Cyclin-dependent kinase inhibitor expression in human heart failure. A comparison with fetal development.

Aims: Terminal differentiation of cardiac myocyte is associated with their permanent withdrawal from the cell cycle. In adult end-stage heart failure, significant numbers of myocytes express proliferating cell nuclear antigen yet fail to progress to cell division. Cyclin dependent kinase inhibitors are powerful inhibitors of the cell cycle and may play a direct role both in myocyte development and in preventing cell division in the adult.

Methods And Results: The expression of the CIP/KIP cyclin dependent kinase inhibitors p21, p27, p57 and the retinoblastoma protein was examined in acute (seen in brain dead transplant donors) and end-stage heart failure by Western blot analysis and compared to that seen in human and rat cardiac development. The expression of p21 showed a gradual increase during development in both rat and man, becoming maximal in adulthood p27. levels showed an initial rise with subsequent continual expression throughout life. p57 expression was detectable at only early stages in rat but persisted throughout life in man. In both acute and end-stage heart failure the levels of p21, p27 and p57 reverted to a pattern similar to that observed in human fetal heart: p21 and p27 declined while p57 expression was significantly increased. In contrast, retinoblast protein levels declined during human heart development but were unaltered in heart failure.

Conclusions: The expression of p21, but not p27 or p57, is consistent with a role in the gradual withdrawal of cardiac myocytes from cell cycle during development. In adult heart failure cyclin dependent kinase inhibitor expression reverts to the fetal pattern but is insufficient to initiate cell cycle activation.