Abstract 11696: Pulmonary Arterial Hypertension Induces Gene Expression Changes in the Right Ventricle in Advance of Right Ventricular Failure that are More Severe in Female Rats
BACKGROUND AND OBJECTIVES: Right ventricular (RV) failure is the leading cause of morbidity and mortality in pulmonary arterial hypertension (PAH), and females represent up to 75% of patients. However, most animal models of PAH focus on males, precluding an analysis of sex-specific changes in RV dysfunction or adaptation. We sought to establish a female rat model of PAH with neointimal formation and RV failure. Further, we analyzed genome-wide RV mRNA expression in both female and male rats to determine whether changes occur prior to the onset of RV failure, whether these changes are similar to those in left ventricular (LV) failure, and whether there are sex-specific biological differences.
METHODS: 6 week-old female and male rats underwent left pneumonectomy or sham surgery followed by 40-60 mg/kg MCT 7 days later. Rats underwent transthoracic echocardiography and continuous ambulatory invasive right heart hemodynamic monitoring. Cardiac tissue was harvested and RNA expression profiles were generated by microarrays from female and male PAH rats 10 days following 50 mg/kg MCT, and from female and male control rats (n=3-4/group).
RESULTS: At 60 mg/kg, females experienced mortality at least as severe as males. Micro-CT showed more severe vascular pruning in females receiving 40 mg/kg MCT as compared to males receiving 50 mg/kg, suggesting that females are more sensitive to MCT. Males and females had severe RV dilation and decrease in fractional shortening at day 21 after MCT. In a separate group, RV RNA expression profiling in rats receiving 50 mg/kg MCT and sacrificed at day 10, before RV dilation or dysfunction, showed that 195 genes were differentially expressed in PAH, in pathways mediating cell hypertrophy, energetics, myocyte contraction, and the extracellular matrix. Further, female PAH rats exhibited more extreme gene expression changes than male PAH rats.
DISCUSSION: Female rats treated with low dose MCT following left pneumonectomy develop a severe, neointimal pulmonary vasculopathy with vascular pruning and RV failure. Gene expression changes in RV of rats with PAH occur prior to the appearance of significant RV dilation or dysfunction. These changes resemble those occurring in LV failure but appear to be more severe in female relative to male rats.
- © 2012 by American Heart Association, Inc.