Single-cell transcriptomics reveals how Shenfu Qiangxin pill ameliorates HFpEF by modulating cardiac cellular...

Heart failure with preserved ejection fraction (HFpEF) has currently emerged as a predominant and challenging subtype of heart failure, with high morbidity and mortality. However, the efficacy of current therapeutic strategies for HFpEF remains unsatisfactory. The traditional Chinese medicine formulation Shenfu Qiangxin pill (SFQX) ameliorates clinical symptoms in patients with heart failure, but its precise mechanisms for HFpEF remain to be elucidated. This study aimed to investigate the therapeutic potential of SFQX for HFpEF and to elucidate the mechanisms underlying its effects.

UPLC-Q-TOF-MS/MS analysis was performed to identify the major active ingredients of SFQX. The HFpEF mouse model was established using a high-fat diet and an Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) to evaluate the therapeutic efficacy of SFQX. We employed an integrated approach combining single-cell RNA sequencing (scRNA-seq) with functional and molecular validation to characterize SFQX-induced changes in cardiac cellular composition, cell-state remodeling, and tissue-level phenotypes in HFpEF.

We show that SFQX exerts therapeutic effects against HFpEF by coordinately modulating maladaptive cardiac cell subsets. Specifically, SFQX was associated with reprogramming of pathogenic immune cell polarization, normalization of fibroblast state heterogeneity, enhanced endothelial metabolic adaptability, and restoration of lymphatic endothelial homeostasis. These multicellular changes were accompanied by improved cardiac structure and function, reduced fibrosis and inflammation, enhanced lymphatic drainage capacity, and alleviated myocardial edema.

Our findings highlight the ability of SFQX, as a multicomponent agent, to precisely regulate the highly heterogeneous pathology of HFpEF at a network level. This work not only establishes a mechanistic link between holistic principles of traditional medicine and modern biology but also provides a novel theoretical basis for SFQX's efficacy in multifactorial diseases.