Periodontal care may improve endothelial function

European Journal of Internal Medicine 18 (2007) 295 – 298 www.elsevier.com/locate/ejim

Original article

Periodontal care may improve endothelial function Arnon Blum a,⁎, Konstantin Kryuger b , Michal Mashiach Eizenberg d , Sameh Tatour a , Fina Vigder b , Zvi Laster c , Eran Front c a

Department of Internal Medicine A, Baruch-Padeh Poriya Medical Center, Lower Galilee 15208, Israel b Department of Imaging, Baruch-Padeh Poriya Medical Center, Lower Galilee 15208, Israel c Dental Surgery Department, Baruch-Padeh Poriya Medical Center, Lower Galilee 15208, Israel d Department of Health System Management, Emek Yesrael College, Israel Received 20 January 2006; received in revised form 24 November 2006; accepted 14 December 2006

Abstract Background: Periodontitis is a chronic, infectious, insidious disease of the tooth-supporting structures that causes a general inflammatory response. The aims of this study were to determine whether periodontitis is associated with endothelial dysfunction leading to cardiovascular events and whether proper management of periodontal disease would improve endothelial function and prevent cardiovascular events in the future. Methods: Twenty-two patients (12 women, 10 men; 40 ± 5 years old) took part in the study. All had severe periodontitis (without systemic disorders) and were all treated conservatively. Thirteen patients returned for a second visit after 3 months of treatment. Endothelial function and periodontal status were evaluated on entry into the study and 3 months following treatment. Ten age-matched, healthy volunteers without periodontal disease served as the control group. Results: There was a significant difference between the patient group and the healthy controls: FMD% 4.12 ± 3.96 vs. 16.60 ± 7.86% (p = 0.0000). Periodontitis improved significantly in all 13 patients who completed 3 months of treatment, and their endothelial function improved as well: FMD% 4.12 ± 3.96% vs. 11.12 ± 7.22% ( p = 0.007). No difference was found in FID% before and after 3 months of treatment: 20.97 ± 10.66% vs.17.94 ± 6.23% ( p = NS). Conclusions: Periodontitis may be an insidious cause of endothelial dysfunction and cardiovascular events. Treating periodontitis can improve endothelial function and be an important preventive tool for cardiovascular disease. © 2007 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Endothelial function; Periodontitis; Atherosclerosis

1. Introduction Acute coronary syndromes (unstable angina pectoris, myocardial infarction, post-PTCA restenosis, sudden death) are commonly due to rupture or erosion of atheromatous plaques in coronary arteries, with exposure of thrombogenic substances within the plaque to blood and rapid development of an occlusive thrombus. Inflammation is increasingly ⁎ Corresponding author. Cardiovascular Branch, NHLBI, National Institutes of Health, USA. E-mail addresses: [email protected], [email protected] (A. Blum).

recognized as a major component of atherosclerosis, especially in plaques associated with acute coronary syndromes, as often demonstrated at necropsy. Chronic infection is now recognized as one of the possible causes of chronic inflammation that could lead to atherogenesis and plaque instability. Periodontitis is an inflammatory reaction (to gram-negative, anaerobic bacterial infections) of the tooth-supporting structures, including the periodontal ligament, cementum, and supporting bone to bacterial invasion. The purpose of this study was to determine whether periodontitis could be an inflammatory/infectious trigger for endothelial dysfunction and vascular inflammation (leading to atherosclerosis) and whether proper management would

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improve endothelial dysfunction and vascular inflammation, thus preventing atherogenesis and atherosclerosis. 2. Methods Twenty-two patients (12 women and 10 men; mean age 40 ± 5 years) with chronic periodontitis were included in the study. None of them smoked or had any of the conventional risk factors for atherosclerosis (hypertension, high cholesterol or triglyceride levels, family history of premature coronary artery or vascular disease, diabetes mellitus, any immunological or known chronic inflammatory condition, or malignancy). All patients signed a consent form before enrollment. Every patient was checked by the periodontist who was in charge of this study as well as by the internist, and only then it was decided whether the patient could join the study. Each patient had at least 18 teeth and 1 interproximal area of 5 mm or greater pocket depth. One calibrated examiner (E. F.) collected the following clinical data. Probing depth (PD) was measured from the free gingival margin (GM) to the base of the pocket. Bleeding on probing (BOP) was considered positive if a site bled within 20 s after probing [1]. Clinical attachment level (CAL) was determined at all sites by measuring the distance from the cemento-enamel junction (CEJ) to the GM, adding the PD at the same site. CAL = PD + (CEJ to GM) (all measurements in millimeters). Plaque index (Pi) [2] was determined at each site. The data were collected and recorded using a standard manual periodontal probe. Six sites per tooth – buccal, mesio-buccal, disto-buccal, lingual, mesio-lingual, and disto-lingual – were used. Data were assessed at baseline and 6 months after active therapy. Therapy included an advanced oral hygiene improvement session followed by two to four consecutive sessions of scaling and root planing by one operator. All patients were treated conservatively with antibiotics (amoxicillin 500 mg + metrinidazole 250 mg T.I.D.) during the first week and had periodontal and gingival treatment as described. A nitrate-restricted diet was followed by all participants 3 days prior to each visit. Every patient was evaluated before the procedure (including endothelial function) and 3 months afterwards. 2.1. Vascular studies These studies were performed in the vascular laboratory using the technique of Celermajer et al. [3,4]. An imaging study of the left brachial artery was performed on all subjects in the supine position using high-resolution ultrasound (7.5 MHz linear array transducer) following 10 min of rest. Baseline images and measurements of the brachial artery were obtained proximal to the antecubital fossa. After finding the clearest view, the skin was marked; the arm stayed in the same position throughout the study. Baseline measurements included brachial artery diameter determination and flow velocity measurements by pulsed Doppler at

approximately 70° to the vessel long axis. Endotheliumdependent vasodilation was assessed by measuring the maximum increase in diameter of the brachial artery during reactive hyperemia created by deflation of an inflated cuff (250 mm Hg for 5 min) on the forearm. After cuff deflation, flow velocity was measured for the first 15 s; then, the arterial lumen was recorded continually for the next 90 s of hyperemia. Fifteen minutes later, a repeat baseline measurement of diameter and flow velocity was recorded, followed by nitroglycerin spray (0.4 mg) to assess endothelium-independent vasodilation. Three minutes later, diameter and flow velocity measurements were recorded. Arterial diameter was measured in millimeters from the intima-media interface on both anterior and posterior walls, coincident with the R-wave on the ECG. All recordings were identified only by a number provided by the research nurse so that the person performing the vascular measurements was unaware of the patient's identity. 2.2. Statistical considerations In order to study the difference in endothelial function between patients and healthy controls, a t-test for independent variables was performed. To check the change in endothelial function after 3 months of treatment, a t-test for dependent variables was performed. 3. Results Twenty-two patients (12 women, 10 men; 40 ± 5 years old) took part in the study. All had severe periodontitis (without systemic disorders) and all were treated conservatively for 3 months with systemic antibiotics and local treatments, as described above. Ten age-matched, healthy volunteers without periodontal disease served as the control group. Thirteen patients came for a second visit after 3 months of treatment. Periodontal clinical parameters improved significantly after 6 months of treatment. The mean PD at baseline was 4.3; after 12 weeks of treatment it had improved to 3.2 ( p = 0.001). The mean CAL was 4.6 and this decreased to 3.7 ( p = 0.01), while BOP % went from 64% to 33% ( p = 0.001) and Pi from 49% to 25% ( p = 0.001; Table 1). On entry into the study, there was a significant statistical difference between the patient group and the group of healthy volunteers: FMD% 4.12 ± 3.96 vs. 16.60 ± 7.86%, respectively ( p = 0.0000; Table 2). Periodontitis improved Table 1 Periodontal studies

PD (mm) BOP (%) PP (%)

Before

After

p value

4.3 64.0 49.0

3.2 32.0 25.0

0.001 0.01 0.01

A. Blum et al. / European Journal of Internal Medicine 18 (2007) 295–298 Table 2 Vascular studies (FMD%) of 22 patients (on entry into the study) compared with the 10 healthy, age-matched controls

FMD%

Periodontitis

Controls

p value

4.12 ± 3.96

16.60 ± 7.86

0.0000

significantly in all 13 patients who completed 3 months of treatment, and their endothelial function improved as well: FMD% 4.12 ± 3.96% vs. 11.12 ± 7.22% ( p = 0.007). No difference was found in FID% before and after 3 months of treatment: 20.97 ± 10.66% vs. 17.94 ± 6.23% ( p = NS; Table 3). 4. Discussion We found that patients with periodontitis had severe endothelial dysfunction, which improved significantly after 3 months of conservative treatment (without surgery). Several studies have described the phenomenon that patients with periodontitis or gingivitis have an impaired lipid profile. In one study, plasma levels of cholesterol, LDL cholesterol, and triglycerides were significantly higher in 46 periodontitis patients aged 50–60 than in age- and sexmatched controls [5]. Aggregation of platelets is induced by the platelet aggregation-associated protein (PAAP) expressed on plaque bacteria, including Streptococcus sanguis and Porphyromonas gingivalis. Intravenous infusion of S. sanguis into rabbits has previously been shown to cause changes in ECG, heart rate, blood pressure, and cardiac contractility. These changes are consistent with the occurrence of myocardial infarction. The ECG changes are now known to begin within 30 s after infusion of PAAP + S. sanguis, followed by alterations in blood pressure and respiratory rate. These changes occurred intermittently over a 30-minute period, then changed within one heartbeat to a normal pattern, and then suddenly went back to an abnormal one [6]. Five longitudinal studies showed that oral conditions were associated with the onset of coronary heart disease while controlling for a variety of established coronary heart disease risk factors. In addition to published evidence, preliminary findings from the Dental Atherosclerosis Risk in Communities study also indicate that periodontal disease is associated with carotid intimal–medial wall thickness, a measure of subclinical atherosclerosis, adjusting for factors known to be associated with both conditions [7]. Another prospective study that was done in the USA investigated the association between dental disease and risk of coronary heart disease. The setting was a national sample of American adults who participated in a health examination survey in the early 1970s. It was found that among the 9760 subjects included in the analysis, those with periodontitis had a 25% increased risk of coronary heart disease relative to those with minimal periodontal disease. Poor oral hygiene, determined by the extent of dental debris and calculus, was also

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associated with an increased incidence of coronary heart disease. In men younger than 50 years, periodontal disease at baseline was a strong risk factor for coronary heart disease; men with periodontitis had a relative risk of 1.72. Both periodontal disease and poor oral hygiene showed stronger associations with total mortality than with coronary heart disease [8]. Another study used combined data from the Normative Aging Study and the Dental Longitudinal Study. Mean bone loss scores and worst probing pocket depth scores per tooth were measured in 1147 men during the period 1971–1986. Information gathered during follow-up examinations showed that 207 men developed coronary heart disease (CHD), 59 died of CHD, and 40 had strokes. Incidence odds ratios adjusted for established cardiovascular risk factors were 1.5, 1.9, and 2.8 for bone loss and total CHD, fatal CHD, and stroke, respectively. Levels of bone loss and cumulative incidence of total CHD and fatal CHD indicated a biologic gradient between severity of exposure and occurrence of disease [9,10]. 4.1. Endothelial function and vascular inflammation Endothelial function is now considered an important target in the pharmaceutical industry. Vascular inflammation affects endothelial function, and lack of NO has been shown to enhance vascular inflammation and cause endothelial dysfunction. This can improve by enhancing NO bioavailability, thus inhibiting vascular (endothelial) inflammation and improving endothelial function, reducing platelet adhesiveness and monocyte-endothelial cell adherence, and inhibiting vascular growth factor production and secretion [3,4]. In an intact endothelium, the response to shear stress is vasodilation; however, in a damaged endothelium or in patients with atherosclerosis (without documented vascular disease) but with risk factors for atherosclerosis (hypertension, hypercholesterolemia, diabetes mellitus, smoking, a positive family history, old age, postmenopausal women), the response is vasoconstriction or a diminished vasodilation instead of a vasodilatatory response [4]. 4.2. Conclusions Periodontitis may be an insidious cause of endothelial dysfunction and future cardiovascular events. Treating periodontitis may improve endothelial function, reverse endothelial dysfunction in patients with severe periodontitis and prevent future cardiovascular disease. Table 3 Comparison of vascular studies (FMD% and FID%) before and after 3 months of periodontal treatment

FMD% FID%

Before

After

p value

4.12 ± 3.96 20.97 ± 10.66

11.12 ± 7.22 17.94 ± 6.23

0.0007 0.448

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5. Learning points 1. Periodontitis is an insidious infectious and inflammatory disease that causes endothelial dysfunction. 2. Periodontitis can be treated successfully in a conservative way in 3 months. 3. Treating periodontitis improves endothelial dysfunction. 4. Treating periodontitis in a routine fashion may be an effective way to fight and prevent atherosclerotic cardiovascular disease. References [1] Chaves ES, Wood RC, Jones AA, Newbald DA, Manwell MA, Kornman KS. Relationship of “bleeding on probing” and “gingival index bleeding” as clinical parameters of gingival inflammation. J Clin Periodontol 1993;20:139–43. [2] Silness J, Löe H. Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal condition. Acta Odontol Scand 1964;22:121–35.

[3] Celermajer DS, Adams MR, Clarkson P. Passive smoking and impaired endothelium-dependent arterial dilation in healthy young adults. N Engl J Med 1996;34:150–4. [4] Celermajer DS, Sorensen KE, Gooch VM. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–5. [5] Syrajanen J, Peltola J, Valtonen V, Iivanainen M, Kaste M, Huttunen J. Dental infections in association with cerebral infarction in young and middle-aged men. J Intern Med 1989;225:179–84. [6] Nery EB, Meister F, Ellinger RF, Eslami A, McNamara TJ. Prevalence of medical problems in periodontal patients obtained from three different populations. J Periodontol 1987;58:564–8. [7] Umino M, Nagao M. Systemic diseases in elderly dental patients. Int Dent J 1993;43:213–8. [8] Beck JD, Pankow J, Tyroler HA, Offenbacher S. Dental infections and atherosclerosis. Am Heart J 1999;138:S528–33. [9] DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell CM. Dental disease and risk of coronary heart disease and mortality. BMJ 1993;306(6879):688–91. [10] Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal disease and cardiovascular disease. J Periodontal 1996;67:1123–37.