This document summarizes findings from the Heart Outcomes Prevention Evaluation (HOPE) study regarding the relationship between various infections and subsequent cardiovascular events. The study analyzed antibodies to Chlamydia pneumoniae, H. Pylori, CMV, and hepatitis A virus in 3,168 patients over 4.5 years of follow up. While C. pneumoniae and H. Pylori antibodies did not correlate with cardiovascular risk, the presence of CMV antibodies was associated with a slightly higher risk. A total pathogen score based on levels of antibodies to all four infections predicted a higher risk of cardiovascular events compared to a score of zero or one.

1. Editorial Slides
VP Watch, January 29, 2003, Volume 4, Issue 4
What is the link between infection and cardiovascular events?

2.  A possible role for infections in
atherosclerosis has been intensely investigated
since the landmark demonstration of herpes
virus-induced atherosclerosis in chickens by
Fabricant in 19781
.

3.  Human atherosclerotic disease has been
associated with previous exposure to several
microorganisms including Chlamydia
pneumoniae, Porphyromonas gingivalis,
CMV, HSV-1, HSV-2, hepatitis A virus,
influenza virus, enterovirus, etc. Prospective
studies are, however, limited.

4. A relatively recent approach suggests that the total
pathologic burden is a stronger predictor of
cardiovascular events than any particular
infection2,3,4
.
 Large randomized trials of antibiotic for
secondary prevention of cardiovascular disease
have been performed or are ongoing5,6
but even
failure of those treatments should not be construed
as evidence that the infectious theories are
incorrect.

5.  As highlighted in VP Watch of this week,
Smieja et al7
, for the Heart Outcomes
Prevention Evaluation (HOPE) study,
analyzed sera from 3168 patients for
antibodies to Chlamydia pneumonia, H.
Pylori, CMV and hepatitis A and followed
the patients over 4.5 years of follow-up.

6. (Figure 1)

7. Figure 1 depicts a Kaplan- Meier plot for
cumulative cardiovascular events by titer
levels of C. pneumoniae IgG (A) and IgA(B).
No statistical significance was found.

8. (Figure 2)

9. Figure 2 depicts a Kaplan- Meier plot for
cumulative cardiovascular events by
presence or absence of antibody to H. pylori,
CMV, and HAV. Serology for CMV shows a
mild predictive correlation with
cardiovascular events with a hazard ratio
(HR) of 1.24.

10. (Figure 3)

11.  Figure 3 depicts a Kaplan-Meier plot for
cumulative cardiovascular events by total
pathogen score (C pneumoniae IgG 512 or
IgA 64; H pylori >40 AU; CMV >0.4
mIU/mL; and HAV >20 IU/mL). HR
compares total pathogen score of 4 versus 0
or 1 combined. A score of 4 had an
adjusted HR of 1.41 versus 0 or 1.

12.  Exposure to CMV but not C. pneumoniae,
H. pylori or HAV was associated with a
slight excess risk of subsequent
cardiovascular events (myocardial
infarction, stroke, cardiovascular death)
Conclusion

13.  Total pathogen score based on these 4
infections predicted an increase hazard of
cardiovascular events compared to the
presence of none or only one of these
infections.
Con’t

14. ReferencesReferences
1. Fabricant CG, Fabricant J, Litrenta MM, et al. Virus-
induced atherosclerosis. J Exp Med. 1978; 148: 335–340.
2. Zhu J, Nieto FJ, Horne BD, et al. Prospective study of
pathogen burden and risk of myocardial infarction or
death. Circulation. 2001; 103: 45–51.
3. Zhu J, Quyyumi AA, Norman JE, et al. Effects of total
pathogen burden on coronary artery disease risk and C-
reactive protein levels. Am J Cardiol. 2000; 85: 140–146
4. Rupprecht HJ, Blankenberg S, Bickel C, et al. Impact of
viral and bacterial infectious burden on long-term
prognosis in patients with coronary artery disease.
Circulation. 2001; 104: 25–31.

15. References
5. Dunne MW. Rationale, and design of a secondary
prevention trial of antibiotic use in patients after
myocardial infarction: the WIZARD (Weekly Intervention
with Zithromax [Azithromycin] for Atherosclerosis and Its
Related Disorders) Trial. J Infect Dis. 2000; 181 (suppl 3):
S572–S578.
6. Jackson LA. Description and status of the Azithromycin
and Coronary Events Study (ACES). J Infect Dis. 2000;
181 (suppl 3): S579–S581.
7. Smieja M, Gnarpe J, Lonn E, Gnarpe H, Olsson G, Yi
Q, Dzavik V, McQueen M, Yusuf S. Heart Outcomes
Prevention Evaluation (HOPE) Study Investigators.
Circulation 2003;107:251-7