## 3 Periodontitis and Cardiovascular Risk  
Numerous mechanisms have been proposed as links between periodontitis and atherosclerotic CVD, but the most important include systemic inflammation, molecular mimicry and direct plaque colonization by periodontal pathogens [38]. Several systematic reviews and meta-analyses have reported an association between periodontal disease and ischaemic heart disease [43; 44; 45; 46; 47]. Some authors have suggested that at clinical explorationlevel, periodontitis and CVD have a weak association, and that, actually, systemic bacterial exposure from periodontitis could be a more plausible risk factor. In this context, [PERSON] et al. [46] reported that periodontitis with increased markers of systemic bacterial exposure (periodontal bacterial burden, periodontitis-related specific serology and CRP) was associated with a greater risk of coronary heart disease compared with subjects without periodontitis [37]. It has also been shown that periodontitis patients present increased levels of inflammatory markers (tumour necrosis factor (TNF), interleukin (IL)-1, 6 and 8) [48]. Short-term adaptive response to inflammation is essential for a correct injury response and cell and tissue repair processes, while long-term consequences of a maintained inflammatory situation are often not beneficial [49]. It has also been reported that low-grade and chronic inflammation are characteristic in cardiometabolic diseases such as obesity, insulin resistance, type 2 diabetes and CVDs [50; 51]. An atypical immune response has been referred in these situations, described as metabolically triggered inflammation or \"metaflammation\", originated by metabolic surplus, which leads to the activation of different inflammatory molecules and signalling pathways [50]. It is worth mentioning that both metabolic and immune systems are regulated by the same cellular processes, through several hormones, cytokines and bioactive lipids that have a role in the metabolic and immune response. The activation of these \"metaflammatory\" pathways has been related to extracellular mediators such as cytokines and lipids, especially saturated fatty acids, and also by intracellular mediators such as endoplasmic reticulum stress and elevated production of mitochondria-derived reactive oxygen species. Fatty acid-binding proteins (FABPs), a family of lipid chaperones, have shown molecular and cellular links with \"metaflammation\", particularly in cases of cardiometabolic diseases such as obesity, diabetes and atherosclerosis [49]. The most recent consensus document regarding association between periodontitis and CVDs was the results from the joint workshop of the European Federation of Periodontology (EFP) and the World Heart Federation (WHF) in February 2019 [52]. According to its recommendations, periodontitis was considered as an established, novel CV risk factor that influences the management of subjects suffering from CVD or at increased CVD. The management of traditional CV risk factors, such as hypertension, is also required in the presence of periodontitis, and a good periodontal health is of great relevance for achieving CV health [53]. However, it remains to be determined if periodontal treatment in subjects with hypertension would translate into a reduced CV risk. Again, inflammation still appears to be one of the main links between CVD and periodontitis [52]. It should be mentioned that the available evidence mainly comes from observational studies, assessing major CV outcomes such as myocardial infarction, stroke, heart failure or CVD death, but few studies have investigated preclinical markers of CVD in subjects with periodontitis. Very interestingly, some studies suggested that healthy subjects with periodontitis may present signs of early atherosclerosis, and thus, periodontitis may be considered as a risk factor in case of CV events that cannot be fully explained by the presence of other commonly used CV risk factors [37; 52].