Mechano-Electric Feedback and Atrial Arrhythmias

Ravelli F.

Publication Details

Numerous clinical evidences as well as experimental studies show an increased vulnerability to atrial arrhythmias by acute stretch of the atrial walls. However, the mechanism by which atrial dilatation favours the development of sustained atrial tachyarrhythmias, such as atrial fibrillation (AF), is not fully understood. The effects of acute atrial dilatation on the substrate of atrial fibrillation were investigated in Langendorff-perfused rabbit heart. Increased atrial pressure resulted in a significant increase in vulnerability to AF, while release of the atrial stretch resulted in prompt cardioversion of AF. Atrial stretch has been shown to modulate the atrial vulnerable parameters. Stretch-induced shortening in atrial refractoriness and impairment of atrial conduction have been demonstrated. Atrial stretch through the modulation of the electrophysiological properties may not only favour the onset of arrhythmias but may also modulate the rate of reentrant arrhythmias. Cyclic variations in atrial volume following ventricular contraction modulate the atrial flutter cycle length and account for the spontaneous variability of the arrhythmia.

Introduction

Atrial stretch and dilatation may play a 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. The atrial arrhythmia mostly associated to atrial dilatation is atrial fibrillation (AF). Large clinical trails established left atrial enlargement as an independent risk factor for the development of AF, suggesting that interventions that maintain left atrial size may be important in the prevention of AF [36, 37]. However, atrial enlargement may not only be the cause, but it may also be a consequence of atrial fibrillation. Echocardiographic studies in patients showed a significant increase in the atrial volume after 20 months of lone atrial fibrillation [29]. Although, all these observations suggest a role of mechanoelectric feedback (MEF) in the development of atrial fibrillation, the mechanisms by which atrial dilatation increases the vulnerability to atrial arrhythmias are not fully understood.

The potential importance of mechanoelectric feedback in arrhythmogenesis has been initially investigated at the ventricular level. Initial studies in isolated cardiac tissue have shown that the membrane potential and duration of the action potential are affected by changes in the length of the ventricular cells [19]. Thereafter, various kinds of myocardial stretch, both in isolated and in situ hearts, have been shown to induce transient depolarizations, and shortening of the monophasic action potential and refractory period [11, 28]. While some of these changes have been shown to give rise to premature beats, no clear evidences exist on the role of MEF in the development of sustained ventricular arrhythmias.

The effects of stretch on atrial tissue have been investigated in more recent years. The effect of atrial dilatation was initially studied in humans and animals by refractoriness measurements. A variety of dilatation protocols have been used which yielded divergent results [25]. One method largely used to raise the atrial pressure was the reduction of the AV delay during sequential pacing or during supraventricular arrhythmias when near simultaneous activation of atrium and ventricle at tachycardia rate occurs. In humans and dogs, when the atrial pressure was raised by reduction of AV delay either a prolongation [7, 8, 16, 17], a shortening [5, 35] or no change of the atrial refractory period [6] were reported. In a different set of experiments atrial pressure was increased by acute volume loading. While an increase of atrial refractoriness was obtained in anaesthetized open-chest dogs by transfusion bleeding [31] and by normal saline loading [30], no significant change in atrial refractory period was found in normal goats by acute volume loading by a plasma expander [40]. Differently, a significant shortening of refractory period was found in dogs in which acute atrial dilatation was produced by inflation of a balloon catheter [32]. 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 timing and intensity of stretch [18]. Moreover, changes in neurohumoral balance may also play a role in creating contrasting results.

To avoid these limitations the author and Allessie [26] developed an experimental model in the isolated rabbit heart in which the right and left atrial pressure could be varied over a wide range of values. By using this model it was demonstrated that acute stretch altered the atrial substrate and favoured the development of atrial fibrillation [26]. This overview will focus on all these evidences. Specifically, the stretch-related AF model will be illustrated as well as the mechanical effects on atrial arrhythmia development and on the vulnerable parameters. Moreover, we will show how atrial stretch may not only favour the onset of arrhythmias but may also modulate the rate of atrial arrhythmias, based on a reentrant mechanism.

Mechanical effects on atrial arrhythmogenesis

Several evidences exist which show an increase in atrial vulnerability by acute stretch both in in vivo experiments and isolated preparations. The onset of afterdepolarizations and premature beats caused by stretch has been shown in isolated atrial preparations. 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 tachyarrhythmias has been clearly shown in the isolated right atrial tissue of both normal and post ventricular infarction rats by microelectrode recordings [15]. The development of early afterdepolarizations coincident with the occurrence of premature beats and atrial tachyarrhythmias was shown in the isolated guinea pig heart when the atrium was stretched by a balloon [23]. Delay afterdepolarizations were also recorded from the isolated rat atria at increasing diastolic pressure levels [34]. In these experiments the probability for stretch to trigger premature beats 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 stretch-induced triggered arrhythmias. The involvement of stretch-activated channels (SACs) in stretch-induced depolarizations and triggered arrhythmias is likely since both streptomycin [22] and gadolinium [34] were able to suppress mechanically induced afterdepolarizations in these preparations, while similar inhibition was not observed by calcium channel blockers [34].

The development of sustained tachyarrhythmias by applying atrial stretch was also documented. Stretch-increased vulnerability to atrial tachyarrhythmias and fibrillation by atrial pacing was shown in both animal models [30,31,32] and humans [2, 7, 35] when atrial pressure was acutely increased by different protocols. However, the mechanisms by which atrial dilatation leads to a substrate of AF were not fully understood. This point was investigated by introducing a stretch-related model of atrial fibrillation.

The stretch-related atrial fibrillation model

To study the effects of stretch on vulnerable parameters and on vulnerability to atrial fibrillation Ravelli and Allessie developed a new experimental model of biatrial dilatation in the Langendorff-perfused rabbit heart [26] (Fig. 1). To vary the atrial pressure and to control the degree of dilatation, the caval and pulmonary veins were ligated and the perfusion fluid entering the right atrium from the coronary sinus was allowed to leave the heart exclusively through a cannula in the pulmonary artery (Fig. 1). The hydrostatic pressure in the right and left atria was measured by a Y-shaped manometer inserted both into the superior caval vein and one of the pulmonary veins. To further guarantee an equal pressure in both atria, in addition the interatrial septum was perforated. In this way the atrial pressure and degree of biatrial dilatation could be varied by simply adjusting the height of the pulmonary outflow cannula. To avoid variation in atrial pressure by contraction of the ventricles, ventricular fibrillation was induced by rapid pacing. Retrograde activation of the atria during ventricular fibrillation was prevented by radiofrequency ablation of the AV junction.

Figure 1. The model of biatrial dilatation in the Langendorff-perfused rabbit heart Left - Schematic diagram of the method to vary the atrial pressure.

Figure 1

The model of biatrial dilatation in the Langendorff-perfused rabbit heart Left - Schematic diagram of the method to vary the atrial pressure. All caval and pulmonary veins were ligated and the perfusion fluid flowing out of the coronary sinus could leave (more...)

In most hearts the atrial pressure was varied between 0 and 15 cm H2O. In Fig. 1, right panels, the dilatation of the right atrium is shown as a result of increasing the atrial pressure from 0 to 10 cm H2O. As can be seen, the dilatation of the right atrium was significant and the surface area of the free wall of the right atrium increased almost twofold.

The electrical activity of the right and left atrium was recorded by two bipolar hook electrodes attached to the right and left atrial appendage. Monophasic action potentials (MAP) were recorded from the right atrial endocardial mid-wall with a contact MAP catheter. The catheter was introduced into the right atrial cavity through the orifice of the inferior caval vein. Programmed electrical stimulation was performed at the right and left mid-atrial wall by an epicardial unipolar electrode embedded in a soft plastic tube and the aortic cannula was used as indifferent electrode.

The effects of stretch on vulnerability to atrial fibrillation

The vulnerability of the atria to fibrillation was quantified by measuring the induction of atrial arrhythmias by single early premature stimuli. 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 [1]. In the small rabbit heart, stretch was the key arrhythmogenic factor since, only when atrial myocardium was preconditioned by stretch, a arrhythmogenic response to electrical stimulation could be induced.

As shown in Fig. 2, in undilated atria, atrial arrhythmias were never induced by a single premature stimulus. However, as the atrial pressure was raised, the atria became progressively more vulnerable to various kinds of atrial arrhythmias. Three classes of atrial arrhythmias were found in the isolated rabbit heart during acute atrial dilatation: 1. rapid repetitive responses, i.e. one or more premature beats immediately following the induced premature impulse, 2. atrial flutter, i.e. a regular rapid rhythm with monomorphic electrogram, 3. atrial fibrillation. Severity of atrial arrhythmias increased with progressively higher values of atrial pressure.

Figure 2. Effects of stretch on atrial arrhythmia vulnerability in the Langendorff-perfused rabbit heart.

Figure 2

Effects of stretch on atrial arrhythmia vulnerability in the Langendorff-perfused rabbit heart. In undilated atria, no atrial arrhythmias were induced by a single premature stimulus. During atrial dilatation, a variety of atrial arrhythmias were induced. (more...)

The inducibility of atrial fibrillation by single early premature stimulus at different atrial pressures was tested in 15 hearts. AF inducibility increased as a function of atrial pressure according to a logistic regression curve (r=0.98) (Fig. 3). No AF episodes were induced at pressures below 6 cm H2O. Above this pressure AF inducibility increased sharply to approach 100% at pressures above 10 cm H2O. Logistic regression analysis calculated a 50% inducibility of AF at an atrial pressure of 7.6 cm H2O.

Figure 3. Inducibility of atrial fibrillation (AF) by single premature stimuli plotted as a function of atrial pressure (left) and atrial refractory period (right).

Figure 3

Inducibility of atrial fibrillation (AF) by single premature stimuli plotted as a function of atrial pressure (left) and atrial refractory period (right). The data points represent the success rate of induction of AF in all hearts (n=15). The drawn curves (more...)

Whereas an increase in intra-atrial pressure favored the induction of AF by premature beat, conversely, lowering of the atrial pressure invariably terminated AF [26]. Two modalities of AF cardioversion by stretch release were observed. Immediate conversion of atrial fibrillation to sinus rhythm or slowing of the arrhythmia rate and AF termination after few minutes. In the upper panel of Fig. 4 a unipolar right atrial electrogram is shown during AF recorded at an atrial pressure of 10 cm H2O. In this case AF terminated 40 seconds after lowering the atrial pressure to zero. The release of the atrial stretch was associated with a clear slowing of the rate of AF (Fig. 4, lower panel). In the 10 cases of AF that were cardioverted by removal of atrial dilatation, the average fibrillation interval increased from 46.0 ± 4.7 ms during sustained AF to 63.4 ± 11.2 ms prior to termination (P<0.05).

Figure 4. Cardioversion of AF by stretch release.

Figure 4

Cardioversion of AF by stretch release. In the upper panel a unipolar atrial electrogram is shown during sustained atrial fibrillatrion at an atrial pressure of 10 cm H2O. The middle panel shows the same electrogram 40 seconds after release of the atrial (more...)

Mechanical modulation of vulnerable parameters

Alterations in the electrophysiological parameters which may promote atrial fibrillation are schematized in Fig. 5. Atrial stretch may contribute to atrial arrhythmias and atrial fibrillation development by inducing early (EADs) and delayed (DADs) afterdepolarizations which in turn precipitate triggered activity, by increasing the atrial mass, by decreasing the refractory period and/or slowing the conduction velocity and by increasing their spatial dispersion [25].

Figure 5. Potential contribution of acute atrial stretch to atrial fibrillation development through the alteration of electrophysiological parameters.

Figure 5

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 (more...)

The effects of stretch on atrial refractoriness

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 atrial stretch on atrial refractoriness. While in vivo studies show heterogeneous results (see Introduction), more consistent results are obtained in isolated preparations under acute stretch conditions. Shortening of the refractory period and action potential duration at early levels of repolarization was found in isolated atrial preparations. The effects of stretch on atrial refractory period and monophasic action potential duration were studied in the Langendorff-perfused rabbit heart [3,26,42]. Increasing of atrial pressure resulted in a progressive shortening of the atrial refractory period and monophasic action potential duration (Fig. 6). As shown in Fig. 6C, 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 (Fig. 6, left). Bi-phasic `crossover' effects of stretch on action potential shape were found in rat atrial preparations [15,33] and isolated guinea pig hearts [23]. Shortening in MAP duration by stretch at early levels of repolarization and prolongation at 90% repolarization were observed. Late prolongation was often due to the development of EADs.

Figure 6. Effects of stretch on atrial refractory period and monophasic action potential (MAP) duration in the Langendorff-perfused rabbit heart.

Figure 6

Effects of stretch on atrial refractory period and monophasic action potential (MAP) duration in the Langendorff-perfused rabbit heart. On the left, the time course of right atrial refractory period following an abrupt change in atrial pressure. In response (more...)

The effects of stretch on atrial conduction

The effects of atrial dilatation on conduction properties were evaluated in only a few studies. Early studies showed prolongation of intra-atrial conduction time by atrial overload, as roughly measured between two recording points [31,32]. However, accurate evaluation of conduction velocity requires the use of a high-density mapping array. Chorro et al. [9] were the first to use high-density mapping during acute atrial dilatation. By stretching the right atrium in the isolated rabbit heart by balloon inflation, they showed a global decrease of conduction velocity of about 25%. However, as shown in Fig. 5 not only slowing of conduction may be a proarrhythmic factor, but also increased heterogeneity in conduction may play an important role in the initiation and perpetuation of reentrant arrhythmias. The effects of acute atrial dilatation on the occurrence of local conduction delays and block was investigated by Eijsbouts et al. [10] by using the stretch-related AF model described in Fig. 1. In this study, areas with slow conduction (10 to 20 cm/sec) and lines of conduction blocks (≤ 10 cm/sec) were identified during pacing from four different directions. It was shown 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 (Fig. 7). This result was explained by the heterogeneous distribution of wall stress during increased atrial pressure which might stretch to a greater extent the thin parts of the atrium than the thicker bundles.

Figure 7. Effects of stretch on atrial conduction in the Langendorff-perfused rabbit heart.

Figure 7

Effects of stretch on atrial conduction in the Langendorff-perfused rabbit heart. Top: Local conduction velocity histograms during control and at atrial pressure of 14 cm H2O. The grey and black bars indicate slow conduction and local conduction block, respectively. (more...)

Determinants of stretch-induced atrial fibrillation

In the isolated rabbit heart, the great increase in atrial dimension, as shown in Fig. 1, was not the unique determinant of stretch-increased vulnerability to atrial fibrillation. In this preparation, a close relationship was found between the vulnerability of the atria to fibrillation and stretch-induced shortening of atrial refractoriness (Fig. 3). As shown in the right panel of Fig. 3, AF was never induced at refractory periods longer than 70 ms. An inducibility of 20% correlated with a refractory period of 57.8 ± 1.5 ms, whereas at an AERP of 53.2 ± 1.1 ms the inducibility of AF was 50%. When the refractory period further shortened to 48.2 ± 0.9 ms the inducibility of AF became more than 80%. A similar AF probability curve, which increased sharply as refractory period shortened, was recently found in humans when atrial pressure was increased by AV synchronization [35]. This result was independent of autonomic tone. Verapamil markedly reduced [35] or abolished [42] the stretch-induced shortening of refractory period and the propensity to atrial fibrillation suggesting again a causal relationship between the two phenomena. In the stretch-related AF model, SACs blocking agents, such as gadolinium and a novel SAC-blocking peptide from tarantula venom, reduced the stretch-induced vulnerability and duration of atrial fibrillation, without preventing the stretch-induced shortening of refractory period [3,4]. These results indicate that besides the shortening of refractoriness also other factors play a role in the development of atrial fibrillation during acute stretch. Although a causal relationship between spatial dispersion of electrophysiological properties and atrial fibrillation development has not been established yet, it is highly probable that impairment of atrial wave front propagation related to the anisotropic properties of the atrial wall, as described by Eijsbouts [10], as well as, nonuniform distribution of local atrial refractory periods, as found in the intact atrium [7, 8, 30, 35], could also establish a basis for stretch-induced atrial fibrillation.

In addition to changes in the substrate, stretch-induced atrial triggers may play a role in atrial fibrillation genesis. Clinical studies suggest that rapid rhythms originating in the region of pulmonary veins (PVs) play a critical role in triggering atrial fibrillation [12, 13]. Recently, selective PV angiography in patients with paroxysmal AF suggested that AF triggers are most frequently located in dilated superior PVs [21, 41]. These clinical observations suggested the hypothesis that clinical atrial fibrillation may start by stretch-activated sources originating from pulmonary veins [41]. The recent observation in the isolated sheep heart of a stretch-induced increase in the rate and organization of waves emanating from the superior pulmonary veins support this hypothesis [14].

Mechanical modulation of atrial reentries: The flutter case

Atrial stretch through the modulation of the electrophysiological properties (i.e. refractory period and conduction velocity) may not only favour the onset of arrhythmias but may also modulate the rate of atrial arrhythmias. A beat-to-beat mechanical modulation of atrial flutter cycle length has been documented by the author et al. [24,27] in a reentrant arrhythmia as atrial flutter. Atrial flutter is a supraventricular arrhythmia, based on a reentrant mechanism, characterized by a very rapid, highly regular rhythm of the atria (240–350 beats/min) and by the presence of some degree of AV block including 2:1, 3:1 or 4:1 ratio and advanced AV block.

As shown in Fig. 8, by the recording during atrial flutter of the intra-atrial pressure as well as of the atrial and ventricular electrical activity, the atrial pressure increases after each ventricular contraction then decreases in a cyclic fashion. Thus, during atrial flutter a mechanoelectric feedback mechanism takes place, since the fast electrical activity of the atria occours during different degrees of stretch and this stretch condition is repetitive.

Figure 8. Mechanoelectric feedback during atrial flutter.

Figure 8

Mechanoelectric feedback during atrial flutter. Simultaneous recording during atrial flutter of electrocardiogram (V1), atrial electrogram (ENDO) and right intra-atrial pressure (RAP). After each ventricular QRS complex, atrial pressure increases then (more...)

Cyclic variations in atrial volume and pressure following ventricular contractions modulate the atrial flutter cycle length on a beat-to-beat basis and account for the spontaneous variability of the arrhythmia [20,24,27]. This phenomenon was investigated in patients by measuring the sequence of atrial intervals from intraesophageal or intra-atrial leads and the onset of QRS complexes from a surface lead. In Fig. 9 the electrocardiogram, the esophageal signal and the interval time series from two episodes of atrial flutter with 2:1 and 4:1 AV conduction are given. Those atrial intervals in which a ventricular beat occurred are indicated by arrows. The time series clearly showed that the small variability of atrial flutter cycle length was modulated by the ventricular rate. The AV conduction ratio determined the period of atrial flutter cycle length oscillation.

Figure 9. Beat-to-beat fluctuations of atrial flutter interval in patients with 2:1 (top) and 4:1 AV conduction (bottom).

Figure 9

Beat-to-beat fluctuations of atrial flutter interval in patients with 2:1 (top) and 4:1 AV conduction (bottom). Electrocardiogram, atrial electrogram and sequential plot of atrial cycle length are shown. Intervals in which a ventricular contraction occurred (more...)

The critical role of ventricular contraction in the modulation of atrial flutter interval variability was evidenced by applying carotid sinus massage (CSM), a maneuver which temporally prevented ventricular activation. As shown in the upper panel of Figure 10, the ventricular asystole caused by the massage abolished the variations in atrial flutter rate.

Figure 10. Phase-relation between variations in atrial flutter cycle length and the ventricular contraction in one patient with advanced AV block and common atrial flutter.

Figure 10

Phase-relation between variations in atrial flutter cycle length and the ventricular contraction in one patient with advanced AV block and common atrial flutter. At the upper panel, the sequence of atrial flutter intervals is plotted. Those intervals (more...)

To obtain further insight in the relation between the variation in atrial flutter interval and the ventricular activity a phase-plot was constructed, in which, the interval was plotted against the time after the previous ventricular complex.

In Fig. 10, the flutter intervals measured in one patient with an advanced AV block were superimposed by time aligning the onset of consecutive QRS complexes. This data representation shows that the interval fluctuations are strictly coupled to the moment of ventricular activation. After the onset of the QRS complex the atrial interval gradually increased and reached a maximum at about 400–500 ms. Thereafter the interval decreased below the average value (dashed line) before returning to the average flutter rate. This phase pattern was common to all analysed patients with common atrial flutter (Fig. 11). The duration of the ventricular cycle, which was different from patient to patient, determined the duration of the atrial interval variability pattern.

Figure 11. Normalized average atrial flutter intervals following a ventricular beat for 11 patients with common atrial flutter.

Figure 11

Normalized average atrial flutter intervals following a ventricular beat for 11 patients with common atrial flutter. An increase of the flutter cycle is followed by a secondary shortening of the interval below the average flutter cycle length (from Lammers, (more...)

Prolongation of atrial flutter cycle coincided with increase in atrial pressure and volume as shown in Fig. 12 (left panel), where variation of atrial flutter cycle length after the ventricular contraction was compared with variation in atrial pressure at the same time scale. The synchronism between changes in flutter cycle length and variations in atrial pressure indicated that variations in atrial flutter cycle length could be directly caused by stretch of the atrial wall which affects the conduction properties of the circulating impulse in the atrium. Since stretch is known to slow down the conduction velocity [9, 10], the prolongation of atrial flutter interval could be explained by an increase in the conduction time which increase the revolution time of an anatomical reentry. This hypothesis was tested in a simulation study, which revealed that the secondary shortening of the flutter interval could be due to the presence of a partial excitable gap between head and tail of the circus movement [20].

Figure 12. Synchronism between changes in atrial flutter cycle length and variations in atrial pressure during common (left) and rapid (right) atrial flutter.

Figure 12

Synchronism between changes in atrial flutter cycle length and variations in atrial pressure during common (left) and rapid (right) atrial flutter. The effects of stretch on flutter rate differ according to the type of reentrant mechanism at the base (more...)

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 [20, 38, 39]. The strain phase of the Valsalva maneuver, passive upright tilt and expirations, three interventions that reduce cardiac size, accelerate the flutter rate, independently of autonomic tone [39]. The development of 1:1 AV conduction during atrial flutter increases the atrial pressure and this in turn slows down the flutter rate [38].

The effects of stretch on arrhythmia rate differ according to the type of reentrant mechanism underlying the arrhythmia (Fig. 12). While increase in atrial pressure slows down the rate of common atrial flutter, which is based on a macroanatomic reentry (Fig. 12, left), it accelerates the rate of the rapid form of atrial flutter, which is thought to be based on a functional reentry (Fig. 12, right) [27]. Consistently, decrease in intra-atrial pressure by stretch release slows down the atrial fibrillation rate in the isolated rabbit heart (see Fig. 4) [26]. These data are consistent with mechanoelectric feedback 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.

Conclusions and perspectives

In the Langendorff-perfused rabbit heart, evidences have been reported that acute atrial stretch increases vulnerability to AF and modulates the electrophysiological substrate of the arrhythmia. Shortening in atrial refractory period and monophasic action potential duration as well as impairment of conduction strictly related to the trabecular architecture of the right atrium have been shown to develop during acute atrial dilatation. Future studies in patients are needed to further characterize electrophysiological changes, i.e. conduction disturbances, in the clinical setting of atrial dilatation. This would involve extensive high-resolution biatrial mapping in patients during controlled dilatation protocols. Moreover, focused clinical studies on the role of pulmonary vein stretch in the development of ectopic activity triggering atrial fibrillation in patients would certainly be worthwhile. On the side of basic research, efforts should converge towards the understanding of primary mechanisms of stretch induced atrial arrhythmias. Although the reduced AF vulnerability by SACs [3, 4] and L-type calcium channel blockers [35, 42] suggests the involvement of stretch-activated channels and calcium loading as potential primary mechanisms of stretch-induced atrial fibrillation, the cellular mechanism underlying all these macroscopic electrophysiological changes remains to be established. Detailed understanding of primary mechanisms of stretch-induced atrial arrhythmias will allow to identify new targets for novel antiarrhythmic drugs.

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