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J Thorac Cardiovasc Surg 1996;111:857-862
© 1996 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Supported by the G. Harold and Leila Y. Mathers Charitable Foundation.
Received for publication Feb. 21, 1995 Accepted for publication June 7, 1995. Address for reprints: Ryuji Tominaga, MD, Division of Cardiovascular Surgery, Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, 3-1-1 Maedashi, Higashi-ku, Fukuoka, 812, Japan.
Abstract
We investigated the effects of stepwise treadmill exercise on animal (calf) hemodynamic variables during chronic nonpulsatile biventricular bypass with ventricular fibrillation. Seven days was allowed for recovery from the effects of anesthesia and surgery; each animal's natural heart was then fibrillated. The pump flows were maintained at nominal rates of 90, 100, and 120 ml · kg-1· min-1for 1 week each, with the order varying from experiment to experiment. A total of 30 incremental exercise tests were performed on five animals. No significant changes in mean aortic pressure were observed during nonpulsatile perfusion at the three nominal flow rates of nonpulsatile flow either before or during exercise. The systemic vascular resistance decreased significantly during exercise (from 705 ± 22 to 547 ± 81 dyne · sec · cm-5, p< 0.01, and from 604 ± 25 to 510 ± 15 dyne ·sec ·cm-5, p< 0.05, at nominal flow rates of 100 and 120 ml ·kg-1 ·min-1, respectively). There were also significant (analysis of variance, Scheffe test, p< 0.05) differences in systemic vascular resistance among three nominal flow rates both before and during exercise. These results suggest that the autonomic nerve reflex control of the cardiovascular system in physical exercise was functioning normally in animals with chronic nonpulsatile blood flow. (J THORACCARDIOVASCSURG1996;111:857-62)
During exercise, the carotid sinus and aortic arch baroreceptors play an important role in regulating the systemic arterial pressure. Several investigations have demonstrated that the shift from pulsatile to static pressure in the isolated carotid sinus or aortic arch attenuates the baroreflex inhibition of sympathetic nerve activity, with a reflexive decrease in the arterial pressure.
1,2 One limitation of such studies is the acute nature of the investigations. This institution has shown long-term survival in animals and human beings with nonpulsatile blood flow. 3-7 This study was undertaken to examine whether any abnormal cardiovascular responses to progressive exercise were observed in awake calves with chronic nonpulsatile systemic blood flow, uninfluenced by the effects of surgery and anesthesia.
Material and methods
These studies were performed on the same animals used for the investigations reported in the other articles of this series. 8,9 These were 4-month-old calves weighing 89.8 to 93.6 kg at time of implant. As already detailed, Hemadyne centrifugal blood pumps supplied by the now defunct Hemadyne Division of Medtronic, Inc. (Minneapolis, Minn.) were attached to the cardiovascular system, right ventricle to pulmonary artery and left ventricle to aorta. Both pumps idled at 3 to 5 L/min until the seventh postoperative day, when the natural heart was fibrillated and flow rates of 90, 100, or 120 ml · kg-1 · min-1 were set for 1 week each in random order. Routinely, the atria in time spontaneously converted to sinus rhythm, although the ventricles never recovered. All animals in this study were managed in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources and published by the National Academy of Sciences (NIH Publication No. 8023, revised 1978).
Treadmill exercise study
Thirty exercise studies were done with the Animil treadmill intended for animal experiments (Gullwing, Inc., Sandusky, Ohio). The speed of the treadmill was increased at zero slope from 0.3 to 2.1 mph, with 0.2 mph increments 3 minutes in duration. Left pump flow rates were set as close as possible to the intended nominal level before exercise, and the pump controls were left fixed throughout the exercise test. As a result, actual flows varied by a small amount, as indicated by the data tables, as a result of changing atrial and aortic pressures and the pump pressure-flow relationship at the set speed. Hemodynamic variables were monitored continuously and recorded every 3 minutes. Pump flows were monitored by transit-time ultrasonic flow probes clamped on the pump outflow tubing (Transonic Systems, Inc., Ithaca, N.Y.). Pressures were measured with Bentley Trantec model 800 (Baxter Healthcare Corp., Deerfield, Ill.) or Statham P23b (Gould, Inc., Oxnard, Calif.) transducers connected to saline solution–purged catheters leading to the appropriate anatomic sites. Atrial heart rate was determined with external electrocardiographic leads. Body temperature measurements verified that no febrile calves were tested. The preexercise hemodynamic values were recorded as a control measurement when the animal was standing on the Animil. Exercise studies were done twice a week after ventricular fibrillation was induced. The body weight of the calf was measured as part of each exercise study. Because of the random flow order, there was no significant difference with respect to average test day after operation of the 90, 100 and 120 ml · kg-1 · min-1 flow data (18.5 ± 1.9, 15.3 ± 1.8, and 14.8 ± 1.4 days).
The data were stored and analyzed with a personal computer. The two-tailed paired t test was used to evaluate statistical significance between the preexercise and postexercise data. Statistical significance in multiple comparisons among independent groups of data, in which an analysis of variance indicated the presence of significant differences, was determined by the Scheffe method. 10 Significance was supposed at a value of p < 0.05. All data are reported as mean ± standard error of the mean.
Results
At 90 ml · kg-1 · min-1 nominal preexercise pump flow with ventricular fibrillation
Table I shows the data at treadmill speeds lower than 1.1 mph because the animals would not maintain treadmill exercise levels higher than 1.3 mph under these conditions. Aortic pressure (Fig. 1) and left atrial pressure showed no significant changes during exercise. A statistically significant (p < 0.02) increase in right atrial pressure was observed at a treadmill speed of 0.3 mph. Pulmonary arterial pressure also increased after exercise; however, there was no statistical significance in this increase. The systemic vascular resistance, which was calculated with the mean aortic pressure, right atrial pressure, and pump flow rate, decreased during exercise; again, however, this change was not statistically significant (Fig. 2). The left pump flow rate increased statistically significantly (p < 0.05), by a maximum of 0.4 L · kg-1 · min-1 or about 5%.
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Table II).
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Table III).
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A critical role of the circulatory system in exercise is to augment the delivery of metabolic substrate and oxygen necessary to generate adenosine triphosphate and maintain the required level of muscular work. Multiple mechanisms operate to make this happen. During exercise, there is a locally mediated vasodilation in the active muscles, a reflex constriction of the splanchnic and renal vascular beds, and an increase in cardiac output, with each proportional to the workload. An increase in sympathetic nervous activity during dynamic exercise plays a major role in hemodynamic changes. 11
The details of the autonomic nervous regulation of arterial pressure have been investigated by a number of researchers. Walgenbach and Donald 12 observed an abnormal rise in systemic pressure during and after exercise when both aortic arch denervation and vascular isolation in addition to carotid sinus pressurization were used to interrupt arterial baroreflexes. With carotid baroreceptors alone, the arterial pressure response to exercise was normal. Several other investigators 13,14 have demonstrated that the shift from pulsatile to steady pressure in the isolated carotid sinus or aortic arch attenuates the baroreflex inhibition of sympathetic nerve activity, resulting in an atypical rise in arterial pressure.
Melcher and Donald 13 showed that dogs without carotid, aortic, or cardiopulmonary baroreceptors became hypotensive and remained hypotensive during mild exercise. During severe exercise, an initial hypotension recovered to the preexercise levels after 90 seconds. McRitchie and colleagues 15 demonstrated the absence of a marked effect of chronically denervated carotid sinus and aortic arch baroreflex afferents on hemodynamic responses to moderate exercise in dogs. Studies conducted in dogs with and without baroreceptor isolation by Vanhoutte, Lacroix, and Leusen 16 also revealed little difference in the cardiovascular response to exercise.
The experiments reported here show no hypertension at any exercise level and show no hypotension at the initial low intensity level, resembling more the results of McRitchie and associates 15 and Vanhoutte, Lacroix, and Leusen. 16 Apparently, other mechanisms can compensate for the lack of a pulsatile baroreceptor reflex. This is especially significant because the cardiovascular system was triply stressed in this study. The pressure was depulsed; the flow level was very low, even at the highest tested flow level; and the demand response was very low. A left-side perfusion of 90 to 100 ml · kg-1 · min-1 has already been shown to be minimal for a resting activity level, 7 and the 5% increase in flow is almost inconsequential compared with the 300% or greater potential capacity increase of a normal, healthy heart. 17,18 The maintenance of normal aortic pressure under these conditions is remarkable.
A moderate increase in aortic pressure is normal during exercise but was not noted here. This may be a result of the very low nominal flow level or of the inability to increase flow with increased demand. 19,20 Sullivan and coworkers 20 saw a similar effect when comparing the response to exercise of normal subjects and patients with congestive heart failure. It is possible that the high right atrial pressure triggered a cardiopulmonary reflex that lowered systemic vascular resistance. The effects of the fibrillated natural heart as a neuroendocrine organ are unexplored. The characteristics of the centrifugal pump system, which has a flow-pressure difference relationship quite different from the flow-afterload-preload characteristics of the natural heart or a conventional artificial heart, could also be a factor.
Shoor and colleagues 21 reported the hemodynamic response to exercise in an unanesthetized calf with biventricular centrifugal pumps, but the natural heart was not fibrillated and dominated the hemodynamic profile during exercise. Our research group has reported on exercise studies showing that depulsed animals were capable of exercise and has noted that the results were comparable to those achieved with calves with pulsatile total artificial hearts. 22,23 This new study adds graded exercise, and selected flow levels to the protocol. At 90 ml · kg-1 · min-1 perfusion, results are consistent with earlier data. With the 10% increase in flow to 100 ml · kg-1 · min-1, the animals' ability to tolerate greater intensity of exercise also increased. Curiously, a further 20% increase in flow did not result in performance of yet higher intensity exercise. It appears that the cardiovascular system does not operate in a simple linear manner when apportioning the available blood flow during exercise.
Clinically, these results suggest that even a non-demand-responsive nonpulsatile ventricular-assist system can maintain a patient in a stable, comfortable state at rest and also give the recipient the ability to independently manage tasks such as shaving, dressing, writing, or slow walking. In human applications, the beating heart would not likely be deliberately fibrillated. With the volume overload removed by the assist device, the myocardium might well establish a new compensated state and make a small but useful contribution to the total systemic flow. The atrial heart rate increases seen during this protocol indicate that the drive to the myocardium does increase with exercise under conditions of nonpulsatile flow.
In conclusion, it appears that the cardiovascular system can adjust to nonpulsatile flow, maintaining stable aortic pressures from rest to moderate exercise levels, across a range of perfusion rates. To understand the physiologic mechanisms involved and guide the design of new generations of heart assistance and replacement devices, further studies are warranted at higher flow rates and with demand-responsive nonpulsatile systems, which use information from atrial pressures, atrial heart rate, or venous oxygen content to increase flow output commensurate with workload.
References
This article has been cited by other articles:
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  T. Nakano, R. Tominaga, S. Morita, M. Masuda, I. Nagano, K.-i. Imasaka, and H. Yasui Impacts of pulsatile systemic circulation on endothelium-derived nitric oxide release in anesthetized dogs Ann. Thorac. Surg., July 1, 2001; 72(1): 156 - 162. [Abstract] [Full Text] [PDF]
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