Myocardial iron depletion exacerbates end-stage heart failure by promoting adverse remodeling and worsening mitochondrial function
Notice bibliographique
Résumé
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)
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».