Abstract 12273: High Mortality in the Fischer Rat Model of Severe Pulmonary Arterial Hypertension Linked to Strain-Specific Deficiency in Right Ventricular Adaptation
Introduction: Inhibition of VEGFR2 with SU5416 (SU), in combination with chronic hypoxia (CH), causes severe, irreversible pulmonary arterial hypertension (PAH) in rats associated with the development of complex intimal and plexiform lesions. In this study, we explored the potential importance of differences in genetic background for the development of severe PAH by comparing the response of Sprague-Dawley (SD) to Fischer rats to SU/CH.
Methods: SU5416 (SU: 20mg/kg), or vehicle (Control) was subcutaneously injected in 6-week-old Sprague-Dawley (SD, Harlan, USA) or Fischer rats (CDF, Charles River) followed by a 3-week exposure to CH (10% oxygen).
Results: In SD (n=6) and Fischer (n=13) rats, SU+CH resulted in similar, marked elevation in RVSP (104± 13 and 102±6 mmHg, respectively; NS) and RV hypertrophy (RV/LV+septum: 68±5% and 72±6%, respectively, NS). Despite comparable hemodynamic abnormalities, there was a remarkable difference in mortality with 100% of SD and only 27% of Fischer rats surviving to 8 weeks (p<0.01). At 4 weeks after SU/CH, both Fischer and SD rats showed similar increases in RV wall thickness and decreased PA acceleration time by echocardiography. However, at 7 to 8 weeks, Fisher (but not SD) rats exhibited evidence of RV enlargement, determined by the ratio of RV to LV internal diameter (RVID/LVID). The RVID/LVID was markedly elevated in the early mortality group of Fischer rats (1.5 ± 0.1) vs SD survivors (0.82 ± 0.05) and Fischer survivors (0.82 ±0.16, p < 0.01, early mortality vs. survivor), consistent with the onset of RV dysfunction. Indeed, RV dilatation was seen only in the Fischer rats that showed early mortality, suggesting that a deficiency in RV adaptation contributed to poor survival in this background strain.
Conclusions: These data identify important strain differences that impact on the outcomes in a clinically relevant model of severe PAH. Although Fischer rats showed similar hemodynamic responses compared with SD rats in the SU/CH model, they exhibited much higher mortality, due to differences in RV adaptation in response to the increased hemodynamic load. Therefore, this model provides a unique opportunity to explore the mechanisms underlying RV failure in severe PAH and develop strategies to restore RV adaptation.
Author Disclosures: B. Jiang: None. C. Suen: None. Y. Deng: None. M. Taha: None. S. Wen: None. D. Courtman: None. D. Stewart: Ownership Interest; Modest; Northern Therapeutics.
- © 2014 by American Heart Association, Inc.