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Cardiovascular Research 2000 45(2):310-320; doi:10.1016/S0008-6363(99)00362-4
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Copyright © 2000, European Society of Cardiology

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

Ruediger Beckera,*, Béla Merkelyb, Alexander Bauera, László Gellérb, Levente Fazekasb, Kirsten D. Freiganga, Frederik Vossa, Julia C. Sengesa, Wolfgang Kueblera and Wolfgang Schoelsa

aDepartment of Cardiology, University of Heidelberg, Bergheimer Strasse 58, 69115 Heidelberg, Germany
bDepartment of Cardiovascular Surgery, Semmelweis Medical University, Budapest, Hungary

* Corresponding author. Tel.: +49-622-156-8855; fax: +49-622-156-5514 ruediger_becker{at}med.uni-heidelberg.de

Received 2 June 1999; accepted 5 October 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objectives: To analyze three-dimensional activation patterns of ventricular arrhythmias induced by endothelin-1 in comparison with ischemia-induced tachycardias. Methods: Following 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. Results: Endothelin-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. Conclusion: The 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.

KEYWORDS AT, activation time; ET-1, endothelin-1; CT, conduction time; i.c., intracoronary; LAD, left anterior descending artery; LIG, LAD ligation; VT, ventricular tachycardia


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Endothelin-1 (ET-1) is a peptide hormone that was first isolated from porcine aortic endothelium [1]. Meanwhile, it has been shown to be expressed by several cell types, including vascular and endocardial endothelium [2]. Intravenous or intracoronary administration of ET-1 not only produces positive inotropic and chronotropic actions, but also marked and long-lasting vasoconstrictive effects in various mammalian species and in humans [2–6]. Elevated plasma endothelin levels have been found in patients with ischemic and nonischemic heart failure, suggesting a potential pathogenetic role of the peptide [7–9]. As shown experimentally, low-dose i.c. administration of ET-1 (30–60 pmol/min) induces ventricular arrhythmias, ranging from premature ventricular contractions to ventricular fibrillation [10–12]. In view of the agent's marked vasoconstrictive potency, these arrhythmias might be exclusively attributed to myocardial ischemia. However, according to previous experimental data [11,12], severe arrhythmias occur even with a moderate reduction in coronary blood flow (24–32%). Furthermore, the occurrence of arrhythmias does not correlate well with the severity of ischemia [13]. Experimental studies in isolated myocardium suggest that ET-1 also exerts direct electrophysiologic effects, which might also provide a basis for arrhythmogenesis [14,15]. Although it might be almost impossible to differentiate suspected direct electrophysiologic effects of ET-1 and the contribution of regional ischemia in vivo, one might still speculate that direct electrophysiologic effects are of relevance if respective arrhythmias were different from those induced by ischemia alone. Thus, a three-dimensional mapping technique was used in dogs to compare low-dose i.c. ET-1 infusion and acute LAD ligation with respect to their effects on conduction and refractoriness and on the activation patterns of induced ventricular arrhythmias.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1996).

2.1 Model preparation
Ten healthy foxhounds weighing 24.3±2.4 (range 21–30) kg were anaesthetized with intravenous pentobarbital (0.5 mg/kg), intubated and ventilated with nitrous oxide–oxygen (70:30). Electrocardiographic leads I, II and III were continuously monitored on a VR 12TM recorder (Electronics for Medicine, Pleasantville, NY, USA). To avoid interference with supraventricular arrhythmias, a transvenous AV node ablation was performed under fluoroscopic guidance in all dogs (Cerablate plusTM 735 catheter, HAT 200TM RF generator; Sulzer Osypka, Grenzach-Wyhlen, Germany). Then the heart was exposed through an extended midsternal approach and the pericardium was removed. Directly proximal to the first diagonal branch, a 16-gauge cannula was inserted into the LAD for i.c. drug infusion in five animals (ET-1 group), and a sling was placed loosely around the vessel for subsequent ligation in the remaining five dogs (LIG group). During the experiments, body temperature was adjusted to 37°C with a heating lamp.

2.2 Mapping technique and electrophysiological measurements
For detailed three-dimensional mapping of ventricular excitation in the in situ canine heart, 60 custom-designed pin electrodes were inserted into both ventricles, organized in five parallel rows from the base to the apex (distance between pins about 1 cm; Fig. 1). Each pin was 1.2 cm in length and contained four bipolar electrodes with an interelectrode distance of 2.5 mm and an interpolar distance of 0.5 mm, allowing for recordings from 240 subendo-, midmyocardial (2x) and subepicardial sites. All electrograms were simultaneously processed through a 256-channel multiplexer and recorded on videotape for off-line digitization (sampling rate 2000 Hz) and computer analysis. The mapping system used was developed at the University of Limburg in Maastricht, The Netherlands [16]. Local ATs were marked automatically on the basis of maximum upstroke velocity [17,18]. Each marking was reviewed and manually revised if necessary. During pacing, ATs were calculated relative to the pacing artifact; during spontaneous rhythms, the earliest local activation during the first beat of an arrhythmia was chosen as a time reference. Based on these ATs, three-dimensional isochronal activation maps were constructed manually at 10-ms intervals. As detailed previously [17,18], conduction block was suspected if the AT of adjacent electrode sites differed by more than 40 ms or if local electrograms in respective regions displayed electrotonic deflections representing distant activation (e.g. double potentials). Local effective refractory periods were determined at twice diastolic threshold amplitude using the extrastimulus technique (Biotronik UHS 20TM stimulator). After eight basic stimuli at a constant cycle length of 400 ms (S1), an extrastimulus was introduced (S2), decreasing the S1S2 coupling interval in steps of 10 ms. The effective refractory period was defined as the maximum S1S2 interval that failed to evoke a propagated ventricular response.


Figure 1
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  		Fig. 1 Plunge electrodes in situ. The pins used for ERP measurements are marked by arrows.

 
2.3 Study protocol
Throughout the experiments, SSI pacing at 70 bpm (Telectronics 4510 implant support device; Telectronics Pacing Systems, Englewood, CO, USA) was introduced from a subendocardial stimulation site at the base of the left ventricle next to the LAD (Fig. 1). In group A, ET-1 (Sigma) was infused into the LAD at a dose of 60 pmol/min. In group B, however, a complete ligation of the vessel was performed. For the following 40 min, electrocardiographic leads I, II, III, aVR, aVL and aVF were continuously recorded together with all 240 intracardiac electrograms. This would allow reconstruction of the activation patterns of all occurring ventricular arrhythmias1. In addition, the following electrophysiologic parameters were determined at baseline and 10 min after infusion or ligation, respectively: (1) Left ventricular conduction time from base to apex, measured in each myocardial layer, and three-dimensional ventricular activation patterns during constant pacing at a cycle length of 400 ms, using the stimulation site mentioned above. (2) Local effective refractory periods at a basic cycle length of 400 ms at all four bipoles of two randomly selected left ventricular pins located in the anterior wall and at one right ventricular (control) pin (1 epi-, one endo- and two midmyocardial sites, respectively).

2.4 Statistics
Data are expressed as mean±standard deviation. Basic comparative statistics were performed using Student's t-test for paired or unpaired data, respectively. A confidence level of 95% was considered statistically significant.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
In one of five dogs included in the LIG group, the study protocol could not be completed due to occurrence of irreversible ventricular fibrillation 27 min after LAD ligation.

3.1 Effects on electrophysiologic parameters
ET-1 had no significant effect on left ventricular conduction time, total ventricular AT and left ventricular refractoriness during constant pacing at a cycle length of 400 ms (Table 1). Accordingly, the three-dimensional ventricular activation pattern of the paced beats also remained unchanged. LIG, however, significantly prolonged left ventricular conduction time and refractoriness in all myocardial layers (Table 1). While refractoriness was homogeneously affected in all layers, left ventricular conduction time was preferentially prolonged in the subendocardium (Table 1). As opposed to left ventricular conduction time, total ventricular AT increased only slightly during LIG (Table 1), with no significant effect on the overall activation pattern. As expected, right ventricular refractoriness was not significantly affected by ET-1 or LIG (209±11 vs. 207±11 ms, control vs. ET-1; 214±13 vs. 209±15 ms, control vs. LIG; P=n.s., respectively).


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  		Table 1 Effects of ET-1 and LIG on total ventricular activation time (TAT), left ventricular conduction time (CT) and left ventricular ERP

 
3.2 Surface ECG characteristics of induced arrhythmias
In both groups, all dogs developed nonsustained VTs. In the LIG group, the total number of episodes was higher than in the ET-1 group (35±24 (14–76) vs. 23±34 (3–83), LIG vs. ET-1, P<0.05). Individual episodes were comprised of 7.7±8.2 beats in the LIG and 5.7±5.8 beats in the ET-1 group. Although this difference was statistically significant, individual salvo length was found to be in a comparable range (3–39 vs. 3–42, LIG vs. ET-1). The ratio of monomorphic versus polymorphic episodes was also comparable in both groups (34 versus 66% in the LIG and 31 versus 69% in the ET-1 group, respectively). Thus, arrhythmias induced by ET-1 and LIG were comparable with respect to surface ECG characteristics. The polymorphic episodes were generally characterized by sudden shifts in QRS axis, but did not exhibit the characteristic rotation of the QRS axis around an imaginary baseline as in torsade-de-pointes. No sustained tachycardias (>30 s) were observed during ET-1 infusion, whereas during LIG, in one dog (no. 3; 27 min after LIG), a fast polymorphic tachycardia occurred that degenerated into ventricular fibrillation after 19 beats. In spite of immediate repetitive internal defibrillations and removal of the ligation, resuscitation failed in this dog. In Table 2, all nonsustained ventricular arrhythmias have been classified with respect to timing of occurrence. During LIG, a fairly uniform distribution of arrhythmias was found, whereas during ET-1 infusion, the number of arrhythmias tended to decrease during the last 10 min.


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  		Table 2 Nonsustained ventricular tachycardias during ET-1 and LIG: number and time of occurrence

 
3.3 Three-dimensional activation pattern of induced arrhythmias
In each dog, up to eight different episodes of mono- and polymorphic ventricular tachycardias were randomly selected for detailed analysis. Specifically, this relates to one mono- and one polymorphic episode for each 10-min interval within the 40-min recording period whenever possible. At least two beats were mapped for each monomorphic VT, and three to twelve beats for each polymorphic VT. Thus, the three-dimensional activation pattern was reconstructed for a total of 257 individual beats.

3.3.1 Arrhythmias induced by ET-1
Because of one dog developing only one mono- and two polymorphic episodes of non-sustained VTs, the number of episodes analysed in the ET-1 group amounted to 35. Three-dimensional mapping revealed that all monomorphic nonsustained tachycardias were based on monofocal activity, whereas polymorphic episodes were consistently found to display a multifocal mechanism. There was no evidence of reentry in any case. Respective foci were primarily located in the subendocardium, preferring the left rather than the right ventricle (Table 3). As compared to arrhythmias induced by LIG, ET-1-induced arrhythmias exhibited a significantly higher number of right ventricular foci (Table 3A). Furthermore, the prevalence of right ventricular foci was found to markedly increase with the duration of ET-1 infusion (Table 3B). Typical examples of ET-1-induced arrhythmias are shown in Figs. 2 and 3Go. The monomorphic tachycardia in Fig. 2 A–B (dog no. 2) was due to a subendocardial focus in the anterior aspect of the left ventricular wall close to the base, firing at a cycle length of 410 ms. In panels C–F, the resolution of the mapping technique is illustrated, supplemented by selected electrogram traces from regions of special interest (focus/functional conduction block). Fig. 3 displays a typical example of a polymorphic VT consisting of six consecutive beats (dog no. 3) with a mean cycle length of 322±51 ms (280–410). The underlying mechanism turned out to be multifocal, with shifting subendocardial foci located in both ventricles.


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  		Table 3 Distribution of foci

 

Figure 2
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  		Fig. 2 Surface ECG (A) and activation patterns (B) of a seven-beat monomorphic VT with a cycle length of 410 ms (dog no. 2). The sites of earliest activation are marked by asterisks. Functional conduction block is represented by heavy solid lines. From the site of earliest activation in the anterior aspect of the left ventricle, excitation spreads rapidly around the circumference of both ventricles and towards the apex. The predominantly craniocaudal spread of activation results in positive QRS complexes in leads II, III and aVF. Total AT is 102 ms, corresponding with the QRS duration in the surface ECG. The site of latest activation consistently occurs in the posterior aspect of the apex. A 308-ms interval of electrical silence separates the latest activation of any beat from the earliest activation of the subsequent beat, respectively. (C) Activation pattern in section 2. (D) Electrogram traces from the 10-ms isochrone encircled in (C). (E) Activation pattern in section 3. To illustrate the resolution of mapping, all activation times obtained in this section are shown. (F) Electrogram traces from the two pins marked by arrows in (E). In all myocardial layers, electrodes distal to the line of block display a difference in activation time of more than 40 ms. The hump preceding the major deflection in trace endo two presumably reflects an electrotonic deflection representing distal activation (‘double potential’).

 

Figure 3
Figure 3
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  		Fig. 3 Surface ECG and activation patterns of a six beat nonsustained VT with a mean cycle length of 322±51 ms (280–410) (dog no. 3). Beat 1 originates from a subendocardial focus in the anterior right ventricular wall (section 2). From there, activation spreads rapidly around the circumference of both ventricles and towards the apex, producing positive QRS complexes in leads II, III and aVF. Total AT is 108 ms, corresponding with the QRS duration in the surface ECG. Latest activation is recorded near the lateral aspect of the left ventricular base in section 1. A short line of transmural conduction block occurs in the left anterior wall next to the septum (the heavy solid line in section 2), forcing activation to proceed unidirectionally around the circumference of the left ventricle. Premature activation (the 80-ms isochrone) on the distal side of the arc of block obviously results from neighbouring wavelets spreading up- and downwards from sections 1 and 3, respectively. After 232 ms of electrical silence, beat 2 starts from a subepicardial focus close to the preceding one. Following the latest activation at 114 ms, an electrical gap of 246 ms precedes beat 3, which is initiated by a subendocardial focus in the posterior aspect of the apex in section 5. The resulting caudocranial spread of activation with latest activation in the anterior part of the base accounts for negative QRS complexes in leads II, III and aVF. Total AT is 95 ms, corresponding with a relatively shorter QRS duration. Again, an electrical gap of 225 ms precedes beat 4, which originates from a subendocardial focus in the lateral aspect of the right ventricle. From there activation spreads centrifugally around the circumference of both ventricles, with no evidence of significant conduction delay or conduction block. Again, the direction of activation is reflected in the polarity of the QRS-complexes on the surface ECG. Beat 5 compares well with beat 4, except that the line of block in the anterior wall, which has been resolved in beats 3 and 4, reappears. Beat 6, finally, exhibits an activation pattern similar to beat 1. However, instead of conduction block, slow conduction is evident in the left anterior wall.

 
In summary, focal mechanisms were suspected to underlie all arrhythmias induced by ET-1 for two reasons: firstly, no continuous electrical activity was found bridging the gap between the latest activation of one beat and the earliest activation of the subsequent beat despite multiple intervening recording sites; a gap of at least 100 ms was evident in each case. And secondly, during each cycle studied, the site of latest activation during one beat was remote from the site of earliest activation of the subsequent beat. However, in ventricular beats demonstrating a spread of excitation perpendicular to the LAD, slow conduction or conduction block was frequently found where the wavefront crossed the vessel, as illustrated in Fig. 3. In none of these cases, however, did reentrant activity emerge.

3.3.2 Arrhythmias induced by LAD ligation
Due to irreversible ventricular fibrillation occurring 27 min after ligation, only six episodes of mono- and polymorphic VT could be analysed in dog no. 3, as opposed to eight episodes in the remaining four dogs. According to the above mentioned criteria, the initial beat of all tachycardias observed during LIG was due to focal activity. In 27 of 38 episodes analyzed, this focal mechanism, either mono- or multifocal, was found to persist for the duration of the VT. Though slow conduction was frequently observed in the anterior and lateral wall of the left ventricle (62%), complete conduction block was a rare finding (14%). Respective blocks were always short and associated with relatively fast conduction throughout both ventricles, so that reentry did not occur. Again, the great majority of foci were of left ventricular origin (Table 3). Comparable with ET-1 induced arrhythmias, subendocardial foci were most prominent, whereas midmyocardial and subepicardial sites were only found in a minority of beats (Table 3).

In 11 episodes of nonsustained VT, a macroreentrant mechanism could be demonstrated to be involved in the maintenance of the arrhythmia. In all of these cases, complete transmural conduction block developed in the anterior or lateral left ventricular wall, giving rise to large reentrant circuits including a zone of slow conduction in the anterior left ventricular wall.

In Fig. 4, a typical example of a fast polymorphic tachycardia has been depicted (dog no. 3). The arrhythmia was induced by a subendocardial focus in the anterolateral aspect of the left ventricular wall and maintained by a macroreentrant circuit with a zone of marked slow conduction in the anteroapical region of the left ventricle (Fig. 4).


Figure 4
Figure 4
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  		Fig. 4 Surface ECG and activation patterns of a nonsustained polymorphic VT with a mean cycle length of 249±33 ms (208–305). From a subendocardial focus in the anterolateral aspect of the left ventricle, excitation spreads centrifugally around the circumference of both ventricles and towards the apex. Slow conduction primarily occurs in the anterior wall, starting in section 3 and extending more markedly through sections 4 and 5. In accordance with the QRS duration in the surface ECG, total AT is 130 ms. After 180 ms of electrical silence, beat 2 starts from the same focus. While the pattern of excitation remains similar to beat 1 in sections 1–3, conduction is further delayed and finally blocks in the former area of slow conduction in sections 4 and 5. This prevents activation to spread anteriorly from the left to the right ventricle. Instead, the impulse proceeds unidirectionally around the posterior aspect of sections 4 and 5. The length of this ‘posterior pathway’ together with marked conduction delay in the anterior wall increases the revolution time of the unidirectional wavefront to an extent that previously excited tissue to the left of the arc of block regains excitability. Consequently, a macroreentrant circuit can establish in section 4, thus maintaining the arrhythmia during the following eight beats. Accordingly, subsequent beats reveal an overall activation pattern similar to beats 3 and 4, as reflected by the relatively uniform appearance of respective QRS complexes on the surface ECG. Termination of the arrhythmia was due to progressive conduction delay in the anterior wall and reoccurrence of focal activation from the left anterior base. This resulted in collision of wavefronts and termination of reentry. As the focus also stopped firing after two consecutive discharges, the underlying paced rhythm finally prevailed (activation maps not shown).

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
To the best of our knowledge, this is the first study to analyze three-dimensional activation patterns of endothelin-induced arrhythmias. Intracoronary ET-1 infusion in dogs with acute AV-block was found to induce ventricular arrhythmias without changing local refractory periods, left ventricular conduction time or the overall activation pattern. Induced tachycardias were exclusively due to mono- or multifocal activation, predominantly originating from the left ventricular subendocardium. Ligation of the LAD, on the other hand, induced local conduction delay, prolonged refractoriness homogeneously in all myocardial layers and produced arrhythmias that were maintained by focal or reentrant mechanisms. The differences in the effects of ET-1 and LAD ligation on electrophysiological properties and the difference in the mechanism of induced arrhythmias support the hypothesis that, apart from vasoconstrictive properties, ET-1 exerts an intrinsic arrhythmogenic effect. Endothelin-related arrhythmogenesis may well be due to a combination of vasoconstrictive and direct electrophysiologic effects, the preponderance of either mechanism potentially depending on the dose applied and the susceptibility of individual animals.

4.1 Comparison with other studies
Previous canine studies demonstrated that i.c. ET-1 can induce ventricular arrhythmias, ranging from premature beats to ventricular fibrillation [11,12]. At comparable ET-1 doses, respective arrhythmias were considerably more severe, possibly related to species [10] or race [11,12] dependent differences in the susceptibility to ET-1. Furthermore, in the present study, accelerated idioventricular rhythms (often sustained) at a rate between 100 and 120 bpm were frequently observed; due to a different rate criterion (>100 bpm), such episodes have been classified as VT in previous studies [11,12]. According to previous experimental data, low-dose i.c. ET-1 infusion (60 pmol/min) reduces the coronary blood flow by only 24–32% and still induces severe ventricular arrhythmias [11,12], with no correlation between the occurrence of arrhythmias and the severity of ischemia [13]. These observations strongly suggest mechanisms other than ischemia to be involved. Supporting this hypothesis, we could demonstrate that ET-1, as opposed to acute ischemia, does not significantly affect refractoriness in any myocardial layer, which includes the left ventricular subendo- and midmyocardium, the suspected location of M cells [19]. A previous study did also not find a prolongation of ERP with ET-1 [11]. However, at long cycle lengths (850 ms), ET-1 can significantly prolong monophasic action potential duration [12] and increase its dispersion [20]. The exclusively focal nature of ET-1-induced arrhythmias suggests abnormal automaticity and/or triggered activity as (an) underlying mechanism(s). Previous experimental findings favor triggered activity, because i.c. ET-1 produces early afterdepolarizations that can induce VTs [11,12]. In isolated canine myocardium, ET-1-induced early afterdepolarizations exclusively occurred in the right bundle branch, pointing to the conduction system as the source of triggered activity [15]. This finding might explain the preponderance of subendocardial foci during ET-1-induced tachycardias. Also compatible with triggered activity, permanent bradycardia was found to increase the incidence of ET-1-induced arrhythmias [21], whereas induction rates with programmed ventricular stimulation were rather low [12]. Supporting our finding that conduction properties remained unaffected by ET-1, the QRS duration in in situ canine hearts as well as the transmembrane action potential upstroke velocity in isolated canine myocardium were not significantly changed [15].

Although ET-1 was infused into the LAD, the percentage of right ventricular foci was considerably higher in the ET-1 as compared to the LIG group (Table 3). Furthermore, the prevalence of respective foci markedly increased with the duration of ET-1 infusion, whereas after LAD ligation, a fairly random distribution of right and left ventricular foci was encountered (Table 3). These observations may be explained by two hypotheses: (1) There is a background focal activity superimposed on ET-1-induced and ischemic arrhythmias, representing a higher proportion of the smaller overall number of arrhythmias seen during ET-1 infusion (Table 3), and (2) with increasing duration of infusion, there is a systemic re-circulation of ET-1, thereby reaching all myocardial regions.

Contrary to ET-1 and in keeping with previous data [22], LAD ligation significantly prolonged left ventricular AT in the present study. Earlier studies in isolated myocardium demonstrated that acute ischemia can prolong refractoriness without significantly affecting transmembrane action potential duration, referred to as ‘postrepolarization refractoriness’ [23]. Supporting this hypothesis, a number of studies performed in in situ canine hearts described a prolongation of ERP in the epicardial layer following coronary occlusion [24–26]. We could demonstrate a fairly homogeneous prolongation of ERP in the endo-, epi- and midmyocardium, with no preferential effect on any individual muscle layer. Conversely, other studies in in situ canine hearts demonstrated a shortening of ERP during acute ischemia [27–29]. These conflicting results might be due to methodological differences such as the choice of pacing mode, the timing of measurements, the selection of electrode sites, the degree of induced ischemia and the tissue temperature [30].

According to our results, reentrant activity contributes to the maintenance of VT induced by acute ischemia. Focal activity, however, seems to consistently account for arrhythmia induction. These findings are in line with previous results of Janse et al. [31] obtained in isolated porcine and canine hearts. Pogwizd et al. [32], however, suggested that intramural reentry is the predominant mechanism of arrhythmias during early myocardial ischemia, even for induction. This difference could result from the fact that the cats used by Pogwizd were in sinus rhythm, with rates as fast as 182 bpm. The fast heart rates are expected to favor conduction delay as a prerequisite for reentry. In our study, dogs were paced at a rate as slow as 70 bpm, presumably avoiding rate dependent slowing of conduction. Interestingly, one study using a comparable three-dimensional mapping technique failed to demonstrate macroreentry during VT induced by acute myocardial ischemia in dogs [33]. Thus, currently available data are inconsistent with respect to the predominant mechanism of acute ischemic arrhythmias. In this and in previous studies, the subendocardium appeared to be the main source of ectopic activity during acute ischemic VTs [25,31,33,34], suggesting Purkinje fibers as the site of origin [34].

4.2 Methodological considerations
A major limitation of our mapping technique was the lack of septal electrodes which did not allow to directly demonstrate septal activation. Thus, possible reentrant circuits confined to the septum might have been missed. Furthermore, with a resolution of about 1 cm, microreentrant circuits cannot be totally excluded. However, even with a microreentrant mechanism, an approximately circular pattern of excitation should prevail. All beats considered to be of focal origin, however, exhibited a centrifugal ventricular excitation, which renders a reentrant mechanism very unlikely. Protected microreentry, i.e., a microreentrant circuit surrounded by a line of functional block with only one exit, still remains a theoretical possibility, even though the existence of such a mechanism has yet to be shown.

Coronary blood flow and coronary venous lactate levels were not measured in our study. However, both parameters would have only been helpful to exclude global myocardial ischemia in the ET-1 group. On the other hand, even if it had been proven that there are no significant changes in coronary blood flow and/or lactate levels, regional ischemia or ischemia on a cellular level would still remain a (theoretical) mechanism underlying the observed arrhythmias.

4.3 Clinical implications
Prospective clinical studies have demonstrated that elevated plasma ET-1 levels are associated with an adverse prognosis in patients with ischemic and non-ischemic cardiomyopathy [35,36], although this does not necessarily reflect causality. Nonsustained VTs have been reported to occur in 40–80% of patients with chronic heart failure and to be associated with an increased risk of sudden cardiac death [37]. Three-dimensional mapping in experimental models and in humans revealed that focal mechanisms play a major role in ventricular arrhythmias, not only in nonischemic, but also in ischemic heart failure [38,39]. Thus, endothelin might well play a pathogenetic role in focal ventricular arrhythmias in the setting of chronic heart failure.

Time for primary review 22 days.


   Acknowledgements
 
This study was supported by a grant of the Deutsche Forschungsgemeinschaft, Bonn, Germany within the Sonderforschungsbereich 320 Herzfunktion und ihre Regulation, University of Heidelberg, Germany.


   Notes
 
1 Definition of VT: ≥three beats, ≥120 bpm; nonsustained ≤30 s, sustained >30 s. Back


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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