{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:58:10Z","timestamp":1785437890427,"version":"3.56.0"},"reference-count":74,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,7,31]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Cardiomyopathies frequently arise from rare, highly penetrant coding variants with variable clinical expressivity. Genome-wide association studies (GWAS) suggest significant polygenic contributions to cardiovascular diseases, including cardiomyopathy. Most GWAS loci map to poorly conserved noncoding regions, requiring human genome context for experimental validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We created engineered heart tissues (EHTs) from human induced pluripotent stem cell-derived cardiomyocytes and primary cardiac fibroblasts. We assayed single-cell gene expression and chromatin accessibility to generate comprehensive genome-wide regulatory maps. Open chromatin regions were integrated with chromatin contact information and used to fine-map cardiomyopathy GWAS single-nucleotide polymorphisms. Single-nucleotide polymorphisms and their associated open chromatin regions were assessed using reporter assays, genome editing, and expression profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      EHT Single-cell RNA-seq recapitulated major cardiac cell types, with advanced cardiomyocyte maturation compared with monolayer human induced pluripotent stem cell cardiomyocytes. More than 400\u2009000 open chromatin regions were resolved to cell types and assayed for transcription factor motifs. Functional fine-mapping of GWAS loci prioritized 5817 variants, and reporter assays validated allele-specific enhancer activity. We identified an intergenic chr3p25.1 locus harboring significant GWAS signals from both dilated cardiomyopathy and left ventricular ejection fraction. Several of these variants lie in open chromatin regions participating in long-range chromatin interactions with\n                      <jats:italic toggle=\"yes\">SLC6A6<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">GRIP2<\/jats:italic>\n                      . Haplotype-resolved and synthetic reporter assays confirmed enhancer activity and narrowed candidate single-nucleotide polymorphisms. CRISPR-deletion of this region reduced expression of both\n                      <jats:italic toggle=\"yes\">SLC6A6<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">GRIP2<\/jats:italic>\n                      , indicating the enhancer regulates the expression of multiple genes. EHTs with the enhancer deletion displayed markedly reduced contractile function, confirming that this enhancer region contributes to myocardial function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>EHTs are an experimentally tractable platform for testing the function of noncoding variants as modifiers of cardiomyopathy. Variants fine-mapped from cardiomyopathies using EHT regulatory maps have functional consequences and provide a set of prioritized sites to advance the study of polygenic heart failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.327506","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T09:00:20Z","timestamp":1782723620000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Engineered Heart Tissues Facilitate Noncoding Variant Studies in Cardiomyopathy"],"prefix":"10.1161","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7085-4533","authenticated-orcid":true,"given":"Zachary T.","family":"Weber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9117-2227","authenticated-orcid":true,"given":"Tanner O.","family":"Monroe","sequence":"additional","affiliation":[{"name":"Now with Cardiovascular Research Institute, Icahn School of Medicine at Mt. Sinai, New York, NY (T.O.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory","family":"Holgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis G.","family":"Thornburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0016-3091","authenticated-orcid":true,"given":"Isabella M.","family":"Salamone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6617-752X","authenticated-orcid":true,"given":"Ivana A.","family":"Chychula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Karthik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7627-7119","authenticated-orcid":true,"given":"Dominic E.","family":"Fullenkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0455-2983","authenticated-orcid":true,"given":"Megan J.","family":"Puckelwartz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5955-6738","authenticated-orcid":true,"given":"Xuanyao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1221-719X","authenticated-orcid":true,"given":"Elizabeth 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