Christian Ellermann

Effective suppression of atrial fibrillation by ivabradine: Novel target for an established drug?

BACKGROUND Ivabradine is an inhibitor of mixed Na+-K+-currents and routinely administered in chronic heart failure. Clinical studies reported divergent trends regarding proarrhythmic and antiarrhythmic effects in atrial fibrillation (AF). METHODS AND RESULTS In 12 isolated rabbit hearts AF was induced in 7 of 12 hearts (13 episodes) under baseline conditions by a standardized protocol employing atrial burst pacing. Thereafter, a combination of acetylcholine and isoproterenol was employed to enhance AF occurrence. Monophasic action potential recordings showed a decrease of atrial action potential duration (aAPD,-37ms, p<0.05) and atrial effective refractory period (aERP;-39ms, p<0.05) after infusion of both acetycholine (1μM) and isoproterenol (1μM) as compared with baseline. This led to induction of AF in 11 of 12 hearts (124 episodes). Simultaneous infusion of ivabradine (3μM) led to a significant reduction of AF (6 of 11 hearts, 63 episodes). Ivabradine induced an increase of aAPD (+9ms) and aERP (+30ms, p<0.05) leading to a marked increase of atrial post-repolarization refractoriness (aPRR), defined as the difference of aERP and aAPD (+21ms, p<0.05). Results were compared to 10 rabbits treated with flecainide. Flecainide treatment also induced a significant increase of aPRR and resulted in induction of AF in 6 of 10 hearts (58 episodes) while 9 of 10 hearts were inducible during sole treatment with acetylcholine and isoproterenol (129 episodes). CONCLUSION In the present experimental study, administration of ivabradine reduced inducibility of AF and therefore may represent a supplemental therapeutic option in AF. Of note, its antiarrhythmic efficacy was comparable to the established agent flecainide.

Interactions of digitalis and class-III antiarrhythmic drugs: Amiodarone versus dronedarone.

BACKGROUND A post hoc analysis of the PALLAS trial suggested possible interactions of dronedarone and digitalis glycosides. The aim of the present study was to compare the effects dronedarone or amiodarone in combination with digitalis glycosides. METHODS AND RESULTS Eleven female rabbits underwent chronic oral treatment with amiodarone (50mg/kg/d for 6weeks). Ten rabbits were treated with dronedarone (50mg/kg/d for 6weeks). Ten rabbits were used as controls. Hearts were isolated and Langendorff-perfused. Monophasic action potentials and ECG showed a moderate prolongation of QT interval and action potential duration (APD). Both drugs also increased effective refractory period. Additional application of ouabain (0.2μM) resulted in a significant decrease of QT interval, APD, and ERP in all groups. Ventricular arrhythmias were induced by programmed ventricular stimulation and aggressive burst stimulation. Reproducible occurrence was defined as occurrence of at least 3 episodes. Under baseline conditions in control hearts, ventricular fibrillation (VF) was inducible in 1 of 10 hearts (7 episodes). After the application of 0.2μM ouabain, 4 of 10 control hearts were inducible (24 episodes). One of 10 dronedarone-pretreated hearts (3 episodes) and 2 of 11 amiodarone-pretreated hearts (6 episodes) showed VF before ouabain infusion. After the application of 0.2μM ouabain, 7 of 10 dronedarone-pretreated hearts were inducible (73 episodes). By contrast, only 4 of 11 amiodarone-pretreated hearts (13 episodes) showed VF. CONCLUSION In the present study, additional treatment with ouabain resulted in an increased ventricular vulnerability in al study groups. Of note, chronically dronedarone-pretreated hearts were significantly more vulnerable than amiodarone-pretreated hearts.

Antiarrhythmic effect of vernakalant in an experimental model of Long-QT-syndrome

Aims The antiarrhythmic drug vernakalant exerts antiarrhythmic effects in atrial fibrillation. Recent experimental data suggest interactions with the late sodium current and antiarrhythmic effects in ventricular arrhythmias. We aimed at investigating whether treatment with vernakalant reduces polymorphic ventricular tachycardia (VT) in an experimental model of Long-QT-syndrome (LQTS). Methods and results Twenty-nine isolated rabbit hearts were assigned to two groups and treated with erythromycin (300 µM, n = 15) or veratridine (0.5 µM, n = 14) after obtaining baseline data. Thereafter, vernakalant (10 µM) was additionally infused. Infusion of erythromycin or veratridine significantly increased action potential duration (APD90) and QT interval. Erythromycin and veratridine also significantly augmented spatial dispersion of repolarization (erythromycin: +43 ms; veratridine: +55 ms, P < 0.01, respectively) and temporal dispersion of repolarization. After lowering extracellular [K+] in bradycardic hearts, 11 of 15 erythromycin-treated hearts and 4 of 14 veratridine-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with vernakalant resulted in a significant reduction of spatial dispersion of spatial dispersion in both groups (erythromycin: -32 ms; veratridine: -35 ms, P < 0.05 each) and a stabilization of temporal dispersion. After additional treatment with vernakalant, only 5 of 15 erythromycin-treated hearts (P = 0.07) and 1 of 14 veratridine-treated hearts (P = 0.32) presented polymorphic VT. Conclusion Vernakalant has antiarrhythmic effects in this experimental model of acquired LQTS. A reduction of spatial dispersion of repolarization and a stabilization of temporal dispersion in hearts showing polymorphic VT represent the major underlying electrophysiological mechanisms.

Antiarrhythmic properties of ivabradine in an experimental model of Short‐ QT ‐ Syndrome

The If channel inhibitor ivabradine is recommended for treatment of chronic heart failure. However, ivabradine also inhibits human ether‐a‐go‐go (hERG) mediated potassium currents. The aim of the present study was to assess the electrophysiologic effects of ivabradine in an experimental model of short‐QT‐syndrome. Twelve rabbit hearts were isolated and Langendorff‐perfused. After obtaining baseline data, pinacidil, an IK‐ATP channel opener, was infused (1 μmol/L). Eight endo‐ and epicardial monophasic action potentials and a 12‐lead ECG showed a significant abbreviation of QT interval (−32 ms, P<.05) and shortening of action potential duration at 90% of repolarization (APD90; −22 ms, P<.05). The shortening of ventricular repolarization was accompanied by a reduction of effective refractory period (ERP; −20 ms, P<.05). Thereafter, hearts were additionally treated with ivabradine (5 μmol/L) leading to an increase of QT interval (+31 ms, P<.05), APD90 (+15 ms, P<.05) as well as of ERP (+38 ms, P<.05) and post‐repolarization refractoriness (PRR, +33 ms, P<.05) as compared with sole pinacidil infusion. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in 3 of 12 hearts (6 episodes). After application of 1 μmol/L pinacidil, 6 of 12 hearts were inducible (22 episodes). Additional infusion of 5 μmol/L ivabradine led to a significant suppression of VF. Only two episodes could be induced in 1 of 12 hearts. In the present study ivabradine reversed the electrophysiologic effects of pharmacologically simulated short‐QT syndrome. Ivabradine demonstrated antiarrhythmic properties based on an increase of both ERP and PRR.

Experimental evidence for a severe proarrhythmic potential of levosimendan

BACKGROUND The calcium sensitizer levosimendan is established for therapy of acutely decompensated congestive heart failure. Clinical experience suggests a possible proarrhythmic potential. The aim of the present study was to assess possible proarrhythmic effects and underlying electrophysiological mechanisms. METHODS AND RESULTS Ten rabbit hearts were isolated and Langendorff-perfused. Thereafter, levosimendan was infused in 3 concentrations (0.5, 1, and 2μM). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a dose-dependent reduction of QT interval (0.5μM: -27ms, 1μM:-33ms, 2μM: -77ms; p<0.05) and action potential duration at 90% of repolarization (APD90; 0.5μM: -12ms, 1μM: -12ms, 2μM: -20ms). There was no significant increase in dispersion of repolarization. The described abbreviation of myocardial repolarization was accompanied by a significant decrease of effective refractory period (ERP; 0.5μM: -16ms, 1μM: -20ms, 2μM:-27ms; p<0.05). Under baseline conditions, ventricular fibrillation was inducible by programmed stimulation and aggressive burst stimulation in 3 of 10 hearts (4 episodes). After application of 1μM levosimendan, 8 of 10 control hearts were inducible (27 episodes). Of note, in 8 of 10 hearts after infusion of up to 2μM levosimendan, incessant ventricular fibrillation that could not be terminated by multiple external defibrillations occurred. CONCLUSION In the present study, acute infusion of levosimendan resulted in an abbreviation of ventricular repolarization and a reduction of ERP. This led to a significantly elevated inducibility of ventricular fibrillation. In 8 of 10 hearts, incessant ventricular fibrillation occurred. These results suggest a proarrhythmic effect of levosimendan and might explain an increased mortality that coincided levosimendan treatment in a few small clinical studies.

Acute infusion of levosimendan enhances atrial fibrillation in an experimental whole-heart model

BACKGROUND The calcium sensitizer levosimendan is clinically employed in decompensated heart failure. The aim of the present study was to assess effects of levosimendan on atrial electrophysiology in an experimental whole-heart model. METHODS AND RESULTS 13 rabbit hearts were isolated and Langendorff-perfused. Thereafter, hearts were paced at cycle lengths of 350ms, 250ms and 200ms in the atrium. A standardized protocol employing atrial burst pacing induced atrial fibrillation (AF) in 4 of 13 hearts under baseline conditions (mean: 3.3±2.1 episodes). Subsequently, levosimendan was administered in two concentrations (0.25μM, 0.5μM). Two monophasic action potential recordings on the left- and two on the right atrial epicardium displayed a decrease of atrial action potential duration (aAPD, -27ms, p<0.05) and atrial effective refractory period (aERP; -29ms, p<0.05) under the influence of 0.5μM levosimendan. The described alterations of atrial electrophysiology led to and increased inducibility of AF. Of note, treatment with 0.25μM levosimendan resulted in induction of AF in 11 of 13 hearts (mean: 8.9±3.5 episodes). Under the influence of 0.5μM levosimendan 12 of 13 hearts were inducible (mean: 9.8±3.8 episodes). CONCLUSION In the present study acute infusion of levosimendan in isolated rabbit hearts resulted in an abbreviation of atrial action potential duration and a reduction of aERP. This led to a significantly elevated inducibility of atrial fibrillation. These results suggest a proarrhythmic effect of levosimendan regarding atrial fibrillation. This aspect should be further investigated in the clinical setting.

Change of sensing vector in the subcutaneous ICD during follow-up and after device replacement: BETTIN et al.

The subcutaneous implantable cardioverter defibrillator (S‐ICD) has been established as a valuable alternative to transvenous ICD for prevention of sudden cardiac death. The system automatically chooses the optimal sensing vector. However, during follow‐up and especially after device replacement we observed a change of the suggested sensing vector in automatic setup. Therefore, we analyzed frequency and reasons of vector change and its impact on inappropriate shocks (IAS).

Broad antiarrhythmic effect of mexiletine in different arrhythmia models

Aims Experimental studies and clinical reports suggest antiarrhythmic properties of mexiletine in different arrhythmias. We aimed at investigating mexiletine in experimental models of atrial fibrillation (AF) as well as in long-QT- (LQTS) and short-QT-syndrome (SQTS). Methods and results In 15 isolated rabbit hearts, erythromycin (300 µM) was infused for simulation of long-QT-2-syndrome. In further 13 hearts, veratridine was administered to simulate long-QT-3-syndrome. Both drugs induced a significant QT-prolongation (erythromycin: +87 ms, P < 0.01; veratridine: +19 ms, P < 0.05) and increased dispersion of repolarization (erythromycin: +55 ms, P < 0.01; veratridine +31 ms, P < 0.01). Additional infusion of mexiletine (25 µM) resulted in a significant reduction of dispersion (erythromycin: -43 ms, P < 0.01; veratridine: -26 ms, P < 0.05). Reproducible induction of torsade de pointes was observed in 13 of 15 erythromycin-treated hearts (192 episodes) and 6 of 13 veratridine-treated hearts (36 episodes). Additional infusion of mexiletine significantly reduced ventricular tachycardia (VT) incidence. With mexiletine, only 3 of 15 erythromycin-treated hearts (27 episodes) and 1 of 13 veratridine-treated hearts (2 episodes) presented polymorphic VT. In additional 9 hearts, the IK-ATP-channel-opener pinacidil was employed to simulate SQTS and significantly abbreviated ventricular repolarization (QT-interval: -18 ms, P < 0.05) and enhanced induction of ventricular fibrillation (VF). Mexiletine reversed the effects of pinacidil, increase refractory period (+127 ms, P < 0.01) and significantly suppressed induction of VF. In further 13 hearts AF was induced by combined treatment with acetylcholine/isoproterenol. Mexiletine also increased atrial refractory period (+80 ms, P < 0.01) and thereby effectively suppressed atrial fibrillation. Conclusion Acute infusion of mexiletine significantly reduced the occurrence of polymorphic VT in the presence of pharmacologically simulated LQTS. Furthermore, mexiletine demonstrated potent antiarrhythmic properties in a model of SQTS and in AF.

Acute electrophysiologic effects of the polyphenols resveratrol and piceatannol in rabbit atria

The natural polyphenol resveratrol and its analogue piceatannol have various beneficial effects including antiarrhythmic properties. The aim of the present study was to examine potential electrophysiologic effects in an experimental whole‐heart model of atrial fibrillation (AF). Simultaneous infusion of resveratrol (50 μmol/L) or piceatannol (10 μmol/L) in rabbit hearts resulted in an increase in atrial refractory period. Both agents induced a significant slowing of atrial conduction and of intrinsic heart rate. In both groups, a trend toward a reduction in AF and a regularization of AF was observed.

Divergent antiarrhythmic effects of resveratrol and piceatannol in a whole-heart model of long QT syndrome

BACKGROUND The polyphenol resveratrol and its metabolite piceatannol have beneficial health effects including antiarrhythmic properties in ischemia/reperfusion. The objective of this study was to determine potential antiarrhythmic effects in acquired long-QT-syndrome (LQTS). METHODS AND RESULTS 26 rabbit hearts were isolated and Langendorff-perfused. The IKr-blocker sotalol (100μM) was infused to mimic LQTS-2. Hearts were assigned to two groups. Sotalol significantly prolonged action potential duration (APD90) and QT-interval in both groups (group 1:APD90: +18ms, p<0.01;QT: +59ms, p<0.01; group 2: APD90: +22ms, p<0.01; QT: +30ms, p<0.01) and also significantly increased dispersion of repolarization (group 1: +21ms, p<0.01; group 2: +23ms, p<0.01). Thereafter, hearts were additionally perfused either with resveratrol (50μM, group 1, n=14) or with piceatannol (10μM, group 2, n=12). Administration of resveratrol significantly reduced APD90 (-29ms, p<0.01), QT-interval(-60ms, p<0.01) and dispersion of repolarization (-26ms, p<0.01). In contrast, piceatannol did not significantly alter APD90 (±0ms) but shortened QT-interval (-19ms, p<0.01) and increased dispersion of repolarization (+15ms, p<0.01). With sotalol, 7 of 14 bradycardic, AV-blocked hearts in group 1 and 8 of 12 in group 2 showed early afterdepolarizations (EAD) after lowering potassium concentration (p<0.01each). Polymorphic ventricular tachycardia (PVT) occurred in 5 of 14 (p<0.05) and 4 of 12 hearts (p=0.09) with a total number of 42 (p<0.05) and 44 episodes (p=0.07), respectively. Additional infusion of resveratrol reduced EAD (2 of 14, p=0.11) and PVT (1 of 14 hearts, p=0.16, 3 episodes, p<0.05). Piceatannol did not suppress EAD or TdP (EAD in 9 of 12 and TdP in 7 of 12 hearts,50 episodes). CONCLUSION Resveratrol showed beneficial antiarrhythmic properties in acquired LQTS. Underlying mechanism is a substantial decrease dispersion of repolarization leading to a suppression of triggered activity.