BackgroundWith chronic ischemia after myocardial infarction, the resulting scar tissue result in electrical and structural remodeling vulnerable to an arrhythmogenic substrate. The cholinergic anti‐inflammatory pathway elicited by vagal nerve via α7 nicotinic acetylcholine receptors (α7‐nAChR) can modulate local and systemic inflammatory responses. Here, we aimed to clarify a novel mechanism for the antiarrhythmogenic properties of vagal nerve during the ischemic cardiomyopathy (ICM).Methods and ResultsLeft anterior descending artery of adult male Sprague‐Dawley rats was ligated for 4 weeks to develop ICM. Western blot revealed that eliciting the cholinergic anti‐inflammatory pathway by nicotine treatment showed a significant reduction in the amounts of collagens, cytokines, and other inflammatory mediators in the left ventricular infarcted border zone via inhibited NF‐κB activation, whereas it increased the phosphorylated connexin 43. Vagotomy inhibited the anti‐inflammatory, anti‐fibrosis, and anti‐arrhythmogenic effect of nicotine administration. And immunohistochemistry confirmed that the nicotine administration‐induced increase of connexin 43 was located in intercellular junctions. Furthermore nicotine treatment suppressed NF‐κB activation in lipopolysaccharide‐stimulated RAW264.7 cells, and α‐bungarotoxin (an α7‐nAChR selective antagonist) partly inhibited the nicotine‐treatment effect. In addition, 4‐week nicotine administration slightly improved the cardiac function, increased cardiac parasympathetic tone, decreased the prolonged QTc, and decreased the arrhythmia score of programmed electric stimulation‐induced ventricular arrhythmia.ConclusionsEliciting the cholinergic anti‐inflammatory pathway exerts anti‐arrhythmogenic effects against ICM‐induced ventricular arrhythmia accompanied by downregulation of cytokines, downgenerating of collagens, decrease in sympathetic/parasympathetic ratio, and prevention of the loss of phosphorylated connexin 43 during ICM. Our findings may suggest a promising therapy for the generation of ICM‐induced ventricular arrhythmia by eliciting the cholinergic anti‐inflammatory pathway.

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Background The neutrophil percentage-to-albumin ratio (NPAR) is a systemic inflammation-based predictor associated with many diseases’ outcomes. Nevertheless, there are few studies on the relationship between NPAR and inflammatory markers, and more importantly, the prognostic value of NPAR in critically ill patients with cardiovascular disease (CVD) remains unknown. Methods The data of this retrospective cohort study were from the Medical Information Mart data for Intensive Care III database (MIMIC-III) and the Second Affiliated Hospital of Wenzhou Medical University. Linear regression, logistic regression model, and Cox regression model were used to assess the associations between NPAR levels and length of stay, renal replacement therapy (RRT) use, and 30-day, 90-day and one-year mortality, respectively. The Pearson correlation coefficient was used to present the correlation between NPAR and C-reactive protein (CRP). Results Our study included 1599 patients in MIMIC-III and 143 patients in the Second Affiliated Hospital of Wenzhou Medical University. The elevated NPAR was independently associated with increased 30-day, 90-day, and one-year all-cause mortality (adjusted HR, 95% CI:1.51 (1.02–2.24); 1.61 (1.14–2.28); 1.53 (1.15–2.03); P trend = 0.0297; 0.0053; 0.0023; respectively), and it was also associated with increase the length of stay in hospital and ICU (β, 95% CI: 2.76 (1.26–4.27); 1.54 (0.62–2.47), respectively, both P trend <0.001). We found that patients with higher NPAR were more likely to receive RRT (OR, 95% CI: 2.50 (1.28–4.89), P trend =0.0023). Moreover, we confirmed that NPAR was statistically positively correlated with CRP (correlation coefficient r = 0.406, P < 0.0001). Conclusion Elevated NPAR on admission was independently associated with increased all-cause mortality and length of stay among CICU patients. The results showed that CICU patients with higher NPAR were more likely to receive RRT. Besides, we also provided the evidence that there is a positive correlation between NPAR and inflammatory indicators (ie, CRP).

Our previous studies have reported that agonist of α7 nicotinic acetylcholine receptors prevented electrophysiological dysfunction of rats with ischaemic cardiomyopathy (ICM) by eliciting the cholinergic anti‐inflammatory pathway (CAP). Adenosine monophosphate‐activated protein kinase (AMPK) signalling is widely recognized exerting cardioprotective effect in various cardiomyopathy. Here, we aimed to investigate whether the protective effects of the CAP are associated with AMPK signalling in ICM. In vivo, coronary artery of rats was ligated for 4 weeks to induce the ICM and then treated with PNU‐282987 (CAP agonist) and BML‐275 dihydrochloride (AMPK antagonist) for 4 weeks. In vitro, primary macrophages harvested from rats were induced inflammation by Lipopolysaccharide (LPS) treatment and then treated with PNU‐282987 and BML‐275 dihydrochloride. In vivo, exciting CAP by PUN‐282987 elicited an activation of AMPK signalling, alleviated ventricular remodeling, modified the cardiac electrophysiological function, reduced the cardiac expression of collagens and inflammatory cytokines and maintained the integrity of ultrastructure in the ischemic heart. However, the benefits of CAP excitation were blunted by AMPK signaling antagonization. In vitro, excitation of the CAP was observed inhibiting the nuclear transfer of NF‐κB p65 of macrophages and promoting the transformation of Ly‐6C high macrophages into Ly‐6C low macrophages. However, inhibiting AMPK signalling by BML‐275 dihydrochloride reversed the CAP effect on LPS‐treated macrophages. Finally, our findings suggest that eliciting the CAP modulates the inflammatory response in ICM through regulating AMPK signalling.

BackgroundHeart failure (HF) is a clinical syndrome caused by ventricular dysfunction, which leads to the decline of activity tolerance and repeated hospitalization, which seriously affects the quality of life and is the main cause of death of the elderly. It has long been observed that the pathophysiological mechanism of HF is associated with systemic inflammation. This study aims to explore the association between the systemic inflammation response index (SIRI), a novel biomarker of inflammation, and outcomes in elderly patients with HF.MethodsData was extracted from the Medical Information Mart data for Intensive Care III (MIMIC-III) database and the Second Affiliated Hospital of Wenzhou Medical University. The primary outcome was 90-day all-cause mortality. The secondary outcomes included 1-year all-cause mortality, the length of hospital or intensive care unit (ICU) stay, and the need for renal replacement therapy (RRT). Cox proportional hazards regression, linear regression, and logistic regression models were used to assess the association between SIRI levels and all-cause mortality, the length of hospital or ICU stay, the need for RRT, respectively. Moreover, Pearson correlation analysis was conducted to evaluate the correlation between SIRI and C-reactive protein (CRP).ResultsThis study cohort included 3,964 patients from the MIMIC-III database and 261 patients from the Second Affiliated Hospital of Wenzhou Medical University. The result suggested that SIRI was independently associated with the 90-day, and 1-year all-cause mortality in elderly patients with HF (tertile 3 vs. tertile 1: adjusted HR, 95% CI: 1.41 (1.18, 1.68), 1.19 (1.03, 1.37); p trend = 0.0013, 0.0260; respectively). Elevated SIRI was associated with increased the length of hospital or ICU stay after adjusting for multiple confounders (tertile 3 vs. tertile 1: β, 95% CI: 0.85 (0.16, 1.54); 0.62 (0.18, 1.06); p trend = 0.0095, 0.0046; respectively). Furthermore, we found that patients with higher SIRI levels were more likely to require RRT (tertile 3 vs. tertile 1: OR, 95% CI: 1.55 (1.06, 2.28); p trend = 0.0459). Moreover, we confirmed that SIRI was statistically positively correlated with CRP (correlation coefficient r = 0.343, p &lt;0.001).ConclusionsSIRI could be a novel promising inflammatory biomarker for predicting all-cause mortality in elderly patients with HF. And the patients with higher SIRI values had the longer length of hospital or ICU stay and were more likely to require for RRT. Of note, this study also verified a statistically significant positive correlation between SIRI and the inflammatory marker CRP, highlighting the importance of systemic inflammation as a determinant of outcome in patients with HF.

Chronic intermittent hypoxia induced structural damage in the hippocampus and increased cannabinoid receptor type 1 and calcium/calmodulin-dependent protein kinase II expression, which may mediate cognitive impairment associated with chronic intermittent hypoxia. Rimonabant had a protective effect against chronic intermittent hypoxia.

Background: Angiotensin II (AngII) induces renal fibrosis, characterized by fibroblast proliferation, inflammatory cell infiltration and excessive extracellular matrix deposition, all of which was relevant closely to hypertension. The vagus nerve-related cholinergic anti-inflammatory pathway (CAP) modulates local and systemic inflammatory responses. The aim of present study was to determine the effect of CAP on renal inflammation and fibrosis.Methods and Results: AngII-induced hypertension was induced in vivo by 14-days low-dose AngII infusion from osmotic minipumps. We used GTS-21 dihydrochloride, a selective nicotinic acetylcholine receptor agonist. Daily intraperitoneal GTS-21 injection and/or vagotomy started after hypertension was confirmed and continued for 4 weeks. The elevated blood pressure caused by AngII was significantly attenuated by GTS-21. Improved baroreflex sensitivity was observed after GTS-21 administration. Masson stain and immunoblotting revealed that deposition of excessive fibrosis and overexpression of inflammatory cytokines induced by AngII was reduced by GTS-21. To determine the role of autonomic control in CAP, unilateral vagotomy was performed. Vagotomy weakened the effect of CAP on AngII-induced hypertension. In vitro, GTS-21 suppressed NF-κB activation, attenuated AngII-induced epithelial-mesenchymal transition and reduced inflammation and fibrosis in NRK-52E cells; α-bungarotoxin (α-Bgt, an α7-nAChR selective antagonist) partly inhibited these effects.Conclusion: CAP protected against AngII-induced hypertension via improvement in autonomic control, suppression of NF-κB activation, and reduction of renal fibrosis and inflammatory response.

BackgroundVentricular arrhythmias (VAs) originating from the left ventricular summit is a challenge for radiofrequency catheter ablation (RFCA). The present study aimed to investigate the appropriate RFCA strategy for VAs originating from the left ventricular summit.MethodsForty-five consecutive patients with VAs arising from the left ventricular summit were successfully ablated at our cardiac electrophysiology center and reviewed in the study.ResultsThirty-two cases of VAs were eliminated in the left ventricular endocardium by retrograde transaortic (n = 22, 22/45, 48.9%) or antegrade transseptal (n = 10, 10/45, 22.2%) approaches, the other 13 cases were eliminated in the left ventricular epicardium by distal great cardiac vein (DGCV) approach (n = 13, 13/45, 28.9%). Though these VAs were similar in electrocardiographic (ECG) morphology, the pseudo delta waves (PDW), intrinsicoid deflection time (IDT), maximal deflection index (MDI) differed among them, PDW >53 ms, IDT > 74 ms, MDI > 0.45 strongly indicated that ablating left ventricular summit VAs by DGCV approach. During mean follow-up of 19.5 ± 13.2 (range, 3-60) months, 2 (4.4%) patients experienced VAs recurrence.ConclusionThis retrospective study showed that VAs of left ventricular summit origin can be effectively cured with RFCA. For these VAs, prolonged PdW, IDT, MDI indicating RFCA by DGCV approach can be attempted firstly.