Transcutaneous Auricular Vagus Nerve Stimulation Ameliorates Heart Failure with Preserved Ejection Fraction Through Regulating Macrophage Polarization Mediated by Alpha7nAChR

Purpose: This study aimed to investigate the effects of transcutaneous auricular vagus nerve stimulation (ta-VNS) on heart failure with preserved ejection fraction (HFpEF) and explore the related mechanisms.

Methods: Sprague-Dawley rats were fed a high-fat diet and N^[w]-nitro-L-arginine methyl ester to establish an HFpEF model. Ta-VNS was achieved by electrical stimulation of the auricular concha. Histology and echocardiography were used to identify changes in cardiac function and pathology. RNA Sequencing was used to explore the underlying mechanism. RT‒PCR, WB, and immunofluorescence staining were used to determine the effects of ta-VNS on macrophage polarization. In vitro, RAW264.7 cells were induced into the M1 or M2 type. An α7nAChR agonist and an α7nAChR inhibitor were used to explore the effects of α7nAChR on macrophage polarization. Finally, an α7nAChR inhibitor was used to determine whether the therapeutic effects of ta-VNS are related to α7nAChR.

Results: In vivo, ta-VNS alleviated cardiac dysfunction and pathological remodeling in rats with HFpEF. RNA Sequencing demonstrated that the protective effects of ta-VNS on HFpEF were related to macrophage-mediated inflammatory responses. Ta-VNS decreased the expression of M1-type macrophage markers but increased the expression of M2-type markers. In vitro studies revealed that the α7nAChR agonist decreased the polarization of macrophages toward the M1 type, whereas the α7nAChR inhibitor reduced the polarization toward the M2 type. Furthermore, the α7nAChR inhibitor abolished the protective effects of ta-VNS on macrophage polarization and myocardial remodeling in rats with HFpEF.

Conclusion: Ta-VNS ameliorated HFpEF-induced cardiac remodeling, which was associated with the modulation of macrophage polarization.

Alpha7nAChR; Heart failure with preserved ejection fraction; Macrophage polarization; Transcutaneous auricular vagus nerve stimulation.