 Abstract | | |
Helicobacter pylori (H. pylori) infection is an important cause of peptic ulcer disease and other gastrointestinal disorders. Since its discovery, a number of extra-gastrointestinal diseases have been reported to be associated with H. pylori infection. Recently, several epidemiological and clinical studies suggested that H. pylori infection has been associated with an increased risk of developing coronary artery disease (CAD). Evidence from animal studies showed that H. pylori plays an important role in the acute phase of myocardial infarction by causing platelet aggregation and inducing pro-coagulant activity in experimentally infected mice. However, results from human studies are conflicting in providing clear evidence for an association between H. pylori and CAD. Therefore, the aim of this article is to critically analyze the available evidence to prove or refute such an association Keywords: H. pylori, coronary artery disease.
How to cite this article:
Khalil MZ. The association of helicobacter pylori infection with coronary artery disease: Fact or fiction?. Saudi J Gastroenterol 2004;10:132-9 |
The work of Marshall and Warren on patients presenting for gastroscopy, has resulted in the identification of the gastric bacterium that was thought to be a new species related to the genus Campylobacter, and it was given the name Campylobacter pyloridis in 1982 [1] . The bacteria were present in almost all patients with active chronic gastritis, duodenal ulcer, or gastric ulcer and proved to be an important factor in the etiology of these diseases.
The interesting discovery of this bacterium has switched-on an active research. Further studies led to its reclassification as Helicobacter pylori  ri), which was first published in 1989 [2] . Ultimately, the understanding of peptic ulcer disease (PUD) has been enlightened by this organism and subsequently; the management of PUD involved the eradication of H. pylori. Researchers throughout the world focused on diseases related to this bug not only in gastroenterology, but also in other disciplines such as cardiology, neurology, and dermatology.
| The organism | |  |
H. pylori are gram-negative, unipolar, multiflagellate, microaerophilic, gently spiral or curved bacilli, measuring approximately 3.5 microns in length and 0.5 microns in width.
Despite being that small and tiny, its armory of urease, motility, spiral shape, flagella, mucolytic enzymes and ability to adhere to gastric epithelium are factors that allow it to survive and proliferate in the dangerous gastric milieu. Moreover, It's equipped with specific receptors that mediate adhesion to the gastric surface epithelium [3],[4],[5],[6],[7],[8] . Although H. pylori is a noninvasive organism, nonetheless, it stimulates an intense inflammatory and immune response that enhances antigen presentation to the lamina propria and facilitates immune stimulation. Consequently, there is increased production of inflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha (TNFa), and most notably, IL-8 [9],[10],[11],[12],[13] .
| Epidemiology | | |
Despite the epidemiological efforts made, the questions of when and how H. pylori originally entered the human population as well as how the infection is transmitted in different communities remains without a clear answer. However, it has been suggested that sheep may be a natural host for H. pylori [14] . Current epidemiologic evidence indicates most infections are acquired during childhood even in Western countries [15],[16] The prevalence of H. pylori among adult population in the Middle East was estimated to be in the range of 70 to 90% [17] . It is suggested that H. pylori may be hyper-endemic among Arab patients with dyspepsia [18] . Moreover, other factors that may increase the risk of H. pylori infection in Saudi Arabia are smoking, lower educational level, and older age [19],[20] .
| Associated illnesses | | |
Ironically, H pylori has been claimed to be associated with many illnesses, some of which are based on documented evidence, however, others are still debatable [Table - 1]. Among the most controversial associations is the link to coronary artery disease (CAD). The clinical implications of such association may reformulate the management strategy for CAD, particularly, in countries with high prevalence of H pylori.
| Infectious etiology of CAD | | |
Classical risk factors for CAD fail to account for all the epidemiological variants of the disease, thus warranting search for novel causal agents. The possible role of inflammation in CAD is being recognized, while markers of inflammation such as C reactive protein (CRP) and infection with Chlamydia pneumoniae (C. pneumoniae), cytomegalovirus (CMV) and H. pylori have been proposed as risk factors for CAD. The hypothesis of an infectious etiology to atherosclerosis in patients with CAD is suggested in a manner similar to gastric mucosal damage induced by H. pylori [22] .
Infectious agents such as CMV, hepatitis A virus, herpes simplex virus I and 2, C. pneumoniae and others were incriminated as possible causative factors in the pathogenesis of CAD, particularly, in the absence of known risk factors for CAD.
Therefore, variation in the prevalence of H. pylori is dominated by the great differences between communities in the incidence of H. pylori infection during childhood. Nonetheless, H. pylori has been described to be the most common chronic bacterial infection in humans [15],[21] .
Some workers reported that not only infection plays an important role in the incidence of myocardial infarction or death but also the risk posed by infection is independently related to the pathogen burden [23] . Moreover, the implication of such hypothesis will be supported by prognostic influence of H. pylori eradication in the treatment of CAD and prevention of restenosis after percutaneous translumenal coronary angioplasty (PTCA) [24],[25] .
| Evidence for association with CAD | | |
Recent study confirmed identification of H. pylori DNA in atherosclerotic plaques of patients with severe coronary artery disease, which supports the hypothesis that H. pylori infection may influence the development of atherosclerosis [26] . These findings may suggest an involvement of H.pylori in the progression and instability of plaques in these patients. Another study suggested that in younger individuals in Japan, H. pylori infection is significantly associated with acute myocardial infarction (AMI) independent of the classic coronary risk factors [27] . Furthermore, the hypothesis that intense humoral response in immunoglobulins (Ig) class G against H. pylori may play a role in the aggravation of symptoms of coronary atherosclerosis is supported by elevated titers of IgG anti-H. pylori in patients with unstable CAD [28] . H. pylori sero-positivity has shown to be correlated with acute-phase proteins associated with higher risk of coronary disease, such as C-reactive protein. This evidence may suggest that H. pylori infection could indirectly contribute to the development and severity of atherosclerosis and cardiovascular disease [29] . Moreover, a recent Japanese study tested the hypothesis that chronic atrophic gastritis induced by H. pylori causes malabsorption of vitamin B 12 and folate in food, leading ultimately to an increase in circulating homocysteine levels. The results of this study suggested that H.pylori-induced chronic atrophic gastritis decreases plasma vitamin B12 and folic acid levels, thereby increasing homocysteine levels, which is a known risk factor for atherosclerosis [30] . Experiments from animal studies demonstrated that H. pylori infection in mice induces the formation of platelet aggregates, making the role of H. pylori significant in the acute phase of myocardial infarction [31] . Therefore, the presented data argue for an evidence for association between H. pylori and CAD [Table - 2].
| Evidence against association with CAD | | |
Investigators looked at serological markers of infection with H. pylori in a group of patients with unstable angina pectoris (UA), however, no relationship was found between UA and H. pylori infection [32] . An interesting study, assessed whether infection with H. pylori is associated with decreased endothelial function, which was determined by flow-mediated brachial vasodilation. There was no association observed between chronic infection with H. pylori and endothelial function [33] . Although H. pylori infection increased the risk for MI, this association was modest and was not evident in non-smokers or when adjusted for education [34] . Furthermore, eradication of H. pylori infection does not appear to influence any changes of coronary risk factors, as reported by one study that compared sugar, lipid and fibrinolytic profiles before and after H. pylori eradication [35] . It has been shown that no benefit of treatment with antibiotics was observed in high-risk patients as reported by trials examining which treatment of infection can prevent the complications of coronary artery disease [36] . Moreover a British study showed no increase in H pylori sero-positivity in subjects with acute myocardial infarction indicating that previous H pylori infection is not a major risk factor for acute myocardial infarction [37] . In Saudi Arabia, where prevalence of H. pylori is reportedly high, no association was found between H. pylori infection and CAD [38] . Similar result was reported by other studies [39],[40],[41],[42]. Interestingly, H pylori sero-positivity was not associated with increased mean intimamedia thickness of the carotid artery, a measure of subclinical atherosclerosis, suggesting that H pylori infection is probably not an important contributor to clinical coronary heart disease events [43] . Further evidence showed that classical risk factors of CAD for patients admitted with acute MI did not differ with or without H. pylori infection [44] . [Table - 3] shows summary of evidence against the association between H pylori and CAD.
In conclusions: The relationship between H pylori and CAD may be due to confounding or co-linearity with socioeconomic status. Seropositivity to H. pylori is associated with a trend towards a greater prevalence of CAD. However, that association is likely to be spurious. Probably, the link between H. pylori infection and CAD, if found in a particular patient, is the vulnerability of that patient to both illnesses but not an association. There is evidence to suggest a relation of H pylori to CAD; nonetheless, eradication of H pylori has not translated into improved outcome of patients with CAD. Despite the strong evidence of a causal relation of H. pylori to PUD, current evidence is not sufficient to reach a verdict in the case of association with CAD.[62]
| References | | |
| 1. | Marshall BJ, Warren JR Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; 1: 1311-5.  |
| 2. | Goodwin CS, Worsley BW. Microbiology of Helicobacter pylori. Gastroenterol Clin North Am 1993; 22: 5-19. [PUBMED] |
| 3. | Wadstrom T, Hirmo S, Boren T. Biochemical aspects of Helicobacter pylori colonization of the human gastric mucosa. Aliment Pharmacol Ther 1996; 10: 17-27. |
| 4. | Logan RP. Adherence of Helicobacter pylori. Aliment Pharmacol Ther 1996; 10: 3-15. [PUBMED] |
| 5. | Rain JC, Selig L, De Reuse H, Battagalia V, Reverdy C, Simon S, et al. The protein-protein interaction map of Helicobacter pylori. Nature 2001; 409: 211-5. |
| 6. | Mobley HL. The role of Helicobacter pylori urease in the pathogenesis of gastritis and peptic ulceration. Aliment Pharmacol Ther 1996; 10: 57-64. [PUBMED] |
| 7. | Weeks DL, Eskandari S, Scott DR, Sachs GA. H+-gated urea channel: the link between Helicobacter pylori urease and gastric colonization. Science 2000; 287: 482-5. |
| 8. | Mobley HL. Defining Helicobacter pylori as a pathogen: Strain heterogeneity and virulence. Am J Med 1996; 100: 2S-9S. [PUBMED] |
| 9. | Crabtree JE. Gastric mucosal inflammatory responses to Helicobacter pylori. Aliment Pharmacol Ther 1996; 10: 29-37. [PUBMED] |
| 10. | Ernst PB, Jin Y, Reyes VE, Crowe SE. The role of the local immune response in the pathogenesis of peptic ulcer formation. Scand J Gastroenterol 1994; 29: 22-8. |
| 11. | Di Tommaso A, Xiang Z, Bugnoli M, Pileri P, Figura N, Bayeli PF, et al. Helicobacter pylorispecific CD4+ T-cell clones from peripheral blood and gastric biopsies. Infect Immun 1995; 63:1102-6. [PUBMED] [FULLTEXT] |
| 12. | Fan XG, Chau A, Fan XJ, Keeling PW. Increased gastric production of interleukin-8 and tumor necrosis factor in patients with Helicobacter pylori infection. J Clin Pathol 1995; 48: 133-6. |
| 13. | Crowe SE, Alvarez L, Dytoc M, Hunt RH, Muller M, Sherman P, et al. Expression of interleukin-8 and CD54 by human gastric epithelium after Helicobacter pylori infection in vitro. Gastroenterology 1995; 108: 65-74. [PUBMED] [FULLTEXT] |
| 14. | Dore MP, Sepulveda AR, El-Zimaity H, Yamaoka Y, Osato MS, Mototsugu K, et al. Isolation of Helicobacter pylori from sheepimplications for transmission to humans. Am J Gastroenterol 2001; 96:1396-401. [PUBMED] [FULLTEXT] |
| 15. | Pounder RE, Ng D. The prevalence of Helicobacter pylori infection in different countries. Aliment Pharmacol Ther 1995; 9: 33-9. |
| 16. | Parsormet J. The incidence of Helicobacter pylori infection. Aliment Pharmacol Ther 1995; 9: 45-51. |
| 17. | Novis BH, Gabay G, Naftali T. Helicobacter pylori: the Middle East scenario. Yale J Biol Med 1998; 71: 135-41. [PUBMED] |
| 18. | Rashed RS, Ayoola EA, Mofleh IA, Chowdhury MN, Mahmood K, Faleh FZ. Helicobacter pylori and dyspepsia in an Arab population. Trop Geogr Med 1992; 44: 304-7. [PUBMED] |
| 19. | Abdullah AM, Gad el Rab MO, Al Ayed I, Kambal AM, Al Sohaibani M, Al Mazyad AL. Helicobacter pylori infection in children in Saudi Arabia. Trop Gastroenterol. 1997; 18: 39-40. |
| 20. | Al-Moagel MA, Evans DG, Abdulghani ME, Adam E, Evans DJ Jr, Malaty HM, Graham DY. Prevalence of Helicobacter (formerly Campylobacter) pylori infection in Saudia Arabia, and comparison of those with and without upper gastrointestinal symptoms. Am Gastroenterol 1990; 85: 944-8. |
| 21. | Cave DR. Transmission and epidemiology of Helicobacter pylori. Am J Med 1996;100: 12-18. |
| 22. | Rupprecht HJ, Blankenberg S, Bickel C, Rippin G, Hafner G, Prellwitz W, et al. AutoGene Investigators. Impact of viral and bacterial infectious burden on long-term prognosis in, patients with coronary artery disease. Circulation 2001; 104: 25-31. |
| 23. | Zhu J, Nieto FJ, Horne BD, Anderson JL, Muhlestein JB, Epstein SE. Prospective study of pathogen burden and risk of myocardial infarction or death. Circulation 2001; 103: 45-51. [PUBMED] [FULLTEXT] |
| 24. | Kowalski M, Konturek -PC, Pieniazek P, Karczewska E, Kluczka A, Grove R, et al. Prevalence of Helicobacter pylori infection in coronary artery disease and effect of its eradication on coronary lumen reduction after percutaneous coronary angioplasty. Dig Liver Dis. 2001; 33: 214-6. |
| 25. | Kowalski M. Helicobacter pylori (H. pylori) infection in coronary artery disease: influence of H. pylori eradication on coronary artery lumen after percutaneous transluminal coronary angioplasty. The detection of H. pylori specific DNA in human coronary atherosclerotic plaque. J Physiol Pharmacol 2001; 52: 3-31. |
| 26. | Kowalski M, Rees W, Konturek PC, Grove R, Scheffold T, Meixner H, et al. Detection of Helicobacter pylori specific DNA in human atheromatous coronary arteries and its association to prior myocardial infarction and unstable angina. Dig Liver Dis. 2002; 34: 398-402. |
| 27. | Kinjo K, Sato H, Sato H, Shiotani I, Kurotobi T, Ohnishi Y, et al. Prevalence of Helicobacter pylori infection and its link to coronary risk factors in Japanese patients with acute myocardial infarction. Circ J. 2002; 66: 805-10. |
| 28. | Rechcinski T, Kasprzak JD, Chmiela M, Krzeminska-Pakula M, Rudnicka W. Patients with unstable angina pectoris present increased humoral response against Helicobacter pylori in comparison with patients with aggravated dyspepsia. Acta Microbiol Pol. 2002; 51: 339-44. |
| 29. | Martinez Torres A, Martinez Gaensly M. Helicobacter pylori: a new cardiovascular risk factor? Rev Esp Cardiol. 2002; 55: 652-6. |
| 30. | Tamura A, Fujioka T, Nasu M. Relation of Helicobacter pylori infection to plasma vitamin B12, folic acid, and homocysteine levels in patients who underwent diagnostic coronary arteriography. Am J Gastroenterol. 2002; 97: 861-6. |
| 31. | Pellicano R, Oliaro E, Mangiardi L, Orzan F, Bergerone S, Gandolfo N, et al. Ischemic cardiovascular diseases. Correlation with Helicobacter pylori infection. Minerva Cardioangiol. 2000; 48: 467-73. |
| 32. | Altannavch TS, Roubalova K, Broz J, Hruba D, Andel M. Serological markers of Chlamydia pneumoniae, cytomegalovirus and Helicobacter pylori infection in diabetic and non-diabetic patients with unstable angina pectoris. Cent Eur J Public Health. 2003; 11: 102-6. |
| 33. | Khairy P, Rinfret S, Tardif JC, Marchand R, Shapiro S, Brophy J, et al. Absence of association between infectious agents and endothelial function in healthy young men. Circulation. 2003; 107:1966-71. |
| 34. | Witherell HL, Smith KL, Friedman GD, Ley C, Thom DH, Orentreich, et al. C-reactive protein, Helicobacter pylori, Chlamydia pneumoniae, cytomegalovirus and risk for myocardial infarction. Ann Epidemiol. 2003; 13: 170-7. |
| 35. | Lu YH, Yen HW, Lin TH, Huang CH, Lee KT, Wang WM, et al. Changes of coronary risk factors after eradication of Helicobacter pylori infection. Kaohsiung J Med Sci. 2002; 18: 266-72. |
| 36. | Frishman WH, Ismail AA. Role of infection in atherosclerosis and coronary artery disease: a new therapeutic target? Cardiol Rev. 2002;10: 199-210. |
| 37. | Rathbone B, Martin D, Stephens J, Thompson JR, Samani NJ. Helicobacter pylori seropositivity in subjects with acute myocardial infarction. Heart. 1996; 76: 308-11. |
| 38. | Al-Nozha MM, Khalil MZ, Al-Mofleh IA, AlGhamdi AS. Lack of association of coronary artery disease with H.pylori infection. Saudi Med J. 2003; 24: 1370-3. |
| 39. | Zhu J, Quyyumi AA, Muhlestein JB, Nieto FJ, Home BD, Zalles-Ganley A, et al. Lack of association of Helicobacter pylori infection with coronary artery disease and frequency of acute myocardial infarction or death. Am J Cardiol 2002; 89: 155-8. |
| 40. | Wald N J, Law M R, Morris J K, Bagnall A M. H. pylori infection and mortality from IHD: negative result from a large prospective study BMJ 1997; 015: 1199-1201. |
| 41. | Woodward M, Morrison C, McCol1 K. An investigation into factors associated with H. pylori infection. J Clin Epidemiol 2000; 53: 175-81. |
| 42. | Cammarota G, Pasceri V, Gasbarrini A, Gasbarrini G. Helicobacter pylori is an aetiological factor for ischaemic heart disease: the case against. Dig Liver Dis 2000; 32: 65-8. [PUBMED] |
| 43. | Folsom AR, Nieto FJ, Sorlie P, Chambless LE, Graham DY. Helicobacter pylori seropositivity and coronary heart disease incidence. Atherosclerosis Risk In Communities (ARIC) Study Investigators. Circulation. 1998; 98: 845-50. |
| 44. | Pellicano R, Parravicini PP, Bigi R,Gandolfo N, Aruta E, Gai V, et al. Infection by Helicobacter pylori and acute myocardial infarction. Do cytotoxic strains make a difference? New Microbiol. 2002; 25: 315-21. |
| 45. | Altannavch Ts, Roubalova K, Broz J, Hruba D, Andel M. Serological markers of Chlamydia pneumoniae, cytomegalovirus and Helicobacter pylori infection in diabetic and non-diabetic patients with unstable angina pectoris. Cent Eur J Public Health. 2003; 11: 102-6. |
| 46. | Moayyedi P, Carter AM, Braunholtz D, Catto AJ. Helicobacter pylori infection in subjects with acute ischaemic stroke. Dig Liver Dis. 2003; 35: 16-9. |
| 47. | Galloway PH, Warner SJ, Morshed MG, Mikelberg FS. Helicobacter pylori infection and the risk for open-angle glaucoma. Ophthalmology. 2003; 110: 2433-4 |
| 48. | Mavromichalis I. The role of Helicobacter pylori infection in migraine. Cephalalgia. 2002; 22: 222-5. |
| 49. | Gasbarrini A, De Luca A, Fiore G, Gambrielli M, Franceschi F, Ojetti V, et al. Beneficial effects of Helicobacter pylori eradication on migraine. Hepatogastroenterology. 1998; 45: 765-70. |
| 50. | Michel M, Cooper N, Jean C, Frissora C, Bussel JB. Does Helicobacter pylori initiate or perpetuate immune thrombocytopenic purpura? Blood. 2004; 103: 890-6. |
| 51. | Portnoi VA. Helicobacter pylori infection and anorexia of aging. Arch Intern Med. 1997; 157: 1771-3. |
| 52. | Kostaki M, Fessatou S, Karpathios T. Refractory iron-deficiency anaemia due to silent Helicobacter pylori gastritis in children. Eur J Pediatr. 2003; 162: 177-9. |
| 53. | Diaz C, O'Callaghan CJ, Khan A, Ilchyshyn A. Rosacea: a cutaneous marker of Helicobacter pylori infection? Results of a pilot study. Acta Derm Venereol. 2003; 83: 282-6. |
| 54. | Deron E, Kiec-Swierczynska M. The role of Helicobacter pyroli in the development of skin diseases. Med Pr. 2002; 53: 333-7. |
| 55. | Alcaraz CL, Escarcega BD, Castrejon VM, Galicia Tapia J, Cano Altamirano S, Angles Rivera JM, et al. Presence of anti-Helicobacter pylori, antithyroid, and high-affinity IgE receptor antibodies in patients with chronic urticaria. Rev Alerg Mex. 2003; 50: 96-102. |
| 56. | Rowland M, Drumm B. Helicobacter pylori and sudden-infant-death syndrome. Lancet. 2001; 357: 1981. |
| 57. | Kini D, Aggarwal R, Saraswat VA, Naik SR. Role of Helicobacter pylori infection in hyperammonemia and subclinical hepatic encephalopathy in cirrhosis of liver. Indian J Gastroenterol. 2001; 20: 237-40. [PUBMED] [FULLTEXT] |
| 58. | Suto H, Azuma T, Ito S, Ohtani M, Dojo M, Ito Y, et al. Helicobacter pylori infection induces hyperammonaemia in Mongolian gerbils with liver cirrhosis. Gut. 2001; 48: 590-1. |
| 59. | Vasconez C, Elizalde JI, Llach J, Gines A, De la Rosa C, Fernandez RM, et al. Helicobacter pylori, hyperammonemia and subclinical portosystemic encephalopathy: effects of eradication. J Hepatol. 1999; 30: 260-4. |
| 60. | Zullo A, Rinaldi V, Hassan C, Folino S, Winn S, Pinto G, et al. Helicobacter pylori and plasma ammonia levels in cirrhotics: role of urease inhibition by acetohydroxamic acid. Ital J Gastroenterol Hepatol. 1998; 30: 405-9. |
| 61. | Csiki Z, Gal I, Sebesi J, Szegedi G. Raynaud syndrome and eradication of Helicobacter pylori. Orv Hetil. 2000; 141: 2827-9. |
| 62. | Gasbarrini A, Massari I, Serricchio M, Tondi P, De Luca A, Franceschi F, et al. Helicobacter pylori eradication ameliorates primary Raynaud's phenomenon. Dig Dis Sci. 1998: 43: 1641-5. |
Correspondence Address:
Mohamed Zakaria Khalil
Department of Medicine, King Khalid University Hospital, P O Box 2925, Riyadh 11461
Saudi Arabia
 Source of Support: None, Conflict of Interest: None  | Check |
PMID: 19861836 
[Table - 1], [Table - 2], [Table - 3] |
