Contractile Function of Isolated Hearts With Preserved and Reduced Ejection Fraction In Vivo

The aim of the study was comparison of contractile function of isolated hearts of rats with doxorubicin-induced myocardial injury which were tentatively divided according to the level of ejection fraction determined by echocardiography in vivo. After 4 weeks of doxorubicin administration (2 mg/kg subcutaneously once a week) about half of animals had normal (86±1%) and the other half reduced (61±4%) ejection fraction. The first group was defined as diastolic heart failure (DHF) and the other as systolic (SHF). The maximal pressure developed by the isolated heart in isovolumic mode was reduced in DHF by 13%, and in SHF by 34%. The relaxation index in both groups was lowed by 22-24%. Both groups were characterized by a decline in the ability to raise developed pressure while increasing coronary perfusion pressure, as well as by the loss of the ability of coronary vessels to maintain a stable flow rate while increasing perfusion pressure. The hearts of control animals were able to raise the cardiac work index (the product of developed pressure and heart rate) during prolonged high frequency (7-9 Hz) stimulation, while the two groups treated with doxorubicin reduced the level of this index. The content of basic energy metabolites (ATP, phosphocreatine, creatine) in both groups was reduced by 20-38%. The results showed that the hearts in DHF and SHF groups showed approximately the same level of reduction of the contractile function and energy metabolism, and hence their difference in vivo was probably due to varying degrees of mobilization of compensatory mechanisms.

доксорубицин, сердечная недостаточность, миокард, сократимость, расслабимость, изолированное сердце, doxorubicin, heart failure, myocardium, contractility, relaxability, isolated heart

1. Ingwall J. S. Energy metabolism in heart failure and remodeling. Cardiovascular Research 2009;81:412-419.

2. Doenst T., Dung Nguyen T., Dale Abel E. Cardiac Metabolism in Heart Failure - Implications beyond ATP production. Circ Res 2013;113 (6):709-724. doi:10.1161/CIRCRESAHA.113.300376.

3. Ventura-Clapier R., Garnier A., Veksler V. Energy metabolism in heart failure. J Physiol 2004;555:1-13.

4. Huss J. M., Kelly D. P. Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 2005;115:547-555.

5. Lygate C. A. and Neubauer S. Metabolic flux as a predictor of heart failure prognosis. Circ Res 2014;114 (8):1228-1230. DOI:10.1161 / CIRCRESAHA.114.303551

6. Hafstad A. D., Nabeebaccus A. A., Ajay M. Shah A. M. Novel aspects of ROS signalling in heart failure. Basic Res Cardiol 2013;108:359. DOI: 10.1007/s00395-013-0359-8

7. Giordano F.J. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 2005;115:500-558.

8. Practical methods in cardiovascular research. S. Dhein, F. W. Mohr, M. Delmar (Eds). Springer-Verlag, Berlin Heidelberg, 2005.

9. Kapelko V. I., Lakomkin V. L., Lakoshkova E. V. et al. Complex study of the rat heart at Isoproterenol damage. Kardiologiia 2014;54 (3):46-56. Russian (Капелько В. И., Лакомкин В. Л., Лукошкова Е. В. и др. Комплексное исследование сердца крыс при поражении изопротеренолом. Кардиология 2014;54 (3):46-56).

10. Lakomkin V. L., Abramov A. A., Gramovich V. V. et al. The time course of formation of systolic dysfunction of the heart in doxorubicin cardiomyopathy. Kardiologiia 2017;57 (1):59-64. Russian (Лакомкин В. Л., Абрамов А. А., Грамович В. В. и др. Динамика формирования систолической дисфункции сердца при доксорубициновой кардиомиопатии. Кардиология 2017;57 (1):59-64).

11. Pelikan P. C. D., Weisfeldt M. L., Jacobus W. E. et al. Acute doxorubicin cardiotoxicity: functional, metabolic and morphologic alteration in the isolated rat heart. J Cardiovasc Pharmacol 1986;8:1058-1066.

12. Lamprecht W., Stein P., Heinz F. et al. Creatine Phosphate. Methods of enzymatic analysis. Ed. Bergmeyer H. U. 2nd ed. N. Y.: Academic Press, 1974. V. 4. P. 1777-1781.

13. Jaworek D., Gruber W., Bergmeyer H. U. Adenosine-5'-diphosphate and Adenosine-5'-monophosphate. Methods of enzymatic analy sis. Ed. Bergmeyer H. U. 2nd ed. N. Y.: Academic Press, 1974. V. 4. P. 2127-2131.

14. Bernt E., Bergmeyer H. U., Mollering H. Creatine. Methods of enzymatic analysis. Ed. Bergmeyer H. U. 2nd ed. N. Y.: Academic Press, 1974. V. 4. P. 1772-1776.

15. Gutman I., Wahlenfeld A. W. L. L-(+)-Lactate. Methods of enzymatic analysis. Ed. Bergmeyer H. U. 2nd ed. N. Y.: Academic Press, 1974. V. 3. P. 1464-1467.

16. Uchiyama M., Mihara M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Analyt Biochem 1978;23:271-278.

17. Kapelko V. I., Saks V. A., Novikova N. A. et al. Adaptation of the cardiac contractile function to conditions of chronic energy deficiency. J Mol Cell Cardiol 1989;21 (suppl 1):79-83.

18. Kapel'ko V. I., Novikova N. A., Kupriianov V. V., Sake V. A. Role of creatine phosphokinase in the energy supply of the pumping function of the heart. Fiziol Zh 1991; 37 (6): 3-9. Russian (Капелько В. И., Новикова Н. А., Куприянов В. В., Сакс В. А. Ключевая роль креатинфосфокиназы в энергобеспечении насосной функции сердца. Физиол жур 1991;37 (6):3-9).

19. Kruger M., Linke W. A. Titin-based mechanical signalling in normal and failing myocardium. J Mol Cell Cardiol 2009;46:490-498.

20. Hamdani N., Herwig M., Linke W. A. Tampering with springs: phosphorylation of titin affecting the mechanical function of cardiomyocytes. Biophys Rev 2017;9 (3):225-237.

21. Sequeira V., Najafi A., McConnell M. et al. Synergistic role of ADP and Ca(2+) in diastolic myocardial stiffness. J Physiol 2015;593 (17):3899-3916.

22. Makarenko I., Opitz C. A., Leake M. C. et al. Passive Stiffness Changes Caused by Upregulation of Compliant Titin Isoforms in Human Dilated Cardiomyopathy Hearts. Circul Res 2004;95:708-716.

23. Farah C., Nascimento A., Bolea G. et al. Key role of endothelium in the eNOS-depen dent cardioprotection with exercise training. J Mol Cell Cardiol 2017;102:26-30. )