HHS Public Access Author manuscript Author Manuscript
Int Dent J. Author manuscript; available in PMC 2016 December 01. Published in final edited form as: Int Dent J. 2015 December ; 65(6): 283–291. doi:10.1111/idj.12185.
Systemic effects of periodontitis: Lessons learned from research on atherosclerotic vascular disease and adverse pregnancy outcomes
Author Manuscript
Panos N. Papapanou Section of Oral and Diagnostic Sciences, Division of Periodontics, Columbia University College of Dental Medicine, 630 West 168th Street, PH 7 E -110, New York, NY 10533, USA, [email protected]
Abstract
Author Manuscript
Studies conducted over the past 25 years have focused on the role of periodontitis, an inflammatory condition of microbial etiology that destroys the tooth supporting tissues, as a systemic inflammatory stressor that can act as an independent risk factor of atherosclerotic vascular disease (AVSD) and adverse pregnancy outcomes (APOs). It has been suggested that periodontitis-associated bacteremias and systemic dissemination of inflammatory mediators produced in the periodontal tissues may result in systemic inflammation and endothelial dysfunction, while bacteria of oral origin may translocate into the feto-placental unit. Epidemiologic studies largely support an association between periodontitis and ASVD / APOs independent of known confounders; indeed, periodontitis has been shown to confer statistically significantly elevated risk for clinical events associated with ASVD and APOs in multivariable adjustments. On the other hand, intervention studies demonstrate that although periodontal therapy reduces systemic inflammation and improves endothelial function, it has no positive effect on the incidence of APOs. Studies of the effects of periodontal interventions on ASVD-related clinical events are lacking. This review summarizes key findings from mechanistic, association and intervention studies and attempts to reconcile the seemingly contradictory evidence that originates from different lines of investigation.
Keywords Inflammation; periodontal; cardiovascular; gestation; therapy; review
Author Manuscript
INTRODUCTION Inflammation is at the heart of several pathologic conditions that have been traditionally considered as non-inflammatory. Consequently, over the last 25 years, a large body of research has focused on the potential effects of periodontitis, a bacterially-driven inflammatory disease, on general health outcomes. After the early publications by Matilla and coworkers (1) on the association between poor dental health and myocardial infarction,
COMPETING INTERESTS None.
Papapanou
Page 2
Author Manuscript
and by Offenbacher and coworkers (2) on the possible link between periodontitis and preterm, low birth weight, a new field of periodontal research has emerged, collectively referred to as “periodontal medicine”. This article provides a concise overview of the association between periodontitis as a potential exposure conferring risk for two broadly defined extra-oral pathologies, namely atherosclerotic vascular disease (ASVD) and adverse pregnancy outcomes (APOs). The text will review aspects of biological plausibility, will summarize the key epidemiologic findings, and will offer thoughts about the appropriate interpretation of the currently available research data.
BIOLOGICAL PLAUSIBILITY
Author Manuscript Author Manuscript
Periodontal diseases are inflammatory disorders that are the product of a polymicrobial perturbation of host homeostasis in the soft and hard tissues that support the teeth (3). Epidemiologic data suggest that their prevalence is high both in the United States (4) and globally (5), therefore, a potential role of these reversible and treatable conditions as systemic inflammatory stressors that may confer risk for extra-oral pathology is critically important from a public health point of view. Periodontitis is characterized by loss of connective tissue attachment and alveolar bone and is accompanied by a conversion of the shallow gingival sulcus into a deep periodontal pocket and a marked proliferation of a dysbiotic subgingival biofilm (6). In cases of generalized periodontitis, the surface area of the epithelial lining of the periodontal pocket is substantial (7), and breach of this epithelial barrier through ulceration allows direct contact between the microbial biofilm and the connective tissue. At the same time, this pocket epithelium/biofilm interface provides a gate of entry through which bacteria and bacterial products including lipopolysaccharide (LPS) challenge the immune system, elicit a local inflammatory response (8), and also enter the circulation. Indeed, transient bacteremias occur frequently as a result of daily activities such as tooth brushing or chewing (9, 10), as well as during invasive oral therapeutic procedures (11, 12). In parallel, inflammatory mediators that are abundantly produced locally in the periodontal tissues (13), including pro-inflammatory cytokines, chemokines, and as recently demonstrated also gingiva-derived C-reactive protein (14), can also be disseminated systemically through the blood stream. A systemic acute phase response, subsequent to processing of antigenic structures by the liver, results in elevated plasma CRP in periodontitis patients. Indeed, a meta-analysis of cross-sectional studies of high sensitivity CRP plasma levels in patients with periodontitis compared to that of periodontally healthy controls demonstrated a statistically significantly higher mean weighted hs-CRP in periodontitis amounting to 1.56 mg/L. This difference can be biologically relevant, as it can potentially shift an individual to the high CRP risk category (> 3 mg/L) (15).
Author Manuscript
As recently reviewed (16, 17), vascular endothelial activation is central to the role of periodontal infection/inflammation as a risk factor for atherosclerosis, but also as an exposure of importance for pre-eclampsia, a pathologic condition occurring during the second trimester of pregnancy characterized by maternal hypertension and proteinuria. In brief, circulating bacterial products such as lipopolysaccharide (LPS), outer membrane vesicles and fimbriae, or inflammatory cytokines and chemokines result in an up-regulation of cell-surface receptors and in expression of adhesion molecules on the endothelial lining of the vasculature. As a result, peripheral blood monocytes are recruited and adhere to the
Int Dent J. Author manuscript; available in PMC 2016 December 01.
Papapanou
Page 3
Author Manuscript Author Manuscript
activated endothelium. “Molecular mimicry” (18), i.e., the process through which antibodies targeted against specific bacterial proteins (e.g., “heat-shock” proteins that are highly homologous with mammalian proteins) act as auto-antibodies, contributes to apoptotic damage of the vascular endothelium. Guided by a chemo-attractant gradient, monocytes migrate into the sub-endothelial space, transform into tissue macrophages, uptake oxidized low density lipoprotein cholesterol (LDL) and become foam cells. Apoptosis of LDL-laden macrophages results in accumulation of lipids in the sub-endothelial space, i.e., in the formation of atheromatic plaques, which are covered by a fibrous cap and facilitate platelet accumulation. Exposure of the fibrous cap after endothelial cell apoptosis and enzymatic degradation of the extracellular matrix results in plaque rupture, exposure of pro-thrombotic plaque components, and subsequent thrombus formation that leads to the occlusion of the vessel. This may be manifested as a clinical ASVD-related event, e.g., a myocardial infarction in the case of an occluded coronary artery, or a stroke in the case of an occluded cerebral vessel. Interestingly, experimental mechanistic studies using oral incocculation with the keystone periodontal pathogen Porphyromonas gingivalis showed accelerated atherosclerosis in apolipoprotein-E null mice, and localization of P. gingivalis DNA in the aortic wall (19). The latter observation is in agreement with findings from human endarterectomy specimens that demonstrated presence of DNA from several periodontal species (20), and with observations of recovered viable Aggregatibacter actinomycetemcomitans and P. gingivalis from human atheromatic plaques (21).
Author Manuscript
With respect to the plausibility of the association between periodontitis and selected APOs (i.e., preterm birth, low birth weight, and preeclampsia), hematogenous spread of periodontal bacteria and their products and subsequent seeding of the placental membranes has been proposed as one of the potential mechanisms (22). Notably, a number of maternal infections including uterine track infections, bacterial vaginosis and chorioamnionitis are established risk factors for preterm birth and low birth weight (23), although approximately 50% of the variance in the incidence of these conditions remains unexplained by the established risk factors (24).
Author Manuscript
Normal parturition is controlled by inflammatory signaling that can be modified by external stimuli including infection and inflammatory stressors (25). As pregnancy progresses, amniotic fluid levels of prostaglandin E2 (PGE2) and inflammatory cytokines, such as TNFα and IL-1β rise steadily until a critical threshold level is reached, at which point they induce rupture of the amniotic sac membranes, uterine contraction, cervical dilation and delivery. Thus, elevation of these mediators in the amniotic sac walls or the myometrium may precipitate a premature onset of parturition. As mentioned above, the stimulus for this inflammatory response can reside either in the vicinity of the feto-placental unit or may originate from more remote loci. Early evidence of the potential role of translocated oral bacteria in APOs was provided by (26), who reported that amniotic fluid cultures from women with vaginosis frequently harbored Fusobacteria of oral origin. These observations were extended by (27) who demonstrated transmission of an uncultivated Bergeyella strain from the oral cavity to the
Int Dent J. Author manuscript; available in PMC 2016 December 01.
Papapanou
Page 4
Author Manuscript
amniotic fluid in a case of preterm birth. Experimental evidence in the pregnant hamster (28, 29) showed that injection of P. gingivalis resulted in intrauterine growth retardation. Subsequent studies in pregnant mice and rabbits (30, 31) confirmed and expanded these observations to include experimental infections by Fusobacterium nucleatum and Campylobacter rectus.
EPIDEMIOLOGIC EVIDENCE Before summarizing key findings from studies in humans on the role of periodontitis as a risk factor for ASDV or APOs, it is important to emphasize three key issues:
Author Manuscript Author Manuscript
The first is that the exposure variable, in our case periodontitis as a potential risk factor, has been defined in epidemiologic studies using a variety of measures, including clinical parameters (probing depths, attachment levels, bleeding on probing), radiographic assessments of alveolar bone loss, self-reported periodontal status, surrogate markers of poor oral health (tooth loss or edentulism), subgingival microbial profiles, or (in some seroepidemiological studies of ASVD) levels of antibodies to periodontal bacteria. It is clear that these variables are not interchangeable, as they reflect different aspects and phases of the disease pathobiology, and in the case of edentulism, a much more complex interplay of oral morbidity, socioeconomic factors, access to care and therapeutic decisions. The second issue is that even studies that have assessed periodontal status by clinical means in a comprehensive manner have not employed a consistent definition of periodontitis, but have used variable composite constellations of gingival inflammation, pocket depths and attachment levels to define a ‘periodontitis case’. The third point, that is one of the key determinants of quality in a epidemiologic study, is whether the association between the exposure under investigation (i.e., periodontitis) and the outcome (i.e., ASVD and APOs) has been adjusted for additional exposures that are known to affect the outcome (e.g., age, hyperlipidemia, hypertension, physical activity, etc.), as well as for potential confounders, i.e., factors that are associated with both the exposure under study, i.e., periodontitis, and the outcomes, i.e., ASVD or APOs (e.g., smoking, race/ethnicity). Thus, it must be recognized that both the differences in exposure definitions across studies and the variable degree of adjustment for additional risk factors may underlie a large proportion of the non-concordant findings in the literature. Periodontal disease and ASVD
Author Manuscript
The available epidemiologic studies between periodontitis and ASVD can be grouped in three major categories: (i) association studies (cross-sectional, case-control or longitudinal cohort studies) focusing on surrogate markers of ASVD; (ii) association studies focusing on clinical events (i.e., coronary heart disease, myocardial infarction, cerebrovascular disease, peripheral artery disease); and (iii) intervention studies, examining the effects of periodontal therapy on AVD-related outcomes (surrogate markers or events). The first group of studies has typically examined measures of systemic inflammation, such as and C-reactive protein (CRP) (32–34), or coagulation markers associated with clinical events, such as fibrinogen (35) (36), and have generally reported higher levels of these mediators in patients with periodontitis that periodontally healthy controls. As mentioned
Int Dent J. Author manuscript; available in PMC 2016 December 01.
Papapanou
Page 5
Author Manuscript Author Manuscript
above, meta-analysis of observation studies demonstrated significantly higher levels of hsCRP in periodontitis than periodontal health (37). Another marker of subclinical atherosclerosis that has been studied in this context is known to be associated with increased risk or myocardial infarction and stroke is intima-media thickness (IMT) (38). (39) analyzed cross-sectional data on 6,017 participants in the Atherosclerosis Risk in Communities (ARIC) study, and demonstrated that severe periodontitis conferred risk for increased IMT. Findings from the Oral Infection and Vascular Disease Epidemiology Study (INVEST) demonstrated in a fully adjusted model that IMT and while blood cell counts increased significantly over tertiles of colonization by specific periodontal bacteria suggestive of bacterial dysbiosis (40). A similar association was observed between subgingival microbial dysbiosis and both diastolic and systolic blood pressure as well as prevalent hypertension (41). Interestingly, serum antibody levels to several periodontal species were found to be positively associated with both prevalent IMT (42) and incident IMT progression (43). Lastly, the latest report from the INVEST study based on 430 participants followed up over a median time of 3 years demonstrated that progression of carotid IMT varied inversely across quartiles of longitudinal improvement in clinical and microbial periodontal status (44).
Author Manuscript
A large number of studies published over the last two decades have examined the association of poor periodontal status and clinical ASVD-related outcomes, including coronary heart disease, myocardial infarction, and stroke. Despite a substantial variability in the findings (expressed through odds ratios, hazard ratios o relative risk estimates), many but clearly not all - publications report statistically significant associations after adjustments for covariates and potential confounders. At least three meta-analyses that summarized the association between periodontal disease and clinical cardiovascular outcomes (45–47) consistently concluded that the available evidence suggests a moderate, positive association. This conclusion was corroborated by two recent narrative reviews (16, 48). A recent metaanalysis focused exclusively on cerebrovascular outcomes reported a positive association between periodontitis and both ischaemic and haemorrhagic stroke (49). Interestingly, the effect of periodontitis on ASVD-related clinical outcomes appears to be differential with age, with stronger associations in younger (
Int Dent J. Author manuscript; available in PMC 2016 December 01. Published in final edited form as: Int Dent J. 2015 December ; 65(6): 283–291. doi:10.1111/idj.12185.
Systemic effects of periodontitis: Lessons learned from research on atherosclerotic vascular disease and adverse pregnancy outcomes
Author Manuscript
Panos N. Papapanou Section of Oral and Diagnostic Sciences, Division of Periodontics, Columbia University College of Dental Medicine, 630 West 168th Street, PH 7 E -110, New York, NY 10533, USA, [email protected]
Abstract
Author Manuscript
Studies conducted over the past 25 years have focused on the role of periodontitis, an inflammatory condition of microbial etiology that destroys the tooth supporting tissues, as a systemic inflammatory stressor that can act as an independent risk factor of atherosclerotic vascular disease (AVSD) and adverse pregnancy outcomes (APOs). It has been suggested that periodontitis-associated bacteremias and systemic dissemination of inflammatory mediators produced in the periodontal tissues may result in systemic inflammation and endothelial dysfunction, while bacteria of oral origin may translocate into the feto-placental unit. Epidemiologic studies largely support an association between periodontitis and ASVD / APOs independent of known confounders; indeed, periodontitis has been shown to confer statistically significantly elevated risk for clinical events associated with ASVD and APOs in multivariable adjustments. On the other hand, intervention studies demonstrate that although periodontal therapy reduces systemic inflammation and improves endothelial function, it has no positive effect on the incidence of APOs. Studies of the effects of periodontal interventions on ASVD-related clinical events are lacking. This review summarizes key findings from mechanistic, association and intervention studies and attempts to reconcile the seemingly contradictory evidence that originates from different lines of investigation.
Keywords Inflammation; periodontal; cardiovascular; gestation; therapy; review
Author Manuscript
INTRODUCTION Inflammation is at the heart of several pathologic conditions that have been traditionally considered as non-inflammatory. Consequently, over the last 25 years, a large body of research has focused on the potential effects of periodontitis, a bacterially-driven inflammatory disease, on general health outcomes. After the early publications by Matilla and coworkers (1) on the association between poor dental health and myocardial infarction,
COMPETING INTERESTS None.
Papapanou
Page 2
Author Manuscript
and by Offenbacher and coworkers (2) on the possible link between periodontitis and preterm, low birth weight, a new field of periodontal research has emerged, collectively referred to as “periodontal medicine”. This article provides a concise overview of the association between periodontitis as a potential exposure conferring risk for two broadly defined extra-oral pathologies, namely atherosclerotic vascular disease (ASVD) and adverse pregnancy outcomes (APOs). The text will review aspects of biological plausibility, will summarize the key epidemiologic findings, and will offer thoughts about the appropriate interpretation of the currently available research data.
BIOLOGICAL PLAUSIBILITY
Author Manuscript Author Manuscript
Periodontal diseases are inflammatory disorders that are the product of a polymicrobial perturbation of host homeostasis in the soft and hard tissues that support the teeth (3). Epidemiologic data suggest that their prevalence is high both in the United States (4) and globally (5), therefore, a potential role of these reversible and treatable conditions as systemic inflammatory stressors that may confer risk for extra-oral pathology is critically important from a public health point of view. Periodontitis is characterized by loss of connective tissue attachment and alveolar bone and is accompanied by a conversion of the shallow gingival sulcus into a deep periodontal pocket and a marked proliferation of a dysbiotic subgingival biofilm (6). In cases of generalized periodontitis, the surface area of the epithelial lining of the periodontal pocket is substantial (7), and breach of this epithelial barrier through ulceration allows direct contact between the microbial biofilm and the connective tissue. At the same time, this pocket epithelium/biofilm interface provides a gate of entry through which bacteria and bacterial products including lipopolysaccharide (LPS) challenge the immune system, elicit a local inflammatory response (8), and also enter the circulation. Indeed, transient bacteremias occur frequently as a result of daily activities such as tooth brushing or chewing (9, 10), as well as during invasive oral therapeutic procedures (11, 12). In parallel, inflammatory mediators that are abundantly produced locally in the periodontal tissues (13), including pro-inflammatory cytokines, chemokines, and as recently demonstrated also gingiva-derived C-reactive protein (14), can also be disseminated systemically through the blood stream. A systemic acute phase response, subsequent to processing of antigenic structures by the liver, results in elevated plasma CRP in periodontitis patients. Indeed, a meta-analysis of cross-sectional studies of high sensitivity CRP plasma levels in patients with periodontitis compared to that of periodontally healthy controls demonstrated a statistically significantly higher mean weighted hs-CRP in periodontitis amounting to 1.56 mg/L. This difference can be biologically relevant, as it can potentially shift an individual to the high CRP risk category (> 3 mg/L) (15).
Author Manuscript
As recently reviewed (16, 17), vascular endothelial activation is central to the role of periodontal infection/inflammation as a risk factor for atherosclerosis, but also as an exposure of importance for pre-eclampsia, a pathologic condition occurring during the second trimester of pregnancy characterized by maternal hypertension and proteinuria. In brief, circulating bacterial products such as lipopolysaccharide (LPS), outer membrane vesicles and fimbriae, or inflammatory cytokines and chemokines result in an up-regulation of cell-surface receptors and in expression of adhesion molecules on the endothelial lining of the vasculature. As a result, peripheral blood monocytes are recruited and adhere to the
Int Dent J. Author manuscript; available in PMC 2016 December 01.
Papapanou
Page 3
Author Manuscript Author Manuscript
activated endothelium. “Molecular mimicry” (18), i.e., the process through which antibodies targeted against specific bacterial proteins (e.g., “heat-shock” proteins that are highly homologous with mammalian proteins) act as auto-antibodies, contributes to apoptotic damage of the vascular endothelium. Guided by a chemo-attractant gradient, monocytes migrate into the sub-endothelial space, transform into tissue macrophages, uptake oxidized low density lipoprotein cholesterol (LDL) and become foam cells. Apoptosis of LDL-laden macrophages results in accumulation of lipids in the sub-endothelial space, i.e., in the formation of atheromatic plaques, which are covered by a fibrous cap and facilitate platelet accumulation. Exposure of the fibrous cap after endothelial cell apoptosis and enzymatic degradation of the extracellular matrix results in plaque rupture, exposure of pro-thrombotic plaque components, and subsequent thrombus formation that leads to the occlusion of the vessel. This may be manifested as a clinical ASVD-related event, e.g., a myocardial infarction in the case of an occluded coronary artery, or a stroke in the case of an occluded cerebral vessel. Interestingly, experimental mechanistic studies using oral incocculation with the keystone periodontal pathogen Porphyromonas gingivalis showed accelerated atherosclerosis in apolipoprotein-E null mice, and localization of P. gingivalis DNA in the aortic wall (19). The latter observation is in agreement with findings from human endarterectomy specimens that demonstrated presence of DNA from several periodontal species (20), and with observations of recovered viable Aggregatibacter actinomycetemcomitans and P. gingivalis from human atheromatic plaques (21).
Author Manuscript
With respect to the plausibility of the association between periodontitis and selected APOs (i.e., preterm birth, low birth weight, and preeclampsia), hematogenous spread of periodontal bacteria and their products and subsequent seeding of the placental membranes has been proposed as one of the potential mechanisms (22). Notably, a number of maternal infections including uterine track infections, bacterial vaginosis and chorioamnionitis are established risk factors for preterm birth and low birth weight (23), although approximately 50% of the variance in the incidence of these conditions remains unexplained by the established risk factors (24).
Author Manuscript
Normal parturition is controlled by inflammatory signaling that can be modified by external stimuli including infection and inflammatory stressors (25). As pregnancy progresses, amniotic fluid levels of prostaglandin E2 (PGE2) and inflammatory cytokines, such as TNFα and IL-1β rise steadily until a critical threshold level is reached, at which point they induce rupture of the amniotic sac membranes, uterine contraction, cervical dilation and delivery. Thus, elevation of these mediators in the amniotic sac walls or the myometrium may precipitate a premature onset of parturition. As mentioned above, the stimulus for this inflammatory response can reside either in the vicinity of the feto-placental unit or may originate from more remote loci. Early evidence of the potential role of translocated oral bacteria in APOs was provided by (26), who reported that amniotic fluid cultures from women with vaginosis frequently harbored Fusobacteria of oral origin. These observations were extended by (27) who demonstrated transmission of an uncultivated Bergeyella strain from the oral cavity to the
Int Dent J. Author manuscript; available in PMC 2016 December 01.
Papapanou
Page 4
Author Manuscript
amniotic fluid in a case of preterm birth. Experimental evidence in the pregnant hamster (28, 29) showed that injection of P. gingivalis resulted in intrauterine growth retardation. Subsequent studies in pregnant mice and rabbits (30, 31) confirmed and expanded these observations to include experimental infections by Fusobacterium nucleatum and Campylobacter rectus.
EPIDEMIOLOGIC EVIDENCE Before summarizing key findings from studies in humans on the role of periodontitis as a risk factor for ASDV or APOs, it is important to emphasize three key issues:
Author Manuscript Author Manuscript
The first is that the exposure variable, in our case periodontitis as a potential risk factor, has been defined in epidemiologic studies using a variety of measures, including clinical parameters (probing depths, attachment levels, bleeding on probing), radiographic assessments of alveolar bone loss, self-reported periodontal status, surrogate markers of poor oral health (tooth loss or edentulism), subgingival microbial profiles, or (in some seroepidemiological studies of ASVD) levels of antibodies to periodontal bacteria. It is clear that these variables are not interchangeable, as they reflect different aspects and phases of the disease pathobiology, and in the case of edentulism, a much more complex interplay of oral morbidity, socioeconomic factors, access to care and therapeutic decisions. The second issue is that even studies that have assessed periodontal status by clinical means in a comprehensive manner have not employed a consistent definition of periodontitis, but have used variable composite constellations of gingival inflammation, pocket depths and attachment levels to define a ‘periodontitis case’. The third point, that is one of the key determinants of quality in a epidemiologic study, is whether the association between the exposure under investigation (i.e., periodontitis) and the outcome (i.e., ASVD and APOs) has been adjusted for additional exposures that are known to affect the outcome (e.g., age, hyperlipidemia, hypertension, physical activity, etc.), as well as for potential confounders, i.e., factors that are associated with both the exposure under study, i.e., periodontitis, and the outcomes, i.e., ASVD or APOs (e.g., smoking, race/ethnicity). Thus, it must be recognized that both the differences in exposure definitions across studies and the variable degree of adjustment for additional risk factors may underlie a large proportion of the non-concordant findings in the literature. Periodontal disease and ASVD
Author Manuscript
The available epidemiologic studies between periodontitis and ASVD can be grouped in three major categories: (i) association studies (cross-sectional, case-control or longitudinal cohort studies) focusing on surrogate markers of ASVD; (ii) association studies focusing on clinical events (i.e., coronary heart disease, myocardial infarction, cerebrovascular disease, peripheral artery disease); and (iii) intervention studies, examining the effects of periodontal therapy on AVD-related outcomes (surrogate markers or events). The first group of studies has typically examined measures of systemic inflammation, such as and C-reactive protein (CRP) (32–34), or coagulation markers associated with clinical events, such as fibrinogen (35) (36), and have generally reported higher levels of these mediators in patients with periodontitis that periodontally healthy controls. As mentioned
Int Dent J. Author manuscript; available in PMC 2016 December 01.
Papapanou
Page 5
Author Manuscript Author Manuscript
above, meta-analysis of observation studies demonstrated significantly higher levels of hsCRP in periodontitis than periodontal health (37). Another marker of subclinical atherosclerosis that has been studied in this context is known to be associated with increased risk or myocardial infarction and stroke is intima-media thickness (IMT) (38). (39) analyzed cross-sectional data on 6,017 participants in the Atherosclerosis Risk in Communities (ARIC) study, and demonstrated that severe periodontitis conferred risk for increased IMT. Findings from the Oral Infection and Vascular Disease Epidemiology Study (INVEST) demonstrated in a fully adjusted model that IMT and while blood cell counts increased significantly over tertiles of colonization by specific periodontal bacteria suggestive of bacterial dysbiosis (40). A similar association was observed between subgingival microbial dysbiosis and both diastolic and systolic blood pressure as well as prevalent hypertension (41). Interestingly, serum antibody levels to several periodontal species were found to be positively associated with both prevalent IMT (42) and incident IMT progression (43). Lastly, the latest report from the INVEST study based on 430 participants followed up over a median time of 3 years demonstrated that progression of carotid IMT varied inversely across quartiles of longitudinal improvement in clinical and microbial periodontal status (44).
Author Manuscript
A large number of studies published over the last two decades have examined the association of poor periodontal status and clinical ASVD-related outcomes, including coronary heart disease, myocardial infarction, and stroke. Despite a substantial variability in the findings (expressed through odds ratios, hazard ratios o relative risk estimates), many but clearly not all - publications report statistically significant associations after adjustments for covariates and potential confounders. At least three meta-analyses that summarized the association between periodontal disease and clinical cardiovascular outcomes (45–47) consistently concluded that the available evidence suggests a moderate, positive association. This conclusion was corroborated by two recent narrative reviews (16, 48). A recent metaanalysis focused exclusively on cerebrovascular outcomes reported a positive association between periodontitis and both ischaemic and haemorrhagic stroke (49). Interestingly, the effect of periodontitis on ASVD-related clinical outcomes appears to be differential with age, with stronger associations in younger (
