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We investigated 3 biomarkers: periostin, galectin-3, and N-terminal prohormone brain natriuretic peptide and applied a K-means clustering resulting in 3 patient clusters. We subsequently measured left ventricular and right ventricular free wall longitudinal strain in each cluster. We then determined the association between each cluster and time to all-cause mortality compared to N-terminal prohormone brain natriuretic peptide, alone.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The 125 patients with systemic sclerosis included in the study were divided into 3 clusters based on biomarker levels (Cluster 1: N\u2009=\u200975; Cluster 2: N\u2009=\u200939; Cluster 3: N\u2009=\u200911). Compared to Cluster 1, Cluster 2 had only elevated periostin levels whereas Cluster 3 had elevated levels of all 3 serum biomarkers and was characterized by reduced left ventricular and right ventricular free wall longitudinal strain, regionally and globally. When adjusted for age, sex, systemic sclerosis disease duration, and forced vital capacity, patients in Cluster 3 had a HR of 14.42 (95% CI: 4.82, 43.18) for all-cause mortality compared to those in Cluster 1.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>In conclusion, combining N-terminal prohormone brain natriuretic peptide, periostin, and galectin-3 as serum biomarkers enhances risk stratification and sensitivity in detection of cardiac disease in patients with systemic sclerosis. However, before implementation in routine care, further prospective studies must refine biomarker sensitivity, specificity, and accuracy together with optimizing detection strategies and establishing clinical protocols for integration.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0328734","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T17:25:19Z","timestamp":1753982719000},"page":"e0328734","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["A multi-biomarker approach to risk stratification and detection of early cardiac disease in systemic sclerosis"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4745-3766","authenticated-orcid":true,"given":"Justin K.","family":"Lui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"El-Adili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2134-411X","authenticated-orcid":true,"given":"Matthew","family":"Cozzolino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Winburn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin A.","family":"Trojanowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa M.","family":"Gopal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"LaValley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth S.","family":"Klings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea M.","family":"Bujor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"issue":"4","key":"pone.0328734.ref001","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1183\/09031936.00091212","article-title":"High prevalence of occult left heart disease in scleroderma-pulmonary hypertension","volume":"42","author":"BD Fox","year":"2013","journal-title":"Eur Respir J"},{"issue":"23","key":"pone.0328734.ref002","first-page":"05932","article-title":"Role of left ventricular dysfunction in systemic sclerosis-related pulmonary hypertension","author":"JK Lui","year":"2023","journal-title":"Chest"},{"issue":"3","key":"pone.0328734.ref003","first-page":"651","article-title":"Hemodynamic response to oral vasodilator therapy in systemic sclerosis-related pulmonary hypertension","volume":"38","author":"JK Lui","year":"2023","journal-title":"Cardiovasc Drugs Ther"},{"issue":"3","key":"pone.0328734.ref004","doi-asserted-by":"crossref","first-page":"101668","DOI":"10.1016\/j.berh.2021.101668","article-title":"Cardiac involvement in systemic sclerosis: getting to the heart of the matter","volume":"35","author":"C Bruni","year":"2021","journal-title":"Best Pract Res Clin Rheumatol"},{"issue":"12","key":"pone.0328734.ref005","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1093\/eurheartj\/ehv512","article-title":"Left ventricular heart failure and pulmonary hypertension","volume":"37","author":"S Rosenkranz","year":"2016","journal-title":"Eur Heart J"},{"issue":"2","key":"pone.0328734.ref006","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1161\/CIRCULATIONAHA.108.844340","article-title":"Ventricular geometry, strain, and rotational mechanics in pulmonary hypertension","volume":"121","author":"S Puwanant","year":"2010","journal-title":"Circulation"},{"issue":"1","key":"pone.0328734.ref007","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.rdc.2007.12.002","article-title":"The heart in scleroderma","volume":"34","author":"HC Champion","year":"2008","journal-title":"Rheum Dis Clin North Am"},{"issue":"4","key":"pone.0328734.ref008","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/S0889-857X(05)70304-5","article-title":"Cardiac involvement in scleroderma","volume":"22","author":"A Deswal","year":"1996","journal-title":"Rheum Dis Clin North Am"},{"issue":"3","key":"pone.0328734.ref009","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1161\/01.CIR.53.3.483","article-title":"Myocardial lesions of progressive systemic sclerosis. 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