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. 2025 Aug 15;137(5):664-681.
doi: 10.1161/CIRCRESAHA.125.326236. Epub 2025 Jul 15.

Vagal Stimulation Rescues HFpEF by Altering Cardiac Resident Macrophage Function

Thamizhiniyan Venkatesan #  1 , Maria Toumpourleka #  1 , Monika Niewiadomska  1 , Kassem Farhat  1 , Lynsie Morris  1 , Khaled Elkholey  1 , Bibi Maryam  2 , Audrey Cordova  2 , Isabella G Darby  2 , Seabrook Whyte  1 , Sarah J Miller  2 , Alex Yashchenko  2 , Alex C Anguiano  3 , Jenny Gipson  3 , Jessica M Reel  4 , Maureen A Cox  4 , Kurt A Zimmerman  2 , Stavros Stavrakis  1
Affiliations

Vagal Stimulation Rescues HFpEF by Altering Cardiac Resident Macrophage Function

Thamizhiniyan Venkatesan et al. Circ Res. .

Abstract

Background: We previously showed in a rat model of heart failure with preserved ejection fraction (HFpEF) that transcutaneous vagus nerve stimulation (tVNS) reduced cardiac fibrosis and inflammation. However, macrophage-mediated mechanisms through which tVNS rescues cardiac function remain poorly understood.

Methods: We induced HFpEF in 8-week-old mice by a combination of a high-fat diet and l-NG-nitro arginine methyl ester for 5 weeks, followed by 4 weeks of tVNS or sham stimulation. At this time, we analyzed cardiac function by echocardiography and immune cell numbers by single-cell RNA sequencing and flow cytometry.

Results: Our data demonstrate that HFpEF mice exhibited diastolic dysfunction, left ventricular hypertrophy, and fibrosis, consistent with HFpEF, and that tVNS significantly improved HFpEF severity. Analysis of merged single-cell RNA sequencing data from control, HFpEF+sham, and HFpEF+tVNS mice showed that HFpEF was associated with the accumulation of Spp1-expressing CCR2 (C-C chemokine receptor type 2)+ cardiac resident macrophages (CRM). Furthermore, treatment with tVNS reduced the number of CCR2+ CRM and the expression of Spp1 while also inducing the expression of Igf1 in TLF+ (Timd4+ [T-cell immunoglobulin and mucin domain containing 4+]/Lyve1+ [Lymphatic vessel endothelial hyaluronan receptor 1+]/Folr2+ [Folate receptor 2+]) and MHC2+(Major histocompatibility complex 2+) CRM. Global deletion of Spp1 or blockade of CCR2+ CRM recruitment improved HFpEF, whereas TLF+/MHC2+ specific deletion of Igf1 reversed the protective effect of tVNS on HFpEF. The benefits of tVNS were also abolished in the setting of disrupted acetylcholine/α7nAChR (α7 nicotinic acetylcholine receptor) signaling, either via pharmacological inhibition of α7nAChR or choline acetyltransferase deletion in CD4+ (cluster of differentiation) T cells.

Conclusions: Collectively, our data indicate that tVNS improves HFpEF by reducing Spp1 expressing CCR2+ CRM and inducing expression of proreparative Igf1 in TLF+/MHC2+ CRM. These effects are mediated through cholinergic signaling, highlighting a neuroimmune pathway in HFpEF.

Keywords: acetylcholine; heart failure; inflammation; macrophages; vagus nerve stimulation.

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Conflict of interest statement

None.

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