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We investigated the extent, biologic characterization, phenotypic specificity, and possible regulation of a β1-adrenergic receptor-linked (β1-AR-linked) gene signaling network (β1-GSN) involved in left ventricular (LV) eccentric pathologic remodeling. A 430-member β1-GSN was identified by mRNA expression in transgenic mice overexpressing human β1-ARs or from literature curation, which exhibited opposite directional behavior in interventricular septum endomyocardial biopsies taken from patients with beta-blocker-treated, reverse remodeled dilated cardiomyopathies. With reverse remodeling, the major biologic categories and percentage of the dominant directional change were as follows: metabolic (19.3%, 81% upregulated); gene regulation (14.9%, 78% upregulated); extracellular matrix/fibrosis (9.1%, 92% downregulated); and cell homeostasis (13.3%, 60% upregulated). Regarding the comparison of β1-GSN categories with expression from 19,243 nonnetwork genes, phenotypic selection for major β1-GSN categories was exhibited for LV end systolic volume (contractility measure), ejection fraction (remodeling index), and pulmonary wedge pressure (wall tension surrogate), beginning at 3 months and persisting to study completion at 12 months. In addition, 121 lncRNAs were identified as possibly involved in cis-acting regulation of β1-GSN members. We conclude that an extensive 430-member gene network downstream from the β1-AR is involved in pathologic ventricular remodeling, with metabolic genes as the most prevalent category.

Background: In dilated cardiomyopathies (DCMs) changes in expression of protein-coding genes are associated with reverse remodeling, and these changes can be regulated by microRNAs (miRs). We tested the general hypothesis that dynamic changes in myocardial miR expression are predictive of β-blocker-associated reverse remodeling., Methods: Forty-three idiopathic DCM patients (mean left ventricular ejection fraction 0.24 ± 0.09) were treated with β-blockers. Serial ventriculography and endomyocardial biopsies were performed at baseline, and after 3 and 12 months of treatment. Changes in RT-PCR (candidate miRs) or array-measured miRs were compared based on the presence (R) or absence (NR) of a reverse-remodeling response, and a miR-mRNA-function pathway analysis (PA) was performed., Results: At 3 months, 2 candidate miRs were selectively changed in Rs, decreases in miR-208a-3p and miR-591. PA revealed changes in miR-mRNA interactions predictive of decreased apoptosis and myocardial cell death. At 12 months, 5 miRs exhibited selective changes in Rs (decreases in miR-208a-3p, -208b-3p, 21-5p, and 199a-5p; increase in miR-1-3p). PA predicted decreases in apoptosis, cardiac myocyte cell death, hypertrophy, and heart failure, with increases in contractile and overall cardiac functions., Conclusions: In DCMs, myocardial miRs predict the time-dependent reverse-remodeling response to β-blocker treatment, and likely regulate the expression of remodeling-associated miRs., Trial Registration: ClinicalTrials.gov NCT01798992., Funding: NIH 2R01 HL48013, 1R01 HL71118 (Bristow, PI); sponsored research agreements from Glaxo-SmithKline and AstraZeneca (Bristow, PI); NIH P20 HL101435 (Lowes, Port multi-PD/PI); sponsored research agreement from Miragen Therapeutics (Port, PI)., Competing Interests: C.C. Sucharov, J.D. Port, and M.R. Bristow have stock (each less than 0.1% of total outstanding shares) in Miragen Therapeutics, and M.R. Bristow is member of the Miragen Scientific Advisory Board.