{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T13:07:03Z","timestamp":1778936823640,"version":"3.51.4"},"reference-count":60,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":130,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cardiovascular Therapeutics"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Heart failure (HF) is a critical condition characterized by the heart\u2032s inability to pump blood effectively, leading to significant morbidity and mortality. Inflammation and metabolic disturbances play key roles in its progression. This study is aimed at elucidating the causal relationships between inflammatory cytokines, metabolites, and HF using Mendelian randomization (MR).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A three\u2010step, two\u2010sample MR analysis was performed using genetic data from genome\u2010wide association studies. The study included data on 91 inflammatory cytokines, over 1400 metabolites, and HF cases from the FinnGen project, comprising 29,672 cases and 382,509 controls. Single\u2010nucleotide polymorphisms with significant associations (\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 1 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      ) were selected as instrumental variables. The inverse variance\u2013weighted method was the primary analytical tool, supplemented by MR\u2010Egger, weighted median, simple mode, and weighted mode methods. Heterogeneity was assessed with Cochran\u2032s\n                      <jats:italic>Q<\/jats:italic>\n                      test, and pleiotropy was evaluated using MR\u2010Egger intercept and MR\u2010PRESSO. Robustness was confirmed through leave\u2010one\u2010out sensitivity analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The MR analysis identified eight inflammatory cytokines significantly associated with HF risk. Elevated levels of three cytokines (FGF19, MMP\u20101, and TNF\u2010\n                      <jats:italic>\u03b2<\/jats:italic>\n                      ) were linked to an increased risk of HF, whereas five cytokines (DNER, IL\u201010, uPA, TNFSF12, and LIFR) were linked to a decreased risk of HF. Additionally, 12 metabolites were found to be significantly associated with HF, with 6 (2PY, BCG, NAG\/NAGal, X\u201024801, X\u201021283, and X\u201022776) enhancing risk and 6 (PC, 3HL, 2\u2010BG, X\u201023659, X\u201025422, and X\u201024546) showing protective effects. Notably, mediation analysis indicated that certain metabolites, X\u201022776, mediated the effect of uPA on HF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides novel genetic evidence supporting the causal role of inflammatory cytokines in HF and highlights the mediating role of metabolites. These findings offer new insights into the pathogenesis of HF and suggest potential biomarkers and therapeutic targets for its prevention and treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/cdr\/6340671","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:13:00Z","timestamp":1778501580000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Evidence Linking Inflammatory Cytokines and Blood Metabolites to Heart Failure 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