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01.06.2014 | Original Paper | Ausgabe 6/2014

Ivabradine therapy to unmask heart rate-independent effects of β-blockers on pulse wave reflections

Zeitschrift:: Clinical Research in Cardiology > Ausgabe 6/2014

Autoren:: Ulrich Fischer-Rasokat, Jörg Honold, Denise Lochmann, Christoph Liebetrau, Jürgen Leick, Christian Hamm, Stephan Fichtlscherer, Helge Möllmann, Ioakim Spyridopoulos

Abstract

Background

Prior studies suggest that β-blockers lead to increased pulse wave reflections, thereby negating the blood pressure lowering effects on cardiovascular mortality. Parts of these effects may be induced by the heart rate reduction under β-blockade. The aim of this study was to unmask heart rate-independent effects of β-blockade on pulse wave reflections by switching therapy from β-blockers to ivabradine, an I _f channel inhibitor without impact on systemic hemodynamics.

Methods

14 male patients (age 61 ± 3 years, LVEF 62 ± 1 %) with arterial hypertension and coronary artery disease (CAD) under chronic β-blocker therapy at moderate dosage and additional renin-angiotensin system-blocking therapy were included. We determined radial augmentation index (rAI) by radial applanation tonometry in patients under β-blockade both at rest and during early recovery after exercise. β-Blockers were then replaced by ivabradine. Six weeks later, patients were re-tested at rest and after exercise under ivabradine therapy.

Results

Mean heart rate (68 ± 3 vs. 63 ± 3 bpm; p = ns) and resting mean arterial pressure (98 ± 2 vs. 98 ± 2 mmHg; p = ns) were not different between β-blocker or ivabradine therapy, respectively. The rAI remained unchanged after switching therapy from β-blocker to ivabradine (86 ± 2 vs. 84 ± 4 %; p = ns). Post exercise, the rAI revealed an identical decrease in both groups (−7.2 ± 2.4 vs. −5.4 ± 2.5 %, p = ns). The increase in heart rate between resting conditions and early recovery post exercise was inversely correlated with the decrease of rAI under β-blockade (r = −0.70; p < 0.01) and showed a trend towards correlation under ivabradine (r = −0.52; p = 0.07).

Conclusion

In men at the age of 60 years and CAD, β-blockade does not exert heart rate-independent, pleiotropic effects on peripheral pulse wave reflections, both at rest or after exercise. Our results fit well within recent studies, demonstrating the fundamental influence of heart rate on rAI.

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Mancia G, Fagard R, Narkiewicz K, Redon J et al (2013) 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 34(28):2159–2219 PubMedCrossRef

Montalescot G, Sechtem U, Achenbach S, Andreotti F et al (2013) ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 34(38):2949–3003

Dahlof B, Devereux RB, Kjeldsen SE, Julius S et al (2002) Cardiovascular morbidity and mortality in the Losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359(9311):995–1003 PubMedCrossRef

Bangalore S, Messerli FH, Kostis JB, Pepine CJ (2007) Cardiovascular protection using beta-blockers: a critical review of the evidence. J Am Coll Cardiol 50(7):563–572 PubMedCrossRef

Bangalore S, Steg G, Deedwania P, Crowley K et al (2012) Beta-blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 308(13):1340–1349 PubMedCrossRef

Williams B, Lacy PS, Thom SM, Cruickshank K et al (2006) Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 113(9):1213–1225 PubMedCrossRef

Casey DP, Curry TB, Joyner MJ, Charkoudian N et al (2012) Acute beta-adrenergic blockade increases aortic wave reflection in young men and women: differing mechanisms between sexes. Hypertension 59(1):145–150 PubMedCentralPubMedCrossRef

Borer JS, Le Heuzey JY (2008) Characterization of the heart rate-lowering action of ivabradine, a selective I(f) current inhibitor. Am J Ther 15(5):461–473 PubMedCrossRef

Vilaine JP (2006) The discovery of the selective I(f) current inhibitor ivabradine. A new therapeutic approach to ischemic heart disease. Pharmacol Res 53(5):424–434 PubMedCrossRef

10.

Heusch G, Skyschally A, Gres P, van Caster P et al (2008) Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction. Eur Heart J 29(18):2265–2275 PubMedCrossRef

11.

Taylor J (2012) The 2012 ESC Guidelines on Heart Failure. Eur Heart J 33(14):1703–1704 PubMedCrossRef

12.

Bohm M, Borer J, Ford I, Gonzalez-Juanatey JR et al (2013) Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol 102(1):11–22 PubMedCrossRef

13.

Werdan K, Ebelt H, Nuding S, Hopfner F et al (2012) Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study. Clin Res Cardiol 101(5):365–373 PubMedCrossRef

14.

Fischer-Rasokat U, Brenck F, Zeiher AM, Spyridopoulos I (2009) Radial augmentation index unmasks premature coronary artery disease in younger males. Blood Press Monit 14(2):59–67 PubMedCrossRef

15.

Nichols WW (2005) Clinical measurement of arterial stiffness obtained from noninvasive pressure waveforms. Am J Hypertens 18(1 Pt 2):3S–10S PubMedCrossRef

16.

Wilkinson IB, MacCallum H, Flint L, Cockcroft JR et al (2000) The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol 525(Pt 1):263–270 PubMedCentralPubMedCrossRef

17.

Casey DP, Curry TB, Charkoudian N, Joyner MJ et al (2013) The effects of acute beta-adrenergic blockade on aortic wave reflection in postmenopausal women. Am J Hypertens 26(4):503–510 PubMedCentralPubMedCrossRef

18.

Millasseau SC, Patel SJ, Redwood SR, Ritter JM et al (2003) Pressure wave reflection assessed from the peripheral pulse: is a transfer function necessary? Hypertension 41(5):1016–1020 PubMedCrossRef

19.

Hirata K, Kojima I, Momomura S (2013) Noninvasive estimation of central blood pressure and the augmentation index in the seated position: a validation study of two commercially available methods. J Hypertens 31(3):508–515 discussion 515 PubMedCrossRef

20.

Rezai MR, Goudot G, Winters C, Finn JD et al (2011) Calibration mode influences central blood pressure differences between SphygmoCor and two newer devices, the Arteriograph and Omron HEM-9000. Hypertens Res 34(9):1046–1051 PubMedCrossRef

21.

Morgan T, Lauri J, Bertram D, Anderson A (2004) Effect of different antihypertensive drug classes on central aortic pressure. Am J Hypertens 17(2):118–123 PubMedCrossRef

22.

Chen CH, Ting CT, Lin SJ, Hsu TL et al (1995) Different effects of fosinopril and atenolol on wave reflections in hypertensive patients. Hypertension 25(5):1034–1041 PubMedCrossRef

23.

Olafiranye O, Qureshi G, Salciccioli L, Weber M et al (2008) Association of beta-blocker use with increased aortic wave reflection. J Am Soc Hypertens 2(2):64–69 PubMedCrossRef

24.

Drouin A, Gendron ME, Thorin E, Gillis MA et al (2008) Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol 154(4):749–757 PubMedCentralPubMedCrossRef

25.

Custodis F, Baumhakel M, Schlimmer N, List F et al (2008) Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation 117(18):2377–2387 PubMedCrossRef

26.

Couvreur N, Tissier R, Pons S, Chetboul V et al (2010) Chronic heart rate reduction with ivabradine improves systolic function of the reperfused heart through a dual mechanism involving a direct mechanical effect and a long-term increase in FKBP12/12.6 expression. Eur Heart J 31(12):1529–1537 PubMedCentralPubMedCrossRef

27.

Yue-Chun L, Teng Z, Na-Dan Z, Li-Sha G et al (2012) Comparison of effects of ivabradine versus carvedilol in murine model with the Coxsackievirus B3-induced viral myocarditis. PLoS One 7(6):e39394 PubMedCentralPubMedCrossRef

28.

Busseuil D, Shi Y, Mecteau M, Brand G et al (2010) Heart rate reduction by ivabradine reduces diastolic dysfunction and cardiac fibrosis. Cardiology 117(3):234–242 PubMedCrossRef

29.

Becher PM, Lindner D, Miteva K, Savvatis K et al (2012) Role of heart rate reduction in the prevention of experimental heart failure: comparison between If-channel blockade and beta-receptor blockade. Hypertension 59(5):949–957 PubMedCrossRef

30.

Colin P, Ghaleh B, Monnet X, Su J et al (2003) Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol 284(2):H676–H682 PubMed

31.

Simon L, Ghaleh B, Puybasset L, Giudicelli JF et al (1995) Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther 275(2):659–666 PubMed

32.

Heusch G, Baumgart D, Camici P, Chilian W et al (2000) Alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 101(6):689–694 PubMedCrossRef

33.

Studinger P, Tabak AG, Chen CH, Salvi P et al (2013) The effect of low-dose carvedilol, nebivolol, and metoprolol on central arterial pressure and its determinants: a randomized clinical trial. J Clin Hypertens (Greenwich)

34.

Briasoulis A, Oliva R, Kalaitzidis R, Flynn C et al (2013) Effects of nebivolol on aortic compliance in patients with diabetes and maximal renin angiotensin system blockade: the EFFORT study. J Clin Hypertens (Greenwich) 15(7):473–479 CrossRef

35.

Eeftinck Schattenkerk DW, van den Bogaard B, Cammenga M, Westerhof BE et al (2013) Lack of difference between nebivolol/hydrochlorothiazide and metoprolol/hydrochlorothiazide on aortic wave augmentation and central blood pressure. J Hypertens

36.

Lund-Johansen P (1979) Hemodynamic consequences of long-term beta-blocker therapy: a 5-year follow-up study of atenolol. J Cardiovasc Pharmacol 1(5):487–495 PubMedCrossRef

37.

Asmar RG, Kerihuel JC, Girerd XJ, Safar ME (1991) Effect of bisoprolol on blood pressure and arterial hemodynamics in systemic hypertension. Am J Cardiol 68(1):61–64 PubMedCrossRef

38.

Ting CT, Chen CH, Chang MS, Yin FC (1995) Short- and long-term effects of antihypertensive drugs on arterial reflections, compliance, and impedance. Hypertension 26(3):524–530 PubMedCrossRef

39.

Heusch G (2008) Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol 153(8):1589–1601 PubMedCentralPubMedCrossRef

40.

Campbell R, Fisher JP, Sharman JE, McDonnell BJ et al (2011) Contribution of nitric oxide to the blood pressure and arterial responses to exercise in humans. J Hum Hypertens 25(4):262–270 PubMedCrossRef

41.

Doonan RJ, Scheffler P, Yu A, Egiziano G et al (2011) Altered arterial stiffness and subendocardial viability ratio in young healthy light smokers after acute exercise. PLoS One 6(10):e26151 PubMedCentralPubMedCrossRef

42.

Sugawara J, Komine H, Hayashi K, Maeda S et al (2007) Relationship between augmentation index obtained from carotid and radial artery pressure waveforms. J Hypertens 25(2):375–381 PubMedCrossRef

43.

Nurnberger J, Keflioglu-Scheiber A, Opazo Saez AM, Wenzel RR et al (2002) Augmentation index is associated with cardiovascular risk. J Hypertens 20(12):2407–2414 PubMedCrossRef

44.

van Trijp MJ, Bos WJ, Uiterwaal CS, Oren A et al (2004) Determinants of augmentation index in young men: the ARYA study. Eur J Clin Invest 34(12):825–830 PubMedCrossRef

45.

Weber T, Auer J, O’Rourke MF, Kvas E et al (2004) Arterial stiffness, wave reflections, and the risk of coronary artery disease. Circulation 109(2):184–189 PubMedCrossRef

46.

Mitchell GF, Parise H, Benjamin EJ, Larson MG et al (2004) Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension 43(6):1239–1245 PubMedCrossRef

47.

Fantin F, Mattocks A, Bulpitt CJ, Banya W et al (2007) Is augmentation index a good measure of vascular stiffness in the elderly? Age Ageing 36(1):43–48 PubMedCrossRef

48.

McEniery CM, Yasmin, Hall IR, Qasem A et al (2005) Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol 46(9):1753–60

Titel: Ivabradine therapy to unmask heart rate-independent effects of β-blockers on pulse wave reflections
Autoren:: Ulrich Fischer-Rasokat
Jörg Honold
Denise Lochmann
Christoph Liebetrau
Jürgen Leick
Christian Hamm
Stephan Fichtlscherer
Helge Möllmann
Ioakim Spyridopoulos
Publikationsdatum: 01.06.2014
DOI: https://doi.org/10.1007/s00392-014-0679-1
Verlag: Springer Berlin Heidelberg
Zeitschrift: Clinical Research in Cardiology
Ausgabe 6/2014
Print ISSN: 1861-0684
Elektronische ISSN: 1861-0692