A PC based waveform acquisition and analysis system has been developed for use in aorta-iliac arterial assessment. A Motorola DSP56001 based system containing dual Analog to Digital converters is used to sample phase quadrature demodulated signals from a commercially available continuous wave Doppler unit. The Power Spectral Density is calculated using an autoregressive model from which the mean velocity waveform is calculated. This waveform is used to calculate the damping factor, vessel compliance and runoff resistance of a simple electrical model of the lower limb arterial circulation using a non-linear regression technique of curve fitting in the time domain. A pilot study using the system shows a significant separation (p < 0.001 Mann Whitney U-test) between the damping factors of a normal control group (quartile range = 0. 15 - 0.25 ; median = 0. 19) and a patient group with angiographically determined aorta-iliac arterial disease (quartile range = 0.45 - 0.89 ; median= 0.49).

Gulf War Illness (GWI) is a medically unexplained illness that is classified by two common case criteria including the CDC chronic multisymptom illness definition and Kansas GWI criteria. It occurred among veterans who served in the Persian Gulf War from August, 1990 to February, 1991. Because of its complex chronic symptoms and multiple potential causes the neuropathological mechanisms and/or successfully clinical treatments for it remain elusive. Those in the theater of this war experienced exposures to many neurotoxicants, suggesting an association between GWI and neurologic dysfunction. In order to better understand the underlying cause of GWI, we have chosen to explore cerebral blood flow. Our hypothesis is that abnormal cerebral blood flow is associated with GWI and ultimately neurological dysfunction. By conducting a comprehensive evaluation of cerebral blood flow we will be able to determine if it has a role in Gulf War Illness. Historically, several techniques have been used to measure cerebral blood flow. Arterial spin labeling (ASL) has been widely used in research as a non-invasive and non-ionizing technique, which has the least adverse effects on the participants. An ASL subtype called pseudo-continuous arterial spin labeling (PCASL) has become a favorable technique in ASL research because it combines the advantages of continuous arterial spin labeling (CASL) and pulsed arterial spin labeling (PASL). PCASL can quantify the absolute cerebral blood flow without the exogenous contrast agents. The cost of PCASL is relatively low as most scanner can run this sequence without additional hardware. It provides higher label efficiency (to CASL) and greater signal-to-noise ratio (to PASL). We utilized the data from an ongoing study with 114 GW veterans study participants aged from 42 to 80. Their regional cerebral blood flow was scanned using a 3T Philips Achieva MRI scanner. Asltoolbox (Wang et al., 2016) was used to calculate the cerebral blood flow, and Freesurfer v6.0 was used to do the co-registration and quantification. The analysis of demographic data suggested that the presence of hypertension was the only variables that made differences between control and GWI case groups (p = 0.02). General linear models indicated that alternations of cerebral blood flow were not a component of GWI at least using CMI definition. Whether cerebral blood flow associates with GWI is still pending on further studies with utilizing a more refined case definition.

Passive hallux adduction has been shown to decrease blood flow in the lateral plantar artery (LPA) in a non-weight-bearing condition. Further research in weight-bearing and shod conditions is necessary to explore relationships between altered blood flow and injury or tissue healing. However, measuring blood flow in a shod foot would require an alternate measurement location to accommodate footwear, such as the more proximal posterior tibial artery (PTA). PURPOSE: To determine changes in blood flow in the PTA and LPA subsequent to passive hallux adduction and to compare the observed changes between the two arteries. Second, to determine if measurement at the PTA is a viable surrogate for measurement at the LPA. METHODS: Forty-one subjects (21 males, 20 females) participated in this study (age 23.5 ± 4.5 years, body mass 72.6 ± 13.7 kg, and height 173.1 ± 10.2 cm). PTA and LPA vessel diameter and velocity were measured via doppler ultrasound (L8-18i transducer GE Logiq S8). LPA was imaged distal to the abductor hallucis and the PTA posterior to the medial malleolus. Each artery was measured for 120 s: 60 s at rest followed by 60 s of passive hallux adduction. PTA and LPA metrics were log transformed and compared using a two-way repeated measures ANOVA, then the log transformed data was assessed with paired t-tests and Bland-Altman plots (alpha = 0.05). RESULTS: There was an expected decrease in blood flow within each artery after passive hallux adduction (p < 0.001). The volume of blood flow differed between the arteries (p < .0001), but the change between baseline to first 5 cardiac cycles after hallux adduction was similar in each artery (p = 0.419). Bland-Altman analysis showed large spread limits of agreement, indicating the PTA underestimated or overestimated measurements at the LPA. CONCLUSIONS: These data suggest that PTA blood flow behaves in a similar manner as LPA blood flow in consequence to passive hallux adduction. There is no significant difference in the absolute change of blood flow during hallux adduction between the LPA and PTA. However, Bland-Altman analysis suggests that the PTA is not a direct surrogate for the LPA due to the large variance in flow between the arteries. Despite this, the PTA can still be a beneficial location of measurement for plantar blood flow. Some reasons are that the PTA has a larger diameter making it an easier artery to image and allows for further research implications due to its ease of access in more applicable circumstances, such as in a shod condition.

Vascular risk factors affect cerebral blood flow (CBF) and cerebral vascular reactivity, contributing to cognitive decline. Hippocampus is vulnerable to both Alzheimer's disease (AD) pathology and ischemia; nonetheless, the information about the impact of vascular risk on hippocampal perfusion is minimal. Cognitively, healthy elderly (NL18, 69.96.7 years) and subjects with mild cognitive impairment (MCI15, 74.98.1 years) were evaluated for the Framingham cardiovascular risk profile (FCRP). All underwent structural imaging and resting CBF assessment with arterial spin labeling (ASL) at 3T magnetic resonance imaging (MRI). In 24 subjects (NL17, MCI7), CBF was measured after a carbon dioxide rebreathing challenge. Across all subjects, FCRP negatively correlated with hippocampal (0.41, P0.049) and global cortical (0.46, P0.02) vasoreactivity to hypercapnia (VRh). The FCRP-VRh relationships were most pronounced in the MCI group: hippocampus (0.77, P=0.04); global cortex (0.83, P=0.02). The FCRP did not correlate with either volume or resting CBF. The hippocampal VR h was lower in MCI than in NL subjects (Z2.0, P=0.047). This difference persisted after age and FCRP correction (F 3,20 4.6, P0.05). An elevated risk for vascular pathology is associated with a reduced response to hypercapnia in both hippocampal and cortical tissue. The VR h is more sensitive to vascular burden than either resting CBF or brain volume.

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Nuclear Engineering, 1981. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Bibliography: leaf 186. / by Thomas James Miller, Jr. / M.S.

Chapter 1: Molecular Mechanism of Mitochondrial Fragmentation and Glucose Metabolism under Disturbed Flow in Endothelial Cells: Focus on the Role of Dynamin-Related Protein 1. The luminal surface of the endothelium is continually exposed to dynamic blood flow patterns that is known to alter immunometabolic phenotypes of the endothelial cells (ECs). Recent literature reported that inhibition of the metabolic reprogramming to glycolysis or enhancement of oxidative phosphorylation (OXPHOS) is considered as an effective strategy to prevent EC proinflammatory activation and eventually the progression of vascular diseases. Endothelial mitochondria are highly dynamic organelles playing versatile roles in maintaining endothelial cell homeostasis working as bioenergetic, biosynthetic, and signaling organelles. The balance between fusion and fission processes modulates mitochondrial network, which is essential for maintaining mitochondrial homeostasis. Disruption of the orchestrated balance, especially toward excessive fission resulting in fragmented and dysfunctional mitochondria, has been shown to be associated with atheroprone phenotypes of ECs. However, there is a key knowledge gap with respect to morphology of EC mitochondria under different flow conditions and its role on EC immunometabolic phenotypes.In chapter 1, the purpose of this study was to investigate the effect of different flow patterns on mitochondrial morphology in ECs and its implication in immunometabolic endothelial phenotype. The overarching hypothesis of the Chapter 1 was that disturbed flow (DF) will increase mitochondrial fragmentation, which will facilitate glycolysis and inflammatory activation in ECs. In the study, mitochondrial morphology was analyzed in ECs at multiple segments of the aorta and arteries in EC-specific photo-activatable mitochondria (EC-PhAM) mice. Increased mitochondrial fragmentation was observed at atheroprone regions (e.g., lesser curvature of the aortic arch, LC) with increased dynamin-related protein 1 (Drp1) activity, compared with the atheroprotective regions (e.g., thoracic aorta, TA). The atheroprone regions also showed a higher level of endothelial activation and glycolysis. Carotid artery partial ligation surgery, as a surgical model of DF, significantly induced mitochondrial fragmentation with elevated Drp1 activity and increased EC activation. in vitro experiments recapitulated in vivo observations. Inhibition of Drp1 activity by mdivi-1 attenuated the DF-induced atheroprone EC phenotypes, showing the close relationship between mitochondrial morphology and atheroprone phenotypes of ECs. As for the molecular mechanism, hypoxia-inducible factor 1 α (HIF-1α) stabilization and its nuclear translocation was significantly increased under DF, which was attenuated by mdivi-1 treatment. Mitochondrial reactive oxygen species (mtROS) and succinate, which are known to reduce prolyl hydroxylase domain 2 (PHD2) activity thereby increasing HIF-1α stabilization, were significantly elevated under DF, but those were attenuated by mdivi-1 treatment. Finally, a 7-week voluntary wheel-running exercise training significantly decreased mitochondrial fragmentation with a down-regulation of VCAM-1 expression at the LC. In conclusion, our data suggest that DF induces mitochondrial fragmentation with increased Drp1 activity, which is associated with an atheroprone EC phenotype. In addition, regular practice of aerobic exercise reduces mitochondrial fragmentation and prevents ECs from an atheroprone endothelial phenotype at the atheroprone regions. Chapter 2: Molecular Mechanisms for Unidirectional Flow (UF)/Exercise-Induced improvement of Mitochondrial Integrity: Focus on phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) /PARKIN-Dependent Mitochondrial Autophagy (Mitophagy) Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) is an essential molecule in the mitophagy process and known to act as a cytoprotective protein involved in several cellular mechanisms in mammalian cells. It has been documented that the loss of PINK1 expression in mice and various cell types enhance susceptibility to stress-induced cell damage, while the overexpression of PINK1 significantly attenuates stress-induced mitochondrial and cellular dysfunction.In chapter 2, the purpose of this study was to investigate PINK1 expression and its subcellular localization under an exercise-mimic laminar shear stress (LSS) condition in human primary endothelial cells and in exercizing mice, and its implications on endothelial homeostasis and cardiovascular disease (CVD) prevention. The overarching hypothesis of the Chapter 2 was that unidirectional flow (UF) will increase cytosolic PINK1 expression through which UF-preconditioned ECs will be more protective against an accumulation of dysfunctional mitochondria via a greater mitophagy induction. In this study, we measured the full-length PINK1 (FL-PINK1) mRNA and protein expression levels in ECs under unidirectional laminar shear stress (LSS). LSS significantly elevated both FL-PINK1 mRNA and protein expressions in ECs. Mitochondrial fractionation assays showed a decrease in FL-PINK1 accumulation in the mitochondria with an increase in the cytosolic FL-PINK1 level under LSS. Confocal microscopic analysis confirmed these subcellular localization patterns suggesting downregulation of mitophagy induction. Indeed, mitophagy flux was decreased under LSS, determined by a mtKeima probe. Mitochondrial morphometric analysis and mitochondrial membrane potential determined by tetraethylbenzimidazolylcarbocyanine iodide (JC-1) showed mitochondrial elongation and increased mitochondrial membrane potential under LSS respectively, suggesting that an elevation of cytosolic PINK1 is not related to an immediate induction of mitophagy. However, increased cytosolic PINK1 elevated mitophagic sensitivity toward dysfunctional mitochondria in pathological conditions. Preconditioned ECs with LSS showed lower mtDNA lesions under angiotensin II stimulation. Moreover, LSS-preconditioned ECs showed rapid Parkin recruitment and mitophagy induction in response to mitochondrial toxin (i.e., carbonyl cyanide chlorophenylhydrazone, CCCP) treatment compared to the control. We measured PINK1 expression at ECs of the thoracic aorta in exercised mice, a physiological LSS-enhanced model, which was significantly elevated compared to sedentary animals. In addition, exercise-preconditioned mice were more protective to angiotensin II-induced mtDNA lesion formation in the mouse abdominal aorta than sedentary mice, suggesting a potential protective mechanism of exercise in a PINK1-dependent manner. In conclusion, LSS increases a cytosolic pool of FL-PINK1, which may elevate the mitophagic sensitivity toward dysfunctional mitochondria or activate other cytoprotective mechanisms in ECs. Our data suggest that exercise may support mitochondrial homeostasis in vascular ECs by enhancing PINK1-dependent cell protection mechanisms. / Kinesiology

<p>The present thesis examined the acute and chronic (training) hemodynamic responses to the unique exercise stimulus of high-intensity "sprint" interval exercise or training (SIT). Previous research has characterized the muscle metabolic and exercise performance adaptations to both short and medium term SIT, however the cardiovascular adjustments and adaptations have not been examined. As part of this thesis two studies were designed to permit evaluations of the chronic cardiovascular responses to a six-week SIT intervention protocol, while two separate studies examined the acute impact of a sprint exercise session on indices of vascular structure and function. Comparisons were made between the SIT and traditional endurance exercise training (ET) in the two exercise training studies, while comparisons were made between a single sprint and that of multiple sprints in the acute exercise studies. The subject population examined in this research was young healthy participants.</p> <p>Our general hypothesis regarding the training adaptations was that similar changes of artery stiffness, vascular endothelial function, blood flow kinetics and oxygen uptake kinetics would occur following SIT compared to ET. Regarding the acute effects of a sprint exercise, we expected arterial stiffness to decrease in the exercising limbs and increase in the central arteries, similar to the responses observed previously immediately following endurance exercise, while we hypothesized that endothelial function would be decreased immediately following the exercise session because of the intense nature of the exercise. The overarching hypothesis guiding these specific hypothesis is that we believe that individual bouts of exercise impact on the arterial wall through the generation of a shear stimulus related to cyclic increases in blood flow and blood pressure. In the short-term the acute response of the artery depends on the composition of the arterial wall and the local stimulus. Over time, functional and structural adjustments occur to normalize the impact of shear forces.</p> <p>Training adaptations in vascular structure and function to SIT were similar to those observed with ET. Both exercise training methods stimulated improved peripheral artery stiffness and endothelial function. The rate of increase in oxygen uptake (kinetic response) was not improved with either training method. However, estimated myocardial demand was reduced with ET but not SIT, which indicates more favourable adaptation in central hemodynamics with ET.</p> <p>Acute sprint exercise markedly reduced peripheral artery stiffness in the exercised limbs well into recovery (~45 minutes), which may benefit central hemodynamics after exercise completion. Sprint exercise also acutely decreased endothelial function, likely because of high oxidative stress generated during the exercise bout and may provide the ideal stimulus for endothelial adaptation.</p> <p>In summary, this thesis highlights the chronic and acute effects of sprint interval exercise and training in young health individuals. The notion that sprint interval exercise provides equivalent benefits to the cardiovascular system as endurance exercise may be true in the peripheral circulation. However, further study focusing is required before the general acceptance of more favorable central hemodynamic effects from endurance exercise training.</p> / Thesis / Doctor of Philosophy (PhD)

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