Evidence for Inflammation as a Driver of Atrial Fibrillation

NLRP3 (NACHT, LRR and PYD domains-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase-1-dependent release of the proinflammatory cytokines, IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical basis of NLRP3 activation and regulation, and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. However, the development of preventative therapies for AF has been disappointing. The infiltration of immune cells and proteins that mediate the inflammatory response in cardiac tissue and circulatory processes is associated with AF. Furthermore, the presence of inflammation in the heart or systemic circulation can predict the onset of AF and recurrence in the general population, as well as in patients after cardiac surgery, cardioversion, and catheter ablation. Mediators of the inflammatory response can alter atrial electrophysiology and structural substrates, thereby leading to increased vulnerability to AF. Inflammation also modulates calcium homeostasis and connexins, which are associated with triggers of AF and heterogeneous atrial conduction. Myolysis, cardiomyocyte apoptosis, and the activation of fibrotic pathways via fibroblasts, transforming growth factor-β and matrix metalloproteases are also mediated by inflammatory pathways, which can all contribute to structural remodelling of the atria. The development of thromboembolism, a detrimental complication of AF, is also associated with inflammatory activity. Understanding the complex pathophysiological processes and dynamic changes of AF-associated inflammation might help to identify specific anti-inflammatory strategies for the prevention of AF.

The role of inflammatory markers in cardiovascular diseases has been studied extensively and a consistent relationship between various inflammatory markers and cardiovascular diseases has been established in the past. Neutrophil to lymphocyte ratio (NLR) is a new addition to the long list of these inflammatory markers. NLR, which is calculated from complete blood count with differential, is an inexpensive, easy to obtain, widely available marker of inflammation, which can aid in the risk stratification of patients with various cardiovascular diseases in addition to the traditionally used markers. It has been associated with arterial stiffness and high coronary calcium score, which are themselves significant markers of cardiovascular disease. NLR is reported as an independent predictor of outcome in stable coronary artery disease, as well as a predictor of short- and long-term mortality in patients with acute coronary syndromes. It is linked with increased risk of ventricular arrhythmias during percutaneous coronary intervention (PCI) and higher long-term mortality in patients undergoing PCI irrespective of indications of PCI. In patients admitted with advanced heart failure, high NLR was reported with higher inpatient mortality. Recently, NLR has been reported as a prognostic marker for outcome from coronary artery bypass grafting and postcoronary artery bypass grafting atrial fibrillation.