{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T07:30:42Z","timestamp":1770967842800,"version":"3.50.1"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Heart failure (HF) is a highly prevalent disease affecting roughly 7 million Americans. A transcriptome-wide analysis revealed <jats:italic>RYR1<\/jats:italic> upregulation in HF patients with severe pulmonary hypertension. Therefore, we aimed to further characterize the role of <jats:italic>RYR1<\/jats:italic> in HF progression and mortality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a mouse model of HF, expression of <jats:italic>Ryr1<\/jats:italic> was compared in cardiac pulmonary, and vascular tissue between HF and control mice. Candidate single nucleotide polymorphisms (SNPs) in the <jats:italic>RYR1<\/jats:italic> gene region were identified, including variants affecting <jats:italic>RYR1<\/jats:italic> expression in relevant tissue types. A Cox proportional hazard model was used to analyze genetic associations of candidate SNPs with all-cause mortality in HF patients. An exploratory analysis assessed significantly associated SNPs with risk of HF and arrhythmia development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the preclinical HF model, left ventricular expression of <jats:italic>Ryr1<\/jats:italic> was increased compared to control (fold change\u2009=\u20092.08; <jats:italic>P<\/jats:italic>\u2009=\u20090.01). In 327 HF patients, decreased mortality risk was associated with two <jats:italic>RYR1<\/jats:italic> SNPs: rs12974674 (HR: 0.59; 95% CI: 0.40\u20130.87; <jats:italic>P<\/jats:italic>\u2009=\u20090.007) and rs2915950 (HR: 0.62, 95% CI: 0.43\u20130.88; <jats:italic>P<\/jats:italic>\u2009=\u20090.008). Based on eQTL data, these SNPs were associated with decreased <jats:italic>RYR1<\/jats:italic> expression in vascular tissue. Two missense variants, in linkage disequilibrium with rs2915950 (rs2915952 and rs2071089) were significantly associated with decreased mortality risk (<jats:italic>P<\/jats:italic>\u2009=\u20090.03) and decreased risk of atrial fibrillation\/flutter (OR: 0.66, 95% CI: 0.44\u20130.96; <jats:italic>P<\/jats:italic>\u2009=\u20090.03 and OR: 0.67, 95% CI: 0.45\u20130.98; <jats:italic>P<\/jats:italic>\u2009=\u20090.04, respectively). Survival associations with these SNPs were replicated in HF patients self-identifying as Black in the UK Biobank, and the arrhythmia associations were replicated in the overall UK Biobank population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Increased <jats:italic>RYR1<\/jats:italic> expression may contribute to HF progression, potentially through the mechanisms associated with calcium handling and arrhythmia development. Our findings suggest that <jats:italic>RYR1<\/jats:italic> should be further studied as a potential therapeutic target for reducing HF-related mortality.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2025.1529114","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T05:19:26Z","timestamp":1740115166000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Genetic variation in RYR1 is associated with heart failure progression and mortality in a diverse patient population"],"prefix":"10.3389","volume":"12","author":[{"given":"Leonardo A.","family":"Guerra","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christelle","family":"Lteif","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yimei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rylie M.","family":"Flohr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandra C.","family":"Nogueira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian E.","family":"Gawronski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julio D.","family":"Duarte","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e347","DOI":"10.1161\/CIR.0000000000001209","article-title":"2024 Heart disease and stroke statistics: a report of US and global data from the American Heart Association","volume":"149","author":"Martin","year":"2024","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","first-page":"5107","DOI":"10.1038\/s41467-018-07606-y","article-title":"Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation","volume":"9","author":"Pyun","year":"2018","journal-title":"Nat Commun"},{"key":"B3","doi-asserted-by":"publisher","first-page":"5091","DOI":"10.1113\/JP280425","article-title":"Distinct features of calcium handling and beta-adrenergic sensitivity in heart failure with preserved versus reduced ejection fraction","volume":"598","author":"Kilfoil","year":"2020","journal-title":"J Physiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"H443","DOI":"10.1152\/ajpheart.00594.2022","article-title":"Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype","volume":"324","author":"Li","year":"2023","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"78","DOI":"10.3389\/fphys.2015.00078","article-title":"Abnormal calcium homeostasis in heart failure with preserved ejection fraction is related to both reduced contractile function and incomplete relaxation: an electromechanically detailed biophysical modeling study","volume":"6","author":"Adeniran","year":"2015","journal-title":"Front Physiol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.coph.2017.03.005","article-title":"Cardiomyocyte ca(2+) homeostasis as a therapeutic target in heart failure with reduced and preserved ejection fraction","volume":"33","author":"Peana","year":"2017","journal-title":"Curr Opin Pharmacol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1007\/5584_2017_106","article-title":"New insights in cardiac calcium handling and excitation-contraction coupling","volume":"1067","author":"Gambardella","year":"2018","journal-title":"Adv Exp Med Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1038\/nrcardio.2012.145","article-title":"Altered sarcoplasmic reticulum calcium cycling\u2013targets for heart failure therapy","volume":"9","author":"Kho","year":"2012","journal-title":"Nat Rev Cardiol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.3389\/fphys.2018.01380","article-title":"Calcium in the pathophysiology of atrial fibrillation and heart failure","volume":"9","author":"Denham","year":"2018","journal-title":"Front Physiol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.ygeno.2014.12.002","article-title":"Li M, consortium M. 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