Jet D.M. Leunissen

Transvenous Cold Mapping and Cryoablation of the AV Node in Dogs: Observations of Chronic Lesions and Comparison to Those Obtained Using Radiofrequency Ablation

Cryoablation of the Proximal AV Node. Introduction: Radiofrequency (RF) is the most commonly used energy source for the treatment of cardiac arrhythmias. Surgical experience has shown that cryoablation also is effective for ablating arrhythmias. The aims of this study were to (I) investigate the feasibility of inducing permanent complete AV block (CAVB). (2) investigate the value of cold mapping to select the cryoablation site to produce permanent CAVB, (3) study the macro‐ and microscopic lesion characteristics 6 weeks later, and (4) compare them to those produced with RF energy.

Contractile Adaptations Preserving Cardiac Output Predispose the Hypertrophied Canine Heart to Delayed Afterdepolarization–Dependent Ventricular Arrhythmias

BackgroundIn 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 ResultsSteady-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. ConclusionsThe alterations responsible for improvement in systolic contractile function in CAVB dogs predispose the hypertrophied heart to DAD-dependent triggered arrhythmias during positive inotropic interventions.

Electrophysiologic parameters and predisposing factors in the generation of drug-induced Torsade de Pointes arrhythmias

When a new (cardiovascular) drug shows signs of QT interval prolongation on the ECG (delay in repolarization time), the regulatory agencies demand screening of its possible proarrhythmic potential before approving it for clinical practice. In this review, identified predisposing factors have been related to specific electrophysiological parameters, allowing quantification of their contribution to Torsade de Pointes arrhythmias. In addition, arrhythmogenic mechanisms involved in the initiation and perpetuation of drug-induced Torsade de Pointes are discussed.

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.

The Effect of Flunarizine and Ryanodine on Acquired Torsades de Pointes Arrhythmias in the Intact Canine Heart

Flunarizine and Ryanodine in Acquired TdP. Introduction: Ryanodine, a specific blocker of the Ca2+ release channel of the sarcoplasmic reticulum, and flunarizine, a[Ca2+], overload blocker, possess antiarrhythmic effects against delayed after depolarizations (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.

Flunarizine allows differentiation between mechanisms of arrhythmias in the intact heart.

The calcium antagonist flunarizine suppresses pathologic accumulation of calcium intracellularly without affecting the fast sodium or the slow calcium channel. To establish its value in differentiating between mechanisms of arrhythmias in the canine heart, the effect of flunarizine was investigated on ventricular tachycardia (VT) induced by ouabain intoxication or occurring 16-24 hours after occlusion of the left anterior descending coronary artery. Four groups of dogs were studied. Group 1 consisted of 13 animals with VT induced by ouabain intoxication (triggered-activity group). Group 2 included nine dogs in whom VT developed 16-24 hours after occlusion of the left anterior descending coronary artery (abnormal automaticity group). Group 3 included six dogs with normally conducted sinus beats, whereas group 4 consisted of six animals having a ventricular escape rhythm. With the exception of group 3, all dogs had surgically induced complete atrioventricular block. All animals were studied while conscious and without premedication. In groups 1 and 2, 2-3 mg/kg flunarizine was given intravenously after VT had persisted for at least 20 minutes. In groups 3 and 4, 2 mg/kg flunarizine was given after the rhythm was registered for 20 minutes. The cycle lengths of the different rhythms were compared before and after flunarizine. In group 1, flunarizine increased the cycle length of the VT from 300 +/- 30 to 410 +/- 50 msec (p less than or equal to 0.001). Termination of VT was seen in 11 out of 13 animals. In group 2, flunarizine resulted in a nonsignificant shortening of the RR interval from 450 +/- 60 to 440 +/- 60 msec. Persistent termination was observed in only one of nine dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Catheter-based cryoablation produces permanent bidirectional cavotricuspid isthmus conduction block in dogs

AbstractIntroduction: Catheter-based cryoablation has been shown to produce punctate and effective cardiac lesions to treat focal targets. However, sequential applications are required to produce a continuous linear lesion needed to cure macroreentrant arrhythmias with large critical isthmuses. The purpose of this study was to compare and contrast linear cardiac lesions produced with sequential applications using a novel cryoablation system to those produced using radiofrequency (RF) energy. Methods and Results: Seven mongrel dogs were prepared for femoral venous insertion of the ablation catheter (either a 10-French, 6-mm tipped, bipolar cryoablation catheter (N = 5, cryo group) or a 7-French, 4-mm tipped, bipolar RF ablation catheter (N = 2, RF group)). Ablation of the cavotricuspid isthmus was performed by delivering applications at sequential locations across the isthmus. The cryo group received 6 to 10 (mean 8 ± 1.4), 5-minute applications at 3 to 5 separate sites with a mean nadir temperature of −74.5 ± 1.6°C. Each dog in the RF group received 9, 90-second applications with a mean temperature and power of 62 ± 0°C and 32 ± 3.6 W. No acute or chronic complications were associated with either form of ablation. Immediately and six weeks after the index procedure, electroanatomical mapping showed the presence of bidirectional isthmus conduction block in all dogs. Gross and histopathologic examination revealed the presence of linear lesions, which were continuous and transmural. Conclusion: Similar to RF ablation, catheter-based cryoablation can produce linear, transmural lesions in the cavotricuspid isthmus resulting in permanent bidirectional isthmus conduction block.

The JT-area indicates dispersion of repolarization in dogs with atrioventricular block.

AbstractHeterogeneity in cardiac repolarization (ΔAPD) is known to be arrhythmic. In the dog model of chronic complete AV-block and acquired long QT syndrome, an increase in ΔMAPD (defined as left ventricular monophasic action potential duration (MAPD) minus right ventricular MAPD) is often associated with changes in T-wave morphology. The purpose of this study was to correlate known changes in ΔMAPD with the planimetric total area of the T-wave on the surface ECG (J∫T,mV · ms). Methods: The relationship between ΔMAPD and total area of the T-wave (i.e., JT-area) was assessed in four different protocols with different types of dispersion: (1) class III drugs followed by levcromakalim (n = 7), (2) LAD coronary artery occlusion and reperfusion (n = 6), (3) dronedarone i.v., an amiodarone like agent (n = 5) and (4) steady state pacing at cycle lengths of 1000 ms and 500 ms (n = 5). Results: Class III drugs increased ΔMAPD (55 ± 40 ms to 120 ± 50 ms#, P < 0.05), which was correlated (r = 0.74, P < 0.001) with JT-area (50 ± 40 mV · ms to 95 ± 35 mV · ms#). Ischemia increased both ΔMAPD (30 ± 25 ms to 90 ± 40 ms#) and JT-area (60 ± 55 mV · ms to 75 ± 50 mV · ms#). Both levcromakalim and reperfusion reversed these conditions. Dronedarone had no effect on ΔMAPD or on JT-area while a faster frequency reduced both ΔMAPD and JT-area. Conclusion: Changes in dispersion of ventricular repolarization are reflected by alterations in JT-area. This non-invasive parameter may therefore be used to indicate changes in heterogeneity in ventricular repolarization.

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.