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(Circulation. 1999;99:1555-1559.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Treatment of Helicobacter pylori and Chlamydia pneumoniae Infections Decreases Fibrinogen Plasma Level in Patients With Ischemic Heart Disease
From the Emergency Department (G.T., R.C., C.M., G.V., T. V. T., G.C.), Institute of Respiratory Disease (F.B., P.T., C.A.), Institute of Hygiene (M.L.R.), and Hemodynamic Unit (R.P.), Ospedale Maggiore, IRCCS, Milan, Italy.
Correspondence to Giuseppe Torgano, MD, Divisione di Medicina d'Urgenza, Ospedale Maggiore-IRCCS, Via F Sforza 35, 20122 Milano, Italy. E-mail medurg1{at}polic.cilea.it
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Chronic Chlamydia pneumoniae and Helicobacter pylori infections could be a risk factor for ischemic heart disease (IHD), possibly by increasing fibrinogen levels. The aim of our study was to evaluate changes in fibrinogen level in patients with IHD and H pylori and/or C pneumoniae positivity randomly assigned to antibiotic treatment.
Methods and Results—Eighty-four patients with chronic IHD, H pylori and/or C pneumoniae antibodies, and normal acute-phase reactants were randomly assigned to treatment or no treatment. Treatment consisted of omeprazole, clarithromycin, and tinidazole in H pylori–positive patients and clarithromycin alone in C pneumoniae–positive patients. The effect of treatment and other baseline variables on fibrinogen levels, determined at 6 months, was evaluated by multivariate analysis. Treatment significantly reduced fibrinogen level at 6 months in the overall study population and in the groups of patients divided according to H pylori or C pneumoniae positivity. In the 43 treated patients, mean (±SD) basal fibrinogen was 3.65±0.58 g/L, and mean final fibrinogen was 3.09±0.52 g/dL (P<0.001), whereas in the 41 untreated patients, mean basal and final fibrinogen levels were 3.45±0.70 and 3.61±0.71 g/L, respectively. The largest decrease was observed in patients with both infections. Fibrinogen changes were also significantly and negatively correlated with age.
Conclusions—Our data suggest that a short, safe, and effective course of antibiotic therapy might be suggested as a means of interacting with an "emerging" risk factor.
Key Words: ischemia • fibrinogen • H pylori • C pneumoniae
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Major factors associated with an increased risk of ischemic heart disease (IHD) are well known, yet they do not completely explain the pathogenesis of the disease.1 Recent data suggest that active inflammation and/or infection, possibly in the coronary arteries, may play a role in IHD.2 The infectious theory has been suggested by epidemiological, serological, immunohistochemical, and in situ hybridization studies, which indicated a possible etiologic role of some viruses and bacteria in the generation of atherosclerotic lesions.3 4 5 Among the microorganisms potentially implicated, Chlamydia pneumoniae is the most extensively studied in the literature. Some reports have shown a serological association of C pneumoniae with both acute and chronic IHD, suggesting that chronic C pneumoniae infection may be a significant risk factor for the development of IHD.6 7 Moreover, Shor et al8 and Kuo et al9 demonstrated the presence of C pneumoniae–like organisms in coronary artery fatty streaks and atheroma plaques.
Helicobacter pylori infection, usually acquired in childhood, has also been recently associated with an increased risk of developing IHD.10 11 12 In other reports concerning normal subjects, some authors found that chronic infections with C pneumoniae and H pylori are associated with higher fibrinogen plasma levels than in noninfected subjects, suggesting that fibrinogen could be a link between chronic infection and increased risk for IHD.13 However, a recent epidemiological study failed to demonstrate an association between H pylori infection and mortality from IHD.14 Moreover, the authors reported that in a subgroup of 206 healthy subjects, plasma fibrinogen levels were virtually the same in those who were positive for H pylori infection and those who were negative.
No data on the effect of H pylori and C pneumoniae infection on fibrinogen levels of IHD patients are available.
The aim of our study was to evaluate changes in plasma fibrinogen level in IHD patients with seropositivity for H pylori and/or C pneumoniae randomly assigned to antibiotic treatment and followed for 6 months.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patients
Patient recruitment began in October 1995 and was completed by March 1997. A total of 163 consecutive patients with chronic IHD who satisfied clinical inclusion criteria (see below) and were admitted to our department or outpatient clinic were evaluated. For all patients, we obtained clinical history, physical examination, and blood samples for the following determinations: white blood cell count, erythrosedimentation rate,
-acid glycoprotein,
C-reactive protein (CRP), cholesterol level, fibrinogen
level, H pylori IgG titer, and C pneumoniae IgG,
IgA, and IgM titers. C pneumoniae IgG and IgA titers were
measured again after 1 month in patients with IgG positivity and IgM
negativity to exclude patients with C pneumoniae
reinfection; patients with basal IgM-positive testing were also
excluded.
The inclusion criteria were as follows: age between 40 and 75 years;
angiographically confirmed IHD with stenosis >70% in 
1
coronary artery and/or history of previous myocardial
infarction (>1 month before enrollment); seropositivity for H
pylori and/or C pneumoniae antibodies (see
Laboratory Methods); absence of acute inflammatory disease, history of
neoplastic disease in the previous 5 years, or history of acquired or
congenital coagulation disorders; and absence of C
pneumoniae acute infection or reinfection.
Six months after randomization, all patients underwent blood sampling for all the determinations listed above.
Laboratory Methods
Serum H pylori–specific IgG titer was determined by
a commercial ELISA (Pyloriset EIA-G, Orin Diagnostica
Espspoo). H pylori seropositivity was defined as an IgG
titer 300. H pylori was considered eradicated when IgG
titer 6 months after the beginning of the treatment was reduced by
50%.15
Serum C pneumoniae–specific IgG, IgA, and IgM titers were
determined by an indirect microimmunofluorescence
method by use of a commercial kit purchased from Labsystems as
described by Wang and Grayston.16 Acute C
pneumoniae infection or reinfection was defined in presence of IgM
positivity or a 4-fold increase in IgG or IgA titer after 1 month.
Seropositivity for C pneumoniae, indicating past or chronic
infection, was defined in the presence of IgG titer of 1:64 or IgA
titer 1:32, according to other authors.17
Plasma fibrinogen level was quantified by means of the Clauss clotting assay (normal range, 1.5 to 4.5 g/L).18 Leukocyte count, acute-phase reactants, and total cholesterol level were determined by standard methods. Reference values for cholesterol and CRP were <200 and 0 to 1 mg/dL, respectively.
Study Design
This was a single-blind, randomized, prospective study. Eligible
patients were randomly allocated to treatment or no treatment. We
performed an a priori statistical analysis to calculate
the number of patients to be included in the study to detect a possible
difference in mean fibrinogen (main variable) between treated and
nontreated patients with a probability of 80%.19 For this
purpose, we used the statistical characteristics (mean and SD for
fibrinogen values) of a population in which fibrinogen levels had been
analyzed according to H pylori or C
pneumoniae infection status.13 The number was 40
patients for each treatment group. All patients gave written informed
consent. Fibrinogen level determinations (main variable) were
performed by the laboratory technician. Treatment allocation of
H pylori–positive patients and H
pylori–negative, C pneumoniae–positive patients was
done according to 2 separate randomization lists generated by a
computer. Treatment of H pylori–positive patients,
regardless of C pneumoniae positivity, consisted of
omeprazole 20 mg orally twice a day for 30 days, clarithromycin 500 mg
orally twice a day for 14 days, and tinidazole 500 mg orally twice a
day for 7 days.20 Treatment of H
pylori–negative, C pneumoniae–positive patients
consisted of clarithromycin 500 mg orally twice a day for 14
days.21 The clarithromycin dosage was chosen because
of its efficacy in the treatment of C pneumoniae
infection.22 All patients were seen 1 month after
randomization for clinical evaluation and a check of adhesion to
treatment; final observation and laboratory examination were done after
6 months in patients who completed the treatment.
Statistical Analysis
Each patient was characterized by the following variables:
age, sex, smoking habit, hypertension, diabetes, fibrinogen level,
cholesterol level, H pylori positivity, and
C pneumoniae positivity. Descriptive statistics (number of
patients, mean, and SD for continuous variables; number of patients
and frequency for dichotomous variables) were calculated for all
these variables in the 2 treatment groups. Comparison of baseline
variables between the 2 treatment groups was done with discriminate
analysis by dummy dependent variable
regression.23
To evaluate the difference in plasma fibrinogen changes in relation to
treatment, with adjustment for the influence of other variables,
main variables were analyzed with the multiple regression
method.24 The dependent variable was the difference
between basal and final fibrinogen level (
FIB), and independent
variables were treatment, age, sex, hypertension, current smoking,
H pylori positivity, C pneumoniae positivity,
H pylori eradication (dichotomous variables), basal
fibrinogen level, and difference between basal and final CRP levels.
The interaction between C pneumoniae positivity and
H pylori eradication was also analyzed. Because of
the high significance of this interaction, the same model was also
applied to the patients divided according to H pylori and
C pneumoniae antibody status. The best subset of
variables included was chosen by use of the Mallow Statistic
(CP).25 The normality of distribution of the
residuals of our model was tested by use of the "runs" method and
the Wilk-Shapiro26 test. Correlations between
variables were evaluated by means of Spearman's rank correlation
corrected for ties.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Ninety-seven patients satisfying the inclusion criteria were randomized to treatment (48 patients) or no treatment (49 patients); 5 patients of the treated group and 8 of the nontreated group did not complete the study because of the need for CABG surgery (1 in the treated group and 2 in the nontreated group) or because of a lack of compliance or withdrawal of consent (4 in the treated group and 6 in the nontreated group). We therefore observed an overall dropout rate of 13.4%.
Clinical and laboratory data in the 84 patients who completed the study
are reported in Table 1
according
to treatment. Discriminate analysis did not detect any
difference in baseline variables between the 2 treatment groups;
thus, the 2 groups of randomization were homogeneous at
baseline.
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According to serology, the number of treated and nontreated patients was the following: H pylori negative, C pneumoniae positive, 6 and 7; H pylori and C pneumoniae positive, 23 and 23; and H pylori positive, C pneumoniae negative, 14 and 11, respectively. The means of basal fibrinogen levels were not significantly different in the groups of patients distributed according to serological pattern (3.50±0.70 g/L in H pylori and C pneumoniae positive versus 3.67±0.76 g/L in H pylori negative, C pneumoniae positive versus 3.60±0.50 g/L in H pylori positive, C pneumoniae negative). A significant correlation was observed between basal fibrinogen and smoking (rs=0.20, P<0.05) and between basal fibrinogen and basal CRP levels (rs=0.43, P<0.01).
Eradication of H pylori infection, defined as a reduction of
basal IgG titers by 50%,15 in treated H
pylori–positive patients was obtained in 35 of 37 patients
(94%), which does not differ from the eradication rates reported in
the literature.19 H pylori infection was
also eradicated in 3 of the 34 nontreated H pylori–positive
patients, who were treated with antibiotics prescribed by their
physician for intercurrent upper respiratory infection.
Mean IgG geometric titer in treated patients with a single C pneumoniae infection decreased significantly from 725±330 to 225±240 (P<0.01), whereas in the control group, mean IgG geometric titer increased after 6 months from 325±470 to 370±480 (P=NS). The difference between mean IgG geometric titers at baseline was not significantly different between the 2 groups.
To evaluate factors influencing final fibrinogen levels, we performed a
multivariate analysis using FIB as a
dependent variable. The R2 of the
model was 0.58; the "runs" and Wilk-Shapiro tests showed that the
distribution of residuals was compatible with a normal distribution.
Multivariate analysis showed that FIB was
significantly related to treatment both in the overall study population
(P=0.02) and in the groups of patients divided according to
H pylori positivity (P<0.001 in the 71 H
pylori–positive patients and P>0.05 in the 13 H
pylori–negative patients) or C pneumoniae positivity
(P=0.001 in the 59 C pneumoniae–positive
patients and P=0.04 in the 25 C
pneumoniae–negative patients), indicating that treatment
significantly reduced fibrinogen levels at 6 months. Furthermore, the
interaction between C pneumoniae positivity and H
pylori eradication was statistically significant
(P<0.001), showing that the decrease in fibrinogen level is
greater in patients who were successfully treated for H
pylori infection and were concomitantly C pneumoniae
positive. FIB was also significantly and negatively correlated with
age (P=0.01).
FIB was not significantly influenced by the other variables
included in the model (smoking, sex, hypertension, initial H
pylori positivity, and difference between basal and final CRP
levels).
Table 2 shows basal and final fibrinogen
levels and FIB in the patients distributed according to treatment
and initial H pylori and C pneumoniae
positivity. In patients who received treatment, FIB was
significantly higher in those seropositive for both H pylori
and C pneumoniae than in those with a single infection. An
increase in fibrinogen levels at 6 months was observed in nontreated
patients (3.45±0.70 versus 3.61±0.71 g/L; P=0.12),
reaching significance in patients positive for both infections
(3.33±0.72 versus 3.70±0.75 g/L; P=0.009).
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CRP in nontreated patients did not vary significantly after 6 months
(0.24±0.22 versus 0.24±0.23 mg/dL; P=0.91).
Conversely, in the treated group, CRP levels decreased significantly at
the end of follow-up (0.29±0.25 versus 0.20±0.15 mg/dL;
P=0.018). Final CRP values and CRP were significantly
related to final fibrinogen and FIB, respectively
(P<0.001). According to serology, CRP levels decreased in
every subgroup yet decreased significantly only in patients with
H pylori infection (0.23±0.19 versus 0.14±0.10
mg/dL; P=0.028).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Recent data suggest that chronic bacterial infections may be involved in the genesis of IHD; in particular, C pneumoniae infection may be involved both by a direct mechanism of colonization and atherosclerotic plaque instability9 27 and by an indirect mechanism of activation of inflammation28 associated with an increase in plasma fibrinogen, which is strongly implicated in coronary heart disease.29 30 More recently, H pylori infection was also found to be epidemiologically associated with IHD10 12 31 although these data were later questioned.14 32 33 Despite the failure to demonstrate the presence of H pylori in atherosclerotic plaques,27 chronicH pylori infection may constitute a risk for IHD by increasing fibrinogen levels13 or through other unknown mechanisms.31 34
Two recent randomized studies about treatment of C pneumoniae infection in IHD patients suggested that treatment with macrolides may be effective in decreasing adverse cardiovascular events; the study of Gupta et al17 showed that azithromycin treatment of C pneumoniae–positive patients reduced the risk of adverse cardiovascular events during an 18-month follow-up period to values similar to those found in C pneumoniae–negative patients. Gurfinkel et al35 found that roxithromycin reduced morbidity and mortality during a 1-month period after non–Q-wave myocardial infarction or unstable angina.
There are no studies about changes in plasma fibrinogen, which is the major link between chronic infection and IHD, after specific antibiotic treatment of either C pneumoniae or H pylori infections. We performed a randomized study using a treatment schedule that allowed H pylori eradication displaying antichlamydial activity. Our study was not placebo controlled; however, the primary end-point variable (fibrinogen level at 6 months) was determined blindly by the laboratory technician. Notwithstanding an overall dropout rate of 13.4%, the 2 groups of patients that completed treatment were relatively well balanced.
The main results of our study are that treatment significantly reduced
fibrinogen levels in IHD patients and that this reduction is detectable
6 months after treatment. The decrease was observed in both the overall
study population and patients with either C pneumoniae or
H pylori infection. Interestingly, the greatest reduction
(
20%) was found in patients seropositive for both organisms.
This observation suggests that the effect of treatment could be long lasting and related to its antimicrobial activity rather than to a possible anti-inflammatory activity of macrolides.36 It also supports the link between C pneumoniae or H pylori infections and fibrinogen, further suggested by the significant increase in fibrinogen level in nontreated patients positive for both infections.
High anti–C pneumoniae titers (more than a cutoff value of 1/64) may be consistent with chronic active infection, as suggested by others,17 given the nearly additive effect of treatment in patients with both infections with respect to patients with a single infection, together with the decrease in IgG antibody titers to C pneumoniae over time.
In the treated group, we observed a reduction in CRP levels that was parallel to the decrease in fibrinogen levels. High CRP concentrations in patients with unstable angina are a strong negative prognostic factor.37 These data support the hypothesis that C pneumoniae and H pylori infections may contribute to the increase in CRP levels.
Although several studies linking C pneumoniae infection and IHD have appeared in the literature, data on the association between H pylori infection and IHD are less convincing. We conclude that the determination of antibody titers to both C pneumoniae and H pylori may be of use in patients with IHD. In fact, antibody prevalence in the general adult population toward both these pathogens reaches 50%38 39 but is higher still in patients with IHD.
The previous inconclusive results on possible links between H pylori and IHD may be due to the fact that so far this agent has been considered a single infective agent and not in association with other pathogens with which it could display a synergistic activity.
Another interesting result is that the reduction in plasma fibrinogen is greater in younger than in older patients. This is particularly significant because the presence of risk factors in younger patients is more likely to have a greater impact on the natural history of the disease.
Should our data be confirmed on a larger population, in the near future a short, safe, and effective course of antibiotic therapy might be suggested as a means of interacting with an "emerging" risk factor, thus obtaining a high epidemiological impact on patients with IHD.
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Acknowledgments |
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We thank Dr Virginio Mandelli for his full cooperation in the statistical analysis.
Received July 27, 1998; revision received November 30, 1998; accepted December 18, 1998.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Nieminen MS, Mattila K, Valtonen V. Infection and inflammation as a risk factor for myocardial infarction. Eur Heart J. 1993;14(suppl K):12–16.
2.
Alexander RW. Inflammation and coronary artery
disease. N Engl J Med. 1994;331:468–469.
3.
Beneditt EP, Barret T, McDougall JK. Viruses and
etiology of atherosclerosis. Proc Natl Acad Sci
U S A. 1983;80:6386–6389.
4. Pesonen E, Siitonen O. Acute myocardial infarction precipitated by infectious diseases. Am Heart J. 1981;101:512–513.[Medline] [Order article via Infotrieve]
5. Spodick DH, Flessas AP, Johnson MM. Association of acute respiratory symptoms with onset of acute myocardial infarction: prospective investigation of 150 consecutive patients and matched control patients. Am J Cardiol. 1984;53:481–482.[Medline] [Order article via Infotrieve]
6. Saikku P. Chlamydia pneumoniae as a risk factor in acute myocardial infarction. Eur Heart J. 1993;14(suppl K):62–65.
7. Saikku P, Leinonen M, Mattila K, Ekman MR, Nieminen MS, Makela PH, Huttunen JK, Valtonen V. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet. 1988;2:983–986.[Medline] [Order article via Infotrieve]
8. Shor A, Kuo CC, Patton DL. Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques. S Afr Med J. 1992;82:158–161.[Medline] [Order article via Infotrieve]
9. Kuo CC, Shor A, Campbell LA, Fukushi H, Patton DL, Grayston JT. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries. J Infect Dis. 1993;167:845–849.
10.
Mendall MA, Goggin PM, Molineaux N, Levy J, Toosy T,
Stracham D, Camm AJ, Northfield TC. Relation of Helicobacter
pylori infection and coronary heart disease. Br
Heart J. 1994;71:437–439.
11.
Aceti A, Mazzacurati G, Amendola MA, Pennica A,
Zecchini B. H pylori and C pneumoniae infections
may account for most acute coronary syndrome. BMJ. 1996;313:428–429.
12. Morgando A, Sanseverino P, Perotto C, Molino F, Gai V, Ponzetto A. Helicobacter pylori seropositivity in myocardial infarction. Lancet. 1995;345:1380. Letter.[Medline] [Order article via Infotrieve]
13. Patel P, Carrington D, Strachan DP, Leatham E, Goggin P, Nothfield T, Mendall MA. Fibrinogen: a link between chronic infection and coronary heart disease. Lancet. 1994;343:1634–1635.[Medline] [Order article via Infotrieve]
14.
Wald NJ, Law MR, Morris JK, Bagnall AM.
Helicobacter pylori infection and mortality from ischaemic
heart disease: negative result from a large, prospective study.
BMJ. 1997;315:1199–1201.
15.
Jones DM, Lessels AM, Eldridge J.
Campylobacter-like organisms on the gastric mucosae:
culture, histological and serological studies.
J Clin Pathol. 1994;37:1002–1006.
16. Wang SP, Grayston JT. Serological relationship between genital TRIC, lymphogranuloma venereum, and related organisms in a new microtiter indirect immunofluorescence test. Am J Ophthalmol. 1970;70:367–374.[Medline] [Order article via Infotrieve]
17.
Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski
JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies,
cardiovascular events, and azithromycin in male
survivors of myocardial infarction. Circulation. 1997;96:404–407.
18. Clauss A. Gerinnungsphysiologische Scellmethode zur Bstimmung des Fibrinogens. Acta Haematol. 1957;17:237–246.[Medline] [Order article via Infotrieve]
19. Pocock SJ. Clinical Trials: A Practical Approach. New York, NY: John Wiley & Sons; 1983:123–130.
20. Bazzoli F, Zagari RM, Fossi S, Pozzato P, Alampi G, Simoni P, Sottili S, Roda A, Roda E. Short term, low dose triple therapy for eradication of Helicobacter pylori. Eur J Gastroenterol Hepatol. 1994;6:773–777.
21.
Hammerschlag MR, Qumei KK, Roblin PM. In vitro activity
of azitromycin, claritromycin, L-ofloxacin and other
antibiotics against Chlamydia pneumoniae. Antimicrob
Agents Chemother. 1992;36:1573–1574.
22. Blasi F, Cosentini R, Tarsia P, Camusso L, Campi E, Arosio C, Allegra L. Chlamydia pneumoniae pneumonia: role of new macrolides. J Chemother. 1995;7:117–118.
23. Armitage P. Statistical Methods in Medical Research. Oxford, UK: Blackwell Scientific Publications; 1971:336.
24. Daniel C, Wood FS. Fitting Equations to Data. New York, NY: Wiley Interscience; 1971:50–59, 83–115.
25. Burton DE. Query: completed runs of length k above and below median. Technometrics. 1967;9:682–694.
26. Wilk MB, Shapiro SS. The joint assessment of normality for several independent samples. Technometrics. 1968;10:825–839.
27. Blasi F, Denti F, Erba M, Cosentini R, Raccanelli R, Rinaldi A, Fagetti L, Esposito E, Ruberti U, Allegra L. Detection of Chlamydia pneumoniae but not Helicobacter pylori in atherosclerotic plaques of aortic aneurysms. J Clin Microbiol. 1996;34:2766–2769.[Abstract]
28.
Gupta S, Camm JA. Chlamydia pneumoniae and
coronary heart disease. BMJ. 1997;314:1778–1779.
29. Ernst E. Fibrinogen as a cardiovascular risk factor: interrelationship with infections and inflammation. Eur Heart J. 1993;14(suppl K):82–87.
30.
Ernst E, Resch KL. Fibrinogen as a
cardiovascular risk factor: meta-analysis and
review of the literature. Ann Intern Med. 1993;118:956–963.
31.
Murray LJ, Bamford K, O'Reilly DPJ, McCrum EE, Evans
AE. Helicobacter pylori infection: relation with
cardiovascular risk factors, ischaemic heart disease,
and social class. Br Heart J. 1995;74:497–501.
32.
Rathbone B, Martin D, Stephens J, Thompson JR, Samani
NJ. Helicobacter pylori seropositivity in subjects with
acute myocardial infarction. Heart. 1996;76:308–311.
33.
Parente F, Maconi G, Imbesi V, Sangaletti O, Poggio M,
Rossi E, Duca P, Bianchi Porro G. Helicobacter pylori
infection and coagulation in healthy people. BMJ. 1997;314:1318–1319.
34.
Sung JJY, Sanderson JE. Hyperhomocysteinaemia,
Helicobacter pylori, and coronary heart disease.
Heart. 1996;76:305–307.
35. Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B, for the ROXIS Study Group. Randomised trial of roxithomycin in non Q-wave coronary syndromes: ROXIS pilot study. Lancet. 1997;350:404–407.[Medline] [Order article via Infotrieve]
36. Agen C, Danesi R, Blandizzi C, Costa M, Stacchini B, Favini P, Del Tacca M. Macrolide antibiotics as antiinflammatory agents: roxithromycin in an unexpected role. Agents Actions. 1993;38:1–2, 85–90.[Medline] [Order article via Infotrieve]
37.
Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi
AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and
serum amyloid A protein in severe unstable angina. N Engl
J Med. 1994;331:417–424.
38. Leinonen M. Pathogenetic mechanisms and epidemiology of Chlamydia pneumoniae. Eur Heart J. 1993;14(Suppl K):57–61.
39. Mégraud F. Epidemiology of Helicobacter pylori infection: where are we in 1995? Eur J Gastroenterol Hepatol. 1995;7:292–295.[Medline] [Order article via Infotrieve]
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 R. Tavendale, D. Parratt, S.D. Pringle, R. A'brook, and H. Tunstall-Pedoe Serological markers of Chlamydia pneumoniae infection in men and women and subsequent coronary events. The Scottish Heart Health Study Cohort Eur. Heart J., February 2, 2002; 23(4): 301 - 307. [Abstract] [Full Text] [PDF]
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 J. Boman and M. R. Hammerschlag Chlamydia pneumoniae and Atherosclerosis: Critical Assessment of Diagnostic Methods and Relevance to Treatment Studies Clin. Microbiol. Rev., January 1, 2002; 15(1): 1 - 20. [Abstract] [Full Text]
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S. C. Johnston, L. M. Messina, W. S. Browner, M. T. Lawton, C. Morris, and D. Dean C-Reactive Protein Levels and Viable Chlamydia pneumoniae in Carotid Artery Atherosclerosis Stroke, December 1, 2001; 32(12): 2748 - 2752. [Abstract] [Full Text] [PDF]
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 I. W. Fong Emerging relations between infectious diseases and coronary artery disease and atherosclerosis Can. Med. Assoc. J., July 1, 2000; 163(1): 49 - 56. [Abstract] [Full Text] [PDF]
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A.J. Camm and K.M. Fox Chlamydia pneumonia (and other infective agents) in atherosclerosis and acute coronary syndromes. How good is the evidence? Eur. Heart J., July 1, 2000; 21(13): 1046 - 1051. [PDF]
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 T. Quaschning and C. Wanner The role of Chlamydia in coronary heart disease--fact or fiction? Nephrol. Dial. Transplant., December 1, 1999; 14(12): 2800 - 2803. [Full Text] [PDF]
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A. Shor and J. I. Phillips Chlamydia pneumoniae and Atherosclerosis JAMA, December 1, 1999; 282(21): 2071 - 2073. [Full Text] [PDF]
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