Investigating the temporal effects of spinal cord injury on cardiac function and structure in male rats with T3 complete transection and determining the primary cause of cardiac decline following spinal cord injury using male rats with T3 or L2 complete transection, or T2 severe contusion

STUDY PURPOSE: High-level spinal cord injury (SCI) alters cardiac function and causes cardiac atrophy in the chronic phase post-injury. How such events manifest over time post-injury and the primary cause of these cardiac changes were unknown. The first study (manuscript Part I) investigated the temporal changes in the heart on the acute-to-chronic continuum post-SCI. The remaining studies (manuscript Part II) investigated whether the primary cause of altered cardiac function post-SCI was the loss of sympathetic control to the heart. DATA COLLECTED: In Part I a total of 66 male Wistar rats (10-11 weeks old at SCI) were randomly assigned to T3 complete transection SCI (performed with microscissors and suction) or a SHAM injury; rats were assessed for outcomes at different time-points along the acute-to-chronic continuum. Part I represents the complete data of 61 rats - the SCI was fatal in 4 rats (6.1% mortality rate, below UBC animal ethical board’s expectations of 10%), while one rat was excluded from data analysis due to poor health at termination. To study cardiac volumes, echocardiography was performed in the same rats over-time, at pre-surgery, 1 day, 2 days, 4 days, 6 days and 8 weeks post-SCI (n=6-10 per time-point). To study cardiac function, we performed left-ventricular (LV) catheterization in different rats at termination: 1 day, 3 days, 5 days, 7 days and 8 weeks post-SCI (n=6-9 per group). To estimate the temporal changes in sympathetic activity post-SCI, we collected blood at 1 day, 7 days and 8 weeks post-SCI to detect plasma norepinephrine (NE) levels via an ELISA (n=4-7 per group). To measure LV cardiomyocyte dimensions, we collected mid-ventricular cross-sectional discs of the heart for histology at 12 hours, 1 day, 3 days, 5 days, 7 days and 8 weeks post-SCI (n=5-9 per group). To investigate whether and when protein degradation pathways were at play post-SCI in the heart causing cardiac atrophy, we collected LV apex tissue at all acute time-points, 12 hours to 7 days, to perform qPCR (n=5 per group). In Part II, we performed three rodent studies. The first study aimed to determine whether the reduction in cardiac function post-SCI was neurally mediated. We performed in order: LV catheterization, a T3 complete transection SCI (same injury model as Part I) and a chemical ganglionic blockade (hexamethonium bromide, HEX; I.V. 20 mg/kg) in male rats (total n=7; n=4 Sprague Dawley 23 weeks old at SCI, n=3 Wistar 11-12 weeks old at SCI). We compared the cardiac functional outcomes nadir post-SCI and post-HEX. The second study (n=20 male Wistar rats, 10-11 weeks old at SCI), investigated the involvement of bulbospinal sympathetic control in reduced cardiac function post-SCI by comparing LV catheterization outcomes at 13 weeks following complete transections (same injury model as Part I) at the T3 (interrupted bulbospinal sympathetic control; n=6) and L2 level (intact bulbospinal sympathetic control; n=7), compared to SHAM controls (n=7). To further isolate the role of the bulbospinal sympathetic control in mediating these reductions, we treated T3 severely contused rats (400 kdyn, 5 second dwell time with Infinite Horizon impactor) with the neuroprotective agent minocycline or a vehicle control (total n=19; male Wistar rats, 10-12 weeks old at SCI). At eight weeks post-SCI, we performed LV catheterization to obtain cardiac functional outcomes (n=5 minocycline treated rats and n=6 vehicle treated controls), and histology to assess preservation of bulbospinal sympathetic fibers in the spinal cord (n=4 per treatment group). Encompassing all sub-studies, this dataset contains the data of 112 rats. DATA USAGE NOTES:

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