Pulmonary hypertension due to HFpEF in rats

Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by pulmonary hypertension (PH), which underlying mechanism remains largely unknown. When present, it is associated with a worse outcome and there are no therapeutic options for PH due to HFpEF. In this context, we sought to characterize the pulmonary circulation in an experimental model of HFpEF in rats, replicating the characteristics of HFpEF observed in patients. Obesity-prone (OP) and -resistant Sprague-Dawley rats were respectively fed with a high-fat diet or a standard rat chow for 12 months (n = 10 rats in each group) and evaluated by echocardiography, left (LV) and right ventricular (RV) catheterization, histological and pulmonary artery vasoactive analyses. In OP rats fed with high-fat diet during 12 months, HFpEF was confirmed with preserved LV ejection fraction, LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) associated to concentric LV hypertrophy and fibrosis. In rats with HFpEF, RV systolic pressure was increased (31.6 ± 1.0 versus 26.3 ± 0.5 mmHg, P < 0.001), with no significant changes in pulmonary artery muscularization and inflammatory infiltration. Echocardiography showed an increase in pulmonary artery (PA) diameter and PA-to-aorta diameter ratio associated with an increased RV/LV ratio. Circulating levels of sST2 were increased in rats with HFpEF, while NT-proBNP levels decreased. Ex vivo pulmonary artery contraction to phenylephrine and endothelin-1 was similar in both groups of rats. Our model shows that rats develop HFpEF associated to typical risk factors and present with PH. However, at this early stage of HFpEF, neither pronounced pulmonary structural changes nor RV functional and structural changes were observed, suggesting that other mechanisms are likely involved in the development of pulmonary vascular disease in HFpEF.