Abstract 5340: Cardiac Resynchronization Therapy Corrects Dyssynchrony-induced Regional Gene Expression Changes on a Genomic Level

Abstract

Purpose: Cardiac Resynchronization Therapy (CRT) improves symptoms and reduces mortality in patients with heart failure (HF). To characterize the molecular processes associated with functional improvement in CRT, we used a genomic approach in a large animal HF model. Methods: After creation of a left bundle branch block (LBBB), dogs in the HF group were subjected to either rapid atrial pacing with 200 bpm for 6 weeks (dyssynchronous HF, DHF, n=10), or 3 weeks of atrial pacing followed by 3 weeks of biventricular stimulation at 200bpm (CRT, n=9). Control animals without LBBB were not paced (NF, n=11). After 6 weeks, RNA from anterior and lateral regions of the LV was hybridized onto canine 44K arrays. Statistical Analysis of Microarrays (SAM) was used for data analysis. Results: Echocardiographically, CRT led to a significant increase in stroke volume (+27%, p=0.03) which translated into a non-significant increase in EF (DHF 25±4%; CRT 31±3% (p=0.15); NF 67±3%). A multiclass analysis of NF, DHF and CRT animals identified 1050 differentially expressed transcripts between anterior and lateral walls with a false discovery rate of 5%. For all these transcripts, dyssynchrony-induced expression changes were reversed by CRT to levels of NF hearts. As a result, CRT samples clustered with NF rather than DHF samples. Of particular interest were genes encoding for signal transduction pathways and contractile processes. Conclusions: By using a whole genome approach, we demonstrate a profound effect of electrical activation on the regional cardiac transcriptome. This is the first study showing that dyssynchrony-induced gene expression changes can be corrected by CRT on a genome-wide level.