Low level transcutaneous vagus nerve stimulation reverses cardiac dysfunction and changes left ventricular gene expression in a rat model of heart failure with preserved ejection fraction

Abstract

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) has become a major public health concern, accounting for approximately half of all heart failure patients. Despite normal or near normal left ventricular ejection fraction, HFpEF is associated with increased morbidity and mortality. The complex pathophysiology of HFpEF is not yet fully understood. Inflammation and fibrosis play a central role in the development of HFpEF. We have previously shown that low-level transcutaneous vagus nerve stimulation (LLTS) is anti-inflammatory. The goal of this study was to determine the effect of chronic intermittent LLTS on cardiac fibrosis, diastolic dysfunction, and left ventricular (LV) gene expression in a rat model of HFpEF. Methods Dahl salt-sensitive (DSS) rats were randomized into high salt (HS, 8% NaCl) or low salt (LS) diet (0.3% NaCl) at 7 weeks of age. The animals were monitored for the development of HFpEF on a daily basis. After 6 weeks of LS or HS diets, HS rats were randomized into 4 groups: HS active LLTS (n=50), HS sham LLTS (n=48), HS plus olmesartan (n=14) and HS active LLTS plus methyllycaconitine (MLA) (n=36), a specific blocker of the α7-nicotinic acetylcholine receptor (a7nAChR), which mediates the anti-inflammatory effects of LLTS. Stimulation was delivered for 30 min daily (20Hz, 3mA) for 4 weeks. Echocardiography was performed at 13 weeks (baseline) and 17 weeks (endpoint). At endpoint, LV histology and gene expression were examined. Results After 6 weeks of diets, HS rats developed hypertension and LV hypertrophy compared to LS rats. At endpoint, LLTS significantly attenuated blood pressure elevation, prevented the deterioration of diastolic function and improved LV circumferential strain, compared to the HS sham LLTS group. LV fibrosis was decreased in the HS active LLTS compared to HS sham LLTS group. MLA attenuated this effect, suggesting that the anti-inflammatory effect of LLTS is necessary to prevent fibrosis in this model (Figure 1). RNA-seq analysis revealed that LLTS significantly changed the expression of genes involved in mitochondrial dysfunction, sitruin signaling pathway, and oxidative phosphorylation. Conclusion Autonomic modulation with LLTS attenuates the unfavorable changes of echocardiographic parameters and LV fibrosis induced by HS diet through its anti-inflammatory effects. The results support our hypothesis that inhibiting the anti-inflammatory effect of LLTS attenuates the antifibrotic effect. The obtained data suggest that LLTS may be used clinically as a novel non-invasive neuromodulation therapy for the treatment of HFpEF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health (NIH)