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This Review synthesizes epidemiologic evidence, summarizes the major mechanisms through which psychological and psychiatric factors may influence cardiovascular function, and focuses on key signaling pathways within the PCIN, including BDNF, PROK/PKR, MAPK, 5-HT/5-HT2A-R, and NLRP3 inflammasome pathways, which may mediate bidirectional brain–heart communication and mental disorder–CVD comorbidity.