Authors’ reply: role of natriuretic peptide receptor C signalling in obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension

摘要

We thank Eroume-A Egom and Kamgang for their interest in our article and the opportunity to further discuss our work,1 particularly in the context of existing literature on the role of the natriuretic peptide clearance receptor (NPRC) in pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF). Growing evidence suggests that lower circulating levels of natriuretic peptides (NPs) in PH-HFpEF and decreased downstream cGMP/PKG signaling are important pathogenic mechanisms.2–4 Since circulating NPs can be decreased either by neprilysin-mediated degradation or NPRC-based clearance, and recently studies have shown a neutral effect of neprilysin inhibition upon outcomes in PH-HFpEF,5 it is plausible that increased expression of NPRC may play an important role in promoting PH-HFpEF as it does in promoting known comorbid conditions such as obesity and metabolic syndrome.6 In general, progress in identifying therapies for PH-HFpEF has been hampered by the lack of pre-clinical models that faithfully recapitulate human manifestations of PH-HFpEF,7 including models that utilize Ang2 stimulation.8–11 Unfortunately, human studies investigating ACE inhibition and ARB therapies have not proven effective in HFpEF,7,12 calling into question the relevance of this model to HFpEF pathobiology. Alternatively, there is a growing acceptance that obesity and metabolic syndrome may play a pathogenic role in the development of PH-HFpEF in a subset of patients.13–17 Thus, while no single model is likely to perfectly recapitulate the heterogeneous syndrome of PH-HFpEF,12 we believe that our model of obesity-induced PH-HFpEF is highly relevant to this important subpopulation of PH-HFpEF and shares similar findings of disproportionate RV remodeling.