Effect of Cardiac Resynchronization Therapy on Myocardial Fibrosis and Relevant Cytokines in a Canine Model with Experimental Heart Failure

INTRODUCTION: Though cardiac resynchronization therapy (CRT) has now proved to be effective on cardiac reverse remodeling, data on the underlying molecular changes are limited. The present study aims to investigate the expression of cytokines concerning myocardial fibrosis in dyssynchronous heart failure (HF) and the potential benefits of CRT. METHODS AND RESULTS: Left bundle branch ablation and rapid pacing was performed to induce a canine model of asynchronous HF. Animals were randomly divided into sham group, HF control group, and CRT group. Echocardiographic data including septum-to-posterior wall motion delay (SPWMD) and standard deviation of the time to peak systolic velocity (Ts-SD) were collected. Histologic samples from lateral left ventricular (LV) and right ventricular (RV) free wall were analyzed and compared among different groups. Serum concentrations of NT-proBNP, TGF-β1 , and osteopontin (OPN) were measured using enzyme-linked immunosorbent assay (ELISA). Protein and mRNA expressions of TGF-β1 /Smad and OPN from myocardial tissues were also detected and compared. CRT improved cardiac function and corrected intraventricular dyssynchrony with increased LV ejection fraction (LVEF) and decreased SPWMD and Ts-SD (P < 0.05). Histological analysis showed that CRT restored cardiomyocyte diameter (from 4.50 to 6.08 μm) and collagen volume fraction (from 19.33% to 11.21%) of LV (P < 0.01), but had little effect on RV. Serum TGF-β1 and OPN level were also reversed toward normal level after CRT (P < 0.05). Compared with sham group, a significantly higher protein and mRNA expressions of TGF-β1 /Smad and OPN were observed in HF control group, which were significantly downregulated in CRT group (P < 0.01). CONCLUSION: By means of coordinating LV dyssynchrony, cellular and molecular reverse remodeling relevant to fibrosis inhibition could also be invoked by CRT.