Abstract 56: Mast Cell Chymase: An Angiotensin II (Ang II)-Independent Therapeutic Target in the Post-Myocardial Infarction Heart
Bibliographic record
Abstract
Mast cell chymase (CHY), a multifunctional protease with Ang II-forming activity, garnered interest due to the success of angiotensin converting enzyme inhibitors (ACEi) in the treatment of heart failure. The VALIANT trial evaluated the contribution of this alternate Ang II pathway by adding an AT 1 Ang II receptor blocker (ARB) to an ACEi post-myocardial infarction (MI), but the combination showed no additional benefit, suggesting CHY was unimportant post-MI. However, the role of CHY, independent of its Ang II-forming activity, remains unaddressed. To test this, we first re-evaluated the role of CHY-generated Ang II by blocking the effects of ACE+CHY-generated Ang II using an ACEi+ARB+AT 2 receptor blocker (PD122139) combination (AAA), and compared this to ACEi monotherapy in wild-type (WT) mice. We then addressed the Ang II-independent role of CHY by comparing these therapies in chymase (MMCP-4)-deficient (KO) vs WT mice. WT and KO mice (N=10-20) underwent sham or MI (90-min ischemia-reperfusion) surgery, and were treated daily with vehicle (Veh), ACEi, or AAA 24h post reperfusion. After 14 days, echocardiographic and hemodynamic analyses indicated no significant inter-genotype differences in sham animals. In post-MI WT mice, ACEi vs Veh resulted in improved ejection fraction (EF) (34±1.8% vs 28±1.7%; p<0.05) and reduced LV end-diastolic dimension (LVEDD) (4.2+0.09 mm vs 4.7±0.1 mm; p<0.05). However, AAA did not result in further improvements in either parameter as compared to ACEi, suggesting that CHY-generated Ang II is unimportant post-MI, confirming VALIANT. While the initial (24-h post-MI) infarct sizes were similar between genotypes (WT: 63±5% vs KO: 65±2% infarct as percent of area at risk; p=0.6), EF was superior in KO vs WT mice in all treatment groups (36±3% vs 28±2% (Veh); 47±3% vs 34±2% (ACEi); 49±3% vs 36±3% (AAA); p<0.05). Further, LV dilatation was also more pronounced in WT mice (LVEDD: 4.7±0.4 mm, WT-Veh vs 4.3±0.5 mm, KO-Veh; p<0.05). ACEi decreased mean arterial pressure post-MI (p<0.01), but not differentially in WT vs KO (Veh: 70±5 mmHg vs 66±3 mmHg; p=0.47; ACEi: 48±3.7 mmHg vs 38±4.8 mmHg; N=6−10; p=0.1). Thus, we conclude that CHY, independent of Ang II, is a potential therapeutic target for the treatment of the post-MI heart.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".