- Email: [email protected]
Inflammatory pathways in atherosclerosis and acute coronary syndromes
Inflammatory Pathways in Atherosclerosis and Acute Coronary Syndromes Jorge Plutzky,
MD
Evidence from a broad range of studies demonstrates that atherosclerosis is a chronic disease that, from its origins to its ultimate complications, involves inflammatory cells (T cells, monocytes, macrophages), inflammatory proteins (cytokines, chemokines), and inflammatory responses from vascular cells (endothelial cell expression of adhesion molecules). Investigators have identified a variety of proteins whose levels might predict cardiovascular risk. Of these candidates, C-reactive protein, tumor necrosis factor-␣, and interleukin-6 have been most widely studied. There is also the prospect of
inflammation as a therapeutic target, with investigators currently debating to what extent the decrease in cardiovascular risk seen with statins, angiotensin-converting enzyme inhibitors, and peroxisome proliferator–activated receptor ligands derives from changes in inflammatory parameters. These advances in basic and clinical science have placed us on a threshold of a new era in cardiovascular medicine. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88(suppl):10K–15K
any lines of evidence, ranging from in vitro experiments to pathologic analysis to epidemiM ologic studies, show that atherosclerosis is intrinsi-
ture appears to be, in part, a late complication of an insidious process of chronic inflammation. Early insight into the role of inflammation in cardiovascular disease came from the seminal observations of pathologists. For example, careful studies of ruptured atherosclerotic plaques led to the recognition of inflammatory cells—specifically, T lymphocytes and monocytes/macrophages—as the predominant cells present in the shoulder region of unstable lesions.8,9 Subsequent work has sought to more precisely define the pathways involved in attracting leukocytes to the arterial wall and the consequences of their presence. Adhesion of circulating leukocytes to the endothelium is 1 of the earliest steps in atherogenesis.10 –14 Leukocytes are drawn to the vascular endothelium in part as a response to the elaboration of chemoattractant cytokines (chemokines) by endothelial cells and other cells in the vessel wall. The entry of inflammatory cells into the arterial wall depends on the interaction between adhesion molecules on the surface of endothelial cells and their counterligands on leukocytes. These endothelial cell adhesion molecules include vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, and P-selectin.15–18 Human atherosclerotic lesions demonstrate increased expression of these adhesion molecules in endothelial cells of plaque microvessels or in endothelial cells overlying the lipid core, a response that may contribute to further leukocyte recruitment to sites of atherosclerosis.19 –22 Inflammatory mediators found in human atheroma, such as tumor necrosis factor-␣ or interleukin-1, can induce adhesion molecule expression in endothelial cells.23 Interestingly, as discussed below, circulating levels of adhesion molecules (soluble adhesion molecules) have been investigated clinically as markers of risk. T lymphocytes are among the key inflammatory cells attracted to sites of atherosclerosis.1 In human atheroma, T cells are among the most common cells
cally an inflammatory disease.1 As a result of this convergence of vascular biology and epidemiology research, investigators are asking if serum inflammatory markers are predictive of future cardiovascular events, and if the beneficial effects of therapies, such as the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and angiotensin converting enzyme (ACE) inhibitors, occur in part by modulation of inflammation.2,3 This review will also discuss the evolving inflammatory hypothesis of atherosclerosis and the potential for inflammatory markers as predictors of cardiovascular risk in the clinical arena.
INFLAMMATION IN ATHEROSCLEROSIS: EVIDENCE FROM VASCULAR BIOLOGY Insight into atherosclerosis and the pathogenesis of its sequelae, such as myocardial infarction (MI), have evolved dramatically over the 100 years since researchers first demonstrated that cholesterol-rich diets induce atherosclerosis in rabbits.1,4 Today, it seems almost inconceivable that Aschoff and other early investigators5,6 had to convince the medical establishment that atherosclerosis was not simply a degenerative disease confined to the elderly. Insight into the disease has advanced beyond notions of progressive occlusion of the coronary artery into recognition that most heart attacks occur after plaque rupture and ensuing thrombus formation in vulnerable lesions of only moderate stenosis.7 This process of plaque rupFrom the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA. Address for reprints: Jorge Plutzky, MD, Brigham and Women’s Hospital, Department of Medicine, 221 Longwood Avenue, LMRC 307, Boston Massachusetts 02115. E-mail: [email protected]. harvard.edu.
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©2001 by Excerpta Medica, Inc. All rights reserved.
0002-9149/01/$ – see front matter PII S0002-9149(01)01924-5
present in atherosclerotic lesions. These cells subsequently secrete proinflammatory cytokines, such as interferon-␥, tumor necrosis factor-␣, and interleukin-2, which further promote the atherosclerotic response.9,24 These cytokines also contribute to the response by activating endothelial cells and modulating macrophage and vascular smooth-muscle cell function.1,25,26 In apolipoprotein E– deficient mice, interruption of the interferon-␥–signaling pathway has been shown to reduce the development of atherosclerotic lesions.27,28 Similar inflammatory proteins may be present in patients with arteriosclerosis and acute coronary syndromes, with perhaps important inflammatory mediators like nuclear factor-B playing a part in changing gene expression in response to inflammation.29 –31 Monocytes/macrophages are another critical constituent of the inflammatory atherosclerotic response. Once resident in the vessel wall, monocytes develop into macrophages as they take up oxidized lowdensity lipoprotein (LDL) and differentiate into foam cells. Macrophages and lipid-laden foam cells are heavily implicated as prime culprits in the molecular events that promote and ultimately complicate atherosclerosis. Monocytes/macrophages are also a source of cytokines that inhibit vascular smooth-muscle cell production of collagen and other extracellular matrix components of the fibrous cap, thus potentially weakening the structure that separates the highly coagulable necrotic lipid core from the circulating coagulation system. In fact, vascular smooth muscle cells in atherosclerotic lesions express major histocompatibility class II HLA-DR antigens, suggesting an activated phenotype.24,25 Destabilization of the fibrous cap likely results, not only from decreased collagen production by vascular smooth muscle cells, but also increased collagen and matrix degradation, primarily by monocytes/macrophages. In response to inflammatory cytokines, monocytes/macrophages elaborate matrix metalloproteinases, a large family of highly regulated proteases that function at neutral pH to degrade collagen.32,33 Current models suggest that monocytes/macrophages in the shoulder regions of plaque contribute to destabilization of the fibrous plaque and subsequent plaque rupture via matrix-metalloproteinase secretion.34 –37 Monocytes/macrophages also produce tissue factor, which renders the necrotic lipid core of the lesion hypercoagulable.37 When circulating blood contacts the lipid core, a thrombus forms.37 Complete occlusion of the artery by thrombus results in ST-segment elevation MI, sometimes accompanied by sudden death. A partial thrombus may lead to presentations of unstable angina and non–ST-segment elevation MI. Angiograms before and after administration of thrombolytic therapy reveal that the vast majority of MIs occur, not in the most stenotic lesions, but rather in those with stenoses of ⱕ70%.37–39 Such lesions have larger lipid cores, thinner fibrous caps, and are extremely numerous; thus, in aggregate, an occlusive thrombus is more likely to occur at 1 of these sites
than at a tighter stenosis, which are much less prevalent. Taken together, a picture emerges of a chronic disease that, from its origins to its ultimate complications, involves inflammatory cells (T cells, monocytes, macrophages), inflammatory proteins (cytokines, chemokines), and inflammatory responses from vascular cells (endothelial cells expression of adhesion molecules). Importantly, in vivo studies in murine models, such as mice that are deficient in apolipoprotein E or LDL receptors, suggest that blocking pathways of inflammation can minimize atherosclerosis. For example, interfering with the chemokine monocyte chemoattractant protein-1 decreases the extent of disease.40,41 Numerous other examples exist.42,43 Given this evidence, the question arises about the ability to measure, or track in some way, these inflammatory responses. Would such nonspecific inflammatory markers predict cardiovascular risk? Certainly, such questions have been the focus of much, recent attention.
INFLAMMATION IN CLINICAL CARDIOLOGY: THE POTENTIAL USE OF MARKERS The prospect that measures of nonspecific markers of chronic low-grade inflammation might predict the risk of future MI 10 or 20 years later, is a powerful one. A number of studies have identified a variety of proteins whose levels may predict cardiovascular risk (Figure 1).44 Early studies found that markers of inflammation such as C-reactive protein (CRP) correlated with unstable angina pectoris in acute coronary syndromes.45– 47 In the Physicians’ Health Study, Ridker et al48 found that CRP and serum amyloid A showed a positive correlation with subsequent risk of MI. Importantly, these CRP values all decreased within a normal range on a high-sensitivity assay. Numerous other studies have supported these findings in a variety of settings.3,49,50 Although initially the observation that several markers corresponded with risk suggested the nonspecific nature of these proteins, more recent work indicates that CRP itself might be involved in the pathogenic response.51 For example, Pasceri et al52,53 found that CRP could induce adhesion molecule expression in endothelial cells with effects on monocyte chemoattractant protein-1. Other studies into the molecular proinflammatory pathways described above have also suggested additional proteins worthy of consideration as candidate markers or as risk factors predictive of cardiovascular events. Levels of tumor necrosis factor-␣ and interleukin-6 have also been analyzed in large epidemiologic cohorts.2,54,55 Regardless of the precise protein or mechanism for inflammatory effects in the vasculature, perhaps most relevant for the clinician is the prospect of inflammation as a therapeutic target.56 Indeed, compelling studies find that CRP levels may predict risk above and beyond a patient’s ratio of total cholesterol to highdensity lipoprotein (HDL) (Figure 2).57,58 Inflammatory markers also appear to be predictive in special
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FIGURE 1. Potential markers of inflammatory activity and their sources. ICAM-1 ⴝ intercellular adhesion molecule-1; VCAM-1 ⴝ vascular cell adhesion molecule-1. (Reproduced with permission from N Engl J Med.44)
FIGURE 2. Relative risk of first myocardial infarction according to tertiles of C-reactive protein and the ratio of total cholesterol to high-density lipoprotein cholesterol. Data were obtained in 14,916 apparently healthy men participating in the Physicians’ Health Study. Tertiles of C-reactive protein are high (>1.69 mg/L), middle (0.72 to 1.69 mg/L), and low (<0.72 mg/L). Tertiles of the ratio of total cholesterol to high-density lipoprotein cholesterol are high (>5.01), middle (3.78 to 5.01), and low (<3.78). CAD ⴝ coronary artery disease; HDL ⴝ high-density lipoprotein. (Reproduced with permission from Circulation.58)
high-risk populations, such as those with diabetes or insulin resistance.59 Interestingly, a lack of correlation between CRP and the presence or extent of calcium in subclinical atherosclerosis has been reported.60 Given the incidence of cardiovascular events, even among those patients receiving active treatment in clinical trials, might future treatments targeted against inflammation offer further decreases in events? Investigators are currently debating to what extent the decrease in risk seen with statins, ACE inhibitors, as well as the possible effects of ligands for peroxisome 12K THE AMERICAN JOURNAL OF CARDIOLOGY姞
proliferator–activated receptor (PPAR) might derive from changes in inflammatory parameters. Statins: In the Cholesterol And Recurrent Events (CARE) trial conducted in patients with a prior MI and average levels of low-density lipoprotein cholesterol (LDL-C), patients defined as having “inflammation present” had greater decreases in cardiovascular events as opposed to those with “inflammation absent” (arbitrary definitions based on defined cut-off values).61 Such responses did not appear to be dependent on the baseline level of LDL-C. More recent data
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suggest that reduction in CRP levels by statins may be a class effect.62,63 The mechanism for this effect on CRP remains to be determined, with the possibility that it stems from secondary effects related to lowering LDL-C. ACE inhibitors: Similar data have also been reported in clinical trials with ACE inhibitors.64 Extensive studies have implicated ACE as an important mediator of pathogenic effects, such as decreases in nitric oxide and bradykinin.65 ACE inhibition can have a variety of vascular benefits, with evidence ranging from lowered blood pressure to improved endothelial activity.66 – 69 Particularly provocative is the recently completed Hypertension Outcomes Prevention Evaluation Study (HOPE) trial, which found significant decreases in cardiovascular events among a large cohort of highrisk patients treated with ramipril.70 The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE), a substudy of HOPE, examined changes in carotid intimal-medial thickness, a surrogate marker for atherosclerosis, and found dose-related effects of ACE inhibition.71 These and other studies suggest that the cardiovascular benefits of ACE inhibition may arise in part from effects on the vascular wall.69,72,73 PPARs: These are members of the nuclear-receptor family of ligand-activated transcription factors. There are 3 known PPAR forms: gamma (␥), alpha (␣), and delta (␦).74 Extensive prior work defined important roles for PPAR-␣ and PPAR-␥ in transcriptional regulation. PPAR-␥ is highly expressed in adipose tissue and is a central mediator in adipogenesis and glucose homeostasis, with ligands that include the synthetic antidiabetic thiazolidinedione class of drugs75,76 and naturally-occurring oxidized linoleic acid (HODEs).77 PPAR-␣ is more widely expressed and appears to control genes involved in fatty acid metabolism.78 Both natural (certain long-chain fatty acids) and synthetic (the fibrate class of lipid-lowering agents) PPAR-␣ ligands have been reported. More recent work has extended the role for PPAR-␥ and PPAR-␣ into other tissues, suggesting their regulation of other pathways and relevance to other diseases. A common, if not uniform, theme to such work has been evidence for PPAR regulation of inflammation. This link has spawned interest in PPAR ligands as therapeutic tools for inflammatory bowel disease,79 rheumatoid arthritis,80 and Alzheimer’s disease.78,81 Of relevance to cardiovascular disease, PPARs have been also shown to be expressed in the vasculature.82,83 PPAR-␥ activators can inhibit chemokine induction, cytokine production, and expression of matrix metalloproteinase-9.84,85 They also decrease atherosclerosis in murine models.83,86 – 88 PPAR-␣ activators inhibit expression of vascular cell adhesion molecule-1,89 tissue factor,90 and interleukin-6, effects,91 which may play a part in the decreased cardiovascular events seen with a fibrate in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) trial, which was conducted in subjects who had average levels of LDL-C (112 mg/dL) and low levels of HDL-C (32 mg/dL).92
INFLAMMATION AND INFLAMMATORY MARKERS IN CARDIOVASCULAR PRACTICE: FUTURE PROSPECTS Despite the impressive gains in understanding atherosclerosis, many questions persist about the use of inflammatory markers in clinical practice.93 Although CRP levels are predictive in research settings, their use clinically remains to be fully defined.94 Many transitory states (eg, upper respiratory infection, subclinical infection, other medications) may alter CRP levels, making interpretation difficult. It is also unclear how to use CRP levels in the prospective management of patients on therapy.95 For example, what should be said to the concerned patient whose CRP levels failed to decrease after initiation of a statin? What seems more certain is that these extensive studies from the realms of basic and clinical science have placed us on a threshold of a new era in cardiovascular medicine. We can anticipate further evidence that existing therapies, such as statins and ACE inhibitors, alter inflammation, and we can hope for greater insight into the mechanisms for these effects. Another potential clinical application for these data may be to allow more precise definition of cardiovascular risk or even response to therapy. Interestingly, the Adult Treatment Panel III, recently released by the National Cholesterol Education Program, chose to not include CRP as a tool in defining risk, no doubt awaiting further data.96 Beyond such early applications, the greatest potential may rest in future therapies that will target inflammation itself. Such interventions will depend on continued basic and clinical insight into these pathways.
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angiotensin-converting enzyme inhibitors: a future therapeutic perspective. J Cardiovasc Pharmacol 2001;37(suppl 1):S3–S9. 74. Mangelsdorf D, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon C, Evans R. The nuclear receptor superfamily: the second decade. Cell 1995;83:835– 839. 75. Henry RR. Thiazolidinediones. Endocrinol Metab Clin North Am 1997;26: 553–573. 76. Auwerx J. PPARgamma, the ultimate thrifty gene. Diabetologia 1999;42: 1033–1049. 77. Rocchi S, Auwerx J. Peroxisome proliferator-activated receptor-gamma: a versatile metabolic regulator. Ann Med 1999;31:342–351. 78. Pineda Torra I, Gervois P, Staels B. Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging. Curr Opin Lipidol 1999;10:151–159. 79. Su CG, Wen X, Bailey ST, Jiang W, Rangwala SM, Keilbaugh SA, Flanigan A, Murthy S, Lazar MA, Wu GD. A novel therapy for colitis utilizing PPARgamma ligands to inhibit the epithelial inflammatory response. J Clin Invest 1999;104:383–389. 80. Kawahito Y, Kondo M, Tsubouchi Y, Hashiramoto A, Bishop-Bailey D, Inoue K, Kohno M, Yamada R, Hla T, Sano H. 15-deoxy-delta(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest 2000;106:189 –197. 81. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE. Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci 2000;20:558 –567. 82. Plutzky J. Peroxisome proliferator-activated receptors in vascular biology and atherosclerosis: emerging insights for evolving paradigms. Curr Atheroscler Rep 2000;2:327–335. 83. Glass CK, Witztum JL. Atherosclerosis: the road ahead. Cell 2001;104:503– 516. 84. Marx N, Schonbeck U, Lazar MA, Libby P, Plutzky J. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 1998;83:1097–1103. 85. Marx N, Sukhova G, Murphy C, Libby P, Plutzky J. Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma (PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am J Pathol 1998;153:17–23. 86. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK.
Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2000;106:523–531. 87. Chen Z, Ishibashi S, Perrey S, Osuga J, Gotoda T, Kitamine T, Tamura Y, Okazaki H, Yahagi N, Iizuka Y, et al. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol 2001;21:372–377. 88. Collins AR, Meehan WP, Kintscher U, Jackson S, Wakino S, Noh G, Palinski W, Hsueh WA, Law RE. Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2001;21:365–371. 89. Marx N, Sukhova GK, Collins T, Libby P, Plutzky J. PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 1999;99:3125–3131. 90. Marx N, Mackman N, Schonbeck U, Yilmaz N, Hombach VV, Libby P, Plutzky J. PPARalpha activators inhibit tissue factor expression and activity in human monocytes. Circulation 2001;103:213–219. 91. Staels B, Koenig W, Habib A, Merval R, Lebret M, Pineda-Torra I, Delerive P, Fadel A, Chinetti G, Fruchart J-C, et al. Activation of human aortic smoothmuscle cells is inhibited by PPAR␣ but not by PPAR␥ activators. Nature 1998;393:790 –793. 92. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410 – 418. 93. Packard CJ, O’Reilly DS, Caslake MJ, McMahon AD, Ford I, Cooney J, Macphee CH, Suckling KE, Krishna M, Wilkinson FE, Rumley A, Lowe GD. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease: West of Scotland Coronary Prevention Study Group. N Engl J Med 2000;343:1148 –1155. 94. Rifai N, Ridker PM. Proposed cardiovascular risk assessment algorithm using high-sensitivity C-reactive protein and lipid screening. Clin Chem 2001;47:28 – 30. 95. Ockene IS, Matthews CE, Rifai N, Ridker PM, Reed G, Stanek E. Variability and classification accuracy of serial high-sensitivity C-reactive protein measurements in healthy adults. Clin Chem 2001;47:444 – 450. 96. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 – 2497.
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MD
Evidence from a broad range of studies demonstrates that atherosclerosis is a chronic disease that, from its origins to its ultimate complications, involves inflammatory cells (T cells, monocytes, macrophages), inflammatory proteins (cytokines, chemokines), and inflammatory responses from vascular cells (endothelial cell expression of adhesion molecules). Investigators have identified a variety of proteins whose levels might predict cardiovascular risk. Of these candidates, C-reactive protein, tumor necrosis factor-␣, and interleukin-6 have been most widely studied. There is also the prospect of
inflammation as a therapeutic target, with investigators currently debating to what extent the decrease in cardiovascular risk seen with statins, angiotensin-converting enzyme inhibitors, and peroxisome proliferator–activated receptor ligands derives from changes in inflammatory parameters. These advances in basic and clinical science have placed us on a threshold of a new era in cardiovascular medicine. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88(suppl):10K–15K
any lines of evidence, ranging from in vitro experiments to pathologic analysis to epidemiM ologic studies, show that atherosclerosis is intrinsi-
ture appears to be, in part, a late complication of an insidious process of chronic inflammation. Early insight into the role of inflammation in cardiovascular disease came from the seminal observations of pathologists. For example, careful studies of ruptured atherosclerotic plaques led to the recognition of inflammatory cells—specifically, T lymphocytes and monocytes/macrophages—as the predominant cells present in the shoulder region of unstable lesions.8,9 Subsequent work has sought to more precisely define the pathways involved in attracting leukocytes to the arterial wall and the consequences of their presence. Adhesion of circulating leukocytes to the endothelium is 1 of the earliest steps in atherogenesis.10 –14 Leukocytes are drawn to the vascular endothelium in part as a response to the elaboration of chemoattractant cytokines (chemokines) by endothelial cells and other cells in the vessel wall. The entry of inflammatory cells into the arterial wall depends on the interaction between adhesion molecules on the surface of endothelial cells and their counterligands on leukocytes. These endothelial cell adhesion molecules include vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, and P-selectin.15–18 Human atherosclerotic lesions demonstrate increased expression of these adhesion molecules in endothelial cells of plaque microvessels or in endothelial cells overlying the lipid core, a response that may contribute to further leukocyte recruitment to sites of atherosclerosis.19 –22 Inflammatory mediators found in human atheroma, such as tumor necrosis factor-␣ or interleukin-1, can induce adhesion molecule expression in endothelial cells.23 Interestingly, as discussed below, circulating levels of adhesion molecules (soluble adhesion molecules) have been investigated clinically as markers of risk. T lymphocytes are among the key inflammatory cells attracted to sites of atherosclerosis.1 In human atheroma, T cells are among the most common cells
cally an inflammatory disease.1 As a result of this convergence of vascular biology and epidemiology research, investigators are asking if serum inflammatory markers are predictive of future cardiovascular events, and if the beneficial effects of therapies, such as the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and angiotensin converting enzyme (ACE) inhibitors, occur in part by modulation of inflammation.2,3 This review will also discuss the evolving inflammatory hypothesis of atherosclerosis and the potential for inflammatory markers as predictors of cardiovascular risk in the clinical arena.
INFLAMMATION IN ATHEROSCLEROSIS: EVIDENCE FROM VASCULAR BIOLOGY Insight into atherosclerosis and the pathogenesis of its sequelae, such as myocardial infarction (MI), have evolved dramatically over the 100 years since researchers first demonstrated that cholesterol-rich diets induce atherosclerosis in rabbits.1,4 Today, it seems almost inconceivable that Aschoff and other early investigators5,6 had to convince the medical establishment that atherosclerosis was not simply a degenerative disease confined to the elderly. Insight into the disease has advanced beyond notions of progressive occlusion of the coronary artery into recognition that most heart attacks occur after plaque rupture and ensuing thrombus formation in vulnerable lesions of only moderate stenosis.7 This process of plaque rupFrom the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA. Address for reprints: Jorge Plutzky, MD, Brigham and Women’s Hospital, Department of Medicine, 221 Longwood Avenue, LMRC 307, Boston Massachusetts 02115. E-mail: [email protected]. harvard.edu.
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©2001 by Excerpta Medica, Inc. All rights reserved.
0002-9149/01/$ – see front matter PII S0002-9149(01)01924-5
present in atherosclerotic lesions. These cells subsequently secrete proinflammatory cytokines, such as interferon-␥, tumor necrosis factor-␣, and interleukin-2, which further promote the atherosclerotic response.9,24 These cytokines also contribute to the response by activating endothelial cells and modulating macrophage and vascular smooth-muscle cell function.1,25,26 In apolipoprotein E– deficient mice, interruption of the interferon-␥–signaling pathway has been shown to reduce the development of atherosclerotic lesions.27,28 Similar inflammatory proteins may be present in patients with arteriosclerosis and acute coronary syndromes, with perhaps important inflammatory mediators like nuclear factor-B playing a part in changing gene expression in response to inflammation.29 –31 Monocytes/macrophages are another critical constituent of the inflammatory atherosclerotic response. Once resident in the vessel wall, monocytes develop into macrophages as they take up oxidized lowdensity lipoprotein (LDL) and differentiate into foam cells. Macrophages and lipid-laden foam cells are heavily implicated as prime culprits in the molecular events that promote and ultimately complicate atherosclerosis. Monocytes/macrophages are also a source of cytokines that inhibit vascular smooth-muscle cell production of collagen and other extracellular matrix components of the fibrous cap, thus potentially weakening the structure that separates the highly coagulable necrotic lipid core from the circulating coagulation system. In fact, vascular smooth muscle cells in atherosclerotic lesions express major histocompatibility class II HLA-DR antigens, suggesting an activated phenotype.24,25 Destabilization of the fibrous cap likely results, not only from decreased collagen production by vascular smooth muscle cells, but also increased collagen and matrix degradation, primarily by monocytes/macrophages. In response to inflammatory cytokines, monocytes/macrophages elaborate matrix metalloproteinases, a large family of highly regulated proteases that function at neutral pH to degrade collagen.32,33 Current models suggest that monocytes/macrophages in the shoulder regions of plaque contribute to destabilization of the fibrous plaque and subsequent plaque rupture via matrix-metalloproteinase secretion.34 –37 Monocytes/macrophages also produce tissue factor, which renders the necrotic lipid core of the lesion hypercoagulable.37 When circulating blood contacts the lipid core, a thrombus forms.37 Complete occlusion of the artery by thrombus results in ST-segment elevation MI, sometimes accompanied by sudden death. A partial thrombus may lead to presentations of unstable angina and non–ST-segment elevation MI. Angiograms before and after administration of thrombolytic therapy reveal that the vast majority of MIs occur, not in the most stenotic lesions, but rather in those with stenoses of ⱕ70%.37–39 Such lesions have larger lipid cores, thinner fibrous caps, and are extremely numerous; thus, in aggregate, an occlusive thrombus is more likely to occur at 1 of these sites
than at a tighter stenosis, which are much less prevalent. Taken together, a picture emerges of a chronic disease that, from its origins to its ultimate complications, involves inflammatory cells (T cells, monocytes, macrophages), inflammatory proteins (cytokines, chemokines), and inflammatory responses from vascular cells (endothelial cells expression of adhesion molecules). Importantly, in vivo studies in murine models, such as mice that are deficient in apolipoprotein E or LDL receptors, suggest that blocking pathways of inflammation can minimize atherosclerosis. For example, interfering with the chemokine monocyte chemoattractant protein-1 decreases the extent of disease.40,41 Numerous other examples exist.42,43 Given this evidence, the question arises about the ability to measure, or track in some way, these inflammatory responses. Would such nonspecific inflammatory markers predict cardiovascular risk? Certainly, such questions have been the focus of much, recent attention.
INFLAMMATION IN CLINICAL CARDIOLOGY: THE POTENTIAL USE OF MARKERS The prospect that measures of nonspecific markers of chronic low-grade inflammation might predict the risk of future MI 10 or 20 years later, is a powerful one. A number of studies have identified a variety of proteins whose levels may predict cardiovascular risk (Figure 1).44 Early studies found that markers of inflammation such as C-reactive protein (CRP) correlated with unstable angina pectoris in acute coronary syndromes.45– 47 In the Physicians’ Health Study, Ridker et al48 found that CRP and serum amyloid A showed a positive correlation with subsequent risk of MI. Importantly, these CRP values all decreased within a normal range on a high-sensitivity assay. Numerous other studies have supported these findings in a variety of settings.3,49,50 Although initially the observation that several markers corresponded with risk suggested the nonspecific nature of these proteins, more recent work indicates that CRP itself might be involved in the pathogenic response.51 For example, Pasceri et al52,53 found that CRP could induce adhesion molecule expression in endothelial cells with effects on monocyte chemoattractant protein-1. Other studies into the molecular proinflammatory pathways described above have also suggested additional proteins worthy of consideration as candidate markers or as risk factors predictive of cardiovascular events. Levels of tumor necrosis factor-␣ and interleukin-6 have also been analyzed in large epidemiologic cohorts.2,54,55 Regardless of the precise protein or mechanism for inflammatory effects in the vasculature, perhaps most relevant for the clinician is the prospect of inflammation as a therapeutic target.56 Indeed, compelling studies find that CRP levels may predict risk above and beyond a patient’s ratio of total cholesterol to highdensity lipoprotein (HDL) (Figure 2).57,58 Inflammatory markers also appear to be predictive in special
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FIGURE 1. Potential markers of inflammatory activity and their sources. ICAM-1 ⴝ intercellular adhesion molecule-1; VCAM-1 ⴝ vascular cell adhesion molecule-1. (Reproduced with permission from N Engl J Med.44)
FIGURE 2. Relative risk of first myocardial infarction according to tertiles of C-reactive protein and the ratio of total cholesterol to high-density lipoprotein cholesterol. Data were obtained in 14,916 apparently healthy men participating in the Physicians’ Health Study. Tertiles of C-reactive protein are high (>1.69 mg/L), middle (0.72 to 1.69 mg/L), and low (<0.72 mg/L). Tertiles of the ratio of total cholesterol to high-density lipoprotein cholesterol are high (>5.01), middle (3.78 to 5.01), and low (<3.78). CAD ⴝ coronary artery disease; HDL ⴝ high-density lipoprotein. (Reproduced with permission from Circulation.58)
high-risk populations, such as those with diabetes or insulin resistance.59 Interestingly, a lack of correlation between CRP and the presence or extent of calcium in subclinical atherosclerosis has been reported.60 Given the incidence of cardiovascular events, even among those patients receiving active treatment in clinical trials, might future treatments targeted against inflammation offer further decreases in events? Investigators are currently debating to what extent the decrease in risk seen with statins, ACE inhibitors, as well as the possible effects of ligands for peroxisome 12K THE AMERICAN JOURNAL OF CARDIOLOGY姞
proliferator–activated receptor (PPAR) might derive from changes in inflammatory parameters. Statins: In the Cholesterol And Recurrent Events (CARE) trial conducted in patients with a prior MI and average levels of low-density lipoprotein cholesterol (LDL-C), patients defined as having “inflammation present” had greater decreases in cardiovascular events as opposed to those with “inflammation absent” (arbitrary definitions based on defined cut-off values).61 Such responses did not appear to be dependent on the baseline level of LDL-C. More recent data
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suggest that reduction in CRP levels by statins may be a class effect.62,63 The mechanism for this effect on CRP remains to be determined, with the possibility that it stems from secondary effects related to lowering LDL-C. ACE inhibitors: Similar data have also been reported in clinical trials with ACE inhibitors.64 Extensive studies have implicated ACE as an important mediator of pathogenic effects, such as decreases in nitric oxide and bradykinin.65 ACE inhibition can have a variety of vascular benefits, with evidence ranging from lowered blood pressure to improved endothelial activity.66 – 69 Particularly provocative is the recently completed Hypertension Outcomes Prevention Evaluation Study (HOPE) trial, which found significant decreases in cardiovascular events among a large cohort of highrisk patients treated with ramipril.70 The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE), a substudy of HOPE, examined changes in carotid intimal-medial thickness, a surrogate marker for atherosclerosis, and found dose-related effects of ACE inhibition.71 These and other studies suggest that the cardiovascular benefits of ACE inhibition may arise in part from effects on the vascular wall.69,72,73 PPARs: These are members of the nuclear-receptor family of ligand-activated transcription factors. There are 3 known PPAR forms: gamma (␥), alpha (␣), and delta (␦).74 Extensive prior work defined important roles for PPAR-␣ and PPAR-␥ in transcriptional regulation. PPAR-␥ is highly expressed in adipose tissue and is a central mediator in adipogenesis and glucose homeostasis, with ligands that include the synthetic antidiabetic thiazolidinedione class of drugs75,76 and naturally-occurring oxidized linoleic acid (HODEs).77 PPAR-␣ is more widely expressed and appears to control genes involved in fatty acid metabolism.78 Both natural (certain long-chain fatty acids) and synthetic (the fibrate class of lipid-lowering agents) PPAR-␣ ligands have been reported. More recent work has extended the role for PPAR-␥ and PPAR-␣ into other tissues, suggesting their regulation of other pathways and relevance to other diseases. A common, if not uniform, theme to such work has been evidence for PPAR regulation of inflammation. This link has spawned interest in PPAR ligands as therapeutic tools for inflammatory bowel disease,79 rheumatoid arthritis,80 and Alzheimer’s disease.78,81 Of relevance to cardiovascular disease, PPARs have been also shown to be expressed in the vasculature.82,83 PPAR-␥ activators can inhibit chemokine induction, cytokine production, and expression of matrix metalloproteinase-9.84,85 They also decrease atherosclerosis in murine models.83,86 – 88 PPAR-␣ activators inhibit expression of vascular cell adhesion molecule-1,89 tissue factor,90 and interleukin-6, effects,91 which may play a part in the decreased cardiovascular events seen with a fibrate in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) trial, which was conducted in subjects who had average levels of LDL-C (112 mg/dL) and low levels of HDL-C (32 mg/dL).92
INFLAMMATION AND INFLAMMATORY MARKERS IN CARDIOVASCULAR PRACTICE: FUTURE PROSPECTS Despite the impressive gains in understanding atherosclerosis, many questions persist about the use of inflammatory markers in clinical practice.93 Although CRP levels are predictive in research settings, their use clinically remains to be fully defined.94 Many transitory states (eg, upper respiratory infection, subclinical infection, other medications) may alter CRP levels, making interpretation difficult. It is also unclear how to use CRP levels in the prospective management of patients on therapy.95 For example, what should be said to the concerned patient whose CRP levels failed to decrease after initiation of a statin? What seems more certain is that these extensive studies from the realms of basic and clinical science have placed us on a threshold of a new era in cardiovascular medicine. We can anticipate further evidence that existing therapies, such as statins and ACE inhibitors, alter inflammation, and we can hope for greater insight into the mechanisms for these effects. Another potential clinical application for these data may be to allow more precise definition of cardiovascular risk or even response to therapy. Interestingly, the Adult Treatment Panel III, recently released by the National Cholesterol Education Program, chose to not include CRP as a tool in defining risk, no doubt awaiting further data.96 Beyond such early applications, the greatest potential may rest in future therapies that will target inflammation itself. Such interventions will depend on continued basic and clinical insight into these pathways.
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A SYMPOSIUM: LIPID MANAGEMENT IN ACUTE AND LONG-TERM SETTINGS
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