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(Circulation. 1999;100:e20-e28.)
© 1999 American Heart Association, Inc.
Circulation Electronic Pages |
Infection and Atherosclerosis
Emerging Mechanistic Paradigms
From the Cardiovascular Research Foundation, Washington Hospital Center, Washington, DC.
Correspondence to Dr Stephen E. Epstein, Cardiovascular Research Foundation, Washington Hospital Center, 110 Irving St NW, Suite 4B-1, Washington, DC 20010. E-mail sxe2{at}mhg.edu
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Abstract |
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Top
Abstract
IntroductionAbstract—Although definitive proof of a causal role of infection contributing to atherogenesis is lacking, multiple investigations have demonstrated that infectious agents evoke cellular and molecular changes supportive of such a role. Moreover, both Chlamydia pneumoniae and cytomegalovirus exacerbate lesion development in animal models of atherosclerosis and restenosis. The fact that multiple pathogens have been associated with atherosclerosis implies that many "atherogenic" pathogens exist, and recent data suggest that the risk of atherosclerosis conveyed by infection relates to the number of atherogenic pathogens with which an individual is infected. It also is evident that variability in host susceptibility to the atherogenic effects of pathogens exists; this variability appears to be related at least in part to whether the host can generate an immune response that successfully controls pathogen inflammatory activity and in part to the specific pattern of immune response—humoral or cellular. The latter may relate to host capacity to control pathogen activity and to a pathogen-induced autoimmune component of the atherogenic process. Additional animal and human studies are necessary to further test the validity of the infection/atherosclerosis link and to provide more insight into the mechanisms by which infection may contribute to atherosclerosis, information critical for devising strategies to reduce or eliminate any contribution to atherosclerosis caused by infection.
Key Words: cytomegalovirus • Chlamydia pneumoniae • immune system • risk factors • coronary disease • atherosclerosis
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Introduction |
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As many as 50% of patients with atherosclerosis lack currently identified risk factors (such as hypertension, smoking, hypercholesterolemia, and diabetes), an observation indicating that additional factors predisposing to atherosclerosis are as yet undetected. Discovery of such factors, along with their accompanying mechanisms of action, would have profound implications for the development of new therapeutic strategies that could reduce the devastating impact this disease is having in the western world and is beginning to have in countries where the populations are adopting western lifestyles.
Injury to the vessel wall and the associated inflammatory response to injury are now generally recognized as the essential components of atherogenesis.1 2 3 4 5 6 7 8 9 10 However, the triggers that initiate and sustain the inflammatory process have not been definitively identified, a fact that has fueled efforts to discover the inflammatory triggers. Among the candidate triggers are oxidized LDL and heat shock proteins (HSPs). These components of the atherosclerotic wall are believed by some investigators to elicit an inflammatory response.11 12 13 14 Antibodies to these proteins also develop, and although controversial, some studies suggest that these antibodies may play a role in causing autoimmune-induced damage to the vessel wall.15 Another candidate trigger of both inflammatory and autoimmune responses—the subject of this perspective—is infection.
Several excellent reviews on the roles of infection16 17 18 19 20 21 22 23 24 and autoimmunity25 in atherogenesis have appeared recently. The purpose of the present article is not to repeat these extensive efforts but to focus more on the cellular, molecular, and immune mechanisms by which infection might contribute to atherosclerosis. We also explore the concept that if autoimmunity is involved in the development of atherosclerosis, the stimuli eliciting the autoimmune responses are probably triggered, at least in part, by infection.
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Infection as a Contributor to Atherosclerosis |
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Evidence began accumulating >25 years ago suggesting that herpesviruses may possibly play a role in the development of atherosclerosis. It was found that Marek's disease virus, an avian herpesvirus, caused typical atherosclerotic lesions in chickens,26 and when smooth muscle cells (SMCs) were infected with the virus in vitro, cholesterol accumulated.27
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Presence of Pathogens in the Vessel Wall and Seroepidemiological Studies |
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Evidence in humans suggesting that infection predisposes to atherosclerosis derived from studies demonstrating that infectious agents reside in the wall of atherosclerotic vessels (initially, cytomegalovirus [CMV] and later Chlamydia pneumoniae), and seroepidemiological studies demonstrating an association between the pathogen-specific IgG antibodies and atherosclerosis.24 28 29 30 31 The first such seroepidemiological associations published related to CMV, which were later followed by the publication of similar associations between atherosclerosis and herpes simplex virus (HSV) types 1 and 2, C pneumoniae, Helicobacter pylori, and most recently, hepatitis A virus.32 33 34 35 36 37 38 39 40 41 42 43 Moreover, prospective studies of the relation between CMV seropositivity and the subsequent development of restenosis after coronary angioplasty revealed increased incidence of restenosis in patients seropositive for CMV.44 45
The data demonstrating a serological or anatomic association between each of these pathogens and atherosclerosis are not entirely consistent. Although some studies show a significant association with coronary artery disease (CAD) or restenosis,24 32 33 34 35 36 37 38 39 40 41 42 43 44 45 others do not.24 39 43 46 47 48 49 50 51 52 53 Moreover, a pathogen resident in an atherosclerotic vessel may be just an "innocent bystander" rather than a causally relevant agent.
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Direct Effects of Infectious Agents on Cellular Components of the Vessel Wall That Could Predispose to Atherosclerosis |
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Additional evidence favoring causality has derived from investigations demonstrating that infection of cells residing in the vessel wall cause cellular and molecular changes conducive to atherogenesis.
SMC Accumulation
Stimulation of SMC Proliferation
Because SMCs in vitro are permissive for CMV replication, which is
followed by cell death, it has not been possible to demonstrate any
direct effect of infection on SMC proliferation. However, many of the
important cellular effects of CMV derive from expression of its
immediate-early (IE) gene products in the absence of early and late
gene expression and of viral replication. In this type of infection,
called an abortive infection, death of the host cell does not occur. It
is likely that abortive infections are of biological relevance,
providing a mechanism whereby intracellular pathogens contribute to
disease progression.
In vitro models of abortive infection can be achieved by infecting cells of 1 species with CMV derived from another. (There are several related types of CMV, and the ability of the different types of CMV to replicate in cells is specific for each host species.) For example, Albrecht and associates54 demonstrated that when hamster embryo fibroblasts are infected with human CMV (causing an abortive infection), the rate of DNA replication and mitotic activity is increased. Moreover, it recently has been shown that infection of rat SMCs with human CMV (also causing an abortive infection) leads to SMC replication.55 Evidence that CMV infection in vivo leads to cellular proliferation was suggested by studies of a rat model of aortic allograft transplantation. CMV infection was associated with a doubling of the proliferation rate of SMCs in the allograft neointima.56
One molecular mechanism by which CMV may increase cellular proliferation is through inhibition of the tumor suppressor gene, p53; the p53 gene product inhibits cell cycle progression57 and therefore cell proliferation.58 IE2–84, 1 of the IE gene products of CMV, is capable of binding to p53 and inhibiting its transcriptional activity.59 60 The inhibitory effect of CMV infection on p53 activity appears to be mediated, at least in part, by the exclusion of p53 from the nucleus by cytoplasmic sequestration.61
Another mechanism by which CMV infection could lead to cellular proliferation is stimulating the secretion of growth factors or increasing the expression of growth factor receptors. Human fibroblasts, when infected with CMV, release a factor or factors that stimulate DNA synthesis of BALB/c 3T3 cells62 and proliferation of human endothelial cells.63 In the rat model of aortic allograft transplantation referred to above,56 it was found that CMV infection is associated with an almost doubling of basic fibroblast growth factor (bFGF; FGF2) mRNA expression, and with increased expression of mRNAs of acidic fibroblast growth factor (aFGF; FGF1), platelet-derived growth factor-BB (PDGF-BB), and epidermal growth factor. CMV infection of SMCs has recently been shown to increase PDGF receptor expression.55
Inhibition of Apoptosis
CMV infection inhibits apoptosis in human
endothelial cells61 and in HeLa cells, an
effect caused at least partly by the IE gene products of the
virus.64 One of the mechanisms by which this occurs is
probably inhibition of the p53-modulated apoptotic
program.57 Thus, 1 of the IE gene products of CMV,
IE2–84, binds to and inhibits the transcriptional activity of
p53.59 60 Consistent with this activity was the
finding that overexpression of IE2–84 (with an adenoviral vector used
for gene transfer) protected human coronary artery SMCs from
p53-induced apoptosis.65 That such an effect is
not limited to CMV was demonstrated by the finding that
Chlamydia-infected cells are resistant to apoptosis
induced by a wide variety of agents.66 If inhibition of
apoptosis occurred in infected SMCs of the vessel wall, such an
effect could lead to excessive accumulation of these cells, thereby
contributing to an increase in the mass of
restenosis/atherosclerosis lesions.
Increased SMC Migration
One mechanism contributing to increasing neointimal
mass in both atherogenesis and restenosis is SMC migration from
the media and adventitia to the developing neointima. Using
a standard in vitro assay system for cell migration, we previously
found that infection of rat SMCs with human CMV (to produce an abortive
infection) increases SMC migration.55 This was associated
with enhanced SMC PDGF receptor expression, a finding compatible with
the demonstration that 1 mechanism responsible for SMCs migrating
toward the lumen after vascular injury involves the PDGF
system.1
Lipid Accumulation
In the 1970s, Minick and associates26 and Fabricant
et al27 demonstrated that infection of chickens with
Marek's disease virus (an avian herpesvirus) caused
atherosclerosis-like lesions in the coronary
arteries and aortas and increased accumulation of
cholesterol in both intracellular and extracellular sites.
Hajjar et al67 demonstrated a potential mechanism for this
effect by showing that HSV infection of human SMCs decreases lysosomal
and cytoplasmic cholesterol ester hydrolytic activity.
Enhanced activity of the scavenger receptor represents an additional mechanism by which pathogens could increase lipid accumulation. We demonstrated that infection of human SMCs with CMV increases uptake of oxidized LDL, an effect mediated, at least in part, by the class A (type I and II) scavenger receptor.68 The increased uptake of oxidized LDL appears mediated by an IE gene product, because this effect was also seen when rat SMCs were infected with human CMV (leading to an abortive infection with expression of only the IE genes of CMV). This conclusion was supported by the finding that 1 of the IE gene products (IE1–72) has the capacity to increase the transcriptional activity of the class A scavenger receptor promoter.68 In addition, C pneumoniae infection of monocyte-derived macrophages incubated with LDL increases the number of foam cells and the accumulation of cholesteryl esters.69 Unlike the CMV findings, it appeared that these Chlamydia-induced changes are not mediated by scavenger receptors, because the response was not attenuated by the scavenger receptor ligand fucoidan.
Endothelial Dysfunction
Procoagulant Effects
Thrombosis contributes importantly to the development of
atherosclerosis and to the precipitation of acute
coronary events. Normal endothelium has
multiple antithrombotic mechanisms, among which are the capacity of the
cells to synthesize heparin sulfate, prostacyclin, nitric oxide,
plasminogen activator, and thrombomodulin.
Several studies, particularly those from the laboratories of Hajjar et
al67 and Vercellotti et al,21 have now
demonstrated that infectious agents can alter
endothelial cells from a phenotype that is
normally anticoagulant to 1 that is procoagulant. For example, HSV
infection of endothelial cells increases
endothelial cell synthesis of tissue factor, the rate
of thrombin generation on the cell surface, and platelet adherence
while it decreases prostacyclin and thrombomodulin
generation.70 71 72 CMV infection of
endothelial cells also causes procoagulant
effects.73
Inhibition of Vasodilator Function
A critical function of endothelial cells is to
modulate vascular tone, and loss of this function is believed to be 1
of the earliest manifestations of CAD. A recent study has demonstrated
that individuals infected with CMV (as evidenced by anti-CMV
antibodies) have impaired endothelium-mediated
coronary vasodilator responses.74 The
endothelial vasodilatory dysfunction seemed to be
related to both nitric oxide– and non–nitric oxide–mediated
pathways.
Increased Expression of Cytokines, Chemokines, and Cellular
Adhesion Molecules
Atherogenesis is believed to develop and progress in response to a
sequence of events triggered by the response to vascular
injury.1 Various types of injury have been shown to affect
the endothelium, causing increased production
of reactive oxygen species (ROS), cytokines, chemokines, and
cellular adhesion molecules. ROS contributes to oxidation of LDL, a
primary player in the development of atherosclerosis,
and chemokines and cellular adhesion molecules lead to the attraction
and adhesion of monocytes to the vessel wall. The adhering monocytes
migrate to the subintimal space, where they differentiate into
macrophages and produce their own proinflammatory,
proatherosclerotic molecules. The processes leading to the expression
of these cytokines, chemokines, and adhesion molecules can be
augmented by infection, because CMV and HSV infection of cells causes
expression of these molecules.75 76 77 Moreover, CMV
infection of SMCs leads to the development of ROS.78
Delivery of Pathogen to the Vessel Wall
Both CMV and C pneumoniae are present in
atherosclerotic arteries,24 28 29 30 31 and CMV DNA has
been found in restenosis lesions.59 It is possible
that these and other pathogens directly infect the vessel wall and
persist in a latent state, produce an abortive infection, or replicate
at a low (and possibly intermittent) level. An alternative possibility
focuses on the circulating monocyte as a "Trojan horse," a vehicle
for delivery of pathogen to the vessel wall. That this can occur is
indicated by the facts that these cells harbor latent
CMV79 80 81 82 83 84 and that C pneumoniae is capable of
replicating in a macrophage cell
line.85 86
With CMV, it is believed that the virus infects monocyte precursors present in bone marrow and that the viral genome persists in these cells.79 80 Given that CMV infection develops in bone marrow transplant recipients seronegative for CMV but whose donors are CMV seropositive, it is likely that myelomonocytic precursor cells act as a reservoir of CMV and that circulating monocytes then act as a vector, delivering the virus to sites of vascular inflammation or injury. For Chlamydia, it is believed that pulmonary alveolar macrophages act as the vector, picking up the pathogen during the course of a pulmonary infection.
Although Chlamydia is capable of replicating in monocytes/macrophages,85 86 this is not the case with CMV. Despite the presence of viral genome in circulating monocytes, viral gene products are not expressed in such cells (ie, the virus is in a latent state). Expression of IE viral gene products occurs only after differentiation of monocytes to form macrophages, which happens after the monocytes have entered the subintimal space.82 83 In this regard, it has been shown that such constituents of the vessel wall as endothelial cells, SMCs, and oxidized LDL increase the activity of the major immediate early promoter of CMV.84 Thus, CMV and perhaps other pathogens may be delivered by circulating monocytes to sites of vascular injury where the vascular milieu contributes to pathogen reactivation, resulting in the induction of pathogen-related effects that contribute to atherogenesis.
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Systemic Alterations Produced by Infectious Agents That Could Predispose to Atherosclerosis Without the Need for Pathogen Residence in the Vessel Wall |
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Given the evidence outlined above, it would be reasonable to conclude that a set of mechanisms by which infection contributes to atherosclerosis consists of direct effects of the pathogen on the vessel wall mediated by mechanisms requiring the actual presence of the pathogen locally (the Table
). However, other
mechanisms not requiring local residence are most likely also
operative. For example, infection causes a spectrum of systemic
effects, producing fever, malaise, myalgias, and a panoply of signs and
symptoms, including alterations in the circulating levels of such
factors as cytokines, acute-phase reactants, white blood cells,
and responses mediated by the immune system, such as an increase in
antibodies targeted to the invading pathogen. These systemic
manifestations of infection can be either profound or subtle;
importantly, however, these changes provide mechanisms other than local
residence-requiring direct vascular effects, whereby pathogens could
influence the course of atherosclerosis.
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That infection might exert effects on an injured vessel wall that do not necessitate pathogen residence in the vessel is suggested by the results of studies to determine whether CMV infection increases the neointimal response to vascular injury in the rat.87 88 Although rats infected with CMV manifested an increased neointimal response to injury, the virus was essentially absent from the injured segment of the vessel; neither replicating virus nor viral proteins could be detected despite the fact that replicating virus could be isolated from such tissues as the spleen and salivary gland.
In the following section, we discuss the mechanisms by which such indirect effects might occur. Because little experimental data exist, the ensuing discussion is meant to be exploratory and hypothesis generating.
Immune Responses Targeted to Self-Proteins Located in the Vessel
Wall: Potential Role of Molecular Mimicry
Molecular mimicry, resulting in the triggering of an immune
response targeted to self-proteins, has been proposed as a mechanism
responsible for the development of autoimmune
diseases.89 90 91 92 93 The concept of molecular mimicry requires
infection by a pathogen that contains peptide sequences homologous with
host protein. The immune response, although initiated by the invading
pathogen and targeted to pathogen antigens, also becomes an autoimmune
attack against host tissues containing the cross-reacting peptide
sequences. In this model of disease, immune-mediated host tissue injury
can occur even if the responsible pathogen is not present in the
target tissue, a mechanism confirmed by the elegant studies from
Oldstone's laboratory.94 Molecular mimicry, although not
definitely proven as a cause of human disease, has been implicated in
such autoimmune diseases as type 1 diabetes mellitus, multiple
sclerosis, and Guillain-Barré syndrome,95 96 97 98 and
more recently has been implicated in the development of
cardiomyopathies99
The most suggestive evidence to date indicating a role of molecular mimicry–induced autoimmune mechanisms in atherogenesis derives from the important studies of Wick and associates.25 100 101 102 103 They pointed out that the vascular wall is subject to various stresses that induce HSP expression. These stresses include hypercholesterolemia, elevated homocysteine levels, cytokines, free radicals, circulating products derived from smoking, and mechanical stresses such as hypertension. They then hypothesized that although the induction of HSPs is a cellular defense mechanism preventing denaturation of cellular proteins caused by perturbations of the cell's environment, the marked overexpression of HSPs may cause them to act as "cryptic antigens," inducing an autoimmune reaction and thereby contributing to the development of atherosclerosis.
These investigators also emphasized that HSPs are a family of proteins that are highly conserved across all species, including bacteria.25 100 They therefore raised an alternative mechanism by which an autoimmune response to HSPs could occur: The immune response stimulated by infection and targeted to the infecting pathogen could, because of the high degree of amino acid sequence homology between pathogen and host HSPs, also target self-HSPs. Although a series of studies by these and other investigators make a compelling case for a possible role of autoimmunity in atherosclerosis, particularly because the immune response targets HSP,25 100 101 102 103 104 105 there are no direct data implicating infection, via molecular mimicry, as the responsible trigger for this autoimmune response.
Other data indirectly support the molecular mimicry/autoimmunity mechanism as being operative in atherosclerosis. Autoantibodies to certain cytokines have been detected in apparently healthy individuals.106 107 That molecular mimicry may be involved in stimulating the expression of these antibodies is suggested by the fact that Epstein-Barr virus contains a peptide sequence homologous to IL-10, and Kaposi's sarcoma–associated herpesvirus contains an IL-6 homologous sequence.108 CMV contains proteins homologous to chemokine receptors.109 110 111 In addition, in preliminary studies from our laboratory, we demonstrated that susceptibility to CMV-related CAD in women occurs in the subgroup with a humoral immune response to CMV infection, whereas those women with an immunodominant cellular response evidenced no such susceptibility.112 This finding raises the possibility of an infection-driven, autoimmune-mediated antibody component of disease.
Finally, some studies relate increased prevalence of periodontal disease to increased prevalence of CAD.24 113 114 115 116 117 118 One hypothesis driving these studies is that chronic periodontal infection leads to CAD through the production of a long-term inflammatory response. In this regard, elevated levels of specific salivary IgA antibodies against mycobacterial HSP65 were found to be significantly increased in patients with gingivitis.119 Mycobacteria HSP65 is highly homologous to human HSP60. The investigators speculated that the pathogens causing the gingivitis expressed HSP; this then stimulated an IgA antibody response in the host, which they suggested may serve as cross-reactive autoantigens that contribute to the gingivitis. It is equally plausible that the development of IgG antibodies, if present, could contribute to an autoimmune-induced atherosclerotic process.
Circulating Pathogen-Derived or Pathogen-Stimulated Factors That
Could Induce Changes in the Vascular Wall
Studies have shown that various circulating pathogen-derived or
pathogen-stimulated factors can elicit changes in
monocyte/macrophages that could be proatherogenic and that
might even contribute to plaque instability. For example, bacterially
derived lipopolysaccharide and chlamydial or human HSP induce
tissue necrosis factor-
secretion by
macrophages,120 a cytokine that stimulates
endothelial cells to express adhesion molecules. These
factors also stimulate endothelial cells and SMCs to
express interleukin (IL)-1 mRNA121 and
IL-6122 and preferentially stimulate
endothelial cells to express E-selectin and
ICAM-1.122 In addition, several surface antigens of
Porphyromonas gingivalis, a Gram-negative bacterium causally
related to periodontitis, stimulate BALB/c peritoneal
macrophages to secrete IL-1-ß.123 Tissue
necrosis factor-, IL-1, IL-6, and ICAM-1 have all been related to
atherogenesis.
The above responses can be considered as possibly contributing to the development of atherosclerosis. In addition, lipopolysaccharide, chlamydial HSP, and human HSP have also been shown to stimulate the secretion of matrix metalloproteinases.120 These enzymes have the capacity to degrade connective tissue and thereby are believed to predispose, by weakening the fibrous cap of atheromatous lesions, to plaque rupture. Thus, pathogens not only may stimulate responses that are proatherogenic but also may contribute to the precipitation of plaque instability and rupture, the most common cause of death from CAD.
Although elevated circulating C-reactive protein (CRP) levels have usually been taken as a systemic marker for inflammation, some evidence also suggests that this acute-phase reactant may play some causal role in atherogenesis. For example, CRP has been shown to colocalize with the terminal complement complex in the intima of early human atherosclerotic lesions.124 This finding suggests some casual link between elevated levels of this acute-phase reactant and atherogenesis, given that CRP activates complement and that complement activation has been implicated in the development of the atherosclerotic plaque.125
The potential role of some circulating, infection-related factor predisposing to plaque destabilization received additional support from the finding that acute respiratory-tract infections are associated with an increased risk of acute myocardial infarction. The data revealed a relative risk of 2.7 for acute myocardial infarction occurring in relation to an acute respiratory-tract infection in the preceding 10 days.
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Individual Variations in Host-Pathogen Interactions That Influence Inflammatory Activity and the Susceptibility to Pathogen-Induced Contribution to Vascular Disease |
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Inflammatory Activity
As noted above, although many epidemiological studies have demonstrated that seropositivity to several infectious agents is associated with increased CAD risk, the data are inconsistent, with other studies showing no increased risk. One possible explanation for this disparity is that whether prior infection, as reflected by seropositivity, contributes to CAD risk may depend, at least in part, on the capacity of the host to suppress pathogen inflammatory activity. The validity of this concept is suggested by a study demonstrating that (1) although some individuals seropositive to CMV have elevated CRP levels, in others, CRP is within the normal range and (2) highest CAD prevalence occurs in the subgroup with combined CMV seropositivity and elevated CRP levels.126 When adjusted for CAD risk factors, the ORs for CAD were 1.3 in the subgroup with CMV seropositivity alone (P=0.7), 2.3 in the subgroup with elevated CRP levels alone (P=0.2), and 4.3 in the subgroup with combined CMV seropositivity and elevated CRP levels (P=0.01).
Humoral and Cellular Immune Responses
A second possible explanation for the disparity in
seroepidemiological studies may relate to the type of immune response
mounted by the host to CMV infection. Thus, CMV appears to be a
significant predictor of CAD in women.112 Importantly,
however, the data showed that the type of immune response to CMV
determines whether CMV predisposes to CAD. In women evaluated for CAD
by coronary angiography, blood samples were tested for humoral
(Ab+) and cellular (Tc+) responses to CMV. Susceptibility to
CMV-related CAD was limited to those women with a humoral immune
response to CMV (Ab+/Tc- or Ab+/Tc+). The prevalence of CAD in those
without an antibody response but with a cellular response (Ab-/Tc+)
was similar to that in women without apparent prior CMV infection
(Ab-/Tc-).
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Pathogen Burden as a Determinant of Elevated CRP and CAD Risk |
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If infection plays a role in atherogenesis, it would be highly likely that multiple pathogens would be causally involved and, importantly, that CAD risk would relate to the aggregate pathogen load (what we have called pathogen burden). This hypothesis was tested in a group of individuals being evaluated for CAD by coronary angiography. The relationship of pathogen burden (aggregate number of a panel of 5 pathogens to which an individual had been exposed, as determined by seropositivity) to CRP levels and CAD risk was determined.127 The pathogens tested were CMV, Chlamydia, hepatitis A virus, and HSV types 1 and 2. A dose-response relationship was found: As the number of seropositive responses an individual had increased, CRP levels and CAD prevalence increased. Although these results must be confirmed in a prospective study, it appears that insofar as infection does predispose to the development of atherosclerosis, CAD risk is related to the aggregate number of potentially atherogenic pathogens to which an individual has been exposed.
Animal Models of Atherosclerosis and
Infection
Given that atherosclerosis is a multifactorial
disease, Koch's postulates to establish causality will never be
satisfied. These postulates were based on infectious diseases caused by
a single pathogen, requiring that all patients with the disease must
have evidence of being infected with the casual agent and that all
individuals infected with the agent develop the disease. In contrast,
the concept developed in this article is that infectious agents are
risk factors for atherosclerosis, neither necessary nor
sufficient for disease development. With this disease paradigm, proof
of causality can be achieved only in terms of probability rather than
as certainty.
One way to determine a higher probability of causality is to establish that the cellular and molecular changes induced by infection predispose to atherosclerosis. The studies detailed in this review, in aggregate, present a compelling case. However, the only direct evidence that can prove a particular infectious agent has the capacity to contribute to atherosclerosis is to demonstrate causality in an animal model of atherosclerosis. This has been achieved by several investigations.
C pneumoniae has been shown to increase atherosclerosis in both a rabbit model and a mouse apoE knockout model of atherosclerosis.128 129 Similar results have been demonstrated for CMV infection in the apoE knockout model.130 In addition, as noted above, in an acute injury model (balloon injury of a rat carotid artery), infection with CMV increases the resulting neointimal response.87 88
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Summary and Conclusions |
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In summary, there is an increasing body of information compatible with the concept that infectious agents contribute to the development of atherosclerosis and to plaque instability and rupture. These possibilities are strengthened by the multiple investigations providing cellular and molecular mechanistic support for such roles and by investigations demonstrating that certain pathogens can exacerbate lesion development in animal models. It is equally clear, however, that no simple relationship exists between infection and atherogenesis. As with other infectious diseases, the propensity for a given infectious agent to contribute to the development of atherosclerosis will depend on host-pathogen interactions. This in turn will determine susceptibility to pathogen inflammatory activity and therefore to atherogenic potential. And if additional studies support an important autoimmune component to atherogenesis, the type of humoral and cellular immune responses mounted by the host to infection may determine whether a particular pathogen will contribute to atherosclerotic lesion development in a particular host (the Figure
).
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As the case for a role of infection grows, the existing paradigms to explain the natural history of the clinical manifestations of CAD can be expanded. For example, it was appreciated many years ago that atherosclerosis does not progress as a slow gradual process; rather, the underlying progressive nature of the disease is punctuated by intermittent acute exacerbations. This has been appreciated both clinically and by morphological investigations of atherosclerotic plaques. The concept that infection plays a role in atherosclerosis fits this model very well. Thus, by producing persistent subclinical infections causing a chronic inflammatory state (leading to activation of inflammatory cells and of immune processes), infectious agents could contribute to gradual plaque enlargement. However, punctuation of this low-grade persistent activity by recurrent acute infections or intermittent reactivation of latent infections, whether clinically overt or silent, could cause acute exacerbations of the atherosclerotic process, including plaque rupture and thrombotic occlusion.
It must be emphasized that evidence definitively proving a causal role of infection in atherosclerosis is lacking. Although the temptation is great to initiate clinical trials testing whether interventions targeted to pathogens will decrease progression of atherosclerosis or its complications, we cannot loose sight of the importance of performing additional animal and human studies that can further test the validity of the concept and provide more mechanistic information as to how pathogens may predispose to atherogenesis. This additional information will be critical for devising intelligent and effective future strategies to reduce or eliminate any contribution to atherosclerosis caused by infection.
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