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