125 Post-genomic atrial and ventricular myocardial proteome of end-stage lamin heart disease: a prospective clinical trial
Notice bibliographique
Résumé
<h3>Background</h3> Lamins A/C (encoded by the LMNA gene) can lead to dilated cardiomyopathy (DCM). LMNA DCM to be ranked clinically as one of the most dreaded forms of DCM because of its high propensity for sudden cardiac death and advanced heart failure. However, lamin heart disease (LHD) remains to be poorly understood. Thus, this study sought to undertake proteomic analysis of myocardial tissue to explore the postgenomic phenotype of end-stage lamin heart disease. <h3>Methods</h3> This prospective clinical trial (NCT03860454) enrolled consecutive patients with end-stage LHD (LMNA-group, n=7) and ischaemic DCM (ICM-group, n=7) who were undergoing heart transplantation. For comparison, samples from healthy unused control donor hearts (CTRL, n=6) collected from the University of Sydney Heart Bank were also included. Samples were obtained from left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV) and interventricular septum (IVS). Liquid chromatography combined with mass-spectrometry (MS) was used to quantify protein concentrations. We compared protein concentrations in cardiac samples between LMNA and ICM groups. Proteins were considered differentially abundant if two simultaneous criteria were met: (1) there was a 1.5-fold increase/decrease, and (2) the p-value passed the correction for multiple testing at a false discovery rate of 0.01 (i.e., q-value<0.05). Given the slight differences in MS methodologies, only qualitative comparisons were made with the CTRL group. Gene ontology (GO) enrichment analysis explored the related biological processes. Biological processes, cellular components and molecular function GO categories with >2 members were considered. <h3>Results</h3> Participant characteristics are presented in Table 1. 4,247 proteins were identified in LMNA and ICM samples, of which 633 were differentially abundant in LA, 39 in LV, 181 in RA, 52 in RV, and 85 in IVS (Table 2). The top 25 differentially abundant proteins ranked by q-value are presented using volcano plots in Figure 1. Abundance of lamin A/C was reduced but lamin B (LMNB) increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV, with lamin B being absent in CTRL septal samples. Across all tissue samples, ECM proteins levels were differently abundant with pro-fibrotic fibrillar proteins being found at higher levels. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM while sarcomeric proteins such as titin and cardiac myosin heavy chain were generally reduced in RA/LA of LMNA. In RV/LV, glycolysis enzymes and sarcoendoplasmic reticulum calcium-binding proteins appeared to be decreased. Protein expression profiling and GO enrichment analysis revealed sarcopenia, extracellular matrix (ECM) remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. For LV, box plots comparing the intensities of the top 25 differentially abundant proteins between LMNA and ICM based on q-value, and the top 20 enriched biological processes are presented in Figure 2. <h3>Conclusion</h3> LHD is a biventricular and biatrial disease, characterized by sarcopenia, aberrant metabolism, and ECM remodeling. LMNB and transthyretin were unexpectedly abundant in the atria and ventricles respectively of patients with end-stage lamin heart disease potentially hinting to the possibility of compensatory responses. <h3>Conflict of Interest</h3> None
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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) | 0,000 | 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 tête enseignante, 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 ».