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Ann Thorac Surg 2001;71:2066-2074
© 2001 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado, USA
Address reprint requests to Dr Selzman, Department of Surgery, University of Colorado Health Sciences Center, Box C-310, 4200 East Ninth Ave, Denver, CO 80262
e-mail: craig.selzman{at}uchsc.edu
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Abstract |
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 Top Abstract IntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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Introduction |
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TopAbstractIntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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What is atherosclerosis? |
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TopAbstractIntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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Atherogenesis and the response to injury |
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TopAbstractIntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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In 1974, Ross and associates [11] postulated that atherogenesis was dependent on cellular interactions in the vessel wall after endothelial injury. Release of growth factors by stimulated monocytes and platelets promoted vascular smooth muscle cell (VSMC) proliferation. The premise that atherogenesis results from an exaggerated response to injury has evolved into an attractive unifying hypothesis of vascular disease and repair (Fig 1). Injury includes more than direct physical trauma, as seen with angioplasty, hypertension, and shear stress (atherosclerotic lesions typically occur at vessel bifurcations). Vessel damage also is initiated by other insults, including viruses, bacteria, nicotine, homocysteine, and oxidized low-density lipoproteins (LDL). Endothelial disruption or dysfunction allows for adhesion and transmigration of circulating monocytes, platelets, and T lymphocytes. Within the developing lesion, these activated cells release potent growth-regulatory molecules that can act in an autocrine or paracrine manner. Under the influence of cytokines and growth factors, VSMCs adapt to a synthetic phenotype and commence proliferation and migration across the internal elastic lamina into the intimal layer. Stimulated VSMCs allow for the deposition of extracellular matrix, thus converting the initial lesion to a fibrous plaque.
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Modification of vascular injury |
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TopAbstractIntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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Oxidants
The oxidative-modification hypothesis postulates that atherogenesis is initiated by oxidation of the lipids in LDL [15]. Native LDL trapped in the subendothelial space is oxidized by resident vascular cells. Oxidized LDL induces monocyte chemotaxis, stimulates macrophage uptake of cholesterol with subsequent foam cell necrosis, and promotes elaboration of toxic free radicals. Along with oxidized LDL itself, released reactive oxygen species (including superoxide and hydrogen peroxide) directly injure vascular cells, impair endothelial vasomotor function, promote platelet aggregation or leukocyte adhesion, and stimulate VSMC proliferation.
The oxidative-modification hypothesis is supported by several epidemiologic studies that show an inverse association between the frequency of coronary artery disease and dietary intake of antioxidant vitamins [16, 17]. Whereas observational and experimental studies provide compelling evidence for a beneficial role for antioxidants, randomized prospective trials have had conflicting results. Patients with known coronary disease who received vitamin E had a 77% reduction in nonfatal myocardial infarctions at 17 months [18]. Conversely, in more than 9,000 high-risk patients, vitamin E therapy had no effect on cardiovascular outcomes [19]. Unfortunately, those studies tested different doses of antioxidants. Furthermore, treated patients suffered from advanced levels of arteriosclerotic disease. Oxidation of LDL is an important event early in arteriosclerosis–including the development of the fatty streak. Antioxidant therapy likely needs to be initiated in younger patients to have maximal antiatherogenic effects. Although intuitively attractive, the cause-and-effect relationship of antioxidant therapy and cardiovascular disease remains speculative.
Homocysteine
Homocysteine is an amino acid intermediate formed by the metabolism of methionine, an essential component of animal and plant proteins. Hyperhomocysteinemia can be secondary to genetic enzyme defect (cystathionine ß-synthase), vitamin deficiency (folate), chronic medical disorder (renal failure), or medication (phenytoin). Homocysteine is oxidized rapidly in plasma and tissue macrophages. The release of damaging reactive oxygen species initiates the inflammatory cascade. Hyperhomocysteinemia is associated experimentally and clinically with increased platelet aggregation, abnormalities of fibrinolysis, global endothelial cell dysfunction, oxidation of LDL, and proliferation of VSMCs, all of which contribute to atherothrombosis.
The relationship between excess homocysteine and cardiovascular disease was described initially in an autopsy study of children with homocysteinuria and diffuse arterial thrombosis [20]. Subsequently, nearly 30 observational studies have corroborated that association [21]. Compared with normal controls, 35% to 45% of patients with known cardiovascular disease have elevated levels of homocysteine. The relative risk of coronary arterial disease in those patients was estimated to be 24 times that of controls [22]. Thus, hyperhomocysteinemia appears to be an independent risk factor for cardiovascular events. Nearly 10% of the risk of coronary arterial disease in the general population is attributable to homocysteine. Comparatively, an increase of 5 µmol/L in plasma homocysteine concentration (normal 5 to 15 µmol/L) raises the risk of coronary disease as much as an increase of 20 to 85 mg/dL in total cholesterol concentration [23, 24].
Should we all take folate with our vitamin E? Folic acid, vitamins B12 and B6, and pyridoxine are important cofactors for the enzymatic processing of homocysteine. Indeed, the reduction in mortality rate from cardiovascular causes since 1960 has been correlated with the increase in vitamin B6 supplementation in the food supply. Furthermore, the United States Food and Drug Administration mandates folic acid fortification in flours and cereal products as a method of preventing arteriosclerotic-related death. Although these supplements might effectively decrease serum homocysteine levels, the expected decrease in cardiovascular events has not yet been documented in prospective, randomized clinical trials. Although treatment appears intuitively sound in patients with moderate to severe hyperhomocysteinemia and known cardiovascular disease, universal screening and treatment for the general population is likely premature [25].
Infectious disease
Infectious diseases have long been associated with atherogenesis. Bacteria include Chlamydia pneumoniae, Helicobacter pylori, Streptococci, and Bacillus typhosus; viruses include influenza, herpes virus, adenovirus, and cytomegalovirus. Studies to implicate those organisms as directly causative pathogens mostly have been inconclusive [26]. Currently, much enthusiasm exists concerning the relationship between C pneumoniae and cardiovascular disease.
The initial epidemiologic description linking chlamydial species to arteriosclerosis was by venerologists in South America in the 1940s. Chlamydia pneumoniae, previously referred to as the TWAR strain, is a ubiquitous respiratory organism. More than 50% of the population has antichlamydial antibodies by age 50 years. The prevalence of this organism makes it difficult to determine its true role in arteriosclerosis. In the Arteriosclerosis Risk in Communities Study, which prospectively studied participants who were free of coronary disease at baseline, C pneumoniae immunoglobulin G titers were found in only 65% of patients who had subsequent cardiovascular events, compared with 55% in the control cohort [27].
Chlamydia pneumoniae has been detected histologically in patients with end-stage cardiomyopathies, nonrheumatic stenotic heart valves, aortic aneurysms, and carotid endarterectomy lesions. Although these observational studies suggest an association between C pneumoniae and arteriosclerosis, it is not known whether this organism is an active participant or an innocent bystander. Chlamydia pneumoniae can infect vascular cells, survive, and actively replicate [28]. Chlamydia pneumoniae has been associated with decreased levels of HDL cholesterol and increased levels of total cholesterol, thus creating an atherogenic milieu. Furthermore, C pneumoniae infection activates inflammatory intracellular transcription factors, promotes cytokine release, and stimulates VSMC proliferation [29, 30]. As such, a scenario can be envisioned where C pneumoniae infects macrophages, endothelial cells, and VSMC and promulgates the vascular response to injury.
Should we all take a macrolide with our folate and vitamin E? Is C pneumoniae the H pylori equivalent for cardiovascular disease? The jury remains undecided. The dynamic nature of arteriosclerosis suggests that eradication of C pneumoniae alone would not have the profound effect on disease as seen with H pylori and peptic ulcer disease. Currently, several small secondary antibiotic prevention trials have been reported. Patients with unstable angina and male survivors of myocardial infarction treated with macrolides had lower titers of antichlamydial antibody and fewer adverse cardiovascular events [31, 32]. Conversely, in patients with known coronary disease, anti-C pneumoniae therapy with azithromycin had no apparent effect on cardiovascular events at 6 months [33]. Conclusions from these studies must be interpreted with several caveats. Each trial enrolled small numbers, examined early outcomes (before 6 months), and gave different doses of antibiotics. Currently, two large trials, which will likely delineate the role of C pneumoniae-directed therapy and coronary disease, are underway, the WIZARD trial (weekly intervention with zithromax against arteriosclerotic-related disorders) and the ACE trial (azithromycin coronary events study). Each study plans to enroll more than 3500 patients with coronary artery disease, treat with antibiotics from 3 to 12 months, and observe for 2.5 to 4 years.
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Cellular response to vascular injury |
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TopAbstractIntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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Endothelial cells
A healthy blood vessel wall is lined by a monolayer of metabolically active endothelial cells [34]. The surface area of the endothelium is approximately 5,000 m2 but comprises only 1% of total body weight. While acting as a physical barrier that protects the underlying vessel and allows formed blood elements to flow freely preventing thrombosis, this seemingly bucolic layer is a control center of vascular physiology. The endothelium is an important docking point for monocytes, neutrophils, and lymphocytes by virtue of its ability to express cell-specific adhesion molecules. The endothelium is also a source of mediators that regulate vascular tone. Factors favoring vessel relaxation include nitric oxide and prostacyclin. Factors favoring vessel constriction include thromboxane, leukotrienes, free radicals, endothelins, and cytokines, including tumor necrosis factor and interleukin-1. Finally, endothelial cells produce stimulatory and inhibitory mitogens that act in both an autocrine and paracrine manner (Fig 2).
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The initial event at sites of vessel injury is the adhesion of circulating cells to endothelial cells, VSMCs, and matrix proteins. These interactions are characterized by a diverse system of surface molecules and receptors broadly categorized as integrins, immunoglobulins, and selectins [35]. When blood monocytes attach and infiltrate into the vessel, they transform into tissue macrophages. These cells are important in the early formation of the fatty streak and the more advanced atheroma. Although macrophages are a potent source of inflammatory mediators, they are probably best know for their abilities to ingest lipids (phenotypically described as a foam cell) and to scavenge oxidized LDL with production of free radicals.
Both T and B lymphocytes interact with macrophages and have been identified within the atherosclerotic plaque. Immune-mediated disease often reflect an imbalance between proinflammatory and anti-inflammatory responses. T-helper-1 lymphocytes (Th1) promote T-lymphocyte and monocyte activation and produce interferon-
, granulocyte-macrophage colony stimulating factor, and interleukins 2 and 3. T–helper-2 lymphocytes (Th2) produce interleukins 4 and 10 and can inhibit Th1 responses. The T lymphocyte classically is activated by the presentation of antigen by cellular glycoprotein receptors encoded by the major histocompatability complex. In atherosclerotic plaques, the endothelial cells, smooth muscle cells, and macrophages all express the HLA-DR receptor and activate T lymphocytes [36]. These observations suggest that a local immune response contributes to vascular inflammation and repair.
The identification of a factor released by platelets that stimulated VSMC proliferation was one of the initial observations in support of the inflammatory hypothesis [11]. This substance, platelet-derived growth factor, is now recognized as deriving from multiple cell types, including platelets. Although platelets contribute to the overall inflammatory milieu, they are central to later stages of arteriosclerosis (types V and VI). Thrombosis is central to the pathogenesis of acute arterial insufficiency and acute coronary and cerebrovascular syndromes, including unstable angina, non-Q-wave myocardial infarction, acute (ST-elevation) myocardial infarction, and vessel occlusion after vascular intervention (eg, angioplasty). The three phases of platelet activation include adhesion, aggregation, and secretion. With exposure of the subendothelial space after vascular injury, platelets adhere to basement membrane proteins, especially collagen. This adhesion is dependent upon binding of endothelial or circulating von Willebrand factor to the platelet membrane glycoprotein Ib receptor. The predominant mechanism of aggregation involves binding of fibrinogen to the platelet glycoprotein Ib or IIIa receptor. Platelet secretion usually follows aggregation. Released products include the contents of dense bodies (serotonin, calcium, and adenosine triphosphate) and alpha granules (von Willebrand factor, fibrinogen, growth factors, platelet factor-4, and coagulation factors).
Vascular smooth muscle cells
Classic models of balloon injury showed a central role of VSMCs in neointimal hyperplasia [37]. The three-wave hypothesis suggested that with injury, contractile VSMCs in the media would assume a synthetic phenotype and proliferate. Subsequently, VSMCs would migrate luminally across the internal elastic lamina. Finally, these intimal VSMCs recommence proliferation. Although intimal hyperplasia is histopathologically distinct from atheromatous lesions, this model addresses the importance of VSMC in atherogenesis. Vascular smooth muscle cells are not idle components of the vessel wall. In addition to their contractile properties governing vasomotor tone, VSMCs, like endothelial cells, are an active organ. Importantly, VSMCs are the principal manufacturers of proteoglycans and collagen. Most of the atheromatous lesion is composed of extracellular matrix deposition.
Mitogenic stimulation of VSMCs, with subsequent VSMC proliferation is central to intimal hyperplasia. Interestingly, VSMCs in advanced lesions often are quiescent [38]. This observation underscores the dynamic nature of VSMCs. For example, tumor necrosis factor-
stimulation might promote both VSMC proliferation and apoptosis [39, 40]. How is it that a given cytokine can produce opposite effects? The VSMC response likely depends on interactions with other inflammatory mediators and the stage of vessel remodeling. In type IV and V lesions, the atheromatous core is protected by a thin fibrous cap with edges composed of VSMC. The pathogenesis of acute coronary syndromes likely involves apoptosis of these VSMC, thus allowing for rupture of the cap into the lesion with subsequent thrombosis [41]. As such, these disparate biologic responses must be considered when contemplating therapeutic manipulation of VSMC physiology.
Adventitia
As one of only three principal layers of the blood vessel wall, the adventitia has been largely ignored. The adventitia is not simply a structural layer. Adventitial fibroblasts can migrate luminally, secrete mitogens and free radicals, and proliferate, activities that abet atherogenesis [42]. The adventita is the site of vessel sympathetic and parasympathetic innervation. Neurotransmitters released from these efferent fibers assist with vasomotor tone and, importantly, can provide compensatory vasodilation during periods of endothelial dysfunction [43]. Finally, the adventitia is a significant site of resident mast cells. Adventitial mast cells appear to be involved in areas of plaque rupture in acute coronary syndromes [44].
The adventitia is a virtual sponge for protein and gene transfer. Fibroblasts avidly take up viral vectors and can be programmed to enhance nitric oxide production [45]. Periadventital delivery of antisense oligonucleotides to proliferative factors has decreased intimal hyperplasia in vivo [46]. As cardiothoracic surgeons, we see epicardial coronary arteries and diseased peripheral vessels every day. Manipulation of the adventitia is an exciting and feasible area of cardiovascular research.
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Intercellular and intracellular response to vascular injury |
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TopAbstractIntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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Cytokines and growth factors regulate leukocyte-endothelial adhesion, chemotaxis, cellular proliferation, apoptosis, and vasomotor tone. These mediators often work synergistically to exert their influence on circulating and resident vascular cells. Although we conveniently group these mediators as cytokines or growth factors, several other substances are inherently involved in the inflammatory response. Endothelins are well recognized as potent vasoconstrictors, but endothelins are also mitogenic for VSMC and promote endothelial cell adhesion molecule expression [49]. Conversely, although prostaglandins promote vasodilation, they also inhibit platelet aggregation and VSMC proliferation. The renin-angiotensin system is often dysfunctional in cardiovascular patients. Similar to endothelins, angiotensin-II is a potent vasoconstrictor, but it also increases adhesion molecule expression and promotes VSMC growth. The antiatherogenic influence of angiotensin blockade, either by converting-enzyme inhibitors or receptor antagonists, appears promising [50, 51]. Cumulatively, the positive and negative interplay between these diverse inflammatory mediators determines the vascular cell’s response to noxious stimuli.
Experimentally, anti-growth factor therapies can inhibit intimal hyperplasia [52]. However, because of the functional redundancy among inflammatory mediators, strategies aimed at inhibiting a single substance are unlikely to succeed. As such, researchers have investigated the effects of manipulating intracellular signal transduction on vascular physiology. These strategies exemplify the notion that a variety of insults will initiate a cascade of events that converge to one or more dominant events. As shown in Figure 3, inflammatory mediators engage cell-surface receptors, which sequentially activate a web of intracellular signals. Interactions between intracellular intermediates ultimately might influence gene transcription, protein translation, and cell-cycle regulation.
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B) is a central regulator of inflammatory signals and is upregulated in arteriosclerotic lesions [53, 54]. NFB will serve as an example of how selective manipulation of intracellular signal transduction can effectively influence the response to injury. NFB is activated by balloon injury, shear stress, and exposure to oxidized LDL, platelet-derived growth factor, fibroblast growth factor, and tumor necrosis factor [55, 56]. When bound by its inhibitory protein, IB, NFB exists in the cytoplasm as an inactive dimer (p50/p65). Upon stimulation, phosphorylation of IB disrupts the NFB:IB complex. Subsequently, NFB is free to translocate to the nucleus, engage DNA, and initiate gene transcription [57]. Once activated, NFB promotes many events that are important in atherogenesis (Fig 4).
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B activity. Hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors are one of few drugs that have induced regression of arteriosclerosis. Although the -statin drugs effectively decrease total and LDL cholesterol, they are also potent inhibitors of NFB activity in macrophages and VSMCs [58]. Epidemiologically, moderate alcohol consumption is inversely associated with coronary disease [59]. Although substances in red wine have antioxidant properties, flavonoid compounds downregulate NFB [60]. Finally, aspirin is the most commonly prescribed drug for cardiovascular patients. Although it is best known as an antiplatelet agent, salicylates are excellent NFB antagonists [61].
Although those diverse therapies likely have multiple points of action, alternative approaches have attacked NFB activity directly. Overexpression of the inhibitory peptide IB, either with transdominant mutants or direct delivery with liposomes, can inhibit VSMC proliferation and other markers of vascular inflammation [39]. Gene therapy strategies have utilized antisense oligonucleotides to the p65 subunit of NFB to prevent intimal hyperplasia after injury to rat carotid arteries [62]. Cumulatively, these studies show that manipulation of intracellular mediators of inflammation is not only feasible but potentially effective.
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Atherosclerosis, inflammation, and therapy |
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TopAbstractIntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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Endothelial cell injury
Promote reendothelialization with angiogenic factors (eg, vascular endothelial growth factor).
Endothelial dysfunction
Restore vasomotor tone with nitric oxide donors (eg, L-arginine) and limit toxic damage with antioxidants (eg, vitamin E).
Attachment of circulating cells
Block adhesion molecules on leukocytes (anti-CD11/18) and endothelial cells (anti-intracellular adhesion molecule (ICAM).
Infiltration of adherent cells
Block leukocyte transmigration (anti-IIIßv integrin).
Inflammatory mediators
Counteract inflammatory mediators with specific (tumor necrosis factor-binding protein) or global (interleukin 10) cytokine antagonist.
Cellular activation
Manipulate intracellular signal transduction (NFB).
VSMC proliferation
Regulate balance between cell growth (cell cycle proteins) and apoptosis (p53).
Collagen deposition
Decrease accumulation and organization of extracellular matrix (metalloproteinase inhibitors).
Plaque rupture
Regulate cellular apoptosis and fibrous cap stability (integrin and metalloproteinase antagonists).
Thrombosis
Inhibit adherence, aggregation, and secretion of platelets (glycoprotein IIb/IIIa receptor antagonists).
Teleologically, one can modify the vascular response by attenuating the unwanted effects while accentuating the desired effects. The functional redundancy within the inflammatory cascade limits attempts to isolate a given cytokine or growth factor. As such, an ideal agent would attack several levels of the response to injury. Experimentally, the anti-inflammatory cytokine, interleukin-10 meets several of these criteria. Interleukin-10 downregulates adhesion molecule expression, inhibits tumor necrosis factor and interleukin-1 release by vascular cells, and inhibits VSMC proliferation [63, 64]. Currently, it is not known whether interleukin-10 can beneficially influence vascular remodeling in vivo. Several studies found the protective effects of estrogens on cardiovascular disease in postmenopausal women. Estrogens attack each level of the inflammatory response;eg, mitigating the "bad" mitogenic influence of growth factors on VSMC and exaggerating the "good" nitric oxide production by the endothelial cell [35].
In conclusion, antiatherosclerosis strategies aim to eliminate injury or the vessel’s pathologic response to that injury. Primary prevention remains the most feasible option. Beneficially modifying traditional cardiovascular risk factors synergistically attenuates cumulative injury. Interestingly, many of the drugs used to treat hyperlipidemia or hypertension are actually anti-inflammatory drugs themselves (eg, statins and calcium-channel blockers). Smoking cessation alone will not eliminate cardiovascular disease. Within the current paradigm, inflammation and injury are dynamic events. Therapy must also be directed at the smoldering inflammation ongoing in the vessel wall.
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Acknowledgments |
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TopAbstractIntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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References |
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TopAbstractIntroductionWhat is atherosclerosis?Atherogenesis and the response...Modification of vascular injuryCellular response to vascular...Intercellular and intracellular...Atherosclerosis, inflammation,...AcknowledgmentsReferences |
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B, and AP-1 in human vascular smooth muscle, and induces cellular proliferation. J Surg Res 2000;90:76-81.[Medline]
B inhibits TNF-induced human vascular smooth muscle proliferation. Circ Res 1999;84:867-875., tumor necrosis factor- and interleukin-1ß. Arterioscler Thromb Vasc Biol 1996;16:19-27.B. Annu Rev Cell Biol 1994;10:405-455.
B and IB- by aortic endothelium in an arterial injury model. Am J Pathol 1996;148:427-438.[Abstract]
B inhibitory peptide, IB, prevents human vascular smooth muscle proliferation. Ann Thorac Surg 1999;67:1227-1232.B- protein promote tolerance to endotoxin. Am J Physiol 1998;275:H1084-H1091.
B inhibit human vascular smooth muscle cell adherence and proliferation and prevent neointima formation in rat carotid arteries. Biochem Biophys Res Commun 1995;213:827-836.[Medline]
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