Oral infections and cardiovascular disease

doi:10.1016/j.tem.2015.03.001

Trends in Endocrinology & Metabolism

Volume 26, Issue 6, June 2015, Pages 315-321

https://doi.org/10.1016/j.tem.2015.03.001 Get rights and content

Highlights

•
There is evidence linking periodontal disease to cardiovascular disease (CVD).
•
Mechanisms linking oral infections to CVD involve actions of oral bacteria on the vasculature.
•
Systemic inflammation is an important component of the role of oral bacteria in the pathogenesis of CVD.
•
Natural inflammation-resolving molecules may help to reduce the inflammation arm of the proposed periodontitis–CVD link without antimicrobial intervention.

Oral infections are the most common diseases of mankind. Numerous reports have implicated oral infections, particularly periodontitis, as a risk factor for atherosclerotic cardiovascular disease (CVD). In this review we examine the epidemiology and biologic plausibility of this association with an emphasis on oral bacteria and inflammation. Longitudinal studies of incident cardiovascular events clearly show excess risk for CVD in individuals with periodontitis. It is likely that systemic exposure to oral bacteria impacts upon the initiation and progression of CVD through triggering of inflammatory processes. Given the high prevalence of periodontitis, any risk attributable to future CVD is important to public health. Unraveling the role of the oral microbiome in CVD will lead to new preventive and treatment approaches.

Section snippets

How strong is the evidence linking oral infections to cardiovascular diseases?

The most common oral infections are periodontal diseases (gingivitis, periodontitis, see Glossary) and dental caries (tooth decay). Teeth are surrounded and anchored to the alveolar process of the jaws by an attachment apparatus comprising the most outer calcified layer of the tooth root (cementum), connected to bone by highly organized collagen fibers called periodontal ligaments. Systemic exposure to dental infections often results from the involvement of these supporting structures in

Mechanisms linking oral infections to CVD

Inflammation plays a major role in both oral infections such as periodontitis and in CVD 11, 12, 13, 14. Oral inflammation is induced by bacteria in biofilms comprising the microbiome that forms on the teeth [15]. Vascular inflammation is induced by hyperlipidemia, hypertension, smoking, and several other known and unknown factors. In the following sections we consider the recent evidence for the role of oral infections in CVD as well as the direct and indirect actions of oral bacteria through

Direct actions of oral bacteria on the vasculature

The surface area of ulcerated epithelium lining periodontal pockets in generalized periodontitis patients has been estimated to be between 8–20 cm² [16]. The bacterial burden in the gingival sulcus approximating the ulceration provides a portal for bacterial entry into systemic circulation, resulting in bacteremia. As a result of this interaction, the interface is heavily populated by phagocytic cells that can also transport bacteria to remote sites [17].

The contribution of periodontal bacteria

Oral infections and systemic inflammation

A clear distinction should be made between active bacterial invasion and an infectious condition that triggers inflammatory disease. Once the inflammatory cascade has been instigated, the elimination of the initiating factor might not be sufficient to stop the series of events that follow. In this context the initial infection becomes an indirect contributing factor (Figure 1). The colocalization of bacteria (initially thought to be Chlamydia species, but recent evidence suggests many species

Intervention trials

Intervention trials perhaps offer the strongest evidence for a direct relationship between periodontitis and CVD because they attempt to address the impact of periodontal therapy on CVD indicators. There are no studies that evaluate the impact of treating periodontal disease on primary events (first myocardial infarction – MI), and only a feasibility study that examined secondary events (preventing second MI) has been published [67]. Several studies have shown that periodontal treatment can

Future research recommendations

Further studies will help answer outstanding questions (Box 2) and to enhance our understanding of the link between periodontal disease and CVD. The generalizability of epidemiological evidence of an association is weakened by the heterogeneity of data collected. Future studies with standardized treatments, measurements, diagnostic criteria, and definitions of disease and health will lead to a more consistent pool of data and stronger evidence. In addition, lack of information regarding the

Concluding remarks

As we move forward, a clearer picture is emerging of how oral bacteria can have a significant impact on systemic inflammation and perhaps initiate local vascular lesions leading to CVD. Of particular interest is the dynamic relationship between inflammation and the oral microbiome, and the potential for modification of bacterial virulence both locally and systemically.

We now have the tools to make significant advances in our understanding of this relationship rapidly, and an opportunity to

Glossary

Actinobacillus actinomycetemcomitans: also known as Aggregatibacter actinomycetemcomitans, a Gram-negative bacterium found in association with periodontitis that is considered to be one of the species that might be implicated in a destructive form of periodontitis.
Dental caries: also known as tooth decay, cavities, or caries, the breakdown of teeth due to bacteria.
Gingival sulcus: the space between a tooth and the surrounding gingival tissue, and is lined by sulcular epithelium.
Lipoxins: a class of

References (75)

P. Libby
Role of inflammation in atherosclerosis associated with rheumatoid arthritis
Am. J. Med.
(2008)
K.M. Fifer
Positron emission tomography measurement of periodontal ¹⁸F-fluorodeoxyglucose uptake is associated with histologically determined carotid plaque inflammation
J. Am. Coll. Cardiol.
(2011)
C. Hayashi
Porphyromonas gingivalis accelerates inflammatory atherosclerosis in the innominate artery of ApoE deficient mice
Atherosclerosis
(2011)
L.V. Norling et al.
The role of omega-3 derived resolvins in arthritis
Curr. Opin. Pharmacol.
(2013)
M. Spite
Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases
Cell Metab.
(2014)
Y.P. Sun
Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation
J. Biol. Chem.
(2007)
H. Aoki
Resolvin E1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma
Biochem. Biophys. Res. Commun.
(2008)
S. Hong
Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation
J. Biol. Chem.
(2003)
C.H. Yeh
Circulating heat shock protein 70 and progression in patients with chronic myeloid leukemia
Leuk. Res.
(2009)
G.J. Debelian
Bacteremia in conjunction with endodontic therapy
Endod. Dent. Traumatol.
(1995)

The pathogenesis of periodontal diseases

J. Periodontol.

(1999)

P.P. Hujoel

The dentogingival epithelial surface area revisited

J. Periodontal. Res.

(2001)

J. Carrion

Microbial carriage state of peripheral blood dendritic cells (DCs) in chronic periodontitis influences DC differentiation, atherogenic potential

J. Immunol.

(2012)

V.I. Haraszthy

Identification of periodontal pathogens in atheromatous plaques

J. Periodontol.

(2000)

E.V. Kozarov

Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis

Arterioscler. Thromb. Vasc. Biol.

(2005)

Z. Armingohar

Bacteria and bacterial DNA in atherosclerotic plaque and aneurysmal wall biopsies from patients with and without periodontitis

J. Oral Microbiol.

(2014)

L. Boring

Decreased lesion formation in CCR2^−/− mice reveals a role for chemokines in the initiation of atherosclerosis

Nature

(1998)

R. Zahn

Antibiotic therapy after acute myocardial infarction: a prospective randomized study

Circulation

(2003)

J.L. Anderson et al.

Antibiotic trials for coronary heart disease

Texas Heart Inst. J.

(2004)

J.L. Anderson et al.

Antibiotic trials for coronary heart disease

Tex Heart Inst. J.

(2004)

R.J. Genco

A proposed model linking inflammation to obesity, diabetes, and periodontal infections

J. Periodontol.

(2005)

R.J. Genco et al.

Prevention: reducing the risk of CVD in patients with periodontitis

Nat. Rev. Cardiol.

(2010)

F.C. Gibson

Porphyromonas gingivalis-specific immunoglobulin G prevents P. gingivalis-elicited oral bone loss in a murine model

Infect. Immun.

(2004)

M. Richardson

Respiratory infection in lipid-fed rabbits enhances sudanophilia and the expression of VCAM-1

Am. J. Pathol.

(1997)

F. D’Aiuto

Periodontitis: from local infection to systemic diseases

Int. J. Immunopathol. Pharmacol.

(2005)

Cited by (146)

Temporal stability of tongue microbiota in older patients – A pilot study
2024, Journal of Dental Sciences
Healthy states of human microbiota depend on a stable community of symbiotic microbes irrespective of external challenges from the environment. Thus, long-term stability of the oral microbiota is of importance, particularly for older patient populations.
We used next-generation sequencing (NGS) to examine the tongue microbiota of 18 individuals receiving long-term care over a 10-month period.
Beta diversity analysis demonstrated temporal stability of the tongue microbiota, as microbial compositions from all time points were indistinguishable from each other (P = 0.0887). However, significant individual variation in microbial composition (P = 0.0001) was observed, underscoring the presence of a unique microbial profile for each patient.
The temporal dynamics of tongue microbiota exhibit long-term stability, providing diagnostic implications for oral diseases within older patient populations.
Myeloperoxidase: A Circulating Marker of Inflammation and Tooth Infection
2023, American Journal of Medicine
Atherosclerotic cardiovascular disease and tooth infection are common in primary care, and both significantly reduce quality of life. Our study aimed to examine signs of vascular inflammation associated with loss of tooth vitality before and after a single tooth extraction.
An observational cohort study was performed with adults who had a nonvital tooth and an indicated desire for tooth extraction. Concentrations of total cholesterol, high-density lipoprotein-cholesterol, high-sensitivity C-reactive protein (hs-CRP), myeloperoxidase (MPO), and troponin T were measured in venous blood serum or plasma at baseline and 6-weeks after tooth extraction.
Circulating hs-CRP levels were > 3 mg/dL in 15 participants (68.2%) and MPO levels were > 350 pmol/L in 9 (40.9%) of 22 participants at baseline. After tooth extraction (n = 18), MPO levels decreased significantly compared with baseline (P < .00006) and hs-CRP levels moved directionally downward. The response rate for MPO was 88.9% (confidence interval: 65.1%-98.6%) from visit 1 to visit 2. Those with high MPO levels at baseline demonstrated larger reductions in MPO levels by visit 2 than those with lower baseline MPO levels (r = .81; P < .0001). A total of 13 individuals (72.2%) achieved MPO levels < 350 pmol/L and 11 (61.1%) achieved hs-CRP levels < 3 mg/dL at visit 2. Total cholesterol, high-density lipoprotein-cholesterol, and troponin T levels did not significantly change from visit 1 to visit 2.
A link between dental infection and circulating levels of inflammation was observed, suggesting that oral infection could be a risk factor for atherosclerotic cardiovascular disease.
Copper functionalized poly (acrylic acid-co-itaconic acid) nanohydrogel: Its antibacterial properties on oral pathogens and biocompatibility
2022, Colloids and Surfaces B: Biointerfaces
Although extensive efforts have been made to explore effective antibiotics, the development of antibiotics lags far behind the emergence of drug-resistant bacteria. Antimicrobial materials as an alternative strategy provide effective functions in aiding in relieving the dose of antibiotics. Herein, we report a novel antibacterial agent with high antibacterial effectivity and low toxicity, which is simply composed of a trace amount of Cu²⁺ ion and nanoscale biocompatible polymer poly (acrylic acid-co-itaconic acid) (PAI-Cu). The polymer shows greatly enhanced antibacterial activity against various Gram-positive and Gram-negative pathogens compared with equal concentrations of copper ion solution, yet shows nearly no toxicity towards human cells. The antibacterial performance and mechanism of copper ionized polymer hydrogel are evaluated in terms of multiple methods, towards various oral bacteria including Streptococcus mutans, Enterococcus faecalis, Lactobacillus acidophilus, Actinomycetes viscosus, Porphyromonas gingivalis, Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia. Bacterial cell membrane and wall damage caused by PAI-Cu nanohydrogel should be regarded as an important antibacterial mechanism. Moreover, PAI-Cu nanohydrogel, as the role of catalytic active center, can activate the surrounding oxygen, and generate hydroxyl radical (·OH), which can destroy the proliferation ability of microbial cells. We suggest that PAI-Cu nanohydrogel is a promising antibacterial agent against dental pathogens and beyond.
Salivary microbiota may predict the presence of esophageal squamous cell carcinoma
2022, Genes and Diseases
The aim is to explore the predictive value of salivary bacteria for the presence of esophageal squamous cell carcinoma (ESCC). Saliva samples were obtained from 178 patients with ESCC and 101 healthy controls, and allocated to screening and verification cohorts, respectively. In the screening phase, after saliva DNA was extracted, 16S rRNA V4 regions of salivary bacteria were amplified by polymerase chain reaction (PCR) with high-throughput sequencing. Highly expressed target bacteria were screened by Operational Taxonomic Units clustering, species annotation and microbial diversity assessment. In the verification phase, the expression levels of target bacteria identified in the screening phase were verified by absolute quantitative PCR (Q-PCR). Receiver operating characteristic (ROC) curves were plotted to investigate the predictive value of target salivary bacteria. LEfSe analysis revealed higher proportions of Fusobacterium, Streptococcus and Porphyromonas, and Q-PCR assay showed significantly higher numbers of Streptococcus salivarius, Fusobacterium nucleatum and Porphyromonas gingivalis in patients with ESCC, when compared with healthy controls (all P < 0.05). The areas under the ROC curves for Streptococcus salivarius, Fusobacterium nucleatum, Porphyromonas gingivalis and the combination of the three bacteria for predicting patients with ESCC were 69%, 56.5%, 61.8% and 76.4%, respectively. The sensitivities corresponding to cutoff value were 69.3%, 22.7%, 35.2% and 86.4%, respectively, and the matched specificity were 78.4%, 96.1%, 90.2% and 58.8%, respectively. These highly expressed Streptococcus salivarius, Fusobacterium nucleatum and Porphyromonas gingivalis in the saliva, alone or in combination, indicate their predictive value for ESCC.
Antibacterial Properties of Rose Bengal Conjugated to Hyaluronic Acid
2024, International Journal of Molecular Sciences
CCL28: A Promising Biomarker for Assessing Salivary Gland Functionality and Maintaining Healthy Oral Environments
2024, Biology

View all citing articles on Scopus

View full text

Trends in Endocrinology & Metabolism

ReviewOral infections and cardiovascular disease

Highlights

Section snippets

How strong is the evidence linking oral infections to cardiovascular diseases?

Mechanisms linking oral infections to CVD

Direct actions of oral bacteria on the vasculature

Oral infections and systemic inflammation

Intervention trials

Future research recommendations

Concluding remarks

Glossary

Am. J. Med.

J. Am. Coll. Cardiol.

Atherosclerosis

Curr. Opin. Pharmacol.

Cell Metab.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Leuk. Res.

Bacteremia in conjunction with endodontic therapy

Endod. Dent. Traumatol.

Bacteraemia following periodontal procedures

J. Clin. Periodontol.

Prevalence of periodontitis in adults in the United States: 2009 and 2010

J. Dent. Res.

Position paper: epidemiology of periodontal diseases

J. Periodontol.

Heart disease and stroke statistics – 2014 update: a report from the American Heart Association

Circulation

The epidemiological evidence behind the association between periodontitis and incident atherosclerotic cardiovascular disease

J. Periodontol.

Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases

J. Periodontol.

Periodontal bacterial invasion and infection: contribution to atherosclerotic pathology

J. Periodontol.

Inflammatory mechanisms linking periodontal diseases to cardiovascular diseases

J. Periodontol.

Evidence that periodontal treatment improves biomarkers and CVD outcomes

J. Periodontol.

The management of inflammation in periodontal disease

J. Periodontol.

Inflammation and periodontal diseases: a reappraisal

J. Periodontol.

High-dose atorvastatin reduces periodontal inflammation: a novel pleiotropic effect of statins

J. Am. Coll. Cardiol.

The pathogenesis of periodontal diseases

J. Periodontol.

The dentogingival epithelial surface area revisited

J. Periodontal. Res.

Microbial carriage state of peripheral blood dendritic cells (DCs) in chronic periodontitis influences DC differentiation, atherogenic potential

J. Immunol.

Identification of periodontal pathogens in atheromatous plaques

J. Periodontol.

Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis

Arterioscler. Thromb. Vasc. Biol.

Bacteria and bacterial DNA in atherosclerotic plaque and aneurysmal wall biopsies from patients with and without periodontitis

J. Oral Microbiol.

Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis

Nature

Antibiotic therapy after acute myocardial infarction: a prospective randomized study

Circulation

Antibiotic trials for coronary heart disease

Texas Heart Inst. J.

Antibiotic trials for coronary heart disease

Tex Heart Inst. J.

A proposed model linking inflammation to obesity, diabetes, and periodontal infections

J. Periodontol.

Prevention: reducing the risk of CVD in patients with periodontitis

Nat. Rev. Cardiol.

Porphyromonas gingivalis-specific immunoglobulin G prevents P. gingivalis-elicited oral bone loss in a murine model

Infect. Immun.

Respiratory infection in lipid-fed rabbits enhances sudanophilia and the expression of VCAM-1

Am. J. Pathol.

Periodontitis: from local infection to systemic diseases

Int. J. Immunopathol. Pharmacol.

Review
Oral infections and cardiovascular disease

Decreased lesion formation in CCR2^−/− mice reveals a role for chemokines in the initiation of atherosclerosis