Doctor of Medicine and Doctor of Philosophy (MDPhD)
Autonomic dysfunction following spinal cord injury: mechanisms, novel treatments, and clinical reality
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.
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.
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.
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.
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.