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M A Vos

Publications and source records attributed to M A Vos.

At least 19 recordsLinked to original sources
PubMed2001

Azimilide and dofetilide produce similar electrophysiological and proarrhythmic effects in a canine model of Torsade de Pointes arrhythmias.

Torsade de Pointes arrhythmias are a feared proarrhythmic effect of (antiarrhythmic) drugs. In dogs with chronic complete AV-block bradycardia-induced volume overload leads to electrical remodeling, which includes increased susceptibility to drug-induced Torsade de Pointes arrhythmias. The IKr channel blocker, dofetilide (Tikosyn, 0.025 mg/kg/5 min), and the less specific ion channel blocker, azimilide (5 mg/kg/5 min), were compared in nine anesthetized dogs at 4 and 6 weeks of AV-block in a randomized cross-over design. Dosages were based on our own dose-dependence studies and on anti-arrhythmic dosages reported in the literature. Monophasic action potential catheters were placed endocardially in both the left and right ventricle to measure action potential duration, visualize early afterdepolarizations, and to assess interventricular dispersion of repolarization (i.e. left ventricular monophasic action potential duration (at 100%) minus right ventricular monophasic action potential duration (at 100%). Cycle length of idioventricular rhythm, QT-time and the occurrence of drug-induced Torsade de Pointes arrhythmias were determined using the surface electrocardiogram (ECG). Before drug administration, the electrophysiological parameters were identical at 4 and 6 weeks. Both azimilide and dofetilide increased monophasic action potential duration, cycle length of idioventricular rhythm, and QT-time. Dissimilar lengthening of left ventricular and right ventricular monophasic action potential duration increased the interventricular dispersion significantly from 55 to 110 ms for both drugs. All dogs had early afterdepolarizations, while, in the majority, ectopic ventricular beats developed (dofetilide 8/9 and azimilide 7/9). Torsade de Pointes arrhythmias incidence was comparable for dofetilide (6/9) and azimilide (5/9). In conclusion, azimilide and dofetilide show similar electrophysiological and proarrhythmic effects in our canine model with a high incidence of Torsade de Pointes arrhythmias.

Action Potentials↗
PubMed2000

Enhanced Ca(2+) release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes: potential link between contractile adaptation and arrhythmogenesis.

BACKGROUND: Ventricular arrhythmias are a major cause of sudden death in patients with heart failure and hypertrophy. The dog with chronic complete atrioventricular block (CAVB) has biventricular hypertrophy and ventricular arrhythmias and is a useful model to study underlying cellular mechanisms. We investigated whether changes in Ca(2+) homeostasis are part of the contractile adaptation to CAVB and might contribute to arrhythmogenesis. METHODS AND RESULTS: In enzymatically isolated myocytes, cell shortening, Ca(2+) release from the sarcoplasmic reticulum (SR), and SR Ca(2+) content were enhanced at low stimulation frequencies. Ca(2+) influx through L-type Ca(2+) channels was unchanged, but Ca(2+) influx via the Na/Ca exchanger was increased and contributed to Ca(2+) loading of the SR. Inward Na/Ca exchange currents were also larger. Changes in Ca(2+) fluxes were less pronounced in the right versus left ventricle. CONCLUSIONS: Enhanced Na/Ca exchange activity may improve contractile adaptation to CAVB but at the same time facilitate arrhythmias by (1) increasing the propensity to Ca(2+) overload, (2) providing more inward current leading to (nonhomogeneous) action potential prolongation, and (3) enhancing (arrhythmogenic) currents during spontaneous Ca(2+) release.

Adaptation, Biological↗
PubMed2000

Contractile adaptations preserving cardiac output predispose the hypertrophied canine heart to delayed afterdepolarization-dependent ventricular arrhythmias.

BACKGROUND: In dogs, chronic complete atrioventricular block (CAVB) results in structural (biventricular hypertrophy) and electrical (delayed repolarization) remodeling, which predisposes the heart to torsade de pointes arrhythmias. We assessed the contractile alterations in the CAVB dog and tested the hypothesis that these adaptations increase delayed afterdepolarization (DAD)-dependent triggered arrhythmias. METHODS AND RESULTS: Steady-state and dynamic (fast pacing: 1 to 68 stimuli) left and right ventricular systolic and diastolic parameters were determined by positive and negative inotropic interventions at acute AVB and CAVB. Concomitantly, left and right ventricular endocardial monophasic action potentials were registered. In CAVB, all systolic contractile parameters were markedly increased, resulting in preserved cardiac output. The increase was most pronounced at low heart rates, altering the force-frequency response. At both acute AVB and CAVB, the degree of potentiation of cardiac function with pacing was dependent on the number of stimuli and showed a maximum at 8 to 13 stimuli. With CAVB, this potentiation curve was shifted upward, and it was only then that pacing resulted in DADs (in 8 of 10 dogs) and ectopic beats (EBs, in 6 of 10 dogs). The incidence of EBs in relation to the number of stimuli also had a maximum at 8 to 13 stimuli. Ouabain increased the incidence of DADs and EBs, whereas the negative inotropic interventions prevented them completely. CONCLUSIONS: The alterations responsible for improvement in systolic contractile function in CAVB dogs predispose the hypertrophied heart to DAD-dependent triggered arrhythmias during positive inotropic interventions.

Adaptation, Biological↗
PubMed2000

Observations on the onset of torsade de pointes arrhythmias in the acquired long QT syndrome.

OBJECTIVE: Premature ectopic beats may create a specific sequence of events (e.g. short-long-short) preceding Torsade de Pointes arrhythmias (TdP) in the long QT syndrome. The relevance of this sequence for the initiation of TdP is not clear. In our dog model of TdP, interventricular dispersion (DeltaAPD=left-right ventricular monophasic action potential duration: APD) is associated with TdP, therefore we tested the hypothesis that the ectopic beats contributes to DeltaAPD. METHODS: In 17 anaesthetized dogs with chronic AV-block, which showed spontaneous TdP after class III medication, APD was analyzed to 1. quantitate the alterations due to (multiple) ectopic beats on the left and right APD (measured with endocardial catheters) and 2. compare the DeltaAPD prior to the occurrence of premature beats (steady state) in dogs with non-sudden onset of TdP (n=10) and sudden onset TdP (n=7). Three phases were distinguished: phase 1: steady state beats prior to ectopic beats, phase II: the beat(s) belonging to the dynamic phase, and phase III: the beat causing TdP. Because the coupling interval of premature beats in this condition often falls within the APD, the DeltaAPD(50) was validated as an alternative for the previously applied DeltaAPD(100) (r=0.51, P<0.01). RESULTS: In steady state (phase I) DeltaAPD(50) is longer in the sudden onset TdP (130+/-35 ms) as in the non-sudden onset TdP (65+/-40 ms). In the non-sudden TdP group the dynamic phase II contribute to the heterogeneity in APD, i.e. LV-APD increases more than RV-APD leading to a DeltaAPD(50) increase to 130+/-100 ms (P<0.01) just preceding TdP (phase III). CONCLUSION: The synergism between ectopic beats (short-long-short sequence) and DeltaAPD create the circumstances for TdP initiation.

Action Potentials↗
PubMed2000

Atrial fibrillation in the goat induces changes in monophasic action potential and mRNA expression of ion channels involved in repolarization.

INTRODUCTION: Sustained atrial fibrillation (AF) is characterized by a marked shortening of the atrial effective refractory period (AERP) and a decrease or reversal of its physiologic adaptation to heart rate. The aim of the present study was to investigate whether the AF-induced changes in AERP in the goat are associated with changes in the atrial monophasic action potential (MAP) and whether an abnormal expression of specific ion channels underlies such changes. METHODS AND RESULTS: Following thoracotomy, MAPs were recorded from the free wall of the right atrium both before induction of AF (control) and after cardioversion of sustained AF (>2 months) in chronically instrumented goats. In control goats, MAP duration at 80% repolarization (MAPD80) shortened (P < 0.01) from 132+/-4 msec during slow pacing (400-msec interval) to 86+/-10 msec during fast pacing (180 msec). After cardioversion of sustained AF, the MAPD80 during slow pacing was as short as 67+/-5 msec (electrical remodeling). Increasing the pacing rate resulted in prolongation (P = 0.02) of the MAPD80 to 91+/-6 msec. Also, MAPD20 (20% repolarization) shortened (P = 0.05) from 32+/-4 msec (400 msec) to 14+/-7 msec (180 msec) in the control goats, whereas it prolonged (P = 0.03) from 20+/-3 msec (400 msec) to 33+/-5 msec (180 msec) in sustained AF. mRNA expression of the L-type Ca2+ channel alpha1c gene and Kv1.5 potassium channel gene, which underlie ICa and IKur, respectively, was reduced in sustained AF compared with sinus rhythm by 32% (P = 0.01) and 45% (P < 0.01), respectively. No significant changes were found in the mRNA levels of the rapid Na+ channel, the Na+/Ca2+ exchanger, or the Kv4.2/4.3 channels responsible for Ito. CONCLUSION: AF-induced electrical remodeling in the goat comprises shortening of MAPD and reversal of its physiologic rate adaptation. Changes in the time course of repolarization of the action potential are associated with changes in mRNA expression of the alpha subunit genes of the L-type Ca2+ channel and the Kv1.5 potassium channel.

Action Potentials↗
PubMed2000

High uniformity of left and right ventricular repolarization dynamics induced by an abrupt decrease in pacing cycle length in a dog is not affected by left ventricular ischemia.

INTRODUCTION: After an abrupt increase in heart rate, action potential duration (APD) will shorten. To assess the effect of ischemia on APD shortening dynamics, we compared right ventricular (RV) and left ventricular (LV) APD shortening induced by an abrupt decrease in pacing cycle length (PCL) during control and LV ischemia. METHODS AND RESULTS: In eight anesthetized AV block dogs, endocardial LV and RV APD were determined simultaneously after an abrupt PCL decrease from 800 to 350 msec. Measurements were repeated during left anterior descending coronary artery (LAD) occlusion. During control, LV and RV APD shortened 97 +/- 27 and 71 +/- 14 msec, respectively (P < 0.05). Shortening was pronounced in a short initial phase and gradual in the longer secondary phase. Linear regression analysis revealed very high uniformity of LV and RV APD shortening dynamics (r2 = 0.96 +/- 0.01). During repeated LAD occlusion, ischemia induced a gradual LV APD shortening from 314 +/- 25 msec to a new steady-state value of 251 +/- 23 msec, whereas RV APD remained stable at 289 +/- 28 msec. The additional PCL decrease resulted in LV and RV APD shortening of 72 +/- 8 and 68 +/- 15 msec, respectively, with the same high uniformity of shortening dynamics as seen during control (r2 = 0.94 +/- 0.03). CONCLUSION: There is a pronounced difference in APD shortening dynamics induced by an abrupt decrease in PCL compared with ischemia. LV shortening dynamics induced by a decrease in PCL are not affected by LV ischemia, preserving a high interventricular uniformity of repolarization dynamics.

Action Potentials↗
PubMed1999

Downregulation of delayed rectifier K(+) currents in dogs with chronic complete atrioventricular block and acquired torsades de pointes.

BACKGROUND: Acquired QT prolongation enhances the susceptibility to torsades de pointes (TdP). Clinical and experimental studies indicate ventricular action potential prolongation, increased regional dispersion of repolarization, and early afterdepolarizations as underlying factors. We examined whether K(+)-current alterations contribute to these proarrhythmic responses in an animal model of TdP: the dog with chronic complete atrioventricular block (AVB) and biventricular hypertrophy. METHODS AND RESULTS: The whole-cell K(+) currents I(TO1), I(K1), I(Kr), and I(Ks) were recorded in left (LV) and right (RV) ventricular midmyocardial cells from dogs with 9+/-1 weeks of AVB and controls with sinus rhythm. I(TO1) density and kinetics and I(K1) outward current were not different between chronic AVB and control cells. I(Kr) had a similar voltage dependence of activation and time course of deactivation in chronic AVB and control. I(Kr) density was similar in LV myocytes but smaller in RV myocytes (-45%) of chronic AVB versus control. For I(Ks), voltage-dependence of activation and time course of deactivation were similar in chronic AVB and control. However, I(Ks) densities of LV (-50%) and RV (-55%) cells were significantly lower in chronic AVB than control. CONCLUSIONS: Significant downregulation of delayed rectifier K(+) current occurs in both ventricles of the dog with chronic AVB. Acquired TdP in this animal model with biventricular hypertrophy is thus related to intrinsic repolarization defects.

Action Potentials↗
PubMed1999

Repolarizing K+ currents ITO1 and IKs are larger in right than left canine ventricular midmyocardium.

BACKGROUND: The ventricular action potential exhibits regional heterogeneity in configuration and duration (APD). Across the left ventricular (LV) free wall, this is explained by differences in repolarizing K+ currents. However, the ionic basis of electrical nonuniformity in the right ventricle (RV) versus the LV is poorly investigated. We examined transient outward (ITO1), delayed (IKs and IKr), and inward rectifier K+ currents (IK1) in relation to action potential characteristics of RV and LV midmyocardial (M) cells of the same adult canine hearts. METHODS AND RESULTS: Single RV and LV M cells were used for microelectrode recordings and whole-cell voltage clamping. Action potentials showed deeper notches, shorter APDs at 50% and 95% of repolarization, and less prolongation on slowing of the pacing rate in RV than LV. ITO1 density was significantly larger in RV than LV, whereas steady-state inactivation and rate of recovery were similar. IKs tail currents, measured at -25 mV and insensitive to almokalant (2 micromol/L), were considerably larger in RV than LV. IKr, measured as almokalant-sensitive tail currents at -50 mV, and IK1 were not different in the 2 ventricles. CONCLUSIONS: Differences in K+ currents may well explain the interventricular heterogeneity of action potentials in M layers of the canine heart. These results contribute to a further phenotyping of the ventricular action potential under physiological conditions.

Action Potentials↗
PubMed1999

Evaluation of the acute electrophysiologic effects of intravenous dronedarone, an amiodarone-like agent, with special emphasis on ventricular repolarization and acquired torsade de pointes arrhythmias.

In the anesthetized dog with complete chronic AV block (CAVB), we evaluated and compared the acute electrophysiologic effects of dronedarone i.v. (Dron, 2 times 2.5 mg/kg/10 min) and amiodarone i.v. (Amio, 2 times 5 mg/kg/10 min). This canine model with a high sensitivity for acquired torsade de pointes (TdP) provides an ideal substrate to evaluate ventricular repolarization abnormalities. Six ECG leads and two endocardial monophasic action potential (MAP) recordings in the left and right ventricle (LV and RV) were simultaneously recorded to measure QT time, action-potential duration (APD), interventricular dispersion (deltaAPD = LV(APD) - RV(APD)), early afterdepolarizations (EADs), ectopic beats (EBs), and TdP. Measurements were made at the spontaneous idioventricular rhythm (IVR) and 1,000-ms steady-state pacing. To investigate its short-term, antiarrhythmic properties, Dron was given after almokalant (0.12 mg/kg)-induced TdP. Furthermore, in another set of experiments, oral Dron (20 mg/kg, b.i.d) was given for 3 weeks to conscious CAVB dogs. Dron, i.v., shortened ventricular repolarization (QT, 435 +/- 60 to 360 +/- 55; LV(APD) 395 +/- 75 to 335 +/- 60 ms; p < 0.05), whereas IVR and ventricular effective refractory period (VERP, 225 +/- 30 to 230 +/- 30 ms) remained similar. Therefore the VERP/QT ratio increased (0.55 +/- 0.04 to 0.61 +/- 0.03; p < 0.05). Similar results were obtained with Amio, i.v.. Almokalant-induced TdP was characterized by an increased repolarization duration, deltaAPD, and EADs. Dron, i.v., suppressed the EADs, EBs, and TdP by a reduction and homogenization of repolarization (LV(APD), 505 +/- 110 to 455 +/- 80 ms, and deltaAPD, 110 +/- 55 to 65 +/- 40 ms). Long-term oral Dron increased the PP interval, CL-IVR, and QT(c) time. In contrast to oral treatment, Dron i.v. shortens ventricular repolarization parameters, resulting in suppression of EAD-dependent acquired TdP. The increased VERP/QT ratio after Dron i.v. may indicate an important second antiarrhythmic property.

Action Potentials↗
PubMed1999

The dynamic behavior of the diastolic slope of monophasic action potential can be related to the occurrence and maintenance of delayed afterdepolarization dependent arrhythmias.

We have described the value of the diastolic slope of the MAP recording at the end of a pacing train as a qualifying marker for the induction of delayed afterdepolarization (DAD) dependent arrhythmias. In the present study (1) the behavior of the slope at different time points during a pacing train was quantified and related to the arrhythmogenic outcome (group A) and (2) termination of DAD dependent VT was related to changes in the slope steepness (group B). In dogs with chronic complete AV block, a MAP was recorded during (1) ventricular pacing, before and after ouabain administration (group A) and (2) 6 spontaneous and 6 lidocaine induced VT terminations (group B). During control (group A), the slope at the end of pacing train was 5 +/- 3 m V/s (mean +/- SD), independent of the pacing duration. During ouabain, this increased to 20 +/- 15 mV/s (P < 0.05), varying with the duration of pacing. The slope was steeper after pacing for 4 seconds, compared to 20 seconds (26 +/- 12 mV/s vs 16 +/- 13 mV/s, P < 0.05) which corresponded with more frequent VT induction. In spontaneously terminating VTs (group B), CL increased from 353 +/- 54 ms at the start to 434 +/- 78 ms (P < 0.05) before VT termination. This corresponded with a decreasing steepness of the slope from 19 +/- 10 mV/s to 6 +/- 5 mV/s (P < 0.05). In lidocaine induced VT termination, the CL and the steepness of the slope showed an identical behavior. There is a dynamic variation in the steepness of the diastolic slope during pacing, which depends on the duration of pacing and predicts arrhythmogenic outcome. Furthermore, a decrease in steepness of the slope during DAD dependent VT can be used to predict VT termination.

Action Potentials↗
PubMed1999

Rate dependent effects of procainamide on the threshold current for pacing in the setting of postrepolarization refractoriness in dogs.

Normally, ventricular APD exceeds the VERP. However, under specific circumstances this relation may change and can become inverse. This phenomenon of postrepolarization refractoriness may be caused by a decrease in excitability. The threshold current (TC) for pacing has never been quantified as a possible explanation for these observations. Using a MAP pacing catheter in the right ventricular apex, the rate dependent behavior of TC, VERP, and APD before and after procainamide (dose 20 mg/kg in 10 min + 5 mg/min infusion) was determined in 17 dogs with chronic complete AV block. Initially, TC was determined with 0.1 mA accuracy. Using a pacing current of at least twice TC, VERP and APD showed a similar, rate dependent shortening for PCLs 800, 575, and 350 ms. Procainamide treatment led to an equal, rate independent VERP and APD increase: no post repolarization refractoriness. Subsequently, accuracy for TC determination was increased to 0.01 mA. Comparing PCLs 800 and 250 ms, TC doubled from 0.05 +/- 0.01 to 0.10 +/- 0.09 mA during control and almost tripled from 0.06 +/- 0.02 to 0.17 +/- 0.10 mA (P < 0.05) after procainamide. Using a fixed pacing current of exactly twice TC found at 800 ms PCL during control, VERP exceeded APD after procainamide treatment at 300 and 250 ms PCL: postrepolarization refractoriness. Increasing the pacing current to twice the rate dependent TC, the relation between VERP and APD normalized: no postrepolarization refractoriness. We conclude that after procainamide, rate dependent TC increase is of major importance for the phenomenon of postrepolarization refractoriness.

Animals↗
PubMed1998

Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling.

BACKGROUND: Chronic, complete AV block (CAVB) in the dog leads to ventricular hypertrophy, which has been described as an independent risk factor for arrhythmias. In this model, we examined (1) whether the short- and long-term electrical adaptations predispose to acquired torsade de pointes arrhythmias (TdP) and (2) the nature of the structural and functional adaptations involved. METHODS AND RESULTS: We determined (1) endocardial right (RV) and left (LV) ventricular APD, DeltaAPD (LV APD-RV APD), presence of EADs at 0 weeks (acute: AAVB), and CAVB (6 weeks) and inducibility of TdP by pacing and d-sotalol (n=10); (2) steady-state and dynamic LV hemodynamics at 0 and 6 weeks (n=6); (3) plasma neurohumoral levels in time (n=7); (4) structural parameters of the LV and RV of CAVB dogs (n=6) compared with sinus rhythm (SR) dogs (n=6); and (5) expression of ventricular mRNA atrial natriuretic factor (ANF) in CAVB (n=4) and SR (n=4) dogs. Compared with AAVB, CAVB led to nonhomogeneous prolongation of LV and RV APD and different sensitivity for d-sotalol, leading to EADs (4 of 14 versus 9 of 18, P<0.05), increased DeltaAPD (45+/-30 versus 125+/-60 ms, P<0.05), and induction of TdP in most dogs (0% versus 60%, P<0.05). CAVB led to biventricular hypertrophy, whereas LV function was similar in AAVB and CAVB. The neurohumoral levels were transiently elevated. The LV and RV collagen and the capillary/fiber ratio remained normal, whereas ventricular ANF mRNA was not detectable. CONCLUSIONS: The electrical remodeling occurring after CAVB predisposes the heart to acquired TdP, whereas the structural changes (hypertrophy) are successfully aimed at maintaining cardiac function.

Action Potentials↗
PubMed1998

Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes.

BACKGROUND: In the dog with chronic complete atrioventricular block (AVB), torsade de pointes arrhythmias (TdP) can be induced reproducibly by class III antiarrhythmic agents. In vivo studies reveal important electrophysiological alterations of the heart at 5 weeks of AVB, resulting in increased proarrhythmia. Autopsy studies indicate the presence of biventricular hypertrophy. In this study, the cellular basis of proarrhythmia and hypertrophy in chronic AVB was investigated. METHODS AND RESULTS: From chronic-AVB dogs with increased heart weights and TdP, left midmyocardial and right ventricular myocytes were isolated by enzymatic dispersion. These myocytes were significantly larger than sinus rhythm (SR) controls. In chronic AVB, the action potential spike-and-dome configuration was preserved. However, the action potential duration (APD) at 95% and 50% of repolarization of the left midmyocardium was significantly larger in chronic AVB than in SR, with little change in the right ventricle, causing enhanced interventricular dispersion of repolarization at slow pacing rates. Treatment with the class III agent almokalant increased the APD to a much larger extent in chronic-AVB than in SR myocytes and resulted in a higher incidence of early afterdepolarizations (EADs). EADs had their takeoff potential between -35 and 0 mV. There was no evidence that spontaneous sarcoplasmic reticulum Ca2+ release underlies these EADs. CONCLUSIONS: In the dog, chronic AVB leads to hypertrophy of both right and left ventricular myocytes. The repolarization abnormalities predisposing for class III-dependent TdP in vivo are the results of cellular electrophysiological remodeling.

Action Potentials↗
PubMed1998

Steady-state and dynamic behavior of ventricular repolarization and refractoriness in the dog: the effect of multiple cycle length changes and d-sotalol administration.

In anesthetized dogs with chronic, complete AV block we studied the characteristics of ventricular repolarization and refractoriness. Therefore, we determined: (1) steady-state values of ventricular effective refractory period (VERP), action potential duration (APD), and stimulus T interval (STI) before and after d-sotalol treatment at various pacing cycle lengths (PCLs); and (2) the dynamics of VERP, APD, and STI before and after d-sotalol treatment after the abrupt PCL decreases. VERP, APD, and STI showed a normal frequency dependency. All three parameters increased significantly after d-sotalol administration. During steady-state and dynamic measurements, STI was always longer than APD and APD was always longer than VERP in an individual animal, irrespective of PCL and conditions. Standard deviations of steady-state and dynamic values indicated a considerable interindividual variation. However, the dynamics of VERP, APD, and STI after an abrupt decrease in PCL were highly correlated (linear regression analysis: r2 > or = 0.93). The best mathematical model to describe these dynamics was a bi-exponential model (r2 > or = 0.98) with a very short first and a much longer second time constant. We found that there was a very consistent relation between VERP, APD, and STI, not only during steady-state but also in the dynamic situation after various abrupt PCL decreases. This relation does not change after the administration of d-sotalol. Therefore, STI could be used to predict steady-state and dynamic values of VERP and APD. Since STI can be made available online in implantable pacing systems this could lead to the development of new features in these devices.

Animals↗
PubMed1998

Superiority of ibutilide (a new class III agent) over DL-sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group.

OBJECTIVE: To compare the efficacy and safety of a single dose of ibutilide, a new class III antiarrhythmic drug, with that of DL-sotalol in terminating chronic atrial fibrillation or flutter in haemodynamically stable patients. DESIGN: Double blind, randomised study. SETTING: 43 European hospitals. PATIENTS: 308 patients (mean age 60 years, 70% men, 48% with heart disease) with sustained atrial fibrillation (n = 251) or atrial flutter (n = 57) (duration three hours to 45 days) were randomised to three groups to receive a 10 minute infusion of 1 mg ibutilide (n = 99), 2 mg ibutilide (n = 106), or 1.5 mg/kg DL-sotalol (n = 103). Infusion was discontinued at termination of the arrhythmia. MAIN OUTCOME MEASURE: Successful conversion of atrial fibrillation or flutter, defined as termination of arrhythmia within one hour of treatment. RESULTS: Both drugs were more effective against atrial flutter than against atrial fibrillation. Ibutilide was superior to DL-sotalol for treating atrial flutter (70% and 56% v 19%), while the high dose of ibutilide was more effective for treating atrial fibrillation than DL-sotalol (44% v 11%) and the lower dose of ibutilide (44% v 20%, p < 0.01). The mean (SD) time to arrhythmia termination was 13 (7) minutes with 2 mg ibutilide, 19 (15) minutes with 1 mg ibutilide, and 25 (17) minutes with DL-sotalol. In all patients, the duration of arrhythmia before treatment was a predictor of arrhythmia termination, although this was less obvious in the group that received 2 mg ibutilide. This dose converted almost 48% of atrial fibrillation that was present for more than 30 days. Concomitant use of digitalis or nifedipine and prolongation of the QTc interval were not predictive of arrhythmia termination. Bradycardia (6.5%) and hypotension (3.7%) were more common side effects with DL-sotalol. Of 211 patients given ibutilide, two (0.9%) who received the higher dose developed polymorphic ventricular tachycardia, one of whom required direct current cardioversion. CONCLUSION: Ibutilide (given in 1 or 2 mg doses over 10 minutes) is highly effective for rapidly terminating persistent atrial fibrillation or atrial flutter. This new class III drug, under monitored conditions, is a potential alternative to currently available cardioversion options.

Adult↗
PubMed1997

Further observations to elucidate the role of interventricular dispersion of repolarization and early afterdepolarizations in the genesis of acquired torsade de pointes arrhythmias: a comparison between almokalant and d-sotalol using the dog as its own control.

OBJECTIVES: We sought to further elucidate the role of early afterdepolarizations (EADs) and interventricular dispersion of repolarization (deltaAPD) in the genesis of acquired torsade de pointes (TdP) arrhythmias. BACKGROUND: Administration of class III agents can be associated with TdP. We developed a dog model in which TdP can be reproducibly induced by pacing after d-sotalol. This model shows reproducible results over weeks. METHODS: In 14 anesthetized dogs with chronic complete atrioventricular block, two separate experiments were performed in which d-sotalol (2 mg/kg body weight) or almokalant (0.12 mg/kg) was administered. Monophasic action potentials were simultaneously recorded from the endocardium of the right and left ventricle to register EADs and to measure the action potential duration (APD). DeltaAPD was defined as the APD of the left ventricle minus that of the right ventricle. RESULTS: Baseline conditions were identical in the serially performed experiments. The cycle length and QT time increased by 16% and 26% after d-sotalol and by 15% and 31% after almokalant, respectively. After both drugs the action potential of the left ventricle prolonged more than that of the right ventricle, thereby increasing deltaAPD (almokalant [mean +/- SD]: 110 +/- 60 ms; d-sotalol: 80 +/- 45 ms, p < 0.05). The incidence of EADs (18 of 22 vs. 11 of 24, p < 0.05) and single ectopic beats (EBs) (1.5 +/- 2 vs. 24 +/- 32, p < 0.01) was more frequently observed after almokalant than after d-sotalol. Moreover, multiple EBs only occurred after almokalant. These beats interfered with the basic rhythm, leading to dynamic changes in left ventricular APD and to additional increases in deltaAPD. Spontaneous TdP was observed in 9 of 14 dogs after almokalant and could be increased to 12 of 14 with programmed electrical stimulation. After d-sotalol, TdP could only be induced by programmed electrical stimulation (5 of 14, p < 0.05). CONCLUSIONS: In the same dog, almokalant induced more delay in repolarization, more EADs, multiple EBs and more ventricular inhomogeneity in APD than d-sotalol. These changes were related to a higher incidence of TdP and thereby confirm a strong association of the occurrence of EADs, multiple EBs and deltaAPD in the genesis of TdP. These findings also show the possible value of our model for evaluating the proarrhythmic potential of different drugs.

Analysis of Variance↗