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Among aetiological subtypes, embolic strokes of undetermined source (ESUS) remain particularly challenging in terms of aetiology, management, and prognosis. The aim of this study was to identify distinct clinical phenotypes of IS with a specific emphasis on delineating the clinical landscape of ESUS. We analysed 1,533 patients with acute IS enrolled in the Perugia Stroke Registry (2005\u20132019). Latent class analysis (LCA) was used to identify clinical phenotypes based on demographics, vascular risk factors, stroke severity, and aetiology. A secondary LCA was performed among ESUS patients to explore sub-phenotypic heterogeneity. The primary composite outcome included all-cause death, cardiac events, and venous thromboembolism during hospital stay. Secondary outcomes included individual components of the primary outcome, haemorrhagic transformation (HT), and poor functional recovery (defined as mRS worsening from 0\u20132 to 3\u20136). Three phenotypes emerged using LCA, as follows: (i) non-cardioembolic (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009761), predominantly male, high cardiovascular burden, moderate severity; (ii) cardioembolic (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009557), older, mostly female, high prevalence of atrial fibrillation, more severe strokes; and (iii) ESUS (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009215), younger, fewer comorbidities, heterogeneous severity. The cardioembolic class showed increased risk of the composite outcome (OR 2.18; 95% CI 1.40\u20133.50), all-cause death (OR 1.73; 95% CI 1.04\u20133.01), cardiac events (OR 2.62; 95% CI 1.42\u20135.34), HT (OR 1.65; 95% CI 0.99\u20132.88), and a trend towards poor functional recovery (OR 1.32; 95% CI 0.92\u20131.91), compared to ESUS. Among ESUS, three sub-phenotypes were identified: \u2018Middle-age Dysmetabolic\u2019, \u2018Cardiovascular Elderly\u2019, and \u2018Low cardiovascular Young\u2019. Compared to low cardiovascular young, both middle-age dysmetabolic and cardiovascular elderly phenotypes were associated with increased risk of the composite outcome (OR 1.52; 95% CI 1.18\u20132.83 and OR 1.56; 95% CI 1.21\u20132.77, respectively). Acute IS is clinically heterogeneous; ESUS differs from cardioembolic strokes in management and short-term outcomes. The three ESUS sub-phenotypes highlight the need for more personalised strategies in diagnosis and secondary prevention.\n                  <\/jats:p>","DOI":"10.1007\/s11739-026-04420-z","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:34:44Z","timestamp":1781073284000},"page":"2521-2533","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical phenotypes of ischaemic stroke patients and early cardiovascular complications: a latent class analysis from the Perugia Stroke Registry"],"prefix":"10.1007","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7119-1254","authenticated-orcid":false,"given":"Andrea Galeazzo","family":"Rigutini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Caso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Bucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giulia","family":"Mosconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Cancelloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Alberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Venti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria Leone","family":"de Magistris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bufi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Urbini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allegra","family":"Gaboni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Marvardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Rapuano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Becattini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory Y. 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Caso received honoraria as a member of the speaker bureau of Boehringer Ingelheim, Bayer, and Daiichi Sankyo. She received honoraria as consultant or advisory board member of Boehringer Ingelheim, Bayer, Daiichi Sankyo, and Pfizer. Becattini received honoraria as a member of the speaker bureau of Bristol Meyer Squibb, Daiichi Sankyo, and Bayer. G.Y.H.L. has been a consultant and speaker for BMS\/Pfizer, Boehringer Ingelheim, Anthos, and Daiichi Sankyo. All the disclosures happened outside the submitted work. He is NIHR Senior Investigator and co-PI of the AFFIRMO project on multimorbidity in AF, TARGET project on digital twins for personalised management of atrial fibrillation and stroke and ARISTOTELES which are all funded by the EU's Horizon Europe Research and Innovation program. The other authors did not report conflicts of interest to disclose outside of the submitted work.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethical approval was waived as this retrospective study collected anonymous data.","order":2,"name":"Ethics","label":"Ethical approval and informed consent","group":{"name":"EthicsHeading","label":"Declarations"}}]}}