Mechano-electric feedback and atrial fibrillation

Progress in Biophysics & Molecular Biology 82 (2003) 137–149

Review

Mechano-electric feedback and atrial fibrillation Flavia Ravelli* Department of Physics, University of Trento and ITC-irst, Via Sommarive 14, Povo-Trento 38050, Italy

Abstract Atrial fibrillation frequently occurs under conditions associated with atrial dilatation suggesting a role of mechano-electric feedback in atrial arrhythmogenesis. Although atrial arrhythmias may be due both to abnormal focal activity and reentrant mechanisms, the majority of sustained atrial arrhythmias have been ascribed to reentrant activity. Atrial stretch may contribute to focal arrhythmias by inducing afterdepolarizations and to reentrant arrhythmias by increasing the atrial surface, by shortening the refractory period and/or slowing the conduction velocity and by increasing their spatial dispersion. Experimental and clinical studies have demonstrated that changes in mechanical loading conditions may modulate the electrophysiological properties of the atria. These studies have, for the most part, involved the effects of acute stretch on atrial refractoriness. While studies in humans and intact animals yield divergent results due to the variety of loading conditions and neurohumoral influences, experimental studies in isolated preparations clearly show that atrial refractory period and action potential duration at early levels of repolarization shorten by acute atrial dilatation. Both experimental and human studies have shown that acute atrial stretch is arrhythmogenic and may induce triggered premature beats and atrial fibrillation. r 2003 Elsevier Science Ltd. All rights reserved. Keywords: Mechano-electric feedback; Atrial fibrillation; Stretch; Atrial arrhythmias; Refractory period; Electrophysiology

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.

MEF as a potential cause of atrial arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . 138 2.1. Mechanisms of atrial arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 2.2. Factors determining atrial arrhythmias: potential targets of MEF . . . . . . . . . . . . 139

3.

Evidences of MEF in the human atrium: modulation of reentrant arrhythmias . . . . . . . .

4.

The effects of acute stretch on atrial RP and action potential duration . . . . . . . . . . . . 140 4.1. In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

*Fax: +39-461-881696. E-mail address: [email protected] (F. Ravelli). 0079-6107/03/$ - see front matter r 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0079-6107(03)00011-7

138

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138 4.2. 4.3.

Isolated preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Ionic mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

5.

Acute atrial stretch and atrial arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 5.1. MEF and afterdepolarizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 5.2. MEF and atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

6.

Determinants of stretch-induced AF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 6.1. The role of refractoriness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 6.2. Other arrhythmogenic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

7.

Editor’s note . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

147

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

147

1. Introduction Numerous clinical evidences show the association between atrial dilatation and atrial fibrillation (AF) (Henry et al., 1976; Vasan et al., 1997). The relation between the two events forms a closed loop since atrial enlargement may not only be the cause but it may also be a consequence of AF (Sanfilippo et al., 1990). Atrial stretch and dilatation may play a potential role in the development of atrial arrhythmias in a wide spectrum of clinical conditions, ranging from the acute effects of supraventricular tachycardia and myocardial infarction to chronic conditions such as cardiac failure and mitral regurgitation. On the other hand several experimental evidences exist, mostly based on acute atrial dilatation, showing that stretch may modulate the basic electrophysiological properties of the atria and promote arrhythmogenic events (Nazir and Lab, 1996a). In this brief review we will relate the basic electrophysiological effects of mechano-electric feedback (MEF) to the development of stretch-induced atrial arrhythmias. To aid in the comprehension of development of atrial arrhythmias by stretch, the basic electrophysiological mechanisms of arrhythmias and the corresponding arrhythmogenic factors will be introduced. We will then examine the main evidences of MEF in the human atrium, the effect of acute stretch on atrial refractoriness and arrhythmias development in both the intact atrium and isolated preparations. Finally, the determinants of stretch-induced AF will be discussed.

2. MEF as a potential cause of atrial arrhythmias 2.1. Mechanisms of atrial arrhythmias Basically two different mechanisms underlying atrial arrhythmias have been proposed: (1) abnormal impulse formation and (2) abnormal impulse conduction leading to some forms of circulating excitation or re-entry. Focal mechanisms may be due either to enhanced normal or abnormal automaticity or to triggered activity which occurs when there are afterdepolarizations of sufficient magnitude to precipitate an extrasystole or repetitive firing. Afterdepolarizations may develop during the process of repolarization or occur after completion of repolarization and are designed, respectively, as early (EAD) or delayed (DAD) afterdepolarization. Although both triggered activity and reentry might be relevant to atrial arrhythmias induced by altered loading conditions, the mechanism underlying the majority of sustained atrial arrhythmias seen clinically

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in pathological conditions is re-entry (Brugada and Wellens, 1985). Experimental and clinical studies have revealed two basically different kinds of reentry: (1) circuits that are based on macroanatomic pathways, (2) functionally determined circuits. Functional reentry can occur in a single circuit, producing rapid regular activity, or it can break into multiple wave fronts producing fibrillatory activity. Numerical (Moe et al., 1964) and high-density mapping studies (Allessie et al., 1985) have shown that the propagation pattern during AF is characterized by the simultaneous presence in the atrium of multiple wave fronts of excitation wandering around areas of functional conduction blocks. More recent observations have challenged the prevailing notion that AF is a fully turbulent process, entirely caused by multiple random wavelets, showing that the arrhythmia may also be triggered either by focal sources localized usually in the pulmonary veins (Haissaguerre et al., 1998) or by a single atrial reentry circuit, which gives rise to wave front fragmentations by virtue of fibrillatory conduction (Jalife et al., 2002). 2.2. Factors determining atrial arrhythmias: potential targets of MEF Although it is not clear to what extent the anatomical and electrophysiological properties of the atrium contribute to the initiation of clinical atrial arrhythmias, some key parameters have been identified which may play a fundamental role in the generation of the arrhythmic events. These may constitute a target for MEF action and precipitate stretch-induced atrial arrhythmias. In order to induce triggered activity, the potential targets of MEF are the primary mechanisms of early and delay afterdepolarizations which include a reduction in the normal repolarizing current, an abnormal prolongation of inward current carried by sodium or calcium channels and intracellular calcium overload. Experimental and clinical studies have shown that the factors determinant for the genesis and persistence of reentrant arrhythmias are basically three (Allessie et al., 1990): (1) inhomogeneity in electrophysiological properties, (2) length of the excitation wave (that is refractory period (RP)  conduction velocity) and (3) tissue mass. An increased spatial dispersion of refractoriness and non-uniform conduction properties are thought to play a role in the initiation of reentry because of the increase likelihood of unidirectional block of premature impulses. A further prerequisite for the creation of reentrant circuit is that the wavelength must be short in relation to the length of the area of block to allow to the impulse to complete the reentrant loop. Atrial mass is a critical factor for reentrant arrhythmias since it determines, together with the wavelength, the maximal number of wavelets which can coexist in a given surface area and thus the stability of AF. The link between atrial stretch and AF, through the alteration of all these parameters, is shown in Fig. 1.

3. Evidences of MEF in the human atrium: modulation of reentrant arrhythmias Atrial stretch through the modulation of the electrophysiological properties (i.e. RP and conduction velocity) may not only favour the onset of arrhythmias but may also modulate the rate of atrial arrhythmias. This phenomenon has been largely documented in reentrant arrhythmias as atrial flutter. Cyclic variations in atrial volume and pressure following ventricular contraction and respiration modulate the atrial flutter cycle length on a beat-to-beat base and account for the spontaneous variability of atrial flutter interval (Ravelli et al., 1994; Yamashita

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DADs

RP CV

EADs

Wavelength

STRETCH Atrial Mass

RP dispersion

CV dispersion

ATRIAL FIBRILLATION

Inhomogeneity

Fig. 1. Potential contribution of acute atrial stretch to atrial fibrillation development through the alteration of electrophysiological parameters. EADs and DADs are, respectively, early and delay afterdepolarizations, RP is refractory period, CV is conduction velocity.

et al., 1994; Ravelli, 1998). The effects of stretch on arrhythmia rate differ according to the type of reentrant mechanism underlying the arrhythmia. Increase in atrial pressure and volume invariably slows down the rate of the common form of atrial flutter, independently from the kind of maneuver used to modulate the atrial pressure or volume (Lammers et al., 1991; Waxman et al., 1991, 1992). Differently, atrial stretch accelerates the rate of the rapid form of atrial flutter (Ravelli et al., 1994). Consistently, decrease in intra-atrial pressure by stretch release slows down the AF rate in the isolated rabbit heart (Ravelli and Allessie, 1997). These data are consistent with MEF in which an increase in atrial pressure leads to a slowing of conduction and to a shortening of refractoriness which in turn slow down the rate of a macroanatomic reentry and accelerate the rate of a functionally determined circuit.

4. The effects of acute stretch on atrial RP and action potential duration 4.1. In vivo studies The effects of acute atrial stretch on the RP have been studied in both humans and animals by using a variety of dilatation protocols (Table 1). One method largely used to raise the atrial pressure in in vivo studies was the reduction of the AV delay during sequential pacing or during supraventricular arrhythmias (SVT) when near simultaneous activation of atrium and ventricle at tachycardia rate occurs. In humans and dogs, either a prolongation (Kaseda and Zipes, 1988; Klein et al., 1990; Chen et al., 1998, 1999), a shortening (Calkins et al., 1992a; Tse et al., 2001) or no change of the atrial RP (Calkins et al., 1992b) were reported. In a different set of experiments atrial pressure was increased by acute volume loading. While an increase of right atrial refractoriness was obtained in anaesthetized open-chest dogs by normal saline loading (Sideris et al., 1994; Satoh and Zipes, 1996), no significant change in atrial RP was found in normal goats by acute volume loading by a plasma expander (Wijffels et al., 1997). Differently, a significant shortening of RP was found in dogs in which acute atrial dilatation was produced by inflation of a balloon catheter (Solti et al., 1989). Apart from possible species differences, the reason of the widely differing outcomes may lay in the variety of experimental conditions, which can lead to different degrees and durations of atrial stretch. It is known that dilatation may influence repolarization in different ways depending on

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Table 1 Summary of the effects of acute stretch on atrial refractoriness in in vivo studies Dilatation models

Species

DP (mmHg)

Atrial RP

Atrial RP dispersion

References

Simultaneous AV pacing

Dog Human Human Human Human Human

5 3.5 4 4 8(peak) 7.4

m m m 2 k k

— — m — — m

Kaseda and Zipes (1988) Klein et al. (1990) Chen et al. (1999) Calkins et al. (1992b) Calkins et al. (1992a) Tse et al. (2001)

SVT

Human Human

2.7 4.5

m m

— m

Klein et al. (1990) Chen et al. (1998)

Volume overload

Dog Dog Goat

X4 1.2 4.5

m m 2

— m —

Sideris et al. (1994) Satoh and Zipes (1996) Wijffels et al. (1997)

Balloon inflation

Dog

8

k

—

Solti et al. (1989)

SVT is supraventricular tachycardia, DP the average change in mean atrial pressure, RP refractory period. The parameter measured increased (m), decreased (k), or did not change (2).

timing and intensity of stretch (Kohl et al., 1998). The influence of time course of stretch on changes in RP was clearly evidenced in the two sets of experiments by Calkins showing that only a transient increase in pressure was able to shorten the RP (Calkins et al., 1992a), while sustained stretch did not change the refractoriness (Calkins et al., 1992b). The importance of the intensity of stretch appears by the global evaluation of the results as summarized in Table 1. Moderate changes in atrial pressure (about 4 mmHg) caused an increase or no change in atrial RP while for greater variations in atrial pressure the RP invariably decreased. Changes in neurohumoral balance may also play a role in creating contrasting results. The recent finding of Tse showing that stretch-induced shortening of RP was enhanced by autonomic blockade suggest the possibility that in intact animals the stretch-induced changes in atrial RP are partially counteracted by changes in neurohumoral balance (Tse et al., 2001). While results are different for the local evaluation of RP, consistent results emerge from the evaluation of spatial dispersion of refractoriness. An increase in RP heterogeneity by stretch, although roughly evaluated as difference in RP between few recording points, was found in all studies (Table 1). Non-uniform distribution of local atrial refractory periods may be due to the inhomogeneous structure of the atria which can create regional differences in wall stress during elevated intra-atrial pressure (Satoh and Zipes, 1996). 4.2. Isolated preparations While in vivo studies show heterogeneous results, more consistent results are obtained in isolated preparations under acute stretch conditions. Shortening of the RP and action potential duration at early levels of repolarization was found. The effects of stretch on atrial RP and monophasic action potential (MAP) duration were studied in the Langendorff-perfused rabbit

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heart (Ravelli and Allessie, 1997) (Fig. 2). Atrial dilatation was obtained by raising the level of an outflow cannula in the pulmonary artery after occlusion of the caval and pulmonary veins. Increasing of atrial pressure resulted in a progressive shortening of the atrial RP and MAP duration. As shown in Fig. 2, shortening of the action potential was mostly due to an increase in the rate of early repolarization, and the plateau phase of the action potential disappeared when the atria were dilated. All these changes were completely reversible after release of the atrial stretch. Shortening of the RP by increasing atrial pressure was reproduced in the isolated rabbit heart by similar dilatation models (Bode et al., 2000; Zarse et al., 2001) and by balloon inflation (Chorro et al., 1998). Shortening in MAP duration by stretch at early levels of repolarization has been found also in isolated guinea pig heart (Nazir and Lab, 1996b). While MAP duration measured at 50% repolarization decreased by transient stretch, MAP duration at 90%

Fig. 2. Effects of stretch on atrial refractory period and monophasic action potential (MAP) duration in the Langendorff-perfused rabbit heart. (A) Right atrial dilatation at 10 cm H2O, compared to the deflated atrium (left). In the dilated atrium, complex structure of atrial wall can be clearly seen, crista terminalis and pectinate muscles forming an interlacing network with myocardium. (B) Right atrial refractory period as a function of atrial pressure. (C) MAPs recorded from right atrium at different atrial pressure are superimposed. Note disappearance of plateau phase when atria were dilated (modified from Ravelli and Allessie (1997), with permission).

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Fig. 3. Effects of stretch on action potential (AP) shape in rat atrial preparations. (A) Sustained stretch of 1.75 mM (solid line) shortened repolarization at 50% and prolonged it at 90% by producing afterdepolarizations (from Kamkin et al., 2000, with permission). (B) Sustained moderate stretch (dashed line) decreased AP duration at positive voltage and increased it at negative voltage (from Tavi et al., 1998, with permission).

repolarization increased, due to the development of EADs. Bi-phasic ‘cross-over’ effects of stretch on action potential shape, as recorded by monophasic action potentials, were confirmed by microelectrode recordings in rat atrial preparations (Tavi et al., 1998; Kamkin et al., 2000) as shown in Fig. 3. 4.3. Ionic mechanisms The ionic mechanisms underlying changes in atrial refractoriness and action potential duration during atrial stretch remain uncertain. Stretch-activated channels (SACs) may theoretically account for the voltage-dependent modulation of action potential shape as found in atrial preparations, since SACs have been reported to have equilibrium potentials which are positive to resting membrane potential (Kim, 1993; Hu and Sachs, 1997). However, the use of inhibitors of stretch-activated channels have yielded differing results. While stretch-induced APD shortening was suppressed by streptomycin (Nazir et al., 1995; Babuty and Lab, 2001), shortening of the RP in the isolated rabbit heart remained unchanged by gadolinium (Bode et al., 2000) and by a SACblocking peptide from a tarantula venom (Bode et al., 2001). Mechanical modulation of intracellular calcium concentration, brought about by modulation of troponin (TnC) sensitivity and/or by stretch-activated calcium influx, is the second well recognized ionic responsible which may account for changes in atrial AP shape and refractoriness. Increase in intracellular calcium concentration by mechanical stretch has been clearly demonstrated (Calaghan and White, 1999). An increase in intracellular calcium concentration may shorten the action potential duration by inhibiting transmembrane calcium influx (Sun et al., 1997) and activating outward potassium currents (Shibata et al., 1989). A more severe depression of the inward calcium current compared with the total outward current may explain the strong depression of plateau phase as shown in the isolated rabbit heart (see Fig. 2C) and in atrial myocytes obtained by dissociation of dilated atria (Le Grand et al., 1994). Results showing that verapamil abolishes stretch-induced changes in atrial RP in both isolated rabbit heart (Zarse et al., 2001) and humans (Tse et al., 2001) indicate that the effects of stretch on atrial refractoriness may

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be mediated by intracellular calcium loading. Increase in calcium transient may also explain the late duration of action potential as found in rat atrial preparations. As shown by mathematical modeling describing intracellular calcium and electrical behavior of single rat atrial myocytes (Tavi et al., 1998), an increase of Ca2+ in short action potentials promotes an inward current via Na+/Ca2+-exchanger which contributes to prolong the duration of action potential. 5. Acute atrial stretch and atrial arrhythmias While the results concerning the effects of stretch on vulnerable parameters are not univocal, the increase vulnerability to atrial arrhythmias by acute stretch is a common finding both in in vivo experiments and isolated preparations. 5.1. MEF and afterdepolarizations Acute atrial stretch induces both early and delay afterdepolarizations which, when large enough, may initiate triggered premature action potentials. The development of stretch-activated depolarizations (SADs) able to trigger premature beats and atrial tachyarrhytmias has been clearly shown in the isolated right atrial tissue of both normal and post-ventricular infarction rats by microelectrode recordings (Kamkin et al., 2000)(Fig. 4). However, SADs in contrast to classical early and delay afterdepolarizations were not triggered by the preceding action potential but they were simply located after the AP. The development of early afterdepolarizations coincident with the occurrence of premature beats and atrial tachyarrhythmias was shown in the isolated guinea pigs hearts when the atrium was stretched by a balloon (Nazir and Lab, 1996b) and in situ pig heart locally stretched by a suction tripodal device (Nazir and Lab, 1996a). Delay afterdepolarizations were also recorded from the isolated rat atria at increasing diastolic pressure levels (Tavi et al., 1996). In these experiments the probability for stretch to trigger premature beats

Fig. 4. Stretch-activated depolarizations (SADs) and premature action potentials as recorded in the right atrial tissue of post-ventricular infarction rats. Stepwise increases in resting force due to stretch up to 0.15 mM produced SADs, which resulted in a premature action potential by a further increase in stretch. Release of stretch resulted in complete reversibility of stretch-induced effects (from Kamkin et al., 2000, with permission).

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increased as a function of degree of atrial stretch and it was higher during volume changes suggesting that the intensity of stretch and the transient phase are the key factors for stretchinduced triggered arrhythmias. The involvement of SACs in stretch-induced depolarizations and triggered arrhythmias is likely since both streptomycin (Nazir et al., 1995) and gadolinium (Tavi et al., 1996) were able to suppress mechanically induced afterdepolarizations in these preparations, while similar inhibition was not observed by calcium channel blockers (Tavi et al., 1996). 5.2. MEF and atrial fibrillation Stretch-increased vulnerability to atrial tachyarrhythmias and fibrillation by atrial pacing was shown in both animal models (Solti et al., 1989; Sideris et al., 1994; Satoh and Zipes, 1996) and humans (Antoniou et al., 1997; Chen et al., 1998; Tse et al., 2001) when atrial pressure was acutely increased by different protocols. The effect of acute atrial dilatation on the substrate of AF was investigated in Langendorff-perfused rabbit heart (Ravelli and Allessie, 1997; Bode et al., 2000, 2001; Zarse et al., 2001). The rabbit atrium in normal conditions is not able to sustain any atrial arrhythmias since, the maximal number of wavelets that such a small atrial mass may contain is well below the fibrillation threshold (Allessie et al., 1990). In the small rabbit heart, stretch was the key arrhythmogenic factor since, only when atrial myocardium was preconditioned by stretch, a fibrillatory response to electrical stimulation could be induced. As illustrated in Fig. 5, the inducibility of AF by single atrial extrastimuli increased from 0% at low pressure to 100% when atrial pressure was >10 cm H2O. A similar inducibility curve was recently found in humans when atrial pressure was increased by AV synchronization (Tse et al., 2001). Spontaneous onset of atrial tachycardia (Solti et al., 1989) and runs of AF initiated by premature depolarizations were occasionally observed at high degree of stretch (Bode et al., 2000). Whereas an increase in intraatrial pressure favored the induction of AF, conversely lowering of atrial pressure invariably terminated AF (Ravelli and Allessie, 1997).

Fig. 5. Effects of atrial pressure on atrial fibrillation (AF) inducibility in the Langendorff-perfused rabbit heart. Earliest possible premature beats at different atrial pressure (left) and inducibility of AF by single premature stimuli plotted as a function of atrial pressure (right). At low pressures not a single case of AF was observed. AF inducibility increased as a function of atrial pressure according to a logistic regression curve (modified from Ravelli and Allessie, 1997, with permission).

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6. Determinants of stretch-induced AF 6.1. The role of refractoriness The increase in atrial dimension by acute stretch was not the only determinant of stretchincreased vulnerability to AF. Shortening of the RP by stretch, contributed to increase the probability of AF, by shortening the wavelength of atrial impulse and thus by increasing the number of wavelets. The role of stretch-induced shortening of atrial refractoriness in the development of AF is shown in Fig. 6, in which results from isolated rabbit heart and humans are compared. In both isolated rabbit heart (Ravelli and Allessie, 1997) and humans (Tse et al., 2001) a close relationship was found between the vulnerability of the atria to fibrillation and stretchinduced shortening of atrial refractoriness. Probability curve of AF induction were similar by increasing sharply as RP shortened. In humans, stretch-increased AF vulnerability was independent of autonomic tone. Verapamil markedly reduced (Tse et al., 2001) or abolished (Zarse et al., 2001) the stretch-induced shortening of RP and the propensity to AF suggesting again a causal relationship between the two phenomena. Differently, in the isolated rabbit heart model SACs blocking agents reduced the stretch-induced vulnerability and duration of AF, without preventing the stretch-induced shortening of RP (Bode et al., 2000, 2001). This result indicates that besides the shortening of refractoriness also other factors play a role in development of AF during acute stretch.

6.2. Other arrhythmogenic factors Other factors important in the development of substrate for AF also have been observed in the setting of acute atrial stretch.

Fig. 6. Correlation between stretch-induced vulnerability to atrial fibrillation (AF) and shortening of atrial refractoriness. Probability of AF induction by a single atrial extrastimulus plotted as a function of the refractory period in the isolated rabbit heart (modified from Ravelli and Allessie, 1997, with permission) and in humans (from Tse et al., 2001, with permission). In humans, AF inducibility was determined in the absence (m) and presence of autonomic blockade (&) during simultaneous AV pacing.

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Non-uniform distribution of local atrial refractory periods probably due to heterogeneous wall stress, as found in the intact atrium (Table 1), could establish a basis for stretch-induced AF. However, the increased spatial dispersion of refractoriness by stretch was simply associated, but not correlated, to the increased vulnerability to AF (Satoh and Zipes, 1996; Tse et al., 2001). Autonomic tone influences may affect the relation between the two phenomena, since it was shown that autonomic blockade facilitate AF maintenance during stretch, by promoting heterogeneity in atrial refractoriness (Tse et al., 2001). Impairment of atrial wave front propagation may also play an important role in stretchinduced AF. In fact, the highly complex structure of the right atrium (see Fig. 2A) constituted by the interceptions of thin tissue and ticker pectinate muscle may provide, under stretch conditions, a optimal substrate for slow and heterogeneous conduction. Prolongation of intra-atrial conduction time, as roughly measured between two recording points (Solti et al., 1989; Sideris et al., 1994), and slow conduction, as determined by mapping system (Chorro et al., 1998), have been shown during atrial dilatation. Preliminary data in the isolated rabbit heart (Eijsbouts et al., 2001) show that acute atrial dilatation not only depressed atrial conduction, but promoted spatial heterogeneity in conduction by causing conduction blocks which occurred parallel to the boundaries of large trabeculae. In addition to changes in the substrate, stretch-induced atrial triggers may play a role in AF genesis. Recently, it has been proposed that clinical AF may start by stretch-activated atrial premature beats originating from pulmonary veins (Yamane et al., 2002). The experimental observations of stretch-induced afterdepolarizations producing triggered atrial arrhythmias (Nazir and Lab, 1996a; Kamkin et al., 2000) and the observation of stretch-induced spontaneous onset of AF initiated by premature beats (Bode et al., 2000) may support this hypothesis. Finally, although the reduced AF vulnerability by SACs blockers (Bode et al., 2000, 2001) and L-type calcium channel blockers (Zarse et al., 2001; Tse et al., 2001) suggests the involvement of stretch-activated channels and calcium loading as potential primary mechanisms of stretchinduced atrial fibrillation, the cellular mechanism underlying all these macroscopic electrophysiological changes remains to be established. 7. Editor’s note Please see also related communications in this volume by Schotten et al. (2003) and Franz and Bode (2003). References Allessie, M.A., Lammers, W.J.E.P., Bonke, F.I.M., 1985. Experimental evaluation of Moe’s multiple wavelets hypothesis of atrial fibrillation. In: Zipes, D.P., Jalife, J. (Eds.), Cardiac Electrophysiology and Arrhythmias. Grune and Stratton Inc, New York, pp. 265–275. Allessie, M.A., Lammers, W.J.E.P., Brugada, J., Smeets, J.L.R.M., Penn, O., Kirchhof, C.J.H.J., 1990. Pathophysiology of atrial fibrillation. In: Zipes, D.P., Jalife, J. (Eds.), Cardiac Electrophysiology: From Cell To Bedside. WB Saunders Co, Philadelphia, PA, pp. 548–559. Antoniou, A., Milonas, D., Kanakakis, J., Rokas, S., Sideris, D.A., 1997. Contraction-excitation feedback in human atrial fibrillation. Clin. Cardiol. 20, 473–476.

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