Biology and the role of mechanoelectric feedback in the heart

Chaos, Solirom

& Fractals

Pergamon

Vol. 5, Nos 314, pp. 371-381, 1995 Elsevier Science Ltd Printed in Great Britain. WI%a779/95$9.50 + .cul

0960-0779(93)EOO29-B

Biology and the Role of Mechanoelectric Feedback in the Heart* MAX J. LAB, CONRAD MURPHY

and SIMON HORNER

British Heart Foundation Cardiac Arrhythmia Research Group, Department of Physiology, Charing Cross & Westminster Medical School, London Wh 8RF, UK

INTRODUCTION

Excitation contraction coupling (Fig. 1) in ventricular muscle, where electrophysiological changes initiate mechanical changes, has been extensively investigated [l]. Mechanoelectric feedback (MEF), where electrophysiological changes follow mechanical changes (Fig. l), reviewed by Lab 1982 [2] and Lab and Dean 1991 [3] is less well understood. This paper contains an extensive bibliography on MEF-not all papers in the reference section are referred to in the text. The existence of myocardial mechanosensitivity and MEF should

--LExcitation

\

M-E Feedback

E-C Coupling

\

/

Contraction Fig. 1. Basic diagram of interaction between excitation-contraction coupling (EC coupling) and mechanoelectric feedback (ME feedback). *Supported by British Heart Foundation, Wellcome Trust and Garfield Weston Trust. 371

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not be too surprising. The heart undergoes profound changes in mechanical wall stress and strain, with a time course comparable to the electrical changes that initiate them. Interaction between excitation-contraction coupling (ECC) and MEF would produce fine tuning of the regulatory processes in myocardium. Moreover, disturbances in this tuning by pathological processes that induce mechanical changes in the heart should produce clinical syndromes, and evidence is accumulating that this could be the case [3]. Although heart disease together with ventricular arrhythmia is a potent cause of death in the Western world the mechanisms are unclear and the treatment unsatisfactory. It is striking that these arrhythmias parallel the degree of myocardial mechanical dysfunction rather than the electrophysiological changes. Finally, any theoretical studies incorporating MEF should produce models or results in keeping with experimental findings, or have some predictive value. EXCITATION-CONTRACTION

COUPLING

PATHWAYS

Figure 2 describes some of the well-established interactions between membrane potential and myocardial contraction-including some possible paths of ME feedback. More comprehensive reviews are available [l, 4-61. Excitation-contraction coupling may be followed by the heavy black arrows (mainly clockwise). Ion fluxes (1-t) determine the membrane potential, which can also provide a driving force for ion movements (1-). The changes in membrane potential are a function of the ionic equilibrium potentials and conductances (g) producing a variety of transmembrane currents as reviewed by Noble (surprising heart). At rest gNa is low and gK is high. The latter mainly contributes to the negative resting potential that is maintained in the long term by an ATP-ase dependant Na/K pump. This keeps the internal Na+ concentration [Na+]i, low and [K’]i high. Extracellular Ca’+,

Fig. 2. Diagram of excitation-contraction

coupling, and possible paths of mechanoelectric

feedback (see text).

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[Ca’+l,,is relatively high while sarcoplasmic Ca2+ concentration [Ca2+lS, is very low. With the upstroke of the action potential g&, is rapidly increased and the fast inward sodium current iNa, reverses the transmembrane potential. Despite the consequent increase in the outward driving forces for potassium, gk decreases and the outward repolarizing current is less than expected. The cardiac action potential is thus prolonged. An inward current, carried mainly by Ca2+, iCa, also prolongs the action potential as does an electrogenic Na/Ca exchange. The channels for iC, are influenced by c-AMP dependent protein kinase. Depolarization (2) causes a rise in sarcoplasmic calcium from the stores (3+) directly, and probably by calcium induced calcium release. In mammalian muscle ica does not normally immediately raise [Ca2+], to any significant degree unless the action potential is long (4+). The calcium combines with troponin-C (tn-c) (5+) which causes troponin-I to allow actin and myosin (act/myo) interaction. The process, which needs ATP, results in force development (6+). As, or probably before, the membrane repolarizes, during relaxation (6-), the sarcoplasmic reticulum sequesters Ca2+ (5- ; 3). Ca2’ can also leave the sarcoplasm by a metabolically dependent Ca2+ pump or by Na/Ca exchange (4-). Greater binding to troponin C can also lower [Ca2+lS, but this is associated with increased force rather than faster relaxation. Length-dependent activation is incorporated in (6+/-). FEEDBACK

PATHWAYS

Force and length changes could link with membrane events (mechanoelectric feedback) by processes depicted by the dotted lines (Fig. 2). For example mechanical changes could change ionic flux by affecting permeability or diffusion gradients directly to change membrane potential (7). Indirectly (6-; 5-), force and length changes could influence the membrane by altering free sarcoplasmic calcium [Ca2+IS. This may influence ionic flux (4-), and hence membrane potential (l+), by modulation of electrochemical gradients for Ca2+, outward potassium currents, ‘leak’ currents and finally, electrogenic Na/Ca exchange. Cyclic AMP and ATP are intimately concerned with both membrane and contractile events in excitation-contraction coupling and could be concerned with mechanosensitivity and mechanoelectric feedback. INSTIGATORS

OF MECHANOELECTRIC

FEEDBACK

Systolic load change- related to calcium

Mechanoelectric feedback during contraction itself may be related to changes in intracellular calcium [7]. Increased myocardial shortening is associated with force deactivation which is explained by a reduction in the affinity of the contractile myofilaments for calcium [7-91. During muscle shortening ‘extra’ calcium comes off the filaments into the sarcoplasm thus reducing (deactivating) the strength of contraction. The calcium changes affect the action potential by calcium dependent currents [lo-121, prolonging it; and possibly producing early afterdepolarizations [13-161. Diastolic/systolic

load changes-related

to mechanically

(stretch) activated channels

Mechanically or stretch-activated ionic channels in the sarcolemma have been described in skeletal muscle [17] and in cardiac muscle [l&19]. These channels allow monovalent and divalent ions through them and so contribute to transmembrane currents influencing membrane and action potential.

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EVIDENCE AND PREVALENCE OF MEF (CELL TO MAN)

There are several aspects of the methodology that are common in the experiments. During the electrical recordings, mechanical loading conditions were changed in a variety of preparations. The results were generally concordant in the different experimental situations in that electrical changes were induced by mechanical changes. Mechanically

induced changes in action potential configuration

The general changes in the membrane and action potential with intra or interbeat mechanical alterations may be as depicted in Fig. 3. The ubiquity and rough concordance of the results, mainly on the action potential, will be described in Fig. 3. A variety of studies and preparations from cell to man [13,15,16,20-251, show that continuous or transient diastolic stretch of healthy heart muscle shortens the action potential duration, which is equivalent to the QT interval of the ecg, and can depolarize the myocardium to generate spontaneous activity [13,26-311. A beat (beat 1) with a large load has a short action potential compared with a contraction which shortens against a reduced load (beat 2). The dotted lines in Fig. 3 diagrammatically represent the results of an intrabeat mechanical decrease of load. This leads to a change in action potential

I

ECG

Fig. 3. Diagram of mechanically-induced changes in electrophysiology. 1 is a high load and 2 is a low load and the muscle develops high and low forces. In this demonstration and low load is associated with muscle-shortening length reduction which is the downward movement. The action potential is shorter (1) with the high load. The ecg shown in the lower trace shows a shorter QT interval and a smaller T-wave. The dashed vertical line indicates a mechanical change within a single beat, accompanied with an afterdepolarization in the action potential (EAD).

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duration of the same beat which can be associated with an ‘early afterdepolarization’ [2,13,15,16,27]. FUNCTIONAL ROLE OF MECHANOELECTRIC

FEEDBACK

Broadly, ME feedback could have a role in fine regulation of electromechanical interaction. For example, if membrane potential or perhaps intracellular Na+ were changed via the mechanically activated channels over many beats, intracellular Ca2+ (Fig. 4, left loop) and thus contractility could be modulated. Myocardial stretch could thus increase force by a mechanism complimentary [25,32,33] to those usually proposed for the Frank Starling phenomenon [34,35]. The type of modulation described at the cell level has been proposed as part of the interbeat interval regulation in the intact heart in situ [36] (see above, and Fig. 4, right loop). Homeometric autoregulation or the Anrep phenomenon [5] in the intact heart describes the situation where an abrupt increase in afterload is accompanied by a slow rise in developed pressure. This has been explained by variations in regional ventricular blood flow [37], however, mechanically induced changes in action potential and/or intracellular calcium may offer an alternative explanation. Electrocardiographic

consequences of mechanically

induced action potential changes

The changes in action potential described above are reflected in changes in myocardial refractoriness and excitability [23,38-401. Analogous with action potential duration changes, the QT interval prolongs with reduced load [2,20,41,42]. The electrocardiogram is the recording of surface potentials and is the manifestation through a volume conductor of electrical vectors derived from the inhomogeneous spread of cellular action potentials through the heart (Fig. 4, left to right loop). The fact that the repolarization is roughly epi to endocardium and base to apexopposite in route to depolarization-produces similar general directions of the resulting

Chaos/Arrhythmia A ECG

F/L

P/V

Fig. 4. Diagram of interaction of excitation-contraction coupling (ECC) and mechanoelectric feedback (MEF) at the cellular level (left-hand side) and gross level (right-hand side) AP = action potential, F/L = force/length, P/V = pressure/volume.

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vectors, giving rise to the anomalous ‘upright’ T-wave of the ecg [43]. Part of the explanation lies in cellular differences in transmembrane currents, for example I,, [44]. However, it is possible that mechanoelectric feedback can play a modulatory role. The T-wave does change with altered mechanical loading 12,411, and this implies an altered repolarization gradient (Fig. 6, right loop). There are, however, alternative, purely physical, explanations for T-wave changes with volume changes [45]. The mechanism of production of the U-wave is also not understood and there have been suggestions as well as indirect evidence that they may be mechanically generated [2,46,47]. U-wave changes in the epicardial ecg during load manipulation in viva have been reported [15] and they may be related to early afterdepolarizations.

CLINICAL SIGNIFICANCE OF MECHANOELECTRIC

FEEDBACK

Ventricular fibrillation is a major cause of sudden death in the Western world [l-4] but progress in its control has been unsatisfactory [48]. It is a premature ventricular beat (ectopic) that precipitates lethal arrhythmia in the first hours of myocardial ischaemia, but the initiating causes of this ectopic are not clear [49]; neither are the reasons for sustaining the arrhythmia. Comparable uncertainties surround sudden death in myocardial failure of diverse aetiology [50,51]. Management of ventricular arrhythmia has been, logically, mostly based on abnormal electrical behaviour with limited success. Perhaps some broad-based phenomenon has escaped detailed scrutiny as an underlying contributory mechanism. Because of the evidence that mechanical changes can initiate electrophysiological changes, and an uncovering, clinically, of previously unrecognized roles played by mechanical factors in arrhythmia, an alternative approach to arrhythmia could be via ME feedback will be very briefly reviewed. Fuller reviews have been presented elsewhere [3,521.

Mechanically

induced changes in electrophysiology

conducive to arrhythmia

The first mechanically induced ventricular ectopic in pathological heart could be produced by several electrophysiological mechanisms, all accepted as conventional mechanisms [53]. These include (1) depolarizing potentials such as diastolic depolarization or afterdepolarization reaching threshold (see above; (2) local intramyocardial current flow due to electrophysiological heterogeneity, where local asymmetry in contraction patterns could produce local differences in electrophysiology [40,54,55]; (3) re-entry, where local dyskinesia could produce local changes in excitability and conduction. The preceding factors would also predispose to re-entry. Re-entry is the most likely process maintaining an arrhythmia that has been initiated, and needs anisotropy with a critical ventricular size to contain the exitation wave rotating around an organizing filament [56]. Clinical correlations between mechanical disturbance and arrhythmia

(sudden death)

The literature indicates some correlations between mechanical dysfunction and/or altered loading and arrhythmia. Regional ischaemia has been associated with these mechanical changes rather than with primary electrophysiological changes [57-601. Chronic heart failure, often associated with a dilated stretched ventricle, carries a high incidence of ventricular arrhythmia and sudden death [61,62], as do other causes of load changes such as hypertension and narrowed aortic valves [63,64].

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THEORETICAL

371

CONSIDERATIONS

This review concentrates on the pathophysiological aspects of mechanoelectric feedback, but brief mention of its theoretical context is relevant. Models involving

mechanoelectric feedback

Pelce (in this issue) has modelled mechanoelectric feedback and other, commercially available models (e.g. ‘HEART’-Oxsoft), developed by Hilgemann and Noble [65], are being explored for this purpose. The application of MEF in the generation of the electrocardiogram, particularly the T-wave and U-wave is also being explored. Nonlinear

dynamics

The application of nonlinear dynamical analysis and chaos to biological rhythms [66] is generating new ways of viewing arrhythmia, and interest is widening in cardiological fields [67]. The evidence and observations presented above strongly suggest that mechanoelectric feedback is involved in arrhythmia and there is, moreover, evidence that chaotic processes are concerned in some arrhythmias [68,69]. Feedback pathways and time delays in a system can increase its range of dynamic behaviour, and this may have bearing on the stability of the system, and thus the generation of chaos and/or cardiac arrhythmias. Parasystole and bigeminy has been recently modelled by Glass and coworkers using nonlinear system analysis [70,71] and these arrhythmias may also be mechanically induced [31]. Similar electromechanical disturbances have been seen in the left ventricular wall following aortic occlusion in the pig [2,72] and dog [15]. Whether the analysis used by Glass and others [70,71] can be applied to mechanically induced ectopy and bigemini is a matter for scrutiny. Moreover, precisely how one might establish the quantitative significance of mechanoelectric feedback as generating arrhythmia needs detailed mathematical exploration. Changes in electrical restitution

Chialvo and Jalife [73] demonstrated a model of deterministic chaos in Purkinje fibres when the nonlinear system showed super-normality in the threshold strength/interval curve, steepening of the electrical restitution curve, and a discontinuity in the electrical restitution curve. Increasing the afterload in intact pig heart in situ produces some analogous observations in the restitution curve (Fig. 5); viz. a ‘supernormal’ period and, importantly, a steepening as well. Mechanoelectrical

alternans

Restitution changes similar to those just described can lead to electrophysiological alternans. Electrophysiological alternans has been regarded as a period-doubling bifurcation which may be a route to chaos [69,74,75]. Altemans in actionpotential duration has been demonstrated to almost invariably precede ventricular fibrillation in experimental regional ischaemia [76]. This in itself does not constitute evidence that a period-doubling cascade to chaos produced the fibrillation [77]. Although changes in electrical restitution per se can lead to alternans in action potential duration it is becoming clear that steady-state electrical alternans as well as mechanical alternans may be secondary to alternans in intracellular calcium [78], and a load change can initiate a calcium change (7).

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TPI I-

II

I I I I 11

11

Test pulse interval (TPI)

I

I

400

600

Test pulse interval (mscc) Fig. 5. Mechanically induced electrical restitution changes-from heart of pig under surgical anaesthesia [23]. (A) Construction of electrical restitution curve. The heart is stimulated at a steady state while monophasic action potentials are recorded (traces at top) from the left ventricle. Test pulses at a different interval are interpolated (T’PI) and the duration of the immediately following action potential (APD) recorded. APD is plotted against TPI. (B) Electrical restitution curves during normal contraction (solid lines) and during contraction against a heavy load-aortic occlusion (dashed lines). Occlusion steepens the early part of the curve, depresses the latter part, and enhances the supernormal period.

This cellular background could be behind the observation that increasing load can produce mechanical alternans (Murphy in this issue). At this stage there are more questions than answers in relating nonlinear dynamics and chaos to mechanoelectric feedback. Other questions include: is mechanoelectric feedback part of a chaotic system? if chaotic, does it normally produce physiological stability and adaptability [79] as suggested for heart rate variability‘? under pathological conditions does it destabilize the situation? can the types of analyses used for electrophysiological alternans [69,74,80] be applied to mechanical alternans? to what extent could mechanoelectric feedback (mechanoelectric alternans) be incorporated in the analyses? In summary, how for example, could one tie the observations and interpretations together to demonstrate persistent lethal ventricular arrhythmia. We suggest that following a premature ventricular beat, which may be mechanically induced, interacting nonlinear time courses of recovery of restitution and excitability (Fig. 4, ECC of left loop) are compounded by an instantaneous feedback (Fig. 4, MEF) between mechanical conditions of the myocardium and these nonlinear recovery processes. Intracellular calcium is most

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likely to be involved in mechanoelectric feedback via its influence on calcium activated currents and electrogenic Na/Ca exchange would facilitate these processes. It has been proposed that intracellular calcium is a linking factor which may be neccessary for generating nonlinearities and chaos in excitable tissues [77]. Mechanoelectric feedback, via changes in intracellular calcium, could contribute to the nonlinearity of electrophysiological parameters in pathological heart so that small changes in initial loading or mechanical conditions could lead to arrhythmia. In the intact ventricle the situation would be compounded by both mechanical and electrical inhomogeneity (Fig. 4, right-hand loop) thus enabling a mileu of altered excitability, arrhythmogenic current flow and re-entry. These proposals highlight the importance of rigourously testing the relationship between chaotic dynamics and mechanoelectric feedback. REFERENCES 1. W. R. Gibbons and A. C. Zygmunt, Excitation-contraction coupling in heart, in The Heart and Cardiovascular System, edited by H. A. Foxxard et al., pp. 1249-1279. Raven Press, New York (1992). 2. M. J. Lab, Contraction-excitation feedback in myocardium: Physiological basis and clinical relevance, Circ. Res. 50, 757-766 (1982). 3. M. J. Lab and J. Dean, Myocardial mechanics and arrhythmia, J. Cardiovasc. Pharmacol. 18 Suppl 2, S72-S79 (1991). 4. R. A. Chapman, Control of cardiac contractility at the cellular level, Am J. Physiol. 245, H535-H552 (1983). 5. W. G. Weir, Intracellular calcium transients during excitation-contraction coupling of mammalian heart, In The Heart and Cardiovascular System, edited by H. A. Foxxard et al., pp. 1241-1248. Raven Press, New York (1992). 6. J. Lytton and D. H. MacLennan, Sarcoplasmic reticulum, in The Heart and Cardiovascular System, edited by H. A. Fozxard et al., pp. 1203-1222. Raven Press, New York (1992). 7. M. J. Lab, D. G. Allen and C. H. Orchard, The effects of shortening on myoplasmic calcium concentration and on the action potential in mammalian ventricular muscle, Circ. Rex 55, 825-829 (1984). 8. P. Housman, N. K. M. Lee and J. R. Blinks, Active shortening retards the decline of the intracellular calcium transient in mammalian heart muscle, Science 221, 159-161 (1983). 9. D. G. Allen and J. C. Kentish, Calcium concentration in the myoplasm of skinned ferret ventricular muscle following changes in muscle length, J. Physiol. 407,489-503 (1988). 10. L. J. Mullins, The generation of electric currents in cardiac fibres by Na/Ca exchange, Am. J. Physiol. 236, c103-Cl10 (1979). 11. J. Kimura, S. Miyamae and A. Noma, Identification of sodium-calcium exchange current in single ventricular cells of guinea-pig, J. Physiol. 384, 199-222 (1987). 12. D. Colquhoun, E. Neher, H. Reuter and C. F. Stevens, Inward current channels activated by intracellular Ca in cultured cardiac cells, Nature Lond. 294, 752-754 (1981). 13. M. J. Lab, Mechanically dependent changes in action potentials recorded from the intact frog ventricle, Circ. Res. 42, 519-528 (1978). 14. J. W. Dean and M. J. Lab, Effect of changes in load on monophasic action potential and segment length of pig heart in situ, Cardiovasc. Res. 23, 887-896 (1989). 15. M. R. Franz, D. Burkhoff, D. T. Yue and K. Sagawa, Mechanically induced action potential changes and arrhythmia in isolated and in situ canine hearts, Cardiovasc. Res. 23, 213-223 (1989). 16. R. L. Kaufman, H. Homburger and H. Wirth, Disorder in E-C coupling of cardiac muscles from cats with experimentally produced right ventricular hypertrophy, Circ. Res. 28, 346-357 (1971). 17. F. Guharay and F. Sachs, Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle, J. Physiol. (Lond) 352, 685-701 (1984). 18. W. Craelius, V. Chen and N. el Sherif, Stretch activated ion channels in ventricular myocytes, Biosci. Rep. 8, 407-414 (1988). 19. C. E. Morris and W. J. Sigurdson, Stretch-inactivated ion channels coexist with stretch-activated ion channels, Science 243,807~809 (1989). 20. M. J. Lab, Transient depolarisation and action potential alterations following. mechanical changes in isolated myocardium, Cardiovasc: Res. 14, 624-637 (1986). 21. S. Y. Khatib and M. J. Lab, Difference in electrical activity in the apex and base of left ventricle produced by changes in mechanical conditions of contraction, J. Physiol. 324, 25-26 (1982) (abstract). 22. B. B. Lerman, D. Burkhoff, D. T. Yue and K. Sagawa, Mechano-electrical feedback: Independent role of Dreload and contractile in modulation of canine ventricular excitabilitv. J. Cfin. Invest. 76. 1843-1850 (1985). 23. J. W. Dean and M. J. Lab, Regional changes in myocardial refractoriness during load’ manipulation in the in-situ pig heart, J. Physiol. 429, 387-400 (1990). 24. P. Taggart, P. M. Sutton, T. Treasure, M. J. Lab et al., Monophasic action potentials at discontinuation of

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