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Chapter Summary

This chapter discusses the role of inflammation in the development of atherosclerotic disease, with lessons from basic science and clinical studies informing future strategies for prevention and treatment. Historically considered a disease driven by dyslipidemia, the central role of inflammation in atherosclerosis has been elucidated in recent years with the concept of residual inflammatory risk as an important contributor to atherosclerotic disease. Various stimuli and insults converge on the immune system leading to activation of multiple immune effectors, including the innate and adaptive immune system, that have key roles in the development of atherosclerosis (see Fuster and Hurst’s Central Illustration). The use of biomarkers and inflammatory intermediaries including C-reactive protein (CRP), interleukin (IL)-1, and IL-6 for risk stratification and mechanistic elucidation is of key interest. Recent therapies targeting inflammatory pathways, including the NLRP3 inflammasome and IL-1 pathway, have shown promise in reducing this residual inflammatory risk for atherosclerosis in high-risk populations, with positive results seen in multiple large clinical trials. In addition, public health efforts to improve nutrition, reduce obesity, and combat environmental pollution will play a role in reducing the inflammatory contribution to atherosclerosis.


The critical role of inflammation in the development and progression of atherosclerotic plaque has opened multiple new avenues for the diagnosis, treatment, and prevention of atherosclerotic cardiovascular disease (ASCVD). Early concepts of ASCVD focused on the critical role of cholesterol deposition in the arterial wall as the main driver of atherosclerosis.1 Cell biology studies then focused on the processes of endothelial dysfunction, smooth muscle cell (SMC) hyperplasia, and SMC proliferation in the arterial intima with subsequent formation of an atherosclerotic plaque.2 The widespread use of statins led to a major leap forward in the prevention and treatment of ASCVD. Yet despite effective anti-lipid therapies, “residual inflammatory risk” has only recently become a target for treatment. As described in this chapter, recent preclinical and clinical trial data have established the key role of inflammation in atherosclerotic disease, ushering in a new paradigm of atherosclerosis.


Immune System Effectors in Atherosclerosis

Pathological examination of atherosclerotic plaques provides insight into the role of the immune system and inflammation in atherosclerosis. Experimental studies in the 1980s revealed that human atherosclerotic plaques contained vascular endothelial cells, smooth muscle cells, lipids, extracellular matrix and lipid- rich debris, and importantly, inflammatory and immune cells including macrophages and T cells.3 Initially, atherosclerotic plaques present as thickening in the intimal layer of the arterial wall. Depending on factors that promote or counteract atherosclerotic disease (such as diet, environmental exposures such as pollution and smoking, blood pressure, lipids, and physical activity), these early atherosclerotic lesions may progress or regress. Mature plaques (atheromas) continue to evolve and have more complex immunological features than these early fatty streaks. ...

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