125 Post-genomic atrial and ventricular myocardial proteome of end-stage lamin heart disease: a prospective clinical trial
Bibliographic record
Abstract
Background 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. Methods 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. Results 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. Conclusion 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. Conflict of Interest None
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".