<scp>IL</scp> ‐6 in the spotlight: From cardiovascular pathophysiology to therapy
Alberto Preda, Amedeo Tirandi, Giulio Leo, Davide Di Vece, Gemma Vilahur, Aldo Bonaventura, Elena Osto, Stefano Ministrini, Simon Kraler, Petra Kleinbogard, Giovanni G. Camici, Federico Carbone, Fabrizio Montecucco, Luca Liberale
Abstract
BACKGROUND: Interleukin-6 (IL-6), a pro-inflammatory cytokine and anti-inflammatory myokine, is involved in immune regulation and metabolic control. Persistent IL-6 activation, particularly via trans-signalling, is implicated in endothelial dysfunction, atherosclerosis, myocardial fibrosis, and adverse remodelling. METHODS: This review summarizes experimental, genetic, and clinical evidence on the role of IL-6 in cardiovascular disease (CVD), focusing on the molecular pathways, prognostic value, and its potential as a therapeutic target. Experimental and genome-wide association studies, as well as clinical trials-including IL-6-targeted interventions-are comprehensively reviewed. RESULTS: While acute activation of IL-6/STAT signalling, that is, before or during myocardial infarction, is protective, chronic activation leads to maladaptive changes in the myocardium. Mechanistically, IL-6 promotes vascular inflammation, monocyte recruitment, coagulation, and fibrosis. Mendelian randomization implies a causal role of IL-6 signalling in coronary artery disease, stroke, and atrial fibrillation. Simultaneously, elevated IL-6 levels predict adverse outcomes in acute coronary syndromes and heart failure. Pharmacological IL-6 inhibition reduces systemic inflammation, with pilot data implying acceptable safety profiles. Large phase III outcome trials are ongoing, shedding light on the impact of IL-6 blockade in high-risk populations, such as those with chronic kidney disease and heart failure with preserved or mildly reduced ejection fraction. CONCLUSIONS: IL-6 plays a dual role-protective versus pathogenic and acute versus chronic. Chronic IL-6 links inflammation and metabolic dysregulation to structural cardiovascular damage. Chronic IL-6 activation requires therapeutic approaches tailored to disease context, timing and signalling mode. The results of ongoing trials will clarify whether IL-6-targeted interventions can be integrated into cardiovascular prevention and management strategies, complementing established therapies and addressing residual inflammatory risk.