This document discusses the relationship between Helicobacter pylori infection and coronary artery disease. It begins with a review of infectious and non-infectious triggers of atherosclerosis. It then examines studies showing a relationship between H. pylori infection, especially strains expressing CagA, and markers of inflammation associated with increased risk of coronary artery disease. The document explores potential pathogenic mechanisms such as inflammatory responses, lipid modification, molecular mimicry of heat shock proteins, and hyperhomocysteinemia. It also notes findings of H. pylori DNA in atherosclerotic plaques and recommends treatment regimens to eradicate H. pylori infection.

1. HELICOBACTER PYLORI
and CORONARY ARTERY
DISEASE
PHUNG TRONG KIEN
MEDIC MEDICAL
CENTER

2. CONTENTS





Review.
Relation between H. pylori infection
and coronary artery disease.
Pathogenic mechanisms.
Treatment.
Conclusion.
2

3. REVIEW
INFLAMMATORY TRIGGERS OF
ATHEROSCLEROSIS:
 NON-INFECTIOUS :
- Modified lipoproteins (e,g: oxidized low-density lipoproteins).
- Diabetes.
- Hypertension (mechanical stress).
- Products of cigarette smoke.
- Sympatho-adrenal activation (physical, emotinal stress).
- Neuro-endocrine factors (increased angiotensin-II).
- Hyperhomocysteinemia.
- Renal insufficiency, uremic factors.
- Other inflammatory mediators, cytokines, oxidants.
(Jeffrey L. Anderson: The role of Infection, chapter 7, from Pierre Theroux’s
Acute coronary syndromes, page 89, Saunders (USA), copyright 2003.)
3

4. REVIEW
INFLAMMATORY TRIGGERS OF
ATHEROSCLEROSIS:
 VIRUSES:
- Cytomegalovirus.
- Herpes simplex virises (HSV-1, HSV-2).
- Epstein-Barr virus.
- Hepatitis A.
- Human immunodeficiency virus (HIV).
- Influenza.
 BACTERIA:
- Chlamydia pneumoniae.
- Helicobacter pylori.
- Priodontal disease (e.g Porphyromonas gingivalis, Streptococcus sanguis,
Streptococcus viridans).
- Mycoplasma pneumoniae.
- Hemophilus influenzae.
- Chronic bacterial respiratory, urinary, dental, other i nfections.
(Jeffrey L. Anderson: The role of Infection, chapter 7, from Pierre Theroux’ s
Acute coronary syndromes, page 89, Saunders (USA), copyright 2003.)
4

5. REVIEW
MOLECULAR AND CELLULAR MECHANISMS BY WHICH
NFECTIOUS AGENTS MAY PROMOTE
ATHEROSCLEROSIS:
 Stimulate inflammation:
- ↑Local and circulating inflammatory mediators:
+↑Chemokines, Cytokines, adhesion molecules.
+↑Matrix-degrading proteases.
- Pathogen (or pathogen-product) directed immune responses.
- Host-directed (auto-immune) responses (molecular mimickry).
 Lipid accumulalion:
- ↑Scavenger receptor activity.
- ↓Cholesterol esterase activity.
 Endothelial Dysfunction:
- Impaired vasodilator function.
- ↓Anticoagulant activity, ↑procoagulant effects.
 Smooth Muscle Cell (SMC) Accumulation:
- ↑SMC proliferation:
+ P53 inhibition.
+ Growth factor/ receptor expression.
- ↑SMC migration.
- ↓SMC apoptosis:
+ P53 inhibition. (Jeffrey L. Anderson: The role of Infection, chapter 7, from Pierre Theroux’ s
Acute coronary syndromes, page 96, Saunders (USA), copyright 2003.)
5

6. REVIEW
6

7. REVIEW
(http://www.numarkpharmacists.com/emis/PILSL/gif/112.gif)
7

8. REVIEW
(http://vbs.ac.vn/upload/news/H_pylori_virulence_factors_en.png)
8

9. REVIEW
Helicobacter pylori:
 Helicobacter pylori is a gram-negative
microaerophilic bacillus. It measures 0.5 mm to 1.0
mm in diameter by 2.5 mm to 5.0 mm long. It requires
an atmosphere of 5% O2 and 5% to 10% CO2 .
 Its morphology is heterogeneous: it can take a
helicoidal, spiral, or curved shape, with 2 to 6 flagella.
In aged cultures it tends to present in coccoid form.
 It products a urease that, via the production of
ammonia, creates a microenvironment with a pH
greater than that of gastric mucous, allowing it to
survive.
9

10. REVIEW
Helicobacter pylori:
 It is considered the etiopathogenic agent of
both benign and malignant gastro duodenal
disease. In fact, it has been classified as a
type 1 carcinogen by the World Health
Organization (WHO).
 In recent years it has been proposed
that H. pylori has a role in the
atherothrombotic process .
10

11. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE
 Case-control epidemiological
studies:
- Mendall M et al (Br Heart J 1994;71:437-9):
A greater prevalence of infection by H. pylori in patients with
coronary cardiopathy and in patients with cerebrovascular
ischemia.
- Pasceri et al (Circulation 1998;97:1675-9):
Revealed a greater prevalence of infection by strains of H.
pylori cagA+ in patients with coronary cardiopathy vs a control
group, while the prevalence of infection by strains of cagA–
did not reveal differences between the patients and the control
group.
11

12. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE
 Case-control epidemiological studies:
- Kowalski M, Konturek
JW et al [J Physiol
Pharmacol 1999; 50
( Suppl 2): A28]:
Frequency of the Hp
infection in patients with
coronariographically
confirmed CAD (one- to
three-vessel-disease and
PTCA or CABG in the past)
was significantly higher than
in the healthy population of
similar age and gender.
12

13. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE

The seroprevalence of H. pylori and
markers of inflammatory processes:
- Niemëla et al (Heart 1996;75:573-5):
Found significant differences between triglyceride and HDL
values among seropositive and seronegative subjects vs H.
pylori.
- Patel et al (BMJ 1995;311:711-4):
Found a significant increase in fibrinogen in seropositive
patients, but did not find differences in the plasma cholesterol or
triglyceride values.
- Ossei-Gerning N et al (Cardiovasc Res 1997;35:1204):
Factor VII has also been studied, but no significant differences
have been found among patients seropositive for H. pylori with
regard to those who were seronegative.
13

14. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE

The seroprevalence of H. pylori and
markers of inflammatory processes:
- Rengström et al (J Int Med 1998;243:109-13):
Did not observe significant differences in plasma fibrinogen,
cholesterol, or triglyceride levels among seropositive and
seronegative patients.
- Liuzzo G et al (N Engl J Med 1994;331:417-24.),
Yarnell J et al (Circulation 1991; 83:836-44) and Xu
Q, Willeit J et al (Lancet 1993;341:255-9):
Some markers of inflammation are associated with a greater
risk of coronary cardiopathy or a worse prognosis, such as C
reactive protein, white blood cell count, plasma fibrinogen or
the presence of heat shock proteins (hsp ).
14

15. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE
 The seroprevalence of H. pylori and
markers of inflammatory processes:
- Patel P et al (BMJ 1995;311:711-4):
Comparison of patients seropositive for H. pylori with seronegative
patients: found a significant elevation in the white blood cell count..
- Birnie D et al (Eur Heart J 1998;19:387-94):
Detected an hsp increase 60/65; and the elevation of C reactive
protein has been associated with a worse prognosis in patients with
unstable angina or recent myocardial infarction.
- Regnström J et al (J Int Med 1998;243:109-13):
The association of coronary cardiopathy with TNF-α values, but
statistically significant differences have not been detected.
15

16. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE
 Presence of H. pylori in atheromatous
plaques:
(Studies have been performed using the polymerase chain reaction
(PCR) to detect ADN of H. pylori in the tissues analyzed):
Cunningham et al (Rev Esp Cardiol 2002; 55(6):652-6 ):
Found the presence of H. pylori in atheromatous plaques.
- Gunn M et al (Heart 2000; 84: 267-271):
+ The significantly higher detection of Hp DNA in considerable
number of atherosclerotic plaques in CagA-positive patients.
+ The H.pylori with CagA-positive may be higher virulent factor to
atherosclerotic plaques.
-
16

17. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE
c
Carotid atherosclerotic
plaques:
Immunostaining for H
pylori, original
magnification 1000:
A, Immunodetection of
the bacillus in
subendothelial clefts.
B, Immunodetection of
the bacillus in the
endothelial lumina.
C, Immunodetection of
ICAM-1 in the cytoplasm
of endothelial cells is
shown.
(http://stroke.ahajournals.org/content/32/2/385.full)
17

18. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE
 Presence of H. pylori in atheromatous
plaques:
- Kowalski M (J Physiol Pharmacol. 2001 Aug; 52 (1 Suppl
1):3-31):
Identification of Hp DNA in atherosclerotic plaques of patients with
severe CAD supports the hypothesis that infection with H. pylori
(especially CagA positive) may influence the development of
atherosclerosis.
- Francesch F et al (Atherosclerosis. 2009 Feb; 202(2):53542. Epub 2008 Jul 3):
Anti-CagA antibodies recognized antigens localized inside coronary
atherosclerotic plaques in all specimens from both stable and
unstable angina patients.
18

19. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE
Detection of
Hp specific
DNA in human
atheromatous
coronary
artery plaques
of patients
with and
without Hp
infection.
[Kowalski M: Helicobacter pylori (H. pylori) infection in coronary
artery disease, Physiol Pharmacol 2001; 52 (Suppl. 1): 3-31)] .
19

20. RELATION BETWEEN H. PYLORI
INFECTION
AND CORONARY ARTERY DISEASE
Mean coronary
artery lumen
reduction (%),
six months after
PTCA with stent
in patients:
- Hp-CagA (+)
(subgroup a)
- Hp-CagA (-)
(subgroup b)
- Hp IgG (-)
(subgroup c).
[Kowalski M: Helicobacter pylori (H. pylori) infection in coronary
artery disease, Physiol Pharmacol 2001; 52 (Suppl. 1): 3-31)] .
20

21. PATHOGENIC
MECHANISMS
 Inflammatory response:
- Crabtree J et al (Gut 1991; 32:1473-7), Fong I et al (J Clin
Microbiol 1997; 35:48-52), Mendall M et al (Heart 1997;
78:273-7):
Changes in some cardiovascular risks factors: coagulation and lipid
factors, ↑fibrinogen, ↑C-RP, ↑TNF-α, ↑IL-6, ↑WBC (→ Prothrombotic
state).
- Ernst P et al (Gastroenterology 1997; 113: S 35-42):
Presence of neutrophils, T lymphocytes, plasma cells and a response
that is as much cellular as it is humural.
- Ossei-Gerning N et al (Cardiovasc Res 1997; 35:120-4),
Bamford K et al (Gastroenterology 1998; 114:482-92):
Specific cellular response: ↑helper-1 lymphocytes → IL-1, IL-6, IL-8,
TNF- α, interferon ɣ.
21

22. PATHOGENIC
MECHANISMS
 Inflammatory response:
- Kalia N et al (Gut 1997; 41:748-52):
Soluble extracts of H. pylori promote platelet aggregation in the
microcirculation.
- Yamaoka Y et al (Gut 1997; 41:442-51):
CagA(+) H.pylori produce a greater variety of cytokines.
- Abdelmouttaleb et al (Am Heart J 1999; 137: 346-351),
Gasbarrini et al
(Ital J Gastroenterol Hepatol 1998; 30: 115-118 ) and Stone
et al (Digest Liver Dis 2000; 32: 62-64 ):
Reported that the host immune response to the bacteria colonizing the
stomach may play an important role in the pathogenesis of vascular
disorders, probably through the action of various vasoactive substances,
such as cytokines, eicosanoids and others.
22

23. PATHOGENIC
MECHANISMS
(http://gut.bmj.com/content/45/suppl_1/I9/F1.large.jpg)
23

24. PATHOGENIC MECHANISMS
 Modification of blood lipids:
- Ellis R et al (J Med Micriobiol 1997; 46:535-9),
Niemelä S et al (Heart 1996;75:573-5: H.pylori
infection induces:
+↑cholesterol and triglyceride levels.
+↓ HDL cholesterol.
 Crossed reactivity with anti-hsp
antibodies:
- Birnie D et al (Eur Heart J 1998; 19:387-94):
H. pylori produces anti-heat shock protein (60 kDa)
similar to human 60 kDa hsp expressed by the
24

25. PATHOGENIC MECHANISMS

Hyperhomocysteinemi
a:
- Clarke R et al (N Engl J
Med 1991; 324:1149-55),
Bunout B et al (Med Chil
1998; 126:905-10),
Markle H (Med
Hypotheses 1997; 49:28992):
H. pylori infection → ↓
absorption vitamin B12 and
folate →
hyperhomocysteinemia. (J J Y Sung, J E Sanderson: Hyperhomocysteinaemia, Helicobacter
pylon, and coronary heart disease, Heart 1996;76:305-307).
25

26. PATHOGENIC MECHANISMS
 Formation of oxidants:
Ellis R et al ( J Med Micriobiol 1997; 46:535-9):
H. pylori →↓ antioxidants → lipid peroxidation →
atherogenesis.
 Socio-economic level:
Nilsson P et al (Scand J Soc Med 1995;23:3-8),
Mendall M et al (Lancet 1992;339:896-7):
+ A greater prevalence of coronary cardiopathy and
cardiovascular events in people at a lower socio-economic
levels.
+ Hp Infected patients is in socio-economic level lower than
in Hp non-infected patients.
26

27. TREATMENT
Eradicatio
n
treatment
(N Engl J Med, Vol. 347, No. 15 · October 10, 2002 · www.nejm.org)
27

28. TREATMENT
Regimens recommended for eradication of H.pylori
infection.
Drug
Dose
Triple therapy:
1. Bismuth subsalicylate (Pepto-Bismol) plus
Eradicatio
n
treatment
2 tablets qid
Metronidazole plus
Tetracycline
250 mg qid
500 mg qid
(a)
2. Ranitidine bismuth citrate plus
400 mg bid
Tetracycline plus
500 mg bid
Clarithromycin or metronidazole
500 mg bid
3. Omeprazol (lansoprazole)
20 mg (30 mg) daily
Clarithromycin plus
250 or 500 mg bid
Metronidazole (b) or
500 mg bid
Amoxicillin (c )
Quadruple therapy
1000 mg bid
Omeprazole (lansoprazole)
20 mg (30 mg) daily
Bismuth subsalicylate (Pepto-Bismol)
2 tablets qid
Metronidazole
250 mg qid
Tetracycline
: Alternative: use prepacked Helidac.
500 mg qid
(a)
(b)
: Alternative: use prepacked Prevpac.
: Use either metronidazole internal medicine, 17
(Harrison’ s Principles of or amoxicilline, not both.
(c)
Pepto-Bismol: 525 mg (tablet).
th
edition, 2008, page 1863 ).
28

29. TREATMENT
Substance
Evidence
Effect
Vitamin C
in vitro; in vivo
↓ H. pylori
(gerbils; humans)
α-Linolenic, Linoleic,
γ-Linolenic,
(humans – fish oil and
Eicosapentaenoic acids
Potential
Alternative
Treatments
for H. pylori
in vitro; in vivo
black currant seed oil)
Lactobacilli
in vitro; in vivo (mice)
↓ H. pylori
in vivo (humans)
↓ antibiotic side effects
in vitro
↑ antibiotic effects
↓ H. pylori
in vivo (humans)
↑ ulcer healing
in vitro
↓ H. pylori
in vivo (humans)
no results
in vitro;
↓ H. pylori
Mastic Gum
Garlic
Berberine
↓ H. pylori
in vivo (humans)
Flavonoids (various)
in vitro; in vivo
↓H. pylori
(Alan R. Gaby, MD: Alternative Medicine Review Volume 6, Number 4 2001).
29

30. TREATMENT
(G. Lester Tarbutton et al: The Journal of applied research, vol. 7, No. 1,
2007).
30

31. TREATMENT
The STAMINA trial (South Thames Trial of Antibiotics
in Myocardial Infarction and Unstable Angina)
(n=325, addressed both C pneumoniae and H pylori).
- Multiple drug therapy using amoxicillin for H pylori and
azithromycin for C pneumoniae, both combined with
metronidazole and omeprazole, were found to reduce
inflammatory markers. This included C-reactive protein (P=0.03)
and fibrinogen (P=0.06).
- At 12 weeks of follow up there was a 36% decrease (P=0.02)
in all end points (cardiac death, revascularization, and
readmission).
- At 1 year there continued to be a significant reduction in end
points of cardiac death or readmission with ACS.
31

32. TREATMENT
- Kowalski M (J Physiol Pharmacol 2001; 52
(Suppl. 1): 3-31):
+ Diameter of the coronary artery lumen six months after PTCA
was significantly different between the patients after the Hp
eradication therapy and those without such therapy.
+ The mean reduction in arterial lumen in Hp-eradicated patients
was about 22%, whereas in those non-eradicated about 41% and
this difference was statistically significant.
- Kowalski M, Konturek PC (Digest Liver Dis
2001; 33: 222-229):
The plasma proinflammatory cytokines:TNF-α, IL-1ß and IL-8,
were significantly attenuated after Hp eradication in patients with
PTCA suggests that the elimination of the inflammation could
contribute to the decline in restenosis mechanism.
32

33. TREATMENT
- Yusuf SW et al (Acta Cardiol
2002; 57: 317-322 ):
The plasma levels of fibrinogen was
significantly reduced after eradication.
- Konturek PC et al (J Physiol
Pharmacol 1999; 50: 695-710):
The plasma levels of fibrinogen, IL-8 and
LDL-cholesterol were significantly declined
after eradication, .
33

34. TREATMENT
Prophylactic vaccination:
- Several key bacterial factors have been identified:
urease, vacuolating cytotoxin, cytotoxin-associated antigen
(cag), the pathogenicity island, neutrophil-activating protein…
- These proteins, in their native or recombinant forms, have been
shown to confer protection against H. pylori in animal models.
- Nevertheless, a number of clinical trials (in healthy volunteers
have been used urease by oral) give limited results.
- Recently, a vaccine (mixture of H. pylori antigens with
aluminium hydroxide as an adjuvant) following intramuscular
administration in H. pylori -negative volunteers was reported to
be highly immunogenic.
- Data show that vaccination against H. pylori is still feasible.
More researches are required to have effective vaccine may be
used in the future.
34

35. CONCLUSION
1. H. pylori is a causal agent of several gastrointestinal diseases and has also been
implicated in coronary artery disease (CAD).
2. Several mechanisms are proposed for the role of H. pylori in CAD:
- H. pylori may act directly on atherosclerotic plaques, because studies have found its
DNA in arterial plaque.
- H. pylori causes in indirect effects to chronic inflammation whereby raises cytokine
levels in the bloodstream, thus it serves as a trigger of the inflammatory cascade.
- H. pylori may induce platelet aggregation, and thereby play a role in the acute phase
of CAD.
- Certain virulent strains of H. pylori (CagA positivity) may provoke an intense immune
response and precipitate coronary events.
3. Eradication therapy:
- Reduce inflammatory markers: C-reactive protein, fibrinogen, LDL-cholesterol,
cytokines: TNF-α, IL-1ß and IL-8…
- Reduce in arterial lumen loss and in all end points (cardiac death, revascularization,
and readmission).
4. Vaccines against H. pylori have still been researching to fulfil.
5. In the present, because of the number of studies still limit, to confirm certainly the
association between Hp infection and CAD, requires further studies with a large group
of patients.
35

36. CONCLUSION
Prediction from Paul
Ewald:
Microbiologist Paul Ewald
” Throughout history most
people have died of
infectious disease, and
most people continue to
die of infectious disease”.
36