SALIVA AS A BIOLOGICAL OBJECT FOR NON-INVASIVE MOLECULAR DIAGNOSIS OF CARDIOVASCULAR DISEASES

DOI: https://doi.org/10.29296/24999490-2018-05-01

M.A. Paltsev(1), G.B. Sarayev(2), V.A. Bunin(2), N.N. Belushkina(1, 3), E.S. Popravka(2, 4), N.S. Linkova(2, 4), K.L. Kozlov(2), E.V. Sedova(5), S.U. Mursalov(2), I.M. Kvetnoy(2, 6, 7) 1-Moscow State University. M.V. Lomonosov Moscow, Faculty of Biology, Leninskie gory, 1/12, Moscow, 119991, Russian Federation; 2-Saint Petersburg Institute of Bioregulation and Gerontology, Dynamo pr., 3, Saint Petersburg, 197110, Russian Federation; 3Institute of Biochemical physics named after N.M. Emanuel, Kosigina str., 4, Moscow, 119334, Russian Federation; 4-Peter the Great Saint Petersburg Polytechnic University, Polytechnicheskaya Str. 29, Saint Petersburg, 195251, Russian Federation; 5-M.F. Vladimirsky Moscow Regional Research Clinical Institute, Shchepkina str., 61/2, Moscow, 129110, Russian Federation; 6-D.O. Ott Research Institute of Obstetrics, Gynecology & Reproductology, Mendeleyevskaya line, 3, Saint Petersburg, 199034, Russian Federation; 7St.Petersburg State University, Universitetskaya embankment, 7/9, Saint Petersburg, 199034, Russian Federation E-mail: [email protected]

Cardiovascular diseases (CVD) are considered to be one of the leading causes of lethality in patients of older age groups. In the last decade, the issue of finding a material for effective non-invasive diagnosis of CVD has become urgent. The review considers the possibility of using saliva for this purpose. C-reactive protein in saliva was established to be a marker of coronary heart disease (CHD), myocardial infarction (MI), arterial hypertension (AH), cardiomyopathy, and atherosclerosis. Elevated salivary concentrations of troponin-1 are characteristic of CHD, MI, atherosclerosis and cardiomyopathy, and MMP-9 for CHD, MI, GB, and cardiomyopathy. An increase in the salivary level of prostaglandin E2 was detected in CHD, AH and atherosclerosis, and leukotriene B4 level – in CHD and AH. Salivary α-amylase level is a predictor of MI and heart failure (HF). Myeloperoxidase, CPK, CK-MB, and myoglobin are markers for the diagnosis of myocardial infarction and cardiomyopathy. MMP-8 and TIMP-1 in saliva are associated with CHD and MI, and TNF-α and IL-1β cytokines – with MI and atherosclerosis. In MI and stroke cases there was revealed a change in salivary cortisol, and increased levels of creatinine and lysozyme were noted in CHD and AH patients. Also, such molecules as selective markers of CHD as ghrelin and obestatin were found in the saliva. For the diagnosis of MI salivary ICAM-1, sCD40L, adiponectin, RANTES, NT-proBNP, and IMA, and for atherosclerosis, IL-6S can serve as specific markers. Thus, saliva can be an alternative biological material for the assessment the risk of developing a wide range of CVD and differential diagnosis of cardiovascular pathology.
Keywords: 
saliva, cardiovascular diseases, signaling molecules, diagnostics

Список литературы: 
  1. Strazhesko I.D., Akasheva D.U., Dudinskaya E.N., Tkacheva O.N. Starenie sosudov: osnovnye priznaki i mehanizmy. Cardiovascular Therapy and Prevention. 2012; 11 (4): 93–100. [Strazhesko I.D., Akasheva D.U., Dudinskaya E.N., Tkacheva O.N. Vascular aging: the main signs and mechanisms. Cardiovascular Therapy and Prevention. 2012; 11 (4): 93–100 (in Russian)]
  2. Javaid M.A., Ahmed A.S., Durand R., Tran S.D. Saliva as a diagnostic tool for oral and systemic diseases. J. of Oral Biology and Craniofacial Research. 2016; 6 (1): 66–75.
  3. Punyadeera C. New frontiers in heart failure detection: Saliva testing. BMJ Innov. 2016; 2: 106–8.
  4. Khurshid Z., Naseem M., Sheikh Z., Najeeb S., Shahab S., Zafar M.S. Oral antimicrobial peptides: Types and role in the oral cavity. Saudi Pharm. J. 2015; 24: 515–24.
  5. Rehman S.A., Khurshid Z., Niazi F.H., Naseem M., Waddani H.A., Sahibzada H.A., Khan R.S. Role of Salivary Biomarkers in Detection of Cardiovascular Diseases (CVD). Proteomes. 2017; 5 (3): 21.
  6. Myakisheva Yu.V., Kolsanov A.V., Vlasov M.Yu., Sokolov A.V Neinvazivnaya diagnostika sostoyaniya obmennyh processov v organizme: markery rotovoy zhidkosti. Sovremennye problemy nauki i obrazovaniya. 2017; 5: 57–62. [Myakisheva Yu.V., Kolsanov A.V., Vlasov M.Yu., Sokolov A.V. Noninvasive diagnostics of metabolic processes in the body: mouth fluid markers. Modern problems of science and education. 2017; 5: 57–62 (in Russian)]
  7. Rosa N., Correia M.J., Arrais J.P., Lopes P., Melo J., Oliveira J.L., Barros M. From the salivary proteome to the OralOme: comprehensive molecular oral biology. Arch Oral Biol. 2012; 57 (7): 853–64.
  8. Kaess B.M., Gala T.H., Zierer A., Meisinger Ch., Wahl S., Peters A., Todd J., Herder Ch., Huth C., Thorand B., Koenig W. Ultra-sensitive troponin I is an independent predictor of incident coronary heart disease in the general population. Eur. J. of Epidemiology. 2017; 32 (7): 583–91.
  9. Klichowska-Palonka M., Załęska-Chromińska K., Bachanek T. Possibility of using saliva as a diagnostic test material in cardiovascular diseases. Wiad Lek. 2015; 68 (3): 354–7.
  10. Bunin V.A., Kozlov K.L., Lin`kova N.S., Pal`ceva E.M. Povyshenie koncentracii troponina-1 v slyune pacientov s ishemicheskoy bolezn`yu serdca korreliruet so stadiey razvitiya zabolevaniya. Kompleksnye problemy serdechno-sosudistyh zabolevaniy. 2017: 13–14. [Bunin V.A., Kozlov K.L., Lin’kova N.S., Paltseva Ye.M. An increase in the concentration of troponin-1 in the saliva of patients with coronary heart disease correlates with the stage of development of the disease. Complex problems of cardiovascular diseases. 2017: 13–14 (in Russian)]
  11. Miller C.S., Foley J.D., Floriano P.N., Christodoulides N., Ebersole J.L., Campbell C.L., Bailey A.L., Rose B.G., Kinane D.F., Novak M.J. et al. Utility of Salivary Biomarkers for Demonstrating Acute Myocardial Infarction. J. Dent. Res. 2014; 93: 72–9.
  12. Labat C., Temmar M., Nagy E., Bean K., Brink C., Benetos A. & Bäck M. Inflammatory mediators in saliva associated with arterial stiffness and subclinical atherosclerosis. J. of Hypertension. 2013; 31 (11): 2251–8.
  13. Janket S., Meurman J.H., Baird A.E., Qvarnström M., Nuutinen P., Ackerson L.K., Van Dyke T.E. Salivary Immunoglobulins and Prevalent Coronary Artery Disease. J. of Dental Research. 2010; 89 (4): 389–94.
  14. Ozbay Y., Aydin S., Dagli A.F., Akbulut M., Dagli N., Kilic N., Rahman A., Sahin I., Polat V., Ozercan H.I., Arslan N., Sensoy D. Obestatin is present in saliva: alterations in obestatin and ghrelin levels of saliva and serum in ischemic heart disease. BMB Rep. 2008; 41 (1): 55–61.
  15. Mirzaii-Dizgah I., Riahi E. Salivary high-sensitivity cardiac troponin T levels in patients with acute myocardial infarction. Oral Dis. 2013; 19 (2): 180–4.
  16. Shen Y.S., Chen W.L., Chang H.Y., Kuo H.Y., Chang Y.C., Chu H. Diagnostic performance of initial salivary alpha-amylase activity for acute myocardial infarction in patients with acute chest pain. J. Emerg Med. 2012; 43 (4): 553–60.
  17. Floriano P.N., Christodoulides N., Miller C.S., Ebersole J.L., Spertus J., Rose B.G., Kinane D.F., Novak M.J., Steinhubl S., Acosta S., Mohanty S., Dharshan P., Yeh C.K., Redding S., Furmaga W., McDevitt J.T. Use of saliva-based nano-biochip tests for acute myocardial infarction at the point of care: a feasibility study. Clin. Chem. 2009; 55 (8): 1530–8.
  18. Miller C.S., Foley J.D., Bailey A.L., Campell C.L., Humphries R.L., Christodoulides N., Floriano P.N., Simmons G., Bhagwandin B., Jacobson J.W., Redding S.W., Ebersole J.L., McDevitt J.T. Current developments in salivary diagnostics. Biomark Med. 2010; 4 (1): 171–89.
  19. Rahim O.H., Rahim M.A., Ahmad Z.H., Hashi W.A. Can saliva proteins be used to predict the onset of acute myocardial infarction among high-risk patients? International Journal of Medical Sciences. 2015; 12: 329–35.
  20. Meurman J.H. Infectious and dietary risk factors of oral cancer. Oral Oncol. 2010; 46 (6): 411–3.
  21. Buduneli E., Mäntylä P., Emingil G., Tervahartiala T., Pussinen P., Bariş N., Akilli A., Atilla G., Sorsa T. Acute myocardial infarction is reflected in salivary matrix metalloproteinase-8 activation level. J. Periodontol. 2011; 82 (5): 716–25.
  22. Cavusoglu E., Ruwende C., Chopra V., Yanamadala S., Eng C. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction. Am. Heart J. 2006; 151: 1101–8.
  23. Tuomainen A.M., Nyyssönen K., Laukkanen J.A., Tervahartiala T., Tuomainen T.P. Serum matrix metalloproteinase-8 concentrations are associated with cardiovascular outcome in men. Arterioscler Thromb Vasc Biol. 2007; 27: 2722–8.
  24. Pussinen P.J., Sarna S., Puolakkainen M., Ohlin H., Sorsa T. The balance of serum matrix metalloproteinase-8 and its tissue inhibitor in acute coronary syndrome and its recurrence. Int. J. Cardiol. 2012; 16.
  25. Mirzaii-Dizgah I., Jafari-Sabet M. Unstimulated whole saliva creatine phosphokinase in acute myocardial infarction. Oral Dis. 2011; 17: 597–600.
  26. Mirzaii-Dizgah I., Hejazi S.F., Riahi E., Salehi M.M. Saliva-based creatine kinase MB measurement as a potential point-of-care testing for detection of myocardial infarction. Clin. Oral Investig. 2012; 16 (3): 775–9.
  27. Vinogradov V.F., Liman T.A., Alekseev D.V. Vozmozhnost` prognozirovaniya letal`nogo ishoda infarkta miokarda po urovnyu kortizola v slyune. Sovremennye problemy nauki i obrazovaniya. 2014; 4: 333–4. [Vinogradov V.F., Lyman T.A., Alekseev D.V. The possibility of predicting the lethal outcome of myocardial infarction by the level of cortisol in saliva. Modern problems of science and education. 2014; 4: 333–4 (in Russian)]
  28. Toker A., Aribas A., Yerlikaya F.H., Tasyurek E., Akbuğa K. Serum and saliva levels of ischemia-modified albumin in patients with acute myocardial infarction. J. Clin. Lab Anal. 2013; 27 (2): 99–104.
  29. Novak M.J. Utility of Salivary Biomarkers for Demonstrating Acute Myocardial Infarction. J. Dent. Res. 2014; 93: 72–9.
  30. Slowik A., Turaj W., Pankiewicz J., Dziedzic T., Szermer P., Szczudlik A. Hypercortisolemia in acute stroke is related to the inflammatory response. J. Neurol. Sci. 2002; 196 (1–2): 27–32.
  31. Iranmanesh F., Sedighi B., Ziaadin B. Prognostic Value of Cortisol in Patients with Acute Ischemic Stroke. Zahedan J. Res. Med. Sci. 2017; 8 (9): 1–8.
  32. Neidert S., Katan M., Schuetz P., Fluri F., Ernst A., Bingisser R. Anterior pituitary axis hormones and outcome in acute ischaemic stroke. J. Intern Med. 2011; 269 (4): 420–32.
  33. Zierath D., Tanzi P., Cain K., Shibata D., Becker K. Plasma alphamelanocyte stimulating hormone predicts outcome in ischemic stroke. Stroke. 2011; 42 (12): 3415–20.
  34. Christensen H., Boysen G., Johannesen H.H. Serum-cortisol reflects severity and mortality in acute stroke. J. Neurol. Sci. 2004; 217 (2): 175–80.
  35. Suska A., Alehagen U., Lundstrom I., Dahlstrom U. Salivary Alpha-Amylase Activity, a New Biomarker in Heart Failure. J. of Clinical & Experimental Cardiology. 2012; 32 (2): 120–3.
  36. Hage F.G., Aqel R., Aljaroudi W., Heo J., Pothineni K., Hansalia S. Correlation between serum cardiac markers and myocardial infarct size quantified by myocardial perfusion imaging in patients with hypertrophic cardiomyopathy after alcohol septal ablation. Am. J. Cardiol. 2010; 105: 261–6.
  37. Heslop C.L., Frohlich J.J., Hill J.S. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J. Am. Coll. Cardiol. 2010; 55: 1102–9.
  38. Khan D.A., Sharif M.S., Khan F.A. Diagnostic performance of high-sensitivity troponin T, myeloperoxidase, and pregnancy-associated plasma protein A assays for triage of patients with acute myocardial infarction. Korean J. Lab Med. 2011; 31: 172–8.
  39. Squire I.B., Evans J., Ng L.L., Loftus I.M., Thompson M.M. Plasma MMP-9 and MMP-2 following acute myocardial infarction in man: correlation with echocardiographic and neurohumoral parameters of left ventricular dysfunction. J. Card Fail. 2004; 10: 328–33.
  40. Bradham W.S., Gunasinghe H., Holder J.R., Multani M., Killip D., Anderson M. et al. Release of matrix metalloproteinases following alcohol septal ablation in hypertrophic obstructive cardiomyopathy. J. Am. Coll. Cardiol. 2002; 40: 2165–73.
  41. Foley J.D., Sneed J.D., Steinhubl S.R., Kolasa J.R., Ebersole J.L., Lin Y., Miller C.S. Salivary Biomarkers Associated with Myocardial Necrosis: Results from an Alcohol Septal Ablation Model. Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology. 2012; 114 (5): 616–23.
  42. Wilson A.M., Ryan M.C., Boyle A.J. The novel role of C-reactive protein in cardiovascular disease: risk marker or pathogen. Int J. Cardiol. 2006; 106 (3): 291–7.
  43. Out D., Hall R.J., Granger D.A., Page G.G., Woods S.J. Assessing salivary C-reactive protein: longitudinal associations with systemic inflammation and cardiovascular disease risk in women exposed to intimate partner violence. Brain Behav Immun. 2012; 26 (4): 543–51.
  44. Saunders J.T., Nambi V., de Lemos J.A. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities Study. Circulation. 2011; 123 (13): 1367–76.
  45. Kosaka T., Kokubo Y., Ono T., Sekine S., Kida M., Kikui M., Yamamoto M., Watanabe M., Amano A., Maeda Y., Miyamoto Y. Salivary inflammatory cytokines may be novel markers of carotid atherosclerosis in a Japanese general population: the Suita study. Atherosclerosis. 2014; 237 (1): 123–8.