Transcriptomic analysis of low-level vagus nerve stimulation effects on cardiac remodeling in pressure overload-induced heart failure

Heart failure (HF) affects approximately 56 million people worldwide with a 5-year mortality rate exceeding 50%. This study investigated the molecular mechanisms underlying the cardioprotective effects of low-level vagus nerve stimulation (LL-VNS) delivered via a biodegradable triboelectric nanogenerator (BTENG) in a murine aortic banding model. Male C57BL/6 mice underwent aortic banding surgery to induce pressure overload-induced heart failure. LL-VNS treatment (4 µA peak-to-peak, 2 Hz) was initiated at different timepoints (1, 2, or 4 weeks post-surgery) to evaluate stage-specific therapeutic effects. Two stimulation durations (10 or 20 minutes daily) were tested for the 1-week intervention group. RNA sequencing was performed on cardiac tissue collected at 8 weeks post-surgery to identify gene expression changes and pathway alterations. Results demonstrate that LL-VNS significantly modulates extracellular matrix remodeling, programmed cell death, and muscle structure development pathways across different intervention timepoints, providing molecular evidence for its therapeutic efficacy in preventing and reversing cardiac remodeling and heart failure progression. Overall design: Seven experimental groups were analyzed with n=3 biological replicates per group: (1) Sham-operated controls, (2) Aortic banding (AB) without therapy, (3) AB with device implant only (no stimulation), (4) AB with 20-minute daily LL-VNS starting at 1 week post-AB (preventive intervention, 7 weeks treatment), (5) AB with 20-minute daily LL-VNS starting at 2 weeks post-AB (early intervention, 6 weeks treatment), (6) AB with 20-minute daily LL-VNS starting at 4 weeks post-AB (late intervention, 4 weeks treatment), and (7) AB with 10-minute daily LL-VNS starting at 1 week post-AB (preventive intervention, 7 weeks treatment). All groups reached the same endpoint at 8 weeks post-surgery for cardiac tissue collection. Paired-end RNA sequencing was performed on Illumina NovaSeq 6000 platform.