|
 
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| REVIEW ARTICLE |
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| Year : 2017 | Volume
: 1
| Issue : 3 | Page : 97-101 |
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Periodontal disease and cardiovascular disease: A native review
Xian-Tao Zeng1, Na Li2, Li-Jun Zhang2, Rong Rong3, Mei-Yan Liu2
1 Department of Stomatology, Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
2 Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
3 Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
| Date of Web Publication | 17-Jul-2018 |
Correspondence Address:
Prof. Mei-Yan Liu
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, 2 Anzhen Road, Chaoyang District, Beijing 100029
China
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_19_17
Periodontal disease (PD) and cardiovascular disease (CVD) are two types of the most prevalent disorders in elderly people, and an increasing number of data have shown a clinically important association between these two diseases. Numerous published studies have revealed a positive association between PD and CVD, such as myocardial infarction, coronary heart disease, peripheral arterial disease, stroke, and hypertension. Besides, periodontal conditions may be an independent predictor of all-cause mortality. Some interventional trials also indicate the effect of periodontal treatment on the CVD. The aim of this paper is to perform a critical review of the observational and interventional studies about this association, and we especially attached importance to the data from systematic reviews and meta-analysis. In addition, several pathogenic mechanisms implicated in the association between these two diseases were also reviewed. We suggest to promote close collaboration between physicians and dentists, thereby contributing to the improvement of prevention and control of cardiovascular conditions. Future researches are warranted to investigate the potential mechanisms. Keywords: All-cause mortality, cardiovascular disease, coronary heart disease, hypertension, periodontal disease, periodontitis, peripheral arterial disease, stroke
How to cite this article:
Zeng XT, Li N, Zhang LJ, Rong R, Liu MY. Periodontal disease and cardiovascular disease: A native review. Heart Mind 2017;1:97-101 |
| Introduction | |  |
Periodontal disease (PD), a chronic infectious disease of periodontal tissues, ranks as the leading cause of tooth loss in Chinese adults, and the incidence of the disease reaches approximately 90% worldwide.[1] Related researches indicate that PD is not only restricted to the periodontal local infection but also a risk factor of systemic diseases.[2] Cardiovascular disease (CVD) is one of the most common diseases threatening human's health and life. Epidemiological investigations demonstrate that in addition to multiple common risk factors such as hyperlipidemia, hypertension, smoking, diabetes mellitus, genetic factor, obesity and age, chronic infection is also another cause of CVD.[3] After the first report suggesting that PD was an independent risk factor of myocardial infarction (MI) in 1989,[4] various epidemiological researches have uncovered a potential relation between PD and CVD, especially coronary heart disease (CHD), peripheral arterial disease (PAD), stroke, and hypertension. In this review, we discussed the association between PD and CVD, their clinical relevance, and future direction for research.
| Periodontal Disease and Atherosclerosis | | |
The pathogenesis of atherosclerosis (AS) remains unclear now. Theory of endothelial injury response is supported by the majority of scholars, presenting that AS is the result of inflammatory-fibrous hyperplastic reactions of the artery when its endothelia are injured.[5] The pathogenic bacteria of PD not only exist in the periodontal infection but also invade into the blood which may cause chronic and recurrent low-level bacteremia and injure the blood vessel endothelium through multi-paths.[6] Zeng et al. performed a meta-analysis involving 17,330 participants and found that PD increased the risk of carotid AS by 1.27 times (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.14–1.41).[7] A recent systematic review by Almeida et al. provided an association between PD and AS in adults mainly on the levels of inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6).[8] The meta-analysis by Orlandi et al. supported that PD was correlated with a mean increase in carotid intima-media thickness (cIMT) of 0.08 mm (mean difference [MD] = 0.08 mm, 95% CI = 0.07–0.09) and a MD in flow-mediated dilation (FMD) of 5.1% (MD = 5.1%, 95% CI = 2.08–8.11%).[9]
Nowadays, there are four possible mechanisms indicating that PD may be a risk factor for AS.[10] The first is that periodontal pathogens or its components go directly into the blood. The pathogenic bacteria in the periodontal tissues, especially the Gram-negative bacteria (such as Porphyromonas gingivalis and P. gingivalis) invade blood circulation, thus resulting in bacteremia; the lipopolysaccharide of oral bacteria may combine with lipid-binding protein and CD14 receptor which is used for mononuclear/macrophage in the blood circulation, and then activate the mononuclear-macrophage and release various cytokines that can damage endothelial cells. The second is to induce systemic inflammatory response. Periodontal inflammation can increase the levels of cytokines in blood, for example, IL-1, IL-6, and tumor necrosis factor (TNF-a), and then lead to the production of intrahepatic inflammatory mediators such as CRP, which may cause systemic inflammation, injure endothelial cells and result in artery plaque formation. Moreover, CRP may first combine with low density lipoprotein and take part in atheromatous plaque formation and complement activation, and then integrate into part of atheromatous plaque or thrombus. The third is to induce systematic immunoreaction. Since heat shock proteins (HSP) of bacteria and humans are very similar in structure, the cross-reaction is easy to take place between HSP60 of P. gingivalis and humans. The over-expression of HSP60 of P. gingivalis can result in the damage of endothelial cells and then promote cellular immunologic response of plaques which will induce inflammation of the plaques. The fourth is to influence lipid metabolism. The periodontal pathogenic bacteria can promote oxidation and aggregation of low-density lipoprotein cholesterin (LDL-C), and after oxidative modification, the LDL-C can been engulfed by macrophages through scavenger receptor. In this process, phagocytes transform into foam cells and then form the earliest fatty streak.
| Periodontal Disease And Coronary Heart Disease | | |
CHD is a multi-factorial disease with high morbidity and mortality worldwide. Studies prove that traditional risk factors of CHD, such as dyslipidemia, hypertension, smoking, obesity, diabetes mellitus, and family medical history, cannot completely account for its pathogeny and severity, while PD has been considered as a novel risk factor for CHD. A meta-analysis of 37 case–control studies revealed that PD exposure significantly increased the incidence of CHD. The incidence of CHD in PD patients was 2.8 times of that in normal controls, indicating that PD might be an independent risk factor of CHD.[11] This significant association was confirmed by another meta-analysis of 15 prospective cohort studies enrolling 230,406 participants (risk ratio [RR] = 1.19, 95% CI = 1.13–1.26).[12]
Recently, the DNA traces of periodontal pathogens were discovered in coronary artery atherosclerotic plaques by some researchers using polymerase chain reaction, which offered evidence for the PD involvement in the formation of coronary artery atherosclerotic plaques.[13] Yang et al. conducted a cross-sectional survey of 853 CHD patients using the Gensini Score (GS) system to evaluate the degree of coronary artery stenosis. Multiple linear regression analysis uncovered that probe depth, plaque index, and gingival index significantly correlated with CHD, and the value of GS was consistent with the severity of clinical symptoms of CHD.[14] A Japanese case–control study suggested that serum IgG antibody levels of Actinobacillus actinomycetemcomitans (Aa) and Prevotella intermedia (Pi) were positively associated with the incidence of CHD and with an evident dose response.[15]
| Periodontal Disease and Myocardial Infarction | | |
MI is a myocardial necrosis disease caused by acute and continuous hypoxia and ischemia of coronary artery. After the first study by Mattila et al. in 1989[4] which indicated PD was a significant risk factor of MI, a meta-analysis including 3456 MI patients and 3875 nonMI controls revealed that PD increased the risk of MI 2.53 times (OR = 2.53, 95% CI = 1.93–3.32).[16] Another meta-analysis based on 22 observational studies including 129,630 participants also confirmed that patients with PD had an increased risk of MI (OR = 2.02, 95%CI = 1.59–2.57).[17]
Periodontal pathogens, especially Tannerella forsythia (Tf) and Pi might be involved in the onset and progression of MI. A case–control study of 313 MI patients and 747normal controls supported that the detectable rates of serum P. gingivalis, Tf, Pi, Camplobacter jejuni (Cr), Fusobacterium nucleatum (Fn), and Eubacterium saburreum  ) were higher in MI group than in normal group; in MI patients, the category of pathogens in periodontal pocket positively correlated with the occurrence of MI (OR = 1.14, 95% CI = 1.03–1.26). The risk of MI was 2.01 times (OR = 2.01, 95% CI = 1.31–3.08) in participants with more than two kinds of pathogens in their periodontal tissues compared with the normal controls.[18] Furthermore, there were significant statistic differences in the medical history and periodontal parameters between acute MI patients and nonMI patients, and amount of gingival bleeding was obviously higher in acute MI patients in India.[19]
| Periodontal Disease and Stroke | | |
Stroke is the leading cause of death and physical disability in China, and infection has been considered as an underlying cause of stroke in recent years.[20] PD as the most common infection in the oral cavity may increase the risk of stroke through activating serum inflammatory markers.[21] Based on the reports that pathogens of PD are detected in the carotid plaques, it is considered that these pathogens may be involved in the carotid plaque formation; moreover, the severity of PD possibly correlates with cIMT.[22]
A lot of studies have been conducted in the past two decades to provide theoretical basis for the hypothesis that PD can promote incidence and severity degree of stroke. A case–control study including 165 hemorrhagic stroke patients and 214 normal controls suggested that the risk of hemorrhagic apoplexy in PD patients with mean attachment loss thicker than 6 mm was 2.5 times of that of normal controls after confounding factors adjustment.[23] Besides, a meta-analysis based on five case–control and three cohort studies also indicated that there was a significant association between PD and ischemic stroke (RR = 2.52, 95% CI = 1.77–3.58 for cohort studies; RR = 3.04, 95% CI = 1.10–8.43 for case–control studies).[24] Another meta-analysis based on cohort studies supported the risk of stroke was significantly increased 1.63 times by the presence of PD (RR = 1.63, 95% CI = 1.25–2.00).[25] Hosomi et al. not only observed that patients with ischemic stroke had higher titers of anti Pi antibody and anti P. gingivalis antibody compared with normal controls, but also found that anti P. gingivalis antibody took part in the formation of carotid atherosclerotic plaque and correlated with atherothrombotic ischemic stroke.[26] The periodontal indices were higher in patients with carotid artery stenosis than in normal controls, and the walls shear stress negatively correlated with periodontal parameters, suggesting that an alteration of hemodynamic profile might contribute to AS in patients with PD.[27] Hence, patients with PD are more easier to suffer from atherosclerotic stroke.
| Periodontal Disease and Hypertension | | |
Hypertension is not only a risk factor for many types of CVDs but also the major cause of CVD mortality. Epidemiological investigations have revealed that PD is implicated in the change of blood pressure and the onset of hypertension.[28] In 2012, the American national health and nutrition examination survey III showed that the amount of bleeding and the levels of inflammatory markers of periodontal tissues were significantly linked to the elevation of systolic blood pressure and the occurrence of hypertension. In the age group of 45–65 years, the systolic blood pressure showed a linear correlation with the severity of PD; the average systolic blood pressure could rise 0.5 mmHg accompanying with every 10% increase in the amount of gingival bleeding after other confounding factors adjustment, and this change also made the diagnosis rate of hypertension increase 10%.[29] The oral infection and vascular disease epidemiology studies have indicated that the load of PD pathogens is positively associated with blood pressure and the prevalence of hypertension increases 3.05 times after adjusting other risk factors.[30] The results of a meta-analysis also confirmed PD, especially severe PD was associated with a higher risk of hypertension.[31]
The obvious increase of the level of inflammatory markers (such as CRP, IL-6, and TNF-a) in the body of moderate to severe PD patients can promote the damage of endothelial cells and aggravate angiosclerosis, thereby increasing the risk of hypertension.[32] A meta-analysis of 18 case–control studies suggested that the concentration of serum CRP in PD group was more than 1.56 mg/L compared with control group.[33] More evidence suggested that the reactive oxygen species (ROS) might be an important contributor to both PD and hypertension because ROS produced by neutrophil infiltration might participate in the destruction of periodontal tissues, and the imbalance of oxidation-antioxidation in oral cavity could negatively affect oxidative status in the whole body.[34]
| Periodontal Disease and Peripheral Arterial Disease | | |
PAD mostly strikes elderly patients, the major cause is that the formation of arterial lipid plaques in lower or upper extremities contributing to the hardening of vessel walls, thus resulting in lumen stenosis or even occlusion of lower limb or upper limb artery. A study by Chen et al. found periodontal pathogens existed in 52% arterial atheromatous plaques of PAD samples, and the risk of PAD in PD patients was 5.45 times of that in nonPD patients, which might be attributed to peripheral vascular injury caused by PD through increasing the levels of serum IL-6 and TNF-a.[35] The results of a cross-sectional study revealed that periodontal attachment loss was significantly related to the onset of PAD after adjusting other traditional risk factors (age, gender, race, economic conditions, etc.,), and this correlation still existed after adjustment of inflammatory markers (CRP, white blood cell count, and fibrinogen).[36] This study also supported that other factors might be involved in the incidence of PAD in patients with PD. A case–control study further confirmed this positive relationship between PD and PAD based on ankle-brachial index, and indicated that patients with PD had an 8.18 times higher risk of developing PAD than normal controls.[37] A recent study clarified that PAD patients had decreased tooth number and worsened oral and periodontal condition with enhanced systemic inflammation.[38]
| Periodontal Disease and All-Cause Mortality | | |
The baseline of periodontal conditions may be an independent predictor of cardiovascular and all-cause mortality. The mortality risk of participants increases around 51% when the alveolar bone loss (ABL) rate increases per 20%, and the highest mortality risk of severity PD can increase 85% compared to health ones.[39] A Swedish cohort study involving over 80-year-old patients suggested that the expected overall survival was shorter in patients with severe PD than in those with mild PD.[40] Through Kaplan-Meier survival analysis and Cox proportional hazard model, Linden et al. found that the all-cause mortality of top tri-sectional quantile ABL patients was 1.57 times of that of bottom tri-sectional quantile ABL patients after a median follow-up of 8.9 years for 1400 males between 60 and 70-year-old in Northern Ireland.[41] Hence, PD can increase all-cause mortality; the rate is increased with the severity degree of PD, whereas the increment is independent of low-grade systemic inflammation.[42]
| Periodontal Treatment and Cardiovascular Disease | | |
Many interventional studies have revealed that the treatment of PD can improve the clinical manifestations and symptoms of CVD patients, probably because the periodontal treatment helps to alleviate inflammation in endothelial cells and then reduce atherosclerotic plaques.[43] An active and effective periodontal treatment can suppress inflammatory markers (e.g., IL-6, CRP) of CVD patients, improve endothelium-dependent vasodilation,[44] and reduce the incidence of AS in children with congenital heart disease by improving blood lipid profile.[45] The results of a meta-analysis indicated that periodontal treatment on FMD showed a mean improvement of 6.64% between test and control groups (MD = 6.64%, 95% CI = 2.83%–10.44%).[9] Another systematic review and meta-analysis based on 25 controlled periodontal intervention trials also revealed that periodontal treatment improved endothelial function and reduced biomarkers of atherosclerotic disease.[46] A randomized controlled trial (RCT) investigating the treatment of periodontitis and endothelial function found that intensive periodontal treatment led to acute, short-term systemic inflammation and endothelial dysfunction; nevertheless, 6 months after therapy, the benefits in oral health were correlated with improvement in endothelial function.[47] Obviously, effective periodontal treatment and good oral hygiene status may render a measurable reduction in the mortality and all-cause mortality of CVD.[48] However, a Cochrane systematic review found very low-quality evidence that was insufficient to support or refute whether periodontal therapy could prevent the recurrence of CVD in patients with chronic periodontitis in the long-term; besides, no evidence on primary prevention has been found.[49] This Cochrane systematic review only included one RCT, and this RCT was judged to be at high risk of bias, and also does not provide any understanding about the effect of the intervention on deaths and timing of periodontal therapy was not assessed. Hence, the results should be interpreted with caution, and more high-quality RCTs are needed to investigate this point.
| Conclusion | | |
PD and CVD share many common risk factors. Numerous studies both in vitro and animal models have indicated that periodontal tissues act as a repository of inflammatory mediators and pathogens, which can increase vascular injuries, promote the formation and progression of AS, and then induce or aggravate CVD. Although a large number of relevant studies have been continuously conducted and published in the past several years, the association between PD and CVD remains unidentified which needs further research. Whether periodontal treatment is a challenge or a possible solution for the prevention of CVD may need more critical evaluation. However, we believe that even a small beneficial effect of periodontal treatment on CVD risk can be very valuable.[50] Hence, clinicians should do well in the propaganda work of oral hygiene and regard the treatment of PD as the primary prevention of CVD. Further researches are still required to clarify the mechanisms of how PD and periodontal treatment affect CVD and CVD outcomes.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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