We have read with great interest a study reported by Kopytek et al1 titled “NETosis is associated with the severity of aortic stenosis: Links with inflammation.” In this study, the authors suggested that neutrophils play a critical role in the progression of aortic valve stenosis (AS).
AS is prevalent in the elderly. Three primary processes including lipid accumulation, inflammation, and calcification are regarded to be involved in the pathophysiology of calcific aortic valve disease. Clinical studies provide evidence that inflammation initiates degenerative valve disease and valvular calcification. The inflammatory system, comprised specialized cells and mediators, is responsible for complex responses to all forms of AS at different stages.2 Inflammation in AS can be activated by leukocytes, macrophages, mast cells, fibroblasts, and endothelial cells. Previously, neutrophils have not been considered in the pathophysiology of atherosclerosis. However, recent studies have demonstrated that an increased ratio of neutrophils to lymphocytes was related to the severity of calcific AS in patients, and current evidence suggests a contributory role of neutrophils in the progression of AS.3 Interestingly, this human study provides the direct evidence that neutrophils may contribute to the progression of AS.
AS has a close association with atherosclerosis, similarly in the progression of chronic inflammation. Because of their relatively short lifespans, neutrophils have received little attention in the pathophysiology of atherosclerosis. Over the past decades, however, advances in techniques have allowed for more sensitive detection of neutrophils in atherosclerotic plaque specimens. This has allowed for investigations into the exact mechanistic role of neutrophils in atherosclerotic lesions.4
Similarly, several mechanistic roles of neutrophils in the development of AS should be considered as follows (Fig. 1).5 First, neutrophils aggravate endothelial dysfunction by inducing changes in endothelial permeability. Elevated lipid levels activate prime neutrophils, which may then secrete the radical species and granule proteins, subsequently inducing endothelial dysfunction. Endothelial dysfunction enhances adhesive cytokine expression and increases leakiness. Second, neutrophils favor the recruitment of monocytes to the aortic valve. It has been shown that neutrophil-derived cytokine enhancement could increase expression of cell adhesion molecules and subsequently increase adhesion of monocytes. Third, neutrophils activate macrophages and promote macrophage polarization. Macrophages participate in the progression of AS at all stages. Neutrophils not only promote macrophage maturation, but also induce the M1 macrophage phenotype. Furthermore, neutrophils promote normal matrix degradation and fibrosis formation. Neutrophil elastase and MMPs secreted by neutrophils may promote cellular proliferation and extracellular matrix remodeling by acting on valvular fibroblasts. Finally, the neutrophil–lymphocyte ratio is associated with coronary artery calcification.6 However, further studies are needed to determine whether neutrophils play a direct role in the calcification.
Taken together, neutrophils affect the progression of AS at all stages with a mechanism similar to mechanisms of inflammation.
1. Kopytek M, Kolasa-Trela R, Ząbczyk M, et al. NETosis is associated with the severity of aortic stenosis: Links with inflammation. Int J Cardiol. 2019;286:121–126.
2. Lee SH, Choi JH. Involvement of immune cell network in aortic valve stenosis: communication between valvular interstitial cells and immune cells. Immune Netw. 2016;16:26–32.
3. Avci A, Elnur A, Göksel A, et al. The relationship between neutrophil/lymphocyte ratio and calcific aortic stenosis. Echocardiography. 2014;31:1031–1035.
4. Rajamannan NM, Evans FJ, Aikawa E, et al. Calcific aortic valve disease: not simply a degenerative process: a review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: calcific aortic valve disease-2011 update. Circulation. 2011;124:1783–1791.
5. Oliver Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res. 2012;110:875–888.
6. Nam SH, Kang SG, Song SW. The neutrophil-lymphocyte ratio is associated with coronary artery calcification in asymptomatic Korean males: a cross-sectional study. Biomed Res Int. 2017;2017:1989417.