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European Heart Journal Advance Access originally published online on March 21, 2007
European Heart Journal 2007 28(7):872-879; doi:10.1093/eurheartj/ehm030
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Conversion of post-systolic wall thickening into ejectional thickening by selective heart rate reduction during myocardial stunning

Laurence Lucats1,2,3, Bijan Ghaleh1,2,3,4, Xavier Monnet1,2,3, Patrice Colin1,2,3, Alain Bizé1,2,3 and Alain Berdeaux1,2,3,4,*

1 INSERM, Unité 841, Créteil, F-94010, France
2 Laboratoire de Pharmacologie, INSERM U 841, Faculté de Médecine, Faculté de Médecine, IFR 10, Université Paris 12, 8, rue du Général Sarrail, Créteil F-94010, France
3 Ecole Nationale Vétérinaire d'Alfort, INSERM U 841, Maisons-Alfort F-94700, France
4 AP-HP, Groupe Mondor-Chenevier, Fédération de Cardiologie, Créteil F-94000, France

Received 3 October 2006; revised 20 February 2007; accepted 23 February 2007; online publish-ahead-of-print 21 March 2007.

* Corresponding author. Tel: +33 1 49 81 36 51; fax: +33 1 49 98 17 77. E-mail address: alain.berdeaux{at}creteil.inserm.fr


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims: Post-systolic wall thickening (PSWT) occurs after aortic valve closure. This waste of thickening does not participate in ejection. PSWT increases with myocardial ischaemia and stunning but the effects of anti-anginal drugs on PSWT during myocardial dysfunction remain unknown. The effects of two heart rate reducing agents, i.e. the ß-blocker atenolol and the selective If current inhibitor ivabradine, were compared on PSWT.

Methods and results: Coronary stenosis was calibrated in six conscious instrumented dogs to suppress increase in coronary blood flow during a 10 min treadmill exercise to induce myocardial stunning. After exercise completion, stenosis was relieved and saline, atenolol or ivabradine (both at 1 mg/kg iv) were administered. For similar heart rate reduction, ivabradine attenuated stunning, whereas atenolol further depressed systolic wall thickening. PSWT to total wall thickening ratio was significantly decreased by ivabradine vs. saline, whereas total wall thickening was similar. Thus, ivabradine devoted a greater part of thickening to systole by converting PSWT into ejectional thickening. In contrast, atenolol failed to reduce PSWT vs. saline. Atrial pacing abolished the effects of ivabradine but not those of atenolol.

Conclusion: Selective heart rate reduction with ivabradine converts PSWT into ejectional thickening but not with atenolol secondary to its negative inotropism.

Key Words: Myocardial stunning • Post-systolic wall thickening • Heart rate • If- channel • ß-blockade


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Reducing immediate post-ischaemic contractile dysfunction is a relevant issue in the management of heart disease. Besides depressed systolic performance, diastolic wall motion abnormalities take part in post-ischaemic contractile mismatch. Among those diastolic alterations, post-systolic wall thickening (PSWT) or shortening is a paradoxical contraction that occurs during diastole after aortic valve closure.1–6 Post-systolic wall motion has been described to occur in the normal heart7,8 and is increased during myocardial ischaemia9–13 as well as during myocardial stunning.14–17 This paradoxical wall motion represents a waste of thickening, that impedes early relaxation18,19 and its increase during ischaemia leads to abnormal ventricular filling.11,20 Post-systolic wall motion is now assessed in humans with the clinical use of echocardiographic tissue Doppler imaging and therefore it has gained interest for quantification of myocardial function.9,10,12,21 Consequently, measurement of post-systolic wall motion might provide additional valuable information concerning myocardial post-ischaemic performance.

In this context, heart rate reduction appears to represent a major goal to achieve improvement of post-ischaemic myocardial wall motion. Indeed, it was suggested that heart rate reduction is a major mechanism in which ß-blockers are effective for restoration of contractile function in a model of left ventricular (LV) dysfunction but these drugs also reduce both contraction and relaxation of the myocardium.22 Ivabradine, a selective inhibitor of the cardiac pacemaker current If, shares a common mechanism leading to its beneficial effect, i.e. it reduces heart rate without exhibiting inotropic or lusitropic effects.23–28 Interestingly, selective heart rate reduction has been demonstrated to improve cardiac function during heart failure.29

Accordingly, the goal of this study was to determine the consequence of heart rate reduction on PSWT by comparing the effects of atenolol and ivabradine during myocardial stunning. For this purpose, we used an experimental model of stunning in which ischaemia resulted from the combination of a treadmill exercise and a partial coronary artery stenosis in conscious dogs.30,31 Administration of saline, atenolol, or ivabradine was started at completion of exercise-induced ischaemia and their effects on post-ischaemic dysfunction were investigated throughout the 6 h of the recovery period, i.e. in the stunned myocardium.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
The animal instrumentation was approved by the veterinary inspection and the ensuing experiments were conducted in accordance with the recommendations of the French Ministry of Agriculture.

Surgical preparation
The present data were derived from the recordings of six chronically instrumented dogs (22–29 kg) included in a previous study.31 Eight dogs were scheduled for surgery, and in all of them, surgery was successful. At the end, six dogs underwent the complete protocol as signals measured in two animals were not suitable for proper systolic and PSWT analyses. After left thoracotomy, fluid-filled catheters were implanted in the descending thoracic aorta and in the left atrium for measurement of blood pressure. A Silastic catheter was introduced into the pulmonary artery for drug administration. A solid-state micromanometer (Konigsberg Instruments, Pasadena, CA, USA) was introduced into the LV. A transonic flow probe and a pneumatic occluder were implanted on the circumflex coronary artery. Two pairs of ultrasonic crystals were placed within the distribution of the circumflex coronary artery (ischaemic zone) and of the left anterior descending coronary artery (non-ischaemic zone) for LV wall thickening measurement. Electrodes were fixed on the left atrial appendage for pacing. All catheters and wires were exteriorized between the scapulae. Cefazolin (1 g, iv) and gentamycin (40 mg, iv) were administered before and during the first week after surgery. Post-operative analgesia was provided with morphine.

Haemodynamic measurements
Aortic and left atrial pressures were measured with a Statham P23ID strain gauge transducer (Gould-Nicolet, Courtaboeuf, France). Because it was measured by a hydraulic technique, aortic pressure could not be accurately recorded during exercise. LV pressure (LVP) was measured using the Konigsberg gauge and LV dP/dt was computed from the LVP signal. The LVP augmentation index was calculated as maximal LVP minus LVP at the first shoulder during ejection divided by (maximal LVP minus end-diastolic LVP). Circumflex coronary artery blood flow was measured with a transit-time flowmeter (Transonic T206, Transonic Systems, Ithaca, NY, USA). Data were recorded and analysed using the data acquisition software Notocord-HEM (Notocord System, Croissy-sur-Seine, France).

Measurements of regional function
Wall thicknesses were obtained by using an ultrasonic transit-time dimension gauge (Module 201, System 6, Triton Technology Inc., San Diego, CA, USA). To determine wall thickening, end-diastolic wall thickness was measured at the initiation of the upstroke of LVP tracing and the end-systolic wall thickness was measured within 20 ms before peak negative LV dP/dt.6

Systolic wall thickening was defined as the difference between end-diastolic and end-systolic wall-thicknesses, i.e. the wall thickening (expressed in mm) that occurs during the ejection period.

Maximal wall thickness was defined as the maximal distance between crystals, measured after aortic valve closure. PSWT was defined as the maximal minus end-systolic wall thicknesses, i.e. the wall thickening that occurs after the ejection period.

A regional myocardial work index was calculated as the sum of the instantaneous LVP–wall thickness product over the time of the cardiac cycle, according to Schulz et al.32 In addition, the part of work corresponding to PSWT was also calculated.

Calculation of isovolumic relaxation time constant ({tau})
As previously described,24 the isovolumic relaxation period was defined as the period elapsed from the time at the peak of negative LV dP/dt to the time when LVP fell to a value of 5 mmHg above LV end-diastolic pressure of the following beat. Using a best-fit monoexponential decay model with non-zero asymptote, the LV relaxation time constant ({tau}) was calculated by the Levenberg–Marquart non-linear regression algorithm to obtain the least squares best-fit curve to the measured LVP.

Experimental protocol
Three weeks after surgery, dogs were installed on a treadmill and baseline parameters were recorded. A partial stenosis of the left circumflex coronary artery was then performed using the pneumatic occluder without altering LV posterior wall thickening at rest. A treadmill exercise (10 min duration, 10 km/h, 13% slope) was then started. The stenosis was maintained during exercise in order to keep mean coronary blood flow at its corresponding baseline value. The occluder was deflated at the end of exercise. All parameters were continuously recorded at baseline, during exercise, and at selected intervals during the first 6 h of the recovery period.

Administration of saline, atenolol, or ivabradine (Laboratoires Servier, Neuilly-sur-Seine, France) was started immediately after the end of exercise, i.e. after ischaemia. This experimental design was set up to investigate the direct effects of heart rate reduction on the already stunned myocardium, thus independently from the potential anti-ischaemic properties of the drugs. Ivabradine was administered as an iv bolus (1 mg/kg over 5 min) followed by a continuous iv infusion (0.5 mg/kg/h) for 6 h using an automatic programmable pump which was fixed on the back of the animal. We previously demonstrated that this regimen of administration of the drug induces a significant heart rate reduction that remains stable during the infusion period.33 Atenolol was administered as an iv bolus (1 mg/kg over 5 min).

Each recording made at rest before exercise and during the recovery period was performed both at spontaneous heart rate and during a 1 min episode of atrial pacing at 150 b.p.m. in order to individualize the effects of heart rate reduction per se. For each animal, three experimental sessions (saline, ivabradine, and atenolol) were performed in a random order using a three-element permutation table with at least a 5-day interval.

Statistical analysis
Data are reported as mean ± SEM. The experiments were conducted as a design in which each dog received all three treatments in a randomized order. Data during stunning were analysed using two-way ANOVA for repeated measures (repeated times nested in treatments) with treatment effect, time effect, and interaction time-treatment (unstructured covariance matrix, time, and treatment as fixed effects). One-way ANOVA was performed to analyse baseline values. The Fisher-Snedecor test was used to test the significance of analysis of variance. We considered that all calculated parameters are independent even when they were measured with the same device. Significance was accepted at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Haemodynamics
As shown in Table 1, haemodynamic values at baseline were not significantly different among treatments. As drugs were administered during the recovery period, heart rate values were similar during exercise among the saline, atenolol, and ivabradine experiments. During recovery, time–treatment interaction was not significant and the reduction of heart rate was similar with atenolol and ivabradine when compared with saline. Concerning the LVP augmentation index, the time–treatment interaction was significant.


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  		Table 1 Hemodynamics

 
Systolic wall thickening
As shown in Figure 1 and Table 2, systolic wall thickening in the ischaemic zone was significantly greater under ivabradine than saline during the recovery period (e.g. 2.0 ± 0.4 and 1.7 ± 0.3 mm, respectively at 1 h), whereas it was depressed under atenolol at spontaneous heart rate (e.g. 1.2 ± 0.2 mm at 1 h). Values in the non-ischaemic zone are shown in Table 3.


Figure 1
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  		Figure 1 Evolution of systolic wall thickening (A) and post-systolic wall thickening (B) in the ischaemic zone measured at baseline (B), during exercise (Ex), and during the recovery period when saline, atenolol, or ivabradine was administered at completion of treadmill exercise. All measurements were made at spontaneous heart rate. *P < 0.001: time—treatment interaction. **P = 0.001: time—treatment interaction.

 

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  		Table 2 Regional function in the ischaemic zone

 

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  		Table 3 Regional function in the non-ischaemic zone

 
Post-systolic wall thickening
As shown in Table 2 and Figure 1, at baseline, PSWT in the posterior wall (ischaemic zone) was similar among treatments. During exercise-induced ischaemia, PSWT increased to the same extent in all exercises. During recovery, differential effects among treatments were detected (time–treatment interaction was significant). As illustrated in Figure 1, ivabradine reduced PSWT during stunning when compared with saline (e.g. at 1 h, 0.18 ± 0.10 vs. 0.48 ± 0.17 mm, respectively) contrasting with atenolol.

As shown in Table 2, differential effects among treatments on PSWT and systolic wall thickening were detected (time–treatment interactions were significant). Although PSWT and systolic wall thickening were different during recovery between ivabradine and saline, total wall thickening did not differ. In contrast, atenolol reduced total wall thickening when compared with saline (e.g. at 1 h, 1.6 ± 0.2 vs. 2.2 ± 0.2 mm, for atenolol and saline, respectively).

As illustrated in Figure 2, analysis of the distribution of wall thickening between ejection and post-systolic time revealed that for a similar total wall thickening under saline and ivabradine, PSWT to total wall thickening ratio was reduced by ivabradine vs. saline, i.e. a greater part of thickening was devoted to ejection and conversely a lower part of thickening was wasted after aortic valve closure. In contrast, atenolol reduced total wall thickening vs. saline, without change in the postsystolic to total wall thickening ratio as compared to saline.


Figure 2
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  		Figure 2 Representative waveforms showing the evolution of left ventricular pressure and myocardial wall thickness recorded in the ischaemic zone at spontaneous heart rate during a single beat recorded from a stunned myocardium at 1 h of reperfusion. These examples were recorded from the same dog during the three sequences: saline (solid line), atenolol (widely dotted line), and ivabradine (tightly dotted line). Systolic and post-systolic distributions of wall thickening are shown in bar graphs.

 
In the non-ischaemic anterior wall, PSWT was not observed and was invariably equal to zero.

Work index
As shown in Table 2, differential effects among treatments on total, systolic, and post-systolic work indexes were detected (time–treatment interactions were significant). Total work index with saline and ivabradine was similar, although it was reduced with atenolol (e.g. at 2 h of reperfusion, 260 ± 55, 286 ± 16 and 156 ± 24 mm mmHg, respectively). This index for post-systole was reduced by ivabradine when compared with saline (e.g. at 2 h of reperfusion, 3 ± 1 vs. 12 ± 4 mm mmHg) but it was not altered by atenolol (e.g. at 2 h of reperfusion, 9 ± 5 mm mmHg). Conversely, the index for systole was increased with ivabradine when compared with saline (e.g. at 2 h of reperfusion, 283 ± 16 vs. 248 ± 52 mm mmHg, respectively). With atenolol, systolic index was decreased when compared with saline (e.g. at 2 h of reperfusion, 146 ± 23 vs. 248 ± 52 mm mmHg, respectively). Ejection time was not altered by ivabradine when compared with saline (e.g. at 2 h of reperfusion, 146 ± 9 and 147 ± 5 ms, respectively) but was increased by atenolol (e.g. at 2 h of reperfusion, 161 ± 5 ms).

Heart rate correction with atrial pacing
All the effects of ivabradine mentioned above in the stunned myocardium, i.e. increased systolic wall thickening as well as reduced PSWT, were abolished by atrial pacing as illustrated in Figure 3. In contrast, atenolol during atrial pacing still decreased systolic wall thickening while PSWT remained similar to saline.


Figure 3
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  		Figure 3 Evolution of systolic wall thickening (A) and post-systolic wall thickening (B) in the ischaemic zone measured at baseline (B), during exercise (Ex), and during the recovery period when saline, atenolol, or ivabradine was administered at completion of treadmill exercise. All measurements were made at controlled heart rate (150 b.p.m.) by atrial pacing.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
The post-ischaemic myocardium exhibits reduced regional contractile function and increases paradoxical wall motion after aortic valve closure, i.e. post-systolic wall motion. Selective heart rate reduction with ivabradine improved regional contractile function, i.e. it reduced myocardial stunning. The present study shows that this beneficial property is not related to a positive inotropic effect of the drug but rather due to an improved use of myocardial thickening, i.e. it is related to a conversion of PSWT to an efficient ejectional thickening. With ivabradine, a greater part of wall thickening is devoted to ejection and a lower part of thickening is wasted. This pharmacological approach used for reducing heart rate appears also to be of major interest as, for a similar heart rate reduction, ivabradine and atenolol exhibited two different contractile patterns. Ivabradine, an agent devoid of inotropic and lusitropic effects, improves ejectional wall thickening and reduces PSWT, whereas atenolol worsens the post-ischaemic function during stunning due to its negative inotropism and is unable to reduce PSWT.

In this study, the combination of a coronary stenosis and exercise induced myocardial ischaemia and subsequent stunning. Stunned myocardium is characterized by both depressed systolic wall thickening and exacerbated PSWT.7,14,34 Ivabradine, administered at completion of exercise, significantly reduced heart rate, enhanced systolic wall thickening, and decreased PSWT concomitantly during stunning. Total wall thickening was similar between ivabradine and saline but the respective contribution of systolic and PSWT was modified by ivabradine when compared with saline. Indeed, the PSWT to total wall thickening ratio was significantly decreased by ivabradine during recovery. Therefore, a greater part of thickening was devoted to ejection and a lower part of thickening was wasted after aortic valve closure. One could ask whether the conversion observed is not just the results of a time-effect. In fact, reducing heart rate might prolong systolic time, i.e. the time of thickening, and modify also the loading sequence. This is unlikely as ejection time was not changed by ivabradine, although PSWT was reduced when compared with saline. In addition, atenolol is known to significantly increase the ejection period and to modify the loading sequence,24 but in our conditions, PSWT as well as the distribution between PSWT and systolic wall thickening with atenolol remained rather close as that observed under saline. Finally, differences in PSWT between ivabradine and atenolol could also be attributed to differences in arterial wave reflection35 as evaluated by the LVP augmentation index. However, the distribution between PSWT and systolic wall thickening under atenolol was rather close to that observed under saline, although atenolol increases the augmentation index and wall stress during the second half of ejection. Nevertheless, we cannot definitely rule out that increased late systolic load could facilitate PSWT.

These beneficial effects observed with ivabradine on regional myocardial function can be interpreted as a conversion of PSWT into ejectional wall thickening since total work index did not change when compared with saline. Such a mechanism is likely because PSWT is active when it occurs with systolic hypokinesia.17 This further supports the concept that reduced contractile function during myocardial stunning does not only represent hypokinesis but rather dyskinesis with wasted thickening during diastole. It is important to emphasize that ivabradine did not increase systolic wall thickening by requiring additive contractility through an inotropic effect but it used already existing wall thickening by transferring part of it from post-systole, i.e. thickening during diastole, to the ejection period. Thus, we are not just facing the absence of a negative inotropic intervention with ivabradine, but lowering heart rate with ivabradine allows a beneficial reorganization of regional function. For a similar total work, a greater part of it was devoted to ejection. Conversely, for similar heart rate reduction as with ivabradine, atenolol did not protect the heart against the waste of thickening as the PSWT to total wall thickening ratio was not reduced when compared with saline. Atenolol further aggravated myocardial stunning because it depressed systolic wall thickening. Although not demonstrated in the present study, it is tempting to speculate that heart rate reduction improves the diastolic time for LV filling, increases the end-diastolic LV volume, and finally enhances the LV regional function through a Frank–Starling mechanism. Therefore, this effect could contribute to reduce the non-uniformity of the LV, i.e. more thickening occurs during the ejection period and PSWT is reduced. Atenolol also increases the diastolic time but its negative inotropic effect impedes such a Frank–Starling mechanism secondary to heart rate reduction. Indeed, the effects of atenolol persisted with heart rate correction during atrial pacing, demonstrating that these effects were not related to heart rate reduction but rather to its negative inotropic properties. In contrast, the effects of ivabradine vanished with heart rate correction during atrial pacing demonstrating that the conversion of PSWT into ejectional wall motion was due to heart rate reduction.

Besides the improvement of systolic function, reduction of PSWT thus appears to be another goal to achieve in the management of post-ischaemic myocardial dysfunction. Indeed, this paradoxical wall motion impedes ventricular relaxation, which is known to be altered in clinical situations with depressed myocardial performances. In this context of post-ischaemic myocardial dysfunction, reducing heart rate is to date an important goal to achieve. However, the present study highlights that, depending on the pharmacological strategy used to reduce heart rate, this approach can be beneficial or surprisingly detrimental. Although not directly demonstrated, selective heart rate reduction with ivabradine appears to improve ventricular efficiency of the post-ischaemic myocardium. Similarly, selective heart rate reduction allows to reduce myocardial oxygen consumption33 and also to improve wall thickening during ejection. It also preserves ventricular relaxation24 as the paradoxical wall thickening that occurs during early diastole is reduced and, importantly, is converted into ejectional wall thickening. ß-Blockade also allows to reduce myocardial oxygen consumption but this beneficial effect is mitigated as atenolol did not prevent PSWT and is known to alter myocardial inotropy and ventricular relaxation.24

In conclusion, reducing heart rate of the stunned myocardium improves systolic wall thickening by converting PSWT into ejectional function. Such effect can be achieved independently from any positive inotropic effect with selective heart rate reducing agents, which are devoid of intrinsic inotropic properties. In contrast, similar heart rate reduction with ß-blockade counteracts the beneficial effect of heart rate reduction as a consequence of its negative inotropic effect. Therefore, interpretation of PSWT as a tool to analyse myocardial performance in the clinical setting needs to take into account not only the pathophysiological situation of the heart but also the effect of drugs administered.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
L.L. was a recipient from the Académie Nationale de Médecine. This study was supported by the Institut de Recherche International Servier (Courbevoie, France). The authors are greatly indebted to F. Malhberg, P. Gluais, M. Bouly, R. Bos, J.P. Mamet, G. Lerebours, and J.P. Vilaine as well as J.X. Mazoit for fruitful discussions during the elaboration of the manuscript.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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