ALTERATIONS IN SHEEP FETAL RIGHT-VENTRICULAR TISSUE WITH INDUCED HEMODYNAMIC PRESSURE-OVERLOAD

We report on the cellular and molecular effects of acute and chronic h emodynamic overload on the fetal sheep heart. In one fetus of a twin g estation, the pulmonary artery was banded to create a condition of hem odynamic pressure overload in the right ventricle. The effects of this overload on the right ventricle (RV), left ventricle (LV), and intra- ventricular septum (IVS) of the heart were studied and compared to tha t in a control, unbanded twin fetus. At the cellular level, the histol ogical data showed that both the size of the nuclei and the overall ce ll size of cardiac myocytes were increased after five days of banding; although, with one hour of banding no effects were detected at the ce llular level. Based on prior studies on connexins which showed their i nvolvement in differentiation, remodeling, and response to load we loo ked at their expression in control and experimental hearts. At the mol ecular level, changes in expression of connexin isoforms, the main gap junction protein in the heart, were observed after both one hour and five days of banding. Changes were observed in expression of connexins 40, 43, and 45. For connexin 43 there was a significant reduction con fined to the right ventricle, in the chronically treated fetus, wherea s, connexins 40 and 45 expression decreased after acute overload. Thes e early molecular changes are significant because the ''functional syn cytium'' of the myocardium is established through the gap junction con nections. Alterations in connexin isoform expression affect the develo pment, mechanical, and electrophysiological properties of the heart mu scle. These changes may contribute to the ultimate result of continued hemodynamic stress on the right ventricle: heart failure.