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Nils Edvardsson - One of the best experts on this subject based on the ideXlab platform.

  • QRS aberration during atrial fibrillation at rest and during exercise. Effect of a selective potassium channel blocking agent
    Journal of Electrocardiology, 2002
    Co-Authors: Birgitta Houltz, Harry J.g.m. Crijns, Börje Darpö, Karl Swedberg, Per Blomström, Steen M. Jensen, Elisabeth Svernhage, Nils Edvardsson
    Abstract:

    Abstract This study assesses the occurrence of and identifies clinical characteristics associated with the development of aberrant conduction during infusion of the I kr -blocker Almokalant. Class III drugs may induce aberrant conduction by prolongation of cardiac repolarization, especially during atrial fibrillation (AF). Ninety-two patients with AF received a 6-hour Almokalant infusion, aiming at conversion to sinus rhythm (SR). Fiftyfive of the patients received an identical infusion during SR. During Almokalant infusion, the number of patients with intermittent QRS aberration during AF increased, from 21% to 80% at rest, and was further increased to 89% during exercise, with predominantly left, and sequential bilateral, bundle branch aberrancy. Patients with aberrant conduction showed signs of more advanced myocardial disease. Predictors of the development of QRS aberration were female gender, arrhythmia duration, and decreased left ventricular ejection fraction, while use of calcium antagonists decreased the probability. No patient showed aberration during regular SR. Twenty-one patients experienced aberrantly conducted supraventricular premature beats. In conclusion, aberrant conduction is common during infusion of the I kr -blocker Almokalant during AF, and seems to be more frequent in females and in patients with more advanced myocardial disease.

  • Computer-based analysis of dynamic QT changes: toward high precision and individual rate correction.
    Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology Inc, 2002
    Co-Authors: Corina Dota, Nils Edvardsson, Bo Skallefell, Gunnar Fager
    Abstract:

    Background: New strategies are needed to improve the results of automatic measurement of the various parts of the ECG signal and their dynamic changes. Methods: The EClysis software processes digitally-recorded ECGs from up to 12 leads at 500 Hz, using strictly defined algorithms to detect the PQRSTU points and to measure ECG intervals and amplitudes. Calculations are made on the averaged curve of each sampling period (beat group) or as means ± SD for beat groups, after being analyzed at the individual beat level in each lead. Resulting data sets can be exported for further statistical analyses. Using QT and R-R measured on beat level, an individual correction for the R-R dependence can be performed. Results: EClysis assigns PQRSTU points and intervals in a sensitive and highly reproducible manner, with coefficients of variation in ECG intervals corresponding to ca. 2 ms in the simulated ECG. In the normal ECG, the CVs are 2% for QRS, 0.8% for QT, and almost 6% for PQ intervals. EClysis highlights the increase in QT intervals and the decrease of T-wave amplitudes during Almokalant infusion versus placebo. Using the observed linear or exponential relationships to adjust QT for R-R dependence in healthy subjects, one can eliminate this dependence almost completely by individualized correction. Conclusions: The EClysis system provides a precise and reproducible method to analyze ECGs. A.N.E. 2002;7(4):289–301

  • Comparison of QT dispersion during atrial fibrillation and sinus rhythm in the same patients, at normal and prolonged ventricular repolarization
    Europace : European pacing arrhythmias and cardiac electrophysiology : journal of the working groups on cardiac pacing arrhythmias and cardiac cellula, 2000
    Co-Authors: Birgitta Houltz, Harry J.g.m. Crijns, Börje Darpö, Karl Swedberg, Per Blomström, Steen M. Jensen, Elisabeth Svernhage, Nils Edvardsson
    Abstract:

    Aims Drug-induced increase in QT dispersion has been associated with increased risk of ventricular proarrhythmia. The aim of the present study was to compare QT dispersion during atrial fibrillation and sinus rhythm in the same patients at normal and prolonged ventricular repolarization. Methods and Results Sixty-one patients who had had chronic atrial fibrillation for 8 +/- 14 months received a 6 h infusion of the I-kr-bIocker Almokalant, the first 90 min of which are used for this analysis. The following day, after conversion to sinus rhythm, by Almokalant (n = 19) or direct current cardioversion (n = 42), an identical 90 min infusion was administered. Prior to infusion, there was no difference in precordial QT dispersion between atrial fibrillation and sinus rhythm (29 +/- 12 vs 36 +/- 17 ms, P = ns). During infusion, at prolonged repolarization, the increase in QT dispersion was greater during sinus rhythm than during atrial fibrillation (58 +/- 49 vs 30 +/- 15 ms, P = 0.0011, after 30 min infusion). No correlation was found between QT dispersion and the QT or RR interval. Conclusion QT dispersion during atrial fibrillation does not differ from QT dispersion during sinus rhythm during normal repolarization, while measurement of QT dispersion during prolonged repolarization, induced by an I-kr-blocker, yielded larger values during sinus rhythm than during atrial fibrillation. (C) 2000 The European Society of Cardiology.

  • Effects of the Ikr-Blocker Almokalant and Predictors of Conversion of Chronic Atrial Tachyarrhythmias to Sinus Rhythm. A Prospective Study
    Cardiovascular Drugs and Therapy, 1999
    Co-Authors: Birgitta Houltz, Harry J.g.m. Crijns, Börje Darpö, Karl Swedberg, Per Blomström, Steen M. Jensen, Elisabeth Svernhage, Johannes Brachmann, Hans Vallin, Nils Edvardsson
    Abstract:

    Purpose: To assess the efficacy of the I_kr-blocker Almokalant attempting to convert chronic atrial tachyarrhythmias, and to find predictors of conversion, to sinus rhythm. Methods: The electrophysiological effects of a 6-hour infusion of Almokalant, to a total dose of 25 ± 4 mg, were assessed by ECG and transesophageal atrial electrograms (TAE) in 100 consecutive patients with atrial fibrillation / flutter (n = 95 / 5) of 8 ± 12 months' duration (range 1 to 99 months). Results: The conversion rate was 32%. The time to conversion was 3.5 ± 2.2 hours. During infusion increases in QT_top (292 ± 35 to 335 ± 44 ms, p < 0.001, after 30 minutes), QT (387 ± 40 to 446 ± 60 ms, p < 0.001), corrected QT (425 ± 30 to 487 ± 44 ms, p < 0.001), and QT dispersion (21 ± 12 to 29 ± 31 ms, p = 0.02), were paralleled by decreases in T wave amplitude (0.31 ± 0.19 to 0.23 ± 0.16 mV, p < 0.001), and atrial rate (425 ± 78 to 284 ± 44 beats per minute (bpm) on ECG, and 396 ± 72 to 309 ± 44 bpm on TAE), with no differences between converters to sinus rhythm and non-converters. Patients with aberrantly conducted beats, and T wave variation, also increased. Calcium antagonists were more common among converters. A decreasing T wave amplitude predicted conversion. Four patients developed torsades de pointes. Conclusions: This study demonstrates class III action of Almokalant, with a conversion rate of 32% of long-standing, chronic atrial tachyarrhytmias. An early decrease in T wave amplitude was associated with conversion to sinus rhythm.

  • Effects of the Ikr-blocker Almokalant and predictors of conversion of chronic atrial tachyarrhythmias to sinus rhythm. A prospective study.
    Cardiovascular drugs and therapy, 1999
    Co-Authors: Birgitta Houltz, Harry J.g.m. Crijns, Börje Darpö, Karl Swedberg, Per Blomström, Steen M. Jensen, Elisabeth Svernhage, Johannes Brachmann, Hans Vallin, Nils Edvardsson
    Abstract:

    Purpose: To assess the efficacy of the Ikr-blocker Almokalant attempting to convert chronic atrial tachyarrhythmias, and to find predictors of conversion, to sinus rhythm.

Leif Carlsson - One of the best experts on this subject based on the ideXlab platform.

  • Block of HERG‐Carried K+ Currents by the New Repolarization Delaying Agent H 345/52
    Journal of cardiovascular electrophysiology, 2003
    Co-Authors: Gregory J Amos, Göran Duker, Ingemar Jacobson, Leif Carlsson
    Abstract:

    Introduction: The aim of this study was to analyze the block of HERG-carried membrane currents caused by H 345/52, a new antiarrhythmic compound with low proarrhythmic activity, in transfected mouse fibroblasts. Methods and Results: Using the whole-cell configuration of the voltage patch clamp technique, it was demonstrated that H 345/52 concentration-dependently blocked HERG-carried currents with an IC50 of 230 nM. H 345/52 preferentially bound to the open channel with unusually rapid kinetics and was trapped by channel closure. Voltage-independent behavior of H 345/52 was observed during both square-pulse and action potential clamp protocols. In contrast, the Class III agents dofetilide (10 nM) and Almokalant (250 nM) demonstrated significant membrane potential-dependent effects during square-pulse clamp protocols. When using action potential clamp protocols, voltage dependence was seen with dofetilide but not with Almokalant. Mathematical simulations of human ventricular action potentials predicted that the different voltage-dependent behaviors would not produce marked variations in action potential duration prolongation patterns. Conclusion: We propose that block of IKr is the principal mechanism by which H 345/52 delays repolarization in human myocardium. The voltage independence of HERG/IKr block is unlikely to underlie the low proarrhythmic potential, and ancillary effects on other membrane currents must be considered. (J Cardiovasc Electrophysiol, Vol. 14, pp. 651-658, June 2003)

  • Potassium and calcium current blocking properties of the novel antiarrhythmic agent H 345/52: implications for proarrhythmic potential.
    Cardiovascular research, 2001
    Co-Authors: Gregory J Amos, Christina Abrahamsson, Göran Duker, Luc M. Hondeghem, Mattias Palmer, Leif Carlsson
    Abstract:

    Objectives: To study the blocking effects of H 345/52 on ionic currents of rabbit ventricular myocytes and how these features translate into a proarrhythmic potential. Methods : The single electrode voltage clamp technique was used to study the effects of H 345/52 on the rapid component of the delayed rectifying potassium current, I Kr, and the L-type calcium current ( I Ca). Differential effects of H 345/52 and Almokalant on APD prolongation were studied in a rabbit Purkinje fibre/ventricular muscle preparation. The temporal variability of the action potential duration (APD) and its relation to proarrhythmias was examined in Langendorff-perfused rabbit hearts administered H 345/52 or Almokalant. Anaesthetised, methoxamine-sensitised rabbits were used to assess the propensity of intravenous H 345/52 and ibutilide to induce torsades de pointes (TdP). Results: H 345/52 potently blocked I Kr (IC50=40 nM) without consequential use-dependency. The I Ca was also blocked, but at higher concentrations (IC50=1.3 μM). Block of I Ca was markedly frequency-dependent (positive) and influenced by membrane potential, such that H 345/52 was more effective following clamp steps from plateau potentials than from −80 mV. In the Purkinje fibre–ventricular muscle preparation, Almokalant prolonged the Purkinje fibre APD preferentially, whereas H 345/52 homogeneously prolonged APD in both tissue types. In the perfused rabbit heart, H 345/52 (1 μM) and Almokalant (0.3 μM) prolonged APD to a similar degree but increased the temporal variability of APD differently, from 3±0.4 ms in control hearts to 8±1.2 ms and to 38±7.5 ms ( P

  • lidocaine and nisoldipine attenuate Almokalant induced dispersion of repolarization and early afterdepolarizations in vitro
    Journal of Cardiovascular Electrophysiology, 1996
    Co-Authors: Christina Abrahamsson, Leif Carlsson, G Duker
    Abstract:

    Attenuation of Almokalant-Induced Proarrhythmias In Vitro. Introduction: Treatment with Class III antiarrhythmic agents may lead to increased dispersion or repolarization and early afterdepolarizations (EADs), which are both likely substrates for torsades de pointes. Recent studies in vivo have shown that the prevalence of proarrhythmias induced by Class III agents may be reduced by Na+ or Ca2+-blocking agents. In the present study, tentative mechanisms for this protective effect were investigated in vitro. Methods and Results: Transmembrane action potentials were recorded simultaneously from rabbit isolated ventricular muscle (VM) and Purkinje fibers (PF). At a basic cycle length (BCL) of 500 msec, the Class III agent Almokalant (0.1 μM) increased the dispersion by prolonging the action potential duration (APD) significantly more in the PF (33%± 4.2%, n = 18) than in the VM (17%± 5.9%, n = 18. P < 0.05). In six of the preparations, addition of 1, 5, and 25 μM lidocaine reduced the Almokalant-induced prolongation in a concentration-dependent manner mainly in the PF, thereby decreasing the dispersion. At 5 μM lidocaine, the remaining prolongation was 7%± 12.2% (P < 0.05 vs time controls) in the PF and 14%± 6.4% in the VM, respectively. In six other preparations, the addition of 0.01, 0.05, and 0.25 μM nisoldipine did not reduce the Almokalant-induced prolongation in the PF and VM, hut attenuated the spike-and-dome appearance of the action potential in the PF. In separate experiments performed at a BCL of 1000 msec, EADs developed in 2 of 6 and 5 of 6 PF during superfusion with Almokalant (0.3 and 1 μM, respectively) at an API) of 828 ± 41.4 msec. In six separate preparations pretreated with lidocaine (5 μ) the Almokalant-induced prolongation in the PF was less pronounced and EADs were not observed. Pretreatment with nisoldipine (0.05 μM) did not influence the response to Almokalant, and in 4 of 6 preparations the APD exceeded 1000 msec. Despite this extensive prolongation, EADs did not appear. Conclusion: At concentrations that did not affect the APD in the VM hut reduced the APD in the PE. lidocaine suppressed Almokalant-induced dispersion and the development of EADs. Nisoldipine, (m the other hand, inhibited Almokalant-induced EADs directly. Hence, (he primary APD-prolonging effect of a Class III agent may he preserved, but the risk of proarrhythmary reduced, during concomitant treatment with low concentrations of a Na+- or Ca2+ blocking agent.

  • Lidocaine and Nisoldipine Attenuate Almokalant‐Induced Dispersion of Repolarization and Early Afterdepolarizations In Vitro
    Journal of cardiovascular electrophysiology, 1996
    Co-Authors: Christina Abrahamsson, Leif Carlsson, G Duker
    Abstract:

    Attenuation of Almokalant-Induced Proarrhythmias In Vitro. Introduction: Treatment with Class III antiarrhythmic agents may lead to increased dispersion or repolarization and early afterdepolarizations (EADs), which are both likely substrates for torsades de pointes. Recent studies in vivo have shown that the prevalence of proarrhythmias induced by Class III agents may be reduced by Na+ or Ca2+-blocking agents. In the present study, tentative mechanisms for this protective effect were investigated in vitro. Methods and Results: Transmembrane action potentials were recorded simultaneously from rabbit isolated ventricular muscle (VM) and Purkinje fibers (PF). At a basic cycle length (BCL) of 500 msec, the Class III agent Almokalant (0.1 μM) increased the dispersion by prolonging the action potential duration (APD) significantly more in the PF (33%± 4.2%, n = 18) than in the VM (17%± 5.9%, n = 18. P < 0.05). In six of the preparations, addition of 1, 5, and 25 μM lidocaine reduced the Almokalant-induced prolongation in a concentration-dependent manner mainly in the PF, thereby decreasing the dispersion. At 5 μM lidocaine, the remaining prolongation was 7%± 12.2% (P < 0.05 vs time controls) in the PF and 14%± 6.4% in the VM, respectively. In six other preparations, the addition of 0.01, 0.05, and 0.25 μM nisoldipine did not reduce the Almokalant-induced prolongation in the PF and VM, hut attenuated the spike-and-dome appearance of the action potential in the PF. In separate experiments performed at a BCL of 1000 msec, EADs developed in 2 of 6 and 5 of 6 PF during superfusion with Almokalant (0.3 and 1 μM, respectively) at an API) of 828 ± 41.4 msec. In six separate preparations pretreated with lidocaine (5 μ) the Almokalant-induced prolongation in the PF was less pronounced and EADs were not observed. Pretreatment with nisoldipine (0.05 μM) did not influence the response to Almokalant, and in 4 of 6 preparations the APD exceeded 1000 msec. Despite this extensive prolongation, EADs did not appear. Conclusion: At concentrations that did not affect the APD in the VM hut reduced the APD in the PE. lidocaine suppressed Almokalant-induced dispersion and the development of EADs. Nisoldipine, (m the other hand, inhibited Almokalant-induced EADs directly. Hence, (he primary APD-prolonging effect of a Class III agent may he preserved, but the risk of proarrhythmary reduced, during concomitant treatment with low concentrations of a Na+- or Ca2+ blocking agent.

  • Rhythm anomalies related to delayed repolarization in vivo: influence of sarcolemmal Ca++ entry and intracellular Ca++ overload.
    The Journal of pharmacology and experimental therapeutics, 1996
    Co-Authors: Leif Carlsson, Lissen Drews, Göran Duker
    Abstract:

    The present study examined how Ca++ entry and intracellular Ca++ overload may contribute to the appearance of torsades de pointes in the setting of delayed repolarization. In anesthetized rabbits, the infusion of methoxamine and the selective I kappa s blocker Almokalant (8.8 micrograms/kg.min) was associated with a lengthening of the QTU interval (37 +/- 2.6 ms, P < .001) and the appearance of torsades de pointes in 9/10 rabbits. In rabbits pretreated with nisoldipine (7.7 or 37 micrograms/kg i.v.), the incidence of Almokalant-induced torsades de pointes was reduced to 7/10 (P = .5820 vs. vehicle) and 1/10 (P = .0006) rabbits, respectively. This occurred without attenuating the QTU-prolonging effect of Almokalant (47 +/- 7.0 ms and 56 +/- 8.6 ms, respectively). Likewise, pretreatment with flunarizine (0.5 or 3.0 mg/kg i.v.) reduced the incidence to 1/6 (P = .0076) and 0/6 animals (P = .0009), respectively. In 10 of the rabbits that were given nisoldipine or flunarizine and did not experience torsades de pointes with Almokalant, BAY K 8644 (0.11 mg/kg) was injected. In six of these rabbits, BAY K 8644 promptly induced torsades de pointes. In four vehicle-pretreated rabbits that experienced torsades de pointes with Almokalant, acute injection of nisoldipine (37 micrograms/kg) abruptly suppressed the proarrhythmia. In separate experiments, rabbits were treated with ryanodine or BAPTA-AM and were subsequently administered Almokalant. Compared with the vehicle-pretreated rabbits, these interventions did not significantly reduce the incidence of torsades de pointes (from 6/5 rabbits to 3/8 and 3/8 rabbits, respectively, P = .1776). The results demonstrate that Ca++ entry through the L-type Ca++ channel may be of crucial importance for the induction of torsades de pointes in the acquired long QT syndrome.

Börje Darpö - One of the best experts on this subject based on the ideXlab platform.

  • QRS aberration during atrial fibrillation at rest and during exercise. Effect of a selective potassium channel blocking agent
    Journal of Electrocardiology, 2002
    Co-Authors: Birgitta Houltz, Harry J.g.m. Crijns, Börje Darpö, Karl Swedberg, Per Blomström, Steen M. Jensen, Elisabeth Svernhage, Nils Edvardsson
    Abstract:

    Abstract This study assesses the occurrence of and identifies clinical characteristics associated with the development of aberrant conduction during infusion of the I kr -blocker Almokalant. Class III drugs may induce aberrant conduction by prolongation of cardiac repolarization, especially during atrial fibrillation (AF). Ninety-two patients with AF received a 6-hour Almokalant infusion, aiming at conversion to sinus rhythm (SR). Fiftyfive of the patients received an identical infusion during SR. During Almokalant infusion, the number of patients with intermittent QRS aberration during AF increased, from 21% to 80% at rest, and was further increased to 89% during exercise, with predominantly left, and sequential bilateral, bundle branch aberrancy. Patients with aberrant conduction showed signs of more advanced myocardial disease. Predictors of the development of QRS aberration were female gender, arrhythmia duration, and decreased left ventricular ejection fraction, while use of calcium antagonists decreased the probability. No patient showed aberration during regular SR. Twenty-one patients experienced aberrantly conducted supraventricular premature beats. In conclusion, aberrant conduction is common during infusion of the I kr -blocker Almokalant during AF, and seems to be more frequent in females and in patients with more advanced myocardial disease.

  • Comparison of QT dispersion during atrial fibrillation and sinus rhythm in the same patients, at normal and prolonged ventricular repolarization
    Europace : European pacing arrhythmias and cardiac electrophysiology : journal of the working groups on cardiac pacing arrhythmias and cardiac cellula, 2000
    Co-Authors: Birgitta Houltz, Harry J.g.m. Crijns, Börje Darpö, Karl Swedberg, Per Blomström, Steen M. Jensen, Elisabeth Svernhage, Nils Edvardsson
    Abstract:

    Aims Drug-induced increase in QT dispersion has been associated with increased risk of ventricular proarrhythmia. The aim of the present study was to compare QT dispersion during atrial fibrillation and sinus rhythm in the same patients at normal and prolonged ventricular repolarization. Methods and Results Sixty-one patients who had had chronic atrial fibrillation for 8 +/- 14 months received a 6 h infusion of the I-kr-bIocker Almokalant, the first 90 min of which are used for this analysis. The following day, after conversion to sinus rhythm, by Almokalant (n = 19) or direct current cardioversion (n = 42), an identical 90 min infusion was administered. Prior to infusion, there was no difference in precordial QT dispersion between atrial fibrillation and sinus rhythm (29 +/- 12 vs 36 +/- 17 ms, P = ns). During infusion, at prolonged repolarization, the increase in QT dispersion was greater during sinus rhythm than during atrial fibrillation (58 +/- 49 vs 30 +/- 15 ms, P = 0.0011, after 30 min infusion). No correlation was found between QT dispersion and the QT or RR interval. Conclusion QT dispersion during atrial fibrillation does not differ from QT dispersion during sinus rhythm during normal repolarization, while measurement of QT dispersion during prolonged repolarization, induced by an I-kr-blocker, yielded larger values during sinus rhythm than during atrial fibrillation. (C) 2000 The European Society of Cardiology.

  • Effects of the Ikr-Blocker Almokalant and Predictors of Conversion of Chronic Atrial Tachyarrhythmias to Sinus Rhythm. A Prospective Study
    Cardiovascular Drugs and Therapy, 1999
    Co-Authors: Birgitta Houltz, Harry J.g.m. Crijns, Börje Darpö, Karl Swedberg, Per Blomström, Steen M. Jensen, Elisabeth Svernhage, Johannes Brachmann, Hans Vallin, Nils Edvardsson
    Abstract:

    Purpose: To assess the efficacy of the I_kr-blocker Almokalant attempting to convert chronic atrial tachyarrhythmias, and to find predictors of conversion, to sinus rhythm. Methods: The electrophysiological effects of a 6-hour infusion of Almokalant, to a total dose of 25 ± 4 mg, were assessed by ECG and transesophageal atrial electrograms (TAE) in 100 consecutive patients with atrial fibrillation / flutter (n = 95 / 5) of 8 ± 12 months' duration (range 1 to 99 months). Results: The conversion rate was 32%. The time to conversion was 3.5 ± 2.2 hours. During infusion increases in QT_top (292 ± 35 to 335 ± 44 ms, p < 0.001, after 30 minutes), QT (387 ± 40 to 446 ± 60 ms, p < 0.001), corrected QT (425 ± 30 to 487 ± 44 ms, p < 0.001), and QT dispersion (21 ± 12 to 29 ± 31 ms, p = 0.02), were paralleled by decreases in T wave amplitude (0.31 ± 0.19 to 0.23 ± 0.16 mV, p < 0.001), and atrial rate (425 ± 78 to 284 ± 44 beats per minute (bpm) on ECG, and 396 ± 72 to 309 ± 44 bpm on TAE), with no differences between converters to sinus rhythm and non-converters. Patients with aberrantly conducted beats, and T wave variation, also increased. Calcium antagonists were more common among converters. A decreasing T wave amplitude predicted conversion. Four patients developed torsades de pointes. Conclusions: This study demonstrates class III action of Almokalant, with a conversion rate of 32% of long-standing, chronic atrial tachyarrhytmias. An early decrease in T wave amplitude was associated with conversion to sinus rhythm.

  • Effects of the Ikr-blocker Almokalant and predictors of conversion of chronic atrial tachyarrhythmias to sinus rhythm. A prospective study.
    Cardiovascular drugs and therapy, 1999
    Co-Authors: Birgitta Houltz, Harry J.g.m. Crijns, Börje Darpö, Karl Swedberg, Per Blomström, Steen M. Jensen, Elisabeth Svernhage, Johannes Brachmann, Hans Vallin, Nils Edvardsson
    Abstract:

    Purpose: To assess the efficacy of the Ikr-blocker Almokalant attempting to convert chronic atrial tachyarrhythmias, and to find predictors of conversion, to sinus rhythm.

  • electrocardiographic and clinical predictors of torsades de pointes induced by Almokalant infusion in patients with chronic atrial fibrillation or flutter a prospective study
    Pacing and Clinical Electrophysiology, 1998
    Co-Authors: Birgitta Houltz, Harry J.g.m. Crijns, Börje Darpö, Nils Edvardsson, Per Blomström, Steen M. Jensen, Elisabeth Svernhage, Johannes Brachmann, Hans Vallin, Karl Swedberg
    Abstract:

    The aim of this study was to identify predictors of torsades de pointes (TdP) in patients with atrial fibrillation (AF) or flutter exposed to the Class III antiarrhythmic drug Almokalant. TdP can be caused by drugs that prolong myocardial repolarization. One hundred patients received Almokalant infusion during AF (infusion 1) and 62 of the patients during sinus rhythm (SR) on the following day (infusion 2). Thirty-two patients converted to SR. Six patients developed TdP. During AF, T wave alternans was more common prior to infusion (baseline) in patients developing TdP 150% vs 4%, P <0.01). After 30 minutes of infusion 1, the TdP patients exhibited a longer QT interval (493 +/- 114 vs 443 +/- 54 ms [mean +/- SD], P ( 0.01), a larger precordial QT dispersion (50 +/- 74 vs 27 +/- 26 ms, P <0.05), and a lower T wave amplitude (0.12 +/- 0.21 vs 0.24 +/- 0.16 mV, P <0.01). After 30 minutes of infusion 2, they exhibited a longer QT interval (672 +/- 26 vs 489 +/- 74 ms, P <0.001), a larger QT dispersion in precordial (82 +/- 7 vs 54 +/- 52 ms, P <0.01) and extremity leads (163 +/- 0 vs 40 +/- 34 ms, P <0.001), and T wave alternans was more common (100% vs 0%, P <0.001). Risk factors for development of TdP were at baseline: female gender, ventricular extrasystoles, and treatment with diuretics; and, after 30 minutes of infusion: sequential bilateral bundle branch block, ventricular extrasystoles in bigeminy, and a biphasic T wave. Patients developing TdP exhibited early during Almokalant infusion a pronounced QT prolongation, increased QT dispersion, and marked morphological T wave changes.

Christina Abrahamsson - One of the best experts on this subject based on the ideXlab platform.

  • Potassium and calcium current blocking properties of the novel antiarrhythmic agent H 345/52: implications for proarrhythmic potential.
    Cardiovascular research, 2001
    Co-Authors: Gregory J Amos, Christina Abrahamsson, Göran Duker, Luc M. Hondeghem, Mattias Palmer, Leif Carlsson
    Abstract:

    Objectives: To study the blocking effects of H 345/52 on ionic currents of rabbit ventricular myocytes and how these features translate into a proarrhythmic potential. Methods : The single electrode voltage clamp technique was used to study the effects of H 345/52 on the rapid component of the delayed rectifying potassium current, I Kr, and the L-type calcium current ( I Ca). Differential effects of H 345/52 and Almokalant on APD prolongation were studied in a rabbit Purkinje fibre/ventricular muscle preparation. The temporal variability of the action potential duration (APD) and its relation to proarrhythmias was examined in Langendorff-perfused rabbit hearts administered H 345/52 or Almokalant. Anaesthetised, methoxamine-sensitised rabbits were used to assess the propensity of intravenous H 345/52 and ibutilide to induce torsades de pointes (TdP). Results: H 345/52 potently blocked I Kr (IC50=40 nM) without consequential use-dependency. The I Ca was also blocked, but at higher concentrations (IC50=1.3 μM). Block of I Ca was markedly frequency-dependent (positive) and influenced by membrane potential, such that H 345/52 was more effective following clamp steps from plateau potentials than from −80 mV. In the Purkinje fibre–ventricular muscle preparation, Almokalant prolonged the Purkinje fibre APD preferentially, whereas H 345/52 homogeneously prolonged APD in both tissue types. In the perfused rabbit heart, H 345/52 (1 μM) and Almokalant (0.3 μM) prolonged APD to a similar degree but increased the temporal variability of APD differently, from 3±0.4 ms in control hearts to 8±1.2 ms and to 38±7.5 ms ( P

  • lidocaine and nisoldipine attenuate Almokalant induced dispersion of repolarization and early afterdepolarizations in vitro
    Journal of Cardiovascular Electrophysiology, 1996
    Co-Authors: Christina Abrahamsson, Leif Carlsson, G Duker
    Abstract:

    Attenuation of Almokalant-Induced Proarrhythmias In Vitro. Introduction: Treatment with Class III antiarrhythmic agents may lead to increased dispersion or repolarization and early afterdepolarizations (EADs), which are both likely substrates for torsades de pointes. Recent studies in vivo have shown that the prevalence of proarrhythmias induced by Class III agents may be reduced by Na+ or Ca2+-blocking agents. In the present study, tentative mechanisms for this protective effect were investigated in vitro. Methods and Results: Transmembrane action potentials were recorded simultaneously from rabbit isolated ventricular muscle (VM) and Purkinje fibers (PF). At a basic cycle length (BCL) of 500 msec, the Class III agent Almokalant (0.1 μM) increased the dispersion by prolonging the action potential duration (APD) significantly more in the PF (33%± 4.2%, n = 18) than in the VM (17%± 5.9%, n = 18. P < 0.05). In six of the preparations, addition of 1, 5, and 25 μM lidocaine reduced the Almokalant-induced prolongation in a concentration-dependent manner mainly in the PF, thereby decreasing the dispersion. At 5 μM lidocaine, the remaining prolongation was 7%± 12.2% (P < 0.05 vs time controls) in the PF and 14%± 6.4% in the VM, respectively. In six other preparations, the addition of 0.01, 0.05, and 0.25 μM nisoldipine did not reduce the Almokalant-induced prolongation in the PF and VM, hut attenuated the spike-and-dome appearance of the action potential in the PF. In separate experiments performed at a BCL of 1000 msec, EADs developed in 2 of 6 and 5 of 6 PF during superfusion with Almokalant (0.3 and 1 μM, respectively) at an API) of 828 ± 41.4 msec. In six separate preparations pretreated with lidocaine (5 μ) the Almokalant-induced prolongation in the PF was less pronounced and EADs were not observed. Pretreatment with nisoldipine (0.05 μM) did not influence the response to Almokalant, and in 4 of 6 preparations the APD exceeded 1000 msec. Despite this extensive prolongation, EADs did not appear. Conclusion: At concentrations that did not affect the APD in the VM hut reduced the APD in the PE. lidocaine suppressed Almokalant-induced dispersion and the development of EADs. Nisoldipine, (m the other hand, inhibited Almokalant-induced EADs directly. Hence, (he primary APD-prolonging effect of a Class III agent may he preserved, but the risk of proarrhythmary reduced, during concomitant treatment with low concentrations of a Na+- or Ca2+ blocking agent.

  • Lidocaine and Nisoldipine Attenuate Almokalant‐Induced Dispersion of Repolarization and Early Afterdepolarizations In Vitro
    Journal of cardiovascular electrophysiology, 1996
    Co-Authors: Christina Abrahamsson, Leif Carlsson, G Duker
    Abstract:

    Attenuation of Almokalant-Induced Proarrhythmias In Vitro. Introduction: Treatment with Class III antiarrhythmic agents may lead to increased dispersion or repolarization and early afterdepolarizations (EADs), which are both likely substrates for torsades de pointes. Recent studies in vivo have shown that the prevalence of proarrhythmias induced by Class III agents may be reduced by Na+ or Ca2+-blocking agents. In the present study, tentative mechanisms for this protective effect were investigated in vitro. Methods and Results: Transmembrane action potentials were recorded simultaneously from rabbit isolated ventricular muscle (VM) and Purkinje fibers (PF). At a basic cycle length (BCL) of 500 msec, the Class III agent Almokalant (0.1 μM) increased the dispersion by prolonging the action potential duration (APD) significantly more in the PF (33%± 4.2%, n = 18) than in the VM (17%± 5.9%, n = 18. P < 0.05). In six of the preparations, addition of 1, 5, and 25 μM lidocaine reduced the Almokalant-induced prolongation in a concentration-dependent manner mainly in the PF, thereby decreasing the dispersion. At 5 μM lidocaine, the remaining prolongation was 7%± 12.2% (P < 0.05 vs time controls) in the PF and 14%± 6.4% in the VM, respectively. In six other preparations, the addition of 0.01, 0.05, and 0.25 μM nisoldipine did not reduce the Almokalant-induced prolongation in the PF and VM, hut attenuated the spike-and-dome appearance of the action potential in the PF. In separate experiments performed at a BCL of 1000 msec, EADs developed in 2 of 6 and 5 of 6 PF during superfusion with Almokalant (0.3 and 1 μM, respectively) at an API) of 828 ± 41.4 msec. In six separate preparations pretreated with lidocaine (5 μ) the Almokalant-induced prolongation in the PF was less pronounced and EADs were not observed. Pretreatment with nisoldipine (0.05 μM) did not influence the response to Almokalant, and in 4 of 6 preparations the APD exceeded 1000 msec. Despite this extensive prolongation, EADs did not appear. Conclusion: At concentrations that did not affect the APD in the VM hut reduced the APD in the PE. lidocaine suppressed Almokalant-induced dispersion and the development of EADs. Nisoldipine, (m the other hand, inhibited Almokalant-induced EADs directly. Hence, (he primary APD-prolonging effect of a Class III agent may he preserved, but the risk of proarrhythmary reduced, during concomitant treatment with low concentrations of a Na+- or Ca2+ blocking agent.

  • Induction of rhythm abnormalities in the fetal rat heart. A tentative mechanism for the embryotoxic effect of the class III antiarrhythmic agent Almokalant
    Cardiovascular research, 1994
    Co-Authors: Christina Abrahamsson, Leif Carlsson, Göran Duker, Mattias Palmer, Catharina Bäärnhielm, Bengt Ljung, Bengt Danielsson
    Abstract:

    Objectives: The aim was to test the hypothesis that the recently reported embryotoxic effect of class III antiarrhythmic agents may be a result of electrophysiological disturbances induced by these agents. Methods: Comparative studies of drug effects in the adult and fetal rat were performed using three experimental models: (1) effects of Almokalant upon pregnancy and fetal mortality in rats given daily doses of 0, 10, 50, 100, or 400 (μmol·kg−1 orally in the diet on days 6-15 of pregnancy; (2) effects of d-sotalol (1-1000 μM), Almokalant (0.1-100 μM) and dofetilide (0.01-10 μM) on the adult and fetal cardiac action potential in vitro; (3) voltage clamp recordings in single fetal and adult ventricular myocytes superfused with Almokalant (0.5 μM). Results: In the groups of rats treated with 100 and 400 μmol·kg−1, respectively, the body weight gain was decreased from day 12 of gestation, and there were no viable fetuses at termination of pregnancy. In atrial as well as ventricular tissue, the class III agents induced a concentration dependent prolongation of the fetal action potential duration, accompanied by a reduction in heart rate and eventually the appearance of rhythm abnormalities and/or early afterdepolarisations. The adult action potential duration remained unaffected. An Almokalant sensitive current (probably the delayed rectifier, IK) could be evoked both in the fetal and in the adult ventricular cells. Conclusions: Class III antiarrhythmic agents were shown to induce fetal mortality and rhythm abnormalities in the rat heart. Although they do not prove a causal relationship between these effects, our observations may have implications for the clinical use of class III antiarrhythmic agents in women of childbearing potential. Cardiovascular Research 1994; 28 :337-344

  • Proarrhythmic effects of the class III agent Almokalant: importance of infusion rate, QT dispersion, and early afterdepolarisations
    Cardiovascular research, 1993
    Co-Authors: Leif Carlsson, Christina Abrahamsson, G Duker, Birgit Andersson, Gunilla Schiller-linhardt
    Abstract:

    Objective: The aim was to study factors contributing to torsade de pointes in the acquired long QT syndrome. Methods: Anaesthetised rabbits or cats were given a continuous infusion of methoxamine and the class III agent Almokalant (at a rate of 5 or 25 nmol·kg−1·min−1, respectively) and the effects on incidence of torsade de pointes and QT dispersion were examined. Effects of Almokalant on action potentials recorded from Purkinje fibres and ventricular cells of rabbits and cats were also studied. Results: “High rate” infusion of Almokalant prolonged the QT, interval [from 162(SEM 6.2) ms to 211(5.3) ms, p

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  • developmental toxicity of the class iii antiarrhythmic agent Almokalant in mice adverse effects mediated via induction of embryonic heart rhythm abnormalities
    Drug Research, 2011
    Co-Authors: Annacarin Skold, Bengt Danielsson
    Abstract:

    Almokalant (ALM, CAS 123955-10-2), a class III antiarrhythmic drug, has been shown to be embryotoxic in rats. In the absence of human pregnancy outcome data, the human relevance of these findings in rats is unknown, and results from other species would indicate if these findings are of more universal interest. Therefore, this study was initiated to evaluate the potential effects in mice. ALM was given to three groups of pregnant mice (~20 mice/group) during gestation days 6-15 at dose levels of 50, 125 and 300 µmol/kg. A fourth group served as a control. In addition, whole embryo culture was performed on gestation day 10 with doses of ALM ranging from 325-5200 nmol/1 (~17 embryos/group) in order to study if ALM had the potential to induce dysrhythmia in the embryonic mouse heart. ALM induced total embryonic death in the high dose group, and in the intermediate group the level of embryonic death was elevated and the mean foetal weights decreased. A slight increase in minor skeletal defects was observed, mainly consisting of reduced calcification of elements in the vertebral column and among the phalanges. ALM caused bradycardia in a concentration dependent manner (13-42% at 650-5200 nmol/1). Irregular heart rhythm and/ or episodes of cardiac arrest were observed in one embryo at 2600 and in seven embryos at 5200 nmol/1. In conclusion, ALM caused embryotoxicity in the mouse, most likely secondary to adverse effects on the embryonic heart. The results may suggest that class III antiarrhythmics are embryotoxic also in humans.

  • New Proposals for Testing Drugs with IKr-Blocking Activity to Determine Their Teratogenic Potential
    Current pharmaceutical design, 2007
    Co-Authors: Miriam Karlsson, Bengt Danielsson, Mats Nilsson, Christian Danielsson, William S. Webster
    Abstract:

    Drugs blocking the potassium current IKr, either as an intended pharmacologic effect (eg antiarrhythmics dofetilide and Almokalant) or as an unwanted side-effect (eg antihistamine astemizole, propulsive drug cisapride, antidepressive drugs and macrolide antibiotics) are potential human teratogens. It is the contention of this paper that the existing repeat dose regimen used in teratology studies to fulfil regulatory requirements, does not properly identify the teratogenic risk of these drugs. Results from conventional studies for dofetilide and Almokalant showed high rates of postimplantation embryonic death with few malformed fetuses. For astemizole and cisapride only embryonic death was seen. These latter results were not considered important because they occurred either in the presence of maternal toxicity and/or at high doses. Subsequent studies have shown that IKr-blockers are highly teratogenic when administered on single gestational days (GD) during a sensitive period of rat pregnancy (GD 10-14) when they induce a high incidence of stage-specific malformations. This teratogenic activity of astemizole and cisapride was missed in the original teratology studies. Mechanistically IKr-blockers cause bradycardia and arrhythmia of the embryonic heart and while an embryo may be able to survive a single day exposure to a teratogenic dose, repeat dosing often leads to death of the embryo. With this review we suggest that new drugs identified at the preclinical stage of development as having IKr-blocking properties, should undergo more comprehensive teratology testing including single GD dosing and studies using embryo culture. This would further help identify and characterise their teratogenic potential.

  • Embryonic cardiac arrhythmia and generation of reactive oxygen species: Common teratogenic mechanism for IKr blocking drugs
    Reproductive toxicology (Elmsford N.Y.), 2007
    Co-Authors: Bengt Danielsson, Christian Danielsson, Mats Nilsson
    Abstract:

    In the adult organism, it is well established that hypoxia followed by reperfusion may be fatal and result in generation of reactive oxygen species (ROS) and subsequent tissue damage. There is also considerable evidence that temporary decrease or interruption in oxygen supply to the embryo and ROS generation during reperfusion result in tissue damage in embryonic tissues. A wide spectrum of different malformations by transient embryonic hypoxia could be produced, depending on the duration, extent, and timing of the hypoxic event. It is the contention of this paper that drugs that block the potassium channel IKr, either as an intended pharmacologic effect or as an unwanted side-effect, are potentially teratogenic by a common ROS related mechanism. Drugs blocking the IKr channel, such as Almokalant, dofetilide, phenytoin, cisapride and astemizole, do all produce a similar pattern of hypoxia-related malformations. Mechanistic studies show that the malformations are preceded by embryonic cardiac arrhythmia and periods of hypoxia/reoxygenation in embryonic tissues. Pretreatment or simultaneous treatment with radical scavengers with capacity to capture ROS, markedly decrease the teratogenicity of different IKr blocking drugs. A second aim of this review is to demonstrate that the conventional design of teratology studies is not optimal to detect malformations caused by IKr blocking drugs. Repeated high doses result in high incidences of embryonic death due embryonic cardiac arrhythmia, thus masking their teratogenic potential. Instead, single dosing on specific days is proposed to be a better way to characterize the teratogenic potential of Ikr blocking drugs.

  • Teratogenicity by the hERG potassium channel blocking drug Almokalant: use of hypoxia marker gives evidence for a hypoxia-related mechanism mediated via embryonic arrhythmia.
    Toxicology and applied pharmacology, 2003
    Co-Authors: Bengt Danielsson, Annacarin Skold, Alf Johansson, Birgitta Dillner, Bo Blomgren
    Abstract:

    Teratogenicity by the hERG potassium channel blocking drug Almokalant : use of hypoxia marker gives evidence for a hypoxia-related mechanism mediated via embryonic arrhythmia.

  • Stage-specific skeletal and visceral defects of the IKr-blocker Almokalant: Further evidence for teratogenicity via a hypoxia-related mechanism
    Teratology, 2001
    Co-Authors: Annacarin Skold, Katrin Wellfelt, Bengt Danielsson
    Abstract:

    Background: As a class effect, potent I Kr -blockers have been shown to induce stage-specific external malformations. The aim of this study was to investigate whether I Kr -blockers also induce stage-specific visceral and skeletal defects and to further elucidate a proposed arrhythmia-hypoxia hypothesis. Methods: Single oral doses of the selective I Kr -blocker Almokalant (ALM) 25-150 μmol/kg, 7-14 dams/ group, were given to Sprague-Dawley rats on gestation days (GD) 10-14, and the fetuses were examined for malformations on GD 21. One group was pretreated with the spin-trapping agent, α-phenyl-N-t-butylnitrone (PBN), given intraperitoneally 1 hr before ALM on GD 11. Results: Cardiac ventricular septum defects and vascular malformations were observed after dosing on GD 10-11 and, to a lesser degree, on GD 12-13. Urogenital defects, absence/malposition of the postcaval lung lobe, and attenuated diaphragm were observed mainly on GD 10-11. Skeletal examination showed a high incidence of vertebral abnormalities on thoracic level on GD 10, on lower thoracic to caudal level on GD 11, and sternebral defects were observed all days. On GD 13 brachy-, oligo-, and syndactyly of the forepaw were induced, and of the hindpaw on GD 14. PBN reduced the incidence of both visceral and skeletal defects. Conclusions: The stage specificity of observed visceral and skeletal defects correlates well with what has been reported in the literature after temporary interruption of oxygen supply during the same stages of development. The protective effect by PBN present further evidence that the teratogenicity of potent I Kr -blockers is related to induction of hypoxia- reoxygenation injury due to embryonic cardiac arrhythmia.