Left ventricular contractile function is critically dependent on descending sympathetic control and can be restored with minocycline after spinal cord injury
Bibliographic record
Abstract
OBJECTIVE We 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/METHOD Male 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, dPdt max ‐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. RESULTS Animals treated with minocycline showed significantly higher max systolic pressure (p=0.008; ) and dPdt max (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; dPdt max ‐EDV: 102.4 ± 16.4 vs. 41.6 ± 18.4; p<0.001). CONCLUSIONS Minocycline 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 Information JW 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).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".