title: Therapeutic Molecular Phenotype of β-Blocker-Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy.
abstract: BACKGROUND
  When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal-adult/contractile protein, natriuretic peptide, SR-Ca(2+)-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 β1-adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes.
  
  
  RESULTS
  Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β1-selective), metoprolol+doxazosin (β1/α1), or carvedilol (β1/β2/α1). 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 ≥0.08 at 12 months or by ≥0.05 at 3 months (Δ left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6, ATP2A2, PLN, RYR2, ADRA1A, ADRB1, MYL3, PDFKM, PDHX, and CPT1B. All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β1-adrenergic signaling.
  
  
  CONCLUSIONS
  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-adult paradigm but may be because of reversal of gene expression controlled by a β1-adrenergic receptor gene network.
  
  
  BACKGROUND
  URL: www.clinicaltrials.gov. Unique Identifier: NCT01798992.
authors: 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, Little Rock (C.D.B.).
authors: David P
authors: DP
authors: Kao
authors: 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, Little Rock (C.D.B.).
authors: Brian D
authors: BD
authors: Lowes
authors: 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, Little Rock (C.D.B.).
authors: Edward M
authors: EM
authors: Gilbert
authors: 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, Little Rock (C.D.B.).
authors: Wayne
authors: W
authors: Minobe
authors: 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, Little Rock (C.D.B.).
authors: L Elaine
authors: LE
authors: Epperson
authors: 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, Little Rock (C.D.B.).
authors: Leslie K
authors: LK
authors: Meyer
authors: 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, Little Rock (C.D.B.).
authors: Debra A
authors: DA
authors: Ferguson
authors: 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, Little Rock (C.D.B.).
authors: Ann Kirkpatrick
authors: AK
authors: Volkman
authors: 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, Little Rock (C.D.B.).
authors: Ronald
authors: R
authors: Zolty
authors: 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, Little Rock (C.D.B.).
authors: C Douglas
authors: CD
authors: Borg
authors: 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, Little Rock (C.D.B.).
authors: Robert A
authors: RA
authors: Quaife
authors: 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, Little Rock (C.D.B.). Michael.Bristow@ucdenver.edu.
authors: Michael R
authors: MR
authors: Bristow
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000096:biosynthesis*; D013318:Stroke Volume / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D009124:Muscle Proteins
keywords: beta-adrenergic blocking agents; cardiomyopathy, dilated; gene expression; myocardial remodeling, ventricular; myocardium
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