Effects of biventricular pacing on interstitial remodelling, tumor necrosis factor-α expression, and apoptotic death in failing human myocardium

Abstract

Recent data from the COMPANION trial have documented that cardiac resynchronization therapy (CRT) with biventricular (BiV) pacing reduces mortality and hospitalization in patients with advanced CHF, but little is known regarding the cellular and molecular mechanisms of CRT. Our aim is to evaluate interstitial remodelling, tumor necrosis factor-alpha (TNF-alpha) expression, and apoptosis in patients with advanced CHF treated with CRT. We performed endomyocardial biopsies in 10 patients, aged 62, with dilated cardiomyopathy before and 6 months after the implantation of a BiV pacing device. Clinical status and left ventricular (LV) architecture and function were assessed as well as myocardial histology, TNF-alpha expression, and apoptotic index. CRT improved clinical status, as shown by a significant reduction of the Minnesota living with heart failure questionnaire (MLHFQ) score (from 53 to 40) and 6-min walked distance (from 290 to 330 m) (all P<0.05 vs. baseline). This was associated with reverse LV remodelling substantiated by significant reductions of LV volumes and end-systolic circumferential wall stress. Examination of myocardial tissue revealed a significant decrease of collagen volume fraction (CVF) (from 25.16 to 18.0%), TNF-alpha expression (from 9.5 to 3.6 pixel x 10(3)), and apoptotic index (from 2030 to 1408 apoptotic nuclei/10(6)), with increased capillary density (from 1801 to 2011 capillary/mm(2)) after 6 months of CRT (all P<0.05 vs. baseline). Moreover, changes in TNF-alpha expression were positively correlated with both CVF and end-systolic circumferential wall stress (r=0.80 and 0.70, respectively). We provide the first evidence that CRT reduces interstitial remodelling, TNF-alpha expression, and apoptosis. The data may explain the beneficial effects of CRT on CHF progression and survival.