Genetics-Informed Mapping Identifies a CRIM1-Associated Endocardial Inflammatory Remodeling State in Acute Myocardial Infarction.

The endocardium exhibited the most prominent infarction-associated increase in TWAS-anchored program activity among cardiac cell types in AMI.

• Analysis integrated a meta-transcriptome-wide association study (TWAS) with a human cardiac single-nucleus RNA-sequencing atlas containing 11 individuals (5 AMI and 6 donor).
• The endocardium showed expansion of program-high states compared to donor controls.
• Higher CytoTRACE scores were observed in the AMI endocardium, suggesting altered developmental or transcriptional state.
• Composite program states were defined by global score quartiles.

A consensus 5-gene panel (RPS8, PLEC, CFDP1, CRIM1, TNS2) was identified for discriminating endocardial transcriptional states in AMI.

• Among 2163 AMI endocardial nuclei from 5 patients, the classifier identified 364 Endo_LTS (endocardial low-transcriptional-state) and 751 Endo_HTS (endocardial high-transcriptional-state) nuclei.
• 1048 Endo_MTS (mid-transcriptional-state) nuclei were excluded from the classification analysis.
• Pooled out-of-fold ROC-AUCs ranged from 0.665 to 0.831 using 5-fold leave-1-patient-out cross-validation.
• The panel was evaluated as a fixed 5-gene set for nucleus-level state discrimination within the AMI endocardium.

The 5-gene panel showed discriminatory value in an independent peripheral-blood AMI-versus-control cohort.

• Discriminatory performance was demonstrated beyond the single-nucleus RNA-seq dataset in peripheral blood samples.
• This suggests the endocardial transcriptional program may have systemic or blood-accessible correlates.
• The panel was originally derived from endocardial single-nucleus data and tested in a complementary cohort design.

CRIM1 silencing in hypoxia-treated hiPSC-derived endocardial endothelial-like cells attenuated multiple inflammatory, metabolic, and structural markers.

• CRIM1 knockdown reduced expression of ACTA2/alpha-SMA, vimentin, LDHA, CCL2, and VEGFA.
• CRIM1 silencing partially restored CD31 expression, a marker of endothelial identity.
• TGF-β remained elevated after CRIM1 silencing, arguing against a simple linear regulatory model.
• Experiments used human induced pluripotent stem cell (hiPSC)-derived endocardial endothelial-like cells under hypoxia treatment as the functional model.

Persistent TGF-β elevation after CRIM1 silencing indicates that CRIM1 does not operate through a simple linear regulatory pathway in endocardial remodeling.

• TGF-β levels were not attenuated by CRIM1 knockdown despite reductions in other remodeling markers.
• The authors conclude this finding 'argues against a simple linear regulatory model and indicates that further mechanistic validation is required.'
• This suggests the remodeling program involves parallel or compensatory pathways beyond CRIM1.

The study used a meta-TWAS integrated with single-nucleus RNA sequencing to identify genetics-informed cellular programs linking genetic AMI risk to specific cardiac cell states.

• The atlas comprised 11 individuals: 5 AMI and 6 donor controls.
• TWAS anchoring was used to identify genes whose genetically predicted expression associates with AMI risk and to map these to cell-type-specific programs.
• This genetics-informed approach was designed to identify cellular contexts linking genetic risk to disease, which was described as previously unclear.