Introduction
Despite better knowledge of the pathophysiology of atrial fibrillation(AF) [
1‐
17] and significant advances in ablation techniques [
18‐
26], its incidence is rising worldwide [
27], resulting in a dramatically increased social and economic burden on the healthcare system [
28‐
31].
The pathophysiology of AF is complex [
32] and it has been found to be associated with inflammation as well as other non-cardiac pathologies [
33‐
35]. Among these, gastrointestinal (GI) disorders share with AF some risk factors such as stress, smoking and inflammation as well as some common symptoms such as chest pain and faintness [
36] and they have often been described in association with AF [
37].
In particular,
Helicobacter pylori (HP) infection has been strongly linked to AF by previous studies leading to the hypothesis that HP could be the cause of AF through systemic inflammatory response [
37‐
39]. Nonetheless, this connection has been questioned by other authors and it is still matter of debate [
40,
41]. Furthermore, available metanalyses include other supra-ventricular arrhythmias other than AF [
42] or include other infections associated to AF [
39].
Therefore, to test the hypothesis whether there is a causal relation between AF and the infection of HP, we performed a systematic review and metanalysis of the studies published reporting this association.
Discussion
Helicobacter pylori is a Gram-negative bacterium affecting nearly half of the world’s population [
49], but only a small percentage of infected patients develop more severe pathologies, such as ulcers (10–15%) and stomach adenocarcinomas (less than 1%) [
57,
58].
The association between atrial fibrillation (AF) and
Helicobacter pylori (HP) infection was first reported by Montenero et al. in 2005 who found higher levels of IgG antibodies in patients with AF compared to healthy volunteers [
37].
This association was believed to be on an inflammatory basis and it has been postulated that the infection might be the substrate of the systemic inflammation manifesting in AF [
38]. Indeed, there is strong evidence to support the influence of inflammation in the pathogenesis of atrial fibrillation [
59] which is associated with increased levels of markers which reflect an underlying inflammatory process [
60]. Actually, the levels of high-sensitivity C-reactive protein (hs-CRP) have been shown to be higher among patients with AF compared with controls in sinus rhythm [
60] and the stronger association of HP and AF in patients with persistent AF [
37] along with the demonstration that persistent AF patients have higher hs-CRP levels than paroxysmal AF patients [
61], would further support the involvement of HP in the chronic atrial inflammation resulting in AF. However, in contrast with these authors, Marcus et al. [
62] failed to find any association between atrial fibrillation and all inflammatory indices (C-protein, TNF-alpha, CD40 ligand, monocyte chemoattractant protein 1, fibrinogen) excluding IL-6. A recent study [
63] has explained that the development of atrial cardiomyopathy, the results of complex of structural, architectural, contractile or electrophysiological changes affecting the atria, creates a substrate which can maintain AF. Nonetheless, not one specific risk factor but multiple concomitant modifiable cardiovascular risk factors determine the manifestation and progression of AF. Recent papers identify the alteration of the gut microbiota (dysbiosis) in most cardiovascular AF risk factors being responsible of AF progression through derived metabolites that affect atrial remodeling [
64,
65]. Nonetheless, whether and how dysbiosis might contribute to atrial remodeling and AF progression remains unknown.
Regarding the causal pathophysiologic mechanism, it has been postulated that, due to the similarity between H+/K+-ATPase of gastric and cardiac cells, autoantibodies to H+/K+-ATPase would hamper the ATP hydrolysis and that this unbalance would trigger AF by determining depolarization delay and inducing premature atrial contractions [
37].
The association of HP and AF was reported also by Whang et al. [
56] in a Chinese population of 285 patients and by Franceschi et al. [
55] who found an epidemiological link between HP and supraventricular dysrhythmias, including AF, and ventricular arrhythmias in 54 arrhythmic patients compared to 50 healthy controls. Finally, Bunch et al. [
52] found that patients with AF were more likely to be seropositive for HP than the non-AF-control group. Furthermore, these authors report that younger patients (< 50 years) showing a higher risk (8%) of AF of those who were HP seropositive. Interestingly, although the oldest group had the highest overall incidence of AF, there was, among them, only a small increase in risk if they were seropositive for HP.
However, the association between HP and AF has been strongly argued by other studies and available reviews and metanalyses have not helped to solve the matter because of their limitations [
39,
42].
For instance, Platonov et al. [
41] who have reported no significant association between atrial fibrillation and H. pylori infection in 72 patients with permanent AF compared 1:1 to controls, despite significantly higher levels of C-reactive proteins in these subjects. These authors stopped the patient recruitment for the study due to a constant reduction in differences between groups. In addition, Lunetta et al. [
40] showed only a small difference in developing AF between HP-positive and HP-negative subjects (21% vs. 18%) thus excluding that inflammation induced from HP might be responsible of new-onset AF.
Our analysis confirms these findings: indeed, the pooled HR was very close to one with a 11% risk difference that it can be easily influenced by other factors not analyzed by papers (sex, familiarity, obesity, race, etc.). Furthermore, we found a weak correlation between the infection of HP and the development of AF (coefficient = 0.05).
Therefore, from our data, it seems that there is no strong pathogenic link between the bacterial infection and the atrial arrhythmias. Hence, it seems more likely that remodeling and atrial damage lead to an increase in C-reactive protein rather than the opposite. This is also supported by the demonstration that such an increase occurs already at first AF onset and in paroxysmal AF [
66], thus apparently excluding any etiopathogenetic role of the HP.
However, if further studies confirm that HP is not responsible either for the initiation or the maintenance of AF, in accordance to our findings, the proposed eradication of HP infection as possible treatment for AF patients, proposed by some authors [
38], it would not be even an option for these patients not only for its low cost-effectiveness, but also for the risk to further spread antibiotic resistance.
However, when HP arrives in the human stomach, it may penetrate the mucin layer and adhere to the gastric epithelial cells or it may pass through the stomach without colonizing the mucosa. In the stomach, after initial colonization, many chemical, biochemical, and immunologic reactions take place that are of importance in the progress of the infection and the development of disease [
67].
In the major part of cases, infections are chronic, whereas acute
H. pylori disease, lasting for a few weeks, and characterized by abdominal pain and infiltration of polymorph nuclear leucocytes in the gastric mucosa, is rarely described [
67]. All papers included in this review reported HP-IgG-positivity, therefore we can assume that in all these patients B lymphocytes were activated by antigen-presenting cells and that a humoral immune response to
H. pylori was initiated as response to HP infection.
Finally, an interesting finding of our metanalysis is that, in contrast with previous papers [
42], the risk ratio of HP was not influenced by the geographic area. This difference might be due to the inclusion by these authors of one study including patients with idiopathic dysrhythmias, leading them to different conclusions. Said that our findings need to be read with caution since the small number of studies coming from Africa and America, these are not surprising. Indeed, the
H. pylori infection rate is higher in Asia and Africa than that in western countries, in relation to different standards of hygiene and socioeconomics [
5], whereas AF shows higher prevalence, disability-adjusted-life years (DALYs) and mortality in high-income countries than low-middle income and developing countries. This difference is significant, but it must be interpreted with caution since it might be related to under-reporting, limited access to health care services and geographically disparity in published data [
27,
68,
69].
Finally, the higher number of studies coming from western countries might justify the high AF prevalence reported (> 30%) and definitely higher than expected in the general population. However, inter-studies heterogeneity also regarding AF prevalence variability was addressed by the random-effect model used for metanalysis.
Study limitations
This metanalysis has some limitations that have to be pointed out.
Firstly, the number of studies is small, and all papers were case–control studies with high-degree of heterogeneity. Secondly, the number of studies in different geographic areas is too small to allow us to draw any final conclusion. Third, different diagnostic methods were employed for the diagnosis of HP infection and it is not reported if the infection is active. Fourth, only a few papers reported the analysis by AF type and this did not allow a subgroup analysis. Fifth, monitoring and detection of AF was not specified in the studies.