Atherosclerosis, the leading cause of mortality in Western societies, affects large elastic arteries, causing focal deposition of proliferative inflammatory and lipid-laden cells within the artery. Several risk factors have been causally implicated in the ???reaction to injury??? hypothesis first described by Ross in 1969. The ???injury??? sustained by endothelial cells may be either mechanical or chemical. Environmental factors have a role in the production of chemical agents that are injurious to the endothelium. Mechanical stresses such as wall tensile stress are proportional to systemic blood pressure and pulse pressure. Essentially, these systemic pressures are fairly evenly distributed throughout the circulation. However, atherosclerotic lesions characteristically occur at focal sites within the human vasculature; at or near bifurcations, within the ostia of branch arteries and at regions of marked or complex curvature, where local haemodynamic abnormalities occur. The most discussed haemodynamic factor seems to be low or highly oscillating wall shear stress which exists on the outer wall of bifurcations and on the inner aspect of curving vessels. The magnitude of these haemodynamic forces may not be great but the subtleties of their variable spatial distribution may help to explain the multifocal distribution of atherosclerotic plaques. With the altered haemodynamics there is endothelial injury and phenotypic changes in the endothelium result, which in turn lead to endothelial cell dysfunction. These haemodynamic variables are difficult to measure directly in vivo. In this work a novel model is developed utilising human autologous vein bypass grafts as a surrogate vessel for the observation of pathological structural changes in response to altered haemodynamics. The influence of haemodynamic factors (such as wall shear stress) in the remodeling of the vein graft wall and the pathogenesis of Myointimal Hyperplasia (MIH) and resultant wall thickening in femoral bypass grafts is analysed. The haemodynamic determinants of MIH (which have been established in many animal models) are similar to those implicated in atherosclerosis. The accelerated responses of the vein (Intimal hyperplasia develops much more rapidly than atherosclerotic lesions in native vessels) make it an ideal model to expediently examine the hypothesised relationships prospectively in an in vivo setting. Furthermore, the utilisation of in vivo data acquired from non-invasive diagnostic methods (such as Magnetic Resonance Angiography (MRA) and Duplex ultrasound) combined with the application of state-of-the-art Computational Fluid Dynamic (CFD) techniques makes the model essentially non-invasive. The following hypotheses are examined: 1) regions of Low shear and High tensile stress should develop disproportionately greater wall thickening, 2) regions of greater oscillatory blood flow should develop greater wall thickening, and 3) regions of lower wall shear should undergo inward (or negative) remodelling and result in a reduction in vessel calibre. The conclusions reached are that abnormal haemodynamic forces, namely low Time-averaged Wall Shear Stress, are associated with subsequent wall thickening. These positive findings have great relevance to the understanding of vein graft MIH and atherosclerosis. It was also evident that with non-invasive data and CFD techniques, some of the important haemodynamic factors are realistically quantifiable (albeit indirectly). The detection of parameters known to be causal in the development of graft intimal hyperplasia or other vascular pathology may improve ability to predict clinical problems. From a surgical perspective this might be employed to facilitate selection of at-risk grafts for more focused postoperative surveillance and reintervention. On a broader stage the utilisation of such analyses may be useful in predicting individuals at greater risk of developing atherosclerotic deposits, disease progression, and the likelihood of clinical events such as heart attack, stroke and threat of limb loss.

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

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Üroloji Anabilim Dalı, 2004. / Bibliyografya var.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2007. / Härtill 4 uppsatser.

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

OBJETIVO: analisar, por meio de morfometria digital, a reação intimal presente na artéria carótida de suínos submetidos à angioplastia isoladamente e à angioplastia seguida de implante de stent de cromo - cobalto. MATERIAIS E MÉTODOS: em oito suínos sadios foi realizada a angioplastia isolada da artéria carótida comum (ACC) direita e angioplastia com implante de um stent de cromo – cobalto expansível por balão na artéria carótida comum esquerda. Após período de quatro semanas, os animais foram submetidos à eutanásia para a retirada de amostras de tecido arterial e preparo de lâminas histológicas divididas do seguinte modo: grupo 1, segmento médio da artéria carótida comum direita (angioplastia isolada); grupo 2, segmento médio da artéria carótida comum esquerda em localização “intra stent”. As imagens das lâminas foram digitalizadas e analisadas por programa de morfometria digital com cálculo da área luminal, área da camada íntima e área da camada média dos cortes histológicos. A análise estatística foi realizada através da média e desvio padrão das áreas em cada grupo, utilizando-se Teste t de Student. O valor de p<0,05 foi considerado significativo. RESULTADOS: na análise das médias das áreas obtidas, foi encontrada maior hiperplasia em resposta ao implante de stent e diferença estatisticamente significativa quando realizada a comparação entre a área do lúmen (5,841 x 106μm2 X 1,287 x 106μm2), da lâmina elástica interna (6,566 x 106μm2 X 1,287 x 106μm2) e lâmina elástica externa (9,832 x 106μm2 X 4,559 x 106μm2) dos dois grupos (ATP + STENT X ATP; medidas em micrômetros quadrados). Não se observou diferença significativa do ponto de vista estatístico quando se realizou a comparação entre as camadas médias dos dois grupos (3,266 x 106μm2 X 3,271 x 106μm2). CONCLUSÃO: o implante de stent de cromo-cobalto expansível por balão na ACC do suíno gerou um espessamento intimal maior do que aquele produzido apenas pela angioplastia, porém este não foi suficiente para afetar o lúmen arterial. / OBJECTIVE: to analyze, through digital morphometry, the intimal reaction in the carotid artery of pigs submitted to isolated angioplasty and angioplasty followed by implantation of cobalt-chromium stent. MATERIALS AND METHODS: eight healthy pigs had their common carotid artery (CCA) submitted to isolated angioplasty in the right side and angioplasty plus stenting in the left side. Four weeks latter, all animals were submitted to euthanasia for arterial tissue sampling and preparation of histological blades sorted as follows: group 1, middle segment of common right carotid artery (isolated angioplasty); group 2, middle segment of common left carotid artery (intra-stent). Blade images were scanned and analyzed through a digital morphometry program with calculation of luminal, intimal and media layers area in the histological sections. The statistical analysis was performed through mean values and standard deviations of the areas in each group, using the Student’s t-Test. The value of p<0.05 was considered significant. RESULTS: When compare to angioplasty alone, the stent group showed greater hyperplasia in response to implantation regarding the lumen area (5.841 x 106μm2 X 1.287 x 106μm2), the internal elastic lamina area (6.566 x 106μm2 X 1.287 x 106μm2) and the external elastic lamina area (9.832 x 106μm2 X 4.559 x 106μm2). No statistically significant difference was observed when comparing the media layers of both groups (3.266 x 106μm2 X 3.271 x 106μm2). CONCLUSION: angioplasty followed by the implantation of a cobalt-chromium balloon expandable stent in the CCA of the pig creates more intimal thickening than angioplasty alone. Nevertheless intimal thickening was not enough to affect the luminal area thanks to a positive elastic remodeling effect.

Objetivo: Avaliar se a administração sistêmica de cilostazol reduz a hiperplasia neointimal nas artérias ilíacas de suínos submetidas a angioplastia com cateter balão. Métodos: O trabalho foi desenvolvido na Unidade de Experimentação Animal do Hospital de Clínicas de Porto Alegre. Vinte suínos foram submetidos a angioplastia com cateter balão 6 x 40 mm na artéria ilíaca comum direita, guiada por ultrassonografia com Doppler. Os animais foram randomizados em dois grupos: grupo 1 (n = 10), no qual foi administrado cilostazol 50 mg em duas doses diárias, e grupo 2 (n = 10), considerado controle. Após 30 dias, os animais foram sacrificados, e as artérias ilíacas preparadas para análise histológica. Os cortes histológicos foram digitalizados e analisados por morfometria digital. A análise estatística foi realizada com o teste t de Student e o de Mann-Whitney. Resultados: Comparando as artérias ilíacas submetidas a angioplastia com as não submetidas a angioplastia, houve hiperplasia neointimal significativa (0,228 versus 0,119 mm2; p = 0,0001). Nas artérias submetidas a angioplastia, não houve diferença entre o grupo 1 (cilostazol) e o grupo 2 (controle) na área do lúmen (2,277 versus 2,575 mm2; p = 0,08), área da íntima (0,219 versus 0,237 mm2; p = 0,64), área da média (2,262 versus 2,393 mm2; p = 0,53) e no percentual de obstrução neointimal (8,857 versus 9,257 %; p = 0,82). Conclusão: O uso de cilostazol 50 mg em duas doses diárias não reduziu a hiperplasia neointimal em artérias ilíacas de suínos submetidas a angioplastia com cateter balão. / Objective: To evaluate whether systemic administration of cilostazol reduces neointimal hyperplasia in the iliac arteries of pigs after balloon angioplasty. Methods: This study was conducted in the Experimental Animal Unit of Hospital de Clínicas de Porto Alegre, Brazil. Twenty pigs underwent angioplasty of the right common iliac artery under Doppler ultrasound guidance using 6x40-mm balloon catheters. The animals were randomized to one of two groups: group 1 (n = 10) received 50 mg cilostazol in two doses a day; and group 2 (n = 10) was the control group. After 30 days, the animals were killed and their iliac arteries were prepared for histological analysis. Histological images were digitalized and analyzed using digital morphometry. The Student t and the Mann-Whitney tests were used for statistical analyses. Results: Iliac arteries that underwent angioplasty had significantly more neointimal hyperplasia than those with no angioplasty (0.228 versus 0.119 mm2; p = 0.0001) Group 1 (cilostazol) and 2 (control) had no significant differences in lumen (2.277 versus 2.575 mm2; p = 0.08), intima (0.219 versus 0.237 mm2; p = 0.64) or media (2.262 versus 2.393 mm2; p = 0.53) area, or in percentage of neointimal obstruction (8.857 versus 9.257 %; p = 0.82). Conclusion: The use of 50 mg cilostazol in two doses a day did not reduce neointimal hyperplasia in iliac arteries of pigs that underwent balloon angioplasty.

OBJETIVO: analisar, por meio de morfometria digital, a reação intimal presente na artéria carótida de suínos submetidos à angioplastia isoladamente e à angioplastia seguida de implante de stent de cromo - cobalto. MATERIAIS E MÉTODOS: em oito suínos sadios foi realizada a angioplastia isolada da artéria carótida comum (ACC) direita e angioplastia com implante de um stent de cromo – cobalto expansível por balão na artéria carótida comum esquerda. Após período de quatro semanas, os animais foram submetidos à eutanásia para a retirada de amostras de tecido arterial e preparo de lâminas histológicas divididas do seguinte modo: grupo 1, segmento médio da artéria carótida comum direita (angioplastia isolada); grupo 2, segmento médio da artéria carótida comum esquerda em localização “intra stent”. As imagens das lâminas foram digitalizadas e analisadas por programa de morfometria digital com cálculo da área luminal, área da camada íntima e área da camada média dos cortes histológicos. A análise estatística foi realizada através da média e desvio padrão das áreas em cada grupo, utilizando-se Teste t de Student. O valor de p<0,05 foi considerado significativo. RESULTADOS: na análise das médias das áreas obtidas, foi encontrada maior hiperplasia em resposta ao implante de stent e diferença estatisticamente significativa quando realizada a comparação entre a área do lúmen (5,841 x 106μm2 X 1,287 x 106μm2), da lâmina elástica interna (6,566 x 106μm2 X 1,287 x 106μm2) e lâmina elástica externa (9,832 x 106μm2 X 4,559 x 106μm2) dos dois grupos (ATP + STENT X ATP; medidas em micrômetros quadrados). Não se observou diferença significativa do ponto de vista estatístico quando se realizou a comparação entre as camadas médias dos dois grupos (3,266 x 106μm2 X 3,271 x 106μm2). CONCLUSÃO: o implante de stent de cromo-cobalto expansível por balão na ACC do suíno gerou um espessamento intimal maior do que aquele produzido apenas pela angioplastia, porém este não foi suficiente para afetar o lúmen arterial. / OBJECTIVE: to analyze, through digital morphometry, the intimal reaction in the carotid artery of pigs submitted to isolated angioplasty and angioplasty followed by implantation of cobalt-chromium stent. MATERIALS AND METHODS: eight healthy pigs had their common carotid artery (CCA) submitted to isolated angioplasty in the right side and angioplasty plus stenting in the left side. Four weeks latter, all animals were submitted to euthanasia for arterial tissue sampling and preparation of histological blades sorted as follows: group 1, middle segment of common right carotid artery (isolated angioplasty); group 2, middle segment of common left carotid artery (intra-stent). Blade images were scanned and analyzed through a digital morphometry program with calculation of luminal, intimal and media layers area in the histological sections. The statistical analysis was performed through mean values and standard deviations of the areas in each group, using the Student’s t-Test. The value of p<0.05 was considered significant. RESULTS: When compare to angioplasty alone, the stent group showed greater hyperplasia in response to implantation regarding the lumen area (5.841 x 106μm2 X 1.287 x 106μm2), the internal elastic lamina area (6.566 x 106μm2 X 1.287 x 106μm2) and the external elastic lamina area (9.832 x 106μm2 X 4.559 x 106μm2). No statistically significant difference was observed when comparing the media layers of both groups (3.266 x 106μm2 X 3.271 x 106μm2). CONCLUSION: angioplasty followed by the implantation of a cobalt-chromium balloon expandable stent in the CCA of the pig creates more intimal thickening than angioplasty alone. Nevertheless intimal thickening was not enough to affect the luminal area thanks to a positive elastic remodeling effect.