Indiana University-Purdue University Indianapolis (IUPUI) / Glaucoma is a multi-factorial ocular disease associated with death of retinal ganglion cells and irreversible vision loss. Many risk factors contribute to glaucomatous damage, including elevated intraocular pressure (IOP), age, genetics, and other diseases such as diabetes and systemic hypertension. Interestingly, alterations in retinal hemodynamics have also been associated with glaucoma. A better understanding of the factors that contribute to these hemodynamic alterations could lead to improved and more appropriate clinical approaches to manage and hopefully treat glaucoma patients. In this thesis, we develop several mathematical models aimed at describing ocular hemodynamics and oxygenation in health and disease. Precisely we describe: (i) a time-dependent mathematical model for the retinal circulation that includes macrocirculation, microcirculation, phenomenological vascular regulation, and the mechanical effect of IOP on the retinal vasculature; (ii) a steady-state mathematical model for the retinal circulation that includes macrocirculation, microcirculation, mechanistic vascular regulation, the effect of IOP on the central retinal artery and central retinal vein, and the transport of oxygen in the retinal tissue using a Krogh cylinder type model; (iii) a steady-state mathematical model for the transport of oxygen in the retinal microcirculation and tissue based on a realistic retinal anatomy; and (iv) a steady-state mathematical model for the production and drainage of aqueous humor (AH). The main objective of this work is to study the relationship between IOP, systemic blood pressure, and the functionality of vascular autoregulation; the transport and exchange of oxygen in the retinal vasculature and tissue; and the production and drainage of AH, that contributes to the level of IOP. The models developed in this thesis predict that (i) the autoregulation plateau occurs for different values of IOP in hypertensive and normotensive patients. Thus, the level of blood pressure and functionality of autoregulation affect the changes in retinal hemodynamics caused by IOP and might explain the inconsistent outcomes of clinical studies; (ii) the metabolic and carbon dioxide mechanisms play a major role in the vascular regulation of the retina. Thus, the impairment of either of these mechanisms could cause ischemic damage to the retinal tissue; (iii) the multi-layer description of transport of oxygen in the retinal tissue accounts for the effect of the inner and outer retina, thereby improving the predictive ability of the model; (iv) a greater reduction in IOP is obtained if topical medications target AH production rather that AH drainage and if IOP-lowering medications are administrated to patients that exhibit a high initial level of IOP. Thus, the effectiveness of IOP-lowering medications depend on a patient’s value of IOP. In conclusion, the results of this thesis demonstrate that the insight provided by mathematical modeling alongside clinical studies can improve the understanding of diseases and potentially contribute to the clinical development of new treatments.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21449号 / 医博第4416号 / 新制||医||1032(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 妹尾 浩, 教授 松原 和夫, 教授 川上 浩司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Cardiovascular diseases, including heart failure, are a global health concern, necessitating advancements in non-invasive diagnostic tools and treatments. Computational modeling offers an invaluable approach to simulate and understand the intricacies of cardiac flow dynamics. This study aims to identify critical blood flow properties in the left atrium, a crucial component of the heart responsible for receiving oxygenated blood from the lungs and pumping it into the left ventricle. Building on previous work, this project implemented an idealized model of the left atrium using Finite Element Method (FEM) and simulated various properties related to its geometry, revealing crucial aspects of fluid dynamics. Specifically, analysis revealed a U-shaped inflow profile, pressure variations due to flow jets and presence of vortices, asymmetrical outflow due to differences in pulmonary vein geometry, and the presence of longitudinal vortex structures within the atrium. These properties can provide valuable insights about the blood flow in a healthy heart. This research presents a foundation for future work aiming to integrate models of the left ventricle and left atrium, offering a more comprehensive understanding of the left heart's functionality and potential pathologies. Further studies should focus on in-depth analysis, extension and validation of these properties using real patient data to enhance their diagnostic potential.

The study aimed to assess whether a short-term, high-intensity cold acclimation protocol would modulate finger vasomotor [i.e., finger temperature (TF), cold induced vasodilation (CIVD)] responses and regional thermo-perception to localized cooling. Six men performed a hand cold provocation (consisting of a 30-min immersion in 8°C water), while being whole-body immersed, once, in 21°C water (i.e., cold trial; HYPO), and, the following day, in 35.5°C water (i.e., normothermic trial; NORM). The local cold provocations were repeated, in the same order, after 10 days. In the intervening period, the subjects undertook a whole-body cold acclimation pro-tocol, consisting of daily whole-body 14°C-water immersions for 5 consecutive days, for a maximum of 2 h, while the skin temperature of the right hand was maintained at 35.6 (0.1)°C. Thermal (rectal temperature, skin temperature, finger temperature) cardiorespiratory (mean arterial pressure (MAP), heart rate and oxygen uptake), and perceptual responses (thermal sensation and comfort, pain, affective valence) were monitored throughout the trials. The acclimation protocol resulted in hypothermic adaptation (i.e., habituation), which was characterized by a modest reduction in shivering and an attenuation of whole-body thermal discomfort. The main finding of the study was that, regardless of subjects’ thermal status, the 5-day whole-body cold acclimation protocol did not alter TF (P > 0.1) and CIVD responses (P > 0.2) during local cold stress. Yet, after the acclimation, the cold-induced increase in MAP was reduced and tended to be reduced during the HYPO (P = 0.05) and NORM (P = 0.14) local cold provocation trials, respectively. Furthermore, the perceived thermal discomfort and pain in the immersed hand appeared to be alleviated in all post-acclimation trials.

An adequate vascular perfusion status is essential not only to maintain life, but to ensure the proper physiology of the different systems that form the animal’s body. Due to its role in the transport of oxygen and nutrients toward, and the removal of cellular waste products away from the body’s tissues, the circulatory system is responsible for the maintenance of body homeostasis. Production related functions in farm animals are not an exception, and directly depend on sufficient vascular physiology. In the past, the study of blood flow in large domestic species was restricted to highly invasive techniques. However, even when such techniques are the foundation for the actual understanding of vascular dynamics in these animals, their limited feasibility and potential impact over the normal vascular physiology represent significant limitations to these approaches. Recently, the development and application of non-invasive technologies (i.e., Doppler and B- mode ultrasound) to the area of animal sciences has provided the potential for the study of vascular dynamics while, the negative implications aforementioned are avoided. In our studies, these technologies were applied to assess the role of the circulatory system on different production related variables such as: temperament, reproduction, and milk production in the bovine. A tendency toward differences in jugular blood flow was associated with the temperament in beef calves in this study. Also, a significant increase in vasodilation in the uterine arteries of beef cows was found to be associated with a numerically higher reproductive efficiency (i.e., pregnancy rates). Moreover, an increase in blood flow towards the mammary gland in dairy cows was associated with administration of bovine somatotropin. In conclusion, B- mode and Doppler ultrasound resulted in tools able to reflect the essential role of an adequate vascular perfusion in the normal physiology and productive performance in the bovine. However, in real farm scenarios the feasibility of these techniques in large domestic species is limited. Therefore, further specialization of this instrument to the conditions existent in such farm scenarios are recommended to improve its feasibility and to significantly accelerate the rate of knowledge acquisition in this area.

Data from the McMaster Occupational Biomechanics Laboratory were consolidated to evaluate overall trends relating to tissue motion and blood flow in the carpal tunnel. Regarding tissue motion, displacements of the flexor digitorum superficialis (FDS) tendon and its subsynovial connective tissue (SSCT) were found to decrease with greater movement speed and a flexed wrist posture. Notably, changes to shear outcomes including relative tendon-SSCT displacement, the shear strain index (SSI), and maximum velocity ratio (MVR) demonstrate that greater movement speed contributes to SSCT damage according to the shear strain mechanism of injury theorised to promote carpal tunnel syndrome (CTS). Median nerve blood flow was also found to be implicated by wrist flexion, and appeared to decrease with greater CTS severity status. Finally, induced blood flow alteration of the carpal tunnel was found to elicit a median nerve blood flow response similar to the level found in CTS subjects, confirming its effectiveness as an intervention to study tissue motion in a CTS-like state. The influence of altered blood flow on tissue motion was differential, where the higher supradiastolic condition altered FDS displacement, and the lower subdiastolic condition affected SSCT displacement and SSI. These findings provide valuable evidence for changes in median nerve blood flow—and by extension, the local fluid environment within the carpal tunnel—not only being a consequence of SSCT fibrosis characteristic of CTS, but potentially also acting as a cause for said changes in carpal tunnel tissue motion. / Thesis / Master of Science in Kinesiology / This thesis aimed to evaluate and summarize key findings from the McMaster Occupational Biomechanics Laboratory relating to tissue motion and blood flow in the carpal tunnel. Performing repetitive finger movements faster and with a flexed wrist posture were found to decrease the distance travelled of the underlying finger tendon. Blood flow of the median nerve, which is implicated in carpal tunnel syndrome (CTS), is higher with forceful exertion and flexed wrist posture, and lower with greater severity of CTS. Finally, altering blood flow to the carpal tunnel was found to create a CTS-like environment, affected tissue motion in the carpal tunnel, and promoted movement disparity between these tissues that is associated with injury. This suggests that fluid/blood flow changes affecting the carpal tunnel is a plausible mechanism for increasing the likelihood of developing CTS.

Umbilical flow velocity waveforms (FVW' s) can be measured non-invasively using Doppler ultrasound. Changes in the FVW's occur long before the warning signs from other conventional monitoring methods. Correct interpretation of the changes in the FVW has the potential of providing the clinician with an early warning of foetal distress. A number of indices have been described in the literature to characterise the FVW including the Pulsatility Index (PI), the Resistance Index (RI) and more recently, the High Resistance State Index (HRSI). Researchers have shown a dependence of the FVW, and thus the indices which describe it, on factors such as the placental resistance (Muijsers et al 1990a) blood pressure pulsatility (Mulders et al 1986), and the foetal heart rate (Downing et al 1991). In order to model the foetal circulation, the dimensions of the foetal vessels were required. These were taken from the literature when available, but had to be supplemented by measurements on post mortem specimens. This information, together with blood pressures and flow rates taken from the literature, was used to design electrical analogous models of the foetal arterial circulation (model 1 and model 2), which were implemented using PSpice, which is an electronic circuit simulator package. The Flow Velocity Waveforms (FVW's) simulated were stored and then analyzed using MATLAB, which is a mathematical package to calculate the waveform indices and both the blood pressure and percentage blood flow to the different anatomical regions of the foetus. Model 1 is a simple model of the umbilical placental unit only, which assumes a rectified sine wave with a D.C. offset as an input waveform while Model 2 is a distributed element model of the complete foetal arterial system, including a realistic representation of the foetal heart. AIM: Simulations of the FVW were used to examine the effects of placental obliteration (raised placental resistance), placental size, foetal heart rate (FHR), blood pressure pulsatility (BPPI), mean blood pressure (BP), and site of measurement of the FVW along the umbilical artery and thus on the waveform indices which are used to describe it (RI, PI and HRSI). RESULTS/ DISCUSSION: The investigations using models 1 and 2 showed that the indices were significantly dependent on the placental resistance, the size of the placenta and the type of placental obliteration. Model 1 was also used to investigate the effect of FHR variations on the indices under the original assumption that the input waveform to the umbilical/placental unit was a rectified sinusoid offset by a constant voltage (D.C.) (Thompson and Trudinger 1990). The result obtained, that is, the FHR does not affect the indices (in particular the PI) needed further investigation because the assumption for the input waveform is not true under all conditions. For this reason, the simulations were repeated using model 2, with the interesting result that there is a difference between short term FHR variations and long-term FHR variation. Short term FHR variations had a pronounced effect on the indices. The blood pressure pulsatility and the indices concerned varied by large amounts in this case, which indicated a link between the blood pressure pulsatility and all the indices. Long term FHR variations had an inconsistent but small effect on the blood pressure pulsatility and in turn had a small effect on the RI and PI. The mean blood pressure in these simulations decreased with increasing FHR which resulted in a pronounced increase in the HRSI which indicated the dependency of this index on the mean blood pressure rather than on the blood pressure pulsatility. It was found that the HRSI is a good index of placental resistance and may be particularly useful in evaluating high placental resistance in cases of absent flow during diastole, since, in these cases it is only slightly affected by the FHR. A value of greater than 34 percent is the recommended HRSI value to indicate severe foetal distress. The results also indicate that the FVW shape varies along the umbilical artery and is far more pulsatile at the aortic (proximal) end than the placental end. This is reflected in the indices which thus have worst case values at the placental end. It is thus recommended that, where possible, the indices are measured at the placental end of the umbilical artery.

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Background: Vascular dysfunction due to hyperglycemia in individuals with diabetes is a factor contributing to distal symmetric polyneuropathy (DSP). Reactive oxygen species (ROS) reduce the bioavailability of nitric oxide (NO), a powerful vasodilator, resulting in reduced circulation and nerve ischemia. Increases in blood NO concentrations and circulation have been attributed to whole body vibration (WBV). The purpose of this study was to the determine the effects of low frequency, low amplitude WBV on whole blood NO concentration and skin blood flow (SBF) in individuals with symptoms of DSP. Research Design and Methods: Ten subjects with diabetes and impaired sensory perception in the lower limbs participated in this cross-over study. Each submitted to two treatment conditions, WBV and sham, with a one week washout period between. Blood draws for NO analysis and Doppler laser image scans of SBF were performed before, immediately after and following a 5 minute recovery of each the treatments. Results: Low frequency, low amplitude WBV vibration significantly increased skin blood flow compared to the sham condition (p=0.0115). Whole blood nitric oxide concentrations did not differ between the WBV and sham condition immediately or 5 minutes post-treatment ( p=0.1813) Conclusions: These findings demonstrate that subjects with diabetes respond to whole body vibration with increased skin blood flow compared to sham condition. The implication is that WBV is a potential non-pharmacological therapy for neurovascular complications of diabetes.