{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T01:17:49Z","timestamp":1792977469947,"version":"4.5.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017445","name":"Science Fund for Distinguished Young Scholars of Shandong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017445","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019446","name":"Medical and Health Science and Technology Development Project of Shandong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019446","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Major depressive disorder (MDD) and cardiovascular diseases (CVD) are mutually amplifying global health burdens, yet the causal directions and immune-determined molecular substructures that link MDD to myocardial infarction (MI) and heart failure (HF) remain poorly resolved.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bidirectional two-sample Mendelian randomization (MR) was applied to large-scale GWAS (1.35 million MDD; 361 K MI; 977 K HF) followed by replication in 11,004 NHANES 2005\u20132020 participants using restricted cubic splines and multivariable logistic regression. Multi-cohort transcriptomics (peripheral blood microarray n = 447; in-house RNA-seq n = 14; left-ventricular tissue from dilated cardiomyopathy (DCM) patients (n = 332) were integrated to identify MDD-driven expression signatures. LASSO regression, CIBERSORT, ssGSEA, consensus clustering and GSVA were employed to derive diagnostic gene panels and immune endotypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR analyses provided genetic evidence consistent with a directional effect of MDD on MI (IVW \u03b2 = 0.01, P = 4.6 \u00d7 10\u207b\n                      <jats:sup>6<\/jats:sup>\n                      ) and HF (IVW \u03b2 = 0.19, P = 1.3 \u00d7 10\u207b\n                      <jats:sup>6<\/jats:sup>\n                      ) without reverse causation. Depression (PHQ-9 \u2265 10) has a dose-dependent nonlinear association with MI and HF (P&amp;lt;0.0001), with adjusted odds ratios (OR) of 1.80 (95% CI: 1.07-3.05) and 2.41 (95% CI: 1.45-4.00), respectively. A total of 202 MDD-related genes were identified through integrated transcriptomic analysis. After cross validation with the MI\/HF dataset, six robust biomarkers (\n                      <jats:italic>TMEM43<\/jats:italic>\n                      ,\n                      <jats:italic>C1orf174<\/jats:italic>\n                      ,\n                      <jats:italic>L3MBTL4<\/jats:italic>\n                      ,\n                      <jats:italic>OR52N4<\/jats:italic>\n                      ,\n                      <jats:italic>SLC25A20<\/jats:italic>\n                      ,\n                      <jats:italic>MISP3<\/jats:italic>\n                      ) were screened. Risk-score models discriminated MI (AUC = 0.90\u20131.00) and HF (AUC = 0.95) in peripheral blood, but HF discrimination in cardiac tissue was modest (AUC = 0.60). Consensus clustering on 184 MDD-correlated genes stratified each CVD into two reproducible subtypes: a \u201chomeostatic\/pro-fibrotic\u201d cluster enriched for ribosomal and cell-cycle pathways and an \u201cinflammatory-metabolic\u201d cluster characterized by NF-\u03baB, TNF-\u03b1, IL-6, complement and coagulation activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Genetic, epidemiological, and multi-omic evidence supports a\u00a0directional association between MDD and increased risk of MI and HF. We\u00a0deliver reproducible blood-based gene panels and immune endotypes that dissect biologically distinct MDD-CVD substructures, offering actionable targets for precision immunomodulatory therapy in cardio-depressive comorbidity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1727699","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T06:40:29Z","timestamp":1769668829000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Mendelian randomization and transcriptome analysis reveal depression-driven regulatory patterns of the immune microenvironment in myocardial infarction and heart failure"],"prefix":"10.3389","volume":"17","author":[{"given":"Zihao","family":"Zhou","sequence":"first","affiliation":[{"name":"School of Life Sciences, Jining Medical University","place":["Rizhao, 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