<p><strong>Abstract:</strong><strong> </strong></p> <p><em>Introduction:</em></p> <p>Because the relationship between pulmonary function and exercise tolerance is highly variable in COPD, other contributing factors were investigated. Physiological factors that contribute to exercise tolerance must contribute to the symptoms limiting exercise, thus the symptoms limiting exercise in COPD and their contributing factors were explored, including an investigation of novel mechanisms to explore the reported tiotropium bromide-mediated improvement in exercise tolerance in COPD.</p> <p><em>Methods:</em></p> <p>We conducted a retrospective, cross-sectional analysis of 4,424 COPD patients and 4,221 healthy subjects; referred to McMaster University Medical Center for exercise testing. Multiple linear regression, ridge regression, and MANOVA were utilized to determine the factors contributing to exercise tolerance, important symptoms limiting exercise, and factors contributing to dyspnea.</p> <p>A randomized, double-blind, placebo-controlled, crossover study of 20 COPD subjects was performed. Repeated measures ANOVA was utilized to determine effects of 3 weeks tiotropium bromide vs. 3 weeks placebo on cardiac output and efficiency of gas exchange during exercise.</p> <p><em> </em></p> <p><em>Results:</em></p> <p>MBC, DL_CO, and quadriceps strength were the three major, independent, contributors to exercise capacity (MPO = -206.3 + 5.1*Quadriceps Strength + 1.8*MBC + 10.0*DL_CO, r² = 0.677). MANOVA further illustrated this.</p> <p>Dyspnea, alone or in equal combination with leg effort, was the most important symptom limiting exercise in COPD. V_E and MBC were the two major, independent, contributors to dyspnea (Dyspnea = 0.95 + 0.08*V_E + -0.01*MBC, r² = 0.457). The increase in dyspnea with V_E was much greater than the decrease with MBC.</p> <p>Tiotropium bromide did not significantly (p = 0.72) improve the efficiency of gas exchange for oxygen, significantly worsened (p = 0.005) the efficiency of gas exchange for carbon dioxide, and did not improve cardiac output.</p> <p><em>Conclusion:</em></p> <p>We concluded the reported tiotropium bromide-mediated improvement in exercise tolerance in COPD is not mediated through improvements in gas exchange efficiency and/or cardiac output.</p> <p><strong><br /></strong></p> / Doctor of Philosophy (Medical Science)

<p>Cancer patients undergoing chemotherapy have an elevated risk for thrombosis. Although thrombosis is a common complication in cancer patients, the mechanisms of chemotherapy-induced thrombosis remain unclear. We investigated the procoagulant effects of lung cancer chemotherapy agents (carboplatin, paclitaxel, cisplatin, and gemcitabine) on endothelial cells, A549 cells, and monocytes. We also investigated the <em>in </em>vivo procoagulant effects of the aforementioned chemotherapeutic agents as well as the anti-angiogenic agent bevacizumab. Tissue factor (TF) activity, TF antigen and phosphatidylserine (PS) levels were measured on chemotherapy-treated human umbilical vein endothelial cells (HUVEC), A549 cells, and monocytes. Treatment of HUVECs, A549 cells, and monocytes with lung cancer single agent and combination chemotherapy resulted in significant increases in TF activity. However, only cisplatin- and gemcitabine- treated monocytes were found to have increased TF antigen levels. PS exposure was increased only on HUVEC and monocytes treated with cisplatin/gemcitabine combination therapy. Interestingly, addition of paclitaxel to carboplatin resulted in reduced levels of PS exposure on monocytes. This study is the first to explore the procoagulant effects of lung cancer chemotherapy agents on monocyte and A549 cell TF activity levels, as well as to investigate the mechanisms by which lung cancer agents may promote TF decryption on these cell lines<strong>.</strong> Our <em>in vivo</em> results demonstrated that treatment of healthy mice with bevacizumab, paclitaxel and carboplatin moderately increased plasma TAT levels in healthy mice. These studies reveal potential mechanisms by which lung cancer chemotherapy may increase the risk of thrombosis. These studies reveal potential mechanisms by which lung cancer chemotherapy agents induce a hypercoagulable state.</p> / Master of Science (MSc)

<p>Pre-clinical imaging has provided pulmonary researchers with a number of valuable tools for studying both the lung and lung disease. A greater understanding of the structure/function relationships within the rodent lung would help to bridge the gap between functional images of the lung and its underlying anatomy.</p> <p>The objectives of this work were to visualize and measure the components of rodent lung anatomy. Contrast-enhanced microCT images were used to visualize the airways and major blood vessels from both the Sprague-Dawley rat and the BALB/c mouse. These observations and measurements were used in the development of a pulmonary lung model containing both the conducting airways and blood vessels. The model can be applied to unenhanced images of the rodent lung to facilitate the regionalization of functional imaging data (SPECT/PET). The model has been used to simulate bronchoconstriction and deposition patterns of inhaled particles. Extensive validation revealed that the model was unable to fully reproduce the rodent lung and that further refinement is necessary.</p> <p>The finer structure of the rodent lung, which could not be resolved using our microCT system, was measured using histological sections of the rodent lung. Software was developed and validated to automatically quantify the increases in airspace size that are associated with several respiratory conditions.</p> <p>Together, this work sheds light on the underlying anatomy of the rodent lung that is present in both anatomical and functional images. The knowledge will help researchers to understand some of the structural changes that are occurring with the development of lung disease.</p> / Doctor of Philosophy (PhD)

<p><strong>Purpose: </strong>Habitual aerobic exercise improves vascular function; however, the acute vascular response to exercise is poorly understood. The present investigation compared the time course of acute changes in vascular function following two different types of aerobic exercise. <strong>Methods: </strong>Ten untrained males (23 ± 2 yrs) completed one bout of sustained moderate-intensity cycling (END) (30 mins at 55% peak power) or high-intensity interval (HIT) cycling (10 one-minute intervals at 80% peak power) on different days. Endothelium-dependent dilation was assessed by brachial artery flow-mediated dilation (baFMD) at baseline, immediately post-exercise, 1 hour post-exercise and 24 hours post-exercise. Endothelium-independent dilation was assessed via nitroglycerin (NTG) at all time points, except 1 hour post-exercise. <strong>Results:</strong> baFMD values were not significantly different between END and HIT at any time point. Immediately post-exercise baFMD values were unchanged from baseline. 1 Hour post-exercise, relative (p £ 0.001) and absolute (p £ 0.05) baFMD values were attenuated compared to all other time points for both HIT (%FMD baseline: 5.9 ± 2.3%; 1 hour post-exercise: 2.5 ± 1.5%) and END (%FMD baseline: 6.8 ± 2.4%; 1 hour post-exercise: 2.6 ± 1.9%). Relative (p £ 0.05) and absolute (p £ 0.05) NTG responses were attenuated immediately post-exercise compared to baseline for both HIT (%NTG baseline: 18.8 ± 4.4%; immediately post-exercise: 12.3 ± 3.1%) and END (%NTG baseline: 18.3 ± 3.1%; immediately post-exercise: 10.9 ± 4.9%). <strong>Conclusions: </strong>Immediately post-exercise, endothelium-dependent dilation is maintained; but reduced 1 hour following exercise cessation. Similar acute vascular responses are found following HIT and END.</p> / Master of Science in Kinesiology

Recent studies have demonstrated that increases in dynamic strength after weight-training in healthy subjects were associated with reductions in heart rate (HR) and arterial blood pressure (ABP) during formal lifting of identical absolute loads (McCartney et al., 1989; Sale et al., 1990). This study investigated whether the effect could be transferred to strength-related activities of daily living in healthy older men. The effects of 10 weeks (30 sessions) of progressive dynamic weightlifting training on HR and ABP in 10 weight-trained (wttrain) subjects were compared with 5 control subjects. Before and after training intra-brachial artery pressure and HR were monitored continuously during: 10 repetitions of single-arm curl (SAC) and single-arm military press (SAMP) at 70 % of initial 1 repetition maximum (1 RM); 12 repetitions of single- (SLP) and double-leg press (DLP) exercise at 80% of initial 1 RM; 10 mins treadmill walking at 2.5 mph, carrying 20 and 30 pound loads between mins 4-6 and 8-10 respectively (T-10); 4 mins of treadmill walking at 3.0 mph up an incline of 8% (T-4); 12 flights of stairclimbing at 60 steps/min on a Stairmaster 6000 Ergometer (STR). In the wttrain group the 1 RM in SAC, SAMP, SLP and DLP increased overall by 61 (p < 0.007), 30 (p < 0.001), 27 (p<0.001) and 27 per cent (p < 0.001), respectively. After training the mean maximal systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and rate-pressure product (RPP; 10^3) values in all 4 weightlifting exercises were lower. The decreases were only significant however, for the DBP in the SAC (144.0 ± 14.9 to 110.0 ± 5.2 Torr; p < 0.001), SAMP (151.0 ± 5.9 to 144.0 ± 5.4 Torr; p < 0.007), the MAP for the DLP ( 154.0 ± 5.0 to 147.0 ±5.0 Torr; p < 0.021) and RPP for the SAC (22.7 ± 2.2 to 19.1 ± 1.4; p < 0.041). The same respective measurements in the control group were either unchanged or higher. After training, there were overall reductions in the SBP (p < 0.05, mins 8-10), DBP , MAP and RPP (P < 0.05, mins 1-4) responses during T-10 with consistently higher values found in the control group. Similar, but nonsignificant patterns emerged for T-4. In contrast, there was little or no reduction in any of the measured parameters during stairclimbing. It was concluded that improved strength in older subjects results in an attenuated HR and ABP response during weightlifting, and there is a modest transfer of this effect to certain activities of daily living which involve the trained muscles. / Thesis / Master of Science (MSc)

Congenital heart valve disease is one of the most common abnormalities in children, with common valve defects being aortic stenosis, mitral stenosis, and valvular regurgitation. Although adult sized mechanical heart valve (MHV) replacements are widely studied and utilized, there are currently no FDA approved prosthetic heart valves available for the pediatric population. This is due to a variety of reasons such as a limited patient pool for clinical trials, limited valve sizes, and complex health histories in children. Much like adult sized mechanical heart valves, potential complications with pediatric heart valve replacements include thrombosis, blood damage due to high shear stresses, and cavitation. Due to pediatric sized MHVs being much smaller in size than adult MHVs, different fluid dynamic conditions and associated complications are expected. In order to accelerate the approval of pediatric sized heart valves for clinical use, it is important to first characterize and assess the fluid dynamics across pediatric sized heart valves. By understanding the hemodynamic performance of the valve, connections can be made concerning potential valve complications such as thrombosis and cavitation. The overall objective of this study is to better characterize and assess the flow field characteristics of a pediatric sized mechanical heart valve using flow visualization techniques in a mock circulatory loop. The mechanical heart valve chosen for this research was a size 17 mm Bjork-Shiley tilting disc valve, as this is a common size valve used for younger patients with smaller cardiovascular anatomy. The mock circulatory loop used in this research was designed to provide realistic pediatric physiological flow conditions, consisting of a Harvard Apparatus Pulsatile blood pump, venous reservoir, and a heart valve testing chamber. In order to expose the valve to realistic pediatric flow conditions, six unique pump operating conditions were tested that involved pre-determined heart rate and stroke volume combinations. In addition, a modified aortic root model was used to hold the mechanical heart valve in place within the loop and to provide more realistic aortic root geometry. This heart valve chamber was made from a transparent acrylic material, allowing for fluid flow visualization. A traditional Particle Image Velocimetry (PIV) experimental set up was used in order to illuminate the particles seeded within the fluid path, and thus allowing for the capture of sequential images using a high speed camera. The data collected throughout this study consisted of flow rate measurements using an ultrasonic flow meter, and the sequential PIV images obtained from the camera in order to analyze general flow characteristics across the pediatric valve. Such information regarding the flow profile across the valve allowed for conclusions to be made regarding the valve performance, such as average flow velocities and regions of regurgitant flow. By gaining a better understanding of the fluid dynamic profile across a pediatric sized heart valve, this may aid in the eventual approval of pediatric sized mechanical heart valves for future clinical use.

Este trabalho apresenta a implementação de um sistema de velocimetria de imagens de partícula (VIP) para estudo do escoamento do sangue em um dispositivo de assistência ventricular para uso pediátrico (DAVP). O sistema VIP implementado é constituído por uma fonte de iluminação composta por um par de lasers de Nd:YAG (pulso de aproximadamente 18mJ de energia e duração de 5ns), um sistema óptico contendo duas lentes convergentes, uma câmera CCD e uma câmara para visualização. O DAVP estudado foi construído em acrílico transparente e é constituído de uma câmara de sangue e uma câmara pneumática, divididas por uma membrana flexível. A câmara sanguínea possui dois orifícios dotados de válvulas de tecido biológico para a entrada e saída de sangue. A câmara pneumática é conectada a um gerador de pulsos de pressão positiva. O fluido foi semeado com esferas de poliestireno (10 \"mu\" de diâmetro). Foram determinadas as distribuições de velocidades instantâneas nas freqüências de batimento de 80, 100 e 120 bpm em três campos (65 mm x 65mm) da câmara paralelos à membrana e um campo situado no canal de entrada do DAVP, usando correlação cruzada com base na transformada rápida de Fourier. Um gerador de pulsos foi utilizado para sincronizar a detecção das imagens pelo sistema VIP com as fases de interesse no ciclo de bombeamento. Na freqüência de batimentos de 80 bpm as velocidades máximas foram de 1,94 m/s no canal de entrada durante o período de enchimento e 1,66 m/s nas regiões próximas à membrana durante o período de ejeção. Em 100 bpm, as velocidades máximas foram de 1,68 m/s no canal de entrada e 1,15 m/s nas regiões próximas a membrana. As distribuições de velocidades instantâneas mostram a ocorrência de pequenos vórtices, principalmente durante a fase de enchimento. Estes vórtices apresentam grande variabilidade ciclo-a-ciclo produzindo turbulências no fluxo e tensões de Reynolds elevadas. No ciclo a 80 bpm, ) parte da energia cinética turbulenta é dissipada devido à desaceleração do fluxo na câmara sanguínea antes do inicio da fase de ejeção. Isto ocorre para as freqüências de 100 e 120 bpm. A máxima tensão de Reynolds foi observada no canal de entrada do DAVP no valor de 222 N/m2 durante o enchimento, persistindo por 25 ms. No plano da membrana a maior tensão encontrada foi igual a 250 N/m2 durante o enchimento, persistindo por 25 ms. O campo de velocidades media contém vórtices permanentes durante a fase de enchimento que influenciam significativamente o fluxo na câmara e cujo numero aumenta com a freqüência de batimentos, provocando aumento de turbulências. Estes resultados indicam que existe maior possibilidade de ocorrer o processo de hemólise durante o enchimento do que durante a ejeção. Vetores com baixas velocidades foram observados na região compreendida entre os canais de entrada e saída do fluxo na câmara sanguínea no período de ejeção, sugerindo a possibilidade de ocorrer à formação de trombos nesta. / --

Increasing numbers of old and sick patients who are no longer eligible for prolonged invasive implantation surgery have encouraged many researchers to investigate the development of a Mechanical Circulatory Support (MCS) device with more reliability and less possible invasive complications, which would benefit the majority of patients. This thesis will test experimentally and numerically the feasibility of installing an MCS device, as a bridge to destination, in the descending aorta, in a series configuration with the heart. To this end, a multi-chamber Simulator of the Cardio-Vascular blood-flow Loop (SCVL) was designed to simulate the in-vitro flow rates, pressures and other parameters representing normal and diseased conditions of the human cardiovascular system. The multi-chamber SCVL includes models for all four chambers of the heart, and the systemic as well as the pulmonic circulations. Next, a comprehensive study was conducted using the SCVL system to compare the novel in-series placement of the pump, in the descending aorta, with traditional in-parallel placements. Then, a comprehensive numerical study was conducted using the modified Concentrated Lumped Parameter (CLP) model developed by the same team. The numerical results are compared and verified by the experimental results under various conditions. The results for the pump installed in the descending aorta show that the pressure drop, upstream of the pump, facilitates the cardiac output as a result of after-load reduction. However, at the same time the generated pressure drop at the proximal part of the descending aorta induces a slight drop in the carotid perfusion which will be autoregulated by the brain in a native system. Further, the pressure rise downstream of the pump improves the blood perfusion in the renal artery. The pulse wave analysis show that the placement of the pump in the descending aorta leads to improved pulsatility which is beneficial for end-organ functionality in the native cardiovascular system.

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