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Wilhelm Haverkamp - One of the best experts on this subject based on the ideXlab platform.
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comparison of the in vitro electrophysiologic and proarrhythmic effects of amiodarone and Sotalol in a rabbit model of acute atrioventricular block
Journal of Cardiovascular Pharmacology, 2004Co-Authors: Peter Milberg, Gunter Breithardt, Wilhelm Haverkamp, Nani Osada, Shahram Ramtin, Gerold Monnig, Kristina Wasmer, Lars EckardtAbstract:The mechanisms for the different proarrhythmic potential of antiarrhythmic drugs in the presence of comparable QT prolongation are not completely understood. The reasons for the lower proarrhythmic potential of amiodarone as compared with other class-III antiarrhythmic drugs such as Sotalol, a fact that has been well established for years, is insufficiently known. Therefore, the aim of our study was to assess the different electrophysiologic effects of amiodarone and Sotalol in a previously developed experimental model of proarrhythmia. In eight male rabbits, amiodarone (280-340 mg/d) was fed over a period of six weeks. Hearts were excised and retrogradely perfused. Up to eight simultaneous epi- and endocardial monophasic action potentials (MAP) were recorded. Results were compared with Sotalol-treated (10-50-100 microM) hearts (n = 13). Amiodarone and Sotalol (50 microM and 100 microM) led to a significant increase in QT interval (mean increase: amiodarone: 31 +/- 6 ms; Sotalol: 41 +/- 4 ms and 61 +/- 9 ms) and MAP-duration (mean increase-MAP90: amiodarone: 20 +/- 5 ms; Sotalol: 17 +/- 5 ms and 25 +/- 8 ms) (P < 0.01). In bradycardic (AV-blocked) hearts, MAP-recordings demonstrated reverse-use dependence and a significant increase in dispersion of repolarization (MAP90) in the presence of Sotalol (P < 0.01), but not in amiodarone-treated hearts (10%; p = ns). Sotalol led to early afterdepolarizations (EAD) and torsade de pointes (TdP) after lowering of potassium concentration (6 of 13 hearts). In amiodarone-treated, hypokalemic hearts, no EAD or TdP occurred. Sotalol changed the MAP configuration to a triangular pattern (ratio-MAP90/50: 1.52 as compared with 1.36 at baseline) whereas amiodarone caused a rectangular pattern of MAP prolongation (ratio-MAP90/50: 1.36). In conclusion, these results show no direct correlation between the occurrence of TdP and the degree of QT prolongation. Several factors including reverse-use dependence, dispersion of repolarization, and the propensity to induce early afterdepolarizations but also differences in the action potential configuration may help to understand proarrhythmic side effects of drugs.
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electrophysiologic characterization of the antipsychotic drug sertindole in a rabbit heart model of torsade de pointes low torsadogenic potential despite qt prolongation
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Lars Eckardt, Gunter Breithardt, Wilhelm HaverkampAbstract:There is growing concern that antipsychotic drugs that prolong the QT interval almost always increase the risk for patients to develop life-threatening ventricular tachyarrhythmias (VTs) of the torsade de pointes type. We therefore sought to compare the electrophysiologic effects of the psychotropic agent sertindole, which prolongs cardiac repolarization by inhibiting the rapid component of the delayed rectifier potassium current ( I Kr) but has a low torsadogenic potential to the antiarrhythmic agent dl -Sotalol. In 18 Langendorff-perfused rabbit hearts, Sotalol (10 μM, n = 8) and sertindole (0.5, 1.0, and 1.5 μM; n = 10) led to significant and comparable QT prolongation. In the presence of Sotalol, torsade de pointes reproducibly occurred in atrioventricular node-blocked hearts after lowering the potassium concentration to 1.5 mM. High doses of sertindole (1.5 μM) only caused monomorphic VT ( n = 4) and nonsustained polymorphic VT ( n = 2) in the presence of QRS prolongation. Multiple simultaneous epi- and endocardial monophasic action potentials and a volume-conducted ECG demonstrated widening of the T/U wave, early afterdepolarizations, and increased dispersion of repolarization in the presence of dl -Sotalol. In contrast to Sotalol, QT and monophasic action potential prolongation were cycle length-independent in the presence of sertindole. Sertindole had no significant effect on transmural or interventricular dispersion of repolarization. Early afterdepolarizations did not occur. Despite comparable QT prolongation, sertindole did not display the proarrhythmic profile typical of other blockers of I Kr such as dl -Sotalol. It is likely that a different mode of interaction between sertindole and the channel and/or additional pharmacological effects of sertindole, e.g., its ability to inhibit I Na and/or its ability to block α1-receptors, play a role. * LQTS : long QT syndrome APD90 : action potential duration at 90% repolarization AV : atrioventricular CL : cycle length EAD : early afterdepolarization HERG : human ether-a-go-go-related gene I Kr : rapid component of delayed rectifier current I Na : sodium current MAP : monophasic action potential TdP : torsade de pointes VT : ventricular tachyarrhythmia
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efficacy and safety of d l Sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest
Journal of the American College of Cardiology, 1997Co-Authors: Wilhelm Haverkamp, Gunter Breithardt, A Martinezrubio, Christiene Hief, Andreas Lammers, Stefan Muhlenkamp, Thomas Wichter, M BorggrefeAbstract:Objectives. The aim of this study was to assess the antiarrhythmic efficacy and safety of d,l-Sotalol in patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) and in survivors of cardiac arrest and to identify the factors that are associated with arrhythmia suppression and therefore might be helpful in predicting drug efficacy. Background. Despite increasing use of the class III antiarrhythmic agent d,l-Sotalol, data on its short- and long-term efficacy in a large patient cohort are lacking. Information on its long-term tolerability and safety is limited. Methods. A total of 396 patients with inducible sustained VT or VF (VT/VF) underwent programmed stimulation before and after receiving oral d,l-Sotalol (240 to 640 mg/day). Patients in whom VT/VF was rendered either noninducible or more difficult to induce (more extrastimuli or faster drive cycle length needed for VT/VF induction) were discharged on a regimen of oral d,l-Sotalol. Results. d,l-Sotalol suppressed VT/VF in 151 patients (38.1%) and rendered the arrhythmia more difficult to induce in 76 patients (19.2%). The extent of drug-induced prolongation of right ventricular refractoriness and a shorter VT cycle length at baseline were independent predictors of immediate drug efficacy. Torsade de pointes developed in seven patients (1.8%). Two hundred ten patients (53%) continued to receive d,l-Sotalol and were followed up for 34 ± 18 months (mean ± SD). The actuarial rates for the absence of arrhythmic recurrence (either VT/VF or sudden death) at 1 and 3 years were 89% and 77%, respectively. Actuarial rates for overall survival at 1 and 3 years were 94% and 86%, respectively. VT/VF suppression by d,l-Sotalol was an independent discriminant variable that separated patients with and without arrhythmia recurrence. However, noninducibility of VT/VF did not predict freedom from sudden death. Conclusions. Oral d,l-Sotalol is effective and safe in patients with VT/VF. However, sudden cardiac death develops in a significant proportion of patients, and programmed stimulation seems to be of limited value for its prediction.
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comparison of d l Sotalol and implantable defibrillators for treatment of sustained ventricular tachycardia or fibrillation in patients with coronary artery disease
Circulation, 1996Co-Authors: Dirk Bocker, Wilhelm Haverkamp, Michael Block, M Borggrefe, Dieter Hammel, G BreithardtAbstract:Background Implantable cardioverter-defibrillators (ICDs) and d,l- Sotalol are widely used to treat ventricular tachyarrhythmia and ventricular fibrillation (VT/VF). The purpose of this study was to compare the long-term efficacy of d,l -Sotalol and ICDs in patients with coronary artery disease. Methods and Results In a case-control study, 50 patients treated with oral d,l -Sotalol were matched to 50 patients treated with ICDs. Both groups were matched for sex (82 men), age (58±10 years), ejection fraction (40±12%), extent of coronary artery disease, presenting arrhythmia, and year that treatment began. In all patients in the Sotalol group, VT/VF was inducible in the drug-free electrophysiological study. Induction of sustained VT/VF was suppressed by d,l -Sotalol (438±95 mg/d). In the ICD group, either VT/VF was not inducible (n=5) or inducible sustained VT/VF was refractory to antiarrhythmic drug treatment (n=45). Sotalol treatment led to a marked reduction in arrhythmic events. Whereas 83% of the patients in the Sotalol group were free of sudden death and nonfatal VT at 3 years, only 33% of the ICD patients did not receive appropriate ICD therapies ( P <.005). Actuarial rates for absence of sudden death at 3 years were 85% in the Sotalol group and 100% in the ICD group ( P <.005). Actuarial rates for overall survival at 3 years were 75% in the Sotalol group and 85% in the ICD group ( P =.02). Conclusions In this case-control study, ICD therapy was more effective than electrophysiologically guided antiarrhythmic treatment with d,l -Sotalol in prevention of sudden death and reduction of total mortality in patients with coronary artery disease. Prospective studies are needed to confirm these results.
Lars Eckardt - One of the best experts on this subject based on the ideXlab platform.
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Effect of ranolazine on ventricular repolarization in class III antiarrhythmic drug-treated rabbits.
Heart rhythm, 2012Co-Authors: Gerrit Frommeyer, Sridharan Rajamani, Luiz Belardinelli, Lars Eckardt, Gunter Breithardt, Dennis Kaiser, Timo Uphaus, Sven Kaese, Nani Osada, Peter MilbergAbstract:BACKGROUND Ranolazine exhibits a synergistic effect in combination with class III drugs to suppress atrial fibrillation. OBJECTIVE To investigate whether a combination therapy affects repolarization and provokes ventricular tachyarrhythmias (VT) in a sensitive model of proarrhythmia. METHODS Thirty-seven rabbits were assigned to 3 groups and fed with amiodarone (50 mg/kg/d; n=10) or dronedarone (50 mg/kg/d; n=10) over a period of 6 weeks. A third group was used as control (n = 17). After obtaining baseline data in Langendorff-perfused control hearts, Sotalol (100 μM) was administered in this group. Thereafter, ranolazine (10 μM) was additionally infused on top of amiodarone, dronedarone, or Sotalol. RESULTS Chronic treatment with amiodarone or dronedarone as well as Sotalol significantly increased action potential duration at 90% repolarization (APD 90 ). Additional treatment with ranolazine further increased APD 90 in amiodarone- and dronedarone-pretreated hearts but not in Sotalol-treated hearts. Ranolazine increased postrepolarization refractoriness as compared with amiodarone or dronedarone alone owing to a marked effect on the refractory period. In contrast to amiodarone and dronedarone, acute application of Sotalol increased dispersion of repolarization ( P + ] in bradycardic hearts, no proarrhythmia occurred in amiodarone- or dronedarone-treated hearts whereas 11 of 17 Sotalol-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with ranolazine reduced the number of VT episodes in Sotalol-treated hearts and did not cause proarrhythmia in combination with amiodarone or dronedarone. CONCLUSIONS Application of ranolazine on top of class III drugs does not cause proarrhythmia despite a marked effect on ventricular repolarization. The effect of ranolazine on the repolarization reserve is associated with the lack of effect on early afterdepolarizations and dispersion of repolarization.
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reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short qt syndrome
Journal of Cardiovascular Electrophysiology, 2007Co-Authors: Peter Milberg, Gunter Breithardt, Nani Osada, Regina Tegelkamp, Rainer Schimpf, Christian Wolpert, Martin Borggrefe, Lars EckardtAbstract:BACKGROUND Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. METHODS AND RESULTS Pinacidil, an I(K-ATP) channel opener, was administered in increasing concentrations (50-100 microM) in 48 Langendorff-perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I(Kr) blocker Sotalol (100 microM) and the class I antiarrhythmic drugs flecainide (2 microM) and quinidine (0.5 microM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with Sotalol and flecainide. Moreover, quinidine, in contrast to Sotalol and flecainide, reduced dispersion of repolarization. CONCLUSION Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with Sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.
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comparison of the in vitro electrophysiologic and proarrhythmic effects of amiodarone and Sotalol in a rabbit model of acute atrioventricular block
Journal of Cardiovascular Pharmacology, 2004Co-Authors: Peter Milberg, Gunter Breithardt, Wilhelm Haverkamp, Nani Osada, Shahram Ramtin, Gerold Monnig, Kristina Wasmer, Lars EckardtAbstract:The mechanisms for the different proarrhythmic potential of antiarrhythmic drugs in the presence of comparable QT prolongation are not completely understood. The reasons for the lower proarrhythmic potential of amiodarone as compared with other class-III antiarrhythmic drugs such as Sotalol, a fact that has been well established for years, is insufficiently known. Therefore, the aim of our study was to assess the different electrophysiologic effects of amiodarone and Sotalol in a previously developed experimental model of proarrhythmia. In eight male rabbits, amiodarone (280-340 mg/d) was fed over a period of six weeks. Hearts were excised and retrogradely perfused. Up to eight simultaneous epi- and endocardial monophasic action potentials (MAP) were recorded. Results were compared with Sotalol-treated (10-50-100 microM) hearts (n = 13). Amiodarone and Sotalol (50 microM and 100 microM) led to a significant increase in QT interval (mean increase: amiodarone: 31 +/- 6 ms; Sotalol: 41 +/- 4 ms and 61 +/- 9 ms) and MAP-duration (mean increase-MAP90: amiodarone: 20 +/- 5 ms; Sotalol: 17 +/- 5 ms and 25 +/- 8 ms) (P < 0.01). In bradycardic (AV-blocked) hearts, MAP-recordings demonstrated reverse-use dependence and a significant increase in dispersion of repolarization (MAP90) in the presence of Sotalol (P < 0.01), but not in amiodarone-treated hearts (10%; p = ns). Sotalol led to early afterdepolarizations (EAD) and torsade de pointes (TdP) after lowering of potassium concentration (6 of 13 hearts). In amiodarone-treated, hypokalemic hearts, no EAD or TdP occurred. Sotalol changed the MAP configuration to a triangular pattern (ratio-MAP90/50: 1.52 as compared with 1.36 at baseline) whereas amiodarone caused a rectangular pattern of MAP prolongation (ratio-MAP90/50: 1.36). In conclusion, these results show no direct correlation between the occurrence of TdP and the degree of QT prolongation. Several factors including reverse-use dependence, dispersion of repolarization, and the propensity to induce early afterdepolarizations but also differences in the action potential configuration may help to understand proarrhythmic side effects of drugs.
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electrophysiologic characterization of the antipsychotic drug sertindole in a rabbit heart model of torsade de pointes low torsadogenic potential despite qt prolongation
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Lars Eckardt, Gunter Breithardt, Wilhelm HaverkampAbstract:There is growing concern that antipsychotic drugs that prolong the QT interval almost always increase the risk for patients to develop life-threatening ventricular tachyarrhythmias (VTs) of the torsade de pointes type. We therefore sought to compare the electrophysiologic effects of the psychotropic agent sertindole, which prolongs cardiac repolarization by inhibiting the rapid component of the delayed rectifier potassium current ( I Kr) but has a low torsadogenic potential to the antiarrhythmic agent dl -Sotalol. In 18 Langendorff-perfused rabbit hearts, Sotalol (10 μM, n = 8) and sertindole (0.5, 1.0, and 1.5 μM; n = 10) led to significant and comparable QT prolongation. In the presence of Sotalol, torsade de pointes reproducibly occurred in atrioventricular node-blocked hearts after lowering the potassium concentration to 1.5 mM. High doses of sertindole (1.5 μM) only caused monomorphic VT ( n = 4) and nonsustained polymorphic VT ( n = 2) in the presence of QRS prolongation. Multiple simultaneous epi- and endocardial monophasic action potentials and a volume-conducted ECG demonstrated widening of the T/U wave, early afterdepolarizations, and increased dispersion of repolarization in the presence of dl -Sotalol. In contrast to Sotalol, QT and monophasic action potential prolongation were cycle length-independent in the presence of sertindole. Sertindole had no significant effect on transmural or interventricular dispersion of repolarization. Early afterdepolarizations did not occur. Despite comparable QT prolongation, sertindole did not display the proarrhythmic profile typical of other blockers of I Kr such as dl -Sotalol. It is likely that a different mode of interaction between sertindole and the channel and/or additional pharmacological effects of sertindole, e.g., its ability to inhibit I Na and/or its ability to block α1-receptors, play a role. * LQTS : long QT syndrome APD90 : action potential duration at 90% repolarization AV : atrioventricular CL : cycle length EAD : early afterdepolarization HERG : human ether-a-go-go-related gene I Kr : rapid component of delayed rectifier current I Na : sodium current MAP : monophasic action potential TdP : torsade de pointes VT : ventricular tachyarrhythmia
Gunter Breithardt - One of the best experts on this subject based on the ideXlab platform.
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Effect of ranolazine on ventricular repolarization in class III antiarrhythmic drug-treated rabbits.
Heart rhythm, 2012Co-Authors: Gerrit Frommeyer, Sridharan Rajamani, Luiz Belardinelli, Lars Eckardt, Gunter Breithardt, Dennis Kaiser, Timo Uphaus, Sven Kaese, Nani Osada, Peter MilbergAbstract:BACKGROUND Ranolazine exhibits a synergistic effect in combination with class III drugs to suppress atrial fibrillation. OBJECTIVE To investigate whether a combination therapy affects repolarization and provokes ventricular tachyarrhythmias (VT) in a sensitive model of proarrhythmia. METHODS Thirty-seven rabbits were assigned to 3 groups and fed with amiodarone (50 mg/kg/d; n=10) or dronedarone (50 mg/kg/d; n=10) over a period of 6 weeks. A third group was used as control (n = 17). After obtaining baseline data in Langendorff-perfused control hearts, Sotalol (100 μM) was administered in this group. Thereafter, ranolazine (10 μM) was additionally infused on top of amiodarone, dronedarone, or Sotalol. RESULTS Chronic treatment with amiodarone or dronedarone as well as Sotalol significantly increased action potential duration at 90% repolarization (APD 90 ). Additional treatment with ranolazine further increased APD 90 in amiodarone- and dronedarone-pretreated hearts but not in Sotalol-treated hearts. Ranolazine increased postrepolarization refractoriness as compared with amiodarone or dronedarone alone owing to a marked effect on the refractory period. In contrast to amiodarone and dronedarone, acute application of Sotalol increased dispersion of repolarization ( P + ] in bradycardic hearts, no proarrhythmia occurred in amiodarone- or dronedarone-treated hearts whereas 11 of 17 Sotalol-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with ranolazine reduced the number of VT episodes in Sotalol-treated hearts and did not cause proarrhythmia in combination with amiodarone or dronedarone. CONCLUSIONS Application of ranolazine on top of class III drugs does not cause proarrhythmia despite a marked effect on ventricular repolarization. The effect of ranolazine on the repolarization reserve is associated with the lack of effect on early afterdepolarizations and dispersion of repolarization.
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reduction of dispersion of repolarization and prolongation of postrepolarization refractoriness explain the antiarrhythmic effects of quinidine in a model of short qt syndrome
Journal of Cardiovascular Electrophysiology, 2007Co-Authors: Peter Milberg, Gunter Breithardt, Nani Osada, Regina Tegelkamp, Rainer Schimpf, Christian Wolpert, Martin Borggrefe, Lars EckardtAbstract:BACKGROUND Short QT syndrome (SQTS) is a newly described ion channelopathy, characterized by a short QT interval resulting from an accelerated cardiac repolarization, associated with syncope, atrial fibrillation, and sudden cardiac death due to ventricular fibrillation. As therapeutic options in SQTS are still controversial, we examined antiarrhythmic mechanisms in an experimental model of SQTS. METHODS AND RESULTS Pinacidil, an I(K-ATP) channel opener, was administered in increasing concentrations (50-100 microM) in 48 Langendorff-perfused rabbit hearts and led to a significant reduction of action potential duration and QT interval, thereby mimicking SQTS. Eight simultaneously recorded monophasic action potentials demonstrated an increase in dispersion of repolarization, especially between the left and the right ventricle. During programmed ventricular stimulation with up to two extrastimuli, pinacidil significantly increased the inducibility of ventricular fibrillation (1 heart under baseline conditions, 29 hearts during pinacidil administration; P = 0.0001). Additional treatment with the I(Kr) blocker Sotalol (100 microM) and the class I antiarrhythmic drugs flecainide (2 microM) and quinidine (0.5 microM) randomly assigned to three groups of 16 hearts led to prolongation of repolarization as well as refractory period. Sotalol or flecainide did not reduce the rate of inducibility of ventricular fibrillation significantly (P = 0.63; P = 0.219). However, quinidine reduced the inducibility of ventricular fibrillation by 73% (P = 0.008). The antiarrhythmic potential of quinidine was associated with a significantly greater prolongation of MAP duration, refractoriness, and postrepolarization refractoriness (PRR) as compared with Sotalol and flecainide. Moreover, quinidine, in contrast to Sotalol and flecainide, reduced dispersion of repolarization. CONCLUSION Pinacidil mimics SQTS via increasing potassium outward currents, thereby facilitating inducibility of ventricular fibrillation. Quinidine demonstrates superior antiarrhythmic properties in the treatment of ventricular fibrillation in this model as compared with Sotalol and flecainide because of its effects on refractoriness, PRR, and by reducing dispersion of repolarization.
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comparison of the in vitro electrophysiologic and proarrhythmic effects of amiodarone and Sotalol in a rabbit model of acute atrioventricular block
Journal of Cardiovascular Pharmacology, 2004Co-Authors: Peter Milberg, Gunter Breithardt, Wilhelm Haverkamp, Nani Osada, Shahram Ramtin, Gerold Monnig, Kristina Wasmer, Lars EckardtAbstract:The mechanisms for the different proarrhythmic potential of antiarrhythmic drugs in the presence of comparable QT prolongation are not completely understood. The reasons for the lower proarrhythmic potential of amiodarone as compared with other class-III antiarrhythmic drugs such as Sotalol, a fact that has been well established for years, is insufficiently known. Therefore, the aim of our study was to assess the different electrophysiologic effects of amiodarone and Sotalol in a previously developed experimental model of proarrhythmia. In eight male rabbits, amiodarone (280-340 mg/d) was fed over a period of six weeks. Hearts were excised and retrogradely perfused. Up to eight simultaneous epi- and endocardial monophasic action potentials (MAP) were recorded. Results were compared with Sotalol-treated (10-50-100 microM) hearts (n = 13). Amiodarone and Sotalol (50 microM and 100 microM) led to a significant increase in QT interval (mean increase: amiodarone: 31 +/- 6 ms; Sotalol: 41 +/- 4 ms and 61 +/- 9 ms) and MAP-duration (mean increase-MAP90: amiodarone: 20 +/- 5 ms; Sotalol: 17 +/- 5 ms and 25 +/- 8 ms) (P < 0.01). In bradycardic (AV-blocked) hearts, MAP-recordings demonstrated reverse-use dependence and a significant increase in dispersion of repolarization (MAP90) in the presence of Sotalol (P < 0.01), but not in amiodarone-treated hearts (10%; p = ns). Sotalol led to early afterdepolarizations (EAD) and torsade de pointes (TdP) after lowering of potassium concentration (6 of 13 hearts). In amiodarone-treated, hypokalemic hearts, no EAD or TdP occurred. Sotalol changed the MAP configuration to a triangular pattern (ratio-MAP90/50: 1.52 as compared with 1.36 at baseline) whereas amiodarone caused a rectangular pattern of MAP prolongation (ratio-MAP90/50: 1.36). In conclusion, these results show no direct correlation between the occurrence of TdP and the degree of QT prolongation. Several factors including reverse-use dependence, dispersion of repolarization, and the propensity to induce early afterdepolarizations but also differences in the action potential configuration may help to understand proarrhythmic side effects of drugs.
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electrophysiologic characterization of the antipsychotic drug sertindole in a rabbit heart model of torsade de pointes low torsadogenic potential despite qt prolongation
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Lars Eckardt, Gunter Breithardt, Wilhelm HaverkampAbstract:There is growing concern that antipsychotic drugs that prolong the QT interval almost always increase the risk for patients to develop life-threatening ventricular tachyarrhythmias (VTs) of the torsade de pointes type. We therefore sought to compare the electrophysiologic effects of the psychotropic agent sertindole, which prolongs cardiac repolarization by inhibiting the rapid component of the delayed rectifier potassium current ( I Kr) but has a low torsadogenic potential to the antiarrhythmic agent dl -Sotalol. In 18 Langendorff-perfused rabbit hearts, Sotalol (10 μM, n = 8) and sertindole (0.5, 1.0, and 1.5 μM; n = 10) led to significant and comparable QT prolongation. In the presence of Sotalol, torsade de pointes reproducibly occurred in atrioventricular node-blocked hearts after lowering the potassium concentration to 1.5 mM. High doses of sertindole (1.5 μM) only caused monomorphic VT ( n = 4) and nonsustained polymorphic VT ( n = 2) in the presence of QRS prolongation. Multiple simultaneous epi- and endocardial monophasic action potentials and a volume-conducted ECG demonstrated widening of the T/U wave, early afterdepolarizations, and increased dispersion of repolarization in the presence of dl -Sotalol. In contrast to Sotalol, QT and monophasic action potential prolongation were cycle length-independent in the presence of sertindole. Sertindole had no significant effect on transmural or interventricular dispersion of repolarization. Early afterdepolarizations did not occur. Despite comparable QT prolongation, sertindole did not display the proarrhythmic profile typical of other blockers of I Kr such as dl -Sotalol. It is likely that a different mode of interaction between sertindole and the channel and/or additional pharmacological effects of sertindole, e.g., its ability to inhibit I Na and/or its ability to block α1-receptors, play a role. * LQTS : long QT syndrome APD90 : action potential duration at 90% repolarization AV : atrioventricular CL : cycle length EAD : early afterdepolarization HERG : human ether-a-go-go-related gene I Kr : rapid component of delayed rectifier current I Na : sodium current MAP : monophasic action potential TdP : torsade de pointes VT : ventricular tachyarrhythmia
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efficacy and safety of d l Sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest
Journal of the American College of Cardiology, 1997Co-Authors: Wilhelm Haverkamp, Gunter Breithardt, A Martinezrubio, Christiene Hief, Andreas Lammers, Stefan Muhlenkamp, Thomas Wichter, M BorggrefeAbstract:Objectives. The aim of this study was to assess the antiarrhythmic efficacy and safety of d,l-Sotalol in patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) and in survivors of cardiac arrest and to identify the factors that are associated with arrhythmia suppression and therefore might be helpful in predicting drug efficacy. Background. Despite increasing use of the class III antiarrhythmic agent d,l-Sotalol, data on its short- and long-term efficacy in a large patient cohort are lacking. Information on its long-term tolerability and safety is limited. Methods. A total of 396 patients with inducible sustained VT or VF (VT/VF) underwent programmed stimulation before and after receiving oral d,l-Sotalol (240 to 640 mg/day). Patients in whom VT/VF was rendered either noninducible or more difficult to induce (more extrastimuli or faster drive cycle length needed for VT/VF induction) were discharged on a regimen of oral d,l-Sotalol. Results. d,l-Sotalol suppressed VT/VF in 151 patients (38.1%) and rendered the arrhythmia more difficult to induce in 76 patients (19.2%). The extent of drug-induced prolongation of right ventricular refractoriness and a shorter VT cycle length at baseline were independent predictors of immediate drug efficacy. Torsade de pointes developed in seven patients (1.8%). Two hundred ten patients (53%) continued to receive d,l-Sotalol and were followed up for 34 ± 18 months (mean ± SD). The actuarial rates for the absence of arrhythmic recurrence (either VT/VF or sudden death) at 1 and 3 years were 89% and 77%, respectively. Actuarial rates for overall survival at 1 and 3 years were 94% and 86%, respectively. VT/VF suppression by d,l-Sotalol was an independent discriminant variable that separated patients with and without arrhythmia recurrence. However, noninducibility of VT/VF did not predict freedom from sudden death. Conclusions. Oral d,l-Sotalol is effective and safe in patients with VT/VF. However, sudden cardiac death develops in a significant proportion of patients, and programmed stimulation seems to be of limited value for its prediction.
L Seipel - One of the best experts on this subject based on the ideXlab platform.
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suppression of sustained ventricular tachyarrhythmias a comparison of d l Sotalol with no antiarrhythmic drug treatment
Journal of the American College of Cardiology, 1999Co-Authors: Volker Kuhlkamp, Christian Mewis, Johannes Mermi, Ralph F Bosch, L SeipelAbstract:Abstract Objectives. This study evaluates the clinical efficacy of d,l-Sotalol in patients with sustained ventricular tachyarrhythmias. Background. D,l-Sotalol is an important antiarrhythmic agent to prevent recurrences of sustained ventricular tachyarrhythmias (VT/VF). However, evidence is lacking that an antiarrhythmic agent like d,l-Sotalol can reduce the incidence of sustained ventricular tachyarrhythmias in comparison to no antiarrhythmic drug treatment. Methods. A prospective study was performed in 146 consecutive patients with inducible sustained ventricular tachycardia or ventricular fibrillation. In 53 patients, oral d,l-Sotalol prevented induction of VT/VF during electrophysiological testing and patients were discharged on oral d,l-Sotalol (Sotalol group). In 93 patients, VT/VF remained inducible and a defibrillator (ICD) was implanted. After implantation of the device patients were randomly assigned to oral treatment with d,l-Sotalol (ICD/Sotalol group, n = 46) or no antiarrhythmic medication (n = 47, ICD-only group). Results. During follow-up, 25 patients (53.2%) in the ICD-only group had a VT/VF recurrence in comparison to 15 patients (28.3%) in the Sotalol group and 15 patients (32.6%) in the ICD/Sotalol group (p = 0.0013). Therapy with d,l-Sotalol, amiodarone or metoprolol was instituted in 12 patients (25.5%) of the ICD-only group due to frequent VT/VF recurrences or symptomatic supraventricular tachyarrhythmias. In nine patients, 17% of the Sotalol group, an ICD was implanted after VT/VF recurrence, three patients (5.7%) received amiodarone. Total mortality was not different between the three groups. Conclusions. D,l-Sotalol significantly reduces the incidence of recurrences of sustained ventricular tachyarrhythmias in comparison to no antiarrhythmic drug treatment.
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effects of the new class iii antiarrhythmic drug d Sotalol on contractile function of postischemic myocardium
Journal of Cardiovascular Pharmacology, 1991Co-Authors: Hans Martin Hoffmeister, S Muller, L SeipelAbstract:The hemodynamic effects of the new class-III antiarrhythmic drug D-Sotalol (2 mg/kg i.v.) on postischemic myocardium were investigated in comparison with the actions of the racemic D,L-Sotalol (2 mg/kg i.v.) in rats. Drug infusion (7 min) was started 20 min after 3 x 4 min of global ischemic injury (oxygen deficiency). The left ventricular isovolumic pressure-generating capacity at the beginning of infusion was reduced by 15%, indicating postischemic dysfunction. Infusion of D-Sotalol caused a highly significant (p less than 0.01) reduction of the left ventricular pressure-generating capacity (to 58 +/- 5%), as well as of the dp/dtmax (to 21 +/- 3%). Stroke volume (to 66 +/- 6%), ejection fraction (to 62 +/- 7%), and cardiac output (to 51 +/- 6%) were also decreased (p less than 0.01). Fifteen minutes after infusion a partial renormalization of the hemodynamic measures (dp/dtmax 41 +/- 5%; stroke volume 94 +/- 8%) was observed. Infusion of the racemic D,L-Sotalol caused similar hemodynamic changes (left ventricular pressure-generating capacity 60 +/- 2%, dp/dtmax 25 +/- 2%), indicating its cardiodepressant action. In contrast to prior findings on normal myocardium, our present results indicate that D-Sotalol, a potential new class-III antiarrhythmic drug, has a considerable negative inotropic effect on postischemic myocardium.
Michael J Reiter - One of the best experts on this subject based on the ideXlab platform.
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Sotalol for ventricular tachyarrhythmias beta blocking and class iii contributions and relative efficacy versus class i drugs after prior drug failure
American Journal of Cardiology, 1997Co-Authors: James A Reiffel, Elizabeth Hahn, Vernon Hartz, Michael J ReiterAbstract:Abstract In the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial, d,l-Sotalol was associated with a lower arrhythmia recurrence and mortality than class I antiarrhythmic drugs. To further evaluate the relative efficacy of d,l-Sotalol compared with class I drugs, and to assess the relative importance of its class II ( β -blocking) and class III effects, 6-year arrhythmia recurrence and mortality in patients receiving Sotalol were compared with those in patients receiving class I drugs, subdivided according to whether they also received coadministered β blockers. Relative efficacy was also determined for Sotalol and for class I drugs as stratified by the presence/absence of prior drug failure. Arrhythmia recurrence was lower for the 84 patients receiving Sotalol than for patients given class I agents with (n = 28) (p = 0.008) or without (n = 184) (p = 0.001) a β blocker. Mortality was lower for patients taking Sotalol than for those given a class I drug without a β blocker ( p = 0.034), but similar ( p = 0.835) if a β blocker was also administered. In contrast to class I drugs, which had lower efficacy rates when prior drug trials had failed, Sotalol maintained its efficacy despite prior drug failures preceding or during the ESVEM trial. Both class II and III actions in the ESVEM trial were important to the clinical superiority of Sotalol in the treatment of ventricular tachyarrhythmias. The Electrophysiologic Study Versus Electrocardiographic Monitoring database was reviewed to compare arrhythmia recurrence and mortality in patients treated with Sotalol versus class I antiarrhythmics with and without concomitant β -blocker administration. Arrhythmia recurrence was lower with Sotalol than with class I drugs, regardless of β -blocker use; mortality was similar with Sotalol and with class I drugs plus a β blocker, and lower than that with class I drugs without a β blocker. Sotalol efficacy was maintained but class I efficacy decreased from the first to the second trial.
