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bioRxiv · 10.64898/2026.03.10.710912

Immune Transcriptional Signatures Across Human Cardiomyopathy Subtypes: A Multi-Cohort Integrative Computational Analysis

Adegboyega, B. B.·Okorie, B.·Courage, P.
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Abstract

BackgroundHeart failure, arrhythmia, and sudden cardiac death are common outcomes of cardiomyopathies, which are molecularly diverse heart muscle disorders marked by structural and functional myocardial dysfunction. The lack of sensitive molecular biomarkers that precede overt physiological deterioration makes early diagnosis difficult despite advancements in imaging and clinical classification. The immune transcriptional landscape across cardiomyopathy subtypes is still poorly understood, despite growing evidence linking both innate and adaptive immune dysregulation, such as macrophage activation and T-cell and inflammatory cytokine networks, as active contributors to myocardial remodelling and disease progression. MethodsWe performed a multi-cohort integrative transcriptomic analysis of 1,068 cardiac tissue samples from five publicly available GEO datasets (GSE57338, GSE5406, GSE36961, GSE141910, GSE47495) spanning dilated, ischemic, hypertrophic, and peripartum cardiomyopathy. Using a fully scripted R and Python pipeline, we conducted differential expression analysis (limma), immune cell deconvolution (xCell), pathway enrichment (clusterProfiler), weighted gene co-expression network analysis (WGCNA), and regularised machine learning classification (LASSO, Random Forest). Cross-dataset validation was performed in two independent cohorts on different microarray platforms. ResultsDifferential expression analysis identified 43 primary DEGs (FDR < 0.05, |log2FC| > 1.0), revealing a coherent immune-fibrotic program characterized by loss of anti-inflammatory macrophage markers (CD163, VSIG4), complement dysregulation (FCN3), innate interferon activation (IFI44L, IFIT2), and ECM remodelling (ASPN, SFRP4, LUM). xCell deconvolution identified coordinated depletion of adaptive immune populations in failing myocardium. WGCNA defined a fibrosis hub module (brown; CTSK, SULF1, SFRP4) and an immune collapse module (turquoise; MYD88, TNFRSF1A, LAPTM5). A nine-gene LASSO classifier achieved a cross-validated AUC of 0.986, with HMOX2 as the top-discriminating feature, implicating ferroptosis in cardiomyocyte death. Cross-platform validation in an independent HCM cohort (GSE36961) demonstrated a directional concordance of 34.9%. ConclusionsThis study defines a reproducible immune-fibrotic transcriptional signature of human cardiomyopathy, nominates HMOX2 and ferroptosis as central pathomechanisms, and provides a validated nine-gene biomarker panel for future translational investigation.

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Adegboyega, B. B., Okorie, B., Courage, P.. 2026-03-13. Immune Transcriptional Signatures Across Human Cardiomyopathy Subtypes: A Multi-Cohort Integrative Computational Analysis. https://doi.org/10.64898/2026.03.10.710912

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