Sıddıka Selva SÜME KEŞİR, Meltem KARŞIYAKA HENDEK, Ebru OLGUN

Periodontal Hastalık ve Kardiyovasküler Hastalıklar

Periodontal ve kardiyovasküler hastalıklar, patogenezinde enflamasyonun rol oynadığı durumlardır. Yakın dönemde yapılan çalışmalar, periodontal hastalığın kardiyovasküler hastalık oluşumu ve ilerlemesi üzerine etkili olabileceğini ortaya koymuştur. Aterom lezyonlarında tespit edilen oral patojenler iki hastalık arasındaki olası ilişkiyi kuvvetlendirmektedir. İltihaplı ve ülsere dişeti epiteli yolu ile periodontal patojenlerin sistemik dolaşıma infiltrasyonu olası mekanizma olarak kabul edilmektedir. Bakteriyel infiltrasyon sonucunda vasküler dokuları etkileyen oral patojenlerin, sistemik dolaşımda ilerleyerek kardiyovasküler sistem için zararlı reaksiyonları başlattıkları düşünülmektedir. Ayrıca, ülsere dişetinden proenflamatuvar sitokin/kemokin sızıntısı akut faz proteinlerinin sentezine neden olabilir. Kronik bakteriyemi kazanılmış bağışıklık cevabını etkileyebilir. Periodontal patojenlere cevap olarak üretilen antikorlar, endotel hücreleri ve modifiye lipidler arasındaki çapraz reaksiyonları uyarabilmektedir. Bu reaksiyonların damar duvarında lipid yoğunluğunu arttırabileceği düşünülmektedir. Bunlara ek olarak, bazı antikorların ve enflamatuvar sitokinlerin T yardımcı hücre-1 cevabını uyararak aterom lezyonlarındaki makrofajların aktivasyonunu arttırdıkları savunulmaktadır. Tüm bu mekanizmaların aterogenezin başlamasına ve ilerlemesine katkıda bulunduğu düşünülmektedir. Bu derleme, periodontal hastalık ve kardiyovasküler hastalık arasındaki ilişkide olası mekanizmalara değinmektedir.

Periodontal Disease and Cardiovascular Diseases

Inflammation plays a role in the pathogenesis of periodontal and cardiovascular diseases. Recent studies have indicated that periodontal disease may have an impact on the development and progression of cardiovascular disease. Oral pathogens detected in atheromatous lesions strengthen the possible link between the two diseases. Systemic circulatory infiltration of periodontal pathogens through inflamed and ulcerated gingival epithelium is considered to be a possible mechanism. Oral pathogens affecting vascular tissues as a result of bacterial infiltration are thought to progress in the systemic circulation and initiate destructive reactions to the cardiovascular structures. Additionally, ulcerated gingival epithelium is a source of proinflammatory cytokines/chemokines that may cause the synthesis of acute phase proteins. Chronic bacteriemia is able to stimulate the acquired immune response. Antibodies produced in response to periodontal pathogens can stimulate cross-reaction between endothelial cells and modified lipids. These reactions are believed to increase the lipid concentration within the vessel wall. Moreover, it is discussed that some antibodies and inflammatory cytokines increase the activation of macrophages in the atheroma by stimulating T helper-1 response. It is believed that all these mechanisms contribute to the initiation and progression of atherogenesis. These review focuses on the possible mechanisms between periodontal disease and cardiovascular disease.

PDF

___

1. Tonetti MS, Van Dyke TE. Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/ AAP Workshop on Periodontitis and Systemic Diseases. J Periodontol 2013; 84: 24-29.
2. Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol 1996; 1:821-78.
3. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006; 3: 442.
4. Mitchell ME, Sidawy AN. The pathophysiology of atherosclerosis. SeminVasc Surg 1998; 11:134-141.
5. Libby P. Inflammation and cardiovascular disease mechanism. Am J Clin Nutr 2006; 83:456-60.
6. Mattila KJ, Nieminen MS, Valtonen VV et al. Association between dental health and acute myocardial infarction. BMJ 1989; 298:779-81.
7. Rutger Persson G, Ohlsson O, Pettersson T, Renvert S. Chronic periodontitis, a significant relationship with acute myocardial infarction. Eur Heart J 2003; 24(23):2108-15.
8. 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.
9. Janket SJ, Baird AE, Chuang SK, Jones JA. Meta-analysis of periodontal disease and risk of coronary heart disease and stroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 95(5):559-69.
10. Lockhart PB, Bolger AF, Papapanou PN, et al. Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association? A scientific statement from the American Heart Association. Circulation 2012; 125(20):2520-2544.
11. Gemmell E, Marshall RI, Seymour GJ. Cytokines and prostaglandins in immune homeostasis and tissue destruction in periodontal disease. Periodontol 2000 1997; 14:112-143.
12. Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontol 2000 2014; 64(1): 57-80.
13. Hinrichs JE, Novak MJ. Classification and Epidemiology of Periodontal Diseases. Newman MG, Takei HH, Kolokkevold PR, Carranza FA, editors. Carranza’s Clinical Periodontology. Saunders/Elsevier Publication; 2012. p 34-35.
14. Flemmig TF. Periodontitis. Ann Periodontol 1999; 4:32-38.
15. Zambon JJ. Periodontal diseases: microbial factors. Ann Periodontol 1996; 1(1):879-925.
16. Graves DT, Fine D, Teng YT, Van Dyke TE, Hajishengallis G. The use of rodent models to investigate host-bacteria interactions related to periodontal diseases. J Clin Periodontol 2008; 35: 89-105.
17. Hou LT, Liu CM, Liu BY, et al. Interleukin-1beta, clinical parameters and matched cellular-histopathologic changes of biopsied gingival tissue from periodontitis patients. J Periodontal Res 2003; 38: 247-254.
18. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 2009; 54, 2129-2138.
19. Van Dyke TE, Van Winkelhoff AJ. Infection and inflammatory mechanisms. J Periodontol 2013; 84(4 suppl):S1–S7.
20. Schenkein HA, Loos BG. Inflammatory mechanisms linking periodontal diseases to cardiovascular diseases. J Periodontol 2013; 84(4 suppl):51-69.
21. Prochnau D, Lehmann M, Straube E, Figulla HR, Rödel J. Human cytomegalovirus induces MMP-1 and MMP-3 expression in aortic smooth muscle cells. Acta Microbiol Immunol Hung 2011; 58(4):303-317.
22. Preshaw PM, Taylor JJ. How has research into cytokine interactions and their role in driving immune responses impacted our understanding of periodontitis? J Clin Periodontol 2011; 38: 60-84.
23. Teles R, Wang CY. Mechanisms involved in the association between periodontal diseases and cardiovascular disease. Oral Dis 2011; 17: 450-461.
24. Gibson FC, Genco CA. Porphyromonas gingivalis mediated periodontal disease and atherosclerosis: disparate diseases with commonalities in pathogenesis through TLRs. Curr Pharm Des 2007; 13: 3665-3675.
25. Abd TT, Eapen DJ, Bajpai A, Goyal A, Dollar A et al. The role of C-reactive protein as a risk predictor of coronary atherosclerosis: implications from the JUPITER trial. Curr Atheroscler Rep 2011; 13: 154-161.
26. Ridker PM. C-reactive protein: eighty years from discovery to emergence as a major risk marker for cardiovascular disease. Clin Chem 2009; 55: 209-215.
27. Anand SS, Yusuf S. C-reactive protein is a bystander of cardiovascular disease. Eur Heart J 2010; 31: 2092-2096.
28. Buhlin K, Gustafsson A, Pockley AG, Frostegard J, Klinge B. Risk factors for cardiovascular disease in patients with periodontitis. Eur Heart J 2003; 24:2099-2107.
29. Pejcic A, Kesic LJ, Milasin J. C-reactive protein as a systemic marker of inflammation in periodontitis. Eur J Clin Microbiol Infect Dis 2011; 30: 407-414.
30. Slade GD, Ghezzi EM, Heiss G, Beck JD, Riche E, Offenbacher S. Relationship between periodontal disease and C-reactive protein among adults in the atherosclerosis risk in communities study. Arch Intern Med 2003; 163:1172-1179.
31. Persson GR, Pettersson T, Ohlsson O, Renvert S. High-sensitivity serum C-reactive protein levels in subjects with or without myocardial infarction or periodontitis. J Clin Periodontol 2005; 32: 219-224.
32. Malali E, Basar I, Emekli-Alturfan E, et al. Levels of C-reactive protein and protein C in periodontitis patients with and without cardiovascular disease. Pathophysiol Haemos Thromb 2010; 37; 49–54.
33. Pradeep AR, Daisy H, Hadge P. Gingival crevicular fluid levels of monocyte chemoattractant protein-1 in periodontal health and disease. Arch Oral Biol 2009; 54 (5):503-9.
34. Pradeep AR, Daisy H, Hadge P. Serum levels of monocyte chemoattractant protein-1 in periodontal health and disease. Cytokine 2009; 47(2):77-81.
35. Kuhlencordt PJ, Gyurko R, Han F, et al. Atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation 2001; 104(4):448-54.
36. Ramírez JH, Arce RM, Contreras A. Periodontal treatment effects on endothelial function and cardiovascular disease biomarkers in subjects with chronic periodontitis: protocol for a randomized clinical trial. Trials 2011; 12:46.
37. Joseph R, Nath SG, Joseraj MG. Elevated plasma homocysteine levels in chronic periodontitis: a hospital-based case-control study. J Periodontol 2011; 82(3):439-44.
38. Bhardwaj S1, Prabhuji ML, Karthikeyan BV. Effect of non-surgical periodontal therapy on plasma homocysteine levels in Indian population with chronic periodontitis: a pilot study. J Clin Periodontol 2015; 42(3):221-7.
39. Page RC. The pathobiology of periodontal diseases may affect systemic diseases: inversion of a paradigm. Ann Periodontol 1998; 3: 108-120.
40. Hajishengallis G, Sharma A, Russell MW, Genco RJ. Interactions of oral pathogens with toll-like receptors: possible role in atherosclerosis. Ann Periodontol 2002; 7:72-78.
41. Behle JH, Sedaghatfar MH, Demmer RT, et al. Heterogeneity of systemic inflammatory responses to periodontal therapy. J Clin Periodontol 2009; 36: 287-294.
42. Tuomainen AM, Jauhiainen M, Kovanen PT, Metso J, Paju S, Pussinen PJ. Aggregatibacter actinomycetemcomitans induces MMP-9 expression and proatherogenic lipoprotein profile in apo E-deficient mice. Microb Pathog 2008; 44:111-117.
43. Kuula H, Salo T, Pirila E, et al. Local and systemic responses in matrix metalloproteinase 8-deficient mice during Porphyromonas gingivalis-induced periodontitis. Infect Immun 2009; 77: 850-859.
44. Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 2012; 34: 43-62.
45. Kweider M, Lowe GD, Murray GD, Kinane DF, McGowan DA. Dental disease, fibrinogen and white cell count; links with myocardial infarction? Scott Med J 1993; 38: 73-74.
46. Sahingur SE, Sharma A, Genco RJ, DeNardin E. Association of increased levels of fibrinogen and the -455G/A fibrinogen gene polymorphism with chronic periodontitis. J Periodontol 2003: 74; 329-337.
47. Taylor BA, Tofler GH, Carey HM, et al. Full-mouth tooth extraction lowers systemic inflammatory and thrombotic markers of cardiovascular risk. J Dent Res 2006; 85: 74-78.
48. Alexander KS, Madden TE, Farrell DH. Association between gamma fibrinogen levels and inflammation. J Thromb Haemost 2011; 105: 605-609.
49. Montebugnoli L, Servidio D, Miaton RA, Prati C, Tricoci P, Melandri, G. Periodontal health improves systemic inflammatory and haemostatic status in subjects with coronary heart disease. J Clin Periodontol 2005; 32: 188-192.
50. Bretz WA, Weyant RJ, Corby PM, et al. Systemic inflammatory markers, periodontal diseases, and periodontal infections in an elderly population. J Am Geriatr Soc 2005; 53: 1532-1537.
51. Van Eden W, Wick G, Albani S, Cohen I. Stress, heat shock proteins, and autoimmunity: how immune responses to heat shock proteins are to be used for the control of chronic inflammatory diseases. Ann N Y Acad Sci 2007; 1113: 217-237.
52. Tabeta K, Yamazaki K, Hotokezaka H, Yoshie H, Hara K. Elevated humoral immune response to heat shock protein 60 (hsp60) family in periodontitis patients. Clin Exp Immunol 2000; 120: 285-93.
53. Yamazaki K, Ohsawa Y, Itoh H, et al. T cell clonality to Porphyromonas gingivalis and human heat shock protein 60s in patients with atherosclerosis and periodontitis. Oral Microbiol Immunol 2004; 19: 160-7.
54. Schenkein HA, Berry CR, Burmeister JA, et al. Anti-cardiolipin antibodies in sera from patients with periodontitis. J Dent Res 2003; 82: 919-922.
55. Blank M, Krause I, Fridkin M, et al. Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest 2002: 109; 797-804.
56. Gunupati S, Chava VK, Krishna BP. Effect of phase I periodontal therapy on anti-cardiolipin antibodies in patients with acute myocardial infarction associated with chronic periodontitis. J Periodontol 2011; 82: 1657-1664.
57. Turkoglu O, Baris N, Kutukculer N, Senarslan O, Guneri, S, Atilla G. Evaluation of serum anti-cardiolipin and oxidized low-density lipoprotein levels in chronic periodontitis patients with essential hypertension. J Periodontol 2008; 79: 332-340.
58. Nibali L., D’Aiuto F, Griffiths G, Patel K, Suvan J, Tonetti MS. Severe periodontitis is associated with systemic inflammation and a dysmetabolic status: a case–control study. J Clin Periodontol 2007; 34: 931-937.
59. Rizzo M., Cappello F, Marfil R, et al. Heat-shock protein 60 kDa and atherogenic dyslipidemia in patients with untreated mild periodontitis: a pilot study. Cell Stress Chaperones 2012; 17: 399-407.
60. Kuramitsu HK, Kang IC, Qi M. Interactions of Porphyromonas gingivalis with host cells: implications for cardiovascular diseases. J Periodontol 2003; 74: 85-89.
61. Hashimoto M, Kadowaki T, Tsukuba T, Yamamoto K. Selective proteolysis of apolipoprotein B-100 by Arg-gingipain mediates atherosclerosis progression accelerated by bacterial exposure. J Biochem 2006; 140: 713-723.
62. Consortium, W. T. C. C. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661-678.
63. Schaefer AS, Richter GM, Groessner-Schreiber B, et al. Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis. PLoS Genet 2009; 5: e1000378.
64. Iwamoto Y, Nishimura F, Soga Y, et al. Antimicrobial periodontal treatment decreases serum C-reactive protein, tumor necrosis factor-alpha, but not adiponectin levels in patients with chronic periodontitis. J Periodontol 2003; 74: 1231-1236.
65. Taylor BA, Tofler GH, Carey HM, et al. Full-mouth tooth extraction lowers systemic inflammatory and thrombotic markers of cardiovascular risk. J Dent Res 2006; 85: 74-78.
66. Vidal F, Figueredo CM, Cordovil I, Fischer RG. Periodontal therapy reduces plasma levels of interleukin-6, C-reactive protein, and fibrinogen in patients with severe periodontitis and refractory arterial hypertension. J Periodontol 2009; 80: 786-791.
67. Ide M, McPartlin D, Coward PY, Crook M, Lumb P, Wilson RF. Effect of treatment of chronic periodontitis on levels of serum markers of acute-phase inflammatory and vascular responses. J Clin Periodontol 2003; 30: 334-340.
68. Yamazaki K, Honda T, Oda T, et al. Effect of periodontal treatment on the C-reactive protein and proinflammatory cytokine levels in Japanese periodontitis patients. J Periodontal Res 2005; 40: 53-58.
69. Ridker P. Intrinsic fibrinolytic capacity and systemic inflammation: novel risk factors for arterial thrombotic disease. Haemostasis 1997; 27(Suppl. 1):2-11.
70. D'Aiuto F, Orlandi M, Gunsolley JC. Evidence that periodontal treatment improves biomarkers and CVD outcomes. J Periodontol 2013; 84(4 suppl):85-105.
71. Freitas CO, Gomes-Filho IS, Naves RC, et al. Influence of periodontal therapy on C-reactive protein level: a systematic review and meta-analysis. J Appl Oral Sci 2012; 20(1):1-8.
72. Higashi Y, Goto C, Hidaka T, et al. Oral infection- inflammatory pathway: periodontitis, is a risk factor for endothelial dysfunction in patients with coronary artery disease. Atherosclerosis 2009; 206(2):604-610.
73. Tonetti M, D’Aiuto F, Nibali L, Donald A, Storry C, Parkar M, et al. Treatment of periodontitis and endothelial function. N Engl J Med 2007; 356:911-20.
74. Losche W, Marshal GJ, Apatzidou DA, Krause S, Kocher T, Kinane DF. Lipoprotein-associated phospholipase A2 and plasma lipids in patients with destructive periodontal disease. J Clin Periodontol 2005; 32: 640-644.
75. Oz SG, Fentoglu O, Kilicarslan A, et al. Beneficial effects of periodontal treatment on metabolic control of hypercholesterolemia. South Med J 2007; 100: 686-691.
76. Montebugnoli L, Servidio D, Miaton RA, et al. Periodontal health improves systemic inflammatory and haemostatic status in subjects with coronary heart disease. J Clin Periodontol 2005; 32: 188-192.
77. Aarabi G, Zeller T, Seedorf H, et al. Genetic Susceptibility Contributing to Periodontal and Cardiovascular Disease. J Dent Res 2017; 96: 610-617.