David P Kao1, Brian D Lowes1, Edward M Gilbert1, Wayne Minobe1, L Elaine Epperson1, Leslie K Meyer1, Debra A Ferguson1, Ann Kirkpatrick Volkman1, Ronald Zolty1, C Douglas Borg1, Robert A Quaife1, Michael R Bristow2. 1. 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.). 2. 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.
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. METHODS AND 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. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique Identifier: NCT01798992.
RCT Entities:
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. METHODS AND 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. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique Identifier: NCT01798992.
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