Abstract 572: Deletion of iNOS in Mice Overexpressing Calcineurin Improves Cardiovascular Phenotype
Bibliographic record
Abstract
Previous studies have reported that overexpression of calcineurin (CN) in mouse myocytes produces cardiac hypertrophy followed by dilation, systolic dysfunction, cardiac fibrosis and sudden cardiac death due to high degree heart block and eventual asystole. In a number of cell types, calcineurin mediates iNOS expression. Since overexpression of iNOS in mice generates phenotypes quite similar to that seen in calcineurin mice, we assessed the hypothesis that deletion of iNOS (iNOS null mice) would improve the cardiovascular phenotype of mice transgenically overexpressing CN. Methods: A complementary breeding program generated CN/iNOS −/− mice. These were compared to CN mice. Results: Similarities exist between the two groups of mice: indices of cardiac hypertrophy as assessed by echocardiography (septal and posterior wall dimension and LV mass index) and heart weight/body weight index were similar. The histologic extent of fibrosis (Masson trichrome) was similar, as was the frequency of episodes of ventricular tachycardia on telemetry monitoring at 14 weeks. However, significant differences were also noted. CN/iNOS −/− mice had significantly greater survival (Kaplan Meier p<0.0003). Fifty percent of CN mice die by 19 weeks compared to 34 weeks in CN/iNOS −/− mice. In addition, at 14 weeks CN/iNOS −/− mice had fewer episodes of high degree AV block; significant and substantial improvements in metrics of systolic wall motion (fractional shortening, LV internal dimension at the end of systole); smaller serum concentrations of TNFα; less interstitial apoptosis as assessed by Tunnel staining; and increased responsiveness of contractility to β1 stimulation with isoproterenol. Activation of iNOS in CN transgenic mice contributes to the cardiovascular phenotypes. Conclusion: While iNOS deletion almost doubles survival and improves most metrics of cardiovascular performance at 14 weeks, it delays, but does not abrogate the consequences of overexpressing calcineurin.
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
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".