| 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  . 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  . 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 ,,,,, . 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 ,,,, .
| 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  . Current epidemiologic evidence indicates most infections are acquired during childhood even in Western countries , The prevalence of H. pylori among adult population in the Middle East was estimated to be in the range of 70 to 90%  . It is suggested that H. pylori may be hyper-endemic among Arab patients with dyspepsia  . Moreover, other factors that may increase the risk of H. pylori infection in Saudi Arabia are smoking, lower educational level, and older age , .
| 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  .
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 , .
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  . 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) , .
| 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  . 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  . 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  . 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  . 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  . 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  . 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  . 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  . 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  . 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  . 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  . 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  . In Saudi Arabia, where prevalence of H. pylori is reportedly high, no association was found between H. pylori infection and CAD  . Similar result was reported by other studies ,,,. 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  . Further evidence showed that classical risk factors of CAD for patients admitted with acute MI did not differ with or without H. pylori infection  . [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.
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Mohamed Zakaria Khalil
Department of Medicine, King Khalid University Hospital, P O Box 2925, Riyadh 11461
Source of Support: None, Conflict of Interest: None
[Table - 1], [Table - 2], [Table - 3]