Periodontitis and atherosclerotic cardiovascular disease

2.1 Introduction

This chapter describes the relationship of peri­odontal disease and atherosclerotic cardiovascular disease (ACVD). Periodontal disease encompasses periodontitis, gingivitis, acute necrotising gingivitis and periodontal abscess. This chapter is focused mainly on periodontitis. First, it will provide the reader with a concise description of the main forms of ACVD that have been associated with periodontitis. Thereafter, the literature will be reviewed regarding the associations of both diseases and the effects of periodontal treatment on the clinical and biochemical parameters of ACVD. Finally, plausible mechanisms of how periodontitis may be causally related to ACVD will be discussed.

2.1.1 Atherosclerotic cardiovascular disease

ACVD comprises a group of conditions that primarily affects the vasculature of vital organs including heart, brain and kidneys, and include fatal and non-fatal events. Traditionally, ACVD is grouped into:

coronary artery disease (CAD)

ischaemic cerebrovascular disease

peripheral arterial diseases

other manifestations1,2.

CAD, also known as ischaemic heart disease, involves the reduction of sufficient blood flow to the heart muscles due to atherosclerotic lesions in coronary arteries. It is the most common form of ACVD and types include stable or unstable angina, myocardial infarction and sudden cardiac death3. Ischaemic cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. The most common presentation is an ischaemic cerebrovascular accident (ischaemic stroke or transient ischaemic accident)4. Peripheral artery disease is a common circulatory problem in which narrowed arteries reduce blood flow to limbs. CAD and ischaemic cerebrovascular disease are the leading causes of death worldwide. They are responsible for 16% of all deaths in developing countries and 50% in developed countries3,5,6. In Europe, 45% of deaths are due to ACVD and four out of five ACVD deaths are due to myocardial infarction and ischaemic cerebrovascular accident7.

The main aetiopathogenic factor in ACVD is atherosclerosis. It is defined as thickening of blood vessel walls due to the accumulation of lipids, inflammatory cells and fibrous components, forming the so called atheromatous plaque. Several factors influence and contribute to atherogenesis (atheroma formation). Longitudinal and large epidemiological studies, such as the Framingham Heart Study, have revealed the different risk factors for ACVD and identified common pathways such as endothelial dysfunction and systemic inflammation. In developed countries the main risk factors include abnormal plasma cholesterol levels (elevated levels of low-density lipoprotein [LDL] and very low-density lipoprotein [vLDL] and insufficiently high levels of high-density lipoprotein [HDL], high blood pressure, tobacco use, alcohol consumption, obesity and diabetes8,9.

In general, multiple risk factors for ACVD have been identified and they have been grouped as ‘common non-modifiable’, ‘non-modifiable’ and modifiable’10, listed in Table 2-1. These risk factors are responsible for around 90% of the cases with myocardial infarction11. Other risk factors reported include acute or chronic stress, excess homocysteine in blood, and abnormal blood coagulation9. Thus, other factors have also been investigated to explain the 20% to 30% of ACVD events without the obvious classic risk factors. Novel indirect risk factors such as acute or chronic stress, insufficient diet, excess homocysteine in blood, and abnormal blood coagulation have been mentioned12.

Table 2-1 Risk factors associated with ACVD

Common non-modifiable Non-modifiable Modifiable
Age Genetic factors (family history) Physical inactivity
Sex Diabetes Tobacco use
Ethnicity Systemic inflammation Unhealthy and insufficient diet
Low socio-economic status Elevated cholesterol
High blood pressure

Adapted from World Heart Federation10.

2.1.2 Atherosclerosis

Since atherosclerosis is at the base of ACVD, further information is important in order to understand the association with periodontitis. Currently, atherosclerosis is understood also to be an inflammatory disease13 in which immune mechanisms interact with the conventional risk factors described above. Atherosclerosis is characterised by an alteration of the vascular endothelium and the formation of atherosclerotic plaques that decrease the lumen of blood vessels. Lipid deposition is a key phenomenon in atherogenesis and plaques are formed by an LDL cholesterol core and a fibrous capsule (Fig 2-1). In this way, vital arteries become progressively narrow and this results in stenosis. Interestingly, it appears that there are predilection places for major atherosclerotic plaque formations, such as in the coronary arteries and in the carotid arteries at the vicinity of the bifurcation in to the internal and external carotid artery14. Atherosclerotic plaques can occlude a blood vessel leading to insufficient oxygen and nutrient transport to the tissue or organs supplied by this blood vessel, causing necrosis and organ failure. On the other hand, the atherosclerotic plaques can also rupture and then the content of the plaque core is exposed. It contains thrombogenic material, which causes the formation of a thrombus at that place, thereby completely occluding the blood vessel lumen. Also, this thrombus/blood clot can migrate downstream and affect a distant organ13,15.

Fig 2-1 Depiction of atherogenesis (atheromatous plaque formation). For the understanding of the aetiopathogenesis of atherosclerosis it is necessary to know the anatomy of blood vessels. They are built of three layers: tunica intima (internal layer), media (middle layer) and externa or adventitia (external layer). The tunica intima consists of the endothelium (dark blue) and the basal elastic lamina (light red), present in both arteries and veins. The tunica media (light blue) is composed of smooth muscle fibres, elastic fibres and collagen, depending on the type of artery. The tunica adventitia (dark red) is formed by loose connective tissue with fibroblasts and collagen.
a Accumulation of lipids (such as low density lipoprotein [LDL]) in the subendothelial layer of the intima, where they also become oxidised in the tissue environment, leading to ox-LDL. This elicits an initial inflammation, attracting monocytes, which migrate into the endothelium and differentiate into macrophages. The cardiovascular vessel becomes stiffer and less elastic.
b Transformation of macrophages into foam cells through phagocytosis of ox-LDL.
c Formation of a necrotic core within the early atheromatous lesion, consisting of necrotic macrophages, lipids and extracellular matrix. The inflammatory process and necrotic tissue leads to the production of cytokines and pro-inflammatory mediators, driving the inflammatory process.
d Migration of smooth muscle cells from the media into the intima and formation of a fibrous cap (grey) on the surface of the lesion.
e The atheroma can either eventually occlude the lumen of the blood vessel or
f rupture and exposition of underlying atherosclerotic plaque leading to thrombosis or blood clot formation that can migrate.

2.1.3 Clinical presentations of ACVD

The atherosclerotic lesions resulting in blood vessel stenosis present clinically in different forms and conditions. They are sub-grouped into major and non-major ACVD events and these are illustrated in Fig 2-2.

Fig 2-2a and b Clinical presentations of ACVD. a Major events; b non-major events.

Myocardial infarction is an acute coronary syndrome resulting from a lack of blood supply to an area of the heart muscle (myocardium) caused by a sudden blockage in a coronary artery, and leads to cell and tissue necrosis. The lack of blood supply causes (unstable) angina pectoris and, if the artery is not opened early, it causes death (necrosis) of the heart tissue. That is the heart attack. Symptoms of (unstable) angina pectoris often mimic those of myocardial infarction: people typically have intermittent pressure or an ache beneath the sternum, possibly in the shoulders, arms, back, neck or jaw3. Interestingly, symptoms between males and females are substantially different in relation to the perception and description of the symptoms. Females have very varied symptoms that make it more difficult to diagnose as myocardial infarction. The most common symptoms are unusual fatigue, shortness of breath, cold sweat or epigastric pain. The preceding days are often accompanied by insomnia, anxiety or weakness. On the other hand, typical chest pain in females is less specific16.

An ischaemic cerebrovascular event (ischaemic stroke) is a condition that occurs when there is poor or a complete lack of blood flow to the brain4. This leads to limited oxygen supply (cerebral hypoxia) and results in cerebral infarction (partial brain tissue necrosis). Signs and symptoms may include an inability to move, unilateral lack of sensation, impairments in vision and speaking, unconsciousness, problems with coordination and weakness of the body. Two main clinical entities of ischaemic cerebrovascular events have been described:

thrombotic stroke, when a blood clot at the site of an atherosclerotic plaque blocks the brain ­artery

embolic stroke or cerebral embolism, when a blood clot from an atherosclerotic plaque located elsewhere (released in the neighbourhood in a brain vessel or released from a distant place elsewhere in the body) blocks the brain artery.

In addition to an ischaemic stroke, there is another type of stroke called ‘haemorrhagic stroke’, but this occurs when a blood vessel somewhere in the brain is weakened and expanded (called an aneurysm) and ruptures4.

Both events described above, a myocardial infarction or an ischaemic cerebrovascular event, can be of such massive magnitude that it results in sudden death of the patient.

One of the first symptoms of systemic atherosclerosis is increased blood pressure. The atherosclerotic plaque formation throughout the major systemic arteries impairs the elastic properties of the arterial wall, leading to the increased blood pressure. Notably, high blood pressure originating either from atherosclerosis or from other causes, reciprocally increases the progression of atherosclerotic alterations. Hypertension is defined as having a sustained blood pressure of 130/80 mmHg or above. However, ideal blood pressure for a physically healthy person is < 120/80 mmHg. The ranges by which blood pressure is classified are presented in Table 2-217.

Table 2-2 Categories of blood pressure in adults17

BP category SBP DBP
Normal < 120 mmHg and < 80 mmHg
Elevated 120 – 129 mmHg and < 80 mmHg
Hypertension Stage 1 130–139 mmHg or 80–89 mmHg
Stage 2 ≥ 140 mmHg or ≥ 90 mmHg

BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure.

Peripheral artery disease (claudicatio intermittens or vascular claudication), is a blood circulation disorder that causes the peripheral arteries or veins to narrow, block or spasm. It is a chronic obstruction of the arteries supplying the lower extremities and is a common manifestation of systemic or local atherosclerosis. Intermittent claudication is the most frequent symptom and is typically experienced as pain, cramping and fatigue in the lower extremities, especially during exercise, that are relieved by rest1820. It has been described that 61% of patients suffering from peripheral artery disease had concomitant CAD and/or ischaemic cerebrovascular disease21.

Vascular cognitive decline refers to a group of diseases that are caused by brain damage from impaired blood flow due to damage of the blood vessels of the brain. This occurs after repeated small, often ‘silent’, ischaemic events to a certain part of the brain. The changes that occur after each blockage may not be apparent, but over time, the combined effect starts to cause symptoms of impairment. Together with stroke, atherosclerosis is the most frequent cause. The presence of multiple cognitive deficits is manifested by impairment of memory, difficulties with daily activities such as thinking, concentration or communication, personality and mood changes (depression or irritability) and problems with movement and/or balance22.

Among the ischaemic conditions is also the condition of erectile dysfunction. This is defined as the persistent or recurrent inability to complete or continue a penile erection sufficient for satisfactory sexual performance23. It is well accepted that this apparently common condition has not only a psychological background. The most common pathophysiological explanation behind erectile dysfunction is atherosclerosis of the vascular system. Therefore, erectile dysfunction is also known as vasculogenic impotence. Epidemiological studies have shown that men with erectile dysfunction most often have a history of ACVD or develop a major ACVD event over some years of follow-up24,25.

2.2 Clinical evidence

The viewpoint that the mouth was a structure isolated from the rest of the organism began to change in 1989, thanks to the observational study published by Finnish scientists, in which it was observed that poor dental and periodontal health status were posi­tively associated with the development of acute myo­cardial infarction and cerebral infarction26. Since then, many studies have been published analysing an association between periodontitis and ACVD.

On several occasions cardiologists and peri­odontists have gathered the available evidence about the possible association between periodontitis and ACVD, and presented these in joint statements2729. They concluded that periodontitis is associated with ACVD events, even when the known confounding factors like smoking and diabetes mellitus have been taken into account. However, to date there is insufficient evidence that periodontitis can be regarded a true causative factor. Nevertheless, many mechanistic studies and periodontal treatment studies do support the hypothesis that periodontitis can be regarded as another risk factor among the well-known risk factors for ACVD.

It is important to highlight that when studying the association between periodontitis and ACVD, and the possible causality, the most suitable primary endpoint to study would be ‘hard endpoints’ in longitudinal studies, i.e. cardiovascular events, such as death, myocardial infarction, ischaemic cerebrovascular event or the need for revascularisation procedures. However, ethical considerations, the large sample sizes and the long follow-up required to analyse differences in the frequency of events in randomised controlled ­trials represent the difficulties to perform these long follow-up studies. Instead, cross-sectional studies and longitudinal ­cohort studies with ‘hard endpoints’ and both cross-sectional and longitudinal studies including surrogate clinical and biochemical parameters (secondary endpoints) have been performed in order to further elucidate the link with periodontitis. In Table 2-3, the endpoints that have been applied in most studies on the association of periodontitis and ACVD are summarised.

Table 2-3 Primary and secondary endpoints used in studies assessing the relationship between periodontitis and ACVD

CRP = C-reactive protein; E-selectin = endothelial adhesion molecule; FMD = flow-mediated dilatation; HDL = high-density lipoprotein; ICAM-1 = intercellular adhesion molecule 1; IL = interleukin; LDL = low-density lipoprotein; MMP-9 = matrix metalloproteinase 9; PAF = platelet-activating factor; PAI-1 = plasminogen activator inhibitor -1; P-selectin = endothelial adhesion molecule; PWV = pulse wave velocity; TNF-α = tumour necrosis factor; VCAM-1 = vascular cell adhesion molecule 1; vLDL = very low-density lipoprotein.

Therefore, epidemiological evidence has been divided into four groups:

association studies with primary endpoints, i.e. events

association studies with secondary endpoints: clinical parameters of ACVD

association studies with secondary endpoints: biochemical parameters of ACVD

intervention studies, observing the effects of periodontal treatment on secondary endpoints of ACVD.

2.2.1 Association studies with primary endpoints

Many studies have been conducted on the epi­demiological relationships between periodontitis and ACVD events; these are listed in Table 2-4. In recent years, several systematic reviews and meta­analyses have been published synthesising the epidemiological evidence available that links ACVD, such as myocardial infarction or ischaemic cerebrovascular event, to periodontitis5658. In a recent systematic review, it was summarised that relatively strong evidence exists of an increased risk of atherosclerotic vascular disease in subjects with periodontitis, independent of other established cardiovascular risk factors; and that it appears that the occurrence of tooth loss is higher in patients with ACVD59.

Table 2-4 Epidemiological association studies evaluating periodontitis and tooth loss with primary ACVD endpoint (studies published since 2000)

ACVD = atherosclerotic cardiovascular disease; BMI = body mass index; BOP = bleeding on probing; CAD = coronary artery disease; CAL = clinical attachment level; CRP, C-reactive protein; DM = diabetes mellitus; DPSI = Dutch Periodontal Screening Index; G = gingivitis; GI, Gingival Index; HDL = high-density lipoprotein; HR = hazard ratio; ICE = ischaemic cerebrovascular event; LDL = low-density lipoprotein; MI = myocardial infarction; n/a = not reported; OR = odds ratio; PD = periodontal disease; PDSI = Periodontal Severity Index (combination of bone loss, tooth loss); PI = Plaque Index; PPD = probing pocket depth; RR = risk ratio; Rx = radiography; TIA = transient ischaemic attack. Coronary artery disease

Bahekar et al58 identified five longitudinal studies, five case-control studies and five cross-sectional studies, which define cases as subjects with fatal or non-fatal CAD and exposure as subjects with defined periodontitis, either by periodontal clinical evaluation, or by self-reporting. The meta-ana­lysis of the five longitudinal studies (86,092 patients) indicated that individuals with periodontitis are 1.14 times more likely to suffer from CAD than controls (relative risk [RR] 1.14, 95% confidence interval [CI] 1.074 to 1.213). The case-control studies (1423 patients) showed an even higher risk of CAD (odds ratio [OR] 2.22, 95% CI 1.59 to 3.117). The prevalence of CAD in the cross-sectional studies (17,724 patients) was significantly higher among individuals with periodontitis (OR 1.59, 95% CI 1.329 to 1.907)58. Likewise, Humphrey et al60 published a systematic review selecting only longitudinal studies in which periodontitis, Framingham risk factors and CAD were assessed. The RR for the different categories of periodontitis was 1.24 (95% CI 1.01 to 1.51) for severe periodontitis and 1.34 (95% CI 1.10 to 1.63) for bone loss60. Blaizot et al56 included in their systematic review with meta-analysis patients with angina pectoris, myocardial infarction and sudden death due to CAD; they obtained an OR for the risk of suffering from CAD in patients with periodontitis of 2.35 (95% CI 1.87 to 2.96), and an RR of 1.34 (95% CI 1.27 to 1.42).

In a recent multicentre observational study of over > 1600 Swedish patients (PAROKRANK study), the relationship between periodontitis and a first myocardial infarction was analysed61. Periodontitis was evaluated objectively by radiographic bone loss. A significantly increased risk for first myocardial infarction was observed in patients diagnosed with severe periodontitis (OR 1.28, 95% CI 1.03 to 1.60) after adjusting for confounding factors (i.e. dia­betes mellitus, smoking habit)61. In general, it can be concluded that most of these studies describe significant associations between periodontitis and CAD (with a range of risk estimate between 1 and 2.4). Although the degree of association has been shown most significantly in individuals under 60 years old and in individuals with a higher severity of periodontitis, it should also be noted that, from the methodological point of view, they are very heterogenous studies, which lack an adequate assessment of risk exposure (measurement of periodontitis), as well as repeated measures of assessment of the periodontal status. Although the findings derived from epidemiological clinical studies point to the existence of a statistically significant relationship between periodontitis and CAD, the cause–effect relationship has not yet been demonstrated. Ischaemic cerebrovascular event

The first evidence of an association between dental diseases and ischaemic cerebrovascular event occurred in 1989, when Syrjänen et al62, in a case-control study, observed a higher prevalence of dental diseases in patients with ischaemic cerebrovascular event at less than 50 years of age. With a large sample size, the study by Elter et al63 was performed on the Atherosclerosis Risk in Communities (ARIC) study data (6436 subjects), and determined that loss of clinical attachment > 3 mm was associated with the occurrence of ischaemic cerebrovascular event (OR 1.3, 95% CI 1.02 to 1.7). Grau et al64, in a study conducted on 303 patients 7 days after having suffered an acute ischaemic event or transient ischaemic attack, and 300 controls, found that severe periodontitis is a risk factor for ischaemic cerebrovascular event in men under 60 years (OR 4.3, 95% CI 1.85 to 10.2). Two more case-control studies have been published in this field. Sim et al65 reported data from a Korean population, and Pradeep et al66 from an Indian population. These studies concluded that peri­odontitis is closely related to ischaemic cerebrovascular event, giving values of OR 4.0 (95% CI 2.3 to 7.0) or 8.5 (95% CI 1.1 to 68.2), respectively65,66. However, despite the value of case-control studies for generating hypotheses, they are weak study models to confirm any association between the exposure (peri­odontitis) and disease (ischaemic cerebrovascular event).

Notably, Beck et al66 in a longitudinal study concluded that there is a close association between peri­odontitis and ischaemic cerebrovascular events (RR 2.8, 95% CI 1.45 to 5.48). Wu et al55, on data from the National Health and Nutrition Examination Survey I (NHANES-I; 9962 adults between 25 and 74 years), also reported that periodontitis is a significant risk for ischaemic cerebrovascular events (RR 2.11, 95% CI 1.30 to 3.42). Subsequently, Joshipura et al54, in a study conducted on 41,380 men, followed their study population for a total of 12 years. They found a significant association between the ischaemic cerebrovascular events and the number of teeth (n < 25) (RR 1.57, 95% CI 1.24 to 1.98) or the presence of periodontitis (RR 1.33, 95% CI 1.03 to 1.70)54. Due to its long follow-up over a period of 34 years, it is also worth mentioning the study by Jimenez et al51, conducted on 1137 veterans. They suggested that radiographic alveolar bone loss is significantly associated with an increase in the ischaemic cerebrovascular event risk rate (RR 3.52, 95% CI 1.59 to 7.81), with this effect being higher in those under the age of 65 years (RR 5.81, 95% CI 1.63 to 20.7)51.

The meta-analysis by Khader et al57, which includes four cohort studies, one cross-sectional and one case-control study, found that the risk of suffering an ischaemic cerebrovascular event in patients with periodontitis is 1.13 (95% CI 1.01 to 1.27). A recent systematic review by Leira et al68 included eight studies (five case-control and three cohort studies) and the analysis showed a statistically significant relationship between periodontitis and ischaemic cerebrovascular events; the OR of the case-control studies was 3.04 (95% CI 1.10 to 8.43) and the RR for cohort studies was 2.52 (95% CI 1.77 to 3.58)68.

In general, it can be concluded that most studies report significant associations between periodontitis and ischaemic cerebrovascular events. It is important to note that many of the studies included in the meta-analyses are of case-control design, thus giving only an OR for association. In addition, the included studies often have a small sample size and many define periodontitis as tooth loss or with self-reported questionnaires. These factors are likely to introduce bias and false-negative or false-positive observations. Therefore, in the recent meta-analysis published by Leira et al68, only studies were included in which periodontitis was defined on the basis of clinical measures such as periodontal attachment loss or deepened pocket depths. Nevertheless, the longitudinal studies reviewed in this section also suggest that periodontitis (or surrogate measures of periodontitis) poses a significant risk for ischaemic cerebrovascular events. In addition, the epidemiological studies have always adjusted their findings for the traditional risk factors of ACVD, yielding properly adjusted RRs. However, the cause–effect relationship is not yet clearly established. Peripheral artery disease

One of the first studies evaluating the association of periodontitis with peripheral artery disease was in a longitudinal study by Mendez et al69. They used data from a cohort of 1231 veterans in the Normative Aging Study and Dental Longitudinal Study of the US Department of Veterans Affairs with a 25- to 30-year follow-up period. Subjects with periodontitis at baseline had a 2.27 increased risk of developing peripheral artery disease (95% CI 1.32 to 3.9)69.

A recent systematic review by Yang et al70 revealed a significant relationship between periodontitis and peripheral artery disease. Seven studies were included with a total of 4307 patients (four case-control studies, two cross-sectional studies and one longitudinal cohort study). The pooled analysis indicated a significant risk of 1.70 (95% CI 1.25 to 2.29). When comparing tooth loss and clinical attachment loss between peripheral artery disease patients and non-peripheral artery disease participants, a significant difference in the number of missing teeth was observed (3.75, 95% CI 1.31 to 6.19). However, no significant difference was found in clinical attachment loss (−0.05, 95% CI 0.03 to 0.19). The results from this systematic review should be viewed with caution because of the high heterogeneity and limited number of included studies70. In summary, there is limited evidence indicating that periodontitis poses a risk for the development of peripheral artery disease, but clearly further high-quality and well-designed studies need to be carried out to strengthen this assumption. Other ACVD

To date, a limited number of well-designed studies have reported an association on the relationship between periodontitis and erectile dysfunction. Most of these studies are cross-sectional studies. In the systematic review by Wang et al23, only four cross-sectional studies were included, those with clear diagnostic criteria for periodontitis and erectile dysfunction. It was found that among the men with erectile dysfunction, the chance of having peri­odontitis simultaneously was about three times higher than men without erectile dysfunction (OR 3.07, 95% CI 1.87 to 5.05). In the subgroup analysis by age it was observed that subjects younger than 30 years had a significantly higher OR for periodontitis among patients with erectile dysfunction23.

2.2.2 Association studies with secondary endpoints: clinical parameters of ACVD

In past years, blood pressure, carotid intima-media thickness (IMT), flow-mediated dilatation (FMD) and pulse wave velocity (PWV) have been used as secondary clinical parameters of ACVD (Table 2-5). These parameters reflect mainly the systemic level of atherosclerosis, but they have been proven to be robust predictors for an ACVD event. In this section, studies on the relationship between periodontitis and the secondary clinical parameters of ACVD will be outlined, and are also listed in Table 2-6.

Table 2-5 Overview of various methods to determine systemic levels of atherosclerosis (clinical parameters of ACVD)

Clinical parameters Method Objective measurement
Blood pressure Blood pressure cuff mmHg
IMT (intima-media wall thickness) Ultrasound Thickness of intima media in mm
FMD (flow-mediated dilatation) Ultrasound % vascular dilatation after provocation
PWV (pulse wave velocity) Registration reflection blood pressure wave with sensors in blood pressure cuff m/sec

Table 2-6 Epidemiological association studies evaluating periodontitis with secondary endpoints: clinical parameters of ACVD (studies published since 2000)

BMI = body mass index; BOP = bleeding on probing; CAL = clinical attachment level; CPI = Community Periodontal Index; DM = diabetes mellitus; GB = gingival bleeding; GI, Gingival Index; HDL = high-density lipoprotein; HR = hazard ratio; LDL = low-density lipoprotein; OR = odds ratio; PD = periodontal disease/periodontitis; PPD = probing pocket depth; PSI = Periodontal Screening Index; RR = risk ratio; SSD = statistically significant difference. Blood pressure

Blood pressure is the most simple and best reproduced way to look at the condition of the blood vessel system. The blood pressure gives an indication of the arterial stiffness and indirectly this non-invasive and easily applicable parameter provides the degree of atherosclerosis. A range of epidemiological studies has been carried out investigating a possible relationship between periodontitis and blood pressure90,92.

A meta-analysis conducted by Martin-Cabezas et al92, including 16 studies, showed that the presence of hypertension was associated with the presence of periodontitis (OR 1.50, 95% CI 1.27 to 1.78). Even after exclusion of those studies that could not provide a secure diagnosis of severe periodontitis and hypertension, an OR of 1.64 (95% CI 1.23 to 2.19) was still present. However, studies with no positive association were also observed. The authors criticised a lack of prospective follow-up studies and the heterogeneity among the studied populations, as well as heterogeneity in periodontal and hypertension diagnosis criteria. The authors further suggest that bias could have been introduced by not distinguishing severe forms of periodontitis in the included studies, as mild and moderate periodontitis would have reduce the strength of the observed association92.

Nevertheless, blood pressure is a simple and fast measure of possible subclinical atherosclerosis, and can be measured in a dental office. The literature shows that periodontitis patients in general have higher blood pressure values than non-periodontitis patients and for research purposes it demonstrates once more the association between this oral condition and risk for ACVD. Carotid intima-media wall thickness

The intima-media thickness (IMT) of the larger arteries that are relatively superficially positioned (e.g., carotid artery) can easily be measured noninvasively using ultrasound (Fig 2-3). An increased IMT appears to be able to predict acute cardiovascular events reasonably well, and in this way the IMT measurements of the carotid arteries are often used as clinical surrogate markers for the degree of atherosclerosis93. There are several studies that have assessed the narrowing of the carotid arteries in relation to periodontitis; the majority of these studies have found higher IMT in patients with periodontitis compared to healthy subjects.

Fig 2-3a to c a The intima-media thickness (IMT) of the carotid arteries is measured by ultrasound. b Histopathological view of the IMT. Measurement of the thickness of intima and media layers, the innermost two layers of the wall of an artery. c An ex­­ample of an ultrasound image of IMT measurement.

Beck et al86 provided the first evidence that peri­odontitis is linked to subclinical atherosclerosis. In a cross-sectional study involving 6017 individuals from the Atherosclerosis Risk in Communities (ARIC) study, they demonstrated that severe peri­odontitis was associated with increased odds for higher IMT (OR 2.09, 95% CI 1.73 to 2.53 for IMT of ≥ 1 mm)86. Since this study, several reports have been published investigating this relationship. Several years later, in 2003, another epidemiology study (INVEST) was published by Desvarieux et al94. Here, 711 individuals were enrolled with no history of cerebrovascular ischaemic event or myocardial infarction; in these individuals a full periodontal examination was performed. It was concluded that in those individuals with > 10 missing teeth, carotid artery plaque prevalence was around 60% (OR 1.9, CI 1.2 to 3.0)92.

In a meta-analysis by Orlandi et al95, seven studies indicated that in patients with periodontitis a significant thickening of the intima media is present in the carotid arteries, suggesting an increased risk for an acute cardiovascular event. The weighted difference between periodontitis and non-periodontitis subjects was 0.8 mm (95% CI 0.07 to 0.09), which indicates that on average, peri­odontitis patients have a thicker vascular wall of carotid arteries, and therefore more atherosclerosis95. Flow-mediated dilatation

FMD is a marker of vascular response and a characteristic of endothelial dysfunction. It is very similar to the previous technique (IMT measurements), as it is also measured using ultrasound, but the parameter FMD is dynamic and determines the elasticity (degree of dilation) of the brachial artery. It evaluates the diameter of the brachial artery after flow insufflation, being a reliable measure of the improvement of vascular function (Fig 2-4). The lower the percentage of dilation, the stiffer the artery, the more atherosclerosis the patient would have96.

Fig 2-4 Flow mediated dilatation (FMD) measurement. The degree of vascular wall elasticity is measured as vascular wall dilation by ultrasound before and after the brachial artery has been occluded for 5 min (provocation). The percentage dilation of the brachial artery following release is measured in response to this provocation.

Several controlled cross-sectional studies have been conducted in which the FMD was assessed in relation to peri­odontal status. Almost all studies reported significant endothelial dysfunction in peri­odontitis patients. However, a relatively large variation in endothelial function was found.

The relationship between peri­odontitis and FMD was investigated in a systematic review by Orlandi et al95, in which seven studies were avail­able for meta-analysis. The authors demonstrated that peri­odontitis was associated with a mean difference in FMD of 5.1% compared to controls (95% CI 2.08 to 8.11%), implicating that peri­odontitis patients have a significantly less elastic brachial artery (lower percentage dilation) than control subjects95. Arterial stiffness (pulse wave velocity)

Arterial stiffness, like IMT and FMD, is accepted as a clinical predictor for the future development of cardiovascular disease, e.g, atherosclerosis97. The degree of arterial stiffness can be assessed by measuring the PWV. PWV is a reproducible and non-invasive measurement with a specially developed blood pressure cuff that allows calculating the pulse wave propagation velocity between two sites. The most used measurement is the aortic (carotid-femoral artery) PWV (Fig 2-5). The increase in aortic PWV by 1 m/s is related to a 15% increase in risk of ACVD events98. In a systematic review by Schmitt et al99, five cross-sectional studies showed a significant association between peri­odontitis and arterial stiffness. It was reported that patients with peri­odontitis have increased arterial stiffness compared to controls (PWV mean difference 0.85 m/s; 95% CI 0.53 to 1.16). However, in three out of these five studies this association was not significant when adjusted for common confounders (smoking, diabetes, age, gender)99.

Fig 2-5 Measuring the pulse wave velocity (PWV). PWV is measured by obtaining a record of the arterial pulse wave at a proximal artery such as the carotid, as well as a distal vessel such as the femoral or brachial artery.

In a recent cross-sectional study by Sanz-Miralles et al100, the authors found that PWV was not significantly different between subjects suffering from peri­odontitis compared to peri­odontally heathy subjects. The latter study participants exhibited significantly lower PWV than controls (median PWV 2.81 m/s vs. 3.35 m/s, respectively)100. By contrast, in the study by Houcken et al101, significantly higher PWV in peri­odontitis patients compared to control subjects (8.01 ± 0.20 vs. 7.36 ± 0.22 m/s, respectively) was seen, and this remained significant after adjustments for ACVD risk factors. Indeed, it was observed that PWV values > 14 m/s were significantly associated with severe peri­odontitis, compared with lower PWV that were associated with peri­odontal health. However, after adjustment for potential confounding factors no significant difference remained102.

The fact that the results from these studies are not consistent is in part due to inherent methodological difficulties in the assessment of PWV, and also to additional factors including the way peri­odontitis was assessed, as well as actual differences in the level of peri­odontitis extent and severity across samples.

2.2.3 Association studies with secondary endpoints: biochemical parameters of ACVD

Surrogate markers for ACVD are also found in blood. Therefore, many studies have used blood plasma or serum for assessment of biochemical parameters that are indicative of the risk for future ACVD events. Van Holten et al103 evaluated their predictive values for future cardiovascular events. These markers are mainly plasma proteins involved in the pathophysiology of atherosclerosis and include mainly C-reactive protein (CRP), fibrinogen, cholesterol, HDL and vitamin D. The authors reported that for primary cardiovascular events, markers with strong predictive potential for ACVD events were mainly associated with ­lipids103. Systemic inflammatory markers

Several systemic inflammatory markers in ACVD have been described that also have been found in high levels in patients with peri­odontitis compared to peri­odontally healthy subjects. Some of these markers have a positive association with the extent of peri­odontitis104107.

Among these markers, CRP has been the most studied and has been the focus of attention as a key marker of atherosclerosis risk at elevated levels. It is considered as a risk for ACVD diseases108. CRP levels show a clear correlation with the occurrence of ACVD. Individuals with CRP concentrations lower than 1 mg/l are considered low risk, concentrations of 1 to 3 mg/l are assigned to a medium risk and concentrations greater than 3 mg/l are considered to pose a high risk to suffer future cardiovascular events109. CRP is an acute phase protein produced in the liver in response to bacteria in the bloodstream and/or in response to pro-inflammatory cytokines (immune mediators such as interleukin [IL]-6). In one of the first cross-sectional studies in the peri­odontal field, significantly higher levels of CRP in peri­odontitis were demonstrated compared to peri­odontally healthy subjects (median 1.45 mg/l vs. 0.90 mg/l, respectively)105. In the systematic review by Paraskevas et al110, significantly higher mean levels of CRP in peri­odontal patients versus controls were observed (3.41 mg/l for peri­odontitis subjects and 1.72 mg/l for peri­odontally healthy individuals); and the weighted mean difference in CRP between patients and controls was 1.56 mg/l (P < 0.00001). This systematic review provides evi­dence that peri­odontitis elicits a mild acute-phase response with elevation of CRP levels compared to healthy controls110. In a sample comprising 5552 individuals from the Atherosclerosis Risk in Communities (ARIC) study, subjects with severe peri­odontitis (≥ 30% of sites with a pocket depth of ≥ 4 mm) had 30% higher CRP levels than participants without or mild peri­odontitis111. It was also observed that peri­odontal clin­ical parameters, such as attachment loss, pocket depth and bleeding on probing were associated with higher levels of CRP111. Since then, more studies have evaluated the evidence that peri­odontitis is associated with elevated levels of systemic CRP.

In addition to CRP, IL-6 has been studied due to the fact that it is a major inducer of the acute-phase reactions stimulating production of CRP in the liver, but also it has been identified as risk marker in itself. Danesh et al112 carried out a systematic review and meta-analysis with all published studies evaluating the levels of IL-6 and its relationship with future cardiovascular events, demonstrating a significant association with a mean risk estimate of 1.9 (CI 95% 1.5 to 2.3). In a study carried out by Loos et al105, the presence of IL-6 was significantly higher in peripheral blood of patients with peri­odontitis compared to peri­odontally healthy subjects (median 0.46 pg/ml vs. 0.20 pg/ml, respectively). A study by Tang et al113 investigated hospitalised patients with CVD and compared them to non-CVD hospitalised patients with regard to serum cytokines and peri­odontal status. They observed significantly higher systemic levels of IL-6 (63.78 ± 8.56 pg/l vs. 45.62 ± 3.37 pg/L, respectively) and tumour necrosis factor-α (TNF-α) (9.33 ± 4.66 pg/l vs. 3.24 ± 3.26 pg/l, respectively) in patients with CVD and peri­odontitis113.

Interestingly, studies evaluating if patients with peri­odontitis and with or without ACVD have different systemic markers have been evaluated. Most of the studies observed that CRP was higher in patients with both pathologies (peri­odontitis and ACVD) and that peri­odontitis was an additive relative to levels found in patients with either condition. For example, Glurich et al114 reported that in subjects with neither peri­odontitis nor ACVD, CRP levels were 1.68 ± 1.42 mg/l; in subjects with peri­odontitis but without ACVD the concentrations were 2.40 ± 1.89 mg/l; in subjects without peri­odontitis but with ACVD CRP levels were 3.35 ± 1.56 mg/l; and in patients with both diseases they were as high as 8.58 ± 1.74 mg/l. It was concluded that in subjects with either pathologies alone, CRP levels were elevated two-fold compared to subjects with neither disease, whereas a three-fold increase was noted in subjects with both peri­odontitis and ACVD114. Also, in the aforementioned study by Tang et al113, after performing a subgroup analysis comparing patients with CAD with or without peri­odontitis, the authors concluded that patients with both clinical pathologies had significantly higher levels of CRP (9.15 ± 2.68 mg/l vs. 6.41 ± 2.14 mg/l), IL-6 (83.66 ± 28.73 pg/l vs. 65.31 ± 11.72 pg/l) and TNF-α (13.34 ± 7.51 pg/l vs. 9.65 ± 3.64 pg/l). Pro-coagulant markers

In general, disturbances in the levels of pro-coagulation molecules lead to a prothrombotic state. A prothrombotic status means that a person can form a small blood clot or clot faster or has increased blood viscosity compared with normal and/or that the clot is removed less efficiently; this is caused by acquired hyper-coagulation and/or hypo-fibrinolysis, respectively. This prothrombotic state has been shown to occur in peri­odontitis. Several prothrombotic biomarkers have been shown to be elevated in the blood plasma of peri­odontitis patients, such as fibrinogen, Von Willebrand factor, P-selectin and PAI-1 (plasminogen activator inhibitor-1)115.

In chronic infectious or inflammatory conditions, often higher levels of fibrinogen in plasma are found, leading to an increase in blood viscosity, thus promoting endothelial cell activation and platelet aggregation106. Several pro-coagulant biomarkers including fibrinogen have been studied in relation to peri­odontitis. For example, in a study by Wu et al106, a statistically significant relationship between higher fibrinogen levels and peri­odontitis was observed. In a study of health in Pomerania, Germany (SHIP), an association between peri­odontitis and high plasma fibrinogen levels was reported. Particularly, after adjustments for multiple co‐variates (age, sex, BMI, education, use of alcohol, aspirin and other medications, LDL levels, smoking, and other pathologic conditions including gastritis, bronchitis and diabetes), the presence of ≥ 15 pockets with a probing depth of ≥ 4 mm was significantly associated with high plasma fibrinogen levels (OR 1.88, 95% CI 1.2 to 2.8)107.

Other thrombotic and haemostatic factors have been related to peri­odontitis in relation to ACVD, such as PAI-1. Reduced PAI-1 levels are indicative of a non-normal functioning of the fibrinolysis system and therefore an increased risk for atherosclerosis. Bizzarro et al116 observed higher levels of PAI-1 in patients with severe forms of peri­odontitis. Indeed, when a full-mouth tooth extraction was performed in severe peri­odontitis patients, a decrease in PAI-1 levels was reported117. Lipid markers: dyslipidaemia

It has been determined that elevated cholesterol plays an essential role in the development of ACVD. The cholesterol is deposited in atherosclerotic plaques and stimulates further atherogenesis. ‘Total cholesterol’ consists mainly of the ‘good’ (protective) cholesterol (high density lipids, i.e., HDL) and of the ‘bad’ cholesterol (low density lipids, i.e., LDL). Elevated blood levels of LDL and the vLDL variant and triglycerides promote atherosclerosis (they are ‘atherogenic’) (Table 2-7).

Table 2-7 Schematic overview of the desired and deviating values of cholesterol in relation to ACVD

Parameter Desired values of cholesterol Risk values for ACVD
Total cholesterol < 5 mmol/l > 5 mmol/l
LDL ≤ 2.5 mmol/l > 3 mmol/l
HDL man/woman ≥ 1 / ≥ 1.2 mmol/l < 1 mmol/l
Triglycerides ≤ 1.7 mmol/l > 2 mmol/l

Many studies show that peri­odontitis is associated with dyslipidaemia, i.e. high levels of lipid markers, such as LDL, total cholesterol and triglycerides118,119. In addition, peri­odontitis has been shown to decrease the levels of anti-atherogenic HDL and to increase the levels of circulating cytokines and inflammatory mediators115. Moreover, there was a trend towards a higher increase of pro-atherogenic lipid and inflammatory protein counts in patients with more severe peri­odontal pathology.

Several clinical studies, summarised in a 2017 meta-analysis, aimed to answer the question whether individuals with peri­odontitis in the absence of other systemic diseases have different serum lipid levels (HDL, LDL, triglycerides and total cholesterol) when compared with healthy subjects. The meta-analysis concluded that peri­odontitis subjects (without other systemic condition) presented significantly higher levels of LDL (mean difference 5.85 mmol/l, 95% CI 1.93 to 9.78) and triglycerides (mean difference 13.07 mmol/l, 95% CI 6.81 to 19.32) compared to peri­odontally healthy subjects. Also, significantly lower HDL levels were observed in peri­odontitis patients than in heathy subjects (mean difference −4.19 mmol/l, 95% CI −5.57 to −0.61)120. However, limitations of this analysis were a relatively small total simple size and a marked heterogeneity regarding the definition of peri­odontitis, where some studies used self-reported peri­odontitis for their diagnosis as well as a lack of clinical information. Due to this heterogeneity and incomplete information, the authors suggested that further large-scale longitudinal studies including ethnically diverse populations should be conducted, with a stringent diagnosis for peri­odontitis and lipid levels. These studies should also investigate observed confounding factors like BMI, exercise, diet and lifestyle behaviours that affect lipid levels and peri­odontitis.

Tang et al113 performed a subgroup analysis comparing patients with CAD with or without peri­odontitis. They concluded that patients with both clinical pathologies had significantly higher levels of LDL (3.22 ± 1.21 mmol/l vs. 2.71 ± 1.16 mmol/l) and oxidised-LDL (618.83 ± 187.85 μg/l vs. 337.76 ± 75.97 μg/l)113.

2.2.4 Intervention studies: the effects of peri­odontal treatment

Data from intervention studies are of particular importance from a public health standpoint, as they reveal whether targeting a particular exposure by means of prevention or therapy translates into tangible benefits in terms of incidence reduction of the disease in question. In other words, do we see an improvement in the cardiovascular system (decrease in endothelial dysfunction) if peri­odontitis is treated carefully? The following is a summary of current knowledge.

Ideally, the value of the interventions should be assessed using randomised, placebo-controlled clinical trials that provide the highest level of evidence and minimise bias. However, this study design has not been the most used so far. In a recent systematic review of clinical intervention trials it was observed that none of the included trials used a cardiovascular event as the outcome parameter (such as angina pectoris, myocardial infarction, cere­brovascular ischaemic event, sudden death)121. Indeed, most studies reported secondary endpoints of ACVD121.

Most treatment studies are actually relatively short term, with follow-up periods of several months. In fact, it would be most relevant to investigate whether peri­odontal treatment can diminish the incidence of acute ischaemic events. But those are controlled studies that are not feasible: researchers would have to randomise a cohort of peri­odontitis patients in a treatment group and an untreated control group and observe after a number of years in which group there was an occurrence of ischaemic events. But for clear ethical reasons and due to frequently seen lack of cooperation from study participants over longer periods of time, such studies are impracticable. Hence, the clinical par­ameters of atherosclerosis are studied usually in uncontrolled studies because of the objections described above; there are also short-term controlled studies.

Therefore, the evidence is moderate for the beneficial effects of peri­odontal treatment on indirect variables within ACVD, such as endothelial function (FMD), subclinical atherosclerosis assessed through the thickness of the intima-media layer of the carotid artery (IMT) and systemic inflammation95. A selection of these is listed in Table 2-8.

Table 2-8 Intervention studies: effects of periodontal treatment (studies published since 2000)

C = control group; CRP = C-reactive protein; CS = coronal scaling; CT = clinical trial; HDL = high-density lipoprotein; HP = periodontally healthy; LDL = low-density lipoprotein; MMP = matrix metalloproteinase; OHI = oral hygiene instructions; PWV = pulse wave velocity; RCCT = randomised controlled clinical trial; SRP = scaling and root planing; SS = statistically significant; SSD = statistically significant difference; T = test group; TNF-α = tumour necrosis factor alpha. Intervention studies with primary endpoints

Studies assessing primary endpoints are rare, but one is the PAVE study. The aim of this study was to provide peri­odontal therapy as a secondary cardiac event prevention model. However, due to an inadequate enrolment and a non-compliance to the study protocol, the study failed to conclude a relationship between peri­odontal scaling and root planing as a preventive measure for future ACVD. There was no significant difference in cardiovascular events when patients who received peri­odontal treatment were compared to those who received community care (RR 0.72, 95% CI 0.23 to 2.22)130,131. Intervention studies with secondary endpoints: clinical parameters of ACVD

Blood pressure

To date few studies have evaluated the effect of peri­odontal treatment on blood pressure. One of the first studies was published in 2006 by D’Aiuto et al,132 who failed to demonstrate a significant reduction in systolic or diastolic blood pressure after 6 months of scaling and root planing with or without antibiotic therapy. In a pilot study conducted by Vidal et al133, a significant reduction in blood pressure was observed after 6 months of scaling and root planing. The systolic pressure reduced from 175 ± 38.8 mmHg to 157 ± 40 mmHg and the dia­stolic pressure from 105 ± 21.3 mmHg to 95 ± 69.2 mmHg133. In this study patients with a diag­nosis of refractory hypertension were selected, and after the peri­odontal treatment, a significant reduction was observed, although they still were hypertensive.

More recently, in a pilot intervention study a significant (but slight) reduction in systolic blood pressure was observed after statistical adjustment for potential covariates, from 119.8 ± 14.6 mmHg at baseline to 116.9 ± 15.1 mmHg after 6 months; however, no differences were observed in diastolic blood pressure after 6 months of peri­odontal therapy101. In contrast, a recent study of Bizzarro et al134 showed that after basic peri­odontal treatment with or without adjunctive antibiotics, there was a significant reduction in the systolic blood pressure in peri­odontitis patients who were otherwise healthy.

Carotid intima-media wall thickness

Intervention studies have been published on the effects of peri­odontal treatment on changes in the IMT value. It is a particularly interesting finding that non-surgical peri­odontal treatment in some way improves the arterial function and/or decreases the severity of atherosclerosis.

Piconi et al123 observed a reduction in IMT after 12 months of peri­odontal treatment, but the main limitations of this study were the absence of a control group and limited information on vascular evaluation. Compared to baseline, the IMT was reduced significantly after peri­odontal treatment after 6 months and persisted after 12 months at the carotid bifurcation (baseline 0.55 ± 0.03 mm; 6 months 0.40 ± 0.04 mm; 12 months 0.45 ± 0.04 mm). A study conducted in Australia, which included 168 Aboriginal participants affected by peri­odontitis, observed an IMT reduction at 12 months after a single period of non-surgical peri­odontal treatment in the experimental group compared with the control group (−0.02 mm, 95% CI −0.05 to −0.002). However, the authors discuss that these results should take into account that only a modest improvement in peri­odontal parameters after peri­odontal therapy was obtained135.

Flow-mediated dilatation

Clinical studies that used FMD response to measure the endothelial/vascular function suggested an improvement of the FMD of the brachial artery from 4 to 28 weeks after scaling and root planing treatment102,127,136.

The clinical trial published by Tonetti et al126 is particularly relevant because of its design. In this study, 120 patients with severe peri­odontitis were selected and randomly assigned to receive intensive hospital-based or community (practice-based) peri­odontal care. Shortly after starting the treatment (24 hours), the FMD was significantly lower in the intensive treatment group than in the control group. However, throughout the study, the FMD values gradually improved and after 60 days they were significantly higher than those of the control group. The degree of improvement of vascular function was significantly associated with the degree of improvement of peri­odontal parameters, which in the intensive treatment group was significantly better than in the control treatment group (r = 0.29, P = 0.003). This study suggests that intense peri­odontal treatment produces an immediate and short-term outbreak of systemic inflammation. However, 6 months after starting the treatment, a significant improvement in endothelial function was observed126.

In contrast, in a recent randomised controlled clinical trial conducted by Saffi et al124, including 69 patients with stable CAD and severe peri­odontitis, and with a follow-up period of 3 months, different results were observed. In this study, the test group received scaling and root planing, whereas in control group no treatment was performed. FMD was assessed before and 3 months after peri­odontal treatment. It was concluded that no differences existed between the control and test group for improvements in FMD (1.37% vs. 1.39%, respectively) in the short term124. The FMD-related results are in contrast to those reported by Tonetti et al126, although both studies had comparable study populations and designs. The discrepancy in the study results could be explained by the fact that Saffi et al124 included only patients with a history of CAD, where all patients were receiving cardiovascular care including medications, whereas Tonetti et al126 excluded such patients. Thus, the beneficial effects of peri­odontal therapy on FMD may have been overridden by the effects of the medication for ACVD.

A recent meta-analysis that gathered data from three controlled trials reported that the effects of peri­odontal treatment on FMD showed a mean improvement of 6.64% (range 3.7% to 9.3%) between peri­odontitis subjects and the control group (95% CI 2.83 to 10.44)53. That is considerably more than reported by Tonetti et al89. This indicates that there is heterogeneity between different studies, which was also noted by Orlandi et al95.

Arterial stiffness (pulse wave velocity)

The effects of non-surgical peri­odontal therapy on the arterial stiffness, measured by PWV, have not been studied widely133,135. In the above-mentioned cohort study by Vidal et al133, 26 peri­odontitis Brazilian patients diagnosed with persistent high blood pressure were enrolled. A significant effect of peri­odontal treatment was observed on PWV of the aorta and superior brachial artery. At the start of the study, the Brazilian peri­odontitis patients had a PWV value of 13.7 m/s, and 6 months after treatment there was a significant decrease to 12.5 m/s (reduction of 0.9 m/s; P < .01)133. Conversely, Kapellas et al135, in their interventional study conducted in 168 Aboriginal peri­odontitis patients in Australia, did not find differences in PWV between the treatment group and the control group without peri­odontal treatment at 3 months (mean difference 0.06 m/s, 95% CI −0.17 to 0.29) and 12 months (mean difference 0.21 m/s, 95% CI −0.01 to 0.43). Taken together, further well-designed randomised controlled clinical trials are needed to obtain conclusive data that show how peri­odontal treatment influences PWV levels. Intervention studies with secondary endpoints: biochemical parameters of ACVD

When evaluating the published evidence on the serum markers of ACVD, a considerable number of intervention studies on different serum biomarkers have been published. On the basis of the publications examined, there is no conclusive evidence on a potential advantage of performing peri­odontal treatment in the reduction of leukocyte counts, lipid fractions, fibrinogen, serum amyloid A protein, TNF-α and other interleukins95. As an improvement marker of the hyper-inflammatory state, the decrease in CRP levels has been the most used as a response variable. Various clinical trials have shown that peri­odontal treatment significantly reduces serum levels of CRP and IL-695,126,132,137140. In a systematic review and meta-analysis by Paraskevas110, it was observed that peri­odontal treatment reduces CRP levels in peri­odontitis patients with a weighted mean difference of CRP reduction after therapy of 0.50 mg/l (95% CI 0.08 to 0.93). Likewise, it has been shown that the extraction of all teeth significantly decreases both markers of systemic inflammation and thrombotic markers, all considered to be markers of cardiovascular risk117.

Vidal et al141, when comparing a group undergoing peri­odontal treatment to a group without treatment, observed a significant reduction in the levels of IL-6, fibrinogen and CRP in the treated group. On the other hand, 3 months later, in the control group the levels of IL-6 and CRP increased significantly during the period without treatment141.

There is also sufficient evidence to claim that peri­odontal (non-surgical) treatment triggers an acute inflammatory response through the increase of CRP, TNF-α, D-dimer (a fibrin degradation product indicative of clot formation and degradation), E-selectin and von Willebrand factor, with vascular implications, and that this disturbance lasts up to a month after the initial treatment session142,143. It was observed in a case series study of 14 patients published by Graziani et al137 and also by Tonetti et al126 in their RCT, that after 24 hours of an intensive non-surgical treatment, CRP was higher, leading to an acute inflammatory response. However, in the longer term, this disturbance is reversed and yields beneficial cardiovascular parameters. Little comparative evidence has been found on the role of peri­odontal treatment on the biological markers of oxidative stress, while the available evidence suggests a possible reduction of these in the medium term.

In a systematic review and meta-analysis by Teeuw et al121, the authors gathered information on ACVD improvement by peri­odontal treatment at three levels: systemic inflammation and thrombosis (CRP, IL-6, TNF-α and fibrinogen), lipid and glucose metabolism (changes in triglycerides, total cholesterol, HDL and LDL), and vascular function (FMD and blood pressure). According to the results on the systemic inflammation and thrombosis, most of the studies included in the systematic review observed a reduction in CRP, IL-6, TNF-α and fibrinogen after peri­odontal therapy. A slight reduction after intervention was observed in other inflammatory biomarkers such as soluble E-selectin. However, in markers such as numbers of monocytes, neutrophils and lymphocytes, plasminogen activator inhibitor-1 and tissue plasminogen activator, no changes were observed. Similarly, no consistent changes in lipid markers were found. Finally, in relation to the changes in vascular function, the authors reported improvement of endothelial function. It was summarised that peri­odontal treatment has a positive effect on changes in CRP (−0.50 mg/l, 95% CI −0.78 to 0.22), IL-6 (−0.48 ng/l, 95% CI −0.90 to 0.06), TNF-α (−0.75 pg/ml, 95% CI −1.34 to 0.17), fibrinogen (−0.47 g/l, 95% CI −0.76 to 0.17), total cholesterol (−0.11 mmol/l, 95% CI 0.21 to 0.01) and HDL cholesterol (0.04 mmol/l, 95% CI 0.03 to 0.06)121.

In a recent randomised controlled clinical trial conducted by Saffi et al124, concentrations of vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1) and P-selectin in serum were assessed before and 3 months after peri­odontal treatment. It was concluded that VCAM-1 and ICAM-1 concentrations increased in the untreated controls, whereas no changes were observed in the test group, resulting in a significant difference between groups124.


There is epidemiological evidence that patients with periodontitis have a higher risk of having ACVD. However, there is not conclusive evidence that this relationship is causal, nor of its magnitude.

Periodontal treatment has been shown to have the following effects on surrogate markers implicated in CVD: reduction in levels of CRP, improvement in endothelial function and reduction in carotid IMT.

Moderate evidence exists of a positive effect of periodontal therapy on reducing IL-6 and lipid levels.

Limited evidence exists of the effects of periodontal therapy on the following surrogates: arter­ial blood pressure, leukocyte counts, fibrinogen, tissue TNF-α, E-selectin, von Willebrand factor, D-dimers, matrix metalloproteinases (MMPs), oxidative stress and CVD events.

Although periodontal interventions result in a reduction of certain surrogate markers, there is no evidence that this is associated with changes in atherogenesis or disease outcomes. There is insufficient evidence that periodontal therapy has an impact on the recurrence of ACVD.

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Sep 4, 2021 | Posted by in Periodontics | Comments Off on Periodontitis and atherosclerotic cardiovascular disease
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