Periodontal pathology and cardiovascular diseases

Introduction

It has now been proved that some systemic diseases can modify the clinical appearances of periodontal diseases, especially by affecting the production or activity of various cytokines. This is the case, for instance, in patients suffering from neutropenia ^{(Mealey, 1996} ; ^{Offenbacher, 1996)}. Conversely, the impact oral pathology, in particular periodontal infection, on general health is less well known. What is at stake is a matter of degree.

Ischaemic cardio-vascular accidents are now one of the main causes of death in the western world. In general, the underlying pathology is linked to atherosclerosis which leads to ischaemic heart disease or cerebral vascular accidents which, taking into account the ageing of the population, represents the most important cause of morbidity and mortality in our societies ^{(Murray and Lopez, 1997)}. As a direct consequence of this elevated prevalence, ischaemic heart disease has been the object of numerous epidemiological studies that have enabled the identification of a number of risk factors such as smoking, hypercholesterolaemia, arterial hypertension and diabetes.

Nevertheless, taken together, these classical risk factors only account for two thirds, or even only half of ischaemic coronary accidents and we are witnessing the emergence of further hypotheses. More and more authors are now putting forward the theory of infection in connection with myocardial infarction and cerebrovascular accidents ^{(Valtonen, 1991} ; ^{Mattila et al., 1998} ; ^{Folsom, 1999} ; ^{Meier et al., 1999)} and periodontal infections are frequently cited as being the source.

Atherosclerosis and ischaemic heart diseases

Ischaemic heart disease has a multifactorial aetiology amongst which a common factor is an imbalance between the myocardial requirements for oxygen and its supply, brought about by a reduction in perfusion. The most frequent cause of myocardial ischaemia is atherosclerosis of the coronary arteries. By reducing the lumen of the vessels, it brings about a reduction of myocardial perfusion in the basal state or restricts an appropriate increase in response to an increased demand of the myocardium for oxygen ^{(Harrison, 2000)}. The characteristic lesions of atherosclerosis are mostly in the walls of large and medium sized arteries and evidenced by a thickening of the intima, a proliferation of smooth muscle cells in the media and an accumulation of macromolecules in the sub-epithelial connective tissue space and the media ^{(Ross, 1986)}.

Atherosclerosis of the coronary segments is due more frequently to the formation of an atheromatous plaque that may be complicated by the formation of fissures, haemorrhage, or thrombosis. Whilst the episodes of ischaemia are transitory, they can cause angina but equally, if they are prolonged, they may cause myocardial necrosis with or without an acute myocardial infarction. Twenty-five percent of cases of acute myocardial infarction pass unnoticed but they still have the same unfavourable prognosis as those cases with the usual clinical features. Amongst the other possible outcomes, arrhythmias due to conductive defects should not be forgotten ^{(Harrison, 2000)}.

Pathogenesis of atherosclerosis and consequential pathology due to ischaemia

Previously, the lesions of atherosclerosis were classified as fatty striations, fibrous plaques and complex lesions. The American Heart Association now recognises 6 different types of which the first three are considered to be precursors of atheromatous plaques. However, type III lesions, or lipid striations, occur in all middle aged subjects (^{Stary et al., 1995} ; ^{Fuster, 1997} ; ^{Wissler and Robert, 1996} ; ^{Virmani et al., 1998)}.

The current theory of atheroma formation presupposes that endothelial cells of the vascular intima are subject to repeated trauma that affects their integrity. Shearing forces and friction are particularly severe in the neighbourhood of orifices and the collateral branches. In these areas, damage to the endothelium brings about an accumulation of monocytes (macrophages) and of lipids. The process may be potentiated by the presence of other risk factors such as hypercholesterolaemia, diabetes, smoking, the presence of vasoactive amines in circulation (immune complexes) and infection ^{(Fuster, 1997} ; ^{Harrison, 2000)}.

Endothelial cells probably play a critical role in the early stages of atheroma formation by the oxidation of low density lipoproteins (LDL). Oxidised LDL could be involved in the initial recruitment of monocytes by inducing the expression of adhesion factors ICAM-1 and VCAM-1 by endothelial cells.

The equilibrium between the formation and elimination of lipids in the vascular wall is particularly influenced by a number of risk factors, leading to :

- stabilisation of the lesion by reducing the passage of lipids across the endothelium ;

- in the opposite case, by transition towards a stage IV and Va lesion ^{(Fuster, 1997)}.

These type IV and Va lesions seem to be responsible for the symptoms in less than two thirds of patients presenting with unstable angina or other signs of acute coronary ischaemia. Fissuring of these lesions brings about the formation of a thrombus (complex, type VI lesion) and it appears that the incidence of coronary thrombosis in acute myocardial infarction is above 90 % ^{(Fuster, 1997} ; ^{Virmani et al., 1998)}.

This fissuring of the lesions could be a « passive » phenomenon linked to the physical forces exerted on the plaques, the fibrous capsules of which are thin. Or, it could be an « active » phenomenon occurring within the lesions where there are a large number of macrophages. These macrophages are capable of degrading the extracellular matrix by phagocytosis and by the release of proteolytic enzymes, in particular metalloproteases (MMPs : collagenase, gelatinase and stromolysin-1, elastase). This process leads to fragility of the fibrous capsule of the atherosclerotic lesion, predisposing to the fissuring. Parietal smooth muscle cells, in the presence of elevated levels of LDL, will liberate large quantities of metalloproteases that contribute to the degradation of the matrix in situ ^{(Zhihe et al., 1996)}. The final and often fatal phase of atherosclerosis is thrombosis resulting from plaque aggregation ^{(Fuster, 1997)}.

The aetiology of atherosclerosis is therefore very complex and can result from many factors, not all of which have been fully identified.

Influence of infection on the development of atheromatous lesions

Epidemiological data, research on animal models, and clinical studies over the last 10 years seem to show that infection can contribute to the progression of atherosclerotic lesions. Infectious agents frequently cited are Chlamydia pneumoniae, herpes viruses, especially cytomegalovirus, Helicobacter pylori and the micro-organisms implicated in periodontal infections ^{(Danesh et al., 1997} ; ^{Folsom, 1999)}.

Indirect evidence concerning the influence of infection on the prevalence of coronary accidents is provided by a recent controlled clinical study ^{(Meier et al., 1999)} which shows that patients who have undergone tetracycline or quinalone treatment for various conditions (of which 40 to 50 % were respiratory infections) had fewer ischaemic coronary accidents than control subjects. The correlation remained statistically significant after adjustment for known risk factors such as hyperlipidaemia, hypertension, smoking, metabolic disorders and, to a degree, socio-economic situation.

Periodontitis and ischaemic cardiac pathology : epidemiological data

^{MacKenzie and Millard (1963)}, who sought to establish a link between diabetes and periodontal disease, noticed that patients presenting with signs of atherosclerosis had an overall greater degree of bone loss compared with control subjects. It was not until nearly 25 years later that this was reinvestigated, this time by a Finish group. ^Syrjänen observed a strong correlation between cerebro-vascular accidents (CVA) and oral infection. Although other risk factors for cerebral ischaemic pathology were not isolated, it appeared that patients who had suffered a CVA had more periodontal and dental infections than the control group who were matched for age and sex.

In the same year ^Mattila confirmed these findings in a controlled clinical study on 100 patients who presented with recent myocardial infarctions. The subjects were mostly male, aged less than 60 years. The state of the mouth was assessed by an index which took into account the presence and depth of the pockets, suppuration, the presence of angular bone defects, periapical lesions, pericoronitis, as well as the presence and amount of caries. Nevertheless, the results were not analysed in relationship to each of these oral pathologies. The scores thus obtained for patients having had an infarction were significantly raised, compared with the control subjects. The association between oral health and ischaemic pathology was upheld even after adjustment for other known factors : age, hypercholesterolaemia, triglyceride levels, arterial hypertension, diabetes and smoking. In contrast, cultural factors linked to lifestyle (diet, physical activity, etc.) were not available for analysis to assess whether they were associated with coronary disease or perhaps also with oral health.

In a subsequent study, ^Mattila analysed the oral state of 100 patients who were comparable to those in his first study, before subjecting them to a coronary angiogram. The results showed an undoubted correlation between the presence of oral infections (measured in the same way as above) and the severity of the coronary atherosclerosis in male patients (88 % of those involved). The validity of the association, even after isolating the classical risk factors for atherosclerosis, suggests that bacterial infection could play a role in the pathogenesis of coronary atherosclerosis.

Later still, ^Mattila showed in a 7-year prospective study of 214 patients suffering from ischaemic coronary pathology, that oral health is a significant predictive factor for coronary accidents and placed it as high as second place after a previous history of myocardial infarction and before diabetes. Socio-economic factors did not affect this association. Also, it seems that periodontal disease and caries raised the oral health index more than periapical lesions and pericoronitis.

If the above studies are considered to involve relatively few subjects, an investigation of public health undertaken in the United States ^{(De Stefano et al., 1993)} involving 9,000 subjects who were followed up for 14 years, confirmed the results obtained by the Finish teams. It seems that patients with periodontitis have a 25 % greater risk of infarction compared with healthy subjects and that the risk rises considerably for males under 50 years of age, which is that section of the population who have a higher level of periodontitis ^{(Lindhe, 1998)}. Within this group, those patients suffering from periodontitis, as for the edentulous subjects, have a 75 % greater risk of ischaemic heart disease compared with those subjects with little or no periodontal disease. In addition, the relative risk of having a myocardial infarction is increased by a factor of 2.86 compared with subjects unaffected by periodontal disease. Also, the authors found a correlation between cardiac pathology and the standard of oral hygiene but not with the presence of caries. These conclusions remained valid after taking into account other factors such as age, sex, race, educational level, family background, blood pressure, body mass, diabetes, smoking, physical activity, alcohol consumption and poverty index.

A second American longitudinal study ^{(Beck et al., 1996)} provided data concerning morbidity and mortality linked to ischaemic heart disease and cerebro-vascular accidents in a population of over 1,000 patients who were followed up for 18 years. The periodontal condition was documented at the beginning of the study and total absence of coronary pathology confirmed.

This study demonstrated an association between the incidence of the occurrence or non-occurrence of fatal ischaemic coronary disease (and of CVA) and the intitial periodontal condition. An increase in severity of bone loss of 20 % carried an increased incidence of ischaemic heart disease of 40 %. This cumulative incidence of ischaemic disease indicates a biological gra dient between exposure to periodontal infection and the development of coronary disease. In those subjects presenting with a mean bone loss of greater than 40 %, the incidence of fatal ischaemic accidents was 2.7 times greater than in those subjects without periodontal disease.

The cardiovascular risk factors that were taken into account are comparable to those in the preceding study and even if the list is not exhaustive, the relationship between periodontal disease and ischaemic heart disease seems to be clearly established.

The number of missing teeth as a risk factor for ischaemic coronary disease was also reported by ^Joshipura in a 6-year prospective study. A questionnaire, the validity of which was evaluated beforehand, was used to assess the oral state of subjects. This was addressed to 44,119 health care professionals, of whom approximately 60 % were dental surgeons. The authors suggest that the number of teeth lost because of periodontal disease is only one indicator of the severity of the condition. This study had the advantage of involving a large population of health care professionals. From the data provided by the questionnaire, it was, to a certain extent, possible to eliminate the effects of diet and to reduce the variability due to socio-economic state and even lifestyle.

More recently still, other studies with less elaborate protocols and with various populations have confirmed the results of previous studies. ^Genco showed, in a population of Pima Indians aged under 60 years, that subjects with periodontal disease had a 2.7 times greater risk of developing ischaemic heart disease than those Indians without periodontal disease. ^Loesche , in a cross-sectional study on 320 veterans, also showed that there was an association between the number of missing teeth and the prevalence of ischaemic heart disease. ^Morrison found that patients suffering from severe gingivitis, characterized by pronounced inflammation with bleeding and ulceration, had a higher risk of a fatal ischaemic accident than subjects not suffering from periodontal disease. ^Arbes confirmed the results of the enquiry into public health by ^{De Stefano} in a large scale study of the American population.

We will end this series of epidemiological data with a study by ^Soikkonen which, in a population of 292 elderly subjects, showed that the presence of intra-osseous lesions was a risk factor for mortality, all other causes taken together. The correlation thus established is comparable with that of smoking. Taken together, these studies show that periodontal disease is a risk factor for ischaemic heart disease but without being able to establish a cause and effect. This is due to the multiplicity of factors to be taken in to account. If ^{Joshipura's study (1996)} involving health care professionals at first sight affirms the dietary factor, other variables are not available for analysis. Therefore, the overall cultural factors and associated lifestyles are never totally apprehended. Today's models which include the known risk factors for cardiovascular disease, as complex as they are, cannot be adequately sensitive. The question remains posed ; whether periodontal disease is the determining factor or whether it is only a reflection of a poor lifestyle and inadequate treatment in certain patients. In this context, possible mechanisms by which periodontal pathology may influence the ischaemic disease could provide a biological basis for the epidemiological data.

Mechanisms and models of pathogenesis

Several mechanisms could explain the association between coronary ischaemic accidents and periodontal diseases. Grouped together, these mechanisms may be direct, indirect or linked to a genetic predisposition. They are not mutually exclusive and are being progressively validated by various studies. In order to explain the reason for the correlation that has been found in epidemiological studies, they all have to be linked in some way to atheroma formation ^{(Danesh et al., 1997} ; ^{Mealey, 1999} ; ^{Scannapieco and Genco, 1999)}.

Direct effects of infectious agents on atheroma formation

In patients suffering from generalised periodontitis, there is a loss of tissue integrity in the pocket epithelium leading to micro-ulceration that allows the passage of bacteria into the general circulation. Although there is no actual threshold value, it seems that patients who present with more than 60 % of their sites with 3 mm or more loss of attachment are those at risk of coronary pathology and for repeated bacteraemias ^{(Beck et al., 1996} ; ^{Offenbacher et al., 1999)}. In these individuals, brushing the teeth, using dental floss or simply mastication can provoke repeated bacteraemias ^{(Durack, 1995} ; ^{Sconyers et al., 1973)}.

From the time at which the pocket epithelium becomes ulcerated, it no longer plays a role in providing a barrier and any of the oral micro-organisms could pass into the general circulation. Streptococcus sanguis, one of the early colonisers of tooth surfaces, could therefore penetrate into the blood stream. ^Herzberg and ⁽¹⁹⁹⁶⁾ have shown that S. sanguis, in vitro, induces plaque aggregation and, when perfused into rabbits, the same organism causes alterations to the electrocardiogram, blood pressure, contractility and to the cardiac rhythm that are comparable to those occurring in myocardial infarction. These data seem to indicate that S. sanguis has a role in thrombus formation.

On the other hand, several teams have shown in vitro and ex vivo evidence from human arterial specimens that Porphyromonas gingivalis has the capacity to invade endothelial and smooth muscle cells. In addition, these bacteria have been identified in atherosclerotic lesions where the tissue is frail and rich in macrophages. The presence of the bacteria is associated with ulceration, with thrombus formation and the presence of markers for cellular apoptosis in the lesions ^{(Deshpande et al., 1998} ; ^{Chiu, 1999} ; ^{Progulske-Fox et al., 1999)}. It is equally possible that P. gingivalis brings about the production of pro-inflammatory cytokines in the lesions where the bacteria are present and which can participate in atheroma formation ^{(Offenbacher et al., 1999)}. Therefore, as well as these « direct » effects of these various infectious agents, it is very probable that products synthesised or degraded by these periodontal pathogens can bring about an inflammatory reaction whose effects are not limited only to the periodontal structures.

Indirect and genetic factors

Early studies found that there were raised levels of plasma fibrinogen, leucocytes and greater synthesis of the Willebrand factor in the endothelial cells in patients suffering from periodontal disease, factors which promote thrombus formation ^{(Kweider et al., 1993} ; ^{Mattila et al., 1989b)}. ^Beck considered that some individuals react to periodontal infection by liberating lipolysaccharide (LPS) into the general circulation through an exaggerated inflammatory response characterised by the formation of large quantities of pro-inflammatory cytokines, PGE₂, IL1β, TNF-α. The monocytes of individuals with a " hyper inflammatory " phenotype can secretes 3 to 10 times as much of the pro-inflammatory cytokines compared with those with a " normal " phenotype. Early onset periodontitis, refractory periodontitis and periodontitis associated with insulin dependent diabetes are the ones associated with this state. Furthermore, this phenotype is not induced by bacterial infection but exists even in the absence of any infection, or after the elimination of periodontal infection ^{(Shapira et al., 1994)}. Therefore, the authors immediately came to the conclusion that there is a genetic predisposition. Monocytes, stimulated by LPS, are central to this concept and may be responsible not only for the variations in the expression of periodontal disease, but also for the varying rates of formation of atherosclerotic plaques. In effect, the adhesion of monocytes to endothelial receptors (ICAM) seems to be an essential factor in atheroma formation. The monocytes are subject to modulation by environmental factors, by means of LDL that can encourage recruitment of these cells and stimulate the production of pro-inflammatory cytokines. In consequence, there is a downward spiral leading to aggravation of the periodontal disease and, specifically, to atheroma formation. Finally, the authors also suggest the possibility of aggregation and plaque adhesion induced by LPS.

^Ebersole in an animal model (monkey Macaca fascicularis) confirmed that, as a potential mechanism, periodontal infection could induce dyslipoproteinaemia, molecules linked to inflammation being involved. In effect, their results showed a correlation between the severity of periodontitis and the amount of LDL-cholesterol, as well as an increase in the levels of interleukin-8 and fibrinogen. In 4 monkeys having received a high fat diet, the correlation between periodontal disease/LDL-cholesterol was more marked than for the remainder of the animals with a normal diet. In addition, these 4 monkeys suffered more severe periodontal disease than those with a normal diet.

The association between periodontal disease and hyper-triglyceridaemia/hypercholesterolaemia has been illustrated by ^Cutler in a controlled clinical study. Even though dietary factors were not strictly taken into account, hyperlipidaemia in patients suffering from periodontal disease could, in part, be provoked by exposure to low concentrations of endotoxins (LPS) over a prolonged period of time. According to a number of in vitro studies and on animal models ^{(Feingold et al., 1992} ; ^{Cutler et al., 1999)}, it is possible that a vicious circle may occur : polymorphs stimulated by LPS produce pro-inflammatory cytokines (notably IL1β), the production of lipoproteins by the liver is augmented in the presence of IL1β and, in return, hyper-triglyceridaemia stimulates the secretion of cytokines by the polymorphs. The relationship between exposure to LPS and hyperlipidaemia observed in ^{Cutler's study (1999)} could actually be cause and effect.

According to a large cross-sectional study which showed a correlation between the periodontal condition and the level of C-reactive protein in the serum (a marker of inflammation and a known risk factor for cardiovascular pathology ^{(Ebersole et al., 1997} ; ^{Ridker et al., 1997)}, ^Slade concluded that periodontal diseases must be seen as a factor that contributes inflammatory reactions in general.

Taken together, these data associate periodontal disease and atherosclerosis. But it is probable that not all individuals suffering from periodontal disease have a major risk of developing ischaemic heart disease. ^Offenbacher consider that periodontal infection and atherosclerosis could share a common ground in the form of a complex or syndrome that the authors called periodontitis-atherosclerosis syndrome (PAS). From the periodontal viewpoint, this syndrome must relate to the generalized forms of the disease (irrespective of severity), with large quantities of bacterial plaque and deep pockets, rather than the localized forms with little plaque.

There seems not to be a critical level of periodontal disease above which patients would be at high risk of cardiovascular disease but more a linear correlation, with a risk proportional to the severity of periodontal disease (with a loss of attachment over 3 mm) ^{(Beck et al., 1996)}. This also corresponds with the concept of the periodontal lesion characterized by progressive loss and a more and more extensive epithelial damage, aggravated by the effects of infection and inflammation.

The starting point for the pathogenesis of this syndrome is the high virulence of the bacteria associated with perio dontal disease and accounts as much for the factors that have been well established, particularly those mentioned above, as for the stated hypothesis that still awaits eventual confirmation. In addition to the factors already mentioned, the authors envisage the occurrence of significant oxidation of LDL during their transport through the toxic environment represented by the capillaries of the infected periodontal tissues. This mechanism could help explain the interaction between perio dontitis and atherosclerosis as well as oxidised LDL playing a major role in atherosclerosis.

On the whole, a number of mechanisms have been evoked to explain the correlation between periodontal disease, atheroma formation and ischaemic heart disease. Not all of the various studies in connection with this provide the necessary level of proof. It is, however, essential that more information is provided by further in vitro studies, animal model and clinical studies, in order to test both the overall hypothesis and its different components. If the periodontitis-atherosclerosis syndrome exists, it must eventually include the concept of genetic predisposition, environmental factors and must identify the common pathogenic mechanisms that periodontal disease and atherosclerosis have in common.

What conclusions can be drawn ? What attitude should we take ?

One concept that emerges from the epidemiological, physiological and pathological data is that foci of perio dontal infection and, more generally, poor oral hygiene represents a risk factor and/or a significant predictor of ischaemic heart disease. This is the same for men as for women. Periodontal infection seems more and more to be a factor that disturbs the homeostatic equilibrium and is liable to bring about pathological changes away from its site of origin. Or else, periodontal disease shares certain unknown risk factors with several systemic diseases and reveals itself to be a remarkable marker for nume rous pathological conditions.

Whatever the situation, intensification of efforts to detect and prevent early onset periodontal diseases is the main objective. Taken together, the data available to us today indicate an increased level of responsibility for dentists. Also, in a patient who is predisposed to atherosclerosis and to ischaemic attacks, the elimination of all risk of potential infection must include a search for sites of infection in the periodontium. This may also be a not inconsiderable factor in the motivation of a patient suffering from periodontal disease.

The year 2000 saw the first report of a minister of health in the United States ^{(Surgeon general's report on oral health slated for June release, 2000)} specifically dedicated to the importance of oral health and to the interrelationships between oral health and general diseases.

Faced with these concepts, the dentist must not remain insensitive to the importance of the need to take appropriate measures to manage the periodontal disease in these patients. If periodontal disease is only a marker for risk of ischaemic heart disease, then this high risk population must be the target for intervention with the object of modifying known cardiovascular risk factors. If a cause and effect relationship is proven, then periodontal treatment, and even more importantly its prevention, could reduce the incidence of ischaemic heart disease. It could therefore become a factor for public health comparable to the struggle against smoking taking into account the morbidity, mortality and the high cost to society of cardiovascular diseases.

Demande de tirés à part

Tudor VAÏDEANU, Faculté de chirurgie dentaire, 1 rue Maurice-Arnoux, 92120 MONTROUGE - FRANCE.

BIBLIOGRAPHY

• ARBES SJ, SLADE GD, BECK D. Association between extent of periodontal attachment loss and self-reported history of heart attack : an analysis of NHANES III data. J Dent Res 1999;78:1777-1782.
• BECK J, GARCIA R, HEISS G, VOKONAS PS, OFFENBACHER S. Periodontal disease and cardiovascular disease. J Periodontol 1996;67(suppl. 10):1123-1137.
• CHIU B. Multiple infections in carotid atherosclerotic plaques. Am Heart J 1999;138(5 Pt 2):S534-S536.
• CUTLER CW, SHINEDLING EA, NUNN M, JOTWANI R, KIM BO, NARES S et al. Association between periodontitis and hyperlipidemia : cause or effect ? J Periodontol 1999;70:1429-1434.
• DANESH J, COLLINS R, PETO R. Chronic infections and coronary heart disease : is there a link ? Lancet 1997;350:430-436.
• DESHPANDE RG, KHAN MB, GENCO CA. Invasion of aortic and heart endothelial cells by Porphyromonas gingivalis. Infect Immun 1998;66:5337-5343.
• DE STEFANO F, AND RF, KAHN HS, WILLIAMSON DF, RUSSEL CM. Dental disease and risk of coronary heart disease and mortality. Br Med J 1993;13(306):688-691.
• DURACK DT. Prevention of infective endocarditis. N Engl J Med 1995;332:38-44.
• EBERSOLE JL, CAPPELLI D, MOTT G, KESAVALU L, HOLT SC, SINGER RE. Systemic manifestations of periodontitis in the non-human primate. J Periodont Res 1999;34:358-362.
• EBERSOLE J, MACHEN R, STEFFEN M, WILLMANN D. Systemic acute-phase reactants, C-reactive protein and haptoglobin in adult periodontitis. Clin Exp Immunol 1997;107:347-352.
• FEINGOLD KR, STAPRANS I, MEMON RA, GRUNFELD C. Endotoxin rapidly induces changes in lipid metabolism that produce hypertriglyceridemia : low doses stimulate hepatic triglyceride production while high doses inhibit clearance. J Lipid Res 1992;33:1765-1776.
• FOLSOM AR. Antibiotics for prevention of myocardial infarction ? Not yet ! J Am Med Assoc 1999;281(5):461-462.
• FUSTER V. Human lesion studies. Ann N Y Acad Sci 1997;811:207-225.
• GENCO R, CHADDA S, GROSSI S, DUNFORD R, TAYLOR G, KNOWLER W. Periodontal disease is a predictor of cardiovascular disease in a native American population [abstract]. J Dental Res 1997;76(suppl.):408.
• HARRISON TR. Principes de médecine interne. In : Wilson JD, Braunwald E, Isselbacher KJ, Petersdorf RG (eds). Paris : Flammarion Médecine-Science, 2000.
• HERZBERG MC, BRINTZENHOFE KL, CLAWSON CC. Aggregation of human platelets and adhesion of Streptococcus sanguis. Infect Immunity 1983;39(3):1457-1469.
• HERZBERG MC, MEYER W. Effects of oral flora on platelets : possible consequences in cardiovascular disease. J Periodontol 1996;67(suppl. 10):1138-1142.
• JOSHIPURA KJ, RIMM EB, DOUGLASS CW, TRICHOPOULOS D, ASCHERIO A, WILLETT WC. Poor oral health and coronary heart disease. J Dent Res 1996;75(9):1631-1636.
• KWEIDER M, LOWE GD, MURRAY GD, KINANE DF, McGOWAN DA. Dental disease, fibrinogen and white cell count ; links with myocardial infarction ? Scott Med J 1993;38(3):73-74.
• LINDHE J. Clinical periodontology and implant dentistry. In : Lindhe J, Karring T, Lang NP (eds). Copenhague : Munksgaard, 1998.
• LOESCHE WJ, SCHORK A, TERPENNING MS, CHEN YM, DOMINGUEZ BL, GROSSMAN N. Assessing the relationship between dental disease and coronary heart disease in elderly US veterans. J Am Dent Assoc 1998;129:301-311.
• MACKENZIE RS, MILLARD HD. Interrelated effects of diabetes, arteriosclerosis and calculus on alveolar bone loss. J Am Dent Assoc 1963;66:192-198.
• MATTILA KJ, NIEMINEN MS, VALTONEN VV, RASI VP, KESANIEMI YA, SYRJALA SL et al. Association between dental health and acute myocardial infarction. Br Med J 1989a;298(6687):1579-1580.
• MATTILA KJ, RASI VP, NIEMINEN MS, VALTONEN VV, KESANIEMI YA, SYRJALA SL et al. Von Willebrand factor antigen and dental infections. Thromb Res 1989b;15:325-329.
• MATTILA KJ, VALLE MS, NIEMINEN MS, VALTONEN VV, HIETANIEMI K. Dental infections and coronary atherosclerosis. Atherosclerosis 1993;103:205-211.
• MATTILA KJ, VALTONEN VV, NIEMINEN MS. Dental infection and the risk of new coronary events : prospective study of patients with documented coronary artery disease. Clin Infect Dis 1995;20:588-592.
• MATTILA KJ, VALTONEN VV, NIEMINEN MS, ASIKAINEN S. Role of infection as a risk factor for atherosclerosis, myocardial infarction, and stroke. Clin Infect Dis 1998;26(3):719-734.
• MEALEY BL. Periodontal implication : medically compromised patients. Ann Periodontol 1996;1:256-321.
• MEALEY BL. Influence of periodontal infections on systemic health. Periodontol 2000 1999;21:197-209.
• MEIER CR, DERBY LE, JICK SS, VASILAKIS C, JICK H. Antibiotics and risk of subsequent first-time acute myocardial infarction. J Am Med Assoc 1999;281(5):427-431.
• MORRISON HI, ELLISON LF, TAYLOR GW. Periodontal disease and risk of fatal coronary heart and cerebrovascular diseases. J Cardiovasc Risk 1999;6:7-11.
• MURRAY CJ, LOPEZ AD. Alternative projections of mortality and disability by cause, 1990-2000 : global burden of disease study. Lancet 1997;349:1498-1504.
• OFFENBACHER S. Periodontal diseases : pathogenesis. Ann Periodontology 1996;1:821-878.
• OFFENBACHER S, MADIANOS PN, CHAMPAGNE CM, SOUTHERLAND JH, PAQUETTE DW, WILLIAMS RC et al. Periodontitis-atherosclerosis syndrome : an expanded model of pathogenesis. J Periodont Res 1999;34:346-352.
• PROGULSKE-FOX A, KOZAROV E, DORN B, DUNN W Jr, BURKS J, WU Y. Porphyromonas gingivalis virulence factors and invasion of cells of the cardiovascular system. J Periodont Res 1999;34:393-399.
• RIDKER PM, CUSHMAN M, STAMPFER MJ, TRACY RP, HENNEKENS CH. Inflammation, aspirin and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979.
• ROSS R. The pathogenesis of atherosclerosis. N Engl J Med 1986;314:488-496.
• SCANNAPIECO FA, GENCO RJ. Association of periodontal infections with atherosclerotic and pulmonary diseases. J Periodont Res 1999;34:340-345.
• SCONYERS JR, CRAWFORD JJ, MORIARTY JD. Relationship of bacteremia to toothbrushing in patients with periodontitis. J Am Dent Assoc 1973;87:616-622.
• SHAPIRA L, SOSKOLNE WA, SELA MN, OFFENBACHER S, BARAK V. The secretion of PGE2, IL-1b and TNFa by monocytes from early onset periodontitis patients. J Periodontol 1994;65:139-146.
• SLADE GD, OFFENBACHER S, BECK JD, HEISS G, PANKOW JS. Acute-phase inflammatory response to periodontal disease in the US population. J Dent Res 2000;79(1):49-57.
• SOIKKONEN K, WOLF J, SALO T, TILVIS R. Radiographic periodontal attachment loss as an indicator of death risk in the elderly. J Clin Periodontol 2000;27:87-92.
• STARY HC, CHANDLER AB, DINSMORE RE, FUSTER V. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Atherosclerosis, American Heart Association. Circulation 1995;92:1355-1374.
• Surgeon general's report on oral health slated for June release. AAP News 2000 ; January/February:7.
• SYRJANEN J, PELTOLA J, VALTONEN V, IVANAINEN M, KASTE M, HUTTUNEN J. Dental infections in association with cerebral infarction in young and middle aged men. J Intern Med 1989;225:179-184.
• VALTONEN VV. Infection as a risk factor for infarction and atherosclerosis. Ann Med 1991;23:539-543.
• VIRMANI R, BURKE A, FARB A. Plaque morphology in sudden coronary death. Cardiologia 1998;43(3):267-271.
• WISSLER RW, ROBERT L. Aging and cardiovascular disease. Circulation 1996;93:1608-1612.
• ZHIHE L, LING L, LAKATTA E. Increased expression of 72 kDa type IV collagenase in human aortic atherosclerotic lesions. Am J Invest Pathol 1996;148:121-128.