In this issue of the Journal of Cardiovascular Pharmacology, van Middendorp et al1 compare 2 antiarrhythmic drugs used for the conversion of atrial fibrillation (AF) with respect to their effects on conduction and contractility in dog ventricles paced for conduction delay. The clinical background is pharmacological conversion of AF in heart failure patients, many of whom are now treated by cardiac resynchronization therapy with biventricular pacing. The experimental protocol is clear and straightforward: compared to the nonselective sodium channel blocker flecainide, the newer atrial-selective drug vernakalant should be superior with respect to hemodynamics “at least in theory.”1 The authors spent much attention on appropriate drug concentrations used for the conversion of AF in humans, and employed sophisticated mapping techniques to detect even small conduction delays. The result of the carefully conducted study is surprising and rather simple: both drugs delay conduction and contractility to a comparable extent. In addition and somewhat unexpectedly, biventricular pacing reversed the negative inotropic effects of both vernakalant and flecainide (only in the setting of induced left bundle branch block tested).
The study presented by van Middendorp et al may have been initiated by the interest to learn more about the extent to which concomitant antiarrhythmic drug therapy affects the hemodynamic benefit of biventricular pacing. However, beyond this point, the present results give important insights into the recent concept of atrial-selective antiarrhythmic drug therapy.2 This concept requires at least 3 conditions:
- Target channels expressed selectively in the atrium.
- Compounds that block atrial-selective channel selectively.
- Blocking of atrial-selective channels results in increased refractoriness.
The first condition seems to be fulfilled because the ultrarapidly activating potassium current (IKur) is conducted by the channel protein Kv1.5 that is predominantly expressed in the atria. IKur is, therefore, one of the candidate targets to achieve atrial-selective antiarrhythmic drug therapy. Low concentrations of the experimental potassium channel blocker 4-AP can be used to block IKur selectively over Ito (a current that is expressed both in atrium and ventricle).3 In analogy to a blockade of potassium channels in ventricles, one would expect IKur-blockade to robustly prolong APD and increase refractoriness without promoting life-threatening arrhythmias in the ventricle. Accordingly, the concept of IKur-blockade has gained a lot of interest and lead to the development of dozens of compounds (for extensive review see Ford and Milnes).4 As expected, one such compound, Xention D0101, neither prolonged APD in human ventricular preparations nor the QTc interval in healthy subjects,5 arguing for the absence of actions on the ventricle. Although Xention D0101 markedly slowed the early phase of repolarization, APD90 was almost unaffected. Similar results were made before with 2 other IKur blockers,6,7 questioning whether IKur block evokes sufficient increases in refractoriness.
The situation with respect to vernakalant is even more complex. Vernakalant started its career as a putative atrial-selective antiarrhythmic drug as a blocker of IKur. Its ability to cause open channel block of IKur was shown in expression systems.8 Such an effect could be principally confirmed in native human atrial cardiomyocytes. However, the effects were unexpectedly small.9 Vernakalant was unable to produce the marked shift of plateau potential to a more positive voltage as seen with the other IKur blockers mentioned above. The reason for the large difference in effect size between expression systems and native human atrial myocytes remains unclear, but may relate to altered stoichiometry of different potassium channel subunits and accessory proteins in recombinant expression systems.10 In any case, the data call in question that vernakalant is in fact an effective blocker of IKur at all.
The question then arises how vernakalant exerts its undisputed clinical antiarrhythmic activity?11 Because vernakalant neither prolongs QTC interval in humans12 nor APD90 in human atrial trabecule,9 a relevant contribution of IKr blockade seems unlikely. Whether the small block of activated IK;ACh9 has antiarrhythmic effects is unclear. The most probable explanation is found in vernakalant's pharmacodynamic profile, which includes inhibition of the classic target of antiarrhythmics: sodium channels. The superiority of “new” class 1 drugs over “old” class 1 drugs (like flecainide) may critically depend on at least some selectivity for atria versus ventricles with respect to sodium channel block. The notion of vernakalant being an atrial-selective sodium channel blocker is based on the finding that it increased the effective refractory period in the atria, but not in the ventricle.10,13 Another class 1 effect is conduction slowing. In contrast to the study by van Middendorp et al, Vernakalant did not prolong QRS in rats, but it should be noted that in the same study even flecainide was ineffective.14
The alarming finding of the study of van Middendorp et al is that vernakalant and flecainide showed similar effects on ventricular conduction and on ventricular force. Because the authors have used doses equally effective in converting AF, these findings suggest that vernakalant is as nonselective with regard to atria/ventricles as flecainide. Careful and systematic measurements of rather simple parameters may give at least a rough estimate whether conduction delay is present. Negative inotropy is another typical consequence of lowering sodium influx. Credit goes to Scholz,15 who could demonstrate negative inotropy by TTX, clearly indicating that sodium channel block per se (and not concomitant block of ICa,L as demonstrated for “dirty” drugs like quinidine) is sufficient to impair contractility.16 However, it should be noted that vernakalant does not block ICa,L in human atrial myocytes,12 implicating sodium channel block as the main reason for negative inotropy observed by van Middendorp et al.1
This study of van Middendorp et al impressively demonstrates that measurements of comparable simple and robust parameters, like inotropy and ECG intervals (best determined at accelerated heart rate), may help to clarify whether atrial-selective actions can be achieved by new antiarrhythmic drugs acting on old targets.
The author thanks Thomas Eschenhagen for critical reading of the manuscript.
1. van Middendorp L, Strik L, Houthuizen P, et al.. Electrophysiological and hemodynamic effects of vernakalant and flecainide during cardiac resynchronization in dyssynchronous canine hearts. J Cardiovasc Pharmacol. 2014;63:25–32.
2. Carlsson L, Duker G, Jacobson I. New pharmacological targets and treatments for atrial fibrillation. Trends Pharmacol Sci. 2010;31:364–571.
3. Amos GJ, Wettwer E, Metzger F, et al.. Differences between outward currents of human atrial and subepicardial ventricular myocytes. J Physiol. 1996;491(pt 1):31–50.
4. Ford JW, Milnes JT. New drugs targeting the cardiac ultra-rapid delayed-rectifier current (IKur): rationale, pharmacology and evidence for potential therapeutic value. J Cardiovasc Pharmacol. 2008;52:105–120.
5. Ford J, Milnes J, Wettwer E, et al.. Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. J Cardiovasc Pharmacol. 2013;61:408–415.
6. Wettwer E, Hála O, Christ T, et al.. Role of IKur in controlling action potential shape and contractility in the human atrium: influence of chronic atrial fibrillation. Circulation. 2004;110:2299–2306.
7. Christ T, Wettwer E, Voigt N, et al.. Pathology-specific effects of the IKur/Ito/IK, ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation. Br J Pharmacol. 2008;154:1619–1630.
8. Fedida D. Vernakalant (RSD1235): a novel, atrial-selective antifibrillatory agent. Expert Opin Investig Drugs. 2007;16:519–532.
9. Wettwer E, Christ T, Endig S, et al.. The new antiarrhythmic drug vernakalant: ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation. Cardiovasc Res. 2013;98:145–154.
10. Radicke S, Vaquero M, Caballero R, et al.. Effects of MiRP1 and DPP6 beta-subunits on the blockade induced by flecainide of Kv4.3/KChIP2 channels. Br J Pharmacol. 2008;154:774–786.
11. Dorian P, Pinter A, Mangat I, et al.. The effect of vernakalant (RSD1235), an investigational antiarrhythmic agent, on atrial electrophysiology in humans. J Cardiovasc Pharmacol. 2007;50:35–40.
12. Roy D, Pratt CM, Torp-Pedersen C, et al.. Atrial Arrhythmia Conversion Trial Investigators. Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebo-controlled trial. Circulation. 2008;117:1518–1525.
13. Bechard J, Gibson JK, Killingsworth CR, et al.. Vernakalant selectively prolongs atrial refractoriness with no effect on ventricular refractoriness or defibrillation threshold in pigs. J Cardiovasc Pharmacol. 2011;57:302–307.
14. Allison B, Yang Y, Pourrier M, et al.. Comparison of the in vivo hemodynamic effects of the antiarrhythmic agents vernakalant and flecainide in a rat hindlimb perfusion model. J Cardiovasc Pharmacol. 2011;57:463–468.
15. Scholz H. Ca-dependent membrane potential changes in the heart and their significance for electro-mechanical coupling. Experiments with tetrodotoxin in Na-containing solutions [in German]. Naunyn Schmiedebergs Arch Pharmakol. 1969;265:187–204.
16. Nawrath H. Action potential, membrane currents and force of contraction in mammalian heart muscle fibers treated with quinidine. J Pharmacol Exp Ther. 1981;216:176–182.