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A quarter of hospitalized patients with CAP experience a major adverse cardiac event (MACE), raising their mortality by four to five times compared with pneumonia alone. Patients with CAP continue to face a significantly greater risk of MACE and cardiovascular-associated death during convalescence. However, the reasons responsible for this remain unclear. To elucidate the molecular mechanism(s) of\n                    <jats:italic>Spn<\/jats:italic>\n                    -induced MACE in convalescence, a mouse model of\n                    <jats:italic>Spn<\/jats:italic>\n                    infection and antibiotic rescue was employed. A marked decline in ejection fraction persisting at least 3\u2009weeks after bacterial eradication with antibiotics was observed. Evidence of enduring cardiac injury was observed at the molecular, biochemical and histology levels. Blood analysis from patients with invasive pneumococcal disease confirmed unresolved inflammation in these individuals. Here we mechanistically identified that S100A8\/A9-TLR4-NLRP3-mediated unresolved inflammation drives cardiac pathologies in\n                    <jats:italic>Spn<\/jats:italic>\n                    convalescent mice. This inflammation was central to the cardiac pathology because interventions with broad-spectrum immunosuppressive hydrocortisone or specific inhibitors of S100A9 (paquinimod) essentially rescued the\n                    <jats:italic>Spn<\/jats:italic>\n                    -induced cardiac pathologies. These results provide critical preclinical data and rationale for a clinical investigation into immunosuppressive interventions for managing\n                    <jats:italic>Spn<\/jats:italic>\n                    -mediated cardiac pathologies in convalescence.\n                  <\/jats:p>","DOI":"10.1038\/s12276-025-01552-8","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T08:42:38Z","timestamp":1760085758000},"page":"2344-2363","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["S100A8\/9-NLRP3-mediated chronic unresolved inflammation drives cardiac pathologies following invasive pneumococcal disease"],"prefix":"10.1038","volume":"57","author":[{"given":"Sultan","family":"Tousif","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Minassian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baldeep","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prachi","family":"Umbarkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvind Singh","family":"Bhati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Mohasin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Erdmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palaniappan","family":"Sethu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8542-4069","authenticated-orcid":false,"given":"Carlos J.","family":"Orihuela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hind","family":"Lal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"1552_CR1","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1161\/CIRCULATIONAHA.111.040766","volume":"125","author":"VF Corrales-Medina","year":"2012","unstructured":"Corrales-Medina, V. 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