Myocardial iron depletion exacerbates end-stage heart failure by promoting adverse remodeling and worsening mitochondrial function
Bibliographic record
Abstract
Abstract Background Heart failure (HF) is highly associated with systemic iron deficiency (ID) yet its association with myocardial iron depletion (MID) remains barely unveiled. Similarly, it has been unclear whether and how MID deteriorates the progression to advanced HF. Furthermore, neither the underlying pathophysiology nor the negative impact of unmet iron availability to the failing heart, at the molecular level, is elucidated. Purpose We aim to integrate clinical information and experimental data from human explanted heart tissues: 1) to establish the defining criterion of MID in advanced HF population; 2) to recapitulate the pathophysiological role MID plays in the progression of HF; and 3) to identify novel HF molecular signatures or potential cures to correct MID status underestimated in the failing hearts. Methods Adult failing hearts (N=143), including dilated (n=76) and ischemic (n=67) cardiomyopathies, and non-failing control hearts (NFC, N=46) were collected per Human Explanted Heart Program. Iron levels were measured directly from both ventricles, which were re-evaluated by cardiac magnetic resonance imaging (CMR) mapping sequences (e.g. T1, T2*, etc.). Mitochondrial metabolic, reactive oxygen species (ROS) and ROS-scavenging profiles were assessed spectrophotometrically. Tissue remodeling and ultrastructure characteristics were captured by confocal and electron microscopies respectively. Meanwhile, the patients' clinical profiles were integrated into the analysis of molecular regulatory mechanism. Results Myocardial iron content in LV was significantly lower in HF versus NFC [121.4 (88.1–150.3) vs. 137.4 (109.2–165.9) μg/g dry weight, p<0.05], while both RVs showed no difference. With a cutoff of 86.1 μg/g iron level in LV, it screened ∼23% HF patients with MID (HF-MID). Compared with non-MID HF patients, depleted iron store weakly correlated with systemic hemoglobin concentration (r=−0.27, p=0.13) but highly with T2* and magnetic susceptibility proving CMR as an exceptional surrogate for non-invasive diagnosis. And it was noted that MID independently predicted ominous endpoints as NYHA grade increased and LV dysfunctions worsened (all p<0.05). Cardiac respiratory chain enzymatic activities from complex I to V (except for COX III) were further suppressed in the iron-deficient failing hearts, indicating altered myocardial metabolism and excessive ROS production. Moreover, the whole anti-ROS defense were severely impaired, consistent with remarkably inverse tissue remodeling and ultrastructure disintegrity in HF-MID. Mechanistically, two iron-regulatory proteins (IRP-1/2) and following iron trafficking pathways were inactivated possibly determine the restricted iron availability to advanced failing hearts. Conclusions MID worsens HF progression primarily mediated by mitochondrial dysfunction and collapsed oxidative protection in LV, independently predicting an inferior prognosis. CMR demonstrates clinical potential to monitor MID. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Canadian Institutes for Health Research (CIHR); Heart & Stroke Foundation (HSF)
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".