Inflammation and Innate Immune Activation During Ex‐Vivo Heart Perfusion
Bibliographic record
Abstract
Introduction Heart transplantation remains the standard treatment for advanced heart failure. However, waiting lists for donor heart continue to rise all over the world due to the discrepancy between the demand and supply of suitable organs. Ex‐vivo heart perfusion (EVHP) has been proposed as a means improving heart preservation and expanding the donor pool. The clinically available EVHP performs in non‐working mode (NWM). Alternatively, EVHP in working mode (WM) may be better in terms of function assessment and preservation. Objectives The generation of circulating mediators of inflammation during EVHP has not been previously investigated. We hypothesized that inflammatory mediators will be activated during EVHP and that the inflammatory response would play a role in declining of donor heart function. Methods The procured porcine hearts were perfused ex vivo in a beating state for 12 hours (normothermic, whole blood‐based perfusate, no steroids) on a custom EVHP apparatus. Group 1 hearts (n=9) were perfused in a working mode (left atrial pressure=6 mmHg, heart rate=100 beats/minutes) for the entire EVHP interval. Group 2 hearts (n=6) were briefly transitioned into a working mode at hours T1, T5, and T11 for inflammatory and functional assessment, but were otherwise perfused in a non‐working mode (left atrial pressure=0 mmHg). In vivo hearts (n=4) without perfusion were treated as baseline control. Cardiac functional parameters were compared between two perfusion modes groups. The pro‐inflammatory cytokine levels in the perfusate and myocardial tissue were measured by ELISA and western blot and compared between two groups. Results Myocardial function declined over time but the function parameters were better preserved in WM (T11 cardiac index (mL/minute/gram): WM=6.9±1.0 vs NWM=2.0±1.2, p=0.02; LV stroke work (mm Hg·mL): WM=1012.5±245.7 vs NWM=303.4±121.6, p=0.03). The perfusate concentration of pro‐inflammatory cytokines TNF‐α, IL‐6, IL‐8, IL‐1α, IL‐1β, IL‐18 increased significantly during the 12‐hour perfusion interval (p<0.05), but were not significantly different between WM and NWM groups. The IL‐6 and TNF‐α increased in the left ventricular tissue after perfusion compared to baseline myocardial samples (p<0.05), with no significant difference between WM and NWM. Conclusions A significant pro‐inflammatory cytokine response is generated during prolonged EVHP in the perfusate and left ventricular tissue, independent of perfusion mode. The inflammatory responses may play role in declining of cardiac function. Further studies are warranted to elucidate the stimulants, consequences of inflammatory responses (I.E. on energy metabolism), and methods to mitigate these effects. Support or Funding Information Canadian National Transplant Research Program, Canadian Institute of Health Research Grant
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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) | 0.003 | 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".