Kirsten D. Freigang

Rate- and Site-Dependent Effects of Propafenone, Dofetilide, and the New IKs-Blocking Agent Chromanol 293b on Individual Muscle Layers of the Intact Canine Heart

BACKGROUNDnRecent in vitro studies have demonstrated regional differences in electrophysiological properties of individual left ventricular muscle layers. Controversy exists on the relevance of these findings for the situation in vivo. Thus, this study was designed to determine whether the in vivo canine heart exhibits regional differences in left ventricular refractoriness and in the susceptibility to sodium and potassium channel blockers.nnnMETHODS AND RESULTSnIn 16 dogs, 36 needle electrodes (12 mm long, 4 bipolar electrodes, interelectrode distance 2.5 mm) were inserted into the left ventricular wall. By use of a computerized multiplexer-mapping system, the spread of activation in epicardial, endocardial, and midmyocardial muscle was reconstructed during ventricular pacing at 300- and 850-ms basic cycle length (BCL). Effective refractory periods (ERPs) were determined at baseline and after application of propafenone (2 mg/kg), dofetilide (30 microg/kg), or chromanol 293b (10 mg/kg) by the extrastimulus technique (BCL 300 and 850 ms). At baseline, activation patterns and ERPs were uniform in all muscle layers. Propafenone homogeneously decreased conduction velocity and moderately prolonged ERPs without any regional differences. Dofetilide and chromanol 293b did not affect the spread of activation. Dofetilide exhibited reverse use-dependent effects on ERP, still preserving transmural homogeneity of refractoriness. Chromanol 293b led to a regionally uniform but more pronounced increase in local ERPs at faster than at slower pacing rates.nnnCONCLUSIONSnAt the heart rates applied, the in vivo canine heart does not exhibit regional differences in electrophysiological properties. Given the homogeneity of antiarrhythmic drug effects, induction of local gradients of refractoriness is obviously not a common mechanism of proarrhythmia in normal hearts.

Ventricular arrhythmias induced by endothelin-1 or by acute ischemia: a comparative analysis using three-dimensional mapping

OBJECTIVESnTo analyze three-dimensional activation patterns of ventricular arrhythmias induced by endothelin-1 in comparison with ischemia-induced tachycardias.nnnMETHODSnFollowing AV node ablation, sixty pin electrodes containing four bipoles each were inserted into both ventricles of ten foxhounds. Using a computerized mapping system, this would allow to simultaneously record 240 endo-, epi- and midmyocardial electrograms for reconstruction of the three-dimensional activation pattern. In five dogs, endothelin-1 was infused into the LAD at 60 pmol/min. In another five animals, the LAD was ligated. During the following 40 min, all ventricular arrhythmias were recorded for subsequent analysis. Furthermore, left ventricular conduction times during constant pacing and local effective refractory periods at eight left ventricular sites were determined before and after either intervention.nnnRESULTSnEndothelin-1 had no significant effect on conduction time and refractoriness, whereas ligation prolonged both parameters significantly. Endothelin-1 as well as ligation induced multiple mono- and polymorphic nonsustained ventricular tachycardias. Endothelin-1-induced arrhythmias were exclusively based on focal mechanisms, whereas during ligation, macroreentrant mechanisms were involved in the maintenance of tachycardias in 29% of episodes.nnnCONCLUSIONnThe differences in the effects of endothelin-1 and LAD ligation on electrophysiologic properties and the difference in the mechanism of induced ventricular tachycardias support the hypothesis that, apart from vasoconstrictive properties, endothelin-1 exerts an intrinsic arrhythmogenic effect.

Cesium chloride induced ventricular arrhythmias in dogs: three-dimensional activation patterns and their relation to the cesium dose applied

AbstractIntroduction: Cesium chloride has widely been used in experimental models to produce various ventricular arrhythmias. The study was designed to evaluate whether type and mechanism of these arrhythmias are dose-dependent.nMethods: In 7 dogs with acute AV-block, 60 pins containing 4 bipolar electrodes each were inserted into both ventricles to provide 240 endo-, epi- and midmyocardial recording sites. A computerized mapping system was used to determine three-dimensional activation patterns of ventricular arrhythmias induced by three injections of 1 mmol/kg cesium chloride at 20 minute intervals.nResults:Out of all arrhythmias induced, 25 ventricular extrasystoles, 31 monomorphic and 47 polymorphic ventricular tachycardias were mapped. Nonsustained ventricular tachycardias were readily inducible by a single bolus of cesium chloride, whereas sustained episodes required repetitive injections (1.45 ± 0.61 vs. 2.61 ± 0.57 doses, p < 0.05). Polymorphic tachycardias were observed more commonly than monomorphic tachycardias (87 vs. 31). Initiation and maintenance of cesium induced arrhythmias were exclusively based on focal mechanisms originating from the subendocardium, irrespective of morphology and dosage. All monomorphic arrhythmias were caused by repetitive firing of single immobile foci located in either the right or the left ventricle. Bi- and multifocal mechanisms, however, were found to underlie the polymorphic episodes.nConclusions: Although there is a dose-dependence as to the sustenance of mono- or polymorphic tachycardias, this does not reflect on the three-dimensional activation pattern of cesium induced arrhythmias, which are due to mono- or multifocal activation originating from the subendocardium.

Electrophysiologic effects of the new IKs-blocking agent chromanol 293b in the postinfarction canine heart

AbstractObjectives. Aim of the present study was to investigate site- and rate dependent effects of the IKs-blocking agent chromanol 293b on conduction and refractoriness in normal, infarcted, and transitional regions of in-situ canine hearts.nMethods. In five dogs with subacute myocardial infarction, three-dimensional mapping was performed after insertion of 6 × 6 needle electrodes in the left ventricle. Before and after application of chromanol 293b (10 mg/kg), activation patterns and local refractory periods (ERPs) at pacing intervals of 300, 500 and 850 ms were obtained for the surviving epicardial muscle layer of the infarct zone (IZ) and for epi-, endo-, and midmyocardial muscle layers of both the normal zone (NZ) and the border zone (BZ) separating normal and infarcted areas.nResults. At baseline, both the NZ and the BZ exhibited uniform ERPs throughout the ventricular wall. Epicardial ERPs were longer in the IZ than in the NZ, and intermediate in the BZ. Chromanol 293b did not affect total activation times. However, at fast heart rates regional areas of slow conduction occurred. Chromanol 293b ubiquitously prolonged local ERPs, most markedly in the IZ. A preferential effect on individual muscle layers of the NZ or BZ and, thus, drug-induced transmural dispersion of ERP could not be observed. Again ubiquitously, the effect on ERP was more pronounced at faster than at slower heart rates, that is, positive use-dependent. At a basic cycle length of 300 ms, chromanol 293b prolonged local ERPs in the IZ by 46 ± 24 %, in the BZ by 34 ± 26 %, and in the NZ by 20 ± 17 %( p ≤ 0.05).nConclusions. At least in theory, the electrophysiologic properties of chromanol 293 b, that is, preferential prolongation of refractoriness in ischemic myocardium, more pronounced at faster than at slower heart rates, but homogeneously throughout in intact ventricular wall, appear to be favorable. Whether this translates into a clinical benefit, particularly in the treatment of ischemia-related ventriular tachyarrhythmias, remains to be determined.

Echocardiographic Fourier phase and amplitude imaging for quantification of ischemic regional wall asynergy: An experimental study using coronary microembolization in dogs

OBJECTIVESnThis study investigated whether echocardiographic Fourier phase and amplitude imaging can be used to evaluate ischemia-related regional wall asynergy.nnnBACKGROUNDnBecause myocardial ischemia delays the onset and peak of endocardial inward motion and reduces its magnitude, Fourier phase and amplitude analysis of two-dimensional echocardiograms may be used to evaluate regional wall motion abnormalities objectively by analyzing temporal sequence and magnitude of endocardial motion.nnnMETHODSnDigital cine loops of left ventricular long- and short-axis views were obtained in six anesthetized dogs at baseline and 1 to 30 min after coronary microembolization and were mathematically transformed using a first-harmonic Fourier algorithm to obtain phase angles and amplitudes of endocardial segments. Mean phase angles and amplitudes were compared with visual wall motion analysis based on a scoring system and quantitative analysis based on segmental fractional area shortening derived from planimetry.nnnRESULTSnMicroembolization delayed segmental phase angles by 47 +/- 44 degrees in mild to moderate hypokinesia (fractional shortening [mean +/- SD] 41 +/- 13%) and by 77 +/- 63 degrees in severe hypokinesia (fractional shortening 13 +/- 5%) and reduced segmental amplitudes from 80 +/- 36 gray level intensity at baseline to 53 +/- 34 in segments developing mild to moderate hypokinesia, and from 93 +/- 36 to 35 +/- 28 gray level intensity in segments developing severe hypokinesia. Shifts in segmental phase angles correlated better with dynamic shifts in segmental fractional area shortening than did changes in wall motion score (r = -0.65 vs. r = 0.52, p < 0.001).nnnCONCLUSIONSnEchocardiographic Fourier phase imaging can be used to evaluate ischemia-related regional wall asynergy, displaying contraction sequence and magnitude in a simple, objective format.

Differential effects of d-sotalol on normal and infarcted myocardium: an experimental study using epicardial mapping

OBJECTIVEnThe aim of the study was to investigate the differential effects of the class III agent, d-sotalol, on conduction and refractoriness on normal and infarcted areas of the canine ventricle.nnnMETHODSnEpicardial mapping studies were performed in 6 dogs 5-7 days after ligation of the left descending coronary artery using a specially designed patch electrode which contained 192 bipolar electrodes. Normal and infarcted areas were differentiated with respect to their macroscopic appearance and electrophysiological properties. Activation maps and local effective refractory periods (ERP) were determined before and after the administration of d-sotalol (1.5 mg/kg) at cycle lengths of 250, 300 and 350 ms.nnnRESULTSnConduction and refractoriness were relatively homogeneous in the normal zone (NZ), contrasting with inhomogeneity in the infarct zone (IZ). In 2 dogs d-sotalol produced regional delay and block of conduction, exclusively in the IZ. The relative increase in refractoriness (delta ERP) after d-sotalol was significantly more pronounced in the IZ than in vs the NZ. In the NZ, delta ERP was most prominent at the longest (350 ms) and least prominent at the shortest (250 ms) basic pacing cycle lengths (11.5 +/- 2.8 vs. 7.3 +/- 1.4%; P < 0.05). The effect of d-sotalol in the IZ was independent of the basic pacing cycle length.nnnCONCLUSIONSnd-Sotalol preferentially prolonged refractoriness in the IZ of the canine ventricle. This effect and the lack of rate-dependence in the IZ could provide a possible explanation for both the potent antiarrhythmic and potential antiarrhythmic effect of d-sotalol.

992–114 Atrial Recordings for the Differentiation of Ventricular and Supraventricular Tachyarrhythmias

Inappropriate shocks due to supraventricular tachyarrhythmias (SVT) are a major concern in patients with implanted defibrillators. To elucidate the role of atrial recordings for the differentiation of ventricular (VT) and SVT, 127 right and left epicardial atrial electrograms were simultaneously recorded during atrial fibrillation (AF), ventricular fibrillation (VF), and rapid ventricular pacing (VP) at the fastest rate with retrograde 1:1 conduction simulating VT in 4 dogs with sterile pericarditis. Mean atrial (ACI) and ventricular cycle-lengths (VCI) were determined before and during adrenaline infusions (1.0xa0 μ g/kg/min). Adrenaline was given to stimulate physical exercise. In 43xa0±xa010% of all atrial recordings, the atrial signal was contaminated by ventricular activity of similar or higher amplitude. Due to a smaller ventricular signal, this was only true for 28xa0±xa011% (* pxa0lxa00,05) of atrial recordings during VF. At selected atrial sites, monophasic atrial signals turned into fragmented electrograms or double potentials with short ACI, due to local conduction delay or block. Thus, apart from “true” ACI measured at sites with clear atrial signals, “false” ACI were measured at electrode sites with complex local activity and/or ventricular interference. Data are summarized in the table below. Control Adrenaline CI (ms) True ACI False ACI VCI True ACI False ACI VCI AF 112xa0±xa020 * 105xa0±xa018 319xa0±xa092 97xa0±xa018 * 90xa0±xa017 290xa0±xa081 VP 343xa0±xa086 172xa0±xa064 * 343xa0±xa086 327xa0±xa075 163xa0±xa059 * 327xa0±xa075 VF 426xa0±xa093 107xa0±xa026 121xa0±xa023 * 358xa0±xa056 101xa0±xa027 114xa0±xa021 * * pxa0lxa00.05 Conclusions ACI clearly differentiates VT and SVT even during adrenaline stress. However, superimposed ventricular activity or tachycardia-dependent complexities of the atrial signal impose a substantial risk of false detections.

944-116 Focal Activation Patterns of Cesium Chloride Induced Torsades-de Pointes Tachycardias

‘Torsades-de-pointes’ tachycardias are probably initiated by early after depolarizations causing triggered activity. Whether successive beats with their constantly changing amplitude and axis result from focal or reentrant mechanisms has not yet been elucidated. Three dimensional mapping was carried out in 4 beagle dogs with polymorphic ventricular tachycardia (PVT) induced by repetitive (every 10 minutes) doses of cesium chloride (CsCI, 1xa0mmo/lkg i.v.). Bradycardia was produced by radiofrequency ablation of the AV node. Bipolar left and right ventricular electrograms were simultaneously recorded from 240 endo-, epi- and intramyocardial sites through 60 pins containing 4 bipolar electrodes each (interelectrode distance 2xa0mm, distance between pins 10–15xa0mm). One (3 dogs) or two (1 dog/ doses of CsCI produced various episodes of PVT, nine of which were analyzed (6.8xa0±xa02.7 consecutive beats). PVT originated from various left (nxa0=xa03) or right (nxa0=xa06) ventricular endocardial sites. Slow conduction or conduction block was not evident, total ventricular activation time during consecutive beats was 75xa0±xa012 msec. Initiation and continuation of PVT appeared to be exclusively due to focal mechanisms. Three different activation patterns were observed: (1) Changing foci from beat to beat, with variable coupling intervals (nxa0=xa02); (2) Two competing endocardial foci firing at variable rates (nxa0=xa03); (3) Periodically changing foci, replacing each other after gradual slowing of respective intrinsic rates (nxa0 = xa04) Conclusions Compatible with triggered activity elicited in Purkinje fibers, CsCI induced PVT demonstrate a focal activation pattern with an endocardial site of earliest activation. Local foci may initially speed up and then slow down in rate. Competing foci apparently rather trigger than suppress activation of each other

977-72 Irregular Atrial Tachycardias in the Canine Sterile Pericarditis Model: Epicardial Activation Pattern

Besides atrial flutter (AF) and atrial fibrillation (AFib), irregular atrial tachycardias (AT) demonstrating irregular “P”-waves on surface-ECG are also inducible in dogs with sterile pericarditis. Afib is due to multiple, variable, simultaneously activated wavelets, whereas a single, stable reentrant circuit is continuously activated in AF. To determine the epicardial activation pattern during irregular AT, 128 bipolar right and left atrial electrograms (electrode distance 3xa0–xa08xa0mm) were simultaneously recorded in 6 dogs after induction of the arrhythmia. Irregular ATs were always non-sustained, with the longest episode lasting for 70 consecutive beats. Mean cycle length was 125xa0±xa032 s, and the mean number of consecutive beats was 36xa0±xa028. Circus movement reentry around pure functional or functional-anatomical obstacles was the mechanism underlying AT in all dogs. Functional obstacles were formed by long arcs of conduction block, and anatomical obstacles were provided by the orifices of the atrial vessels. As in AF, only one reentrant circuit was active during AT. However, similar to Afib, the central obstacle differed in size and location from beat-to-beat. A marked area of slow conduction was not evident. Spontaneous termination of AT was typically associated with reentry around a small central obstacle. This resulted in a relatively short revolution time of the circulating impulse, which then encountered refractory tissue. Conclusions Linking the single, stationary circuits in AF and the multiple, variable circuits in AFib, irregular ATs are due to single but variable reentrant circuits. The instability of this type of reentry may be contributed to the lack of a marked area of slow conduction and/or the absence of long arcs of functional conduction block.