Published Online
on May 15, 2009

A more recent version of this article appeared on August 1, 2009

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Original Article

Cardiac Resynchronization Therapy Corrects Dyssynchrony–induced Regional Gene Expression Changes on a Genomic Level

Andreas S. Barth¹; Takeshi Aiba; Victoria Halperin; Deborah DiSilvestre; Khalid Chakir; Carlo Colantuoni; Richard S. Tunin; Victoria Lea Dimaano; Wayne Yu; Theodore P. Abraham; David A. Kass and Gordon F. Tomaselli

Johns Hopkins University, Baltimore, MD

¹ E-mail: abarth3{at}jhmi.edu

Background—Cardiac electromechanical dyssynchrony causes regional disparities in workload, oxygen consumption, and myocardial perfusion within the left ventricle. We hypothesized that such dyssynchrony also induces region-specific alterations in the myocardial transcriptome that are corrected by cardiac resynchronization (CRT).

Methods and Results—Adult dogs underwent left bundle branch ablation (LBBB) and right atrial pacing at 200 bpm for either 6 weeks (dyssynchronous heart failure, DHF, n=12) or 3 weeks followed by 3 weeks of resynchronization by bi-ventricular pacing at the same pacing rate (CRT, n=10). Control animals without LBBB were not paced (NF, n=13). At 6 weeks, RNA was isolated from the anterior and lateral LV walls and hybridized onto canine-specific 44K microarrays. Echocardiographically, CRT led to a significant decrease in the dyssynchrony index, while DHF and CRT animals had a comparable degree of LV dysfunction. In DHF, changes in gene expression were primarily observed in the anterior LV, resulting in increased regional heterogeneity of gene expression within the left ventricle. Dyssynchrony-induced expression changes in 1050 transcripts were reversed by CRT to levels of NF hearts (false discovery rate <5%). CRT remodeled transcripts with metabolic and cell signaling function and greatly reduced regional heterogeneity of gene expression compared with DHF.

Conclusions—Our results demonstrate a profound effect of electromechanical dyssynchrony on the regional cardiac transcriptome, causing gene expression changes primarily in the anterior LV wall. CRT corrected the alterations in gene expression in the anterior wall, supporting a global effect of biventricular pacing on the ventricular transcriptome that extends beyond the pacing site in the lateral wall.

Key Words: conduction • electrical stimulation • heart failure • remodeling • cardiac resynchronization therapy • gene expression • microarray

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This article has been cited by other articles:

				A. Cheng, R. H. Helm, and T. P. Abraham Pathophysiological mechanisms underlying ventricular dyssynchrony Europace, November 1, 2009; 11(suppl_5): v10 - v14. [Abstract] [Full Text] [PDF]

				R. C. Deo and F. P. Roth Pathways of the Heart Circ Cardiovasc Genet, August 1, 2009; 2(4): 303 - 305. [Full Text] [PDF]