{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T12:13:37Z","timestamp":1781180017921,"version":"3.54.1"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              Pathogenic variants in the\n              <jats:italic toggle=\"yes\">lamin A\/C<\/jats:italic>\n              (\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              ) gene cause an aggressive form of dilated cardiomyopathy (DCM), marked by higher rates of advanced conduction disease, malignant ventricular tachyarrhythmias, and advanced heart failure compared with other causes of nonischemic cardiomyopathy. However, the mechanisms that drive the development and progression of\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              DCM are incompletely understood.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              To identify proteins and biological pathways associated with likely pathogenic\/pathogenic\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              variants, we measured \u22483000 plasma proteins using the OLINK platform in a genetic DCM cohort consisting of\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              (n=41) and sarcomeric (n=18) DCM, along with phenotype-negative individuals from family-based cascade screening (n=55) with (\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              , n=16; sarcomere, n=12) or without the family variant (genotype negative, n=27).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We identified several novel proteins associated with\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              DCM compared with sarcomeric DCM, including EDA2R (ectodysplasin A2 receptor; per log2 fold change in relative protein abundance, \u03b2=3.0;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =4\u00d710\n              <jats:sup>\u2212<\/jats:sup>\n              \u00b3) and\n              <jats:italic toggle=\"yes\">MYL4<\/jats:italic>\n              (myosin light chain 4; \u03b2=2.32;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =5\u00d710\n              <jats:sup>\u2212<\/jats:sup>\n              \u00b3). Among the proteins associated with\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              DCM, 26 showed concordant differential gene expression from single-cell sequencing in cardiomyocytes from myocardial biopsies in advanced\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              heart failure compared with control hearts (false discovery rate, &lt;5%). We performed principal component analyses on these 26 proteins to identify proteomic signatures of\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              DCM and found the first principal component to be associated with left ventricular ejection fraction and complete heart block in the\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              DCM cohort. Six proteins\u2014EDA2R, MYL4, CRIM1 (cysteine-rich transmembrane bone morphogenetic protein regulator 1), TPR (translocated promoter region), FSTL3 (follistatin-like 3), and NFYA (nuclear transcription factor Y)\u2014were associated with\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              pathogenic variants across phenotype-negative individuals, DCM, and their respective cardiomyocyte RNA expression profiles in advanced heart failure.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              Proteomic profiling in individuals with likely pathogenic\/pathogenic\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              variants illuminated integral pathways across the spectrum of\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              DCM. These findings may help advance genotype-driven biomarker discovery and tailored therapeutic development in\n              <jats:italic toggle=\"yes\">LMNA<\/jats:italic>\n              DCM.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.124.004924","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T05:00:12Z","timestamp":1749790812000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Plasma Proteomics Reveals Dysregulated Pathways Across the Spectrum\n            <i>LMNA<\/i>\n            Cardiomyopathy"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3657-6082","authenticated-orcid":true,"given":"Usman A.","family":"Tahir","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (U.A.T., J.L.B., G.T., L.F.)."},{"name":"Harvard Medical School, Boston, MA (U.A.T., D. Reichart, C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Reichart","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA (U.A.T., D. Reichart, C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."},{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, MA (D. Reichart, A.P., J.E.M., D. Roy, J.P., C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8029-8358","authenticated-orcid":true,"given":"Anisha","family":"Purohit","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, MA (D. Reichart, A.P., J.E.M., D. Roy, J.P., C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob L.","family":"Barber","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (U.A.T., J.L.B., G.T., L.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2540-6005","authenticated-orcid":true,"given":"Gaurav","family":"Tiwari","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (U.A.T., J.L.B., G.T., L.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-527X","authenticated-orcid":true,"given":"Laurie","family":"Farrell","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (U.A.T., J.L.B., G.T., L.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0380-9263","authenticated-orcid":true,"given":"Julia E.","family":"Marine","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, MA (D. Reichart, A.P., J.E.M., D. Roy, J.P., C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0978-1664","authenticated-orcid":true,"given":"Darius","family":"Roy","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, MA (D. Reichart, A.P., J.E.M., D. Roy, J.P., C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5086-2002","authenticated-orcid":true,"given":"Joshen","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, MA (D. Reichart, A.P., J.E.M., D. Roy, J.P., C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine G.","family":"Ireland","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA (U.A.T., D. Reichart, C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."},{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, MA (D. Reichart, A.P., J.E.M., D. Roy, J.P., C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7334-7924","authenticated-orcid":true,"given":"Carolyn Y.","family":"Ho","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA (U.A.T., D. Reichart, C.G.I., C.Y.H., C.E.S., R.E.G., N.K.L.)."},{"name":"Division of Cardiovascular Medicine, Brigham and Women\u2019s Hospital, Boston, MA (D. Reichart, A.P., J.E.M., D. 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