Abstract 4548: Cellular Senescence in Hypoplastic Left Heart Syndrome: Young Patients with Old Hearts
Senescence or aging (permanent cell cycle arrest) is a protective cellular response to damaging environmental stimuli. We investigated if cellular senescence contributes to impaired LV growth in hypoplastic left heart syndrome (HLHS). LV myocardial samples were obtained at autopsy from 16 fetuses with HLHS (gestational age, 22±2 wks) and 9 age-matched normal hearts. We measured
Vascular endothelial growth factor (VEGF), thymosin β-4,
stem cells/progenitors (CD133, c-Kit, Nkx2.5, CD34, Flk-1),
myocyte/capillary density (vWf),
DNA damage (γH2AX, ph-p53),
cell senescence (β-galactosidase), apoptosis (TUNEL), cell differentiation (actin, myosin) and cell cycling (Ki67, CDK4).
The effect of hypoxia and growth factor deprivation was assessed in vitro in mouse cardiac HL-1 cell lines.
The LV in fetal HLHS showed reduction in VEGF, thymosin β-4, progenitors, differentiated myocytes (625±116 vs 1004±121, p<0.05), and capillary density vs controls (0.04±0.01 vs 0.09±0.02, p<0.01). The LV showed extensive DNA damage, increased ph-p53, and cell cycle arrest, but no apoptosis (Fig 1⇓).
In mouse cardiac cell lines, hypoxia/serum deprivation reproduced the HLHS phenotype i.e. reduced VEGF, reduced progenitors, increased senescence and cell cycle arrest.
This is the first study to show that DNA damage and cell senescence may cause loss of cell replication and differentiation in the LV in HLHS during fetal life. Interventions to augment LV growth in HLHS should target pathways that can prevent the damaging cellular effects of hypoxia and growth factor deficiency.