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Am J Physiol Heart Circ Physiol 286: H1008-H1014, 2004; doi:10.1152/ajpheart.00724.2003
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Stretch-induced regional mechanoelectric dispersion and arrhythmia in the right ventricle of anesthetized lambs

Ruo L. Chen, Daniel J. Penny, Gottfried Greve, and Max J. Lab

National Heart and Lung Institute, Imperial College of Science, Technology, and Medicine, London SE1 7BH, United Kingdom

Submitted 18 August 2003 ; accepted in final form 31 October 2003


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Regional mechanical and electrophysiological changes accompany most ventricular arrhythmias and, it has been suggested, by mechanoelectric feedback. We hypothesized that an intervention producing regional mechanical dispersion was associated with regional, proarrhythmic electrical dispersion and studied the regional mechanoelectric feedback in the right ventricle (RV) of anesthetized lambs. Ten lambs were deeply anesthetized, and their hearts were exposed. Three tripodal devices, each incorporating three monophasic action potential electrodes and an integrated strain-gauge system, were placed on the RV apex outflow and inflow regions. Measurements were made before, during, and after 10-s pulmonary arterial occlusion. Pulmonary arterial occlusion increased RV pressure and overall regional segment length. Length excursion became out of phase with RV pressure beats immediately after occlusion, and the strain patterns were different in the three regions at the peak of occlusion. The occlusion resulted in different alterations in regional monophasic action potential morphology, including reduction in monophasic action potential amplitude and duration by different amounts and early afterdepolarizations that were unevenly distributed in the monophasic action potential recordings. This was associated with dispersion of repolarization and recovery time. The combination of electromechanical events precipitated a variety of arrhythmias. Acute RV distension is proarrhythmic, possibly through a causal relationship among mechanically induced afterdepolarizations, dispersion (heterogeneity) of mechanical strain, and dispersion of electrical recovery. The relationship among the different wall motions, the dispersion of repolarization, and arrhythmia underscored mechanoelectric feedback as an important part of arrhythmogenesis in pulmonary embolism and commotio cordis.

mechanoelectric feedback; early afterdepolarizations

STRETCH OF THE HEART ALTERS myocardial electrophysiological properties (19, 20). This phenomenon is termed "mechanoelectric feedback" (MEF) and has been found in myocardium from many species and preparations ranging from single myocyte to patches of membrane to conscious humans (8, 21, 32). The mechanical changes alter many electrophysiological measures including action potential (AP) duration and amplitude (9), conduction velocity (30, 35), effective refractory period (10, 23), and diastolic potential (31). These changes may be arrhythmogenic by facilitating a variety of mechanisms, including reentry and abnormal automaticity (29). These mechanical changes are all intrinsic (intracardiac) stresses and strains, but they can also be extracorporeal (22), in which case they can be therapeutic by restarting the heart with a precordial thump (7) or even pacing the heart (16). By contrast, it has also been suggested as underlying an extra cardiac phenomenon described as "commotio cordis" or cardiac concussion (17), in which a blunt impact to the front of the chest produces arrhythmic death without structural damage, often in children or young adults during sports injuries (1, 24). It also occurs in adults and can have medicolegal implications (2, 10).

Although there are several studies on global ventricular distension and arrhythmia, there is a paucity of systematic studies of the precise relationship between regional mechanical behavior and electrophysiology in a single ventricular chamber. We set out to study the electrical and mechanical behavior in three regions of the thin-walled right ventricle (RV) during the mechanical perturbation produced by outflow obstruction to mechanically strain the RV while recording pressures and epicardial monophasic APs (MAPs). We chose the RV of lambs in this study for several reasons: 1) the RV is anatomically anterior and directly in line for absorbing the mechanical energy of precordial impact in commotio cordis, and lambs were chosen because there is an increased pediatric susceptibility to arrhythmia in commotio cordis; 2) this model is capable of producing mechanically generated premature ventricular beats (PVB); 3) the RV is thin walled and endoepicardial inhomogeneity is not a major problem; and 4) RV arrhythmia together with abnormal wall motion (dyskinesia), so-called "arrhythmogenic RV dysplasia," has been observed in several studies (25) of the RV in patients with no ischemic heart disease. It would be of interest to see whether the present studies show dyskinesia of the RV wall associated with arrhythmias.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The investigation was performed in accordance with the Home Office Guidance on the Operation of the Animal (Scientific Procedures) (Act 1986, published by Her Majesty's Stationary Office, London, UK).

Surgical preparation. Ten mixed-breed lambs aged 6–12 wk, weighing 18.6 ± 0.6 kg (mean ± SE) were anesthetized with an intramuscular injection of ketamine (5 mg/kg) and xylazine (0.1 mg/kg), and an intravenous bolus of propofol (2 mg/kg). Animals were intubated with a cuffed endotracheal tube and ventilated with an O2-N2O (4:1) mix and halothane (1–1.5%) by using a Manley large animal respirator (Blease Medical Instruments). The skin over the hindlimb was incised and a polyvinyl catheter was advanced through the posterior tibial artery to the descending aorta for pressure measurement and blood sampling. A median sternotomy was performed, the heart was suspended in a pericardial cradle, and the main pulmonary artery (PA) was dissected free of surrounding tissue and snared.

Instrumentation. Tripodal devices, each incorporating three suction electrodes for measurement of MAPs and an integrated strain-gauge system for measurement of regional segment length (SL) (14), were placed on the RV apex outflow and inflow regions. A micromanometer-tipped catheter (Millar Instruments; Houston, TX) was passed along the RV long axis through a purse-string suture in the RV outflow tract for measurement of RV pressure. Aortic pressure was measured with a pressure transducer (Linten Instruments), which was calibrated before each experiment. Hypodermic needles were inserted into the limbs for ECG recording.

Measurement variables. The recording outputs were amplified (Lectromed MT8) and digitized at 1,000 Hz with an analog-to-digital converter (model 1401; Cambridge Electronic Design, Cambridge, UK). Data were stored by using a digital acquisition program (Spike 2; Cambridge Electronic Design) and an analog tape recorder and then analyzed off-line with customized software (Spike 2; Cambridge Electronic Design). Pressure-SL loops in different ventricular regions were constructed by using the customized Spike 2 software (Cambridge Electronic Design).

Protocol. Hemodynamics were monitored for at least 15 min to ensure stability of the experimental preparation. With ventilation held at end expiration for 15-s electromechanical recordings before, during, and after a 10-s PA occlusion (snare, or sometimes manually if the snare was ineffective). Each intervention took 2 min and was duplicated in each lamb.

Analysis. The interval from the onset of the QRS complex to the MAP upstroke was defined as the activation time (AT). MAP amplitude was defined as the difference in mV between the diastolic baseline and crest of the plateau. MAP duration was measured at 25% (MAPD25), 50% (MAPD50), 70% (MAPD70), and 90% (MAPD90) repolarization. Recovery time (RT) was then calculated as AT + MAPD90. Dispersion of MAPD90 was measured as the spread of values in all analyzable MAP recordings, i.e., the difference between the longest and shortest MAPs (MAPD90max – MAPD90min). Dispersion of RT was similarly calculated as the range of RTs (RTmax – RTmin). Only recordings without arrhythmia or those with an isolated simple PVB were analyzed (the PVB and its after beat were not measured). A PVB was characterized by an early ventricular upstroke in the MAP and a short preceding interval, wide or bizarre QRS complex without P wave, and a T wave different from those during sinus beats in ECG. Five-beat samples were averaged before PA occlusion, just after occlusion, and 10 s after release.

Statistical analysis. Results were expressed as means ± SE. A two-way ANOVA was used for comparison of SL and MAP duration before, during, and after occlusion of PA. Linear relation analysis was performed to characterize the relationship between SL and MAP. Analysis was performed by using the SPSS-PC statistical software package. A P value <0.05 indicated statistical significance.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Dispersion in regional SL changes. PA occlusion produced a significant fall in aortic pressure from 92 ± 4 to 43 ± 3 mmHg, and a significant increase in RV end-systolic pressure from 18 ± 2 to 38 ± 3 mmHg (all P < 0.01). Overall, SLs progressively increased as the RV pressure rose, i.e., the Frank-Starling effect (Fig. 1). Whereas the SLs of the three regions were physiologically (chronologically) in phase with ventricular pressure before occlusion, i.e., all shortening during ventricular ejection (see open bar), immediately after occlusion, the SLs increased but were out of phase within the first few beats (see shaded bar) (2 ± 2 beats/occlusion) (Fig. 1). To clearly demonstrate the out-of-phase beats, we constructed regional SL (x)-RV pressure (y) loops. Figure 2 shows three regional loops at baseline (preocclusion) and just postocclusion in a representative PA occlusion (the same as that in Fig. 1). Baseline loops at apex, outflow, and inflow regions were physiologically in phase with pressure and each other (open loops, Fig. 2). That is, all three described roughly anticlockwise rectangular loops. Just postocclusion they were regionally out of phase with pressure and each other (shaded loops, Fig. 2). Segments at outflow and inflow tracts were stretched during isovolumic contraction and shortened during isovolumic relaxation; however, there was almost no segment motion at the apex at any stage of the cardiac cycle. These loops were different in not only the shape but also in direction. Well into the occlusion, the overall SLs increased but with different strains in different regions.



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  		Fig. 1. Right ventricular (RV) pressure and regional wall motion changes in a representative pulmonary artery (PA) occlusion. PA occlusion increased RV pressure and overall regional (i.e., apex, outflow, and inflow) segment lengths (SLs). Whereas the SLs of the three regions were physiologically (chronologically) in phase with ventricular pressure before occlusion (open bar), immediately after occlusion the SLs increased but were out of phase over the first few beats (shaded bar). Both open and shaded bars crossed only part of a beat.

 


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  		Fig. 2. Three regional RV SLs and pressure loops in a representative PA occlusion (the same occlusion as that in Fig. 1). Baseline loops (open loops; the beat crossed by the open bar in Fig. 1) were physiologically in phase. They displayed characteristic anticlockwise, roughly rectangular loops, whereas the loops at the early occlusion (shaded loops; the beat crossed by the filled bar in Fig. 1) showed out of phase. They displayed irregular form loops with different directions; the loop at inflow and outflow were anticlockwise, but that at apex was clockwise.

 

Regional MAPs. Increase of regional SL was linearly and inversely related to the decrease of the corresponding MAPD between 25 and 70% repolarization (Fig. 3). In this particular example, the slope at the apex was the greatest. However, there was no clear regional consistency throughout the preparations, but, in virtually all of the preparations, there were regional differences. Pooling the data shows MAP durations at all levels of repolarization and in all regions, decreased significantly by PA occlusion (all P < 0.01) (Fig. 4). These reductions were greater in MAPD25 than in either MAPD50 or MAPD70. Consequently, the interval MAPD25–50 and MAPD25–70 increased by 11 ± 2 and 21 ± 4 ms at the apex region, by 7 ± 2 and 10 ± 3 ms at the outflow region, and by 4 ± 1 and 14 ± 3 ms at the inflow region (all P < 0.05). They were returned at the baseline levels by the time of the recovery measurements. Heart rate was essentially unchanged, only beginning to increase during the latter half of the occlusion from 101 ± 3 to 102 ± 4 beats/min (P = 0.1).



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  		Fig. 3. Linear relationship between the change in regional SL and monophasic action potential (MAP) duration (MAPD) at 70% repolarization (MAPD70) in a representative PA occlusion. Reductions of MAPD70 were reversed, linearly related to the increase in SL70 in all the three regions, i.e., RV apex (A), outflow (B), and inflow (C) during the occlusion.

 


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  		Fig. 4. Group data of the reductions in MAPD at 25, 50, and 70% repolarization in the 3 RV regions during occlusion of the PA. A: at the apex region, MAPD25 decreased from 259 ± 3 to 226 ± 2 ms, MAPD50 decreased from 285 ± 2 to 263 ± 2 ms, and MAPD70 decreased from 326 ± 3 to 307 ± 3 ms. B: at the outflow region, MAPD25 decreased from 245 ± 3 to 220 ± 3 ms, MAPD50 decreased from 258 ± 3to237 ± 3 ms, and MAPD70 decreased from 308 ± 5 to 291 ± 4 ms. C: at the inflow region, MAPD25 decreased from 298 ± 4 to 270 ± 4 ms, MAPD50 decreased from 305 ± 4 to 282 ± 3 ms, and MAPD70 decreased from 332 ± 4 to 316 ± 4 ms. They were returned to baseline levels by the time of the recovery measurements.

 

Early afterdepolarization. Early afterdepolarization (EAD) was common during PA occlusion. All but 2 of 20 PA occlusions induced EADs. These EADs did not necessarily appear in each MAP recording but did so in one or more in a total of nine MAP recordings in each PA occlusion. Their amplitudes and durations were often different in the three regions (Fig. 5). Some large EADs had sufficient amplitudes to lengthen MAPD90. By contrast, if there was no big EAD, MAPD90 was reduced significantly. We measured three MAP electrodes in each tripod in 10 PA occlusions that did not show arrhythmia or only contained simple isolated RV premature beats. At the peak of occlusion, MAPD90 was shorten in 11 but lengthened in 19 MAP recordings at apex region (Fig. 6A), shortened in 15 but lengthened in 15 at outflow region (Fig. 6B), and shortened in 9 but lengthened in 21 MAP at inflow region (Fig. 6C).



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  		Fig. 5. Simultaneous recording of 5 MAPs at 3 regions in the RV, a surface ECG, RV pressure, and regional SL during occlusion of the PA. PA occlusion increased RV pressure and overall regional SLs, resulting in early afterdepolarizations (EADs) and precipitated premature ventricular beats (*). The EAD was seen in MAP recordings of inflow 2 and outflows 1 and 2 but was not seen in the rest. In addition, the size of these EADs were different among these recordings. MAP1 and MAP2 were named arbitrarily for one of three MAP recordings in a region.

 


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  		Fig. 6. Group data of the alternations of MAPD90 repolarization in 3 regions of the RV during pulmonary arterial occlusion. A: at the apex region, MAPD90 was prolonged in 11 of 30 MAP recordings from 346 ± 3 to 400 ± 7 ms, whereas MAPD90 was reduced in the remainder from 346 ± 3 to 330 ± 3 ms (P < 0.01). B: at the outflow region, MAPD90 was prolonged in 15 of 30 MAP recordings from 301 ± 4 to 356 ± 4 ms (P < 0.01), whereas MAPD90 was reduced in the remainder from 341 ± 4 to 335 ± 3 ms (P < 0.01). C: at the inflow region, MAPD90 was prolonged in 9 of 30 MAP recordings from 350 ± 5 to 370 ± 7 ms (P < 0.01), whereas MAPD90 was reduced in the remainder from 343 ± 2 to 329 ± 2 ms (P < 0.01).

 

Dispersion of repolarization and RT. The foregoing clearly indicate a mechanically induced regional dispersion in repolarization. This was particularly at the later stages of repolarization. The occurrence, amplitude, and duration of mechanically induced EADs could vary from region to region. PA occlusion dramatically increased the dispersion of MAPD90 from 40 ± 4 to 83 ± 6 ms (Fig. 7). It is important that this was manifested in a dispersion of RT from 48 ± 5 to 91 ± 8 ms (all P < 0.05), whereas neither AT (12.5 ± 3 vs. 14 ± 4 ms, P = 0.9) or the dispersion of AT (7.9 ± 1.6 vs. 8.5 ± 1.5 ms, P = 0.5) was changed.



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  		Fig. 7. Example of 9 simultaneous MAP recordings during a representative PA occlusion. MAPD90 and recovery time (RT) are indicated by numerals for each action potential. At the peak of occlusion, dispersion of MAPD90 and recovery time (B) were significantly larger than those at baseline (A), which were mainly due to early afterdepolarization. C: after release of occlusion, the dispersion returned to baseline.

 

Mechanically induced arrhythmias. The foregoing mechanically induced electrophysiological changes are proarrhythmic. Dispersion in RT could promote regional current flow and also reentry mechanisms. EADs increased their amplitude and duration after the increase of RV pressure and regional SL during PA occlusion (see Fig. 5), and the increase of the amplitude of EAD was linearly and positively related to the increase of the corresponding regional SL (Fig. 8). These EADs were strongly associated with RV premature beats. Seventeen of a total of 20 PA occlusions (85%) eventually (i.e., sometimes toward the latter part of the PA occlusion) gave rise to a variety of RV arrhythmias: PVBs (7), bigemini (5), salvos (3), and ventricular tachycardia (2).



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  		Fig. 8. Graph of SL plotted against the amplitude of early afterdepolarisation (EAD) in a representative pulmonary arterial occlusion. As the SL was stretched, amplitude of EAD was increased (r = 0.96, n = 20, P < 0.01). Inset: derivation of measurements. Amplitude of EAD was measured from the diastolic potential preceding the pulmonary arterial occlusion to the maximum transient depolarization. SL was measured at the time of EAD occurrence.

 


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Increased mechanical loading of the heart is often associated with arrhythmias (8, 20, 29, 32), the so-called "stretch-induced arrhythmias." This often occurs in some clinical conditions. Although the associations are strong, they are indirect. One relatively undisputed mechanical cause of arrhythmia is during heart concussion, or commotio cordis. Because the RV is anterior, we proposed that a RV regional mechanical distortion produced sudden arrhythmic death and investigated this hypothesis in the RV of anesthetized lambs. In these experiments, PA occlusion stretched the RV and raised intraventricular pressure. The mechanical changes resulted in an alteration of repolarization and PVB. PVB often occurred in the presence of an EAD on the falling phase of MAP. This depolarization was frequently seen to progressively increase in size in the period preceding PVB. This is one of the few studies in which regional wall motion was monitored in multiple areas at the same time as MAP from these areas. PA occlusion increased SL and produced inhomogeneous contraction patterns in different regions, i.e., mechanical dispersion. It is important that electrophysiological dispersion was also evident. The combination of electromechanical events was associated with arrhythmia, including paired APs or bigemini.

The RV is an irregular crescent-shaped chamber and its inflow and outflow tracts differ with respect to origin, morphology, innervation, and function (27, 28). Changes in enddiastolic pressure of filling volume are not uniformly distributed within the ventricular lumen (26), and, as a result, local contractile function of myocardial fibers would vary at different locations in the ventricular wall. The different wall motions were enhanced by some interventions. Zwissler et al. (36) found out-of-phase movement of inflow and outflow tracts of canine RV after acute pulmonary microembolization. Normalized end-diastolic SL increased in the inflow tract but simultaneously decreased in the outflow tract. Chuong et al. (5) found that PA occlusion only deformed the outflow region, with no effect in either inflow or midventricular regions. Greyson et al. (11) observed an immediate RV regional dysfunction after brief RV pressure overload. We found out-of-phase beats immediately after PA occlusion, which was similar to the observation of Zwissler et al. (36). PA occlusion produced mechanical disturbances within a given region, and among regions in RV. This result is consistent with that of Waldman et al. (33, 34) who showed that three principal strain components at a given region of the left ventricle (LV) did not always align themselves with the local fiber direction.

The inhomogeneous contraction pattern and increased RV regional SLs during PA occlusion were converted into different electrophysiological alterations by MEF. The increase of regional SL was found to be linearly and inversely related to the decrease of the corresponding MAPD25–70. Characteristically, PA occlusion shortened MAP duration between phases 2 and 3 of repolarization (MAPD50), but increased duration at MAPD90, the latter often taking the form of an EAD. Heart rate did not increase significantly during these short (10 s) PA occlusions, in keeping with an effect unrelated to extrinsic autonomic reflexes. These observations are consistent with other studies on the LV (9, 21, 30, 31) and indicate that MEF also exists in the RV. Similar alterations in response to stretch in different parts of heart indicated that the same mechanisms underlie this response. One potential mechanism of MEF is through activation of stretch-sensitive or activated channels, which have a marked increase in opening probability in response to stretch, with a reversal potential of approximately –30 mV (6, 12). If the channel is opened during the plateau phase of AP, an outward current is activated, tending to bring the membrane potential toward the reversal potential of the channel, abbreviating the plateau phase of AP. Conversely, activation of the channel later during repolarization would activate an inward current that would tend to depolarize the myocardium, prolonging phase 3 depolarization and increasing the potential for afterdepolarizations (13).

EAD was common during PA occlusion and may increase MAPD90 if their amplitude and duration are large enough. Whereas MAPD90 was increased in some MAP recordings due to the large EAD during occlusion, MAPD90 in the remaining recordings was shortened. Thus the dispersion of MAPD90 during occlusion was significantly larger than that during baseline recordings. Therefore, although the dispersion of AT did not change significantly, the dispersion of RT increased significantly during occlusion. This is potentially arrhythmogenic. For example, when the dispersion of repolarization becomes critical, impulse propagation through the area with a short MAP duration (refractory period) could encounter a conduction block in the area with a long MAP duration and create conditions favorable for reentry (18).

Mechanically induced EAD in MAP recording was argued as the result of motion artifact, because mechanical changes in the epicardium may alter the tissue-electrode interface to produce electrical artifact. However, the monophasic EADs may be real, because consistent, mechanically induced EADs have been observed with microelectrodes (9, 19, 30, 31). The association between EADs and apparent threshold depolarizations is a strong argument for the EADs being real and not artifact (9, 30), although the strength of the association needs to be established. Our recorded EADs are unlikely to be movement artifact because they are accompanied by PVBs whose APs had reduced amplitude as is expected when the membrane is partially depolarized by the EAD. Moreover, the observation that both EAD and PVB were eliminated or reduced by pacing from the right atrium in these lambs (4) reinforced the notion that our recorded EADs were real.

The appearance of EAD was strongly associated with the mechanically induced arrhythmias. This observation is consistent with the studies in LV (9, 30, 31). Franz et al. (9) observed PVBs in 18 of 23 episodes of aortic occlusion and EADs were present in 82% of these cases. In our study, all arrhythmic PA occlusions contained EADs. The reason for the more frequent observation of arrhythmic EADs in our study might be that we monitored nine MAPs over three different regions of RV, whereas Franz et al. (9) only recorded a single MAP. In our study, EAD was not observed in only a few MAP recordings (Fig. 5). EAD may precipitate arrhythmia in two ways: 1) if the magnitude of EAD exceeds a threshold excitation, it may directly induce premature beats causing a type of trigger activity; and 2) if one area has a marked EAD and a prolonged MAPD90 and therefore a refractory period while the other area has a reduced MAPD90 and a refractory period, this could increase electrophysiological dispersion that favors the development of reentry and/or predisposes activation of abnormal current flow between the two areas (15).

In conclusion, PA occlusion results in enhanced inhomogeneous RV regional wall motion, producing arrhythmogenic changes in electrophysiology, i.e., mainly MAP dispersion and EADs. These mechanically induced electrical changes could explain some clinical sudden deaths. Cardiac concussion in commotio cordis probably involves the anterior RV but is suggested to involve the anterior LV, especially the apex as well. Nonetheless, our study is a good model of pulmonary embolism-induced hypertension. Interaction among dispersion of regional wall motion, repolarization, and arrhythmia is another manifestation of the importance of MEF in arrhythmogenesis.


   ACKNOWLEDGMENTS
 
GRANTS

This study was supported by the British Heart Foundation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. L. Chen, Dept. of Physiology, Block 9, St. Thomas Campus, King's College, Univ. of London, Lambeth Palace Rd., London SE1 7BH, UK (E-mail: ronnie.chen{at}kcl.ac.uk).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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