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(Circulation. 1996;94:1131-1136.)
© 1996 American Heart Association, Inc.

Articles

Cycle Length Dependence of the Electrophysiological Effects of Increased Load on the Myocardium

S.M. Horner, MA, MBBS, MD, MRCP; D.J. Dick, BSC; C.F. Murphy, MA, MBBS, MRCP; M.J. Lab, MD, PhD

the British Heart Foundation Cardiac Arrhythmia Research Group, Department of Physiology, Charing Cross and Westminster Medical School, London, UK.

Correspondence to Prof M. J. Lab, Department of Physiology, Charing Cross and Westminster Medical School, London W6 8RF, UK.

	Abstract

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Background Mechanoelectric feedback, the process by which changes in mechanical activity change the electrophysiology of the myocardium, has been linked to the genesis of arrhythmias. We investigated possible arrhythmogenic mechanisms by measuring changes in steady-state action potential duration and, more particularly, electrical restitution on a transiently applied load change, because action potential recovery may provide clues to arrhythmogenesis.

Methods and Results Pigs were anesthetized and their hearts exposed. A snare was placed around the aorta, and the right atrium was paced. Ventricular pressure, monophasic action potential, and segment motion were recorded from the left ventricle. The action potential duration was measured before and during transient aortic occlusion. Electrical restitution curves were constructed from the records obtained during normal loading or during transient aortic occlusion. The degree of shortening of action potential duration on aortic occlusion decreased with decreases in the steady-state beat-to-beat interval (P=.0008). Control restitution curves had the typical configuration, with a rapid initial, usually monotonic, rise toward a plateau. Some curves showed a marginal "supernormal" section. Increased load reduced the action potential duration at the plateau of the restitution curve (9.4 ms, P<.0001) but increased the action potential duration at the start of the restitution curve (8.7 ms, P=.03). Increased loading increased the maximum slope of the electrical restitution curve by 32 ms/100 ms (P=.04). Increased load also increased the supernormal period of the electrical restitution curves.

Conclusions Mechanoelectric feedback produces changes in rate-dependent electrophysiology, which could favor a matrix conducive to arrhythmogenesis.

Key Words: arrhythmia • electrophysiology • intervals • potentials • vagus nerve

	Introduction

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Mechanoelectric feedback is found extensively in myocardium,^{1 2 3 4 5 6 7} and there is evidence that mechanoelectric feedback may be involved in arrhythmias.^{3 5} The action potential duration and refractory period shorten with increased myocardial load, and these changes vary in magnitude in different regions of the ventricle, thus increasing dispersion of refractory periods.² Conduction velocity does not change significantly with an increase in myocardial loading.⁷ Taken together, these factors decrease the wavelength for reentry⁸ and so create conditions favorable to arrhythmogenesis.⁹ Mechanoelectric feedback has also been implicated in the triggering of arrhythmias.^{1 3 5 10 11} It has been suggested that mechanoelectric feedback may play an important role in arrhythmogenesis in the failing ventricle, in which abnormal mechanical factors are associated with arrhythmia and sudden death.¹² Moreover, compounds that block stretch-activated channels, a possible mechanism for mechanoelectric feedback, almost completely abolish stretch-induced arrhythmias.¹¹ These observations suggest new therapeutic approaches, especially because current antiarrhythmic drugs have enjoyed only limited success.^{13 14}

Changes in myocardial electrophysiology with beat-to-beat interval influence the genesis and dynamics of arrhythmias; thus, the variation of mechanoelectric feedback with beat-to-beat interval needs to be understood. We investigated the effect of beat-to-beat interval on mechanoelectric feedback in the in situ porcine heart. The in situ heart has the advantage over isolated preparations of an intact autonomic nervous system, an important consideration in investigating changes in the electrophysiology of the myocardium, which may have a bearing on the mechanisms of arrhythmogenesis. We investigated the influence of changes in steady-state beat-to-beat interval and transient changes in beat-to-beat interval on mechanoelectric feedback by measuring action potential duration during an increased ventricular load imposed by brief occlusion of the aorta. We also measured electrical restitution, which is a useful way of gleaning information about basic electrophysiological mechanisms,^{15 16} in the intact heart in situ. The characteristics of the electrical restitution curve can also give information about possible arrhythmogenic processes.

	Methods

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Experimental Preparation
Twenty Landrace/Large White pigs of either sex weighing 18 to 26 kg were premedicated with ketamine (10 to 20 mg/kg) and anesthetized with intravenous methohexital sodium via the marginal ear vein. The animals were intubated and ventilated while anesthesia was maintained with 1% to 1.5% halothane in an equal-volume mixture of nitrous oxide and oxygen. Tidal volume was set at levels that maintained physiological values of arterial pH (7.4±0.03), PO₂ (95±5 mm Hg), and PCO₂ (40±2 mm Hg), and this was checked by blood gas analysis every hour. Arterial pressure was recorded via the left common carotid artery with a 7F Gaeltec micromanometer catheter advanced into the aorta. An intravenous cannula was introduced into the right jugular vein for infusion of 0.9% saline solution. The anterior chest wall was removed at the costochondral junctions. The pericardium was opened and the heart supported in a pericardial cradle. A pneumatically operated clamp was placed around the aorta above the coronary arteries but below the right brachiocephalic artery. A 7F Millar Mikrotip micromanometer cannula inserted into the left ventricle through an apical stab incision continuously monitored left ventricular pressure. The right atrium was paced with a beat-to-beat interval of 300 to 600 ms. The right ventricle was also paced for restitution curves.

Electromechanical Recordings
Monophasic action potentials were recorded from the left ventricle with suction electrodes.¹⁷ These electrodes allow ease of placement and recordings for up to 30 minutes from a single placement. The epicardial segment length was recorded with a tripodal device. Briefly, a tripod made of phosphor bronze with strain gauges on each leg was attached to the epicardium by suction. Movement of the segment under the device bends each leg and thus strains the gauge to produce a change in resistance. The strain gauges are connected in series, and the device is paired with a temperature-compensating resistor and forms one arm of a Wheatstone bridge. The technical details and validation of this device have been published previously.^{17 18} The output is linear over the range of movement studied, and we calibrated the device via three micrometer-screw gauges arranged at 120° to each other.

All the signals were amplified by high-impedance DC amplifiers (Lectromed MT8P) and displayed on a Tektronic 5103 N oscilloscope during the experiment. The signals were stored on magnetic tape (TEAC XR-501) for later analysis and also digitized at 1000 Hz with a Cambridge Electronic Design CED 1401 and IBM PC-AT-compatible computer.

Another IBM PC-AT-compatible computer was used to control the pacing and apply the pneumatically activated clamp during the restitution curves with a custom-written pacing program and an Advantech PCL818 data acquisition card.

Study Protocol
The heart was paced at beat intervals of 300 to 600 ms. At least 300 beats were allowed for the myocardium to reach a steady state. The aorta was occluded for 5 seconds, and the shortening of the action potential so produced was measured at each of the different heart rates.

For the restitution curves, test occlusions were performed, and if the aortic clamp produced premature beats, it was slackened in increments until the occlusion of the aorta no longer produced premature beats. We constructed electrical restitution curves as follows. We paced at a steady cycle length at 20 bpm faster than the intrinsic heart rate, and 5 minutes was allowed to reach a steady state. After a fixed number of beats, we interposed a beat at a different cycle length; the cycle length of the interposed beat was then progressively lengthened or shortened.

The restitution curves started at a test pulse interval of 120 to 160 ms, which was below the refractory period, and the interval was increased by 10 to 20 ms up to 400 ms. Thereafter, we increased it by 20 to 40 ms until escape beats occurred. During the curves with mechanical intervention, we applied the aortic clamp 5 beats before the test pulse interval and released it 2 beats after the test pulse interval. We used 30 beats of steady-state pacing between test pulse intervals. Pacing trains that were interrupted by premature beats or ventricular tachycardia were excluded from analysis. Initially, we compared restitution curves with both atrial and then ventricular pacing. However, we found that the early part of the restitution curve could not be determined with atrial pacing; therefore, we subsequently performed all restitution curves with simultaneous atrial and ventricular pacing. Only the ventricular restitution curves are presented here, but the atrial curves showed the same changes.

The investigation was performed in accordance with the Home Office Guidance on the Operation of Animals (Scientific Procedures) Act 1986, published by Her Majesty's Stationery Office, London.

Data Analysis
Data were measured by a computer with software custom written by Cambridge Electronic Design. This measured the monophasic action potential duration at 70% of repolarization. The electrical restitution curve is formed from the plot of diastolic interval (on the x axis) after the steady-state train of beats against action potential duration (on the y axis). Diastolic interval was defined as the test pulse interval minus the action potential duration. This was done for recordings taken with and without increased load. The curves were measured at several points: A, the earliest test pulse interval at which data were present on both curves; B, 25 ms after A, the point at which the supernormal period was seen to increase; and C, the plateau of the restitution curve or the last point on the curve if the plateau was not reached. The maximum slope of the early part of the curve was measured by fitting a polynomial curve to the restitution curve and differentiating. The height of the supernormal period was measured as the deviation of the restitution curve from a simple, continuously increasing curve drawn through the data points. In addition, a computer program was used to measure the restitution curves at the slowest rate in each experiment; this measured each curve every 20 ms up to 400 ms and thereafter every 40 ms. At each point along the restitution curve, we calculated the mean and SEM of the action potential duration for the group.

Data were tested for normality. For the comparison of changes in action potential duration with changes in beat-to-beat interval, repeated measures ANOVA was used. For other comparisons, if the data were normally distributed, paired t tests were used to compare groups and Pearson product-moment correlation was used to investigate the relationship between variables. If the data were not normally distributed, the Wilcoxon signed rank pairs test was used to compare groups and the Spearman rank correlation to investigate the relationship between variables.

	Results

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Steady-State Changes in Action Potential Duration
Aortic occlusion increases left ventricular pressure, increases overall segment length (Fig 1A), and shortens the action potential duration. The change in action potential duration is clearly seen with the expanded time scale (Fig 1B). There is less shortening of action potential duration during increased loading at higher heart rates. Fig 2 shows the magnitude of action potential shortening with beat-to-beat interval change. The degree of action potential duration shortening on aortic occlusion decreases as a function of beat-to-beat interval (P=.0008).

View larger version (22K): [in this window] [in a new window]   Figure 1. A, Monophasic action potential, myocardial segment length, and ventricular pressure recordings during an aortic occlusion. B, Time scale is expanded and the monophasic action potential superimposed to show the changes more clearly. Dotted line indicates the tracings taken after occlusion of the aorta.

View larger version (65K): [in this window] [in a new window]   Figure 2. Mean±SEM values of action potential shortening on aortic occlusion as a function of beat-to-beat interval.

Mechanoelectrical Correlations
Segment length was measured simultaneously. End-diastolic length was used as a measure of preload, which is thought to be an important determinant of mechanoelectric feedback.¹⁹ Action potential shortening increased as the change in end-diastolic length on aortic occlusion increased (P<.001). The shortening of the action potential duration also increased with the increase in peak-systolic ventricular pressure on aortic occlusion, expressed as a percentage of the control developed pressure (P<.001). After action potential duration changes were normalized for the change in end-diastolic length and change in peak-systolic ventricular pressure, there was still a significant relationship between the change in action potential duration and beat-to-beat interval. This was one of the reasons for investigating beat interval further.

Restitution Curve Changes
The electrical restitution curve is a standardized method for investigating the effect of transient changes in beat-to-beat interval on the electrophysiology of the myocardium. We obtained the data for electrical restitution curves by interpolating beats at variable intervals. At the longer intervals, the action potential duration associated with the high load is shorter than that during ejection. However, this does not apply to the smaller intervals. Fig 3A shows the interpolation of a short test pulse interval that produces the expected short action potential duration. During an increase in loading, the action potential duration of the premature beat compared with that of the normally loaded premature beat was relatively prolonged (Fig 3B).

View larger version (11K): [in this window] [in a new window]   Figure 3. Monophasic action potentials and left ventricular pressure recordings during a short test pulse interval. A, Upper two traces are taken during normal loading and bottom two during increased loading caused by aortic occlusion. B, Monophasic action potentials from before (solid line) and during increased loading (dashed line) have been superimposed. The left superimposed pair is the last of the steady-state recordings. The right pair is after the short test pulse interval.

The electrical restitution curve has two main phases: an initial, steeply increasing phase and a second, more gradually increasing phase (Fig 4A). In Fig 4A, the first phase of the curve starts at a diastolic interval of 20 ms (at which the action potential duration is 122 ms) and rises sharply to 54 ms (at which the action potential duration is 186 ms). The more gradual phase starts at the last phase of the first curve and increases to a diastolic interval of 385 ms and an action potential duration of 219 ms. The overall curve is rounded and is convex upward.

View larger version (19K): [in this window] [in a new window]   Figure 4. A, Restitution curves: normal (solid line, open circles) and with the application of a mechanical load (dashed line, solid triangles). B, Curves in A with the time scale expanded to show the initial phase more clearly.

The restitution curves in this preparation show the same exponential rise to a plateau that has been seen in preparations ranging from isolated myocardium to humans (Fig 4A). During increased mechanical loading, the action potential duration during the initial part of the curve was greater (Fig 4B) at any particular test pulse interval than in the normally loaded curve. During the plateau, the action potential duration was shorter (Fig 4A and 4B). Consequently, there was a point at which the two curves crossed.

The results of the computerized measurements of the curves at the slowest steady-state heart rates are shown in Fig 5. The method for obtaining these curves is described with the rationale in the "Methods" section. At the origin of the restitution curve, the action potential duration was greater during increased load (mean increase, 8.7 ms; P=.03). The action potential duration during the initial phase of the restitution curve, 25 ms after the origin of the curve, was increased by increased mechanical load (mean increase, 5.5 ms; P=.02). In loaded compared with unloaded myocardium, the plateau of the restitution curve was displaced downward (mean decrease, 9.4 ms; P<.001). The maximum slope of the restitution curve was greater after the increase in mechanoelectric feedback (mean increase, 32 ms/100 ms; P=.04).

View larger version (23K): [in this window] [in a new window]   Figure 5. Mean restitution curves for the whole group with standard error bars at the slowest heart rate in each case. Normal (solid line, open circles) and with the application of a mechanical load (dashed line, solid triangles). Action potential duration is normalized relative to action potential duration in the steady-state control conditions (see "Methods"). Asterisks mark the points at which the curves are statistically significantly different.

The "supernormal phase" is a phase in the restitution curve, usually occurring at the point at which the plateau is reached, when the action potential duration over a short range of test pulse intervals becomes longer than would be expected if a monoexponential curve were followed.^{20 21} We found evidence of supernormality in the control curves. However, increased loading of the heart increased the supernormal section of the restitution curve (Fig 4A and 4B) overall by a mean of 8 ms (P=.002).

	Discussion

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We found that (1) increased heart rate decreased the expression of mechanoelectric feedback, as evidenced by the degree of action potential shortening on transiently increased ventricular loading; (2) increased mechanoelectric feedback increased the action potential duration on the initial part of the restitution curve; (3) increased loading increased the supernormal period of the restitution curve; and (4) increased loading decreased the action potential duration on the plateau of the restitution curve.

Mechanistic Implications
The three currently postulated mechanisms for mechanoelectric feedback are as follows. (1) There may be stretch-activated ion channels in the myocyte membrane that open when the cell is stretched.^{22 23 24 25} (2) There may be a change in binding of calcium to troponin C, for example, a decrease in the affinity of the contractile apparatus to bind calcium as the cell contracts, with the calcium released from the myofilaments. This deactivates contraction. The "extra" calcium is exchanged for sodium via the sodium/calcium exchanger, leading to a net inward current and a longer action potential. During increased load, the cell does not shorten as much, the calcium transient is smaller²⁶ (less calcium is exchanged for sodium), and hence the net inward current is decreased and so the action potential shortens. (3) Recently, stretch enhancement of conventional ion channels, for instance L-type calcium channels,²⁷ has been reported and provides a possible mechanism for the electrophysiological effects of mechanoelectric feedback. These mechanisms of mechanoelectric feedback interacting with rate-dependent transmembrane currents could explain our finding of decreased mechanoelectric feedback with increased steady-state heart rate.

The supernormal period of the restitution curve is thought to be caused by the quicker recovery of the calcium current relative to I_to, with the inward calcium current causing the prolonged action potential duration of the supernormal period.²⁸ Consequently, the increased supernormal period seen with increased loading of the myocardium could be caused by a direct action on L-type calcium channels to increase their conductance. The increase in the supernormal period that we found with mechanoelectric feedback may explain why a supernormal period has been seen in some experimental situations^{29 30 31 32} but not all^{15 33 34 35} : potentially because of different degrees of mechanical loading. We find that increased loading lengthens the action potential duration at short cycle lengths and shortens it at longer test pulse intervals. These findings are interesting and important enough to require further detailed comment. There are ways in which mechanical changes can prolong the action potential. One is related to previously described types of afterdepolarizations.^{1 36} Franz et al³⁶ considered these to be effective prolongations of action potential duration if measured at T₉₀. The notion we entertain is that the circumstances producing these electrophysiological changes occur relatively earlier in contraction during premature beats and produce action potential prolongation throughout most of the action potential. Membrane permeability changes relative to equilibrium potentials could contribute to this¹ via stretch-activated channels as outlined by Hansen.³⁷ One way of explaining this is that the equilibrium potential related to stretch and relative to the timing of the mechanical change moves in a depolarizing direction during a premature beat. This is also possible given potassium accumulation in narrow extracellular spaces and clefts.³⁸

Alternatively, invoking mechanism 2 above, intramyocardial force in the segment of interest could be deactivated during early beats. This raises intracellular calcium (it comes off the contractile proteins) and produces a depolarizing current via sodium-calcium exchange.

These changes in the early part of the restitution curve could be important, because there is evidence that the form ventricular arrhythmias take can be explained by the action potential duration and recovery of excitability.³⁹ Features of the restitution curve that have been found to lead to irregular dynamics of arrhythmias are an increased steepness of the initial part of the restitution curve and a curve that is not monotonic^{40 41} ; both of these features were augmented by increased loading. That is, there is a prolongation of action potential duration for a given test pulse and an enhanced supernormal period.

Clinical Implications
The dispersion of the recovery of excitability is an important feature in the genesis of arrhythmias by reentry and current flow. In areas of the myocardium with different mechanical functions, mechanoelectric feedback may lead to action potential duration dispersion. The mechanoelectric contribution to dispersion would decrease as steady-state heart rate increased but could be marked during premature beats with very short beat-to-beat intervals, because dispersion is a feature of premature beats.⁴² The added dispersion would probably not be sufficient in its own right to lead to the genesis of reentry arrhythmias, since a dispersion of 100 ms⁴³ is probably necessary. However, even if this effect is not enough in its own right, it could be an important modulating factor that causes the normal degree of dispersion in the myocardium to exceed threshold, especially after one or more ventricular premature beats, which may markedly increase dispersion in the myocardium.^{44 45}

Dispersion can also arise by the temporal variation of the restitution curve being converted into spatial dispersion by conduction delay.⁴⁶ That is, a slight delay in conduction to one part of the myocardium (area 1) will allow it to have longer to restitute than the neighboring myocardium (area 2). The action potential durations in the two areas will be determined by the restitution curves, and so the difference in action potential duration will depend on the slope of the curves. At short cycle intervals, on the steep part of the curve, a small time difference in the cycle length experienced by the two areas of myocardium as a result of conduction delay may lead to markedly different action potential durations. This occurs because any conduction delay to area 1 will allow it to have longer to recover. On the steep initial part of the restitution curve, slight differences in recovery time will lead to marked differences in action potential duration. Increased loading increases the steepness of the initial phase of the restitution curve and so would amplify this effect, leading to further increased dispersion. This effect could be amplified by different loading in the two areas or by the slow propagation of ventricular premature beats.

The absolute duration of inexcitability is also important in the initiation of reentry, with arrhythmias being most likely at shorter durations of inexcitability.⁴⁷ In myocardium that is not ischemic, the recovery of excitability is determined by repolarization. Increased mechanoelectric feedback shortens the action potential duration and refractory period in parallel.² We found that although the contribution of mechanoelectric feedback to this shortening decreases as heart rate increases, it still has a significant effect in shortening the action potential duration even at the highest heart rates. Thus, the shortest periods of inexcitability and hence the greatest opportunity for reentry in the presence of a steady beat-to-beat interval always occurs with increased mechanoelectric feedback. Our results have some bearing on those of Reiter et al,⁷ who showed that the rate of a tachycardia caused by reentry around a fixed obstacle could double if a load was applied to the tissue, because as the wavelength decreased, two wavelets of reentry could fit within the circuit.

Study Limitations
One of the limitations of this experimental setup is the use of anesthetics, but a concomitant advantage of the in situ heart is that there is an intact autonomic nervous system. A further limitation is that the method we used to increase loading increases both systolic and diastolic loading and does not differentiate between them.

Conclusions
Although mechanoelectric feedback decreases in magnitude with an increase in steady-state heart rate, the earliest repolarization, and hence the greatest tendency for reentry arrhythmias, is present during increased rather than normal load. The changes in the initial phase of the restitution curve on increased loading could favor an increase in electrophysiological dispersion. The dispersion would be generated by minor differences in conduction delay between regions during a premature beat.

In addition, the increase in slope and supernormal period of the electrical restitution curve may increase the tendency toward chaos and arrhythmias.

The increase in supernormal period with increased loading may explain why some investigators but not all have found a supernormal period in the electrical restitution curve. We suggest that therapy aimed at terminating or preventing arrhythmias might be further refined by analysis of the effect of antiarrhythmic drugs on such features of the electrical restitution curve as its initial slope and the supernormal period, as well as their effect on conduction velocity and refractory period.

	Acknowledgments

 
This study was supported by a grant from the British Heart Foundation.

Received February 9, 1995; revision received March 6, 1996; accepted March 13, 1996.

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