Vascular inflammation

Journal of the American Society of Hypertension 1(1) (2007) 68 – 81

Vascular inflammation Valentin Fuster, MD, PhD*, and Javier Sanz, MD The Zena and Michael A. Wiener Cardiovascular Institute/Marie-Josee and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, New York, USA Manuscript received and accepted November 10, 2006

Abstract Inflammation of the vessel wall is involved in all stages of the course of atherothrombotic disease, from the development of early lesions to the occurrence of clinical events. Significant advances in recent years have largely improved our understanding of this phenomenon and of its influence not only on atherogenesis, but also on other intimately related disorders such as arterial hypertension or the metabolic syndrome. Emerging imaging technologies as well as measurement of serum concentrations of specific biomarkers offer the possibility to detect and, to some extent, quantify the degree of chronic vascular inflammation in vivo. In addition, many standard and novel antiatherosclerotic therapies may exert beneficial effects through antiinflammatory actions. As a result, detection and treatment of vascular inflammation are certain to become increasingly important in the management with patients of cardiovascular disease. © 2007 American Society of Hypertension. All rights reserved. Keywords: Atherosclerosis; inflammation; imaging; biomarkers.

Arterial hypertension (HTN) is a well-known risk factor for the development of atherosclerotic disease, in turn a major determinant of clinical outcome in hypertensive subjects. There is increasing evidence that the pro-atherogenic effects of HTN are, at least in part, mediated through inflammatory mechanisms.1 At the same time, inflammation plays key pathogenic roles at all stages of atherosclerotic disease, from the formation of early lesions to the development of acute complications leading to clinical events (Figure 1). Therefore, inflammatory processes exert a crucial influence in the pathogenesis of vascular disease related both to HTN and atherothrombotic disease. This review focuses on the inflammatory components of atherothrombosis, and potential

Conflict of interest: none. *Corresponding author: Valentin Fuster, MD, PhD, The Mount Sinai Medical Center, One Gustave I. Levy Place, 1190 5th Avenue, New York, New York 10029. Tel: 212-241-7911; fax: 212423-9488. E-mail: [email protected]

implications in the diagnosis and management of cardiovascular disease. Inflammation in Atherothrombosis Formation and Progression of Atherosclerotic Lesions Endothelial dysfunction is traditionally considered the initial event in atherogenesis. Both mechanical and chemical factors may lead to loss of normal endothelial physiology. Low or oscillatory shear stress, typically near bifurcations or bending areas, predisposes to the development of atherosclerotic lesions by modulating gene expression/ repression.2 Traditional cardiovascular risk factors cause endothelial damage through various biohumoral mechanisms such as chemical irritants, advanced glycation end-products, or increased plasmatic concentrations of cholesterol, vasoactive amines, and immunocomplexes.3 The final consequence is a reduction in nitric oxide (NO) through a combination of impaired activity of endothelial NO synthase (eNOS) and enhanced

1933-1711/07/$ – see front matter © 2007 American Society of Hypertension. All rights reserved. doi:10.1016/j.jash.2006.11.005

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Figure 1. Scheme of atherogenesis with special emphasis on the role of inflammatory processes. Explanation in Inflammation in Atherothrombosis section. AGE, advanced glycation end products; CAM, cell adhesion molecules; IC, immunocomplex; IEL, internal elastic lamina; LDL, low-density lipoprotein cholesterol; MMP, matrix metalloproteinase; ROS, reactive oxygen species; TF, tissue factor; VSMC, vascular smooth muscle cell. Modified with permission from J Am Coll Cardiol 2005;46:937–54.3

degradation of NO by reactive oxygen species (ROS). NO is the central molecule in the metabolic activity of the endothelium, and exerts multiple anti-atherogenic (including anti-inflammatory) effects.4 The loss of endothelial function favors the internalization of low-density lipoproteins (LDLs), which can be then modified through oxidation or enzymatic action. Modified LDL is retained within the intima and acts as a potent trigger for inflammation.5 Modified LDL as well as shear stress induces the expression in the endothelial cell surface of various cell adhesion molecules (such as vascular cell adhesion molecule-1, intercellular adhesion molecule [ICAM]1, E-selectin, or P-selectin) and inflammatory mediators.3,6 Adhesion molecules enable attachment and internalization of leukocytes into the vessel wall, and different chemokines, such as monocyte chemoattractant protein-1 (MCP-1), promote recruitment of monocytes, T-lymphocytes, and mast cells. Within the plaque, macrophage-colonystimulating factor causes monocytes to differentiate into macrophages, which is accompanied by up-regulation of pattern-recognition scavenger receptors SR-A and CD-36. Through these receptors, macrophages internalize modified LDL, becoming foam cells. Activated macrophages are a source of cytokines, ROS, growth factors, and metalloproteinases (MMPs) with important roles

in perpetuation of the inflammatory response, proliferation of vascular smooth muscle cells (VSMCs), and formation of extracellular matrix. All of these processes contribute to plaque growth and expansion. Moreover, activated T-cells release cytokines such as interferon-␥, tumor necrosis factor (TNF), and interleukins (ILs) such as IL-6 or IL-1 that further activate macrophages, endothelial cells, and VSMCs.7 In addition to these innate (non-specific) immune responses, there is evidence that adaptive (antigen-specific) immunity plays a role in atherosclerosis. Candidate-triggering antigens include oxidized LDL (oxLDL), heat shock proteins, phospholipids, or microorganisms.8 In addition to surface receptors, oxLDL may bind to nuclear receptors such as liver X receptors (involved in macrophage activation as well as cholesterol metabolism) or Toll-like receptors (TLRs).8 TLRs, like scavenger receptors, are part of the innate immune system, although, as opposed to the latter, they can initiate an intracellular signaling activation cascade.7 The activation of TLRs leads to expression of pro-inflammatory genes with a globally pro-atherosclerotic influence in the vessel wall, as suggested by both experimental and epidemiological studies.9,10 Exogenous ligands for TLRs include components of different micro-organisms, representing another

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possible link between chronic infections and atherogenesis.11 There are also endogenous ligands that can be found in atherosclerotic lesions, such as heat shock protein, necrotic cells, markers of apoptosis, or, importantly, oxLDL.12 One central mediator of atherogenesis is the nuclear factor (NF) ␬B, a family of transcription factors involved in the regulation of dozens of genes with roles in the formation of early atherosclerotic lesions, cell survival, and proliferation, or inflammatory and immune responses. NF␬B is sensitive to oxidative stress levels, and its activation also occurs through signaling pathways triggered by cell membrane receptor activated by TNF, ILs, TLRs, or the complex CD40-CD40 ligand.13,14 Another important group of ligand-activated transcription factors is the peroxisome proliferatoractivated receptor (PPAR) family. Current evidence supports an antiatherogenic role of the PPAR-␣ and PPAR-␥ subtypes, which favor cholesterol efflux from macrophages and reverse cholesterol transport.15 PPAR activation, in part through interference with the NF␬B pathway, globally exerts anti-inflammatory actions in the vascular wall.16 –18 Plaque Disruption Inflammation also plays a prominent role in advanced stages of atherosclerosis where it strongly influences the likelihood of plaque disruption. Most acute coronary syndromes are triggered by the rupture of the plaque’s fibrous cap, more common in lesions with a large lipid core and a thin cap. Ruptured plaques often demonstrate dense inflammatory infiltrates, particularly at the site of disruption, and this finding is more prominent in diabetic patients.19,20 Inflammatory cells may favor plaque rupture by releasing MMPs that induce degradation of the fibrous cap collagen, eccentric remodeling, or disruption of the internal elastic lamina.21–23 In approximately one third of acute coronary syndromes, no plaque rupture is noted, although superficial endothelial erosion can be seen. This may be mediated by apoptotic death of endothelial cells induced by activated macrophages or inflammatory cytokines.24,25 Cells undergoing ap-

optosis release tissue factor (TF), a potent procoagulant with increased concentration in human atherosclerotic plaques.26 Intraplaque TF levels correlate with the degree of macrophage infiltration, and co-localize with apoptotic macrophages present in lipid-rich lesions.27,28 These findings suggest that macrophages, possibly a defense mechanism attracted to the plaque in an attempt to eliminate extracellular excess lipid, undergo apoptotic death perhaps after failing to achieve their mission. When TF is exposed to the circulating blood upon plaque rupture, it can act as a trigger for acute thrombosis. Moreover, activated platelets interacting with circulating monocytes can be another source of TF that increases blood thrombogenicity in a manner modulated by cardiovascular risk factors.29 Plaque Neovascularization There is increasing evidence of a significant role of neovascularization both in early and advanced stages of atherosclerosis. Neovessels grow from peri-arterial vasa vasorum into the adventitia and media when intima thickening results in impaired oxygen diffusion from the lumen. Hypoxia leads to the activation of hypoxia-inducible factor (HIF)-␣ that up-regulates multiple target genes, including pro-angiogenic growth factors.30 Interestingly, HIF-␣ can also be activated through oxygen-independent mechanisms that involve inflammatory cytokines, indicating a crucial role of inflammation in the angiogenic response.3 In advanced lesions, the extent of neovascularization correlates with the degree of macrophage and lymphocyte T infiltration, and is associated with features of plaque vulnerability and with plaque rupture.31 Newly formed capillaries appear to act as a pathway for the entry of macrophages into the plaque,32 suggesting that they may develop in an attempt to “deliver” phagocytes with the ability to remove excess extracellular fat. However, due to increased permeability of these neovessels, red blood cell extravasation and even intraplaque hemorrhage, a promoter of plaque growth, may occur.33,34 After red blood cell degradation, free extracellular hemoglobin acts as a potent prooxidant and pro-inflammatory stimulus. Hapto-

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globin rapidly binds to extracellular hemoglobin in attempt to prevent this toxicity, and the complex is phagocytosed by macrophages through specific scavenger receptors.35 Interestingly, polymorphisms of the haptoglobin gene confer different antioxidant protection and cardiovascular risk, particularly in the diabetic population.36,37 In summary, microvessels, though initially constitute probably a defense mechanism, paradoxically may facilitate an excessive inflammatory reaction with final deleterious consequences. Metabolic Syndrome (MS)/Diabetes Mellitus The metabolic syndrome (MS) is intimately related to HTN and associated with increased risk for the development of type 2 diabetes and atherosclerotic disease (Figure 2). Resistance to insulin, a hormone with direct anti-inflammatory properties, is a key etiopathogenic component of the syndrome. Growing evidence supports a proinflammatory state as the underlying substrate for the development and potentiation of insulin resistance in MS. Adipocytes release adipokines with both pro-inflammatory (leptin, resistin) or antiinflammatory (adiponectin) actions.7 In addition, the adipose tissue in obese subjects is a source of inflammatory mediators, such as IL-6, TNF, or complement reactive protein (CRP).38 Release of a large enough amount of such mediators may result in interference with insulin transduction at the receptor level, as well as pro-atherogenic endothelial dysfunction and oxidative stress.38,39 Indeed, elevated inflammatory markers predict the development of type 2 diabetes.40 Inflammation and HTN HTN is associated with activation of circulating monocytes that results in increased production of cytokines, as well as with inflammatory infiltration of damaged target organs.41 Several lines of evidence suggest an inflammatory component in the genesis of HTN. Angiotensin-converting enzyme (ACE) is produced locally in atherosclerotic lesions in areas of inflammatory infiltration.42 Cytokines such as TNF-␣ can induce endothelial and

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smooth muscle cell dysfunction as well as sympathetic activation, thus contributing to blood pressure elevation.43 There are significant correlations between the degree of HTN and the plasmatic levels of IL-6 or ICAM-1.44 Similarly, elevated levels of CRP correlate with pulse pressure and portend increased risk of future development of HTN.45,46 Whether CRP is a mere bystander or plays a pathogenetic role remains controversial.47 Potential mechanisms by which CRP might directly favor the development of HTN include increases in angiotensin II receptors or endothelin1.48,49 In addition, HTN itself may promote vascular inflammation. Angiotensin II increases the production of ROS in the vessel wall, exerts proinflammatory actions (mediated, in part, by reductions in NO availability and activation of NF␬B), and can activate macrophages through specific membrane receptors.41,50 Endothelin-1 also has NF␬B-mediated pro-inflammatory effects that can be ameliorated with endothelin receptor blockers.51 In addition, HTN-related mechanical stress per se may induce production of adhesion molecules or chemokines from endothelial cells, smooth muscle cells, or macrophages.41,52 Imaging of Vascular Inflammation The ability to directly visualize vascular inflammation as an index of disease activity could have important prognostic and therapeutic implications. Several invasive techniques, most commonly used for the evaluation of the coronary arteries, offer such potential. Optical coherence tomography has superb spatial resolution (5 to 20 ␮m) and has been shown to directly visualize macrophage accumulation.53 Thermography catheters can measure temperature heterogeneity associated with inflammatory processes. This is larger in unstable patients, and the degree of temperature elevation correlates with the extent of macrophage infiltration.54 Several non-invasive modalities offer the potential for direct imaging of inflammatory activity. This ability will be further enhanced in the

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Figure 2. Inter-relation between cardiovascular risk factors, obesity, inflammation, and the metabolic syndrome. IL-6 indicates interleukin-6; TNF-␣, tumor necrosis factor- ␣ . Reproduced with permission from J Am Coll Cardiol 2004; 44:2293–300.106

near future with fusion technology (the combination of different modalities in a single platform). Positron emission tomography (PET) using 18fluorodeoxyglucose, a glucose analogue that accumulates preferentially in cells with high metabolic rates, allows for in vivo detection of plaque inflammation. As a result, the amount of uptake directly correlates with macrophage concentration and plaque activity, regardless of the degree of luminal stenosis.55,56 Because of relatively limited spatial resolution, image co-registration with computed tomography (CT) is often performed (Figure 3). Magnetic resonance imaging (MRI) is particularly well suited for the visualization of the arterial wall because of its high spatial resolution. Specific imaging features of the wall, such as increased thickness, high signal intensity on T2weighted images (suggestive of edema), or the degree of enhancement after conventional contrast agents, appear to correlate with the plasmatic concentrations of inflammatory biomarkers.57 Another type of magnetic contrast agent, superparamagnetic iron oxide particle, is phagocytosed by macrophages, and can, therefore, be used to visualize plaque inflammatory infiltration.58,59 Contrast agents with high affinity to specific targets (molecular imaging) constitute the next step in the visualization of molecular processes in athero-

sclerotic disease with various imaging modalities.60 In the case of inflammation, one of the most attractive targets is the family of vascular adhesion molecules, due to its early participation in atherogenesis.61 It has also been shown recently that protease-activatable near-infrared fluorescence probes can reveal protease activity in experimental atherosclerosis.62 Besides inflammation, several imaging modalities can also depict other intimately related processes, such as intraplaque hemorrhage63 or neovascularization. Dynamic, contrast-enhanced MRI and ultrasound offer the potential to visualize vasa vasorum and estimate the degree of neovascularization.64 Enhancement of advanced plaques with gadofluorine, a novel MRI contrast agent, is also correlated with the density of neovessels.65 In addition, molecular contrast agents targeted to ␣v␤3-integrin can be also used to detect plaque neovascularization.66 Serum Inflammatory Biomarkers An alternative approach to direct imaging of plaque inflammation is the measurement of the plasmatic concentrations of inflammatory biomarkers. The underlying principle is that low-grade chronic inflammation in the vessel wall is associ-

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Figure 3. Positron emission tomography-computed tomography images of the aorta in a patient with diabetes mellitus and hypertension. Panel A shows the non-enhanced computed tomography images, panel B the positron emission tomography study, and panel C the co-registration of both images. Intense radioisotope uptake is noted in the arch (white arrows) and the infra-renal abdominal aorta (black arrows). Courtesy of Dr. James H. Rudd.

ated with increased serum concentrations of different components of the inflammatory response, including cells, adhesion molecules, cytokines, etc. Multiple inflammatory markers (Table) have been identified during the last few years as potential tools for improved identification of those individuals with subclinical disease, as well as for refined estimation of cardiovascular risk. Among this myriad of biomarkers, CRP (an acute phase reactant produced by the liver in reTable Serum markers of low-grade inflammatory activity in cardiovascular disease Leukocyte count Fibrinogen C-reactive protein Adhesion molecules (ICAM-1, VCAM-1, P-selectin) Interleukins (IL-1, IL-6, IL-10, IL-18) Tumor necrosis factor-␣

Myeloperoxidase Matrix metalloproteinase-9 Serum amyloid A Pregnancy-associated plasma protein A CD40 ligand Heat-shock protein Lipoprotein-associated phospholipase A2

ICAM-1 indicates intercellular adhesion molecule-1; IL, interleukin; VCAM-1, vascular adhesion molecule-1.

sponse to inflammatory mediators such as IL-6) has emerged as the most appealing for widespread use. This is due to a combination of ease of use, good reproducibility, and a large body of evidence demonstrating ability to improve cardiovascular risk stratification beyond traditional risk factors in a variety of clinical scenarios.67 Moreover, elevated concentrations of CRP as well as other inflammatory biomarkers are associated with disease progression both in the coronary and extracoronary circulation.68,69 CRP may very well serve as an example of some of the advantages and limitations of serum markers in the assessment of atherothrombosis. The predictive power of CRP undoubtedly highlights the importance of inflammation in the development and progression of atherosclerosis. As such, it reflects our current, more global understanding of the disease as a highly dynamic “inflammatory” process in comparison with the more static, purely “metabolic” view. CRP is nonetheless a universal marker of inflammation, and therefore non-specific for vascular involvement. Although additive to conven-

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tional risk factors, the predictive value of CRP and other inflammatory markers is modest.70 Moreover, it is unclear whether CRP represents merely a bystander of the disease process, or actually exerts deleterious effects contributing to atherosclerosis progression. Supporting the latter notion, several recent investigations have shown pro-atherogenic actions of CRP such as stimulation of NF␬B; induction of secretion from endothelial cells of MMPs, MCP-1, or cell adhesion molecules; reductions in eNOS activity; facilitation of LDL uptake by macrophages; induction of apoptosis in smooth muscle cell; or impairment of survival, differentiation, and function of endothelial progenitor cells (EPCs).71,72 The in-vivo significance of these effects remains controversial.73 As a consequence, it is unclear if inflammation itself could specifically constitute a therapeutic target in atherothrombosis. “Anti-Inflammatory” Therapy for Vascular Disease A variety of pharmacologic and non-pharmacologic measures may be beneficial in the management of atherosclerotic disease in part due to their inflammatory actions. It is likely that the combination of such therapies is more effective than one single approach alone.74 Because of the crucial role of endothelial function in the genesis of atherosclerosis and vascular inflammation, lifestyle changes associated with reduced cardiovascular risk factors and improved endothelial function can lead to decreases in the concentrations of inflammatory biomarkers.75,76 One of the research areas attracting most interest in the present time is the role of stem cells in cardiovascular homeostasis. Endogenous reparative ability of damaged endothelium is mediated, in part, by EPCs and can be enhanced by several pharmacologic agents.77,78 Interestingly, the number of EPCs correlates inversely with the cardiovascular risk profile and with the probability of cardiovascular events.79 – 81 These findings suggest a delicate balance between endothelial damage, EPC availability, EPC recruitment into the injured endothelium (mediated, in part, by inflammatory cytokines),

and atherogenesis. A potential “anti-inflammatory” approach for atherosclerosis may, therefore, consist of decreasing risk factors and enhancing endogenous endothelial repair, which would eventually lead to decreased pro-inflammatory stimulus. In addition to their lipid-lowering actions, statins have been shown to have potent anti-inflammatory effects through multiple mechanisms including up-regulation of eNOS activity, inhibition of the production of inflammatory cytokines, or others.82– 84 These effects have translated into reductions of circulating inflammatory biomarkers in clinical studies,85,86 and have been associated with improved cardiovascular outcome.87 Nonetheless, the clinical impact of non-lipid-lowering actions of statins is still a matter of debate.88 The ongoing JUPITER trial (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) will test the hypothesis of targeting CRP rather than LDL levels as an indication for statin therapy. Interestingly, many of the effects of statins and other drug therapies on the vessel wall can be evaluated non-invasively with advanced imaging technology.89 High-density lipoprotein (HDL) promotes reverse cholesterol transport from macrophages to the liver, and may induce lesion regression as demonstrated both in experimental and human atherosclerosis.90,91 Raising HDL levels is concomitantly accompanied by a reduction in macrophage content92 and cell apoptosis.93 Therefore, it seems that HDL-induced decrease in plaque cholesterol content could reduce one of the earliest stimuli for plaque inflammation. In addition, HDL displays direct anti-inflammatory actions.94 Novel therapeutic options for raising HDL levels include cholesteryl ester transfer protein inhibitors, apolipoprotein A-1 variants, oral HDL-mimetics, or liver X receptor agonists, recently shown to enhance reverse cholesterol transport.95 Activation of PPAR can have anti-atherogenic effects, potentially mediated through decreases in inflammatory activity. Fibrates, a class of PPAR-␣ agonists, have been shown to reduce expression of adhesion molecules and inflamma-

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tory cytokines, as well as cardiovascular events.96 PPAR-␥ agonists, including thiazolidinediones, also decrease inflammatory markers and exhibit protective effects against atherosclerosis development.97,98 Although more often considered globally pro-atherogenic, the actions of activated NF␬B are complex, and some are actually protective. Therefore, overall inhibition of NF␬B as a therapeutic target in atherosclerosis might have deleterious consequences.13 As suggested by the aforementioned considerations on the pro-inflammatory actions of angiotensin, antagonism of the renin angiotensin system by ACE inhibitors, angiotensin receptor blockers, and, aldosterone receptor blockers leads to reductions in inflammatory biomarkers.99 –102 Aspirin, a potent cyclooxygenase (COX) inhibitor, may exert some of its beneficial influence through anti-inflammatory actions,103 although the more novel COX-2 inhibitors have been associated with increased rates of cardiovascular events. Inhibiting angiogenesis as a therapeutic modality may also decrease plaque macrophage content and progression, although concern has been raised regarding potential undesired effects in other organs.104,105 Conclusions Chronic inflammation of the vessel wall is strongly linked to the development of cardiovascular atherosclerotic disease, and increasing evidence demonstrates a similar role in the pathogenesis of HTN. The abilities to detect increased vascular inflammatory activity and to develop therapies that can counteract this pro-inflammatory state open a novel window of opportunities in the management of cardiovascular disorders. Many of the imaging modalities (MRI, CT, PET), risk factor profiles (inflammatory markers, EPCs, etc.), as well as therapeutic options (strict metabolic control, HDL-mimetics, PPAR agonists, etc.) discussed in the preceding text will be studied in the ongoing FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial. This and other studies will be cru-

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