Heart Failure With Preserved Ejection Fraction in Women

Visual Abstract
Highlights • The role of ERα non-nuclear signaling in female heart failure was investigated, using a novel mouse line in which ERα non-nuclear signaling was selectively disrupted by inhibiting the interaction between ERα and striatin, a scaffold protein residing at caveolae. • ERα non-nuclear signaling was linked to myocardial PKG activity in female hearts and ameliorated cardiac maladaptive remodeling induced by pressure overload. • ERα non-nuclear signaling was indispensable to the therapeutic efficacy of cGMP-PDE5 inhibition in heart failure but not to that of sGC stimulation. • sGC stimulation potently ameliorated cardiac remodeling, regardless of estrogen conditions, in sharp contrast to PDE5 inhibition. • The study provided the first in vivo evidence for the role of ERα non-nuclear signaling in heart failure, linking it to cGMP-PKG pathways. The data also supported the advantage of sGC stimulation over PDE5 inhibition as a potential therapeutic strategy in treating heart failure in post-menopausal women, highlighting the need for female-specific therapeutic strategies.
Summary Using genetically engineered mice lacking estrogen receptor-α non-nuclear signaling, this study demonstrated that estrogen receptor−α non-nuclear signaling activated myocardial cyclic guanosine monophosphate-dependent protein kinase G and conferred protection against cardiac remodeling induced by pressure overload. This pathway was indispensable to the therapeutic efficacy of cyclic guanosine monophosphate−phosphodiesterase 5 inhibition but not to that of soluble guanylate cyclase stimulation. These results might partially explain the equivocal results of phosphodiesterase 5 inhibitor efficacy and also provide the molecular basis for the advantage of using a soluble guanylate cyclase simulator as a new therapeutic option in post-menopausal women. This study also highlighted the need for female-specific therapeutic strategies for heart failure.