Abstract 3250: Functional Myocardial Improvement With CRT Correlates With Normalization of Dyssynchrony-induced Regional Gene Expression Rather Than Correction of Heart Failure Transcriptional Patterns
Purpose: To date, CRT is the only heart failure treatment that can both acutely and chronically increase systolic function and prolong survival, something not yet achieved by drug therapy. To characterize the molecular processes associated with functional improvement in CRT, we used a genomic approach in a well-controlled large animal model.
Methods: 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=11). Control animals without LBBB were not paced (NF, n=14). Echocardiography and invasive hemodynamic measurements were performed at 3 and 6 weeks. At 6 weeks, RNA was isolated from the anterior and lateral LV as well as from the left and right atrial appendages and hybridized to canine 44K microarrays. Data were analyzed using Significance Analysis of Microarrays (multi-class and two-class modes).
Results: Echocardiographically, DHF ventricles displayed marked dyssynchrony that was restored to normal levels with CRT. Both DHF and CRT hearts remained dilated and had evidence of failure with similarly elevated end-diastolic pressure. However, significant differences were observed in EF (increase of 8.3±2.4%), stroke volume, and contractility (dP/dTmax) with CRT. While CRT completely restored dyssynchrony-induced regional gene expression changes between the anterior and lateral LV walls to levels of NF hearts (1050 transcripts, false discovery rate FDR<5%), global heart failure-related gene expression patterns, encompassing ~2400 and ~5300 transcripts in ventricles and atria, respectively, were largely unaffected by CRT. Statistical significant changes between DHF and CRT were identified for only 8 and 6 transcripts in atria and ventricles, respectively (FDR<5%).
Conclusions: Our results indicate that functional myocardial improvements in CRT correlate with normalization of dyssynchrony-induced regional gene expression within the LV wall, but occur in the absence of widespread normalization of pathological HF-related transcriptional patterns.