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Роль галектина-3 в диагностике и контроле эффективности фармакотерапии хронической сердечной недостаточности
Роль галектина-3 в диагностике и контроле эффективности фармакотерапии хронической сердечной недостаточности
Гямджян К.А., Кукес В.Г. Роль галектина-3 в диагностике и контроле эффективности фармакотерапии хронической сердечной недостаточности. CardioСоматика. 2017; 8 (4): 5–10.
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Аннотация
Актуальность. В настоящее время остается актуальной разработка новых биомаркеров, способных служить инструментом ранней диагностики заболевания с целью подбора фармакотерапии и дальнейшего мониторинга ее эффективности.
Цель – оценка клинической ценности определения галектина-3 у пациентов с хронической сердечной недостаточностью (ХСН).
Материалы и методы. В исследование включены 53 пациента (31 женщина, 22 мужчины) с ХСН II–III функционального класса (ФК) по Нью-Йоркской кардиологической ассоциации (New York Heart Association – NYHA). Средний возраст пациентов составил 71 год (95% доверительный интервал 68,99–74,37). Группу пациентов с ХСН II ФК по NYHA составили 14 человек, группу пациентов с ХСН III ФК по NYHA – 39. Медиана начального уровня N-концевого мозгового натрийуретического пептида (NT-proBNP) составила 65,7 пмоль/л, медиана исходного уровня галектина-3 – 8,37 пмоль/л.
Результаты. Выявлена взаимосвязь повышенного уровня галектина-3 со сниженной фракцией выброса, % (r=-0,26, p=0,04), повышенным уровнем креатинина (r=0,26, p=0,04) и повышенным уровнем NT-proBNP плазмы (r=0,3, p=0,02). С другими клиническими показателями, такими как систолическое и диастолическое артериальное давление, частота сердечных сокращений, индекс массы тела, тест 6-минутной ходьбы, индекс массы миокарда левого желудочка, уровень глюкозы, общий холестерин, скорость клубочковой фильтрации, статистически значимой связи найдено не было. Получена умеренная корреляционная связь между уровнями NT-proBNP и галектина-3 плазмы (r=0,3, p=0,02). Снижение уровня галектина-3 после проведенного лечения было выявлено у 84,3% пациентов.
Заключение. Галектин-3 может служить дополнительным диагностическим биомаркером ХСН.
Ключевые слова: галектин-3, мозговой натрийуретический пептид, биомаркер, хроническая сердечная недостаточность, мониторинг.
The goal is to evaluate the clinical value of the definition of galectin-3 in patients with chronic heart failure (CHF).
Materials and methods. The study included 53 patients (31 women, 22 men) with CHF II–III functional class (FC) of the New York Heart Association (NYHA). The mean age of the patients was 71 years (95% confidence interval 68.99–74.37). A group of patients with NYHA FCh II CHF made up 14 people, a group of patients with NYHA-39 CHF III FC. The median of the initial level of the N-terminal brain natriuretic peptide (NT-proBNP) was 65.7 pmol/L, the median of the initial level of galectin-3 – 8.37 pmol/l.
Results. The relationship of increased level of galectin-3 with reduced ejection fraction,% (r=-0.26, p=0.04), increased creatinine level (r=0.26, p=0.04) and increased level of NT-proBNP plasma (r=0.3, p=0.02). With other clinical indicators, such as systolic and diastolic blood pressure, heart rate, body mass index, 6-minute walk test, left ventricular mass index, glucose level, total cholesterol, glomerular filtration rate, no statistically significant association was found. A moderate correlation was obtained between the levels of NT-proBNP and galectin-3 plasma (r=0.3, p=0.02). Reduction in the level of galectin-3 after the treatment was detected in 84.3% of patients.
The conclusion. Galectin-3 can serve as an additional diagnostic biomarker of CHF.
Key words: galectin-3, brain natriuretic peptide, biomarker, chronic heart failure, monitoring.
Цель – оценка клинической ценности определения галектина-3 у пациентов с хронической сердечной недостаточностью (ХСН).
Материалы и методы. В исследование включены 53 пациента (31 женщина, 22 мужчины) с ХСН II–III функционального класса (ФК) по Нью-Йоркской кардиологической ассоциации (New York Heart Association – NYHA). Средний возраст пациентов составил 71 год (95% доверительный интервал 68,99–74,37). Группу пациентов с ХСН II ФК по NYHA составили 14 человек, группу пациентов с ХСН III ФК по NYHA – 39. Медиана начального уровня N-концевого мозгового натрийуретического пептида (NT-proBNP) составила 65,7 пмоль/л, медиана исходного уровня галектина-3 – 8,37 пмоль/л.
Результаты. Выявлена взаимосвязь повышенного уровня галектина-3 со сниженной фракцией выброса, % (r=-0,26, p=0,04), повышенным уровнем креатинина (r=0,26, p=0,04) и повышенным уровнем NT-proBNP плазмы (r=0,3, p=0,02). С другими клиническими показателями, такими как систолическое и диастолическое артериальное давление, частота сердечных сокращений, индекс массы тела, тест 6-минутной ходьбы, индекс массы миокарда левого желудочка, уровень глюкозы, общий холестерин, скорость клубочковой фильтрации, статистически значимой связи найдено не было. Получена умеренная корреляционная связь между уровнями NT-proBNP и галектина-3 плазмы (r=0,3, p=0,02). Снижение уровня галектина-3 после проведенного лечения было выявлено у 84,3% пациентов.
Заключение. Галектин-3 может служить дополнительным диагностическим биомаркером ХСН.
Ключевые слова: галектин-3, мозговой натрийуретический пептид, биомаркер, хроническая сердечная недостаточность, мониторинг.
________________________________________________
The goal is to evaluate the clinical value of the definition of galectin-3 in patients with chronic heart failure (CHF).
Materials and methods. The study included 53 patients (31 women, 22 men) with CHF II–III functional class (FC) of the New York Heart Association (NYHA). The mean age of the patients was 71 years (95% confidence interval 68.99–74.37). A group of patients with NYHA FCh II CHF made up 14 people, a group of patients with NYHA-39 CHF III FC. The median of the initial level of the N-terminal brain natriuretic peptide (NT-proBNP) was 65.7 pmol/L, the median of the initial level of galectin-3 – 8.37 pmol/l.
Results. The relationship of increased level of galectin-3 with reduced ejection fraction,% (r=-0.26, p=0.04), increased creatinine level (r=0.26, p=0.04) and increased level of NT-proBNP plasma (r=0.3, p=0.02). With other clinical indicators, such as systolic and diastolic blood pressure, heart rate, body mass index, 6-minute walk test, left ventricular mass index, glucose level, total cholesterol, glomerular filtration rate, no statistically significant association was found. A moderate correlation was obtained between the levels of NT-proBNP and galectin-3 plasma (r=0.3, p=0.02). Reduction in the level of galectin-3 after the treatment was detected in 84.3% of patients.
The conclusion. Galectin-3 can serve as an additional diagnostic biomarker of CHF.
Key words: galectin-3, brain natriuretic peptide, biomarker, chronic heart failure, monitoring.
Полный текст
Список литературы
1. Lok DJ, Van Der Meer P, de la Porte PW et al. Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study. Clin Res Cardiol 2010; 99 (5): 323–8.
2. De Boer RA, Lok DJA, Jaarsma T et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 2011; 43 (1): 60–8.
3. De Boer RA, van der Velde A, Mueller C et al. Galectin-3: A Modifiable Risk Factor in Heart Failure. Cardiovasc Drugs Ther 2014; 28: 237–46.
4. Liu YH, d’Ambrosio M, Liao TD et al. N-Acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growthregulatory lectin. Am J Physiol Heart Circ Physiol 2009; 296: H404–12.
5. Kim H et al. Expression and immunohistochemical localization of galectin-3 in various mouse tissues. Cell Biol Int 2007; 31 (7): 655–62.
6. Tang WH, Shrestha K, Shao Z et al. Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival. Am J Cardiol 2011; 108: 385–90.
7. Ueland T, Aukrust P, Broch K et al. Galectin-3 in heart failure: high levels are associated with all-cause mortality. Int J Cardiol 2011; 150: 361–4.
8. Lopez-Andrès N, Rossignol P, Iraqi W et al. Association of galectin-3 and fibrosis markers with long-term cardiovascular outcomes in patients with heart failure, left ventricular dysfunction, and dyssynchrony: insights from the CARE-HF (Cardiac Resynchronization in Heart Failure) trial. Eur J Heart Fail 2012; 14: 74–81.
9. Мареев В.Ю., Агеев Ф.Т., Арутюнов Г.П. и др. Национальные рекомендации ОССН, РКО и РНМОТ по диагностике и лечению ХСН (четвертый пересмотр). Сердечная недостаточность. 2013; 14 (7): 379–472. / Mareev V.Iu., Ageev F.T., Arutiunov G.P. i dr. Natsional'nye rekomendatsii OSSN, RKO i RNMOT po diagnostike i lecheniiu KhSN (chetvertyi peresmotr). Serdechnaia nedostatochnost'. 2013; 14 (7): 379–472. [in Russian]
10. Mueller T et al. Diagnostic accuracy of B type natriuretic peptide and amino terminal proBNP in the emergency diagnosis of heart failure. Heart 2005; 91: 606–12.
11. Anand IS et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the valsartan heart failure trial (Val-HeFT). Circulation 2003; 107: 1278–83.
12. Felker GM, Fiuzat M, Shaw LK et al. Galectin-3 in ambulatory patients with heart failure: results from the HF-ACTION study. Circ Heart Fail 2012; 5 (1): 72–8.
13. Motiwala S et al. Serial measurement of galectin-3 in patients with chronic heart failure: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study. Eur J Heart Fail 2013; 15: 1157–63.
14. Anand IS et al. Baseline and serial measurements of galectin-3 in patients with heart failure: relationship to prognosis and effect of treatment with valsartan in the Val-HeFT. Eur J Heart Fail 2013; 15: 511–8.
15. Van Kimmenade RR et al. Utility of amino-terminal probrain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol 2006; 48: 1217–24.
16. Batlle M et al. Data on clinical characteristics of a heart failure patients’ cohort with reduced ejection fraction and analysis of the circulating values of five different heart failure biomarkers; high sensitivity troponin T, galectin-3, C-terminal propeptide of type I procollagen, soluble AXL and BNP. Data Brief 2016; 9: 876–82.
17. Januzzi JL et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. Am J Cardiol 2005; 95: 948–54.
18. Calvier L et al. Galectin-3 mediates aldosterone-induced vascular fibrosis. Atheroscler Thromb Vasc Biol 2013; 33 (1): 67–75.
19. Deveci OS et al. A novel BioTarget in Treatment of Heart Failure: Changes in Serum Galectin-3 Levels after Spironolactone Therapy. J Hypertens 2015; 4: 1.
20. McCullough PA et al. Galectn-3: A novel Blood Test for the Evaluation and Management of Patients with Heart Failure. Rev Cardiovasc Med 2011; 12 (4): 200–10.
2. De Boer RA, Lok DJA, Jaarsma T et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 2011; 43 (1): 60–8.
3. De Boer RA, van der Velde A, Mueller C et al. Galectin-3: A Modifiable Risk Factor in Heart Failure. Cardiovasc Drugs Ther 2014; 28: 237–46.
4. Liu YH, d’Ambrosio M, Liao TD et al. N-Acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growthregulatory lectin. Am J Physiol Heart Circ Physiol 2009; 296: H404–12.
5. Kim H et al. Expression and immunohistochemical localization of galectin-3 in various mouse tissues. Cell Biol Int 2007; 31 (7): 655–62.
6. Tang WH, Shrestha K, Shao Z et al. Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival. Am J Cardiol 2011; 108: 385–90.
7. Ueland T, Aukrust P, Broch K et al. Galectin-3 in heart failure: high levels are associated with all-cause mortality. Int J Cardiol 2011; 150: 361–4.
8. Lopez-Andrès N, Rossignol P, Iraqi W et al. Association of galectin-3 and fibrosis markers with long-term cardiovascular outcomes in patients with heart failure, left ventricular dysfunction, and dyssynchrony: insights from the CARE-HF (Cardiac Resynchronization in Heart Failure) trial. Eur J Heart Fail 2012; 14: 74–81.
9. Mareev V.Iu., Ageev F.T., Arutiunov G.P. i dr. Natsional'nye rekomendatsii OSSN, RKO i RNMOT po diagnostike i lecheniiu KhSN (chetvertyi peresmotr). Serdechnaia nedostatochnost'. 2013; 14 (7): 379–472. [in Russian]
10. Mueller T et al. Diagnostic accuracy of B type natriuretic peptide and amino terminal proBNP in the emergency diagnosis of heart failure. Heart 2005; 91: 606–12.
11. Anand IS et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the valsartan heart failure trial (Val-HeFT). Circulation 2003; 107: 1278–83.
12. Felker GM, Fiuzat M, Shaw LK et al. Galectin-3 in ambulatory patients with heart failure: results from the HF-ACTION study. Circ Heart Fail 2012; 5 (1): 72–8.
13. Motiwala S et al. Serial measurement of galectin-3 in patients with chronic heart failure: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study. Eur J Heart Fail 2013; 15: 1157–63.
14. Anand IS et al. Baseline and serial measurements of galectin-3 in patients with heart failure: relationship to prognosis and effect of treatment with valsartan in the Val-HeFT. Eur J Heart Fail 2013; 15: 511–8.
15. Van Kimmenade RR et al. Utility of amino-terminal probrain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol 2006; 48: 1217–24.
16. Batlle M et al. Data on clinical characteristics of a heart failure patients’ cohort with reduced ejection fraction and analysis of the circulating values of five different heart failure biomarkers; high sensitivity troponin T, galectin-3, C-terminal propeptide of type I procollagen, soluble AXL and BNP. Data Brief 2016; 9: 876–82.
17. Januzzi JL et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. Am J Cardiol 2005; 95: 948–54.
18. Calvier L et al. Galectin-3 mediates aldosterone-induced vascular fibrosis. Atheroscler Thromb Vasc Biol 2013; 33 (1): 67–75.
19. Deveci OS et al. A novel BioTarget in Treatment of Heart Failure: Changes in Serum Galectin-3 Levels after Spironolactone Therapy. J Hypertens 2015; 4: 1.
20. McCullough PA et al. Galectn-3: A novel Blood Test for the Evaluation and Management of Patients with Heart Failure. Rev Cardiovasc Med 2011; 12 (4): 200–10.
2. De Boer RA, Lok DJA, Jaarsma T et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 2011; 43 (1): 60–8.
3. De Boer RA, van der Velde A, Mueller C et al. Galectin-3: A Modifiable Risk Factor in Heart Failure. Cardiovasc Drugs Ther 2014; 28: 237–46.
4. Liu YH, d’Ambrosio M, Liao TD et al. N-Acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growthregulatory lectin. Am J Physiol Heart Circ Physiol 2009; 296: H404–12.
5. Kim H et al. Expression and immunohistochemical localization of galectin-3 in various mouse tissues. Cell Biol Int 2007; 31 (7): 655–62.
6. Tang WH, Shrestha K, Shao Z et al. Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival. Am J Cardiol 2011; 108: 385–90.
7. Ueland T, Aukrust P, Broch K et al. Galectin-3 in heart failure: high levels are associated with all-cause mortality. Int J Cardiol 2011; 150: 361–4.
8. Lopez-Andrès N, Rossignol P, Iraqi W et al. Association of galectin-3 and fibrosis markers with long-term cardiovascular outcomes in patients with heart failure, left ventricular dysfunction, and dyssynchrony: insights from the CARE-HF (Cardiac Resynchronization in Heart Failure) trial. Eur J Heart Fail 2012; 14: 74–81.
9. Мареев В.Ю., Агеев Ф.Т., Арутюнов Г.П. и др. Национальные рекомендации ОССН, РКО и РНМОТ по диагностике и лечению ХСН (четвертый пересмотр). Сердечная недостаточность. 2013; 14 (7): 379–472. / Mareev V.Iu., Ageev F.T., Arutiunov G.P. i dr. Natsional'nye rekomendatsii OSSN, RKO i RNMOT po diagnostike i lecheniiu KhSN (chetvertyi peresmotr). Serdechnaia nedostatochnost'. 2013; 14 (7): 379–472. [in Russian]
10. Mueller T et al. Diagnostic accuracy of B type natriuretic peptide and amino terminal proBNP in the emergency diagnosis of heart failure. Heart 2005; 91: 606–12.
11. Anand IS et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the valsartan heart failure trial (Val-HeFT). Circulation 2003; 107: 1278–83.
12. Felker GM, Fiuzat M, Shaw LK et al. Galectin-3 in ambulatory patients with heart failure: results from the HF-ACTION study. Circ Heart Fail 2012; 5 (1): 72–8.
13. Motiwala S et al. Serial measurement of galectin-3 in patients with chronic heart failure: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study. Eur J Heart Fail 2013; 15: 1157–63.
14. Anand IS et al. Baseline and serial measurements of galectin-3 in patients with heart failure: relationship to prognosis and effect of treatment with valsartan in the Val-HeFT. Eur J Heart Fail 2013; 15: 511–8.
15. Van Kimmenade RR et al. Utility of amino-terminal probrain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol 2006; 48: 1217–24.
16. Batlle M et al. Data on clinical characteristics of a heart failure patients’ cohort with reduced ejection fraction and analysis of the circulating values of five different heart failure biomarkers; high sensitivity troponin T, galectin-3, C-terminal propeptide of type I procollagen, soluble AXL and BNP. Data Brief 2016; 9: 876–82.
17. Januzzi JL et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. Am J Cardiol 2005; 95: 948–54.
18. Calvier L et al. Galectin-3 mediates aldosterone-induced vascular fibrosis. Atheroscler Thromb Vasc Biol 2013; 33 (1): 67–75.
19. Deveci OS et al. A novel BioTarget in Treatment of Heart Failure: Changes in Serum Galectin-3 Levels after Spironolactone Therapy. J Hypertens 2015; 4: 1.
20. McCullough PA et al. Galectn-3: A novel Blood Test for the Evaluation and Management of Patients with Heart Failure. Rev Cardiovasc Med 2011; 12 (4): 200–10.
________________________________________________
2. De Boer RA, Lok DJA, Jaarsma T et al. Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 2011; 43 (1): 60–8.
3. De Boer RA, van der Velde A, Mueller C et al. Galectin-3: A Modifiable Risk Factor in Heart Failure. Cardiovasc Drugs Ther 2014; 28: 237–46.
4. Liu YH, d’Ambrosio M, Liao TD et al. N-Acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growthregulatory lectin. Am J Physiol Heart Circ Physiol 2009; 296: H404–12.
5. Kim H et al. Expression and immunohistochemical localization of galectin-3 in various mouse tissues. Cell Biol Int 2007; 31 (7): 655–62.
6. Tang WH, Shrestha K, Shao Z et al. Usefulness of plasma galectin-3 levels in systolic heart failure to predict renal insufficiency and survival. Am J Cardiol 2011; 108: 385–90.
7. Ueland T, Aukrust P, Broch K et al. Galectin-3 in heart failure: high levels are associated with all-cause mortality. Int J Cardiol 2011; 150: 361–4.
8. Lopez-Andrès N, Rossignol P, Iraqi W et al. Association of galectin-3 and fibrosis markers with long-term cardiovascular outcomes in patients with heart failure, left ventricular dysfunction, and dyssynchrony: insights from the CARE-HF (Cardiac Resynchronization in Heart Failure) trial. Eur J Heart Fail 2012; 14: 74–81.
9. Mareev V.Iu., Ageev F.T., Arutiunov G.P. i dr. Natsional'nye rekomendatsii OSSN, RKO i RNMOT po diagnostike i lecheniiu KhSN (chetvertyi peresmotr). Serdechnaia nedostatochnost'. 2013; 14 (7): 379–472. [in Russian]
10. Mueller T et al. Diagnostic accuracy of B type natriuretic peptide and amino terminal proBNP in the emergency diagnosis of heart failure. Heart 2005; 91: 606–12.
11. Anand IS et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the valsartan heart failure trial (Val-HeFT). Circulation 2003; 107: 1278–83.
12. Felker GM, Fiuzat M, Shaw LK et al. Galectin-3 in ambulatory patients with heart failure: results from the HF-ACTION study. Circ Heart Fail 2012; 5 (1): 72–8.
13. Motiwala S et al. Serial measurement of galectin-3 in patients with chronic heart failure: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study. Eur J Heart Fail 2013; 15: 1157–63.
14. Anand IS et al. Baseline and serial measurements of galectin-3 in patients with heart failure: relationship to prognosis and effect of treatment with valsartan in the Val-HeFT. Eur J Heart Fail 2013; 15: 511–8.
15. Van Kimmenade RR et al. Utility of amino-terminal probrain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol 2006; 48: 1217–24.
16. Batlle M et al. Data on clinical characteristics of a heart failure patients’ cohort with reduced ejection fraction and analysis of the circulating values of five different heart failure biomarkers; high sensitivity troponin T, galectin-3, C-terminal propeptide of type I procollagen, soluble AXL and BNP. Data Brief 2016; 9: 876–82.
17. Januzzi JL et al. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. Am J Cardiol 2005; 95: 948–54.
18. Calvier L et al. Galectin-3 mediates aldosterone-induced vascular fibrosis. Atheroscler Thromb Vasc Biol 2013; 33 (1): 67–75.
19. Deveci OS et al. A novel BioTarget in Treatment of Heart Failure: Changes in Serum Galectin-3 Levels after Spironolactone Therapy. J Hypertens 2015; 4: 1.
20. McCullough PA et al. Galectn-3: A novel Blood Test for the Evaluation and Management of Patients with Heart Failure. Rev Cardiovasc Med 2011; 12 (4): 200–10.
Авторы
К.А.Гямджян*, В.Г.Кукес
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М.Сеченова Минздрава России». 119991, Россия, Москва, ул. Трубецкая, д. 8, стр. 2
*karina.gyamdjyan@gmail.com
I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation. 119991, Russian Federation, Moscow, ul. Trubetskaia, d. 8, str. 2
*karina.gyamdjyan@gmail.com
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М.Сеченова Минздрава России». 119991, Россия, Москва, ул. Трубецкая, д. 8, стр. 2
*karina.gyamdjyan@gmail.com
________________________________________________
I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation. 119991, Russian Federation, Moscow, ul. Trubetskaia, d. 8, str. 2
*karina.gyamdjyan@gmail.com
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