INTRODUÇÃO: O objetivo deste estudo é determinar as propriedades biomecânicas e histológicas de fragmentos da parede anterior de aneurismas da aorta abdominal. MÉTODOS: Dos pacientes submetidos à correção cirúrgica aberta de aneurisma da aorta abdominal, foram removidos fragmentos da parede anterior do saco aneurismático, divididos em dois espécimes. Um, destinado à análise histológica, para a quantificação de fibras colágenas, elásticas, musculares lisas e grau de atividade inflamatória e outro, pareado, submetido a teste destrutivo uniaxial, obtendo-se características biomecânicas, como, força, tensão e estresse de falência do fragmento. As médias das variáveis paramétricas foram avaliadas com teste t-Student ou análise de variância. Quando significante, utilizou-se teste de Tukey para discriminar as diferenças. As distribuições das variáveis não paramétricas foram avaliadas com teste Mann-Whitney ou análise de Kruskal-Wallis. Quando significante, utilizou-se teste de Dunn para discriminar as diferenças. Os valores de p<0,05 foram considerados estatisticamente significantes. RESULTADOS: Foram considerados os resultados das análises de fragmentos de 90 indivíduos. Os valores médios encontrados para as propriedades biomecânicas relacionadas à resistência do tecido aórtico (falência) foram força = 4,98±2,22 N, tensão = 13,18±5,98 N/cm e estresse = 103,14±47,09 N/cm2. A deformação média dos fragmentos até a falência foi de 0,39±0,12. Os fragmentos dos aneurismas de diâmetros transversos máximos maiores ou iguais a 5,5 cm apresentaram valores médios de força, tensão e estresse de falência (5,32±2,07 N, 13,83±5,58 N/cm e 103,02 N/cm2) maiores que os fragmentos de aneurismas de diâmetros menores que 5,5 cm (4,1±2,41 N, 10,82±6,48 N/cm, 77,03 N/cm2), com significância estatística para os três parâmetros de resistência do material. Não foram identificadas diferenças entre os valores médios de deformação de falência entre estes grupos (0,41±0,12 x 0,37±0,14 p = 0,260), bem como entre os valores médios de espessura dos fragmentos (1,58±0,41 x 1,53±0,42 mm p = 0,662). Os valores percentuais médios na composição dos fragmentos foram para as fibras colágenas (coloração de tricrômico de Masson) de 44,34±0,48%, para as fibras colágenas (coloração de picrosirius) de 61,85±10,14%, para as fibras musculares lisas (imuno histoquímica/alfa actina) de 3,46±2,23% e para as fibras elásticas (coloração de Verhoeff) inferior a 1% (traços). Não foram identificadas diferenças entre o percentual destes elementos na composição de fragmentos provenientes da parede anterior de aneurismas de diâmetro transverso máximo >= 5,5 cm e < 5,5 cm. Foi caracterizada uma atividade inflamatória mais intensa nos fragmentos provenientes de aneurismas de diâmetro transverso máximo >= 5,5 cm quando comparados aos fragmentos provenientes de aneurismas de diâmetro transverso máximo < 5,5 cm (grau 3 - 70% x 28,6% p = 0,011). Comparando-se os aneurismas sintomáticos versus os assintomáticos não foram identificadas diferenças significativas para as propriedades biomecânicas de falência dos fragmentos (força = 5,32±2,36 x 4,65±2,05 N, p = 0,155; tensão = 14,08±6,11 x 12,81±5,77 N/cm, p = 0,154; estresse = 103,02 x 84,76 N/cm2, p = 0,144 e deformidade = 0,38±0,12 x 0,41±0,13, p = 0,287), assim como para a espessura (1,56±0,41 x 1,57±0,41 mm p = 0,848) e composição histológica (fibras colágenas 44,67±11,17 x 44,02±13,79 % p = 0,808; fibras musculares lisas 2,52 x 2,35 %, p = 0,751; fibras elásticas inferior a 1%). CONCLUSÃO: Os fragmentos provenientes da parede anterior do saco aneurismático de aneurismas maiores mostraram-se mais resistentes, não se identificando diferenças entre os fragmentos quanto à espessura e conteúdo da matriz protéica. A maior resistência dos fragmentos de aneurismas maiores provavelmente está relacionada à adaptação da parede para suportar maior grau de sobrecarga hemodinâmica à medida que o diâmetro aumenta. Neste estudo esta adaptação não foi revelada pela análise histológica realizada e demonstra a limitação do estudo de fragmentos isolados de aneurismas para estimar o risco de ruptura dos mesmos / INTRODUCTION: The objective of this study was to determine the biomechanical and histological properties of fragments isolated from the anterior wall of abdominal aortic aneurysms. METHODS: Fragments of the anterior aneurysm wall were excised from the aneurysmatic sac of patients who underwent open surgery for repair of abdominal aortic aneurysm and divided into two specimens. One specimen was sent for histological analysis for quantification of collagen fibers, elastic fibers, smooth muscle cells and degree of inflammatory activity and the other, by uniaxial testing, was used to assess biomechanical properties, such as force, tension, and stress at the time of failure of the material. The means of parametric variables were evaluated with Student\'s t test or analysis of variance. When significant, we used the Tukey test to discriminate differences. The distributions of non-parametric variables were evaluated with Mann- Whitney or Kruskal-Wallis test. When significant, we used Dunn\'s test to discriminate differences. A p-value of less than 0.05 was considered statistically significant. RESULTS: Anterior-wall fragments from a total of 90 patients were considered. The average values of biomechanical parameters related to the resistance of the aorta (failure) were as follows: strength, 4.98±2.22 N; tension, 13.18±5.98 N/cm; and stress 103.14±47.09 N/cm2. The average deformation of the fragments at the time of the failure was 0.39±0.12. Fragments of aortic aneurysm with a maximum transverse diameter larger or equal to 5.5 cm showed average values for strength, tension, and stress at the time of the failure of the material (5.32±2.07 N, 13.83±5.58 N/cm, and 103.02 N/cm2, respectively), which were higher than those of fragments of aneurysms with diameters less than 5.5 cm (4.1±2.41 N, 10.82±6.48 N/cm, 77.03 N/cm2, respectively). The differences in the 3 parameters were statistically significant. However, no differences were observed between the groups in relation to average failure deformation (0.41±0.12 × 0.37±0.14; p = 0.260) and thickness of the analyzed fragments (1.58±0.41 × 1.53±0.42 mm; p = 0.662). The average values of fiber compositions of the fragments were as follows: collagen fibers, 44.34±0.48% and 61.85±10.14% (assessed using Masson trichrome staining and picrosirius red staining, respectively); smooth muscle cells, 3.46±2.23% (immunohistochemistry/alpha-actin); and elastic fibers, less than 1% (traces) (Verhoeff-van Gieson staining). No differences in fiber percentages were observed in the fragments from aneurysms with a maximum transverse diameter >= 5.5 cm and < 5.5 cm. A more intense inflammatory activity was assessed in fragments from aneurysms with maximum transverse diameter >= 5.5 cm than in fragments from aneurysms with maximum transverse diameter < 5.5 cm (grade 3 - 70% × 28.6%; p = 0.011). Compared to asymptomatic aneurysms, fragments from symptomatic aneurysms showed no significant differences in the biomechanical properties at the time of the failure (strength, 5.32±2.36 × 4.65±2.05 N, p = 0.155; tension, 14.08±6.11 × 12.81±5.77 N/cm, p = 0,154; stress, 103.02 × 84.76 N/cm2, p = 0.144; and deformity, 0.38±0.12 × 0.41±0.13, p = 0.287), thickness of the fragments (1.56±0.41 × 1.57±0.41 mm, p = 0.848) and histological composition (collagen fibers, 44.67±11.17 × 44.02±13.79%, p = 0.808; smooth muscle fibers, 2.52 × 2.35%, p = 0.751; elastic fibers, <1%). CONCLUSION: Fragments of the anterior wall removed from the aneurysmatic sac of large aneurysms appeared to be more resistant than those from small aneurysms. No differences between the aneurysm fragments were observed with respect to thickness and matrix protein content. The high resistance of fragments of larger aneurysms is probably attributable to the adaptation of the wall to support a high hemodynamic stress as the diameter of the aorta increases. In this study, this adaptation was not shown by histological analysis. This suggests a limitation of this study for assessing the risk of rupture based on isolated aneurysm fragments

Submitted by isabela.moljf@hotmail.com (isabela.moljf@hotmail.com) on 2016-08-12T11:35:34Z No. of bitstreams: 1 rafaelladesouzasalomaozanette.pdf: 856423 bytes, checksum: c95ae99e7ef9f490e08fd22c64f7237f (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-08-15T13:04:26Z (GMT) No. of bitstreams: 1 rafaelladesouzasalomaozanette.pdf: 856423 bytes, checksum: c95ae99e7ef9f490e08fd22c64f7237f (MD5) / Made available in DSpace on 2016-08-15T13:04:26Z (GMT). No. of bitstreams: 1 rafaelladesouzasalomaozanette.pdf: 856423 bytes, checksum: c95ae99e7ef9f490e08fd22c64f7237f (MD5) Previous issue date: 2016-02-25 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O coração é um órgão vital, que bombeia o sangue permitindo a sua circulação pelo corpo. A valva aórtica, e as suas estruturas de apoio ventriculares, formam a peça central do coração. Todas as câmaras do coração estão relacionadas diretamente à valva e seus folhetos são incorporados diretamente no esqueleto cardíaco. Falhas dos folhetos aórticos são as mais comuns entre as doenças relacionadas às valvas do coração, tendo como consequência o impacto negativo na vida do paciente, bem como nas despesas dos sistemas de saúde em todo o mundo. O desenvolvimento de materiais capazes de substituir com eficácia o tecido danificado da valva aórtica é de grande interesse na medicina regenerativa e engenharia de tecidos. As valvas mecânicas e biológicas têm sido amplamente estudadas, mas várias questões relacionadas com a integração ao hospedeiro ainda não foram resolvidas. Promissores protocolos para descelularização de tecidos de valva cardíaca têm sido investigados como uma alternativa para a preparação do material de substituição e para ser empregado como um substrato para a recelularização da matriz. No entanto, alguns protocolos de descelularização utilizados hoje em dia têm algumas limitações, uma vez que ainda não existe um método que permita a descelularização e ao mesmo tempo mantenha a estrutura da matriz extracelular para a posterior recelularização, evitando a rejeição após a implantação e futura substituição da prótese. Assim, o presente trabalho visa a obtenção de uma matriz biológica que satisfaça esses requisitos, por meio da descelularização dos folhetos aórticos de suínos e sua recelularização com células-tronco da polpa dentária humana. Foram testados três protocolos de descelularização, sendo que os protocolos que utilizaram tripsina foram reprodutíveis e forneceram matrizes com menor quantidade de DNA, quando comparados com o protocolo que utilizou apenas detergente e não foi reprodutível. As células-tronco podem ser isoladas de dentes decíduos (SHEDs) humanos e pesquisas apontam sua importância na medicina regenerativa visando à reconstrução de folhetos aórticos. Nesse trabalho, as SHEDs foram obtidas e caracterizadas fenotipicamente, sendo positivas para marcadores mesenquimais e embrionários e negativas para marcadores hematopoiéticos, além de apresentarem, in vitro, potencial de diferenciação osteogênica. Tais células foram então cultivadas em placas de petri com as matrizes descelularizadas, porém não houve sucesso na recelularização. Para tentar contornar esse problema, foi construído um biorreator a fim de aumentar a eficiência da recelularização do tecido, no entanto os resultados estão sendo testados. Vários pontos ainda devem ser abordados a fim de superar os obstáculos da técnica de descelularização do tecido para obter sucesso na recelularização. / Heart is a vital organ that pumps blood allowing its circulation through the body. The aortic valve and their ventricular support structures form the centerpiece of the heart. All chambers of the heart are directly related to the valve, and its leaflets are directly incorporated into the heart skeleton. Amongst heart valves diseases, failures in the aortic leaflets are the most common ones, leading to negative impacts on patients’ life, as well as increases on the costs for health systems worldwide. For regenerative medicine and tissue engineering, the development of materials capable of effectively replace damaged aortic valve tissue is of great interest. The mechanical and biological valves have been widely studied, but several issues related to integration to the host have not yet been resolved. Promising decellularization protocols for tissue heart valve have been investigated as an alternative for the preparation of replacement material and to serve as a substrate for matrix repopulation. However, some of the decellularization protocols used today have some limitations, since until now there is still no method which can achieve a complete decellularization while maintaining the structure of extracellular matrix for later repopulation, avoiding rejection after implantation and future replacement of the prosthesis. Thus, the present work aims at obtaining a biological matrix that satisfies such requirements through the decellularization of pigs aortic leaflets and its repopulation with stem cells isolated from human dental pulp. So far, we tested three decellularization protocols. The protocols using trypsin were shown reproducible and yielded a smaller amount of DNA, when compared to the protocol where only detergent was employed, which was also not reproducible. About the stem cells, they can be isolated from human deciduous teeth (SHEDs), with studies indicating its importance in regenerative medicine aimed at the reconstruction of aortic leaflets. In this work, SHEDs were obtained and phenotypically characterized, being positive for mesenchymal and embryonic markers and negative for hematopoietic markers, in addition to presenting in vitro osteogenic differentiation potential. The SHEDs were then cultured in Petri plates with the decellularized matrices, however there was no success in the matrix repopulation. In an attempt to overcome such problem, a bioreactor was built in order to increase the tissue repopulation efficiency, however the results are being tested. Several points still need to be addressed in order to overcome the obstacles of tissue decellularization technique and then achieve a successful recellularization.

Abstract Calcific aortic valve disease (CAVD) is the most common valvular heart disease in the Western world. Although it shares mainly the same risk factors as coronary heart disease (CHD), i.e. similar initial events in both diseases but with time, they lead to different clinical outcomes. Thus, when it affects the coronary arteries, the disease leads to an obstructive or rupture-prone plaque whereas in the aortic valve, it causes massive calcification and ossification. This obstructs the blood flow from the left cardiac ventricle, causing myocardial hypertrophy, and if left untreated, heart failure and death. Many of the pathobiological differences between CAVD and CHD remain unknown. Currently, there are no effective lifestyle- or pharmacologic treatments for CAVD and the only therapy is a valve replacement operation. In this thesis, several studies utilizing large-scale methods were undertaken to profile the molecular events leading to CAVD. Surgically removed valves from patients in different stages of the disease were obtained and gene transcripts, microRNA-molecules and several proteins were identified as being differentially expressed. Several of these were investigated further, including two pro-inflammatory CC-type chemokine ligands 3 and 4 (CCL3 and CCL4), microRNA-125b, several granzyme-proteins and heat-shock protein 90. The results of this thesis provide a large dataset of hundreds of molecular changes associated with CAVD. It is proposed that they can be used as a basis for the generation of new hypotheses and assist in the design of experiments to clarify the mechanisms driving CAVD. / Tiivistelmä Aorttaläpän kalkkeutuva ahtauma on länsimaiden yleisin sydänläppäsairaus. Riskitekijät ovat pääosin samat kuin sepelvaltimotaudissa, ja molemmat saavat alkunsa samalla tavalla. Ajan myötä ne kuitenkin johtavat varsin erilaisiin kliinisiin ilmenemismuotoihin: sepelvaltimoihin kasvaa ahtauttavia ja repeytymisherkkiä plakkeja, kun taas aorttaläppään muodostuu runsaasti kalkkia ja luuta. Se haittaa verenvirtausta sydämen vasemmasta kammiosta aorttaan, mikä aiheuttaa sydänlihaksen paksuuntumista. Hoitamattomana tauti johtaa lopulta sydämen vajaatoimintaan ja kuolemaan. Monet syyt eroihin sepelvaltimotaudin ja aorttaläpän ahtauman välillä ovat edelleen tuntemattomia. Tällä hetkellä aorttaläpän ahtaumaan ei ole olemassa tehokasta elintapa- tai lääkehoitoa, ja ainoa hoitomuoto onkin vioittuneen aorttaläpän korvaaminen proteesilla. Tässä väitöskirjatyössä tehtiin useita laaja-alaisia molekyylitason profilointitutkimuksia, joilla selvitettiin aorttaläpän ahtaumaan mahdollisesti johtavia mekanismeja. Aineistona oli leikkauksessa potilailta poistettuja, erilaisissa taudin vaiheissa olevia aorttaläppiä. Niistä kerättiin tietoja kaikkien geenien ilmentymisestä, mikroRNA-molekyyleistä sekä koko proteomitason muutoksista. Useat tunnistetuista molekyyleistä valittiin jatkotutkimuksiin niiden tarkempien ominaisuuksien selvittämiseksi. Näitä olivat tulehdusta välittävät kemokiinit CCL3 ja CCL4, mikroRNA-125b, useat grantsyymiproteiinit sekä lämpöshokkiproteiini 90. Väitöskirjatyön tuloksista voidaan muodostaa ainutlaatuinen aineisto sadoista erilaisista aorttaläpän ahtaumaan johtavista molekyylitason muutoksista. Sitä voidaan hyödyntää uusien tutkimushypoteesien muodostamisessa sekä aorttaläpän ahtauman tarkempien mekanismien selvittämiseen tähtäävien kokeellisten tutkimusten suunnittelussa.

Abstract Endovascular aneurysm repair (EVAR) is a minimally invasive alternative to open surgery to exclude an abdominal aortic aneurysm from the circulation to avert a rupture. The aim of this thesis was to evaluate the early and mid-term results of EVAR using the Zenith® stent-graft (Cook Inc, Bloomington, IN, USA) in asymptomatic and symptomatic abdominal aortic aneurysm (AAA) patients in three Finnish university hospitals. Furthermore, the aim was to study whether preoperative embolization of the inferior mesenteric artery (IMA) before EVAR decreases the incidence of a type II endoleak or has an effect on the aneurysm sac shrinkage. Finally, the results after secondary interventions for a type II endoleak were evaluated. Two hundred six patients underwent elective endovascular repair of an intact AAA. The use of the Zenith® stent-graft was associated with good early and mid-term results. The thirty-day mortality rate (2.9%) was in accordance with other EVAR studies. Only one late aneurysm-related death occurred in this series, whilst no patients died of a late aneurysm rupture. No stent-graft migrations or fractures were observed. Endoleak, defined as persistent blood flow outside the graft and within the aneurysm sac, remains a long-term problem with EVAR. The overall endoleak incidence was 34.6%. A type II endoleak (retrograde perfusion via aortic side branches) occurred in 52 patients (25.4%). EVAR was performed for 14 patients with a symptomatic, unruptured AAA. The median delay from admission to intervention was 4 days. EVAR of a symptomatic, unruptured AAA was associated with a favourable outcome even in patients with a very high operative risk. There were no perioperative deaths. Altogether forty patients treated at Kuopio University Hospital had a patent IMA on preoperative computed tomography (CT) and were treated successfully with coil embolization before EVAR. Thirty-nine patients who underwent EVAR at Oulu University Hospital without preoperative embolization of a patent IMA served as a control group. Preoperative coil embolization of the IMA significantly reduced the incidence of type II endoleaks after EVAR, but the present study failed to show any influence on late postoperative aneurysm sac shrinkage. Overall, 14 patients underwent a secondary intervention to repair the type II endoleak. Ten patients had transarterial embolization and four patients had translumbar embolization. The results were unsatisfactory; clinical success after the first secondary intervention was achieved in only two patients in the transarterial embolization group and three patients in the translumbar embolization group. These results seem to favour direct translumbar embolization rather than transarterial embolization. In conclusion, EVAR with the Zenith® stent-graft is effective in excluding AAAs from the circulation and is associated with good mid-term results.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-04-12T15:21:22Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese de Zoraya versão definitiva 131015 aceita.pdf: 2706371 bytes, checksum: 83da3cf5bbbffb2d66214831901498f3 (MD5) / Made available in DSpace on 2016-04-12T15:21:22Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese de Zoraya versão definitiva 131015 aceita.pdf: 2706371 bytes, checksum: 83da3cf5bbbffb2d66214831901498f3 (MD5) Previous issue date: 2015-02-27 / Esta tese teve como objetivo estudar um marcador de aterosclerose subclínica, a rigidez aórtica, medida através da velocidade de onda de pulso aórtica, diante da importância de se identificar os pacientes com risco maior de desenvolver doenças cardiovasculares (DCV), hoje, uma das principais causas de morbidade e mortalidade, não relacionada à síndrome da imunodeficiência adquirida (AIDS) em pessoas vivendo com o vírus da imunodeficiência humana (PVHIV). Entre setembro de 2011 e janeiro de 2013, a população do estudo composta por homens e mulheres vivendo com o vírus da imunodeficiência humana (HIV), participantes da coorte HIV/AIDS-PE, no nordeste do Brasil, iniciada em 2007, foi submetida a dois desenhos de estudos visando identificar os fatores de risco cardiovasculares tradicionais e emergentes associados com a rigidez aórtica e sua progressão.Visando identificar fatores de riscos cardiovasculares emergentes, incluindo a perda de massa óssea, realizamos um estudo transversal em mulheres vivendo com HIV que haviam realizado densitometria mineral óssea, no período entre Outubro de 2010 a Novembro de 2011. A densidade mineral óssea (DMO), foi medida pela absorciometria de energia dupla de raio-x de (DXA) nas regiões da coluna lombar, colo de fêmur e fêmur total e a rigidez aórtica, foi medida pela velocidade de onda de pulso aórtica (VOPa). O resultado principal deste estudo foi a correlação negativa significante entre a DMO do colo de fêmur e do fêmur total com a VOPa mesmo ajustada para idade, síndrome metabólica e pressão arterial média. Sugerindo que mulheres vivendo com HIV com perda de massa óssea deverão ser avaliadas para doença cardiovascular aterosclerótica. Para investigar a progressão da rigidez aórtica, foram acompanhados por uma média de 2,9 anos, homens e mulheres vivendo com HIV que haviam realizado a primeira avaliação da rigidez aórtica entre Abril e Novembro de 2009. O achado mais importante deste estudo foi a verificação de uma acelerada progressão da rigidez aórtica associada a fatores de risco tradicionais, idade, sexo masculino e hipertensão arterial e uma correlação negativa com a duração da infecção em uma população sob bom controle virológico. Os dados favorecem intensificar medidas para melhor controle da hipertensão arterial e da imunodeficiência. / This thesis aimed to study a marker of Subclinical Atherosclerosis, aortic stiffness measured by aortic pulse wave velocity, given the importance of identifying the patient with higher risk of developing cardiovascular diseases, today, one of the leading causes of morbidity and mortality, not related to AIDS. Between September 2011 and January 2013, the study population comprised of men and women living with human immunodeficiency virus (HIV), HIV/AIDS cohort participants-PE, in northeastern Brazil, initiated in 2007, have undergone two designs of studies aimed at identifying the factors of traditional and emerging cardiovascular risk associated with aortic stiffness and its progression. Aiming to identify emerging cardiovascular risk factors, including the loss of bone mass, we performed a cross-sectional study in women living with HIV who had performed bone mineral densitometry in the period between October 2010 to November 2011. Bone mineral density was measured by dual-energy x-ray absorptiometry (DXA) in regions of the lumbar spine, neck femur and total femur and aortic stiffness was measured by aortic pulse wave velocity (aPWV). The main result of this study was the significant negative correlation between the BMD of the femoral neck and total femur aPWV even adjusted for age, metabolic syndrome and mean arterial pressure. Suggesting that women living with HIV with low of bone mass should be assessed for atherosclerotic cardiovascular disease. To investigate the progression of aortic stiffness, were accompanied by an average of 2.9 years, men and women living with HIV who had carried out the initial evaluation of aortic stiffness between April and November 2009 .The most important finding of this study was the verification of an accelerated progression of aortic stiffness associated with traditional risk factors, age, male and hypertension and a negative correlation with duration of infection in a population under good viral control. The data favor the aggressive measures of intensify and immunodeficiency hypertension.

Introduction and Objectives Calcific aortic valve disease (CAVD) is the most common valvular disease, accounting for 50% of all valve disorders and is the third most common cardiovascular disease following coronary disease and hypertension.[1,2] Currently, there is no pharmacological agent capable of reversing or slowing down the progression of CAVD and treatment of severe cases consists of surgical repair or valve replacement[2]. Hence, there is a crucial need for earlier detection using predictive biomarkers that will allow for preventative intervention as opposed to post-symptomatic disease treatment or management. Namely, one target of particular interest is the expression of matrix metalloproteinases (MMPs) (specifically MMP-1, -2, and -9) which are upregulated in CAVD prior to calcification events and have been previously shown to serve as an attractive molecular imaging target.1–3 The primary objective of this study is to assess the feasibility of detecting biomarkers of CAVD by various in vivo imaging modalities, such as PET and echocardiography. In addition, this study assesses disease progression in various mouse strains to qualify an appropriate CAVD animal model. Methods In vivo and ex vivo imaging of C57Bl/6 and ApoE-/- (n = 8 per strain cohort) mouse models are used to link unique features of matrix remodelling with CAVD progression. At baseline and longitudinal follow-up (4, 8, and 12 months), in vivo hemodynamic impairment is assessed through echocardiography, and calcification and MMP activity are measured using PET with a series of radiotracers: [18F]NaF for calcification, [18F]BR351 for the molecular targets of MMP-2 and -9, and [18F]FMBP with molecular target specificity for MMP-13. Following imaging, aortic valve (AV) tissue is harvested, sectioned, and analyzed for calcification, inflammatory markers, collagen types, and MMP activity in AV leaflets. Tracer autoradiography, immunofluorescence, and in situ zymography are used to confirm in vivo imaging results with improved resolution and quantification in valves. Histological sample preparation, experimentation, and analyses are then repeated in human AV tissue samples for relative comparison of biomarker expression in animal models. Results Echocardiography suggests positive signs of disease progression in experimental animal models. In comparison to WT, ApoE-/- mice show: increased peak velocity (p<0.0001), decreased aortic valve area (p<0.001), and irregular valve dynamics. [18F]NaF PET imaging shows expected bone uptake and low calcium-burden in young and WT animals. [18F]FMBP shows increased uptake in the valve area of diseased models at later timepoints, 1.530 compared to <0.001 %ID/g (p<0.005), in disease vs control animals respectively. Furthermore, confirmation of sought-after biomarkers has also been assessed by analysis of various histological sample preparations including the presence of leaflet calcification, upregulation of MMP-2, -9, and -13, matrix remodelling, lipids, inflammatory markers, and activated MMP expression. Conclusion Findings from this study suggest that molecular imaging techniques using target-specific radiotracers, as well as echocardiography for assessment of hemodynamic impairment, are feasible solutions in predicting disease onset in CAVD specific animal models.

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Risk assessment models developed from administrative and clinical databases are used for clinical decision making. Since these models are derived from a database, they have an inherent limitation of being as good as the data they are derived from. Many of these models under or overestimate certain clinical outcomes particularly mortality in certain group of patients. Undeniably, there is significant variability in all these models on account of patient population studied, the statistical analysis used to develop the model and the period during which these models were developed. This review aims to shed light on development and application of risk assessment models for cardiac surgery with special emphasis on risk stratification in severe aortic stenosis to select patients for transcatheter aortic valve replacement.

Transcatheter aortic heart valve replacement (TAVR) is a procedure to replace a failing aortic valve and is becoming the new standard of care for patients that are not candidates for open-heart surgery [2]. However, this minimally invasive technique has shown to cause ischemic brain lesions, or “silent infarcts”, in 90% of TAVR patients, which can increase the patient’s risk for stroke by two to four times in future years [3]. Claret Medical Inc., a medical device company, has developed a cerebral protection system that filters and captures embolic debris released during endovascular procedures, such as TAVR. This thesis utilized CT scans from Claret Medical to create a physical construct of the aortic arch to experimentally validate a theoretical computer model through flow visualization. The hypothesis was that the empirical model can accurately mimic the fluid dynamic properties of the aortic arch in order validate an in silico model using the finite elements program COMSOL MultiPhysics® Modeling Software. The physical model was created from a patient CT scan of the aortic arch using additive manufacturing (3D printing) and polymer casting, resulting in the shape of the aortic arch within a transparent, silicone material. Fluid was pumped through the model to visualize and quantify the velocity of the fluid within the aortic arch. COMSOL MultiPhysics® was used to model the aortic arch and obtain velocity measurements, which were statistically compared to the velocity measurements from the physical model. There was no significant difference between the values of the physical model and the computer model, confirming the hypothesis. Overall, this study successfully used CT scans to create an anatomically accurate physical model that was validated by a computer model using a novel technique of flow visualization. As TAVR and similar procedures continue to develop, the need for experimental evaluation and visualization of devices will continue to grow, making this project relevant to many companies in the medical device industry.

Background: Coronary artery disease (CAD) is a frequent comorbidity in patients undergoing transcatheter aortic valve implantation (TAVI). If significant CAD can be excluded on coronary CT-angiography (cCTA), invasive coronary angiography (ICA) may be avoided. However, a high plaque burden may make the exclusion of CAD challenging, particularly for less experienced readers. The objective was to analyze the ability of machine learning (ML)-based CT-derived fractional flow reserve (CT-FFR) to correctly categorize cCTA studies without obstructive CAD acquired during pre-TAVI evaluation and to correlate recategorization to image quality and coronary artery calcium score (CAC). Methods: In total, 116 patients without significant stenosis (≥50% diameter) on cCTA as part of pre-TAVI CT were included. Patients were examined with an electrocardiogram-gated CT scan of the heart and high-pitch scan of the torso. Patients were re-evaluated with ML-based CT-FFR (threshold = 0.80). The standard of reference was ICA. Image quality was assessed quantitatively and qualitatively. Results: ML-based CT-FFR was successfully performed in 94.0% (109/116) of patients, including 436 vessels. With CT-FFR, 76/109 patients and 126/436 vessels were falsely categorized as having significant CAD. With CT-FFR 2/2 patients but no vessels initially falsely classified by cCTA were correctly recategorized as having significant CAD. Reclassification occurred predominantly in distal segments. Virtually no correlation was found between image quality or CAC. Conclusions: Unselectively applied, CT-FFR may vastly increase the number of false positive ratings of CAD compared to morphological scoring. Recategorization was virtually independently from image quality or CAC and occurred predominantly in distal segments. It is unclear whether or not the reduced CT-FFR represent true pressure ratios and potentially signifies pathophysiology in patients with severe aortic stenosis.