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Contribution of subthreshold SpNS on myocardial I/R injury and translational prospective of intravascular SpNS. (A) Subthreshold SpNS reduces cardiomyocytes apoptosis, oxidative stress, inflammation and autonomic nerve remodeling by activating CAP in myocardial I/R injury. (B) Intravascular SpNS might become a novel minimally invasive technology for treating patients with cardiovascular diseases related to excessive activation of immune system. SpNS, splenic nerve stimulation; I/R, ischemia–reperfusion; CAP, cholinergic anti-inflammatory pathway; β2AR, beta2-adrenoceptors; ChAT+, choline acetyltransferase-positive; CG, celiac ganglion. [Display omitted] • Subthreshold SpNS prevents apoptosis, inflammation, oxidative stress and cardiac remodeling after myocardial ischemia-reperfusion injury. • Subthreshold SpNS inhibits the proinflammatory cytokines expression by activating the cholinergic anti-inflammatory pathway. • SpNS might become a novel minimally invasive technology in patients with diseases related to excessive activation of the immune system. Clinical outcomes following myocardial ischemia–reperfusion (I/R) injury are strongly related to the intensity and duration of inflammation. The splenic nerve (SpN) is indispensable for the anti-inflammatory reflex. This study aimed to investigate whether splenic nerve stimulation (SpNS) plays a cardioprotective role in myocardial I/R injury and the potential underlying mechanism. Sprague-Dawley rats were randomly divided into four groups: sham group, I/R group, SpNS group, and I/R plus SpNS group. The highest SpNS intensity that did not influence heart rate was identified, and SpNS at this intensity was used as the subthreshold stimulus. Continuous subthreshold SpNS was applied for 1 h before ligation of the left coronary artery for 45 min. After 72 h of reperfusion, samples were collected for analysis. SpN activity and splenic concentrations of cholinergic anti-inflammatory pathway (CAP)-related neurotransmitters were significantly increased by SpNS. The infarct size, oxidative stress, sympathetic tone, and the levels of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6, were significantly reduced in rats subjected to subthreshold SpNS after myocardial I/R injury compared with those subjected to I/R injury alone. Subthreshold SpNS ameliorates myocardial damage, the inflammatory response, and cardiac remodelling induced by myocardial I/R injury via neuroimmunomodulation of proinflammatory factor levels. SpNS is a potential therapeutic strategy for the treatment of myocardial I/R injury. [ABSTRACT FROM AUTHOR]