The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats

Figures

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  FIGURE 1. Free plasma concentration of XAF-1407 during the experiments in conscious goats. The data from four animals show that the dosing regimen reached stable plasma concentration of XAF-1407 in both applied doses. Time 0 corresponds with the beginning of the intravenous infusion.

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  FIGURE 2. The effect of XAF-1407 on atrial refractoriness. (A) Prolongation of aERP at all burst cycle lengths (BCL) was observed in normal (N = 5) and electrically remodeled atria (N = 5) after the administration of 0.3 and 3.0 mg/kg of XAF-1407. (B) Compared to normal atria, the effect of XAF-1407 was larger after electrical remodeling for both applied doses of the drug. (C) Additional experiments with atropine showed that vagal inhibition does not alter the effect of XAF-1407 on atrial refractoriness. Mixed model, ***p < 0.001.

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  FIGURE 3. Changes in electrophysiological parameters during administration of XAF-1407 in conscious animals. Prolongation of RR (A), QTc (B), PQ (C) and QRS (D) intervals was observed in goats with normal atria and electrically remodeled atria (N = 9). Statistical comparisons were made between baseline and the doses of 0.3 and 3.0 mg/kg of XAF-1407. Friedman’s test, *p < 0.05. An example of electrocardiogram demonstrating LA pacing (BCL 300 ms) during baseline and after the administration of 3.0 mg/kg of XAF-1407 illustrate the presence of second degree AV block after the drug administration (E). Prolongation of Wenckebach cycle length was observed after the administration of 3.0 mg/kg of XAF-1407 in normal atria (F) as well as in electrically remodeled atria (G). Log-rank test, *p < 0.05, N = 9.

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  FIGURE 4. Atrial fibrillation cycle length (AFCL) prolongation and cardioversion during administration of XAF-1407 and vernakalant. (A) Left atrial electrograms illustrating the fast and irregular rhythm during AF at baseline and 60 s before cardioversion with XAF-1407 and (B) vernakalant. (C) Examples of gradual prolongation of AFCL during the administration of XAF-1407 with cardioversion occurring during the maintenance phase after the dose of 0.3 mg/kg and (D) 3.0 mg/kg of XAF-1407. Prolongation of AFCL during the cardioversion attempt with vernakalant in the same animal is depicted for comparison. (E) Comparison of AFCL at baseline (N = 9) and 60 s before cardioversion (N = 8 and N = 5 for XAF-1407 and vernakalant, respectively). Mann Whitney test, *p < 0.05. (F) XAF-1407 showed higher cardioversion efficacy than vernakalant (*p < 0.05, Log-rank test, N = 9). The loading and maintenance phases of the applied dosing are highlighted.

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  FIGURE 5. The effect of XAF-1407 on atrial refractoriness, wavelength and conduction velocity during pacing. (A) XAF-1407 induced a dose-dependent prolongation of atrial effective refractory period (aERP). (B) The degree of aERP prolongation was larger in the right atrium. (C) A strong, dose-dependent prolongation of wavelength was observed in both atria during pacing. (D) Similarly, the prolongation of wavelength was more pronounced in right atrium. For aERP and wavelength, the sample sizes are stated in the brackets next to the burst cycle length (BCL). (E) Dose-dependent decrease of conduction velocity was observed in both atria. Presented as estimated mean ± standard error of the mean. *p < 0.05.

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  FIGURE 6. XAF-1407 reduces the complexity of atrial fibrillation in LA and RA. (A) Median atrial fibrillation cycle length (AFCL), (B) mean wave size, expressed as a number of electrodes assigned to one fibrillatory wave, (C) number of waves per AF cycle, (D) number of breakthrough waves per AF cycle, (E) fractionation index and, (F) maximum wave dissociation. Friedman’s test, *p < 0.05, N = 9.

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  FIGURE 7. The effect of XAF-1407 on fibrillation patterns. Wave maps of three consecutive beats at baseline, 10 s before cardioversion and 2 s before cardioversion are shown. Each map displays the territory of individual fibrillation waves within the mapped area of LA free wall during a single AF cycle. The color-coding depicts the sequence of wave appearance. The isochronal lines within waves are separated by 10 ms. AF complexity decreased 1.5–2 s before pharmacological cardioversion with XAF-1407. However, there was only a moderate reduction in AF complexity in the last 10 s preceding this rapid organization period.