京都大学 / 新制・課程博士 / 博士(医学) / 甲第23607号 / 医博第4794号 / 新制||医||1055(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 溝脇 尚志, 教授 木村 剛, 教授 濵﨑 洋子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>Randomised controlled trials (RCT) have demonstrated a net benefit of carotid endarterectomy (CEA) in stroke prevention for patients with severe carotid artery stenosis as compared to best medical treatment. Results in routine clinical practice must not be inferior to those in the RCTs. The carotid arteries are clamped during CEA which may impair the cerebral perfusion. </p><p>The aim of this thesis was to assess population-based outcomes from CEA, investigate risk factors for perioperative complications/late mortality and to evaluate effects of carotid clamping during CEA. In the Swedish vascular registry 6182 CEAs were registered during 1994-2003. Data on all CEAs were retrieved, analysed and validated. In the validation process no death or disabling stroke was unreported. The perioperative stroke or death rate was 4.3% for those with symptomatic and 2.1% for asymptomatic stenosis (the latter decreasing over time). Risk factors for perioperative complications were age, indication, diabetes, cardiac disease and contralateral occlusion. Median survival time was 10.8 years for the symptomatic and 10.2 years for the asymptomatic group. </p><p>Tolerance to carotid clamping during CEA under general anaesthesia was evaluated in 62 patients measuring cerebral oximetry, transit time volume flowmetry and stump pressure. High internal carotid artery flow before clamping and low stump pressure was associated with decreased oxygenation after clamping suggesting shunt indication. </p><p>In 18 patients undergoing CEA, jugular bulb blood samples demonstrated significantly altered levels of marker for inflammatory activation (IL-6) and fibrinolytic activity (D-dimer and PAI-1) during carotid clamping as compared to radial artery levels. This indicates a cerebral ischaemia due to clamping although clinically well tolerated. </p><p>In conclusion, the perioperative outcome after CEA in Sweden compared well with the RCTs results. Tolerance to carotid clamping may be evaluated by combining stump pressure and volume flow measurements. Although clinically tolerated clamping may induce a cerebral ischaemic response.</p>

Randomised controlled trials (RCT) have demonstrated a net benefit of carotid endarterectomy (CEA) in stroke prevention for patients with severe carotid artery stenosis as compared to best medical treatment. Results in routine clinical practice must not be inferior to those in the RCTs. The carotid arteries are clamped during CEA which may impair the cerebral perfusion. The aim of this thesis was to assess population-based outcomes from CEA, investigate risk factors for perioperative complications/late mortality and to evaluate effects of carotid clamping during CEA. In the Swedish vascular registry 6182 CEAs were registered during 1994-2003. Data on all CEAs were retrieved, analysed and validated. In the validation process no death or disabling stroke was unreported. The perioperative stroke or death rate was 4.3% for those with symptomatic and 2.1% for asymptomatic stenosis (the latter decreasing over time). Risk factors for perioperative complications were age, indication, diabetes, cardiac disease and contralateral occlusion. Median survival time was 10.8 years for the symptomatic and 10.2 years for the asymptomatic group. Tolerance to carotid clamping during CEA under general anaesthesia was evaluated in 62 patients measuring cerebral oximetry, transit time volume flowmetry and stump pressure. High internal carotid artery flow before clamping and low stump pressure was associated with decreased oxygenation after clamping suggesting shunt indication. In 18 patients undergoing CEA, jugular bulb blood samples demonstrated significantly altered levels of marker for inflammatory activation (IL-6) and fibrinolytic activity (D-dimer and PAI-1) during carotid clamping as compared to radial artery levels. This indicates a cerebral ischaemia due to clamping although clinically well tolerated. In conclusion, the perioperative outcome after CEA in Sweden compared well with the RCTs results. Tolerance to carotid clamping may be evaluated by combining stump pressure and volume flow measurements. Although clinically tolerated clamping may induce a cerebral ischaemic response.

Darbo tikslas – įvertinti miego arterijų angioplastikos ir stentavimo ankstyvuosius ir vėlyvuosius rezultatus bei poveikį darančius veiksnius. Metodai. Tyrimo metu vertintos VMAS procedūros atliktos 2006-2013 metais. Iš viso buvo atliktos 227 procedūros 211 pacientų; iš jų 156 (75,3 proc.) vyrams ir 55 (24,7 proc.) moterims. Rezultatai. Tyrimas atskleidė, kad esant 3 aortos lanko tipui VMAS procedūros trukmė buvo reikšmingai ilgesnė, o mikroembolai apsaugos sistemose buvo nustatyti dažniau. Mikroembolai apsaugos sistemose buvo nustatyti dažniau kai VMAS procedūra truko ilgiau. Apsaugos sistemos atliekant VMAS procedūrą buvo naudotos 70,9 proc. pacientų. Vyrams ir jaunesnio amžiaus pacientams VMAS procedūros metu apsauga buvo taikyta dažniau. Mikroembolai apsaugos sistemose buvo nustatyti 17,6 proc. pacientų ir dažniau buvo nustatyti naudojant FilterWire EZ ir Embo-shield-NAV apsaugos sistemas. Didesnė dešinės VMA stenozė buvo dažnesnė rūkantiems pacientams, o kairės VMA sirgusiems miokardo infarktu bei rūkantiems. Apsauga dažniau buvo taikyta pacientams kurie turėjo didelio laipsnio kairės VMA stenozę. Ankstyvuoju po procedūriniu periodu vyrų ir moterų mirštamumas atitinkamai buvo 1,2 proc. ir 1,8 proc., o 2 metų laikotarpyje buvo 18,7 proc. ir 28,6 proc. Pacientų mirštamumas 2 metų laikotarpyje, kuriems buvo naudotos apsaugos sistemos buvo mažesnis. Galimybę patirti komplikacijas (GSI ar PSIP) didino 3 aortos lanko tipas ir dešinės bendrosios miego arterijos stenozė, mažino... [toliau žr. visą tekstą] / The aim - to assess the carotid artery angioplasty and stenting early and late results and influencing factors. Methods. The study assessed CAS procedures performed in 2006-2013. A total of 227 procedures performed in 211 patients, of which 156 (75.3%) males and 55 (24.7%) females. Results. The study revealed that CAS procedure duration among patient with 3 aortic arch type was significantly longer and the microemboli protection systems were used more frequently. Protection systems were used more frequently when the CAS procedure lasted longer. Protection systems in CAS procedure was used in 70.9% patients. In men and younger patients protection system has been used more frequently. Microemboli in the protection systems have been identified by 17.6% patients and were more determined using the EZ FilterWire and Emboshield-NAV protection system. Increased right ICA stenosis was more common in patients who smoke, and left ICA with a history of myocardial infarction and smoking. Protection system was often used in patients who have had severe left ICA stenosis. The lethality rate in the early post procedural period among men and women was 1.2% and 1.8%, and in 2-year period was 18.7% and 28.6%, respectively. The lethality rate during 2-year period, which have been used for protective systems have been lower. The possibility to experience complications (stroke or TIA) increased 3 aortic arch type and the right common carotid artery stenosis, reduced protection systems using. Focal... [to full text]

The aim - to assess the carotid artery angioplasty and stenting early and late results and influencing factors. Methods. The study assessed CAS procedures performed in 2006-2013. A total of 227 procedures performed in 211 patients, of which 156 (75.3%) males and 55 (24.7%) females. Results. The study revealed that CAS procedure duration among patient with 3 aortic arch type was significantly longer and the microemboli protection systems were used more frequently. Protection systems were used more frequently when the CAS procedure lasted longer. Protection systems in CAS procedure was used in 70.9% patients. In men and younger patients protection system has been used more frequently. Microemboli in the protection systems have been identified by 17.6% patients and were more determined using the EZ FilterWire and Emboshield-NAV protection system. Increased right ICA stenosis was more common in patients who smoke, and left ICA with a history of myocardial infarction and smoking. Protection system was often used in patients who have had severe left ICA stenosis. The lethality rate in the early post procedural period among men and women was 1.2% and 1.8%, and in 2-year period was 18.7% and 28.6%, respectively. The lethality rate during 2-year period, which have been used for protective systems have been lower. The possibility to experience complications (stroke or TIA) increased 3 aortic arch type and the right common carotid artery stenosis, reduced protection systems using. Focal... [to full text] / Darbo tikslas – įvertinti miego arterijų angioplastikos ir stentavimo ankstyvuosius ir vėlyvuosius rezultatus bei poveikį darančius veiksnius. Metodai. Tyrimo metu vertintos VMAS procedūros atliktos 2006-2013 metais. Iš viso buvo atliktos 227 procedūros 211 pacientų; iš jų 156 (75,3 proc.) vyrams ir 55 (24,7 proc.) moterims. Rezultatai. Tyrimas atskleidė, kad esant 3 aortos lanko tipui VMAS procedūros trukmė buvo reikšmingai ilgesnė, o mikroembolai apsaugos sistemose buvo nustatyti dažniau. Mikroembolai apsaugos sistemose buvo nustatyti dažniau kai VMAS procedūra truko ilgiau. Apsaugos sistemos atliekant VMAS procedūrą buvo naudotos 70,9 proc. pacientų. Vyrams ir jaunesnio amžiaus pacientams VMAS procedūros metu apsauga buvo taikyta dažniau. Mikroembolai apsaugos sistemose buvo nustatyti 17,6 proc. pacientų ir dažniau buvo nustatyti naudojant FilterWire EZ ir Embo-shield-NAV apsaugos sistemas. Didesnė dešinės VMA stenozė buvo dažnesnė rūkantiems pacientams, o kairės VMA sirgusiems miokardo infarktu bei rūkantiems. Apsauga dažniau buvo taikyta pacientams kurie turėjo didelio laipsnio kairės VMA stenozę. Ankstyvuoju po procedūriniu periodu vyrų ir moterų mirštamumas atitinkamai buvo 1,2 proc. ir 1,8 proc., o 2 metų laikotarpyje buvo 18,7 proc. ir 28,6 proc. Pacientų mirštamumas 2 metų laikotarpyje, kuriems buvo naudotos apsaugos sistemos buvo mažesnis. Galimybę patirti komplikacijas (GSI ar PSIP) didino 3 aortos lanko tipas ir dešinės bendrosios miego arterijos stenozė, mažino... [toliau žr. visą tekstą]

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13259号 / 論医博第2177号 / 新制||医||1037(附属図書館) / (主査)教授 横出 正之, 教授 富樫 かおり, 教授 湊谷 謙司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18882号 / 医博第3993号 / 新制||医||1009(附属図書館) / 31833 / 京都大学大学院医学研究科医学専攻 / (主査)教授 宮本 享, 教授 小泉 昭夫, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

O acidente vascular cerebral (AVC) e a primeira causa de obito no Brasil e a principal de incapacidade no mundo. A doenca aterosclerotica carotidea esta associada a cerca de 15% dos AVC. A endarterectomia cirurgica e o tratamento padrao-­ouro para as estenoses carotideas sintomaticas. A angioplastia carotidea com stent via endovascular (ACS) e uma alternativa terapeutica a endarterectomia. O desenvolvimento de dispositivos de protecao embolica levou a reducao das taxas de complicacao durante a ACS. A tecnica de protecao mais utilizada na pratica clinica e a protecao distal com filtro. As estrategias de protecao proximal, por bloqueio ou reversao do fluxo carotideo, tem revelado resultados promissores em relacao a protecao distal com filtro durante a ACS. Assim, o objetivo do estudo foi comparar a reversao de fluxo e o filtro de protecao durante a ACS. Os objetivos primarios foram a incidencia, o numero e o tamanho das lesoes cerebrais isquemicas por ressonancia magnetica pela sequencia diffusion-­weighted-­imaging (DWI) apos a ACS. Os objetivos secundarios foram as complicacoes cardiacas e eventos cerebrovasculares (CCEC), ataque isquemico transitorio (AIT) e as lesoes cerebrais isquemicas definitivas na imagem por ressonancia magnetica pela sequencia fluid-­attenuated inversion recovery (FLAIR) no seguimento de tres meses. As lesoes isquemicas foram obtidas por ressonancia magnetica (RM) de campo 3 Tesla. Os pacientes foram avaliados quanto aos desfechos neurologicos atraves das escalas do National Institutes of Health Stroke Scale (NIHSS) e modified Rankin Scale (mRS). Quarenta pacientes foram incluidos randomicamente no estudo. Comparado a reversao de fluxo (n=21) o filtro de protecao (n=19) resultou em uma reducao significativa na incidencia (15,8% vs. 47,6%, p=0,03), no numero (0,73 vs. 2,6, p=0,05) e no tamanho (0,81 vs. 2,23 mm, p=0,05) das novas lesoes cerebrais isquemicas. Dois pacientes, um de cada grupo, apresentaram AIT no seguimento de tres meses. Nao foram observadas CCEC na internacao ou no seguimento de tres meses. Neste estudo, o filtro de protecao mais eficaz que a reversao de fluxo na protecao cerebral durante a angioplastia carotidea com stent por acesso femoral. / Objectives: Carotid artery stenting (CAS) has become an alternative treatment for patients presenting symptomatic carotid artery stenosis. The improvement in clinical outcomes with CAS has been associated with the development of embolic protection devices. The trial aim is to compare flow-­reversal versus filter protection during CAS through femoral access. Methods: Patients were randomly enrolled in CAS using flow-­reversal or filter protection. The primary endpoints were the incidence, number and size of new ischemic brain lesions after CAS. The secondary endpoints included major adverse cardiac and cerebrovascular events (MACCE), transient ischemic attack (TIA) and definitive ischemic brain lesions on fluid-­attenuated inversion recovery magnetic resonance image (FLAIR-­MRI) at a three-­month follow-­up. Ischemic brain lesions were assessed by a 3T-­MRI. Neurological outcomes were evaluated by means of the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). Results: Forty consecutive patients were randomly assigned. Compared to flow-­reversal (n=21), filter protection (n=19) resulted in a significant reduction in the incidence (15.8% vs. 47.6%, p=0.03), number (0.73 vs. 2.6, p=0.05) and size (0.81 vs. 2.23 mm, p=0.05) of new ischemic brain lesions. Two patients, one from each group, presented TIA at the three-­month follow-­up. There were no MACCE in the hospital or at the three-­month follow-­up. Conclusions: In this small sample size trial, filter protection was more effective than flow-­reversal in reducing ischemic brain lesions during CAS through femoral approach.

O acidente vascular cerebral (AVC) e a primeira causa de obito no Brasil e a principal de incapacidade no mundo. A doenca aterosclerotica carotidea esta associada a cerca de 15% dos AVC. A endarterectomia cirurgica e o tratamento padrao-­ouro para as estenoses carotideas sintomaticas. A angioplastia carotidea com stent via endovascular (ACS) e uma alternativa terapeutica a endarterectomia. O desenvolvimento de dispositivos de protecao embolica levou a reducao das taxas de complicacao durante a ACS. A tecnica de protecao mais utilizada na pratica clinica e a protecao distal com filtro. As estrategias de protecao proximal, por bloqueio ou reversao do fluxo carotideo, tem revelado resultados promissores em relacao a protecao distal com filtro durante a ACS. Assim, o objetivo do estudo foi comparar a reversao de fluxo e o filtro de protecao durante a ACS. Os objetivos primarios foram a incidencia, o numero e o tamanho das lesoes cerebrais isquemicas por ressonancia magnetica pela sequencia diffusion-­weighted-­imaging (DWI) apos a ACS. Os objetivos secundarios foram as complicacoes cardiacas e eventos cerebrovasculares (CCEC), ataque isquemico transitorio (AIT) e as lesoes cerebrais isquemicas definitivas na imagem por ressonancia magnetica pela sequencia fluid-­attenuated inversion recovery (FLAIR) no seguimento de tres meses. As lesoes isquemicas foram obtidas por ressonancia magnetica (RM) de campo 3 Tesla. Os pacientes foram avaliados quanto aos desfechos neurologicos atraves das escalas do National Institutes of Health Stroke Scale (NIHSS) e modified Rankin Scale (mRS). Quarenta pacientes foram incluidos randomicamente no estudo. Comparado a reversao de fluxo (n=21) o filtro de protecao (n=19) resultou em uma reducao significativa na incidencia (15,8% vs. 47,6%, p=0,03), no numero (0,73 vs. 2,6, p=0,05) e no tamanho (0,81 vs. 2,23 mm, p=0,05) das novas lesoes cerebrais isquemicas. Dois pacientes, um de cada grupo, apresentaram AIT no seguimento de tres meses. Nao foram observadas CCEC na internacao ou no seguimento de tres meses. Neste estudo, o filtro de protecao mais eficaz que a reversao de fluxo na protecao cerebral durante a angioplastia carotidea com stent por acesso femoral. / Objectives: Carotid artery stenting (CAS) has become an alternative treatment for patients presenting symptomatic carotid artery stenosis. The improvement in clinical outcomes with CAS has been associated with the development of embolic protection devices. The trial aim is to compare flow-­reversal versus filter protection during CAS through femoral access. Methods: Patients were randomly enrolled in CAS using flow-­reversal or filter protection. The primary endpoints were the incidence, number and size of new ischemic brain lesions after CAS. The secondary endpoints included major adverse cardiac and cerebrovascular events (MACCE), transient ischemic attack (TIA) and definitive ischemic brain lesions on fluid-­attenuated inversion recovery magnetic resonance image (FLAIR-­MRI) at a three-­month follow-­up. Ischemic brain lesions were assessed by a 3T-­MRI. Neurological outcomes were evaluated by means of the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). Results: Forty consecutive patients were randomly assigned. Compared to flow-­reversal (n=21), filter protection (n=19) resulted in a significant reduction in the incidence (15.8% vs. 47.6%, p=0.03), number (0.73 vs. 2.6, p=0.05) and size (0.81 vs. 2.23 mm, p=0.05) of new ischemic brain lesions. Two patients, one from each group, presented TIA at the three-­month follow-­up. There were no MACCE in the hospital or at the three-­month follow-­up. Conclusions: In this small sample size trial, filter protection was more effective than flow-­reversal in reducing ischemic brain lesions during CAS through femoral approach.

Carotid artery stenosis (CAS) develops from atherosclerotic lesions and plaques. Plaque rupture or stenosis may result in occlusion of the carotid artery. Accordingly, the asymptomatic disease becomes symptomatic, characterized by ischemic stroke or transient ischemic attacks, indicating an urgent need for better understanding of the underlying molecular mechanisms and eventually prevent symptomatic CAS. NOX4, a member of the NADPH oxidase family, has anti-atherosclerotic and anti-inflammatory properties in animal models of early atherosclerosis. We hypothesized that NOX4 mRNA expression is linked to protective mechanisms in CAS patients with advanced atherosclerotic lesions as well. Indeed, NOX4 mRNA expression is lower in patients with symptomatic CAS. A low NOX4 mRNA expression is associated with an increased risk of the development of clinical symptoms. In fact, NOX4 appears to be linked to plaque stability, apoptosis and plaque hemorrhage. This is supported by cleaved caspase-3 and glycophorin C and correlates inversely with plaque NOX4 mRNA expression. Even healing of a ruptured plaque appears to be connected to NOX4, as NOX4 mRNA expression correlates to fibrous cap collagen and is reciprocally related to MMP9 activity. In conclusion, low intra-plaque NOX4 mRNA expression is associated with an increased risk for symptomatic outcome and with reduced plaque stabilizing mechanisms suggesting protective effects of NOX4 in human advanced atherosclerosis.