pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2023-11-6-494-508pmedpharm-1401Research ArticleОРИГИНАЛЬНАЯ СТАТЬЯRESEARCH ARTICLEВлияние инсерционно-делеционного полиморфизма гена ангиотензинпревращающего фермента на эффективность антигипертензивной терапии блокаторов рецептора ангиотензина IIEffect of insertion/deletion polymorphism of angiotensin-converting enzyme gene on efficacy of antihypertensive therapy with angiotensin II receptor blockershttps://orcid.org/0000-0002-4374-9754РеброваЕ. В.RebrovaE. V.

кандидат медицинских наук, доцент кафедры клинической фармакологии и пропедевтики внутренних болезней, ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова» Минздрава России (Сеченовский университет). 

119991, Россия, г. Москва, ул. Трубецкая, д. 8, стр. 2

Candidate of Sciences (Medicine), Associate Professor of the Department of Clinical Pharmacology and Propaedeutics of Internal Diseases, Sechenov First Moscow State Medical University (Sechenov University).

Bldg. 2, 8, Trubetskaya Str., Moscow, Russia, 119991

 

katrina1987@rambler.ruhttps://orcid.org/0000-0001-6589-7654ШихЕ. В.ShikhE. V.

доктор медицинских наук, профессор, заведующий кафедрой клинической фармакологии и пропедевтики внутренних болезней, ФГАОУ ВО «Первый МГМУим. И.М. Сеченова»  Минздрава России(Сеченовский университет).

119991, Россия, г. Москва, ул. Трубецкая, д. 8, стр. 2

Doctor of Sciences (Medicine), Professor, Head of the Department of Clinical Pharmacology and Propaedeutics of Internal Diseases, Sechenov First Moscow State Medical University (Sechenov University).

Bldg. 2, 8, Trubetskaya Str., Moscow, Russia, 119991

chih@mail.ruФедеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет имени И.М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский университет)РоссияSechenov First Moscow State Medical University (Sechenov University)Russian Federation202330012024116494508Copyright © Реброва Е.В., Ших Е.В., 20242024Реброва Е.В., Ших Е.В.Rebrova E.V., Shikh E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/1401

Эффективность антигипертензивной терапии может быть связана с генетическими факторами, которые могут влиять не только на степень повышения артериального давления (АД), но и способствовать межиндивидуальной вариабельности ответа на антигипертензивное лечение.

Цель

Цель. Изучить фармакодинамические показатели эффективности терапии блокаторами рецепторов ангиотензина II в виде монотерапии и в составе комбинированных препаратов у пациентов с артериальной гипертензией в зависимости от генетических особенностей пациентов – полиморфизма гена, кодирующего ангиотензинпревращающий фермент или I/D-полиморфизма.

Материалы и методы

Материалы и методы. В исследование включено 179 пациентов Московского региона с впервые выявленной артериальной гипертензией (АГ) 1–2 степени, среди которых 141 (78,8%) женщины и 38 (21,2%) мужчины в возрасте от 32 до 69 лет. Пациенты случайным образом были распределены по группам, принимавшим ирбесартан и валсартан в виде моно- или комбинированной терапии с гидрохлортиазидом методом простой рандомизации. Через 3 недели фармакотерапии определяли наличие генетического полиморфизма rs4646994 Alu Ins / Del гена ангиотензинпревращающего фермента ACE и минимальную равновесную концентрацию блокаторов рецепторов ангиотензина II (БРА).

Результаты

Результаты. Пациенты, получавшие терапию ирбесартаном, носители генотипа D/D достоверно реже достигали целевых цифр АД и им чаще требовалась интенсификация фармакотерапии по сравнению с гетерозиготами I/D (р=0,042 и р=0,058 соответственно) и гомозиготами I/I (р=0,011 и р=0,011 соответственно). Пациенты, получавшие терапию валсартаном, носители генотипа D/D достоверно чаще достигали целевых цифр АД и достоверно реже требовалась интенсификация фармакотерапии, чем носителям I/D генотипа (р=0,05 и р=0,05 соответственно). При этом достижение целевых цифр АД по результатам показателей измерения офисного АД и суточного мониторирования АД на момент окончания исследования не было достоверно взаимосвязано с I/D полиморфизмом гена ACE.

Заключение

Заключение. При персонализации терапии АГ пациентам Московского региона, носителям генотипа I/I по I/D полиморфизму гена ACE, можно рекомендовать в качестве стартовой терапии БРА ирбесартан в виде моно- или двухкомпонентной терапии; носителям генотипа D/D может быть рекомендован валсартан. Более выраженное снижение показателей вариабельности систолического АД (САД) дневного, диастолического АД (ДАД) дневного и САД ночного у пациентов группы валсартана, носителей D-аллели может свидетельствовать о более стойком эффекте антигипертензивной терапии.

The efficacy of the antihypertensive therapy may be related to genetic factors that can influence not only the degree of the blood pressure (BP) elevation but also contribute to the interindividual variability of response to the antihypertensive treatment.

The aim of the work was to study pharmacodynamic parameters of the therapy efficacy with angiotensin II receptor blockers in the form of monotherapy and as part of combined drugs in patients with the arterial hypertension depending on the genetic features of patients – polymorphism of the gene encoding angiotensin-converting enzyme, or I/D-polymorphism.

Materials and methods

Materials and methods. The study included 179 patients of the Moscow region with a first-diagnosed arterial hypertension (AH) of 1–2 degree, including 141 (78.8%) women and 38 (21.2%) men aged from 32 to 69 years. By a simple randomization method, the patients were randomly allocated into groups receiving irbesartan and valsartan as mono- or combination therapy with hydrochlorthiazide. After 3 weeks of this pharmacotherapy, the presence of rs4646994 Alu Ins / Del genetic polymorphism of the angiotensin-converting enzyme (ACE) gene and the minimum equilibrium concentration of angiotensin II receptor blockers (ARBs) were determined.

Results

Results. The patients treated with irbesartan, the D/D genotype carriers, were significantly less likely to reach the target BP and more likely to require a pharmacotherapy intensification compared to I/D heterozygotes (p=0.042 and p=0.058, respectively) and I/I homozygotes (p=0.011 and p=0.011, respectively). The patients treated with valsartan, the D/D genotype carriers, significantly more often reached the target BP and significantly less often required a pharmacotherapy intensification than the I/D genotype carriers (p=0.05 and p=0.05, respectively). Herewith, at the end of the study, according to the results of the office BP measurements and daily BP monitoring, the target BP achievement was not significantly correlated with the I/D polymorphism of the ACE gene.

Conclusion

Conclusion. When personalizing the AH therapy in patients of the Moscow region, the genotype I/I carriers by I/D polymorphism of the ACE gene, can be recommended irbesartan in the form of mono- or bicomponent therapy as a starting therapy of ARBs; the D/D genotype carriers can be recommended valsartan. A more pronounced decrease in the daytime systolic BP (SBP), the daytime diastolic BP (DBP) and the nighttime SBP variabilities in the valsartan group of patients, the D allele carriers may indicate a more persistent effect of the antihypertensive therapy.

артериальная гипертензияангиотензинпревращающий ферментACEАПФI/D полиморфизмarterial hypertensionangiotensin-converting enzymeACEACEI/D polymorphismДанное исследование не имело финансовой поддержки от сторонних организаций.This study did not have financial support from outside organizations.ReferencesOliveira-Paula G.H., Pereira S.C., Tanus-Santos J.E., Lacchini R. Phamacogenomics and hypertension: Current insights // Pharmgenomics Pers Med. – 2019. – Vol. 12. – P. 341–359. DOI: 10.2147/PGPM.S230201Oliveira-Paula GH, Pereira SC, Tanus-Santos JE, Lacchini R. Phamacogenomics and hypertension: Current insights. Pharmgenomics Pers Med. 2019;12:341-59. DOI: 10.2147/PGPM.S230201Wang Z., Hou J., Zheng H., Wang D., Tian W., Zhang D., Yan J. Genetic and phenotypic frequency distribution of ACE, ADRB1, AGTR1, CYP2C9*3, CYP2D6*10, CYP3A5*3, NPPA and factors associated with hypertension in Chinese Han hypertensive patients // Medicine (Baltimore). – 2023. – Vol. 102, No. 10. – Art. ID: e33206. DOI: 10.1097/MD.0000000000033206Wang Z, Hou J, Zheng H, Wang D, Tian W, Zhang D, Yan J. Genetic and phenotypic frequency distribution of ACE, ADRB1, AGTR1, CYP2C9*3, CYP2D6*10, CYP3A5*3, NPPA and factors associated with hypertension in Chinese Han hypertensive patients. Medicine (Baltimore). 2023;102(10): e33206. DOI: 10.1097/MD.0000000000033206Rysz J., Franczyk B., Rysz-Górzyńska M., Gluba-Brzózka A. pharmacogenomics of hypertension treatment // Int J Mol Sci. – 2020. – Vol. 21, No. 13. – Art. ID: 4709. DOI: 10.3390/ijms21134709.Rysz J, Franczyk B, Rysz-Górzyńska M, Gluba-Brzózka A. pharmacogenomics of hypertension treatment. Int J Mol Sci. 2020; 21(13):4709. DOI: 10.3390/ijms21134709Luizon M.R., Pereira D.A., Sandrim V.C. Pharmacogenomics of hypertension and preeclampsia: focus on gene-gene interactions // Front Pharmacol. – 2018. – Vol. 9. – Art. ID: 168. DOI: 10.3389/fphar.2018.00168Luizon MR, Pereira DA, Sandrim VC. Pharmacogenomics of hypertension and preeclampsia: focus on gene-gene interactions. Front Pharmacol. 2018;9:168. DOI:10.3389/fphar.2018.00168Padmanabhan S., Joe B. Towards precision medicine for hypertension: A review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans // Physiol Rev. – 2017. – Vol. 97, No. 4. – P. 1469–1528. DOI: 10.1152/physrev.00035.2016Padmanabhan S, Joe B. Towards precision medicine for hypertension: A review of genomic, epigenomic, and microbiomic effects on blood pressure in experimental rat models and humans. Physiol Rev. 2017;97( 4):1469-528. DOI:10.1152/physrev.00035.2016Cacabelos R., Martinez-Bouza R., Carril J.C., Fernandez-Novoa L., Lombardi V., Carrera I., Corzo L., McKay A. Genomics and pharmacogenomics of brain disorders // Curr Pharm Biotechnol. – 2012. – Vol. 13, No. 5. – P. 674–725. DOI: 10.2174/138920112799857576Cacabelos R, Martinez-Bouza R, Carril JC, Fernandez-Novoa L, Lombardi V, Carrera I, Corzo L, McKay A. Genomics and pharmacogenomics of brain disorders. Curr Pharm Biotechnol. 2012;13(5): 674–725. DOI: 10.2174/138920112799857576Torrellas C., Carril J.C., Cacabelos R. Benefits of pharmacogenetics in the management of hypertension // J Pharmacogenomics Pharmacoproteomics. – 2014. – Vol. 5. – Art. ID: 126. DOI: 10.4172/2153-0645.1000126Torrellas C, Carril JC, Cacabelos R. Benefits of pharmacogenetics in the management of hypertension. J Pharmacogenomics Pharmacoproteomics. 2014;5:126. DOI: 10.4172/2153-0645.1000126Johnson J.A. Advancing management of hypertension through pharmacogenomics // Ann Med. – 2012. – Vol. 44 Suppl 1, No. 01. – P. S17–22. DOI: 10.3109/07853890.2011.653399Johnson JA. Advancing management of hypertension through pharmacogenomics. Ann Med. 2012;44(1,Suppl.1):S17-22. DOI:10.3109/07853890.2011.653399Patel D.D., Parchwani D.N., Dikshit N., Parchwani T. Analysis of the pattern, alliance and risk of rs1799752 (ACE I/D polymorphism) with essential hypertension // Indian J Clin Biochem. – 2022. – Vol. 37, No. 1. – P. 18–28. DOI: 10.1007/s12291-020-00927-0Patel DD, Parchwani DN, Dikshit N, Parchwani T. Analysis of the pattern, alliance and risk of rs1799752 (ACE I/D polymorphism) with essential hypertension. Indian J Clin Biochem. 2022;37(1):18–28. DOI: 10.1007/s12291-020-00927-0Mocan O., Radulescu D., Buzdugan E., Cozma A., Leucuta D.C., Procopciuc L.M. Association between M235T-AGT and I/D-ACE polymorphisms and carotid atheromatosis in hypertensive patients: A cross-sectional study // In Vivo. – 2020. – Vol. 34, No. 5. – P. 2811–2819. DOI: 10.21873/invivo.12107Mocan O, Radulescu D, Buzdugan E, Cozma A, Leucuta DC, Procopciuc LM. Association between M235T-AGT and I/D-ACE polymorphisms and carotid atheromatosis in hypertensive patients: A cross-sectional study. In Vivo. 2020;34( 5): 2811-19. DOI:10.21873/invivo.12107Тимохина Е.В., Стрижаков А.Н., Игнатко И.В., Белоусова В.С., Ибрагимова С.М. Полиморфизм гена ангиотензин-превращающего фермента ACE существенно увеличивает риск развития преэклампсии // Биохимия. – 2019. – Т. 84. – С. 181–186. DOI: 10.1134/S0006297919020093Timokhina EV, Strizhakov AN, Ignatko IV, Belousova VS, Ibragimova SM. Genetic Aspects of Preeclampsia: The Role of Polymorphisms in the Genes of the Renin-Angiotensin System. Biochemistry (Mosc). 2019 Feb;84(2):181-186. doi: 10.1134/S0006297919020093.Павлова О.С., Огурцова С.Э., Горбат Т.В., Ливенцева М.М., Афонин В.Ю., Малюгин В.И., Мрочек А.Г. Полигенные ассоциации полиморфизма генов ренин-ангиотензин-альдостероновой системы при эссенциальной артериальной гипертензии // Артериальная гипертензия. – 2016. – Т. 22, № 3. – С. 253–262. DOI: 10.18705/1607-419X-2016-22-3-253-262Pavlova OS, Ogurtsova SE, Gorbat TV, Liventseva MM, Afonin VYu, Malugin VI, Mrochek AG. Polygenic association of the renin-angiotensinaldosterone system polymorphisms in essential arterial hypertension. "Arterial’naya Gipertenziya" ("Arterial Hypertension"). 2016;22(3):253-62. DOI: 10.18705/1607-419X-2016-22-3-253-262 RussianSabir J.S.M., Omri A.E., Ali Khan I., Banaganapalli B., Hajrah N.H., Zrelli H., Omar A.M.S., Alharbi M.G., Alhebshi A.M., Jansen R.K., Altaf A., Shaik N.A., Khan M. ACE insertion/deletion genetic polymorphism, serum ACE levels and high dietary salt intake influence the risk of obesity development among the Saudi adult population // J Renin Angiotensin Aldosterone Syst. – 2019. – Vol. 20, No. 3. – Art. ID: 1470320319870945. DOI: 10.1177/1470320319870945Sabir JSM, Omri AE, Ali Khan I, Banaganapalli B, Hajrah NH, Zrelli H, Omar AMS, Alharbi MG, Alhebshi AM, Jansen RK, Altaf A, Shaik NA, Khan M. ACE insertion/deletion genetic polymorphism, serum ACE levels and high dietary salt intake influence the risk of obesity development among the Saudi adult population. J Renin Angiotensin Aldosterone Syst. 2019;20(3):1470320319870945. DOI:10.1177/1470320319870945Krishnan R., Sekar D., Karunanithy S., Subramanium S. Association of angiotensin converting enzyme gene insertion/deletion polymorphism with essential hypertension in south Indian population // Genes Dis. – 2016. – Vol. 3, No. 2. – P. 159–163. DOI: 10.1016/j.gendis.2016.03.001Krishnan R, Sekar D, Karunanithy S, Subramanium S. Association of angiotensin converting enzyme gene insertion/deletion polymorphism with essential hypertension in south Indian population. Genes Dis. 2016;3(2):159-63. DOI:10.1016/j.gendis.2016.03.001Liu M., Yi J., Tang W. Association between angiotensin converting enzyme gene polymorphism and essential hypertension: A systematic review and meta-analysis // J Renin Angiotensin Aldosterone Syst. – 2021. – Vol. 22, No. 1. – Art. ID: 1470320321995074. DOI: 10.1177/1470320321995074Liu M, Yi J, Tang W. Association between angiotensin converting enzyme gene polymorphism and essential hypertension: A systematic review and meta-analysis. J Renin Angiotensin Aldosterone Syst. 2021;22(1):1470320321995074. DOI: 10.1177/1470320321995074Mathew J., Basheeruddin K., Prabhakar S. Differences in frequency of the deletion polymorphism of the angiotensin-converting enzyme gene in different ethnic groups // Angiology. – 2001. – Vol. 52, No. 6. – P. 375–379. DOI: 10.1177/000331970105200602Mathew J, Basheeruddin K, Prabhakar S. Differences in frequency of the deletion polymorphism of the angiotensin-converting enzyme gene in different ethnic groups. Angiology. 2001;52(6):375–9. DOI: 10.1177/000331970105200602Lee Y.J., Tsai J.C. ACE gene insertion/deletion polymorphism associated with 1998 World Health Organization definition of metabolic syndrome in Chinese type 2 diabetic patients // Diabetes Care. – 2002. – Vol. 25, No. 6. – P. 1002–1008. DOI: 10.2337/diacare.25.6.1002Lee YJ, Tsai JC. ACE gene insertion/deletion polymorphism associated with 1998 World Health Organization definition of metabolic syndrome in Chinese type 2 diabetic patients. Diabetes Care. 2002;25(6):1002-8. DOI: 10.2337/diacare.25.6.1002Saab Y.B., Gard P.R., Overall A.D. The geographic distribution of the ACE II genotype: a novel finding // Genet Res. – 2007. – Vol. 89, No. 4. – P. 259–267. DOI: 10.1017/S0016672307009019Saab YB, Gard PR, Overall AD. The geographic distribution of the ACE II genotype: a novel finding. Genet Res. 2007;89(4):259-67. DOI: 10.1017/S0016672307009019Heidari F., Vasudevan R., Mohd Ali S.Z., Ismail P., Etemad A., Pishva S.R., Othman F., Abu Bakar S. Association of insertion/deletion polymorphism of angiotensin-converting enzyme gene among Malay male hypertensive subjects in response to ACE inhibitors // J Renin Angiotensin Aldosterone Syst. – 2015. – Vol. 16, No. 4. – P. 872–879. DOI: 10.1177/1470320314538878Heidari F, Vasudevan R, Mohd Ali SZ, Ismail P, Etemad A, Pishva SR, Othman F, Abu Bakar S. Association of insertion/deletion polymorphism of angiotensin-converting enzyme gene among Malay male hypertensive subjects in response to ACE inhibitors. J Renin Angiotensin Aldosterone Syst. 2015;16(4):872-9. DOI: 10.1177/1470320314538878Yu H., Zhang Y., Liu G. Relationship between polymorphism of the angiotensin-converting enzyme gene and the response to angiotensin-converting enzyme inhibition in hypertensive patients // Hypertens Res. – 2003. – Vol. 26, No. 11. – P. 881–886. DOI: 10.1291/hypres.26.881Yu H., Zhang Y., Liu G. Relationship between polymorphism of the angiotensin-converting enzyme gene and the response to angiotensin-converting enzyme inhibition in hypertensive patients. Hypertens Res. 2003;26(11):881-6. DOI: 10.1291/hypres.26.881Kurland L., Melhus H., Karlsson J., Kahan T., Malmqvist K., Ohman K.P., Nyström F., Hägg A., Lind L.; Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) Trial. Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients // J Hypertens. – 2001. – Vol. 19, No. 10. – P. 1783–1787. DOI: 10.1097/00004872-200110000-00012Kurland L, Melhus H, Karlsson J, Kahan T, Malmqvist K, Ohman KP, Nyström F, Hägg A, Lind L. Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) Trial. Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients. J Hypertens. 2001;19(10):1783-7. DOI: 10.1097/00004872-200110000-00012Arnett D.K., Davis B.R., Ford C.E., Boerwinkle E., Leiendecker-Foster C., Miller M.B., Black H., Eckfeldt J.H. Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of Hypertension-Associated Treatment (GenHAT) study // Circulation. – 2005. – Vol. 111, No. 25. – P. 3374–3383. DOI: 10.1161/CIRCULATIONAHA.104.504639Arnett DK, Davis BR, Ford CE, Boerwinkle E, Leiendecker-Foster C, Miller MB, Black H, Eckfeldt JH. Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of Hypertension-Associated Treatment (GenHAT) study. Circulation. 2005;111(25):3374-83. DOI: 10.1161/CIRCULATIONAHA.104.504639Parving H.H., de Zeeuw D., Cooper M.E., Remuzzi G., Liu N., Lunceford J., Shahinfar S., Wong P.H., Lyle P.A., Rossing P., Brenner B.M. ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy // J Am Soc Nephrol. – 2008. – Vol. 19, No. 4. – P. 771–779. DOI: 10.1681/ASN.2007050582Parving HH, de Zeeuw D, Cooper ME, Remuzzi G, Liu N, Lunceford J, Shahinfar S, Wong PH, Lyle PA, Rossing P, Brenner BM. ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy. J Am Soc Nephrol. 2008;19(4):771-9. DOI: 10.1681/ASN.2007050582Rohman M.S., Fajar J.K., Kuncahyo B.H., Yunita L., Sidarta E.P., Belinda Saka P.N., Heriansyah T., Widodo N. Angiotensin-converting enzyme (ACE) I/D and bradykinin B2 receptor T/C genes polymorphism in patients with ACE inhibitors-related cough // Egypt J Med Hum Gen. – 2018. – Vol. 19, No. 4. – P. 307–313. DOI: 10.1016/j.ejmhg.2018.05.006Rohman MS, Fajar JK, Kuncahyo BH, Yunita L, Sidarta EP, Belinda Saka PN, Heriansyah T, Widodo N. Angiotensin-converting enzyme (ACE) I/D and bradykinin B2 receptor T/C genes polymorphism in patients with ACE inhibitors-related cough. Egypt J Med Hum Gen. 2018;19(4);307-13. DOI: 10.1016/j.ejmhg.2018.05.006Conrady A.O., Kiselev I.O., Usachev N.I., Krutikov A.N., Yakovleva O.I., Polunicheva E.V., Ovchinnikova O.A., Panov A.V. Effect of 24-week treatment with telmisartan on myocardial structure and function: relationship to insertion/deletion polymorphism of the angiotensin-converting enzyme gene // J Int Med Res. 2005. – Vol. 33, Suppl 1. – P. 30A–38A. DOI: 10.1177/14732300050330S105Conrady AO, Kiselev IO, Usachev NI, Krutikov AN, Yakovleva OI, Polunicheva EV, Ovchinnikova OA, Panov AV. Effect of 24-week treatment with telmisartan on myocardial structure and function: relationship to insertion/deletion polymorphism of the angiotensin-converting enzyme gene. J Int Med Res. 2005;33(Suppl 1):30A–38A. DOI: 10.1177/14732300050330S105Реброва Т.Ю., Муслимова Э.Ф., Панова Н.В., Серебрякова В.Н., Комарова Е.Е., Афанасьев С.А., Гарганеева А.А., Трубачева И.А. I/D полиморфизм гена ангиотензинпревращающего фермента у больных ибс разного пола и возраста // Российский кардиологический журнал. – 2014. – № 10. – С. 77–81. DOI: 10.15829/1560-4071-2014-10-77-81Rebrova TYu, Muslimova EF, Panova NV, Serebryakova VN, Komarova EE, Afanasieva SA, Garganeeva AA, Trubacheva IA. I/D polymorphism of angiotensine converting enzyme in CHD patients of different age and gender. Russian Journal of Cardiology. 2014;(10):77-81. DOI: 10.15829/1560-4071-2014-10-77-81 Russian.

The authors declare that there are no conflicts of interest present.