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Jordan Squair
Doctor of Medicine and Doctor of Philosophy (MDPhD)
Research Topic
Autonomic dysfunction following spinal cord injury: mechanisms, novel treatments, and clinical reality
Sympathetic control of the circulation (Basic NSERC-funded stream)
Interventions to promote beneficial spinal plasticity following spinal cord injury (Health stream)
Acute hemodynamic management of spinal cord injury
The ideal applicant would have a strong background and interest in systems physiology and experience working with small animal models. Technical expertise with any of the following would be an asset: 1) small animal surgery; 2) animal husbandry/handling; 3) histology/IHC; 4) MATLAB/R-Studio; 5) Electrophysiology
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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
No abstract available.
Purpose: High-thoracic spinal cord injury (SCI) markedly impairs cardiac function. The purpose of this dissertation was to explore whether acute intermittent hypoxia (AIH), one of the most promising therapies in the field of SCI, has the potential to restore cardiac function in a rodent model of high-thoracic SCI. Prior to doing so, we first tested and validated multiple single-beat metrics of cardiac contractility that would allow us to track changes in cardiac inotropic function prior to, immediately after, and following the intervention of interest (i.e., AIH) in the present dissertation. Methods: Chapter 2: In a cross-species (i.e., rats, pigs, dogs) study consisting of eight experiments, we comprehensively tested whether the majority of previously reported/tested single-beat surrogates of cardiac contractility, together with two new proposed metrics, meet the assumptions required to be considered valid metrics for gauging cardiac contractile function in small and large animal models. Chapter 3: Through four experiments conducted in rodents, we tested whether 1) high-thoracic SCI reduces sympathetic nerve activity (SNA) and cardiac function in an animal model, 2) such reduced SNA post-injury contributes to cardiac functional decline in these animals, 3) AIH can mitigate sympathetic hypoactivity post-injury, and 4) AIH-induced sympathetic plasticity can be translated to end-organ function and improve cardiac function post-injury in these rodents. Results and conclusions: Findings from experiments in Chapter 2 confirmed that several, but not all, single-beat metrics of contractility can be used to measure cardiac contractile function in both small and large animal models. Findings from experiments in Chapter 3 demonstrated that high-thoracic SCI impairs cardiac function due to sympathetic hypoactivity that can be reversed with a single session of AIH when animals are treated at two weeks post-injury. These findings advance our understanding regarding the application of AIH in the field and set the stage for examining the potential cardiovascular benefit of therapeutic AIH in future clinical trials with a focus on improving cardiovascular function in individuals with SCI.
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Cervical spinal cord injury (C-SCI) is a devastating condition that leads to significant impairments in both the cardiovascular and respiratory response to aerobic exercise. As the heart and lungs share space within the thoracic cavity it follows that changes in one system will affect the other. Therefore, the purpose of this thesis was to examine heart-lung interactions in C-SCI and to utilize this knowledge to enhance exercise capacity in athletes with C-SCI.The aims of this thesis were to (1) compare the cardiorespiratory response to maximal and sub-maximal exercise following C-SCI to able-bodied individuals, with a particular focus on operating lung volumes (Study #1, Chapter 3); (2) to examine the effects of respiratory loading on lung volumes and left-ventricular function during head-up tilt (Study #2, Chapter 4); and (3) to assess the effects of a combined inspiratory and expiratory respiratory muscle training (i.e. RMT) intervention in elite athletes with C-SCI (Study #3, Chapter 5).Laboratory-based incremental arm ergometry testing demonstrated that C-SCI is associated with a limited exercise capacity compared to able-bodied individuals along with an altered respiratory pattern that is characterized by dynamic hyperinflation and reduced tidal volume. By manipulating inspiratory and expiratory esophageal pressure in individuals with C-SCI, it was demonstrated that expiratory loading elicited dynamic hyperinflation that was associated with impaired left-ventricular filling, likely due to direct ventricular interaction and/or mediastinal constraint. Finally, a six-week RMT intervention in elite athletes with C-SCI was found to significantly enhance respiratory muscle strength and measures of pulmonary function and prevent dynamic hyperinflation during exercise. These changes in pulmonary function were accompanied by enhanced exercise capacity during an incremental arm ergometry test and were partly ameliorated following six-weeks of wash-out (i.e., no RMT).This thesis demonstrates that dynamic hyperinflation in individuals with C-SCI, which likely occurs due to expiratory muscle weakness, limits left ventricular filling and is associated with an attenuated exercise capacity compared to able-bodied individuals. RMT improved respiratory muscle strength and prevented dynamic hyperinflation in individuals with C-SCI and enhanced exercise capacity.
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Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Traumatic spinal cord injury (SCI) causes an initial injury followed by a protracted phase of spinal cord tissue hypoxia. This tissue hypoxia contributes to secondary injury, leading to worse motor and autonomic outcomes in the chronic setting. We have demonstrated that taking a cardio-centric approach to hemodynamic management following SCI by augmenting cardiac contractility and mean arterial pressure (MAP) with the B1-adrenoceptor agonist dobutamine (DOB), and further coupling DOB infusion with the inhalation of ethyl nitrite (ENO), an S-nitrosylating agent, is associated with improved spinal cord oxygenation in the acute phase post-SCI. Moreover, a major yet commonly over-looked outcome of chronic high-level spinal cord injury is the reduction in cardio-autonomic function due to damaged descending sympathetic tracts. As such, I aimed to determine the influence of a cardio-centric approach to hemodynamic management with added ENO inhalation following SCI on long term outcomes of blood pressure regulation. I hypothesized that treatment with DOB and ENO in the acute phase following SCI would mitigate secondary injury and improve cardiovascular outcomes in the chronic setting. To accomplish this, a total of 36 male Wistar rats underwent a T3 contusion injury (300 kdyn) and were assigned into 4 treatment groups: control (n=6), ENO (n=6), DOB (n=12), and combined DOB and ENO (n=12). At 12-weeks post-SCI, rodents were anesthetized with intravenous urethane (2.440.50 g/kg) and instrumented with a solid-state pressure transducer in the carotid artery to measure MAP. We observed a higher MAP in both DOB (113.611.4 mmHg; p=0.030) and ENO+DOB (116.714.6 mmHg; p=0.013) treated groups when compared with controls (94.6511.62 mmHg). The MAP of ENO treated animals (91.67.3 mmHg; p=0.97) was not different from controls. No difference in resting sympathetic nerve activity or -adrenergic receptor sensitivity was observed. Baroreflex sensitivity, quantified by the slope of the linear regression for % change in SNA and DBP, was greater in DOB (-0.9620.361 %/mmHg) vs. controls (-0.4330.297 %/mmHg; p=0.022) but not ENO+DOB (-0.7790.388 %/mmHg; p=0.616). Collectively, these data suggest that DOB treatment, alone or in combination with ENO, may improve systemic hemodynamics while DOB alone improves baroreflex sensitivity in the chronic high-thoracic SCI setting.
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Contemporary discussion of the baroreflex includes the efferent vascular-sympathetic and cardio-vagal arms. Because sympathetic pre/post-ganglionic neurons innervate the LV, however, the heart may also undergo sympathetically mediated increases in cardiac contractility during baroreceptor unloading, but this has not been adequately investigated using a load-independent index of contractility. We aimed to a) determine whether left-ventricular (LV) contractility increases in response to baroreceptor unloading, and b) parse out whether the increase in contractility is mediated via the sympathetic or parasympathetic nervous system. 10 male rats were anesthetized (1.9 ± 0.4 g/kg urethane) and instrumented with arterial and LV pressure-volume catheters to measure mean arterial pressure (MAP) and contractility [maximal rate of pressure normalized to end-diastolic volume (dP/dtmax–EDV mmHg/s/µl)], respectively, and placed in a servo-controlled lower-body negative pressure (LBNP) chamber to reduce MAP by 10% to mechanically unload baroreceptors. LBNP was repeated in each animal following infusions of esmolol (beta-blocker which blocks cardiac sympathetic transmission), atropine (blocks cardiac parasympathetic transmission), and esmolol + atropine (full cardiac autonomic blockade). Under control conditions, dP/dtmax–EDV increased during baroreceptor unloading (26 ± 6 vs 31 ± 9 mmHg/s/µl, p=0.031) Blocking cardiac sympathetic transmission abolished this response (11 ± 2 vs. 12 ± 2 mmHg/s/µl, p=0.125). In contrast, contractility increased during baroreceptor unloading when blocking cardiac parasympathetic transmission (26 ± 6 vs. 31 ± 9 mmHg/s/µl, p=0.019), suggesting sympathetic activation, not parasympathetic withdrawal, is the key regulator of the contractile response to baroreceptor unloading. Full cardiac autonomic was associated with statistically significant increase in LV contractility (12 ± 3 vs. 15 ± 4 mmHg/s/µl, p=0.046), but the magnitude of which may be of limited functional relevance. The results of this study provide evidence of a sympathetically mediated cardio-contractile arm of the baroreflex in anesthetized rats.
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High-level spinal cord injury (SCI) causes the loss of descending sympathetic control to the heart which, in addition to other secondary consequences (i.e., changes in physical activity and metabolism), leads to premature onset and increased risk for cardiovascular disease. Our research team reported that chronic high-level experimental SCI is associated with systolic dysfunction, cardiomyocyte atrophy and up-regulation of the two main proteolytic pathways in cardiac tissue. How such events manifest over time post-injury is presently unknown. Therefore, the aim of this thesis was to investigate the temporal effects of high-thoracic SCI on cardiac function, structure and proteolysis. To achieve so, we used a pre-clinical rodent model which underwent complete transection SCI at the third thoracic spinal level (T3-SCI). Rats were terminated at different time-points along the acute timeline: 12 hours, 1 day, 3 days, 5 days and 7 days post-SCI. SHAM rats were used as controls and underwent dorsal durotomy with no SCI. Echocardiography was performed on the 7-day SCI and SHAM groups pre-surgery and on days 1, 2, 4 and 6 post-surgery to assess temporal changes in cardiac volumes and function. At termination time-points, left-ventricle (LV) catheterization was performed to assess cardiac function in all groups except in the 12-hour T3-SCI group. Additionally, cardiac tissue was collected for histological and gene expression analysis to quantify cardiomyocyte dimensions and the regulation of proteolytic pathways, respectively. We found a significant reduction in load-dependent and -independent systolic function with ventricular-arterial uncoupling as early as 1 day post-SCI which persisted into the chronic setting, but no changes in diastolic function. These results indicate a rapid onset of cardiac dysfunction following T3-SCI, implying that loss of cardiac sympathetic control and cardiac unloading are key determinants in reduced systolic performance post-SCI. Furthermore, in T3-SCI cardiac tissue, we report elevated gene expression of targets involved with the ubiquitin proteasome system, one of the two main proteolytic pathways. Although no significant cardiomyocyte atrophy was observed, our results suggest that the molecular events ultimately causing chronic cardiac atrophy are initiated acutely post-SCI. Together, our findings imply that reduced cardiac function precedes structural remodelling following high-thoracic SCI.
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High thoracic and cervical spinal cord injuries (SCI) are detrimental to autonomic function, increasing cardiovascular disease prevalence and impairing cardiac, cerebrovascular and arterial function. Complete SCI to the third thoracic segment (T3) or higher is known to be detrimental to the structure and intrinsic function of the left ventricle (LV). In addition, injuries to T6 or higher are known to impair the cortically-derived cardiovascular response to postural change, causing episodes of low systemic blood pressure known as orthostatic hypotension (OH) up to 28 times each day. While these frequent episodes of OH following SCI are associated with impairments in cerebrovascular function and an increased risk of coronary artery disease, it is not clear whether there is a direct relationship between OH and cardiac dysfunction following SCI. The purpose of this thesis was, therefore, to examine the impact of regular bouts of OH on cardiac function following SCI. To do so, we developed a preclinical model of OH simulation using lower body negative pressure (LBNP) in a rodent model of experimental SCI. The impact of either sham injury, T3 transection alone or T3 transection with 8 weeks of daily simulated OH on cardiac structure and function was assessed in vivo using pressure-volume catheterization and echocardiography, and ex vivo via histological analysis of myocardial tissue. We found that daily simulation of OH caused an uncoupling of the ventricular-arterial interaction following SCI, indicating a decrease in the efficiency and adaptability of the cardiovascular system that was driven by decreased LV contractile function. Additionally, we found evidence of atrophy and remodeling of cardiomyocytes following SCI and an increase in myocardial collagen following OH simulation in SCI animals. Together, the findings of this thesis imply that frequent occurrence of OH following T3 SCI may accelerate the onset of cardiac dysfunction that follows SCI and subsequently increase the risk of cardiovascular disease. Future clinical investigations are needed to understand whether these differences translate to the bedside, and apply more direct measures of ventricular mechanics and arterial function to provide context to our PV data and drive the development of informed treatment protocols.
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Spinal cord injury (SCI) is associated with cardiac atrophy, impaired systolic and diastolic function, and vascular stiffening. In able-bodied (AB) individuals, the heart and vasculature act in unison to ensure efficient coupling between the heart and the peripheral vasculature. The evaluation of the interaction between the vascular system and the heart is performed by measuring the vascular load imposed on the heart (arterial elastance), cardiac contractility (end-systolic elastance), and their ratio “ventricular-arterial coupling” (VAC). More specifically, arterial elastance (EA) is a parameter of the compliant properties of the arterial system and end-systolic elastance (Ees) determines the effectiveness of the heart as a pump. The VAC ratio is an important index of cardiac performance, linked to exercise capacity and predictor of both heart failure and cardiovascular (CV) mortality. Taken together these indices evaluate the mechanical efficiency of the cardiovascular system to meet the metabolic demands. A way to accurately evaluate this CV coupling is invasive and almost exclusively performed in animal models. However, a non-invasive approach to estimate VAC in the clinical scenario is through cardiac imaging and blood pressure measurement. In the field of SCI, research has only focused on evaluating these parameters in animal models, while in humans the heart and vasculature have been evaluated as independent units without investigating their “coupling.” The primary objective of this research was, therfore, to compare invasive and non-invasive parameters of cardiac systolic function in a validated SCI rodent model and translate these findings to humans. Additionally, to determine the parameter that better reflects the impaired systolic function in SCI, I will investigate two non-invasive approaches to assess systolic function and their vascular “coupling” in elite athletes with chronic cervical SCI, non-athlete chronic cervical SCI individuals and AB.
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Individuals with spinal cord injury (SCI) are at greatly increased risk of cardiovascular disease (CVD). This is likely due to physical inactivity and impaired sympathetic control of the heart and blood vessels, resulting in cardiovascular dysfunction. Cardiovascular dysfunction in individuals with SCI is associated with injury level, whereby individuals with higher lesions exhibit greater dysfunction. In people without SCI, cardiac dysfunction predicts CVD. The studies that have investigated cardiac indices in individuals with SCI tend to agree that cardiac atrophy and impaired systolic function occur following SCI. Physical activity is a key method to decrease CVD risk and improve cardiac function, yet few studies have examined the relationship between cardiac function and physical activity in individuals with SCI. Those that have investigated this relationship have used subjective measures of physical activity. The current guidelines for physical activity participation for individuals with SCI were based on a systematic review of the evidence on the benefits of physical activity, yet there was inadequate evidence to prescribe activity intensity and duration to improve cardiovascular health in this population. Individuals with SCI also experience numerous barriers and facilitators to physical activity participation that affect their ability to meet the guideline recommendations. The objectives of this thesis, therefore, were: 1) to objectively measure physical activity in individuals with SCI, using wrist-worn accelerometry during a six-day physical activity monitoring period, and to evaluate the utility of group based wrist accelerometry cut-points to estimate physical activity intensity by comparing MVPA determined by individual cut-points to MVPA determined by group-based cut-points; 2) to determine the relationship between objectively measured physical activity and cardiac structure and function in individuals with SCI across a range of injury levels, and 3) to explore the barriers and facilitators to physical activity participation experienced by individuals with SCI during a six-day physical activity monitoring period.
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Previous work has demonstrated that mobility is consistently one of the most, if not the most important function persons with a spinal cord injury (SCI) desire following their injury. By increasing functional mobility, even slightly, there may be improved independence, leading to improved quality of life. While the current clinical examination for determining the level and severity of an SCI has proven to be very reliable and useful for standardizing SCI classification, it still has significant limitations that may limit a patient’s future mobility. For example, the measures used to assess motor function in the limb following a SCI may not be sensitive enough to detect minimal levels of preserved motor function, as they are limited to manual palpation and/or visual inspection. Furthermore, the extent of preservation of trunk musculature and the vestibulospinal pathway following an SCI remains unclear. Therefore, there is a need for more sensitive measures of remaining motor activity and a need to examine the integrity of individual motor pathways. Using transcranial magnetic stimulation (TMS) and vestibular evoked myogenic potentials (VEMPs), this thesis examined the integrity of the cortico- and vestibulospinal pathways in 16 persons with a motor-complete SCI and 16 able-bodied (AB) matched controls. Despite being clinically classified as motor-complete, persons with an SCI showed some observable muscle activity to cortico- and vestibulospinal stimulation, as well as in response to voluntary contractions. In general, the corticospinal responses in the SCI group were delayed compared to their AB matched controls. The muscle activity detected using TMS related to voluntary activation; however, TMS appears to detect preserved muscle activity below that which can be voluntarily activated. Overall, the results from this thesis provide evidence for the use of TMS and VEMPs to assist in determining the neurophysiological integrity of various motor pathways in persons with a motor-complete SCI. Using these techniques may provide clinicians with more accurate information about the state of various motor pathways and may offer a method to more accurately target rehabilitation.
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