No description available.

Une des complications qui survient chez 1/3 des patients dans les 6 mois suivant une angioplastie est la resténose, réponse myoproliférative du muscle lisse vasculaire. Cette formation néointimale (LIU et al., 1989), nécessite souvent une angioplastie ultérieure ou un pontage aortocoronarien chez l'homme. Dans un modèle animal, cette resténose a été partiellement supprimée par des doses élevées d'inhibiteurs et d'antagonistes reliées au système rénine angiotensine. Nous avons démontré récemment sur ce modèle qu'une infusion intralésionelle de Br[indice inférieur 5]Ang, un antagoniste peptidique non-sélectif de longue durée d'action de l'angiotensine II (Ang), peut prévenir une formation néointimale (LAPORTE et ESCHER, 1992). Ces résultats démontrent que l'Ang est un médiateur nécessaire mais n'identifie pas le type de récepteur par lequel cette réponse est médiée. Pour résoudre cette question, une expérience avec des antagonistes sélectifs fut effectuée. L'angioplastie des artères carotides de rats Sprague-Dawley fut suivie d'un traitement continu de 14 jours par infusion intra-artérielle de losartan (antagoniste sélectif au récepteur AT[indice inférieur 1] de l'angiotensine II), de PD123319 (antagoniste sélectif au récepteur AT[indice inférieur 2] de l'angiotensine II), d'une combinaison de losartan et de PD123319 ou d'une infusion de salin. La morphométrie des coupes histologiques des artères recueillies 14 jours après l'angioplastie a permis de calculer la lumière vasculaire et l'épaisseur néointimale moyenne. Ces calculs démontrent une réduction de la resténose dans le groupe traité avec le losartan lorsque comparé au groupe contrôle. Cette réduction de la resténose est égale à celle observée avec la combinaison de losartan et de PD123319. Le PD123319 seul n'a pas reéduit la resténose de façon significative. Il semble alors que le récepteur AT[indice inférieur 1] de l'angiotensine II soit responsable en partie de la resténose post-angioplastique chez le rat Sprague-Dawley. Le récepteur AT[indice inférieur 2] de l'angiotensine II ne semble pas être impliqué de façon significative dans ce processus.

No description available.

The incorporation of drugs into phosphorylcholine (PC) polymers coated onto coronary stent surfaces is one potential method of treatment for reducing restenosis, the reclosure of the artery after angioplasty treatment. This work on the characterisation of the swelling performance of thin PC polymer films represents a further extension of the study on biocompatible polymers. The broad aim of this work is to relate the PC polymer structure and film processing conditions to their swelling, drug loading and release kinetics. As the two highly sensitive and powerful techniques in film structure determination, both ellipsometry and neutron reflection have proved to be useful in characterising PC polymer films and drug release processes. Following an established ellipsometry measurement method, a two stage process consisting of diffusion and relaxation has been observed during the PC film swelling: this suggests an anomalous mechanism, and this performance is well described by the coupled diffusion and relaxation model developed by Berens and Hopfenberg. Furthermore, the swelling of PC polymer films was investigated as a function of cross-linking, annealing temperature, chemical composition, hydrophilic/hydrophobic ratios, film thickness and environmental conditions by ellipsometry measurements, and their effects on swelling kinetics well quantified. The structures of the PC polymer films (PC100B) with cross-linking groups have been further characterised by neutron reflection. The segregation of hydrophobic and hydrophilic domains was found in the PC films with different dimensions. The PC100B with deuterated dodecyl chains was used to highlight the interfacial structures of the PC films. The hydrophilic segments, including phosphorylcholine groups and hydroxypropyl groups, are preferentially adsorbed at the polymer/substrate interface. The hydrophobic dodecyl chains are expelled away from the silicon oxide surface. The main part of PC100B films is the middle uniform region with 40% of water in the sample annealed at 150°C, and 55% of water in the sample annealed at 50°C. The combination of the ellipsometry results and the drug release profiles from UV measurements indicates that the drug release pattern is strongly affected by the film swelling kinetics when the drug molecules and polymer matrix interact weakly. Otherwise, a strong interaction between the drug and the polymer will dominate the drug release behaviour from the PC polymer films.

Les maladies cardio-vasculaires sont responsables de la vaste majorité des décès dans les pays industrialisés. La plupart de ces maladies sont dues à l'athérosclérose, processus manifesté par le développement de lésions (plaques d'athéromes) dans les parois vasculaires. La présence de ces plaques conduit à la réduction de la lumière du vaisseau et, par conséquent, à des complications graves, tel que l'infarctus du myocarde. Les patients ont pour issue la méthode d'angioplastie qui consiste à écraser la plaque athéromateuse à l'aide d'un ballonnet pour accroître la lumière du vaisseau obstrué. Toutefois, cette intervention entraîne une abrasion de l'endothélium et un étirement important des cellules musculaires lisses (CML) situées dans la profondeur de la paroi. Chez environ un tiers à la moitié des patients, la multiplication des CMLs conduit à une nouvelle réduction de la lumière artérielle. C'est la resténose. Les travaux de recherche ont permis le déploiement de plusieurs thérapies pharmacologiques et mécaniques mais les résultats tant anticipés suite aux études animales ne sont pas reproductibles chez l'humain pour la vaste majorité des tactiques. Notre équipe s'est intéressée au Système Rénine-Angiotensine (SRA) car son implication dans la resténose est non-négligeable. De plus, le succès des inhibiteurs de l'enzyme de conversion de l'angiotensine (iECA) chez l'animal a confirmé son rôle. Cependant, les essais cliniques ne sont guère convaincants et c'est ce qui a incité plusieurs à s'intéresser aux récepteurs de !'angiotensine II (Ang Il). Nos études antérieures avec le modèle de la carotide de rat ont révélé que les antagonistes non-peptidiques de l' Ang II sélectifs pour AT[indice inférieur 1] diminuaient partiellement la prolifération néointimale. Parallèlement, nous avions traité nos animaux avec un antagoniste peptidique non-sélectif pour réaliser que ce dernier en inhibait la presque totalité. Notre hypothèse de travail est que les antagonistes nonpeptidiques et les iECAs ont une efficacité limitée sur la réduction myointimale. Nous avons effectué une courbe dose-réponse avec un antagoniste non-peptidique sélectif pour AT[indice inférieur 1] et une seconde courbe avec un antagoniste non-peptidique mais sélectif pour les deux sous-types de récepteurs (AT[indice inférieur 1] et AT[indice inférieur 2]. De plus, nous avons traité nos animaux avec un iECA seul et combiné avec un antagoniste non-peptidique. Le bilan confirme l'efficacité limitée des antagonistes non-peptidiques de I' Ang II et établit que la coapplication de drogues ne suffit pas pour réduire la prolifération néointimale avec la même efficacité qu'observée avec l'antagoniste peptidique. Dans un deuxième temps, nous avons cherché à développer un nouveau modèle animal de la resténose afin de palier aux critiques dont font l'objet les modèles actuels et aussi permettre la validation de nos données antérieures. Nous suggérons que le furet pourrait devenir une bonne alternative aux modèles existants.

Atherosclerosis is a leading cause of morbidity and mortality worldwide and type 2 diabetes and obesity-associated metabolic syndrome, both characterized by insulin resistance, are potent risk factors. These conditions also increase the risk for restenosis after revascularization procedures used for treatment of atherosclerosis. Studies have shown that insulin and resveratrol (RSV), a red wine polyphenol, decrease neointimal growth after vessel injury in models of restenosis, demonstrating a protective effect on the vasculature. However, oral glucose and sucrose were used in insulin studies to maintain normoglycemia, and their effect on neointimal formation was not assessed. Several studies have shown that nitric oxide (NO) production is stimulated by insulin and RSV, and since NO can decrease neointimal growth, the objective of this thesis was to address the mechanism of action of insulin or RSV to protect against restenosis, and determine whether NO production mediates these effects. To examine this, we treated rats with insulin or RSV and performed arterial balloon injury. In Study 1, insulin reduced neointimal area after injury in rats receiving oral glucose but not oral sucrose. Oral glucose alone had no effect on neointimal formation or insulin sensitivity whereas oral sucrose increased neointimal growth and induced insulin resistance. In Study 2, insulin decreased neointimal area and cell migration, and increased re-endothelialization. These effects were abolished by nitric oxide synthase (NOS) inhibition. In addition, insulin increased eNOS protein expression in the vessel. In Study 3, RSV reduced neointimal growth, cell proliferation, and migration after injury, without affecting re-endothelialization. Most of these effects were abolished by NOS inhibition, except for the decrease in cell migration. Insulin sensitivity and systolic blood pressure were not affected by RSV. Together, the results demonstrate that insulin, independent of glycemic effects, and RSV have a protective effect on the vessel against restenosis, which is mediated by NO. Since both insulin and RSV decrease neointimal formation without negatively impacting re-endothelialization, insulin or RSV treatment could provide some advantage over anti-mitogenic agents currently used in drug-eluting stents, which delay re-endothelialization. These studies suggest that insulin or RSV may have clinical potential in the prevention of restenosis after angioplasty.

Restenosis is one of the major adverse outcomes of Percutaneous Coronary Intervention (PCI). Previous studies have shown conflicting reports for homocysteine as a predictor of restenosis following PCI. The conflicting reports may be due to oxidative factors (stimulation of polymorphonuclear leukocyte [PMNL]-induced reactive oxygen species generation, xanthine- xanthine oxidase, and arachidonic acid metabolism) other than homocysteine which could cause endothelial cell dysfunction leading to restenosis. Malondialdehyde (MDA), a lipid peroxidation product, is a marker for oxidative stress and is related to all oxidative factors. Therefore, it is possible that serum MDA may be a better predictor of restenosis than plasma homocysteine. The purpose of this study is to determine whether or not the pre-procedural serum MDA and plasma homocysteine levels are elevated in patients who develop restenosis post PCI. <p>The study included fifty-one patients undergoing elective PCI who consented to participate in a protocol that was approved by the Ethics Committee of the University of Saskatchewan. Homocysteine and malondialdehyde were measured in the plasma and serum respectively. Blood samples were collected pre-procedural, 0 time, 8 hours, 24 hours, and 6 months post-procedure. Exercise tolerance tests were performed at two weeks, and six months post-procedure to determine if there was any evidence of restenosis. <p>The results of the study showed that pre-procedural values of plasma homocysteine in the restenosis and non-restenosis groups were 10.37 ± 0.46 and 10.73 ± 0.49 respectively. These values were not significantly different (p=0.60) between the groups. The pre-procedural levels of plasma homocysteine were not significantly different (p=0.08) from the post-PCI values of those patients who did not develop restenosis at the 6-month time interval. However, the pre-procedural levels of plasma homocysteine were significantly different from the post-PCI values of those patients in the restenosis group at the 24hr (p=0.04) and 6-month (p=0.002) time intervals. In the restenosis group there was a significant increase (24%) after six months in the values of homocysteine from the pre-procedural levels. Thus, this indicates that restenosis is associated with higher post-PCI levels of homocysteine. <p>The pre-procedural levels of serum MDA in the restenosis and non-restenosis groups were 0.124± 0.16 and 0.147± 0.02 respectively. There was no significant difference (p=0.60) between the two groups. There was also no significant difference (p=0.053) between the pre-procedural values and the 6-month post-PCI values in those patients who did not develop restenosis. However, there was a significant difference (p=0.001) between the pre-procedural values and the 6-month post-PCI values in those patients who developed restenosis. The levels of serum MDA in patients with restenosis at 6-months increased by 109% and were significantly different (p=0.001) in the restenosis group. <p>The results suggest that pre-procedural levels of plasma homocysteine and serum MDA were not predictors of restenosis following PCI. However, the post-PCI six-month levels of both homocysteine and MDA are predictors of restenosis. Moreover, the post-PCI levels of MDA were better predictors of restenosis than the post-PCI levels of homocysteine because the increase in MDA levels were greater at six months than the rise in homocysteine levels at the same time interval.

Atherosclerosis is a leading cause of morbidity and mortality worldwide and type 2 diabetes and obesity-associated metabolic syndrome, both characterized by insulin resistance, are potent risk factors. These conditions also increase the risk for restenosis after revascularization procedures used for treatment of atherosclerosis. Studies have shown that insulin and resveratrol (RSV), a red wine polyphenol, decrease neointimal growth after vessel injury in models of restenosis, demonstrating a protective effect on the vasculature. However, oral glucose and sucrose were used in insulin studies to maintain normoglycemia, and their effect on neointimal formation was not assessed. Several studies have shown that nitric oxide (NO) production is stimulated by insulin and RSV, and since NO can decrease neointimal growth, the objective of this thesis was to address the mechanism of action of insulin or RSV to protect against restenosis, and determine whether NO production mediates these effects. To examine this, we treated rats with insulin or RSV and performed arterial balloon injury. In Study 1, insulin reduced neointimal area after injury in rats receiving oral glucose but not oral sucrose. Oral glucose alone had no effect on neointimal formation or insulin sensitivity whereas oral sucrose increased neointimal growth and induced insulin resistance. In Study 2, insulin decreased neointimal area and cell migration, and increased re-endothelialization. These effects were abolished by nitric oxide synthase (NOS) inhibition. In addition, insulin increased eNOS protein expression in the vessel. In Study 3, RSV reduced neointimal growth, cell proliferation, and migration after injury, without affecting re-endothelialization. Most of these effects were abolished by NOS inhibition, except for the decrease in cell migration. Insulin sensitivity and systolic blood pressure were not affected by RSV. Together, the results demonstrate that insulin, independent of glycemic effects, and RSV have a protective effect on the vessel against restenosis, which is mediated by NO. Since both insulin and RSV decrease neointimal formation without negatively impacting re-endothelialization, insulin or RSV treatment could provide some advantage over anti-mitogenic agents currently used in drug-eluting stents, which delay re-endothelialization. These studies suggest that insulin or RSV may have clinical potential in the prevention of restenosis after angioplasty.

Restenosis is one of the major adverse outcomes of Percutaneous Coronary Intervention (PCI). Previous studies have shown conflicting reports for homocysteine as a predictor of restenosis following PCI. The conflicting reports may be due to oxidative factors (stimulation of polymorphonuclear leukocyte [PMNL]-induced reactive oxygen species generation, xanthine- xanthine oxidase, and arachidonic acid metabolism) other than homocysteine which could cause endothelial cell dysfunction leading to restenosis. Malondialdehyde (MDA), a lipid peroxidation product, is a marker for oxidative stress and is related to all oxidative factors. Therefore, it is possible that serum MDA may be a better predictor of restenosis than plasma homocysteine. The purpose of this study is to determine whether or not the pre-procedural serum MDA and plasma homocysteine levels are elevated in patients who develop restenosis post PCI. <p>The study included fifty-one patients undergoing elective PCI who consented to participate in a protocol that was approved by the Ethics Committee of the University of Saskatchewan. Homocysteine and malondialdehyde were measured in the plasma and serum respectively. Blood samples were collected pre-procedural, 0 time, 8 hours, 24 hours, and 6 months post-procedure. Exercise tolerance tests were performed at two weeks, and six months post-procedure to determine if there was any evidence of restenosis. <p>The results of the study showed that pre-procedural values of plasma homocysteine in the restenosis and non-restenosis groups were 10.37 ± 0.46 and 10.73 ± 0.49 respectively. These values were not significantly different (p=0.60) between the groups. The pre-procedural levels of plasma homocysteine were not significantly different (p=0.08) from the post-PCI values of those patients who did not develop restenosis at the 6-month time interval. However, the pre-procedural levels of plasma homocysteine were significantly different from the post-PCI values of those patients in the restenosis group at the 24hr (p=0.04) and 6-month (p=0.002) time intervals. In the restenosis group there was a significant increase (24%) after six months in the values of homocysteine from the pre-procedural levels. Thus, this indicates that restenosis is associated with higher post-PCI levels of homocysteine. <p>The pre-procedural levels of serum MDA in the restenosis and non-restenosis groups were 0.124± 0.16 and 0.147± 0.02 respectively. There was no significant difference (p=0.60) between the two groups. There was also no significant difference (p=0.053) between the pre-procedural values and the 6-month post-PCI values in those patients who did not develop restenosis. However, there was a significant difference (p=0.001) between the pre-procedural values and the 6-month post-PCI values in those patients who developed restenosis. The levels of serum MDA in patients with restenosis at 6-months increased by 109% and were significantly different (p=0.001) in the restenosis group. <p>The results suggest that pre-procedural levels of plasma homocysteine and serum MDA were not predictors of restenosis following PCI. However, the post-PCI six-month levels of both homocysteine and MDA are predictors of restenosis. Moreover, the post-PCI levels of MDA were better predictors of restenosis than the post-PCI levels of homocysteine because the increase in MDA levels were greater at six months than the rise in homocysteine levels at the same time interval.

Intravascular brachytherapy is the primary treatment for coronary in-stent restenosis. We hypothesized that differences in dose delivered to target may contribute to treatment failures. We compared dose distribution between arteries that developed recurrent restenosis (treatment failures) and those that remained patent at nine-months (treatment success). A cohort of 207 patients receiving brachytherapy for coronary in-stent restenosis with four radiation delivery devices was followed to identify treatment failures and successes. This cohort was examined to establish which patient and lesion characteristics had an effect on outcome. A nested case-control construct was then used in which treatment failures (n=14) were compared 1:2 to treatment successes (n=28) matched by two variables: radiation delivery system and angiographic pattern of in-stent restenosis. At baseline, the groups had similar patient and lesion characteristics. The dose absorbed by 90% of the artery encompassed by the external elastic membrane (D90EEM) was calculated using intravascular ultrasound (IVUS) images taken at 2-mm intervals along the treated lesion. Dose calculations were performed using dose kernel integration techniques; the dose kernels were generated from Monte Carlo simulations. The mean D90EEM minimum dose in treatment failures was 7.46±1.98 Gy, while for treatment success the mean D90EEM minimum dose was significantly higher: 8.87±1.13 Gy (p=0.007). Using a dose threshold of 8.4 Gy, a D90EEM minimum dose < 8.4 Gy occurred in 13 (93%) patients with treatment failure, but in only 9 (32%) with treatment success (p<0.001). No confounding variables were found to be statistically significant. In conclusion, current brachytherapy dose prescriptions result in significant inter- and intra-lesion variation in dose at the EEM. Arteries that receive < 8.4 Gy at any point along the EEM are more likely to be treatment failures. IVUS guided dosimetry may be critical to assure adequate dose regardless of radiation delivery system.