Vagus Nerve Stimulation Reverses Heart Failure by Reprogramming Immune Cells
Transcutaneous vagus nerve stimulation rescues HFpEF by shifting cardiac macrophage populations toward repair via cholinergic signaling.
Summary
Researchers at the University of Oklahoma found that transcutaneous vagus nerve stimulation (tVNS) significantly improved heart failure with preserved ejection fraction (HFpEF) in mice by reshaping cardiac immune cell populations. HFpEF was associated with an accumulation of pro-inflammatory CCR2+ cardiac resident macrophages expressing Spp1. tVNS reduced these harmful macrophages while boosting protective Igf1 expression in reparative TLF+/MHC2+ macrophages. The benefits depended on intact acetylcholine signaling through α7 nicotinic receptors and cholinergic CD4+ T cells, revealing a neuroimmune pathway linking vagal tone to cardiac repair.
Detailed Summary
Heart failure with preserved ejection fraction (HFpEF) affects nearly half of all heart failure patients and lacks effective disease-modifying therapies. Chronic low-grade inflammation and cardiac fibrosis are central features, yet the immune mechanisms driving HFpEF and potential therapeutic targets remain poorly defined. This study investigated how transcutaneous vagus nerve stimulation (tVNS), a non-invasive neuromodulation approach, protects the failing heart at the cellular and molecular level.
Researchers induced HFpEF in 8-week-old mice using a two-hit model: a high-fat diet combined with L-NAME (an NOS inhibitor) for five weeks, producing diastolic dysfunction, left ventricular hypertrophy, and cardiac fibrosis consistent with clinical HFpEF. Animals then received four weeks of tVNS or sham stimulation. Cardiac function was assessed by echocardiography, and immune cell populations were characterized using single-cell RNA sequencing (scRNA-seq) and flow cytometry.
scRNA-seq analysis revealed that HFpEF was associated with a striking accumulation of CCR2+ cardiac resident macrophages (CRM) expressing Spp1 (osteopontin), a pro-fibrotic and pro-inflammatory mediator. tVNS significantly reduced the number of these CCR2+/Spp1+ macrophages. Simultaneously, tVNS induced expression of Igf1 (insulin-like growth factor 1) in reparative Timd4+/Lyve1+/Folr2+ (TLF+) and MHC2+ CRM subpopulations. Mechanistic validation confirmed these findings are causally important: global genetic deletion of Spp1 or pharmacological blockade of CCR2+ macrophage recruitment improved HFpEF phenotype, while conditional deletion of Igf1 specifically in TLF+/MHC2+ macrophages reversed the protective effects of tVNS.
The study also delineated the upstream neuroimmune signaling cascade. The benefits of tVNS were abolished when acetylcholine (ACh)/α7 neuronal ACh receptor (α7nAChR) signaling was disrupted, either by pharmacological α7nAChR blockade or by deletion of choline acetyltransferase specifically in CD4+ T cells. This implicates a vagal → cholinergic T cell → cardiac macrophage axis as the operative pathway.
These findings establish a previously unrecognized neuroimmune circuit in HFpEF and position tVNS as a mechanistically grounded therapeutic strategy. The dual action — suppressing Spp1-driven inflammation and amplifying Igf1-mediated cardiac repair — offers a compelling framework for future clinical translation, particularly given that tVNS is already approved and in use for other indications.
Key Findings
- HFpEF mice accumulated pro-inflammatory CCR2+/Spp1+ cardiac macrophages; tVNS significantly reduced this population.
- tVNS induced protective Igf1 expression in reparative TLF+/MHC2+ cardiac resident macrophages.
- Genetic Spp1 deletion or CCR2+ macrophage blockade independently improved HFpEF severity.
- Igf1 deletion in reparative macrophages abolished tVNS cardiac benefit, confirming causality.
- tVNS benefits required intact α7nAChR signaling and cholinergic CD4+ T cells, revealing a neuroimmune axis.
Methodology
HFpEF was induced in mice via five weeks of high-fat diet plus L-NAME, followed by four weeks of transcutaneous vagus nerve stimulation or sham. Cardiac function was measured by echocardiography; immune profiling used single-cell RNA sequencing and flow cytometry. Mechanistic causality was tested using global Spp1 knockout, CCR2 blockade, conditional Igf1 deletion, α7nAChR pharmacological inhibition, and CD4+ T cell-specific choline acetyltransferase deletion.
Study Limitations
The study used a mouse model that approximates but may not fully recapitulate the heterogeneous human HFpEF syndrome. All mechanistic interventions are preclinical and require validation in larger animal models and ultimately human trials. The contribution of sex differences, aging, and comorbidities prevalent in human HFpEF patients was not fully explored.
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