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Cardiovascular Research 1998 38(1):181-191; doi:10.1016/S0008-6363(97)00314-3
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Mechanical modulation of stretch-induced premature ventricular beats: induction of a mechanoelectric adaptation period

David J Dick* and Max J Lab

Department of Physiology, Charing Cross and Westminster Medical School, St. Dunstans Road, Hammersmith, London W6 8RP, UK

* Corresponding author. Tel.: +44 (181) 8467643; fax: +44 (181) 8467338; e-mail: d.dick@cxwms.ac.uk

Received 1 April 1997; accepted 17 November 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Mechanoelectric Feedback, a mechanical intervention inducing an electrical change, is gaining credence as a cause of cardiac arrhythmia in the clinical situation. However, the precise mechanism is unknown. To elucidate this we investigated mechanical and chemical modulation of stretch-induced premature ventricular beats. Methods: We positioned a balloon in the left ventricle of an isolated heart (New Zealand White rabbit), perfused by the Langendorff technique. Balloon inflation regularly produces premature ventricular beats. Monophasic action potentials, ECG's and pressure recordings monitored changes during mechanical intervention. The hearts were subjected to (i) variations in the degree of preload and duration of inflation, and (ii) cytoskeletal disrupters, colchicine and cytochalasin-B. Results: Mechanical dilation of the left ventricle can not only induce premature ventricular beats, but also induce a period during which premature beats cannot be re-induced on a subsequent inflation, i.e. a mechanoelectric adaptation period. The trigger for the mechanoelectric adaptation period seems to occur immediately on balloon inflation and required up to 60 s to recover. This period started with an undershoot in the diastolic component of the monophasic action potential as well as in the peak systolic pressure, with return to control levels within the period. Deflation produced an overshoot (rather than undershoot) in the monophasic action potential duration, but this also returned to control levels within the period. Changes in preload, duration of inflation and disruption of the cytoskeleton failed to modulate the mechanically induced premature beats, or the mechanoelectric adaptation period. Conclusions: Transient ventricular stretch produces arrhythmia, followed by an antiarrhythmic adaptive period. Possible mechanisms are related to a mechanical influence on stretch-activated channels, changes in ionic concentration or diffusion, or second messenger systems, which influence membrane potential. The arrhythmic adaptation does not appear to be related to the mechanical properties of the cytoskeleton. Final elucidation of the mechanism of the mechanoelectric adaptation period demonstrated, may prove important in determining the mechanism of stretch-induced premature ventricular beats and consequently arrhythmia management.

KEYWORDS Premature beats; Arrhythmia; Mechanoelectric feedback; Cytoskeleton; Stretch; Ventricle; New Zealand white rabbit


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Heart disease with diverse aetiology, and the associated ventricular arrhythmias, is a prominent cause of sudden death in the developing world [1, 2], yet their precise mechanisms remain unclear. It is also unclear why patients with heart failure and dilated ventricles are more prone to lethal arrhythmias [3]. Serious ventricular arrhythmias occur due to abnormalities in impulse formation, conduction and myocardial inhomogeneities [4, 5]. Metabolic derangement, various pharmacological agents and high levels of catecholamines all promote arrhythmia [6]. However, left ventricular dilatation and dysfunction are common features in the patients most at risk. Poor ejection fraction is a better prognostic indicator than electrophysiological parameters [6, 7]. This has led to the entertainment of the concept of a mechanical event influencing the electrical activity of the heart, in a process now widely termed mechanoelectric feedback or mechanoelectric transduction (recently reviewed [8]). Importantly it may figure highly in the genesis of arrhythmia in the clinical setting [6–12].

Precisely how currently accepted arrhythmogenic mechanisms relate to a stretch-activated arrhythmogenic mechanism is unclear, although there are several features in common. Mechanically induced mechanisms for arrhythmia include afterdepolarisations, re-entry, changes in action potential duration, which in turn may lead to changes in refractoriness, wavelength and dispersion (see relatively recent reviews [8, 10]). Stretch-activated channels, originally described by Sachs' group [13]and comprehensively reviewed [14, 15]is the most popular mechanism proposed for these mechanically induced arrhythmia [10, 11, 16]. The permeant ion is thought to move towards its equilibrium potential, altering membrane electrophysiology.

Our preliminary study shows that not only can a mechanical intervention be arrhythmogenic, it can also be transiently anti-arrhythmic against a subsequent mechanically induced arrhythmia [17]. The anti-arrhythmic effect depends on the period between the first mechanical intervention and the subsequent one. We suggested that this was due to a type of time-dependent refractory mechanism. Hamill and McBride have demonstrated an ion channel current adaptation [18]to a maintained mechanical stimulus. Because the phenomenon we are studying is related to mechanoelectric transduction, we will ‘borrow’ from neurophysiological terminology in sensory mechanotransducers, and suggest that during this period there is ‘adaptation’ or ‘accommodation’. That is, a time over which the mechano-electric feedback process adapts — a ‘mechanoelectric adaptation period’. We will also refer to this in later text, as an ‘adaptive’ or ‘adaptation period’. (This choice is for want of a better term. It is not as accurate as we would like, but a short phrase is more convenient than a cumbersome descriptive sentence each time we refer to the phenomenon).

We wanted to address the mechanism behind the inhibitory time-dependent phenomenon of the mechanoelectric adaptation period in our preparation, by characterising some of the electrophysiological and mechanical changes during this period. The cytoskeleton is involved in the stretch-activated channel [15], and has been linked with the operation of several ion channels and transport proteins [19]. Using colchicine and cytochalasin-B, to disrupt the cytoskeleton [20], we addressed the possible role of the cytoskeletal matrix in this stretch-induced arrhythmia and the mechanoelectric adaptation period. Clarification of the mechanism of the mechanoelectric adaptation period may provide some insight into the mechanism of stretch-induced premature beats in intact hearts. This may be clinically relevant, for stretch-induced arrhythmia is increasingly linked with serious arrhythmia [6–8, 12, 21].


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Preparation and recordings
New Zealand White rabbits (n=25), of either sex, weighing 2–2.5 kg were given a lethal dose of barbitone sodium (200 mg/ml) via a marginal ear vein. The hearts were excised and retrogradely perfused by the Langendorf method [22](Fig. 1), using oxygenated (carbogen) Krebs solution, containing (mM): NaCl(50), NaHCO3(25), NaH2PO4(1.5), MgSO4.7H2O(1.5), KCl(4), NaCOOCH3(20), Glucose(10), CaCl2(1.8).


Figure 1
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  		Fig. 1 Arrangement of the Langendorf isolated heart preparation, showing the inflatable fluid-filled latex balloon system positioned in the left ventricle, and the recording devices. (MAP=monophasic action potentials, LVP=left ventricular pressure, RV=right ventricle, LA=left atrium, LV=left ventricle, PT=pressure transducer, CTL=control perfusate, EXPTL=experimental perfusate).

 
The right ventricle was paced with square pulses, 2 ms long and twice stimulation threshold at an initial rate of 15 beats above intrinsic heart rate. (Through retrograde conduction, atrial rate was also maintained at the preselected pacing rate). A latex balloon (constructed from the tip of a condom in all but system-test cases) on a catheter, attached to a pressure transducer, was inserted via the left atrium into the left ventricle and secured. The Thebesian circulation was drained, by insertion of a 0.5 mm diameter cannula, throughout the experiment. The pressure transducer monitored left ventricular pressure and the timing of balloon inflation. Suction electrodes recorded monophasic action potentials and ECG's [23]from the left atrium and left ventricle (Fig. 1).

Inflation of the balloon produced premature ventricular beats. These sometimes needed careful identification. This is because a combination of retrograde conduction, and the variation in relative timings between the signals monitored, could cause complex sequences. A premature ventricular beat is described with the aid of guidelines in the Lambeth convention [24]— briefly, a combination of the following: (i) an action potential with an abnormally short preceding beat interval, (ii) absence of preceding premature atrial action potential, (iii) an ECG with an abnormal QRS complex. We also used changes in the intra-ventricular systolic pressure trace (a small pressure accompanies a premature beat), and closely scrutinised the order in which the signals occurred.

2.2 Protocol
The balloon was inflated from zero volume using a computer controlled pump in steps of 0.5 ml or less. A servo controlled system was unnecessary for our purposes. The frequency of any artefactual oscillation in the system was orders of magnitude less than the period of interest (See Fig. 3). A pressure volume relationship was constructed using these volumes and resultant pressures. This ensured that the inflation volume was within physiological limits. The number of premature ventricular beats produced at each inflation volume was also counted. When further increases in inflation volume (within the physiological pressure volume limits) failed to increase the induced premature ventricular beats, the volume was denoted as 100%. Seventy to 80% of this volume was then used as the mechanical intervention, for the remainder of the experiment.


Figure 3
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  		Fig. 3 Pressure and oscillatory characteristics of the pressure recording system, with an inflation and deflation of the balloon prior to positioning into the left ventricle. (A) Minor mechanical oscillations are apparent at the transient phase of inflation and deflation. Investigation of the oscillations, by expanding horizontally, are shown in (B) balloon inflation and (C) balloon deflation. All major oscillations are over in about 50 ms. Also shown and important to note here is the inherent baseline shift on inflation in our system. Note: In order to exaggerate the pressure changes, and to ensure we could detect any slow creep in the system, we used three times maximum inflation, with a smaller and a stiffer latex balloon than that used in the experiments.

 
Premature beats could be observed throughout the inflation period. However they were more evident during its onset, (with some occasionally observed on deflation). Although these mechanically induced premature beats could have different mechanisms [25], they all appeared to show this mechanoelectric adaptation period being studied, and we did not attempt to differentiate between them at this stage.

Twenty minutes' equilibration was allowed after set-up was complete. Several inflation durations were assessed and a five-second inflation selected, as this allowed stabilisation of electrical and mechanical signals. A series of ten pre-experimental readings involved a five-second mechanical intervention, at the predetermined volume and pacing rate, with 90 s between each inflation. This allowed verification and standardisation of the number of premature ventricular beats observed on each inflation. We then allowed five minutes equilibration prior to experimental readings.

The experimental reading consisted of paired inflations (Fig. 2). The first was a 5-s control inflation, inducing premature ventricular beats (comparable in number to the pre-experimental single inflations). The second 5-s inflation, of the pair, induced a variable number of premature ventricular beats. These were normalised as a percentage of the control readings and used when the data was pooled. The interval between the first and the second interventions (t) was varied from less than 1 s to 30 s in steps of five seconds. We varied the interval in an incremental, decremental and quasi-random fashion. It is during this interval that the mechanoelectric adaptation period is thought to operate. The final recovery interval allowed between the paired interventions was 90 s, as 60 s produced complete recovery.


Figure 2
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  		Fig. 2 Demonstration of the experimental dual inflation protocols used, and the adaptation period post balloon deflation. In (A) the first 5 s balloon inflation (INFL1) produces premature ventricular beats (V), however the second inflation (INFL2) within 1 s (t<1 s), fails to illicit premature ventricular beats. (B) Shows another dual inflation protocol, where t=30 s; premature ventricular beats are now also induced on the second inflation. (LVMAP=left ventricular monophasic action potential, LVECG=left ventricular ECG).

 
We also varied the duration of balloon inflation (from 5 to 30 s), and the starting volume of inflation (0.5, 1.0, 1.5 and 2.0 ml). This allowed investigations into some of the characteristics of the mechanical stimulus, per se, in relation to the number of premature ventricular beats.

To address the possible role of the cytoskeletal matrix in the transduction mechanism responsible for mechanically induced premature beats and the mechanically induced adaptation period, we disrupted the cytoskeleton by infusing Colchicine (100 µM, n=7) or Cytochalasin-B (2.5 ng/ml, n=6; and 5 µg/ml, n=6), (Sigma-Aldrich Company, Dorset UK), and the mechanical intervention protocols repeated. Although this started reducing pressure within a minute or so, it was important to wait at least 15 min before beginning the protocol (cf. Galli and DeFelice [26]).

2.3 Passive mechanical characteristics of recording system
The adaptation seen in mechanical signals following deflation could be mechanical artefact — a ‘creep’ in the recording system. The re-inflation after one second would encounter a relatively larger apparatus volume. An important issue is what contribution is made by the mechanical properties of the injection and recording system per se in the mechanical measures. Fig. 3A shows an inflation and deflation of the entire pressure system without the heart in the system, i.e. with the intraventricular balloon alone. To exaggerate the passive pressure changes, the injection volume was 2–3 times that used in the actual experiments, and the balloon was of stiffer latex than the condom teat. (The latter was used in all the studies, but when the former was tested or used, the arrhythmia results were unaltered.) With the stiff latex, the balloon pressure was high but the major oscillations were complete in about 50 ms (Fig. 3B and C), with no following slow changes. The mechanical properties of the apparatus are therefore not a contributory factor to the results investigated in this study, for our mechanical period of interest is over about 20–60 s.

Our laboratory consistently finds (see Fig. 5) that ventricular passive tension, when inflating, is relatively high. However, this level of tension is not remarkably different from a previous systematic study of length-dependent activation in a Langendorff system [27]. Working on the ascending part of the pressure–volume curve, we estimate that their study shows the ratio of the developed pressure to the rise in passive pressure to be 3.7. The ratio estimated from our Fig. 5 is 2.5, although we sometimes found ratios that were a little higher. An analogous result comes from another Langendorff study [28]. This investigation shows a steep pressure–volume relation. Roughly, a 20% inflation, of their maximum, produced a 20 mmHg rise in diastolic pressure. This is also comparable to our studies, but, as with the previous authors [27], our ventricles were a little stiffer. We surmise that this passive tension is a particular property of the (our) Langendorff preparation. (The high tension is not a property of the condom teat, for the teat is larger than the ventricular cavity, and we can find it without a balloon in the ventricle.) We have not ascertained the cause to our satisfaction. An element of interstitial oedema is one distinct possibility. Another [28]is that diastolic intracellular calcium may interact to a small degree with the contractile elements in a Langendorff type preparation. This seems unlikely, because it appears as if this factor operated mainly at small volumes. This also seems unlikely from a study of rat trabeculae [29](see also Section 4). We tended to accept our ‘Langendorff situation’, firstly because of the broadly comparable findings above, secondly, we could not find any effects on any other physiological process that we could measure. Third, the preparation could last for up to 6–12 h without any deterioration in electromechanical function that would affect our results. Finally, stretch-induced arrhythmia, our study endpoint, is also found in a variety of preparations including blood perfused intact heart in situ [8, 12]where, with comparable volume increases, the rise in passive pressure is relatively low.


Figure 5
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  		Fig. 5 Characteristics of the left ventricular pressure recorded during an inflation and deflation protocol. (A) Left ventricular pressure (LVP) trace before, during and after an inflation and deflation of a balloon in the left ventricle. A slow creep in peak systolic and diastolic pressure is just discernible on inflation and deflation. In a different preparation, (B) and (C) are expanded amplitudes of the upper and lower extremes of the ‘Post Deflation Period’. Both peak systolic (PSLVP) (B) and end diastolic (EDLVP) (C) left ventricular pressures demonstrate a recovery period, of differing time scales, following balloon deflation, during which time we suggest an adaptive mechanism to be operative. Note: the lowish intraventricular pressures are because the ventricles are only partially filled. That is, the preparation is on the ascending part of the Frank–Starling pressure–volume curve. The relatively high passive pressure is discussed in Section 2.

 
2.4 Signal processing
The signals were fed into a bank of amplifiers (Lectromed, UK). The analogue signals were simultaneously stored on tape (TEAC) and digitised, at 1000 Hz (CED 1401 A/D converter, ‘CHART’ software Cambridge Electronic Design, Cambridge UK, and a PC) to allow off-line analysis. Electrical and mechanical signals were analyzed using custom software (CED, Cambridge UK) producing several values from the various signals recorded, for example action potential duration, diastolic depolarisation levels, and peak systolic and end diastolic left ventricular pressures.

Statistical analysis of the data was done using the Paired or unpaired T-test, depending on whether the data was being compared within one experiment or between experiments after normalisation. The results from such analysis was considered significant for a P-value <0.05.

Animal husbandry and all procedures carried out during this investigation were done strictly in accordance with the Home Office Animals (Scientific Procedures) Act 1986, UK, and also conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NHI Publication No. 85-23, revised 1985).


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Mechanically induced arrhythmia
The basic phenomenon of a stretch-induced arrhythmia is well documented [8, 10, 11, 16]. In our preparation the mechanical intervention, balloon dilatation of the left ventricle, induces premature beats of ventricular and, rarely, atrial origin. We consider only premature beats originating in the left ventricle. Premature ventricular beats originating from premature atrial beats are discounted. Fig. 2 shows that mechanical intervention cannot only induce premature beats but can also render the heart refractory to subsequent mechanically induced premature beats. An initial five-second inflation, INFL-1, induces premature ventricular beats (V) (comparable in number to the pre-experimental single inflation protocol readings). This first inflation, of the pair, modulates the response to the second inflation (INFL-2) of the pair, depending on the time (t) allowed between the two.

If the balloon is re-inflated within 1 s (Fig. 2A), the second inflation (INFL-2) fails to elicit premature ventricular beats. In Fig. 2B, the dual inflation protocol is repeated, however the interval (t) between the first and second inflations is now extended to 30 s. The first inflation induces premature ventricular beats, and after this 30-s interval the second inflation can again induce premature ventricular beats, comparable in number to the first, control, inflation of the pair.

The number of premature ventricular beats induced on inflation was normalised (see Section 2) and the percentage change plotted against the time between the inflations. Fig. 4 shows that as the interval between the first and second inflation increases, the number of stretch-induced premature beats increases with complete recovery within 60 s.


Figure 4
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  		Fig. 4 Bar chart of normalised premature ventricular beat (PVB) number plotted against the interval (t), between the first and second inflations of a pair of inflations. As the interval between inflations increases from 0 to 30 s, the number of induced premature ventricular beats during the second inflation also increases, achieving control values by 30–60 s. (n=15).

 
Time courses of recoveries of electrical and mechanical signals (see later) were attempted in order to characterise the data. However, the data defied ‘curve fitting’ and the exercise proved ineffective as a reasonable means of presenting the data. We thus present the actual time of recoveries for each set of data.

3.2 Mechanical changes during post deflation period
We investigated the effects on the adaptation seen in some inflation characteristics, by varying the duration of inflation (2, 5 and 30 s) and the pre-inflation (pre-load) volume (0 ml, 0.5 ml, 1.0 ml, and 2.0 ml). The final (optimal) inflation volume was unchanged. There were no statistically significant differences between the various durations or preloads. Thus, as described in Section 2, a 5-s inflation using a volume just below the volume required for maximum developed pressure was used throughout the remainder of the experiment.

Clearly, there is a mechano-electric transduction process involved in the stretch-induced premature ventricular beats. Activation of this process produces circumstances which need time before it can be fully activated again, i.e. a mechano-electric adaptation period. Clues to the adaptation process could be found within the stretch time, or the recovery time. Since the interval between inflations seems to govern the number of premature beats induced on a repeat inflation we scrutinised the interval post deflation; and it is during the early part of this time we suggest a mechano-electric adaptation period occurs. The mechanism explaining the adaptation period may reside in physical changes, (e.g. stretch-induced physical tissue recoil or creep), electrophysiological changes (e.g. ion diffusion), or in some other complex transduction process (e.g. establishment of signal transduction equilibria).

Fig. 5A shows the left ventricular pressure, in response to balloon inflation and deflation. It is not immediately obvious from Fig. 5A that there is any form of a mechanical adaptation, other than very minor ‘ringing’ (see Fig. 3). However, vertically expanding the upper and lower extremes of Fig. 5A, during the ‘Post Deflation Period’, clearly demonstrate an adaptation does occur in peak systolic (Fig. 5B) and end diastolic (Fig. 5C) left ventricular pressures.

3.3 Electrophysiological changes during post deflation period
Fig. 6A shows left ventricular monophasic action potential and left ventricular pressure before, during and after a mechanical intervention. Fig. 6B shows a vertically expanded diastolic portion of the action potential. Inflation produces a diastolic depolarisation (Fig. 6A) which returns slowly to control values without reaching them in this 5-s period before deflation. Deflation produces an undershoot (Fig. 6B) compared with control, followed by a adaptation, recovering to control values within 50 s.


Figure 6
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  		Fig. 6 Characterisation of the monophasic action potential before, during and following balloon inflation and deflation in the left ventricle. (A) Left ventricular monophasic action potential (LVMAP) and left ventricular pressure (LVP) on balloon inflation, deflation and the subsequent adaptation period. (B) is a vertical expansion of the lower portion of LVMAP from (A). A clear adaptation period is seen in the level of diastolic depolarisation post balloon deflation.

 
The action potential spike also showed amplitude changes (Fig. 6A). However, the amplitude of the upstroke or spike of the monophasic action potential is an unreliable index of the transmembrane spike [30]. We therefore concentrated on the action potential duration, known to be a reliable indicator of the time course of repolarisation of the transmembrane action potential [30]. The action potential duration at 90% repolarisation (APD90), is the time taken for the action potential to achieve 90% repolarisation; 100% being fully repolarised.

Fig. 7 shows action potential duration at 90% repolarisation plotted against time, before, during and after balloon deflation. In the run-up 20-s control period, 0–20 s on the graph, the action potential duration is constant. On balloon inflation the APD90 drops significantly. On balloon deflation the action potential duration rises steeply, exceeding pre-inflation values, undergoing an adaptation, recovering to pre-stretch values over the next 40 s. All intervention and post intervention values are statistically significantly different (p<0.001) from control, until 40 s post balloon deflation.


Figure 7
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  		Fig. 7 A plot of the action potential duration at 90% repolarisation (APD90) against time, during balloon inflation, deflation and subsequent adaptation (n=7). The control 20 s prior to balloon inflation had a mean APD90 of 151 ms. During the inflation, mean APD90 was 143 ms. A biphasic response was seen following balloon deflation: an immediate overshoot, mean APD90 of 157 ms, followed by a slow return to pre-stretch values. All values until 40 s post deflation were significantly different to pre-stretch, values (*=P<0.05).

 
We are considering the time period post balloon deflation, as this is when, we suggest, a mechanoelectric adaptation period occurs. We selected the action potential duration during the post deflation period and plotted it against time (Fig. 8A). Peak systolic left ventricular pressure data from the same deflation period is used for Fig. 8B. Fig. 8C shows a strong linear relationship between the adaptation seen in peak systolic pressure and action potential duration during the post deflation period.


Figure 8
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  		Fig. 8 Plots of electromechanical measures against time post balloon deflation (n=7). (A) action potential duration at 90% repolarisation (APD90). (B) peak systolic left ventricular pressure (PSLVP). (C) plot of PSLVP against APD90, demonstrating a linear relationship during the post balloon deflation period (r value=0.84).

 
3.4 Cytoskeleton investigation
To investigate the mechanoelectric transduction process in more detail, the cytoskeletal framework was disrupted using colchicine for the microtubular system, or cytochalasin-B for the actin filament structure. Both colchicine and cytochalasin, at the concentrations infused caused a significant reduction in the pressure recording within 30 s. This was seen as a strong indicator (but not conclusive as we did not stain for the filaments), of disruption of the cytoskeletal matrix. However Colchicine (100 µM), produced no significant change in the degree of arrhythmia or adaptation seen in any of the electrical or physical parameters measured. Cytochalasin-B infused at 5 µg produced atrio-ventricular block, and balloon inflation produced ventricular fibrillation in six preparations. The concentration of Cytochalasin-B infused was decreased in a stepwise fashion, and 2.5 ng was found to be the maximum usable concentration without an inflation induced ventricular fibrillation. At 2.5 ng, Cytochalasin-B infusion reduced developed pressure by over 50% within 30 s. The adaptation, following balloon deflation, seen in peak systolic left ventricular pressure was unchanged from control conditions; but the time taken for end diastolic pressure to recover showed a statistically significant increase to 30 s. However, there was no difference to control in the number of premature ventricular beats induced. We were not confident in drawing definitive conclusions from the action potential durations or the depolarisation shifts, as inflation produced a deteriorating signal-to-noise ratio as well as conduction disturbances. This made analysis along the foregoing lines unreliable.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
A single transient inflation of a balloon in the left ventricle induces premature ventricular beats. This inflation is followed by a period during which a second inflation within one second or so fails to induce them. However, the second inflation gradually regains its ability to produce premature beats, comparable in number to control values, after a recovery period of greater than 20–30 s between the inflations. As described in Section 1, by analogy with sensory mechanotransduction, and for want of a better term we will call this a type of ‘adaptation’ period. On balloon deflation a beat-to-beat increase appears in peak systolic and diastolic pressures over 30 seconds or so. This return to control values, of what could be related to some visco-elastic ‘creep’, is comparable in time to when the inflation-induced premature beats and other electrophysiological changes return to control.

The stretch-induced premature beats we see are in keeping with those using short-duration stretch protocols in other laboratories [16, 31], where less than one second mechanical interventions are applied. In similar vein, we find that altering the inflation volume characteristics, for example changing the starting volume but keeping the final balloon volume constant, fails to change the parameters measured compared to control (also shown in those laboratories [16, 31]).

The inflation/deflation also induces electrophysiological changes in the monophasic action potential, with comparable recovery times. The monophasic action potential duration is a valid indication of the transmembrane action potential duration [32, 33]. Hoffman and Cranefield [32]suggested that their observed depolarisations in the monophasic action potential, now called ‘early afterdepolarisations’, were artefact. However, the consensus seems to be that depolarisation (or early afterdepolarisation) in the monophasic action potential are real electrophysiological phenomena [34–36], and produce electrophysiological behaviour commensurate with that of a true depolarisation. We feel confident in the use of the duration measurements from the action potentials, and also that useful information albeit qualitative, can be gleaned from the depolarisation shifts (Fig. 6). During the adaptation period, therefore, the correlations between changes in diastolic depolarisation, action potential duration and peak systolic pressure may have functional significance.

The phenomenon of a mechanical intervention inducing electrical changes, termed mechanoelectric feedback or transduction, has been shown in many cardiac preparations [8]. It is becoming increasingly recognised as a possible major factor contributing to lethal arrhythmias in the clinical setting [6, 7, 12, 37]. It is especially seen in the pathological state where the mechanical contribution to arrhythmic mechanisms is amplified [38, 39]. (It is also entering some classifications of arrhythmic mechanisms [40].) The mechanism of its operation, including mechanically induced premature beats, remains to be clarified and we touch on various possibilities below. Whatever the mechanism of stretch-induced premature beats, we see an adaptation [17]. Although it is possible that the correlations between mechanical and electrophysiological changes do not imply causality, the observed patterns suggest that they are causally related. A greater understanding of this adaptation may allow insight to the mechanisms of stretch-induced arrhythmia, and it warrants some speculation, if cautious.

The mechanical distortion produces a geometrical redistribution of stress and strain throughout the preparation. This would include surface membrane (stretch-activated channels, and focal adherence proteins, e.g. integrins), intracellular cytoskeleton (F actin and microtubules) and extracellular structures (collagen, intercellular clefts). In our preparation, recovery of this stress/strain redistribution manifests in global mechanical changes in systolic and diastolic pressures.

Several types of stretch-activated channels or mechanosensitive channels have been described (as reviewed [14, 15]) and implicated in stretch-induced arrhythmia [8, 16, 31, 41]. This would be through ionic movement along electrochemical gradients which in turn produces threshold depolarisations (premature beats) [36, 42]. After the first transient stretch, the channels could require time to regain their original conformation, and a second stretch at this stage is incapable of producing further ionic current flow to activate the membrane. There is some evidence at the single channel level that the equivalent to our accommodation resides in the membrane [18]. However, the time courses were much faster. Hu and Sachs [43]have produced preliminary results showing analogous single channel opening times with comparable time courses to ours. Still at the ‘subcellular level’, but now considering the mechanical properties, there is also evidence that viscoelastic measures change with time after a mechanical change [29]. In this case the mechanical change is contraction, and time is one diastole. The changing diastolic mechanical properties seemed to be a complex interaction between sarcomere length, force, calcium, with oscillations in sarcomeres and calcium. The changes were over a second or so; much faster than our period of interest. However, their study did not address the effects of stretch, nor beat-to-beat changes. Also, the mechanical architecture of the intact ventricular wall is substantially different [44].

The degree of pressure drop with cytochalasin or colchicine we saw could be related to the contribution the cytoskeleton makes to the series elastic component in cardiac muscle. We do not know of any work covering this, particularly in the intact ventricle. It is possible that a very small change in series elasticity could produce the fall in developed force we observed. Also much depends on the degree of internal shortening in our almost isovolumic intact ventricle. This could be fairly substantial during the rearrangement of myocardial fibres during pressure development. Moreover, comparisons between mechanical situations in isolated cells verses intact preparations are difficult (see review by Brady [44]). For example contraction in isolated cells is without cytoskeletal connections to the extracellular matrix through membrane cytoskeletal proteins such as integrins. Force distributions must be remarkably different in the two types of preparation.

The cytoskeletal matrix contributes to passive tension [45]. The cytoskeleton has also been implicated in ion channel function and transport protein interaction [19]and probably transmits the force changes to the stretch-activated channels through adhesion or focal proteins in the membrane. We infused colchicine (100 µM) and cytochalasin-B (2.5 ng), known to disrupt microtubular structure and actin filament structure respectively [20]. (An indication of disruption was the marked fall in recorded pressures. We did not stain the cytoskeletal components). This did not influence the mechanically induced arrhythmia [with higher concentrations of cytochalasin-B (5 µg) balloon inflation induces ventricular fibrillation [46]]. It appears at this stage that the cytoskeletal matrix is not involved in stretch-induced premature beats or the adaptation in this preparation.

The extracellular matrix could be implicated via attachments to transmembranous proteins. However, precisely how one could investigate the possible role of extracellular filaments in transmitting mechanical changes in the intact heart is not easily apparent. Nonetheless this extracellular mechanism needs ultimate exclusion, because cell-to-cell interactions in multi-cellular preparations may hold the key to the mechanisms involved.

An ionic accumulation or diffusion could be implicated. Narrow extracellular spaces or intercellular clefts can act as ionic diffusion barriers [47, 48]. The adaptation period could be due to mechanical recovery of the deformed clefts or time-dependent ionic diffusion. The potassium ion is a possible contender, as it has been shown to accumulate in these spaces or clefts [48, 49]. We [50]and others [51]have shown that raised extracellular potassium can inhibit stretch-induced arrhythmia. The calcium ion is also a contender. Increases in intracellular calcium have been seen both with mechanical distortion [52–54], and release of stretched myocardium [55]. In the latter case, these are attributed to contractile-dependent changes in calcium affinity to troponin C (contraction or shortening against a low load reduces affinity). These calcium changes and calcium-activated currents could be involved in modulating membrane potential [56], and the action potential duration and thus possibly inducing arrhythmia [54]. We see the same changes in the recorded potential with stretch as previously described; depolarisation and reduction in action potential duration [42, 57]. De-stretch reverses these, and an effective de-stretch of superfused papillary muscle produces analogous results in that it prolongs the action potential [58](probably due to the intracellular calcium changes just described [55]). (In our preparation the switch is from isovolumic contraction at a high load to isovolumic contraction at virtually zero load, where there would be significant internal shortening.) The important comparison to our results is that return to control of mechanical measures as well as action potential duration in papillary muscle are over the same time periods as the mechanical changes and the stretch-induced arrhythmia in our intact ventricle. In the arrhythmia context, prolongation of the action potential duration, and thus refractory period, is generally regarded as antiarrhythmic. As the stress relaxation is taken up, the load increases, the action potential and refractory period would shorten. This would be regarded as a return to the arrhythmic mechanism. (Similarly, fibrillation thresholds are reduced as load increases [59].)

A less direct mechanism of stretch-induced arrhythmia and its adaptation is related to neurotransmitter release and re-uptake in autonomic transmission. In the present case there may be stretch modulation of endogenous catecholamines, and these are arrhythmogenic. Myocardial stretch releases endogenous catecholamines [60]. We have presented preliminary results in keeping with this possibility in that bretylium tosylate, known to deplete catecholamine stores [61, 62]curtails stretch-induced arrhythmia [63]. The adaptation would involve the replenishment of stretch-reduced stores by re-uptake or synthesis. (Alternatively, the first stretch desensitises the release apparatus, which then requires a time to regain its control conformation and mechanosensitivity.)

Arrhythmia in cardiac pathology is potentially lethal. The time-dependent accommodation of the mechanical induction of arrhythmia could be regarded as ‘protective’, and albeit distantly, comparable to the protection offered during ischaemic preconditioning [64]; but in this case more related to stretch preconditioning [65]. Brief periods of ischaemia, i.e. ‘control’ coronary occlusion, are protective by reducing myocardial damage and arrhythmia produced by a subsequent ischaemia [66–68]. Our results may have a bearing on ischaemic preconditioning when arrhythmia is the study end point. Regional ischaemia produces bulging and stretching of the myocardium, and a tentative link between ischaemic preconditioning and the protection afforded by stretch has been suggested [65]if myocardial damage is taken as the end point. We had previously suggested such a link in that a mechanical ‘conditioning’ of the myocardium could provide protection from mechanically induced arrhythmia [17]. However, although linking mechanical adaptation with ischaemic preconditioning may ultimately prove clinically relevant, we feel that further in-depth speculation along these lines is hazardous.

Final elucidation of the mechanism of this mechanically induced adaptation period we demonstrate may prove important, not only in identifying the mechanism of mechanically induced premature beats, but also in the wider context of arrhythmia management. Ventricular arrhythmia remains one of the major causes of sudden death in the developing world and the mechanical induction of arrhythmia is becoming increasingly acknowledged as a possibly important contributory factor [6–8, 21, 69, 70], and mechanically based therapy may even be possible. A preliminary report has recently described the successful application of a direct purely mechanical intervention to manage potentially lethal ventricular arrhythmia which was refractory to normal pharmacological therapy [71].

Time for primary review 35 days.


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

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