名古屋大学博士学位論文 学位の種類 : 博士(医学)(課程) 学位授与年月日:平成21年3月25日 靍見有史氏の博士論文として提出された

First degree relatives (FDRs) of subjects with early onset of coronary heart disease (CHD) have higher risk of developing cardiovascular disease. We verified early CHD by angiography in the index patients and extensively phenotyped their FDRs to investigate the relationship of traditional and non-traditional cardiovascular risk factors to carotid ultrasound and coronary calcium scoring findings. B-mode carotid ultrasound was used to assess the combined intima-media thickness and plaque burden in 111 FDRs. The biochemical and anthropometrical characteristics of the FDRs were compared with those of healthy controls matched for sex, age, ethnicity and BMI. Odds ratios indicate that FDRs are more likely to have positive carotid ultrasound findings compared to controls; 2.23 (95% CI 1.14 – 4.37) for intima-media thickness and 2.3 (95% CI 1.22 - 4.35) for average total thickness. In multivariate analysis positive carotid ultrasound findings were higher in FDRs independent of age, gender, total cholesterol over HDL-c ratio, systolic blood pressure and smoking but not homocysteine which had higher values in FDRs compared to controls. In conclusion FDRs of patients with angiographically confirmed CHD have higher burden of subclinical atherosclerosis even when considered in the context of traditional risk factors. Coronary artery calcium scoring (CAC), assessed by 64-slice multi-detector computed tomography (MDCT), was used to assess burden of subclinical atherosclerosis in 57 FDRs compared to controls. FDRs have a two-fold increase in risk of having CAC positive findings; odds ratios for the 75th percentile was 1.96 (95%CI 1.04 – 3.67, p<0.05) while for the 90th percentile odds ratio was 2.59 (95% 1.232 – 5.473, p<0.05). In summary, the risk of significant CAC findings, measured by 64-slice MDCT, is two-fold higher in FDRs than controls. These findings correlate highly with carotid ultrasound findings in the same cohort. Different thresholds for CAC may be appropriate when assessing male versus female FDRs. Together increased carotid ultrasound findings and CAC scoring results in FDRs of patients with validated early onset of CHD suggest these imaging techniques as potentially useful tools in cardiovascular risk assessment that will go above and beyond the current diagnostic algorithms.

First degree relatives (FDRs) of subjects with early onset of coronary heart disease (CHD) have higher risk of developing cardiovascular disease. We verified early CHD by angiography in the index patients and extensively phenotyped their FDRs to investigate the relationship of traditional and non-traditional cardiovascular risk factors to carotid ultrasound and coronary calcium scoring findings. B-mode carotid ultrasound was used to assess the combined intima-media thickness and plaque burden in 111 FDRs. The biochemical and anthropometrical characteristics of the FDRs were compared with those of healthy controls matched for sex, age, ethnicity and BMI. Odds ratios indicate that FDRs are more likely to have positive carotid ultrasound findings compared to controls; 2.23 (95% CI 1.14 – 4.37) for intima-media thickness and 2.3 (95% CI 1.22 - 4.35) for average total thickness. In multivariate analysis positive carotid ultrasound findings were higher in FDRs independent of age, gender, total cholesterol over HDL-c ratio, systolic blood pressure and smoking but not homocysteine which had higher values in FDRs compared to controls. In conclusion FDRs of patients with angiographically confirmed CHD have higher burden of subclinical atherosclerosis even when considered in the context of traditional risk factors. Coronary artery calcium scoring (CAC), assessed by 64-slice multi-detector computed tomography (MDCT), was used to assess burden of subclinical atherosclerosis in 57 FDRs compared to controls. FDRs have a two-fold increase in risk of having CAC positive findings; odds ratios for the 75th percentile was 1.96 (95%CI 1.04 – 3.67, p<0.05) while for the 90th percentile odds ratio was 2.59 (95% 1.232 – 5.473, p<0.05). In summary, the risk of significant CAC findings, measured by 64-slice MDCT, is two-fold higher in FDRs than controls. These findings correlate highly with carotid ultrasound findings in the same cohort. Different thresholds for CAC may be appropriate when assessing male versus female FDRs. Together increased carotid ultrasound findings and CAC scoring results in FDRs of patients with validated early onset of CHD suggest these imaging techniques as potentially useful tools in cardiovascular risk assessment that will go above and beyond the current diagnostic algorithms.

Ischemic stroke is the most common cause of handicap in adults and the third most common cause of death in Sweden. Internal carotid artery atherosclerosis is an important cause and accounts for 20% of ischemic strokes. Screening for carotid atherosclerosis has been debated over the past two decades. The aims of this thesis were (I) to study the prevalence of and risk factors associated with carotid artery atherosclerosis among 65 year old men, (II) to evaluate a simplified ultrasound protocol (the grayscale/mosaic method) for the exclusion of significant carotid artery stenosis for screening purpose, (III) to evaluate the required effect of primary preventive therapy in reducing risk of stroke among patients with asymptomatic carotid disease in order for screening to be cost-effective and (IV) to study natural history of carotid atherosclerosis and outcome five years after screening in 65-year old men. The prevalence of atherosclerotic plaques was high (25%), while the prevalence of &gt;50% stenosis was relatively low (2.0%). Smoking, hypertension, diabetes mellitus and coronary artery disease were independent risk factors and individuals with several risk factors had a higher prevalence of stenosis. Most of those at risk were not on any preventive medication. A simplified grayscale/mosaic method was found to have a high negative predictive value for significant carotid stenosis. The minimum stroke risk reduction effect required for preventive intervention to be cost effective was 22%. Carotid atherosclerotic plaque and stenosis 50-79% has a relatively benign development during five years if treated with BMT and risk factor adjustment. Very few progressed to symptomatic disease. More severe stenosis (80-99%) had higher rate of neurological events, and may benefit from additional intervention. In conclusion, prevalence of silent atherosclerotic disease in carotid arteries was common among 65-year-old men. Most of those at risk had no secondary prevention. There is a simple DUS method that could be used for screening purpose. Screening for carotid disease is only cost-effective if the preventive strategy lowers the risk of stroke by 22%. Men with plaques and moderate stenosis have a good prognosis, but among those with severe stenosis there is a need for further intervention. / Screening for asymptomatic carotid atherosclerosis

First degree relatives (FDRs) of subjects with early onset of coronary heart disease (CHD) have higher risk of developing cardiovascular disease. We verified early CHD by angiography in the index patients and extensively phenotyped their FDRs to investigate the relationship of traditional and non-traditional cardiovascular risk factors to carotid ultrasound and coronary calcium scoring findings. B-mode carotid ultrasound was used to assess the combined intima-media thickness and plaque burden in 111 FDRs. The biochemical and anthropometrical characteristics of the FDRs were compared with those of healthy controls matched for sex, age, ethnicity and BMI. Odds ratios indicate that FDRs are more likely to have positive carotid ultrasound findings compared to controls; 2.23 (95% CI 1.14 – 4.37) for intima-media thickness and 2.3 (95% CI 1.22 - 4.35) for average total thickness. In multivariate analysis positive carotid ultrasound findings were higher in FDRs independent of age, gender, total cholesterol over HDL-c ratio, systolic blood pressure and smoking but not homocysteine which had higher values in FDRs compared to controls. In conclusion FDRs of patients with angiographically confirmed CHD have higher burden of subclinical atherosclerosis even when considered in the context of traditional risk factors. Coronary artery calcium scoring (CAC), assessed by 64-slice multi-detector computed tomography (MDCT), was used to assess burden of subclinical atherosclerosis in 57 FDRs compared to controls. FDRs have a two-fold increase in risk of having CAC positive findings; odds ratios for the 75th percentile was 1.96 (95%CI 1.04 – 3.67, p<0.05) while for the 90th percentile odds ratio was 2.59 (95% 1.232 – 5.473, p<0.05). In summary, the risk of significant CAC findings, measured by 64-slice MDCT, is two-fold higher in FDRs than controls. These findings correlate highly with carotid ultrasound findings in the same cohort. Different thresholds for CAC may be appropriate when assessing male versus female FDRs. Together increased carotid ultrasound findings and CAC scoring results in FDRs of patients with validated early onset of CHD suggest these imaging techniques as potentially useful tools in cardiovascular risk assessment that will go above and beyond the current diagnostic algorithms. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Vascular diseases are among the leading causes of death in Canada and around the globe. A major underlying cause of most such medical conditions is atherosclerosis, a gradual accumulation of plaque on the walls of blood vessels. Particularly vulnerable to atherosclerosis is the carotid artery, which carries blood to the brain. Dangerous narrowing of the carotid artery can lead to embolism, a dislodgement of plaque fragments which travel to the brain and are the cause of most strokes. If this pathology can be detected early, such a deadly scenario can be potentially prevented through treatment or surgery. This not only improves the patient's prognosis, but also dramatically lowers the overall cost of their treatment. Medical imaging is an indispensable tool for early detection of atherosclerosis, in particular since the exact location and shape of the plaque need to be known for accurate diagnosis. This can be achieved by locating the plaque inside the artery and measuring its volume or texture, a process which is greatly aided by image segmentation. In particular, the use of ultrasound imaging is desirable because it is a cost-effective and safe modality. However, ultrasonic images depict sound-reflecting properties of tissue, and thus suffer from a number of unique artifacts not present in other medical images, such as acoustic shadowing, speckle noise and discontinuous tissue boundaries. A robust ultrasound image segmentation technique must take these properties into account. Prior to segmentation, an important pre-processing step is the extraction of a series of features from the image via application of various transforms and non-linear filters. A number of such features are explored and evaluated, many of them resulting in piecewise smooth images. It is also proposed to decompose the ultrasound image into several statistically distinct components. These components can be then used as features directly, or other features can be obtained from them instead of the original image. The decomposition scheme is derived using Maximum-a-Posteriori estimation framework and is efficiently computable. Furthermore, this work presents and evaluates an algorithm for segmenting the carotid artery in 3D ultrasound images from other tissues. The algorithm incorporates information from different sources using an energy minimization framework. Using the ultrasound image itself, statistical differences between the region of interest and its background are exploited, and maximal overlap with strong image edges encouraged. In order to aid the convergence to anatomically accurate shapes, as well as to deal with the above-mentioned artifacts, prior knowledge is incorporated into the algorithm by using weak geometric priors. The performance of the algorithm is tested on a number of available 3D images, and encouraging results are obtained and discussed.

Vascular diseases are among the leading causes of death in Canada and around the globe. A major underlying cause of most such medical conditions is atherosclerosis, a gradual accumulation of plaque on the walls of blood vessels. Particularly vulnerable to atherosclerosis is the carotid artery, which carries blood to the brain. Dangerous narrowing of the carotid artery can lead to embolism, a dislodgement of plaque fragments which travel to the brain and are the cause of most strokes. If this pathology can be detected early, such a deadly scenario can be potentially prevented through treatment or surgery. This not only improves the patient's prognosis, but also dramatically lowers the overall cost of their treatment. Medical imaging is an indispensable tool for early detection of atherosclerosis, in particular since the exact location and shape of the plaque need to be known for accurate diagnosis. This can be achieved by locating the plaque inside the artery and measuring its volume or texture, a process which is greatly aided by image segmentation. In particular, the use of ultrasound imaging is desirable because it is a cost-effective and safe modality. However, ultrasonic images depict sound-reflecting properties of tissue, and thus suffer from a number of unique artifacts not present in other medical images, such as acoustic shadowing, speckle noise and discontinuous tissue boundaries. A robust ultrasound image segmentation technique must take these properties into account. Prior to segmentation, an important pre-processing step is the extraction of a series of features from the image via application of various transforms and non-linear filters. A number of such features are explored and evaluated, many of them resulting in piecewise smooth images. It is also proposed to decompose the ultrasound image into several statistically distinct components. These components can be then used as features directly, or other features can be obtained from them instead of the original image. The decomposition scheme is derived using Maximum-a-Posteriori estimation framework and is efficiently computable. Furthermore, this work presents and evaluates an algorithm for segmenting the carotid artery in 3D ultrasound images from other tissues. The algorithm incorporates information from different sources using an energy minimization framework. Using the ultrasound image itself, statistical differences between the region of interest and its background are exploited, and maximal overlap with strong image edges encouraged. In order to aid the convergence to anatomically accurate shapes, as well as to deal with the above-mentioned artifacts, prior knowledge is incorporated into the algorithm by using weak geometric priors. The performance of the algorithm is tested on a number of available 3D images, and encouraging results are obtained and discussed.