periodontitis and atrial fibrillation

 Prior studies have found a relationship between periodontitis and atrial fibrillation (AF); a recent study found that a causative agent of periodontal disease (especially the highly pathogenic Porphyromonas gingivalis) migrated to the left atrium in a way that could explain a causal relationship between periodontitis and the development of AF (see afib periodontitis cause Circ2025 in dropbox, or doi.org/10.1161/CIRCULATIONAHA.124.071310 )

 

Details, in brief

-- susceptible mice were infected with P gingivalis, inoculated into the pulp of their molars to see if the P gingivalis was found in the left atrium

-- intracardiac stimulation was used to assess atrial fibrillation (AF) inducibility in these mice

-- human left atrial appendage specimens were evaluated pathologically from 68 patients with AF

    -- quantitative periodontal severity had been assessed prior to the surgery by PCR 

Results:

-- there was evident translocation of the P gingivalis in the mice, moving from the dental granuloma to the left atrium

-- these mice, vs control mice, also had higher degrees of:

    -- atrial fibrosis: 21.9% vs 16.3%, p=0.0003

    -- AF inducibility: 30% vs 5%, p=0.04 [an impressive 6-fold difference]

    -- up-regulation of GAL3 (galactin 3) and transforming growth factor-beta 1 was detected in the left atrium (these affect cell growth, cell differentiation, inflammation and fibrosis)

-- analysis of the human left atrial appendages found that the number of P gingivalis in the atrial tissue positively correlated with:

    -- periodontal epithelial surface area (p=0.004)

    -- periodontal inflamed surface area, PISA (p<0.0001)

    -- the degree of atrial fibrosis (p=0.002)

 

Commentary:

-- as we know, atrial fibrillation is the most common cardiac arrhythmia and can have devastating consequences (stroke, heart failure, etc)

    -- and its incidence in increasing at a rate of about 3%/year, likely from the aging population with more age-related comorbidities that are associated with increased AF risk, such as hypertension, obesity, diabetes, chronic lung disease, obstructive sleep apnea, chronic kidney disease, etc: https://pmc.ncbi.nlm.nih.gov/articles/PMC7455855/

-- several studies have documented a relationship between human periodontitis and atrial fibrillation (for a systematic review, see https://www.sciencedirect.com/science/article/pii/S2405844022004492):

    -- one study from a large Korean National Insurance Database of 1.2 million people and followed 14.3 years found that of 25K (2% of them) developed AF, and AF risk was most commonly found as a gradient: most in those with chronic periodontal disease, less in those with resolved periodontal disease and least in those without periodontal disease at all,  p<0.001 for the trend; these associations were found in their multivariate analysis: https://pmc.ncbi.nlm.nih.gov/articles/PMC10329345/

    -- other studies have reiterated this association finding a specific risk for cardioembolic strokes related to periodontal disease, also finding that oral disease prevention and treatment was associated with lower AF risk

    -- a Japanese study found a relationship between periodontitis and atrial fibrosis in the left atrial appendages in 76 patients with AF, particularly in those with high PISA (periodontal inflamed surface area) : https://pubmed.ncbi.nlm.nih.gov/36697200/ 

-- this current study was done to elucidate a potential mechanism for the association of periodontal disease and AF, one that might have more robust data to document a mechanistic link

    -- prior to this, the speculation about the mechanism highlighted the chronic systemic inflammatory state associated with periodontitis (this certainly does seem to correlate with lots of bad outcomes, as noted in oh-so-many prior blogs), which has been found to correlate with higher recurrence rates of AF after radiofrequency catheter ablation: https://www.ahajournals.org/doi/10.1161/JAHA.123.033740, a study of 288 patients having AF ablation, found that those people with recurrent AF post-ablation had higher quantitative indices of periodontal inflammation (PISA), as well as being more common in females, and those having had longer AF duration, and larger left atrial volume. And the 97 patients with high PISA indices who underwent periodontal treatment had significantly fewer AF recurrences:

        -- there was a relationship with the inflammatory interleukins: interleukin-1b, interleukin-4, interleukin-6, interleukin-10, and interleukin-17A

        -- though there was no correlation between AF recurrences and baseline CRP levels, there was one between patients with high hs-CRP and high- vs low-PISA levels: https://www.jacc.org/doi/10.1016/j.jacep.2022.08.018

        -- those treated for periodontitis overall did better:

             -- individuals with treated high-PISA levels had dramatic difference within the first 90 days, with 12-month difference having about 50% of the recurrences (p=0.005) and improvement at up to 3 years (p=0.01)

-- many studies in the past have found an association between periodontal disease and cardiovascular disease, attributed to either the systemic inflammation or endothelial dysfunction; one study randomized 120 patients with severe periodontitis to intensive periodontal treatment vs usual care, finding that the former was associated with significant improvement in endothelial function within 24 hours and for up to 6 months later (doi: 10.1056/NEJMx180022)

 

-- this research article found a few important clues suggesting a direct role for P gingivalis in the later development of AF:

    -- P gingivalis translocation to the left atrium correlates with the clinical severity of periodontitis

    -- this translocation is associated with increased atrial fibrosis and higher AF inducibility

    -- activation of the galactin-3/transforming growth factor beta 1 pathway provides a mechanistic linkage between atrial translocation of P gingivalis to the exacerbation of atrial fibrosis

-- and, by the way, P gingivalis also seems to be a culprit for Alzheimer's disease (it colonizes the brain: it is found in human neurons, tau tangles and beta-amyloid in autopsies of people with Alzheimer's; and animal studies (in mice who were infected with oral P gingivalis) have found that inhibitors of gingipains (P gingivalis proteases) mitigate their neurotoxic effects: https://pmc.ncbi.nlm.nih.gov/articles/PMC7689719/ .

-- P gingivalis  has also been associated with diabetes risk and has been found to lead to poorer diabetes control: http://pmc.ncbi.nlm.nih.gov/articles/PMC9588948/

-- and some studies have found a relationship with rheumatoid  arthritis

Limitations:

-- the major limitation here is that this was mostly an animal study, with some consistent pathologic findings in humans (though there was no granular data on those humans, such as other AF risk factors, etc). 

    -- we really need a human randomized controlled trial to be certain

    -- periodontitis is quite common (about 42% of US adults over age 30 had periodontitis in a CDC report, with 7.8% having severe periodontitis and 34.4% nonsevere (https://www.nidcr.nih.gov/research/data-statistics/periodontal-disease/adults). 

        -- it would be useful to know the extent of the relationships with AF: how long having severe and nonsevere periodontitis is associated with increased AF risk? what would be the absolute AF risk in those with prolonged mild periodontitis, since 1/3 of the population has that? how often should people have dental exams to detect and treat their periodontitis? though P gingivalis seems to be the bad actor here, is there a role of other associated bacteria (eg Treponema denticola  and Bacteroides forsythus)?  there are more than 500 bacterial species residing in the subgingival plaque associated with periodontitis (https://www.ncbi.nlm.nih.gov/books/NBK2496/). do any of these bacteria also migrate to the left atrium? are any of them individually or as a group also associated with AF?

      -- though, one could easily argue that:

           -- periodontitis is not good anyway and leads to significant dental problems

           -- for whatever mechanism, there seems to be a high likelihood of association with many bad human diseases

           -- and, even from the information we have now, it is reasonable to reinforce with individual patients and in a population/public health way of the importance of good dental hygiene

so,

-- this study added to the prior ones finding that periodontitis is associated with atrial fibrillation, and that treating periodontitis may well be one of the reversible/treatable causes of AF

-- there is some interesting information about a relationship of P gingivalis with Alzheimer's, diabetes, other cardiovascular diseases, etc

-- which all means that we clinicians should really reinforce the importance of good dental care, brushing teeth/flossing/regular dental check-ups/etc, as a likely important part of our overall constellation of items for preventive health care evaluation and education

geoff

-----------------------------------

If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@bidmc.harvard.edu

to get access to all of the blogs:  go to http://gmodestmedblogs.blogspot.com/ to see the blogs in reverse chronological order

or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them