Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Luong Le; Hayley Duckles; Torsten Schenkel; Marwa M. Mahmoud; Jordi L. Tremoleda; Marzena Wylezinska-Arridge; Majid Ali; Neil P. Bowden; Mari-Cruz Villa-Uriol; Kim Van der Heiden; Ruoyu Xing; Frank J. Gijsen; Jolanda J. Wentzel; Allan Lawrie; Shuang Feng; Nadine Arnold; Willy Gsell; Angela Lungu; Rodney Hose; Tim Spencer; Ian Halliday; Victoria Ridger; Paul C. Evans

doi:10.1160/TH16-03-0214

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2016; 116(01): 181-190
DOI: 10.1160/TH16-03-0214

Atherosclerosis and Ischaemic Disease

Schattauer GmbH

Heart rate reduction with ivabradine promotes shear stress-dependent anti-inflammatory mechanisms in arteries

Authors

Luong Le

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Hayley Duckles

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Torsten Schenkel

³Department of Engineering & Mathematics, Sheffield Hallam University, UK
Marwa M. Mahmoud

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Jordi L. Tremoleda

⁵Trauma Sciences, Queen Mary University of London, UK
Marzena Wylezinska-Arridge

⁶MRC Clinical Sciences Centre, Imperial College London, UK
Majid Ali

⁷Division of Cardiovascular and Diabetes Research, University of Leeds, UK
Neil P. Bowden

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Mari-Cruz Villa-Uriol

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Kim Van der Heiden

⁸Erasmus MC, Rotterdam, the Netherlands
Ruoyu Xing

⁸Erasmus MC, Rotterdam, the Netherlands
Frank J. Gijsen

⁸Erasmus MC, Rotterdam, the Netherlands
Jolanda J. Wentzel

⁸Erasmus MC, Rotterdam, the Netherlands
Allan Lawrie

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Shuang Feng

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Nadine Arnold

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
Willy Gsell

⁹Maccine Pte Ltd, Department of Imaging, Singapore
Angela Lungu

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Rodney Hose

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Tim Spencer

⁴Materials and Engineering Research Institute, Sheffield Hallam University, UK
Ian Halliday

⁴Materials and Engineering Research Institute, Sheffield Hallam University, UK
Victoria Ridger

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK
Paul C. Evans

¹Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK

²INSIGNEO Institute for in silico Medicine, University of Sheffield, Sheffield, UK

Abstract

Summary

Blood flow generates wall shear stress (WSS) which alters endothelial cell (EC) function. Low WSS promotes vascular inflammation and atherosclerosis whereas high uniform WSS is protective. Ivabradine decreases heart rate leading to altered haemodynamics. Besides its cardio-protective effects, ivabradine protects arteries from inflammation and atherosclerosis via unknown mechanisms. We hypothesised that ivabradine protects arteries by increasing WSS to reduce vascular inflammation. Hypercholesterolaemic mice were treated with ivabradine for seven weeks in drinking water or remained untreated as a control. En face immunostaining demonstrated that treatment with ivabradine reduced the expression of pro-inflammatory VCAM-1 (p<0.01) and enhanced the expression of anti-inflammatory eNOS (p<0.01) at the inner curvature of the aorta. We concluded that ivabradine alters EC physiology indirectly via modulation of flow because treatment with ivabradine had no effect in ligated carotid arteries in vivo, and did not influence the basal or TNFα-induced expression of inflammatory (VCAM-1, MCP-1) or protective (eNOS, HMOX1, KLF2, KLF4) genes in cultured EC. We therefore considered whether ivabradine can alter WSS which is a regulator of EC inflammatory activation. Computational fluid dynamics demonstrated that ivabradine treatment reduced heart rate by 20 % and enhanced WSS in the aorta. In conclusion, ivabradine treatment altered haemodynamics in the murine aorta by increasing the magnitude of shear stress. This was accompanied by induction of eNOS and suppression of VCAM-1, whereas ivabradine did not alter EC that could not respond to flow. Thus ivabradine protects arteries by altering local mechanical conditions to trigger an anti-inflammatory response.

Keywords

Inflammation - Atherosclerosis - haemodynamics

Volltext

Referenzen

References
1 Fox K, Borer JS, Camm AJ. et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007; 50: 823-830.
2 Perski A, Olsson G, Landou C. et al. Minimum heart-rate and coronary atherosclerosis - independent relations to global severity and rate of progression of angiographic lesions in men with myocardial-infarction at a young age. Am Heart J 1992; 123: 609-616.
3 Kjekshus JK. Importance of heart-rate in determining beta-blocker efficacy in acute and long-term acute myocardial-infarction intervention trials. Am J Cardiol 1986; 57: F43-F49.
4 Kaplan JR, Manuck SB, Clarkson TB. The influence of heart-rate on coronaryartery atherosclerosis. J Cardiovasc Pharmacol 1987; 10: S100-S103.
5 Beere PA, Glagov S, Zarins CK. Experimental atherosclerosis at the carotid bifurcation of the cynomolgus monkey - localization, compensatory enlargement, and the sparing effect of lowered heart-rate. Arterioscler Thromb 1992; 12: 1245-1253.
6 Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart-rate on coronary atherosclerosis. Science 1984; 226: 180-182.
7 Swedberg K, Komajda M, Boehm M. et al. Ivabradine and outcomes in chronic heart failure (shift): A randomised placebo-controlled study. Lancet 2010; 376: 875-885.
8 Tardif JC, Ford I, Tendera M. et al. Initiative I. Efficacy of ivabradine, a new selective i-f inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005; 26: 2529-2536.
9 Fox K, Ford I, Steg PG. et al. Investigators B. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (beautiful): A randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 807-816.
10 Fox K, Ford I, Steg PG. et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014; 371: 1091-1099.
11 Drouin A, Gendron ME, Thorin E. et al. Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Brit J Pharmacol 2008; 154: 749-757.
12 Baumhakel M, Custodis F, Schlimmer N. et al. Heart rate reduction with ivabradine improves erectile dysfunction in parallel to decrease in atherosclerotic plaque load in apoe-knockout mice. Atherosclerosis 2010; 212: 55-62.
13 Custodis F, Baumhaekel M, Schlimmer N. et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein e-deficient mice. Circulation 2008; 117: 2377-2387.
14 Koniari I, Mavrilas D, Papadaki H. et al. Structural and biomechanical alterations in atherosclerotic thoracic aortas of hyperlipidemic rabbits treated with simvastatin and ivabradine. Eur Heart J 2011; 32: 510.
15 Kwak BR, Baeck M, Bochaton-Piallat ML. et al. Biomechanical factors in atherosclerosis: Mechanisms and clinical implications. Eur Heart J 2014; 35: 3013-3020.
16 Suo J, Ferrara DE, Sorescu D. et al. Hemodynamic shear stresses in mouse aortas: Implications for atherogenesis. Arterioscler Thromb Vasc Biol 2007; 27: 346-351.
17 Samady H, Eshtehardi P, McDaniel MC. et al. Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease. Circulation 2011; 124: 779-788.
18 Cuhlmann S, Van der Heiden K, Saliba D. et al. Disturbed blood flow induces rela expression via c-jun n-terminal kinase 1 a novel mode of nf-kappa b regulation that promotes arterial inflammation. Circ Res 2011; 108: 950-959.
19 Chiu JJ, Lee PL, Chen CN. et al. Shear stress increases icam-1 and decreases vcam-1 and e-selectin expressions induced by tumor necrosis factor-alpha in endothelial cells. Arterioscler Thromb Vasc Biol 2004; 24: 73-79.
20 Iiyama K, Hajra L, Iiyama M. et al. Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res 1999; 85: 199-207.
21 Cheng C, Haperen RV, Waard MD. et al. Shear stress affects the intracellular distribution of enos : Direct demonstration by a novel in vivo technique plenary paper shear stress affects the intracellular distribution of enos : Direct demonstration by a novel in vivo technique. Blood 2005; 106: 3691-3698.
22 Lauzier B, Vaillant F, Gelinas R. et al. Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts. Am J Physiol Heart Circ Physiol 2011; 300: H845-H852.
23 Warboys CM, de Luca A, Amini N. et al. Disturbed flow promotes endothelial senescence via a p53-dependent pathway. Arterioscler Thromb Vasc Biol 2014; 34: 985-995.
24 Van Doormaal MA, Kazakidi A, Wylezinska M. et al. Haemodynamics in the mouse aortic arch computed from mri-derived velocities at the aortic root. J Roy Soc Int 2012; 09: 2834-2844.
25 Hameed AG, Arnold ND, Chamberlain J. et al. Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (trail) reverses experimental pulmonary hypertension. J Exp Med 2012; 209: 1919-1935.
26 Schenkel T, Malve M, Reik M. et al. Mri-based cfd analysis of flow in a human left ventricle: Methodology and application to a healthy heart. Ann Biomed Eng 2009; 37: 503-515.
27 Amini N, Boyle JJ, Moers B. et al. Requirement of jnk1 for endothelial cell injury in atherogenesis. Atherosclerosis 2014; 235: 613-618.
28 Feintuch A, Ruengsakulrach P, Lin A. et al. Hemodynamics in the mouse aortic arch as assessed by mri, ultrasound, and numerical modeling. Am J Physiol. Heart Circ Physiol 2007; 292: 884-892.
29 Ragueneau I, Laveille C, Jochemsen R. et al. Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers. Clin Pharmacol Ther 1998; 64: 192-203.
30 Huo Y, Guo X, Kassab GS. The flow field along the entire length of mouse aorta and primary branches. Ann Biomed Eng 2008; 36: 685-699.
31 Tsou JK, Gower RM, Ting HJ. et al. Spatial regulation of inflammation by human aortic endothelial cells in a linear gradient of shear stress. Microcirculation 2008; 15: 311-323.
32 Bolduc V, Drouin A, Gillis M-A. et al. Heart rate-associated mechanical stress impairs carotid but not cerebral artery compliance in dyslipidemic atherosclerotic mice. Am J Physiol-Heart Circ Physiol 2011; 301: H2081-H2092.
33 Weber TF, von Tengg-Kobligk H, Kopp-Schneider A. et al. High-resolution phase-contrast MRI of aortic and pulmonary blood flow during rest and physical exercise using a mri compatible bicycle ergometer. Eur J Radiol 2011; 80: 103-108.
34 Suh G-Y, Les AS, Tenforde AS. et al. Hemodynamic changes quantified in abdominal aortic aneurysms with increasing exercise intensity using mr exercise imaging and image-based computational fluid dynamics. Ann Biomed Eng 2011; 39: 2186-2202.
35 Trachet B, Bols J, Degroote J. et al. An animal-specific fsi model of the abdominal aorta in anesthetized mice. Ann Biomed Eng 2015; 43: 1298-1309.
36 De Wilde D. Wall shear stress metrics and their relation to atherosclerosis: an experimental and computational study in mice. Gent, Belgium. ISBN 978-90-8578-875-1..
37 Natarajan R, Gupta S, Fisher BJ. et al. Nitric oxide suppresses il-8 transcription by inhibiting c-jun n-terminal kinase-induced ap-1 activation. Exp Cell Res 2001; 266: 203-212.
38 Dekker RJ, van Soest S, Fontijn RD. et al. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung kruppel-like factor (klf2). Blood 2002; 100: 1689-1698.
39 Zakkar M, Chaudhury H, Sandvik G. et al. Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis. Circ Res 2008; 103: 726-732.

Zusatzmaterial

(PDF)