Multimorbidity increases susceptibility to myocardial injury via dysregulated cardiac macrophage activation and the development of a cardiomyopathy phenotype
Bibliographic record
Abstract
Abstract Background This study investigated mechanisms underlying the association between multimorbidity (MM) and increased susceptibility to myocardial injury and organ failure following cardiac surgery. Methods K-means clustering was performed using data from five cardiac surgery cohorts with high prevalence of MM. The resulting Clusters were explored using single nuclei RNA sequencing (snRNAseq) of atrial biopsies collected at surgery from one of the study cohorts. Mechanisms were validated using causal inference methods in UK Biobank and aged cardiomyocytes exposed to ischaemia reperfusion injury (IRI) in vitro . Results K-means clustering using pre-surgery biomarkers of haematopoietic, cardiac, metabolic, liver, and renal disease identified two MM clusters. Cluster 1, characterised by higher baseline troponin I and interleukin-6 values, iron deficiency, anaemia, and immunological ageing, demonstrated significantly higher rates of myocardial injury (66% versus 52%) and multiple organ dysfunction (81% versus 57%) relative to Cluster 2. snRNAseq data from Cluster 1 demonstrated inflammageing characterised by enrichment for cardiomyopathy networks in cardiomyocytes, NF-kB and IL2 in monocyte derived macrophages (MDM), and pro-fibrotic and redox inflammation signaling in tissue resident macrophages (TRM). Cluster 2 showed enrichment for translation, type 1 inflammation, and immune activation in cardiomyocytes, and acute-phase immune responses in MDM and TRM. In UK Biobank, genetic modification of genes differentially expressed between clusters altered 90-day mortality post-surgery. Gene silencing of key regulatory nodes enriched in Cluster 1 cardiomyocytes including PDE1c (Ca 2+ homeostasis) and SNAI1 (TGFβ-SMAD), attenuated cardiomyocyte de-differentiation and susceptibility to IRI in vitro . Conclusions Inflammageing associated cardiomyocyte dedifferentiation represents a target for myocardial protection in people with MM. Study Schematic MaRACAS, the Observational Case Control Study to Identify the Role of MV and MV Derived Micro-RNA in Post CArdiac Surgery AKI, REVAKI-2, Revatio® for the Prevention of AKI -2 trial, REDWASH, Red Cell washing for the Prevention of Organ Injury after Cardiac Surgery Trial, OBCARD, the Case Control Study to Identify the Role of Epigenetic Regulation of Genes Responsible for Energy Metabolism and Mitochondrial Function in the Obesity Paradox in Cardiac Surgery, COPTIC, the Coagulation and Platelet Laboratory Testing in Cardiac Surgery study.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".