Novel pharmacological approaches for antiarrhythmic therapy
Arrhythmias are caused by the perturbation of physiological impulse formation, impaired conduction, or disturbed electrical recovery. Currently available antiarrhythmic drugs—perhaps with exception of amiodarone—are not sufficiently effective and are burdened by cardiac and extracardiac side effects that may offset their therapeutic benefits. Detailed knowledge about electrical and structural remodelling may provide a better understanding of the mechanisms leading to generation and maintenance of arrhythmias especially in the setting of underlying heart disease and accompanying autonomic dysfunction. Thus, targets for new pharmacological interventions could include atrial-selective ion channels (e.g. atrial INa, IKur and IK,ACh), pathology-selective ion channels (constitutively active IK,ACh, TRP channels), ischemia-uncoupled gap junctions, proteins related to malfunctioning intracellular Ca2+ homeostasis (e.g. “leaky” ryanodine receptors, overactive Na+,Ca2+ exchanger) or risk factors for arrhythmias (“upstream” therapies). In ventricular arrhythmias implantable cardioverter-defibrillator devices rather than antiarrhythmic drugs are the safest treatment option. The domain for new approaches to drug treatment is atrial fibrillation.
KeywordsAtrial and ventricular arrhythmia Electrical and structural remodelling Non-conventional cardiac ion channels
The author thanks Dobromir Dobrev and Niels Voigt for critical reading of the manuscript and helpful suggestions. The author receives financial support from Fondation Leducq (07 CVD 03, “Leducq European-North American Atrial Fibrillation Research Alliance”) and the German Federal Ministry of Education and Research (Atrial Fibrillation Competence Network, member of the steering committee; New Antiarrhythmic Drugs, Research project 03FPB00226).
- Burashnikov A, Di Diego JM, Zygmunt AC, Belardinelli L, Antzelevitch C (2007) Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine. Circulation 116:1449–1457CrossRefPubMedGoogle Scholar
- Gierten J, Ficker E, Bloehs R, Schlomer K, Kathofer S, Scholz E, Zitron E, Kiesecker C, Bauer A, Becker R, Katus HA, Karle CA, Thomas D (2008) Regulation of two-pore-domain (K2P) potassium leak channels by the tyrosine kinase inhibitor genistein. Br J Pharmacol 154:1680–1690CrossRefPubMedGoogle Scholar
- Gierten J, Ficker E, Bloehs R, Schweizer PA, Zitron E, Scholz E, Karle C, Katus HA, Thomas D (2009) The human cardiac K(2P)3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone. Naunyn Schmiedebergs Arch Pharmacol (in press)Google Scholar
- Kaab S, Dixon J, Duc J, Ashen D, Nabauer M, Beuckelmann DJ, Steinbeck G, McKinnon D, Tomaselli GF (1998) Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. Circulation 98:1383–1393PubMedGoogle Scholar
- Ledoux J, Werner ME, Brayden JE, Nelson MT (2006) Calcium-activated potassium channels and the regulation of vascular tone. Physiology (Bethesda) 21:69–78Google Scholar
- Li N, Timofeyev V, Tuteja D, Xu D, Lu L, Zhang Q, Zhang Z, Singapuri A, Albert TR, Rajagopal AV, Bond CT, Periasamy M, Adelman J, Chiamvimonvat N (2009) Ablation of a Ca2+ -activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J Physiol 587:1087–1100CrossRefPubMedGoogle Scholar
- Savelieva I, Kourliouros A, Camm J (2009) Primary and secondary prevention of atrial fibrillation with statins and polyunsaturated fatty acids: review of evidence and clinical relevance. Naunyn Schmiedebergs Arch Pharmacol (in press)Google Scholar
- Valdivia CR, Chu WW, Pu J, Foell JD, Haworth RA, Wolff MR, Kamp TJ, Makielski JC (2005) Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J Mol Cell Cardiol 38:475–483Google Scholar
- Van Wagoner DR, Voigt N, Bunnell B, Barnard J, Schotten U, Nattel S, Ravens U, Dobrev D (2009) Transient receptor potential canonical (TRPC) channel subunit remodeling in clinical and experimental AF. Heart Rhythm AbstractPO06-77Google Scholar
- Voigt N, Friedrich A, Bock M, Wettwer E, Christ T, Knaut M, Strasser RH, Ravens U, Dobrev D (2007) Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK, ACh channels in patients with chronic atrial fibrillation. Cardiovasc Res 74:426–437CrossRefPubMedGoogle Scholar
- Voigt N, Rozmaritsa N, Trausch A, Zimniak T, Christ T, Wettwer E, Matschke K, Dobrev D, Ravens U (2009) Inhibition of I(K, ACh) current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation. Naunyn Schmiedebergs Arch Pharmacol. doi: 10.1007/s00210-009-0452-6 PubMedGoogle Scholar
- Xu Y, Tuteja D, Zhang Z, Xu D, Zhang Y, Rodriguez J, Nie L, Tuxson HR, Young JN, Glatter KA, Vazquez AE, Yamoah EN, Chiamvimonvat N (2003) Molecular identification and functional roles of a Ca(2+)-activated K+ channel in human and mouse hearts. J Biol Chem 278:49085–49094CrossRefPubMedGoogle Scholar