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Risk factors such as obesity and hypertension contribute to cardiac inflammation, metabolic defects, and pathological remodelling that impair ventricular filling in diastole. Titin based stiffness is a main determinant of diastolic function and can be adjusted by the splicing regulator RNA binding motif protein 20 (RBM20). Inhibition of RBM20 using antisense oligonucleotides (ASOs) induces expression of compliant titin isoforms, which reduce stiffness. However, dose finding and documenting utility in primarily cardiometabolic disease remains challenging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Here, we optimized RBM20-ASO dosing in a HFpEF mouse model that closely mimics human disease, characterized by metabolic syndrome and comorbidities, but without primary defects in titin or RBM20. Partial inhibition of RBM20 (\u223c50%) selectively increased compliant titin isoforms, improving diastolic function while preserving systolic performance. This intervention reduced left ventricular stiffness, enhanced relaxation, and mitigated cardiac hypertrophy, despite ongoing systemic comorbidities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings demonstrate that targeting titin stiffness with Rbm20-ASOs can serve as an alternative or adjunctive therapeutic strategy for HFpEF to restore cardiac function and prevent further organ damage. The approach may offer benefits even in the presence of phenotypic heterogeneity and unresolved systemic comorbidities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf171","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T11:57:56Z","timestamp":1758628676000},"page":"2027-2041","source":"Crossref","is-referenced-by-count":9,"title":["Rbm20 antisense oligonucleotides alleviate diastolic dysfunction in a mouse model of cardiometabolic heart failure (HFpEF)"],"prefix":"10.1093","volume":"121","author":[{"given":"Mei","family":"Methawasin","sequence":"first","affiliation":[{"name":"Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona , 1656 E Mabel ST, MRB 340, Tucson, AZ 85724 ,","place":["USA"]},{"name":"Medical Pharmacology and Physiology, University of Missouri , MA415 Medical Science Building, Columbia, MO 65212 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Meinke","sequence":"additional","affiliation":[{"name":"Translational Cardiology and Functional Genomics, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association , Robert R\u00f6ssle Str. 10, Berlin 13125 ,","place":["Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin , Berlin 10785 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H","family":"Radke","sequence":"additional","affiliation":[{"name":"Translational Cardiology and Functional Genomics, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association , Robert R\u00f6ssle Str. 10, Berlin 13125 ,","place":["Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin , Berlin 10785 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrie P","family":"Farman","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona , 1656 E Mabel ST, MRB 340, Tucson, AZ 85724 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaynab","family":"Hourani","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona , 1656 E Mabel ST, MRB 340, Tucson, AZ 85724 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"3rd","given":"John E","family":"Smith","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona , 1656 E Mabel ST, MRB 340, Tucson, AZ 85724 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Animal and Dairy Sciences, University of Wisconsin-Madison , Madison, WI 53706 ,","place":["USA"]},{"name":"Cardiovascular Research Center, University of Wisconsin-Madison , Madison, WI 53706 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9516-407X","authenticated-orcid":false,"given":"Henk","family":"Granzier","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona , 1656 E Mabel ST, MRB 340, Tucson, AZ 85724 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1788-3172","authenticated-orcid":false,"given":"Michael","family":"Gotthardt","sequence":"additional","affiliation":[{"name":"Translational Cardiology and Functional Genomics, Max Delbr\u00fcck Center for Molecular Medicine in the Helmholtz Association , Robert R\u00f6ssle Str. 10, Berlin 13125 ,","place":["Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin , Berlin 10785 ,","place":["Germany"]},{"name":"Department of Cardiology, Charit\u00e9 Universit\u00e4tsmedizin Berlin , Berlin 10115 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"2025102811280953500_cvaf171-B1","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1093\/cvr\/cvaa217","article-title":"Metabolic inflammation in heart failure with preserved ejection fraction","volume":"117","author":"Schiattarella","year":"2021","journal-title":"Cardiovasc 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