The role of endosarcomeric cytoskeleton proteins in the mechanisms of left ventricular diastolic dysfunction: focus on titin

Recognizing the fact that isolated left ventricular (LV) diastolic dysfunction (DD) underlies approximately 50% of all heart failure cases requires a deep understanding of its principal mechanisms so that effective diagnostic and treatment strategies can be developed. Despite abundance of knowledge about the mechanisms underlying DD, many important questions regarding the pathophysiology of diastole remain unresolved. In particular, the role of endosarcomeric cytoskeleton pathology in the deterioration of the so-called active (relaxation of the LV myocardium and the atrioventricular pressure gradient at the beginning of diastole, closely related to it in a healthy heart) and passive (myocardial stiffness) characteristics of diastole needs to be clarified.

The lecture briefly discusses the complex hierarchy of DD mechanisms (from the sarcomere to the whole heart) and covers the role of the giant protein titin in the latter, which is the main determinant of intracellular stiffness. Impairment of myocardial relaxation and deterioration of its wall compliance under a wide range of pathological conditions (pressure overload, ischemia, inflammation, cardiotoxic effects, oxidative stress, etc.) underlying DD can be explained by a shift in titin expression toward its more rigid N2B isoform, hypophosphorylation by protein kinases A and G or dephosphorylation by serine / threonine phosphatase 5 of its molecule in the extensible protein segment containing a unique N2B sequence, hyperphosphorylation of PEVK regions of titin by protein kinase C, as well as inhibition of the Ca²+-dependent titin – actin interaction.

The results of deciphering these mechanisms can become a tool for developing new approaches to targeted therapy for diastolic heart failure that currently does not have effective treatment, on the one hand, and the key to understanding the therapeutic effects of drugs already used to treat chronic heart failure with preserved LV ejection fraction, on the other hand.

1. Nazário Leão R., Marques da Silva P. Diastolic dysfunction in hypertension. Hipertens. Riesgo Vasc. 2017;34(3):128−139. DOI: 10.1016/j.hipert.2017.01.001.

2. Samuel T.J., Beaudry R., Sarma S., Zaha V., Haykowsky M.J., Nelson M.D. Diastolic stress testing along the heart failure continuum. Curr. Heart Fail. Rep. 2018;15(6):332−339. DOI: 10.1007/s11897-018-0409-5.

3. Bayes-Genis A., Bisbal F., Núñez J., Santas E., Lupón J., Rossignol P. et al. Transitioning from preclinical to clinical heart failure with preserved ejection fraction: a mechanistic approach. J. Clin. Med. 2020Apr.13;9(4):1110. DOI: 10.3390/jcm9041110.

4. Ge H. Is diastolic dysfunction a new windsock in the risk stratification of patients with coronary heart disease? Int. J. Cardiol. 2022Jan.1;346:103−104. DOI: 10.1016/j.ijcard.2021.11.037.

5. Bertacchini F., Agabiti Rosei C., Buso G., Cappellini S., Stassaldi D., Aggiusti C. et al. Subclinical HMOD in hypertension: left ventricular diastolic dysfunction. High Blood Press. Cardiovasc. Prev. 2022Nov.10. DOI: 10.1007/s40292-022-00548-z.

6. Zhou D., Yan M., Cheng Q., Feng X., Tang S., Feng Y. Prevalence and prognosis of left ventricular diastolic dysfunction in community hypertension patients. BMC Cardiovasc. Disord. 2022Juny13;22(1):265. DOI: 10.1186/s12872-022-02709-3.

7. Cianciulli T.F., Saccheri M.C., Papantoniou A., Méndez R.J., Gagliardi J.A., Prado N.G. et al. Use of tissue doppler imaging for the early detection of myocardial dysfunction in patients with the indeterminate form of Chagas disease. Rev. Soc. Bras. Med. Trop. 2020Feb.21;53:e20190457. DOI: 10.1590/0037-8682-0457-2019.

8. Echeverría L.E., Gómez-Ochoa S.A., Rojas L.Z., García-Rueda K.A., López-Aldana P., Muka T. et al. Cardiovascular biomarkers and diastolic dysfunction in patients with chronic chagas cardiomyopathy. Front. Cardiovasc. Med. 2021Nov.29;8:751415. DOI: 10.3389/fcvm.2021.751415.

9. Saraiva R.M., Mediano M.F.F., Quintana M.S.B., Sperandio da Silva G.M., Costa A.R., Sousa A.S. et al. Two-dimensional strain derived parameters provide independent predictors of progression to Chagas cardiomyopathy and mortality in patients with Chagas disease. Int. J. Cardiol. Heart Vasc. 2022Jan.10;38:100955. DOI: 10.1016/j.ijcha.2022.100955.

10. Калюжин В.В., Кулаков Ю.А. Соотношения вегетативных, эмоциональных и соматических нарушений при хроническом описторхозе. Клиническая медицина. 1996;74(6):27−29.

11. Хардикова С.А., Берендеева Е.П., Калюжин В.В., Белобородова Э.И. Диастолическая дисфункция левого желудочка у больных псориазом на фоне хронического описторхоза до и после антигельминтной терапии. Клиническая медицина. 2009;87(10):29−32.

12. Калюжин В.В., Тепляков А.Т., Рязанцева Н.В., Вечерский Ю.Ю., Хлапов А.П., Колесников Р.Н. Диастола сердца. Физиология и клиническая патофизиология. Томск: Изд-во ТПУ, 2007: 212.

13. Ferreira-Martins J., Leite-Moreira A.F. Physiologic basis and pathophysiologic implications of the diastolic properties of the cardiac muscle. J. Biomed. Biotechnol. 2010;2010:807084. DOI: 10.1155/2010/807084.

14. Janssen P.M.L. Myocardial relaxation in human heart failure: Why sarcomere kinetics should be center-stage. Arch. Biochem. Biophys. 2019;661:145−148. DOI: 10.1016/j.abb.2018.11.011.

15. Драпкина О.М., Кабурова О.М. Диастолическая сердечная недостаточность: механизмы развития и перспективы воздействия на них. Журнал сердечная недостаточность. 2012;13(5/73):310−316.

16. Калюжин В.В., Тепляков А.Т., Калюжин О.В. Сердечная недостаточность. М.: Медицинское информационное агентство, 2018:376.

17. Лакомкин В.Л., Абрамов А.А., Студнева И.М., Уланова А.Д., Вихлянцев И.М., Просвирнин А.В. и др. Ранние изменения энергетического метаболизма, изоформного состава и уровня фосфорилирования титина при диастолической дисфункции. Кардиология. 2020;60(2):4−9. DOI: 10.18087/cardio.2020.3.n531.

18. Bull M., Methawasin M., Strom J., Nair P., Hutchinson K., Granzier H. Alternative splicing of titin restores diastolic function in an HFpEF-like genetic murine model (TtnΔIAjxn). Circ. Res. 2016;119(6):764−772. DOI: 10.1161/CIRCRESAHA.116.308904.

19. Gevaert A.B., Kataria R., Zannad F., Sauer A.J., Damman K., Sharma K. et al. Heart failure with preserved ejection fraction: recent concepts in diagnosis, mechanisms and management. Heart. 2022;108(17):1342−1350. DOI: 10.1136/heartjnl-2021-319605.

20. Loescher C.M., Hobbach A.J., Linke W.A. Titin (TTN): from molecule to modifications, mechanics, and medical significance. Cardiovasc. Res. 2022;118(14):2903−2918. DOI: 10.1093/cvr/cvab328.

21. Zhou Y., Zhu Y., Zeng J. Research update on the pathophysiological mechanisms of heart failure with preserved ejection fraction. Curr. Mol. Med. 2023;23(1):54−62. DOI: 10.2174/1566524021666211129111202.

22. Van der Velden J., Stienen G.J.M. Cardiac disorders and pathophysiology of sarcomeric proteins. Physiol. Rev. 2019;99(1):381−426. DOI: 10.1152/physrev.00040.2017.

23. Crocini C., Gotthardt M. Cardiac sarcomere mechanics in health and disease. Biophys. Rev. 2021;13(5):637−652. DOI: 10.1007/s12551-021-00840-7.

24. Knight W.E., Woulfe K.C. Dysfunctional sarcomeric relaxation in the heart. Curr. Opin. Physiol. 2022;26:100535. DOI: 10.1016/j.cophys.2022.100535.

25. Martin A.A., Thompson B.R., Hahn D., Angulski A.B.B., Hosny N., Cohen H. et al. Cardiac sarcomere signaling in health and disease. Int. J. Mol. Sci. 2022;23(24):16223. DOI: 10.3390/ijms232416223.

26. Rosas P.C., Solaro R.J. Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis. Front. Cardiovasc. Med. 2023Jan.24;9:1060716. DOI: 10.3389/fcvm.2022.1060716.

27. Kass D.A., Bronzwaer J.G., Paulus W.J. What mechanisms underlie diastolic dysfunction in heart failure? Circ. Res. 2004;94(12):1533−1542. DOI: 10.1161/01.RES.0000129254.25507.d6.

28. Rosas P.C., Liu Y., Abdalla M.I., Thomas C.M., Kidwell D.T., Dusio G.F. et al. Phosphorylation of cardiac myosin-binding protein-C is a critical mediator of diastolic function. Circ. Heart Fail. 2015;8(3):582−594. DOI: 10.1161/CIRCHEARTFAILURE.114.001550.

29. Sheng J.J., Feng H.Z., Pinto J.R., Wei H., Jin J.P. Increases of desmin and α-actinin in mouse cardiac myofibrils as a response to diastolic dysfunction. J. Mol. Cell. Cardiol. 2016;99:218−229. DOI: 10.1016/j.yjmcc.2015.10.035.

30. Valero-Muñoz M., Saw E.L., Hekman R.M., Blum B.C., Hourani Z., Granzier H. et al. Proteomic and phosphoproteomic profiling in heart failure with preserved ejection fraction (HFpEF). Front. Cardiovasc. Med. 2022Aug.25;9:966968. DOI: 10.3389/fcvm.2022.966968.

31. Li N., Hang W., Shu H., Zhou N. RBM20, a therapeutic target to alleviate myocardial stiffness via titin isoforms switching in HFpEF. Front. Cardiovasc. Med. 2022Jun.16;9:928244. DOI: 10.3389/fcvm.2022.928244.

32. Lamber E.P., Guicheney P., Pinotsis N. The role of the M-band myomesin proteins in muscle integrity and cardiac disease. J. Biomed. Sci. 2022;29(1):18. DOI: 10.1186/s12929-022-00801-6.

33. Gilbert G., Demydenko K., Dries E., Puertas R.D., Jin X., Sipido K. et al. Calcium signaling in cardiomyocyte function. Cold Spring Harb. Perspect. Biol. 2020;12(3):a035428. DOI: 10.1101/cshperspect.a035428.

34. Denniss A.L., Dashwood A.M., Molenaar P., Beard N.A. Sarcoplasmic reticulum calcium mishandling: central tenet in heart failure? Biophys. Rev. 2020;12(4):865−878. DOI: 10.1007/s12551-020-00736-y.

35. Benitah J.P., Perrier R., Mercadier J.J., Pereira L., Gómez A.M. RyR2 and calcium release in heart failure. Front. Physiol. 2021;12:734210. DOI: 10.3389/fphys.2021.734210.

36. Rouhana S., Farah C., Roy J., Finan A., Rodrigues de Araujo G., Bideaux P. et al. Early calcium handling imbalance in pressure overload-induced heart failure with nearly normal left ventricular ejection fraction. Biochim. Biophys. Acta Mol. Basis Dis. 2019;1865(1):230−242. DOI: 10.1016/j.bbadis.2018.08.005.

37. De Genst E., Foo K.S., Xiao Y., Rohner E., de Vries E., Sohlmér J. et al. Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure. Nat. Commun. 2022;13(1):3018. DOI: 10.1038/s41467-022-29703-9.

38. Maruyama K., Imanaka-Yoshida K. The Pathogenesis of Cardiac Fibrosis: A Review of Recent Progress. Int. J. Mol. Sci. 2022;23(5):2617. DOI: 10.3390/ijms23052617.

39. Budde H., Hassoun R., Mügge A., Kovács Á., Hamdani N. Current understanding of molecular pathophysiology of heart failure with preserved ejection fraction. Front. Physiol. 2022 July7;13: 928232. DOI: 10.3389/fphys.2022.928232.

40. Zile M.R., Baicu C.F., Gaasch W.H. Diastolic heart failure – abnormalities in active relaxation and passive stiffness of the left ventricle. N. Engl. J. Med. 2004;350(19):1953−1959. DOI: 10.1056/NEJMoa032566/

41. Калюжин В.В., Тепляков А.Т., Беспалова И.Д., Калюжина Е.В., Черногорюк Г.Э., Терентьева Н.Н. и др. Диастолическая сердечная недостаточность: границы применения термина. Бюллетень сибирской медицины. 2023;22(1):113– 120. DOI: 10.20538/1682-0363-2023-1-113-120.

42. Беленков Ю.Н., Агеев Ф.Т., Мареев В.Ю. Знакомьтесь: диастолическая сердечная недостаточность. Журнал сердечная недостаточность. 2000;1(2):40–44.

43. Zile M.R. Heart failure with preserved ejection fraction: is this diastolic heart failure? J. Am. Coll. Cardiol. 2003;41(9):1519−1522. DOI: 10.1016/s0735-1097(03)00186-4.

44. Калюжин В.В., Тепляков А.Т., Черногорюк Г.Э., Калюжина Е.В., Беспалова И.Д., Терентьева Н.Н. и др. Хроническая сердечная недостаточность: синдром или заболевание? Бюллетень сибирской медицины. 2020;19(1):134–139. DOI: 10.20538/1682-0363-2020-1-134–139.

45. Mashali M.A., Saad N.S., Canan B.D., Elnakish M.T., Milani-Nejad N., Chung J.H. et al. Impact of etiology on force and kinetics of left ventricular end-stage failing human myocardium. J. Mol. Cell. Cardiol. 2021;156:7−19. DOI: 10.1016/j.yjmcc.2021.03.007.

46. Triposkiadis F., Xanthopoulos A., Parissis J., Butler J., Farmakis D. Pathogenesis of chronic heart failure: cardiovascular aging, risk factors, comorbidities, and disease modifiers. Heart Fail. Rev. 2022;27(1):337−344. DOI: 10.1007/s10741-020-09987-z.

47. Fayol A., Wack M., Livrozet M., Carves J.B., Domengé O., Vermersch E. et al. Aetiological classification and prognosis in patients with heart failure with preserved ejection fraction. ESC Heart Fail. 2022;9(1):519−530. DOI: 10.1002/ehf2.13717.

48. Калюжин В.В., Тепляков А.Т., Беспалова И.Д., Калюжина Е.В., Терентьева Н.Н., Гракова Е.В. и др. Перспективные направления лечения хронической сердечной недостаточности: совершенствование старых или разработка новых? Бюллетень сибирской медицины. 2022;21(3):181−197. DOI: 10.20538/1682-0363-2022-3-181-197.

49. Капелько В.И. Почему расслабление миокарда всегда замедляется при патологии сердца? Кардиология. 2019;59(12):44−51. DOI: 10.18087/cardio.2019.12.n801.

50. Калюжин В.В., Тепляков А.Т., Соловцов М.А. Роль систолической и диастолической дисфункции ЛЖ в клинической манифестации хронической сердечной недостаточности у больных, перенесших инфаркт миокарда. Терапевтический архив. 2002;74(12):15−18.

51. Капелько В.И. Диастолическая дисфункция. Кардиология. 2011;51(1):79−90.

52. Bronzwaer J.G., Paulus W.J. Matrix, cytoskeleton, or myofilaments: which one to blame for diastolic left ventricular dysfunction? Prog. Cardiovasc. Dis. 2005;47(4):276−284. DOI: 10.1016/j.pcad.2005.02.003.

53. Münch J., Abdelilah-Seyfried S. Sensing and responding of cardiomyocytes to changes of tissue stiffness in the diseased heart. Front. Cell Dev. Biol. 2021Feb.26;9:642840. DOI: 10.3389/fcell.2021.642840.

54. Капелько В.И. Роль саркомерного белка титина в насосной функции сердца. Успехи физиологических наук. 2022;53(2):39−53. DOI: 10.31857/S0301179822020059.

55. Wadmore K., Azad A.J., Gehmlich K. The role of Z-disc proteins in myopathy and cardiomyopathy. Int. J. Mol. Sci. 2021March17;22(6):3058. DOI: 10.3390/ijms22063058.

56. Van Wijk S.W., Su W., Wijdeveld L.F.J.M., Ramos K.S., Brundel B.J.J.M. Cytoskeletal protein variants driving atrial fibrillation: potential mechanisms of action. Cells. 2022;11(3):416. DOI: 10.3390/cells11030416.

57. Wang Z., Grange M., Pospich S., Wagner T., Kho A.L., Gautel M. et al. Structures from intact myofibrils reveal mechanism of thin filament regulation through nebulin. Science. 2022Feb.18;375(6582):eabn1934. DOI: 10.1126/science.abn1934.

58. Granzier H.L., Irving T.C. Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys. J. 1995;68(3):1027−1044. DOI: 10.1016/S0006-3495(95)80278-X.

59. Fukuda N., Granzier H., Ishiwata S., Morimoto S. Editorial: recent advances on myocardium physiology. Front. Physiol. 2021May26;12:697852. DOI: 10.3389/fphys.2021.697852.

60. Herzog W. What can we learn from single sarcomere and myofibril preparations? Front. Physiol. 2022Apr.27;13:837611. DOI: 10.3389/fphys.2022.837611.

61. Labeit S., Kolmerer B., Linke W.A. The giant protein titin. Emerging roles in physiology and pathophysiology. Circ. Res. 1997;80(2):290−294. DOI: 10.1161/01.res.80.2.290.

62. Azad A., Poloni G., Sontayananon N., Jiang H., Gehmlich K. The giant titin: how to evaluate its role in cardiomyopathies. J. Muscle Res. Cell Motil. 2019;40(2):159−167. DOI: 10.1007/s10974-019-09518-w.

63. Helmes M., Trombitás K., Granzier H. Titin develops restoring force in rat cardiac myocytes. Circ. Res. 1996;79(3):619−626. DOI: 10.1161/01.res.79.3.619.

64. Linke W.A. Titin gene and protein functions in passive and active muscle. Annu. Rev. Physiol. 2018Feb.10 80:389−411. DOI: 10.1146/annurev-physiol-021317-121234.

65. Овчинников А.Г., Потехина А.В., Ожерельева М.В., Агеев Ф.Т. Дисфункция левого желудочка при гипертоническом сердце: современный взгляд на патогенез и лечение. Кардиология. 2017;57(S2):367–382. DOI: 10.18087/cardio.2393.

66. Najafi A., van de Locht M., Schuldt M., Schönleitner P., van Willigenburg M., Bollen I. et al. End-diastolic force pre-activates cardiomyocytes and determines contractile force: role of titin and calcium. J. Physiol. 2019;597(17):4521−4531. DOI: 10.1113/JP277985.

67. Koser F., Loescher C., Linke W.A. Posttranslational modifications of titin from cardiac muscle: how, where, and what for? FEBS J. 2019;286(12):2240−2260. DOI: 10.1111/febs.14854.

68. Trombitás K., Wu Y., Labeit D., Labeit S., Granzier H. Cardiac titin isoforms are coexpressed in the half-sarcomere and extend independently. Am. J. Physiol. Heart Circ. Physiol. 2001;281(4):H1793−H1799. DOI: 10.1152/ajpheart.2001.281.4.H1793.

69. Van Heerebeek L., Borbély A., Niessen H.W., Bronzwaer J.G., van der Velden J., Stienen G.J. et al. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006;113(16):1966−1973. DOI: 10.1161/CIRCULATIONAHA.105.587519.

70. Katz A.M., Zile M.R. New molecular mechanism in diastolic heart failure. Circulation. 2006;113(16):1922−1925. DOI: 10.1161/CIRCULATIONAHA.106.620765.

71. Калюжин В.В., Тепляков А.Т., Соловцов М.А., Калюжина Е.В., Беспалова И.Д., Терентьева Н.Н. Ремоделирование левого желудочка: один или несколько сценариев? Бюллетень сибирской медицины. 2016;15(4):120−139. DOI: 10.20538/1682-0363-2016-4-120-139.

72. Lewis G.A., Schelbert E.B., Williams S.G., Cunnington C., Ahmed F., McDonagh T.A. et al. Biological phenotypes of heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 2017;70(17):2186−2200. DOI: 10.1016/j.jacc.2017.09.006.

73. Neagoe C., Kulke M., del Monte F., Gwathmey J.K., de Tombe P.P., Hajjar R.J. et al. Titin isoform switch in ischemic human heart disease. Circulation. 2002;106(11):1333−1341. DOI: 10.1161/01.cir.0000029803.93022.93.

74. Wu Y., Bell S.P., Trombitas K., Witt C.C., Labeit S., LeWinter M.M. et al. Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation. 2002;106(11):1384−1389. DOI: 10.1161/01.cir.0000029804.61510.02.

75. Lahmers S., Wu Y., Call D.R., Labeit S., Granzier H. Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ. Res. 2004;94(4):505−513. DOI: 10.1161/01.RES.0000115522.52554.86.

76. Weeland C.J., van den Hoogenhof M.M., Beqqali A., Creemers E.E. Insights into alternative splicing of sarcomeric genes in the heart. J. Mol. Cell. Cardiol. 2015Apr.;81:107−113. DOI: 10.1016/j.yjmcc.2015.02.008.

77. Eldemire R., Tharp C.A., Taylor M.R.G., Sbaizero O., Mestroni L. The sarcomeric spring protein titin: biophysical properties, molecular mechanisms, and genetic mutations associated with heart failure and cardiomyopathy. Curr. Cardiol. Rep. 2021;23(9):121. DOI: 10.1007/s11886-021-01550-y.

78. Kötter S., Krüger M. Protein quality control at the sarcomere: titin protection and turnover and implications for disease development. Front. Physiol. 2022Juny30;13:914296. DOI: 10.3389/fphys.2022.914296.

79. Krüger M., Linke W.A. Titin-based mechanical signalling in normal and failing myocardium. J. Mol. Cell. Cardiol. 2009;46(4):490−498. DOI: 10.1016/j.yjmcc.2009.01.004.

80. Anderson B.R., Granzier H.L. Titin-based tension in the cardiac sarcomere: molecular origin and physiological adaptations. Prog. Biophys. Mol. Biol. 2012;110(2-3):204−217. DOI: 10.1016/j.pbiomolbio.2012.08.003.

81. Radke M.H., Polack C., Methawasin M., Fink C., Granzier H.L., Gotthardt M. Deleting full length titin versus the titin m-band region leads to differential mechanosignaling and cardiac phenotypes. Circulation. 2019;139(15):1813−1827. DOI: 10.1161/CIRCULATIONAHA.118.037588.

82. Zhu C., Yin Z., Ren J., McCormick R.J., Ford S.P., Guo W. RBM20 is an essential factor for thyroid hormone-regulated titin isoform transition. J. Mol. Cell. Biol. 2015;7(1):88−90. DOI: 10.1093/jmcb/mjv002.

83. Борисов А.А., Гвоздева А.Д., Агеев Ф.Т. Сердечная недостаточность с сохраненной фракцией выброса у пациентов с сахарным диабетом 2 типа: от патогенеза к лечению. Медицинский вестник Юга России. 2021;12(2):6−15. DOI: 10.21886/2219-8075-2021-12-2-6-15.

84. Krüger M., Babicz K., von Frieling-Salewsky M., Linke W.A. Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy. J. Mol. Cell. Cardiol. 2010May;48(5): 910−916. DOI: 10.1016/j.yjmcc.2010.02.012.

85. Zhu C., Yin Z., Tan B., Guo W. Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR kinase axis in a RBM20-dependent manner. Biochim. Biophys. Acta Mol. Basis Dis. 2017;1863(9):2363−2371. DOI: 10.1016/j.bbadis.2017.06.023.

86. Bernal J., Pitta S.R., Thatai D. Role of the renin-angiotensin-aldosterone system in diastolic heart failure: potential for pharmacologic intervention. Am. J. Cardiovasc. Drugs. 2006;6(6):373−381. DOI: 10.2165/00129784-200606060-00004.

87. Останко В.Л., Калачева Т.П., Калюжина Е.В., Лившиц И.К., Шаловай А.А., Черногорюк Г.Э., Беспалова И.Д. и др. Биологические маркеры в стратификации риска развития и прогрессирования сердечно-сосудистой патологии: настоящее и будущее. Бюллетень сибирской медицины. 2018;17(4):264−280. DOI: 10.20538/1682-0363-2018-4-264-280.

88. Cai H., Zhu C., Chen Z., Maimaiti R., Sun M., McCormick R.J. et al. Angiotensin II Influences Pre-mRNA splicing regulation by enhancing RBM20 transcription through activation of the MAPK/ELK1 signaling pathway. Int. J. Mol. Sci. 2019;20(20):5059. DOI: 10.3390/ijms20205059.

89. Rocha R., Almeida-Coelho J., Leite-Moreira A.M., Neves J.S., Hamdani N., Falcão-Pires I. et al. Titin phosphorylation by protein kinase G as a novel mechanism of diastolic adaptation to acute load: PS146. Porto Biomed. J. 2017;2(5):185. DOI: 10.1016/j.pbj.2017.07.024.

90. Michel K., Herwig M., Werner F., Špiranec Spes K., Abeßer M., Schuh K. et al. C-type natriuretic peptide moderates titin-based cardiomyocyte stiffness. JCI Insight. 2020Nov.19;5(22):e139910. DOI: 10.1172/jci.insight.139910.

91. Herwig M., Kolijn D., Lódi M., Hölper S., Kovács Á., Papp Z. et al. Modulation of titin-based stiffness in hypertrophic cardiomyopathy via protein kinase D. Front. Physiol. 2020Apr.15;11:240. DOI: 10.3389/fphys.2020.00240.

92. Murphy S., Frishman W.H. Protein kinase C in cardiac disease and as a potential therapeutic target. Cardiol. Rev. 2005;13(1):3−12. DOI: 10.1097/01.crd.0000124914.59755.8d.

93. Hidalgo C., Hudson B., Bogomolovas J., Zhu Y., Anderson B., Greaser M., Labeit S. et al. PKC phosphorylation of titin’s PEVK element: a novel and conserved pathway for modulating myocardial stiffness. Circ. Res. 2009;105(7):631–638. DOI: 10.1161/CIRCRESAHA.109.198465.

94. Soetkamp D., Gallet R., Parker S.J., Holewinski R., Venkatraman V., Peck K. et al. Myofilament phosphorylation in stem cell treated diastolic heart failure. Circ. Res. 2021;129(12):1125−1140. DOI: 10.1161/CIRCRESAHA.119.316311.

95. Krysiak J., Unger A., Beckendorf L., Hamdani N., von Frieling-Salewsky M., Redfield M.M. et al. Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes. Nat. Commun. 2018Jan.17;9(1):262. DOI: 10.1038/s41467-017-02483-3.

96. Manilall A., Mokotedi L., Gunter S., Le Roux R., Fourie S., Flanagan C.A. et al. Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats. BMC Cardiovasc. Disord. 2022Dec.9;22(1):539. DOI: 10.1186/s12872-022-02977-z.

97. Gömöri K., Herwig M., Budde H., Hassoun R., Mostafi N., Zhazykbayeva S. et al. Ca2+/calmodulin-dependent protein kinase II and protein kinase G oxidation contributes to impaired sarcomeric proteins in hypertrophy model. ESC Heart Fail. 2022;9(4):2585−2600. DOI: 10.1002/ehf2.13973.

98. Bevere M., Morabito C., Mariggiò M.A., Guarnieri S. The oxidative balance orchestrates the main keystones of the functional activity of cardiomyocytes. Oxid. Med. Cell. Longev. 2022Jan.10;2022:7714542. DOI: 10.1155/2022/7714542.

99. Nagueh S.F. Heart failure with preserved ejection fraction: insights into diagnosis and pathophysiology. Cardiovasc. Res. 2021;117(4): 999−1014. DOI: 10.1093/cvr/cvaa228.

100. Røe Å.T., Ruud M., Espe E.K., Manfra O., Longobardi S., Aronsen J.M. et al. Regional diastolic dysfunction in post-infarction heart failure: role of local mechanical load and SERCA expression. Cardiovasc. Res. 2019; 15(4):752−764. DOI: 10.1093/cvr/cvy257.

101. Eisner D.A., Caldwell J.L., Trafford A.W., Hutchings D.C. the control of diastolic calcium in the heart: basic mechanisms and functional implications. Circ. Res. 2020;126(3):395−412. DOI: 10.1161/CIRCRESAHA.119.315891.

102. Granzier H., Labeit S. Cardiac titin: an adjustable multi-functional spring. J. Physiol. 2002;541(Pt2):335−342. DOI: 10.1113/jphysiol.2001.014381.

103. Liu C., Lai Y., Pei J., Huang H., Zhan J., Ying S. et al. Clinical and genetic analysis of KATP variants with heart failure risk in patients with decreased serum ApoA-I levels. J. Clin. Endocrinol. Metab. 2021;106(8):2264−2278. DOI: 10.1210/clinem/dgab336.

104. Liu C., Lai Y., Guan T., Zhan J., Pei J., Wu D. et al. Associations of ATP-sensitive potassium channel’s gene polymorphisms with type 2 diabetes and related cardiovascular phenotypes. Front. Cardiovasc. Med. 2022March23;9:816847. DOI: 10.3389/fcvm.2022.816847.