Galore International Journal of Health Sciences and Research DOI: https://doi.org/10.52403/gijhsr.20210403 Vol.6; Issue: 2; April-June 2021 Website: www.gijhsr.com Review Article P-ISSN: 2456-9321

Mechanisms Linking and : A Review and Update

Kamalkishor Mankar1, Pranjali Bawankar2,

1Associate Professor, 2Lecturer, VSPM Dental College & Research Centre, Department of Periodontology, Digdoh Hills, Hingna Road, Nagpur-440019

Corresponding Author: Pranjali Bawankar

ABSTRACT Keywords: Coronary Artery Disease, Chronic Periodontitis, Interrelationship, Periodontal Aim: To present review of current literature disease, Systemic conditions. regarding association between periodontal and cardiovascular diseases and the mechanisms INTRODUCTION involved in the association. Concept of periodontal medicine Materials and Methods: Thorough search was which explores relationship between carried out on PUBMED, MEDLINE databases periodontal disease and systemic diseases and Google on the association between has been introduced in 1996, by periodontal disease and cardiovascular diseases .[1] and the mechanisms involved selected literature Offenbacher Periodontitis is a chronic inflammatory disease caused by bacterial included review articles, observational studies, [2] case control studies, randomized control trials infection of tooth supporting tissues, and and meta-analysis. Priority was placed on papers is the most common oral condition affecting published within last 10 years. Brief description human population.[3] According to a survey of periodontal disease and atherosclerosis in united states about 50% of adults above underlying has also been 30 years have some periodontitis, and nearly included. 10% have severe disease.[4] Annually CVD Results and Conclusion: Preponderance of data accounts for 40% of all deaths worldwide, appears to support the concept that a potential with atherosclerosis as underlying etiology link does exist between periodontal disease and in majority of cases.[5,6] Atherosclerosis is a CVD independent of confounding factors. Interventional trials have shown that periodontal disease process in which fatty deposits, therapy is associated with reduction in surrogate inflammation, cells and scar tissue buildup markers of atherosclerotic cardiovascular within the walls of arteries. Inflammation disease. Prospective interventional studies are plays a central role in the pathogenesis of required to determine the exact link between PD atherosclerosis, from its initial stage to and CVD as well as to evaluate whether development of clinical signs and periodontal treatment may reduce the risk of symptoms.[7] Several factors are defined as developing CVD. risk factors for cardiovascular diseases; Clinical Significance Pre assessment of however incidence of atherosclerosis cannot developing cardiovascular disease using be explained by traditional factors alone.[8] biomarkers can help in diagnosis of developing American Heart Association (AHA) or worsening periodontal diseases at earlier stages and can aid in providing screening working group concluded that periodontal services and advice to seek immediate dental disease is associated with atherosclerotic care. vascular disease (ASVD) independent of [9] known confounders. This relationship was demonstrated with level A evidence. The proposed by William

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Hunter in 1909 was revisited in 1951 by the bacteria disrupt host mechanisms involved American Dental Association and a in bacterial clearance by activating many confirmation of the link of periodontal host immunoinflammatory processes. Host diseases and systemic diseases was inflammatory processes are dependent on established. [10’11] European society of environmental, genetic and acquired risk cardiology concluded that “oral health has factors. Although periodontitis is initiated an influence on systemic health in general by microbes, host modifying factors play an and on cardiovascular disease (CVD) in important role in determining severity and particular. Therefore we should promote extent of disease. oral health in general and periodontal health Periodontal disease occurs due to a in particular as part of a healthy life style complex interplay of bacterial infection and and hence as an important component in the host response. [18] Bacteria interacts with prevention of CVD.[12] Several systematic host through there virulence factors and reviews have shown a significant induce an innate and humoral immune association between periodontal disease and response.[19,20] Immune response to bacterial atherosclerotic cardiovascular disease, challenge shows interindividual variations independent of known confounders. [13,14,15] [21] and leads to release of proinflammatory Patients with periodontal disease share factors, PGE2, IL-1β.[22] Inflammatory many of the same risk factors as patients processes at periodontium results in increase with CVD including age, gender level of CRP and other mediators such as (predominantly male), lower socioeconomic fibrinogen leading to systemic response. status, stress, and smoking.[16] Several direct Cytokine and MMP levels also increase in and indirect mechanisms have been periodontitis. Increase in levels of MMPs proposed as pathophysiological links along with proliferation of bacteria lead to between chronic periodontitis and activation of different cells, such as atherosclerotic cardiovascular disease.[9] In fibroblasts, keratinocytes, macrophages and order to ensure optimal treatment it is endothelial cells. Macrophages secrete large important for cardiologists to be aware of all amount of TNF and IL-1 β leading to bone of the potential risk factors for CVD. This resorption. review provides an overview of research on the relationship between periodontal disease Atherosclerosis and CVD in the light of current literature. Atherosclerosis is a chronic inflammatory disease; inflammatory Pathophysiology of periodontitis processes are the vital part of If biofilms on the teeth are not pathophysiology of atherosclerosis and are disrupted on regular basis, it leads to supposed to be involved from initiation to emergence of gram negative bacteria. Low final stages of infarction. Normally redox potential, supply of nutrients in endothelial cells does not allow for the crevicular fluid and limited amount of attachment of leukocytes to vessel wall. oxygen in periodontal pocket provides Dysfunctional lipid homeostasis plays a favorable environment for survival and vital role in initiation and progression of multiplication of gram negative bacteria. endothelial alterations. When initial damage Periodontal disease is caused by bacteria in of epithelium occurs, either by infection or dental plaque, pathogens frequently by an atherogenic diet, endothelial cells associated with periodontal disease include express adhesion molecules that allow Aggregatibacter actinomycetemcomitans, leukocytes to bind vessel wall. Adhesion Capnocytophaga, Campylobacter rectus, molecules are called vascular cell adhesion Fusobacterium nucleatum, Porphyromonas- molecule (VCAM), intercellular adhesion gingivalis, Prevotella intermedia, Tannerella molecule (ICAM). Selectins and integrins forsythia and Treponema denticola.[17] These also support leukocyte attachment.

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Endothelial dysfunction is considered as initiate coagulation, when in contact with primary step in pathogenesis of platelets and cause thromboembolism. atherosclerosis, and may act as risk marker Following are the potential for future cardiovascular events. [23, 24, 25, 26] mechanisms linking periodontitis to After adhesion to arterial wall, cardiovascular disease: monocyte penetrates the vessel wall by diapedesis or migration between endothelial a) Direct bacterial effects on platelets and cells. This accumulation of monocytes in host cells. vessel intima leads to development of fatty b) Systemically or locally induced streak, an early atherosclerotic lesion. Fatty inflammatory mediators. streak develops at 11-12 years and fibrous c) Autoimmune responses. plaque at 15-30 years.[27] LDLs (low density lipoproteins) play a key role in development a. Bacteremias and endotoxemias of atherosclerotic lesions.[28,29,30] LDLs Inflamed periodontal tissue give accumulated under intima layer are access to periodontal bacteria and its subsequently phagocytosed by macrophages products, into bloodstream through inflamed and transform them into foam cells. periodontal tissues, especially after dentaltreatment,[31,32,33] gentle mastication or Accumulation of foam cells in [32,34] subendothelial space is the hallmark of fatty tooth brushing. Bacteria may access the streak. Foam cells along with altered circulation during daily routine, oral endothelium release various growth factors hygiene procedures and during periodontal and cytokines, which stimulates migration therapy. Virulent Gram-negative organisms of smooth muscle cells from tunica media in the blood stream causes recurrent and [23] transient bacteremia, as well as low-grade into tunica intima. Smooth muscle cells [32,33,35] synthesize majority of extracellular matrix systemic inflammation. Systemic of complex plaque, forming the typical inflammation caused by periodontal atherosclerotic plaque. Accumulation of pathogens or virulence factors affects all fibrous tissue in vessel is characteristic of stages of atherosclerotic process. Locally advanced atherosclerotic lesion, complex secreted pro-inflammatory cytokines such as plaque. Inflammation influences integrity of TNF-α, IL-1 and IL-6 enter circulation, fibrous cap not only by blocking creation of trigger the release of acute-phase reactants new collagen fibers but also by stimulating (e.g. C-reactive protein) and promote cell destruction of existing collagen. activation. Bacteremia is transient, bacteria Smooth muscle cells secrete specific are undetectable in the blood within 15 to 30 minutes, it can lasts longer in patients with enzymes (metalloproteinase’s) on [32] inflammatory stimulation. periodontitis. Metalloproteinase’s may disintegrate Host cells (macrophages, endothelial fibrous capsule leading to rupture of plaque. cells, and gingival epithelial cells) are migrated leukocytes release susceptible to invasion by certain proinflammatory cytokines (IL-1,IL- periodontopathogenic bacteria 6,TNFα).foam cells formation further (Porphyromonasgingivalis, Aggregatibacter increases release of proinflammatory actinomycetemcomitans, and Fusobacterium nucleatum) through invasion or adhesion. cytokines IL-1,IL-6,TNFα.Activated T cells [36] may stimulate MMP production by Platelets play a critical role in hemostasis macrophages, MMP causes destruction of and thrombosis. Staphylococcus aureus and Streptococcus sanguis can induced platelet fibrous capsule leading to activation of [37,38,39] clotting system with thrombosis and aggregation in vitro. Platelet aggregation and increase in protease activity subsequent arterial occlusion, that may be [40, 41, 42] responsible for many cases of MI. Rupture can be induced by P. gingivalis. of plaque releases thrombotic factors that When P. gingivalis was added to human

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 15 Vol.6; Issue: 2; April-June 2021 Kamalkishor Mankar et.al. Association of periodontitis and cardiovascular disease platelet rich plasma (PRP) sharp and rapid treatment could lower the levels of CRP increase of small-sized platelet aggregates after therapy.[63]Results of multi centered was observed followed by the formation of randomized study showed that periodontal medium and large-sized aggregates within treatment can lower CRP levels from high 2-3 min.[43]P. gingivalis through its fimbriae to moderate levels in non-obese periodntitis can invade aortic and heart endothelial patients.[64]Results from studies indicate that cells.[44]When macrophages are incubated plasma CRP concentration can be used as a with P.gingivalis and low density risk indicator for future MI and lipoprotein bacteria get internalized in stroke.[65,66]Concentration of CRP shows macrophages and increases foam cell dose dependency, higher in patients with formation.[45]ICAM-1 and VCAM-1 in advanced periodontitis as compared to human umbilical vein endothelial cells moderate periodontitis, and higher crp level (HUVECs) is upregulated by LPS fraction in both groups compared to control of P.gingivalis, and facilitate mononuclear group.[67]A positive correlation has also cell adhesion to HUVECs.[46] been found between CRP levels and markers of endothelial dysfunction.[68,69] b. Inflammatory cytokines & acute phase protein Tumor Necrosis Factor-α (TNF-α) A number of inflammatory cytokines TNF-α is released by , and various molecules (IL-1, TNF-α, IL-2, macrophages, T cells and other cells. TNF-α ICAM, VCAM, Heat shock proteins [HSPs] performs a modulator like role not only in and fibrinogen) which are involved in the immune system but also in bone atherothrombogenesis are found to be formation and resorption.[70]In the elevated due to periodontal disease.[47, 48, 49] pathogenesis of cardiovascular diseases TNF-α and IL-6 play certain role and it also C – Reactive Protein (CRP) has significant systemic effects. [71,72] Rise in concentration of CRP an According to several studies TNF-α not acute phase reactant to inflammation can be only induces but also advances coronary induced by local and systemic tissue artery diseases. [73,74] It has been found that damage, infection and inflammation.CRP is patients with periodontitis have higher level produced mainly by liver in reponse to IL-6, of TNF-α, and correlation has also been extrahepatic production also occurs in the reported between increase in TNF-α and endothelium of atherosclerotic plaque, periodontitis and peripheral arterial disease. smooth muscle cells, infiltrated [75,76] Some studies showed that periodontal macrophages and inflammed gingival therapy has an effect on serum TNF-α tissues.[50,51,52] High sensitivity CRP is concentration,[77,78,79] while other studies regarded as one of the consistent markers of failed to find any effect of periodontal systemic inflammation and poor therapy on serum TNF-α concentration.[80] cardiovascular prognosis.[53,54] CRP is associated with atherogenesis through Interleukin – 6 (IL-6) production of cytokines (IL-1,IL-6,TNF-α IL-6 a proinflammatory cytokine is and interferon-α),CRP also mediate released from macrophages, monocytes, T binding of LDL and formation of foam cells and fibroblast, which act in an cells.[55,56,57,58]Various studies have shown a autocrine manner.IL-6 trigger systemic positive association between increased inflammation and production of acute phase levels of CRP and periodontitis. [59,60,61,62] proteins such as CRP, βfibrinogen, CRP is found to be elevated in patient with amyloidA, C3 complement component and periodontitis in comparison to control ceruloplasmin.[50,51,81] IL-6 release without periodontitis, moreover meta leukocytes and platelets into systemic analysis also indicated that periodontal circulation, alters hepatic or endothelial

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 16 Vol.6; Issue: 2; April-June 2021 Kamalkishor Mankar et.al. Association of periodontitis and cardiovascular disease synthesis and release of plasma proteins, foam cells which are found in fatty streak. thereby seems to be promoting vascular [30,95] Endothelial dysfunction can be thrombosis.[82] IL-6 levels were found to be evaluated by observing values of different higher in patients who had myocardial factors, such as acute phase proteins (CRP), infarction compared to those who did not TNF-α and IL-6 which are found to be have myocardial infarction in a 6 years long elevated in periodontitis patients.[96,63,80] follow-up study on healthy individuals.[83] Flow mediated dilation is found to be This indicates that IL-6 levels can be used reduced in patients with severe periodontal as a predictable risk marker for future disease.[97] P.gingivalis has the ability to myocardial infarction in healthy individuals. adhere, invade and proliferate in coronary Several studies reported that patients with endothelial cells causing endothelial cell periodontitis have higher levels of IL-6.[67,84] damage, thereby affecting physiological When levels of IL-6 were compared dilatory function of vessels. [44,98,99,100] between patients with coronary heart Increase in the carotid intima media wall disease along with periodontitis and thickness has also been reported in patients coronary heart disease alone, it was found with periodontal disease.[101,102] that patients having both coronary heart disease and periodontitis have higher IL-6 d. levels than those having coronary heart When local immune response is disease alone.[85] Regarding effect of induced by periodontal bacteria, it cross periodontal therapy on levels of IL-6 reacts with self expressed on the evidence is not conclusive, several studies vascular epithelium leading to vascular showed decrease in IL-6 levels following inflammation and atherosclerosis. Immune periodontal treatment while others showed response to bacterial heat shock genes and no significant effect of periodontal heat shock proteins might be the mechanism treatment on IL-6 levels.[86,87,88,89] by which infection may initiate and facilitate the progression of atherosclerosis. c. Endothelial dysfunction: All cells when exposed to various forms of Endothelial dysfunction is a stress (temperature, oxidative injury and pathological state of endothelium which is infection) express HSPs.[103,104]Heat shock characterized by imbalance between proteins have high molecular resemblance vasodilatory and vasoconstricting with each other,[105]therefore immune substances produced by endothelium. system may not be able to differentiate Arteries synthesize and release various between self HSP and bacterial HSP vasoactive substances, such as nitric oxide (GroEL). generated by host which act as vasodilator protecting against immune system for bacterial HSP could initiation and progression of atherosclerosis. result in an autoimmune response to In the initiation and progression of identical human HSP (hHSP) in the host.[103] endothelial alterational dysfunctional lipid Endothelial dysfunction leading to homeostasis plays a crucial role.[90,28,30,29] development of atherosclerosis may result Oxidized-LDLs (Ox-LDLs) are considered from cross reactivity of antibodies to as the major causative factor in the bacterial HSP with hHSP60 on endothelial atherosclerotic plaque development, and are cells.[106,107] Increase in morbidity and the major lipids found in atherosclerotic mortality due to atherosclerosis in patients lesions.[91] Ox-LDLs also plays a role in the with high anti-HSP 60/65 titers has development of endothelial dysfunction, as been demonstrated.[108]Antibody to Hhsp60 it act as a potent inflammatory agent, cross- reacts with periodontopathic bacterial thereby stimulating expression of adhesion GroEL as GroEL antigens share high degree molecules on endothelial cells.[92,93,94] of homology with hHSP60 proteins.[109] It Macrophages take up Ox-LDLs to form has been reported that patients with

Galore International Journal of Health Sciences and Research (www.gijhsr.com) 17 Vol.6; Issue: 2; April-June 2021 Kamalkishor Mankar et.al. Association of periodontitis and cardiovascular disease atherosclerosis have highest levels of Acknowledgement: None antibody to human Hhsp60 and P.gingivalis HSP60 (GroEL), followed by periodontitis Conflict of Interest: None patients and healthy subjects.[110] P.gingivalis has an Hsp60 and an Hsp90 Ethical Approval: This manuscript being a homologue which were found to cross react review article, no human or animal trial was with corresponding human Hsp.[111,112] It has performed. been demonstrated that periodontal destruction is less in patients with higher REFERENCES levels of anti-Hsp antibodies,[113] whereas 1. Offenbacher S: Periodontal diseases: inability to produce anti-Hsp antibodies pathogenesis. Ann Periodontol 1996, 1: might result in tissue destruction induced by 821–878. pathogens. In the serum and atheromas of 2. Eke P I, Page R C, Wei L, Thornton- patients with periodontal disease and Evans G, Genco R J. Update of the case atherosclerosis a T-cell response specific to definitions for population-based Hsp60 of P.gingivalis has been observed. surveillance of periodontitis. J Periodontol [114,115,] Presence of Anti-hsp65/60 2012 Dec; 83:1449-1454. antibodies in the saliva of patients with 3. Raitapuro-Murray T, Molleson TI, chronic periodontitis has been reported.[116] Hughes FJ. The prevalence of periodontal disease in a Romano-British population c

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