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(Circulation. 2000;102:1917.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Cytomegalovirus Seropositivity and C-Reactive Protein Have Independent and Combined Predictive Value for Mortality in Patients With Angiographically Demonstrated Coronary Artery Disease
From LDS Hospital (J.B.M., B.D.H., J.F.C., T.E.M., T.L.B., R.R.P.) and the University of Utah (J.B.M., J.F.C., J.L.A.), Salt Lake City.
Correspondence to Joseph B. Muhlestein, MD, Division of Cardiology, LDS Hospital, 8th Ave and C St, Salt Lake City, UT 84143. E-mail ldbmuhle{at}ihc.com
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Abstract |
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Background—The role of inflammation in coronary artery disease (CAD) is being increasingly recognized. Markers of inflammation (eg, C-reactive protein [CRP]) and infection (eg, seropositivity to Chlamydia pneumoniae, cytomegalovirus [CMV], and Helicobacter pylori) have been proposed as risk factors for CAD, but these associations require further evaluation.
Methods and Results—We prospectively tested whether CRP levels
and IgG seropositivity to C pneumoniae, CMV, and
H pylori are predictors of subsequent mortality in 985
consecutive patients with angiographically demonstrated CAD
(stenosis 
70%). Patients were followed for an average of 2.7
years (range 1.5 to 4.0 years). Patients averaged 65 years of age; 77%
were men; and 110 (11.2%) died during follow-up. CRP levels were
significantly elevated in nonsurvivors compared with survivors (mean
CRP 3.1 mg/dL versus 1.5 mg/dL, P=0.003). After
controlling for all known baseline variables, the 2nd and 3rd
tertiles of CRP compared with the 1st produced a Cox hazard ratio (HR)
for mortality of 2.4 (P=0.001). Of the 3 infectious
markers tested, only seropositivity to CMV (HR=1.9,
P<0.05) was predictive of mortality. The majority of
mortality risk associated with elevated CRP or CMV seropositivity
occurred when both risk factors were present (P for
trend <0.0001). Other independent predictors of increased risk of
mortality were age (HR=1.07 per year, P<0.0001), left
ventricular ejection fraction (HR=0.97 per percent,
P<0.0001), and diabetes mellitus (HR=1.7,
P=0.02).
Conclusions—CMV seropositivity and elevated CRP, especially when in combination, are strong, independent predictors of mortality in patients with CAD. This suggests an interesting hypothesis that a chronic, smoldering infection (CMV) might have the capacity to accelerate the atherothrombotic process.
Key Words: coronary disease • risk factors • survival • antibodies • follow-up studies
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Coronary artery disease, which frequently becomes manifest as myocardial infarction, continues to exact an enormous toll in Western society. Despite progress in its prevention, detection, and treatment, it continues to be a leading cause of death.1 Several risk factors for coronary artery disease have been well documented including hyperlipidemia, hypertension, smoking, diabetes, a positive family history, and obesity.2 However, these factors explain only part of attributable cardiovascular disease, and other factors must be involved.3
A growing body of evidence supports the concept that local and systemic inflammation may play a role in the initiation and progression of atherosclerosis and its complications.4 5 6 7 8 C-reactive protein (CRP), an acute-phase reactant marker for underlying systemic inflammation, has long been known to be elevated in patients with acute myocardial infarction.9 10 It has also been shown to predict risk of recurrent ischemic events in patients with stable angina,11 unstable angina,12 13 and prior myocardial infarction.14 It has even been shown to predict risk for future ischemic events in previously healthy individuals.15
The underlying cause of this chronic inflammation and how it specifically relates to coronary artery disease is unknown. CRP elevation might come from noninfectious sources such as oxidized LDL16 or other as-yet unknown noninfectious sources, but the possibility also exists that there is a chronic infectious or antigenic source. A distant infection might generate circulating cytokines. Alternatively, a persistent local infectious process within the atherosclerotic plaque might provide the ongoing stimulus. Chlamydia pneumoniae17 18 19 20 21 22 23 24 and cytomegalovirus (CMV)25 26 27 are intracellular pathogens that might serve as a source of chronic local infection. Helicobacter pylori, demonstrated to be a primary pathogen of peptic ulcer disease, is a candidate organism that might be a chronic source of distant inflammation.28 29 Seropositivity to each of these infectious agents has, to various degrees, been associated with the diagnosis of coronary artery disease. However, whether these markers of infection, either alone or in combination with CRP, predict risk of future adverse events among patients with angiographically documented coronary artery disease has not been adequately evaluated. Such knowledge might provide useful insight into the pathophysiology of and general risk factors associated with coronary artery disease.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Hypothesis
Our objectives were to determine whether, during long-term follow-up of patients with angiographically defined significant coronary artery disease, (1) higher levels of baseline CRP are predictive of mortality; (2) baseline seropositivity for C pneumoniae, CMV, or H pylori is predictive of mortality; and (3) whether there is any interaction between elevated plasma CRP levels, positive infectious serologies, and mortality.
Patients
Between August 15, 1994, and February 28, 1997, 1707 consenting
patients undergoing coronary arteriography at LDS Hospital were
enrolled in a cardiovascular registry (Intermountain
Heart Study). Subjects were of unrestricted age and sex who gave
written informed consent for blood to be drawn at angiography for use
in confidential blood bank studies approved by the hospital’s
institutional review board. Of these patients, 985 were found to have
significant coronary artery disease as defined by a 70%
stenosis of at least 1 major coronary artery and were
included in the study.
Assessment of coronary artery disease was made by review of
angiograms by the patient’s cardiologist and entered into the computer
database in a format modified after the coronary artery surgery
study (CASS) protocol.30 On the basis of this angiographic
evaluation, the patients were determined to have single-, double-, or
triple-vessel disease as defined by the presence of a 70%
stenosis in each major vessel counted. Assessment of
coronary artery disease was performed blinded to results of
blood testing for inflammatory and serological markers. When available,
and as determined by echocardiography or left
ventriculography, the patient’s ejection fraction at the time of entry
into the study was also recorded. Echocardiographic
determination of the presence or absence of left
ventricular hypertrophy was also recorded.
Immediately after the baseline cardiac catheterization
procedure and just before leaving the cardiac
catheterization laboratory, a blood specimen was
obtained from each patient and stored for further analysis.
After undergoing arteriography, patients were treated as was seen fit
by their primary physicians and either received continued medical
treatment, percutaneous coronary intervention,
or coronary bypass graft surgery. Key demographic
characteristics were captured on computerized data forms. These
included age, sex, diabetes mellitus, hypertension, smoking, family
history of coronary heart disease, presenting diagnosis,
clinical interventions, renal failure, and left ventricular
ejection fraction (LVEF). Diabetes was defined as a history of fasting
blood sugar >126 mg/dL or a glycosylated hemoglobin >7.5%.
Hypertension was defined as a history of a systolic blood
pressure >160 mm Hg or a diastolic blood pressure
>90 mm Hg. Family history was considered positive if a
first-order relative had had cardiovascular death,
myocardial infarction (MI), or coronary
revascularization before age 65 years. Tobacco use
was considered present in subjects who were active smokers or who
had a smoking history of >10 pack-years. The clinical
presentation at index hospitalization was categorized as
stable angina (stable exertional symptoms only), unstable angina
(progressive symptoms or symptoms at rest), or MI (creatine kinase
[CK]-MB >6 mg/dL and CK-MB index >3%). The clinical treatments at
index hospitalization were categorized as medical therapy (only),
percutaneous coronary interventions (including
balloon angioplasty, atherectomy, and/or stenting), and CABG. Renal
failure was regarded as present if serum creatinine was
2.0 mg/dL.
After successful discharge from the index hospitalization, long-term survival of each patient was determined by telephone contact or use of a computerized national death index. Through these two techniques, survival status was determined in 100% of cases. Deaths were not adjudicated between cardiac or some other cause.
Determination of CRP
Testing for CRP was performed with the use of a
fluorescence polarization immunoassay (Abbott
Diagnostics). All serum was analyzed by the
high-sensitivity (0.05 mg/dL), low-range (0 to 6.5 mg/dL) CRP protocol
(protocol C). Any serum with a CRP exceeding that range was
reanalyzed by the lower-sensitivity (1.5 mg/dL), high-range (0
to 26 mg/dL) protocol A. After determination of all baseline CRP
levels, the cohort was divided into tertiles (CRP 1st tertile <1.2
mg/dL; 2nd tertile 1.2 to 1.7 mg/dL; 3rd tertile >1.7 mg/dL), based on
individual patient CRP values.
Testing for Infectious Serology
ELISA was used to determine levels of anti-cytomegalovirus IgG
antibodies (Wampole Laboratories, Cranbury, NJ), species-specific
anti–C pneumoniae IgG antibodies (Savyon
Diagnostics, Ashdod, Israel), and anti–H pylori
IgG antibodies (Meridian Diagnostics, Cincinnati, Ohio).
Seropositivity or seronegativity was assigned according to the
specifications of each product. Evaluable serological results for
all 3 infectious agents were obtained in 93% of patients.
Statistical Considerations
Differences of average CRP levels and the prevalence of
seropositivity for infectious markers, between survivors and
nonsurvivors at long-term follow-up, were evaluated by
univariate proportional hazards analysis through
the generalized likelihood ratio test to determine whether an increased
incidence of mortality was found in patients with elevated CRP (as
defined by the upper two tertiles) or seropositivity to C
pneumoniae, CMV, or H pylori.
To confirm the associations to mortality determined by univariate analysis, multivariate Cox Regression analysis (SPSS, version 9.0) was performed to determine hazard ratios corrected for confounding factors. Available baseline risk factors used in this adjustment model included age, sex, clinical presentation, initial form of cardiovascular treatment, history of diabetes, hyperlipidemia, hypertension, positive family history of cardiovascular disease, smoking, renal failure, prior myocardial infarction, prior coronary bypass grafting, left ventricular hypertrophy, LVEF, number of diseased coronary vessels, and baseline total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels.
To evaluate possible joint effect modification on mortality by CRP and seropositivity, a test of trend was performed for combined CRP/seropositivity variables that were coded as normal/seronegative, normal/seropositive, high/seronegative, and high/seropositive. The results are presented as a P for trend for only those infectious agents showing univariate significance. Two-tailed probability values are presented with 0.05 designated as nominally significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patient Population and Baseline Markers
The 985 subjects were followed for an average of 2.7 years (range 1.5 to 4.0 years), during which time 110 (11.2%) patients did not survive. Baseline clinical characteristics and laboratory values of the population (n=985) according to survival status, with the associated probability value from univariate Cox regression, are summarized in Table 1
. In general, severity of illness
varied greatly, ranging from a presentation with stable
angina, single-vessel coronary artery disease, and normal left
ventricular function to a presentation with
acute myocardial infarction, triple-vessel disease, and markedly
reduced left ventricular function. Overall, CRP was
moderately elevated to a level similar to that of prior reports of
patients with documented coronary artery disease, as were
results of infectious serologies and average lipid
levels.31
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CRP and Survival
Figure 1 is a box-and-whisker plot
showing CRP concentrations based on long-term survival. CRP levels were
significantly elevated in nonsurvivors compared with survivors (mean
CRP 3.1±3.3 mg/L versus 1.5±2.4 mg/L, P<0.0001). Figure 2 shows the Kaplan-Meier survival curves
of patients on the basis of CRP tertiles. There was nearly a 3-fold
increase in mortality from the 1st to the 3rd tertile. The hazard ratio
for mortality of these patients (1st compared with 2nd and 3rd CRP
tertiles) by univariate analysis was 2.8 (95% CI
1.7, 4.8, P<0.0001). Figure 3
shows the effect of CRP levels on future mortality, based on initial
clinical presentation. Interestingly, the effect of CRP was
greater in patients with stable or unstable angina than with acute MI.
After controlling for all known baseline variables,
multivariate regression analysis produced a Cox
hazard ratio of 2.4 (95% CI 1.4, 4.1, P=0.001), verifying
an independent effect.
|
). Medians are shown
as solid lines, means as dashed lines.
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Infectious Serology and Survival
Infectious serologies were frequently positive both in patients
who survived as well as nonsurvivors (see Table 1
). No
significant differences in seropositivity to C pneumoniae or
H pylori were detected in survivors versus
nonsurvivors, but seropositivity to CMV was significantly higher in
nonsurvivors (88% versus 74%, P=0.002).
Figure 4 shows the Kaplan-Meier survival
curves for patients on the basis of seropositivity to C
pneumoniae, H pylori, or CMV. No significant
hazard rate ratio increase was noted for seropositivity to C
pneumoniae or H pylori. A significant hazard ratio of
2.5 (95% CI 1.4, 4.8, P=0.001) by univariate
analysis and 1.9 (95% CI 1.01, 3.6, P<0.05) after
multivariate Cox regression analysis was found
for CMV seropositivity. Figure 5 shows
the frequency of seropositivity to the 3 infectious agents tested,
stratified by CRP tertile. No significant association between CRP and
seropositivity to any of the 3 agents, including CMV, was noted.
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Other Predictors of Mortality
Table 2 lists all baseline
variables found to be independent predictors of mortality in this
study. The model was built beginning with all study variables, and
the final model considered (but excluded because of age and LVEF) sex,
hyperlipidemia, smoking, HDL,
triglycerides, total cholesterol (TC)/HDL
ratio, renal failure, index clinical treatment, and number of severe
vessels. The only confounder of the inflammatory or infectious factors
was age, which confounded CMV; despite this, however, CMV retained
statistical significance. Interestingly, the independent predictive
value of CRP and seropositivity to CMV on mortality was greater than a
number of more traditional risk factors including diabetes,
hyperlipidemia, hypertension, and a history of smoking.
The effect on mortality of CRP and the 3 infectious serologies is shown
for the whole study cohort as well as stratified by the initial
clinical presentation in Figure 6. No significant difference in the
effects of CRP or CMV were noted, based on an initial
presentation with stable or unstable angina or acute
MI.
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Interaction Between CRP and Seropositivity to CMV
Because seropositivity to neither C pneumoniae nor
H pylori was found to be predictive of future mortality,
further evaluation of these results was not performed. An evaluation of
the effect of the combination of elevated CRP and seropositivity to
CMV, however, was performed. Figure 7
shows the effect on mortality of seropositivity to CMV in those with
high (2nd and 3rd tertiles) and low CRP (1st tertile) levels. The
highest mortality rate was noted in seropositive patients with elevated
CRP levels. In contrast, seropositivity to CMV or elevated CRP alone
had little effect on mortality. Linear trend analysis of this
interaction gives an adjusted hazard ratio of 2.2
(P=0.0001).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Summary of Key Findings
In our prospectively studied, angiographically defined cohort with significant coronary artery disease, we demonstrated an independent association between future mortality and the inflammatory marker CRP. This association was important (>2-fold increase in mortality) and highly significant (P<0.002). Interestingly, the association between CRP and mortality was greater in patients with stable angina than with acute MI, perhaps because the acute rise in CRP during MI actually diluted the predictive value of the baseline pre-MI CRP level.
In addition, seropositivity to CMV was found to be an independent predictor of mortality in this study group. An interaction between CRP and seropositivity to CMV was noted such that the majority of increased mortality came in those who were CMV seropositive and were not in the low range of CRP levels (tertiles 2/3). In contrast, seropositivity to neither C pneumoniae nor H pylori was predictive of mortality during long-term follow-up.
Inflammation and Its Effect on Survival
In this study, the risk of mortality associated with elevations of
CRP was independent of other known cardiovascular risk
factors including smoking status, hypertension, diabetes, baseline
lipid levels, and so forth. These data further extend previous reports
that CRP predicts primary15 32 33 34 and
secondary11 12 13 14 ischemic risk and adds further
support to the inflammatory concept of coronary
atherosclerosis. The fact that baseline CRP levels
predict mortality in patients with existing coronary artery
disease also suggests that chronic inflammation may, in some way,
influence the individual progression rates of the atherosclerotic
process.
Infectious Serologies
Our study confirms previously reported findings of a high
prevalence of seropositivity among patients with documented
coronary artery disease for 3 agents (CMV,25
H pylori,28 and C
pneumoniae19 ) postulated to play a role in the
pathophysiology of atherosclerosis. However, only
seropositivity to CMV was predictive of increased mortality in patients
with known coronary artery disease. This finding appears to
contrast with results recently reported by Ridker et al,35
in which, among previously healthy patients enrolled in the
Physicians’ Health Study, seropositivity to CMV did not appear to
predict an increased risk of a first cardiovascular
event. The interaction between inflammation and CMV seropositivity
found in this study is similar to the findings of a cross-sectional
angiographic study by Zhu et al,36 in which they
correlated CMV seropositivity and CRP levels to the presence of
coronary artery disease. There they noted that "CMV elicits a
subclinical inflammatory response, but only in certain individuals, and
individuals with an inflammatory response appear susceptible to the
atherogenic effects of CMV, whereas those without appear
resistant." It is appealing to speculate that relative
elevation of CRP in CMV-seropositive patients indicates an active,
"smoldering" infectious/inflammatory process (arteritis?) that
accelerates atherothrombotic progression, whereas low CRP in
CMV-seropositive patients suggests a resolved or inactive infection.
The actual pathophysiological mechanisms
responsible for these findings are speculative, however, and remain to
be conclusively demonstrated.
We also found that neither C pneumoniae nor H pylori seropositivity predicted increased mortality in patients with angiographically defined coronary artery disease. This does not eliminate the possibility, however, that they are associated with the initiation and early development of coronary atherosclerosis, as has been proposed by some prior studies.17 18 19 20 28 29 Additionally, lack of a serological association does not eliminate the possibility of a pathogenic association with chronic active infection because serological studies only document previous exposure rather than provide specific information regarding a resolved versus ongoing active infectious process.
Potential Limitations and Strengths of the Present
Study
This study, although prospective, is observational. Associations
with mortality may be either causal or noncausal. Groups seropositive
to CMV (or other agents) may have differed in other ways (eg,
socioeconomically); therefore, a potential for confounding of
variables exists. This limitation was addressed by the use of
multivariate Cox regression analysis, taking
into account all major recognized potential confounding variables.
Although the study included nearly 1000 patients, there still exists
the potential, if an even larger population were available, that other
clinical variables, such as initial clinical
presentation, might also demonstrate independent predictive
value of future mortality. A strength of this study is that all
patients were angiographically diagnosed at baseline with
coronary artery disease. Also, all laboratory markers were
performed by investigators blinded to the clinical results of the
study. To obtain more complete information regarding the primary end
point of all-cause mortality, a national death index was used to
supplement telephone follow-up, which resulted in 100% follow-up.
Conclusions
In a large, angiographically defined patient population, followed
prospectively, the combination of seropositivity to CMV and relative
elevation of CRP predicted future mortality. Although requiring
validation, this finding suggests the possibility that chronic
inflammation (represented by elevated CRP) caused by
smoldering CMV infection is an independent risk factor for progression
of the atherothrombotic process to a fatal outcome. If true, this
finding may have important implications for risk-stratification and
intervention trials.
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Acknowledgments |
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We gratefully acknowledge the financial support of the LDS Hospital Deseret Foundation, Salt Lake City, Utah.
Received April 6, 2000; revision received May 30, 2000; accepted May 30, 2000.
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 M. S. V. Elkind, W. Tai, K. Coates, M. C. Paik, and R. L. Sacco High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke. Arch Intern Med, October 23, 2006; 166(19): 2073 - 2080. [Abstract] [Full Text] [PDF]
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 H. K. Salem, P. Ranjzad, A. Driessen, C. E. Appleby, A. M. Heagerty, and P. A. Kingston Beta-Adrenoceptor Blockade Markedly Attenuates Transgene Expression From Cytomegalovirus Promoters Within the Cardiovascular System Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2267 - 2274. [Abstract] [Full Text] [PDF]
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M. Charakida, A. E. Donald, M. Terese, S. Leary, J. P. Halcox, A. Ness, G. D. Smith, J. Golding, P. Friberg, N. J. Klein, et al. Endothelial Dysfunction in Childhood Infection Circulation, April 5, 2005; 111(13): 1660 - 1665. [Abstract] [Full Text] [PDF]
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I. Volanen, O. T. Raitakari, R. Vainionpaa, M. Arffman, J. Aarnisalo, S. Angle, K. Kallio, and O. Simell Serum Lipid Profiles Poorly Correlate With Chlamydia pneumoniae, Helicobacter pylori, and Cytomegalovirus Seropositivity in Prospectively Followed-Up Healthy Children Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 827 - 832. [Abstract] [Full Text] [PDF]
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 M. Leis, M. Marschall, and T. Stamminger Downregulation of the cellular adhesion molecule Thy-1 (CD90) by cytomegalovirus infection of human fibroblasts J. Gen. Virol., July 1, 2004; 85(7): 1995 - 2000. [Abstract] [Full Text] [PDF]
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M. Weis, T. N. Kledal, K. Y. Lin, S. N. Panchal, S. Z. Gao, H. A. Valantine, E. S. Mocarski, and J. P. Cooke Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway: Role of Asymmetric Dimethylarginine in Transplant Arteriosclerosis Circulation, February 3, 2004; 109(4): 500 - 505. [Abstract] [Full Text] [PDF]
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 P. L. Nerheim, J. L. Meier, M. A. Vasef, W.-G. Li, L. Hu, J. B. Rice, D. Gavrila, W. E. Richenbacher, and N. L. Weintraub Enhanced Cytomegalovirus Infection in Atherosclerotic Human Blood Vessels Am. J. Pathol., February 1, 2004; 164(2): 589 - 600. [Abstract] [Full Text] [PDF]
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P. Khairy, S. Rinfret, J.-C. Tardif, R. Marchand, S. Shapiro, J. Brophy, and J. Dupuis Absence of Association Between Infectious Agents and Endothelial Function in Healthy Young Men Circulation, April 22, 2003; 107(15): 1966 - 1971. [Abstract] [Full Text] [PDF]
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 D. J. Angiolillo, G. Liuzzo, S. Pelliccioni, E. De Candia, R. Landolfi, F. Crea, A. Maseri, and L. M. Biasucci Combined role of the Lewis antigenic system, Chlamydia pneumoniae, and C-reactive protein in unstable angina J. Am. Coll. Cardiol., February 19, 2003; 41(4): 546 - 550. [Abstract] [Full Text] [PDF]
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J. B. Muhlestein and J. L. Anderson Infectious Serology and Atherosclerosis: How Burdensome Is the Risk? Circulation, January 21, 2003; 107(2): 220 - 222. [Full Text] [PDF]
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B. D. Horne, J. B. Muhlestein, J. F. Carlquist, T. L. Bair, T. E. Madsen, N. I. Hart, J. L. Anderson, and for the Intermountain Heart Collaborative (IHC) St Statin Therapy Interacts With Cytomegalovirus Seropositivity and High C-Reactive Protein in Reducing Mortality Among Patients With Angiographically Significant Coronary Disease Circulation, January 21, 2003; 107(2): 258 - 263. [Abstract] [Full Text] [PDF]
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C. A. Allen Maycock, J. B. Muhlestein, B. D. Horne, J. F. Carlquist, T. L. Bair, R. R. Pearson, Q. Li, J. L. Anderson, and Intermountain Heart Collaborative Study Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1777 - 1785. [Abstract] [Full Text] [PDF]
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T. Maisch, B. Kropff, C. Sinzger, and M. Mach Upregulation of CD40 Expression on Endothelial Cells Infected with Human Cytomegalovirus J. Virol., November 13, 2002; 76(24): 12803 - 12812. [Abstract] [Full Text] [PDF]
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M. J. LaMonte, J. L. Durstine, F. G. Yanowitz, T. Lim, K. D. DuBose, P. Davis, and B. E. Ainsworth Cardiorespiratory Fitness and C-Reactive Protein Among a Tri-Ethnic Sample of Women Circulation, July 23, 2002; 106(4): 403 - 406. [Abstract] [Full Text] [PDF]
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A. Prasad, J. Zhu, J. P.J. Halcox, M. A. Waclawiw, S. E. Epstein, and A. A. Quyyumi Predisposition to Atherosclerosis by Infections: Role of Endothelial Dysfunction Circulation, July 9, 2002; 106(2): 184 - 190. [Abstract] [Full Text] [PDF]
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 C. Stollberger and J. Finsterer Role of Infectious and Immune Factors in Coronary and Cerebrovascular Arteriosclerosis Clin. Vaccine Immunol., March 1, 2002; 9(2): 207 - 215. [Full Text] [PDF]
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J. S. Zebrack, J. B. Muhlestein, B. D. Horne, J. L. Anderson, and Intermountain Heart Collaboration Study Group C-reactive protein and angiographic coronary artery disease: independent and additive predictors of risk in subjects with angina J. Am. Coll. Cardiol., February 20, 2002; 39(4): 632 - 637. [Abstract] [Full Text] [PDF]
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 G. J. Blake and P. M. Ridker Novel Clinical Markers of Vascular Wall Inflammation Circ. Res., October 26, 2001; 89(9): 763 - 771. [Abstract] [Full Text] [PDF]
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 D. N. Streblow, S. L. Orloff, and J. A. Nelson Do Pathogens Accelerate Atherosclerosis? J. Nutr., October 1, 2001; 131(10): 2798S - 2804. [Abstract] [Full Text] [PDF]
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J. A. Paramo, O. Beloqui, and J. Diez Atherosclerosis: Is it Time for a New Name? Circulation, August 14, 2001; 104 (7): e38 - e38. [Full Text] [PDF]
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B. Freedman, J. B. Muhlestein, B. D. Horne, J. F. Carlquist, T. E. Madsen, T. L. Bair, R. R. Pearson, and J. L. Anderson Cytomegalovirus Seropositivity and C-Reactive Protein Have Independent and Combined Predictive Value for Mortality in Patients With Angiographically Demonstrated Coronary Artery Disease Response Circulation, July 31, 2001; 104 (5): e20 - e21. [Full Text] [PDF]
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H. J. Rupprecht, S. Blankenberg, C. Bickel, G. Rippin, G. Hafner, W. Prellwitz, W. Schlumberger, and J. Meyer Impact of Viral and Bacterial Infectious Burden on Long-Term Prognosis in Patients With Coronary Artery Disease Circulation, July 3, 2001; 104(1): 25 - 31. [Abstract] [Full Text] [PDF]
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S. Blankenberg, H. J. Rupprecht, C. Bickel, C. Espinola-Klein, G. Rippin, G. Hafner, M. Ossendorf, K. Steinhagen, and J. Meyer Cytomegalovirus Infection With Interleukin-6 Response Predicts Cardiac Mortality in Patients With Coronary Artery Disease Circulation, June 19, 2001; 103(24): 2915 - 2921. [Abstract] [Full Text] [PDF]
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A. W. Chan, D. L. Bhatt, D. P. Chew, M. J. Quinn, D. J. Moliterno, E. J. Topol, and S. G. Ellis Early and Sustained Survival Benefit Associated With Statin Therapy at the Time of Percutaneous Coronary Intervention Circulation, February 12, 2002; 105(6): 691 - 696. [Abstract] [Full Text] [PDF]
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