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A variety of secreted factors from multiple organs\/tissues (proteins, nucleic acids and lipids) have been implicated in facilitating organ cross\u2010talk that may contribute to the development of multimorbidity. Secreted proteins have received the most attention, with the greatest body of research related to factors released from adipose tissue (adipokines), followed by skeletal muscle (myokines). To date, there have been fewer studies on proteins released from the heart (cardiokines) implicated with organ cross\u2010talk. Early evidence for the secretion of cardiac\u2010specific factors facilitating organ cross\u2010talk came in the form of natriuretic peptides which are secreted via the classical endoplasmic reticulum\u2013Golgi pathway. More recently, studies in cardiomyocyte\u2010specific genetic mouse models have revealed cardiac\u2010initiated organ cross\u2010talk. Cardiomyocyte\u2010specific modulation of microRNAs (miR\u2010208a and miR\u201023\u201027\u201024 cluster) and proteins such as the mediator complex subunit 13 (MED13), G\u2010protein\u2010coupled receptor kinase 2 (GRK2), mutant \u03b1\u2010myosin heavy\u2010chain (\u03b1MHC), ubiquitin\u2010like modifier\u2010activating enzyme (ATG7), oestrogen receptor alpha (ER\u03b1) and fibroblast growth factor 21 (FGF21) have resulted in metabolic and renal phenotypes. These studies have implicated a variety of factors which can be secreted via the classical pathway or via non\u2010classical mechanisms including the release of extracellular vesicles. Cross\u2010talk between the heart and the brain has also been described (e.g. via miR\u20101 and an emerging concept, interoception: detection of internal neural signals). Here we summarize these studies taking into consideration that factors may be secreted in both settings of health and in disease.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16528-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1113\/jp287400","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T06:45:56Z","timestamp":1738305956000},"page":"6572-6600","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Heart\u2010derived factors and organ cross\u2010talk in settings of health and disease: new knowledge and clinical opportunities for multimorbidity"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6407-632X","authenticated-orcid":false,"given":"Melodi G.","family":"Sen","sequence":"first","affiliation":[{"name":"Baker Heart and Diabetes Institute  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1610-3000","authenticated-orcid":false,"given":"Roger","family":"Chooi","sequence":"additional","affiliation":[{"name":"Baker Heart and Diabetes Institute  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8316-1066","authenticated-orcid":false,"given":"Julie R.","family":"McMullen","sequence":"additional","affiliation":[{"name":"Baker Heart and Diabetes Institute  Melbourne Victoria Australia"},{"name":"Heart Research Institute  Newtown New South Wales Australia"},{"name":"Monash Alfred Baker Centre for 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