Phenylacetylglutamine increases the susceptibility of ventricular arrhythmias in heart failure mice by exacerbated activation of the TLR4/AKT/mTOR signaling pathway

Background: Intestinal microbial metabolites are a risk factor for cardiovascular diseases, and phenylacetylglutamine (PAGln) is a newly discovered intestinal metabolite in the latest study. In addition, elevated plasma PAGln concentration was associated with increased mortality and hospitalization rates in patients with heart failure (HF). However, the mechanism of PAGln leading to increased HF mortality is unclear. The present study was performed to investigate whether the PAGln deteriorated the susceptibility of ventricular arrhythmias (VAs) in the setting of HF. Methods: Thoracic aortic coarctation (TAC) was used to construct an animal model of HF in mice. Intraperitoneal injection of PAGln for 4 weeks intervened in HF mice. The concentration of PAGln was quantitatively determined by liquid chromatography-tandem mass spectrometry. Cardiac function was assessed by echocardiography; assessment of cardiac electrophysiological indexes was measured by electrocardiogram (ECG) and programmed electrical stimulation in isolated cardiac perfusion. Masson was stained for collagen deposition, and wheat germ agglutinin (WGA) was stained for the cross-sectional area of the myocytes. The qRT-PCR and Western Blotting were used to determine target gene expression in vivo and in vitro. Results: PAGln promoted the activation of cardiac inflammation and fibrosis and deteriorated cardiac function in HF mice. Moreover, PAGln extended APD90, shortened the ERP/APD90 and increased the incidence of VAs following HF in isolated heart perfusion. Mechanistically, PAGln significantly enhanced the activation of the TLR4/AKT/mTOR signaling pathway in vivo and in vitro. Conclusions: PAGln increased the susceptibility of VAs in HF mice by activating the TLR4/AKT/mTOR signaling pathway.