{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T20:10:22Z","timestamp":1777320622039,"version":"3.51.4"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2015,4]]},"abstract":"\n Background\u2014<\/jats:title>\n \n When \u03b2-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal\u2013adult\/contractile protein, natriuretic peptide, SR-Ca\n 2+<\/jats:sup>\n -ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal\/adult expression predominance, are thyroid hormone-responsive, and are regulated by \u03b2\n 1<\/jats:sub>\n -adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results\u2014<\/jats:title>\n \n Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24\u00b10.09) were randomized to the adrenergic-receptor blockers metoprolol (\u03b2\n 1-<\/jats:sub>\n selective), metoprolol+doxazosin (\u03b2\n 1<\/jats:sub>\n \/\u03b1\n 1<\/jats:sub>\n ), or carvedilol (\u03b2\n 1<\/jats:sub>\n \/\u03b2\n 2<\/jats:sub>\n \/\u03b1\n 1<\/jats:sub>\n ). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by \u22650.08 at 12 months or by \u22650.05 at 3 months (\u0394 left ventricular ejection fraction, 0.21\u00b10.10). Changes in gene expression in responders versus nonresponders were decreases in\n NPPA<\/jats:italic>\n and\n NPPB<\/jats:italic>\n and increases in\n MYH6<\/jats:italic>\n ,\n ATP2A2<\/jats:italic>\n ,\n PLN<\/jats:italic>\n ,\n RYR2<\/jats:italic>\n ,\n ADRA1A<\/jats:italic>\n ,\n ADRB1<\/jats:italic>\n ,\n MYL3<\/jats:italic>\n ,\n PDFKM<\/jats:italic>\n ,\n PDHX<\/jats:italic>\n , and\n CPT1B<\/jats:italic>\n . All except\n PDHX<\/jats:italic>\n involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of \u03b2\n 1<\/jats:sub>\n -adrenergic signaling.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions\u2014<\/jats:title>\n \n In addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal\u2013adult paradigm but may be because of reversal of gene expression controlled by a \u03b2\n 1<\/jats:sub>\n -adrenergic receptor gene network.\n <\/jats:p>\n <\/jats:sec>\n \n Clinical Trial Registration\u2014<\/jats:title>\n \n URL:\n www.clinicaltrials.gov<\/jats:ext-link>\n . Unique Identifier: NCT01798992.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circgenetics.114.000767","type":"journal-article","created":{"date-parts":[[2015,1,31]],"date-time":"2015-01-31T07:45:30Z","timestamp":1422690330000},"page":"270-283","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["Therapeutic Molecular Phenotype of \u03b2-Blocker\u2013Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy"],"prefix":"10.1161","volume":"8","author":[{"given":"David P.","family":"Kao","sequence":"first","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian D.","family":"Lowes","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward M.","family":"Gilbert","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne","family":"Minobe","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. Elaine","family":"Epperson","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leslie K.","family":"Meyer","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debra A.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann Kirkpatrick","family":"Volkman","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald","family":"Zolty","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. Douglas","family":"Borg","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert A.","family":"Quaife","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R.","family":"Bristow","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology, Department of Medicine, University of Colorado School of Medicine, Aurora (D.P.K., W.M., L.E.E., L.K.M., D.A.F., R.A.Q., M.R.B.); Division of Cardiology, Department of Medicine, University of Nebraska Medical Center, Omaha (B.D.L.); Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City (E.M.G., A.K.V.); Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY (R.Z.); and Heart Clinic of Arkansas,..."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.174287"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119776"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012630"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2006.01.006"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00017.2006"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00067.2011"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.8.1089"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.94.9.2285"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(95)00012-S"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)04440-2"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(97)89342-3"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-199907000-00005"},{"key":"e_1_3_4_14_2","first-page":"11","volume-title":"How to Detect and Handle Outliers","author":"Iglewicz B","year":"1993","unstructured":"Iglewicz B, Hoaglin DC.How to Detect and Handle Outliers. 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