Abstract 106

Aim: This study aims to assess the effect of chronic hypoxia on the process of myocardial cell death utilizing an animal model mimicking cyanotic heart disease. Ceramide, a sphingolipid breakdown product, and a possible regulator of the apoptotic response will be measured. Methods: Rats were placed in a hypoxic environmental at birth and oxygen levels were maintained at 10% in an air-tight Plexiglas chamber. Controls remained in room air. Animals were sacrificed at the ages of 1 and 4 weeks (n=10 and n=11, respectively). The hearts were harvested and ceramide levels in the right ventricle (RV) and left ventricle (LV) were determined using the diglyceride kinase assay and were normalized to lipid phosphate levels. Hematocrit levels were assessed in all studied groups. Results: Hematocrit (Hct.) levels were significantly higher in the hypoxic (H) rats at 1 and 4 weeks (wks.) as compared to controls (C) [Hct. Of 51% (H) vs. 35%(C) at 1 wk, p<0.0001; and Hct (H) of 55% vs. 41% (C) at 4 wks, p<0.0001]. There was significant increase in the RV and LV masses indexed to body weight in the hypoxic rats as compared to controls at 1 and 4 weeks. RV mass (H) was 192% and 278% that of the (C) at 1 and 4 weeks, respectively. There was no significant change in the RV ceramide accumulation in the hypoxic and control groups at 1 week of age [Ceramide/Phosphate ratio (C/P) of 1.39 ± 0.14(H) versus 1.19 ± 0.21 (C), p=0.50]. RV ceramide accumulation was significantly decreased in the (H) rats at the age of 4 wks [1.48 ± 0.08 (H) versus 1.98 ± 0.14 (C), p=0.0001]. There was no significant difference in the LV ceramide levels between hypoxic and control groups at the age of 1 week. However, ceramide levels in the LV were significantly increased at 4 wks in the hypoxic rats compared to controls (C/P: 0.48 ± 0.17 (H) versus 0.41 ± 0.20 (C) at 1 wk, p=0.20; C/P: 0.77 ± 0.03 (C) versus 0.91 + 0.05 (H) at 4 wks., p=0.02). Conclusion: Ceramide production increased in both LV and RV with age and was higher in the RV than LV. The downregulation of the RV ceramide levels at 4 weeks in response to chronic hypoxia, is probably an adaptive mechanism to suppress apoptosis and allow RV myocardial proliferation, because of pulmonary hypertension and hypoxemia. Ceramide production, in response to chronic hypoxemia, is different between the RV (downregulation) and LV (upregulation), and the duration of hypoxia, is an important factor to the ceramide production in both ventricles. Further evaluation of modulators and morphological parameters of apoptosis will help to better study the effects of hypoxia in our model of cyanotic heart disease.