Abstract 20348: Persistent Perinatal Cardiomyocyte Hyperplasia is an Early Response in Severe Familial Hypertrophic Cardiomyopathy
Introduction: Familial hypertrophic cardiomyopathy (HCM) affects ~1 in 200 individuals. The majority of HCM results from mutations in either β-myosin heavy chain (MYH7) or cardiac myosin binding protein C (MYBPC3). The pathway(s) by which these mutations lead to HCM are poorly understood, but it is largely accepted that myocyte hypertrophy is responsible for cardiac enlargement. Mice lacking MyBP-C (MyBP-C-/-) are normal at birth but rapidly develop severe HCM by postnatal day (PND) 9. The mechanism underlying the rapid transition from a morphologically normal heart to enlargement is not known.
Methods & Results: Microarray revealed upregulation of cell cycling genes in cMyBP-C-/- vs. wild type (WT) mouse hearts at PND1 validated by qPCR. Immunohistochemistry revealed increased Ki-67, a cell cycling marker, in cMyBP-C-/- hearts at PND1 and 2. By PND9, cell cycling was not different and “hypertrophic cardiomyopathy” became the most differentially regulated pathway between the WT and cMyBP-C-/- hearts. Elevated cell cycling in cMyBP-C-/- hearts was coincident with an increased heart weight (HW) to body weight (BW) ratio at PND2, which preceded cellular hypertrophy. Heterozygotes (cMyBP-C+/-) showed intermediate transcriptional activation of cell cycling pathways with no evidence of hyperplasia at PND2, and no activation of hypertrophic pathways or hypertrophy at PND9.
Conclusions: The elevation in cardiomyocyte proliferation in cMyBP-C-/- vs WT mice, coincident with an increased HW to BW ratio, and occurring prior to the onset of cardiomyocyte hypertrophy, suggests that a higher number of cardiomyocytes in cMyBP-C-/- hearts contributes to the hypertrophic phenotype. The graded differential gene expression in cMyBP-C+/- vs cMyBP-C-/- hearts may indicate a role for hyperplasia to impact the severity of HCM presentation. This may correlate with HCM in humans, where more severe manifestations occur in individuals homozygous for a single mutation, or in compound heterozygotes harboring two distinct mutations. In the immature heart, the interplay between hyperplasia and hypertrophy signaling could represent a novel early target for medical intervention.
Author Disclosures: E.T. Farrell: None. A.C. Grimes: None. A.E. Armstrong: None. W.J. de Lange: None. J. Ralphe: None.
- © 2016 by American Heart Association, Inc.