Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel class of hypoglycemic drugs, show excellent cardiovascular benefits, and have further improved heart failure outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status. However, the efficacy of SGLT2 inhibitors in pulmonary arterial hypertension (PAH) and right ventricular (RV) dysfunction remains unknown. This study aimed to evaluate the effects of dapagliflozin in rats with PAH and RV dysfunction. PAH was induced in rats by monocrotaline (MCT) subcutaneous injection (60 mg/kg). Isolated RV dysfunction was induced in another group of rats by pulmonary trunk banding (PTB). Dapagliflozin (1.5 mg/kg) was administered daily via oral gavage one day (prevention groups) or two weeks (reversal groups) after modeling. Echocardiography and hemodynamic assessments were used to observe pulmonary vascular resistance and RV function. Histological staining was used to observe pulmonary vascular and RV remodeling. As compared with MCT group, dapagliflozin treatment did not significantly improve the survival of rats. Pulmonary arterial media wall thickness in MCT group was significantly increased, but dapagliflozin did not significantly improved vascular remodeling both in the prevention group and reversal group. In MCT group, RV hypertrophy index, RV area, the fibrosis of RV increased significantly, and RV function decreased significantly. Consistently, dapagliflozin did not show protective effect on the RV remodeling and function. In the PTB model, we also did not find the direct effect of dapagliflozin on the RV. This is a negative therapeutic experiment, suggesting human trials with dapagliflozin for PAH or RV failure should be cautious.
Highlights
Pulmonary arterial hypertension (PAH) is defined as a resting mean pulmonary artery pressure of 25 mmHg or above, and its prevalence varies from 11 to 26 cases per million adults globally (Thenappan et al, 2018)
During the five-weeks observation period, four rats died in MCT + vehicle group, five rats died in MCT + prevention group, and three rats died in MCT + reversal groups
MCTP causes endothelial cell damage and pulmonary artery smooth muscle cells (PASMCs) proliferation, which leads to pulmonary arterial medial hypertrophy and obstructive pulmonary vascular remodeling (Gomez-Arroyo et al, 2012)
Summary
Pulmonary arterial hypertension (PAH) is defined as a resting mean pulmonary artery pressure of 25 mmHg or above, and its prevalence varies from 11 to 26 cases per million adults globally (Thenappan et al, 2018). The pathological changes of PAH are characterized by proliferative and obstructive remodeling of the pulmonary arteries, together with excessive vasoconstriction and Dapagliflozin’s Negative Effect on PAH increased pulmonary vascular resistance (PVR), leading to right ventricular (RV) hypertrophy and dysfunction (Humbert et al, 2019). Fourteen specific medications are currently available for PAH (Tuder et al, 2013), they all focus on dilating the partially occluded vessels and none of them target the adverse vascular remodeling. The 3-years survival rate of PAH patients is estimated to be between 54 and 84.4% (Jang and Chung, 2019).
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