Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. It represents a major health problem and causes substantial morbidity and mortality in the general population.
Despite recent therapeutic advances, current pharmacological treatments have modest efficacy and substantial risks, making the development of new therapeutic strategies crucial.
There is a clear unmet need to develop novel mechanistically based therapeutic options with improved efficacy and favourable safety profiles.
In recent years, substantial efforts have been invested in developing treatments that target the underlying mechanisms of AF, and several new compounds are under development.
In this Review, we discuss the mechanistic rationale for the development of new anti-AF drugs, the molecular and structural motifs that they target, and the results obtained in experimental and clinical studies.
New insights into the mechanisms underlying AF have identified promising new approaches, including the modulation of atrium-specific ion channels, connexins and the ryanodine receptor, the prevention of remodelling processes that lead to the arrhythmia as well as specific molecular events involved in arrhythmia generation.
The validation of newer approaches based on microRNA targeting and gene therapy strategies, as well as the discovery of novel pathophysiological mechanisms and targets through genetic technology, may lead to the development of additional novel AF therapies.
Atrial fibrillation is the most common type of cardiac arrhythmia, and is responsible for substantial morbidity and mortality in the general population. Current treatments have moderate efficacy and considerable risks, especially of pro-arrhythmia, highlighting the need for new therapeutic strategies. In recent years, substantial efforts have been invested in developing novel treatments that target the underlying molecular determinants of atrial fibrillation, and several new compounds are under development. This Review focuses on the mechanistic rationale for the development of new anti-atrial fibrillation drugs, on the molecular and structural motifs that they target and on the results obtained so far in experimental and clinical studies.
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Peters, N. S., Schilling, R. J., Kanagaratnam, P. & Markides, V. Atrial fibrillation: strategies to control, combat, and cure. Lancet 359, 593–603 (2002).
Benjamin, E. J. et al. Prevention of atrial fibrillation: report from a National Heart, Lung, and Blood Institute workshop. Circulation 119, 606–618 (2009).
Dobrev, D. & Nattel, S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet 375, 1212–1223 (2010).
Wilber, D. J. et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA 303, 333–340 (2010).
Naccarelli, G. V. & Gonzalez, M. D. Atrial fibrillation and the expanding role of catheter ablation: do antiarrhythmic drugs have a future? J. Cardiovasc. Pharmacol. 52, 203–209 (2008).
Rostock, T. et al. Long-term single- and multiple-procedure outcome and predictors of success after catheter ablation for persistent atrial fibrillation. Heart Rhythm 8, 1391–1397 (2011).
Connolly, S. J. et al. Dronedarone in high-risk permanent atrial fibrillation. N. Engl. J. Med. 365, 2268–2276 (2011).
Echt, D. S. et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo — the cardiac arrhythmia suppression trial. N. Engl. J. Med. 324, 781–788 (1991).
Waldo, A. L. et al. Effect of D-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 348, 7–12 (1996).
Nattel, S. & Opie, L. H. Controversies in atrial fibrillation. Lancet 367, 262–272 (2006).
Iwasaki, Y., Nishida, K., Kato, T. & Nattel, S. Atrial fibrillation pathophysiology: implications for management. Circulation 124, 2264–2274 (2011).
Olesen, J. B., Lip, G. Y. & Lane, D. A. An epidemic of atrial fibrillation? Europace 13, 1059–1060 (2011).
Nattel, S., Maguy, A., Le Bouter, S. & Yeh, Y. H. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol. Rev. 87, 425–456 (2007).
Wakili, R., Voigt, N., Kaab, S., Dobrev, D. & Nattel, S. Recent advances in the molecular pathophysiology of atrial fibrillation. J. Clin. Invest. 121, 2955–2968 (2011).
Yeh, Y. H. et al. Calcium-handling abnormalities underlying atrial arrhythmogenesis and contractile dysfunction in dogs with congestive heart failure. Circ. Arrhythm. Electrophysiol. 1, 93–102 (2008).
Nishida, K. et al. Mechanisms of atrial tachyarrhythmias associated with coronary artery occlusion in a chronic canine model. Circulation 123, 137–146 (2011).
Lemoine, M. D. et al. Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model. Cardiovasc. Res. 92, 67–74 (2011).
Dobrev, D. Electrical remodeling in atrial fibrillation. Herz 31, 108–112 (2006).
Nattel, S., Burstein, B. & Dobrev, D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ. Arrhythm. Electrophysiol. 1, 62–73 (2008).
Dhein, S. et al. Improving cardiac gap junction communication as a new antiarrhythmic mechanism: the action of antiarrhythmic peptides. Naunyn Schmiedebergs Arch. Pharmacol. 381, 221–234 (2010).
Allessie, M., Ausma, J. & Schotten, U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc. Res. 54, 230–246 (2002).
Duytschaever, M., Blaauw, Y. & Allessie, M. Consequences of atrial electrical remodeling for the anti-arrhythmic action of class IC and class III drugs. Cardiovasc. Res. 67, 69–76 (2005).
Tieleman, R. G. et al. Does flecainide regain its antiarrhythmic activity after electrical cardioversion of persistent atrial fibrillation? Heart Rhythm 2, 223–230 (2005).
Dobrev, D., Voigt, N. & Wehrens, X. H. The ryanodine receptor channel as a molecular motif in atrial fibrillation: pathophysiological and therapeutic implications. Cardiovasc. Res. 89, 734–743 (2011).
Fynn, S. P. et al. Clinical evaluation of a policy of early repeated internal cardioversion for recurrence of atrial fibrillation. J. Cardiovasc. Electrophysiol. 13, 135–141 (2002).
Tse, H. F., Lau, C. P. & Ayers, G. M. Heterogeneous changes in electrophysiologic properties in the paroxysmal and chronically fibrillating human atrium. J. Cardiovasc. Electrophysiol. 10, 125–135 (1999).
Shinagawa, K., Shiroshita-Takeshita, A., Schram, G. & Nattel, S. Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone. Circulation 107, 1440–1446 (2003).
Fareh, J., Martel, R., Kermani, P. & Leclerc, G. Cellular effects of β-particle delivery on vascular smooth muscle cells and endothelial cells: a dose–response study. Circulation 99, 1477–1484 (1999).
Dobrev, D. Cardiomyocyte Ca2+ overload in atrial tachycardia: is blockade of L-type Ca2+ channels a promising approach to prevent electrical remodeling and arrhythmogenesis? Naunyn Schmiedebergs Arch. Pharmacol. 376, 227–230 (2007).
Pandit, S. V. et al. Ionic determinants of functional reentry in a 2D model of human atrial cells during simulated chronic atrial fibrillation. Biophys. J. 88, 3806–3821 (2005).
Van Wagoner, D. R. et al. Atrial L-type Ca2+ currents and human atrial fibrillation. Circ. Res. 85, 428–436 (1999).
Voigt, N. et al. Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation. Cardiovasc. Res. 74, 426–437 (2007).
Dobrev, D. et al. The G protein-gated potassium current IK,ACh is constitutively active in patients with chronic atrial fibrillation. Circulation 112, 3697–3706 (2005). This is the first demonstration of potentially pro-arrhythmic receptor-independent I K,ACh activity in atrial myocytes from patients with chronic AF.
Cha, T. J. et al. Kir3-based inward rectifier potassium current: potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias. Circulation 113, 1730–1737 (2006). This study demonstrated for the first time that inhibition of constitutively active I K,ACh with the highly selective honeybee toxin tertiapin suppresses shortening of APD and AF in atrium-remodelled preparations, thus directly linking constitutive I K,ACh with AF pathogenesis.
Christ, T. et al. L-type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation 110, 2651–2657 (2004).
Ehrlich, J. R. et al. Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium. J. Physiol. 557, 583–597 (2004).
Dobrev, D. et al. Molecular basis of downregulation of G-protein-coupled inward rectifying K+ current (IK,ACh) in chronic human atrial fibrillation: decrease in GIRK4 mRNA correlates with reduced IK,ACh and muscarinic receptor-mediated shortening of action potentials. Circulation 104, 2551–2557 (2001).
Yue, L. et al. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ. Res. 81, 512–525 (1997). This study is the first report of atrial tachycardia-induced changes in atrial ion channel function that contribute to the action potential shortening that supports the maintenance of AF.
Voigt, N. et al. Changes in IK,ACh single-channel activity with atrial tachycardia remodelling in canine atrial cardiomyocytes. Cardiovasc. Res. 77, 35–43 (2008).
Caballero, R. et al. In humans, chronic atrial fibrillation decreases the transient outward current and ultrarapid component of the delayed rectifier current differentially on each atria and increases the slow component of the delayed rectifier current in both. J. Am. Coll. Cardiol. 55, 2346–2354 (2010).
Brundel, B. J. et al. Ion channel remodeling is related to intraoperative atrial effective refractory periods in patients with paroxysmal and persistent atrial fibrillation. Circulation 103, 684–690 (2001).
Qi, X. Y. et al. Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. Circ. Res. 103, 845–854 (2008).
Lu, Y. et al. microRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation 122, 2378–2387 (2010).
Cunha, S. R. et al. Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation. Circulation 124, 1212–1222 (2011).
Levy, S. et al. Molecular basis for zinc transporter 1 action as an endogenous inhibitor of L-type calcium channels. J. Biol. Chem. 284, 32434–32443 (2009).
Greiser, M. et al. Pharmacological evidence for altered src kinase regulation of I (Ca,L) in patients with chronic atrial fibrillation. Naunyn Schmiedebergs Arch. Pharmacol. 375, 383–392 (2007).
El-Armouche, A. et al. Molecular determinants of altered Ca2+ handling in human chronic atrial fibrillation. Circulation 114, 670–680 (2006).
Van Wagoner, D. R., Pond, A. L., McCarthy, P. M., Trimmer, J. S. & Nerbonne, J. M. Outward K+ current densities and Kv1.5 expression are reduced in chronic human atrial fibrillation. Circ. Res. 80, 772–781 (1997).
Workman, A. J., Kane, K. A. & Rankin, A. C. The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation. Cardiovasc. Res. 52, 226–235 (2001).
Christ, T. et al. Pathology-specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation. Br. J. Pharmacol. 154, 1619–1630 (2008).
Brundel, B. J. et al. Alterations in potassium channel gene expression in atria of patients with persistent and paroxysmal atrial fibrillation: differential regulation of protein and mRNA levels for K+ channels. J. Am. Coll. Cardiol. 37, 926–932 (2001).
Girmatsion, Z. et al. Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation. Heart Rhythm 6, 1802–1809 (2009).
Voigt, N. et al. Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation. Circ. Arrhythm. Electrophysiol. 3, 472–480 (2010).
Luo, X. et al. Abstract 19435: critical role of microRNAs miR-26 and miR-101 in atrial electrical remodeling in experimental atrial fibrillation. Circulation 122, A19435 (2010).
Makary, S. et al. Differential protein kinase C isoform regulation and increased constitutive activity of acetylcholine-regulated potassium channels in atrial remodeling. Circ. Res. 109, 1031–1043 (2011).
Lesh, M. D., Pring, M. & Spear, J. F. Cellular uncoupling can unmask dispersion of action potential duration in ventricular myocardium. A computer modeling study. Circ. Res. 65, 1426–1440 (1989).
Chaldoupi, S. M., Loh, P., Hauer, R. N., de Bakker, J. M. & van Rijen, H. V. The role of connexin40 in atrial fibrillation. Cardiovasc. Res. 84, 15–23 2009).
Gaborit, N. et al. Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation. Circulation 112, 471–481 (2005).
Kostin, S. et al. Structural correlate of atrial fibrillation in human patients. Cardiovasc. Res. 54, 361–379 (2002).
Akar, F. G. et al. Dynamic changes in conduction velocity and gap junction properties during development of pacing-induced heart failure. Am. J. Physiol. Heart Circ. Physiol. 293, H1223–H1230 (2007).
Vest, J. A. et al. Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation 111, 2025–2032 (2005).
Neef, S. et al. CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. Circ. Res. 106, 1134–1144 (2010).
Voigt, N. et al. Abstract 16909: sarcoplasmic reticulum calcium leak and enhanced NCX increase occurrence of delayed afterdepolarisations in atrial myocytes from patients with chronic atrial fibrillation. Circulation 122, A16909 (2010).
Priori, S. G. & Chen, S. R. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. Circ. Res. 108, 871–883 (2011).
Chelu, M. G. et al. Calmodulin kinase II-mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice. J. Clin. Invest. 119, 1940–1951 (2009). This is the first description of a key role of CaMKII in AF pathophysiology and of the potential of selective CaMKII inhibition to suppress arrhythmia.
Li, N. et al. Inhibition of CaMKII phosphorylation of RyR2 prevents induction of atrial fibrillation in FKBP12.6 knockout mice. Circ. Res. 110, 465–470 (2012).
Voigt, N., Trafford, A. W., Ravens, U. & Dobrev, D. Abstract 2630: cellular and molecular determinants of altered atrial Ca2+ signaling in patients with chronic atrial fibrillation. Circulation 120, S667–S668 (2009).
Tessier, S. et al. Regulation of the transient outward K+ current by Ca2+/calmodulin-dependent protein kinases II in human atrial myocytes. Circ. Res. 85, 810–819 (1999).
Dobrev, D. & Wehrens, X. H. Calmodulin kinase II, sarcoplasmic reticulum Ca2+ leak, and atrial fibrillation. Trends Cardiovasc. Med. 20, 30–34 (2010).
Carr, A. N. et al. Type 1 phosphatase, a negative regulator of cardiac function. Mol. Cell Biol. 22, 4124–4135 (2002).
El-Armouche, A. et al. Phosphatase inhibitor-1-deficient mice are protected from catecholamine-induced arrhythmias and myocardial hypertrophy. Cardiovasc. Res. 80, 396–406 (2008).
Wittkopper, K. et al. Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging. J. Clin. Invest. 120, 617–626 (2010).
Pogwizd, S. M., Schlotthauer, K., Li, L., Yuan, W. & Bers, D. M. Arrhythmogenesis and contractile dysfunction in heart failure: roles of sodium-calcium exchange, inward rectifier potassium current, and residual β-adrenergic responsiveness. Circ. Res. 88, 1159–1167 (2001).
Schotten, U. et al. Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort. Cardiovasc. Res. 53, 192–201 (2002).
Lenaerts, I. et al. Ultrastructural and functional remodeling of the coupling between Ca2+ influx and sarcoplasmic reticulum Ca2+ release in right atrial myocytes from experimental persistent atrial fibrillation. Circ. Res. 105, 876–885 (2009).
Nattel, S. New ideas about atrial fibrillation 50 years on. Nature 415, 219–226 (2002).
Dobrev, D. & Nattel, S. Calcium handling abnormalities in atrial fibrillation as a target for innovative therapeutics. J. Cardiovasc. Pharmacol. 52, 293–299 (2008).
Fareh, S., Benardeau, A. & Nattel, S. Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs. Cardiovasc. Res. 49, 762–770 (2001).
Benardeau, A., Fareh, S. & Nattel, S. Effects of verapamil on atrial fibrillation and its electrophysiological determinants in dogs. Cardiovasc. Res. 50, 85–96 (2001).
Ravens, U. & Wettwer, E. Ultra-rapid delayed rectifier channels: molecular basis and therapeutic implications. Cardiovasc. Res. 89, 776–785 (2011).
Voigt, N. et al. Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation. Naunyn Schmiedebergs Arch. Pharmacol. 381, 251–259 (2010).
Blaauw, Y. et al. “Early” class III drugs for the treatment of atrial fibrillation: efficacy and atrial selectivity of AVE0118 in remodeled atria of the goat. Circulation 110, 1717–1724 (2004).
Grandi, E. et al. Human atrial action potential and Ca2+ model: sinus rhythm and chronic atrial fibrillation. Circ. Res. 109, 1055–1066 (2011). This is the first modelling study that combined human atrial cellular electrophysiology with Ca2+ signalling to demonstrate how Na+ and Ca2+ homeostasis crucially mediates abnormal repolarization in AF.
Olson, T. M. et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum. Mol. Genet. 15, 2185–2191 (2006).
Machida, T. et al. Effects of a highly selective acetylcholine-activated K+ channel blocker on experimental atrial fibrillation. Circ. Arrhythm. Electrophysiol. 4, 94–102 (2011). This is a comprehensive in vivo demonstration of the potential of selective I K,ACh inhibition to suppress the induction of AF.
Guerra, J. M., Everett, T. H., Lee, K. W., Wilson, E. & Olgin, J. E. Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation. Circulation 114, 110–118 (2006).
Shiroshita-Takeshita, A., Sakabe, M., Haugan, K., Hennan, J. K. & Nattel, S. Model-dependent effects of the gap junction conduction-enhancing antiarrhythmic peptide rotigaptide (ZP123) on experimental atrial fibrillation in dogs. Circulation 115, 310–318 (2007).
Nishida, K., Michael, G., Dobrev, D. & Nattel, S. Animal models for atrial fibrillation: clinical insights and scientific opportunities. Europace 12, 160–172 (2010).
Wetzel, U. et al. Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart 91, 166–170 (2005).
Hilliard, F. A. et al. Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass. J. Mol. Cell Cardiol. 48, 293–301 (2010).
Hwang, H. S. et al. Inhibition of cardiac Ca2+ release channels (RyR2) determines efficacy of class I antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia. Circ. Arrhythm. Electrophysiol. 4, 128–135 (2011).
Zhou, Q. et al. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nature Med. 17, 1003–1009 (2011). This study demonstrates that selective RYR2 channel inhibitors are a promising new drug class for the treatment of arrhythmias.
Mochizuki, M. et al. Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure. J. Am. Coll. Cardiol. 49, 1722–1732 (2007).
Reiken, S. et al. β-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure. Circulation 107, 2459–2466 (2003).
Wayman, G. A., Lee, Y. S., Tokumitsu, H., Silva, A. J. & Soderling, T. R. Calmodulin-kinases: modulators of neuronal development and plasticity. Neuron 59, 914–931 (2008).
Backs, J. et al. The γ isoform of CaM kinase II controls mouse egg activation by regulating cell cycle resumption. Proc. Natl Acad. Sci. USA 107, 81–86 (2010).
Xie, L. H., Chen, F., Karagueuzian, H. S. & Weiss, J. N. Oxidative-stress-induced afterdepolarizations and calmodulin kinase II signaling. Circ. Res. 104, 79–86 (2009).
Erickson, J. R. et al. A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell 133, 462–474 (2008).
Purohit, A. et al. Abstract 14037: angiotensin II promotes atrial fibrillation in mice by CaMKII oxidation. Circulation 124, A14037 (2011).
Van Wagoner, D. R. Oxidative stress and inflammation in atrial fibrillation: role in pathogenesis and potential as a therapeutic target. J. Cardiovasc. Pharmacol. 52, 306–313 (2008).
Goette, A. et al. Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles. Eur. Heart J. 30, 1411–1420 (2009).
Swaminathan, P. D. et al. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J. Clin. Invest. 121, 3277–3288 (2011).
Prosser, B. L., Ward, C. W. & Lederer, W. J. X-ROS signaling: rapid mechano-chemo transduction in heart. Science 333, 1440–1445 (2011).
Savelieva, I., Kourliouros, A. & Camm, J. Primary and secondary prevention of atrial fibrillation with statins and polyunsaturated fatty acids: review of evidence and clinical relevance. Naunyn Schmiedebergs Arch. Pharmacol. 381, 1–13 (2009).
Wittkopper, K., Dobrev, D., Eschenhagen, T. & El-Armouche, A. Phosphatase-1 inhibitor-1 in physiological and pathological β-adrenoceptor signalling. Cardiovasc. Res. 91, 392–401 (2011).
Iwamoto, T., Watanabe, Y., Kita, S. & Blaustein, M. P. Na+/Ca2+ exchange inhibitors: a new class of calcium regulators. Cardiovasc. Hematol. Disord. Drug Targets 7, 188–198 (2007).
Dobrev, D. Atrial Ca2+ signaling in atrial fibrillation as an antiarrhythmic drug target. Naunyn Schmiedebergs Arch. Pharmacol. 381, 195–206 (2010).
Ehrlich, J. R. Inward rectifier potassium currents as a target for atrial fibrillation therapy. J. Cardiovasc. Pharmacol. 52, 129–135 (2008).
Furutani, K., Ohno, Y., Inanobe, A., Hibino, H. & Kurachi, Y. Mutational and in silico analyses for antidepressant block of astroglial inward-rectifier Kir4.1 channel. Mol. Pharmacol. 75, 1287–1295 (2009).
Whorton, M. R. & Mackinnon, R. Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium. Cell 147, 199–208 (2011).
Rodriguez-Menchaca, A. A. et al. The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel. Proc. Natl Acad. Sci. USA 105, 1364–1368 (2008). This study shows the structural basis of Kir channelinhibition by chloroquine, and provides the structural framework for the design of novel anti-arrhythmic drugs with selective Kir channel-blocking properties.
Noujaim, S. F. et al. Structural bases for the different anti-fibrillatory effects of chloroquine and quinidine. Cardiovasc. Res. 89, 862–869 (2011).
Noujaim, S. F. et al. Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets. FASEB J. 24, 4302–4312 (2010).
Ramu, Y., Klem, A. M. & Lu, Z. Short variable sequence acquired in evolution enables selective inhibition of various inward-rectifier K+ channels. Biochemistry 43, 10701–10709 (2004). This was a key discovery that a short sequence in the N terminus of acetylcholine-dependent Kir channels underlies the high selectivity of the honeybee toxin tertiapin for these channels, thus providing a lead for the development of novel non-peptideinhibitors.
Ramu, Y., Xu, Y. & Lu, Z. Engineered specific and high-affinity inhibitor for a subtype of inward-rectifier K+ channels. Proc. Natl Acad. Sci. USA 105, 10774–10778 (2008).
Jin, W., Klem, A. M., Lewis, J. H. & Lu, Z. Mechanisms of inward-rectifier K+ channel inhibition by tertiapin-Q. Biochemistry 38, 14294–14301 (1999).
Yow, T. T. et al. Naringin directly activates inwardly rectifying potassium channels at an overlapping binding site to tertiapin-Q. Br. J. Pharmacol. 163, 1017–1033 (2011).
van der Heyden, M. A. & Sanchez-Chapula, J. A. Toward specific cardiac IK1 modulators for in vivo application: old drugs point the way. Heart Rhythm 8, 1076–1080 (2011).
Long, S. B., Campbell, E. B. & Mackinnon, R. Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science 309, 903–908 (2005).
Gonzalez, T., David, M., Moreno, C., Macias, A. & Valenzuela, C. Kv1.5–Kvβ interactions: molecular determinants and pharmacological consequences. Mini Rev. Med. Chem. 10, 635–642 (2010).
Wu, H. J. et al. Acacetin causes a frequency- and use-dependent blockade of hKv1.5 channels by binding to the S6 domain. J. Mol. Cell Cardiol. 51, 966–973 (2011).
Decher, N., Kumar, P., Gonzalez, T., Pirard, B. & Sanguinetti, M. C. Binding site of a novel Kv1.5 blocker: a “foot in the door” against atrial fibrillation. Mol. Pharmacol. 70, 1204–1211 (2006).
Eldstrom, J. et al. The molecular basis of high-affinity binding of the antiarrhythmic compound vernakalant (RSD1235) to Kv1.5 channels. Mol. Pharmacol. 72, 1522–1534 (2007).
Yang, Q. et al. Structure-based virtual screening and electrophysiological evaluation of new chemotypes of Kv1.5 channel blockers. ChemMedChem 5, 1353–1358 (2010). This is a detailed report on structure-based screening, and identifies new selective Kv1.5 channel blockers as potential candidates for atrium-selective therapy in AF.
Du, Y. M. et al. Molecular determinants of Kv1.5 channel block by diphenyl phosphine oxide-1. J. Mol. Cell Cardiol. 48, 1111–1120 (2010).
Aonuma, S., Kohama, Y., Komiyama, Y. & Fujimoto, S. Gastric ulcerogenic and biological activities of N-3′a-propyphenazonyl-2-acetoxybenzamide. Chem. Pharm. Bull. (Tokyo) 28, 1237–1244 (1980).
Butera, J. A. et al. Discovery of (2S,4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid hydrochloride (GAP-134)13, an orally active small molecule gap-junction modifier for the treatment of atrial fibrillation. J. Med. Chem. 52, 908–911 (2009).
Kjolbye, A. L., Haugan, K., Hennan, J. K. & Petersen, J. S. Pharmacological modulation of gap junction function with the novel compound rotigaptide: a promising new principle for prevention of arrhythmias. Basic Clin. Pharmacol. Toxicol. 101, 215–230 (2007).
Ek-Vitorin, J. F. et al. pH regulation of connexin43: molecular analysis of the gating particle. Biophys. J. 71, 1273–1284 (1996).
Shibayama, J. et al. Identification of a novel peptide that interferes with the chemical regulation of connexin43. Circ. Res. 98, 1365–1372 (2006).
Lewandowski, R. et al. RXP-E: a connexin43-binding peptide that prevents action potential propagation block. Circ. Res. 103, 519–526 (2008).
Verma, V. et al. Novel pharmacophores of connexin43 based on the “RXP” series of Cx43-binding peptides. Circ. Res. 105, 176–184 (2009). This was the first description of gap junction enhancers that were based on the structure of CX43 and had potential anti-arrhythmic properties.
Wehrens, X. H. et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 304, 292–296 (2004).
Sood, S. et al. Intracellular calcium leak due to FKBP12.6 deficiency in mice facilitates the inducibility of atrial fibrillation. Heart Rhythm 5, 1047–1054 (2008).
Chen, Y. J., Chen, Y. C., Wongcharoen, W., Lin, C. I. & Chen, S. A. Effect of K201, a novel antiarrhythmic drug on calcium handling and arrhythmogenic activity of pulmonary vein cardiomyocytes. Br. J. Pharmacol. 153, 915–925 (2008).
Kumagai, K., Nakashima, H., Gondo, N. & Saku, K. Antiarrhythmic effects of JTV-519, a novel cardioprotective drug, on atrial fibrillation/flutter in a canine sterile pericarditis model. J. Cardiovasc. Electrophysiol. 14, 880–884 (2003).
Bellinger, A. M. et al. Remodeling of ryanodine receptor complex causes “leaky” channels: a molecular mechanism for decreased exercise capacity. Proc. Natl Acad. Sci. USA 105, 2198–2202 (2008).
Kobayashi, S. et al. Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor. J. Am. Coll. Cardiol. 53, 1993–2005 (2009). This is a clear demonstration of the potential therapeutic value of stabilizing RYR2to treat cardiac arrhythmias.
Suetomi, T. et al. Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca2+ release leading to catecholaminergic polymorphic ventricular tachycardia. Circulation 124, 682–694 (2011).
Xu, X. et al. Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. Biochem. Biophys. Res. Commun. 394, 660–666 (2010).
Meissner, A., Min, J. Y., Haake, N., Hirt, S. & Simon, R. Dantrolene sodium improves the force-frequency relationship and β-adregenic responsiveness in failing human myocardium. Eur. J. Heart Fail. 1, 177–186 (1999).
Wakili, R. et al. Multiple potential molecular contributors to atrial hypocontractility caused by atrial tachycardia remodeling in dogs. Circ. Arrhythm. Electrophysiol. 3, 530–541 (2010).
Wettwer, E. et al. Role of IKur in controlling action potential shape and contractility in the human atrium: influence of chronic atrial fibrillation. Circulation 110, 2299–2306 (2004).
Schotten, U. et al. Cellular mechanisms of depressed atrial contractility in patients with chronic atrial fibrillation. Circulation 103, 691–698 (2001).
Shan, J., Chen, B. & Marks, A. R. Abstract 2726: atrial fibrillation in two mouse models with human CPVT ryanodine receptor mutations. Circulation 120, S687 (2009).
Watanabe, H. et al. Mutations in sodium channel β1- and β2-subunits associated with atrial fibrillation. Circ. Arrhythm. Electrophysiol. 2, 268–275 (2009).
Choi, W. S. et al. Kv1.5 surface expression is modulated by retrograde trafficking of newly endocytosed channels by the dynein motor. Circ. Res. 97, 363–371 (2005).
McEwen, D. P. et al. Rab-GTPase-dependent endocytic recycling of Kv1.5 in atrial myocytes. J. Biol. Chem. 282, 29612–29620 (2007).
Schumacher, S. M. & Martens, J. R. Ion channel trafficking: a new therapeutic horizon for atrial fibrillation. Heart Rhythm 7, 1309–1315 (2010).
Zadeh, A. D. et al. Internalized Kv1.5 traffics via Rab-dependent pathways. J. Physiol. 586, 4793–4813 (2008).
Drolet, B., Simard, C., Mizoue, L. & Roden, D. M. Human cardiac potassium channel DNA polymorphism modulates access to drug-binding site and causes drug resistance. J. Clin. Invest. 115, 2209–2213 (2005).
Schumacher, S. M. et al. Antiarrhythmic drug-induced internalization of the atrial-specific K+ channel Kv1.5. Circ. Res. 104, 1390–1398 (2009). This is an important study revealing that modulation of ion channel trafficking might represent a novel therapeutic approach for AF.
Burstein, B. & Nattel, S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J. Am. Coll. Cardiol. 51, 802–809 (2008).
Yue, L., Xie, J. & Nattel, S. Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. Cardiovasc. Res. 89, 744–753 (2011).
Everett, T. H. & Olgin, J. E. Atrial fibrosis and the mechanisms of atrial fibrillation. Heart Rhythm 4, S24–S27 (2007).
Savelieva, I. & Camm, A. J. Polyunsaturated fatty acids for prevention of atrial fibrillation: a 'fishy' story. Europace 13, 149–152 (2011).
Nodari, S. et al. n-3 polyunsaturated fatty acids in the prevention of atrial fibrillation recurrences after electrical cardioversion: a prospective, randomized study. Circulation 124, 1100–1106 (2011).
Du, J. et al. TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation. Circ. Res. 106, 992–1003 (2010).
van Rooij, E. et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl Acad. Sci. USA 105, 13027–13032 (2008).
Dawson, K. et al. Abstract 12545: potential role of microRNA-29b in atrial fibrillation-promoting fibrotic remodeling. Circulation 122, A12545 (2010).
Duisters, R. F. et al. miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ. Res. 104, 170–178 (2009).
Chen, Y. et al. Abstract 12988: microRNA changes and atrial arrhythmogenic remodeling in tachycardiomyopathic heart failure. Circulation 122, A12988 (2010).
Thum, T. et al. microRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008). This is a key demonstration of how abnormal miRNA regulation impairs cardiac function, and of the potential of miRNA targeting for the treatment of cardiovascular diseases.
Lundstrom, K. Micro-RNA in disease and gene therapy. Curr. Drug Discov. Technol. 8, 76–86 (2011).
Sotillo, E. & Thomas-Tikhonenko, A. Shielding the messenger (RNA): microRNA-based anticancer therapies. Pharmacol. Ther. 131, 18–32 (2011).
Kikuchi, K., McDonald, A. D., Sasano, T. & Donahue, J. K. Targeted modification of atrial electrophysiology by homogeneous transmural atrial gene transfer. Circulation 111, 264–270 (2005).
Amit, G., Qin, H. & Donahue, J. K. Biological therapies for atrial fibrillation. J. Cardiovasc. Pharmacol. 52, 222–227 (2008).
Bikou, O. et al. Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc. Res. 92, 218–225 (2011).
Ellinor, P. T. et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nature Genet. 42, 240–244 (2010).
Skibsbye, L., Diness, J. G., Sorensen, U. S., Hansen, R. S. & Grunnet, M. The duration of pacing-induced atrial fibrillation is reduced in vivo by inhibition of small conductance Ca2+-activated K+ channels. J. Cardiovasc. Pharmacol. 57, 672–681 (2011).
D.D. received support from the European Union through the European Network for Translational Research in Atrial Fibrillation (EUTRAF; grant no. 261057), the German Federal Ministry of Education and Research via the Atrial Fibrillation Competence Network (01GI0204) and the German Center for Cardiovascular Research, as well as the Deutsche Forschungsgemeinschaft (Do 769/1-3). S.N. is supported by grants from the Canadian Institutes of Health Research (MOP-44365 and MGP-6957) and the Quebec Heart and Stroke Foundation. D.D. and S.N. are co-principal investigators of the European/North American Atrial Fibrillation Research Alliance (ENAFRA; no. 07CVD03) network grant of Fondation Leducq. O. Fjellström, Medicinal Chemistry, AstraZeneca R&D, Sweden, is acknowledged for the illustration of the inwardly rectifying K+ channel depicted in Figure 4a.
D.D. has received consulting fees/honoraria from: BIOTRONIK, AstraZeneca, Boehringer Ingelheim, Merck Sharpe & Dohme and Sanofi. Travel support has been provided by the European Heart Rhythm Association and the European Society of Cardiology.
S.N. has been a consultant for Cardiome Pharma, Bayer/Schering Pharma, St Jude Medical and Merck Pharmaceuticals. His invited lectures have been sponsored by Biosense Webster, Sanofi Aventis and Pfizer. He has received research grants from AstraZeneca Pharmaceuticals and Xention Discovery. He is also an inventor on patents belonging to the Montreal Heart Institute.
L.C. declares no competing financial interests.
- Congestive heart failure
A condition in which the suboptimal performance of cardiac muscle leads to reduced cardiac output (causing fatigue and inadequate organ perfusion) as well as retention of salt and water, causing ankle swelling and shortness of breath owing to interstitial fluid accumulation in the lungs.
- Ischaemic heart disease
A condition in which narrowing of the coronary arteries leads to inadequate blood supply to cardiac muscle, causing chest pain on exertion. When an artery is completely blocked, it causes myocardial necrosis or infarction, commonly called a heart attack.
Termination of atrial fibrillation by applying an electrical shock to stop the arrhythmia and allow the normal heart pacemaker to take over.
- Sinus rhythm
The normal cardiac rhythm resulting from regular firing of pacemaker cells in the sinus node of the heart.
(PLN). An inhibitor of cardiac muscle sarcoendoplasmic reticulum Ca2+ ATPase (Serca) in the unphosphorylatedstate. PLN phosphorylation disinhibits SERCA and increases Ca2+ uptake into the sarcoplasmic reticulum.
- Ventricular pro-arrhythmia
The paradoxical induction or worsening of ventricular arrhythmias by drugs used to treat arrhythmias.
- Class I anti-arrhythmic drug
A drug that suppresses arrhythmias by blocking cardiac Na+ channels.
- Mitral regurgitation
A condition in which the mitral valve, which is located between the left atrium and left ventricle, is leaky, causing blood to back up and engorge the left atrium; this leads to atrial damage and eventually to atrial fibrillation.
- Pacing-induced AF
Atrial fibrillation (AF) initiated by a rapid burst of firing from an artificial pacemaker in the atrium, which exposes a tissue anomaly, usually resulting from remodelling, that allows an arrhythmia to be sustained.
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Dobrev, D., Carlsson, L. & Nattel, S. Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov 11, 275–291 (2012). https://doi.org/10.1038/nrd3682
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