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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

Background and Purpose – The relationship between abdominal body fat and cardiovascular health is not completely understood. This study investigated the association between percent body fat, fat distribution and intima-media thickness (IMT) in healthy middle-aged women. Methods – 224 middle-aged (mean age = 43.1 years ± 3.0), nonsmoking women were included in this study. The women were assessed with a B-mode, high-resolution ultrasonograph to measure the intima-media thickness of the right common carotid artery (CCA). Measurements for percent body fat and fat distribution were assessed using Bod Pod and waist circumference (WC) measured at the umbilicus, respectively.Results – Data were separated into quartiles with the middle two groups combined in order to identify potential differences in IMT based on waist circumference and body fat percent groups. Mean IMT for the entire sample was .569 mm ± .06. Multiple regression with and without control for potential confounding factors yielded insignificant results for all analyses. Conclusions – In the present study, using a sample of healthy middle-aged women, there were no differences in IMT based on overall body fat percent or waist circumference measurements. This finding is somewhat unexpected, however, regional body fat and CCA-IMT have been shown in some, but not all studies to be positively associated with IMT. More research is needed in this area in order to more clearly identify and understand early risk for cardiovascular disease in women.

Carotid intima-media thickness (cIMT) is a valid measure of cardiovascular disease (CVD). Physical activity appears to improve cIMT, however, research is inconclusive. This study investigated the relationship between physical activity (physical activity rating (PA-R)) and cardiovascular fitness (predicted VO2max , perceived functional ability (PFA)) and cIMT. Data collected from 341 seniors (≥50 years) competing in the Huntsman World Senior Games (HWSG) included blood lipids, inflammatory makers, blood glucose, blood pressure (BP) and anthropometric measurements of obesity and central adiposity. Multiple regression analysis was used to determine correlations of measured variables with cIMT. Two of the fitness related variables, PFA (r ≈ 0.1359; p = 0.012) and predicted VO2max (r ≈ 0.1475; p = 0.007) were significantly correlated to cIMT without controlling for confounding factors, but lost significance when adjustments for other CVD risk factors were included. PAR (r ≈ 0.0869; p = 0.111) was not significantly correlated to cIMT. Regression analysis indicated that the most predictive variables of cIMT we investigate were: age (t = 7.166, p = 0.000), gender (t = 3.310, p = 0.001), BMI (t = 1.892, p = 0.05), SBP (t = 3.952, p = 0.000), total cholesterol (TC) (t = 4.184, p = 0.000) and triglycerides (TRG) (t ≈ 3.466, p = 0.000), our R2 = .299, thus indicating these 6 variables account for about 30% of the variance in cIMT in seniors competing at HWSG. Physical activity and cardiovascular fitness influence other CVD risk factors and consequently may have an indirect impact on cIMT.

Carotid artery wall stiffness has been widely considered as an index of vascular health, and has been associated with occurrence of cardiovascular events, such as stroke. In addition, the blood flow patterns in the carotid artery can yield crucial information on atherosclerosis progression and cerebrovascular impairment. Pulse wave imaging (PWI) is a non-invasive ultrasound imaging technique that tracks the propagation of the arterial pulse wave, providing thus regional arterial wall stiffness mapping. Moreover, towards enabling accurate visualization of blood flow patterns, ultrasound-based vector flow imaging (VFI) modalities have been developed. Building upon PWI and VFI techniques, the overall goal of this dissertation is to develop ultrasound-based methodologies that can provide simultaneous imaging of the carotid artery wall mechanics and blood flow dynamics at high temporal and spatial resolutions. The developed techniques are validated through vessel phantom experiments and simulations. Furthermore, their potential to diagnose pre-clinical stages of carotid artery disease and provide additional insights in risk for stroke assessment, is demonstrated in an atherosclerotic swine study and human subjects in vivo. More specifically: A method is presented that analyzes the pattern of arterial wall motion derived by PWI, in order to detect spatial mechanical inhomogeneity across an imaged artery, and provide piecewise arterial wall stiffness estimates. The proposed technique is validated in a phantom consisting of a soft and a stiff segment, while its feasibility is demonstrated to identify inhomogeneous wall properties in atherosclerotic human carotid arteries, as well as provide atherosclerotic plaque mechanical characterization in vivo. Subsequently, PWI is integrated with VFI techniques in the same ultrasound acquisition sequence, in order to enable simultaneous and co-localized imaging of arterial wall stiffness and blood vector flow velocity. The performance of the technique is investigated through experiments and FSI simulations. Moreover, its feasibility was shown to investigate associations between carotid artery Pulse Wave Velocity and blood flow patterns, in vivo. Based on the previously developed PWI and VFI modalities, a novel ultrasound-based technique is developed that combines high frame rate vector flow imaging with a data clustering approach, in order to enable direct and robust wall shear stress measurements. The performance of the proposed method is evaluated through vessel phantom experiments and simulations, while its feasibility is shown to detect pre-clinical stages of carotid artery disease in a swine model in vivo. In addition, a pilot clinical study is presented involving application of the developed modality in normal and atherosclerotic human carotid arteries in-vivo. Moving forward, the developed imaging modalities are used to implement novel clinical biomarkers based on carotid artery arterial wall mechanics and blood flow dynamics, that can potentially assist in risk for stroke assessment. The patterns of those biomarkers are investigated in the common carotid arteries of subjects with low degree of stenosis and medical history of stroke, against subjects without history of stroke. The same biomarkers are also analyzed with respect to stroke symptomatology in atherosclerotic patients with moderate to high degree of stenosis. Moreover, the developed techniques are used to identify vulnerable plaque components in subjects with fully developed plaques, as compared with CTA scans. Finally, a deep learning-based approach for motion tracking of the arterial wall throughout the cardiac cycle is proposed. A neural network is trained to learn the motion patterns of the carotid artery and potentially improve the quality of PWI. The performance of the technique is assessed in vessel phantom experiments and its feasibility is demonstrated in healthy human carotid arteries in-vivo.

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Carotid intima-media thickness (IMT) is a measure of atherosclerosis. A large carotid IMT may be indicative of an impaired blood-brain barrier, providing a pathway for infections and inflammation to more readily enter the brain to contribute to neuronal damage as proposed by the ‘microbial hypothesis’. However, no consensus exists regarding the effects of carotid IMT and infections on cognitive decline. Therefore, the goal of my dissertation was to investigate the potential mechanisms proposed by the ‘microbial hypothesis’ that may result in the outcome of cognitive decline. This goal was accomplished through investigating three specific aims. First, I conducted a scoping review to examine and synthesize existing literature assessing the effects of either carotid IMT or infections on the outcome of change in cognition over at least two years. Secondly, I empirically assessed the association between mid-life carotid IMT and late-life cognitive function at baseline and over time in a well characterized cohort. Finally, in the same cohort, I examined the association between mid- to late-life hospitalized infections and late-life cognitive function at baseline and change over time. Studies included in the scoping review moderately supported an association between carotid IMT and decline in global cognition, though evidence for an association between infections and cognitive decline is lacking. Infections most commonly were identified using antibodies, which are representative of past infections and may explain null findings. When examining carotid IMT empirically, I found no association between mid-life carotid IMT on 6-year change in late-life global cognitive function, however there was a significant association between greater carotid IMT and decreasing executive function scores over time. In a secondary analysis, I was able to expand follow-up time for global cognition up to 21 years, beginning in mid-life immediately following last carotid IMT measurement and found a significant association with change over time with this approach. This may support the need for interventions for reducing or preventing atherosclerosis earlier in the life course to prevent cognitive decline and potentially halt progression to dementia. In the same cohort, I found no significant associations between mid- to late-life hospitalized infections and 6-year change in late-life cognition for global cognition or domains. However, a history of having a hospitalized infection was significantly associated with baseline global cognition and baseline scores for language and executive function, but not memory. This may support theories that infections may result in faster rates of decline immediately following infections while then returning to normal rates in later life, however further examination of trajectories immediately after infections is needed. Results from this dissertation do not directly support the ‘microbial hypothesis’, however, they do provide insight that may be applicable to future studies examining these relationships.

Brain stroke is considered as one of the three diseases that threaten human health all over the world. Hypertension and cerebral arteriosclerosis are thought to be the most dangerous risk factors of brain stroke, and they frequently occur together, leading to ischemia of brain tissue. Unfortunately, it is not clear whether the pathological changes resulting from hypertension are related to those resulting from cerebral arteriosclerosis. There have been no ideal animal models mimicking the pathological changes in such a combined condition. In this thesis, an animal model of hypertension combined with cerebral arteriosclerosis in rats was established by occlusion of both the left and right common carotid arteries in spontaneous hypertension rats. Pien Tze Huang (PTH), a reputed traditional Chinese medicinal complex, contains Radix notoginseng, snake bile, calculus bovis, and musk and some other components that are known to protect vessels and cells from injuries. Since different tissue injuries share many common cellular mechanisms, the protection by PTH to in nerves and the circulation systems may also be benefical to cerebrovascular conditions as well. In present experiments, PTH was used to treat hypertension rats that also developed chronic brain ischemia as a result of the bilateral carotid occlusion, and its protective role for neurons and blood vessels was investiaged. / From the data above, more severe damage could be caused by hypertension combined with chronic ischemia. The model of SHR with bilaterally occluded common carotid artery can be used to study pathological changes resulted from hypertension combined with chronic ischemia. PTH was able to protect neurons in stroke. / In the initial part of the work, patients from clinics in two cities in South and North China were compared and analysed; they had been suffering from brain ischemic stroke. About two thirds of the stroke patients were found to have hypertension before the onset of stroke. Their prognosis was significantly worse than those stroke patients without hypertension. In the hypertensive rats with occluded arteries, mean of functional magnetic resonance imaging (fMRI) examination showed that brain blood flow was very weak or even transiently became undetectable at the beginning of the acute stage of brain ischemia, but was restored one hour after the occlusion surgery. In addition, pathological changes in brains of hypertensive rats with induced brain ischemia (carotid occlusion) were examined by Nissl staining, TUNEL staining, cell death ELISA and anti-oxidation enzymes. At day 15 after ischemia, a large number of pyramid cells in the hippocampus of SHR were lost and a great deal of apoptotic cells were found in the CA1 of the hippocampus, while activities of some enzyme including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were increased. At day 30 and 60, some degenerative changes appeared to have subsided and the cells appeared morphologically normal. The activities of the above enzymes were also decreased at day 60. In WKY control rats with normal blood pressure, neurons in the CA1 were found less damaged after the bilateral carotid occlusion. It was found that apoptotic and dead cells were significantly reduced in rats with hypertension combined with chronic brain ischemia if they had been pre-treated with PTH. Moreover, brain stroke damage was less severe in this pretreated rats. / Zhang, Lihong. / "March 2010." / Adviser: WH Kwong. / Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 116-134). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

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Hintergrund: Das Auftreten von frühen postinterventionellen Komplikationen nach Stenting der Arteria carotis interna (ACI) wird auf die Embolisierung von Material aus dem Stentsegment zurückgeführt. Zerebrale Thrombembolien können nicht invasiv mittels transkraniellem Dopplerultraschall (TCD) als mikroembolische Signale (MES) detektiert werden. Studienziel : Die Studie wurde durchgeführt um Prädiktoren zu finden, welche eine hohe Anzahl von MES im Intervall einer Stunde nach dem Eingriff voraussagen könnten. Methodik: Bei 134 konsekutiven Patienten, die ein Stenting der ACI erhielten, wurde postinterventionell über eine Stunde eine TCD der ipsilateralen Arteria cerebri media durchgeführt. Zur Identifizierung von klinischen, morphologischen und prozedurabhängigen Parametern für vermehrte MES, wurde eine multivariate logische Regressionsanalyse durchgeführt. Ergebnisse: Bei 134 Patienten (111 männlich, 23 weiblich, mittleres Alter 69,7 Jahre) wurden in 38% MES detektiert (Mittelwert 4 MES/h; Streuung von 1-62MES/h). Zwei Variablen waren mit einer erhöhten postinterventionellen MES Rate vergesellschaftet. Diese waren: Symptomatische Läsionen (p=0,048) und erhöhtes Gesamtcholesterin (p=0,037). Die duale Thrombozytenaggregationshemmung (ASS und Clopidogrel) konnte als unabhängiger Prädiktor (p=0,0001) für eine erniedrigte MES Rate festgestellt werden. Schlussfolgerungen: Postinterventionelle MES konnten am häufigsten bei symptomatischen Läsionen und bei Patienten mit Hypercholesterinämie festgestellt werden. Deren Anzahl viel im Verlauf ab. Das Stentdesign hatte keinen Einfluss auf die Anzahl der gemessenen MES. Die Kombinationstherapie mit ASS und Clopidogrel war ein Prediktor für eine erniedrigte cerebrale Embolisationsrate. Die TCD der MES Rate könnte eine brauchbare Methode sein um mögliche Risikofaktoren für neurologische Komplikationen nach Stenting der ACI zu entdecken und somit die Sicherheit der Stentingprozedur der ACI zu verbessern.