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Cardiovascular Research 2000 48(1):120-128; doi:10.1016/S0008-6363(00)00149-8
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Copyright © 2000, European Society of Cardiology

Regional electrophysiological effects of left ventricular hypertrophy in isolated rabbit hearts under normal and ischaemic conditions

Robert Wolka, Kenneth P. Sneddonb, John Dempsterc, Kathleen A. Kanec, Stuart M. Cobbeb and Martin N. Hicksb,*

aDepartment of Cardiology, Medical Center for Postgraduate Education, Grochowski Hospital, Grenadierow 51/59, 04-073 Warsaw, Poland
bDepartment of Medical Cardiology, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK
cDepartment of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, 27 Taylor Street, Glasgow, G4 0NR, UK

* Corresponding author. Tel.: +44-141-211-0461; fax: +44-141-552-4683 m.n.hicks{at}clinmed.gla.ac.uk

Received 10 February 2000; accepted 26 May 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
Objectives: Left ventricular hypertrophy (LVH) has been reported to produce differential electrophysiological effects in isolated epicardial and endocardial cells. This study aimed to examine regional electrophysiological effects of LVH in normal and ischaemic conditions in the whole heart. Methods: LVH was secondary to perinephritis-induced hypertension. Monophasic action potential duration (MAPD90), effective refractory period (ERP) and conduction delay were measured in paced, isolated working rabbit hearts either at one right ventricular and two left ventricular sites (apical and basal epicardium) or at three left ventricular sites (apical and basal epicardium, apical endocardium). The hearts were subjected to 30 min of regional ischaemia and 15 min of reperfusion. Results: In non-ischaemic conditions, LVH produced uniform prolongation of MAPD90 and ERP in the left ventricular epicardium, but not in the endocardium. After coronary artery occlusion, LVH significantly increased ischaemia-induced transepicardial dispersion of repolarisation, but not refractoriness. LVH did not affect arrhythmogenesis in either non-ischaemic or ischaemic conditions. Conclusions: Differential effects of LVH on epicardial and endocardial electrophysiological parameters are also observed in the whole heart. In addition, the sensitivity of hypertrophied myocardium to ischaemia is increased and leads to an increase in ischaemia-induced dispersion of repolarisation. However, neither dispersion of refractoriness nor arrhythmogenesis are affected by LVH in non-ischaemic or ischaemic conditions in this experimental model.

KEYWORDS Hypertrophy; Ischaemia; Repolarisation; Ventricular arrhythmias


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 5 Conclusions
 References
 
In a clinical setting, the Framingham study has demonstrated that left ventricular hypertrophy (LVH) increases the risk of sudden death [1]. LVH has also been shown to be associated with an increased incidence of ambulatory ventricular arrhythmias [2,3]. The electrophysiological bases for the pro-arrhythmic effects of LVH are not fully understood. Various intrinsic electrophysiological abnormalities have been identified in hypertrophied hearts and implicated in the pathogenesis of arrhythmias [4,5]. One of these is an increase in electrical heterogeneity, which may be the substrate for arrhythmias based on re-entry. For example, hypertrophy induced action potential prolongation is more pronounced in epicardial compared to endocardial myocytes which could alter the normal pattern of ventricular repolarisation [6–8]. Although these differential regional effects of LVH have been described in isolated cells, it has not been established whether they exist in the whole working heart (exposed to mechanical influences and electrotonic interactions) and are related to arrhythmogenesis.

Although both LVH and ischaemia can be pro-arrhythmic in their own right and are often observed to coexist clinically, it can be argued that their coexistence could create a particularly arrhythmogenic milieu [9]. One possible electrophysiological mechanism is accentuation of action potential shortening during ischaemia by LVH [10,11]. This could lead to an increase in electrical dispersion which is required for the establishment of re-entry circuits. However, in these previous reports, dispersion of repolarisation during ischaemia was not directly measured and its existence was inferred indirectly from a greater degree of ischaemia-induced action potential shortening observed in hypertrophied hearts [12].

Consequently, the aims of this study were two-fold. Firstly, to investigate the effects of LVH on regional (i.e. epicardial and endocardial) electrophysiological characteristics in the isolated working rabbit heart. Secondly, to measure directly the magnitude of ischaemia-induced electrical dispersion in hypertrophied hearts and its relation to arrhythmogenesis. To this end, the model of perinephritis-induced LVH in the rabbit was used, which has been previously well characterized with respect to the hypertrophy produced [8,12,13].


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 5 Conclusions
 References
 
2.1 Induction of myocardial hypertrophy
The study conforms with the provisions of the United Kingdom, Animals (Scientific procedures) Act 1986.

Male New Zealand white rabbits (weight: 2–3.5 kg) were pre-medicated with fentanyl citrate (0.095 mgkg–1) and fluanisone (3 mgkg–1) (Hypnorm, Janssen) administered intramuscularly, followed by inhalation anaesthesia with halothane, nitrous oxide and oxygen through a facemask. The left kidney was exposed via a flank incision and tightly wrapped in an envelope of cellophane which was held in place with a silk suture. The envelope was secured in such a way as to ensure the entire surface of the kidney was in contact with the cellophane but that blood and urine flow was not obstructed. The right kidney was exposed via a separate right flank incision and removed. In sham-operated animals the left kidney was mobilized and manipulated (but not wrapped) and the right kidney was removed. Post-operative analgesia was provided by 150 mg buprenorphine (Temgesic, Reckitt and Coleman) administered intramuscularly every 8–12 h over two days.

Conscious mean arterial pressure was recorded before and at 2-weekly intervals after the 4th week postoperatively using an 18-gauge cannula (Vygon UK) inserted into the central ear artery and attached to a pressure transducer (model: P23XL, Gould, USA). Only those animals in the wrap group which had a mean arterial blood pressure in excess of 100 mmHg for at least 2 weeks were used. In this study, wrap-operated animals fulfilled these criteria 8 to 14 weeks post-operatively and sham-operated animals were used as time-matched controls.

2.2 Whole heart preparation
The isolated working rabbit heart preparation used in the present study has been previously described [14,15]. The rabbits received heparin (2000 IU) and were euthanised with sodium pentobarbitone (100 mgkg–1). The hearts were excised and perfused with oxygenated-modified Tyrode solution (pH=7.4; composition in mM: Na+ 142.0, K+ 4.0, Ca2+ 1.8, Mg2+ 1.0, Cl– 121.0, HCO3– 28.0, H2PO4– 0.4, glucose 11.0) in a working heart mode (preload: 10 cm H2O; afterload: 75 cm H2O). In all the experiments, the right atrium was paced at a cycle length of 300 ms and epicardial temperature was maintained at 35°C. In order for a preparation to be included in the study, a minimum baseline aortic forward flow of 80 mlmin–1, measured using an in-line flow meter, was required.

2.3 Electrophysiological and other measurements
Epicardial monophasic action potentials (MAPs) were recorded using custom-made suction electrodes. In the first series of experiments, one electrode was located in the apical part of the area of the left ventricle that subsequently was made ischaemic by coronary occlusion (apical epicardium), and the other electrodes were placed in a non-ischaemic area above the area at risk (basal epicardium) and in the lower half of the right ventricle. In the second series of experiments, suction electrodes were located in the apical and basal epicardium, and a contact electrode catheter (EP Technologies, UK) was placed in the apical part of the left ventricular endocardium (opposite the respective epicardial suction electrode) in the area that was subsequently made ischaemic (apical endocardium). We confirmed in a series of preliminary experiments that MAPs recorded from the epicardial surface with a suction electrode were comparable with those recorded with a contact electrode in respect of MAP duration. Whenever a MAP signal of amplitude less than 10 mV before ischaemia and less than 5 mV during ischaemia, the presence of an unstable baseline or electrical noise the electrode was repositioned at the same site to improve the quality of the signal. MAPs recorded with suction electrodes have been shown to be an accurate indicator of the action potential duration recorded with intracellular microelectrodes in rabbit hearts [16].

Effective refractory periods (ERPs) were recorded from all epicardial sites and from the endocardium using bipolar stimulating electrodes and the contact electrode catheter, respectively. ERPs were determined during local ventricular pacing by the extra-stimulus technique as previously described [14,15].

An in-line flow meter (model T106, Transonic Systems, Ithaca NY, USA) was used for continuous recording of mean aortic forward flow.

At the end of the reperfusion period the coronary artery was occluded again, at the same site as previously, and Evans blue dye was injected into the perfusate to distinguish the area at risk (calculated as a percentage of the left ventricular mass). The area at risk was similar in the sham and in the wrap groups, the respective values being 26±1 and 25±1%. Wet heart weights as well as dry right and left ventricular weights were measured in order to assess the degree of hypertrophy.

2.4 Experimental protocol
The hearts were perfused in a working heart mode for 60 min during which time all electrodes and other measuring devices were inserted. At the end of this period the perfusing solution was renewed and an equilibration period of 15–20 min was allowed, after which electrophysiological recordings were started. MAPs and conduction delays were recorded simultaneously at all sites. ERPs and diastolic stimulation thresholds were measured in turn first in the right ventricle, followed immediately by ERP in the basal and apical epicardium (first series) or in the basal and apical epicardium followed by ERP in the endocardium (second series). Measurements were made twice with a 30-min interval between them. After completing the second set of measurements, the solution was renewed for a second time. Once a new equilibrium had been established, all electrophysiological measurements were repeated at another two time-points, 30 min apart. Typically, diastolic stimulation thresholds were 1 V, were not different between the groups and were unaffected by ischaemia.

Subsequently, a period of 30 min of ischaemia and 15 min of reperfusion was induced. During this period, local MAPs were measured continuously in all three areas and ERPs were measured 15 min into ischaemia and 15 min into reperfusion, in the same order as previously. When any sustained arrhythmia appeared spontaneously or was induced by the stimulation protocol, defibrillation was used after 30 s to restore normal rhythm.

2.5 Study groups
Two series of experiments were performed. In the first series ten sham and nine LVH hearts were used and in the second series there were seven sham and eight LVH hearts.

2.6 Data analysis
The MAP signals were recorded on a videotape recorder and were analysed off-line using a modified version of WCP analysis package (J. Dempster, Strathclyde University, Glasgow, UK). The action potential duration was measured at 90% repolarisation (MAPD90) and the conduction delay was taken as the time from the atrial pacing trigger to the onset of the MAP. Transepicardial MAPD90 dispersion was calculated as: MAPD90 in the basal epicardium–MAPD90 in the apical epicardium. In addition, transepicardial dispersion of repolarisation was calculated as: (MAPD90+conduction delay in the basal epicardium)–(MAPD90+conduction delay in the apical epicardium). ERP dispersion and dispersion of refractoriness (which takes into account changes in conduction delay) were calculated in a manner similar to that for MAPD90 dispersion and dispersion of repolarisation, respectively. Transmural dispersions were calculated as differences in the appropriate parameters between the apical epicardium and the apical endocardium.

Statistical analysis was carried out with SIGMASTAT statistical software (Jandel Scientific Software). Student's t-test and analysis of variance (ANOVA) were used to compare the electrophysiological data within and between the groups and the exact probability test was utilised to compare any observed differences in arrhythmogenesis. P values of less than 0.05 were considered statistically significant. All data are expressed as mean±S.E.M.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 5 Conclusions
 References
 
3.1 Experimental animals
The wrap and sham groups of animals did not differ with respect to whole animal body weight at baseline (2713±98 vs. 2650±77 g in the wrap and in the sham group, respectively, ns) or at the time when isolated heart experiments were performed (3246±65 vs. 3218±99 g, respectively, ns). In the wrap group, the mean arterial pressure increased post-operatively from 64±2 to 113±2 mmHg, (P<0.05), but it did not change markedly in the sham group (64±1 and 69±2 mmHg before and after the procedure, respectively, ns). Left ventricular hypertrophy was observed in the wrap group, with no change in the right ventricle (Table 1).


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  		Table 1 Left and right ventricular wet and dry weights, left ventricular to body weight and to right ventricular weight ratios in the sham and in the wrap group

 
3.2 Effects of myocardial hypertrophy on baseline electrophysiological and haemodynamic characteristics
In the normal hearts, MAPD90 was significantly longer in the apical endocardium than the epicardium and ERP was significantly longer in the basal epicardium than the apical endocardium. In addition, conduction delay was significantly less in the endocardium than the epicardium. LVH produced a statistically significant prolongation in both MAPD90 and ERP in the epicardium, without any effect in the endocardium (Table 2). No differences in conduction delay (Table 2) or dispersion of repolarisation and refractoriness between the LVH and the sham group were found at baseline. Therefore, the greater MAPD90 in the endocardium than the epicardium observed in sham-operated controls was lost in hypertrophied hearts. In sham-operated hearts, the mean ratio of apical endocardial to epicardial MAPD90 was 1.1±0.03 ms. This ratio was significantly less in the hypertrophied hearts at 0.9±0.02 ms (P<0.05).


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  		Table 2 Effects of myocardial hypertrophy on left ventricular MAPD90, ERP and conduction delay in isolated working rabbit hearts

 
Significant differences were also found with respect to the haemodynamic parameters measured. Mean forward flow and peak intraventricular systolic pressure were greater in the LVH than in the sham group (141±8 vs. 110±5 ml/min, respectively, for mean forward flow, P<0.05; and 110±2 vs. 98±3 mm Hg, respectively, for peak systolic pressure, P<0.05).

3.3 Electrophysiological effects of regional ischaemia in the absence and presence of myocardial hypertrophy
3.3.1 Epicardial action potential duration and conduction delay
As shown in Fig. 1, in the non-hypertrophied hearts, occlusion of the coronary artery resulted in a significant shortening of MAPD90 in the apical epicardium (from 119±2 to 58±5 ms at 15 min of ischaemia, P<0.05). Ischaemia similarly shortened MAPD90 in the epicardium of the hypertrophied hearts (from 127±4 to 56±6 ms, P<0.05). MAPD90 in the non-ischaemic basal epicardial area was not affected by coronary artery occlusion. In the sham group, there was a significant increase in conduction delay during ischaemia in the epicardium (from 106±2 to 118±3 ms at 15 min of ischaemia, P<0.05). Changes in conduction delay were similar in the LVH group (from 105±3 to 114±3 ms, P<0.05).


Figure 1
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  		Fig. 1 Monophasic action potential duration (MAPD90) in the epicardium of hypertrophied and non-hypertrophied hearts subjected to regional ischaemia and reperfusion. ‘#’ and ‘*’ indicate statistically significant differences from pre-ischaemic values and from non-hypertrophied hearts, respectively (P<0.05). For clarity, symbols for statistical differences are only shown for the pre-ischaemic values and for those at 15 min of ischaemia and reperfusion when appropriate.

 
Regional ischaemia resulted in a marked increase in transepicardial dispersion of both MAPD90 and repolarisation (which takes into account changes in conduction delay) in the sham group (from 1±2 to 68±5 ms, P<0.05, and from 2±2 to 57±4 ms, P<0.05, respectively). Hypertrophy significantly increased the magnitude of ischaemia-induced transepicardial dispersion of MAPD90 (Fig. 2) and repolarisation (data not shown), the ischaemia-induced changes in hypertrophied hearts being from 3±3 to 79±5 ms and 4±3 to 72±5 ms, respectively, (P<0.05 for both parameters).


Figure 2
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  		Fig. 2 Transepicardial dispersion of MAPD90 in hypertrophied and non-hypertrophied hearts subjected to regional ischaemia and reperfusion. ‘#’ and ‘*’ indicate statistically significant differences from pre-ischaemic values and from the non-hypertrophied group (P<0.05). For clarity, symbols for statistical differences are only shown for the pre-ischaemic values and for those at 15 min of ischaemia and reperfusion when appropriate.

 
3.3.2 Endocardial action potential duration and conduction delay
In the sham group there was some shortening of MAPD90 in the endocardium (from 125±4 to 96±10 ms at 15 min of ischaemia, P<0.05) but this shortening was significantly less than in the epicardium (Fig. 3, top panel). This differential sensitivity of the apical epicardium and the endocardium to ischaemia was not affected by hypertrophy (Fig. 3, bottom panel). In contrast to the epicardium, ischaemia did not affect conduction delay in the endocardium in either sham (89±2 vs. 90±2 ms) or hypertrophied (92±4 vs. 91±4 ms) hearts.


Figure 3
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  		Fig. 3 Monophasic action potential duration (MAPD90) in the epicardium and endocardium of hypertrophied (bottom panel) and non-hypertrophied (top panel) hearts subjected to regional ischaemia and reperfusion. ‘#’ and ‘*’ indicate statistically significant differences from pre-ischaemic values and from the endocardium (P<0.05). For clarity, symbols for statistical differences are only shown for the pre-ischaemic values and for those at 15 min of ischaemia and reperfusion when appropriate.

 
Fig. 4 shows the transmural dispersion of both MAPD90 (top panel) and repolarisation (which takes into account changes in conduction delay; bottom panel) throughout the experimental protocol. It should be noted that prior to ischaemia there were significant differences in both variables between the sham and hypertrophied hearts such that in the LVH hearts the dispersions were negative because hypertrophy reversed the order of repolarisation by differentially prolonging the MAPD90 in the epicardium but not the endocardium. In non-hypertrophied hearts, transmural dispersion of MAPD90 increased significantly after 15 min of ischaemia from 6±3 to 40±9 ms (P<0.05) with similar results in the hypertrophied hearts from –16±6 to 22±8 ms (P<0.05; Fig. 4, top panel). However it should also be noted that if dispersion of MAPD90 is calculated by taking zero as the reference level and ignoring the direction of repolarisation this influences the values obtained in the hypertrophied hearts. In this case transmural dispersion of MAPD90 was not significantly increased by ischaemia in the LVH group (17±6 to25±6 before and at 15 min of ischaemia respectively). Transmural dispersion of repolarisation also increased after 15 min in both the non-hypertrophied (–8±6 to 17±9 ms, P<0.05) and hypertrophied hearts (–27±6 to 4±8 ms, P<0.05) (Fig. 4, bottom panel).


Figure 4
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  		Fig. 4 Transmural dispersion of MAPD90 (top panel) and repolarisation (bottom panel) in hypertrophied and non-hypertrophied hearts subjected to regional ischaemia and reperfusion. ‘#’ and ‘*’ indicate statistically significant differences from pre-ischaemic values and from the non-hypertrophied group (P<0.05). For clarity, symbols for statistical differences are only shown for the pre-ischaemic values and for those at 15 min of ischaemia and reperfusion when appropriate.

 
3.3.3 Epicardial ERP
In the sham group, occlusion of the coronary artery resulted in a significant shortening of ERP in the ischaemic epicardium (from 132±3 to 80±4 ms at 15 min of ischaemia, P<0.05; Fig. 5). The magnitude of the observed changes in ERP was not affected by hypertrophy, ERP shortening in the epicardium being from 136±4 to 83±4 ms (P<0.05).


Figure 5
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  		Fig. 5 Effective refractory period (ERP) in the epicardium and endocardium of hypertrophied (bottom panel) and non-hypertrophied (top panel) hearts subjected to regional ischaemia and reperfusion. ‘#’ and ‘*’ indicate statistically significant differences from pre-ischaemic values and from the endocardium (P<0.05).

 
In the non-hypertrophied hearts, regional ischaemia resulted in a marked increase in transepicardial dispersion of both ERP and refractoriness (from 6±3 to 62±4 ms, P<0.05, and from 7±3 to 51±6 ms, P<0.05, respectively). None of these parameters was affected by hypertrophy, with ischaemia increasing dispersion of ERP and refractoriness from 7±3 to 61±3 ms (P<0.05) and from 7±4 to 53±3 ms (P<0.05), respectively.

3.3.4 Endocardial ERP
In the sham group, shortening of ERP in the endocardium was from 116±5 to 92±7 ms at 15 min of ischaemia (P<0.05). Like MAPD90, ERP shortening was greater in the epicardium than in the endocardium (Fig. 5). The magnitude of these observed changes in ERP was not affected by hypertrophy, with ERP shortening in the endocardium from 117±4 to 81±4 ms (P<0.05). Like non-hypertrophied hearts, ERP shortening in hypertrophied hearts was greater in the epicardium than in the endocardium (Fig. 5). In both the sham and hypertrophied hearts, ischaemia significantly increased transmural dispersion of ERP (–8±8 to 14±9 ms in sham and –14±7 to 4±4 ms in the hypertrophied hearts, P<0.05 both groups). Transmural dispersion of refractoriness was significantly decreased by ischaemia in the LVH group (–31±7 to –13±4 ms, P<0.05) but any change in the sham group failed to reach significance (–25±12 to –7±8 ms, ns). As described for transmural dispersion of APD90, if the direction of the recovery of excitability is taken into account in the hypertrophied hearts, ischaemia no longer increases dispersion of ERP (15±7 to 9±3 ms).

3.3.5 Arrhythmias
Fig. 6 illustrates the incidence of arrhythmias (spontaneous and induced) during ischaemia and reperfusion in hypertrophied and non-hypertrophied hearts. In both groups, during ischaemia there were no spontaneous arrhythmias, but VF was usually induced during the measurement of ERP. During reperfusion, VF occurred spontaneously or during the ERP protocol. No significant difference in the incidences of either ischaemia or reperfusion-induced arrhythmias was observed between the groups.


Figure 6
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  		Fig. 6 Incidence of ventricular arrhythmias (spontaneous and induced) during ischaemia (top panels) and reperfusion (bottom panels) in hypertrophied and non-hypertrophied hearts.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
5 Conclusions
 References
 
4.1 Electrophysiological effects of myocardial hypertrophy in non-ischaemic conditions
This study reports a differential effect of LVH on various electrophysiological parameters in the epicardium and in the endocardium in the whole working heart. Specifically, while the duration of MAPD90 and ERP was increased by LVH in the epicardium, no significant effect was seen in the endocardium. These findings are in agreement with some previous reports in isolated cells, in which hypertrophy was found to prolong action potential duration in the epicardium, with a much smaller prolongation [8], no change [6] or shortening [7] seen in the endocardium (depending on the species involved and on the model of LVH). In contrast to our results, however, no effect of hypertrophy on ERP was found in canine hearts in vivo [17]. It cannot be excluded that, in the latter report, the electrophysiological recordings were affected by extracardiac neuro-endocrine factors [18]. In the present study, hypertrophy-induced MAPD90 and ERP prolongation was uniform across the epicardium and, consequently, transepicardial electrical dispersion was not increased. Although hypertrophy had a differential effect on MAPD90 and ERP in the epicardium and in the endocardium, these differences were relatively small, and any effects on transmural dispersion of repolarisation and refractoriness were not sufficient to influence the inducibility of arrhythmias prior to ischaemia in the present study.

The magnitude of the prolongation of MAPD90 in the present study was smaller than that reported in the isolated cells in the same model of LVH [8]. One possible explanation is differences in the pacing rate. Specifically, it has been suggested that pacing at higher stimulation frequencies can abolish or attenuate hypertrophy induced action potential prolongation [8,19]. In the above mentioned study in the model of perinephritis-induced hypertrophy [8], the magnitude of action potential prolongation was found to be negatively correlated with a stimulation rate in single ventricular myocytes over the range of stimulation frequencies 0.1–1.5 Hz. In the experiments in the present study the stimulation frequency of 3.3 Hz was used, which may explain the small magnitude of the observed effect. From the pathophysiological point of view, it is possible that action potential prolongation and its pro-arrhythmic consequences may be more important at slower heart rates. On the other hand, it is possible that the electrophysiological effects of LVH in working hearts are different in magnitude due to mechanical influences and intercellular electrotonic interactions.

4.2 Electrophysiological effects of myocardial hypertrophy in ischaemic conditions.
The present results are the first report in which dispersion of repolarisation was measured directly in isolated hypertrophied hearts during regional ischaemia. A greater degree of regional ischaemia-induced action potential shortening might be expected in hypertrophied hearts due to an increased open-state probability of the KATP channels at lowered pH levels and depleted ATP conditions in hypertrophied myocytes or by an increased magnitude of the calcium current reduction during metabolic inhibition [20–22]. Although our results demonstrate that LVH did not significantly increase the magnitude of MAPD90 shortening, it was still associated with an increase in ischaemia-induced dispersion of repolarisation across the epicardium. However it was difficult to interpret hypertrophy induced changes in transmural dispersion of MAPD90 and repolarisation due to the hypertrophy induced reversal in the transmural direction of repolarisation where the repolarisation in the endocardium precedes that in the epicardium. Hypertrophy did not increase dispersion of refractoriness during regional ischaemia (in spite of a significant increase in dispersion of repolarisation). This suggests that changes in dispersion of repolarisation cannot be simply extrapolated to dispersion of refractoriness, a finding we have previously noted in this model [14,15]. We also did not observe an enhancement of arrhythmogenesis with LVH and ischaemia, in contrast to previous studies [10,11]. A previous study using this model clearly demonstrated that the susceptibility of hypertrophied hearts to arrhythmias albeit not associated with ischaemia is increased, at least under conditions of high external load [13]. It is, therefore, possible that the electrophysiological consequences of acutely unloading the hypertrophied hearts, as was done in the present study, masked or attenuated the effects of ischaemia and might suggest that it would be appropriate to maintain the hypertrophied hearts working against an afterload similar to that seen in vivo. Since the incidence of VF induced during ERP measurement during ischaemia was 100% in the hearts from sham-operated animals, the only pro-arrhythmic effect of LVH that could be observed in this model is a change in the incidence of spontaneous arrhythmias. The fact that we did not observe such a change could be due to the following. Firstly, a lack of triggering factors or too small an electrical dispersion during atrial pacing in the present model could be responsible. Secondly, the area at risk in the ‘positive’ studies ranged from 31% to 62%, whereas in the present study it was only approximately 25%. Thirdly, some of the ‘positive’ studies employed in vivo preparations which are subjected to reflex sympathomimetic influences [23] and the sensitivity of hypertrophied myocardium to electrophysiological effects of sympathomimetics is known to be increased [24]. Finally, the discrepancies between the present and other studies may be related to the different species used (rats and dogs were used by other authors and those species may be more prone to arrhythmias which are observed even in non-hypertrophied hearts), to the model as well as the degree of hypertrophy and fibrosis.


   5 Conclusions
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusions
References
 
Our results demonstrate that, in the whole working heart, left ventricular hypertrophy exerts differential electrophysiological effects in the epicardium and endocardium with the consequence that the normal direction of repolarisation is reversed. The sensitivity of hypertrophied myocardium to ischaemia was shown to be increased and results in an increase in ischaemia-induced dispersion of transepicardial repolarisation. However, dispersion of refractoriness was not affected by LVH during ischaemia and consequently the incidence of arrhythmias was not increased.

Time for primary review 27 days.


   Acknowledgements
 
Robert Wolk held a University of Strathclyde postgraduate scholarship and an ORS award. Kenneth Sneddon held a University of Glasgow postgraduate scholarship.


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

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