NLRP3 inflammasome-driven inflammation as a cause of atrial fibrillation: potential synergistic inhibition of the NLRP3 via upstream magnesium repletion and targeting NLRP3 with a downstream inhibitor

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia. Current therapeutic approaches (antiarrhythmic/rate control medications, anticoagulation, cardioversion, catheter ablation, and cardiac surgery) are effective in selected patients but are associated with adverse effects and significant recurrence rates. These limitations underscore the need for novel adjunctive therapeutic strategies. Substantial biomarker and histopathologic evidence demonstrates chronic inflammation in AF; however, the mechanisms that initiate and sustain this process remain incompletely defined. Emerging evidence suggests that cytokine-driven innate immune activation, rather than adaptive autoimmune mechanisms, is involved, supporting the concept that AF represents a previously unrecognized autoinflammatory disorder. The most widely studied inflammasome protein in AF is NLRP3, a central regulator of innate immunity and a key mechanism controlling the release of the pro-inflammatory cytokines IL-1β and IL-18 that can initiate influx of inflammatory cells causing unchecked inflammation and end-stage fibrosis. Intracellular calcium (Ca 2 +) can stimulate the NLRP3 inflammasome, which can be inhibited upstream by elemental magnesium (Mg 2+ ). The hypothesis proposes that AF is, in part, a dysregulated autoinflammatory condition driven by persistent activation of NLRP3 inflammasome (NLRP3) from endogenous danger-associated molecular patterns (DAMPs) derived from common cardiometabolic conditions, such as obesity, type 2 diabetes mellitus, hypertension, along with AF triggers, especially excessive alcohol and tobacco consumption. Furthermore, NLRP3-mediated inflammation, combined with Mg 2+ deficiency, may contribute to an energy deficit in sinoatrial (SA) node cardiomyocytes, thereby impairing the electrical automaticity that generates sinus rhythm (SR). Lastly, it is hypothesized reduced AF burden may occur by a synergistic therapeutic strategy combining pharmacokinetic-based oral Mg 2+ supplementation with downstream inhibitors of NLRP3. Reports in the medical literature indicating inconsistent clinical efficacy of oral Mg 2+ controlling AF may reflect underappreciation of Mg 2+ pharmacokinetics involving slow intracellular repletion, and suboptimal Mg 2+ formulations. Addressing these factors may bridge the translational gap and enable standardized oral Mg 2+ based adjunctive therapy for AF.