A newly discovered mechanism of cell death, programmed necrosis (necroptosis), combines features of both necrosis and apoptosis. Necroptosis is tightly modulated by a series of characteristic signaling pathways. Activating necroptosis by ligands of death receptors requires the kinase activity of receptor-interacting protein 1 (RIP1), which mediates the activation of receptor-interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) two critical downstream mediators of necroptosis. Recently, different cytokines have been found participating in this mechanism of cell death. Necroptosis has been proposed as an important component to the pathophysiology of heart disease such as vascular atherosclerosis, ischemia-reperfusion injury, myocardial infarction and cardiac remodeling. Targeting necroptosis signaling pathways may provide therapeutic benefit in the treatment of cardiovascular diseases.

Activation of the cholinergic anti-inflammatory pathway, which relies on the α7nAchR (alpha 7 nicotinic acetylcholine receptor), has been shown to decrease proinflammatory cytokines. This relieves inflammatory responses and improves the prognosis of patients with experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, pancreatitis, arthritis and other inflammatory syndromes. However, whether the cholinergic anti-inflammatory pathway has an effect on acute viral myocarditis has not been investigated. Here, we studied the effects of the cholinergic anti-inflammatory pathway on acute viral myocarditis. In a coxsackievirus B3 murine myocarditis model (Balb/c), nicotine and methyllycaconitine were used to stimulate and block the cholinergic anti-inflammatory pathway, respectively. Relevant signal pathways were studied to compare their effects on myocarditis, survival rate, histopathological changes, ultrastructural changes, and cytokine levels. Nicotine treatments significantly improved survival rate, attenuated myocardial lesions, and downregulated the expression of TNF-α and IL-6. Methyllycaconitine decreased survival rate, aggravated myocardial lesions, and upregulated the expression of TNF-α and IL-6. In addition, levels of the signaling protein phosphorylated STAT3 were higher in the nicotine group and lower in the methyllycaconitine group compared with the untreated myocarditis group. These results show that nicotine protects mice from CVB3-induced viral myocarditis and that methyllycaconitine aggravates viral myocarditis in mice. Because nicotine is a α7nAchR agonist and methyllycaconitine is a α7nAchR antagonist, we conclude that α7nAchR activation increases the phosphorylation of STAT3, reduces the expression of TNF-α and IL-6, and, ultimately, alleviates viral myocarditis. We also conclude that blocking α7nAchR reduces the phosphorylation of STAT3, increases the expression of TNF-α and IL-6, aggravating viral myocarditis.

Many studies have found that abnormalities in the proportion and differentiation of CD4⁺ T cells (Th cells) are closely related to the pathogenesis of viral myocarditis (VMC). Our previous research indicates that the cholinergic anti-inflammatory pathway (CAP) attenuates the inflammatory response of VMC and downregulates the expression of cytokines in Th1 and Th17 cells. This suggests that the cholinergic anti-inflammatory pathway likely attenuates the inflammatory response in VMC by altering Th cell differentiation. The aim of this study is to investigate the effect of CAP on CD4⁺ T cell differentiation in VMC mice. CD4⁺ T cells in the spleen of VMC mice were obtained and cultured in the presence of nicotine or methyllycaconitine (MLA). Cells were harvested and analyzed for the percentage of each Th cell subset by flow cytometry and transcription factor release by Western blot. Then, we detected the effect of CAP on the differentiation of Th cells in vivo. Nicotine or MLA was used to activate and block CAP, respectively, in acute virus-induced myocarditis. Nicotine treatment increased the proportion of Th2 and Treg cells, decreased the proportion of Th1 and Th17 cells in the spleen, reduced the level of proinflammatory cytokines, and attenuated the severity of myocardium lesions and cellular infiltration in viral myocarditis. MLA administration had the opposite effect. Our result demonstrated that CAP effectively protects the myocardium from virus infection, which may be attributable to the regulation of Th cell differentiation.

Background: In recent years, catheter ablation has increasingly been used for ablation of idiopathic premature ventricular complexes (PVCs) or ventricular tachycardias (IVTs). However, the mapping and catheter ablation of the arrhythmias originating from the vicinity of tricuspid annulus (TA) may not be fully understood. This study aimed to investigate electrophysiologic characteristics and effects of radiofrequency catheter ablation (RFCA) for patients with symptomatic PVCs and IVTs originating from the vicinity of TA. Methods: Characteristics of body surface electrocardiogram (ECG) and electrophysiologic recordings were analyzed in 35 patients with symptomatic PVCs/ IVTs originating from the vicinity of TA. RFCA was performed using pace mapping and activation mapping. Results: Among the 35 patients with PVCs/IVTs arising from the vicinity of TA, complete elimination of PVCs/IVTs could be achieved by RFCA in 32 patients (success rate 91.43%) during a median follow-up period of 21 months. PVCs/IVTs originating from the vicinity of TA had distinctive ECG characteristics that were useful for identifying the precise origin. An rS pattern was recorded in lead V1 in 93.1% of patients with PVCs/IVTs from the free wall of TA, vs 16.7% of patients with PVCs/IVTs from the septal TA, whereas a QS pattern in lead V1 occurred in 83.3% of patients with PVCs/IVTs from the septal TA vs 6.9% of patients with PVCs from the free wall of the TA. The precordial R wave transition occurred by lead V3 or earlier in all patients with PVCs/IVTs originating from the septal portion of the TA, as compared to transition beyond V3 in all patients with PVCs/IVTs from the free wall of the TA. Conclusions: RFCA is an effective curative therapy for symptomatic PVCs/IVTs originating from the vicinity of TA. There are specific characteristics in ECG and the ablation site could be located by ECG analysis.