Neonatal cardiomyocyte ploidy reveals critical windows of heart development

Background: The aim of our study was to find out, whether cardiomyocyte genome duplication participates in developmental programming of adult hypertension and impaired heart aerobic capacity, and if it does, whether ploidy-related programming is reversible and what are the timeframes of the most critical window. For this propose we studied the effect of the well-known factors of programming, including growth retardation, infection, and cardiac overload on the level of neonatal cardiomyocyte ploidy, protein content and shape. Methods: Using the model of rat cryptosporidial gastroenteritis, we shifted the time point of infection day by day through the neonatal period and traced the immediate and postponed effects of disease on isolated cardiomyocyte ploidy, phenotype, and protein content. Results: We found that gastroenteritis caused cardiac atrophy and a burst-like premature genome accumulation, elongation, narrowing and protein loss in the cardiomyocytes. These changes resulted in sharp increase of DNA content at the expense of contractile proteins. We also revealed clear indications of critical window of heart development during the peak of cardiomyocyte transition from proliferation to hypertrophy. After the rehabilitation, the atrophy of heart and cardiomyocyte remodelling showed a conspicuous restoration, whereas the hyperpolyploidization did not regress. An irreversible manner of excessive genome duplication and its well-known ability to alter gene expression confirm our suggestion that it is implicated in the ontogenetic programming of heart development. Conclusion: We provided the first evidence that developmental programming can operate through cardiomyocyte genome duplication and that the critical window coincides with cell transition from proliferation to hypertrophy. Our data help determine the timing of critical window for human heart and would allow successful prevention of human cardiac abnormalities even before they become tangible. (C) 2008 Elsevier Ireland Ltd. All rights reserved.