The relationship between periodontal disease and cardiovascular disease has been extensively studied over the past decades through in vitro studies, animal models, case-control studies, cohort studies, randomized clinical trials and in multiple systematic reviews and meta-analyses.
The mechanisms are similar to other systemic diseases and disorders affected by chronic periodontal disease, and are based on the interaction between microorganisms of the subgingival biofilm and host inflammatory response.
The following is an explanation of the pathogenic mechanisms of the association, the epidemiology and evidence that periodontal treatment can improve some cardiovascular markers, and ultimately, the close relationship between periodontal disease and cardiovascular disease.
There are two. The first is when bacteria enter the bloodstream, which is known as bacteraemia, and the other is through the local or systemic production of inflammatory mediators.
- Inflammatory mechanisms
The initiation and propagation of early atherosclerotic lesions, atherosclerotic plaques, increase among patients with periodontitis, because the bacteria themselves or their products, and the inflammatory response they induce in the host, activate the T-lymphocyte cell-mediated immune response, contributing to endothelial dysfunction, LDL modification, attraction and maturity of monocytes, increased receipt of lipids and an attraction and promotion of Th1 lymphocytes. Atherosclerotic plaque maturation is produced when smooth muscle cells migrate to populate the intima, causing progressive fibrosis and calcification of the plaque. Different proinflammatory cytokines such as IL-6, IL-8, TGF-β, etc. are involved in this process and contribute to progressive maturation. During this maturation, vascular risk also exists within the plaque, which, if damaged, would favour the production of thrombin and prothrombin and fibrin and fibrogen, leading to coagulation cascade. The production of thrombin and inflammatory mediators could be associated with rupture of the plaque and thrombi and myocardial infarction.
So, both periodontitis and cardiovascular disease share inflammatory models that are interrelated and vary from individual to individual depending on their own genetic susceptibility. In studies so far it has been observed that inflammatory mediators and markers are elevated in patients with periodontitis, which could occur two ways. One is that the mediators travel from the periodontal lesion to other parts of the body potentially causing long-distance damage and inducing the formation of acute phase reactive compounds in the liver, such as C-reactive protein. The other way is for bacteria themselves or their products to enter the bloodstream, inducing a long-distance inflammatory response, even settling on the atherosclerotic plaques themselves (Teles & Wang 2011). Also, the inflammatory response can be affected by various types of periodontal disease-related antibodies and antibodies that can interact with antigens from the host, thereby inducing or accelerating atherosclerotic processes. Other studies have proven that there is an increase in potentially inflammatory lipids, such as LDLs, triglycerides and VLDLs, which may enter the atherosclerotic plaques and accelerate their formation and maturation. Finally, all of these mechanisms can occur simultaneously in the same patient, having a joint impact on systemic inflammation.
- Infectious mechanisms
Infectious theories relate to bacterial ability to directly interact and invade endothelial cells, smooth muscle cells, leukocytes, and platelets, or indirectly stimulate the release of paracrine factors that modulate the function of these cells.
Cell invasion by periodontal pathogenic bacteria is a key virulence factor for their survival and spread in certain environments and for the evasion of host defense. One of the most studied bacteria, both in vitro and in vivo, is P. gingivalis and its fimbrial adhesins (fimA) for endothelial cells and microphages. This invasion induces the migration of monocytes and significantly increases proinflammatory cytokine production. It also causes procoagulant effects in the aortic endothelial cells, causes apoptosis and increases the adhesion of mononuclear cells to endothelial cells. There also appears to be in vitro transmission between cells. Lastly, and within the host cell, it can modify the autophagic pathways necessary for cell protection, ultimately increasing inflammation and atherosclerotic processes.
Other bacteria such as A.actinomycetemcomitans, P. intermedia, T.forsythia, F.nucletaum, etc. have also been studied, which depending on their strain and on their different mechanisms, can invade host endothelial cells.
Clinical evidence that periodontal bacteria can cause cardiovascular disorders is based on several principles. The first, which has been widely proven, is that bacteria reach the vascular system through bacteraemia that are produced daily through brushing or even chewing. This can also be caused by professional procedures such as oral cleanings or tooth extractions. The second principle, also proven, is that the bacteria must be found in the affected tissues. Several studies have found genetic material from bacteria in atherosclerotic lesions, although it is not always possible to verify whether or not these bacteria are viable, as few studies have been able to grow them. The third and proven principle is that in vitro studies and animal studies have shown the invasive capacity and the capacity to form atherosclerotic plaques of certain periodontal pathogenic species such as P.g. The fourth, also proven, is that less invasive species cause less disease. The last, which has yet to be demonstrated, is that the species collected from human atherosclerotic plaques can cause atherosclerotic phenomena in animal models.
It is very important to remember that not all strains within the same species behave equally, and only the most virulent strains are able to cause cardiovascular damage.
For the epidemiological study of the relationship between periodontal disease and cardiovascular disease, the most studied types of cardiovascular disease are primary coronary disease, cerebrovascular disease and periphery arterial disease. Furthermore, periodontal disease is clinically defined by measuring probing depths and attachment levels and through radiographic study. In the majority of case-control and cohort studies conducted up until now, a clear association has been found between the extension and severity of periodontal disease and the emergence of atherosclerotic heart disease, independently from other risk factors such as smoking. The groups most affected according to some studies seem to be men and young adults. More study is needed to determine the association between the incidence of secondary cardiovascular events and periodontal disease in patients with established cardiovascular disease.
Evidence that periodontal treatment improves CVD biomarkers and outcomes
Cardiovascular disease continues to be the leading cause of death in the world, and any strategy or intervention aimed at controlling this epidemic is well received by the scientific community, by governments and by the general public. In this sense, chronic infectious diseases like periodontitis may play an important role in the aetiopathogenesis of atherosclerotic heart disease, and the presence of periodontal disease has been observed to double the risk of death even when all other risk factors are controlled.
Studies conducted until now have assessed the effects of periodontal therapy on traditional CVD risk factors such as lipids and blood pressure, on indirect CVD endpoint criteria such as endothelial function, average thickness of the carotid intima or subclinical atherosclerosis, and cardiovascular mortality/morbidity, and lastly, on new CVD risk factors including inflammatory markers, white blood cell counts and differentiation, acute phase proteins such as C-reactive protein, fibrogen and A-seric amyloid, cytokines such as interleukins and tumour necrosis factor-alpha, circulating cell adhesion molecules, haemostatic factors, matrix metaloproteinases and oxidative stress.
The most significant results have been lipid reduction, improved endothelial function, reduction of IL-6 and reduction of C-reactive protein following non-surgical periodontal therapy. For the remaining endpoints, the evidence is still limited, and more multicentre, long-term interventional studies are needed on large populations to validate the link between periodontal therapy and the decrease of cardiovascular risk on the short and long term.
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