Shifts in gut microbiome and metabolome are associated with risk of recurrent atrial fibrillation.

Alternations of gut microbiota (GM) in atrial fibrillation (AF) with elevated diversity, perturbed composition and function have been described previously. The current work aimed to assess the association of GM composition with AF recurrence (RAF) after ablation based on metagenomic sequencing and metabolomic analyses and to construct a GM-based predictive model for RAF. Compared with non-AF controls (50 individuals), GM composition and metabolomic profile were significantly altered between patients with recurrent AF (17 individuals) and non-RAF group (23 individuals). Notably, discriminative taxa between the non-RAF and RAF groups, including the families Nitrosomonadaceae and Lentisphaeraceae, the genera Marinitoga and Rufibacter and the species Faecalibacterium spCAG:82, Bacillus gobiensis and Desulfobacterales bacterium PC51MH44, were selected to construct a taxonomic scoring system based on LASSO analysis. After incorporating the clinical factors of RAF, taxonomic score retained a significant association with RAF incidence (HR = 2.647, P = .041). An elevated AUC (0.954) and positive NRI (1.5601) for predicting RAF compared with traditional clinical scoring (AUC = 0.6918) were obtained. The GM-based taxonomic scoring system theoretically improves the model performance, and the nomogram and decision curve analysis validated the clinical value of the predicting model. These data provide novel possibility that incorporating the GM factor into future recurrent risk stratification.

Disordered gut microbiota and alterations in metabolic patterns are associated with atrial fibrillation.

BACKGROUND: With the establishment of the heart-gut axis concept, accumulating studies suggest that the gut microbiome plays an important role in the pathogenesis of cardiovascular diseases. Yet, little evidence has been reported in characterizing the gut microbiota shift in atrial fibrillation. METHODS: We include the result of the global alterations that occur in the intestinal microbiota in a cohort of 50 patients with atrial fibrillation and 50 matched controls based on a strategy of metagenomic and metabolomic analyses. RESULTS: The alterations include a dramatic elevation in microbial diversity and a specific perturbation of gut microbiota composition. Overgrowth of Ruminococcus, Streptococcus, and Enterococcus, as well as reduction of Faecalibacterium, Alistipes, Oscillibacter, and Bilophila were detected in patients with atrial fibrillation. A gut microbial function imbalance and correlated metabolic pattern changes were observed with atrial fibrillation in both fecal and serum samples. The differential gut microbiome signatures could be used to identify patients with atrial fibrillation. CONCLUSIONS: Our findings characterize the disordered gut microbiota and microbial metabolite profiles in atrial fibrillation. Further research could determine whether intervention strategies targeting intestinal microbiome composition might be useful to counteract the progression of atrial fibrillation.

Potential Impact of Oral Inflammations on Cardiac Functions and Atrial Fibrillation.

Inflammation may be a risk factor for atrial fibrillation (AF). Oral infections frequently lead to chronic inflammation, such as gingivitis, periodontitis, and endodontic lesions. In this narrative review, we consider five basic pathogenic mechanisms that involve oral infections and inflammations in the pathogenesis of AF: (1) low level bacteremia by which oral bacteria enter the blood stream at inflamed sites of the oral cavity and invade the heart; (2) Systemic inflammation induced by inflammatory mediators, which are released from the sites of oral inflammation into the blood stream, affecting cardiac remodeling; (3) autoimmunity against molecular structures expressed in the heart caused by the host immune response to specific components of oral pathogens; (4) potentially arrhythmic effects mediated by activation of the autonomous nervous system triggered by oral inflammations; and (5) arrhythmic effects resulting from specific bacterial toxins that are produced by oral pathogenic bacteria. A number of studies support the involvement of all five mechanisms, suggesting a potentially complex contribution of oral inflammations to the pathogenesis of AF.

Cause-Specific Mortality in Patients with Chronic Kidney Disease and Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with death in patients with chronic kidney disease (CKD). We examined the associations between AF and cause-specific mortality in a large CKD population. METHODS: We included 62,459 patients with estimated glomerular filtration rate 15-59 mL/min/1.73 m2 (6,639 patients with AF and 55,820 without AF) followed in a large health care system. Outcomes included overall and cause-specific deaths (a) cardiovascular; (b) malignancy; and (c) non-cardiovascular/non-malignancy causes. Cox regression models for overall mortality and separate competing risk models for each major cause of death category were used to evaluate their respective associations with AF. RESULTS: During a median follow-up of 4.1 years, 19,094 patients died; cause of death was known for 18,854 patients. After multivariable adjustment (demographics, comorbidities, relevant laboratory data, medication use, and kidney function), AF was associated with 23% (95% CI 18-29%) higher risk of all-cause mortality, 45% (95% CI 31-61%) higher risk of cardiovascular mortality and 13% (95% CI 3-22%) lower risk of malignancy-related mortality. Exclusion of patients with malignancy yielded similar results except for a lack of association between AF and malignancy-related deaths. Results were consistent across various stages of CKD. CONCLUSIONS: In a non-dialysis-dependent CKD population, the presence of AF was associated with higher all-cause and cardiovascular mortality. These data suggest that patients with both CKD and AF are at high cardiovascular risk, and thus clinical practice (or trials) should aim at reducing the overall excess cardiovascular mortality (not stroke alone) in patients with AF and CKD.

Gut-Derived Serum Lipopolysaccharide is Associated With Enhanced Risk of Major Adverse Cardiovascular Events in Atrial Fibrillation: Effect of Adherence to Mediterranean Diet.

BACKGROUND: Gut microbiota is emerging as a novel risk factor for atherothrombosis, but the predictive role of gut-derived lipopolysaccharide (LPS) is unknown. We analyzed (1) the association between LPS and major adverse cardiovascular events (MACE) in atrial fibrillation (AF) and (2) its relationship with adherence to a Mediterranean diet (Med-diet). METHODS AND RESULTS: This was a prospective single-center study including 912 AF patients treated with vitamin K antagonists (3716 patient-years). The primary end point was a composite of MACE. Baseline serum LPS, adherence to Med-diet (n=704), and urinary excretion of 11-dehydro-thromboxane B2 (TxB2, n=852) were investigated. Mean age was 73.5 years; 42.9% were women. A total of 187 MACE (5.0% per year) occurred: 54, 59, and 74 in the first, second, and third tertile of LPS, respectively (log-rank test P=0.004). Log-LPS (hazard ratio 1.194, P=0.009), age (hazard ratio 1.083, P<0.001), and previous cerebrovascular (hazard ratio 1.634, P=0.004) and cardiac events (hazard ratio 1.822, P<0.001) were predictors of MACE. In the whole cohort, AF (versus sinus rhythm) (ß 0.087, P=0.014) and low-density lipoprotein cholesterol (ß 0.069, P=0.049) were associated with circulating LPS. Furthermore, Med-diet score (ß -0.137, P<0.001) was predictive of log-LPS, with fruits (ß -0.083, P=0.030) and legumes (ß -0.120, P=0.002) negatively associated with log-LPS levels. Log-LPS and log-TxB2 were highly correlated (r=0.598, P<0.001). Log-LPS (ß 0.574, P<0.001) and Med-diet score (ß -0.218, P<0.001) were significantly associated with baseline urinary excretion of TxB2. CONCLUSIONS: In this cohort of AF patients, LPS levels were predictive of MACE and negatively affected by high adherence to Med-diet. LPS may contribute to MACE incidence in AF by increasing platelet activation.

Unusual cause of upper gastrointestinal bleed, when OGD could be fatal.

A 57-year-old man presented with chest pain, dyspnoea and coffee grounds emesis. He was haemodynamically stable without significant drop in haemoglobin. He suddenly developed cardiac arrest with wide complex tachycardia and became comatose. CT scan of the head revealed pneumocephalus and multiple infarcts. Given the recent history of radiofrequency ablation for atrial fibrillation, atrio-oesophageal fistula (AOF) was suspected. CT angiography of the thorax showed a 5 mm diverticulum on the posterior wall of the left atrium, also raising suspicion for AOF. The patient was taken to the operating room. An AOF was found and repaired. He did not have any further gastrointestinal bleeding. There was no neurological recovery at day 11 and life support was withdrawn per his family's request. This case highlights the importance of obtaining history of recent cardiac procedures in patients presenting with an upper gastrointestinal bleed. An oesophagogastroduodenoscopy in this patient could have been instantaneously deadly.

Using new non-invasive quick method to detect Borrelia Burgdorferi (B.B.) infection from specific parts of the heart in "seemingly normal" ECGs, and from the ECGs of Atrial Fibrillation (AF), a majority of AF ECGs are found to have: 1) Significant B.B. infection, 2) Markedly increased ANP, 3) Increased Cardiac Troponin I & 4) Markedly reduced Taurine. These 4 factors were mainly localized at infected areas of the SA node area, R-&L-Atria & pulmonary veins at the L-atrium.

Lyme disease is found in a majority of people we tested. Once Borrelia Burgdorferi (B.B.) spirochete enters human body, it not only causes pain by infecting joints, but it also often enters the brain and the heart. Infection of brain can be quickly detected from the pupil and infection of the heart by ECGs non-invasively. By evaluating recorded ECGs of atrial fibrillation (AF), using U.S. patented non-invasive highly sensitive electromagnetic field (EMF) resonance phenomenon between 2 identical molecules or between a molecule and its antibody, we examined 25 different AF patients' ECGs and found the majority of them suffer from various degrees of B.B. spirochete infection in SA node areas, also in the right & left atria, and pulmonary vein near and around its junction at left atrium & lesser degrees of infection at the AV node & His Bundle. When B.B. infection reaches over 224-600ng or higher at these areas, AF often appears in the majority of all AF analyzed. In order to develop AF, the 4 abnormal factors must be present simultaneously: 1) B.B. infection must be increased to 224-600ng or higher, 2) Atrial Natriuretic Peptide (ANP) must be markedly reduced from normal value of less than 4ng to over 100-400ng, 3) A significant increase of Cardiac Troponin I from normal value of less than 3ng to over 12ng and 4) Taurine must also be markedly reduced from normal value of 4-6ng to 0.25ng. These 4 changes were mainly found only at infected sites of the SA node area, both atria and between the end of the T wave & the beginning of the SA node area, which corresponds to U waves at recorded ECG. Origin of the U wave is mainly due to abnormal electrical potential of pulmonary vein at L-atrium. If all 4 factors do not occur at the infection site, no AF will develop. In seemingly normal ECGs, if using this method, one can detect invisible B.B. infection in early stages. Long before AF appears, AF can be prevented by improved treatment with Amoxicillin 500ng 3 times/day + Taurine 175mg x 3 times/day, with or without EPA 180 mg & DHA 120 mg, to avoid serious current limitations in the use of Doxycycline 100 mg 2 times/day, for 4 weeks.

[Immune status of patients with persistent atrial fibrillation and coronary heart disease].

We estimated the strength of immune response to chlamydial infection in patients with CHD. It was most pronounced in CHD patients with atrial fibrillation (AF). There was close relationship between past chlamydial infection and markers of inflammation (CRP and TNF-alpha). The study demonstrated high prognostic value of these markers for the development of AF during CHD and their relationship with characteristics of structural and functional remodeling of myocardium during CHD with AF. The study confirmed the role of inflammation in pathogenesis of AF in CHD patients.

Cardiac involvement in leptospirosis.

Leptospirosis is a neglected global disease with significant morbidity and mortality. Cardiac complications such as chest pain, arrhythmias, pulmonary oedema and refractory shock have been reported in patients with severe disease. However, the frequency and extent of cardiac involvement in leptospirosis, are under-reported and poorly understood. Multiple factors may contribute to clinical manifestations that suggest cardiac involvement, causing diagnostic confusion. A variety of electrocardiographic changes occur in leptospirosis, with atrial fibrillation, atrioventricular conduction blocks and non-specific ventricular repolarization abnormalities being the most common. Electrolyte abnormalities are likely to contribute to electrocardiographic changes; direct effects on Na(+)-K(+)-Cl(-) transporters in the renal tubules have been postulated. Echocardiographic evidence of myocardial dysfunction has not been adequately demonstrated. The diagnostic value of cardiac biomarkers is unknown. Histopathological changes in the myocardium have been clearly shown, with myocardial inflammation and vasculitis present in postmortem studies. Nonetheless, the pathophysiology of cardiac involvement in leptospirosis is poorly understood. Cardiac involvement, demonstrated electrocardiographically or clinically, tends to predict poor outcome. No specific therapies are available to prevent or treat cardiac involvement in leptospirosis; current management is based on correction of deranged homeostasis and supportive therapy. Evidence suggests that direct myocardial damage occurs in patients with severe leptospirosis, and further studies are recommended to elucidate its pathophysiology, clinical features and contribution to overall prognosis, and to identify appropriate diagnostic investigations and specific therapies.

Frequency of vacuolating cytotoxin A (VacA)-positive Helicobacter pylori seropositivity and TGF-ß1 decrease in atrial fibrillation.

The study was performed to determine whether there were any associations of VacA positive Helicobacter pylori and TGF-ß1 with atrial fibrillation (AF). The serum levels of antibodies to H. pylori and VacA, and cytokines were assessed using ELISA in 96 subjects. While elevated levels of TNF-α, IL-6 and CRP were associated with AF, TGF-ß(1) was significantly lowered in AF patients (p=0.021). In addition, AF was associated with elevated levels of antibodies to VacA (p=0.023), compared to the control group. Accordingly, the chronic infection of VacA(+)H. pylori may increase the risk for AF by inducing systemic inflammation mediated, partly by suppressed TGF-ß(1) and elevated proinflammatory cytokines.

Relation of multiple inflammatory biomarkers to incident atrial fibrillation.

Basic and clinical studies have suggested that inflammation predisposes to atrial fibrillation (AF). We assessed the association of 12 circulating inflammatory biomarkers (i.e., C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II) with incident AF in 2863 Framingham Offspring Study participants (mean age 60.7 years, SD = 9.4, 55% women). During follow-up (median 6 years), 148 participants (43% women) developed incident AF. In the multivariable proportional hazards models, the inflammatory biomarker panel was associated with incident AF (p = 0.03). With stepwise selection (p <0.01 for entry and retention), log-transformed osteoprotegerin was associated with incident AF (hazard ratio per SD 1.30, 95% confidence interval 1.08 to 1.56, p = 0.006). Adjusting for interim myocardial infarction or heart failure attenuated the association between osteoprotegerin and incident AF (hazard ratio 1.18, 95% confidence interval 0.98 to 1.43, p = 0.09). In conclusion, circulating osteoprotegerin concentration was significantly associated with incident AF in our community-based sample, possibly mediated by interim cardiovascular events.

Permanent atrial fibrillation in patients without structural heart disease is not associated with signs of infection by Chlamydia pneumoniae and Helicobacter pylori.

OBJECTIVE: The objective of this study was to explore the role of Chlamydia pneumoniae and Helicobacter pylori infections in patients with idiopathic permanent atrial fibrillation. METHODS AND RESULTS: Sera from 72 patients with permanent atrial fibrillation without structural heart disease (mean age 69.6 years, 23 women) were analysed for IgG antibodies against Chlamydia pneumoniae and Helicobacter pylori and compared in a I:I age- and sex-matched case:control manner with those pooled from a healthy reference population of 72 individuals from the same geographical area. After excluding patients with other possible or definite factors known either to cause atrial fibrillation or to affect the prevalence of seropositivity to these agents, the frequency of seropositivity due to one or both of the infectious agents was compared. Serum C-reactive protein (CRP) level was assessed using immunoturbidimetry technique. Both agents were equally common in men and women. Neither seropositivity to Chlamydia pneumoniae (76% vs. 83%, patients vs. control subjects, ns) nor to Helicobacter pylori (57% contra 55%, patients vs. controls, ns) alone reached significance in the comparisons between patients with atrial fibrillation and control subjects. Serum CRP was higher in patients with AF (5.3 mg/L vs. 2.8 mg/L, P < 0.001). CONCLUSIONS: Though presence of permanent AF is associated with elevated CRP levels, this elevation is not the result of earlier infections with Chlamydia pneumoniae or Helicobacter pylori or their combination.

New-onset atrial fibrillation in bacteremia is not associated with C-reactive protein, but is an indicator of increased mortality during hospitalization.

BACKGROUND: Several studies have associated elevated C-reactive protein (CRP) levels to the occurrence of atrial fibrillation (AF). We sought to estimate the frequency and prognostic impact of AF in patients with bacteremia, and to study the possible association between AF and CRP as well as between AF and mortality in this population. METHODS: We retrospectively evaluated patient charts of patients with bacteremia with Escherichia coli or Streptococcus pneumoniae admitted to the Aker University Hospital in Oslo between 1994 and 2004. Known cardiac risk factors for AF, signs and mode of conversion of AF, and, if applicable, date of death were registered, as were characteristics of infection, such as systemic inflammatory response syndrome and white blood cell count. Initial CRP values were categorized into 4 strata. Odds ratios of the 3 highest CRP categories compared with the lowest were obtained from logistic models adjusting for known cardiac risk factors for AF as well as possible factors that may have had an impact on the odds ratios for the different CRP levels. Cox regression analysis was used to compare new-onset AF and death during the first 2 weeks after hospitalization. RESULTS: A total of 672 patient charts were studied; 104 patients (15.4%) had new-onset AF. Peak incidence of new-onset AF occurred on the day of admission. Peak CRP values were reached during the following 2 days. High CRP level at admission did not predict the occurrence of AF. The observed mortality was higher among patients with new-onset AF (p = 0.001) during the first 2 weeks after hospitalization, but this effect disappears when adjusted for relevant factors. CONCLUSIONS: The frequency of new-onset AF in bacteremia is substantial. Initial CRP levels or white blood cell count do not seem to predict new-onset AF, as opposed to systemic inflammatory response syndrome. On the other hand, in patients with bacteremia, new-onset AF should be viewed as an indicator of increased mortality and morbidity.

Is there a link between atrial fibrillation and certain bacterial infections?

The pathogenesis of atrial fibrillation (AF), the most common cardiac dysrhythmia, remains unknown. However, many recent studies point to an association between AF and inflammation because of a demonstrable significant correlation between the dysrhythmia and various biomarkers of inflammation. For example, C-reactive protein (CRP), a sensitive biomarker of systemic inflammation, has been reported to be significantly higher in patients with AF compared with a control group with no history of atrial dysrhythmias. Histological anomalies in the atria of patients with AF have also been observed. These anomalies may have an inflammatory basis, although it is not known if the structural changes within the atria of patients with AF are a cause or consequence of the dysrhythmia. Given the suggested involvement of inflammation with this dysrhythmia, an initiating factor for inflammation has been sought. Chronic bacterial infection is the most likely event to initiate and maintain an inflammatory process. Recently, bacteria infections have been hypothesized to be involved in the pathogenesis of AF, and Helicobacter pylori and Chlamydia pneumoniae are two bacteria that have aroused interest. Here, we give a brief overview of AF and then specifically explore the recent evidence that suggests that AF may be caused by bacterial infection(s) in certain patients.

Endotoxemia, inflammation, and atrial fibrillation.

There is emerging evidence to support a link between inflammation and atrial fibrillation (AF). Lipopolysaccharide (LPS) infusion is a well established experimental model used to investigate host systemic inflammatory responses. It was hypothesized that LPS challenge, by virtue of its provoked host inflammatory response, might increase the propensity to the development of new-onset AF. A post hoc analysis was performed of prospective data collected for 652 healthy men (mean age 27+/-5 years, all without history of AF) who were challenged with LPS according to a standard experimental protocol. All subjects underwent a detailed health screening before inclusion. After LPS challenge, all subjects underwent continuous cardiac monitoring for a minimum of 8 hours and were reviewed again using rhythm assessments at 24 hours and after 7+/-3 days. Effects of LPS on high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and neutrophil counts as indexes of an inflammatory response were also assessed. LPS led to overall marked increases in high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and neutrophil counts (all p<0.0001) and an average temperature increase of 1.1 degrees C. There was no evidence of new-onset AF in the subjects challenged. In conclusion, experimental LPS challenge led to a significant increase in acute inflammatory indexes, but did not increase the propensity to new-onset AF in a young low-risk population.

Cytotoxin-associated gene-A bearing strains of Helicobacter pylori and atrial fibrillation due to ischemic origin: is there a link?

BACKGROUND: Helicobacter pyloriCagA strains could increase the risk for atrial fibrillation in patients with coronary artery disease METHODS: Serological status for H. pyloriCagA using enzyme-linked immunosorbent assay, C-reactive protein, total leucocytic count and atrial size were determined in 185 coronary artery disease patients (with and without atrial fibrillation) and 80 healthy subjects (control). RESULTS: CagA strain showed a higher prevalence in the atrial fibrillation group. Atrial dimension and C-reactive protein (independent predictors of atrial fibrillation) were significantly increased in the CagA seropositive subgroup CONCLUSIONS: There is a strong liaison between H. pylori CagA infection and atrial fibrillation in coronary artery disease. Increased C reactive protein and atrial size in atrial fibrillation patients may reflect atrial inflammatory remodeling.

Inflammation and atrial fibrillation: is Chlamydia pneumoniae a candidate pathogen of atrial fibrillation?

Atrial fibrillation is the most common arrhythmia, however, the mechanism of atrial fibrillation is not well explained. It has been considered that inflammation plays a role in atrial fibrillation, recently. Patients undergoing coronary artery bypass graft are at high risk for developing postoperative atrial fibrillation. The peak levels of C-reactive protein (CRP) were paralleled to the incidence of postoperative atrial fibrillation. In general population, CRP was also higher in patients with atrial fibrillation than in control people. Persistent atrial fibrillation patients had a higher CRP level than paroxysmal atrial fibrillation patients. CRP was not only associated with the presence of atrial fibrillation but may also predict patients at increased risk for future development of atrial fibrillation. Why inflammation markers in atrial fibrillation are high is a puzzling problem. We hypothesized that Chlamydia pneumoniae infection is a possible cause of atrial fibrillation by initiating inflammation response. It was demonstrated that infection of endothelial cells with C. pneumoniae elicited the production of Monocyte Chemoattractant Protein-1, interleukin-1, interleukin-8, interleukin-18, tumor necrosis factor, interferon and soluble intercellular adhesion molecule. Most of these cytokines play a crucial role in inflammation response that associate with the initiating and maintenance of atrial fibrillation. There are so many pathogens that can trigger inflammation. Some evidences showed that C. pneumoniae was the most likely pathogen of atrial fibrillation. In epidemic study, the incidence of atrial fibrillation increased from younger to elder and atrial fibrillation was more common in men than in women. C. pneumoniae has the same epidemic trend as the incidence of atrial fibrillation. Hypertension, myocardial infarction and reduced lung function are predictors of atrial fibrillation. C. pneumoniae infection is high in the patients with the above diseases. C. pneumoniae was found in endomyocardial biopsy samples, which supported C. pneumoniae was the candidate pathogen, too. Chlamydia infection can cause myocardial interstitial fibrosis and inflammation cells infiltration. The pathology characters of C. pneumoniae infection are similar to that found in atrial fibrillation. Seroepidemic study should be carried out to evaluate if there is relationship between C. pneumoniae and atrial fibrillation. If the hypothesis is confirmed, macrocyclic lactone antibiotics may be used to eliminate the pathogen. It will be a new target point to treat atrial fibrillation.

Three cases of cardiac complications associated with Campylobacter jejuni infection and review of the literature.

Presented here are three cases of acute cardiac disease (myocarditis, myopericarditis, and acute atrial fibrillation) associated with Campylobacter jejuni infection, followed by a review of the corresponding literature. Since Campylobacter jejuni is the most common cause of human bacterial enteritis in developed countries, these cases emphasize the importance of keeping cardiac complications in mind when treating patients with acute gastroenteritis due to this pathogen.