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 cardio- acceleration 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 out- put 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 hemo- dynamic 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 gan- glion, all branches of which were severed except the anterior subclavian, was electri- cally 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 inten- sity of the stimulation was set at a level such that it would not produce atrio-ventri- cular 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 ap- proximately 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 be- tween 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, how- ever, 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 pres- sure 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 maxi- mum 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 con- trol 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).