京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18864号 / 医博第3975号 / 新制||医||1008(附属図書館) / 31815 / 京都大学大学院医学研究科医学専攻 / (主査)教授 木村 剛, 教授 坂田 隆造, 教授 山下 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: In patients with diabetes, high blood pressure is an established risk factor for cardiovascular disease. The aim of this thesis was to explore the associations between blood pressure levels measured with different techniques and during different circumstances, and the degree of cardiovascular organ damage and subsequent prognosis in patients with diabetes. Methods: We analysed baseline data from patients with type 2 diabetes who participated in the observational cohort study CARDIPP (Cardiovascular Risk factors in Patients with Diabetes – a Prospective study in Primary care), and longitudinal data from patients registered in the Swedish national quality registry RIKS-HIA (Register of Information and Knowledge about Swedish Heart Intensive care Admissions). Patients in CARDIPP underwent nurse-recorded, 24-hour ambulatory and non-invasive central blood pressure measurements. Patients in RIKS-HIA had their systolic blood pressure measured upon hospitalisation for acute chest pain. Results: In CARDIPP, nearly one in three patients with office normotension (<130/80 mmHg) were hypertensive during the night (≥120/70 mmHg). This phenomenon, masked nocturnal hypertension, was significantly associated with increased arterial stiffness and increased central blood pressure. Furthermore, nearly one in five CARDIPP patients with office normotension had high central pulse pressure (≥50 mmHg), and there was a significant association between high central pulse pressure and increased carotid intima-media thickness and increased arterial stiffness. Among CARDIPP patients who used at least one antihypertensive drug, those who used beta blockers had significantly higher central pulse pressure than those who used other antihypertensive drugs, but there were no significant between-group differences concerning office or ambulatory pulse pressures. In CARDIPP patients with or without antihypertensive treatment, ambulatory systolic blood pressure levels were significantly associated with left ventricular mass, independently of central systolic blood pressure levels. When RIKS-HIA patients, admitted to hospital for chest pain, were stratified in quartiles according to admission systolic blood pressure levels, the risk for all-cause one-year mortality was significantly lower in patients with admission systolic blood pressure in the highest quartile (≥163 mmHg) than in patients with admission systolic blood pressure in the reference quartile (128-144 mmHg). This finding remained unaltered when the analysis was restricted to include only patients with previously known diabetes. Conclusions: In patients with type 2 diabetes, ambulatory or central blood pressure measurements identified patients with residual risk factors despite excellent office blood pressure control or despite ongoing antihypertensive treatment. Ambulatory systolic blood pressure predicted left ventricular mass independently of central systolic blood pressure. In patients with previously known diabetes who were hospitalised for acute chest pain, there was an inverse relationship between systolic blood pressure measured at admission and the risk for one-year all-cause mortality.

Lorsqu’elle est comparée à la pression artérielle (PA) brachiale, la PA centrale est un meilleur reflet du stress hémodynamique infligé aux organes cibles. Les objectifs de ce mémoire sont de clarifier le rôle de la PA centrale pour la prédiction du risque cardiovasculaire (CV), de définir un seuil permettant le diagnostic d’une hypertension centrale et de définir l’effet sur la PA centrale de certains paramètres, tels que les statines et le cholestérol LDL. La base de données CARTaGENE comportant 20 004 sujets a été utilisée. La PA centrale était connue (mesurée à l’aide de l’appareil SphygmoCor Px qui utilise une calibration de type I), ainsi que les autres facteurs de risques CV. Des données prospectives permettant de connaître l’incidence d’événements CV majeurs étaient disponibles. Dans un premier temps, des modèles de régression de Cox et des mesures de discrimination et de reclassification ont permis de comparer la PA systolique centrale et brachiale pour la prédiction du risque CV. Un seuil permettant le diagnostic d’une hypertension centrale a aussi été déterminé à l’aide de l’index de Youden. L’association entre la PA centrale, le cholestérol LDL et les statines a été déterminée à l’aide de régressions linéaires et d’ANOVA. Une analyse de médiation a permis d’éclairer l’effet des statines sur la PA centrale, à savoir si celui-ci est médié par une baisse concomitante du cholestérol LDL. Ces analyses ont permis de déterminer que la PA centrale ne procure qu’une amélioration marginale dans la prédiction du risque cardiovasculaire lorsque comparé à celle de la PA brachiale. Une PA systolique centrale de 120 mmHg a été identifiée comme le meilleur seuil pour poser le diagnostic d’une hypertension centrale lorsqu’évaluée avec un appareil avec calibration de type I. De plus, la PA centrale est influencée par la prise de statines et son effet n’est que partiellement médié par une baisse concomitante du cholestérol LDL. / Compared to brachial blood pressure (BP), central BP is thought to be a better reflection of the hemodynamic strain on target organs. It is unclear though whether this translates into improved cardiovascular (CV) risk stratification when central BP is compared to brachial BP. The objectives of this thesis are to clarify the role of central BP in CV risk stratification, to define a threshold for the diagnosis of central hypertension and to determine what are the impacts of parameters, such as statins and LDL cholesterol, on central BP. The CARTaGENE database, which is comprised of 20,004 individuals, was used for these studies. The central BP (measured with the SphygmoCor Px device and type I calibration) as well as other CV risk factors were known. Prospective data for the incidence of major adverse cardiovascular events (MACE) was available. Cox proportional hazard models and measures of discrimination and reclassification were used to compare central systolic BP and brachial systolic BP in their ability to predict CV risk. A central hypertension threshold was determined using Youden’s index. The association between central BP, LDL cholesterol and statins were assessed using linear regression models and ANOVA. The interactions between central BP, statins and cholesterol LDL were assessed with a mediation analysis. Central BP was only marginally superior to brachial BP in CV risk prediction. A central hypertension threshold of 120 mmHg was identified. Statins reduced both brachial and central BP in a similar fashion, and cholesterol LDL was only partially responsible for the effect of statins on BP. To conclude, central BP, when assessed using type I calibration, is not superior to brachial BP in CV risk prediction. These studies also clarified the central hypertension threshold and the impact of statins and cholesterol LDL on central BP.

No description available.

Cardiovascular disease varies by ethnicity in the UK. South Asians (SA) have higher coronary heart disease (CHD) and diabetes prevalence, while African-Caribbeans (AfC) have greater stroke, but intriguingly lower CHD rates despite higher blood pressures and diabetes risk than Europeans. Conventional risk factors do not fully explain such differences. This cross-sectional study tested the hypothesis that the hormones, vitamin D measured as 25(OH)D and aldosterone, would be independently associated with intermediate cardiovascular outcome markers in these ethnic groups. Community-dwelling men 40-80 years old (AfC: n=67, 55±10yr; SA: n=68, 55±10yr; European: n=63, 57±8yr) were sampled from Greater Manchester’s multi-ethnic population. The intermediate markers examined were aortic pulse wave velocity (aPWV), left ventricular (LV) mass and function, and carotid intima media thickness (CIMT), measured non-invasively by ultrasound, and hemodynamic profiling methods (the Arteriograph) in the total sample and by magnetic resonance imaging (MRI) in a subsample of 50. Adjusted for age, systolic blood pressure and diabetes, mean(SE) aPWV by the Arteriograph, was 0.5(0.2) m/s higher in SA than AfC and Europeans (p=0.01), which paralleled known cross-ethnic CHD risk differences in the UK. By MRI, aPWV along the descending aorta in SA was 0.7(0.3) and 0.8(0.3) m/s higher than that in AfC and Europeans, but aPWV along the aortic arch was not significantly different. Unlike aldosterone, 25(OH)D was independently and inversely correlated with aPWV (unstandardised B(SE)=-0.013[0.004] m/s, p<0.001), and partly explained the ethnic variation in aPWV. Similar inverse correlations were found between 25(OH)D and LV concentricity measured by echocardiography and MRI. Compared to Europeans, SA and AfC, had 21(3) and 14(3) nmol/L lower mean(SE) 25(OH)D, respectively (p<0.01). Mean(SE) of relative wall thickness, an index of LV concentricity by echocardiography, was 0.05(0.01) higher in SA and AfC than Europeans. Lower 25(OH)D levels were also associated with higher myocardial deformation rates measured by MRI myocardial tagging (n=50), supporting previous animal experimental evidence. A one standard deviation (SD) decrease in 25(OH)D was associated with a 0.38 SD increase in absolute systolic strain rate (p=0.003) and 0.22 SD rise in diastolic strain rate (p=0.04). Right and left CIMT showed different relations with 25(OH)D and aldosterone. Left-right CIMT differences varied by ethnicity and were related to SA ethnicity and aldosterone levels. Two related technical studies investigated the relatively new method of hemodynamic profiling, the Arteriograph, used here. The results suggested a standardisation method of aortic length estimation for purely central aPWV, which significantly improved aPWV agreement between the Arteriograph and MRI (reference method here), and was used for calibrating the Arteriograph aPWV in the above-mentioned results for the total sample. Future well-designed trials are necessary to investigate any cause-effect relationship between vitamin D deficiency and the unfavourable cardiovascular intermediate outcomes found here in a cross-sectional design and multi-ethnic background.