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Am J Physiol Heart Circ Physiol 275: H400-H408, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 2, H400-H408, August 1998

Dynamic sympathetic regulation of left ventricular contractility studied in the isolated canine heart

Hiroshi Miyano1, Yasunori Nakayama1, Toshiaki Shishido1, Masashi Inagaki1, Toru Kawada1, Takayuki Sato1, Hiroshi Miyashita1, Masaru Sugimachi1, Joe Alexander Jr.2, and Kenji Sunagawa1

1 Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Osaka 565, Japan; and 2 Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Appendix A
Appendix B
References

We investigated the dynamic sympathetic regulation of left ventricular end-systolic elastance (Ees) using an isolated canine ventricular preparation with functioning sympathetic nerves intact. We estimated the transfer function from both stellate ganglion stimulation to Ees and ganglion stimulation to heart rate (HR) for both left and right ganglia by means of the white noise approach and transformed those transfer functions into corresponding step responses. The HR response was much larger with right sympathetic stimulation than with left sympathetic stimulation (4.3 ± 1.4 vs. 0.7 ± 0.6 beats · min-1 · Hz-1, P < 0.01). In contrast, the Ees responses without pacing were not significantly different between left and right sympathetic stimulation (0.72 ± 0.34 vs. 0.76 ± 0.42 mmHg · ml-1 · Hz-1). Fixed-rate pacing significantly decreased the Ees response to right sympathetic stimulation (0.53 ± 0.43 mmHg · ml-1 · Hz-1, P < 0.01), but not to left sympathetic stimulation (0.67 ± 0.32 mmHg · ml-1 · Hz-1, not significant). Although the mechanism by which the sympathetic nervous system regulates cardiac contractility is different depending on whether the left or right sympathetic nerves are activated, this difference does not affect the apparent response of Ees to dynamic sympathetic stimulation.

left ventricular end-systolic elastance; transfer function; sympathetic nervous system; inotropic action; force-frequency mechanism

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Appendix A
Appendix B
References

IT HAS BEEN WELL ESTABLISHED that the sympathetic nervous system regulates contractility (10, 11, 21-23, 32, 38, 39). Previous investigations have shown that tonic electrical stimulation of the stellate ganglia (16, 22), middle cervical ganglia (16), or left inferior cardiac nerves (10) increased both heart rate (HR) and contractility. It has been shown that, because of the spatial inhomogeneity of sympathetic innervation of the heart (1, 2, 27, 28, 30), the chronotropic effect is stronger with right than with left sympathetic nerve stimulation, whereas the inotropic effect is stronger with left sympathetic nerve stimulation (10, 22, 29, 30). Hence, it appears that the left sympathetic nerves regulate cardiac contractility primarily by means of a direct inotropic mechanism, whereas the right sympathetic nerves regulate contractility by taking advantage of a force-frequency mechanism.

In those investigations, however, ventricular contractility was assessed with the use of indexes known to depend on loading conditions, such as maximum rate of rise in pressure (10, 11), left ventricular pressure (29), local isometric force of the left ventricular surface (2, 38), or intramyocardial pressure (16). Thus any changes in loading conditions that might result from sympathetic stimulation could alter the apparent contractility in those experiments even though true contractility might remain unchanged. Those studies, furthermore, have focused on the cardiac responses to tonic sympathetic stimulation. Because sympathetic nerve activity is dynamically regulated under physiological conditions (7, 14, 15, 26), a clarification of the dynamic characteristics of the sympathetic regulation of cardiac contractility is critical in understanding how the sympathetic nervous system regulates contractility.

The purpose of this investigation was to examine the dynamic cardiac responses to sympathetic stimulation by means of the white noise approach (7, 15, 20, 34) using an isolated, innervated canine heart model. This preparation enabled us to precisely control the loading conditions of the left ventricle and, hence, allowed us to accurately estimate the dynamic response of contractility to sympathetic stimulation. We assessed left ventricular contractility by means of the end-systolic elastance (Ees) that is known to be a load-insensitive index of left ventricular contractility (17, 31, 33). The results indicate that, although the mechanism by which the sympathetic nervous system regulates Ees is different depending on whether the right or left sympathetic nerves are activated, this does not affect the dynamic sympathetic regulation of Ees under spontaneously beating conditions.

    MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Appendix A
Appendix B
References

Surgical preparations. Experiments were performed in the isolated, cross-circulated, blood-perfused canine heart. Animal care was in accordance with institutional guidelines. We used adult mongrel dogs of either sex in this study. In each experiment, two mongrel dogs weighing 15-25 kg were anesthetized with pentobarbital sodium (25 mg/kg iv) after premedication with ketamine hydrochloride (5 mg/kg im) and were artificially ventilated (SNA-480-6, Shinano, Tokyo, Japan). The ventilator was adjusted so as to keep arterial pH, arterial PO2, and arterial PCO2 within their respective normal ranges. Additional doses of pentobarbital sodium (2.0-3.0 mg/kg) were administered as needed to maintain an adequate level of anesthesia. After heparinization (10,000 U/dog iv), arterial and venous cannulas for cross circulation were inserted into the bilateral carotid arteries and the right jugular vein of the support dog, respectively. The chest of the donor dog was opened midsternally as cannulas connected to cross circulation lines were placed in both the left subclavian artery, at a site distal to the origin of the vertebral artery, and the right ventricle via the right atrial appendage.

Bilaterally, the upper and lower poles of the stellate ganglia as well as their spinal cord branches were cut. The jugular veins, carotid arteries, and vagosympathetic trunks were ligated and cut in the midcervical region. The right subclavian artery was ligated and cut at a site distal to the origin of the right internal mammary artery. Branches of the right subclavian artery were also cut at their origins. We ligated the descending aorta, inferior vena cava, azygous vein, and pulmonary hili, whereupon we initiated cross circulation. We excised the heart en bloc with the bilateral stellate ganglia. After the chordae tendineae of the mitral valve were cut, a latex balloon was placed in the left ventricle. The balloon was filled with water and connected to a servo-pump to control ventricular volume. Left ventricular pressure was recorded with a 5-F catheter-tip micromanometer (SPC-350, Millar Instruments, Houston, TX) inserted in the balloon. Pairs of bipolar electrodes were applied to each of the stellate ganglia. To prevent desiccation and to provide insulation, the stimulation electrodes and nerves were immersed in a mixture of white petrolatum (Vaseline) and paraffin. A pair of stainless steel electrodes was sutured at the left atrial appendage for constant atrial pacing.

Arterial pressure of the donor dog was continuously monitored through the use of a fluid-filled transducer (Statham, Gould, Oxnard, CA) placed in the side arm of the perfusion circuit. Premedication with indomethacin (1 mg/kg iv) and diphenhydramine hydrochloride (30 mg im) was used to prevent systemic hypotension of the support dog during cross circulation. Homologous blood collected from the donor dog and/or 10% dextran solution were used, if necessary, to keep mean arterial pressure of the support dog at or near 100 mmHg.

Experimental protocol. Under stable inotropic conditions, we fixed left ventricular volume at a level that provided a peak left ventricular isovolumic pressure of ~80 mmHg. To estimate the dynamic cardiac response to sympathetic stimulation, we stimulated the right stellate ganglion for 12 min using a frequency-modulated, band-limited binary white noise sequence (15, 20, 34) in eight hearts. The stimulation frequency was altered from 0 to 5 Hz or from 5 to 0 Hz according to the binary random sequence. The resultant power spectral density of the input stimulation frequency was flat below 0.5 Hz. The pulse duration of electrical stimulation was set to 20 ms. We adjusted the amplitude of stimulation to yield a 50% increase in Ees above the control condition at 5-Hz stimulation. This resulted in an average amplitude of 2.5 ± 1.1 (mean ± SD) V. Random stimulation was repeated under conditions of constant atrial pacing to eliminate rate-dependent changes in Ees. We selected the pacing rate so as to override the maximum HR response induced by the 5-Hz tonic stimulation of the right stellate ganglion. Consequently, the average pacing rate was 165 ± 22 beats/min. In the remaining eight hearts, we stimulated the left stellate ganglion with and without pacing. The average amplitude of stimulation was 3.1 ± 0.9 V. The average pacing rate was 167 ± 18 beats/min. There were no significant differences in either the amplitudes of stimulation or the average pacing rates between the left and right sympathetic nerve stimulation protocols.

We could have run the right and left sympathetic stimulation protocol in a single heart to allow paired comparisons. Our pilot study indicated, however, that the variance resulting from the time-dependent deterioration of cardiac function in completing the two protocols in a single heart offset any potential statistical advantage. Thus we purposefully separated the two groups and ran each protocol in each group.

During random stimulation, left ventricular pressure, left ventricular volume, and the command signal were sampled at 200 Hz with a 12-bit resolution analog-to-digital converter (AD12-16, Contec, Tokyo, Japan) and stored on the hard disk of a dedicated laboratory computer system (9821 AP, NEC, Tokyo, Japan) for subsequent analyses.

Data analysis. We detected peak isovolumic pressure and calculated Ees in each beat by dividing the peak pressure by end-diastolic volume in excess of V0, where V0 is the end-systolic volume at which peak isovolumic pressure equals zero. We also calculated instantaneous HR from the beat-to-beat cardiac cycle length. Both Ees and HR were linearly interpolated every 5 ms.

After applying an anti-aliasing filter with a corner frequency of 4 Hz, we resampled the time series of the command signal, Ees, and HR at 8 Hz. We then subdivided the time series into eight overlapping (50%) segments. The length of each segment was 128 s in duration. The Blackman-Harris window was applied individually to all segments to minimize spectral leakage (8). This was followed by Fourier transformation to obtain corresponding frequency spectra. We obtained the cross-power spectrum between the command signal and Ees and between the command signal and HR, as well as the power spectrum of each of the signals. We ensemble averaged those estimated spectra across all eight segments to reduce spectral variance. Finally, we obtained the transfer function over the frequency range of 0.0078-0.5 Hz with a resolution of 0.0078 Hz using the following equation (24)
<IT>H</IT>( <IT>f</IT> ) = <FR><NU><IT>S</IT><SUB>in ⋅ out</SUB>( <IT>f</IT> )</NU><DE><IT>S</IT><SUB>in ⋅ in</SUB>( <IT>f</IT> )</DE></FR>
where Sin · out( f ) is cross power between the input and output, and Sin · in( f ) is power of the input. We obtained the modulus, |H( f )|, and phase shift, theta ( f ), by calculating the amplitude and arctangent of the transfer function according to the following equations
‖<IT>H</IT>( <IT>f</IT> )‖ = <RAD><RCD><IT>H</IT><SUB>real</SUB>( <IT>f</IT> )<SUP>2</SUP> + <IT>H</IT><SUB>imag</SUB>( <IT>f</IT> )<SUP>2</SUP></RCD></RAD>
&thgr;( <IT>f</IT> ) = tan<SUP>−1</SUP> <FR><NU><IT>H</IT><SUB>imag</SUB>( <IT>f</IT> )</NU><DE><IT>H</IT><SUB>real</SUB>( <IT>f</IT> )</DE></FR>
where Hreal( f ) is the real part and Himag( f ) is the imaginary part of H( f ). We hereafter refer to the modulus as the "gain" of the transfer function.

We also estimated the magnitude squared coherence (Coh) function, which is a frequency-domain measurement of linear correlation between the input and the output, using the following equation
Coh(<IT> f</IT> ) = <FR><NU>‖<IT>S</IT><SUB>in ⋅ out</SUB>( <IT>f</IT> )‖<SUP>2</SUP></NU><DE><IT>S</IT><SUB>in ⋅ in</SUB>( <IT>f</IT> ) ⋅ <IT>S</IT><SUB>out ⋅ out</SUB>( <IT>f</IT> )</DE></FR>
where Sout · out( f ) is power of the output.

After estimating the transfer functions, we used the inverse Fourier transformation of the transfer function to determine the associated step responses of both Ees and HR to a 1-Hz input sympathetic stimulation. The length of each step response was 64 s. We calculated the maximum response by averaging the last 5 s of the estimated step response. We referred to the maximum step response as dynamic gain.

Because the general characteristics of the transfer functions from sympathetic stimulation frequency to both Ees and HR resembled those of a second-order low-pass filter, we adopted this model to parameterize the measured transfer functions (See APPENDIX A).

Statistics. Numerical data are presented as means ± SD. The standard deviations of the gains of the transfer functions at each frequency were calculated after logarithmic transformation. We applied a paired t-test to examine the differences in Ees response between the protocols with and without atrial pacing. An unpaired t-test was used for assessing the differences in the Ees responses between the right and left sympathetic stimulation protocols. Differences in the HR responses to each stimulation of the stellate ganglion were tested using the Mann-Whitney test because of the inhomogeneity of the variance. P values <0.05 were considered significant (6).

    RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Appendix A
Appendix B
References

Mean values of Ees and HR during random sympathetic stimulation are summarized in Table 1. Ees and HR before nerve stimulation without pacing were not significantly different for left and right sympathetic stimulation protocols. Sympathetic stimulation significantly increased Ees independent of pacing. Random sympathetic stimulation also significantly increased HR.

                              
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  		Table 1.   Summary data of mean values of heart rate and left ventricular end-systolic elastance before and during random sympathetic stimulation

The rate of left atrial pacing was not significantly different between the two stimulation protocols. As anticipated, the pacing itself significantly increased Ees. However, the mean values of Ees during random stimulation were not significantly different between the protocols with and without pacing.

Changes in HR and Ees during random sympathetic stimulation. Figure 1 shows the effects of sympathetic stimulation on HR and Ees. As shown in Fig. 1A, random right sympathetic stimulation significantly alters both Ees and HR. In contrast, as shown in Fig. 1B, despite the significant response of Ees, left sympathetic stimulation can raise the baseline HR but fails to elicit dynamic alterations in HR.


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  		Fig. 1.   Representative records of sympathetic stimulation, heart rate (HR), and left ventricular end-systolic elastance (Ees). A: right sympathetic stimulation changes both Ees and HR. B: left sympathetic stimulation changes Ees without changing HR.

Dynamic transfer characteristics from sympathetic stimulation to HR. Figure 2 shows the transfer functions from sympathetic stimulation frequency to HR along with their corresponding step responses. As shown in Fig. 2A, the gain of the transfer function from right sympathetic stimulation to HR is relatively constant below 0.02 Hz and decreases above that frequency. The phase was almost in phase in the low frequency range. The natural frequency was 0.030 ± 0.010 Hz. The magnitude squared coherence was over 0.7 up to 0.1 Hz and decreased above that frequency. HR was predominantly linearly dependent on right sympathetic stimulation below 0.1 Hz.


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  		Fig. 2.   A: averaged transfer functions from right sympathetic stimulation frequency to HR and corresponding step responses. Gain of the transfer function from right sympathetic stimulation frequency to HR is relatively constant below 0.02 Hz and decreases above that frequency. B: although transfer function from left sympathetic stimulation frequency to HR is somewhat noisy, gain in the low frequency range was much smaller with left sympathetic stimulation than with right. Marked differences in gains of transfer functions are evidenced as the smaller dynamic gain of estimated step responses for left sympathetic stimulation compared with right (bottom). Solid lines indicate means, and dotted lines represent SE; bpm, beats/min.

Figure 2B shows the transfer function from left sympathetic stimulation to HR. Although the transfer function is somewhat noisy, its gain in the low frequency range was much smaller than that observed in right sympathetic stimulation. The fact that its coherence was also lower indicates that the linear HR response to sympathetic stimulation was less with left sympathetic stimulation than with right sympathetic stimulation.

The marked differences in the gains of the transfer functions were evidenced as the smaller dynamic gain of the estimated step response to left sympathetic stimulation compared with that to right sympathetic stimulation (left: 0.7 ± 0.6 vs. right: 4.3 ± 1.4 beats/min, P < 0.01) as shown in Fig. 2 (bottom).

Dynamic transfer characteristics from right sympathetic stimulation to Ees. Figure 3 shows the transfer functions from right sympathetic stimulation to Ees with and without constant rate pacing, along with their respective step responses. When the heart was not paced, as shown in Fig. 3A, the gain of the transfer function was relatively constant below 0.03 Hz and decreased at higher frequencies. The phase was in phase in the low frequency range and increasingly delayed with higher frequencies, becoming completely out of phase at 0.05-0.06 Hz. The coherence was ~0.7 in the low frequency range and increased to 0.8 with frequency up to 0.07 Hz, indicating that most of the response in Ees was linear in the low frequency range.


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  		Fig. 3.   Averaged transfer functions from right sympathetic stimulation frequency to Ees and calculated step response without [pacing (-); A] and with left atrial pacing [pacing (+); B]. Solid lines indicate means, and dotted lines represent SE.

Figure 3B shows the transfer function from right sympathetic stimulation to Ees with fixed-rate pacing. As can be seen, general characteristics of gain, phase, and coherence of the transfer function do not change with pacing, except that the gain in the low frequency range appears to be decreased.

Comparison of the step responses shown in Fig. 3 (bottom) indicates that pacing significantly decreased the dynamic gain (control: 0.76 ± 0.42 vs. pacing: 0.52 ± 0.43 mmHg/ml, P < 0.01); however, pacing did not significantly alter the natural frequency (control: 0.028 ± 0.006 vs. pacing: 0.029 ± 0.004 Hz).

Dynamic transfer characteristics from left sympathetic stimulation to Ees. Figure 4 shows the transfer functions from left sympathetic stimulation frequency to Ees with and without fixed-rate pacing, along with their corresponding step responses. As shown in Fig. 4A, when the heart was not paced, the transfer function from left sympathetic stimulation to Ees and its coherence resembled those from nonpaced right sympathetic stimulation (see Fig. 3A). The natural frequency of the transfer function from left sympathetic stimulation frequency to Ees was 0.030 ± 0.003 Hz. This was not significantly different from that obtained with right sympathetic stimulation.


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  		Fig. 4.   Averaged transfer functions from left sympathetic stimulation frequency to Ees and the calculated step response without (A) and with atrial pacing (B). Solid lines indicate means, and dotted lines represent SE.

Figure 4B shows the transfer function from left sympathetic stimulation to Ees with the corresponding step response under fixed-rate left atrial pacing. Pacing did not significantly alter the natural frequency of the transfer function (0.032 ± 0.005 Hz).

As shown in Fig. 4 (bottom), the dynamic gains as assessed by the steady-state gains of the step responses were not significantly different between the conditions with and without pacing (control: 0.72 ± 0.34 vs. pacing: 0.67 ± 0.32 mmHg/ml).

    DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Appendix A
Appendix B
References

Relative contributions of direct and indirect inotropic effects in the sympathetic regulation of ventricular contractility. We have shown in isolated canine left ventricles that the dynamic gain of the inotropic response to right cardiac sympathetic stimulation without pacing was not significantly different from that obtained with left sympathetic stimulation. However, when HR was held constant, the dynamic gain significantly decreased by ~30% with right sympathetic stimulation, but not with left sympathetic stimulation. Thus the left sympathetic nerve regulates ventricular contractility primarily by its direct inotropic action, whereas the right sympathetic nerve does so by both its direct inotropic action and indirect action resulting from its positive chronotropic effect.

Because there was no significant difference in the stimulation amplitude between right and left sympathetic stimulations (see Experimental protocol), it appears that the dynamic, direct inotropic action of the left sympathetic nerve is stronger than that of the right sympathetic nerve. This does not mean, however, that the left sympathetic nerve is more important than the right sympathetic nerve in regulating contractility under physiological conditions. It is well known that rate-dependent contractility is most manifest in the HR range below 120 beats/min (25). Control HR in the current investigation was significantly larger than 120 beats/min. In such an HR range, it is conceivable that the right sympathetic nerve, through a rate-dependent mechanism, might predominate over the left sympathetic nerve in the regulation of contractility.

The right cardiac sympathetic nerve distributes predominantly to the atria and nodal tissues and minimally to the ventricles. In contrast, the left cardiac sympathetic nerves, to a large extent, innervate the ventricles (2, 27-30), with some distributions to the atrioventricular node (32, 39) and atrium (2, 28, 30). Moreover, the nerves from the left stellate ganglion predominantly affect the electrical activity of the posterior ventricular wall, whereas those from the right stellate ganglion influence electrical activity of the anterior ventricular wall (38). These differences in the innervation of the heart by the right and left sympathetic nerves may explain, at least in part, the left sympathetic dominance in positive inotropic action and the right sympathetic dominance in positive chronotropic action.

Previous investigations have shown that the inotropic effect is stronger with left sympathetic stimulation than with right sympathetic stimulation even under spontaneously beating conditions (16, 22, 29, 30). Although these results appear inconsistent with ours, differences in the methodology used, such as stimulation frequency, amplitude, and pattern, as well as the indexes used for assessing ventricular contractility, might account for these discrepancies.

Linearity of the dynamic sympathetic regulation of Ees. As shown in Figs. 3 and 4, the coherence value was 0.6-0.9 in the frequency range below ~0.1 Hz. The corresponding P values were 0.024-0.0003, indicating that changes in Ees are quite linearly coupled with those in sympathetic stimulation. The lower of the coherence values in the low frequency range might be manifestations of slow changes in contractility unrelated to changes in sympathetic stimulation. For instance, because the segment length of analysis in deriving the transfer function was 128 s, even a few extra systoles over 12 min could significantly lower the coherence value in the low frequency range. Other factors, such as the time-dependent deterioration of isolated hearts and the instability of the hemodynamic conditions of the support dogs, both of which could affect ventricular contractility of the isolated heart, might also lower the coherence in the low frequency range. Thus, even though the coherence is a measure of linearity of a system, a relatively low coherence as observed in the low frequency range in this case does not necessarily imply true system nonlinearity. Rather, it could suggest the presence of slow changes in contractility unrelated to sympathetic stimulation.

In the higher frequency range above 0.1 Hz, the coherence values decreased despite the fact that the bandwidth of the input sympathetic stimulation was guaranteed up to 0.5 Hz. Although the exact mechanism by which the coherence value was reduced remains unknown, we speculate that a decreased gain in the high frequency range is responsible for this observation. As shown in the equation for the magnitude squared coherence function (see Data analysis), the coherence quantifies the variability of the output explainable by the input. Hence, if the noise in the output unrelated to the input has a constant level of variability over a wide frequency range, a decreased output variability resulting from a decreased gain in the high frequency range would inevitably lower the coherence value. Thus the low coherence value in the frequency range above 0.1 Hz does not necessarily indicate nonlinearity of the system in this frequency range.

For these reasons, we think that predominantly ventricular contractility is linearly coupled with sympathetic stimulation, at least under the tested conditions.

Effects of sympathetic stimulation on ventricular-arterial coupling. Previous studies have shown that the ratio of Ees to effective arterial elastance (Ea) dictates the efficiency of mechanical energy transfer from the left ventricle to the arterial system (36, 37). Because Ea depends not only on arterial resistance but also on HR, the fact that the right and left sympathetic nerves have different effects on Ees and HR suggests that they have different effects on energy transfer efficiency as well.

To examine the differential contributions of the right and left sympathetic nerves to ventricular-arterial coupling, we used the step responses derived from the relevant transfer functions to simulate the transient changes in the ratio of Ea to Ees (Ea/Ees) that would be observed in response to a 10-Hz step input of right or left sympathetic stimulation. Details of the derivation of the transient responses are provided in APPENDIX B. Figure 5 shows the transient responses of Ea/Ees. As can be seen, right sympathetic stimulation, although initially increasing the ratio by 10%, ultimately decreases it by 18%. On the contrary, left sympathetic stimulation decreased the ratio by more than 43%. Thus, under normal conditions in which the ventricle and the arterial system are likely to be matched, that is, when Ea/Ees is 0.5-1 (3, 9), right sympathetic stimulation has minimal influence over ventricular-arterial coupling and energy transmission efficiency. However, left sympathetic stimulation would result in considerable mismatch, which would in turn lead to inefficient energy transmission from the heart to the arterial system. However, when ventricular contractility is depressed, that is, when Ea/Ees is >2 (3), left sympathetic stimulation will improve matching more than will right sympathetic stimulation.


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  		Fig. 5.   Simulated transient responses of ratio of arterial elastance (Ea) to Ees (Ea/Ees) to a 10-Hz right (solid line) or left (dashed line) sympathetic stimulation step input. Percent change in Ea/Ees from initial value before stimulation is shown. Details of derivation of this simulation are provided in APPENDIX B.

Although it remains unknown whether the left and right sympathetic nerves are selectively regulated under physiological conditions, the differential effects of left and right sympathetic nerves on Ees and HR provide the potential for the regulatory system to neurally manipulate ventricular-arterial coupling under various conditions. Further studies are needed to clarify its physiological implication.

Methodological considerations. The isolated, cross-circulated canine heart preparation has been used for examining left ventricular mechanics (4, 12, 13, 25, 33, 35, 37) because this preparation makes it possible to precisely regulate left ventricular loading condition and, hence, to precisely estimate left ventricular contractility. However, because the autonomic innervation is lost during surgical preparation, it has been impossible to use this preparation for examining the autonomic regulation of left ventricular contractility. To overcome this disadvantage, we developed the method to isolate the heart while preserving the autonomic innervation to the heart. Although Ees significantly responded to sympathetic stimulation, the surgical preparation for isolating hearts might damage sympathetic nerves and thus make the heart less responsive to sympathetic stimulation. However, the mean increase in Ees during sympathetic stimulation in this study was compatible with that observed in conscious dogs during exercise (9). Therefore, we think that the results obtained from this study would be applicable in understanding cardiovascular pathophysiology under more intact conditions.

In this study we kept left ventricular volume constant. However, the end-systolic pressure-volume relationship has been shown to be somewhat different between the isovolumic beat and the ejecting beat. Namely, Ees of the small or normal ejection beat exceeds that of the isovolumic beat, i.e., ejecting activation (4, 12, 13, 35). On the other hand, large ejection has a negative effect on end-systolic pressure generation at the same end-systolic volume, i.e., ejecting deactivation (13, 35). Therefore, Ees would depend not only on contractility but also on loading conditions. Because the sympathetic activation alters contractility, afterload, and venous return (preload) simultaneously in the in situ heart, the net effect on the Ees response to sympathetic stimulation is uncertain from the present results. However, the fact that ejecting activation and ejecting deactivation counteract each other may make Ees less sensitive to changes in loading conditions (12, 13, 35). Thus the similar dynamic Ees response to sympathetic stimulation would be observed even in the in situ hearts.

Limitations. There are some limitations in this study. We used the white noise approach to identify the dynamic transfer characteristics from sympathetic stimulation to Ees (7, 15, 20, 34). Although this approach made it possible to identify the unbiased linear transfer function, input sympathetic stimulation was obviously nonphysiological. However, the fact that coherence values were rather high in the frequency range below 0.1 Hz, where the dynamic sympathetic regulation of Ees was by far most effective, indicates that sympathetic inotropic regulation is indeed reasonably linear. Therefore, from a mathematical point of view, similar linear responses would be expected to result even from the natural sympathetic stimulus as long as the amplitude and frequency bandwidth of the natural stimulus were within the tested range. Whether generalizations of our current observations beyond our test conditions are truly valid remains to be investigated.

We only stimulated the sympathetic nerves in this study. However, previous investigations have shown the existence of an interaction between sympathetic and vagal nerves in the regulation of cardiac contractility (11, 21). Kawada et al. (18, 19) also showed a dynamic sympathovagal interaction in the regulation of heart rate. Therefore, simultaneous stimulation of both sympathetic and vagal nerves may induce different dynamic responses in Ees through their interaction. Further investigation is necessary to clarify the possible role of dynamic sympathovagal interaction in the modulation of Ees.

In conclusion, both the right and left sympathetic nerves can induce the same degree of dynamic Ees response under spontaneously beating conditions. The right sympathetic nerve dynamically regulated cardiac contractility by both a direct inotropic mechanism and the force-frequency mechanism, whereas the left sympathetic nerve regulated cardiac contractility primarily by a direct inotropic mechanism. However, this difference in mechanisms does not significantly affect the apparent dynamic transfer characteristics from sympathetic stimulation to Ees.

    APPENDIX A
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Appendix A
Appendix B
References

The following algebraic equation describes the transfer function of the second-order model [Hm( f )]
<IT>H</IT><SUB>m</SUB>( <IT>f</IT> ) = <FR><NU><IT>K</IT></NU><DE><FENCE>1 + 2&xgr; <FR><NU><IT>f</IT></NU><DE><IT>f</IT><SUB>n</SUB></DE></FR> <IT>j</IT> − <FENCE><FR><NU> <IT>f</IT></NU><DE><IT> f</IT><SUB>n</SUB></DE></FR></FENCE><SUP>2</SUP></FENCE></DE></FR> ⋅ <IT>e</IT><SUP>−2&pgr; <IT>fjL</IT></SUP>
where j is an imaginary unit and f is frequency. The parameters K, fn, xi , and L are the steady-state gain, natural frequency, damping coefficient, and lag time, respectively. We calculated these parameters using an iterative, nonlinear least-squares fitting technique (5).

    APPENDIX B
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Appendix A
Appendix B
References

The effective Ea is the product of arterial resistance (R) and HR (37). Therefore, the ratio of the transient change in Ea/Ees [Ea/Ees(t)] is calculated as
<FR><NU><IT>E</IT><SUB>a</SUB></NU><DE><IT>E</IT><SUB>es</SUB></DE></FR> (<IT>t</IT>) = <FR><NU><FR><NU>&Dgr;HR(<IT>t</IT>) ⋅ &Dgr;<IT>R</IT>(<IT>t</IT>)</NU><DE>&Dgr;<IT>E</IT><SUB>es</SUB>(<IT>t</IT>)</DE></FR></NU><DE><FR><NU>HR ⋅ <IT>R</IT></NU><DE><IT>E</IT><SUB>es</SUB></DE></FR></DE></FR>
where HR, R, and Ees are the initial values of heart rate, arterial resistance, and end-systolic elastance, respectively. Delta HR(t), Delta R(t), and Delta Ees(t) are the transient responses of each from the initial values to 10-Hz sympathetic stimulation. With the assumption that R does not change during cardiac sympathetic stimulation [Delta R(t) = R], rearrangement of the above equation yields the following equation
<FR><NU><IT>E</IT><SUB>a</SUB></NU><DE><IT>E</IT><SUB>es</SUB></DE></FR> (<IT>t</IT>) = <FR><NU>1 + <FR><NU>&Dgr;HR(<IT>t</IT>)</NU><DE>HR</DE></FR></NU><DE>1 + <FR><NU>&Dgr;<IT>E</IT><SUB>es</SUB>(<IT>t</IT>)</NU><DE><IT>E</IT><SUB>es</SUB></DE></FR></DE></FR>
Therefore, percent changes in Ea/Ees from the initial Ea/Ees are calculated as
% <FR><NU><IT>E</IT><SUB>a</SUB></NU><DE><IT>E</IT><SUB>es</SUB></DE></FR> (<IT>t</IT>) = <FENCE><FR><NU><IT>E</IT><SUB>a</SUB></NU><DE><IT>E</IT><SUB>es</SUB></DE></FR> (<IT>t</IT>) − 1</FENCE> × 100
We used the averaged step responses of HR and Ees during random sympathetic stimulation (Figs. 2-4, bottom) as Delta HR(t) and Delta Ees(t), respectively. The initial values of Ees and HR in this simulation are 8 mmHg/ml and 80 beats/min, respectively.

    ACKNOWLEDGEMENTS

This study was supported by a grant from the Science and Technology Agency of Japan, Encourage System of the Center of Excellence.

    FOOTNOTES

Address for reprint requests: H. Miyano, Dept. of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan.

Received 29 December 1997; accepted in final form 21 April 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
Appendix A
Appendix B
References

1.   Armour, J. A., and D. A. Hopkins. Localization of sympathetic postganglionic neurons of physiologically identified cardiac nerves in the dog. J. Comp. Neurol. 202: 169-184, 1981[Medline].

2.   Armour, J. A., and W. C. Randall. Functional anatomy of canine cardiac nerves. Acta Anat. (Basel) 91: 510-528, 1975[Medline].

3.   Asanoi, H., S. Sasayama, and T. Kameyama. Ventriculoarterial coupling in normal and failing heart in humans. Circ. Res. 65: 483-493, 1989[Abstract/Free Full Text].

4.   Burkhoff, D., P. P. de Tombe, W. C. Hunter, and D. A. Kass. Contractile strength and mechanical efficiency of left ventricle are enhanced by physiological afterload. Am. J. Physiol. 260 (Heart Circ. Physiol. 29): H569-H578, 1991[Abstract/Free Full Text].

5.   Denis, J. E. Nonlinear Least Squares, State of the Art in the Numerical Analysis. New York: Academic, 1977, p. 269-312.

6.   Glantz, S. A. Primer of Biostatistics (3rd ed.). New York: McGraw-Hill, 1992.

7.   Harada, S., S. Ando, T. Imaizumi, Y. Hirooka, K. Sunagawa, and A. Takeshita. Arterial baroreflex control of cardiac and renal sympathetic nerve activities is uniform in frequency domain. Am. J. Physiol. 261 (Regulatory Integrative Comp. Physiol. 30): R296-R300, 1991[Abstract/Free Full Text].

8.   Harris, F. J. On the use of the windows for harmonic analysis with the discrete Fourier transform. Proc. IEEE 66: 51-83, 1978.

9.   Hayashida, K., K. Sunagawa, M. Noma, M. Sugimachi, H. Ando, and A. Takeshita. Mechanical matching of the left ventricle with the arterial system in exercising dogs. Circ. Res. 71: 481-489, 1992[Abstract/Free Full Text].

10.   Henning, R. J., and I. Khalil. Autonomic nervous stimulation affects left ventricular relaxation more than left ventricular contraction. J. Auton. Nerv. Syst. 28: 15-25, 1989[Medline].

11.   Henning, R. J., I. R. Khalil, and M. N. Levy. Vagal stimulation attenuates sympathetic enhancement of left ventricular function. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H1470-H1475, 1990[Abstract/Free Full Text].

12.   Hunter, W. C. End-systolic pressure as a balance between opposing effects of ejection. Circ. Res. 64: 265-275, 1989[Abstract/Free Full Text].

13.   Igarashi, Y., C. P. Cheng, and W. C. Little. Left ventricular ejection activation in the in situ heart. Am. J. Physiol. 260 (Heart Circ. Physiol. 29): H1495-H1500, 1991[Abstract/Free Full Text].

14.   Ikeda, Y., T. Kawada, M. Sugimachi, O. Kawaguchi, T. Shishido, T. Sato, H. Miyano, W. Matuura, J. J. Alexander, and K. Sunagawa. The neural arc of the baroreflex optimizes dynamic arterial pressure regulation in achieving both stability and quickness. Am. J. Physiol. 271 (Heart Circ. Physiol. 40): H882-H890, 1996[Abstract/Free Full Text].

15.   Imaizumi, T., Y. Harasawa, S. Ando, M. Sugimachi, and A. Takeshita. Transfer function analysis from arterial baroreceptor afferent activity to renal nerve activity. Am. J. Physiol. 266 (Heart Circ. Physiol. 35): H36-H42, 1994[Abstract/Free Full Text].

16.   Janes, R. D., D. E. Johnstone, and J. A. Armour. Chronotropic, inotropic, and coronary artery blood flow responses to stimulation of specific canine sympathetic nerves and ganglia. Can. J. Physiol. Pharmacol. 62: 1374-1381, 1984[Medline].

17.   Kass, D. A., W. L. Maughan, Z. M. Guo, A. Kono, K. Sunagawa, and K. Sagawa. Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships. Circulation 76: 1422-1436, 1987[Abstract/Free Full Text].

18.   Kawada, T., Y. Ikeda, M. Sugimachi, T. Shishido, O. Kawaguchi, T. Yamazaki, J. Alexander, Jr., and K. Sunagawa. Bidirectional augmentation of heart rate regulation by autonomic nervous system in rabbits. Am. J. Physiol. 271 (Heart Circ. Physiol. 40): H288-H295, 1996[Abstract/Free Full Text].

19.   Kawada, T., M. Sugimachi, T. Shishido, H. Miyano, Y. Ikeda, R. Yoshimura, T. Sato, H. Takaki, Joe Alexander, Jr., and K. Sunagawa. Dynamic vagosympathetic interaction augments heart rate response irrespective of stimulation patterns. Am. J. Physiol. 272 (Heart Circ. Physiol. 41): H2180-H2187, 1997[Abstract/Free Full Text].

20.   Kubota, T., J. Alexander, Jr., R. Itaya, K. Todaka, M. Sugimachi, K. Sunagawa, Y. Nose, and A. Takeshita. Dynamic effects of carotid sinus baroreflex on ventriculoarterial coupling studied in anesthetized dogs. Circ. Res. 70: 1044-1053, 1992[Abstract/Free Full Text].

21.   Levy, M. N., M. Ng, P. Martin, and H. Zieske. Sympathetic and parasympathetic interactions upon the left ventricle of the dog. Circ. Res. 19: 5-10, 1966[Abstract/Free Full Text].

22.   Levy, M. N., M. L. Ng, and H. Zieske. Functional distribution of the peripheral cardiac sympathetic pathways. Circ. Res. 19: 650-661, 1966[Abstract/Free Full Text].

23.   Levy, M. N., and H. Zieske. Autonomic control of cardiac pacemaker activity and atrioventricular transmission. J. Appl. Physiol. 27: 465-470, 1969[Free Full Text].

24.   Marmarelis, P. Z., and V. Z. Marmarelis. The white noise method in system identification. In: Analysis of Physiological Systems. New York: Plenum, 1978, p. 131-221.

25.   Maughan, W. L., K. Sunagawa, D. Burkhoff, W. L. Graves, W. C. Hunter, and K. Sagawa. Effect of heart rate on the canine end-systolic pressure-volume relationship. Circulation 72: 654-659, 1985[Abstract/Free Full Text].

26.   Miyano, H., T. Kawada, T. Shishido, T. Sato, M. Sugimachi, Joe Alexander, Jr., and K. Sunagawa. Inhibition of NO synthesis minimally affects the dynamic baroreflex regulation of sympathetic nerve activity. Am. J. Physiol. 272 (Heart Circ. Physiol. 41): H2446-H2452, 1997[Abstract/Free Full Text].

27.   Randall, W. C., and J. A. Armour. Gross and microscopic anatomy of the cardiac innervation. In: Neural Regulation of the Heart, edited by W. C. Randall. New York: Oxford Univ. Press, 1977, p. 13-41.

28.   Randall, W. C., J. A. Armour, W. P. Geis, and D. B. Lipponcott. Regional cardiac distribution of the sympathetic nerves. Federation Proc. 31: 1199-1208, 1972[Medline].

29.   Randall, W. C., H. McNally, J. Cowan, L. Caliguiri, and W. G. Rohse. Functional analysis of the cardioaugmentor and cardioaccelerator pathways in the dogs. Am. J. Physiol. 191: 213-217, 1957.

30.   Randall, W. C., D. Priola, and R. H. Ulmer. A functional study of distribution of cardiac sympathetic nerves. Am. J. Physiol. 205: 1227-1231, 1963.

31.   Sagawa, K., L. Maughan, H. Suga, and K. Sunagawa. Physiological determinants of the ventricular pressure-volume relationship. In: Cardiac Contraction and the Pressure-Volume Relationship. New York: Oxford Univ. Press, 1988, p. 110-170.

32.   Spear, J. F., and N. Moore. Influence of brief vagal and stellate nerve stimulation on pacemaker activity and conduction within the atrioventricular conduction system of the dog. Circ. Res. 32: 27-40, 1973[Abstract/Free Full Text].

33.   Suga, H., K. Sagawa, and A. A. Shoukas. Load independence of the instantaneous pressure-volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ. Res. 32: 314-322, 1973[Abstract/Free Full Text].

34.   Sugimachi, M., T. Imaizumi, K. Sunagawa, Y. Hirooka, K. Todaka, A. Takeshita, and M. Nakamura. A new method to identify dynamic transduction properties of aortic baroreceptors. Am. J. Physiol. 258 (Heart Circ. Physiol. 27): H887-H895, 1990[Abstract/Free Full Text].

35.   Sugiura, S., W. C. Hunter, and K. Sagawa. Long-term versus intrabeat history of ejection as determinants of canine ventricular end-systolic pressure. Circ. Res. 64: 255-264, 1989[Abstract/Free Full Text].

36.   Sunagawa, K., K. Hayashida, M. Sugimachi, K. Todaka, T. Kubota, R. Itaya, A. Chiaki, and A. Takeshita. Optimal ventricle versus optimal afterload. In: Recent Progress in Failing Heart Syndrome, edited by S. Sasayama, and H. Suga. Tokyo, Japan: Springer-Verlag, 1991, p. 161-185.

37.   Sunagawa, K., W. L. Maughan, D. Burkhoff, and K. Sagawa. Optimal arterial resistance for maximal stroke work studied in isolated canine left ventricle. Circ. Res. 56: 586-595, 1985[Abstract/Free Full Text].

38.   Yang, T., and M. N. Levy. Sequence of excitation as a factor in sympathetic-parasympathetic interactions in the heart. Circ. Res. 71: 898-905, 1992[Abstract/Free Full Text].

39.   Yanowitz, F., B. A. James, J. B. Preston, and J. A. Abildskov. Functional distribution of right and left stellate innervation to the ventricles. Circ. Res. 18: 416-428, 1965[Abstract/Free Full Text].

Am J Physiol Heart Circ Physiol 275(2):H400-H408
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