SAMMAMFATTNING Bakgrund: Reaktiv hyperemi definieras som ett övergående ökat blodflöde över det normala efter en tids ischemi. Det kan registreras med laserdopplerteknik. Att registrera reaktiv hyperemi är ett sätt att värdera mikrocirkulationen. Det finns många flödesvariabler att studera varav tid till maxflöde efter ocklusion är en. Det har gjorts studier som undersöker om det finns ett samband mellan reaktiv hyperemi och fysisk aktivitet/syreupptagningsförmåga. Det har inte gjorts någon studie som undersöker tid till maxflöde och fysisk aktivitet. Syftet var att undersöka om det finns ett samband mellan fysisk aktivitet och reaktiv hyperemi med avseende på tid till maxflöde. Material och metod: Testpersoner fick bära en accelerometer en vecka under dygnets alla vakna timmar samt göra en registrering av reaktiv hyperemi med laserdoppler. För statistiska beräkningar användes oparat T-test för att undersöka skillnad mellan olika grad av fysisk aktivitet och tid till maxflöde. Resultat: Ingen statistiskt signifikant skillnad mellan olika aktivitetsgrad och tid till maxflöde kunde observeras. Slutsats: Den här studien visade inte på statistiskt signifikant samband mellan blodflöde och fysisk aktivitet.

An age-related decline in cerebral blood flow (CBF) is widely acknowledged. However, uncertainty exists as to whether this reduction is the result of a reduced metabolic demand (cerebral atrophy) or an impaired delivery system (cerebrovascular disease). The purpose of these experiments was to examine the relationship of CBF and dynamic cerebrovascular regulation with changes in common carotid intima-media thickness (cIMT), brachial-ankle pulse wave velocity (baPWV) and common carotid distensibility. Additionally, we took an exploratory view into the effect of vascular aging and CBF reduction on brain function, as expressed through the performance of motor and cognitive tasks. An important finding in elderly participants was that seated anterior CBF declined as a function of arterial stiffness, independently of age. Linear regression analysis developed a model that predicts CBF drops 22 ml/min (95% confidence interval (CI): 6, 38) for each 100 cm/s increase in baPWV and 8 ml/min (95% CI: 1, 15) for each additional year in age. The effect of baPWV appears to be mediated through an increase in cerebrovascular resistance (r2 = 0.84, p < 0.0001). Additionally, CBF showed postural dependency and the volume of the drop in CBF between supine and seated positions was greatest in elderly participants (YOUNG: 65 ± 81 ml/min; ELDERLY: 155 ± 119 ml/min; p = 0.001). Despite this negative impact of vascular aging on steady state flow, dynamic regulation does not appear to be affected. Cerebrovascular responses to an acute drop in blood pressure or to activation of the motor cortex were not attenuated in the elderly participants. Finally, seated CBF had modest directionally relevant relationships with perceptuo-motor and complex sequencing processes; while cIMT appeared to influence performance on initiation and inhibition tasks.

Introduction and Purpose: Vascular pathologies play an important role in the etiology and progression of number of ocular diseases. Many instruments are developed to monitor retinal hemodynamics, including the Canon Laser Blood Flowmeter (CLBF), in an attempt to better understand the pathophysiology of the disease (Chapter 2). The purpose of this thesis is to determine the impact of light scatter on retinal arteriolar hemodynamic measurement assessed by the CLBF as intraocular light scatter is an inevitable consequence of ageing and particularly cataract. Methodology: Chapter 4 – Artificial light scatter model: One eye from each of 10 healthy young subjects between the ages of 18 and 30 (23.6 ± 3.4) was randomly selected. To simulate light scatter, cells comprising a plastic collar and two plano lenses were filled with solutions of differing concentrations of polystyrene microspheres (Polysciences Inc., USA). 0.002%, 0.004%, 0.006%, 0.008% were prepared, as well as distilled water only. After a preliminary screening to confirm subject eligibility, seven arteriolar hemodynamic measurements were taken by randomly placing the cells between the CLBF objective lens and the subjects’ cornea. Chapter 5 – Ten patients scheduled for extracapsular cataract extraction using phacoemulsification and intraocular lens implantation between the ages of 61 and 84 (mean age 73 years, SD ± 8) were prospectively recruited. Two visits were required to complete the study; One prior to the surgery and one at least six weeks after the surgery to allow for full post-operative recovery. The severity of cataract was documented using the Lens Opacity Classification System (LOCS, III) at the first visit. Each subject underwent visual function assessment at both visits using logMAR Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts and the Brightness Acuity Tester (BAT). Retinal arteriolar hemodynamics were measured at both visits using the high intensity setting of the Canon Laser Blood Flowmeter. Results: Chapter 4: Our light scatter model resulted in an artifactual increase of retinal arteriolar diameter (p<0.0001) and thereby increased retinal blood flow (p<0.0001). The 0.006% and 0.008% microsphere concentrations produced significantly higher diameter and flow values than baseline. Centerline blood velocity, however, was not affected by light scatter. Retinal arteriolar diameter values were significantly less with the high intensity laser than with the low intensity laser (p=0.0007). Chapter 5: Group mean retinal arteriolar diameter and blood flow were reduced following extracapsular cataract extraction (Wilcoxon signed-rank test, p=0.022 and p=0.028 respectively); however, centerline blood velocity was unchanged (Wilcoxon signed-rank test, p=0.074). Conclusions: Using an artificial light scatter model (Chapter 3), we demonstrated that the densitometry assessment of vessel diameter is increasingly impacted as the magnitude of artificial light scatter increases; this effect can be partially negated by increasing laser intensity. We showed similar results in the presence of cataract (Chapter 4) by measuring the retinal arteriolar hemodynamics before and after removal of cataract. Care needs to be exercised in the interpretation of studies of retinal vessel diameter that use similar densitometry techniques as cataract is an inevitable consequence of aging.

Abnormal leukocyte adhesion (i.e. leukostasis) to retinal vascular endothelial cells occurs in early diabetes. The processes of leukostasis have been clearly demonstrated in the vascular endothelium of patients with diabetes. In non-proliferative DR, clinical outcomes are manifested by excessive permeability from inflammatory progression leading to inner blood retinal barrier disruption, endothelial cell damage and widespread capillary nonperfusion. Diabetes promotes vascular leakage in DR by upregulation of adhesion molecules. Moreover, many of the pathological changes in NPDR are related to abnormalities in retinal blood flow. Studies have shown that specific circulating markers of inflammatory activity and endothelial dysfunction are associated with clinical signs of diabetic retinopathy. However, few have found an association between circulating levels of inflammatory and endothelial dysfunctional markers and abnormal retinal hemodynamics in patients with non-proliferative DR. The specific aims of this thesis are as follows: (Chapter 3)To correlate baseline levels of inflammatory and endothelial dysfunction markers and 1) baseline retinal arteriolar hemodynamics and 2) any disturbance in retinal hemodynamics over 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow. In Chapter 4: To correlate circulating levels of inflammatory and endothelial dysfunction markers and 1) baseline vascular reactivity and 2) any disturbance in vascular reactivity after 6-month time in terms of vessel diameter, blood velocity, maximum-to-minimum velocity ratio and volumetric flow in patients with increasing non-proliferative diabetic retinopathy (NPDR) severity. Methods for Chapter 3: Diabetes subjects were stratified into either mild-to-moderate (Group 2) or moderate-to-severe (Group 3) NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls (Group 1). Forearm blood sample was collected to determine baseline levels of inflammatory and endothelial dysfunctional markers. At visit 1, baseline retinal hemodynamics was acquired using Canon Laser Blood Flowmeter. Patients returned for a visit 2 (6 month follow-up visit) and retinal hemodynamics was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both baseline and change in retinal hemodynamic parameters over 6-month time. For Chapter 4: Diabetes subjects were stratified into either mild-to-moderate NPDR or moderate-to-severe NPDR based on their retinopathy status. Age-matched non-diabetics were recruited as controls. At visit 1, forearm blood sample was collected to determine levels of inflammatory and endothelial dysfunctional markers and baseline vascular reactivity response was acquired. Retinal blood flow data was acquired while subjects breathed air. Retinal blood flow measurements were then acquired after exposure to isocapnic hyperoxic stimuli. At visit 2 (6 month follow-up), retinal vascular reactivity was reassessed. Baseline levels of inflammatory and endothelial dysfunctional markers compared between groups and correlated with both magnitude of baseline and change in vascular reactivity in terms of retinal hemodynamics. Results of Chapter 3: Maximum-to-minimum velocity ratio (max: min) was found to be significantly elevated in the group 3 compared to group 1 at baseline (0.72 vs. 0.49, after Bonferroni correction P<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p=0.04). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (234.0 vs. 151.5 ng/ml, P=0.02 and 53.4 vs. 27.6 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (7.9 vs. 5.6 % , P<0.01). There were no significant associations found between baseline markers of inflammation and baseline retinal hemodynamics across all groups. The Δ velocity was correlated with the baseline sICAM-1 (r=0.42, p=0.02) and A1c levels (r=0.37, p=0.04) in patients with NPDR. After adjustment for all other variables (A1c, hsCRP and vWF), Δ velocity, sICAM-1 and A1c were found not to be reliable predictors of baseline retinal hemodynamics. For Chapter 4: There were no significant differences in magnitude of retinal vascular reactivity in hemodynamic parameters between groups at visit 1 or visit 2. Over 6 months time, compliance was found to be significantly reduced in patients of Group 3 compared to Group 2 (-0.4 vs. 0.1, t-test p<0.01). Both sICAM-1 and sE-selectin were significantly elevated as a function of group (ANOVA p=0.02 and p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher in both sICAM-1 and sE-selectin levels compared to Group 1 (243.4 vs. 157.3ngml, P<0.01 and 57.0 vs. 29.3 ng/ml, P<0.01, respectively). Hemoglobin A1c was significantly elevated across the groups (ANOVA p<0.01). A post hoc Bonferroni test showed that Group 3 had significantly higher hemoglobin A1c level compared to Group 1 (8.8 vs. 5.6 % , P<0.01). Baseline VR in blood velocity weakly correlates with sE-selectin (r=0.31, p=0.04) across all groups while sVCAM-1 was associated with VR in terms of blood flow (r=-0.62, p<0.01) in patients with mild-to-moderate NPDR. The ∆ blood flow after 6 months was found to be weakly associated with sE-selectin (r=0.46, p=0.03) across all groups. Finally, the ∆ blood velocity after 6 month time was found to be moderately correlated with baseline vWF Ag level (r=-0.78, p=0.02). Multiple regression analysis found that vascular inflammatory and endothelial function markers had weak predictive power for Δ hemodynamic parameters. Conclusions Chapter 3: We found weak associations between circulating markers and baseline or the disturbance in retinal hemodynamics after 6 months time. Overall, we found both an increase in rigidity of the arteriolar circulation and elevated inflammatory adhesion markers (sICAM-1 and sE-selectin) within the same population sample. Change in velocity over the follow-up period was correlated with sICAM-1 and A1c levels in patients with NPDR but the level of association was such that neither sICAM-1 nor A1c proved to reliably predict retinal hemodynamics. Finally, in Chapter 4 we demonstrated two important characteristics in early NPDR; 1) a disturbance in vascular reactivity in terms of compliance and 2) an increase in systemic markers of inflammation were found in patients with NPDR. Although systemic markers of vascular inflammation and endothelial dysfunction are not predictive of hemodynamic parameters, our study found moderate associations between baseline and disturbances in VR after 6 months time. Therefore, there is evidence that inflammation and vascular function may be related with respect to their development in NPDR.

The adaptations of vessel diameter represented by vascular conductance (VC), muscle blood flow (MBF) and oxygen delivery (DO2est) were investigated during rest and exercise using the effects of gravity to manipulate muscle perfusion pressure (MPP) by placing the heart above (head-up tilt) and below (head-down tilt) the level of the muscle. This experimental paradigm was used to explore VC and MBF regulation and related control mechanisms during rest and exercise. Study 1 tested the repeatability of Doppler ultra- sound measurements of muscle blood flow velocity (MBV), arterial diameter, MBF and VC. The adaptations in VC and MBF (Study 2) and changes in anterograde and retro- grade MBV patterns (Study 3) were investigated during postural challenges at rest. Study 4, determined the peak VC and its fractional recruitment during transitions from rest to lower (LPO) and higher power output (HPO) calf muscle exercise in HDT and HUT. Study 5 investigated the combined effects of altered MPP and hypoxia during exercise. During rest-HDT, increases in VC compensated for the MPP reduction to maintain MBF, while in rest-HUT, MBF was reduced. Following the start of LPO and HPO exercises, MBF and VC responses were delayed in HDT and accelerated in HUT. During LPO, MBF steady- state was reduced in HUT compared to horizontal (HOR), while the greater increase in VC during HDT maintained MBF at a similar level as HUT. Post-exercise MBF recovered rapidly in all positions after LPO exercise but did not after HPOHDT. During HPOHDT, MBF was reduced despite the increase in VC, while in HPOHUT MBF was similar to that in HPOHOR. The hypoxic challenge added in exercise was met during LPOHDT by in- creased VC to compensate reduced MPP and O2 availability such that MBF maintained DO2est. However, during HPOHDT in hypoxia, VC reached maximal vasodilatory capacity, compromising MBF and DO2est. Together, these findings indicate that LPOHDT in nor- moxia or hypoxia VC increased to maintain MBF and DO2est, but during HPO functional limitation for recruitment of VC constrained MBF and DO2 in normoxia and hypoxia. Elevated muscle electromyograpic signals in HPOHDT were consistent with challenged aer- obic metabolism. MPP reduction in HDT caused slower adaptation of MBF limiting O2 availability would result in a greater O2 deficit that could contribute to an increase in the relative stress of the exercise challenge and advance the onset of muscle fatigue.

Nailfold capillary microscopy is simple, non-invasive, no injuries and easy to observe human`s microcirculation and micro blood stream directly. Due to these advantages, it plays a significant role in diseases diagnoses, treatments and prognosis. The observation of microcirculation focuses on hand, foot naildfold, conjunctival, lingual surface and lips. Nailfold microcirculation is usually performed on the ring finger. However, when measuring the speed of blood flow, difficulty to stabilize the region of interest (ROI) is often encountered. This problem becomes more serious when the magnification of microscope increases. Fixture to stabilize finger will inevitably affect the speed of blood flow under observation. The Laser Doppler blood flow velocimetry method, is expensive, only can be used in bigger capillary or to measure the average flow velocity of lager observed area, lacking of diversified morphological features of capillary, it¡¦s precision is worse than microscopy image capture method, and because of the regular contraction and relaxation of arterioles it can only measure the local blood flow velocity, cannot describe whole details of capillary blood flow velocity, some important information of microcirculation will be ignored easily. This thesis employs computer vision technique to operate displacement compensation of microscopy image sequence to stabilize observed area and extract area of capillary. Then the morphological and hemodynamic pathology features will be derived and analyzed to evaluate the status of a person¡¦s health. Not only morphological features, e.g., length, density and color, but also hemodynamic features, e.g., blood flow velocity will be measured to assess the microcirculation in end capillary. The most significant characteristic of this project is to combine three-dimensional models reconstruction technology of computer graphic to reconstruct three-dimensional capillary models and perform the three-dimensional dynamic blood flow visualization. Thus, the capillary blood flow can be adjusted and observed in the desired orientation, magnification and viewpoint. A variety of pathologically significant features of nailfold microcirculation will be extracted in the project proposed. These features can be classified into morphological and hemodynamic features. The morphological features extracted include the number, width/height, density, arteriolar limb caliber, curved segment caliber, venular limb caliber, blood color, tortuosity, and width of the curved segment of capillaries. On the other hand, hemodynamic features including velocity, direction of blood flow will also be extracted. By integrating both morphological and hemodynamic features, the status of a person¡¦s health can be evaluated by the doctor. The novel system proposed is not only easy to operate, low-cost but also has the great potential to be utilized clinically.

Based on many studies and experiments, blood flow patterns are associated with cardiovascular diseases and it usually is a sign of cardiovascular disease when the blood flow becomes unusual. Magnetic resonance (MR) imaging is a non-invasive medical technique and the characteristic of phase contrast can use to measure the flow velocity and patterns in vivo. As far as we know, for the cardiovascular of region of interest, 4D Flow-sensitive MRI technology is good at spatial coverage and temporal resolutions.It is easier for the researcher to analyze blood flow patterns in the clinical diagnosis by visualization processing. EnSight (CEI, USA), a kind of commercial software, is often used to do visualization processing of data of 4D Flow-sensitive MRI. However, before visualization of the data, several actions must be completed, such as ROI selection, correction or conversion of data, and etc. Therefore, our thesis hopes to develop a simple but practical user interface tool for 4D Flow-sensitive MRI data. From reading the file and ROI selection to correction and conversion of data as well as the visualization processing are completed by this tool. It provides researchers a rapid examination of data and analysis of blood flow patterns in the diagnosis.

Atherosclerosis is a disease of the cardiovascular system where a stenosis may develop in an artery which is an abnormal narrowing in the blood vessel that adversely affects the blood flow. Due to the constriction of the blood vessel, the flow is disturbed, forming a jet and recirculation downstream of the stenosis. Dynamic pressure fluctuations on the inner wall of the blood vessel leads to the vibration of the vessel structure and acoustic energy is propagated through the surrounding tissue that can be detected on the skin surface. Acoustic energy radiating from the interaction of blood flow and stenotic blood vessel carries valuable information from a diagnostic perspective. In this study, a constricted blood flow is modeled by using ADINA finite element analysis software together with the blood vessel in the form of a thin cylindrical shell with an idealized blunt constriction. The flow is considered as incompressible and Newtonian. Water properties at indoor temperature are used for the fluid model. The diameter of the modeled vessel is 6.4 mm with 87% area reduction at the throat of the stenosis. The flow is investigated for Reynolds numbers 1000 and 2000. The problem is handled in three parts which are rigid wall Computational Fluid Dynamics (CFD) solution, structural analysis of fluid filled cylindrical shell, and Fluid Structure Interaction (FSI) solutions of fluid flow and vessel structure. The pressure fluctuations and consequential vessel wall vibrations display broadband spectral content over a range of several hundred Hz with strong fluid-structural coupling. Maximum dynamic pressure and vibration amplitudes are observed around the reattachment point of the flow near the exit of the stenosis and this effect gradually decreases along downstream of flow. Results obtained by the numerical simulations are compared with relevant studies in the literature and it is concluded that ADINA can be used to investigate these types of problems involving high frequency pressure fluctuations of the fluid and the resulting vibratory motion of the surrounding blood vessel structure.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成5年9月14日 加藤亨嗣氏の博士論文として提出された

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成8年3月8日 辻井洋一郎氏の博士論文として提出された