Heritable pathologic cardiac hypertrophy in adulthood is preceded by neonatal cardiac growth restriction

Enzo R. Porrello, James R. Bell, Jonathan D. Schertzer, Claire L. Curl, Julie R. McMullen, Kimberley M. Mellor, Rebecca H. Ritchie, Gordon S. Lynch, Stephen B. Harrap, Walter G. Thomas, Lea M.D. Delbridge

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Abstract

The identification of genetic factors influencing cardiac growth independently of increased load is crucial to an understanding of the molecular and cellular basis of pathological cardiac hypertrophy. The central aim of this investigation was to determine how pathological hypertrophy in the adult can be linked with disturbances in cardiomyocyte growth and viability in early neonatal development. The hypertrophic heart rat (HHR) model is derived from the spontaneously hypertensive rat and exhibits marked cardiac hypertrophy, in the absence of a pressure load at maturity. Hearts were harvested from male HHR, and control strain normal heart rats (NHR), at different stages of postnatal development [neonatal (P2), 4 wk, 6 wk, 8 wk, 12 wk, 20 wk]. Isolated neonatal cardiomyocytes were prepared to evaluate cell size, number, and binucleation. At postnatal day 2, HHR hearts were considerably smaller than control NHR (4.3 ± 0.2 vs. 5.0 ± 0.1 mg/g, P ± 0.05). Cardiac growth restriction in the neonatal HHR was associated with reduced myocyte size (length and width) and an increased proportion of binucleated cardiomyocytes. Furthermore, the number of cardiomyocytes isolated from HHR neonatal hearts was significantly less (∼29%) than NHR. We also observe that growth stress in the neonate is associated with accentuated PI3K and suppressed MAPK activation, although these signaling pathways are normalized in the adult heart exhibiting established hypertrophy. Thus, using the HHR model, we identified novel molecular and cellular mechanisms involving premature exit from the cell cycle, reduced cardiomyocyte endowment, and dysregulated trophic signaling during early development, which are implicated in the etiology of heritable cardiac hypertrophy in the adult.

Original languageEnglish
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume296
Issue number3
DOIs
Publication statusPublished - 1 Mar 2009
Externally publishedYes

Keywords

  • Apoptosis
  • Cardiac development
  • Developmental origins of adult disease
  • Genetics
  • Physiological and pathological cardiac hypertrophy
  • Proliferation

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