The Effects of High-Thoracic Spinal Cord Injury on the Heart Transcriptome

It is becoming increasingly recognized that high-level spinal cord injury (SCI) is associated with altered heart structure and function, as well as a significantly elevated risk for heart disease. Despite this knowledge, we know remarkably little about the temporal molecular changes that occur in the heart following SCI and how these relate to functional decline. In the present study, we addressed this shortcoming by combining bulk RNA sequencing (RNA-seq) of left ventricle (LV) tissue with matching in vivo cardiac function assessments (i.e., pressure-volume loops obtained via LV catheterization) from the same animals. We studied rats at either the acute (1 and 3d post-SCI) or chronic (12wk post-SCI) stage of SCI to establish temporal patterns and compared findings to sham-injured rats. We found that SCI induces marked, time-dependent changes in cardiac gene expression and function. Acute (1-3d) and chronic (12w) SCI display distinct, often opposing transcriptomic signatures, with thousands of genes differentially expressed versus SHAM. Acute SCI is characterized by suppressed immune, inflammatory, cell cycle, and stress-response pathways with altered metabolism. Chronic SCI shows upregulated immune signaling, impaired oxidative phosphorylation, extracellular matrix remodeling, and stress responses. Functionally, cardiac systolic dysfunction occurs early post-SCI and persists to the chronic phase. Reduced systolic function is strongly correlated with changes in immune, hypoxia, and cholesterol-related genes at the acute timepoints and with immune and hormone-signaling pathways at the chronic timepoint. Collectively, our data provide novel insight into the cardiac transcriptome post-SCI and identify the molecular pathways that most strongly correlate with functional decline.