From the Cardiovascular Division and the Division of Preventiv Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Dr Paul M Ridker, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 E-mail pmridker{at}bics.bwh.harvard.edu
Despite
substantial gains in the prevention and treatment of acute myocardial
infarction, many atherothrombotic events occur among individuals
without readily apparent risk factors. Several lines of basic research
indicate that inflammation and perhaps chronic infection may play
important roles in the initiation and progression of
atherosclerosis. For example, pathological studies
demonstrate that atherosclerotic lesions are heavily infiltrated with
cellular components associated with inflammation, influx of neutrophils
into the walls of the epicardial vessels has been demonstrated in
response to acute ischemia, and sites of acute plaque rupture
are preferentially associated with inflammatory
components.1 2 3 4 5 6 Further, proinflammatory
cytokines as well as cellular adhesion molecules involved in
the attachment of monocytes to the endothelial wall
appear to be critical in early atherogenesis.7 8
With regard to chronic infection, evidence of prior exposure to
Chlamydia pneumoniae, cytomegalovirus, and
Helicobacter pylori has been detected within human
atherosclerotic tissues,9 10 11 12 13 14 and it has been
hypothesized that these organisms may activate
vessel-associated leukocytes or lead to a transformation of vascular
smooth muscles or endothelial
cells.15 In addition, animal studies suggest that
infection with cytomegalovirus and perhaps other agents can lead to
endothelial lesions similar to that of human
atherosclerosis.16 17
From an epidemiological perspective, however, the role of
inflammation and infection as potential cardiovascular
risk factors is far from certain. Although several studies have
reported associations between exposure to various infectious agents and
prevalent coronary disease,18 19 20 21 22 23 24 25 these
data derive almost exclusively from cross-sectional or retrospective
studies that cannot establish a temporal relation between exposure and
disease. Furthermore, it is difficult for cross-sectional and
retrospective studies to exclude the possibility that observed
associations are the result of inadvertent selection bias
or residual confounding on the basis of age, smoking pattern, and
socioeconomic status. For example, individuals with greater
inflammatory and infectious burdens may be at increased
coronary risk simply because they are older, have poorer health
habits, and have less access to care. In addition, both inflammation
and infection are more prevalent among smokers. Thus, whether
relationships between inflammation, infection, and
atherosclerosis are causal or largely due to
confounding requires careful consideration.26
Fortunately, prospective epidemiological studies that can control for
many of these effects have recently become available, at least with
respect to clinical evidence of inflammation. In particular, several
prospective studies have been presented that indicate that
mildly elevated levels of C-reactive protein, a nonspecific marker for
systemic inflammation, are present among individuals with stable
and unstable angina at risk for future myocardial infarction, elderly
patients at risk for symptomatic coronary heart
disease, those at high risk for infarction primarily because of
smoking, and apparently healthy middle-aged men at risk for first-ever
myocardial infarction or stroke.27 28 29 30 31 32
Data from the prospective Physicians Health Study (PHS) have been
particularly informative because that study evaluated a group of
low-risk men with no prior history of cardiovascular
disease and low rates of cigarette consumption.27
Overall, data from the PHS indicate that initially healthy men with
baseline levels of C-reactive protein in the highest quartile had a
threefold increase in risk of developing future myocardial infarction
(relative risk, 2.9; P<.001) and twice the risk of
developing stroke (relative risk, 1.9; P=.02) compared with
men with levels in the lower quartile. These risk estimates were stable
over an 8- to 10-year follow-up period, were not modified by smoking
status, and were independent of other cardiovascular
risk factors, including total and HDL cholesterol,
triglycerides, lipoprotein(a), and fibrinogen. Moreover,
measurement of C-reactive protein adds to the predictive value of
lipids in determining vascular risk.33 For
example, a fivefold increase in risk of future myocardial infarction
was observed among those with high baseline levels of both C-reactive
protein and total cholesterol, a risk estimate greater than
the product of the risks associated with isolated elevations of
either C-reactive protein or total cholesterol
alone.33 Elevated baseline levels of C-reactive
protein are also associated with a fourfold increase in the risk of
developing clinically severe peripheral
arterial disease, again independent of usual risk
factors.34
Whether C-reactive protein has direct vascular effects or is simply a
marker for systemic inflammation remains uncertain. However, there
appears to be no association between levels of C-reactive protein and
risks of venous thrombosis,27 suggesting that
this acute-phase reactant does not induce a hypercoagulable state.
Furthermore, other acute-phase reactants, including fibrinogen and
serum amyloid A, appear to be associated with vascular
risk.29 35 Recent prospective data indicate that
plasma concentrations of the soluble intercellular adhesion molecule
(sICAM-1) are elevated many years in advance of a first-ever myocardial
infarction and that levels of sICAM-1 correlate with C-reactive
protein.36 Because cellular adhesion molecules,
such as ICAM-1, are critical in the adhesion of circulating leukocytes
to the endothelial cell and subsequent
endothelial transmigration, these data provide further
epidemiological evidence that cellular mediators of inflammation have a
critical role in atherogenesis.7 8 36
By contrast, prospective epidemiological data relating evidence of
infection to future vascular risk are sparse. Thus, investigations
evaluating whether infection is a cause of chronic inflammation and
whether infection is a risk factor for cardiovascular
disease have relied primarily on cross-sectional and retrospective
approaches. Despite epidemiological limitations, these study approaches
provide opportunities to generate new hypotheses and gain substantial
pathophysiological insight.
Such is the case for an intriguing paper in this issue of
Circulation in which Pasceri and
colleagues37 present data describing an
association between virulent Helicobacter pylori strains and
prevalent ischemic heart disease. In a thoughtful retrospective
case-control study design, the prevalence of infection with
Helicobacter pylori among 88 case subjects with a history of
ischemic heart disease was compared with the prevalence of
infection among a group of 88 age- and sex-matched control subjects of
similar social background who were free of coronary disease. On
an a priori basis, Pasceri and colleagues also sought to determine
whether Helicobacter pylori strains associated with
increased inflammatory virulence caused by possession of the
cytotoxin-associated gene-A (Cag-A) might confer a particularly high
risk of ischemic heart disease.
Three findings in this study are particularly noteworthy. First,
overall prevalence of Helicobacter pylori infection was
significantly higher among patients than control subjects (62% versus
40%, P=.004), data consistent with prior
observational studies relating prevalence of Helicobacter
pylori to coronary disease.21 38 39
Second, much of this effect appeared to be mediated through Cag-A
positivity, an intriguing finding because this genetically mediated
virulence factor may be associated with a greater inflammatory
burden.40 Specifically, patients with
ischemic heart disease had a significantly higher prevalence of
Cag-A positive strains of Helicobacter pylori (43% versus
17%, P<.001) compared with patients without
ischemic heart disease. In contrast, prevalence of
Cag-A–negative Helicobacter pylori strains was similar
between patients and control subjects (19% versus 23%,
P=.8). Third, despite an association between
Helicobacter pylori positivity and ischemic heart
disease, there was no association between seropositivity and severity
of coronary disease defined at angiography.
These data provide yet another potential link between inflammation,
infection, and vascular disease. Prior work suggests that Cag-A
positivity may be associated with an increased inflammatory response,
at least in the setting of duodenal ulcer
disease.40 41 Thus, if the association between
Helicobacter pylori and vascular disease proves valid and
indeed relates to the virulence of this bacterium, then infection with
Helicobacter pylori may influence
atherosclerosis through the generation of a persistent
low-grade inflammatory stimulus. The fact that C-reactive protein
levels increase with increasing prevalence of exposure to
Helicobacter pylori provides indirect support for this
hypothesis.42
Pasceri and colleagues37 note that their data
must be interpreted cautiously. Despite attempts to draw case and
control subjects from a similar social background, case subjects with
Helicobacter pylori positivity were of lower socioeconomic
status than were those without evidence of infection, once again
raising the possibility that Helicobacter pylori
seropositivity may be a surrogate for reduced access to care and poorer
health outcomes. Pasceri and colleagues further note that their results
require confirmation in prospective controlled populations. To date, at
least three such studies have been presented. In the first of
these, IgG antibodies directed against Helicobacter pylori
were determined among residents of 24 British towns who were then
prospectively followed for myocardial infarction and
stroke.43 In that study, unadjusted
analysis suggested a positive association. However,
Helicobacter pylori infection was also associated with lower
social class, increased cigarette consumption, and several traditional
cardiovascular risk factors. When these confounding
factors were adjusted for, no statistically significant association was
found between Helicobacter pylori and risk (P=.4
for myocardial infarction, P=.9 for
stroke).43 Similarly, in the large-scale British
United Provident Association (BUPA)44 study as
well as in the Atherosclerosis Risk in Communities
(ARIC)45 study, no associations between
Helicobacter pylori seropositivity and future
ischemic heart disease or coronary mortality were
observed. However, in each of these studies, prevalence of infection
was again associated with lower socioeconomic
status.44 45 Although none of these three
prospective studies specifically evaluated for Cag-A positivity, they
do indicate that retrospective associations must be interpreted with
caution.
How good, then, is the clinical evidence relating inflammation,
infection, and cardiovascular risk? With regard to
inflammation, the available prospective data are highly
consistent and provide strong evidence that inflammatory
parameters are independent risk factors for
coronary disease that may well add to our ability to predict
risk, even among otherwise low-risk
individuals.33 Moreover, clinical evidence
relating inflammation to vascular risk complements a large body of
basic laboratory and experimental work demonstrating a fundamental role
for inflammatory mediators in the atherothrombotic process. The
strength of these observations suggests that ongoing work evaluating
therapies that interfere with the inflammatory component of
atherosclerosis is a potentially important line of
research.
With regard to infection, provocative hypotheses such as
that raised by Pasceri and colleagues37
concerning Cag-A positivity and vascular disease deserve careful
consideration, as do hypotheses concerning Chlamydia
pneumoniae and cytomegalovirus. At a minimum, large-scale
prospective studies evaluating early life infection with these agents
and subsequent vascular disease need completion, preferably in
populations homogenous for socioeconomic status and with long-term
follow-up.
Until such studies are completed, the role of infectious pathogens in
coronary disease will remain uncertain. However, in the wake of
two small studies that suggest that macrolide antibiotics might reduce
cardiovascular event rates,46 47
it is increasingly difficult to ignore the possibility that infection
may be a novel cardiovascular risk factor. Large scale
clinical trials will provide direct evidence as to whether eradication
of infection has a role in cardiovascular disease
prevention. If appropriately designed, such trials will enable
scientists to clearly discern whether associations between infection
and ischemic heart disease are causal or due to residual
confounding.
Acknowledgments
Dr Ridker is supported by an Established Investigator Grant from
the American Heart Association.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
© 1998 American Heart Association, Inc.
Editorials
Inflammation, Infection, and Cardiovascular Risk
How Good Is the Clinical Evidence?
Key Words: Editorials • inflammation • infection • Helicobacter pylori • Chlamydia pneumoniae • C-reactive protein
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