Neue Antiarrhythmika in der Therapie des Vorhofflimmerns

II. Nicht-Ionenkanalblocker
  • M. Hammwöhner
  • A. D’Alessandro
  • D. Dobrev
  • P. Kirchhof
  • A. Goette
BEITRAG ZUM THEMENSCHWERPUNKT

Zusammenfassung

Die Behandlung des Vorhofflimmerns (VHF) ist schwierig und für den behandelnden Arzt eine Herausforderung. Die medikamentöse Therapie mit den „klassischen“ ionenkanalblockierenden Substanzen ist in der Effektivität limitiert und birgt insbesondere das Risiko der Proarrhythmie. Ziel dieses Artikels ist es, alternative Behandlungsstrategien mit „Nicht-Ionenkanalblockern“ aufzuzeigen, welche zum Teil schon Einzug in den klinischen Alltag gefunden haben und zum Teil, wie einige gentherapeutische Ansätze, noch im experimentellen Stadium sind. Anders als klassische Antiarrhythmika besteht ihr Wirkprinzip vor allem in der Beeinflussung des strukturellen Remodeling der Vorhöfe. Daher kommt ihnen auch eine Bedeutung im Rahmen der Primärprävention des VHF zu.

Schlüsselwörter

Vorhofflimmern Angiotensin Pathophysiologie Gentherapie 

New antiarrhythmic drugs for therapy of atrial fibrillation: II. Non-ion channel blockers

Summary

The therapeutic approach to atrial fibrillation is difficult and challenging. The effect of “classical” antiarrhythmic agents is based on their inhibitory effects on various ion channels. However, therapeutic benefit of these agents is often limited. The primary goal of this article is to discuss new therapeutic approaches using non-ion channel blocking drugs in the treatment of atrial fibrillation. Some of the substances discussed in this article have been used already in the clinical practice. Others, for example gentherapeutic approaches, are still in the experimental state. In contrast to ion channel blocking agents their efficacy is based on the suppression of structural remodeling. Hence, it can be assumed that due to these effects they may also be beneficial in the primary prevention of atrial fibrillation.

Key words

Atrial fibrillation angiotensin pathophysiology gene therapy 

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Literatur

  1. 1.
    Berk BC (1998) Angiotensin II receptors and angiotensin II-stimulated signal transduction. Heart Failure Rev 3:87–99CrossRefGoogle Scholar
  2. 2.
    Brand FN, Abbott RD, Kannel WB, Wolf PA (1985) Characteristics and prognosis of lone atrial fibrillation: 30 years follow-up in the Framingham Study. JAMA 254:3449–3453PubMedCrossRefGoogle Scholar
  3. 3.
    Bukowska A, Lendeckel U, Hirte D, Wolke C, Striggow F, Rohnert P, Huth C, Klein HU, Goette A (2006) Activation of the calcineurin signaling pathway induces atrial hypertrophy during atrial fibrillation. J Cell Mol Life Sci 63:333–342CrossRefGoogle Scholar
  4. 4.
    Cai H, Li Z, Goette A, Mera F, Honeycutt C, Feterik K, Wilcox JN, Dudley SC Jr, Harrison DG, Langberg JJ (2002) Downregulation of nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke. Circulation 106:2854–2858PubMedCrossRefGoogle Scholar
  5. 5.
    Carnes CA, Chung MK, Nakayama T, Nakayama H, Baliga RS, Piao S, Kanderian A, Pavia S, Hamlin RL, McCarthy PM, Bauer JA, Van Wagoner DR (2001) Ascorbate attenuates atrial pacing-induced peroxynitrite formation and electrical remodeling and decreases the incidence of postoperative atrial fibrillation. Circulation Res 89:e32–e38PubMedGoogle Scholar
  6. 6.
    Christ T, Boknik P, Wöhrl S, Wettwer E, Graf EM, Bosch RF, Knaut M, Schmitz W, Ravens U, Dobrev D (2004) L-Type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation 110:2651–2657PubMedCrossRefGoogle Scholar
  7. 7.
    Francis GS (2000) ACE inhibition in cardiovascular diseases. N Engl J Med 342:201–202PubMedCrossRefGoogle Scholar
  8. 8.
    Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM (1994) Prevalence of atrial fibrillation in elderly subjects. Am J Cardiol 74:236–241PubMedCrossRefGoogle Scholar
  9. 9.
    Gensini F, Padeletti L, Fatini C, Sticchi E, Gensini GF, Michelucci A (2003) Angiotensin-converting enzyme and endothelial nitric oxide synthase polymorphisms in patients with atrial fibrillation. Pacing Clin Electrophysiol 26:295–298PubMedCrossRefGoogle Scholar
  10. 10.
    Goette A, Lendeckel U (2006) Morphologisches Remodeling bei Vorhofflimmern. Herz 31 (im Druck)Google Scholar
  11. 11.
    Goette A, Honeycutt C, Langberg JJ (1996) Electrical remodeling in atrial fibrillation: time course and mechanisms. Circulation 94:2968–2974PubMedGoogle Scholar
  12. 12.
    Goette A, Staack T, Arndt M, Röcken C, Geller C, Huth C, Ansorge S, Klein HU, Lendeckel U (2000) Increased expression of extracellular-signal regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation. J Am Coll Cardiol 35:1669–1677PubMedCrossRefGoogle Scholar
  13. 13.
    Hart RG, Halperin JL (2001) Atrial fibrillation and stroke: concepts and controversies. Stroke 32:803–808PubMedGoogle Scholar
  14. 14.
    Hove-Madsen L, Llach A, Bayes-Genis A, Roura S, Rodriguez Font E, Aris A, Cinca J (2004) Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes. Circulation 110(11):1358–1363PubMedCrossRefGoogle Scholar
  15. 15.
    Kikuchi K, McDonald AD, Sasano T, Donahue JK (2005) Targeted modification of atrial electrophysiology by homogeneous transmural atrial gene transfer. Circulation 111:264–270PubMedCrossRefGoogle Scholar
  16. 16.
    Kim YM, Zhang YH, Guzik TJ, Kattach H, Pillai R, Channon KM, Casadei B (2003) A myocardial nox2 containing NADPH oxidase contributes to oxidative stress in human atrial fibrillation. Circulation 108(Suppl):IV-45 (abstract)CrossRefGoogle Scholar
  17. 17.
    Kumagai K, Nakashima H, Gondo N, Saku K (2003) Antiarrhythmic effects of JTV-519, a novel cardioprotective drug, on atrial fibrillation/flutter in a canine sterile pericarditis model. J Cardiovasc Electrophysiol 14:880–884PubMedCrossRefGoogle Scholar
  18. 18.
    Kizana E, Ginn SL, Allen DG, Ross DL, Alexander IE (2005) Fibroblasts can be genetically modified to produce excitable cells capable of electrical coupling. Circulation 111:394–398PubMedCrossRefGoogle Scholar
  19. 19.
    Li D, Fareh S, Leung TK, Nattel S (1999) Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 100:87–95PubMedGoogle Scholar
  20. 20.
    Li D, Shinagawa K, Pang L, Leung TK, Cardin S, Wang Z, Nattel S (2001) Effects of angiotensin-converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation 104:2608–2614PubMedGoogle Scholar
  21. 21.
    Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C (2002) Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 106:331–336PubMedCrossRefGoogle Scholar
  22. 22.
    Matsumoto T, Wada A, Tsutamoto T, Ohnishi M, Isono T, Kinoshita M (2003) Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure. Circulation 107:2555–2558PubMedCrossRefGoogle Scholar
  23. 23.
    Mihm MJ, Yu F, Carnes CA, Reiser PJ, McCarthy PM, Van Wagoner DR, Bauer JA (2001) Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 104:174–180PubMedGoogle Scholar
  24. 24.
    Nattel S (2002) New ideas about atrial fibrillation 50 years on. Nature 415:219–226PubMedCrossRefGoogle Scholar
  25. 25.
    Shiroshita-Takeshita A, Schram G, Lavoie J, Nattel S (2004) Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation 110:2313–2319PubMedCrossRefGoogle Scholar
  26. 26.
    Shiroshita-Takeshita A, Brundel BJ, Lavoie J, Nattel S (2006) Prednisone prevents atrial fibrillation promotion by atrial tachycardia remodeling in dogs. Cardiovasc Res 69(4):865–875PubMedCrossRefGoogle Scholar
  27. 27.
    Urata H, Healy B, Stewart RW, Bumpus FM, Husain A (1990) Angiotensin II-forming pathways in normal and failing hearts. Circ Res 66:883–890PubMedGoogle Scholar
  28. 28.
    Vest JA, Wehrens XH, Reiken SR, Lehnart SE, Dobrev D, Chandra P, Danilo P, Ravens U, Rosen MR, Marks AR (2005) Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 111(16):2025–2032PubMedCrossRefGoogle Scholar

Copyright information

© Steinkopff-Verlag 2006

Authors and Affiliations

  • M. Hammwöhner
    • 1
  • A. D’Alessandro
    • 1
  • D. Dobrev
    • 2
  • P. Kirchhof
    • 3
  • A. Goette
    • 1
  1. 1.Otto-von-Guericke Universitätsklinik Magdeburg, Klinik für Kardiologie, Angiologie und PneumologieMagdeburgGermany
  2. 2.Technische Universität Dresden, Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav CarusDresdenGermany
  3. 3.Universitätsklinikum Münster, Medizinische Klinik und Poliklinik C, Kardiologie und AngiologieMünsterGermany

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