Экспрессия гена адипонектина в адипоцитах локальных жировых депо у пациентов с ишемической болезнью сердца в зависимости от степени поражения коронарного русла
Экспрессия гена адипонектина в адипоцитах локальных жировых депо у пациентов с ишемической болезнью сердца в зависимости от степени поражения коронарного русла
Белик Е.В., Груздева О.В., Акбашева О.Е. и др. Экспрессия гена адипонектина в адипоцитах локальных жировых депо у пациентов с ишемической болезнью сердца в зависимости от степени поражения коронарного русла. Терапевтический архив. 2020; 92 (4): 23–29. DOI: 10.26442/00403660.2020.04.000537
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Аннотация
Цель. Выявить зависимость экспрессии гена адипонектина подкожными, эпикардиальными и периваскулярными адипоцитами от степени поражения коронарного русла при ишемической болезни сердца.
Материалы и методы. Обследованы 84 пациента с ишемической болезнью сердца. Из них у 39 человек по шкале SYNTAX Score выявлена умеренная степень атеросклеротического поражения коронарного русла (меньше или равно 22 баллов), у 20 – тяжелая (22–31 балл) и у 25 – крайне тяжелая (более 32 баллов). При поступлении в стационар всем больным проведено эхокардиографическое исследование (Acuson, Германия) с расчетом значения фракции выброса (ФВ) левого желудочка (ЛЖ) для оценки его систолической функции. Во время планового оперативного вмешательства (коронарного шунтирования) проводился забор адипоцитов подкожной, эпикардиальной (ЭЖТ) и периваскулярной жировой ткани (ПВЖТ). Экспрессию гена адипонектина оценивали с методом полимеразной цепной реакции в реальном времени с использованием зондов TaqMan. Статистический анализ выполнен с помощью программы Statistica 9.0.
Результаты. Максимальный уровень экспрессии адипонектина выявлен в адипоцитах ПВЖТ, а минимальный – ЭЖТ. С увеличением степени атеросклеротического поражения коронарного русла значительно снижается экспрессия гена адипонектина в адипоцитах локальных депо (r=-0,82; p=0,023). При этом низкий уровень экспрессии гена в ЭЖТ коррелировал с уменьшением ФВ ЛЖ (r=0,73; p=0,03). В адипоцитах подкожной жировой ткани и особенно ПВЖТ экспрессия гена была самой высокой у пациентов с умеренной степенью поражения коронарного русла.
Заключение. Низкая экспрессия гена адипонектина в ЭЖТ ассоциирована с увеличением степени атеросклеротического поражения коронарного русла и уменьшением ФВ ЛЖ.
Ключевые слова: экспрессия адипонектина, эпикардиальная жировая ткань, периваскулярная жировая ткань, фракция выброса, шкала SYNTAX Score.
Materials and methods. 84 patients with coronary artery disease were examined. Of these, 39 people showed a moderate degree of atherosclerotic lesion of the coronary bed (less than or equal to 22 points) on the SYNTAX Score scale, 20 – severe (22–31 points), and 25 – extremely severe (more than 32 points). Upon admission to the hospital, all patients underwent an echocardiographic study (Echocardiography, Acuson, Germany) with the calculation of the ejection fraction (EF) of the left ventricle (LV) to assess its systolic function. During a planned surgical intervention (coronary bypass surgery, CABG), adipocytes of subcutaneous, epicardial (EAT) and perivascular adipose tissue (PVAT) were taken. Adiponectin gene expression was evaluated by polymerase chain reaction (real-time PCR) using TaqMan probes. Statistical analysis was performed using Statistica 9.0.
Results. The maximum level of adiponectin expression was detected in adipocytes of PVAT, and the minimum – EAT. With an increase in the degree of atherosclerotic lesion of the coronary bed, the expression of the adiponectin gene in adipocytes of local depots significantly decreases r=-0.82; p=0.023. Moreover, the low level of gene expression in EAT correlated with a decrease in LV EF by r=0.73; p=0.03.
In adipocytes of subcutaneous and especially PVAT, gene expression was the highest in patients with a moderate degree of coronary lesion.
Conclusions. Low adiponectin gene expression in EAT is associated with an increase in the degree of atherosclerotic lesion of the coronary bed and a decrease in LV EF.
Keywords: adiponectin expression, epicardial adipose tissue, perivascular adipose tissue, ejection fraction, SYNTAX Score scale.
Материалы и методы. Обследованы 84 пациента с ишемической болезнью сердца. Из них у 39 человек по шкале SYNTAX Score выявлена умеренная степень атеросклеротического поражения коронарного русла (меньше или равно 22 баллов), у 20 – тяжелая (22–31 балл) и у 25 – крайне тяжелая (более 32 баллов). При поступлении в стационар всем больным проведено эхокардиографическое исследование (Acuson, Германия) с расчетом значения фракции выброса (ФВ) левого желудочка (ЛЖ) для оценки его систолической функции. Во время планового оперативного вмешательства (коронарного шунтирования) проводился забор адипоцитов подкожной, эпикардиальной (ЭЖТ) и периваскулярной жировой ткани (ПВЖТ). Экспрессию гена адипонектина оценивали с методом полимеразной цепной реакции в реальном времени с использованием зондов TaqMan. Статистический анализ выполнен с помощью программы Statistica 9.0.
Результаты. Максимальный уровень экспрессии адипонектина выявлен в адипоцитах ПВЖТ, а минимальный – ЭЖТ. С увеличением степени атеросклеротического поражения коронарного русла значительно снижается экспрессия гена адипонектина в адипоцитах локальных депо (r=-0,82; p=0,023). При этом низкий уровень экспрессии гена в ЭЖТ коррелировал с уменьшением ФВ ЛЖ (r=0,73; p=0,03). В адипоцитах подкожной жировой ткани и особенно ПВЖТ экспрессия гена была самой высокой у пациентов с умеренной степенью поражения коронарного русла.
Заключение. Низкая экспрессия гена адипонектина в ЭЖТ ассоциирована с увеличением степени атеросклеротического поражения коронарного русла и уменьшением ФВ ЛЖ.
Ключевые слова: экспрессия адипонектина, эпикардиальная жировая ткань, периваскулярная жировая ткань, фракция выброса, шкала SYNTAX Score.
________________________________________________
Materials and methods. 84 patients with coronary artery disease were examined. Of these, 39 people showed a moderate degree of atherosclerotic lesion of the coronary bed (less than or equal to 22 points) on the SYNTAX Score scale, 20 – severe (22–31 points), and 25 – extremely severe (more than 32 points). Upon admission to the hospital, all patients underwent an echocardiographic study (Echocardiography, Acuson, Germany) with the calculation of the ejection fraction (EF) of the left ventricle (LV) to assess its systolic function. During a planned surgical intervention (coronary bypass surgery, CABG), adipocytes of subcutaneous, epicardial (EAT) and perivascular adipose tissue (PVAT) were taken. Adiponectin gene expression was evaluated by polymerase chain reaction (real-time PCR) using TaqMan probes. Statistical analysis was performed using Statistica 9.0.
Results. The maximum level of adiponectin expression was detected in adipocytes of PVAT, and the minimum – EAT. With an increase in the degree of atherosclerotic lesion of the coronary bed, the expression of the adiponectin gene in adipocytes of local depots significantly decreases r=-0.82; p=0.023. Moreover, the low level of gene expression in EAT correlated with a decrease in LV EF by r=0.73; p=0.03.
In adipocytes of subcutaneous and especially PVAT, gene expression was the highest in patients with a moderate degree of coronary lesion.
Conclusions. Low adiponectin gene expression in EAT is associated with an increase in the degree of atherosclerotic lesion of the coronary bed and a decrease in LV EF.
Keywords: adiponectin expression, epicardial adipose tissue, perivascular adipose tissue, ejection fraction, SYNTAX Score scale.
Список литературы
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10. Kumada M, Kihara S, Ouchi N, et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation. 2004;109:2046-9. doi: 10.1161/01.cir.0000127953.98131.ed
11. Koenig W, Khuseyinova N, Baumert J, et al. Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany. J Am Coll Cardiol. 2006;48:1369-77. doi: 10.1016/j.jacc.2006.06.053
12. Pischon T. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004;291:1730-7. doi: 10.1001/jama.291.14.1730
13. Kumada M, Kihara S, Sumitsuji S, et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol. 2003;23:85-9. doi: 10.1161/01.atv.0000048856.22331.50
14. Matthias B, Shai I, Rimm E. Adiponectin and Future Coronary Heart Disease Events Among Men With Type 2 Diabetes. Am J Epidem. 2007;165:164-74.
15. Wannamethee SG, Whincup PH, Lennon L, Sattar N. Circulating adiponectin levels and mortality in elderly men with and without cardiovascular disease and heart failure. Arch Intern Med. 2007;167:1510-7. doi: 10.1001/archinte.167.14.1510
16. George J. Circulating adiponectin levels predict outcome in patients with severe congestive heart failure. Heart. 2006;92:1420-4. doi: 10.1136/ hrt.2005.083345
17. Kistorp C, Faber J, Galatius S, et al. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation. 2005;112:1756-62. doi: 10.1161/circulationaha.104.530972
18. Vela D, Buja LM, Madjid M, et al. The role of periadventitial fat in atherosclerosis: An adipose subset with potential diagnostic and therapeutic implications (Review). Arch Pathol Lab Med. 2007;131(3):481-7.
19. Sacks H, Fain J. Human epicardial adipose tissue: A review. Am Heart J. 2007;153(6):907-17. doi: 10.1016/j.ahj.2007.03.019
20. Iacobellis G, Pistilli D, Gucciardo M, Leonetti F. Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease. Cytokine. 2005;29(6):251-5. doi: 10.1016/ j.cyto.2004.11.002
21. Bambacea C, Telescab M, Zoicoa E, et al. Adiponectin gene expression and adipocyte diameter: a comparison between epicardial and subcutaneous adipose tissue in men. Cardiovasc Pathology. 2011;20:
е153–e156. doi: 10.1016/j.carpath.2010.07.005
22. Nacci C, Leo V, De Benedictis L, et al. Infliximab therapy restores adiponectin expression in perivascular adipose tissue and improves endothelial nitric oxide-mediated vasodilation in mice with type 1 diabetes. Vasc Pharmacol. 2016;87:83-91. doi: 10.1016/j.vph.2016.08.007
23. Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem. 2003;278:2461-8. doi: 10.1074/jb
24. Eiras S, Teijeira-Fernández E, Shamagian LG, et al. Extension of coronary artery disease is associated with increased IL-6 and decreased adiponectin gene expression in epicardial adipose tissue. Cytokine. 2008;43(2):174-80. doi: 10.1016/j.cyto.2008.05.006
25. Chatterjee TK, Stoll LL, Denning GM, et al. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ Res. 2009;104:541-9. doi: 10.1161/circresaha.108.182998
26. Maahs DM, Ogden LG, Kinney GL, et al. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation. 2005;111:747-53. doi: 10.1161/01.cir.0000155251.03724.a5
27. Araki T, Emoto M, Teramura M, et al. Effect of adiponectin on carotid arterial stiffness in type 2 diabetic patients treated with pioglitazone and metformin. Metabolism. 2006;55:996-1001. doi: 10.1016/j.metabol. 2006.03.008
2. Neeland IJ, Patel RS, Eshtehardi P, et al. Coronary angiographic scoring systems: An evaluation of their equivalence and validity. Am Heart J. 2012;164:547-52. doi: 10.1016/j.ahj.2012.07.007
3. Sianos G, Morel MA, Kappetein AP, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease.
EuroInterv. 2005;1:219-27.
4. Gruzdeva OV, Akbasheva OE, Dyleva YuA, et al. Adipokine and cytokine profiles of epicardial and subcutaneous adipose tissue in patients with coronary artery disease. Bulletin of Experimental Biology and Medicine. 2017;63(5):560-3 (In Russ.)
5. Dyleva YuA, Gruzdeva OV, Belik EV, et al. Gene expression and adiponectin content in adipose tissue in patients with coronary artery disease. Biomeditsinskaya Khimiya. 2019;65(3):239-44 (In Russ.)
6. Kershaw EE, Flier JS. Adipose tissue as an endocrine оrgan. J Clin Endocrinol Metabolism. 2004;89(6):2548-56. doi: 10.1210/jc.2004-0395
7. Pineiro R, Iglesias MJ, Gallego R, et al. Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett. 2005;579:5163-9. doi: 10.1016/j.febslet.2005.07.098
8. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868-74. doi: 10.1038/nature01323
9. Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone? Diabetes Care. 2003;26:2442-50. doi: 10.2337/diacare.26.8.2442
10. Kumada M, Kihara S, Ouchi N, et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation. 2004;109:2046-9. doi: 10.1161/01.cir.0000127953.98131.ed
11. Koenig W, Khuseyinova N, Baumert J, et al. Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany. J Am Coll Cardiol. 2006;48:1369-77. doi: 10.1016/j.jacc.2006.06.053
12. Pischon T. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004;291:1730-7. doi: 10.1001/jama.291.14.1730
13. Kumada M, Kihara S, Sumitsuji S, et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol. 2003;23:85-9. doi: 10.1161/01.atv.0000048856.22331.50
14. Matthias B, Shai I, Rimm E. Adiponectin and Future Coronary Heart Disease Events Among Men With Type 2 Diabetes. Am J Epidem. 2007;165:164-74.
15. Wannamethee SG, Whincup PH, Lennon L, Sattar N. Circulating adiponectin levels and mortality in elderly men with and without cardiovascular disease and heart failure. Arch Intern Med. 2007;167:1510-7. doi: 10.1001/archinte.167.14.1510
16. George J. Circulating adiponectin levels predict outcome in patients with severe congestive heart failure. Heart. 2006;92:1420-4. doi: 10.1136/ hrt.2005.083345
17. Kistorp C, Faber J, Galatius S, et al. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation. 2005;112:1756-62. doi: 10.1161/circulationaha.104.530972
18. Vela D, Buja LM, Madjid M, et al. The role of periadventitial fat in atherosclerosis: An adipose subset with potential diagnostic and therapeutic implications (Review). Arch Pathol Lab Med. 2007;131(3):481-7.
19. Sacks H, Fain J. Human epicardial adipose tissue: A review. Am Heart J. 2007;153(6):907-17. doi: 10.1016/j.ahj.2007.03.019
20. Iacobellis G, Pistilli D, Gucciardo M, Leonetti F. Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease. Cytokine. 2005;29(6):251-5. doi: 10.1016/ j.cyto.2004.11.002
21. Bambacea C, Telescab M, Zoicoa E, et al. Adiponectin gene expression and adipocyte diameter: a comparison between epicardial and subcutaneous adipose tissue in men. Cardiovasc Pathology. 2011;20:
е153–e156. doi: 10.1016/j.carpath.2010.07.005
22. Nacci C, Leo V, De Benedictis L, et al. Infliximab therapy restores adiponectin expression in perivascular adipose tissue and improves endothelial nitric oxide-mediated vasodilation in mice with type 1 diabetes. Vasc Pharmacol. 2016;87:83-91. doi: 10.1016/j.vph.2016.08.007
23. Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem. 2003;278:2461-8. doi: 10.1074/jb
24. Eiras S, Teijeira-Fernández E, Shamagian LG, et al. Extension of coronary artery disease is associated with increased IL-6 and decreased adiponectin gene expression in epicardial adipose tissue. Cytokine. 2008;43(2):174-80. doi: 10.1016/j.cyto.2008.05.006
25. Chatterjee TK, Stoll LL, Denning GM, et al. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ Res. 2009;104:541-9. doi: 10.1161/circresaha.108.182998
26. Maahs DM, Ogden LG, Kinney GL, et al. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation. 2005;111:747-53. doi: 10.1161/01.cir.0000155251.03724.a5
27. Araki T, Emoto M, Teramura M, et al. Effect of adiponectin on carotid arterial stiffness in type 2 diabetic patients treated with pioglitazone and metformin. Metabolism. 2006;55:996-1001. doi: 10.1016/j.metabol. 2006.03.008
2. Neeland IJ, Patel RS, Eshtehardi P, et al. Coronary angiographic scoring systems: An evaluation of their equivalence and validity. Am Heart J. 2012;164:547-52. doi: 10.1016/j.ahj.2012.07.007
3. Sianos G, Morel MA, Kappetein AP, et al. The SYNTAX Score: an angiographic tool grading the complexity of coronary artery disease.
EuroInterv. 2005;1:219-27.
4. Груздева О.В., Акбашева О.Е., Дылева Ю.А. и др. Адипокиновый и цитокиновый профили эпикардиальной и подкожной жировой ткани у пациентов с ишемической болезнью сердца. Бюллетень экспериментальной биологии и медицины. 2017;63(5):560-3 [Gruzdeva OV, Akbasheva OE, Dyleva YuA, et al. Adipokine and cytokine profiles of epicardial and subcutaneous adipose tissue in patients with coronary artery disease. Bulletin of Experimental Biology and Medicine. 2017;63(5):560-3 (In Russ.)].
5. Дылева Ю.А., Груздева О.В., Белик Е.В. и др. Экспрессия гена и содержание адипонектина в жировой ткани у пациентов с ишемической болезнью сердца. Биомедицинская химия. 2019;65(3):239-44 [Dyleva YuA, Gruzdeva OV, Belik EV, et al. Gene expression and adiponectin content in adipose tissue in patients with coronary artery disease. Biomeditsinskaya Khimiya. 2019;65(3):239-44 (In Russ.)].
6. Kershaw EE, Flier JS. Adipose tissue as an endocrine оrgan. J Clin Endocrinol Metabolism. 2004;89(6):2548-56. doi: 10.1210/jc.2004-0395
7. Pineiro R, Iglesias MJ, Gallego R, et al. Adiponectin is synthesized and secreted by human and murine cardiomyocytes. FEBS Lett. 2005;579:5163-9. doi: 10.1016/j.febslet.2005.07.098
8. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868-74. doi: 10.1038/nature01323
9. Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone? Diabetes Care. 2003;26:2442-50. doi: 10.2337/diacare.26.8.2442
10. Kumada M, Kihara S, Ouchi N, et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation. 2004;109:2046-9. doi: 10.1161/01.cir.0000127953.98131.ed
11. Koenig W, Khuseyinova N, Baumert J, et al. Serum concentrations of adiponectin and risk of type 2 diabetes mellitus and coronary heart disease in apparently healthy middle-aged men: results from the 18-year follow-up of a large cohort from southern Germany. J Am Coll Cardiol. 2006;48:1369-77. doi: 10.1016/j.jacc.2006.06.053
12. Pischon T. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004;291:1730-7. doi: 10.1001/jama.291.14.1730
13. Kumada M, Kihara S, Sumitsuji S, et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol. 2003;23:85-9. doi: 10.1161/01.atv.0000048856.22331.50
14. Matthias B, Shai I, Rimm E. Adiponectin and Future Coronary Heart Disease Events Among Men With Type 2 Diabetes. Am J Epidem. 2007;165:164-74.
15. Wannamethee SG, Whincup PH, Lennon L, Sattar N. Circulating adiponectin levels and mortality in elderly men with and without cardiovascular disease and heart failure. Arch Intern Med. 2007;167:1510-7. doi: 10.1001/archinte.167.14.1510
16. George J. Circulating adiponectin levels predict outcome in patients with severe congestive heart failure. Heart. 2006;92:1420-4. doi: 10.1136/ hrt.2005.083345
17. Kistorp C, Faber J, Galatius S, et al. Plasma adiponectin, body mass index, and mortality in patients with chronic heart failure. Circulation. 2005;112:1756-62. doi: 10.1161/circulationaha.104.530972
18. Vela D, Buja LM, Madjid M, et al. The role of periadventitial fat in atherosclerosis: An adipose subset with potential diagnostic and therapeutic implications (Review). Arch Pathol Lab Med. 2007;131(3):481-7.
19. Sacks H, Fain J. Human epicardial adipose tissue: A review. Am Heart J. 2007;153(6):907-17. doi: 10.1016/j.ahj.2007.03.019
20. Iacobellis G, Pistilli D, Gucciardo M, Leonetti F. Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease. Cytokine. 2005;29(6):251-5. doi: 10.1016/ j.cyto.2004.11.002
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20. Iacobellis G, Pistilli D, Gucciardo M, Leonetti F. Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease. Cytokine. 2005;29(6):251-5. doi: 10.1016/ j.cyto.2004.11.002
21. Bambacea C, Telescab M, Zoicoa E, et al. Adiponectin gene expression and adipocyte diameter: a comparison between epicardial and subcutaneous adipose tissue in men. Cardiovasc Pathology. 2011;20:
е153–e156. doi: 10.1016/j.carpath.2010.07.005
22. Nacci C, Leo V, De Benedictis L, et al. Infliximab therapy restores adiponectin expression in perivascular adipose tissue and improves endothelial nitric oxide-mediated vasodilation in mice with type 1 diabetes. Vasc Pharmacol. 2016;87:83-91. doi: 10.1016/j.vph.2016.08.007
23. Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis. J Biol Chem. 2003;278:2461-8. doi: 10.1074/jb
24. Eiras S, Teijeira-Fernández E, Shamagian LG, et al. Extension of coronary artery disease is associated with increased IL-6 and decreased adiponectin gene expression in epicardial adipose tissue. Cytokine. 2008;43(2):174-80. doi: 10.1016/j.cyto.2008.05.006
25. Chatterjee TK, Stoll LL, Denning GM, et al. Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ Res. 2009;104:541-9. doi: 10.1161/circresaha.108.182998
26. Maahs DM, Ogden LG, Kinney GL, et al. Low plasma adiponectin levels predict progression of coronary artery calcification. Circulation. 2005;111:747-53. doi: 10.1161/01.cir.0000155251.03724.a5
27. Araki T, Emoto M, Teramura M, et al. Effect of adiponectin on carotid arterial stiffness in type 2 diabetic patients treated with pioglitazone and metformin. Metabolism. 2006;55:996-1001. doi: 10.1016/j.metabol. 2006.03.008
Авторы
Е.В. Белик1, О.В. Груздева1, О.Е. Акбашева2, Ю.А. Дылева1, Д.А. Бородкина1, М.Ю. Синицкий1, А.В. Сотников1, К.А. Козырин1, Н.К. Брель1, Д.Ю. Наумов1, А.А. Шилов1, Е.Е. Бычкова1, В.Н. Каретникова1, О.Л. Барбараш1
1 ФГБНУ «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Россия;
2 ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава России, Томск, Россия
1 Research Institute for Complex Issues of Cardiovascular Disease, Kemerovo, Russia;
2 Siberian State Medical University, Tomsk, Russia
1 ФГБНУ «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний», Кемерово, Россия;
2 ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава России, Томск, Россия
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1 Research Institute for Complex Issues of Cardiovascular Disease, Kemerovo, Russia;
2 Siberian State Medical University, Tomsk, Russia
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