Влияние ингибиторов натрий-глюкозного котранспортера 2‑го типа на диастолическую функцию левого желудочка: текущее состояние вопроса и перспективы

Ингибиторы натрий-глюкозного котранспортера 2‑го типа (иНГЛТ2), или глифлозины – новый класс сердечно-сосудис­тых препаратов, клиническая эффективность и благоприятное влияние на прогноз у пациентов с сердечной недостаточностью с сохраненной фракцией выброса (СНсФВ) которых доказаны. Нарушение диастолической функции (ДФ) левого желудочка (ЛЖ) – важный элемент патогенеза СНсФВ. В экспериментальных исследованиях выявлено наличие у глифлозинов внутриклеточных механизмов так называемых диастолических эффектов. На лабораторных моделях с воссозданной в эксперименте СНсФВ продемонстрировано позитивное влияние дапаглифлозина и эмпаглифлозина на эластические свойства миофиламентов кардиомиоцитов, динамику фиброза миокарда, внутриклеточный гомеостаз натрия и кальция. Экспериментально установлено значение противовоспалительных, антиоксидантных свойств глифлозинов в улучшении ДФ кардиомиоцитов. Доказанное в относительно небольших клинических исследованиях влияние иНГЛТ2 на показатели ДФ ЛЖ у пациентов из группы высокого риска развития сердечно-сосудистых заболеваний и их осложнений обусловлено первичными кардиальными и вторично обусловленными эффектами. Результаты отдельных исследований подтвердили протективные (в отношении релаксации миокарда) свойства глифлозинов в условиях диастолического стресс-теста. Регресс показателей диастолической дисфункции ЛЖ, выявленный на фоне применения иНГЛТ2 в небольших наблюдениях, важен в контексте доказанного в крупных рандомизированных клинических исследованиях достоверного положительного влияния эмпаглифлозина и дапаглифлозина на прогноз сердечно-сосудистых заболеваний у пациентов с СНсФВ.

1. Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences. Diabetes and Vascular Disease Research. 2015;12(2):78–89. DOI: 10.1177/1479164114561992

2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015;373(22):2117–28. DOI: 10.1056/NEJMoa1504720

3. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2019;380(4):347–57. DOI: 10.1056/NEJMoa1812389

4. Mazidi M, Rezaie P, Gao H, Kengne AP. Effect of Sodium‐Glucose Cotransport‐2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta‐Analysis of 43 Randomized Control Trials With 22 528 Patients. Journal of the American Heart Association. 2017;6(6):e004007. DOI: 10.1161/JAHA.116.004007

5. Verdecchia P, Cavallini C, Angeli F. Advances in the Treatment Strategies in Hypertension: Present and Future. Journal of Cardiovascular Development and Disease. 2022;9(3):72. DOI: 10.3390/jcdd9030072

6. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. 2021;42(36):3599–726. DOI: 10.1093/eurheartj/ehab368

7. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895–1032. DOI: 10.1161/CIR.0000000000001063

8. Bozkurt B. Proposed New Conceptualization for Definition of Decompensated HF. JACC: Heart Failure. 2023;11(3):368–71. DOI: 10.1016/j.jchf.2023.02.001

9. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. New England Journal of Medicine. 2021;385(16):1451–61. DOI: 10.1056/NEJMoa2107038

10. Solomon SD, Vaduganathan M, Claggett BL, De Boer RA, DeMets D, Hernandez AF et al. Baseline Characteristics of Patients With HF With Mildly Reduced and Preserved Ejection Fraction. JACC: Heart Failure. 2022;10(3):184–97. DOI: 10.1016/j.jchf.2021.11.006

11. Sciatti E, Gori M, D’elia E, Iacovoni A, Senni M. Empagliflozin in heart failure with preserved ejection fraction: first success in mission impossible. European Heart Journal Supplements. 2022;24(Suppl I):I153–9. DOI: 10.1093/eurheartjsupp/suac106

12. Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovascular Diabetology. 2017;16(1):9. DOI: 10.1186/s12933-016-0489-z

13. Hammoudi N, Jeong D, Singh R, Farhat A, Komajda M, Mayoux E et al. Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes. Cardiovascular Drugs and Therapy. 2017;31(3):233–46. DOI: 10.1007/s10557-017-6734-1

14. Moellmann J, Klinkhammer BM, Droste P, Kappel B, Haj-Yehia E, Maxeiner S et al. Empagliflozin improves left ventricular diastolic function of db/db mice. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2020;1866(8):165807. DOI: 10.1016/j.bba-dis.2020.165807

15. Pabel S, Wagner S, Bollenberg H, Bengel P, Kovács Á, Schach C et al. Empagliflozin directly improves diastolic function in human heart failure. European Journal of Heart Failure. 2018;20(12):1690–700. DOI: 10.1002/ejhf.1328

16. Connelly KA, Zhang Y, Visram A, Advani A, Batchu SN, Desjardins J-F et al. Empagliflozin Improves Diastolic Function in a Nondiabetic Rodent Model of Heart Failure With Preserved Ejection Fraction. JACC: Basic to Translational Science. 2019;4(1):27–37. DOI: 10.1016/j.jacbts.2018.11.010

17. Franssen C, González Miqueo A. The role of titin and extracellular matrix remodelling in heart failure with preserved ejection fraction. Netherlands Heart Journal. 2016;24(4):259–67. DOI: 10.1007/s12471-016-0812-z

18. Borbély A, van der Velden J, Papp Z, Bronzwaer JGF, Edes I, Stienen GJM et al. Cardiomyocyte Stiffness in Diastolic Heart Failure. Circulation. 2005;111(6):774–81. DOI: 10.1161/01.CIR.0000155257.33485.6D

19. Linke WA, Hamdani N. Gigantic business: titin properties and function through thick and thin. Circulation Research. 2014;114(6):1052–68. DOI: 10.1161/CIRCRESAHA.114.301286

20. Hamdani N, Krysiak J, Kreusser MM, Neef S, Dos Remedios CG, Maier LS et al. Crucial Role for Ca2+/Calmodulin-Dependent Protein Kinase-II in Regulating Diastolic Stress of Normal and Failing Hearts via Titin Phosphorylation. Circulation Research. 2013;112(4):664–74. DOI: 10.1161/CIRCRESAHA.111.300105

21. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. Journal of the American College of Cardiology. 2013;62(4):263–71. DOI: 10.1016/j.jacc.2013.02.092

22. Greene SJ, Gheorghiade M, Borlaug BA, Pieske B, Vaduganathan M, Burnett JC et al. The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction. Journal of the American Heart Association. 2013;2(6):e000536. DOI: 10.1161/JAHA.113.000536

23. Xue M, Li T, Wang Y, Chang Y, Cheng Y, Lu Y et al. Empagliflozin prevents cardiomyopathy via sGC-cGMP-PKG pathway in type 2 diabetes mice. Clinical Science. 2019;133(15):1705–20. DOI: 10.1042/CS20190585

24. Kolijn D, Pabel S, Tian Y, Lódi M, Herwig M, Carrizzo A et al. Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation. Cardiovascular Research. 2021;117(2):495–507. DOI: 10.1093/cvr/cvaa123

25. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Garcia-Ropero A, Ishikawa K, Watanabe S et al. Empagliflozin Ameliorates Diastolic Dysfunction and Left Ventricular Fibrosis/Stiffness in Nondiabetic Heart Failure. JACC: Cardiovascular Imaging. 2021;14(2):393–407. DOI: 10.1016/j.jcmg.2020.07.042

26. Pabel S, Reetz F, Dybkova N, Shomroni O, Salinas G, Mustroph J et al. Long-term effects of empagliflozin on excitation-contraction-coupling in human induced pluripotent stem cell cardiomyocytes. Journal of Molecular Medicine. 2020;98(12):1689–700. DOI: 10.1007/s00109-020-01989-6

27. Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation. 2015;131(14):1247–59. DOI: 10.1161/CIRCULATIONAHA.114.013215

28. Sweeney M, Corden B, Cook SA. Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle? EMBO Molecular Medicine. 2020;12(10):e10865. DOI: 10.15252/emmm.201910865

29. Lee H-C, Shiou Y-L, Jhuo S-J, Chang C-Y, Liu P-L, Jhuang W-J et al. The sodium–glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovascular Diabetology. 2019;18(1):45. DOI: 10.1186/s12933-019-0849-6

30. Lee T-M, Chang N-C, Lin S-Z. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radical Biology and Medicine. 2017;104:298–310. DOI: 10.1016/j.freeradbiomed.2017.01.035

31. Li C, Zhang J, Xue M, Li X, Han F, Liu X et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovascular Diabetology. 2019;18(1):15. DOI: 10.1186/s12933-019-0816-2

32. Shi L, Zhu D, Wang S, Jiang A, Li F. Dapagliflozin Attenuates Cardiac Remodeling in Mice Model of Cardiac Pressure Overload. American Journal of Hypertension. 2019;32(5):452–9. DOI: 10.1093/ajh/hpz016

33. Ye Y, Bajaj M, Yang H-C, Perez-Polo JR, Birnbaum Y. SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor. Cardiovascular Drugs and Therapy. 2017;31(2):119–32. DOI: 10.1007/s10557-017-6725-2

34. Pabel S, Hamdani N, Singh J, Sossalla S. Potential Mechanisms of SGLT2 Inhibitors for the Treatment of Heart Failure With Preserved Ejection Fraction. Frontiers in Physiology. 2021;12:752370. DOI: 10.3389/fphys.2021.752370

35. Baartscheer A, Schumacher CA, Wüst RCI, Fiolet JWT, Stienen GJM, Coronel R et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60(3):568–73. DOI: 10.1007/s00125-016-4134-x

36. Mustroph J, Wagemann O, Lücht CM, Trum M, Hammer KP, Sag CM et al. Empagliflozin reduces Ca/calmodulin‐dependent kinase II activity in isolated ventricular cardiomyocytes. ESC Heart Failure. 2018;5(4):642–8. DOI: 10.1002/ehf2.12336

37. Eisner DA, Caldwell JL, Trafford AW, Hutchings DC. The Control of Diastolic Calcium in the Heart: Basic Mechanisms and Functional Implications. Circulation Research. 2020;126(3):395–412. DOI: 10.1161/CIRCRESAHA.119.315891

38. Philippaert K, Kalyaanamoorthy S, Fatehi M, Long W, Soni S, Byrne NJ et al. Cardiac Late Sodium Channel Current Is a Molecular Target for the Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin. Circulation. 2021;143(22):2188–204. DOI: 10.1161/CIRCULATIONAHA.121.053350

39. Trum M, Riechel J, Wagner S. Cardioprotection by SGLT2 Inhibitors – Does It All Come Down to Na+? International Journal of Molecular Sciences. 2021;22(15):7976. DOI: 10.3390/ijms22157976

40. Zhazykbayeva S, Pabel S, Mügge A, Sossalla S, Hamdani N. The molecular mechanisms associated with the physiological responses to inflammation and oxidative stress in cardiovascular diseases. Biophysical Reviews. 2020;12(4):947–68. DOI: 10.1007/s12551-020-00742-0

41. Barsukov AV, Korovin AE, Churilov LP, Borisova EV, Tovpeko DV. Heart Dysfunction in Essential Hypertension Depends on Systemic Proinflammatory Influences: A Retrospective Clinical Pathophysiological Study. Pathophysiology. 2022;29(3):453–68. DOI: 10.3390/pathophysiology29030036

42. Rangaswami J, Bhalla V, Blair JEA, Chang TI, Costa S, Lentine KL et al. Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the American Heart Association. Circulation. 2019;139(16):e840–78. DOI: 10.1161/CIR.0000000000000664

43. Yaribeygi H, Atkin SL, Butler AE, Sahebkar A. Sodium–glucose cotransporter inhibitors and oxidative stress: An update. Journal of Cellular Physiology. 2019;234(4):3231–7. DOI: 10.1002/jcp.26760

44. Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashizaki Y et al. Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats. Journal of Pharmacy and Pharmacology. 2014;66(7):975–87. DOI: 10.1111/jphp.12223

45. Franssen C, Chen S, Unger A, Korkmaz HI, De Keulenaer GW, Tschöpe C et al. Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC. Heart failure. 2016;4(4):312–24. DOI: 10.1016/j.jchf.2015.10.007

46. Juni RP, Kuster DWD, Goebel M, Helmes M, Musters RJP, Van Der Velden J et al. Cardiac Microvascular Endothelial Enhancement of Cardiomyocyte Function Is Impaired by Inflammation and Restored by Empagliflozin. JACC: Basic to Translational Science. 2019;4(5):575–91. DOI: 10.1016/j.jacbts.2019.04.003

47. Cappetta D, De Angelis A, Ciuffreda LP, Coppini R, Cozzolino A, Miccichè A et al. Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium. Pharmacological Research. 2020;157:104781. DOI: 10.1016/j.phrs.2020.104781

48. Soga F, Tanaka H, Tatsumi K, Mochizuki Y, Sano H, Toki H et al. Impact of Dapagliflozin on the Left Ventricular Diastolic Function in Diabetic Patients with Heart Failure Complicating Cardiovascular Risk Factors. Internal Medicine. 2021;60(15):2367–74. DOI: 10.2169/internalmedicine.6127-20

49. Wee CF, Teo YH, Teo YN, Syn NL, See RM, Leong S et al. Effects of Sodium/Glucose Cotransporter 2 (SGLT2) Inhibitors on Cardiac Imaging Parameters: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Journal of Cardiovascular Imaging. 2022;30(3):153–68. DOI: 10.4250/jcvi.2021.0159

50. Heinzel FR, Hohendanner F, Jin G, Sedej S, Edelmann F. Myocardial hypertrophy and its role in heart failure with preserved ejection fraction. Journal of Applied Physiology. 2015;119(10):1233–42. DOI: 10.1152/japplphysiol.00374.2015

51. Verma S, Mazer CD, Yan AT, Mason T, Garg V, Teoh H et al. Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation. 2019;140(21):1693–702. DOI: 10.1161/CIRCULATIONAHA.119.042375

52. Verma S, Garg A, Yan AT, Gupta AK, Al-Omran M, Sabongui A et al. Effect of Empagliflozin on Left Ventricular Mass and Diastolic Function in Individuals With Diabetes: An Important Clue to the EMPAREG OUTCOME Trial? Diabetes Care. 2016;39(12):e212–3. DOI: 10.2337/dc16-1312

53. Brown AJM, Gandy S, McCrimmon R, Houston JG, Struthers AD, Lang CC. A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes: the DAPALVH trial. European Heart Journal. 2020;41(36):3421–32. DOI: 10.1093/eurheartj/ehaa419

54. Shim CY, Seo J, Cho I, Lee CJ, Cho I-J, Lhagvasuren P et al. Randomized, Controlled Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients With Type 2 Diabetes Mellitus: The IDDIA Trial. Circulation. 2021;143(5):510–2. DOI: 10.1161/CIRCULATIONAHA.120.051992

55. Овчинников А.Г., Борисов А.А., Жеребчикова К.Ю., Рябцева О.Ю., Гвоздева А.Д., Масенко В.П. и др. Влияние эмпаглифлозина на переносимость нагрузки и диастолическую функцию левого желудочка у пациентов с сердечной недостаточностью с сохраненной фракцией выброса и сахарным диабетом типа 2: проспективное одноцентровое пилотное исследование. Российский Кардиологический Журнал. 2021;26(1):137-51. DOI: 10.15829/1560-4071-2021-4304

56. Prochaska JH, Jünger C, Schulz A, Arnold N, Müller F, Heidorn MW et al. Effects of empagliflozin on left ventricular diastolic function in addition to usual care in individuals with type 2 diabetes mellitus – results from the randomized, double-blind, placebo-controlled EmDia trial. Clinical Research in Cardiology. 2023;112(7):911–22. DOI: 10.1007/s00392-023-02164-w

57. Nassif ME, Qintar M, Windsor SL, Jermyn R, Shavelle DM, Tang F et al. Empagliflozin Effects on Pulmonary Artery Pressure in Patients With Heart Failure: Results From the EMBRACE-HF Trial. Circulation. 2021;143(17):1673–86. DOI: 10.1161/CIRCULATIONAHA.120.052503

58. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. New England Journal of Medicine. 2019;381(21):1995–2008. DOI: 10.1056/NEJMoa1911303

59. Omar M, Jensen J, Ali M, Frederiksen PH, Kistorp C, Videbæk L et al. Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial. JAMA Cardiology. 2021;6(7):836–40. DOI: 10.1001/jamacardio.2020.6827

60. Wang Y, Zhong Y, Zhang Z, Yang S, Zhang Q, Chu B et al. Effect of sodium-glucose cotransporter protein-2 inhibitors on left ventricular hypertrophy in patients with type 2 diabetes: A systematic review and meta-analysis. Frontiers in Endocrinology. 2023;13:1088820. DOI: 10.3389/fendo.2022.1088820

61. Rai A, Connelly KA, Verma S, Mazer CD, Teoh H, Ng M-Y et al. Empagliflozin does not affect left ventricular diastolic function in patients with type 2 diabetes mellitus and coronary artery disease: insight from the EMPA-HEART CardioLink-6 randomized clinical trial. Acta Diabetologica. 2022;59(4):575–8. DOI: 10.1007/s00592-021-01823-6

62. Dhingra A, Garg A, Kaur S, Chopra S, Batra JS, Pandey A et al. Epidemiology of heart failure with preserved ejection fraction. Current Heart Failure Reports. 2014;11(4):354–65. DOI: 10.1007/s11897014-0223-7