Amlodipine rescues advanced iron overload cardiomyopathy in hemojuvelin knockout murine model: Clinical implications
Bibliographic record
Abstract
Background Iron overload cardiomyopathy (IOC) is a major co-morbidity of genetic hemochromatosis and secondary iron overload with limited therapeutic options. We aim to investigate mechanisms of rescue action of amlodipine in the murine model of iron overload, characterize changes in human cardiac tissue due to IOC, and compare them to the changes in the animal model of IOC. Methods and results As an animal model, we used male hemojuvelin knockout (HJVKO) mice, which lacked hemojuvelin (a co-receptor protein for hepcidin expression). The mice were fed a high-iron diet from 4 weeks to 1 year of age. As a rescue, iron-fed mice received the Ca 2+ channel blocker, amlodipine, from 9 to 12 months. Iron overload resulted in systolic and diastolic dysfunctions and changes in the cardiac tissue similar to the changes in the explanted human heart with IOC. An IOC patient (β-thalassemia) with left-ventricular ejection fraction (LVEF) 25% underwent heart transplantation. The murine model and the explanted heart showed intra-myocyte iron deposition, fibrosis, hypertrophy, oxidative stress, remodeling of Ca 2+ cycling proteins, and metabolic kinases typical of heart failure. Single-myocyte contractility and Ca 2+ release were diminished in the murine model. The amlodipine-treated group exhibited normalization of cellular function and reversed fibrosis, hypertrophy, oxidative stress, and metabolic remodeling. We also report a clinical case of primary hemochromatosis successfully treated with amlodipine. Conclusions The aged HJVKO murine model on the iron-rich diet reproduced many features of the human case of IOC. The use of amlodipine in the murine model and clinical case reversed IOC remodeling, demonstrating that amlodipine is effective adjuvant therapy for IOC.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| 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) | 0.000 | 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 teacher head, 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".