P5997GLP-1(28-36) prevents progression of ischemic heart failure in mice
Bibliographic record
Abstract
Abstract Background Glucagon-like peptide-1 (GLP-1), its metabolites and related drugs have demonstrated cardioprotective benefits in several animal models of cardiovascular disease (CVD) and select clinical trials. Indeed, large cardiovascular outcome trials (CVOT) of GLP-1 analogs showed significant reductions in major adverse cardiovascular events (MACE). However, smaller studies in patients with heart failure (HF) (e.g. FIGHT), and secondary analyses of some CVOT (e.g. LEADER), have suggested that the cardiovascular benefits of GLP-1 analogs may be muted in select patients. Speculating on how this may be due to undesirable increases in heart rate caused by activation of sinoatrial GLP-1 receptors (Glp1r), we have explored the Glp1r-independent cardioprotective actions of GLP-1(28–36), a neutral endopeptidase (NEP)-derived metabolite of GLP-1. We have shown that the cardioprotective effects of GLP-1(28–36) are mediated by mitochondrial trifunctional protein-α (MTPα)-dependent metabolic shift from fatty acid- to glucose oxidation in coronary vascular cells. As metabolic perturbations are believed to contribute to the pathophysiology of HF, we hypothesized that treatment with GLP-1(28–36) may have beneficial effects on this condition. Purpose To evaluate if treatment with GLP-1(28–36) can prevent onset of HF and/or reverse established HF in a post-MI mouse model. Methods and results Permanent LAD ligation was performed in 10–12wk old male C57BL/6J wild-type mice (wt). Immediately post-MI, mice were assigned to receive either GLP-1(28–36) or scrambled peptide [Scram(28–36)] at 18.5nmol/kg/d (N=30/group) subcutaneously (s.c.) via osmotic mini-pumps for 4wk. Although, treatment with GLP-1(28–36) did not improve post-MI survival, triphenyltetrazolium chloride (TTC)-stained hearts 28d post-MI reveal smaller infarct size in GLP-1(28–36)- vs. Scram(28–36)-treated mice (35.3±1.9% vs. 41.2±1.7%, N=12–15/group, P<0.05). Echocardiography at 28d post-MI showed improved LVEF in mice treated with GLP-1(2–36) (30.1±2.3% vs. 24.2±3.7%, N=12–15/group, P<0.05). Similarly, treatment with GLP-1(28–36) reduced heart/body weight ratio (7.9±0.3 vs. 8.8±0.4 mg/g, N=12–15/group, P<0.05). Next, we tested if GLP-1(28–36) might reverse ischemic HF in this model. After permanent LAD ligation of 10–12wk old male wt mice, only those with echocardiography-defined LVEF between 20–35% at 28d post-MI were randomized to treatment with GLP-1(28–36) or Scram(28–36) [18.5nmol/kg/d (N=15/group)] via s.c. mini-pumps for 4wk. Echocardiography at 56d post-MI (i.e. 28d post-treatment start) revealed that GLP-1(28–36) preserved LV function with no deterioration in LVEF vs. Scram(28–36)-treated controls [−3.1±4.9% vs. −22.8±4%, relative change, N=15/group, P<0.001]. Conclusion In a post-MI mouse model of HF, treatment with GLP-1(28–36) prevents progression to HF, and preserves LV function after the development of established HF. Acknowledgement/Funding This study was funded by a Fellowship from Ted Rogers Centre for Heart Research and a Project Grant from Heart and Stroke Foundation, Canada
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".