Sympathetic Decentralization after Spinal Cord Injury is Associated with Cardiac Atrophy, Increased Protein Degradation, and Systolic Dysfunction.

Spinal cord injury (SCI) is known to cause systolic and to a lesser extent diastolic cardiac dysfunction. However, the structural changes that accompany this functional decline are less well defined. Here we characterized the changes in cardiac structure (MRI) and function (pressure‐volume [PV] catheterization) that accompany SCI. We also took a histological and molecular approach to determine changes in the size of the cardiomyocytes as well as changes in the genes known to govern the two main protein degradation pathways in the cell, the ubiquitin‐proteasome system (UPS) and autophagy. 12 male ZDF‐Lepr + rats were evenly assigned to either a complete high‐thoracic spinal cord injury (T3 spinal level) or sham injury. 12 weeks following SCI, transthoracic MRI was performed followed by PV surgery. After completion of the PV surgery, the heart was excised, weighed, and a small section of the apex was removed for gene analysis after which the remaining heart was post‐fixed. Quantitative PCR was performed to determine changes in the expression of genes that govern UPS or autophagy and immunohistochemistry was performed to determine cardiomyocyte size. We found that SCI caused a reduction in left‐ventricular end‐diastolic volume (p=0.001), end‐diastolic wall volume (p=0.004), and wet heart mass to femur length ratio (p<0.001), as well as a reduction in all load‐independent systolic indices (i.e., end‐systolic elastance and preload recruitable stroke work; both p<0.005). Blood work revealed that SCI reduces circulating norepinephrine (p<0.001). Histological analysis indicated a significant decrease in cardiomyocyte width and length in SCI (both p=0.005). Gene expression analysis indicated an upregulation of autophagy components in SCI (i.e., BECN1 and ATG12; all p<0.01) and UPS (i.e., MuRF1 and MAFbx; all p<0.05). SCI is associated with a reduction in left‐ventricular size, systolic dysfunction, and cardiomyocyte atrophy, the latter of which occurs via activation of both UPS and autophagy. We suggest that chronically reduced norepinephrine levels in SCI may provide the stimulus for cardiac atrophy. Support or Funding Information Heart and Stroke Foundation of Canada; Michael Smith Foundation for Health Research; Rick Hansen Institute 1Spinal cord injury causes systolic dysfunction (left panels; reduction in end systolic elastence [Ees = slope of the end‐systolic pressure‐volume relationship]), cardiac atrophy (middle panels, reduction in left‐ventricular size), and an upregulation of the genes involved in autophagy (ATG12 and BECN1) and the ubiquitin‐proteasome system (MuRF1 and MAFbx). *p<0.05