Research program; Periodontal disease and myocardial infarction (PAROKRANK)

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1 Research program; Periodontal disease and myocardial infarction (PAROKRANK) Contact Principal Investigators (Odontology): Anders Gustafsson tel , Björn Klinge tel , Aims PAROKRANK explores the hypothesis that there is a causal relationship between periodontitis and cardiovascular disease. If this hypothesis is confirmed the plan is to clarify whether elimination of periodontitis will decrease the risk for further cardiovascular events Background Background The connection between periodontitis and cardiovascular disease has been debated during several years. Periodontitis and cardiovascular disease are common and the latter linked to a high morbidity and mortality. Several risk factors behind cardiovascular disease are well known. Although these risk factors may explain a large proportion of cardiovascular disease there are other risk factors as well and among them chronic inflammatory diseases. Periodontitis has been discussed in this connection (1). Periodontal disease Periodontal disease is an inflammatory disease, which exists in variable severity from gingivitis (prevalence in Sweden 50%) to moderate ( 35%) and serious ( 5-8%) periodontitis. The disease engages the surroundings of the teeth, starting in marginal gingival tissues. Poor oral hygiene lead to dental plaques, which initiates an inflammatory reaction. The plaques contain micro-organisms, possibly up to 700 different species. The most important are Porphorymonas gingivalis, Actinobacillus actinomycetemcomitans and Tannerella forsythensis (2-5). Periodontitis induces an immunological defence reaction which may be strong and harmful. Periodontitis is diagnosed by clinical investigation and the diagnosis and severity can be further graded by an ortho-radial panoramic tomography. An example of serious periodontitis is shown in the figure. Available treatment is mechanical infection control supported by antibiotics and the elimination of plaques, sometimes also regenerative periodontal surgery. Such combined 1

2 treatment may eliminate the chronic, sub-clinical inflammatory reaction induced by periodontitis (6). Cardiovascular disease in Sweden Despite a favourable development during the last decades cardiovascular disease still causes about 50% of all mortality and a considerable morbidity. The total number of people Figure Left panel: clinical expression of periodontitis. The space between the teeth indicates serious disease. Right panel: The X-ray reveals a considerable loss of bone (>2/3 of the dental root). living with cardiovascular disease has increased due to an enhanced longevity and increased survival of cardiovascular disease manifestations. Further efforts to decrease cardiovascular disease are mandatory. Shared risk factors Cardiovascular disease is more common in patients with than among those without periodontitis. Several risk factors are shared by the two conditions. Periodontitis may, however, be a risk factor for cardiovascular disease in itself and it is important to study the possible connection between these two diseases, controlling for shared risk factors and other confounders. Among shared risk factors are: family history, age, overweight, dietary conditions and socio-economic factors. Pathophysiological similarities It is established that systemic inflammation is a factor of importance for atherosclerosis (8,9). Patients with chronic inflammatory diseases (rheumatoid arthritis, inflammatory gastrointestinal diseases and systemic lupus erythematosus) have an accelerated progress of atherosclerosis compared to age-and sex matched controls (10). Epidemiological studies revealed an association between increased CRP-levels in the population and subsequent coronary artery disease (11). Inflammatory activation is important for plaque rupture in 2

3 coronary arteries and thrombotic occlusions causing myocardial infarction (12). It has been hypothesized that inflammatory involvement of the vascular intima may be a response to damage caused by smoking, hypertension, oxidized lipoproteins and hyperglycemia. Chewing and tooth brushing may transfer micro-organisms from dental pockets into the blood stream causing bacteraemia (13). Experimental studies show that such bacteraemia may contribute to increased atherosclerotic vascular damage, aggregation of platelets and development of thrombotic material. Moreover DNA from micro-organisms from affected teeth has been identified in atherosclerotic plaques (14-15). Cytokines (prostaglandin E2, interleukin-1-β, tromboxan B2 and TNF-α) released in the periodontal disease process may have role in the initiation of atherosclerosis and increased release of inflammatory mediators contained in dental pockets may increase the risk for cardiovascular disease (16). Previous studies Several studies have been performed regarding the association of periodontitis and cardiovascular disease. The most important information from various publications, such as study design and population, outcome, statistical adjustments and concerns, is summarised in a table (appendix 1). There is still no clear evidence for a causal relation, something that is important to explore further. The explanation to this short coming relates to a number of methodological problems in available reports. Among them are too small population samples, information based on questionnaires rather than direct examinations, lack of precise definitions regarding dental involvement, incomplete consideration of potential confounding risk factors and lack of thorough information on exact inclusion and exclusion criteria. Moreover no studies explored the impact of intervention against periodontitis on progression of atherosclerosis and event rate. Further information may be achieved from the appended table and from a report from SBU (17). Patient related impact The establishment of a causal relationship between periodontitis and cardiovascular disease will have a profound impact on the attitude to treatment of periodontitis from the present aim to improve dental health to decreasing cardiovascular disease. Considering the high prevalence of these two diseases it has a potential to importantly improve public health. Work plan and research platforms PAROKRANK is a prospective case-control study. The study differs from previous investigations by a considerably more extensive and modern investigation of the periodontitis and potential confounders. The continued, longitudinal follow-up of patients offers an 3

4 opportunity to study whether the existence and severity of periodontitis influences subsequent coronary events and mortality. The outcome of the first part of PAROKRANK will make it possible to evaluate whether a continuation studying the impact of intervention on future cardiovascular events is feasible. Sweden is an ideal country for the study due to the availability of comprehensive morbidity and mortality registries on patients with myocardial infarction. This design makes it possible to study the hypothesis with reasonable investments as regards population size, time and funds. Patients and controls Patients are recruited when admitted for a first myocardial infarction to a coronary care unit at a Swedish coronary care unit reporting to RIKS-HIA. Hospitals selected for the study will be those where dental clinics are available and have expressed an interest to participate in PAROKRANK (see Appendix 2). They will be followed during a period of two years as regards new cardiovascular events (myocardial infarction, stroke and mortality). Information on the patients will be based on data derived from their routine care supplemented by more specific sampling as defined by the protocol. Controls are age-and gender matched subjects, free from previously known myocardial infarction, randomly chosen from the population registry in the area surrounding the respective hospitals. They will be approached via mail and telephone interviews by a research nurse. Eligible controls, consenting to participation will be subjected to a careful health examination and blood sampling according to the protocol. Patients and controls will undergo a thorough dental investigation including a dental x-ray. Controls will be investigated when recruited and patients as soon as possible following the myocardial infarction. Periodontitis will be graded according to a strictly defined protocol. Investigational results from different clinics will be harmonized by the application of clinical and radiological calibrations according to defined criteria. Follow-up will be based on available registry information (myocardial infarction, stroke and mortality). The existence of coronary events during two years of follow up will be related to the dental status at the time of recruitment. Monitoring and data collection will be administered by a central study office at the Unit for Cardiology, Department of Medicine, Karolinska Institutet as regards clinical information and a corresponding unit at the Paradontological Department at Huddinge University Hospital. Earlier results Please see the bibliography on own work in the field and the appended table, which includes work done by the applicants. 4

5 Scientific network PAROKRANK is led by researchers with a background in various fields of importance for the research. It is collaboration between the medical and odontological faculties at Karolinska Institutet. The investigation will utilize available Swedish registries such as RIKS-HIA, SEPHIA, Coronary Interventions and mortality. Patients will be recruited at a large number of Swedish coronary care units in hospitals with dental services (see appendix 2). The protocol was planned based upon a scientific seminar involving clinicians and clinical and basic scientist with experience from epidemiology, cardiology, periodontitis, infectious diseases, inflammatory diseases, psychiatry, atherosclerosis basic research and insurance medicine. Steering Committee PAROKRANK is led by a Steering Committee as listed below. As can be seen representation is available for the various disciplines of interest for the study. The members of the steering committee are co-applicants for the research grant. Professor emeritus Lars Rydén (chair) Responsible for the cardiovascular parts Professor Björn Klinge (vice chair) Responsible for the periodontological parts Professor emeritus Åke Nygren Prevention Professor Ulf de Faire Cardiovascular Epidemiology Odont dr Kåre Buhlin Principal investigator periodontology Professor Anders Gustafsson Dental inflammatory diseases Med dr Anna Norhammar Principal investigator cardiology Med dr Elisabet Svenungson Inflammatory diseases Docent Bertil Lindahl RIKS-HIA and other registries Docent John Öhrvik Statistics Referenser 1. Buhlin K. The role of periodontitis in cardiovascular disease. Thesis. Karolinska University Press Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol 1996;67:

6 3. Hugoson A, Norderyd O, Slotte C, Thorstensson H. Oral hygiene and gingivitis in a Swedish adult population 1973, 1983 and J Clin Periodontol 1998;25: Papapanou PN. Epidemiology of periodontal diseases: an update. J Int Acad Periodontol. 1999;1: Zambon JJ. Periodontal diseases: microbial factors. Ann Peroidontol 1996;1: Lindhe J, Nyman S. Treatment Planning. In: Lindhe J, Karring T, Lang NP, editors. Clinical Periodontology and Implant Dentistry. 3 rd ed. Copenhagen: Munksgaard; p Socialstyrelsen. (The National Board of Health and Welfare). Centre of Epidemiology. Statistics-Health and Diseases. Causes of death In official statistics of Sweden Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. New Engl J Med. 2005;352: Ross R. Atherosclerosis an inflammatory disease. N Engl J Med 1999;340: Roman MJ. Moeller E. Davis A. Paget SA. Crow MK. Lockshin MD. Sammaritano L. Devereux RB. Schwartz JE. Levine DM. Salmon JE. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Intern Med. 2006;144: Danesh J. Whincup P. Walker M. Lennon L. Thomson A. Appleby P. Gallimore JR. Pepys MB. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321: Libby P. Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets. Nature Medicine. 2002;8: Heimdahl A, Hall G, Hedberg M, Sandberg H, Söder PÖ, Tuner K et al. Detection and quantitation by lysis-filtration of bacteremia after different oral surgical procedures. J Clin Microbiol 1990;28: Herzberg MC, Meyer MW. Dental plaque, platelets, and cardiovascular diseases. Ann Periodontol 1998;3: Li L, Messas E, Batista EL Jr, Levine RA, Amar S. Porphyromonas gingivalis infection accelerates the progression of atherosclerosis in a heterozygous apolipoprotein E-deficient murine model. Circulation 2002;105: Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal disease and cardiovascular disease. J Periodontol 1996;67: Statens Beredning för Medicinsk Utvärdering (SBU). Kronisk parodontit som risk för utveckling av andra sjukdomar. In: Kronisk parodontit prevention, diagnostik och behandling p

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