Patricia Kraft

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

BACKGROUND Recent 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. METHODS AND RESULTS In 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. CONCLUSIONS At 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.

Effects of the IKr-Blocking Agent Dofetilide and of the IKs-Blocking Agent Chromanol 293b on Regional Disparity of Left Ventricular Repolarization in the Intact Canine Heart

Recent in vitro studies have described regional differences of ion current expression and function, possibly accounting for reduced homogeneity of repolarization in the heart. In 11 intact canine hearts regional disparity of repolarization was determined at baseline and after administration of the IKr blocking agent dofetilide (30 &mgr;g/kg) and the IKs-blocking agent chromanol 293b (10 mg/kg). Effective refractory periods (ERPs) were determined through up to 10 needle electrodes inserted into basal, midwall and apical regions of the left ventricular wall using the extrastimulus technique (cycle length [CL] 300 and 850 ms). At baseline (CL of 850 ms), ERPs were significantly longer in epicardial muscle layers of the apex compared to the base. In deeper muscle layers regional differences of ERPs were not detectable. Administration of dofetilide increased apico-basal disparity of repolarization, due to a more marked increase of ERPs in the apex than in the base. In contrast, homogeneous ERPs were evident along the apico-basal axis after administration of chromanol 293b. Transmural dispersion of refractoriness could not be observed in any region at baseline, or after drug-administration. In the intact canine heart, apico-basal disparity of repolarization varies between individual muscle layers. Dependent on their current specificity, antiarrhythmic agents may enhance or diminish regional disparity of repolarization.

Role of sodium channels in ventricular fibrillation: a study in nonischemic isolated hearts.

Because the role of sodium channels in the initiation and maintenance of VF is not fully elucidated, we studied the significance of sodium channel activity in VF using sodium channel blockers. In nonischemic isolated feline hearts, the following electrophysiologic parameters were measured before and after application of tetrodotoxin (5 x 10(-7) M, n = 6) or lidocaine (1 x 10(-5) M, n = 8): (a) during pacing, epicardial conduction time; refractoriness; the fastest rate for 1:1 pacing/response capture, and all tissue resistivity, indirectly reflecting intercellular electrical resistance; (b) during 8 min of electrically induced tachyarrhythmias, all tissue resistivity; peak frequency (to measure average frequency based on fast-Fourier transformation analysis); and normalized entropy (to measure the degree of arrhythmia organization). In nonischemic isolated rabbit hearts (n = 4), three-dimensional mapping was performed before and after application of lidocaine (1 x 10(-5) M). In feline hearts, lidocaine and tetrodotoxin application resulted in: (a) more spontaneous arrhythmia termination (63-67%) than in nontreated hearts (7%); (b) transformation from mainly VF into ventricular tachycardia with increased organization; and (c) prolongation of conduction time (155-248%) (p < 0.01 for all parameters). The ventricular refractory period was slightly prolonged by tetrodotoxin in the right ventricle and exhibited rate-dependent shortening in control and with lidocaine. Tetrodotoxin and lidocaine reduced the pacing rate for 1:1 pacing/response capture, and all tissue resistivity was not significantly affected. Peak frequency was decreased by tetrodotoxin and lidocaine mainly in the left ventricle (p < 0.01). In nontreated left ventricles, peak frequency was increased over time but was attenuated by lidocaine. In isolated rabbit hearts, several simultaneous wave fronts were detected during VF in nontreated hearts and were reduced to only one or two major wavefronts after application of lidocaine. Suppression of sodium channel activity that primarily slowed conduction time and had little or no effect on ventricular refractory period and all tissue resistivity resulted in less stable and more organized arrhythmias and reduced tachyarrhythmia rate compared with nontreated hearts. These results suggest an active role for sodium channels in the maintenance of ventricular fibrillation.

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. Methods. 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. Results. 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). Conclusions. 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.

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

OBJECTIVE The 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. METHODS Epicardial 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. RESULTS Conduction 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. CONCLUSIONS d-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.

The new selective IKs–blocking agent HMR 1556 restores sinus rhythm and prevents heart failure in pigs with persistent atrial fibrillation

AbstractBackgroundAntiarrhythmic drugs for treatment of atrial fibrillation in patients with heart failure are limited by proarrhythmia and low efficacy. Experimental studies indicate that the pure IKs blocking agents chromanol 293b and HMR 1556 prolong repolarization more markedly at fast than at slow heart rates and during β–adrenergic stimulation. These properties may overcome some of the above quoted limitations.Methods and resultsTen domestic swine underwent pacemaker implantation (PM) and atrial burst pacing to induce persistent AF. Four days after onset of persistent AF, pigs were randomized to HMR 1556 (30 mg/kg, p.o., 10 days) or placebo. All animals receiving HMR 1556 converted to SR (5.2 ± 1.9 days), whereas placebo pigs remained in AF. Pigs treated with placebo developed high ventricular rates (297 ± 5 bpm) and severe heart failure, whereas pigs treated with HMR 1556 remained hemodynamically stable. Left ventricular ejection fraction on the day of euthanization was significantly lower in the placebo compared to the HMR 1556 group (30 ± 4% vs. 69 ± 5%, p < 0.005). Similar results were seen with epinephrine levels (placebo 1563 ± 193 pmol/l vs. HMR 613 ± 196 pmol/l, p < 0.05). Right atrial monophasic action potentials were significantly longer in the HMR 1556 compared to the placebo group (230 ± 7 ms vs. 174 ± 13 ms, p < 0.05).ConclusionsThe new IKs blocker HMR 1556 efficiently and safely restores SR and prevents CHF in a model of persistent AF. Restoration of SR is most likely linked to a marked prolongation of atrial repolarization even at high heart rates.

Effects of propafenone on anisotropic conduction properties within the three-dimensional structure of the canine ventricular wall

AbstractBackground Structural complexities of the intact ventricular wall cause a very complex spread of activation. The effects of regional tissue damage and of antiarrhythmic drugs on directional differences in activation should help to further elucidate intramural conduction patterns. Methods and results In 10 healthy dogs and in 5 dogs with subacute anterior wall infarction, 6 parallel rows of 6 needle electrodes with 4 bipolar electrode pairs per needle were inserted into the left anterior ventricular wall. Using a computerized multiplexer-mapping system, the spread of activation in epi-, endo- and midmyocardial muscle layers and in the surviving epicardium, respectively, was reconstructed. Marked differences in conduction velocities relative to fiber orientation were evident in the surviving epicardium of infarcted hearts. Directional differences in conduction velocities, although less pronounced, were still preserved throughout the intact ventricular wall. Epicardial transverse conduction in intact hearts was significantly faster than transverse conduction in infarcted hearts (0.87 ± 0.11 m/s vs 0.68 ± 0.1 m/s). In normal hearts, propafenone (2 mg/kg) decreased conduction velocities primarily in longitudinal directions (−27 ± 10%), but also moderately in transverse directions (−13 ± 7%) of all muscle layers, with no significant effect on straight (−4 ± 8%), but on oblique transmural conduction (−33 ± 18%). In infarcted hearts propafenone decreased conduction particularly in longitudinal direction (−23 ± 14%) without affecting conduction transverse to the fiber orientation (+3 ± 6%). Conclusions Longitudinal intramural shortcircuits reduce directional differences in activation. Transmural infarction results in a loss of alternative intramural pathways, unmasking marked anisotrophy in the surviving epicardium. Conduction delay in intramural pathways explains the effects of propafenone on transverse and oblique transmural conduction. Primarily longitudinal conduction delay results in reduced tissue anisotropy.

Refractoriness and Conduction Interaction During Modulation of Non-Ischemic Ventricular Fibrillation by Flecainide

AbstractPurpose: To study refractoriness and conduction interaction during modulation of non-ischemic ventricular fibrillation (VF) by flecainide. Methods: Isolated feline and rabbit hearts were used. (a) In the feline hearts (n = 8), electrophysiological parameters were measured before and after flecainide administration (0.6, 1.2 × 10−6 M). During pacing the parameters were: epicardial conduction time, refractoriness and 1:1 pacing/response capture. During 8 min of electrically-induced tachyarrhythmias they included heart rate and normalized entropy reflecting the degree of organization. (b) In rabbit hearts (n = 4), three-dimensional mapping was performed before and after flecainide administration (2 × 10−6 M). To follow changes in organization, local RR-intervals and differences in activation time between adjacent epicardial electrodes were measured immediately and 80 sec after VF induction. Results: In feline hearts with flecainide, fibrillation was more difficult to induce, more frequently terminated spontaneously and was slower and more organized; conduction time was markedly lengthened, and refractoriness less than 1:1 capture, was moderately prolonged. An inverse correlation was observed between arrhythmia properties, rate and organization, and changes in refractoriness and conduction time. In rabbit, the number of wave fronts was reduced, RR-intervals were prolonged but at the same time activation time differences between adjacent electrodes were smaller following flecainide administration. Conclusions: It is suggested that flecainide modulation of VF properties is associated with conduction suppression and refractoriness prolongation, which act in a synergistic, additive way.

Effects of acute ischemia, early extrabeats and propafenone on complex activation patterns in intact and ischemic canine hearts.

Although, sodium channel blockers have the ability to suppress nonsustained ventricular arrhythmias, an excessive drug-associated arrhythmic death rate has been reported in patients with coronary heart disease (CHD). Sodium channel blockers should prevent initiation of reentry activation by reducing directional differences in cardiac conduction (anisotropy). However, in vitro data demonstrated, that reduction of membrane excitability, e.g. by lowering the inward Na+ current, increases the risk for conduction failure and associated reentry arrhythmias. In 11 dogs the effects of myocardial ischemia, premature epicardial stimulation (PES) and propafenone on anisotropic conduction properties were tested using three-dimensional mapping techniques. The epicardial (longitudinal and transverse to fiber orientation) and transmural (oblique and straight) spread of activation was reconstructed during constant and PES. At baseline, conduction velocities (CV) were higher along (1.20 +/- 0.41 m/s) than across (0.91 +/- 0.19 m/s; p < 0.05) epicardial muscle fibers as well as along oblique (1.77 +/- 0.75 m/s) compared to straight (0.39 +/- 0.09 m/s, p < 0.05) transmural pathways. Acute ischemia did not significantly reduce tissue anisotropy. PES and additional administration of propafenone epicardially eliminated and transmurally profoundly reduced tissue anisotropy (longitudinal 0.58 +/- 0.09 m/s, transverse 0.69 +/- 0.08 m/s, oblique 0.69 +/- 0.28 m/s, straight 0.27 +/- 0.07 m/s). However, reduced anisotropy was associated with a higher probability for conduction block along myocardial fibers in the epicardium and along oblique transmural pathways. Our data show, that propafenone exhibits both potential pro- and antiarrhythmic effects in dogs with acute myocardial ischemia. These results possibly provide more insights in mechanisms underlying the excessive drug-associated arrhythmic death rate in patients with CHD.