Immunopathogenesis and biomarkers of recurrent atrial fibrillation following ablation therapy in patients with preexisting atrial fibrillation

Abstract

Recurrent atrial fibrillation (RAF) following ablation therapy occurs in about 50% of patients. The pathogenesis of RAF is unknown, but is believed to be driven by atrial remodeling in the setting of background inflammation. Structural, electrophysiological and mechanical remodeling has been associated with atrial fibrillation (AF). Inflammation and fibrotic remodeling are the major factors perpetuating AF, as mediators released from the atrial tissues and cardiomyocytes due to mechanical and surgical injury could initiate the inflammatory process. In this article, we have critically reviewed the key mediators that may serve as potential biomarkers to predict RAF. Areas covered: Damage associated molecular patterns, heat shock proteins, inflammatory cytokines, non-inflammatory markers, markers of inflammatory cell activity, and markers of collagen deposition and metabolism are evaluated as potential biomarkers with molecular treatment options in RAF. Expert commentary: Establishing biomarkers to predict RAF could be useful in reducing morbidity and mortality. Investigations into the role of DAMPs participating in a sterile immune response may provide greater insight into the pathogenesis of RAF. Markers evaluating immune cell activity, collagen deposition, and levels of heat shock proteins show the greatest promise as potential biomarkers to predict RAF and develop novel therapies.

Keywords: Arrhythmia; atrial fibrillation; danger associated molecular patterns; fibrosis; heat shock proteins; inflammation; surgical ablation.

Figure 1:

This figure depicts the proposed immunopathogenesis of recurrent atrial fibrillation in the setting of preexisting atrial fibrillation. Existing atrial fibrillation is often due to ectopic focal firing, reentrant pathways, heterogenous impulse conduction, atrial remodeling, and is often associated with background inflammation. Atrial fibrillation is often treated via ablation therapy. Ablation therapy may result in increased levels of damage-associated molecular patterns (DAMPs), inflammatory cytokines, inflammatory cell migration and activity, and collagen remodeling. Together these processes are believed to contribute to atrial remodeling and ultimately recurrent atrial fibrillation. The second half of the diagram below the dashed line shows more specific mediators believed to play a role in the immunopathogenesis of recurrent atrial fibrillation. DAMPs, such as high mobility group box-1 (HMGB-1), mitochondrial DNA (mtNDA), and NLRP3 inflammasome, may be released from cardiomyocytes in response to stress and generate a sterile immune response causing the release of inflammatory cytokines through toll- like receptor (TLR) activation. DAMPs, including heat shock proteins (HSP) 27, 70, and 60, may also play a role in the sterile immune response associated with increased DAMP levels. However, certain HSPs may also have a cardioprotective effect and do not contribute to the pathogenesis of recurrent atrial fibrillation. Inflammatory cytokines, such as C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), and interleukin-6 (IL-6), have been associated with recurrent atrial fibrillation. The major contribution of these inflammatory cytokines in the progression of recurrent atrial fibrillation includes the recruitment of inflammatory cells such as polymorphonucleocytes (PMNs), macrophages, and fibroblasts. Once recruited, these cells infiltrate the atria and begin removing cell debris and increase metabolism of the extracellular matrix (ECM). Additionally, cytokines such as transforming growth factor-beta 1 (TGF-β1) stimulate fibroblasts to increase ECM, mainly through collagen deposition. TGF-β1 may be secreted in response to increased levels of angiotensin-II (AT-II). Increased inflammatory cell activity leads to increased ECM metabolism and ultimately fibrotic remodeling of the atria, which is believed to be the major factor leading to recurrent atrial fibrillation.

Figure 2:

This figure depicts different roles of intracellular and extracellular heat shock proteins (HSPs). The left panel demonstrates the protective effects of intracellular HSPs. Cells are exposed to stress such as ischemia, reactive oxygen species, or inflammation, which result in increased activity of intracellular HSPs like HSP27, HSP70 and HSP60. These HSPs act as molecular chaperones to prevent protein misfolding and degradation, and ultimately serve to mitigate cellular remodeling. The panel on the right depicts the events when a cardiomyocyte is exposed to severe stress. The cardiomyocyte responds by upregulating HSPs until they are present on the surface of the cell in the extracellular environment. Extracellular HSPs are proinflammatory, and their presence may result in myocyte injury or myolysis, contributing to atrial remodeling.

Figure 3:

This figure depicts the potential mechanism of collagen deposition associated with atrial fibrosis. TGF-β1 transforms fibroblast into myofibroblast and encourages procollagen synthesis. Inflammatory cytokines, including IL-2, IL-6, TNF-α, act with myofibroblasts to promote collagen deposition. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) influence ECM remodeling and create collagen breakdown byproducts. Fibrotic remodeling is the strongest factor perpetuating atrial fibrillation and is most likely the most influential process driving recurrence.