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The University of Calgary master and doctoral theses archive. Full text is made available when possible.
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Browsing Graduate Studies by Department "Cardiovascular & Respiratory Sciences"
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Item Open Access A murine model of emery-dreifuss muscular dystrophy(2003) Grattan, Michael James; Giles, Wayne R.Item Open Access A novel approach to mitral flow(1995) MacRae, Jennifer Marie; Tyberg, John V.Item Open Access A Pharmacodynamics Analysis of Glucocorticoid Receptor-Mediated Gene Expression in BEAS-2B Human Airway Epithelial Cells(2016) Joshi, Taruna; Giembycz, Mark; Newton, Robert; McKay, Derek; von der Weid, Pierre; Hirota, Simon; Cameron, LisaInternational treatment guidelines recommend that inhaled glucocorticoids be used as a monotherapy to control mild-to-moderate asthma. However, a combination of an inhaled glucocorticoid with a long-acting β2-adrenoceptor agonist is recommended for managing moderate-to-severe asthma, which cannot be controlled by glucocorticoids alone. Increasing evidence supports the idea that glucocorticoids acting through the glucocorticoid receptor (GR) can attenuate inflammatory responses either by inducing anti-inflammatory genes (a process called transactivation) or by suppressing pro-inflammatory genes (a process called transrepression). Gene transactivation by glucocorticoids was initially thought to be responsible for causing the metabolic side-effects and, hence, is relatively understudied when compared to transrepression. However, it has become increasingly clear that transactivation plays an important role in the anti-inflammatory actions of glucocorticoids. Moreover, the extent to which clinically-relevant glucocorticoids are equivalent in their ability to promote gene expression is unclear. This thesis describes the first pharmacodynamic approach to evaluate the transactivation potential of a panel of glucocorticoids alone and in combination with indacaterol (Ind), a long-acting β2-adrenoceptor agonist. Pharmacodynamic analyses showed that magnitude of luciferase gene induction was agonist dependent (i.e. seven different glucocorticoids tested displayed varying degrees of agonism). In addition, there were significant differences in agonist potency and, more importantly, the relationship between GR occupancy and response. To complement the reporter studies, similar analyses were performed on four glucocorticoid-inducible candidate genes. Three of these (GILZ, p57kip2 and CRISPLD2) are genes with potential anti-inflammatory activity and a fourth gene, PDK4 is predicted to promote metabolic side-effects. Similar to the luciferase reporter system, the expression of these genes was agonist-dependent and displayed markedly different GR occupancy-response relationships. Furthermore, Ind, when combined with the seven GR agonists tested, synergistically enhanced transactivation, the magnitude of which was agonist and gene dependent. These studies demonstrate that when gene transactivation is used as a functional output, glucocorticoids used to treat asthma are not biologically-equivalent. It is proposed that these differences may be exploited to therapeutic advantage. Thus, the generation of gene expression ‘fingerprints’ in target and off-target human tissues may allow new GR agonists to be rationally designed for asthma with an improved therapeutic index.Item Open Access A study of the effects of left ventricular contractility and coronary tone on coronary flow dynamics using wave intensity analysis(2001) Sun, Yi-Hui; Tyberg, John V.Item Open Access Acquired Mechanisms of Bicuspid Aortic Valve-Associated Aortopathy(2018-07-05) Guzzardi, David G.; Fedak, Paul; O'Brien, Edward; Di Martino, Elena S.Bicuspid aortic valve (BAV)-associated aortopathy is characterized by progressive aortic extracellular matrix (ECM) remodeling leading to aneurysm, dissection or rupture. The cause of this aortopathy is unclear; a genetically-driven basis has been favoured, but recent studies implicating an acquired valve-mediated hemodynamic mechanism have challenged this long-standing view despite no clear link between aortic hemodynamics and ECM remodeling having been delineated. We hypothesized that aortopathy in human BAV patients is influenced by valve-mediated wall shear stress (WSS) in a regionally-dependent manner. Aortic tissue specimens from BAV patients that received pre-operative 3-dimensional time-resolved phase-contrast magnetic resonance imaging (4D flow MRI) to compute regional WSS were assessed quantitatively for their expression of aortopathy. Compared to aortic tissue subjected to normal WSS, adjacent tissue from the same BAV aortas subjected to regionally-elevated WSS exhibited demonstrably worse elastic fiber histopathology, increased protease expression and elevated levels of transforming growth factor β-1 (TGFβ-1) consistent with maladaptive aortic ECM remodeling. We also observed that incremental increases in aortic WSS in the human BAV aorta correlate with increased severity of elastic fiber histopathology, and that this association is most strongly observed in BAV patients with primary stenosis and in mildly-dilated (< 4.5 cm) aortas in the earlier stages of disease. These novel data support a critical role for valve-mediated hemodynamics in coordinating the expression of BAV-associated aortopathy and dispute the assumption that aortic pathology in these patients is primarily driven by genetics. Fluoroquinolone (FQ) antibiotic use constitutes another acquired mechanism of aortopathy that may place BAV patients with pre-existing aortic pathology at risk of disease exacerbation. However, no cellular mechanism has been provided underlying this association. We hypothesized that in aortic myofibroblast cells from BAV-associated aortopathy patients, FQ exposure would alter the proteolytic profile favouring ECM dysregulation and modulate collagen expression. We observed that FQ exposure generates a functional increase in ECM degradation driven by reduced tissue inhibitors of matrix metalloproteinases (TIMPs) alongside impaired compensatory collagen-1 expression. These findings may explain the increased incidence of acquired FQ-associated aortopathy and encourage judicious use of FQ in BAV patients with pre-existing aortic pathology.Item Open Access Age-dependent effects of furosemide on cardiovascular control in conscious lambs(1999) Thomson, Julie J.; Smith, Francine G.Item Open Access Alpha adrenoceptors and their signal transduction pathways in vascular smooth muscle(1996) Li, Xiao-Fang; Triggle, Chris R.Item Open Access Alterations in current density and transmural regional heterogeneity of cardiac repolarization K+ currents in left ventricular hypertrophy(2000) Geonzon, Radzfel; Duff, Henry J.Item Open Access Application of the reservoir-wave approach to the renal circulation(2012) Handkamer, Kristen Claire; Tyberg, John V.The reservoir-wave approach provided the idea that systemic vascular resistance could be modeled as several component resistors arranged in series. The purpose of this investigation was to apply the reservoir-wave approach to the renal circulation and examine how a renal venous constriction (RVC) or a renal arterial infusion of vasoactive agents into one kidney altered conductance, P oo, and series resistances. Endothelin-1 and Angiotensin 11 reduced conductance to 39.6 ± 5.1 and 64.4 ± 4.3%; total renal resistance increased but arterial reservoir resistance decreased to 64.8 ± 6.3 and 80.0 ± 6.1 % of the control respectively. Endothelin-1 and Angiotensin II also increased Poo by 14.5 ± 2.7 and l 0.2 ± 3.6 mmHg, and the microcirculatory plus venous resistance to 187.2 ± 21.0 and 180.0 ± 35.8% ofthe control respectively. RVC increased conductance to I 12.3 ± 4.4% of the control, in apparent compensation. The reservoir-wave approach is applicable to the renal circulation and its use in subsequent investigations is warranted.Item Open Access Architecture of the asthmatic lung(1999) Boser, Stacey; Green, FrancisItem Open Access Assessment of left atrial mechanics and energetics in dogs using wave intensity analysis(2006) Hobson, Tracy Nicole; Tyberg, John V.Item Open Access Assessment of left ventricular diastolic suction using wave-intensity analysis(2003) Jalali, Fereshteh; Tyberg, John V.Left ventricular diastolic suction (LV DS) is defined as the property of the LV to refill itself during early diastole, independent of any force from the left atrium (LA). Two different mechanisms have been developed to explain this phenomenon. The first mechanism relates DS to the decrease in L V elastance. The second theory, relates DS to negative L V pressure, suggesting that the smaller the end-systolic volume, the greater the DS. In an attempt to reconcile these two mechanisms, wave-intensity analysis was used. The purpose of this study was to illustrate that Iw-BE (L V generated backward expansion wave) depends on both decreasing elastance and the L Vend-systolic volume. It was found that the energy ofLV DS is inversely proportional to -c and LV end-systolic volume. From these data a 3-D plot was formed demonstrating the non-linear dependence of L V DS on both of these variables.Item Open Access Association between glycemic load and cognitive function in community-dwelling older adults: results from the Brain in Motion study(2017) Garber, Anna; Poulin, Marc; Friedenreich, Christine; Csizmadi, Ilona; Longman, Richard S.; Sajobi, Tolulope; Shearer, JaneBackground: Impaired glucose tolerance is a risk factor for non-age-related cognitive decline and is also associated with measures of physical activity (PA) and cardiorespiratory fitness (CRF). A low glycemic load (GL) diet can aid in the management of blood glucose levels, but little is known about its effect on cognition with poor glucoregulation. Objective: The aim of this thesis was to assess the relation between GL and cognitive function by glucoregulation, and possible mediatory effects by CRF and PA, in older adults. Design: A cross-sectional analysis of 194 cognitively healthy adults aged ≥55 years (mean=65.7, SD=6.1) was conducted. GL was assessed using a quantitative food frequency questionnaire, and glucoregulation was characterized on the HOMA-IR index. Subjects also completed a cognitive assessment, CRF testing, a validated self-reported PA questionnaire, and a blood draw. Multiple linear regression models adjusted for significant covariates were used to evaluate the relation between GL and cognition, and mediation analysis was used to assess potential mediatory effects by CRF and PA. Results: GL was inversely associated with global cognition (β=-0.014; 95% CI -0.024, -0.0036) and figural memory (β =-0.035; 95% CI -0.052, -0.018) in subjects with poor glucoregulation. Neither CRF nor PA mediated these relations. In subjects with good glucoregulation, no association was found between GL and cognitive function (p>0.05). Conclusions: A low GL diet is associated with better cognitive function in older adults with poor glucoregulation. This study provides supportive evidence for the role of GL in maintaining better cognitive function during the aging process.Item Open Access Biochemcial and functional studies of phoshorylation of cardiac ryanodine receptor by calcium/calmodulin dependent protein kinase II(2007) Zhong, Guo-Feng; Chen, S. R. WayneItem Open Access Bioinductive Effects of Acellular Biologic Scaffolds Promote Adaptive Cardiac Repair Following Myocardial Infarction(2018-09-17) Svystonyuk, Daniyil A.; Fedak, Paul; Tibbles, Lee Anne; Duff, Henry J.; Giles, Wayne R.Ischemic injury may lead to structural remodeling and progressive loss of function, resulting in eventual decompensation to heart failure. Acellular biologic ECM scaffolds retain their native 3-D architecture along with a profile of bioactive constituents that may be leveraged surgically to support myocardial healing. In a proof of concept study, we have previously identified FGF-2 bound to the acellular ECM scaffolds. As such, we hypothesized that FGF-2-dependent bioinductive signaling from surgically implanted acellular scaffolds may attenuate maladaptive structural remodeling and improve functional recovery post-myocardial infarction (MI). First, we observed that FGF-2 has potent anti-fibrotic properties that limited human cardiac fibroblast activation and cell-mediated ECM dysregulation in an in vitro 3-D model. Biochemical characterization showed that ECM scaffolds intact with bioactive constituents released FGF-2 under passive conditions. In a rodent model of myocardial infarction, animals that received intact ECM scaffolds following ischemic injury showed improved functional recovery with evidence of new blood vessel assembly underlying the implantation site. The functional benefits and neovascularization processes were absent in animals that received inactivated scaffolds where FGF-2 bioavailability was limited. The FGF-2-dependent bioinductive effect favorably targeted cardiac fibroblasts, who demonstrated phenotypic plasticity away from a pro-fibrotic phenotype and towards a pro-reparative vasculogenic phenotype. The anti-fibrotic effects of acellular ECM scaffold-derived FGF-2 were consistent with our in vitro studies, however the phenotypic change was unexpected. The redirection in fibroblast phenotype was associated with a modified cardiac scar characterized by a pro-vasculogenic paracrine microenvironment capable of supporting new blood vessel formation and attenuating fibrotic processes. Once again, limiting FGF-2 bioavailability from the ECM scaffolds or blocking FGF receptors in cardiac fibroblasts abolished the induced vasculogenic phenotype. We extended our observations to human subjects where biologic scaffolds were surgically implanted at the site of ischemic injury as an adjunct to standard surgical revascularization. In patients with severe microvascular obstruction and concomitant cardiac dysfunction, acellular biologic scaffolds improved global scar volume and stimulated regional recovery of resting myocardial perfusion. In summary, acellular biologic scaffolds stimulate myocardial healing following ischemic injury through FGF-2-dependent bioinductive signaling that modifies the ischemic scar to support neovascularization, adaptive remodeling, and functional recovery.Item Open Access Ca2+ calmodulin-dependent protein kinase II (camk II) dependent short-term synaptic plasticity between identified lymnaea neurons(2007) Hassan, Atiq Ul; Syed, Naweed I.Item Open Access Cardiac function during mechanical ventilation in a canine model of oleic acid-induced acute lung injury(2008) Mitchell, Jamie R.; Tyberg, John V.Item Open Access Cardiac muscle function after coronary artery ligation in rat(2002) Davidoff, Allen Warren; ter Keurs, Henk E.D.J.Item Open Access Cardiovascular Magnetic Resonance Imaging in Cardiometabolic Disease(2016-01-26) Schmidt, Anna; Anderson, Todd; Friedrich, Matthias; White, James; Pacaud, Danièle; Lau, DavidThe unrelenting incidence of obesity and type 2 diabetes has become a global public health concern. Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in these cohorts. Cardiovascular Magnetic Resonance (CMR) imaging is a robust imaging modality with techniques to provide sensitive detection of early cardiovascular changes in obesity and diabetes. In a prospective study of obese adolescents (n=11, 10 to 20 years old) and a healthy weight control group (n=14), we found obesity was associated with increases in Left ventricular (LV) mass, LV wall thickness and mass:volume ratio. In this “early stage” of remodeling, these structural changes were not associated with elevations in Native T1, a surrogate marker of tissue fibrosis. Strain analysis, by novel CMR tissue tracking analysis, revealed a hyper-contractile state, likely representing a combined contribution of elevated systolic blood pressure with compensatory myocyte hypertrophy. Obese subjects were additionally enrolled in a comprehensive 6-month lifestyle intervention; subjects did not experience weight loss or any change in cardiac parameters after 6 months. Further along the natural history of CVD as related to metabolic disease, the second study looked to examine possible sub-clinical changes in the hearts of otherwise healthy diabetic patients. This study examined twenty-eight healthy type 2 diabetic patients without any observable vascular complications. The complementary use of CMR-based T1 mapping and 3-dimensional strain analysis demonstrated expansion of the extracellular matrix and a reduction in global longitudinal strain. In the endpoint of the cardiometabolic disease spectrum, we analyzed individuals with known or suspected Coronary Artery Disease. This study explored the relationship between intra-thoracic fat volume (ITFV) and 4D myocardial strain-based markers of adverse remodeling. In non-infarcted myocardium, ITFV is associated with reductions in myocardial strain. These findings suggest ITFV to be a potentially important marker of adverse ventricular remodeling. The findings of these three studies suggest a capacity of contemporary CMR to identify early changes in cardiometabolic disease and also lend insight into the progression of diabetic heart disease. CMR provides a non-invasive, accurate and reproducible imaging modality with the potential to be useful in screening and CVD risk-stratification.Item Open Access CaV3.2 Channels and BKCa-Mediated Feedback in Vascular Smooth Muscle(2018-06-28) Hashad, Ahmed Mohamed; Welsh, Donald Gordon; Chen, Sui Rong; Altier, Christophe; von der Weid, Pierre-YvesThe vascular T-type Ca2+ channel, CaV3.2, regulates arterial tone by triggering Ca2+ sparks and activating large conductance Ca2+-activated K+ (BKCa) channels. Despite being an integral element of an arterial feedback loop, little is known of its regulation and how key receptors and signaling pathways use this channel to influence tissue perfusion. This thesis will begin to fill key knowledge gaps, undertaking experiments that progress from individual smooth muscle cells to whole arteries, and which entail the use of patch clamp electrophysiology, Ca2+ imaging, pressure myography, immunohistochemistry, quantitative polymerase chain reaction (qPCR) and computational modeling. In initial work, perforated patch electrophysiology was used in concert with Ca2+ imaging to illustrate the coordinated interplay between CaV3.2 and two other Ca2+ permeable conductances in setting voltage-dependent Ca2+ spark production and BKCa channel activation. A second layer of experiments subsequently revealed that caveolae help couple CaV3.2 to Ca2+ sparks generation by placing this T-type Ca2+ channel in close proximity to its intracellular target, ryanodine receptors (RyR). Disruption of the structural arrangement impaired the ability of CaV3.2 to mediate BKCa-mediated feedback in intact resistance arteries. Final experiments revealed that CaV3.2 channels are targeted by common vasoactive stimuli through unique signaling pathways. Of note, was the ability of Angiotensin II to suppress CaV3.2 channel activity through the generation of reactive oxygen species (ROS) by NADPH oxidase (Nox). In summary, this thesis advances our knowledge of Ca2+ handling in vascular smooth muscle by providing new regulatory insight into CaV3.2, a T-type Ca2+ channel involved in optimizing arterial tone and tissue perfusion.