Z. Bilous1, О. Abrahamovych1, N. Mazur2, S. Ryabokon2, N. Ilenkiv2, N. Bevza2
1Danylo Halytsky Lviv National Medical University
2Clinical Hospital “Lviv Railway”, branch of the health care center on transport of PJSC “Ukrzaliznytsia”
Introduction. Despite the significant advances in the study of pathogenesis, clinics, diagnostics and treatment of acute coronary syndrome (ACS), it remains one of the most common cardiovascular diseases, the severity of which is complicated by concomitant type 2 diabetes mellitus, since atherosclerosis in patients with type 2 diabetes develops 10-15 years earlier than in the general population, and it is characterized by accelerated damage of large subepicardial vessels, its severity increases faster and more often leads to complications. Diabetes mellitus almost doubles the risk of death from cardiovascular diseases, which is comparable to the risk after transferred myocardial infarction, because there is a high frequency of multiple damage of the coronary vessels, increased activation of intra-vascular inflammation on the background of hyperglycemia and hyperinsulinemia, increased activity of all parts of the hemostasis system. There is a marked increase in the risk of cardiovascular death, not only in case of true diabetes, but also in case of its subclinical forms, glucose intolerance. In case of diabetes mellitus, high mortality rate is also high, and its percentage increases in the next 1-5 years after the myocardial infarction. Therefore, patients with type 2 diabetes mellitus remain the most vulnerable group, as their mortality rate decrease is negligible.
The results of the study have shown that intensive glycemic control significantly reduces the risk of microvascular complications of diabetes, but does not significantly affect the macrovascular complications and overall mortality.
The aim of the study. To make a review of the literature and a description of the clinical case in order to clarify the peculiarities of the clinical condition and pathogenesis of acute coronary syndrome in patients with type 2 diabetes.
Materials and methods. Cochrane Library, Research Gate for the key words: GKS, diabetes, acute coronary syndrome, diabetes mellitus, hypercholesterolemia, dyslipidemia, insulin resistance, hyperglycemia. 130 sources were analyzed in the English and Ukrainian languages. Sources are selected, which highlight the clinical and pathogenetic features of ACS in patients with type 2 diabetes. A clinical case is described.
Results. ACS in patients with diabetes mellitus often occurs with less severe pain syndrome (often complete absence of typical pain syndrome), shortness of breath while walking, palpitations. The frequency of asymptomatic ischemia is 2.0-4.0 % in the general population of patients with type 2 diabetes mellitus and in 30.0-50.0 % of patients with type 2 diabetes mellitus with ischemic heart disease. The absence of pain in the cardiac area is due to the neuropathy of the nerves branched out in the cardiac muscle, and the absence of an initial irritation signal during ischemia, as well as myocardial infarction with necrosis of the sensitive receptors. The absence of pain means the loss of the limiting factor of physical activity, which, accordingly, increases the risk of acute myocardial infarction and sudden cardiogenic death in diabetic patients.
The main mechanisms of vascular lesions in patients with diabetes mellitus: mechanical obstruction (atherosclerotic plaque), dynamic obstruction (spasm of normal or atherosclerotically changed arteries), microvascular dysfunction. Specific risk factors for vascular damage in the presence of type 2 diabetes mellitus include: hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia.
Pathologic mechanisms that underlie diabetes mellitus and its macrovascular complications include oxidative stress and inflammation. According to modern presentations, diabetes is considered a condition of acute inflammation with prothrombogenic changes in hemostasis and fibrinolysis, which increases the risk of vascular damage. Proinflammatory cytokines in patients with diabetes mellitus affect not only the formation of insulin resistance of peripheral tissues, but also play an important role in reducing the insulin-producing capacity of the pancreas.
The main mechanisms for the implementation of the effect of hyperglycemia include: activation of the polyolic pathway of glucose metabolism (sorbitol/aldose reductase); glycosylation of proteins; the effect of oxidative stress; increase of the role of diacylglycerols and activation of protein kinase isoforms as a result of enhanced formation of superoxide radical by inflammatory blood cells, smooth muscle cells, endothelial cells. In patients with diabetes mellitus the glycosylation of lipoproteins with the acquisition of proatherogenic properties is present. The process of glycosylation of proteins, especially apo-proteins of very low density and low density lipoproteins, arises as a result of the ability of glucose to non-enzymatically attach to them, which complicates the recognition of these modified lipoproteins by tissue B, E-receptors, causes inhibition of their elimination from the blood and enhanced capture by macrophages, followed by the formation of foam cells. In addition, glucose is capable of auto-oxidation and activation of free radical processes, which is one of the most important mechanisms of modification of lipoproteins.
When combined ACS with type 2 diabetes mellitus there is a sharp decline in functional activity of the endothelium of the vascular wall: flow-dependent vasodilation, anticoagulant, antiplatelet and anti-fibrinolytic activity, which correlate with the severity of carbohydrate metabolism violations. The pathogenetic mechanisms of endothelial damage on the background of insulin resistance contribute to the prevalence of thromboembolic complications, threatening arrhythmias, and the development of congestive heart failure precisely in patients with acute myocardial infarction with concomitant type 2 diabetes mellitus.
It is known that in case of hyperglycemia the structure of the intercellular matrix and the basal membrane are violated. The reason of this is the development of insulin resistance, which causes the activation of components of the extracellular matrix: MMP and TIMMP, which leads to remodeling of the basal membrane in case of type 2 diabetes mellitus and, as a consequence, contributes to heart failure severity increase.
Conclusions. Consequently, the key problems in managing the patients with ACS and diabetes mellitus are timely and accurate diagnosis, risk assessment, disease prognosis and the adequate treatment algorithm administering.
In view of this, it is important to consider the peculiarities of the connections between the individual pathogenetic mechanisms of accelerated atherogenesis in patients with diabetes, which will expand the therapeutic potential of these processes. The role of insulin resistance, endothelial dysfunction, disorders in the system of metalloproteinases and cytokines, immunoinflammatory markers of adipose tissue in the destabilization of the atherosclerotic process and the correlation of these factors with lipid disorders are still insufficiently studied. The problem of the influence of insulin resistance on the system of extracellular matrix is controversial. The effect of each individual pathogenic marker on the clinical course and complications of these patients remains undetermined; therefore, the study of the clinical course of ACS with comorbid type 2 diabetes mellitus and the prediction of complications are important for improving the prognosis in these patients.
Therefore, a detailed study of the pathogenetic foundations, mechanisms, and approaches to timely diagnosis can not only reduce the risk but also lead to a qualitatively new strategic position in the prevention and treatment of such patients.
- Abrahamovych М, Abrahamovych О, Farmaha M. The content of some vasoactive humoral-metabolic factors in patients with cirrhosis and their participation in pathogenesis of comorbid syntropical damages of cardiovascular system. Lviv Clinical Bulletin. 2017;4(20):40-53. (Ukrainian)..
- Altunina N. Cytokine imbalance in patients with type 2 diabetes mellitus who have had non-Q-myocardial infarction. Problems of Endocrine Pathology. 2016;4:7-13. (Ukrainian).
- Amosova K, Tkachenko L, Rokita O. The endothelium conditions of the arterial bed with early post-infarction angina and factors determining it. Ukrainian Journal of Cardiology. 2009;2:11-15. (Ukrainian).
- Belovol A, Kravchun P, Trifonova N, Ryndina N. The state of the pro-inflammatory cytokine level in patients with unstable angina and type 2 diabetes mellitus depending on functional class of chronic heart failure. International Medical Journal. 2013;2:40-42. (Russian).
- Bilovol O, Kravchun P. The activity of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in patients with ischemic heart disease (IHD) combined with diabetes mellitus type 2 (DM 2). Medicine of Ukraine. 2008;8(144):101-103. (Ukrainian).
- Bilous Z, Аbrahamovych О. The Peculiarities of the Endothelial Function, Blood Lipid Spectrum and Heart Rate Variability in Patients with Stable Angina, Depending on the Heart Rate Frequency. Lviv Clinical Bulletin. 2016;4(16):8-14. (Ukrainian).
- Valueva S, Denisyuk V. The pilot registry of acute coronary syndromes with ST segment elevation «STIMUL»: results of in-hospital medical care depending on the method of treatment. Ukrainian Journal of Cardiology. 2013;6:22-26. (Ukrainian).
- Gavrilenko T, Slobodskyi V, Kornilina O. Cytokine-production activity of momonuclears and endithelin level in plasma of patients with stable angina. Ukrainian Medical Journal. 2012;2(88):134-136. (Ukrainian).
- Golovchenko Y, Trishchynska M. Modern conception of cerebral vessel endothelium physiology and pathology. Consilium Medicum Ukraina. 2008;11:38-40. (Russian).
- Hontsaryuk D, Khristich T, Fediv O, Teleki J. Predictive value of C-reactive protein in the development of chronic inflammatory response, atherosclerosis, insulin resistance in patients with a combination of atherosclerosis and chronic pancreatitis. The Practical Angiology. 2012;3-4(52-53):26-32. (Ukrainian).
- Grebenuk M, Mykulyak V, Zorja L. Dynamics of level of nitric oxide in patients with acute myocardial infarction on the background of complex treatment with L-arginine use. Bukovinian Medical Herald. 2013;3(67):142-144. (Ukrainian).
- Grin V, Bassov O, Vatutin N, Vorobyov A. The role of matrix metalloproteinases and their tissue inhibitors system in the formation of post-infarction cardiac remodeling. Bukovinian Medical Herald. 2012;16(2):152-156. (Ukrainian).
- Gumenuk A. View on the problem of rational treatment of patients with cardio-vascular pathology and polymorbid conditions. Ukrainian Medical Journal. 2009;5(73):25-32. (Ukrainian).
- Denisyuk V, Valueva S. Endothelial dysfunction as a predictor of cardiovascular disease. Heart & Vessels. 2006;3:104-107. (Ukrainian).
- Dzyak G, Bilchenko O. Family physician tactics in managing patients with the most common cardiovascular disease: methodical recommendations. Kyiv: Medical Cards; 2012. 88 с. (Ukrainian).
- Dunaeva I. Features of anti-inflammatory cytokine link in patients with coronary heart disease and type 2 diabetes. Problems of Endocrine Pathology. 2013;2:28-32. (Ukrainian).
- Ershova O, Belova K, Novikova I. The role of cytokines in the development of cardiovascular disease and osteoporosis. Osteoporosis and Osteopathy. 2011;3:33-35. (Russian).
- Zaikina T, Tsivenko V, Glebova O, Sapricheva L, Leonidova V. Dynamics of endothelial damage markers – SVE-cadherin, von Willebrand factor in patients with acute myocardial infarction and concomitant diabetes mellitus type 2. Actual Problems of Modern Medicine. 2015;15(2):93-98. (Ukrainian).
- Zubkova S, Trunko N. Heart in endocrine diseases: monography. Kyiv; 2006. 200 с. (Ukrainian).
- Kovalyova O, Kolosov E, Belaya N, Bolokadze E. Matrix metalloproteinase-1 system and formation of left ventricular remodeling in hypertensive disease. Heart & Vessels. 2006;2(14):60-65. (Russian).
- Kovalenko V, Kornatskyi V, Kyrychenko A et al. Diseases of the circulatory system as medical-social and socio-political problem. Kyiv; 2014. 279 с. (Ukrainian).
- Kovalenko V, Kornatskyi V. Regional medical and social problems of cardiovascular diseases: analytical and statistical manual. Kyiv; 2013. 69 с. (Ukrainian).
- Kovalenko V, Lysenko G, Himion L, Garmysh, O. The role of immune-inflammatory and lipid factors in the progression of atherosclerosis and the development of vascular complications in patients with rheumatoid arthritis. Family Medicine. 2012;2:97-101. (Ukrainian).
- Kolesnyk M. Influence of insulin resistance on the structural and functional state of the myocardium of left ventricle in males with uncomplicated hypertension. Bukovinian Medical Herald. 2014;18(4):55-59. (Ukrainian).
- Korkushko O, Lishnevskaya V, Duzak H. Age features a functional state of the microvascular endothelium. Circulation and Hemostasis. 2007;4:5-11. (Russian).
- Koteljuh M, Kravchun P. The role of extracellular matrix components in the development of acute myocardial infarction and type II diabetes mellitus. Problems of Endocrine Pathology 2015;4:111-118. (Ukrainian).
- Kravchun I, Babadzhan V, Zaikina T. Influence of fibrinolytic therapy on the incidence of complications during the acute period of myocardial infarction in patients with diabetes mellitus type. Problems of Endocrine Pathology. 22015;3:38-43. (Ukrainian).
- Kriachok T, Vavilova L. Hyperglycemia as a component of metabolic syndrome and the main important factor of its progression. Bukovinian Medical Herald. 2014;18(1):54-57. (Ukrainian).
- Kukharchuk V. Disputable and unsolved problems in the first decade of the XXI century. Therapeutic Archive. 2009;81(5):14-22. (Ukrainian).
- Lapovets L, Lutsyk B, Lebed H. Manual of Laboratory Immunology. Lviv; 2014. 290 с. (Ukrainian).
- Lutay М, Golikova I, Slobodskoy V. Role of endothelial dysfunction, inflammation and dyslipidemia in atherogenesis. Ukrainian Journal of Cardiology. 2007;5:37-47. (Russian).
- Milyutina O, Chicherina E. Prognostic role of C-reactive protein and cardiac event risk. Russian Journal of Cardiology. 2011;1(87):71-73. (Russian).
- Netyazhenko V, Barna O, Solomenchuk T. Atherosclerosis in type II diabetes mellitus: a strategy for the treatment of dyslipidemias. Medicine of Ukraine. 2003;10:4-10. (Ukrainian).
- Petina M, Gorokhovskaya G, Martynov A. Endothelial dysfunction in patients with coronary heart disease and type 2 diabetes mellitus. Russian Journal of Cardiology. 2011;2(88):32-36. (Russian).
- Popkova T, Novikov D, Nasonov E. Role of interleukin-6 in the development of atherosclerosis in rheumatoid arthritis. Rheumatology Science and Practice. 2011;4:64-72. (Russian).
- Rebrov A, Voskoboy N. The role of inflammatory and infectious factors in the development of atherosclerosis. Therapeutic Archive. 2004;1:78-81. (Russian).
- Ruda M, Parfenova E, Karpov Y. Circulating precursors of endothelial cells: role in restoring endothelial function and prospects for therapeutic use. Cardiology. 2008;1:66-73. (Russian).
- Sergienko O, Yefimov A, Yefimov D, Sergienko V. Diabetic Cardiomyopathy. Lviv; Kyiv: Quart; 2007. 341 с. (Ukrainian).
- Serik S, Chenchik T, Serdobinskaia-Kanivets E, Bondar T. Interleukin-10 and рro-/anti-inflammatory cytokine balance in heart failure patients with type 2 diabetes mellitus. Ukrainian Therapeutically Journal. 2012;3-4:58-63. (Russian).
- Sybirna N, Lyuta M, Klymyshyn N. Molecular mechanisms of nitric oxide deposition in erythrocytes. Studia Biologica. 2010;4(1):143-160. (Ukrainian).
- Syvolap V, Mykhailovskaya N. Features of postinfarction cardiac remodeling in patients with Q-myocardial infarction diabetes mellitus type 2. Zaporozhye Medical Journal. 2012;2(71):56-59. (Ukrainian).
- Skybchyk A. Insulin resistance and changes in lipid profile in patients with acute myocardial infarction and type 2 diabetes. Circulation and Hemostasis. 2007;4:63-67. (Ukrainian).
- Skybchyk V. Insulin resistance and system inflammation in patients with acute myocardial infarction and type 2 diabetes: clinical meaning. Acta Medica Leopoliensia. 2007;2:72-77. (Ukrainian).
- Skybchyk VA. Insulin resistance: the current state of the problem. Medicines of Ukraine. 2006;106/2007;107:57-64. (Ukrainian).
- Skybchyk V. The nitric oxide in patients with myocardial infarction and type 2 diabetes mellitus. Acta Medica Leopoliensia. 2007;4:72-78. (Ukrainian).
- Sokolov Y. Damage to the myocardium and blood vessels in diabetes. Therapeutic Archive. 2005;12:9-13. (Ukrainian).
- Talaeva T, Bratus V. Atherosclerosis: multifactorial and systemic pathogenesis. Ukrainian Journal of Cardiology. 2007;5:101-111. (Russian).
- Tashchuk V, Ivanchuk P, Turubarova-Leunova N. Ischemic heart disease. Factors of destabilization. Bukovinian Medical Herald. 2008;2:39-41. (Ukrainian).
- Shevchenko O, Slesareva Y, Shevchenko A. Levels of plasma protein A and other inflammatory markers in acute coronary syndrome: comparative analysis. Russian Journal of Cardiology. 2008;6:45-50. (Russian).
- Shumakov V, Malynovska I, Tereshkevysh L, Voloshyna O, Kisilevych L. Clinical, statistical and functional indices in patients with acute myocardial infarction with concomitant diabetes mellitus. Ukrainian Journal of Cardiology. 2013;1:33-36. (Ukrainian).
- Agostoni P, Banfi C. Matrix metalloproteinase and heart failure: is it time to move from research to clinical laboratories? Eur Heart J. 2007;28(6):659-660.
- Al Faleh H, Elasfar AA, UllahA, AlHabibKF, Hersi A, Mimish L et al. Acute heart failure with and without acute coronary syndrome: clinical correlates and prognostic impact (From the HEARTS registry). BMC Cardiovasc. Disord. 2016;16(1):98.
- Armstrong EJ, Morrow DA, Sabatine MS. Inflammatory biomarkers in acute coronary syndromes. Part I: Introduction and cytokines. Circulation. 2006;113(6):72-75.
- Asghar O, Al-Sunni A, Khavandi K, Khavandi A, Withers S, Greenstein A et al. Diabetic cardiomyopathy. Clin Sci (London). 2009;116(10):741-760.
- Banerjee D, Biggs ML, Mercer L, Mukamal K, Kaplan R, Barzilay J et al. Insulin resistance and risk of incident heart failure: Cardiovascular Health Study. Circ Heart Fail. 2013;6(3):364-370.
- Banks WA, Willoughby LM, Thomas DR, Morley JE. Insulin resistance syndrome in the elderly. Assessment of functional, biochemical, metabolic, and inflammatory status. Diabetes Care. 2007;30(9):2369-2373.
- Ben-Dor I, Hasdai D, Behar S, Zahger D, Leor J, Hammerman H et al. Prognostic implications of increased cardiac biomarkers and ST segment depression in non-ST elevation acute coronary syndromes: lessons from the acute coronary syndrome Israeli survey (ACSIS). Heart. 2011;92(4):547-548.
- Böger RH. The pharmacodynamics of L-arginine. J Nutr. 2007;137:1650-1655.
- Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and CVD in men and women with diabetes compared with non-diabetic people: a population – based retrospective cohort study. Lancet. 2006;368:29-36.
- Brieger D, Eagle KA, Goodman SG, Steg PG, Budaj A, White K et al. Acute Coronary Syndromes Without Chest Pain, An Underdiagnosed and Undertreated High-Risk Group. Chest. 2004;126(2):461-469.
- Brophy S, Cooksey R, Gravenor MB, Weston C, Macey SM, John G et al. Population based absolute and relative survival to 1 year of people with diabetes following a myocardial infarction: a cohort study using hospital admissions data. BMC Pub. Health. 2010;10:338.
- Bryan NS, Bian K, Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci (Landmark Ed). 2009;14:1-18.
- Campbell-Scherer D. Multimorbidity: a challenge for evidence-based medicine. Evid Based Med. 2010;15(6):165-166.
- Caughey GE, Ramsay EN, Vitry AI, Gilbert AL, Luszcz MA, Ryan P et al. Comorbid chronic diseases, discordant impact on mortality in older people: a 14-year longitudinal population study. J Epidemiol Community Health. 2010;64(12):1036-1042.
- Cefalu WT. Insulin resistance and cardiometabolic risk. In: Atlas of cardiometabolic risk. Cefal WT, Cannon ChP, editors. New-York; London: Informa Healthcare; 2007:27-37.
- Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R et al. Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 2008;57(5):1349-1354.
- Chan D, Ng LL. Biomarker end acute myocardial infarction. BMC Medicine. 2010;34(8):1-11.
- De Luca G, Gibson CM, Bellandi F, Noc M, Dudek D, Zeymer U et al. Diabetes mellitus is associated with distal embolization, impaired myocardial perfusion, and higher mortality in patients with ST-segment elevation myocardial infarction treated with primary angioplasty and glycoprotein IIb-IIIa inhibitors. Atherosclerosis. 2009;207(1):181-185.
- Diamant M, Lamb HJ, Smith JWA. Diabetic cardiomyopathy in uncomplicated type 2 diabetes is associated with the metabolic syndrome and systemic inflammation. Diabetologia. 2005;48(12):1669-1670.
- Dinh W, Lankisch M, Nickl W, Scheyer D, Scheffold T, Kramer F et al. Insulin resistance and glycemic abnormalities are associated with deterioration of left ventricular diastolic function: a cross-sectional study. Cardiovasc Diabetol. 2010;9:63.
- Dudzinski DM, Igarashi J, Greif D, Michel T. The regulation and pharmacology of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol. 2006;46:232-276.
- Elesber AA, Redfield MM, Rihal CS, Prasad A, Lavi S, Lennon R et al. Coronary endothelial dysfunction and hyperlipidemia are independently associated with diastolic dysfunction in humans. Am Heart J. 2007;153(6):1081-1088.
- Evans JL, Goldfine ID, Maddux BA, GrodskyGM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes. 2003;52(1):1-8.
- Evans JL, Maddux BA, Goldfine ID. The molecular basis for oxidative stressinduced insulin resistance. Antioxid Redox Signal. 2005;7(7-8):1040-1052.
- Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation. 2011;123(7):798-813.
- Feskens EJ, Kromhout D. Glucose tolerance and the risk of cardiovascular disease: the Zutphen Study. J Clin Epidemiol. 2005;45(11):1327-133.
- Fisman EZ, Benderly M, Esper RJ, Behar S, Boyko V, Adler Y et al. Interleukin-6 and the risk of future cardiovascular events in patients with angina pectoris and/or healed myocardial infarction. Am J Cardiol. 2012;98(1):14-18.
- Frueh J, Maimari N, Homma T, Bovens SM, Pedrigi RM, Towhidi L et al. Systems biology of the functional and dysfunctional endothelium. Cardiovasc Res. 2013;99(2):334-341.
- Fu G, Jia L, Zhao X, Wang Y, Chen X, Yang Y et al. A Comparison of Intracoronary with Intravenous Glyco-protein IIb/IIIa Inhibitors During Percutaneous Coronary Intervention in 157 Patients with Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials. J Interv Cardiol. 2012;25(3):223-234.
- Garduño-Diaz SD, Khokhar S. Prevalence, risk factors and complications associated with type 2 diabetes in migrant South Asians. Diabetes Metab Res Rev. 2012;28(1): 6-24.
- Giraldez RR, Clare RM, Lopes RD, Dalby AJ, Prabhakaran D, Brogan GX et al. Prevalence and clinical outcomes of undiagnosed diabetes mellitus and prediabetes among patients with high-risk non-ST-segment elevation acute coronary syndrome. Am Heart J. 2013;165(6):918-925.
- Gkaliagkousi E, Ritter J, Ferro A. Platelet-derived nitric oxide signaling and regulation. Circ Res. 2007;101(7):654-662.
- Granger C. Another biomarker for risk as sessment in acute myocardial infarction? J Am Coll Cardiol. 2014;64(16):1708-1710.
- Gruppetta M, Calleja N, Fava S. Long-term survival after acute myocardial infarction and relation to type 2 diabetes and other risk factors. Clin Cardiol. 2010;33(7):424-429.
- Halper J, Kjaer M. Basic components of connective tissues and extracellular matrix: elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins. Adv Exp Med Biol. 2014;802:31-47.
- Hansson G. Іmmune mechanisms in atherosclerosis. Atherosclerosis, Thrombosis and Vascular Biology. 2001;21:187-188.
- Hokanson JE, Austin MA. Plasma triglyceride levelis а risk factor for cardiovascular disease in dependent of high-density lipoproteincholesteroll evel: а meta-analysis of population-based prospective studies. J Cardiovasc Risk. 2006;3(2):213-219.
- Hu Y, Zhou X, Guo DH, Liu P. Effect of JYTK on Antioxidant Status and Inflammation in Patients With Type 2 Diabetes: A Randomized Double-Blind Clinical Trial. Int J Endocrinol Metab. 2016;14(1):e34400.
- Hurst RT, Lee RW. Increased incidence of coronary atherosclerosis in type 2 diabetes mellitus: mechanisms and management. Ann Intern Med. 2003;18:824-834.
- Ingelsson E, Larson MG, Fox CS, Yin X, Wang TJ, Lipinska I et al. Clinical Correlates of Circulating Visfatin Levels in a Community-Based Sample. Diabetes Care. 2007;30(5):1278-1280.
- Ketete M, Cherqaoui R, Maqbool AR, Kwagyan J, Xu S, Randall OS. Endothelial dysfunction: The contribution of diabetes mellitus to the risk factor burden in a high risk population. J Biomed Sci Eng. 2013;6:593-597.
- Khan SQ, Dhillon O, Struck J, Quinn P, Morgenthaler NG, Squire IB et al. C-terminal pro-endotelin-1 offers additional prognostic information in patients after acute miocardial infarction: leicester acute miocardial infarctsion peptide study. Am Heart J. 2007;154(4):736-742.
- Laczik R, Szodoray P, Veres K, Szomják E. Assessment of IgG antibodies to oxidized LDL in patients with acute coronary syndrome. Lupus. 2011;20(7):730-735.
- Libby P. Molecular bases of the acute coronary syndromes. Circul. 2010;91:2844-2850.
- Lubos E, Handy DE, Loscalzo J. Role of oxidative stress and nitric oxide in atherothrombosis. Front Biosci. 2009;13:5323-5344.
- Mahaffey KW, Hafley G, Dickerson S, Burns S, Tourt-Uhlig S, White J et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J. 2013;166(2):240-249.
- Malmberg K, Rydén L, Wedel H, Birkeland K, Bootsma A, Dickstein K et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J. 2005;26(7):650-661.
- Mayranpaa MI, Heikkila HM, Lindstedt KA. Desquamation of human coronary artery endothelium by human mast cell proteases: implications for plaque erosion. Coronary Artery Disease. 2006;17:611-621.
- Melendez-Zajgla J, Del Pozo L, Ceballos G, MaldonadoV.Tissue inhibitor of metalloproteinases-4. The road less traveled. Molecular Cancer. 2008;7:1-11.
- Midwood KS, Hussenet T, Langlois B, Orend G. Advances in tenascin-C biology. Cell Mol Life Sci. 2011;68(19):3175-3199.
- Monesi L, Baviera M, Marzona I, Avanzini F, Monesi G, Nobili A et al. Prevalence, incidence and mortality of diagnosed diabetes: evidence from an Italian population-based study. Diabet Med. 2012;29(3):385-392.
- Moohebati M, Kabirirad V, Ghayour-Mobarhan M, Esmaily H, Tavallaie S, Akhavan Rezayat A et al. Investigation of serum oxidized low-density lipoprotein IgG levels in patients with angiographically defined coronary artery disease. Int J Vasc Med. 2014;2014:845960.
- Newby AC. Matrix metalloproteinase inhibition therapy for vascular diseases. Vascul Pharmacol. 2012;56(5-6):232-244.
- Newby AC. Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates. Cardiovasc Res. 2006;69(3):614-624.
- Newby AC. Metalloproteinase Expressionin Monocytes and Macrophages and its Relationshipto Atherosclerotic Plaque Instability. Arterioscler Thromb Vasc Biol. 2008;28(12):2108-2114.
- Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in heal thand disease: Doppler echocardiography is the clinician’s Rossetastone. J Am Coll Cardiol. 2007;60:8-18.
- Oikonen M, Wendelin-Saarenhovi M, Siitonen N, Sainio A, Juonala M, Kähönen M et al. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) in a population of young adults: relations to cardiovascular risk markers and carotid artery intima-media thickness. The Cardiovascular Risk in Young Finns Study. Scand J Clin Lab Invest. 2012;72(7):540-546.
- Paoletti R, Gotto AM, Hajjar DP. Inflammation in atherosclerosis and implications for therapy. Circulation. 2004;109:20-26.
- Pilgrim T, Vranckx P, Valgimigli M, Stefanini GG, Piccolo R, Rat Jetal. Risk and timing of recurrent ischemic events among patients with stable ischemic heart disease, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction. Am Heart J. 2016;175:56-65.
- Porter KE, Turner NA. Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Ther. 2009;123(2):255-278.
- Preda I, Bencze J, Vargova K. Endotelial function and ischemic heart disease. Orv Hetil. 2005;146:1047-1053.
- Rhodes ET, Prosser LA, Hoerger TJ, Lieu T, Ludwig DS, Laffel LM. Estimated morbidity and mortality in adolescents and young adults diagnosed with Type 2 diabetes mellitus. Diabet Med. 2012;29(4):453-463.
- Rodríguez-Hernández H, Simental-Mendía LE, Rodríguez-Ramírez G, Reyes-Romero MA. Obesity and inflammation: epidemiology, risk factors, and markers of inflammation [Internet]. Int J Endocrinol. 2013;2013:11. Available from: http:// www.hindawi.com/journals/ije/2013/678159/.
- Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28(1):88-136.
- Sautin Y, Nakagawa T, Zharikov S, Johnson RJ. Adverse effect of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative nitrosative stress. Am J Physiol Cell. 2007;293(2):C584-C596.
- Scholten BJ, Reinhard H, Hansenetal TV. Marcer of inflammation and endothelial dysfunction are associated with incident cardiovascular disease, all-cause mortality and progression of coronary calcification in type 2 diabetes patients with microalbuminuria. J Diabets Complications. 2016;30(2):248-255.
- Selvin E, Lazo M, Chen Y, Shen L, Rubin J, McEvoy JW et al. Diabetes mellitus, prediabetes, and incidence of subclinical myocardial damage. Circulation. 2014;130(16):1374-1382.
- Shaw JE, Sicree RA, Zimmet PZ.Globales timates of the prevalence of diabet esfor 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4-14.
- Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793-1801.
- Steg PG, James SK, Atar D, Badano LP, Blömstrom-Lundqvist C, Borger MA et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J. 2012;33(20):2569-2619.
- Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD et al. Task Force for the Universal Definition of Myocardial Infarction. Eur Heart J. 2012;33(20): 2551-2567.
- Tuomainen AM, Kormi I, Havulinna AS, Tervahartiala T, Salomaa V, Sorsa T et al. Serum Tissue-Degrading Proteinases and Incident Cardiovascular Disease Events. Eur J Prev Cardiol. 2012;21(7):806-812.
- Valderas JM, Starfield B, Sibbald B, Salisbury C, Roland M. Defining comorbidity: implications for understanding health and health services. Ann Fam Med. 2009;7(4):357-363.
- Vanhoutte D, HeymansS. TIMPs and cardiac remodeling: Embracing the MMP-independent-side of the family. J Mol Cell Cardiol. 2010;48(3):445-453.
- Vazzana N, Ranalli P, Cuccurullo C, Davì G. Diabetes mellitus and thrombosis. Thromb Res.2012;129(3):371-377.
- Wilmot EG, Edwardson CL, Achana FA, Davies MJ, Gorely T, Gray LJ et al. Sedentary time in adult sand the association with diabetes, cardiovascular disease and death: systematic review and meta-analysis. Diabetologia. 2012;55(11):2895-2905.
- Yarbrough WM, Baicu C, Mukherjee R, Van Laer A, Rivers WT, McKinney RA et al. Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol. 2014;307(5):752-761.
- Zakynthinos E, Pappa N. Inflammatory biomarkers in coronary artery disease. J Cardiology. 2009;53(3):317-333.
- Zozulinska D, Wierusz-Wysocka B. Type 2 diabetes mellitusas inflammatory disease. Diabetes Res Clin Pract. 2006;74:12-16.