Aspects of the intercellular communication in aged hearts: effects of the gap junction uncoupler palmitoleic acid.

Abstract

Although cardiac arrhythmia is among the most common causes of death and the percentage of aged people in our population is steadily increasing, only little is known on age-dependent changes in intercellular coupling, anisotropy and electrophysiology in mammalian heart. Thus, we wanted to investigate electrophysiology and anisotropy in aged vs. young rabbit heart, as well as the response to the gap junction uncoupler palmitoleic acid. Spontaneously beating hearts of young mature (6+/-1 months, n=14) and aged (32+/-5 months, n=9) male White New Zealand rabbits (Langendorff technique) were submitted to epicardial 256-channel potential mapping. Cumulative concentration-response curves for palmitoleic acid (0.2-20.0 microM) were carried out. At certain time points anisotropy was measured by application of rectangular pulses and the determination of longitudinal and transversal conduction velocity. Finally, hearts were processed histologically for Van Gieson staining or connexin43 immunostaining. In spontaneously beating aged hearts we found enhanced dispersion of activation-recovery intervals (15.9+/-1.6 ms vs. 10.8+/-2.0 ms, P<0.05), prolonged (31.2+/-1.4 ms vs. 25.2+/-1.8 ms, P<0.05) and fractionated QRS complexes. We found reduced transversal velocity (0.22+/-0.01 m/s vs. 0.27+/-0.02 m/s, P<0.05) and enhanced anisotropy (2.6+/-0.2 vs. 2.0+/-0.1, P<0.05) in aged hearts, while longitudinal velocity was not changed. Histologically, in ventricles from aged hearts we found diffuse deposition of collagen lateral to the fibers and more pronounced expression of connexin43 at lateral cell borders. The functional changes in ventricles from aged hearts were mimicked by application of palmitoleic acid to young hearts in a concentration-dependent manner. In aged hearts this concentration-response curve started at higher initial values, but finally reached similar maximum values. In aged hearts ventricular intercellular coupling transverse to the fiber axis is reduced. Correlates are increased dispersion, slowed transverse conduction and increased anisotropy, and enhanced Cx43 immunostaining at the lateral cell borders. The functional age-dependent changes can be mimicked in young hearts by the gap junction uncoupler palmitoleic acid.