effects of estrogen on CP function and arterial blood pressure (MAP) during development of aortic coarctation-induced hypertension (HT). M and F rats, (15-18 wks.) in four groups: normotensive (NT), hypertensive (HT), ovariectomized (OVX), and OVX estrogen-replaced (OE), underwent abdominal aortic coarctation or sham surgery (NT). At 14 days, SQ 29,548 (SQ, Thromboxane A2 (TXA2) receptor antagonist) was given i.v. to the groups. In another experiment, rats received Ridogrel (TXA2 receptor antagonist+TXA2 synthase (TXS) inhibitor) or vehicle (methyl cellulose) daily, for 14 days. Thoracic aortae were analyzed for morphology, incubated in Kreb’s Henseleit Buffer (KHB) ± angiotensin II (ANG II), or underwent continuous pulsatile flow and pressure experiments (PFP) with KHB ± ANG II. Perfusate was analyzed for thromboxane B2 (TXB2) and prostaglandin F1α (PGF1α). RT-PCR and immunohistochemistry were performed for TXS. MAP was higher in F-HT than in M-HT after 14 days. SQ infusion reduced MAP substantially more in F-HT and OE-HT than in others. Ridogrel prevented increases in MAP in F/OE-HT rats, but not M/OVX-HT. Basal release of TXB2 and PGF1α increased to a greater extent in F-HT than in M-HT relative to their controls. ANG II-stimulated TXB2 and PGF1α release increased to a greater extent in F-HT than in M-HT. With or without ANG II, TXB2 production in HT during PFP increased with estrogen. PGF1α increased during PFP with estrogen, however not with ANG II. Pressurization resulted in less diameter change in F and OE-HT than in OVX-HT. Elastin increased with HT (inhibited by Ridogrel) in all but M. Collagen increased in HT with estrogen (inhibited by Ridogrel). Neither OVX-HT nor Ridogrel had any effect on morphology. Estrogen increased TXS with HT. Estrogen enhanced vascular CP and MAP in F-HT by increased expression of TXS and collagen density in the vasculature indicating that in aortic coarctation-induced HT, CP are upregulated by estrogen. Specific forms of HT in human beings may involve estrogen-induced vascular CP upregulation.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Renal failure in patients undergoing Aortic surgery is associated with a poor outcome. The shortcomings of serum creatinine for measuring renal function are well documented. We examined the value of alternative markers in diagnosing and predicting renal damage in patients undergoing abdominal aortic surgery and those exposed to intravascular contrast media. Cystatin C lacks some of the reservations associated with serum creatinine when used as a marker of glomerular filtration rate. The protease inhibitor alpha-glutathione Stransferase (a-GST) is recovered in urine after injury to proximal tubular cells. Urine microalbumin is a marker of glomerular permeability. Together we used all four assays to detect and characterize the nature of renal injury after surgery and contrast exposure. Cystatin C had a marginally better sensitivity than serum creatinine at detecting baseline renal impairment. It also showed earlier changes in individual patients whose renal dysfunction deteriorated over time. The urinary markers showed an earlier significant rise after the onset of surgery when compared to serum markers, but only a-GST rose significantly after contrast exposure. Patients undergoing a supra-renal cross-clamp showed significantly higher a-GST levels (and not the other three markers) when compared to the infra-renal group. Cystatin C appears to have better sensitivity and specificity for predicting the need for dialysis in patients undergoing surgery. Peak serum creatinine and cystatin C after contrast exposure show good correlation with peak values after surgery. Cystatin C is equivalent to and may be better than serum creatinine in detecting preexisting and deteriorating renal impairment. Although the urinary assays are earlier markers of renal injury, their clinical significance needs to be determined. Elevation in creatinine and cystatin C after contrast exposure parallel those after surgical intervention and may be helpful in selecting out high-risk patients prior to surgery. / Thesis (M.Med.Sc.)-University of Natal, 2003.

Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Met lit. opg. en een samenvatting in het Nederlands.

BACKGROUND: Arterial stiffness (AS), or loss of elastic compliance of large arteries, is an independent risk factor for cardiovascular events1. A recent study demonstrated that single nucleotide polymorphisms (SNPs) in a genetic locus downstream of the gene Bcl11b are associated with AS2. However, how this genetic locus and Bcl11b regulate AS is unknown. OBJECTIVES: To determine the molecular mechanisms by which Bcl11b effects the aortic wall and AS. METHODS: Vascular smooth muscle (VSM) cells were isolated from aortas of wildtype (WT) mice and mice with VSM-specific Bcl11b deletion (BKO). mRNA levels of Bcl11b, vascular contractile markers (myosin heavy chain 11 (MYH11), smooth muscle -actin (ACTA2), and myocardin (MYOCD)) and a cell proliferation marker (Ki67) were measured in WT and BKO VSM cells isolated from murine aortas. VSM cell contractility in response to angiotensin II (angII), a contractile stimulus, was measured in WT and BKO VSM cells using an optimized collagen gel contractility assay. RESULTS: BKO VSM cells had decreased expression of contractile markers compared to WT cells, which resulted in impaired collagen gel contraction in response to angII. CONCLUSIONS: Bc111b is expressed in aortic smooth muscle cells and it regulates the expression of VSM contractile proteins. Our data strongly supports the hypothesis that Bcl11b regulates AS by regulating the contractile function of VSM cells in the aortic wall. / 2019-07-11T00:00:00Z

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Engenharia Mecânica. / Made available in DSpace on 2012-10-23T06:57:13Z (GMT). No. of bitstreams: 1 247163.pdf: 4006529 bytes, checksum: e7a528d6f793d8321326c765de5e8a49 (MD5) / Com o crescente desenvolvimento tecnológico na área da saúde e melhorias na área social, a população brasileira apresentou um aumento de 14,86% em sua expectativa de vida, passando de 62,6 anos em 1980 para 71,9 anos em 2005 segundo o IBGE. Com a elevação da expectativa, cresceram também os problemas relacionados à idade, como o surgimento de aneurismas, que atingem entre 5 e 7% dos homens com mais de 60 anos de idade. O aneurisma é uma dilatação superior a 50% de um segmento de uma artéria ou de um vaso sangüíneo, cuja evolução é a ruptura e óbito. Como forma de tratamento, existem duas soluções: o reparo tradicional ou aberto, e o reparo endoluminal ou minimamente invasivo. Segundo a literatura atual, o reparo minimamente invasivo apresenta diversas vantagens comparadas ao reparo tradicional. Nele, é usada uma endoprótese feita de uma estrutura metálica chamada de stent e coberto com uma película de PTFEe. Segundo as normas existentes atualmente, a endoprótese deve funcionar por um período mínimo de 10 anos. Com o passar dos anos, o stent tende a apresentar problemas de fadiga devido ao esforço submetido no mesmo. Isso justifica o teste de fadiga ao qual o material deve ser submetido antes de vendido ao mercado. Neste contexto, a presente pesquisa apresenta o desenvolvimento de uma nova solução de sistema automatizado de teste de fadiga em comparação às existentes no mercado, previamente patenteadas. Além disto, o trabalho aponta também algumas falhas nas soluções que existem até o momento, que atendem às normas, mas contudo, não simulam bem uma situação real. Como resultado adicional, o trabalho poderá ser usado como subsídio para o desenvolvimento de uma norma de teste nacional, que inexiste até o momento. With the increasing technological development in the health#s area and improvements in the social area, the Brazilian population had presented an increase of 14,86% in its life expectancy, passing of 62,6 years in 1980 to 71,9 years in 2005 according to IBGE. With the rise of the expectation, the problems related to age presented also an improvment, as the occurrence of aneurysms, that reach between 5 and 7% of the men with older then 60 years old. The aneurysm is a superior dilatation bigger than 50% of an artery segment or a sanguine vase, whose evolution is the rupture and death. As treatment solutions, there are: the traditional repair or opened repair, and the endoluminal repair or minimally invasive repair. According to current literature, the minimally invasive repair presents diverse comparative advantages to the traditional repair. In this solution, a endoprosthesis is used, made of a metallic structure called stent and covered with a PTFEe film. According to the currently existing norms, the endoprosthesis must work for a minimum period of 10 years. After any years of use, stent tends to present fatigue problems due to the efforts submitted in it. This problem justifies the fatigue test that the material must be submitted before be sold to the market. In this context, the present research presents the development of a new solution of automatized system of fatigue test in comparison to the existing ones in the market, previously patented. Moreover, the work also points some imperfections in the solutions that exist until this moment, that satisfy the norms, but however, does not simulate with precision a real situation. As additional result, this work could be used as I subsidize for the development of a national norm test, that inexists until the moment.