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Eur J Cardiothorac Surg 2003;24:912-919
© 2003 Elsevier Science NL
Haemodynamic Research Center (HemoLiege), University of Liege, Liege, Belgium
Received 18 April 2003; received in revised form 27 August 2003; accepted 16 September 2003.
* Corresponding author. Department of Medicine, Medical Intensive Care Unit, University Hospital of Liege, CHU Sart Tilman (B35), 4000 Liege, Belgium. Tel.: +32-4-3667191; fax: +32-4-3667723
e-mail: b.lambermont{at}chu.ulg.ac.be
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Key Words: Autonomic nervous system • Baroreflex • Hemodynamics • Left ventricular function
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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One example of this problem is how the left ventricle (LV) reacts to an increase in afterload. In an isolated heart preparation, it is possible to fix LV end-diastolic volume and to impose several afterload conditions [1]. However, in the intact organism, any afterload augmentation induces a recruitment of the preload reserve mechanism, such that LV end-diastolic volume secondarily increases [2]. Because a progressive augmentation in myofiber length increases cardiac performance secondary to an heterometric adaptation, the integrated response to increased afterload of an intact organism may indeed differ from the response observed in an isolated heart preparation.
Therefore, the aim of this experimental study was to evaluate, in vivo, the LV response to an afterload augmentation, obtained by means of a proximal aortic banding. In addition, in order to assess the role of baroreflex intervention under these circumstances, we compared the effects of the aortic banding on the intact cardio-vascular system, and when the baroreflex mechanism was inhibited by hexamethonium and atropine infusion.
Chamber properties and energetics were analyzed with the pressure–volume relationship, and LV afterload was assessed using a four-element windkessel model.
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2. Methods |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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All animals were premedicated with intramuscular administration of ketamine (20 mg/kg) and diazepam (1 mg/kg). Anesthesia was then induced and maintained by a continuous infusion of sufentanil (0.5 µg kg-1 h-1) and sodium pentobarbital (3 mg kg-1 h-1). Spontaneous movements were prevented by pancuronium bromide (0.1 mg/kg). After endotracheal intubation through a cervical tracheostomy, the pigs were connected to a volume-cycled ventilator (Evita 2, Dräger, Lübeck, Germany) set to deliver a tidal volume of 10 ml/kg at a respiratory rate of 20/min. End-tidal CO2 measurements (Capnomac, Datex, Helsinki, Finland) were used to monitor the adequacy of ventilation. Respiratory settings were adjusted to maintain end-tidal CO2 between 30 and 35 mmHg. Arterial oxygen saturation was monitored closely and maintained above 95% by adjusting the FIO2 as necessary. Temperature was maintained at 37 °C by means of a heating blanket. A standard lead electrocardiogram was used for the monitoring of heart rate (HR).
The chest was opened with a mid-sternotomy, the pericardium was incised and sutured to the chest wall to form a cradle for the heart, and the root of the aorta was dissected clear of adherent fat and connective tissue. A 7-F, 12-electrode (8-mm interelectrode distance) conductance micromanometer-tipped catheter (CD Leycom, Zoetermeer, The Netherlands) was inserted through the right carotid artery and advanced into the left ventricle. A micromanometer-tipped catheter (Sentron pressure measuring catheter, Cordis, Miami, FL, USA) was inserted through the right femoral artery and advanced into the ascending aorta. A 14-mm diameter perivascular flow probe (Transonic Systems Inc., Ithaca, NY, USA) was closely adjusted around the aorta 2 cm downstream to the aortic valve. The micromanometer-tipped catheter was manipulated so that the pressure sensor was positioned just distal to the flow probe. Also, a second micromanometer-tipped catheter was advanced in the descending thoracic aorta through the left femoral artery, for measurement of distal aortic pressure. Right atrial pressure was measured with a micromanometer-tipped catheter inserted into the cavity through the superior vena cava. A 6-F Fogarty balloon catheter (Baxter Healthcare Corp., Oakland, CA, USA) was advanced into the inferior vena cava through a right femoral venotomy. Inflation of this balloon produced a gradual leftward shift in pressure–volume loops by reducing venous return. Thrombus formation along the catheters was prevented by administration of 100 U/kg of heparin sodium intravenously just before the insertion. The surgical preparation is illustrated in Fig. 1 .
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After this second set of hemodynamic measures, aortic banding was removed. After 30 min of rest, hemodynamic measurements were obtained (Basal 2).
The autonomic nervous system was then inhibited by atropine sulfate (intravenous injection of 0.2 mg/kg, followed by infusion at 1 mg kg-1 h-1) and hexamethonium chloride (intravenous injection of 6 mg/kg, followed by infusion at 3 mg kg-1 h-1). When mean aortic pressure and HR were stabilized, another set of hemodynamic measures was obtained (Hexa).
Finally, the aortic banding was then reinstalled and, after another resting period of 30 min, the measurements were repeated (Band Hexa). Care was taken as to always reinstall the banding at the same location on the ascending aorta in both experimental situations. Furthermore, a mark was drawn on the banding to ensure the exact same degree of constriction, with and without autonomous system blockade.
For each animal, three sets of measures were obtained at each state. Blood samples were collected for hematocrit measurements at Basal, Band and Band Hexa states.
2.3. Data collection
The conductance catheter was connected to a Sigma-5 signal-conditioner processor (CD Leycom, Zoetermeer, The Netherlands). The ultrasonic flow probe was connected to a flow-meter (HT 207, Transonic Systems Inc., Ithaca, NY, USA), and each micromanometer-tipped catheter to the appropriate monitor (Sentron pressure monitoring, Cordis, Miami, FL, USA).
All analog signals and ventricular pressure–volume loops were displayed on screen for continuous monitoring. The analog signals were continuously converted to digital form with an appropriate software (Codas, DataQ Instruments Inc., Akron, OH, USA) at a sampling frequency of 200 Hz.
2.4. Data analysis
2.4.1. Ventricular systolic function
Left ventricular volumes were inferred using the dual field conductance catheter technique [3,4]. Calibration of the conductance signal to obtain absolute volume was performed by the hypertonic saline method [3]. Therefore, a small volume (1–2 ml) of 10% NaCl solution was injected into the pulmonary artery during continuous data acquisition.
2.4.2. LV contractile function was assessed by the end-systolic pressure–volume relation (ESPVR), and the stroke work (SW)
The instantaneous pressure–volume relationship was considered in terms of a time-varying elastance E(t), defined by the following relationship:
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2.4.3. Myocardial energetics
Myocardial energetics was assessed by computation of pressure-volume area (PVA). In the time-varying elastance model of the ventricle, the total energy generated by each contraction is represented by the total area under the end-systolic pressure–volume relation line and the systolic segment of the pressure–volume loop, and above the end-diastolic pressure volume relation curve, and denoted by PVA (Fig. 3)
[5]. PVA is the sum of SW, or the energy that the ventricle delivers to the blood at ejection, and potential energy (PE), necessary to overcome the viscoelastic properties of the myocardium itself. It has been demonstrated that PVA was highly correlated with myocardial oxygen consumption [6].
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2.4.4. Arterial properties
Arterial properties were assessed from ascending aortic pressure and flow measurements and represented with a four-element windkessel model (WK4) [7]. An electrical analog of the WK4 is displayed in Fig. 2. In this model, the resistor R2 represents the resistive properties of the systemic bed, which are considered to reside primarily in the arteriolar system. The capacitor C, placed in parallel with R2, represents the compliant properties of the systemic vessels. The resistor R1 represents the characteristic impedance, which level depends prominently on the elastic properties of the aorta. Finally, an inductance, L, is introduced to take blood inertia into account. Furthermore, L restores positive phase angles at high frequencies of the impedance spectrum [8].
The values of R1, R2, C, and L were estimated by a method previously described [9].
Effective arterial elastance (Ea) was calculated according to the equation [10]:
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Ventriculo-arterial coupling was appreciated through the ratio Ees/Ea.
2.5. Statistical analysis
Data are expressed as mean±standard error of the mean (S.E.M.).
Statistical comparison of data during the different experimental conditions was conducted by a two-way analysis of variance for repeated measurements with experimental condition and pig as factors, followed by Scheffe's multiple comparisons test if the analysis of variance resulted in a P value <0.05.
Results of statistical tests were considered significant for a level of uncertainty of 5% (P<0.05). Statistical tests were performed using Statistica software (Statsoft Inc., Tulsa, OK, USA).
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.2. Effects of aortic banding, with and without autonomic blockade, on windkessel model parameters values
As shown in Table 2, after aortic banding (with and without autonomic blockade), R1 and L increased, while C decreased. However, after aortic banding alone, R2 increased significantly while, after aortic banding and autonomic blockade, R2 decreased significantly (P<0.001). Integrating these parameters, Ea increased by 36% (P<0.001) after aortic banding with intact baroreflex and by 13% after aortic banding and autonomic blockade. Such a difference between the two experimental conditions was significant (P<0.01).
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3.4. Effects of aortic banding, with and without autonomic blockade, on left ventricular function
As shown in Table 4 and Fig. 4
, after aortic banding, Ees increased by 31% (P<0.001) and Vd decreased from -3.6±0.2 to -6.8±0.3 ml (P=0.001). As a consequence, Ees/Ea remained stable and close to the optimal value. After aortic banding and autonomic blockade, Ees increased by 15% (P<0.01), Vd decreased significantly (P=0.01), and Ees/Ea remained stable.
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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In the intact cardio-vascular system, the systemic pressure drop distal to the aortic banding is perceived by the baroreceptors, mainly located in the transverse aortic and carotid arteries wall. This results in a stimulation of the baroreflex, with increase in R2 as a vascular effect. The significant increase in HR that we observe can also be interpreted as an expression of baroreflex stimulation.
On the opposite, when the autonomic nervous system is inhibited, the decrease in systemic pressure, distal to the aortic banding, is not associated with peripheral vasoconstriction. In addition, under these circumstances, HR remains constant.
These changes in the parameters characterizing the systemic vasculature are responsible for a significant increase in Ea, which is of a greater magnitude when the autonomic nervous system remains intact.
This afterload increase is associated with an augmentation of LV performance, as demonstrated by increased Ees and SW, at constant end-diastolic volume, and by ESPVR leftward shift (decrease of Vd). Therefore, Ees/Ea remains close to baseline value. This augmentation of LV performance is unaffected by the inhibition of the baroreflex.
Several experimental studies have evaluated the effect of afterload on LV performance, in isolated heart preparations and on intact animals. The results were contradictory.
Indeed, Sunagawa et al. [1] and Freeman [11] have observed that afterload augmentation induced a leftward shift of ESPVR, without changing Ees.
On the opposite, Baan and Enno [12] and Asanoi et al. [13]have found that the increase in Ea was associated with an augmentation of Ees, in addition to ESPVR leftward shift. All these experiments were conducted under autonomic nervous system inhibition. However, it should be emphasized that Asanoi et al. [13] obtained an afterload increase by infusing angiotensin II, a substance with powerful vasoconstrictive properties, but which can also directly affect myocardial contractility.
Several studies [14,15] also investigated the influence of autonomic nervous system on ESPVR and found results that were substantially similar to ours. Assessing the determinants of ESPVR during acute regional ischemia in open-chest dogs, Kass et al. [14] showed that the amount of rightward shift and the decrease in the slope of ESPVR were independent of baroreflex integrity. In another study performed on open-chest dogs, Schipper et al. [15] demonstrated that cardiac sympathetic denervation did not change the load dependence of ESPVR.
A too strict interpretation of the changes in ESPVR would conclude that a leftward shift, without slope variations, reflects that an afterload augmentation is not associated with an increase in myocardial contractility per se. However, as correctly emphasized by Sagawa et al. [10], the controversy regarding the interpretation of ESPVR should prevent the use of isolated slope or volume intercept values to characterize the contractile state. Since in all of these studies, the end-systolic point under afterload augmentation is always to the left of the control point in the pressure–volume plane, LV performance always appears increased.
In our study, while afterload augmentation is accompanied by an increase in LV performance, we observe a decrease in the efficiency of the energetic transfer from PVA to external mechanical work. This alteration in mechanical efficiency is independent of baroreflex integrity. Our results are in accordance with similar observations on anesthetized close-chest dogs [11,16].
What are the mechanisms that could explain such an augmentation of LV performance in the face of increased afterload?
Studies on isolated heart preparations [17] and in situ [18,19] have shown LV performance to be increased at longer end-diastolic ventricular length, probably due to increased myofiber sensitivity to calcium. However, in our study, the augmentation of LV performance in the face of increased afterload is observed at matched end-diastolic volumes. Therefore, the mechanism of length-dependant activation is unlikely to play a significant role in our observations.
Our results support the theory of homeometric autoregulation, which was described by Sarnoff et al. [20]on an isolated heart preparation. The homeometric autoregulation suggests a mechanism by which the heart can maintain a constant stroke volume in the face of increased afterload, without using the Starling mechanism. It has been suggested that homeometric regulation is explained by an increased coronary perfusion secondary to the increased aortic pressure. Indeed, Abel et al. demonstrated that increased coronary perfusion results in an improvement of the contractile performance of the left ventricle [21].
Another potential explanation for the improved LV contractile performance lies on increased wall tension. Effectively, increased end-systolic pressure could act on mechanical stretch-activated channels. Deformation of the cell membrane by increase in transmembrane pressure gradient could be sufficient to increase calcium release from the endoplasmic reticulum [22]. Another endogenous stimulus for adjustment of contractile performance could originate from the endocardial endothelium, which acts as a sensing system and plays an obligatory role in regulating cardiac function [23].
There are several possible to our study. First, our experimental protocol take some time (about 2 h from the basal measurements), and to ensure equal volumes by infusion to a certain central venous pressure could cause a considerable hemodilution which in itself would influence the resting cardiovascular state. At the same time, a substantial amount of blood loss could occur because the pigs are partially heparinized. However, our hematocrit measurements rule out such an experimental limitation.
Second, we lack one control group, which is to follow pigs over time with the same interventions, but without autonomic blockade. If there is a change in the cardiovascular status of the pigs throughout the experiment, then we cannot really rely on the animals as their own control. However, our hemodynamic results show that the experimental preparation is very stable. Furthermore, we have recently published the data from a different protocol (ischemia preparation), including a true control group with sham-operated animals, showing no significant hemodynamic changes over 6 h [24].
Our data confirm the results of Schipper et al. who demonstrated that improved LV contractile performance in response to an increased afterload is not abolished by sympathetic and parasympathetic denervation [15]. Such mechanisms of autoregulation, independent of the autonomic nervous system, are of paramount importance in heart transplant patients. Indeed, such patients, although lacking cardiac innervation, can adapt their cardiac output, stroke volume, end-systolic and end-diastolic pressures without simultaneous changes in heart rate.
In conclusion, our results demonstrate that an increase in LV afterload has a composite effect on LV function. Ventricular performance is increased, as expressed by ESPVR leftward shift, increase in Ees and SW but mechanical efficiency is decreased. These changes are observed independently of baroreflex integrity.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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