Mineralocorticoid receptor antagonist treatment of established pulmonary arterial hypertension improves interventricular dependence in the SU5416-hypoxia rat model

Abstract

Treatment with mineralocorticoid receptor (MR) antagonists beginning at the outset of disease, or early thereafter, prevents pulmonary vascular remodeling in pre-clinical models of pulmonary arterial hypertension (PAH). However, the efficacy of MR blockade in established disease, a more clinically relevant condition, remains unknown. Therefore, we investigated the effectiveness of two MR antagonists, eplerenone (EPL) and spironolactone (SPL), after development of severe right ventricular (RV) dysfunction in the rat SU5416-hypoxia (SuHx) PAH model. Cardiac magnetic resonance imaging (MRI) in SuHx rats at the end of week 5, prior to study treatment, confirmed features of established disease including reduced RV ejection fraction, RV hypertrophy, pronounced septal flattening with impaired left ventricular filling and reduced cardiac index. Five weeks of treatment with either EPL or SPL improved left ventricular filling and prevented the further decline in cardiac index compared to placebo. Interventricular septal displacement was reduced by EPL while SPL effects were similar, but not significant. Although MR antagonists did not significantly reduce pulmonary artery pressure or vessel remodeling in SuHx rats with established disease, animals with higher drug levels had lower pulmonary pressures. Consistent with effects on cardiac function, EPL treatment tended to suppress MR and pro-inflammatory gene induction in the RV. In conclusion, MR antagonist treatment led to modest, but consistent beneficial effects on interventricular dependence after the onset of significant RV dysfunction in the SuHx PAH model. These results suggest that measures of RV structure and/or function may be useful endpoints in clinical trials of MR antagonists in PAH patients.

Therapeutic targeting of mineralocorticoid receptors in pulmonary hypertension: Insights from basic research

“…Those experimental studies have employed MRAs spironolactone, eplerenone, or finerenone in several models of PH ( Tables 1 , 2 ). The overall finding of those studies is that MRAs can prevent and partially reverse pulmonary vascular remodeling and improve pulmonary hemodynamics in PH ( 43 , 47 , 51 – 53 ) ( Tables 1 , 2 ). Preventive application MRAs attenuated the development of adverse pulmonary vascular remodeling as assesses by attenuated PA muscularization and wall thickening along with decreased PA pressure ( 27 , 44 , 46 , 47 , 51 , 52 , 54 ) ( Table 1 ).…”

“…Preventive application MRAs attenuated the development of adverse pulmonary vascular remodeling as assesses by attenuated PA muscularization and wall thickening along with decreased PA pressure ( 27 , 44 , 46 , 47 , 51 , 52 , 54 ) ( Table 1 ). Initiation of MRA therapy after the disease phenotype had established was able to decrease PA muscularization and wall thickening and improve pulmonary hemodynamics ( 26 , 43 , 44 , 46 , 53 ) ( Table 2 ). This applied both to steroidal as well as the novel non-steroidal MRA finerenone ( 43 ).…”

“…In one recent study, MRAs initiated after the onset of significant RV failure in the hypoxia-sugen rat PH model led to modest, but consistent beneficial effects on cardiac function and remodeling ( 53 ). Specifically, MRI imaging of the heart in hypoxia-sugen rats, revealed that MRAs improved cardiac index, the RVEDV/LVEDV ratio, and the degree of septal displacement although no significant reductions in either PA pressure or vessel remodeling were observed ( 53 ).…”

“…In one recent study, MRAs initiated after the onset of significant RV failure in the hypoxia-sugen rat PH model led to modest, but consistent beneficial effects on cardiac function and remodeling ( 53 ). Specifically, MRI imaging of the heart in hypoxia-sugen rats, revealed that MRAs improved cardiac index, the RVEDV/LVEDV ratio, and the degree of septal displacement although no significant reductions in either PA pressure or vessel remodeling were observed ( 53 ). The cardioprotective effect of MRAs in this study may be related at least in part to the attenuated pro-inflammatory gene expression in the RV ( 53 ), which is considered as a crucial mediator of adverse RV remodeling in response to pressure overload ( 55 ).…”

“…Specifically, MRI imaging of the heart in hypoxia-sugen rats, revealed that MRAs improved cardiac index, the RVEDV/LVEDV ratio, and the degree of septal displacement although no significant reductions in either PA pressure or vessel remodeling were observed ( 53 ). The cardioprotective effect of MRAs in this study may be related at least in part to the attenuated pro-inflammatory gene expression in the RV ( 53 ), which is considered as a crucial mediator of adverse RV remodeling in response to pressure overload ( 55 ). In contrast to that, application of the MRA eplerenone after 1-week of PAB surgery in mice did not improve RV function and remodeling at 3 weeks ( 51 ).…”