EFFICACY OF IVABRADINE THERAPY ON RIGHT HEART PARAMETERS AND PROGNOSIS IN PATIENTS WITH SEVERE SYSTOLIC CHRONIC HEART FAILURE

The aim of study was to assess the efficacy of ivabradine (I, up to 15 mg) therapy on prognosis, right ventricular (RV) and atrial (RA) functional parameters, BNP, NT-pro-BNP and high sensitivity С reactive protein (CRP) levels in patients (pts) with III- IV NYHA FC systolic CHF. Methods. 76 pts with DCM (age 57.4) were randomly assigned to groups A (n=38, non receiving ivabradin, I) and group В (n=38, receiving I, 15 mg) in addition to ACEIs, diuretics, beta-blockers and digoxin. 1-, 2- and З-year mortality were 34.2, 39.5 and 50% in group A and 21.1, 28.9 and 39.5% in group B. Survival analysis revealed lower probability of 1-year, 2-year and З-year mortality (RR reduction at 38.3,26.8 and 21%) in pts, treated with I (p<0.05) compared to group A. Combined use of I and beta-blockers has resulted to significant improvement of symptoms and right heart functional parameters, decrease of BNP., NT-pro-BNP and CRP levels after 3 months of therapy with further improvement to 6, 12, 24 and 36 months. Conclusions. 1) Decrease of BNP, NT-pro-BNP >50%, hsCRP>40% and HR>40% and increase of RV EF and E/A at >25%, TAPSE>50% and RA functional index >60% after 1 year identified pts with cardiac events reduction. 2) Prognostic benefit, associated with I use, seems to be related to improvement of right heart parameters, neurohormonal and inflammation status and HR reduction.

хроническая сердечная недостаточность, правый желудочек, правое предсердие, прогноз, мозговой натрийуретический пептид, NT-промозговой натрийуретический пептид высокочувствительный С-реактивный белок, ивабрадин, chronic heart failure, rightventriculum, right atrium, prognosis, BNP, NT-proBNP, high sensitivity С reactive protein, ivabradine

1. Kjekshus J., Gullestad L. Heart rate as a therapeutic target in heart failure. Eur Heart J. 1999; 1: H64-H69.

2. Sajadieh A., Nielsen O.W., Rasmussen V., et al. Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J. 2004; 25: 363-370.

3. Giannoglou G.D., Chatzizisis Y.S., Zamboulis C., et al. Elevated heart rate and atherosclerosis: an overview of the pathogenetic mechanisms. Int J. Cardiol 2008; 126: 302-312.

4. Packer M., Bristow M.R., Cohn J.N. et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J. Med 1996; 334: 1349-1355.

5. CIBIS Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9-13.

6. Guyatt G.H., Sullivan M.S., Thompson P.J., et al. The six-minute walk: a new measure of exercise 6pacity in patients with chronic heart failure. Can Med Assoc J. 1985; 132, No 8: 919-923.

7. Lechat P., Garnham S.P., Desche P., Bounhoure J.-P. Efficacy and acceptability of perindopril in mild to moderate chronic congestive heart failure. Am Heart J. 1996; 126, No3: 798-806.

8. Gheorghiade M., Follath F., Ponikowski P. et al. Assessing and grading congestion in acute heart failure: a scientific statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine. European Journal of Heart Failure (2010) 12, 423-433.

9. Gottdiener J.S., Bednarz J., Devereux R., et al. American Society of Echocardiography. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J. Am Soc Echocardiogr 2004; 17: 1086-119.

10. Galderisi M., Henei M., D'hooge J., et al. On behalf of the European Association of Echocardiography. Recommendations of the European Association of Echocardiography. How to use echo-Doppler in clinical trials: different modalities for different purposes. European Journal of Echocardiography (2011) 12, 339-353.

11. Joyce J.J., Denslow S., Kline C.H., et al. Estimation of right ventricular free-wall mass using two-dimensional echocardiography. Pediatr Cardiol 2001; 22(4): 306-14.)

12. Tei C., Dujardin K.S., Hodge D.O., et al. Doppler echocardiographic index for assessment of global right ventricular function. J. Am Soc Echocardiogr 1996; 9: 838-47.

13. Zoghbi W.A., Habib G.B., Quinones M.A. Doppler assessment of right ventricular filling in a normal population. Circulation 1990; 82: 1316-24.

14. Tumasyan L.R., Adamyan K.G. Comparative efficacy of carvedilol and ivabradine in severe chronic heart failure of ischemic origin with baseline heart rate below and above 70 beat per minute. European Heart Journal 2009; Vol. 30, (Abstract Supplement): p. 427.

15. Dedkov E.l., Zheng W., Christensen L.P., Weiss R.M., et al. Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen. Am J. Physiol Heart Circ Physiol 2007; 293: H590-H598.

16. Christensen L.P., Zhang R.L., Zheng W., et al. Postmyocardial infarction remodeling and coronary reserve: effects of ivabradine and beta blockade therapy. Am J. Physiol Heart Circ Physiol 2009; 297: H322-H330.

17. Lucats L., Ghaleh B., Monnet X., et al. Conversion of postsystolic wall thickening into ejectional thickening by selective heart rate reduction during myocardial stunning. Eur Heart J. 2007; 28: 872-879.

18. Tumasyan L.R., Adamyan K.G. Comparative efficacy of carvedilol and ivabradine in severe chronic heart failure of ischemic origin with baseline heart rate below and above 70 beat per minute. European Heart Journal 2009; Vol. 30, (Abstract Supplement): p. 427.

19. Fox K., Ford I., Steg Ph., et al. on behalf of the BEAUTIFUL Investigators. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. European Heart Journal (2009) 30, 2337-2345.

20. DiFrancesco D. Cardiac pacemaker I (f) current and its inhibition by heart rate reducing agents. Curr Med Res Opin 2005; 21: 1115-1122.

21. Cerbai E., Sartiani L., DePaoli P., et al. The properties of the pacemaker current I(F) in human ventricular myocytes are modulated by cardiac disease. J. Mol Cell Cardiol 2001; 33: 441-448.

22. Michels G., Brandt M.C., Zagidullin N., Khan I.F., et al. Direct evidence for calcium conductance of hyperpolarization-activated cyclic nucleotide-gated channels and human native If at physiological calcium concentrations. Cardiovasc Res 2008; 78: 466-475.

23. Tumasyan L.R., Adamyan K.G., Chilingaryan A.L. Efficacy of ivabradine therapy on right heart parameters and prognosis in patients with severe systolic chronic heart failure. European Heart Journal 2012; Vol. 33. (Abstract Supplement), N 88618.

24. Maczewski M., Mackiewicz U. Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart. Cardiovasc Res 2008; 79: 42-51.

25. Tumasyan L.R., Nargizyan A.B., Adamyan K.G. Independent and additive influence of carvedilol and ivabradine on long-term prognosis in patients with severe chronic heart failure of ischemic origin. European Heart Journal (2008), 29 (Abstract Supplement), p. 769.

26. Schulz R., Rose J., Skyschally A., Heusch G. Bradycardic agent UL-FS 49 attenuates ischemic regional dysfunction and reduces infarct size in swine: comparison with the beta-blocker atenolol. J. Cardiovasc Pharmacol 1995; 25: 216-228.

27. Heusch G. Pleiotropic action(s) of the bradycardic agent ivabradine: cardiovascular protection beyond heart rate reduction. Br J. Pharmacol 2008; 155: 970-971.