Inflammatory processes in cardiovascular disease: a route to targeted therapies

Abstract

Inflammatory processes are firmly established as central to the development and complications of cardiovascular diseases. Elevated levels of inflammatory markers have been shown to be predictive of future cardiovascular events. The specific targeting of these processes in experimental models has been shown to attenuate myocardial and arterial injury, reduce disease progression, and promote healing. However, the translation of these observations and the demonstration of clear efficacy in clinical practice have been disappointing. A major limitation might be that tools currently used to measure 'inflammation' are insufficiently precise and do not provide information about disease site and activity, or discriminate between functionally important activation pathways. The challenge, therefore, is to make measures of inflammation that are more meaningful, and which can guide specific targeted therapies. In this Review, we consider the roles of inflammatory processes in the related pathologies of atherosclerosis and acute myocardial infarction, by providing an evaluation of the known and emerging inflammatory pathways. We highlight contemporary techniques to characterize and quantify inflammation, and consider how they might be used to guide specific treatments. Finally, we discuss emerging opportunities in the field, including their current limitations and challenges that are the focus of ongoing study.

Figure 1

Biological pathways central to the pathogenesis of acute myocardial infarction (AMI). Immediately following AMI, a number of local processes are activated with release of reactive oxygen species and cytokines with infiltration of circulating neutrophils and monocytes resulting in acute myocardial injury. Simultaneously a number of remote sites are also activated (e.g. spleen, bone marrow) via signalling pathways that result in further activation of the immune system and injury. Following this, a reparative phase ensues predominantly mediated by monocytes and T-lymphocytes resulting in tissue repair and recovery with upregulation of processes involved in angiogenesis and extracellular matrix deposition. Abbreviations: ROS: reactive oxygen species; TLR: toll-like receptors; DAMPS: damage associated molecular patterns; HSP: heat shock proteins; HMGB1: high mobility group box 1 protein; VCAM: vascular cell adhesion molecule; NLR: NOD-like receptor; NLRP3: NOD-like receptor family pyrin domain containing 3; IL: interleukin; TNF: tumour necrosis factor; IFN: interferon; CX3CR1: CX3 chemokine receptor 1; miRNA: micro ribonucleic acid; CRP: C reactive protein; SAA: serum amyloid A.

Figure 2

Biological processes central to the pathogenesis of atherosclerosis. Endothelial cells, lymphocytes, smooth muscle cells, monocytes, and macrophages are all involved in the pathogenesis of atherosclerosis from earliest foam cell formation through to development of advanced plaques. Initial activation of the endothelium from disruptions to normal shear stress result and facilitate deposition of lipid in the subendothelial space. Endothelial activation also promotes recruitment of circulating monocytes where they terminally differentiate into macrophage or differentiate and locally proliferate into distinct functional phenotypes. Activated macrophages take up lipid and results in their transformation into macrophage-derived foam cells. As the foam cell population grows within lesions in the arterial wall, the rate of accumulation exceeds the rate of clearance, and eventually the foam cells coalesce into a lipid-rich necrotic core. Abbreviations: VCAM: vascular cell adhesion molecule; ICAM: intercellular cell adhesion molecule; CCR: chemokine-chemokine receptor; CX3CR1: CX3 chemokine receptor; IL: interleukin; TNF: tumour necrosis factor; ApoB: Apoliporotein B; CRP: C reactive protein; SAA: serum amyloid A; MMP: matrix metalloproteinase; NLRP3: NOD-like receptor family pyrin domain containing 3; VSMC: vascular smooth muscle cells.