ReviewExtrinsic and Intrinsic Responses in the Development and Progression of Atherosclerosis
Introduction
Atherosclerosis is recognised as a multifactorial disease that is thought to be primarily inflammatory in origin. Given the contribution of inflammation to the development and progression of atherosclerosis, other conditions that are characterised by a dysregulated inflammatory response have also been proposed to play a role, either via enhanced risk, increased progression or increased cardiovascular events. The purpose of this review is to organise and present the various inflammatory processes which may affect atherosclerosis into two broad categories: extrinsic or host-independent and intrinsic or host-dependent. A review of findings from recent clinical trials investigating treatments to reduce inflammation is also provided, along with the discussion of their impact on our knowledge of cardiovascular disease (CVD) and events. Finally, we propose a classification system that incorporates the contribution of inflammatory conditions in the pathogenesis of atherosclerosis (Figure 1).
Section snippets
Atherosclerosis – An Inflammatory Disease of the Cardiovascular System
Atherosclerosis is a disease that was once thought of as an accumulation of cholesterol in the arterial wall, further complicated by smooth muscle cell proliferation and endothelial damage. Later work identified the existence of immune cells and mediators in atherosclerotic lesions, suggestive of a role for inflammation [1]. Now, inflammation is recognised as playing a key regulatory role in the development and progression of atherosclerosis, linking multiple risk factors and altered arterial
Extrinsic Host-Independent Processes and Their Contribution to Atherosclerosis
Extrinsic contributions to inflammatory response are external, host-independent causes, including biologic and chemical/physical factors. Following exposure to these factors, the body produces an immune or inflammatory response, which may contribute to the development and/or progression of atherosclerosis. Below are the individual extrinsic contributions and their proposed role in atherosclerosis.
Intrinsic Host-Dependent Processes and Their Contribution to Atherosclerosis
Intrinsic contributions to inflammatory response include internal, host-dependent causes, including autoimmune responses, neurological and other metabolic processes. Following exposure to these internal changes, the body can produce an immune or inflammatory response which may contribute to the development and/or progression of atherosclerosis.
The Complement Activation System
The contribution of complement activation to the development and progression of atherosclerosis is also important to acknowledge. Given its role as a rapid effector system in vasculature injury to promote platelet activation and fibrin formation as well as impair fibrinolysis, this process may also play a role in atherosclerosis [105]. A small study has revealed associations between complement factors and cardiovascular risk in patients who were followed for 7 years. Although relatively small,
Anti-Inflammatory Treatments and Atherosclerosis
Given its role in the initiation and progression of atherosclerosis, reducing inflammation may represent a key strategy to reduce CVD. Several trials have investigated the impact of reducing inflammation on cardiovascular events and mortality. The Canakinumab Antiinflammatory Thrombosis Outcome (CANTOS) trial investigated the use of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β (IL-1β) in patients with a previous myocardial infarction and elevated hsCRP levels.
Conclusions
Inflammation is now recognised as a key regulator in the initiation and development of atherosclerosis. Many other chronic inflammatory diseases are also thought to increase the risk of CVD through enhanced inflammation and/or increased cardiovascular events. As a result, treatments that reduce inflammation have been proposed to be beneficial in reducing cardiovascular events. Several large trials conducted to date have had mixed results. This may be due to several factors including the patient
Funding Sources
This work did not receive any funding.
Conflicts of Interest
The authors declare no competing or conflicts of interest.
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