CCL4 Enhances Left Stellate Ganglion Sympathetic Activity and Aggravates Ventricular Arrhythmias After Myocardial Ischemia Reperfusion

Background: Excessive left stellate ganglion (LSG) activity contributes to ventricular arrhythmias (VAs) after myocardial ischemia reperfusion (I/R). C-C motif chemokine ligand 4 (CCL4) is an inflammatory chemokine involved in neuroimmune signaling. However, whether CCL4 contributes to LSG activation and VAs after myocardial I/R remains unclear. Methods: We enrolled 98 patients with acute myocardial infarction undergoing emergency percutaneous coronary intervention (PCI) and assessed circulating CCL4, norepinephrine (NE), heart rate variability, and 24-h VAs. In beagles, CCL4 or CCL4 plus a neutralizing antibody was locally microinjected into the LSG before myocardial I/R. LSG neural activity and function, myocardial sympathetic and inflammatory indices, ventricular electrophysiology, and VAs were evaluated. C-C chemokine receptor type 5 (CCR5) expression and localization, together with local immune inflammatory changes, were assessed within the LSG. Results: Patients who developed VAs during post-PCI monitoring had higher circulating CCL4 levels both before PCI and at 1 h after PCI reperfusion, and the increase in CCL4 from pre-PCI to 1 h post-PCI was significantly greater. CCL4 at 1 h post-PCI correlated with sympathetic-related indices and 24-h ventricular premature beat burden, and remained independently associated with VAs after multivariable adjustment. In beagles, myocardial I/R increased endogenous CCL4 mRNA expression in the LSG. Local CCL4 administration enhanced LSG neural activity and function, increased myocardial TH-positive area and pro-inflammatory cytokine mRNA expression, shortened effective refractory period and action potential duration at 90% repolarization, and promoted VAs, whereas CCL4 neutralization attenuated these effects. CCR5 partially colocalized with tyrosine hydroxylase-positive sympathetic neurons. CCR5 expression and c-Fos activation were increased after I/R and further enhanced by CCL4. CCL4 also increased the numbers of Iba1-, CD3-, and CD11c-positive cells and inflammatory responses within the LSG. Conclusions: Clinically, circulating CCL4 was associated with VAs after PCI. In the canine I/R model, local CCL4 administration enhanced LSG sympathetic activity and ventricular arrhythmia susceptibility, potentially involving CCR5-related and local inflammatory processes.