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Heart rate as a determinant of cardiac output in dogs with arteriovenous fistula
Experimental
Studies
Heart Rate as a Determinant of Cardiac Output in Dogs with Arteriovenous Fistula
ALLEN W. COWLEY, Jr., PhD ARTHUR C. GUYTON, MD, FACC Jackson,
Mississippi
From the Department of Physiology and of Mississippi Biophysics, University School of Medicine, Jackson, Miss. This work was supported by American Heart Association Grant 65495. and grants HE11678 and HE-08375 from the National Institutes of Health, Bethesda, Md. Manuscript received July 20, 1970, accepted September 16, 1970. Address for reprints: Allen W. Cowley, Jr., PhD, Department of Physiology and University of Mississippi Bioohvsics. Schoo\ of Medicine, 2500 North State St., Jackson, Miss. 39216.
VOLUME 28, SEPTEMBER 1971
The importance of heart rate in the control of cardiac output under conditions of a high level of venous return was studied in a series of 17 anesthetized open chest dogs with the atrioventrlcular bundle cut. The results show that high heart rates do not increase cardiac output under conditions of normal venous return. On the other hand, when venous return is markedly increased above normal by opening large arteriovenous fistulas, maximal cardiac output is achieved only at very high heart rates. As venous return increases, the heart rates at which maximal values of cardiac output are obtained are progressively increased. Norepinephrine or sympathetic stimulation further elevates the heart rate required for maximal cardiac output. These observations help to explain why tachycardia and the other cardiostimulant actions of the sympathetic nervous system play an important role in the regulation of cardiac output.
Many investigators in recent years have deemphasized the importance of heart rate as one of the factors helping to regulate cardiac output. This is a result partly of experiments that have shown that increasing heart rate as much as 100 percent with an artificial pacemaker fails to increase the resting cardiac output by more than a few percent.1-3 Furthermore, evidence from various sources indicates that the denervated heart can provide increased cardiac output during exercise by relying predominantly upon venous return and the Frank-Starling mechanism.4-” Thus, the heart has adequate stroke volume reserve to pump resting levels of venous return and much of the added load during exercise. Yet, under most normal conditions increased cardiac output is associated with increased heart rate but little or no increase in ventricular stroke volume.*s1+13 Therefore, the relation between venous return, heart rate and cardiac output is not clear. With the exception of one study,3 no attempt has been made to measure the effect of venous return on the relation of heart rate and ,cardiac output. In our experiments we examined the importance of heart rate in enhancing cardiac output when venous return is greatly increased by opening a large arteriovenous fistula. The results demonstrate that under these conditions, maximal levels of cardiac output can be achieved only when the heart rate is increased.
Met hods Seventeen mongrel dogs weighing 16 to 25 kg Animal preparation: were anesthetized with sodium pentobarbital, 30 mg/kg body weight. A right retroperitoneal opening was made to insert a large arteriovenous fistula between the abdominal aorta and inferior vena cava. Glass
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Figure 1. Effect of heart rate on cardiac output during control conditions (C); atteriovenous shunt partially open (RO); the shunt fully open (FO); shunt fully open with 3 pg/kg per min of norepinephrine infusion (NE). (Dog weight 23 kg.)
cannulas connected with polyvinyl tubing, 18 mm lumen in diameter, were used for the fistula, and the flow was controlled by an adjustable screw clamp placed on the tube. The distal ends of the aorta and inferior vena cava were ligated. The chest was opened at the +ight fourth intercostal space, while artificial ventilation was maintained with a Harvard respirator. The atrioventricular (A-V) bundle of the heart was blocked according to the technique of Taufic et a1.14 Briefly, both the venae cavae and the azygos vein were temporarily occluded with loops of umbilical tape. The right atrium was opened, and a heavy silk stitch was placed in the area of the ventricular septum containing the A-V bundle. This stitch was then tightened and the enclosed tissue transected or severely crushed. Care was taken to prevent the formation of an interventricular or interatrial communication. After placing the stitch, the atrium was allowed to fill with blood to expel air, and a clamp was used to close the incision. This procedure required less than 2 minutes, and if heart block was not produced, the procedure was repeated until successful. In some animals the atrium was then sutured; in others the clamp was kept in place, with care being taken to prevent obstruction of venous return. Postmortem examinations were performed on all hearts, and data were discarded from those animals with a septal defect. ?.@ ,_,..__
.i
_c
_
.._._.......
&_._
. . .._ .A
..-....-
-*
/-.,./
\
\
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E 9
20.
~
_._... -.--
\ “______X
.---
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Figure 2. Effect of Cushing reflex maneuver on cardiac output-heart rate relationship. Control conditions (C); arteriovenous shunt fully open (FO); shunt fully open with 3 &kg per min norepinephrine infusion (NE); shunt fully open during Cushing reflex stimulation ‘(CR). (Dog weight 17.2 kg.)
322
A unipolar electrode was attached to the epicardial surface of the ventricle near the interventricular septum, and the ventricles were paced with a Grass stimulator (model S-5) using a square pulse wave of 2 msec duration and 3 to 5 v intensity. Cardiac output was measured continuously using the Fick principle with an instrument designed in our laboratory.15 The instrument consists of a unit to determine photoelectrically arteriovenous oxygen difference, a paramagnetic oxygen analyzer to record oxygen consumption, and an analog computer to divide oxygen consumption by arteriovenous oxygen difference to give a continuous cardiac output recording. After heparinization of the dog with 10,000 units of heparin, the blood for the arteriovenous oxygen meter was continuously sampled by circulating blood from the pulmonary artery into the instrument and back to the jugular vein for venous oxygen measurement, and from the central end of a sectioned carotid artery and back again to the peripheral end of the same artery for the arterial oxygen sampling. The external jugular veins were used to insert all venous catheters, and the carotid arteries were used for the arterial catheters. A catheter was also inserted into the right atrium and the other carotid artery for blood pressure measurements. Statham transducers were used for pressure measurements, which were recorded on a Beckman type R recorder. Experimental procedure: In all 17 dogs cardiac output was continuously measured while heart rate was increased in steps, beginning at a heart rate of 50 beats/min and increasing to rates at which cardiac output was depressed by tachycardia. Cardiac output levels were allowed to reach a steady state before the heart rate was changed to the next step, which generally required 2 to 3 minutes. Tyrode’s solution, 15 ml/ kg, was infused at the beginning of the experiment to prevent an excessive decrease in blood pressure when the large arteriovenous fistula was opened. A slow infusion of Tyrode’s solution, 1.0 ml/min, was continued throughout the experiment. Changes in cardiac output caused by increasing heart rate were studied first with the fistula closed to obtain control records, then with the fistula open. The sequence was reversed in 5 dogs, and there was no significant change in results. In 8 dogs the cardiac output was determined by first increasing the heart rates, and then by decreasing rates back to the starting point to see if direction of change had any influence. In 13 dogs a curve was also determined with the fistula open and infusion of norepinephrine (2 to 4 &kg per min). In 2 dogs a curve was determined while a strong sympathetic Cushing response was being elicited. This was achieved by subjecting the brain to increased intracranial pressure.16 A 12 mm hole was trephined in the parietal bone, and a conical metal adapter was wedged tightly into the opening. Pressure was applied and maintained at about 200 mm Hg by attaching the adapter to a pressure bottle filled with saline solution.
Results . The effect of increased venous return on the relation between heart rate and cardiac output is shown for a typical experiment (Fig. 1). As the
The
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of CARDIOLOGY
CARDIAC
venous return was increased by opening the arteriovenous fistula, the heart rate at which the maximal cardiac output occurred was increased. With the fistula closed, cardiac output rose only 7.7 percent as the heart rate was increased in steps from 55 to 108 beats/min. There was a plateau at heart rates between 108 to 148 beats/ min before cardiac output began to fall at still higher heart rates. When the fistula was partially opened, there was an initial rise of 46 percent in cardiac output at 55 beats/min. Then this increased to a maximum of 115 percent at heart rates between 124 and 178 beats/min. When the fistula was fully opened, the cardiac output increased only 15 percent at 50 beats/min, but this steadily increased to a maximum of 169 percent at heart rates between 178 and 200 beats/min. Addition of norepinephrine shifted the curve even further upward and to the right, showing a 208 percent rise in cardiac output, with a plateau at heart rates between 148 and 240 beats/min. Values for cardiac output were not affected significantly by the direction in which the heart rates were changed experimentally (Fig. 1, third and fourth from the bottom). The relation was almost identical during both increasing (closed circles) and decreasing (open circles) heart rates. Similar results were observed in the remaining animals. The effect of eliciting a strong sympathetic reflex by the Cushing maneuver is seen in Figure 2. In this dog the maximal levels of cardiac output occurred at heart rates between 86 and 124 beats/ min with the fistula closed. The heart rates at which maximal levels of output occurred increased to 124 to 148 beats/min when the fistula was fully open. Addition of norepinephrine with the fistula open resulted in a maximal 208 percent increase in cardiac output at heart rates between 148 and 178 beats/min. Cardiac output rose a maximum of 300 percent from initial control values during the Cushing response and was maintained at this level at heart rates between 124 and 240 beats/min. Experiments of this type indicated that the curve is further elevated and that the maximal levels of cardiac output are sustained at even higher heart rates than during norepinephrine infusions. Figure 3 presents average results in 17 dogs, relating heart rate and the percent change in cardiac output at various levels of venous return. Cardiac output was elevated a maximum of only 10 percent over the entire range of heart rates under control conditions, peaking slightly at 100 beats/min. After partial opening of the arteriovenous fistula, the cardiac output rose 50 percent at heart rates of 55 beats/min but reached a 130 percent maximal rise at rates between 100 and 148 beats/min. With the fistula fully opened, the cardiac output rose 78 percent at 55 beats/min but increased rapidly to a maximal increase of 190 percent at heart rates between 148 and 200 beats/
VOLUME
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SEPTEMBER
1971
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Figure 3. Average resultsfrom 17 dogs showing the range of heart rates at which maximal cardiac outputs occur under control conditions (C); when the arteriovenous fistula is partially open (PO); when fully open (FO); and when fully open with norepinephrine (NE). Standard errors of the mean are indicated by vertical bars.
min. Infusion of norepinephrine while the fistula was fully open elevated the average level of cardiac output another 25 percent, which was sustained at heart rates as high as 240 beats/min. If the maximal percent increase in cardiac output, calculated from a control heart rate of 55 beats/min, is plotted against the corresponding heart rate that is found to exist at that maximal output level, the relation seen in Figure 4 is obtained. This shows that the optimal heart rate for the maximal cardiac output becomes increasingly greater as venous return is increased. An inverse relation was found between heart rate and stroke volume output in all experiments, 220 210
i
?-114+026X r =0.626 PC 0001
I
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200 CARDIAC
300 OUTPUT
400 (%
(%I
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Figure 4. Regression line calculated by least-square method. A significant correlation is shown illustrating that the optimal heart rate for maximal level of cardiac output is greater at increased levels of venous return.Solid dots = values with no arteriovenous fistula. Open triangles = values at various degrees of fistula opening.
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both in control conditions and when the arteriovenous fistula was open. During control curves, the level of right atria1 pressure declined from an average 3.4 -t 0.5 (SEM) mm Hg at a heart rate of 55 beats/mm to 2.3 -t 0.4 at 86/min, then climbed steadily to 3.0 % 0.4 at 200/min. When the fistula was open at heart rates of 55 beats/min, the level of right atria1 pressure rose to an average 4.9 t 0.6 mm Hg, then fell to 3.6 2 0.4 at 124/min and climbed steadily to 3.8 * 0.4 at 200/min.
Discussion The results show that as the level of venous return increases above normal, increasingly higher heart rates are necessary to achieve maximal levels of cardiac output. Under conditions of normal venous return, changes in heart rate have little effect on cardiac output, as demonstrated previously by several other investigators.2*3*g Miller et a1.l found cardiac output to be rate-dependent only at heart rates of less than 60/min. Our experiments show that when increased levels of venous return were provided by opening an arteriovenous fistula, heart rate assumed a permissive role in the regulation of cardiac output. That is, tachycardia had to occur if maximal levels of cardiac output were to be reached and sustained. This is demonstrated by the average data of Figure 3, which show that the 78 percent rise in cardiac output obtained by increasing venous return at heart rates of 55/min was increased to a maximum of 190 percent as heart rate increased. Therefore, cardiac output can be increased by merely opening an arteriovenous fistula at a constant heart rate, but maximal levels of cardiac output are not obtained until heart rate is also increased. Figures 3 and 4 show that the optimal heart rate, or range of heart rates, required to achieve maximal levels of cardiac output is shifted to a higher level as venous return is increased. The pumping reserve of the heart becomes inadequate at high levels of venous return, and heart rate then becomes one of the major determinants of cardiac output. The advantages gained by the increased heart rate becomes less and less as heart rate approaches 200 beats/min ; this has been shown to be due primarily to decreased diastolic filling period, incomplete ventricular relaxation and increasing viscous resistance to ventricular distension.IJ’J8 These factors of mechanical impedance were probably operative in our experi-
ments as seen by the consistent decrease in cardiac stroke volume with tachycardia. The plateau shown on all curves in Figures 1 to 3 is a result of decreasing stroke volume as heart rate is increased. However, at high levels of venous return, this impedance to ventricular filling does not appear to offset the advantage gained from increased heart rate until rates exceed 200 beats/min. Effect of sympathetic activity: Catecholamines or reflex sympathetic activity reinforces the effects of heart rate upon cardiac output, as can be seen by the upward and rightward shift of the curves in Figures 1 to 3. Since sympathetic activity and increased heart rate normally occur together, these effects can be expected to reinforce each other in the normal intact animal. A family of curves is suggested by Figure 2, describing the relation between heart rate and cardiac output at various levels of heart rate and sympathetic activity. The curves shift upward and to the right at constant levels of venous return as the sympathetic activity increases. Maximal cardiac output is, therefore, probably not obtained in the intact animal without the reflex changes in heart rate that are normally observed. Donald et a1.5Jgreached a similar conclusion after comparing the racing performance of normal and cardiac denervated greyhounds with beta adrenergic receptor blockade. The method used to control heart rate could have resulted in some degree of depression of cardiac output. For instance, ventricular pacing was shown by WiggerPJ1 to be less efficient than atria1 pacing due to less synchronous ventricular contractions and to a certain degree of mitral regurgitation. Clinical implications : In conclusion, these data demonstrate the importance of heart rate in determining cardiac output under conditions of increased venous return. At normal levels of venous return, heart rate within wide limits is of little importance in determining cardiac output. When venous return is increased, maximal levels of cardiac output are not obtained unless heart rate is also increased. At high levels of venous return, the levels of cardiac output become maximal at heart rates of 160 to 200 beats/min, and these effects are enhanced still further by catecholamines and sympathetic stimulation. These observations help to explain why tachycardia and the other cardiostimulant actions of the sympathetic nervous system play an important role in the control of cardiac output during exercise.
References 1. Miller DE, Gleason WL, Whalen RE, et al: Effect of ventricular rate on the cardiac output in the dog with chronic heart block. Circ Res 10:658-663,1962 2. Nakano J: Effects of atrial and ventricular tachycardia on cardiovascular dynamics. Amer J Physiol 206:547552, 1964 3. Sugimotb T, Sagawa K, Guyton AC: Effect of tachycardia on cardiac output during normal and increased venous 324
return. Amer J Physiol 211:288-292, 1966 Bronha L, Cannon WB, Dill DB: The heart rate of the sympathectomized dog in rest and exercise. J Physiol (London) 87:345-359, 1936 5. Donald DE, Ferguson DA, Milburn SE: Effect of B-adrenergic receptor blockade on racing performance of greyhounds with normal and denervated hearts. CirC Res 22:127-134, 1968
4.
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6. Donald DE, Shepherd JT: with cardiac 1963
denervation.
Response to exercise in dogs Amer J Physiol 205:393-400,
7. Donald DE, Shepherd JT: Initial cardiovascular adjustment to exercise in dogs with chronic cardiac denervation. Amer J Physiol 20731325-1329,1964 8. Donald DE, Shepherd JT: Sustained capacity for exercise in dogs after complete cardiac denervation. Amer J Cardiol 14:853-859, 1964 Regulation of cardiac output 9. Warner HR, Toronto AF: through stroke volume. Circ Res 8:549-552, 1960 10. Franklin DL. Ellis RM. Rushmer RF: Aortic blood flow in dogs during treadmill exercise. J Appl Physiol 14:809812,1959 11. Khouri EM, Gregg DE, Rayford CR: Effect of exercise on cardiac output, left coronary flow, and myocardial metabolism in the unanesthetized dog. Circ Res 17:427437,1965 12. Rushmer RF: Constancy of stroke volume in ventricular response to excretion. Amer J Physiol 196:745-750, 1959 13. Wang Y, Marshall RJ, Shepherd JT: Stroke volume in the dog during graded exercise. Circ Res 8:558-563, 1960 14. Taufic M, Bashour FA, Lewis FJ: Production of heart
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16.
17.
18.
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block in dogs, under direct vision. Surg Forum 5:96-100, 1954 Guyton AC, Farish CA, Abernathy JB: A continuous cardiac output recorder employing the Fick principle. Circ Res 7:661-665, 1959 Richardson TQ, Fermoso JD: Elevation of mean circulatory pressure in dogs with cerebral ischemia-induced hypertension. J Appl Physiol 19:1133-1134, 1964 Braunwald E. Frve RL. ROSSJ Jr: Studies on Starliruz’s law of the hear-t: determination of the relationship i;el tween left ventricular end-diastolic pressure and circumference. Circ Res 8:1254-1263, 1960 Buckley NM, Ogden E, Linton DS Jr: The effects of work load and heart rate on filling of the isolated right ventricle of the dog heart. Circ Res 3:434446, 1955 Donald DE, Milburn SE, Shepard JT: Effect of cardiac denervation on the maximal capacity for exercise in the racing greyhound. 19:849-852, J APP~ Physiol 1964 Wiggers CJ: The muscular reactions of the mammalian ventricles to artificial surface stimuli. Amer J Physiol 73:346-378, 1925 The interpretation of the intraventricular Wiggers CJ: pressure curve on the basis of rapidly summated fractionate contractions. Amer J Physiol 80:1-l 1, 1927
325
Studies
Heart Rate as a Determinant of Cardiac Output in Dogs with Arteriovenous Fistula
ALLEN W. COWLEY, Jr., PhD ARTHUR C. GUYTON, MD, FACC Jackson,
Mississippi
From the Department of Physiology and of Mississippi Biophysics, University School of Medicine, Jackson, Miss. This work was supported by American Heart Association Grant 65495. and grants HE11678 and HE-08375 from the National Institutes of Health, Bethesda, Md. Manuscript received July 20, 1970, accepted September 16, 1970. Address for reprints: Allen W. Cowley, Jr., PhD, Department of Physiology and University of Mississippi Bioohvsics. Schoo\ of Medicine, 2500 North State St., Jackson, Miss. 39216.
VOLUME 28, SEPTEMBER 1971
The importance of heart rate in the control of cardiac output under conditions of a high level of venous return was studied in a series of 17 anesthetized open chest dogs with the atrioventrlcular bundle cut. The results show that high heart rates do not increase cardiac output under conditions of normal venous return. On the other hand, when venous return is markedly increased above normal by opening large arteriovenous fistulas, maximal cardiac output is achieved only at very high heart rates. As venous return increases, the heart rates at which maximal values of cardiac output are obtained are progressively increased. Norepinephrine or sympathetic stimulation further elevates the heart rate required for maximal cardiac output. These observations help to explain why tachycardia and the other cardiostimulant actions of the sympathetic nervous system play an important role in the regulation of cardiac output.
Many investigators in recent years have deemphasized the importance of heart rate as one of the factors helping to regulate cardiac output. This is a result partly of experiments that have shown that increasing heart rate as much as 100 percent with an artificial pacemaker fails to increase the resting cardiac output by more than a few percent.1-3 Furthermore, evidence from various sources indicates that the denervated heart can provide increased cardiac output during exercise by relying predominantly upon venous return and the Frank-Starling mechanism.4-” Thus, the heart has adequate stroke volume reserve to pump resting levels of venous return and much of the added load during exercise. Yet, under most normal conditions increased cardiac output is associated with increased heart rate but little or no increase in ventricular stroke volume.*s1+13 Therefore, the relation between venous return, heart rate and cardiac output is not clear. With the exception of one study,3 no attempt has been made to measure the effect of venous return on the relation of heart rate and ,cardiac output. In our experiments we examined the importance of heart rate in enhancing cardiac output when venous return is greatly increased by opening a large arteriovenous fistula. The results demonstrate that under these conditions, maximal levels of cardiac output can be achieved only when the heart rate is increased.
Met hods Seventeen mongrel dogs weighing 16 to 25 kg Animal preparation: were anesthetized with sodium pentobarbital, 30 mg/kg body weight. A right retroperitoneal opening was made to insert a large arteriovenous fistula between the abdominal aorta and inferior vena cava. Glass
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Figure 1. Effect of heart rate on cardiac output during control conditions (C); atteriovenous shunt partially open (RO); the shunt fully open (FO); shunt fully open with 3 pg/kg per min of norepinephrine infusion (NE). (Dog weight 23 kg.)
cannulas connected with polyvinyl tubing, 18 mm lumen in diameter, were used for the fistula, and the flow was controlled by an adjustable screw clamp placed on the tube. The distal ends of the aorta and inferior vena cava were ligated. The chest was opened at the +ight fourth intercostal space, while artificial ventilation was maintained with a Harvard respirator. The atrioventricular (A-V) bundle of the heart was blocked according to the technique of Taufic et a1.14 Briefly, both the venae cavae and the azygos vein were temporarily occluded with loops of umbilical tape. The right atrium was opened, and a heavy silk stitch was placed in the area of the ventricular septum containing the A-V bundle. This stitch was then tightened and the enclosed tissue transected or severely crushed. Care was taken to prevent the formation of an interventricular or interatrial communication. After placing the stitch, the atrium was allowed to fill with blood to expel air, and a clamp was used to close the incision. This procedure required less than 2 minutes, and if heart block was not produced, the procedure was repeated until successful. In some animals the atrium was then sutured; in others the clamp was kept in place, with care being taken to prevent obstruction of venous return. Postmortem examinations were performed on all hearts, and data were discarded from those animals with a septal defect. ?.@ ,_,..__
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Figure 2. Effect of Cushing reflex maneuver on cardiac output-heart rate relationship. Control conditions (C); arteriovenous shunt fully open (FO); shunt fully open with 3 &kg per min norepinephrine infusion (NE); shunt fully open during Cushing reflex stimulation ‘(CR). (Dog weight 17.2 kg.)
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A unipolar electrode was attached to the epicardial surface of the ventricle near the interventricular septum, and the ventricles were paced with a Grass stimulator (model S-5) using a square pulse wave of 2 msec duration and 3 to 5 v intensity. Cardiac output was measured continuously using the Fick principle with an instrument designed in our laboratory.15 The instrument consists of a unit to determine photoelectrically arteriovenous oxygen difference, a paramagnetic oxygen analyzer to record oxygen consumption, and an analog computer to divide oxygen consumption by arteriovenous oxygen difference to give a continuous cardiac output recording. After heparinization of the dog with 10,000 units of heparin, the blood for the arteriovenous oxygen meter was continuously sampled by circulating blood from the pulmonary artery into the instrument and back to the jugular vein for venous oxygen measurement, and from the central end of a sectioned carotid artery and back again to the peripheral end of the same artery for the arterial oxygen sampling. The external jugular veins were used to insert all venous catheters, and the carotid arteries were used for the arterial catheters. A catheter was also inserted into the right atrium and the other carotid artery for blood pressure measurements. Statham transducers were used for pressure measurements, which were recorded on a Beckman type R recorder. Experimental procedure: In all 17 dogs cardiac output was continuously measured while heart rate was increased in steps, beginning at a heart rate of 50 beats/min and increasing to rates at which cardiac output was depressed by tachycardia. Cardiac output levels were allowed to reach a steady state before the heart rate was changed to the next step, which generally required 2 to 3 minutes. Tyrode’s solution, 15 ml/ kg, was infused at the beginning of the experiment to prevent an excessive decrease in blood pressure when the large arteriovenous fistula was opened. A slow infusion of Tyrode’s solution, 1.0 ml/min, was continued throughout the experiment. Changes in cardiac output caused by increasing heart rate were studied first with the fistula closed to obtain control records, then with the fistula open. The sequence was reversed in 5 dogs, and there was no significant change in results. In 8 dogs the cardiac output was determined by first increasing the heart rates, and then by decreasing rates back to the starting point to see if direction of change had any influence. In 13 dogs a curve was also determined with the fistula open and infusion of norepinephrine (2 to 4 &kg per min). In 2 dogs a curve was determined while a strong sympathetic Cushing response was being elicited. This was achieved by subjecting the brain to increased intracranial pressure.16 A 12 mm hole was trephined in the parietal bone, and a conical metal adapter was wedged tightly into the opening. Pressure was applied and maintained at about 200 mm Hg by attaching the adapter to a pressure bottle filled with saline solution.
Results . The effect of increased venous return on the relation between heart rate and cardiac output is shown for a typical experiment (Fig. 1). As the
The
American
Journal
of CARDIOLOGY
CARDIAC
venous return was increased by opening the arteriovenous fistula, the heart rate at which the maximal cardiac output occurred was increased. With the fistula closed, cardiac output rose only 7.7 percent as the heart rate was increased in steps from 55 to 108 beats/min. There was a plateau at heart rates between 108 to 148 beats/ min before cardiac output began to fall at still higher heart rates. When the fistula was partially opened, there was an initial rise of 46 percent in cardiac output at 55 beats/min. Then this increased to a maximum of 115 percent at heart rates between 124 and 178 beats/min. When the fistula was fully opened, the cardiac output increased only 15 percent at 50 beats/min, but this steadily increased to a maximum of 169 percent at heart rates between 178 and 200 beats/min. Addition of norepinephrine shifted the curve even further upward and to the right, showing a 208 percent rise in cardiac output, with a plateau at heart rates between 148 and 240 beats/min. Values for cardiac output were not affected significantly by the direction in which the heart rates were changed experimentally (Fig. 1, third and fourth from the bottom). The relation was almost identical during both increasing (closed circles) and decreasing (open circles) heart rates. Similar results were observed in the remaining animals. The effect of eliciting a strong sympathetic reflex by the Cushing maneuver is seen in Figure 2. In this dog the maximal levels of cardiac output occurred at heart rates between 86 and 124 beats/ min with the fistula closed. The heart rates at which maximal levels of output occurred increased to 124 to 148 beats/min when the fistula was fully open. Addition of norepinephrine with the fistula open resulted in a maximal 208 percent increase in cardiac output at heart rates between 148 and 178 beats/min. Cardiac output rose a maximum of 300 percent from initial control values during the Cushing response and was maintained at this level at heart rates between 124 and 240 beats/min. Experiments of this type indicated that the curve is further elevated and that the maximal levels of cardiac output are sustained at even higher heart rates than during norepinephrine infusions. Figure 3 presents average results in 17 dogs, relating heart rate and the percent change in cardiac output at various levels of venous return. Cardiac output was elevated a maximum of only 10 percent over the entire range of heart rates under control conditions, peaking slightly at 100 beats/min. After partial opening of the arteriovenous fistula, the cardiac output rose 50 percent at heart rates of 55 beats/min but reached a 130 percent maximal rise at rates between 100 and 148 beats/min. With the fistula fully opened, the cardiac output rose 78 percent at 55 beats/min but increased rapidly to a maximal increase of 190 percent at heart rates between 148 and 200 beats/
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Figure 3. Average resultsfrom 17 dogs showing the range of heart rates at which maximal cardiac outputs occur under control conditions (C); when the arteriovenous fistula is partially open (PO); when fully open (FO); and when fully open with norepinephrine (NE). Standard errors of the mean are indicated by vertical bars.
min. Infusion of norepinephrine while the fistula was fully open elevated the average level of cardiac output another 25 percent, which was sustained at heart rates as high as 240 beats/min. If the maximal percent increase in cardiac output, calculated from a control heart rate of 55 beats/min, is plotted against the corresponding heart rate that is found to exist at that maximal output level, the relation seen in Figure 4 is obtained. This shows that the optimal heart rate for the maximal cardiac output becomes increasingly greater as venous return is increased. An inverse relation was found between heart rate and stroke volume output in all experiments, 220 210
i
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I
I+-
100 MAXIMUM
200 CARDIAC
300 OUTPUT
400 (%
(%I
increase)
Figure 4. Regression line calculated by least-square method. A significant correlation is shown illustrating that the optimal heart rate for maximal level of cardiac output is greater at increased levels of venous return.Solid dots = values with no arteriovenous fistula. Open triangles = values at various degrees of fistula opening.
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both in control conditions and when the arteriovenous fistula was open. During control curves, the level of right atria1 pressure declined from an average 3.4 -t 0.5 (SEM) mm Hg at a heart rate of 55 beats/mm to 2.3 -t 0.4 at 86/min, then climbed steadily to 3.0 % 0.4 at 200/min. When the fistula was open at heart rates of 55 beats/min, the level of right atria1 pressure rose to an average 4.9 t 0.6 mm Hg, then fell to 3.6 2 0.4 at 124/min and climbed steadily to 3.8 * 0.4 at 200/min.
Discussion The results show that as the level of venous return increases above normal, increasingly higher heart rates are necessary to achieve maximal levels of cardiac output. Under conditions of normal venous return, changes in heart rate have little effect on cardiac output, as demonstrated previously by several other investigators.2*3*g Miller et a1.l found cardiac output to be rate-dependent only at heart rates of less than 60/min. Our experiments show that when increased levels of venous return were provided by opening an arteriovenous fistula, heart rate assumed a permissive role in the regulation of cardiac output. That is, tachycardia had to occur if maximal levels of cardiac output were to be reached and sustained. This is demonstrated by the average data of Figure 3, which show that the 78 percent rise in cardiac output obtained by increasing venous return at heart rates of 55/min was increased to a maximum of 190 percent as heart rate increased. Therefore, cardiac output can be increased by merely opening an arteriovenous fistula at a constant heart rate, but maximal levels of cardiac output are not obtained until heart rate is also increased. Figures 3 and 4 show that the optimal heart rate, or range of heart rates, required to achieve maximal levels of cardiac output is shifted to a higher level as venous return is increased. The pumping reserve of the heart becomes inadequate at high levels of venous return, and heart rate then becomes one of the major determinants of cardiac output. The advantages gained by the increased heart rate becomes less and less as heart rate approaches 200 beats/min ; this has been shown to be due primarily to decreased diastolic filling period, incomplete ventricular relaxation and increasing viscous resistance to ventricular distension.IJ’J8 These factors of mechanical impedance were probably operative in our experi-
ments as seen by the consistent decrease in cardiac stroke volume with tachycardia. The plateau shown on all curves in Figures 1 to 3 is a result of decreasing stroke volume as heart rate is increased. However, at high levels of venous return, this impedance to ventricular filling does not appear to offset the advantage gained from increased heart rate until rates exceed 200 beats/min. Effect of sympathetic activity: Catecholamines or reflex sympathetic activity reinforces the effects of heart rate upon cardiac output, as can be seen by the upward and rightward shift of the curves in Figures 1 to 3. Since sympathetic activity and increased heart rate normally occur together, these effects can be expected to reinforce each other in the normal intact animal. A family of curves is suggested by Figure 2, describing the relation between heart rate and cardiac output at various levels of heart rate and sympathetic activity. The curves shift upward and to the right at constant levels of venous return as the sympathetic activity increases. Maximal cardiac output is, therefore, probably not obtained in the intact animal without the reflex changes in heart rate that are normally observed. Donald et a1.5Jgreached a similar conclusion after comparing the racing performance of normal and cardiac denervated greyhounds with beta adrenergic receptor blockade. The method used to control heart rate could have resulted in some degree of depression of cardiac output. For instance, ventricular pacing was shown by WiggerPJ1 to be less efficient than atria1 pacing due to less synchronous ventricular contractions and to a certain degree of mitral regurgitation. Clinical implications : In conclusion, these data demonstrate the importance of heart rate in determining cardiac output under conditions of increased venous return. At normal levels of venous return, heart rate within wide limits is of little importance in determining cardiac output. When venous return is increased, maximal levels of cardiac output are not obtained unless heart rate is also increased. At high levels of venous return, the levels of cardiac output become maximal at heart rates of 160 to 200 beats/min, and these effects are enhanced still further by catecholamines and sympathetic stimulation. These observations help to explain why tachycardia and the other cardiostimulant actions of the sympathetic nervous system play an important role in the control of cardiac output during exercise.
References 1. Miller DE, Gleason WL, Whalen RE, et al: Effect of ventricular rate on the cardiac output in the dog with chronic heart block. Circ Res 10:658-663,1962 2. Nakano J: Effects of atrial and ventricular tachycardia on cardiovascular dynamics. Amer J Physiol 206:547552, 1964 3. Sugimotb T, Sagawa K, Guyton AC: Effect of tachycardia on cardiac output during normal and increased venous 324
return. Amer J Physiol 211:288-292, 1966 Bronha L, Cannon WB, Dill DB: The heart rate of the sympathectomized dog in rest and exercise. J Physiol (London) 87:345-359, 1936 5. Donald DE, Ferguson DA, Milburn SE: Effect of B-adrenergic receptor blockade on racing performance of greyhounds with normal and denervated hearts. CirC Res 22:127-134, 1968
4.
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of CARDIOLOGY
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6. Donald DE, Shepherd JT: with cardiac 1963
denervation.
Response to exercise in dogs Amer J Physiol 205:393-400,
7. Donald DE, Shepherd JT: Initial cardiovascular adjustment to exercise in dogs with chronic cardiac denervation. Amer J Physiol 20731325-1329,1964 8. Donald DE, Shepherd JT: Sustained capacity for exercise in dogs after complete cardiac denervation. Amer J Cardiol 14:853-859, 1964 Regulation of cardiac output 9. Warner HR, Toronto AF: through stroke volume. Circ Res 8:549-552, 1960 10. Franklin DL. Ellis RM. Rushmer RF: Aortic blood flow in dogs during treadmill exercise. J Appl Physiol 14:809812,1959 11. Khouri EM, Gregg DE, Rayford CR: Effect of exercise on cardiac output, left coronary flow, and myocardial metabolism in the unanesthetized dog. Circ Res 17:427437,1965 12. Rushmer RF: Constancy of stroke volume in ventricular response to excretion. Amer J Physiol 196:745-750, 1959 13. Wang Y, Marshall RJ, Shepherd JT: Stroke volume in the dog during graded exercise. Circ Res 8:558-563, 1960 14. Taufic M, Bashour FA, Lewis FJ: Production of heart
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block in dogs, under direct vision. Surg Forum 5:96-100, 1954 Guyton AC, Farish CA, Abernathy JB: A continuous cardiac output recorder employing the Fick principle. Circ Res 7:661-665, 1959 Richardson TQ, Fermoso JD: Elevation of mean circulatory pressure in dogs with cerebral ischemia-induced hypertension. J Appl Physiol 19:1133-1134, 1964 Braunwald E. Frve RL. ROSSJ Jr: Studies on Starliruz’s law of the hear-t: determination of the relationship i;el tween left ventricular end-diastolic pressure and circumference. Circ Res 8:1254-1263, 1960 Buckley NM, Ogden E, Linton DS Jr: The effects of work load and heart rate on filling of the isolated right ventricle of the dog heart. Circ Res 3:434446, 1955 Donald DE, Milburn SE, Shepard JT: Effect of cardiac denervation on the maximal capacity for exercise in the racing greyhound. 19:849-852, J APP~ Physiol 1964 Wiggers CJ: The muscular reactions of the mammalian ventricles to artificial surface stimuli. Amer J Physiol 73:346-378, 1925 The interpretation of the intraventricular Wiggers CJ: pressure curve on the basis of rapidly summated fractionate contractions. Amer J Physiol 80:1-l 1, 1927
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