Duration of hypoxia in Sugen-Hypoxia model of severe pulmonary arterial hypertension does not affect the severity of pulmonary hypertension

Rationale: Pulmonary arterial hypertension (PAH) is a devastating pulmonary vascular disease characterized by pulmonary vascular rarefaction, elevated pulmonary vascular resistance and pressure, and right ventricular (RV) failure. While various models are used to study PAH, the SU5416-chronic hypoxia (SUHx) model is considered to be the gold-standard model. This model had always been theorized to be due to the two-hit nature of the model; however, it has never been optimized since discovery. Importantly, exposure to hypoxia requires specific animal hypoxia system and is a major limitation in experiment involving this model. Therefore, in this project, we assessed whether the length of hypoxia exposure affects the severity of the model. Methods: Fischer CDF rats were injected with SU5416 (20 mg/kg in DMSO, sc) and subjected to 3 weeks of hypoxia (10% O2) followed by 1 week of normoxia (SUHx-3 group, conventional model) or 2 weeks of hypoxia followed by 2 weeks of normoxia (SUHx-2 group, shortened Hx model). Echocardiography to assess cardiac structure and function, and RV systolic pressure (RVSP) measurements were performed for all rats at the 4-week time-point. Lung and heart samples from these rats were collected and histology analysis was performed to assess muscularization of pulmonary arteries and RV remodelling. Results: We observed similar increase in RVSP in SUHx-3 and SUHx-2 groups (108 mmHg and 102 mmHg, respectively) compared to controls (30 mmHg). Similarly, pulmonary artery acceleration time/pulmonary ejection time ratio was similarly reduced in SUHx-3 and SUHx-2 groups (0.212 and 0.165, respectively) compared to controls (0.33). No significant difference in RV structure was observed between SUHx-3 and SUHx-2 group as demonstrated by similar RV wall thickness (1.24 mm and 1.08 mm) and RV internal diameter (3.87 mm and 3.62 mm), Furthermore, RV functional parameters were also similar between SUHx-3 and SUHx-2 (Fractional shortening: 25.0% vs 24.9%; Tricuspid annular plane systolic excursion or TAPSE: 1.35 mm vs 1.32 mm; stroke volume index: 0.94 vs 0.92 mL/g). Conclusions: Duration of hypoxia exposure in SUHx model of severe PAH does not affect severity of pulmonary hypertension or RV remodelling. Canadian Institutes of Health Research, Canada Foundation for Innovation, Dalhousie University-Faculty of Medicine. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.