Abstract 15168: Circulating Cell-free DNA Correlates With Markers of Disease Severity in the Rat Sugen/hypoxia Model of Pulmonary Arterial Hypertension

Abstract

Introduction: Cell-free DNA (cfDNA) is released into circulation following tissue injury and cell turnover. In cancer and allograft rejection, cfDNA serves as a valuable biomarker for monitoring disease severity, progression, and response to therapy. The goal of the current study is to determine the temporal relationship between plasma cfDNA and disease severity in a PAH rodent model. Methods: Blood collection was performed weekly (weeks 4-11) in both sugen/hypoxia PAH rats (n=12) and age-matched, normoxia controls (n=12). cfDNA was isolated from plasma and concentration was determined by qRT-PCR. Cardiac MRI, cardiac catheterization and necropsy were performed at the end of study. Log-transformed concentrations of cfDNA were compared using linear mixed models. Pearson correlation coefficients were calculated to identify associations between rates of change in cfDNA and measures of disease severity. Results: Plasma cfDNA concentrations were significantly higher in PAH rats beginning at week 5 and continuing through week 10 (P < 0.05 for the comparison at each week; Figure 1). From weeks 4 to 11, there was an overall trend toward increasing cfDNA concentration over time in PAH rats (P = 0.07), whereas concentrations in control rats remained unchanged (P = 0.52). In PAH rats, the rate of change in log-transformed cfDNA concentration correlated inversely with RVEF (r = -0.80, P = 0.003), stroke volume index (r = -0.67, P = 0.02), and positively with total pulmonary resistance index (r = 0.62, P = 0.04). There were non-significant trends between the rate of change in cfDNA concentration and LV end-diastolic volume index (r = -0.54, P = 0.09), and Fulton index (r = 0.55, P = 0.08). Conclusions: Plasma cfDNA is elevated in the rat sugen/hypoxia PAH model and significantly correlated with markers of disease severity. Circulating cfDNA may reflect ongoing pulmonary vascular injury and remodeling, RV strain or both and thus may serve as a novel biomarker of PAH disease progression.