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Dronedarone reduces arterial thrombus formation

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Abstract

Dronedarone has been associated with a reduced number of first hospitalisation due to acute coronary syndromes. Whether this is only due to the reduction in ventricular heart rate and blood pressure or whether other effects of dronedarone may be involved is currently elusive. This study was designed to investigate the role of dronedarone in arterial thrombus formation. C57Bl/6 mice were treated with dronedarone and arterial thrombosis was investigated using a mouse photochemical injury model. Dronedarone inhibited carotid artery thrombus formation in vivo (P < 0.05). Thrombin- and collagen-induced platelet aggregation was impaired in dronedarone-treated mice (P < 0.05), and expression of plasminogen activator inhibitor-1 (PAI1), an inhibitor of the fibrinolytic system, was reduced in the arterial wall (P < 0.05). In contrast, the level of tissue factor (TF), the main trigger of the coagulation cascade, and that of its physiological inhibitor, TF pathway inhibitor, did not differ. Similarly, coagulation times as measured by prothrombin time and activated partial thromboplastin time were comparable between the two groups. Dronedarone inhibits thrombus formation in vivo through inhibition of platelet aggregation and PAI1 expression. This effect occurs within the range of dronedarone concentrations measured in patients, and may represent a beneficial pleiotropic effect of this drug.

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References

  1. Breitenstein A, Camici GG, Tanner FC (2009) Tissue factor: beyond coagulation in the cardiovascular system. Clin Sci 118:159–172. doi:10.1042/CS20080622

    Article  PubMed  Google Scholar 

  2. Breitenstein A, Tanner FC, Luscher TF (2010) Tissue factor and cardiovascular disease: quo vadis? Circ J 74:3–12. doi:10.1253/circj.CJ-09-0818

    Article  PubMed  CAS  Google Scholar 

  3. Bukowska A, Hammwohner M, Sixdorf A, Schild L, Wiswedel I, Rohl FW, Wolke C, Lendeckel U, Aderkast C, Bochmann S, Chilukoti RK, Mostertz J, Bramlage P, Goette A (2012) Dronedarone prevents microcirculatory abnormalities in the left ventricle during atrial tachypacing in pigs. Br J Pharmacol 166:964–980. doi:10.1111/j.1476-5381.2011.01784.x

    Article  PubMed  CAS  Google Scholar 

  4. Camici GG, Steffel J, Akhmedov A, Schafer N, Baldinger J, Schulz U, Shojaati K, Matter CM, Yang Z, Luscher TF, Tanner FC (2006) Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation 114:1512–1521. doi:10.1161/CIRCULATIONAHA.106.638460

    Article  PubMed  CAS  Google Scholar 

  5. Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum A, Blomstrom P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacretaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB, Heidbuchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsanyi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH (2011) Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 365:2268–2276. doi:10.1056/NEJMoa1109867

    Article  PubMed  CAS  Google Scholar 

  6. Dobrev D, Nattel S (2010) New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet 375:1212–1223. doi:10.1016/S0140-6736(10)60096-7

    Article  PubMed  CAS  Google Scholar 

  7. Dorian P (2010) Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation. J Cardiovasc Pharmacol Ther 15:15S–18S. doi:10.1177/1074248410367792

    Article  PubMed  CAS  Google Scholar 

  8. Engelhorn T, Schwarz MA, Heusch G, Doerfler A, Schulz R (2011) Reduction of cerebral infarct size by dronedarone. Cardiovasc Drugs Ther 25:523–529. doi:10.1007/s10557-011-6336-2

    Article  PubMed  CAS  Google Scholar 

  9. Farrehi PM, Ozaki CK, Carmeliet P, Fay WP (1998) Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice. Circulation 97:1002–1008. doi:10.1161/01.CIR.97.10.1002

    Article  PubMed  CAS  Google Scholar 

  10. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 285:2370–2375. doi:10.1001/jama.285.18.2370

    Article  PubMed  CAS  Google Scholar 

  11. Guiraudou P, Pucheu SC, Gayraud R, Gautier P, Roccon A, Herbert JM, Nisato D (2004) Involvement of nitric oxide in amiodarone- and dronedarone-induced coronary vasodilation in guinea pig heart. Eur J Pharmacol 496:119–127. doi:10.1016/j.ejphar.2004.05.046

    Article  PubMed  CAS  Google Scholar 

  12. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, Stijnen T, Lip GY, Witteman JC (2006) Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 27:949–953. doi:10.1093/eurheartj/ehi825

    Article  PubMed  Google Scholar 

  13. Heusch G, Schulz R (2012) Pleiotropic effects of dronedarone on ischemia/reperfusion injury in heart and brain. Cardiovasc Drugs Ther 26:257–263. doi:10.1007/s10557-012-6379-z

    Article  PubMed  CAS  Google Scholar 

  14. Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ (2009) Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 360:668–678. doi:10.1056/NEJMoa0803778

    Article  PubMed  CAS  Google Scholar 

  15. Kawasaki T, Dewerchin M, Lijnen HR, Vermylen J, Hoylaerts MF (2000) Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice. Blood 96:153–160

    PubMed  CAS  Google Scholar 

  16. Kimmelstiel C (2012) The effect of differing pharmacologic strategies on infarct size in primary PCI-more confirmatory data for bivalirudin. Catheter Cardiovasc Interv 79:1090–1091. doi:10.1002/ccd.24455

    Article  PubMed  Google Scholar 

  17. Kober L, Torp-Pedersen C, McMurray JJ, Gotzsche O, Levy S, Crijns H, Amlie J, Carlsen J, Dronedarone Study Group (2008) Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 358:2678–2687. doi:10.1056/NEJMoa0800456

    Article  PubMed  Google Scholar 

  18. Mackman N (2008) Triggers, targets and treatments for thrombosis. Nature 451:914–918. doi:10.1038/nature06797

    Article  PubMed  CAS  Google Scholar 

  19. Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, Radzik D, Aliot EM, Hohnloser SH (2007) Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 357:987–999. doi:10.1056/NEJMoa054686

    Article  PubMed  CAS  Google Scholar 

  20. Skyschally A, Heusch G (2011) Reduction of myocardial infarct size by dronedarone in pigs—a pleiotropic action? Cardiovasc Drugs Ther 25:197–201. doi:10.1007/s10557-011-6300-1

    Article  PubMed  CAS  Google Scholar 

  21. Sobel BE, Woodcock-Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H (1998) Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: a potential factor predisposing to thrombosis and its persistence. Circulation 97:2213–2221. doi:10.1161/01.CIR.97.22.2213

    Article  PubMed  CAS  Google Scholar 

  22. Steffel J, Luscher TF, Tanner FC (2006) Tissue factor in cardiovascular diseases: molecular mechanisms and clinical implications. Circulation 113:722–731. doi:10.1161/CIRCULATIONAHA.105.567297

    Article  PubMed  CAS  Google Scholar 

  23. Thygesen K, Alpert JS, White HD (2007) Universal definition of myocardial infarction. J Am Coll Cardiol 50:2173–2195. doi:10.1016/j.jacc.2007.09.011

    Article  PubMed  Google Scholar 

  24. Touboul P, Brugada J, Capucci A, Crijns HJ, Edvardsson N, Hohnloser SH (2003) Dronedarone for prevention of atrial fibrillation: a dose-ranging study. Eur Heart J 24:1481–1487. doi:10.1016/S0195-668X(03)00321-X

    Article  PubMed  CAS  Google Scholar 

  25. Varro A, Takacs J, Nemeth M, Hala O, Virag L, Iost N, Balati B, Agoston M, Vereckei A, Pastor G, Delbruyere M, Gautier P, Nisato D, Papp JG (2001) Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone. Br J Pharmacol 133:625–634. doi:10.1038/sj.bjp.0704106

    Article  PubMed  CAS  Google Scholar 

  26. Weber AA, Reimann S, Schror K (1999) Specific inhibition of ADP-induced platelet aggregation by clopidogrel in vitro. Br J Pharmacol 126:415–420. doi:10.1038/sj.bjp.0702276

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the Swiss National Science Foundation (Grant no. 310030-135781/1 to FCT, Grant no. 3100-068118.02/1 to TFL; Berne, Switzerland), the Bonizzi-Theler Foundation (Zurich, Switzerland), Velux Foundation (Zurich, Switzerland), Wolfermann Nägeli Foundation (Zurich, Switzerland), MERCATOR Foundation (Essen, Germany), Sanofi-Aventis (Geneva, Switzerland), and the Swiss Heart Foundation (Berne, Switzerland).

Conflict of interest

The current study was supported by Sanofi-Aventis with a restricted research grant. Dr Steffel and Dr Duru have received consulting honoraria from Sanofi-Aventis.

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Authors and Affiliations

  1. Cardiology, Cardiovascular Center, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland

    Alexander Breitenstein, Jan Steffel, Giovanni G. Camici, Firat Duru, Thomas F. Luscher & Felix C. Tanner

  2. Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland

    Alexander Breitenstein, Susanna H. M. Sluka, Alexander Akhmedov, Simona Stivala, Jan Steffel, Giovanni G. Camici, Firat Duru, Thomas F. Luscher & Felix C. Tanner

  3. Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

    Alexander Breitenstein, Susanna H. M. Sluka, Alexander Akhmedov, Simona Stivala, Jan Steffel, Giovanni G. Camici, Firat Duru, Thomas F. Luscher & Felix C. Tanner

  4. Cardiovascular Therapy Research Laboratory, Center for Clinical Research, University Hospital Zurich, Zurich, Switzerland

    Huy H. Riem

  5. Cantonal Hospital Baden, Baden, Switzerland

    Hans-Jurg Beer

  6. Hematology, University Hospital Zurich, Zurich, Switzerland

    Jan-Dirk Studt

Authors
  1. Alexander Breitenstein
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  2. Susanna H. M. Sluka
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  3. Alexander Akhmedov
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  4. Simona Stivala
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  5. Jan Steffel
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  6. Giovanni G. Camici
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  7. Huy H. Riem
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  9. Jan-Dirk Studt
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  10. Firat Duru
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  11. Thomas F. Luscher
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  12. Felix C. Tanner
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Corresponding author

Correspondence to Felix C. Tanner.

Additional information

A. Breitenstein and S. H. M. Sluka contributed equally to this work.

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Breitenstein, A., Sluka, S.H.M., Akhmedov, A. et al. Dronedarone reduces arterial thrombus formation. Basic Res Cardiol 107, 302 (2012). https://doi.org/10.1007/s00395-012-0302-4

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  • DOI: https://doi.org/10.1007/s00395-012-0302-4

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