This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Folsom, A. R. Articles by Graham, D. Y. Search for Related Content PubMed PubMed Citation Articles by Folsom, A. R. Articles by Graham, D. Y.

(Circulation. 1998;98:845-850.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Helicobacter pylori Seropositivity and Coronary Heart Disease Incidence

Aaron R. Folsom, MD; F. Javier Nieto, MD, PhD; Paul Sorlie, PhD; Lloyd E. Chambless, PhD; David Y. Graham, MD; ; for the Atherosclerosis Risk In Communities (ARIC) Study Investigators

From the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis (A.R.F.); School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Md (F.J.N.); National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, Md (P.S.); Collaborative Studies Coordinating Center, Chapel Hill, NC (L.E.C.); and Department of Medicine, Veterans Affairs Medical Center, Baylor College of Medicine, Houston, Tex (D.Y.G.).

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—Several epidemiological and clinical reports have suggested seropositivity for Helicobacter pylori may be a risk factor for coronary heart disease. However, there has been no prospective study of this association involving an ethnically diverse sample of middle-aged men and women.

Methods and Results—Using a prospective, case-cohort design, we determined H pylori seropositivity in relation to coronary heart disease incidence over a median follow-up period of 3.3 years among middle-aged men and women. There were 217 incident coronary heart disease cases and a cohort sample of 498. We determined H pylori antibody status by measuring IgG antibody to the high-molecular-weight cell-associated proteins of H pylori using a sensitive and specific ELISA. The prevalence of H pylori seropositivity was higher in blacks than whites, in those with less than high school education, in those with lower plasma pyridoxal 5'-phosphate and higher homocyst(e)ine concentrations, in those who did not use vitamin supplements, in those with higher fibrinogen levels, and in those seropositive for cytomegalovirus and herpes simplex type I (all P<0.05). The age-, sex-, race-, and field center–adjusted hazard ratio of coronary heart disease for H pylori seropositivity was 1.03 (95% CI=0.68 to 1.57). After adjustment for other risk factors, including fibrinogen, cytomegalovirus seropositivity, and herpes simplex type I seropositivity, the hazard ratio was 0.85 (95% CI=0.43 to 1.69). H pylori seropositivity also was not associated with increased mean intima-media thickness of the carotid artery, a measure of subclinical atherosclerosis.

Conclusions—H pylori infection is probably not an important contributor to clinical coronary heart disease events.

Key Words: Helicobacter pylori • coronary disease • epidemiology

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Almost half of the adult population has serological evidence of infection with Helicobacter pylori, a contributor to gastritis, peptic ulcer, and gastric cancers. In 1994, Mendall and colleagues¹ reported that H pylori seropositivity was twice as common in coronary heart disease (CHD) patients as in control subjects. Danesh et al² recently reviewed 20 full or preliminary reports on H pylori and CHD published during 1994 to 1996. They concluded that evidence for a causal association between H pylori and CHD was weak because many of the studies were small, did not use population-based samples, and did not control well for confounding variables. Most of the better-designed studies had odds ratios close to 1.0.

Several mechanisms have been proposed for how H pylori might increase CHD risk.² For example, Patel et al^{3 4 5} hypothesized that infection-related chronic inflammation from H pylori infection may increase CHD risk, because the CHD risk factors plasma fibrinogen, C-reactive protein, and blood leukocyte count have been elevated in seropositive subjects. Sung and Sanderson⁶ hypothesized but offered no data to prove that H pylori gastritis could cause a B vitamin deficiency, leading to hyperhomocysteinemia and thus increased risk of CHD. H pylori also can stimulate leukocyte procoagulant activity.⁷ However, 2 studies found no evidence of H pylori in the atherosclerotic plaques of abdominal aortic aneurysms⁸ or carotid arteries⁹ of patients who were seropositive for H pylori.

Only 4 prospective studies^{10 11 12 13} have examined whether H pylori seropositivity is associated with cardiovascular disease occurrence (Table 1). The CIs of the estimated relative risks in these studies have all included 1.0. To provide an additional prospective test of the H pylori and CHD hypothesis, using a large and diverse sample of middle-aged adults, we undertook a case-cohort analysis within the Atherosclerosis Risk In Communities (ARIC) study.

View this table: [in this window] [in a new window]   Table 1. Summary of Previous Prospective Epidemiological Studies of Helicobacter pylori and Cardiovascular Disease

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Study Population
The ARIC study¹⁴ is a longitudinal epidemiological study of cardiovascular disease. In 1987 through 1989, we used driver's license lists or residential sampling to recruit a population-based cohort of persons aged 45 to 64 years from Forsyth County, North Carolina; Jackson, Miss (blacks only); the northwest suburbs of Minneapolis, Minn; and Washington County, Maryland. We included all age-eligible individuals within selected households and excluded only those who were institutionalized, had definite plans to move soon, or could not visit the ARIC clinic for physical or cognitive reasons. Approximately 46% of eligible individuals in Jackson and 65% in the other 3 communities completed a home interview and clinic examination,¹⁵ yielding a total of 15 792 participants. We reexamined participants in 1990 to 1992 (93% of those still living returned for the examination) and in 1993 to 1995 (86% of the living returned). We also monitored the cohort for incident CHD events. All participants signed a consent form approved by human subjects research review committees at our institutions.

Baseline Measurements
Trained technicians measured blood pressure 3 times using a random-zero sphygmomanometer. We used the mean of the last 2 measurements for analysis. We expressed physical activity as a sport index ranging from 0 (low) to 5 (high).¹⁶ Technicians measured circumferences of the waist (umbilical level). We computed body mass index (kg/m²) from participants' weight and height in scrub suits. Technicians measured average carotid intima-media thickness using standardized B-mode ultrasonography.^{17 18} We defined prevalent CHD at baseline, for exclusion, as a reported history of a physician-diagnosed heart attack, prior myocardial infarction (MI) by ECG, prior cardiovascular surgery, or prior coronary angioplasty. ARIC also measured prior stroke or transient ischemic attack through a standardized interview.

Technicians drew fasting blood from an antecubital vein into vacuum tubes containing sodium citrate (hemostatic factors), EDTA (lipids, stored leukocytes), or a serum separator gel (glucose). They centrifuged the 2 anticoagulant tubes immediately, and the serum tube after clotting 30 to 45 minutes, at 3000g for 10 minutes at 4°C. They quickly froze aliquots at 70°C until analysis. Within a few weeks, ARIC investigators measured plasma fibrinogen,¹⁹ total cholesterol,²⁰ triglycerides,²¹ and HDL cholesterol²² and calculated LDL cholesterol.²³ We measured serum glucose by the hexokinase method and defined diabetes as fasting glucose 140 mg/dL, nonfasting glucose 200 mg/dL, a physician diagnosis of diabetes, or pharmacological treatment for diabetes. Laboratories in each community counted leukocytes by automated cell counters.

Ascertainment and Classification of Incident CHD Cases
We monitored each participant and identified²⁴ and included for this analysis CHD events that occurred between ARIC visit 1 and December 31, 1991. The median follow-up time was 3.3 years (maximum 5.1 years). We defined CHD incidence as (1) a definite or probable MI,²⁴ (2) ECG evidence²⁵ of a silent MI between the first 2 ARIC examinations, (3) a definite CHD death,²⁴ or (4) a coronary revascularization.

Cohort Sample and Analysis of Stored Baseline Samples
We used a case-cohort design for this analysis in which H pylori antibody status was determined only for CHD cases and a stratified random sample of the ARIC cohort. We defined 8 strata for sampling the cohort, based on age (2 levels), sex, and carotid intima-media thickness (2 levels). We did this because other analyses on this sample also focused on comparing thick versus thin carotid artery walls. To account for the sampling design in analyses, we weighted each observation by the inverse of the sampling fraction, thereby recreating the original frequency distribution of the strata in the entire cohort.

In 1995, after ARIC had identified the incident cases and cohort sample, technicians pulled these participants' baseline samples, frozen in 1987 to 1989. The sera for this study had been thawed previously for other assays. We have considerable experience that shows that freeze-thawing up to 6 cycles does not affect H pylori antibody titers (D.Y.G., unpublished data, 1997). We measured IgG antibody to the high-molecular-weight cell-associated proteins of H pylori using an ELISA (HM-CAP, EPI) that has a sensitivity and specificity of 95%.^{26 27 28} There is no cross-reactivity with Campylobacter jejuni or other common human pathogens. On the basis of 33 random serum specimens that were split, masked, and analyzed for the present study, laboratory agreement on H pylori seropositivity (positive versus negative) was 88% (ie, 29 of 33 agreed). Two of the 4 disagreements were in the uncertain area of the assay (typically 2% are in this uncertain area).

We also measured antibodies to cytomegalovirus (CMV) and herpes simplex virus (HSV) type I^{29 30} and IgG titers to Chlamydia pneumoniae.^{31 32} We measured homocyst(e)ine using high-pressure liquid chromatography and electrochemical detection.^{33 34 35} We measured plasma folate and vitamin B₁₂ by the Quantiphase II Radioassay (Bio-Rad Diagnostics Group) and pyridoxal 5'-phosphate using a radioenzymatic assay supplied by Bühlmann Laboratories AG through American Laboratory Products.

Data Analysis
Before analysis, we excluded participants identified as having prevalent CHD, stroke, or transient ischemic attack. We did not exclude 6.7% of participants who were positive for angina by the Rose questionnaire³⁶ (or for whom information to assess angina was missing) because the validity of the questionnaire, especially in women, has been questioned.³⁷ We also excluded 109 of 814 participants with missing H pylori antibody measurements because of insufficient sample. Those with antibody data present (n=705) versus missing were similar (P>0.05) on all but 3 of the characteristics in Table 2. Blacks were less likely to have missing antibody measurements than were other participants (5% versus 16%); hypertensives were less likely than were normotensives (8% versus 15%); and those with carotid intima-media thickness 1 mm were less likely than were those with values <1 mm (0% versus 12%).

View this table: [in this window] [in a new window]   Table 2. Prevalence of Helicobacter pylori Seropositivity by Risk Factor Strata in the Cohort Random Sample, ARIC

We first used logistic regression to compute the age-, race-, sex-, and field center–adjusted prevalence of H pylori seropositivity for CHD cases and noncases after appropriate weighting for the stratified random sampling design and then computed a weighted average of these to get an estimate for the full cohort, weighting by the cohort disease probability. To determine the relation of seropositivity with other risk factors, we computed its prevalence according to categories of risk variables. We computed hazard ratios (HRs) and 95% CIs of CHD in relation to categories of study variables using a weighted proportional hazards regression, accounting for the case-cohort design and the stratified random sampling by Barlow's method.³⁸ This method weights each sampling stratum so that the estimated model coefficients approximate those that would have arisen from the full cohort and also accounts for the sampling scheme in computing the variance of the estimators of the coefficients. Covariates used in an initial model were age (continuous), sex, race (blacks, whites), and ARIC field center. We then adjusted for potentially confounding factors, that is, major risk factors or risk factors associated with H pylori antibody status: education (< high school graduate, high school graduate), smoking status (never, former, current), vitamin supplementation (yes, no), total cholesterol (continuous), waist circumference (continuous), systolic blood pressure (continuous), and use of antihypertensive medication (yes, no). We then adjusted for factors that might be on the causal path between H pylori infection and CHD to determine if their inclusion was consistent with this possibility: fibrinogen (continuous), plasma pyridoxal 5'-phosphate (continuous), and homocyst(e)ine (continuous). Finally, to be sure any association for H pylori was not due to generally increased infection rates, we adjusted for 2 other markers of chronic infections potentially related to CHD in this cohort³⁰ : CMV seropositivity (yes, no) and HSV type I seropositivity (yes, no). We tested 4 hypothesized interactions (H pylori seropositivity by age, race, sex, and fibrinogen level) by entering cross product terms into the regression models.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The sample included 217 incident CHD cases (27 fatal, 190 nonfatal) and a cohort stratified random sample of 498 (of whom 10 were also CHD cases). The age-, race-, sex-, and field center–adjusted prevalence of H pylori seropositivity was identical in CHD cases and the ARIC cohort itself (51%, P=0.95).

As Table 2 shows, the prevalence of H pylori seropositivity was higher in blacks than whites, in those with less than high school education, in those with lower plasma pyridoxal 5'-phosphate and higher homocyst(e)ine concentrations, in nonusers of vitamin supplements, in those with higher fibrinogen levels, and in those who were seropositive for CMV and HSV type I (all P<0.05). When vitamin supplement users were excluded, H pylori seropositivity was still higher in those with homocyst(e)ine levels 15 versus <15 µmol/L (79% versus 52%, P=0.06) and in those with plasma pyridoxal 5'-phosphate <10 versus 10 nmol/L (75% versus 52%, P=0.03). H pylori seropositivity was not statistically significantly associated with the other major CHD risk factors and specifically was not associated with baseline carotid intima-media thickness.

Adjusted for age, sex, race, and field center (Table 3), the HR of CHD in relation to H pylori seropositivity (yes versus no) was 1.03 (95% CI=0.68 to 1.57). The HR for fatal CHD events was 1.42 (0.63 to 3.25). There was no statistically significant association when estimated separately for men (HR=0.92) or women (HR=1.26) or when estimated separately by age group (not shown) or race (HR=1.03 for both blacks and whites). Correspondingly, the tests of interactions of H pylori seropositivity by age, race, and sex were not significant.

View this table: [in this window] [in a new window]   Table 3. Hazard Ratio (HR) of CHD in Relation to Helicobacter pylori Seropositivity, ARIC

After additional adjustment for education level, smoking status, vitamin use, waist circumference, systolic blood pressure, and use of antihypertensive medications (Table 3), CHD incidence was still not statistically significantly associated with H pylori seropositivity (HR=0.97, 95% CI=0.52 to 1.78). The covariate that reduced the HR the most (from 1.03 to 0.97) was smoking. Additional adjustment for factors potentially on the causal pathway [fibrinogen, plasma pyridoxal 5'-phosphate, and homocyst(e)ine] yielded an HR of 0.90 (95% CI=0.45 to 1.80). Of these added covariates, fibrinogen adjustment had the biggest impact on the HR. There was no evidence of a statistical interaction between fibrinogen and H pylori seropositivity in relation to CHD incidence. After further adjustment for CMV and HSV type I seropositivity, H pylori seropositivity was still not associated with CHD (HR=0.85, 95% CI=0.43 to 1.69).

Because our blind duplicate assessment suggested the measurement of H pylori status had a 12% misclassification rate (see Methods), we estimated the potential effect of this misclassification on the HR estimates. Assuming the misclassification was independent and random,³⁹ we estimated that the age-, race-, and sex-adjusted HR was biased toward the null value of 1.0 by 5%. Thus, laboratory measurement error does not seem to explain the lack of association between H pylori seropositivity and CHD incidence.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We found little evidence in this prospective study that H pylori seropositivity was associated with CHD incidence. The overall HR after accounting for other CHD risk factors was 0.97, although the CI for this estimate was wide (between 0.52 and 1.78). H pylori seropositivity also was not materially associated with increased baseline carotid intima-media thickness, a measure of subclinical carotid atherosclerosis. Thus, despite suggestive evidence from some cross-sectional and clinical reports^{1 2} and plausible mechanisms,^{2 3 4 5 6 7} this and other prospective studies (Table 1) have failed to confirm an association of H pylori and CHD. The fact that studies of better design and more complete control of confounders do not find an independent association between H pylori and CHD suggests that bias may explain the positive reports.

The higher H pylori seropositivity among blacks, those with less formal education, nonusers of vitamin supplements, and those seropositive for CMV and HSV type I is consistent with epidemiological studies showing that infection is higher in those who are socioeconomically disadvantaged.^{40 41 42} Higher seropositivity with lower plasma pyridoxal 5'-phosphate and higher homocyst(e)ine concentrations is partly consistent with Sung and Sanderson's hypothesis of H pylori gastritis causing a vitamin deficiency,⁶ although it is not clear why there was not also an association with plasma folate and vitamin B₁₂. The positive association of H pylori seropositivity with fibrinogen, reported previously^{4 42} but not uniformly,^{13 42 43} may be the result of H pylori infection or confounding by the many other correlates of fibrinogen.⁴⁴ If H pylori infection indeed elevates fibrinogen, then statistical adjustment for fibrinogen would be overadjustment. However, we included fibrinogen in some regression models to see if it attenuated the HR, as would be expected from a factor in the causal path. It had a minor impact and did not alter the conclusion that H pylori was not appreciably associated with CHD in the cohort.

Some investigators have reported H pylori seropositivity may be increased in patients with diabetes.^{45 46 47} However, our population-based results offer no evidence for this (Table 2).

Drawbacks of the present study are its relatively short follow-up (median of 3.3 years) and its inability to distinguish whether H pylori infection was current or only in the past. As a result, we may have missed an association between H pylori and CHD if it was very weak or if H pylori was involved primarily in early atherogenesis. This study nevertheless is one of the largest studies on H pylori and CHD to date and one of the few to include women and participants of African descent.

Although H pylori could still be a contributor to coronary atherosclerosis but not to acute coronary events, our study examining the carotid artery ultrasonographically and pathology studies of the aorta⁸ and carotid⁹ found no link between H pylori and atherosclerosis. Considering all available evidence, we agree with Danesh et al² that existing evidence suggests H pylori infection is probably not an important contributor to CHD.

	Acknowledgments

 
The ARIC Study was funded by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 from the US National Heart, Lung, and Blood Institute. The authors thank Drs Michael Osato, M. René Malinow, David Hess, Thomas Grayston, and Ervin Adam for laboratory measurements; Laura Kemmis and Joy Liao for technical assistance on this manuscript; and the following staff for important contributions to ARIC: Phyllis Johnson, Marilyn Knowles, and Catherine Paton from the University of North Carolina, Chapel Hill, NC; Amy Haire, Kim Jones, Delilah Posey, and Dawn Scott from the University of North Carolina, Forsyth County, North Carolina; Agnes Hayes, Jane Johnson, Penny Lowery, and Patricia Martin from the University of Mississippi Medical Center, Jackson; Laurie Wormuth, Virginia Wyum, Karen Birkholz, and Dot Buckingham from the University of Minnesota, Minneapolis; Patricia Hawbaker, Joel Hill, Kathleen Hunt, and Mary Hurt from Johns Hopkins University, Baltimore, Md; Valarie Stinson, Pam Pfile, Hogan Pham, and Teri Trevino from the University of Texas Medical School, Houston; Wanda Alexander, Doris Harper, Charles Rhodes, and Selma Soyal from the Methodist Hospital, Atherosclerosis Clinical Laboratory, Houston, Tex; Kelli Collins, Delilah Cook, Bob Ellison, and Julie Fleshman from the Bowman-Gray School of Medicine, Ultrasound Reading Center, Winston-Salem, NC; and Lily Wang, Climmon Walker, Kiduk Yang, and Ding-Yi Zhao from the ARIC Coordinating Center, University of North Carolina, Chapel Hill.

	Footnotes

 
Reprint requests to Aaron R. Folsom, MD, Division of Epidemiology, School of Public Health, University of Minnesota, Suite 300, 1300 S Second St, Minneapolis, MN 55454-1015.

Received February 10, 1998; revision received April 16, 1998; accepted April 20, 1998.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Mendall MA, Goggin PM, Molineaux N, Levy J, Toosy T, Strachan D, Camm AJ, Northfield TC. Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J. 1994;71:437–439.[Abstract/Free Full Text]
   
2. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: Is there a link? Lancet. 1997;350:430–436.[Medline] [Order article via Infotrieve]
   
3. Patel P, Mendall MA, Carrington D, Strachan DP, Leatham E, Molineaux N, Levy J, Blakeston C, Seymour CA, Camm AJ, Northfield TC. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ. 1995;311:711–714.[Abstract/Free Full Text]
   
4. Patel P, Carrington D, Strachan DP, Leatham E, Goggin P, Northfield TC, Mendall MA. Fibrinogen: a link between chronic infection and coronary heart disease. Lancet. 1994;343:1634–1635.[Medline] [Order article via Infotrieve]
   
5. Mendall MA, Patel P, Ballam L, Strachan D, Northfield TC. C Reactive protein and its relation to cardiovascular risk factors: a population-based cross-sectional study. BMJ. 1996;312:1061–1065.[Abstract/Free Full Text]
   
6. Sung JJY, Sanderson JE. Hyperhomocysteinaemia, Helicobacter pylori, and coronary heart disease. Heart. 1996;76:305–307.[Abstract/Free Full Text]
   
7. Miragliotta G, Del Prete R, Mosca A. Helicobacter pylori infection and coronary heart disease. Lancet. 1994;344:751. Comment.[Medline] [Order article via Infotrieve]
   
8. Blasi F, Ranzi ML, Erba M, Tarsia P, Raccanelli R, Fagetti L, Allegra L. No evidence for the presence of Helicobacter pylori in atherosclerotic plaques in abdominal aortic aneurysm specimens. Atherosclerosis. 1996;126:339–340.[Medline] [Order article via Infotrieve]
   
9. Chiu B, Viira E, Tucker W, Fong IW. Chlamydia pneumoniae, cytomegalovirus, and herpes simplex virus in atherosclerosis of the carotid artery. Circulation. 1997;96:2144–2148.[Abstract/Free Full Text]
   
10. Whincup PH, Mendall MA, Perry IJ, Strachan DP, Walker M. Prospective relations between Helicobacter pylori infection, coronary heart disease, and stroke in middle-aged men. Heart. 1996;75:568–572.[Abstract/Free Full Text]
    
11. Strandberg TE, Tilvis RS, Vuoristo M, Lindroos M, Kosunen TU. Prospective study of Helicobacter pylori seropositivity and cardiovascular diseases in a general elderly population. BMJ. 1997;314:1317–1318.[Free Full Text]
    
12. Aromaa A, Knekt P, Reunanen A, Rautelin HI, Kosunen TU. Helicobacter infection and the risk of myocardial infarction. Gut. 1996;39(suppl 2):A91. Abstract.
    
13. 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.[Abstract/Free Full Text]
    
14. The ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am J Epidemiol. 1989;129:687–702.[Abstract/Free Full Text]
    
15. Jackson R, Chambless LE, Yang K, Byrne T, Watson R, Folsom A, Shahar E, Kalsbeek W. Differences between respondents and nonrespondents in a multicenter community-based study vary by gender and ethnicity. J Clin Epidemiol. 1996;49:1441–1446.[Medline] [Order article via Infotrieve]
    
16. Baecke JAH, Burema J, Frijters JER. A short questionnaire for the measurement of habitual physical activity in epidemiological studies. Am J Clin Nutr. 1982;36:936–942.[Abstract/Free Full Text]
    
17. Bond MG, Barnes R, Riley WA, Wilmoth SK, Chambless LE, Howard G, Owens B. High resolution B-mode ultrasound scanning methods in the Atherosclerosis Risk in Communities Study (ARIC). J Neuroimaging. 1991;1:68–73.[Medline] [Order article via Infotrieve]
    
18. Riley WA, Barnes R, Bond MG, Evans GW, Chambless L, Heiss G. High resolution B-mode ultrasound reading methods in the Atherosclerosis Risk in Communities Study (ARIC). J Neuroimaging. 1991;1:168–172.[Medline] [Order article via Infotrieve]
    
19. Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol. 1957;17:237–246.[Medline] [Order article via Infotrieve]
    
20. Siedel J, Hegele EO, Ziegenhorn J, Wahlefeld AW. Reagent for the enzymatic determination of total serum cholesterol with improved lipolytic efficiency. Clin Chem. 1983;29:1075–1080.[Abstract/Free Full Text]
    
21. Nagele U, Hagele EO, Sauer G, Wiedemann E, Lehmann P, Wahlefeld AW, Gruber W. Reagent for the enzymatic determination of serum total triglycerides with improved lipolytic efficiency. J Clin Chem Clin Biochem. 1984;22:165–174.[Medline] [Order article via Infotrieve]
    
22. Warnick GR, Benderson JM, Albers JJ. Quantitation of high-density-lipoprotein subclasses after separation by dextran sulfate and Mg²⁺ precipitation. Clin Chem. 1982;28:1574. Abstract.
    
23. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499–502.[Abstract]
    
24. White AD, Folsom AR, Chambless LE, Sharrett AR, Yang K, Conwill D, Higgins M, Williams OD, Tyroler HA. Community surveillance of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) Study: methods and initial two years' experience. J Clin Epidemiol. 1996;49:223–233.[Medline] [Order article via Infotrieve]
    
25. Prineas RJ, Crow RS, Blackburn H. The Minnesota Code Manual of Electrocardiographic Findings: Standards and Procedures for Measurement and Classification. Littleton, Mass: John Wright; 1982.
    
26. Evans DJ Jr, Evans DG, Graham DY, Klein PD. A sensitive and specific serologic test for detection of Campylobacter pylori infection. Gastroenterology. 1989;96:1004–1008.[Medline] [Order article via Infotrieve]
    
27. Graham DY, Evans DJ Jr, Peacock J, Baker JT, Schrier WH. Comparison of rapid serologic tests (FlexSure HP and QuickVue) with conventional ELISA for detection of Helicobacter pylori infection. Am J Gastroenterol. 1996;91:942–948.[Medline] [Order article via Infotrieve]
    
28. Marchildon PA, Ciota LM, Zamaniyan FZ, Peacock JS, Graham DY. Evaluation of three commercial enzyme immunoassays compared to the C-13 urea breath test for detection of Helicobacter pylori infection. J Clin Microbiol. 1996;34:1147–1152.[Abstract]
    
29. Melnick JL, Petrie BL, Dreesman GR, Burek J, McCollum CH, DeBakey ME. Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet. 1983;2:644–647.[Medline] [Order article via Infotrieve]
    
30. Sorlie PD, Adam E, Melnick SL, Folsom A, Skelton T, Chambless LE, Barnes R, Melnick JL. Cytomegalovirus/herpes virus and carotid atherosclerosis: the ARIC study. J Med Virol. 1994;42:33–37.[Medline] [Order article via Infotrieve]
    
31. Grayston JT, Kuo C, Wang S, Altman J. A new Chlamydia psittaci strain, TWAR, isolated in acute respiratory tract infections. N Engl J Med. 1986;315:161–168.[Abstract]
    
32. Melnick SL, Shahar E, Folsom AR, Grayston JT, Sorlie PD, Wang SP, Szklo M, for the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Past infection by Chlamydia pneumoniae strain TWAR and asymptomatic carotid atherosclerosis. Am J Med. 1993;95:499–504.[Medline] [Order article via Infotrieve]
    
33. Smolin LA, Schneider JA. Measurement of total plasma cysteamine using high-performance liquid chromatography with electrochemical detection. Anal Biochem. 1988;168:374–379.[Medline] [Order article via Infotrieve]
    
34. Malinow MR, Kang SS, Taylor LM, Wong PWK, Coull B, Inahara T, Mukerjee D, Sexton G, Upson B. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation. 1989;79:1180–1188.[Abstract/Free Full Text]
    
35. Malinow MR, Sexton G, Averbuch M, Grossman M, Wilson D, Upson G. Homocyst(e)inemia in daily practice: levels in coronary artery disease. Coron Artery Dis. 1990;1:215–220.
    
36. Rose GA, Blackburn H, Gillum RF, Prineas RJ. Cardiovascular Survey Methods. 2nd ed. Basel, Switzerland: World Health Organization; 1982. World Health Organization monograph series 56.
    
37. Garber CE, Carleton RA, Heller GV. Comparison of "Rose Questionnaire Angina" to exercise thallium scintigraphy: different findings in males and females. J Clin Epidemiol. 1992;45:715–720.[Medline] [Order article via Infotrieve]
    
38. Barlow WE. Robust variance estimation for the case-cohort design. Biometrics. 1994;50:1064–1072.[Medline] [Order article via Infotrieve]
    
39. Thomas D, Stram D, Dwyer J. Exposure measurement error: influence on exposure-disease: relationships and methods of correction. Annu Rev Public Health. 1993;14:69–93.[Medline] [Order article via Infotrieve]
    
40. Mendell MA, Goggin PM, Molineaux N, Levy J, Toosy T, Strachan D, Northfield TC. Childhood living conditions and Helicobacter pylori seropositivity in adult life. Lancet. 1992;339:986–987.[Medline] [Order article via Infotrieve]
    
41. Whitaker CJ, Dubiel AJ, Galpin OP. Social and geographical risk factors in Helicobacter pylori infection. Epidemiol Infect. 1993;111:63–70.[Medline] [Order article via Infotrieve]
    
42. Murray LJ, Bamford KB, 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.[Abstract/Free Full Text]
    
43. Parente F, Maconi G, Imbesi V, Sangaletti O, Poggio M, Rossi E, Duca P, Porro GB. Helicobacter pylori infection and coagulation in healthy people. BMJ. 1997;314:1318–1319.[Free Full Text]
    
44. Folsom AR, Wu KK, Davis CE, Conlan MG, Sorlie PD, Szklo M, for the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors. Atherosclerosis. 1991;91:191–205.[Medline] [Order article via Infotrieve]
    
45. Oldenburg B, Diepersloot RJA, Hoekstra JBL. High seroprevalence of Helicobacter pylori in diabetes mellitus patients. Dig Dis Sci. 1996;41:458–461.[Medline] [Order article via Infotrieve]
    
46. Perdichizzi G, Bottari M, Pallio S, Fera MT, Carbone M, Barresi G. Gastric infection by Helicobacter pylori and antral gastritis in hyperglycemic obese and in diabetic subjects. Microbiologica. 1996;19:149–154.[Medline] [Order article via Infotrieve]
    
47. Kojecky V, Roubalik J, Bartonikova N. Helicobacter pylori in patients with diabetes mellitus. Vnitr Lek. 1993;39:581–584.[Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				R Tsuru, H Kondo, Y Hojo, M Gama, O Mizuno, T Katsuki, K Shimada, M Kikuchi, and T Yashiro Increased granzyme B production from peripheral blood mononuclear cells in patients with acute coronary syndrome Heart, March 1, 2008; 94(3): 305 - 310. [Abstract] [Full Text] [PDF]

				C. Espinola-Klein, S. Blankenberg, and T. Munzel Editorial Comment--Is Heme Oxygenase-1 a Causal Player for Plaque Stability? Stroke, September 1, 2005; 36(9): 1901 - 1903. [Full Text] [PDF]

				M. Ihrig, M. T. Whary, C. A. Dangler, and J. G. Fox Gastric Helicobacter Infection Induces a Th2 Phenotype but Does Not Elevate Serum Cholesterol in Mice Lacking Inducible Nitric Oxide Synthase Infect. Immun., March 1, 2005; 73(3): 1664 - 1670. [Abstract] [Full Text] [PDF]

				A. W. Haider, P. W. F. Wilson, M. G. Larson, J. C. Evans, E. L. Michelson, P. A. Wolf, C. J. O'Donnell, and D. Levy The association of seropositivity to Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus with risk of cardiovascular disease: A prospective study J. Am. Coll. Cardiol., October 16, 2002; 40(8): 1408 - 1413. [Abstract] [Full Text] [PDF]

				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]

				J. E Roeters van Lennep, H.T. Westerveld, D.W. Erkelens, and E. E van der Wall Risk factors for coronary heart disease: implications of gender Cardiovasc Res, February 15, 2002; 53(3): 538 - 549. [Abstract] [Full Text] [PDF]

				L. Y Lee, W. DeBois, K. H Krieger, L. N Girardi, L. Russo, J. McVey, W. Ko, N. K Altorki, R. A Brodman, and O W. Isom The effects of platelet inhibitors on blood use in cardiac surgery Perfusion, January 1, 2002; 17(1): 33 - 37. [Abstract] [PDF]

				A. Galante, A. Pietroiusti, M. Vellini, P. Piccolo, G. Possati, M. De Bonis, R. L. Grillo, C. Fontana, and C. Favalli C-reactive protein is increased in patients with degenerative aortic valvular stenosis J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1078 - 1082. [Abstract] [Full Text] [PDF]

				P. M. Ridker, J. Danesh, L. Youngman, R. Collins, M. J. Stampfer, R. Peto, and C. H. Hennekens A Prospective Study of Helicobacter pylori Seropositivity and the Risk for Future Myocardial Infarction among Socioeconomically Similar U.S. Men Ann Intern Med, August 7, 2001; 135(3): 184 - 188. [Abstract] [Full Text] [PDF]

				S. Kiechl, G. Egger, M. Mayr, C. J. Wiedermann, E. Bonora, F. Oberhollenzer, M. Muggeo, Q. Xu, G. Wick, W. Poewe, et al. Chronic Infections and the Risk of Carotid Atherosclerosis : Prospective Results From a Large Population Study Circulation, February 27, 2001; 103(8): 1064 - 1070. [Abstract] [Full Text] [PDF]

				D J Dedman, D Gunnell, G D. Smith, and S Frankel Childhood housing conditions and later mortality in the Boyd Orr cohort J. Epidemiol. Community Health, January 1, 2001; 55(1): 10 - 15. [Abstract] [Full Text] [PDF]

				S A Morre, W Stooker, W K Lagrand, A J C van den Brule, and H W M Niessen Microorganisms in the aetiology of atherosclerosis J. Clin. Pathol., September 1, 2000; 53(9): 647 - 654. [Abstract] [Full Text] [PDF]

				C. Espinola-Klein, H.-J. Rupprecht, S. Blankenberg, C. Bickel, H. Kopp, G. Rippin, G. Hafner, U. Pfeifer, and J. Meyer Are Morphological or Functional Changes in the Carotid Artery Wall Associated With Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus, or Herpes Simplex Virus Infection? Stroke, September 1, 2000; 31(9): 2127 - 2133. [Abstract] [Full Text] [PDF]

				S. C. Silvestry and P. K. Smith Current status of cardiac surgery in the abciximab-treated patient Ann. Thorac. Surg., August 1, 2000; 70(2): S12 - 19. [Abstract] [Full Text] [PDF]

				J. H. Lemmer Jr Clinical experience in coronary bypass surgery for abciximab-treated patients Ann. Thorac. Surg., August 1, 2000; 70(2): S33 - 37. [Abstract] [Full Text] [PDF]

				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]

				P. Whincup, J. Danesh, M. Walker, L. Lennon, A. Thomson, P. Appleby, C. Hawkey, and J. Atherton Prospective Study of Potentially Virulent Strains of Helicobacter pylori and Coronary Heart Disease in Middle-Aged Men Circulation, April 11, 2000; 101(14): 1647 - 1652. [Abstract] [Full Text] [PDF]

				W. Koenig, D. Rothenbacher, A. Hoffmeister, M. Miller, G. Bode, G. Adler, V. Hombach, W. Marz, M. B. Pepys, and H. Brenner Infection With Helicobacter pylori Is Not a Major Independent Risk Factor for Stable Coronary Heart Disease : Lack of a Role of Cytotoxin-Associated Protein A-Positive Strains and Absence of a Systemic Inflammatory Response Circulation, December 7, 1999; 100(23): 2326 - 2331. [Abstract] [Full Text] [PDF]

				A. W. Haider, M. Luna, S. Patel, J. M. Gaziano, L. Glenn, L. M. Golub, R. A. Greenwald, R. W. Thompson, D. L. Hahn, M. R. Hammerschlag, et al. Antibiotic Use and Risk of Myocardial Infarction JAMA, December 1, 1999; 282(21): 1997 - 1999. [Full Text] [PDF]

				J P Pell, J Sirel, A K Marsden, and S M Cobbe Seasonal variations in out of hospital cardiopulmonary arrest Heart, December 1, 1999; 82(6): 680 - 683. [Abstract] [Full Text]

				P. M. Ridker, C. H. Hennekens, J. E. Buring, R. Kundsin, and J. Shih Baseline IgG Antibody Titers to Chlamydia pneumoniae, Helicobacter pylori, Herpes Simplex Virus, and Cytomegalovirus and the Risk for Cardiovascular Disease in Women Ann Intern Med, October 19, 1999; 131(8): 573 - 577. [Abstract] [Full Text] [PDF]

				P.-Y. Lovey, A. Morabia, D Bleed, O Péter, G Dupuis, and J Petite Long term vascular complications of Coxiella burnetii infection in Switzerland: cohort study BMJ, July 31, 1999; 319(7205): 284 - 286. [Abstract] [Full Text]

				S. E. Epstein, Y. F. Zhou, and J. Zhu Infection and Atherosclerosis : Emerging Mechanistic Paradigms Circulation, July 27, 1999; 100 (4): e20 - e28. [Abstract] [Full Text] [PDF]

				*H. pylori* Probably Does Not Cause Coronary Disease Journal Watch (General), September 15, 1998; 1998(915): 2 - 2. [Full Text]

				F. Mach, G. K. Sukhova, M. Michetti, P. Libby, and P. Michetti Influence of Helicobacter pylori Infection During Atherogenesis In Vivo in Mice Circ. Res., January 11, 2002; 90 (1): e1 - e4. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF)