Submitted on November 12, 2008
Revised on December 17, 2008
Accepted on January 5, 2009
HERITABLE PATHOLOGIC CARDIAC HYPERTROPHY IN ADULTHOOD IS PRECEDED BY NEONATAL CARDIAC GROWTH RESTRICTION
Enzo R. Porrello1, James R Bell2, Jonathan D. Schertzer3, Claire L. Curl1, Julie R. McMullen4, Kimberley M. Mellor1, Rebecca H. Ritchie5, Gordon S Lynch6, Stephen B. Harrap2, Walter G Thomas7, and Lea M.D. Delbridge1*
1 University of Melbourne Faculty of Medicine
2 University of Melbourne
3 The Hospital for Sick Children
4 Baker IDI Heart and Diabetes Institute
5 Baker IDI Heart & Diabetes Institute
6 The University of Melbourne
7 The University of Queensland
* To whom correspondence should be addressed. E-mail: lmd{at}unimelb.edu.au.
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 post-natal development (p2, 4wk, 6wk, 8wk, 12wk, 20wk). Isolated neonatal cardiomyocytes were prepared to evaluate cell size, number and binucleation. At post-natal 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, novel molecular and cellular mechanisms involving premature exit from the cell cycle, reduced cardiomyocyte endowment and dysregulated trophic signaling during early development are identified and implicated in the etiology of heritable cardiac hypertrophy in the adult.
