冠心病的炎症,是一篇很好的参考文献Inflammation in coronary artery diseases

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Medical progress

Inflammation in coronary artery diseases

LI Jian-jun

Keywords: coronary artery disease; atherosclerosis; inflammation

The concept that atherosclerosis is an inflammation has been increasingly recognized, and subsequently resulted in great interest in revealing the inflammatory nature of the atherosclerotic process. More recently, a large body of evidence has supported the idea that inflammatory mechanisms play a pivotal role throughout all phases of atherogenesis, from endothelial dysfunction and the formation of fatty streaks to plaque destabilization and the acute coronary events due to vulnerable plaque rupture. Indeed, although triggers and pathways of inflammation are probably multiple and vary in different clinical entities of atherosclerotic disorders, an imbalance between anti-inflammatory mechanisms and pro-inflammatory factors will result in an atherosclerotic progression. Vascular endothelial dysfunction and lipoprotein retention into the arterial intima have been reported as the earliest events in atherogenesis with which inflammation is linked. Inflammatory has also been extended to the disorders of coronary microvasculature, and associated with special subsets of coronary artery disease such as silent myocardial ischemia, myocardial ischemia-reperfusion, cardiac syndrome X, variant angina, coronary artery ectasia, coronary calcification and in-stent restenosis. Inflammatory biomarkers, originally studied to better understand the pathophysiology of atherosclerosis, have generated increasing interest among researches and clinicians. The identification of inflammatory biomarkers and cellular/molecular pathways in atherosclerotic disease represent important goals in cardiovascular disease research, in particular with respect of the development of therapeutic strategies to prevent or reverse atherosclerotic diseases.

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ardiovascular diseases are the major cause of mortality in the western world, and it is expected that this will remain so during the foreseeable future.1 Among them, atherosclerotic disease is the most important underlying cause of the death from cardiovascular diseases.2 Over the past few decades, our understanding of the vascular biology of atherogenesis, and its clinical presentations has evolved enormously. More recently, a large body of evidence has supported the idea that inflammatory mechanisms play an important role throughout all phases of atherogenesis, from the formation of fatty streaks to the acute coronary event due to vulnerable plaque rupture.3-5 Indeed, although triggers and pathways of inflammation are probably multiple and different in different clinical entities of atherosclerotic disorders, an imbalance between anti-inflammatory mechanisms and pro-inflammatory factors, will result in atherosclerotic progression.6,7 Accordingly, the concept that atherosclerosis is an inflammatory disease has become a stimulator for investigators to explore the inflammatory nature of the atherosclerotic process, and our knowledge concerning inflammatory atherosclerotic events at the level of both the basic and clinical entity has advanced substantially.

INFLAMMATION IS A BASIC FEATURE OF THE

ATHEROSCLEROTIC PROCESS

Although atherosclerosis is considered to be a multi-factorial disease in which genetic, environmental, and metabolic factors have been implicated, gaps remain

C

in our knowledge of the etiopathogenesis of atherosclerosis.5 Inflammation is a reaction that bears on diverse human diseases of non-pathogenic origin.8 Recently, the concept that inflammation is a basic feature of atherosclerosis has been increasingly recognized, and subsequently resulted in a great interest in revealing the inflammatory nature of the atherosclerotic process. In fact, definition of atherosclerosis is a complex multifactorial disease developing in the arterial wall in response to various forms of injurious stimuli and resulting in excessive inflammatory and fibro-proliferative reactions.3

Investigations have defined the progression of inflammation in atherosclerosis, beginning with the recruitment of leukocytes, the cells that sustain and amplify the inflammatory response in the atherosclerotic lesion.9,10 Cardiovascular risk factors, including dyslipidemia, smoking, hypertension, and diabetes can

DOI: 10.3760/cma.j.issn.0366-6999.2011.21.024

Divison of Dyslipidemia, Cardiovascular Medicine, Fu Wai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China (Li JJ) (Email:lijnjn@http://wendang.chazidian.com)

This article was partly supported by grants from theFu Wai Hospital (No. 2004190), National Natural Science Foundation of China (Nos. 30670861, No. 30871055 and No. 81070171), Beijing Natural Science Foundation (No. 7082081), National Project in the Five-year Period Grant, and Specialized Research Fund forthe Doctoral Program of Higher Education of China (No. 20060023044 and No. 20070023047). Conflict of interest: None.

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damage the vascular endothelium and promote an inflammatory response, and result in endothelial activation. Endothelial cell activation is accompanied by the enhanced expression of cell adhesion molecules, such as vascular cell adhesion molecule-1, a significant reduction in nitric oxide production, and a remarkable increase in the formation of reactive oxygen species. As a result, endothelial function is impaired and the inflammatory cascade is activated.11 Furthermore, increased permeability across the endothelium allows the uptake of low-density lipoprotein (LDL) into the arterial intima, where it is oxidized to ox-LDL, increasing its atherogenicity and the inflammatory reactions.9 At the same time, the expression of cell adhesion molecules permits circulating monocytes to adhere to the endothelial surface, from where they subsequently migrate into the subendothelial space and differentiate into macrophages. The activated endothelial cells also release cytokines and growth factors, which over time contribute to the increasing complexity of the developing inflammatory atherosclerotic lesion.10 These factors stimulate migration and proliferation of vascular smooth muscle cells and fibroblasts, thereby allowing formation of a fibrous cap over the atherosclerotic lesion. Release of proteolytic enzymes may weaken the cap, leading to plaque rupture, exposure of underlying collagen to platelets, and subsequent thrombus formation. As a result of this inflammatory cycle, atherosclerotic progress is made and cardiovascular events are eventually detectable. Inflammation, therefore, is a common feature of the atherosclerotic process, and is present in all stages of the disease.

ENDOTHELIAL DYSFUNCTION IS THE EARLIEST SIGN OF THE ATHEROSCLEROTIC

PROCESS

Endothelial cells are the first cells to experience the impact of stimuli, and are permanently exposed to various types of biochemical forces from their surroundings.11 They in particular occupy a strategic position to initiate and propagate the inflammatory reactions by regulation of inflammatory cell migration, activation and their contribution to thrombosis.12 Over the past several years, it has been reported that vascular endothelial dysfunction and lipoprotein retention in the arterial intima are the earliest events in atherogenesis, promoting cytokine and chemokine release; both of which are responsible for leukocytes recruitment.11 In fact, initiation of the atherosclerotic process involves alteration of the endothelial monolayer, which in the normal state resists prolonged contact with leukocytes. Risk factors, such as elevated LDL, lead to endothelial changes. Accordingly, the vascular endothelium’s role in the long preclinical phase has been a major focus of research.

It is well known that a variety of insults may damage endothelial structure and function; these include physical injuries, biochemical injury, and immune mediated

damage.11 These insults cause alteration in endothelial physiology resulting in impairment or loss of its normal function. The development of an imbalance in the release of vasoconstrictor and vasodilator agents from the endothelium results in impaired endothelial dependent vasodilatation, the hallmark of endothelial dysfunction, which may initiate the atherosclerotic process.13 Over the past decade, the study of nitric oxide dependent regulation of vascular tone in response to pharmacological and physical stimuli in different vascular beds has become possible. Various invasive and noninvasive techniques have shown that patients with atherosclerotic disease and those with increased cardiovascular risk factor profiles present with dysfunctional endothelium.11 Both traditional and novel risk factors for cardiovascular disease trigger a chronic inflammatory process, which is accompanied by loss of vasodilatory and antithrombotic properties of the vascular endothelium. Therefore, attempts to restore endothelial dysfunction are beneficial for reversing or stopping the development of atherosclerotic progression.

INFLAMMATION IS A KEY TRIGGER OF ATHEROSCLEROTIC PLAQUE RUPTURE

It is an accepted theory that acute coronary syndrome is caused by rupture of the atherosclerotic plaque with superimposed thrombus. This is a complex process involving a number of different stages that is responsible for the vast majority of acute ischemic syndromes.5 In nearly 75% of cases the thrombus overlies a disrupted or ruptured plaque with superficial endothelial erosion.14 Over the past several years, it has been recognized that plaque composition rather than plaque size or stenosis severity is important for plaque rupture and subsequent thrombosis. This is an extremely important finding for understanding the pathophysiology of acute ischemic events. Fissure or rupture of the fibrous cap is the underlying basis for the most coronary thrombi with extension of the thrombus into the plaque as well as into the lumen, and with propagation of the thrombus upstream from the site of cap rupture.15 A number of studies have shown that ruptured plaques contain more inflammatory and immune effector cells than intact plaques, and are often found adjacent to the site of fibrous cap rupture and around the lipid core as well as in the adventitia around areas of neovascularization.16-20 These inflammatory and immune effector cells are mostly monocyte-derived macrophages, but also include activated T-cells, dendritic cells and activated degranulating mast cells expressing the proteolytic enzymes tryptase and chymase.17 Our clinical studies 19,20 also showed that a persistent and enhanced inflammatory responsiveness to pro-inflammatory stimulators, such as C-reactive protein (CRP), are involved in the pathogenesis of unstable coronary disease. The inflammatory response presents as elevated plasma inflammatory cytokines and activation of nuclear factor-kappa B. Apparently, inflammation is a major

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trigger for acute coronary syndrome.

Ruptured plaques, and by inference, plaques prone to rupture, tend to be large in size with associated expansive atreial remodeling, thin fibrous caps with a thick or large necrotic lipid core with immuno-inflammatory cell infiltration in the fibrous cap and adventitia and increased plaque neovascularity and intraplaque hemorrhage.14 The size of the necrotic lipid core and extent and location of plaque inflammation appear to be key factors in determining plaque instability.15 Inflammation and immune cell activation appears to play a key role in the loss of collagen in the fibrous cap, a prelude to fibrous cap rupture, through release of collagen degrading enzymes.18 Furthermore, inflammation may also play a key role in the death of collagen synthesizing smooth muscle cells, which further contributes to loss of fibrous cap integrity.14 Inflammation is also likely a key player in the ensuing thrombosis that follows plaque disruption through the elaboration of the pro-coagulant protein, tissue factor. An improved understanding of the pathophysiology of plaque vulnerability and subsequent atheropthrombosis should provide novel insights into improved prevention of athero-thrombotic cardiovascular events.18-20

INFLAMMATION IS A RELATING FACTOR OF

CORONARY MICROCIRCULATION

Recently, our understanding of inflammatory events at the level of the microcirculation has advanced substantially. Themyocardial microcirculation is a heterogeneous vascular compartment consisting of vessels with diameters of <500 ?m including small arteries, arterioles, capillaries, and post capillary venules, that are responsible for distributing blood and transferring of water and solutes to the working cardiocytes.21 Inflammation is presently perceived as a chronic inflammatory process that extends into the microvasculature, and has received special interest.

For example, myocardial ischemia-reperfusion induces all the characteristics of an acute inflammatory response.21-23 A vast amount of data have indicated that reperfusion can induce an inflammatory response following ischemia. A study showed that reperfusion induces tumor necrosis factor-? expression in the coronary microvasculature, and tumor necrosis factor-? can impair the endothelium- dependent coronary flow reserve and augment myocardial microvascular permeability.22 Treatment with anti-tumor necrosis factor-? antibodies can reduce myocardial infarct size and improve cardiac function.8 Human study data indicated that myocardial ischemia-reperfusion, which occurs after thrombolysis, angioplasty, or stenting, is associated with increased circulating levels of various markers of inflammation; including cytokines, acute phase reactant, cell adhesion molecules, products of lipid perioxidation, and acute neutrophils.23

Inflammatory mechanisms are also an apparent factor in other coronary microcirculation disorders. Cardiac syndrome X is defined as typical angina pectoris, a positive treadmill exercise test, negative intravenous ergonovine test and normal coronary angiography.24,25 The pathogenesis of cardiac syndrome X has previously been ascribed to myocardial ischemia that may be caused by microvascular dysfunction and increased sensitivity to intracardiac pain.26 Despite extensive studies, the pathophysiological mechanisms in cardiac syndrome, however, remain unclear. Recent data have suggested that chronic inflammation is associated with cardiac syndrome X. Our recent data suggested that low-grade, chronic inflammation might contribute to the development of cardiac syndrome X manifested by increased plasma levels of inflammatory cells and inflammatory markers.25 In addition, the evidence, including data from our group, for this hypothesis shows that inflammatory markers are increased, and associated with the disease activity in patients with cardiac syndrome X.25-27 And also, statin, a lipid-lowering and anti-inflammatory drug, has been demonstrated to significantly modify the disease process in this special syndrome.27

INFLAMMATION IS A DETERMINANT OF A SPECIAL SUBSETS OF CORONARY ARTERY

DISEASES

Inflammation in other unique types of coronary artery diseases is also receiving special interest. Patients with silent myocardial ischemia are commonly considered as having variability of the defective warning system.28,29 The recent data, however, indicated that significant increases of levels of anti-inflammatory cytokines together with the decrease of leukocyte adhesion molecule expression might identify one of the mechanisms for silent myocardial ischemia.29 More recently, intriguing observations have shown that there is a particular biochemical pattern of inflammation, such as increased production of inflammatory cytokines that explains the lack of anginal symptoms in patients with silent myocardial ischemia.30 That is, pain perception may result from the microenvironmental balance between pro-inflammatory and anti-inflammatory reactions.

Variant angina is a variant type of coronary artery disease first described in 1959, and usually caused by episodic coronary spasm. However, growing evidence has shown that vasospastic coronary disease has an inflammatory component.31 Attention was first paid to inflammation in variant angina in a case report in 1978.32 This patient suffered a sudden death and showed normal coronary arteries in autopsy, but acute pericarditis and arteritis. Therefore, inflammation that elicited severe spasm of the coronary artery was logically established by investigators. Subsequent studies suggested that activated mast cells are to be found in the adventitia of patients with variant angina. Pathological studies also showed that the immune response and inflammation might play an important role in the pathogenesis of coronary spasm. A recent report found that the percentage of T-lymphocytes in variant

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angina patients was significantly higher than in stable effort angina and in control participants.33 Our data showed that white blood cell counts and monocyte counts were significantly higher in patients with variant angina than in patients with stable angina or in normal controls; suggesting that inflammation may play an important role in coronary vasomotion.34

Finally, coronary artery ectasia is also increasingly recognized as an inflammatory-relating disease.35-41 In spite of the mechanisms responsible for coronary ectasia formation during the atheroscleorotic process being unclear, atherosclerosis-induced ectasia derives primarily from thinning and/or destruction of the media.36 Ectasia may occur during the development of coronary atherosclerosis. However, the ectatic process may also be independent from the atherosclerotic process because it can be found isolated in coronary and other vascular systems.37-41 Although congenital and acquired causes are well defined in particular patients with ectasia in pediatric populations, they are less well defined in focal or more diffuse ectasia in adult populations with risk factors for coronary artery disease. Recent data have definitely shown that coronary ectasia is associated with an inflammatory response that presented as elevated inflammatory cytokines and markers.35-37 Primarily, the studies have suggested a cytokine-induced tissue inflammation in the pathogenesis of abdominal aortic aneurysms. Accumulating data have demonstrated an increased level of circulating inflammatory markers including pro-inflammatory cytokines, adhesion molecules, acute phase reactant, and inflammatory- related cells.

In our recent study, the data suggested that higher white blood cell, neutrophil and monocyte counts were found in patients with isolated coronary ectasia compared with obstructive coronary artery disease patients or normal controls.38 Univariate analysis showed that the sex, current smoking, numbers of white blood cells, neutrophils, monocytes, levels of CRP and IL-6 were related with isolated coronary ectasia, while the monocyte count was independently linked with a diagnosis of isolated coronary ectasia. CRP was the independent variable most strongly associated with ectasia by multivariate analysis.

Taken together, the above studies have demonstrated that a significant chronic inflammation might be linked with the pathogenesis of silent myocardial ischemia, variant angina and isolated coronary ectasia. Inflammation is associated with not only inflammatory markers but also inflammatory cells of special subsets in coronary artery diseases.

INFLAMMATION IS AN ACCOMPLICE OF

CORONARY CALCIFICATION

In the general population, vascular calcification increases with age and is often associated with medial sclerosis.42

In addition, the coronary calcification score has been positively correlated with duration of diabetes mellitus, hypertension, serum creatinine, and the presence of clinically evident coronary artery disease.43 Coronary calcification frequently coexists with coronary atherosclerotic restenosis. In histological preparations, extensive calcification is associated with significant coronary artery stenosis.44 Vascular calcification was long thought to be the final stage of atherosclerosis. However, recent studies have identified a continuous development of vascular calcification even at early stages of atherosclerosis.43 The data indicate that coronary calcification begins as early as the second decade of life, just after fatty streak formation.45 Furthermore, some studies have demonstrated that coronary calcification is a marker for significant coronary atherosclerosis, and that patients with high coronary calcification scores are at an increased risk for coronary events.43 Recent histopathological studies have revealed that plaque calcification is present in 69% of ruptured plaques in sudden coronary death.46 Vascular calcification has long been regarded as a degenerative process leading to mineral deposition in the vascular wall characteristic of late stages of atherosclerosis. However, a recent study identified vascular calcification is an active, regulated process.42

Although intensive studies have been performed, the mechanism of coronary calcification is still unclear. Over the last decades, several studies have identified active and highly regulated processes controlling vascular calcification. These include signaling molecules such as metabolites of vitamin K metabolism, matrix Gla protein, leptin, osteopontin, osteoprotegrin and the RANK/RANKOL system. More recently, inflammatory mechanisms have been demonstrated to be involved in the development of atherosclerosis, and its clinical manifestation.42

Several mediators of inflammation such as oxidation, carbonyl stress, CRP, and cytokines have been suggested to directly stimulate vascular calcification in chronic kidney disease.43 In prospective epidemiologic studies, plasma levels of inflammatory markers, particularly CRP, predict not only myocardial infarction and cardiovascular death, but also coronary calcification. Coronary artery calcification might be useful in identifying novel risk factors for coronary atherosclerosis in asymptomatic subjects.42 Coronary artery calcification has also been shown to play an important role in the development of atherosclerosis and a strong association with total plaque burden has been proven in previous histological studies. Accordingly, several recent studies have also focused the relation between CRP and coronary calcification. Prospective reports indicate that high coronary artery calcification scores, like high CRP levels, may predict an increased risk of cardiac events. A study examined the relationship between CRP levels and coronary calcification in a well-characterized, community-based cohort from samples of the Framingham Heart Study.47

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They studied a stratified random sample of 321 men and women (mean age 60 years) who were free of clinically apparent cardiovascular disease. Patients were subjected to assess the number of coronary calcification and the coronary calcification Agatston score. Spearman correlation coefficients between CRP and calcification score were calculated and adjusted for age, age plus individual risk factors, and age plus the Framingham coronary heart disease risk score. They found that for both sexes, CRP was significantly correlated with the Agatston score. Consistent with the above study, Erbel et al48 evaluated the sex related cardiovascular risk stratification based on quantification of subclinical atherosclerosis and inflammation in this population-based cohort. In their study, Framingham risk score groups and National Cholesterol Education Program in Adult Treatment Panel III (NCEP ATP III) based risk categories were calculated. Alterations in risk classification were analyzed using the coronary artery calcification score (CACS) and CRP categories: (1) CACS <100, 100–399 and ?400 or 75th percentile, (2) CRP ?1, 1–3, >3 mg/L, and (3) a combined CACS and CRP score. They found that NCEP ATP III risk categories are significantly and sex-dependently altered using coronary calcification and CRP. It is suggested that coronary calcification is of the highest value in men. CRP seems to be only a complementary value in women. They conclude that measurements of atherosclerotic inflammation may improve sex-related risk prediction in a general population. Similar to CRP, Ammirati et al49 reported that in peritoneal dialysis patients, coronary calcification is highly prevalent, and conditions such as inflammation, as determined by soluble Fas levels and mineral disturbances, are associated with coronary calcification.

INFLAMMATION IS OF MAJOR IMPORTANCE

TO THE RESTENOTIC PROCESS

In-stent restenosis following coronary intervention has long been attributed to elastic recoil immediately following balloon deflation, neointimal proliferation triggered by injury to the vessel wall, and late negative remodeling.50 A number of studies carried out in the last decade have consistently indicated that inflammatory mechanisms play a pivotal role in the process of neointimal proliferation and stent restenosis.51-59

An experimental study showed that leukocyte recruitment could be detected at the level of the coronary segment injured by the stent within 10–15 minutes of stent deployment.54 Leukocyte invasion is also associated with massive deposition of activated platelets. The invading neutrophils, platelets and coronary endothelium injured by the stent undergo functional changes manifested by a significant increase of the cellular surface expression of a variety of ligands; platelets activate their inducible fibrinogen receptors and neutrophils up-regulate Mac-1 and L-selection receptors.60 Of note, none of these changes occurs across stenotic non-dilated coronary artery segments.

Several clinical studies have focused on the early markers or initiators of inflammatory response following coronary stenting. Aggarwal et al61 demonstrated that comparing inflammatory markers including CRP, interleukin-6, and interleukin-1 receptor antagonist, soluble CD40 ligand (sCD40L) exhibited the greatest relative rise in the first 10 minutes after coronary stenting. This indicates that sCD40L may be an early marker of the initiation of inflammation after coronary stenting. In our time course study of the inflammatory response after renal artery stenting, we found that stenting could trigger an inflammatory response as evidenced by increased plasma levels of CRP and interleukin-6. Interleukin-6, however, was early initiator of inflammatory cytokines, and CRP was a later marker of a systemic inflammatory response to renal artery stenting.53 Those early markers of inflammatory response following coronary stenting may be a trigger for the inflammatory cascade and a target for controlling in-stent restenosis.

The magnitude of the local inflammatory response may affect the process of restenosis. The data indicate that patients with a higher release of interleukin-6 immediately after stent deployment have a higher risk of restenosis.62 Additionally, it is likely that the magnitude and persistence of the local inflammatory reaction are partly controlled by individual genetic factors. Even the exposure of the metal strut of the stent may trigger a persistent inflammatory response to a “foreign body” in susceptible patients that, in turn, may affect neointimal proliferation and stent restenosis.63

Local inflammation caused by stent deployment elicits a systemic inflammatory response initially mediated by inflammatory cytokines such as interleukin-1, interleukin-6 and tumor necrosis factor-?.54,64 These molecules cause a production of acute phase reactants such as CRP in the liver that rapidly increase in the blood and may directly amplify the local response to the inflammatory stimulus.65 Our previous study showed that increased levels of interleukin-6 and CRP could be detected at 30 minutes and 6 hours following both renal and coronary artery stenting.55,57-59 In patients with stable angina, single vessel disease with normal baseline CRP plasma levels, successful stent implantation is followed by a rapid increase of CRP with a peak level 48 hours after stenting. Interestingly, patients with persistent elevated CRP levels at 72 hours showed an increased risk of cardiac events during the follow-up.57 This finding strongly supports the hypothesis that genetic factors might affect local and systemic responses to the inflammatory stimulus represented by the stent. Therefore, the risk of restenosis seems dependent on the magnitude and persistence of local inflammation.

Finally, the development of drug eluting stents has further revolutionized the field of interventional cardiology.