Cardioception is the bidirectional communication between the brain and heart. It regulates the cardiovascular function through endocrine, neural, and immune pathways. Following myocardial infarction (MI), altered sympathetic and sensory signaling drives heart failure, inflammation, and ventricular remodeling, yet the responsible neural circuits remain poorly defined. Vagal sensory neurons (VSNs) are central to heart-brain communication, but their specific subtypes and roles after MI are unclear. In a recent study published in A Cell Press journal, scientists used single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, imaging, chemogenetics, and viral tracing to identify a distinct transient receptor potential vanilloid-1 (TRPV1)-expressing VSN subset that expands after MI and worsens outcomes. Ablation of these neurons improved cardiac function, reduced inflammation, and revealed a hypothalamic-sympathetic pathway via the cervical ganglia, establishing MI as a brain-heart-immune disorder and highlighting a novel therapeutic target.
In this study, all animal experiments were performed in adult female and male mice (2-6 months). Multiple transgenic mouse lines were used and housed under standard conditions with ad libitum food and water. Pharmacological treatments, antibodies, and viral vectors were administered via targeted ganglia, cardiac, or stereotaxic injections. Myocardial infarction was induced using left anterior descending coronary artery ligation. Cardiac function was evaluated by histological analysis, measurements of blood pressure, echocardiography, and electrocardiogram (ECG) recordings. Light-sheet imaging, immunohistochemistry, neural tracing, and tissue clearing were performed to assess neurovascular remodeling. Cardiac structure and infarct size were estimated using trichrome sequencing and triphenyl tetrazolium chloride (TTC). Molecular profiling included spatial transcriptomics and single-nucleus RNA sequencing, followed by integrative bioinformatic and statistical evaluation through GraphPad Prism or R. Â Â
Results showed that scRNA-seq of nodose-jugular ganglia identified TRPV1-expressing VSNs as a transcriptionally distinct population from piezo-type mechanosensitive ion channel component 2 (PIEZO2) mechanosensory neurons. Following MI, TRPV1+ VSN numbers increased, accompanied by marked expansion of TRPV1-positive nerve fibers in the ventricular border zone observed through whole-heart tissue clearing, immunohistochemistry, and viral tracing methods. Selective ablation of TRPV1 VSNs via nodose-jugular reiniferatoxin (NRTX) preserved ECG conduction, normalized QRS complexes, improved ejection fraction, reduced infarct size, and limited ventricular remodeling post-MI. These effects occurred without systemic changes in blood pressure, body temperature, or body weight.
NRTX-treated hearts showed reduced tyrosine hydroxylase-positive sympathetic fibers, decreased levels of tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), and enhanced angiogenesis, which was marked by increased expression of Ki67, vascular endothelial growth factor (VEGF), and CD31. Single-nucleus RNA sequencing and spatial transcriptomics revealed that TRPV1 VSN ablation reduced infarct and inner border zone (BZ) size, expanded myocardium, and altered cardiomyocyte gene programs related to junction organization, angiogenesis, antioxidant defense, and contractility.
MI activated AT1aR-expressing neurons in the hypothalamic paraventricular nucleus (PVN). Chemogenetic inhibition of these neurons mimicked ablation of TRPV1 VSN.  Downstream, the superior cervical ganglion (SCG) exhibited IL-1β-driven neuroinflammation and increased cardiac innervation. Targeted SCG IL-1β blockade reduced sympathetic fibers, infarct size, and cardiac dysfunction, whereas IL-1β delivery to the SCG induced MI-like pathology.
This study’s limitations include the potential involvement of immune mediators beyond IL-1β and TNF-α and possible systemic immune effects of TRPV1 VSN ablation. Mechanisms linking TRPV1-VSN signaling to sympathetic activation remain unclear. Contributions from DRG afferents and stellate ganglia were not examined.
Overall, this study’s findings identify that TRPV1-expressing VSNs are a critical sensory node linking myocardial injury to adverse cardiac remodeling, central autonomic activation, and sympathetic inflammation.
Reference: Yadav S, Ninh VK, Lovelace JW, et al. A triple-node heart-brain neuroimmune loop underlying myocardial infarction. Cell. 2026. doi:10.1016/j.cell.2025.12.058
