Abstract 4356291: Early renal denervation reduces ventricular arrhythmogenesis by improving Angiotensin II-disrupted expression of connexin 43 after acute myocardial infarction

Background: Renal denervation ( RDN ) has been widely studied to treat ventricular arrhythmias. Besides the neuronal and structural remodeling, electrical remodeling of the infarcted heart plays a crucial role in ventricular arrhythmogenesis after acute myocardial infarction ( AMI ). Given that connexin 43 ( Cx43 ) serves as one of the most important ventricular gap junction proteins for maintaining normal cardiac electrical conduction, our study aims to test whether RDN achieves its antiarrhythmic effect through modulating Cx43-regulated electrical activity of the AMI heart. Methods and Results: Rat AMI was induced by surgical ligation of the left anterior descending coronary artery. Completed bilateral RDN was performed immediately after AMI. Terminal experiments were performed at 2 weeks post-AMI. Data from ELISA demonstrated that early RDN reduced AMI-elevated Angiotensin II ( Ang II ) levels in the serum and border zone ( BZ ) of the infarcted heart. IF staining showed that Cx43 demonstrated a linear staining pattern with a homogeneous distribution in the sham heart, whereas its expression was lateralized and illustrated a cluster staining pattern with a heterogeneous distribution in the BZ of the AMI heart. Data from cardiac optical mapping demonstrated that AMI markedly reduced conduction velocity and elongated action potential durations in the left ventricle. More importantly, alongside restoring AMI-decreased protein expression of Cx43, early RDN also improved AMI-induced lateralization and heterogeneous distribution of Cx43 in the BZ of the infarcted heart. 24-hour ECG telemetry recording in conscious rats found that early RDN not only improved AMI-increased heterogeneity of ventricular electrical activity but also reduced the incidence and cumulative duration of ventricular arrhythmias in AMI rats. To validate the contribution of Ang II on cardiac electrical remodeling, Ang II (1.44mg/kg/day) was subcutaneously infused into sham rats for 2 weeks. Our data showed that Ang II infusion induced the lateralization of Cx43 in the sham heart, which was accompanied by an increased heterogeneity of ventricular electrical activity with elevated susceptibility to ventricular arrhythmias in sham rats. Conclusions: These data suggest that early RDN reduces ventricular arrhythmogenesis by damping Ang II-promoted electrical remodeling of the AMI heart. Targeting the Ang II/Cx43 signaling could be a novel therapeutic strategy to treat ventricular arrhythmias after AMI.