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Anti-inflammatory therapeutics for the treatment of atherosclerosis

Nature Reviews Drug Discovery volume 10, pages 365–376 (2011)Cite this article

Subjects

Key Points

  • Atherosclerosis is the primary cause of major adverse cardiovascular events (MACE) — that is, coronary artery disease, heart attacks and stroke — and is thus the underlying pathology of the leading causes of death in the western world.

  • Traditionally, atherosclerosis was conceptualized as a progressive narrowing of artery lumen resulting from accumulation of cholesterol-rich plaque, which ultimately leads to plaque rupture, thrombosis and MACE. Accordingly, therapeutic efforts were directed at lowering blood cholesterol levels and addressing other cardiovascular risk factors.

  • Although cardiovascular risk can be substantially lowered by hydroxy-3-methylglutaryl-CoA reductase inhibitors or statins, which reduce low-density lipoprotein cholesterol, or antihypertensives and antithrombotics, the residual risk of another MACE in these patients is estimated to be 70–80%.

  • It is becoming increasingly clear that inflammation within the arterial vessel wall and development of atherosclerotic plaques represent equally important and poorly treated contributors to MACE. Evidence now indicates that inflammation is a driver of cardiovascular mortality.

  • Several major clinical trials with statins — which have an anti-inflammatory action — have demonstrated that reducing inflammation has a major therapeutic benefit.

  • Several key anti-inflammatory targets have been identified and associated therapeutics are now being developed for the treatment of MACE — these include phospholipase A2 inhibitors, antileukotrienes and anticytokine therapeutics.

  • However, difficulties remain in assessing the potential of novel anti-inflammatory therapeutics to reduce MACE because of the high cost, duration and large numbers of patients required to conduct cardiovascular outcome clinical trials. In addition, there are currently no accepted surrogate end points for the reduction of MACE, although recent advances have been made in the use of biomarkers and imaging techniques.

Abstract

Atherosclerosis is the primary cause of heart disease and stroke and is thus the underlying pathology of the leading causes of death in the western world. Although risk can be reduced by lowering lipid levels, the equally important contribution of inflammation to the development of cardiovascular disease is not adequately addressed by existing therapies. Here, we summarize the evidence supporting a role for inflammation in the pathogenesis of atherosclerosis, discuss agents that are currently in the clinic and provide a perspective on the challenges faced in the development of drugs that target vascular inflammation.

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Figure 1: Model of an atherosclerotic plaque showing some of the key inflammatory mechanisms involved.
Figure 2: The phospholipase A2 pathways that result in the generation of foam cells and atherogenic lipids, and the leukotriene pathway with enzymatic steps depicted.

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Acknowledgements

The authors would like to thank D. Jones for his assistance in the preparation of this manuscript. This work was supported by the US National Institutes of Health grant R01 HL052773 (I.C.).

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Authors and Affiliations

  1. Gladstone Institute of Cardiovascular Disease, 1650 Owens Street #149, San Francisco, 94158, California, USA

    Israel F. Charo

  2. Research & Development, VIA Pharmaceuticals, 500 Office Center Drive, Suite 400, Fort Washington, 19034, Pennsylvania, USA

    Rebecca Taub

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Correspondence to Israel F. Charo or Rebecca Taub.

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Competing interests

Israel F. Charo is a member of the scientific advisory boards of ChemCentryx Inc. and VIA Pharmaceuticals, and a consultant for Bay City Capital.

Rebecca Taub is an employee, stockholder and officer of VIA Pharmaceuticals, which has an interest in developing therapeutics including leukotriene inhibitors to treat cardiovascular disease.

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Glossary

Low-density lipoprotein

(LDL). LDL is one of the five major groups of lipoproteins that enable lipids such as cholesterol and triglycerides to be transported within the bloodstream.

Major adverse cardiovascular events

(MACE). A composite of cardiovascular events, typically including unstable angina, myocardial infarction, stroke and cardiovascular-related death.

Myocardial infarction

(MI). An event caused by occlusion of coronary blood flow, typically resulting from the rupture of a coronary atherosclerotic plaque and subsequent thrombosis leading to damage to the heart muscle.

Acute coronary syndrome

(ACS). Acute cardiovascular ischaemia resulting in unstable angina pectoris or myocardial infarction owing to impairment of blood flow within a coronary artery.

ST-segment elevation

An ST-segment elevation refers to a finding on a 12-lead electrocardiogram, in which the trace in the ST-segment is abnormally high above the isoelectric line. The finding of ST-segment elevations in select leads is consistent with myocardial infarction.

LDL cholesterol

(LDL-C). A measurement of the amount of cholesterol in the blood that is associated with low-density lipoprotein (LDL) particles. High LDL-C is associated with atherosclerotic cardiovascular disease.

High density lipoprotein

(HDL). A dense lipoprotein that forms complexes with cholesterol, which is typically composed of a number of lipoproteins such as apolipoprotein A1, apolipoprotein A2 and other components. HDL transports cholesterol from the peripheral tissue in the body to the liver where it is secreted as biliary cholesterol or bile salts.

Intima medial thickness

(IMT). The thickness of the intima within the carotid arteries as measured by an echocardiogram is correlated with the level of atherosclerotic disease.

C-reactive protein

[CRP]. An acute phase protein that correlates with inflammatory disease processes, including atherosclerotic cardiovascular disease.

High-sensitivity CRP

(hsCRP). An assay that was developed to more accurately measure levels of C-reactive protein (CRP) in the blood, particularly relatively low levels of CRP.

Myeloperoxidase

(MPO). A protein that is expressed in the granules of most leukocytes, including neutrophils and monocytes. It is linked to inflammation and oxidative stress, and correlates with cardiovascular risk. MPO is released by leukocytes in a state of inflammation and it catalyses the formation of several reactive species. It has a role in the host defence against microorganisms.

Troponin

A complex of three proteins (troponin T, troponin I and troponin C) that bind to the thin filament (actin) of striated muscle, which regulates muscle contraction. Following injury to heart muscle cells, the intact troponin complex, along with free troponin subunits, is released into the blood. The amino acid sequences for cardiac troponin T and troponin I isoforms are considerably different from their skeletal muscle counterparts and levels of troponin T can therefore be used to measure heart damage.

Intravascular ultrasound

(IVUS). An invasive technique in which an ultrasound device is inserted into the coronary arteries via a catheterization procedure.

Phospholipase A2

(PLA2). A series of phospholipases that hydrolyse the N2 ester bond of phospholipids to release fatty acid products and lysophospholipids.

Lipoprotein-associated PLA2

(Lp-PLA2; also known as PAFAH). A phospholipase A2 (PLA2) enzyme that travels mainly with low-density lipoprotein (LDL). It is an enzyme that is produced by inflammatory cells and hydrolyses oxidized phospholipids in LDL.

Secretory PLA2

A group of several secreted phospholipases, some of which are induced during inflammatory responses and/or are associated with oxidized low-density lipoprotein (LDL)-cholesterol particles. Proposed to be involved in the generation of atherogenic fatty acids.

Leukotrienes

Inflammatory mediators that are produced mainly by white blood cells, macrophages and mast cells, and are composed of leukotriene B4 (LTB4) and cysteinyl leukotrienes LTC4, LTD4 and LTE4.

Arachidonate 5-lipoxygenase

(5-LO).The rate limiting enzyme in the production of leukotrienes.

5-LO-activating protein

(FLAP). A protein that is responsible for activating the arachidonate 5-lipoxygenase (5-LO) enzyme within the leukotriene pathway.

Chemokine CC motif ligand 2

(CCL2; also known as MCP1). A peptide that binds to the chemokine CC motif receptor 2 (CCR2) and is important in monocyte migration and inflammation.

Chemokine receptor 2

A chemokine receptor for chemokine CC motif ligand 2 (CCL2), which is a chemokine that specifically mediates monocyte chemotaxis and inflammation.

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Charo, I., Taub, R. Anti-inflammatory therapeutics for the treatment of atherosclerosis. Nat Rev Drug Discov 10, 365–376 (2011). https://doi.org/10.1038/nrd3444

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