The Cardiac Output-Heart Rate Relationship Under Different Conditions

The Japanese Journal of Physiology 17, pp.538-555, 1967

THE CARDIAC OUTPUT-HEART RATE RELATIONSHIP UNDER DIFFERENT CONDITIONS

Mamoru KUMADA,Takehiko AZUMA AND Kojiro MATSUDA

Department of Physiology, Faculty of Medicine, University of Tokyo, Tokyo

Cardiac output is defined as the product of stroke volume and heart rate. Stroke volume, however, is influenced by heart rate in various manners under different conditions. For example, tachycardia artificially induced by electrical stimulation of the heart always diminishes stroke volume,1-3) whereas cardioacceleration during exercise is accompanied by a slight increase in stroke volume.14) This indicates that the relationship between heart rate and stroke volume or cardiac output can be modified by circumstancial factors. Thus, for the prediction or analysis of alterations in stroke volume or cardiac output as heart rate changes under various circumstances, it becomes necessary to have families of curves which relate the output to heart rate with variously controlled neural and hemodynamical parameters. The purpose of this study was to obtain the above stated knowledge in an open-chest, paced heart preparation. Five different parametric factors were examined in the study as to how each one of these factors modifies the heart rate-output relationship. Besides stroke volume, two additional hemodynamic variables of physiological importance (peak aortic flow and ejection time) were also measured to aid the analysis of basic mechanisms which are responsible for the observed differences in cardiac response to the given en- vironments.

METHODS Experiments were performed on fourty three dogs of either sex, weighing from 8 to 14kg. The dogs were anesthetized with an intravenous injection of thiopenthal (150-250mg), followed 15 to 30 minutes later by an intravenous infusion of chloralose (50mg/kg) and urethane (500mg/kg). Under artificial respiration the chest was opened through a midsternal incision and the heart was suspended in a pericardial cradle. An electromagnetic flow probe was placed around the root of the aorta, and a Kolin-type (gated sine wave) flowmeter circuit designed and constructed in our laboratory was used to record the flow (left ventricular output minus coronary flow). Spontaneous

Received for publication January 14, 1967. 熊田衛,東健彦,松田幸次郎

538 CARDIAC OUTPUT-HEART RATE RELATIONSHIP 539

rhythm of the heart was reduced as low as 50 to 70/min by clamping the sinus node region with a hemostat. The heart was then paced at a fixed rate through a pair of stimulating electrodes attached to the right auricular appendage. Arterial pressure was measured at the left common carotid artery with a heparinized catheter strain- gauge manometer system and recorded continuously on an ink-writing oscillograph together with aortic flow. Stroke volume, ejection time and peak flow velocity were measured from the recorded aortic flow traces. The mean value of these variables was determined on consecutive heart beats for 5 to 10 seconds. Stroke volume (minus stroke coronary flow) was estimated in an arbitrary unit by planimetry of the area under the aortic flow curve. Cardiac output was calculated as the product of mean stroke volume and heart rate. These four cardiac variables were expressed in terms of percent the control values obtained at the heart rate of 160/min and plotted as the function of heart rate. The following five sets of experiments were carried out in which the heart rate was stepwise changed from 60 to 250/min in most cases and over narrower ranges in others. In the first group (21 dogs) the effect of heart rate per se was examined leaving other experimental conditions intact. The second group (10 dogs) was used to study the effect of the cardiac sympathetic nerve stimulation. The lef t stellate ganglion, all branches of which were severed except the anterior subclavian, was electrically stimulated with square pulses (10-20 volts in intensity, 1 msec in duration and 2-10 pulses/sec) for 30 to 50 seconds at every fixed heart rate. In the third group (12 dogs) the effect of vagus nerve stimulation was investigated. The right and left vagus nerves were isolated in the middle neck region and electrical stimulation of 50 pulses/sec was applied to the peripheral cut end on both sides. The maximum intensity of the stimulation was set at a level such that it would not produce atrio-ventricular block (usually 1-5 volts). In the fourth group (8 dogs) isotonic dextran saline solution was infused into the femoral vein in order to observe the effect of increase in circulating blood volume. In the fifth group (9 dogs) the load to the left ventricle was altered by partial compression of the thoracic aorta just distal to the subclavian artery. In some dogs of all the groups simultaneous measurements were done of right atrial pressure and combined ventricular volume. Right atrial pressure was recorded through a catheter which was introduced into the atrium via the right jugular vein and connected with a strain-gauge electric manometer. The combined ventricular volume was measured with an air-filled cardiometer.

RESULTS

1. Effect of heart rate change on ventricular performance. Successive changes in heart rate caused responses in the aortic flow, arterial pressure and right atrial pressure as illustrated by the experimental record in FIG.1 and the graphical presentations in FIG.2. Stroke volume, ejection time and peak flow velocity always decreased with increase in heart rate. Up to the rate of approximately 100/min, the rate of reduction in stroke volume was less than that of the increase in heart rate, so that cardiac output rose as the rate was increased. Over the range of heart rate approximately from 100 to 200/min, cardiac output remained almost unaltered at the maximum level because the falling stroke volume canceled out the effect of increasing heart rate. Above the rate of approximately 200/min cardiac output began to decrease. Alter- 540 M. KUMADA, T. AZUMA AND K. MATSUDA

FIG.1. Effects of heart rate on aortic flow (AF), blood pressure (BP), and right atrial pressure (RAP). Heart rate was controlled by atrial pacing. Heart rates in A to E are 84, 124, 160, 203 and 248/min, respectively.

FIG.2. One example of the relation of heart rate to stroke volume, cardiac output,:ejection:time and peak flow velocity. Values at the heart rate of 160/min were taken as 100% on the ordinate. CARDIAC OUTPUT-HEART RATE RELATIONSHIP 541

nating beat was frequently observed when heart rate was raised as high as 250/min (FIG.1E). Thus the curve relating cardiac output to heart rate exhibited a plateau at the mid-range of the investigated heart rate as depicted by the graph in FIG.2. Twenty similar curves were examined to determine the heart rate range over which cardiac output was more than 95 per cent of the maximum value observed. In the majority of the cases, the range was found to be between 110 and 200/min. Mean arterial pressure varied usually in parallel with cardiac output, though the percent change of the former variable was less than that of the latter one.

2. Effect of cardiac sympathetic nerve stimulation. Electrical stimulation of the isolated left stellate ganglion while keeping heart rate constant caused

FiG.3. Effects of left stellate ganglion stimulation on aortic flow (AF), volume of the ventricles (Vol), blood pres. sure (I3P), and right atrial pressure (RAP) at two different fixed heart rates. Heart rate was maintained constant at 160/min in A and 236/min in B by atrial pacing. Stellate stimulation (10 volts, 1 msec and 10/sec) was started at the points indicated by arrows. 542 M. KUMADA, T. AZUMA AND K. MATSUDA marked changes in aortic flow curve, combined ventricular volume curve, blood pressure and right atrial pressure compared with the controls as shown in FIG.3. The maximum responses in the observed variables were reached between 8 and 12 seconds after the beginning of the stimulation and sustained thereafter. As a result of the striking increase in peak flow velocity, stroke volume increased despite the concomitant curtailment of the ejection time in reference to the control state (FIG.3A). End diastolic volume of the ventricles was usually diminished by the stimulation. At a very high heart rate, however, the stimulation brought about an increase in the volume (FIG.3B). A. rise in mean arterial pressure during stimulation was associated with a charac- teristic increase in the magnitude of pulse pressure. Mean right atrial pressure usually fell to a mild degree. Although augmentation of stroke volume and cardiac output from the control level were observable at every fixed heart rate following the stimulation, the effect was more prominent at the higher rate range (FIG.4). Consequently cardiac output remained nearly the maximum level even at a rate as high as 250/min. The graphs in FIG.4 indicate that increase in stroke volume by sympathetic stimulation in such a high pacing rate region was brought about not only by increased peak flow velocity but also by the relative prolongation of ejection time compared with the control ejection time over the initial rate range, due to the less steep reduction in this variable with heart rate under the sympathetic stimulation.

FIG.4. Influence of left stellate ganglion stimulation on the relation- ships between heart rate and four cardiac variables. Solid circles: control, open circles: stellate stimulation (10 volts, 1 msec and 10/sec). CARDIAC OUTPUT-HEART RATE RELATIONSHIP 543

3. Effect of vagal stimulation. Moderate decreases in stroke volume, cardiac output and peak flow velocity were observed during the stimulation of the bilateral vagal nerves while heart rate was kept constant (FIG.5). These changes were accompanied by a slight decrease in blood pressure and end

FIG.5. Hemodynamic influence of bilateral cervical vagus stimulation (2 volts, 1 msec and 50/sec). Heart rate was held constant at 205/min by atrial pacing. Abbreviations are the same as in FiG.3. diastolic volume of the ventricles and by a small rise in right atrial pressure. Since the difference in changes of ejection time with heart rate was insigni- ficant before and after vagal stimulation, the greater reduction of stroke volume during vagal stimulation can he ascribed to the more significant diminishment in peak fiow velocity. These hemodynamic changes resultant to the stimulation became more obvious as the pacing rate was increased. In order to clearly illustrate the pattern of the changes brought about by vagal stimulation, curves from an example in which particularly marked variations occurred were shown in FIG.6. In most cases the shifts of these curves were less than those in this figure and confined to the rate range above 180/min. For the purpose of determining whether the above mentioned changes resulted solely from vagal inhibition on the atrium or also from its effect on the ventricular contractility, the pacing site was shifted from the right auricular appendage to the ventricular apex. The decrease of stroke volume caused by vagal stimulation during atrial pacing were no longer observed when the ventricle was paced (FIG.7). It therefore follows that the vagus nerve does not affect the force of ventricular contraction, at least under the condition instituted in the present study. 544 M. KUMADA, T. AZUMA AND K. MATSUDA

FIG.6. Influence of bilateral cervical vagus stimulation on the relationship between heart rate and four cardiac variables. Solid circles: control, open circles: vagal stimulation (2 volts, 1 msec and 50/sec).

FIG.7. Influence of bilateral cervical vagus stimulation on cardiac output. The heart was paced either at the atrium or at the ventricle. Solid lines represent the cardiac output- heart rate relationship when the atrium was paced, while the broken line was obtained under the ventricular pacing. Solid circles: control, open circles: vagal stimulation (2 volts, 1 msec and 50/sec). CARDIAC OUTPUT-HEART RATE RELATIONSHIP 545

4. Effect of infusion. FIG.8 illustrates the hemodynamic changes caused by infusion of isotonic dextran saline solution (5ml/kg), which was performed in 1 to 2 minutes through a catheter placed in the right femoral vein. FIG.8A and B are the records prior to and 10 minutes after the infusion respectively. Stroke volume, end diastolic volume of the ventricles and mean right atrial pressure were found to be increased after the infusion, while blood pressure remained almost unchanged. From an example shown in FIG.9 it will be seen that at every heart rate a concomitant increase was observed in ejection time and peak flow velocity, combination of which undoubtedly contributed to the rise in stroke volume. However, up to the rate of approximately 120/min, there was a tendency that the higher the heart rate, the greater the increment

FIG.8. Ilemodynamic influence of dextran saline infusion (5ml/kg). A: control, B: 10 minutes after infusion was ended. IIeart rate was held constant at 157/min by atrial pacing. Abbreviations are the same as in FIG.3. in stroke volume or cardiac output was. At rates between 120 and 160/min, the maximum and relatively uniform output was obtained. On the other hand cardiac output tended to diminish with further increase of heart rate. The plateau range over which cardiac output was more than 95 per cent of the maximum value observed was examined in five experiments in which infusion of 5ml/kg was performed. The plateau range thus defined was between 120 and 180/min in average. The pattern of the curves relating heart rate to the four cardiac variables was independent of the volume of infusion within the volume range from 5 to 20ml/kg, except that the rate range of the plateau became narrower and narrower with increase in the volume because the plateau was reached at a higher heart rate range. 546 M. KUMADA, T. AZUMA AND K. MATSUDA

FIG.9. Effects of infusion on the relationship between heart rate and four cardiac variables. Solid circles: control, open circles: 10 minutes after intravenous infusion of dextran saline solution (5ml/kg) was ended.

5. Effect of increased resistance. FIG.10 shows the representative hemodynamic changes brought about by a sudden and sustained increase in resistance to ventricular ejection. A few seconds after the resistance was increased, once elevated blood pressure began to fall probably due to baroceptor reflexes and after 10 to 15 seconds a lower stable level was reached. The following changes in cardiac variables were observed at this equilibrated stage. Stroke volume showed a marked decrease with a simultaneous increase in end diastolic volume of ventricles. Diminished stroke volume was associated with decreased peak flow velocity and slightly prolonged ejection time. A moderate rise was observed in right atrial pressure. Typical relations between heart rate and four cardiac variables were shown in FIG.11. In this experi- ment blood pressure at the heart rate of 160/min rose from 121 to 195 mmHg immediately after resistance was increased and finally settled down to 150 mmHg, under which circumstance the calculated total peripheral resistance was increased by 70 per cent of the control. At every fixed heart rate stroke volume diminished after increasing aortic resistance. The decrease being more marked at higher heart rates, the fall in cardiac output became more prominent over the range above 130/min which was the plateau range before increasing the resistance. However, a definite reduction was always observed in stroke volume and cardiac output at normal and subphysiological rates, too. CARDIAC OUTPUT-HEART RATE RELATIONSHIP 547

FIG.10. Hemodynamic effect of increasing arterial resistance by partial compression of the thoracic aorta. Peripheral resistance was increased by 1.7 times by this procedure. Heart rate was kept constant at 180/min by atrial pacing. Abbreviations are the same as in FIG.3.

FIG.11. Effect of peripheral resistance increase on the relationship between heart rate and four cardiac variables. Peripheral resistance was increased by 1.7 times by partial compression of thoracic aorta. Solid circles: control, open circles: after increasing peripheral resistance. 548 M. KUMADA, T. AZUMA AND K. MATSUDA

DISCUSSION

Effect of heart rate per se on cardiac output. Several studies have been carried out on the relationship between heart rate and cardiac output in dogs and human sub jects.2,3,6-19) The majority of them coincide in conclusion that cardiac output remained relatively unchanged within a certain range of heart rates and thus the cardiac output-heart rate relation exhibited a plateau. However, there is some disagreement among the investigators as to the extent of rate range over which the plateau was obtained. According to MILLER et al.,3) who performed a series of experiments in which the experimental conditions were sometimes almost exactly identical with the present authors', the plateau extended from the rate of 90 to 150/min in contrast to the present results which indicated the plateau over the range between 110 and 200/min. Since the same anesthetics was used in a similar dosage in both experiments, the discrepancy can not be ascribed to the difference in anesthesia. A prob- able explanation is the different site of pacing: MILLER et alli's experiments were performed under ventricular pacing while the present experiments were carried out mostly with atrial pacing. When the site of stimulaion was shifted in some of the present experiments from the atrium to the ventricle without changing the rate at all, the lengthening of the systole and consequent shortening of diastole were brought about, which in turn resulted in curtailed intervals for the ventricular filling. The faster the rate, the greater the reduction in the cardiac output due to the curtailment of diastolic filling will be. Therefore, lowering of the higher limit of the plateau rate range is to be expected if the driving stimuli are given to the ventricle instead of the atrium. In fact, it was revealed in the present study that when the ventricle was paced cardiac output began to fall at rates exceeding about 150/min (FIG.7). For the same reason, cardiac output would reach the plateau level at a lower rate in the case of ventricular pacing than in the case of atrial pacing. This probably accounts for the different lower margins of the plateau rate range in those two experiments. A similar difference in the extent of the plateau was reported also in human subjects. Many investigators13-18) reported that, with ventricular pacing, cardiac output usually began to decrease at rates above 80/min. On the contrary, Ross et al.19) observed no appreciable reduction in cardiac output by atrial pacing until the rate was elevated to 150/min. The significance of the pericardium as one of the determinants of cardiac output should also be taken into consideration, because it restricts the filling of the heart and thus con- stitutes part of inflow resistance of the heart.20) The pericardium having been cut open in the present study, the cardiac output determined might be an overestimation especially in the low heart rate range. In some of the present experiments the ventricular volume curve was CARDIAC OUTPUT-HEART RATE RELATIONSHIP 549

FIG.12. Ventricular volume curves at various heart rates. All traces begin from the onset of diastole and end in the same phase of the next heart beat. Upward de- flection indicates filling.

recorded (FIG.12). In accordance with the LINDEN'S observation") a period of diastasis was seen only at rates slower than about 110/min, below which less marked increase in stroke volume occurred with decrease in heart rate. This is obviously the reason why cardiac output diminished with further reduction of the pacing rate. When heart rate exceeded about 200/min, on the other hand, a distinct depression of the ventricular filling was observed with increased right atrial pressure owing to the marked shortening of diastole. According to WALLACE et al.22) the interval between the onset of atrial and ventricular systole (As-Vs interval) prolongs progressively as heart rate in- creases. When heart rate rose approximately over 200/min, the prolongation of As-Vs interval is so marked that atrial contraction occurs either partially or entirely while the mitral valve is still closed from the preceding ventricular systole. Impaired ventricular filling evoked in this way seems to sufficiently explain the observed fall in cardiac output over the rate range greater than 200/min. Cardiac output is considered to be regulated physiologically at least by the following four extrinsic factors: the activity of cardiac sympathetic and vagus nerves, venous return and peripheral resistance of the arterial system. For this reason effects of these four factors were studied on cardiac output- heart rate relationship. Effect of sympathetic stimulation. Sympathetic stimulation usually in- creases both rate and minute output of the spontaneously beating heart.23,24) As shown in FIG.2, increased heart rate per se does not produce parallel augmentation of cardiac output beyond a critical rate value. Cardioacceleration caused by sympathetic stimulation, however, is always accompanied by an upward shift of cardiac output-heart rate relationship curve resulted from an increased contractility as well as augmented ventricular filling due to the prolongation of diastole.25) As FIG.3 clearly demonstrates, the effects of sympathetic stimulation are marked increase in cardiac output at every clamped rate and extended plateau rate range to the right. The extended plateau indicates that cardiac output was kept at the maximum level at those high 550 M. KUMADA, T. AZUMA AND K. MATSUDA pacing rates which depressed cardiac output in the control. Thus, the cardioacceleration seems to play only a minor role in producing the observed augmentation of cardiac output following the sympathetic stimulation. The change of the ventricular end diastolic volume (EDV) caused by sympathetic stimulation deserves further discussion. Unless heart rate exceeds approximately 200/min, a decrease in EDV and a slight fall of right atrial pressure together with the increase in stroke volume and arterial pressure were observed following sympathetic stimulation (FIG.3A). The observed changes such as the more complete and rapid emptying of the ventricle and the consequent increase both in filling interval and in pressure gradient for the transfer of blood from the atrium to the ventricle are the factors which amply explain the augmented cardiac output. On the other hand, when heart rate was increased above 200/min, the rise in stroke volume and arterial pressure were accompanied by an increase in EDV and marked decrease in right atrial pressure (FIG.3B). Reasons for the changes of these two latter variables in opposite directions are not readily understandable. If the ventricle had been filled exclusively by vis a tergo, increased EDV ought to have been accompanied by the same directional change in right atrial pressure. The above result rather suggests that, in the heart paced at such a high rate, ventricular suction was brought into action by the sympathetic stimulation and this suction played a role in producing the marked augmentation of the output with the concomitant fall in atrial pressure. There still remains another possibility pointed out by WALLACE et al.22) and SAR- NOFF.26) As stated above, impaired ventricular filling occurs because of prolongation of As-Vs interval when heart rate exceeds about 200/min. The sympathetic stimulation which lengthens the diastolic filling period and shortens the As-Vs interval enables the atrium to perform more vigorous and properly timed contractions and leads to an increase in ventricular diastolic filling accompanied by a reduction in right atrial pressure. Effect of vagal stimulation. It is generally accepted that the vagal nerves depress the contractility of the atrium. But evidences regarding their effect on the performance of the ventricle are contradictory.27-33) SARNOFF et al.31) studied the effect of vagal stimulation on the relation of left ventricular end diastolic pressure to stroke work (left ventricular function curve) and con- cluded that the contractility of the ventricle is not affected by vagal stimulation, since no change was detected in the left ventricular function curve. On the other hand, DEGEEST et al.32) observed an inhibitory shift of the function curve caused by the stimulation. These two experiments were carried out under the essentially identical conditions. The present result seems to support SARNOFF'S view. As stated before a decrease in output brought about by vagal nerve stimulation could be observed in the atrially paced hearts but not in the ventricle paced hearts. This suggests that (1) ventricular pacing CARDIAC OUTPUT-HEART RATE RELATIONSHIP 551 largely eliminates the effect of varied atrial contribution to the degree of ventricular filling before and after vagal stimulation, and (2) no significant change takes places in the ventricular contractility as a result of vagal stimulation. Since the ventricular contractility appears to be unaffected by vagal stimulation, the observed shift of the cardiac output-heart rate relationship in the atrially paced hearts is to be attributed solely to the diminished atrial contractility. Further evidence for this interpretation was provided by the fact that the end diastolic ventricular volume was reduced by vagal stimulation in the atrially paced hearts (FIG.5). In the spontaneously beating heart, supraliminal vagal stimulation diminishes both the rate and output. The cardiac output-heart rate relationship curve obtained from the present study indicated only a slight downward shift confined to the super-normal range of heart rate. It therefore follows that the reduced output of the spontaneously beating heart during vagal stimulation is accounted for mainly by the cardiac deceleration and the shift of the cardiac output-heart rate relationship revealed in the present study probably bears little importance under physiological circumstances. Effect of changes in venous return and arterial resistance. The significance of filling pressure as a determinant of the cardiac output-heart rate relationship was examined by SUGIMOTO et al.34) Their study, in which cardiac output-heart rate relationship was measured under variously fixed atrial pressure, revealed that the optimal heart rate for maximal cardiac output shifts to a higher rate region as atrial pressure was elevated. Although the shift to a higher heart rate of the lowest rate of the plateau coincides with the present result, the same directional shift of the highest rate of the plateau was seldom observed in the present study. One possible reason for this discrepancy is a difference in magnitude of the pressor response to sinoaortic stimuli. In their study bilateral vagal nerves were severed at the cervical region. Consequently part of the efferent path of the sino-aortic reflex was eliminated as well as the afferent path. As shown before the efferent vagal stimuli exerts a definite influence on cardiac output especially at high heart rates. Moreover they anesthetized the animal with sodium pentobarbital, which is said to reduce the pressor response elicited by sino-aortic reflex,35) whereas chloralose used in this study is reputed to maintain or even facilitate the reflex.36,37) The pressor response is more prominent at the high heart rate region because of the rate sensitive property of the sino-aortic baroceptors.38,39) Therefore, the above mentioned difference at high heart rate region may be attributed to the different efficiency of the sino-aortic pressor reflex. A decrease in cardiac output due to the increased peripheral resistance produced by mechanical compression of the aorta has already been noticed in the innervated closed circulatory system.40,41) In these experiments cardiac output was measured under the steady state attained sufficiently after the 552 M. KUMADA, T. AZUMA AND K. MATSUDA

increase of resistance. In the study of MATTOS et al.41) the rise of blood pressure caused by the compression of the brachiocephalic artery did not induce the fall of cardiac output, because carotid sinus pressure was not raised by the compression. This suggests that the elevated carotid sinus pressure is primarily responsible for the decrease in cardiac output followed by the compression of the aorta.

SUMMARY

1. In anesthetized open-chested dogs, relations of electrically paced heart rate to cardiac output and to other related variables were studied before and after changing one of the following four parameters: cardiac sympathetic activity, cardiac vagal activity, venous return and arterial resistance. 2. When heart rate was elevated from 40 to 60/min in control experiments, cardiac output kept increasing until the rate reached approximately 110/min, remained almost constant between 110 and 200/min, and decreased above 200/min. 3. At every pacing rate a marked augmentation of cardiac output and stroke volume occurred with curtailed ejection time following stimulation of the left stellate ganglion. The faster the rate, the more prominent augmentation was observed. Cardiac output thus maintained the maximum level even at rates beyond 200/min. The marked augmentation of peak flow velocity seemed to be responsible for the increased stroke volume. 4. Vagal stimulation usually caused, exclusively over a high heart rate range (usually beyond 180/min), a slight but definite fall in cardiac output and stroke volume with decreased peak flow velocity and unchanged ejection time. Since the ventricular contractility was found unaffected, the observed fall was ascribed to the inhibitory vagal action on the atrium. 5. An increase in cardiac output and stroke volume was observed at every pacing rate following infusion of dextran saline solution. Ejection time and peak flow velocity were both increased by infusion. 6. Cardiac output and stroke volume were always decreased by compression of the descending aorta. The decrease was marked at high heart rates and associated with diminished peak flow velocity and prolonged ejection time.

The authors are deeply grateful to Drs. H. KANAI and J. IRIUCHIJIMAwho designed and constructed the electromagnetic flowmeter used in this study, and to Dr. K. SAGAWA for his valuable advice and criticism. Thanks are also due to Dr. I. MATSUBARAfor his help throughout this study. The expense needed for this study was defrayed, in part, by the grant of Ministery of Education awarded to one of the authors (M). CARDIAC OUTPUT-HEART RATE RELATIONSHIP 553

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