Myocyte cytoskeletal disorganization and right heart failure in hypoxia-induced neonatal pulmonary hypertension

Previous studies have demonstrated that environmentally or genetically indu ced changes in the intracellular proteins that compose the cytoskeleton can contribute to heart failure. Because neonatal right ventricular myocytes a re immature and are in the process of significant cytoskeletal change, we h ypothesized that they may be particularly susceptible to pressure stress. N ewborn calves exposed to hypobaric hypoxia (barometric pressure = 430 mmHg) for 14 days developed severe pulmonary hypertension (pulmonary arterial pr essure = 101 +/- 6 vs. 27 +/- 1 mmHg) and right heart failure compared with age-matched controls. Light microscopy showed partial loss of myocardial s triations in the failing neonatal right but not left ventricles and in neit her ventricle of adolescent cattle dying of altitude-induced right heart fa ilure. In neonatal calves, immunohistochemical analysis of the cytoskeletal proteins (vinculin, metavinculin, desmin, vimentin, and cadherin) showed s electively, within the failing right ventricles, patchy areas characterized by loss and disorganization of costameres and intercalated discs. Within m yocytes from the failing ventricles, vinculin and desmin were observed to r edistribute diffusely within the cytosol, metavinculin appeared in disorgan ized clumps, and vimentin immunoreactivity was markedly decreased. Western blot analysis of the failing right ventricular myocardium showed, compared with control, vinculin and desmin to be little changed in total content but redistributed from insoluble (structural) to soluble (cytosolic) fractions ; metavinculin total content was markedly decreased, tubulin content increa sed, particularly in the structural fraction, and cadherin total content an d distribution were unchanged. We conclude that hypoxic pulmonary hypertens ive-induced neonatal right ventricular failure is associated with disorgani zation of the cytoskeletal architecture.