A reduction in cardiac function precedes structural adaptations in experimental spinal cord injury

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.Education, Faculty ofKinesiology, School ofGraduat