Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure.

Abstract

Congestive heart failure (CHF) causes arrhythmogenic remodeling in both atria and ventricles, but differences between atrial and ventricular remodeling in CHF have not been well characterized. We examined atrial and ventricular tissues from dogs with CHF induced by ventricular tachypacing (220-240/min) for 0 (control) or 24 h, or 1, 2 or 5 weeks. Histopathology was used to assess apoptosis, fibrosis, white blood cell infiltration and cell death, ELISA to measure angiotensin-II concentration and Western blot to evaluate protein expression. Ventricular tachypacing-induced CHF was associated with substantially more fibrosis in left atrium (maximum 10 +/- 1% at 5 weeks) than in left ventricle (0.4 +/- 0.1% at 5 weeks, P < 0.01 versus left atrium). Tissue angiotensin-II concentration increased to steady state in atrial tissue at 24 h but increased more slowly in left ventricle, with a maximum that was significantly higher in atrium than ventricle. Ventricular tachypacing caused tissue apoptosis, inflammatory cell infiltration and cell death, with maximum changes in left atrium being faster, transient and larger than in left ventricle. Mitogen activated protein kinase activation was rapid (within 24 h) in left atrium, but smaller and slower (p38, c-Jun N-terminal kinase) or non-significant (extracellular signal-related kinase) in left ventricle. The 25-kDa activated form of transforming growth factor-beta1, a particularly important profibrotic mediator in atrium, increased significantly in left atrium, from 2.6 +/- 0.6 (control) to 9.2 +/- 1.7 (24 h) and 8.1 +/- 1.8 optical density units (1 week), but was not significantly changed in ventricle. There are qualitative and quantitative differences in atrial versus ventricular remodeling in experimental ventricular tachypacing-induced CHF, with potentially important consequences for understanding underlying mechanisms and developing new therapeutic approaches.