Brushing teeth frequently is linked with lower risks of atrial fibrillation and heart failure, according to a study published today in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).
Previous research suggests that poor oral hygiene leads to bacteria in the blood, causing inflammation in the body.
Inflammation increases the risks of atrial fibrillation (irregular heartbeat) and heart failure (the heart’s ability to pump blood or relax and fill with blood is impaired).
This study examined the connection between oral hygiene and occurrence of these two conditions.
The retrospective cohort study enrolled 161,286 participants of the Korean National Health Insurance System aged 40 to 79 with no history of atrial fibrillation or heart failure. Participants underwent a routine medical examination between 2003 and 2004. Information was collected on height, weight, laboratory tests, illnesses, lifestyle, oral health, and oral hygiene behaviours.
During a median follow-up of 10.5 years, 4,911 (3.0%) participants developed atrial fibrillation and 7,971 (4.9%) developed heart failure.
Tooth brushing three or more times a day was associated with a 10% lower risk of atrial fibrillation and a 12% lower risk of heart failure during 10.5-year follow up.
The findings were independent of a number of factors including age, sex, socioeconomic status, regular exercise, alcohol consumption, body mass index, and comorbidities such as hypertension.
While the study did not investigate mechanisms, one possibility is that frequent tooth brushing reduces bacteria in the subgingival biofilm (bacteria living in the pocket between the teeth and gums), thereby preventing translocation to the bloodstream.
Senior author Dr. Tae-Jin Song of Ewha Womans University, Seoul, Korea noted that the analysis was limited to one country and as an observational study does not prove causation. But he added: “We studied a large group over a long period, which adds strength to our findings.”
An accompanying editorial states: “It is certainly too early to recommend tooth brushing for the prevention of atrial fibrillation and congestive heart failure”. It adds: “While the role of inflammation in the occurrence of cardiovascular disease is becoming more and more evident, intervention studies are needed to define strategies of public health importance.”
Atrial fibrillation (AF) is the most common persistent cardiac arrhythmia occurring in clinical practice.
In Europe, around 6 million people suffer from AF; in the entire western world 1.5–2% of the population is affected, with more men than women.
The prevalence of AF is age-dependent, rising from <0.5% in 40–50-year-old individuals to 5–15% in 80-year-olds and will continue to increase over the next 50 years [1,2].
After reaching the age of 40, 25% of men and women are at risk of developing AF during their later life [3].
Around 70% of affected patients are between 65 and 85 years old [4].
Atrial fibrillation is a risk factor for heart failure, dementia, and stroke [5,6,7].
Risk factors for AF include age, gender, high body mass index, hypertension, cardiovascular disease, valvular disease, and heart failure among others [3].
However, these conventional risk factors explain only a minor fraction of all AF cases, suggesting that additional risk factors may be relevant.
Among these additional risk factors, a substantial heritable component is of note [2]. Large twin studies estimated the total heritability of AF to be as high as 62% [8] and recent genome-wide association studies led to the identification of risk variants at over 100 genetic loci [9], many of which located at genes implicated in heart defects, ion channels, and heart muscle structure and function.
In addition to these genetic markers, there is a contribution of inflammation to AF risk that is likely not sufficiently covered by the existing risk models [10].
That inflammation may contribute to AF is supported by a number of clinical observations: (i) AF is associated with pericarditis [11]; (ii) the incidence of post-operative AF is influenced by IL-6 genotype and level [12]; and (iii) the observation that 25% to 40% of people develop AF after cardiac surgery [13]. It could be demonstrated that the time course of AF after cardiac surgery coincides with the activation of the complement system and the release of pro-inflammatory cytokines [13,14].
Humans are affected by a great number of infections and chronic inflammations.
Over a lifetime, oral infections are important, because of their longstanding nature and high frequency in the population.
Infective endocarditis, for instance, which is caused by bacteria that colonizes the teeth, often results from bacteremia after toothbrushing [15].
Participants with high plaque and calculus scores were at a 3.78- and 4.43-fold increased risk of developing bacteremia and bleeding induced by toothbrushing was associated with an almost eight-fold increased risk for bacteremia [16].
In a recent study, 14 of 22 cases of pericarditis were positive for endodontitis-related bacteria (63.6%), while eight were positive for periodontis-related bacteria (36.4%) [17].
It appears conceivable that cardiac arrhythmias could potentially also be affected by the systemic inflammation, which is known to accompany oral inflammations and/or by autoimmunity against molecular structures expressed in the heart caused by the host immune response to specific oral pathogens.
Finally, arrhythmic effects resulting from activation of the autonomic nervous system and from specific bacterial toxins that are produced by oral pathogenic bacteria could also play a role. To evaluate these potential mechanisms, we screened the published literature and reviewed the most important findings in this context.
Frequent Forms of Chronic Oral Infections Potentially Associated with Atrial Fibrillation
Oral infections potentially associated with AF include infections of the teeth, such as caries, which may lead to endodontic lesions, and infections of the gingival tissues surrounding the teeth, such as gingivitis and periodontitis, the latter affecting the tooth-supporting structures [18] (see Figure 1 for examples).
Gingivitis develops when bacteria, which form a biofilm at the tooth surface, infect the surrounding gingiva and trigger an immune response, resulting in swelling, redness and bleeding of the gingiva [19].
The inflammation can progress to periodontitis, if the bacteria and the accompanying inflammation migrate along the root surface and penetrate into the tooth supporting structures [20].
In Europe, almost 50% of over 30 years old individuals are affected by some form of periodontitis and over 10% have severe chronic periodontitis [21].
In most populations, 5–20% are affected by severe, generalized periodontitis [22,23].
Endodontic inflammations result mostly from deep dental caries, when the infection penetrates through the teeth’s root canal to the apex of the teeth’s root where a periapical abscess is formed [24].
Thirty to sixty percent of middle-aged Scandinavians [25,26] and Canadians [27] were shown to be affected by at least one periapical abscess, suggesting that a large fraction of the population is exposed to this kind of inflammation.
Oral inflammation affecting the teeth, gingiva, and the periodontium. Shown are examples of a tooth affected by severe caries, a tooth with abscess formation revealed by orthopantomography, a denture with severe periodontitis with evidence of extensive loss of attachment and gingival recession at most teeth, and an example of gingivitis with extensive calculus formation and a swollen and reddened inflamed gingiva.
Potential Role of Bacteremia
The oral microbiome, which is composed of more than 700 different bacterial species, populate all oral hard and soft surfaces [19]. To prevent bacteria from entering the body, gingival epithelial cells provide a mechanical barrier and release antimicrobial peptides (i.e., hBD-2, hBD-3, cathelicidin LL-37).
If bacteria still invade the tissue, immune cells and monocytes, which can release a wide range of pro-inflammatory mediators, are attracted by chemo-attractans, such as interleukins 1 and 8 (IL-1 and IL-8) [28,29,30,31].
The edematous gingival and periodontal tissues are prone to bleeding, which facilitates the penetration of oral bacteria into the bloodstream.
In addition, the bacteria can enter the body after internalization, together with phagocytic immune cells [32,33].
Transient bacteremias were demonstrated to occur in patients with periodontitis after tooth brushing and following periodontal treatment [33,34,35]. Oral bacteria and/or their DNA have been detected in human atherosclerotic lesions, the pericardial fluid, heart valves, and thrombi in many studies [17,36,37,38,39,40].
A recent meta-analysis of 63 studies that included 1791 patients confirmed the presence of 23 oral bacterial species in atherosclerotic plaques [41]. Campylobacter rectus, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, and Prevotella nigrescens were only detected in cardiac tissue, whereas the other species showed a more widespread distribution.
Bacteria from endodontic lesions, such as Streptococcus mutans, could be detected in biopsies from heart valves (40% positive) and atheromas (48% positive) [42]. The polymerase chain reaction (PCR) signals for this bacterium were stronger than those of bacterial species related to periodontitis.
Collectively, these results provide convincing evidence for the ability of a wide range of oral bacteria to invade the body most likely via the blood stream. However, evidence for their presence within the myocardium and their association with the cardiac conduction system is still lacking.
Potential Role of Systemic Inflammation
Higher C-reactive protein (CRP), which is a sensitive biomarker for systemic inflammation, was associated with AF in the Cardiovascular Health Study.
More individuals in the fourth CRP quartile had AF than in the first quartile (7.4% vs. 3.7%, adjusted odds ratio (OR) 1.8, 95% confidence interval (CI) 1.2 to 2.5; p = 0.002) and baseline CRP level predicted the risk for developing future AF (fourth vs. first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; p = 0.005), indicating that CRP is not only associated with the presence of AF, but also predicts patients at increased risk for future development of AF [10].
It is well known that oral infections elevate systemic CRP levels consistently [43,44,45,46,47,48].
The highest levels have been observed in patients with acute and chronic endodontic lesions (alveolar abscesses) [49,50]. In addition to CRP, oral inflammation affects the circulating levels of many other inflammatory markers and cytokines (see Table 1 for details) [50,51].
The pro-inflammatory mediator IL-6 stimulates the production of CRP and fibrinogen by the liver, resulting in an acute-phase reaction that has pro-inflammatory and pro-atherogenic effects [46]. Clinical studies have shown that circulating IL-6 is not only elevated in patients with periodontitis, but also in patients with heart failure—a major risk factor for AF (see review by Wollert and Drexler [52]).
Interleukin-6 stimulates cardiomyocyte hypertrophy and apoptosis and may contribute to fibrosis during heart failure thereby altering cardiac conduction and contributing to AF. In renal failure patients, elevated circulating IL-6 was identified as a risk factor for AF [53] and increased circulating IL-6 levels have been demonstrated in coronary heart disease CHD patients with AF [54].
Circulating IL-6 also correlated with the extent of left ventricular hypertrophy of the heart, which is an important risk factor for AF, in a large group of 971 patients [55]. Finally, it could be shown that polymorphisms in the promoter of the IL-6 gene, which influence the concentration of circulating IL-6, were associated with the risk of post-operative AF [12,56]. In conclusion, the published data suggest that IL-6 may favor AF due to its direct effects on electrophysiological remodeling of the heart.
Table 1
Cytokines Linked to Oral Inflammations
| Cytokine | Function |
|---|---|
| IL-8, MIP-1, MCP-1, RANTES | Chemotactic |
| IL-1α, IL-1β, TNFα, IL-6, PAF | Pro-inflammatory |
| IL-1RA, IL-4, IL-10 | Anti-inflammatory |
| IFN-γ, IL-2, IL-4, IL-5, IL-7 | Immunoregulatory |
| PDGF, EGF, FGF, IGF, VEGF | Growth factor |
EGF, epidermal growth factor; FGF, fibroblast growth factor; IFN, interferon; IGF insulin-like growth factor; IL, interleukin; IL-1RA, interleukin-1-receptor antagonist; MIP, macrophage inflammatory protein; MCP, monocyte chemotactic protein; PAF, platelet activating factor; PDGF, platelet derived growth factor; RANTES, regulated upon activation, normal T cell expressed and secreted; VEGF, vascular endothelial growth factor.
In contrast to IL-6, there is little evidence in the literature for a direct effect on cardiac electrophysiological remodeling for CRP [57]. Although circulating CRP is associated with AF [58], it cannot be ruled out that it is merely a bystander of cardiac remodeling involved in disease progression. Marott et al. were able to show that four CRP gene variants, which, in total, were associated with a 63% increase in circulating CRP, did not contribute to an increase in AF risk [59].
However, elevated CRP may predispose patients to persistence of AF via triggering arrhythmogenic foci, which worsen the arrhythmia over time and lead to worsened outcomes [10]. High CRP could reflect ongoing ventricular remodeling, as was also suggested previously for acute coronary syndromes, in which high CRP was associated with worsened mortality and left ventricular dysfunction [60].
The proposed link between inflammation and AF has potential therapeutic implications, because there are therapeutic strategies available, which target systemic inflammation (i.e., statins, canakinumab [61,62]).
A recent systematic review of controlled trials with statins, which included six studies comprising 3557 patients in sinus rhythm, showed that statins led to a decreased risk of AF compared to controls ((OR) 0.39, 95% CI 0.18 to 0.85, p = 0.02). Statins appeared to be more effective if used in secondary prevention of AF (OR 0.33, 95% CI 0.10 to 1.03, p = 0.06) than in new-onset or postoperative AF (OR 0.60, 95% CI 0.27 to 1.37, p = 0.23) [63].
However, it could not be differentiated to what degree the potential benefit of statin treatment in patients with AF were due to lowering low density lipoprotein (LDL) cholesterol and inhibiting coronary artery disease (CAD) progression as opposed to their anti-inflammatory effects. Statins were also demonstrated to have beneficial effects on the periodontal status in hyperlipidemic patients, which were interpreted to be due to their anti-inflammatory effects [64,65].
Potential Role of Autoimmunity in Atrial Fibrillation
Atrial fibrillation occurring at young age has been observed in several autoantibody-associated diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome [66,67,68].
Among the many self-antigens that have been proposed as potential targets of the self-directed immune responses to the heart [69], heat shock proteins (HSPs) are of special interest, because changes in cardiac HSP60/65 expression have been observed in patients with AF [70,71] and auto-reactivity to HSPs has been observed patients with periodontal disease [72].
Heat shock proteins are ubiquitous molecular chaperones functioning in cellular stress protection, which are evolutionary highly conserved [73].
Porphyromonas gingivalis and many other bacteria involved in oral infections, express homologs to human HSPs [74]. The HSP60/65 homolog of Porphyromonas gingivalis (called GroEL) has the ability to induce a humoral and cellular immune response in humans which is cross-reacting with the endogenous HSPs expressed by the host [75].
An association between antibodies to HSP60/65 and the occurrence of postoperative AF was reported, suggesting a potential involvement of HSP60/65 antibodies in the pathogenesis of AF. It was postulated that individuals with high preoperative levels of HSP60/65 antibodies could develop a harmful autoimmune reaction under the stressful operative conditions leading to induction of HSP expression and presence of HSPs on the surface of cardiomyocytes [76], which could subsequently cause myocyte injury and finally AF.
Activation of the HSP autoimmunity mechanism has been firmly established to operate in patients with periodontitis infected with Porphyromonas gingivalis [77,78,79,80]. Humoral and cellular immunity against HSPs is thought to be a normal feature of healthy humans, which participates in the protection against microbial infections [81].
The ability of the immune system to induce this potentially dangerous immune response depends on the strength of the HSP60/65 immunoresponse, which is elevated in patients with periodontitis. In addition, interaction with highly polymorphic major histocompatibility complex (MHC) class I and II epitopes on the cells’ surface is required to trigger the response [82].
More information: Chang Y, Woo HG, Park J, et al. Improved oral hygiene care is associated with decreased risk of occurrence for atrial fibrillation and heart failure: A nationwide population-based cohort study. Eur J Prev Cardiol. 2019. DOI: 10.1177/2047487319886018
Meyre P, Conen D. Does tooth brushing protect from atrial fibrillation and heart failure? Eur J Prev Cardiol. 2019. DOI: 10.1177/2047487319886413
