Clinical Physiology of Circulation

Chief Editor

Leo A. Bockeria, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, President of Bakoulev National Medical Research Center for Cardiovascular Surgery


Early prevention of cardiotoxicity: focus on inhibitors of sodium-glucose co-transporter 2

Authors: Buziashvili Yu.I.1, Stilidi I.S.2, Matskeplishvili S.T.1, Asymbekova E.U.1, Tugeeva E.F.1, Artamonova E.V.2, 3, 4, Akhmedyarova N.K.1, Akildzhonov F.R.1

Company:
1 Bakoulev National Medical Research Center for Cardiovascular Surgery, Moscow, Russian Federation
2 National Medical Research Center of Oncology named after N.N. Blokhin, Moscow, Russian Federation
3 N.I. Pirogov Russian National Research Medical University, Moscow, Russian Federation
4 Moscow Regional Research and Clinical Institute named after M.F. Vladimirsky, Moscow, Russian Federation

E-mail: Сведения доступны для зарегистрированных пользователей.

DOI: https://doi.org/10.24022/1814-6910-2023-20-3-288-299

UDC: 616.12-008.46:615.355

Link: Clinical Physiology of Blood Circulaiton. 2023; 3 (20): 288-299

Quote as: Buziashvili Yu.I., Stilidi I.S., Matskeplishvili S.T., Asymbekova E.U., Tugeeva E.F., Artamonova E.V., Akhmedyarova N.K., Akildzhonov F.R. Early prevention of cardiotoxicity: focus on inhibitors of sodium-glucose co-transporter 2. Clinical Physiology of Circulation. 2023; 20 (3): 288–99 (in Russ.). DOI: 10.24022/1814-6910-2023-20-3-288-299

Received / Accepted:  15.07.2023 / 17.08.2023

Full text:
Subscribe 🔒

Abstract

Objective. Analysis of echocardiographic parameters of the cardiovascular system in patients with breast cancer while receiving sodium-glucose co-transporter 2 (SGLT-2) during neoadjuvant chemotherapy (NAС).

Material and methods. The prospective study included 131 patients with a confirmed diagnosis of breast cancer during NAC, who underwent echocardiography at rest; assessed the main indicators of systolic, contractile and diastolic function before and after the end of NAC in two groups of patients: in the main group (n = 60), patients took dapagliflozin at a dose of 10 mg/day throughout the course of chemotherapy, and in the control group (n = 71) – without the use of dapagliflozin.

Results. Patients in the control group showed an increase in end-systolic volume. On average, the degree of decrease in ejection fraction (EF) in the group differed significantly: in patients who received dapagliflozin simultaneously with NAC, it was 4.2 ± 5.7%, and in the control group 7.3 ± 5.9% (p = 0.002). Moreover, treatment with dapagliflozin was clearly associated with a decrease in EF in a smaller number of patients (χ2 = 4.2, p = 0.04). NAC in the control group was accompanied by a significant deterioration in left ventricle (LV) myocardial relaxation. There were significantly more patients with deterioration in diastolic function during the course of NAC in the control group than in the main group. The most significant were the stiffness coefficient, LV systolic filling fraction, the ratio of the systolic wave of the pulmonary venous blood flow to the diastolic wave.

Conclusion. The use of SGLT-2 drugs during chemotherapy is accompanied by positive effects – less deterioration in systolic and diastolic function of the left ventricle compared to the control group.

References

  1. Lotrionte M., Biondi-Zoccai G., Abbate A., Lanzetta G., D'Ascenzo F., Malavasi V. Review and metaanalysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am. J. Cardiol. 2013; 112 (12): 1980–4. DOI: 10.1016/j.amjcard.2013.08.026
  2. Бузиашвили Ю.И., Стилиди И.С., Мацкеплишвили С.Т., Асымбекова Э.У., Тугеева Э.Ф., Артамонова Е.В. и др. Сердечно-сосудистые и онкологические заболевания – фокус на модифицируемых факторах риска и современные патогенетические аспекты. Вестник РАМН. 2023; 78 (2): 132–40. DOI: 10.15690/vramn8359
  3. Hou Y., Zheng C., Yen T., Lu K. Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection. Int. J. Mol. Sci. 2020; 21 (21): 7833. DOI: 10.3390/ijms21217833
  4. Бузиашвили Ю.И., Асымбекова Э.У., Мацкеплишвили С.Т., Тугеева Э.Ф., Артамонова Е.В., Акилджонов Ф.Р. Динамика эхокардиографических показателей при проведении неоадъювантной химиотерапии у больных раком молочной железы. Креативная кардиология. 2022; 16 (4): 520–32. DOI: 10.24022/1997-3187-2022-16-4-520-532
  5. Bergler-Klein J., Rainer P., Wallner M., Zaruba M.-M., Dörler J., Böhmer A. et al. Cardio-oncology in Austria: cardiotoxicity and surveillance of anti-cancer therapies: position paper of the Heart Failure Working Group of the Austrian Society of Cardiology. Wien Klin. Wochenschr. 2022; 134 (17-18): 654–74. DOI: 10.1007/s00508-022-02031-0 6.
  6. Antonucci S., Di Sante M., Tonolo F., Pontarollo L., Scalcon V., Alanova P. et al. The determining role of mitochondrial reactive oxygen species generation and monoamine oxidase activity in doxorubicin-induced cardiotoxicity. Antioxid. Redox. Signal. 2021; 34 (7): 531–50. DOI: 10.1089/ars.2019.7929
  7. Sabbatino F., Conti V., Liguori L., Polcaro G., Corbi G., Manzo V. et al. Molecules and mechanisms to overcome oxidative stress inducing cardiovascular disease in cancer patients. Life (Basel). 2021; 11 (2): 105. DOI: 10.3390/life11020105
  8. D'Oria R., Schipani R., Leonardini A., Natalicchio A., Perrini S., Cignarelli A. et al. The role of oxidative stress in cardiac disease: from physiological response to injury factor. Oxid. Med. Cell. Longev. 2020; 2020: 5732956. DOI: 10.1155/2020/5732956
  9. Lima M., Brito H., Mitidieri G., de Souza E., Sobral A., Melo H. et al. Cardiotoxicity in cancer patients treated with chemotherapy: a systematic review. Int. J. Health. Sci. (Qassim). 2022; 16 (6): 39–46.
  10. Kim C., Choi K. Effects of anticancer drugs on the cardiac mitochondrial toxicity and their underlying mechanisms for novel cardiac protective strategies. Life Sci. 2021; 277: 119607. DOI: 10.1016/j.lfs.2021.119607
  11. Carrasco R., Castillo R., Gormaz J., Carrillo M., Thavendiranathan P. Role of oxidative stress in the mechanisms of anthracycline-induced cardiotoxicity: effects of preventive strategies. Oxid. Med. Cell. Longev. 2021; 2021: 8863789. DOI: 10.1155/2021/8863789
  12. García-Carro C., Vergara A., Agraz I., Jacobs-Cachá C., Espinel E., Seron D., Soler M.J. The new era for reno-cardiovascular treatment in type 2 diabetes. J. Clin. Med. 2019; 8 (6): 864. DOI: 10.3390/jcm8060864
  13. Kowalska K., Walczak J., Femlak J., Młynarska E., Franczyk B., Rysz J. Empagliflozin – a new chance for patients with chronic heart failure. Pharmaceuticals (Basel). 2021; 15 (1): 47. DOI: 10.3390/ph15010047
  14. Lopaschuk G., Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic. Transl. Sci. 2020; 5 (6): 632–44. DOI: 10.1016/j.jacbts.2020.02.004
  15. Chang W., Lin Y., Ho C., Chen Z., Liu P., Shih J. Dapagliflozin suppresses ER stress and protects doxorubicin-induced cardiotoxicity in breast cancer patients. Arch. Toxicol. 2021; 95 (2): 659–71. DOI: 10.1007/s00204-020-02951-8
  16. Tanaka Y., Nagoshi T., Yoshii A., Oi Yu., Takahashi H., Kimura H. et al. Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity. Free Radic. Biol. Med. 2021; 162: 298–308. DOI: 10.1016/j.freeradbiomed. 2020.10.303
  17. Sabatino J., De Rosa S., Tammè L., Iaconetti C., Sorrentino S., Polimeni A. et al. Empagliflozin prevents doxorubicin-induced myocardial dysfunction. Cardiovasc. Diabetol. 2020; 19 (1): 66. DOI: 10.1186/s12933-020- 01040-5
  18. Quagliariello V., De Laurentiis M., Rea D., Barbieri A., Monti M.G., Carbone A. et al. The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in nondiabetic mice treated with doxorubicin. Cardiovasc. Diabetol. 2021; 20 (1): 150. DOI: 10.1186/s12933-021-01346-y
  19. Timm K., Tyler D. The Role of AMPK activation for cardioprotection in doxorubicin-induced cardiotoxicity. Cardiovasc. Drugs. Ther. 2020; 34 (2): 255–69. DOI: 10.1007/s10557-020-06941-x
  20. Baartscheer A., Schumacher C., Wüst R., Fiolet J., Stienen G., Coronel R., Zuurbier C. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger. Diabetologia. 2017; 60 (3): 568–73. DOI: 10.1007/s00125-016-4134-x
  21. Maayah Z., Takahara S., Dyck J. The beneficial effects of reducing NLRP3 inflammasome activation in the cardiotoxicity and the anti-cancer effects of doxorubicin. Arch. Toxicol. 2021; 95 (1): 1–9. DOI: 10.1007/ s00204-020-02876-2
  22. Yun C., Han Y., Lee S. PGC-1α controls mitochondrial biogenesis in drug-resistant colorectal cancer cells by regulating endoplasmic reticulum stress. Int. J. Mol. Sci. 2019; 20 (7): 1707. DOI: 10.3390/ijms20071707
  23. Elrakaybi A., Laubner K., Zhou Q., Hug M., Seufert J. Cardiovascular protection by SGLT2 inhibitors – do anti-inflammatory mechanisms play a role? Mol. Metab. 2022; 64: 101549. DOI: 10.1016/j.molmet.2022.101549
  24. Gongora C., Drobni Z., Quinaglia Araujo Costa Silva T., Zafar A., Gong J., Zlotoff D. et al. Sodium-glucose cotransporter-2 inhibitors and cardiac outcomes among patients treated with anthracyclines. JACC Heart Fail. 2022; 10 (8): 559–67. DOI: 10.1016/j.jchf.2022.03.006
  25. Акилджонов Ф.Р., Бузиашвили Ю.И., Асымбекова Э.У., Тугеева Э.Ф., Алимов В.П. Ранняя профилактика кардиотоксичности у онкологических пациентов: фокус на медикаментозной терапии. Креативная кардиология. 2021; 15 (3): 322–31. DOI: 10.24022/1997-3187-2021-15-3-322-331
****
  1. Lotrionte M., Biondi-Zoccai G., Abbate A., Lanzetta G., D'Ascenzo F., Malavasi V. Review and metaanalysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am. J. Cardiol. 2013; 112 (12): 1980–4. DOI: 10.1016/j.amjcard.2013.08.026
  2. Buziashvili J.I., Stilidi I.S., Mackeplishvili S.T., Asymbekova E.U., Tugeeva E.F., Artamonova E.V. et al. Cardiovascular and oncological diseases – focus on modifiable risk factors and modern pathogenetic aspects. Annals of the Russian Academy of Medical Sciences. 2023; 78 (2): 132–40 (in Russ.). DOI: 10.15690/vramn8359
  3. Hou Y., Zheng C., Yen T., Lu K. Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection. Int. J. Mol. Sci. 2020; 21 (21): 7833. DOI: 10.3390/ijms21217833
  4. Buziashvili Yu.I., Asymbekova E.U., Matskeplishvili S.T., Tugeeva E.F., Artamonova E.V., Akildzhonov F.R. Dynamics of echocardiographic parameters during neoadjuvant chemotherapy in patients with breast cancer. Creative Cardiology. 2022; 16 (4): 520–32 (in Russ.). DOI: 10.24022/1997-3187-2022-16-4-520-532
  5. Bergler-Klein J., Rainer P., Wallner M., Zaruba M.-M., Dörler J., Böhmer A. et al. Cardio-oncology in Austria: cardiotoxicity and surveillance of anti-cancer therapies: position paper of the Heart Failure Working Group of the Austrian Society of Cardiology. Wien Klin. Wochenschr. 2022; 134 (17-18): 654–74. DOI: 10.1007/s00508-022-02031-0 6.
  6. Antonucci S., Di Sante M., Tonolo F., Pontarollo L., Scalcon V., Alanova P. et al. The determining role of mitochondrial reactive oxygen species generation and monoamine oxidase activity in doxorubicin-induced cardiotoxicity. Antioxid. Redox. Signal. 2021; 34 (7): 531–50. DOI: 10.1089/ars.2019.7929
  7. Sabbatino F., Conti V., Liguori L., Polcaro G., Corbi G., Manzo V. et al. Molecules and mechanisms to overcome oxidative stress inducing cardiovascular disease in cancer patients. Life (Basel). 2021; 11 (2): 105. DOI: 10.3390/life11020105
  8. D'Oria R., Schipani R., Leonardini A., Natalicchio A., Perrini S., Cignarelli A. et al. The role of oxidative stress in cardiac disease: from physiological response to injury factor. Oxid. Med. Cell. Longev. 2020; 2020: 5732956. DOI: 10.1155/2020/5732956
  9. Lima M., Brito H., Mitidieri G., de Souza E., Sobral A., Melo H. et al. Cardiotoxicity in cancer patients treated with chemotherapy: a systematic review. Int. J. Health. Sci. (Qassim). 2022; 16 (6): 39–46.
  10. Kim C., Choi K. Effects of anticancer drugs on the cardiac mitochondrial toxicity and their underlying mechanisms for novel cardiac protective strategies. Life Sci. 2021; 277: 119607. DOI: 10.1016/j.lfs.2021.119607
  11. Carrasco R., Castillo R., Gormaz J., Carrillo M., Thavendiranathan P. Role of oxidative stress in the mechanisms of anthracycline-induced cardiotoxicity: effects of preventive strategies. Oxid. Med. Cell. Longev. 2021; 2021: 8863789. DOI: 10.1155/2021/8863789
  12. García-Carro C., Vergara A., Agraz I., Jacobs-Cachá C., Espinel E., Seron D., Soler M.J. The new era for reno-cardiovascular treatment in type 2 diabetes. J. Clin. Med. 2019; 8 (6): 864. DOI: 10.3390/jcm8060864
  13. Kowalska K., Walczak J., Femlak J., Młynarska E., Franczyk B., Rysz J. Empagliflozin – a new chance for patients with chronic heart failure. Pharmaceuticals (Basel). 2021; 15 (1): 47. DOI: 10.3390/ph15010047
  14. Lopaschuk G., Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic. Transl. Sci. 2020; 5 (6): 632–44. DOI: 10.1016/j.jacbts.2020.02.004
  15. Chang W., Lin Y., Ho C., Chen Z., Liu P., Shih J. Dapagliflozin suppresses ER stress and protects doxorubicin-induced cardiotoxicity in breast cancer patients. Arch. Toxicol. 2021; 95 (2): 659–71. DOI: 10.1007/s00204-020-02951-8
  16. Tanaka Y., Nagoshi T., Yoshii A., Oi Yu., Takahashi H., Kimura H. et al. Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity. Free Radic. Biol. Med. 2021; 162: 298–308. DOI: 10.1016/j.freeradbiomed. 2020.10.303
  17. Sabatino J., De Rosa S., Tammè L., Iaconetti C., Sorrentino S., Polimeni A. et al. Empagliflozin prevents doxorubicin-induced myocardial dysfunction. Cardiovasc. Diabetol. 2020; 19 (1): 66. DOI: 10.1186/s12933-020- 01040-5
  18. Quagliariello V., De Laurentiis M., Rea D., Barbieri A., Monti M.G., Carbone A. et al. The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in nondiabetic mice treated with doxorubicin. Cardiovasc. Diabetol. 2021; 20 (1): 150. DOI: 10.1186/s12933-021-01346-y
  19. Timm K., Tyler D. The Role of AMPK activation for cardioprotection in doxorubicin-induced cardiotoxicity. Cardiovasc. Drugs. Ther. 2020; 34 (2): 255–69. DOI: 10.1007/s10557-020-06941-x
  20. Baartscheer A., Schumacher C., Wüst R., Fiolet J., Stienen G., Coronel R., Zuurbier C. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger. Diabetologia. 2017; 60 (3): 568–73. DOI: 10.1007/s00125-016-4134-x
  21. Maayah Z., Takahara S., Dyck J. The beneficial effects of reducing NLRP3 inflammasome activation in the cardiotoxicity and the anti-cancer effects of doxorubicin. Arch. Toxicol. 2021; 95 (1): 1–9. DOI: 10.1007/ s00204-020-02876-2
  22. Yun C., Han Y., Lee S. PGC-1α controls mitochondrial biogenesis in drug-resistant colorectal cancer cells by regulating endoplasmic reticulum stress. Int. J. Mol. Sci. 2019; 20 (7): 1707. DOI: 10.3390/ijms20071707
  23. Elrakaybi A., Laubner K., Zhou Q., Hug M., Seufert J. Cardiovascular protection by SGLT2 inhibitors – do anti-inflammatory mechanisms play a role? Mol. Metab. 2022; 64: 101549. DOI: 10.1016/j.molmet.2022.101549
  24. Gongora C., Drobni Z., Quinaglia Araujo Costa Silva T., Zafar A., Gong J., Zlotoff D. et al. Sodium-glucose cotransporter-2 inhibitors and cardiac outcomes among patients treated with anthracyclines. JACC Heart Fail. 2022; 10 (8): 559–67. DOI: 10.1016/j.jchf.2022.03.006
  25. Akildzhonov F.R., Buziashvili Yu.I., Asymbekova E.U., Tugeeva E.F., Alimov V.P. Early prevention of cardiotoxicity in cancer patients: focus on medical therapy. Creative Cardiology. 2021; 15 (3): 322–31 (in Russ.). DOI: 10.24022/1997-3187-2021-15-3-322-331

About Authors

  • Yuriy I. Buziashvili, Dr. Med. Sci., Professor, Academician of the Russian Academy of Sciences, Head of Clinical and Diagnostic Department; ORCID
  • Ivan S. Stilidi, Dr. Med. Sci., Professor, Academician of the Russian Academy of Sciences, Director; ORCID
  • Simon T. Matskeplishvili, Dr. Med. Sci., Professor, Corresponding Member of the Russian Academy of Sciences, Chief Researcher; ORCID
  • Elmira U. Asymbekova, Dr. Med. Sci., Leading Researcher; ORCID
  • Elvina F. Tugeeva, Dr. Med. Sci., Senior Researcher; ORCID
  • Elena V. Artamonova, Dr. Med. Sci., Leading Researcher; ORCID
  • Nazli K. Akhmedyarova, Cand. Med. Sci., Researcher; ORCID
  • Firdavsdzhon R. Akildzhonov, Postgraduate; ORCID

 If you found mistakes, select text and press Alt+A