Biomedical subjects

M A Vos

Publications and source records attributed to M A Vos.

At least 37 records · Page 2Linked to original sources

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↗

PubMed1997

Similarities between early and delayed afterdepolarizations induced by isoproterenol in canine ventricular myocytes.

OBJECTIVES: This study aims at clarifying the role of cellular Ca2+ overload and spontaneous sarcoplasmic reticulum (SR) Ca2+ release in the generation of early afterdepolarizations (EAD) by isoproterenol. The involvement of a Ca(2+)-activated membrane current in isoproterenol-induced EAD is investigated. METHODS: Membrane potential and contraction (an indicator of SR Ca2+ release) were recorded in canine left ventricular myocytes at pacing cycle lengths (CL) of 300-4000 ms. Threshold concentration for EAD was 20-50 mmol/l isoproterenol. Ni2+ (2.0-5.0 mmol/l) was used at normal and high (5.4 mmol/l) [Ca2+]o to examine the role of Ca2+ current and/or Na(+)-Ca2+ exchange (1Na-Ca) in EAD. RESULTS: In all cells delayed afterdepolarizations (DAD) appeared during isoproterenol. In most (approximately equal to 70%) cells EAD were also generated, which were fast-pacing dependent, occurring only at CL of 400-1000 ms. EAD were always initiated by a delay in repolarization. Early aftercontractions preceded the EAD upstrokes, often occurring without them. They coincided with the initial delays in repolarization. During treatment with isoproterenol, Ni2+ and high [Ca2+]o, EAD and DAD were suppressed despite the continued presence of early and delayed aftercontractions. CONCLUSIONS: Our data indicate that beta-adrenergic EAD share a common ionic mechanism with DAD in terms of cellular Ca2+ overload and spontaneous SR Ca2+ release. beta-Adrenergic EAD consist of two phases: (1) a conditional phase coinciding with the onset of an early aftercontraction, often followed by (2) an EAD upstroke. A Ca2(+)-activated membrane current, probably I Na-Ca, is necessary at least for the initiation of these EAD.

Action Potentials↗

PubMed1997

Role of interventricular dispersion of repolarization in acquired torsade-de-pointes arrhythmias: reversal by magnesium.

OBJECTIVE: The mechanism of acquired torsade-de-pointes arrhythmias (TdP) is not clear but is suggested to be based on several parameters including early afterdepolarizations (EADs) and/or dispersion of repolarization (delta APD). In our animal model of TdP (anaesthetized dogs with chronic AV block), we assessed the relevance of interventricular dispersion for the initiation of TdP. METHODS: In 24 experiments, multiple endocardial monophasic action potential (MAP) recordings were made at baseline, after d-sotalol (2 mg/kg), and after MgSO4 (100 mg/kg, n = 11) to measure regional differences in action potential duration (APD). Rate-dependent behavior of the interventricular delta APD (APD of left minus right ventricle) and intraventricular dispersion was studied under the different circumstances. RESULTS: Dogs with induction of TdP by d-sotalol and pacing (11/20 = 55%) had longer cycle lengths of idioventricular rhythm, longer QT-durations, increased presence of EADs (14/22 vs 5/18 MAPs, P < 0.05) and increased interventricular delta APD (135 +/- 55 vs 60 +/- 40 ms. P < 0.05) compared with non-inducible dogs. There were no differences in intraventricular dispersion. MgSO4 diminished delta APD (110 +/- 45 to 55 +/- 60 ms, P < 0.05) and prevented TdP (4/4). In contrast to intraventricular dispersion, interventricular delta APD is clearly bradycardia-dependent. CONCLUSIONS: Next to bradycardia, prolonged repolarization, and EADs, we propose that delta APD should be added to the relevant factors for the initiation of TdP. Interventricular dispersion is much larger than intraventricular dispersion and demonstrates a very strong bradycardia dependence.

Action Potentials↗

PubMed1996

Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia.

Efficacy of procainamide and lidocaine in terminating spontaneous monomorphic ventricular tachycardia (VT) was assessed in a randomized parallel study. Patients with acute myocardial infarction and those with poor hemodynamic tolerance of VT were excluded. Procainamide 10 mg/kg was given intravenously with an injection speed of 100 mg/min, and lidocaine was administered at an intravenous dose of 1.5 mg/kg in 2 minutes. Fourteen patients were randomized to lidocaine and 15 to procainamide. Termination occurred in 3 of 14 patients after lidocaine and in 12 of 15 patients after procainamide (p <0.01). Procainamide stopped 8 of 11 VTs not responding to lidocaine, and lidocaine stopped 1 of 1 not responding to procainamde. Of a total of 41 VT episodes, 4 of 15 responded to lidocaine and 20 of 26 to procainamide (p <0.01). Because of VT recurrences, 16 patients could be studied repeatedly with drugs given in the reversed order. This resulted in a total of 55 trials of 79 drug injections. Lidocaine terminated 6 of 31 VTs and procainamide 38 of 48 (p <0.001). The protocol was stopped in 4 cases because of adverse effects. A comparison of the QRS width and QT interval before and at the end of the injection revealed significant lengthening of these values after procainamide but no change after lidocaine. In conclusion, procainamide is superior to lidocaine in terminating spontaneously occurring monomorphic VT.

Anti-Arrhythmia Agents↗

PubMed1995

Combining monophasic action potential recordings with pacing to demonstrate delayed afterdepolarizations and triggered arrhythmias in the intact heart. Value of diastolic slope.

BACKGROUND: In the intact heart, methodological difficulties hamper the direct visualization of delayed afterdepolarizations (DADs) responsible for triggered arrhythmias. Therefore, we tested the hypothesis that a combination of pacing and the recording of a monophasic action potential (MAP) could facilitate the recognition of ouabain-induced DADs and triggered arrhythmias by demonstrating an increase in the diastolic baseline slope (dV/dT) of the MAP recording at the end of a pacing train. METHODS AND RESULTS: In anesthetized dogs with chronic atrioventricular block, a right ventricular endocardial MAP was recorded during (1) control (n = 11), (2) 15 to 45 minutes after administration of ouabain (45 +/- 10 micrograms/kg, n = 11), (3) 10 minutes after administration of lidocaine (3 mg/kg, n = 5), and (4) during lidocaine washout (n = 3). Pacing was performed with the MAP catheter. Also, the protocol was performed in 3 dogs with conducted sinus rhythm during control and ouabain circumstances. During control, the slope value was 2 +/- 2 mV/s (mean +/- SD), the incidence of DADs after the stimulation train was 6%, and no ventricular tachycardias (VTs) were induced in dogs with atrioventricular block. During ouabain administration, the slope and DAD incidences increased to, respectively, 26 +/- 14 mV/s and 74% (P < .05 for both). VTs were induced frequently. Lidocaine prevented VT induction by decreasing the slope and the incidence of DADs. This effect disappeared after lidocaine washout. During conducted sinus rhythm, similar results were found. CONCLUSIONS: By combining pacing and MAP recordings, the diastolic slope observed on MAP recordings in ouabain-intoxicated hearts can be used as a marker for DADs and triggered arrhythmias. This finding may be helpful in identifying triggered activity in the intact heart.

Action Potentials↗

PubMed1995

Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block.

It has been well established that antiarrhythmic drugs can also have proarrhythmic effects such as torsade de pointes (TdP) arrhythmias. It was the purpose of this study to create an animal model with a high incidence of reproducible TdP that occurs under clinically relevant circumstances. Experiments were performed in anesthetized dogs that had been in chronic atrioventricular block for 9 +/- 6 weeks. TdP inducibility was attempted using different pacing modes before and after the administration of 2 mg/kg d-sotalol. In some experiments, endocardial monophasic action potentials were recorded. d-Sotalol increased the cycle length of the idioventricular rhythm (1475 +/- 460 to 1730 +/- 570 ms, P < .01) and the QT time (390 +/- 65 to 480 +/- 85 ms, P < .01). In 10% of the experiments, spontaneous TdP occurred after d-sotalol. The incidence of pacing-dependent TdP was 52% (P < .01). In the inducible group, the cycle length of idioventricular rhythm and QT time were significantly longer despite equal percentage increases in these parameters after d-sotalol in both groups. The pacing modes consisting of more than one frequency change had a higher TdP induction rate (P < .05). Reproducibility of TdP induction (three times or more using the same pacing train) remained present for approximately 60 minutes after d-sotalol and was greater than 90% within the same animal over weeks. TdP induction was related to the presence of early afterdepolarizations on the monophasic action potential recordings: five of six in the inducible group versus two of six in the nonresponders. Inducibility could be further increased to 89% when a second bolus of d-sotalol was administered to noninducible dogs. On the other hand, decreasing QT time by faster basic pacing or administration of isoproterenol, or MgSO4 prevented TdP induction. This effect of MgSO4 coincided with the disappearance of early afterdepolarizations. Our animal model shows a high incidence of reproducible acquired TdP arrhythmias, allowing study of the mechanism and treatment of TdP. TdP induction was related to the combination of a slow ventricular rate, the prolongation of QT time, a sudden induced rate change that often required two or more cycle length changes, and the presence of early afterdepolarizations.

Action Potentials↗

PubMed1995

The effect of flunarizine and ryanodine on acquired torsades de pointes arrhythmias in the intact canine heart.

INTRODUCTION: Ryanodine, a specific blocker of the Ca2+ release channel of the sarcoplasmic reticulum, and flunarizine, a [Ca2+]i overload blocker, possess antiarrhythmic effects against delayed afterdepolarizations (DADs) and DAD-dependent arrhythmias. In vitro controversy exists about their effect on early after-depolarizations (EADs): no effect was reported on cesium-induced EADs, while ryanodine did prevent EADs induced by isoproterenol. To study the possible role of intracellular Ca2+ overload in acquired EAD-dependent torsades de pointes (TdP) arrhythmias, we tested the effects of flunarizine and ryanodine in our animal model of TdP. METHODS AND RESULTS: Anaesthetized dogs with chronic AV block received d-sotalol or almokalant followed by pacing. A subset of dogs with reproducible TdP (> or = 3 times) were selected to receive flunarizine (2 mg/kg per 2 min) or ryanodine (10 micrograms/kg per 10 min). After d-sotalol, TdP was induced at a mean cycle length of the idioventricular rhythm (CL-IVR) of 2070 +/- 635 msec and a QT(U) interval of 535 +/- 65 msec. Induction of TdP was prevented by flunarizine in all experiments (8/8): electrophysiologically this was associated with a decrease in CL-IVR, QT(U), and QTc interval (390 +/- 100 to 320 +/- 45, P < 0.05). Ryanodine prevented TdP induction in 4 of 5 experiments and decreased the CL-IVR, QT(U), and the QTc interval from 385 +/- 75 to 320 +/- 20 msec (P < 0.05). Both drugs also suppressed the almokalant-induced EADs and related ectopic activity. This antiarrhythmic action corresponded with the inability to reinduce TdP by pacing. CONCLUSIONS: Blockade of the Ca2+ release channel of the sarcoplasmic reticulum by ryanodine or the reduction of [Ca2+]i overload by flunarizine prevents induction of EAD-dependent acquired TdP arrhythmias, suggesting a role for [Ca2+]i overload in acquired TdP.

Action Potentials↗

PubMed1994

Action of MgSO4 differs from moricizine and verapamil on ouabain-induced ventricular tachycardia in normomagnesemic conscious dogs.

We performed a comparative study to determine whether acute administration of MgSO4, moricizine, and verapamil to conscious dogs with normal plasma magnesium levels (0.75 +/- 0.06 mM) terminates ouabain-induced ventricular tachycardia (VT). This arrhythmia is dependent on triggered activity (TA) resulting from delayed afterdepolarizations (DADs). In animals with surgically induced complete atrioventricular (AV) block, monomorphic VT was induced by programmed ventricular stimulation during continuous intravenous (i.v.) infusion of ouabain. At the moment of drug administration, VT persisted for at least 20 min, while the rate was stable for at least 5 min. A single dose of MgSO4 (100 mg/kg i.v.) abolished only VTs with cycle lengths > or = 320 ms (335 +/- 10 ms); VTs with faster cycle lengths (300 +/- 20 ms) were merely slowed, although the increase in plasma magnesium levels was considerable and comparable in both groups (3.9 +/- 1.6 and 4.8 +/- 1.9 mM). In contrast, moricizine (2 mg/kg i.v.) and verapamil (0.5-1.0 mg/kg i.v.) terminated both fast and slow VTs. The cycle length of VT ranged from 280 to 320 ms (mean 300 +/- 15 ms) for moricizine and 260-330 ms (mean 300 +/- 25 ms) for verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

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