{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T01:48:29Z","timestamp":1789264109153,"version":"build-2803163510"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">ACTA2<\/jats:italic>\n                      pathogenic variants predispose to thoracic aortic disease, and a subset of variants lead to early onset atherosclerotic cardiovascular disease (ASCVD). The molecular pathway linking misfolded SMA (\u03b1-smooth muscle actin) monomers to augmented atherosclerosis\u2013associated smooth muscle cell phenotypic modulation can be modeled in vitro by stably expressing the\n                      <jats:italic toggle=\"yes\">ACTA2<\/jats:italic>\n                      p.R149C variant in\n                      <jats:italic toggle=\"yes\">Acta2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      smooth muscle cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      The Montalcino Aortic Consortium patient registry was used to identify cases with\n                      <jats:italic toggle=\"yes\">ACTA2<\/jats:italic>\n                      pathogenic\/likely pathogenic missense variants. These patients were surveyed, and medical records were reviewed, to identify cases with early onset ASCVD. The variants for these cases, as well as other recurrent\n                      <jats:italic toggle=\"yes\">ACTA2<\/jats:italic>\n                      missense variants, were individually expressed in\n                      <jats:italic toggle=\"yes\">Acta2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      smooth muscle cells, and transcript and protein levels, HSF1 (heat shock factor 1) activation, HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) expression and activity, cholesteryl ester levels, and downstream smooth muscle cell phenotypic modulation were assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Early onset ASCVD included coronary artery disease, peripheral vascular disease, and atherosclerotic plaques identified by imaging in the arch, descending, or abdominal aorta, along with the celiac, iliac, renal, or vertebral arteries. Twelve\n                      <jats:italic toggle=\"yes\">ACTA2<\/jats:italic>\n                      variants were identified to be associated with early onset ASCVD. Early onset ASCVD was correlated with HSF1 activation (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.035), cellular cholesteryl ester levels (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.0031), and having one family member with the specific\n                      <jats:italic toggle=\"yes\">ACTA2<\/jats:italic>\n                      pathogenic variant who had early onset ASCVD (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.0001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Assays assessing the molecular mechanism that leads to early onset ASCVD can identify which\n                      <jats:italic toggle=\"yes\">ACTA2<\/jats:italic>\n                      pathogenic variants will trigger this condition. Ultimately, this information informs precision medical care for individuals with\n                      <jats:italic toggle=\"yes\">ACTA2<\/jats:italic>\n                      pathogenic variants, with the ultimate goal of preventing thoracic aortic disease and ASCVD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005169","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T10:00:14Z","timestamp":1769421614000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["<i>ACTA2<\/i>\n                    Pathogenic Variants Activating Heat Shock Factor 1 and Increasing Cholesterol Biosynthesis in Smooth Muscle Cells Predispose to Early Onset Atherosclerosis"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2000-2815","authenticated-orcid":true,"given":"Maura 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