Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy. (April 2015)

• Record Type: Journal Article
• Authors: Kao, David P.; Lowes, Brian D.; Gilbert, Edward M.; Minobe, Wayne; Epperson, L. Elaine; Meyer, Leslie K.; Ferguson, Debra A.; Volkman, Ann Kirkpatrick; Zolty, Ronald; Borg, C. Douglas; Quaife, Robert A.; Bristow, Michael R.
• Is Part Of: Circulation. Volume 8:Number 2(2015)
• Publication Date: 2015-04
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.114.000767
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal–adult/contractile protein, natriuretic peptide, SR-Ca<sup>2+</sup>-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 β<sub>1</sub>-adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes.</p> </sec> <sec> <title>Methods and Results—</title> <p>Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β<sub>1-</sub>selective), metoprolol+doxazosin (β<sub>1</sub>/α<sub>1</sub>), or carvedilol (β<sub>1</sub>/β<sub>2</sub>/α<sub>1</sub>). 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 <italic>NPPA</italic> and <italic>NPPB</italic> and increases in <italic>MYH6</italic>, <italic>ATP2A2</italic>, <italic>PLN</italic>, <italic>RYR2</italic>, <italic>ADRA1A</italic>, <italic>ADRB1</italic>, <italic>MYL3</italic>, <italic>PDFKM</italic>, <italic>PDHX</italic>, and <italic>CPT1B</italic>. All except <italic>PDHX</italic> involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β<sub>1</sub>-adrenergic signaling.</p> </sec> <sec> <title>Conclusions—</title> <p>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 β<sub>1</sub>-adrenergic receptor gene network.</p> </sec> <sec> <title>Clinical Trial Registration—</title> <p>URL: <ext-link ext-link-type="uri" xlink:href="www.clinicaltrials.gov" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">www.clinicaltrials.gov</ext-link>. Unique Identifier: NCT01798992.</p> </sec> </abstract>