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To elucidate whether sex and prevalent cardio-metabolic co-morbidities affect ICI-induced cardiotoxicity, we randomized 17-month-old male and female mice to receive control diet (CON) or high-fat diet (HFD)\u2009+\u2009L-NAME\u2014a well-established mouse model of cardio-metabolic co-morbidities\u2014for 17\u00a0weeks (<jats:italic>n<\/jats:italic>\u2009=\u20095\u20137), and evaluated markers of T-cell function in the spleen. As expected, HFD\u2009+\u2009L-NAME significantly increased body- and heart weight, and serum cholesterol levels, and caused no systolic dysfunction, however, led to diastolic dysfunction, cardiomyocyte hypertrophy, and increased fibrosis only in males compared to corresponding CON. Western blot analyses of splenic immune checkpoint protein levels showed differential expression depending on sex and prevalent cardio-metabolic co-morbidities, suggesting T-cell exhaustion in both sexes on HFD\u2009+\u2009L-NAME, but more pronounced in males. In a sub-study with a similar setup, we tested cardiotoxic manifestations of ICI by treating mice with anti-PD-1 monoclonal antibody (ICI) for the last 2\u00a0weeks of diet administration (<jats:italic>n<\/jats:italic>\u2009=\u20095\u20137). After 2\u00a0weeks of ICI treatment, cardiac systolic functions significantly decreased in CON, but not in HFD\u2009+\u2009L-NAME groups of both sexes compared to baseline (before ICI administration). In conclusion, in this exploratory study using aged mice, we describe for the first time that ICI-related systolic dysfunction is diminished in both sexes when obesity and hypercholesterolemia are present, possibly due to obesity-related T-cell exhaustion.<\/jats:p>","DOI":"10.1007\/s00395-024-01088-4","type":"journal-article","created":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T17:32:40Z","timestamp":1731087160000},"page":"207-223","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Effects of sex and obesity on immune checkpoint inhibition-related cardiac systolic dysfunction in aged mice"],"prefix":"10.1007","volume":"120","author":[{"given":"Nabil V.","family":"Sayour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1niel","family":"Kucsera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayham R.","family":"Alhaddad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikt\u00f3ria \u00c9.","family":"T\u00f3th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s G.","family":"Gergely","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsombor I.","family":"Heged\u0171s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rk E.","family":"Jakab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Ferdinandy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2758-0784","authenticated-orcid":false,"given":"Zolt\u00e1n V.","family":"Varga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,8]]},"reference":[{"key":"1088_CR1","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/j.immuni.2020.04.014","volume":"52","author":"J-C Beltra","year":"2020","unstructured":"Beltra J-C, Manne S, Abdel-Hakeem MS, Kurachi M, Giles JR, Chen Z, Casella V, Ngiow SF, Khan O, Huang YJ, Yan P, Nzingha K, Xu W, Amaravadi RK, Xu X, Karakousis GC, Mitchell TC, Schuchter LM, Huang AC, Wherry EJ (2020) Developmental relationships of four exhausted CD8(+) T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. 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