Left ventricular contractile function is critically dependent on descending sympathetic control and can be restored with minocycline after spinal cord injury

Abstract

OBJECTIVEWe and others have shown that individuals with spinal cord injury (SCI) have significantly impaired cardiac function, which likely explains this population's increased odds of developing heart disease. We recently determined that pressure and volume generating capacity are both reduced following SCI and that only volumetric indices could be restored with passive rehabilitation (i.e. passive hind‐limb cycling). Conversely, we were able to partially restore pressure generating capacity using Dobutamine, directly showing that sympathetic input to the heart is critical for the maintenance of left ventricular pressure generating capacity. To this end, we sought to determine if minocycline, which has previously been shown to preserve descending supraspinal motor connections after SCI, could restore pressure generating capacity of the heart after severe spinal cord contusion in the rodent.DESIGN/METHODMale Wistar rats (n=11) underwent T3 contusion SCI and were randomly stratified into either a treated (minocycline; n=5) or vehicle control (n=6). Minocycline was given intraperitoneally at one‐hour post injury (90mg/kg) and then every 12 hours for 14 days (45mg/kg). At two months post injury animals were anesthetized with urethane and ventilated via tracheotomy. A left ventricular pressure volume catheter was inserted via a right carotid, closed chest approach and placed into the left ventricle under pressure guidance. Basal left ventricular function was immediately assessed, followed by preload manipulation and subsequent determination of load‐independent (i.e. Ees, PRSW, dPdtmax‐EDV) function using inferior vena cava occlusions. Between group differences in load‐dependent and load‐independent function were assessed using independent samples t‐tests with significance offset at p<0.05.RESULTSAnimals treated with minocycline showed significantly higher max systolic pressure (p=0.008; Figure) and dPdtmax (p=0.040) compared to vehicle. No differences in heart rate were observed between groups. Load‐independent left ventricular function was significantly higher with treatment of minocycline compared to vehicle (Ees: 1.36 ± 0.46 vs. 0.72 ± 0.35; p=0.028; dPdtmax‐EDV: 102.4 ± 16.4 vs. 41.6 ± 18.4; p<0.001).CONCLUSIONSMinocycline is currently in Phase III clinical trial for the improvement of motor function after SCI. Our data provide clear evidence that minocycline is able to improve load dependent and independent left ventricular function after SCI, likely due to increased sparing of descending sympatho‐excitatory pathways to the heart and adrenal medulla. Collectively, these results demonstrate a clear line of treatment that is able to restore pressure generating capacity of the left ventricle in this population.Support or Funding InformationJW Squair is supported by: Frederick Banting and Charles Best Canada Graduate Scholarship, MD/PhD Studentship from the Canadian Institutes of Health Research, Killam Doctoral Scholarship and Four Year Fellowship from the University of British Columbia. This work was principally supported by the Heart and Stroke Foundation of Canada (CR West) and a seed grant from the International Collaboration on Repair Discoveries (AV Krassioukov).