determining factor in this adaptation has been shown to be the dilatation of the heart cavities rather than the pressure within them, so that

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1 THE MECHANICAL REGULATION OF THE HEART BEAT IN THE TORTOISE. BY S. KOZAWA, M.D. (Osaka). (From the Institute of Physiology, University College, London.) IN recent papers(l) from this laboratory on the regulation of the mammalian heart beat, it has been shown that the heart is able to adapt its performance to the varying demands made upon it, either by increased peripheral resistance or by increased diastolic inflow, so that alterations in arterial pressure within wide limits do not alter the ventricular output, while the heart is able to deal with and send on into the arteries whatever blood it receives from the veins, and so is able to increase its output in proportion to increased inflow. The determining factor in this adaptation has been shown to be the dilatation of the heart cavities rather than the pressure within them, so that it was concluded that it is length rather than tension of the muscle fibres which determines the energy of their contraction. The heart muscle of mammals is therefore subject to the same laws as those determined by Blix and by A. V. Hill for the mechanical and thermal response to excitation in frogs' skeletal muscle. The work on the warm-blooded heart suffers from the disadvantage that it is not possible, without seriously interfering with the physiological condition of the heart, to obtain a true isometric contraction. Moreover alterations in the volume of inflow bring about corresponding alterations in the pulse pressure, so that the heart beat and the tension on the cardiac muscle with a low inflow are not strictly comparable with those occurring under conditions of large inflow. Both these drawbacks can be avoided by having recourse to the heart of coldblooded animals, such as the frog and tortoise, where, as Frank(2) has shown, it is possible to investigate either the isometric or the isotonic response of the heart under varying conditions of inflow, tension and filling, and arterial resistance. The attempt by R oh d e (3) to obtain the same conditions in the warm-blooded heart cannot be regarded as altogether successful.-

2 234 S. KOZA WA. At Professor Sturling's suggestion I have therefore attempted to discover whether a reinvestigation of the contraction of the coldblooded heart by methods somewhat similar to those employed by Frank might not result in a confirmation of the conclusions arrived at by the authors named in their work on the warm-blooded heart, and whether it might not be possible to get a clearer idea of the conditions of activity of the heart muscle by an investigation of its action in an animal in which our methods of experiment would be physically more perfect than was possible in the warm-blooded animal. I especially desired to find whether in the frog's heart the determining factor for the energy of the contraction was to be regarded as the initial tension or the initial length of the muscle fibre. I. ISOMETRIC CONTRACTION. In the tortoise heart I have investigated the relationship between the filling and the pressure during diastole and the pressure developed during systole, the filling representing the length of the muscle fibres while the pressure developed represents the tension exerted by these fibres. The arrangement of the experiment is similar to that adopted by Frank. The isolated ventricle of the tortoise is tied on to a Kronecker's perfusion cannula, which is introduced through the atrio-ventricular orifice. The aorta is ligatured (Fig. 1). One branch of the cannula is connected to a HUrthle's manometer, T, by means of a lead tube. In the course of this tube is placed a three-way glass tap A. The other branch is connected by a lead tube with another three-way tap B. By this tap the tube is in connection with a reservoir R, and a measuring tube formed by a 1 c.c. pipette graduated in -Lths, M. Both the latter are filled with G6thlin's modification of Ringer's solution. After tying on the heart, the Ringer's solution is allowed to flow freely from the reservoir R through the heart to C. When the beats of the heart are regular, tap B is turned off, and when the heart has thoroughly emptied itself, the tap is turned so as to put its cavity in connection with the Hiirthle manometer. If the lever of the tambour shows no movement, tap B is turned so as to allow the desired quantity of fluid from M to run into the ventricle. As soon as the heart contains some fluid, its contractions are recorded by movements of the membrane of the manometer, which are recorded

3 REGULATION OF HEART BEAT. 235 on a slowly moving drum. In this way we can obtain the isometric tracing of the ventricular contraction with gradually increasing filling Fig. 1. Arrangement of apparatus for recording isometric contractions of tortoise ventricle under varying degrees of filling. -I Fig. 2. Isometric and cardiometric tracings of tortoise heart (upper curves = isometric contractions, lowest line=volume of heart). The figures refer to the volume of the heart contents. of the heart. In the case of the frog's heart the fluid is admitted 01 c.c. at a time; with a large tortoise heart the fluid is admitted

4 236 S. KOZA WA. *2 c.c. at a time, a tracing of the contraction being taken with each degree of filling. That the curves are really isometric may be shown by enclosing the heart in a plethysmograph by the method described later on in this paper. This is shown in the tracing given in Fig. 2. It will be seen that as fluid is allowed to flow into the heart, the volume increases at once, but the change during each beat (due to the slight movement of the rubber membrane of the manometer) is not noticeable. The absence of change of volume is a satisfactory control of the rigidity of the tubes connecting the heart with the manometer. Thus no appreciable alteration in the volume of the heart takes place when it contracts and gives an excursion of the manometer lever. In this way we obtain curves an example of which is given in Fig. 3. The results of -two such experiments are given in the following tables. to S itto 1.5 2O 2, n Fig. 3. Isometric contractions of tortoise ventricle (from a large tortoie) with varying filling. The figures below each curve refer to the volume of fluid contained by the ventricle in c.c. Exp. 1. Large tortoise heart. Room temp C. Filling Initial tension Maximum tension -Absolute value c.c. mm. Hg mm. Hg mm. Hg :0

5 REGULATION OF HEART BEAT. 237 Exr. 2. Large tortoise heart. Filling Initial tension Maximum tension Absolute value cc. mm. Hg mm. Hg mm. Hg * * *0 43* *0 2* a * * It will be seen that as the filling of the ventricles gradually increases there is a slight increase in the diastolic pressure within the heart cavity, so that the ventricular muscle commences to beat with a certain positive tension. On the other hand, the maximal tension developed during the contraction rises rapidly with increased filling of the ventricles, and this rise applies not only to the maximal tension developed but also to its "absolute value," i.e. the difference between the diastolic and the systolic pressures. As the filling is increased beyond a certain limit, which varies with the size of the heart but in the two experiments quoted was about 3 c.c., the initial or diastolic pressure begins to rise rapidly, while the rate of rise of the maximal pressure developed slows off, so that the absolute value of the pressure developed during the contraction diminishes. We may therefore in the tortoise, as in the warm-blooded heart, speak of an optimal state of distension of the heart cavities, or an optimal length of the muscle fibres. Thus the tension of the muscle fibres with increasing dilatation becomes less and less effective in producing a mechanical change which would be effective in carrying out the work of the heart. The relation between volume of the heart and initial and final tensions is shown in Fig. 4, where the ordinates represent the volume of the ventricle and the abscissa represents pressure developed during diastole and during systole. It is evident from this diagram that with increasing filling up to a certain point the absolute tension developed by the isometric contraction of the heart muscle increases to a maximum. Beyond this point the absolute tension begins to diminish. Before this optimum is arrived at the filling is always such as to produce a certain small positive pressure in the ventricles during diastole; but whereas the rise in absolute tension is at first proportional to the increase in the volume of the heart and in the length of its fibres, there is no such close relation between initial tension and final tension developed, so that when an

6 238 S. KOZA WA. appreciable rise of initial tension really occurs, the ventricular muscle is already approaching the limits of its performance. so O,S 40 4S, 21o 2,5 3,O 3.S 4,O Fig. 4. Diagram showing relation between filling, initial tension and final tension in a heart contracting isometrically (abscissa = volume of heart contents, ordinates = tension in mm. Hg.). so *10 60 so Jo 3o ,0 4,s5 ;O 2,S 3,o 3,5 4,o Fig. 5. Diagram showing relation between filling, initial and final tensions in a heart contracting isometrically under influence of increased CO2 tension. The effect of carbon dioxide. It has been shown by Patterson(4) that any increase in the carbon dioxide tension of the blood circulating

7 REGULATION OF HEART BEAT. 239 through the warm-blooded heart causes diminished functional capacity of the heart muscle, so that to develop the same amount of energy the muscle fibres have to be longer and the heart therefore dilates. The same story is told by a record of the isometric contractions of a tortoise ventricle fed by Ringer's solution which has been shaken up with a mixture of carbonic acid gas and air. The results of such an experiment are shown diagrammatically in Fig. 5. It will be seen from this that the response, i.e. the pressure developed during contraction, remains still small with a filling of 1-5 c.c., which produced an almost maximal systolic pressure in the experiment recorded in Fig. 4. With increasing filling there was a slight increase in the amount of energy set free but the rise of the lines showing systolic and diastolic tensions respectively will be observed to run almost parallel. The maximal absolute tension was obtained with a filling of 3.5 c.c., but in this case the diastolic tension was already over 30 mm. Hg. II. ISOTONIC CONTRACTION. In order to obtain isotonic contractions of the heart and to determine their relation (a) to filling, (b) to arterial pressure, the heart was placed in an oncometer connected with a piston recorder. The arrangement of the experiment is shown in Fig. 6. The isolated ventricle, V, of the tortoise heart is tied into a perfusion cannula. One limb of the cannula is connected by means of a rubber tube to a Marriotte's flask filled with Ringer's solution and serving as a reservoir. The other limb is connected by a piece of rubber tubing to a glass tube, d. This tube leads into a vessel C, the lower two-thirds of which contains mercury and the upper third Ringer's solution. By means of a screw adjustment the vessel C can be moved up or down, so that the tube d dips into the mercury to any desired extent. Both the tubes attached to the limbs of the perfusion cannula are provided with valves of goldbeaters' skin, which present practically no resistance to the flow of fluid but allow the flow to occur only in one direction, namely, from the reservoir to the heart and from the heart to the tube dipping into the vessel C. The use of the vessel C is to give a pressure of any desired extent which the heart must overcome to expel fluid. It represents an adjustable arterial resistance. The oncometer is made of a thistle funnel, over the mouth of which is stretched a thick rubber membrane. The cannula and heart are passed through a hole in this

8 240 S. KOZA WA. membrane, which is then tied tightly round the cannula. Variations in the size of the heart are recorded by means of a piston recorder attached to the oncometer. (a) Reaction of the heart to varying arterial resistance. By this arrangement it is possible to investigate whether the reaction of the tortoise heart to varying arterial resistance is the same as that of a mammalian heart. If the venous pressure, represented by the height a % 1c Fig. 6. Arrangement of apparatus for recording volume changes of tortoise heart, with variable filling and variable arterial resistance. of the inflow from the Marriotte's flask, and the temperature are maintained constant, shall we find the output within wide limits independent of the arterial pressure? That this is the case is shown by the following record of two experiments. In Exp. 3 the output remained practically constant between arterial pressures of 12 and 32 mm. Hg., i.e. 6-8 c.c. per minute. In Exp. 4 the output was constant between 9-1 and 9-4 c.c. per minute between arterial pressures of 6 and 16 mm. Hg. With a very low resistance the fluid could flow freely from the flask through the ventricle to the cylinder during diastole, so that the output measured by the fluid

9 REGULATION OF HEART BEAT. 241 Exp. 3. Large tortoiae heart. Height of inflow 7 cm. H3O. Temp C. Enr. 4. Height of inflow 7c.c. H20. Temp C. Resistance mm. Hg Friction only ExP. 3. Output per min. c.c x x x *4 Exp. 4. Resistance Output per min. mm. Hg c.c X *1 0 (return) 10-5 dropping from the side tube of the vessel C no longer gave the true systolic output of the ventricle. In this case the aortic pressure is lower than the venous pressure, a condition which never occurs under normal circumstances. When the resistance is still further increased the output diminishes in proportion to its height, i.e. the systolic volume is increased to such an extent that the difference between the diastolic volume determined by the venous pressure and the systolic volume determined by the pressure which the heart has to overcome is insufficient to maintain the previous output. Up to the optimum limit there is with rising arterial resistance increase both of systolic and diastolic volumes, but so long as the output remains constant the volume change at each beat is also constant. Above the limit, in Exp. 3, 32 mm. Hg. and in Exp. 4, 16 mm. Hg., the change in volume diminishes in proportion to the diminution in the output. The results obtained in this series of experiments therefore corroborates the conclusions arrived at from a study of the isometric contractions of the heart under varying conditions of distension. The adaptation of the heart muscle to wide variations of resistance is carried out by a variation in the length of the muscle fibres, the energy of contraction being proportional within limits to the length of these fibres. (b) The reaction of the heart to variations in the volume of inflow. These experiments were carried out in the same way as those described

10 242 S. KOZA WA. in the preceding section, the arterial pressure being maintained constant at a moderate height, while the inflow was varied by alterations in the height of the venous reservoir. Under these conditions it is found that the diastolic volume of the ventricle and its output increase in proportion to the volume of the inflow. The results of two such exp6riments are given in the following tables. Exp. 5. Large tortoiue heart. Temp C. Arterial resistance 16mm. Hg. Height of venous Output per min. reservoir cm. H20 c.c. Rate per min. 2* *2 12* * * *0 24*4 22* Exp. 6. Large tortoise heart. Temp C. Arterial pressure 32 mm. Hg. 2*0 1' * X *0 12*3 13* * (12-7) irregular On the other hand the systolic volume remains practically constant within wide limits, so that it is the excursion of the cardiometric lever, i.e. the difference between the systolic and diastolic volumes, which increases in proportion to the increased pressure of inflow. This is seen in the accompanying cardiometric tracing (Fig. 7). This result differs from those obtained by Patterson, Piper and Starling on the mammalian heart, in which increasing venous inflow always increased the systolic volume as well as diastolic volume, although the increase in the latter was the more marked. The results obtained in the tortoise heart are due to a more perfect realisation of the desired experimental conditions. A contracted muscle fibre has a certain length which depends on the tension to which it is subjected.

11 REGULATION OF HEART BEAT. 243 The volume of the heart at the end of systole will depend on the pressure in its cavity and therefore on that in the aorta at the end of systole. In the mammalian heart lung preparation, although it is possible to maintain the mean arterial pressure constant by relaxing the resistance with increasing inflow, the pulse pressure, i.e., the oscillations of pressure in the aorta with each heart beat, is increased with increase in the volume of the output of the heart. Although therefore the mean arterial pressure is the same as before, the systolic pressure is higher and the diastolic pressure is lower than with a smaller inflow. The tension on the muscle fibres of the ventricle at the end of systole is therefore A I) C X {F j"xi Fig. 7. Cardiometer tracings ot tortoise heart with different venous filling, the arterial resistance being maintained constant. Height of venous reservoir above heart, A, 2*0; B, 4*8; C, 7-6; D, 10-4; E, 13-2; F, 16-0; G, 18-8; H, 21-6; J, 24-4; K, 34-4 cm. increased by increasing the venous inflow. Their length, and the systolic volume of the heart, must therefore be increased in proportion. In my experiments on the tortoise heart the capacity of the tubes forming the arterial system is relatively so large and the rate of expulsion of the fluid from the ventricle so slow that the contraction of the ventricular muscle is almost perfectly isotonic, the pulse pressure is practically absent, and the arterial pressure can be regarded as constant throughout the whole of systole. If this is maintained constant the systolic volume of the heart must also remain constant. The diastolic volume of the heart depends however on the venous pressure and will increase in proportion to the latter, and the work done by the ventricle PH. XLIX. 16

12 244 S. KOZA WA. therefore increases in direct proportion to the venous filling of the heart and to the initial length of its muscle fibres. This is shown in the diagram (Fig. 8). When the venous pressure becomes too high the contraction becomes irregular, so that, as in Exp. 6, its output does not increase proportionally. On the other hand, in Exp. 5, the venous pressure was increased until it finally became higher than the arterial pressure itself and the results were no longer of value in throwing light on the activity of the heart muscle. A number of experiments of the same description as those detailed above were carried out on the frog's heart. In some respects they are easier than those on the tortoise heart because of the greater automaticity of the isolated frog's ventricle. The results were similar to 1.,0 ~~~~~~ wo 0so 4oo 45o 2Soo t5o 300 3SowvntMO. eue-, Fig. 8. Diagram showing influence of variationslin venous pressure on the output of the heart per beat, as measured by the comparison of systolic and diastolic volumes. Abscissa=ht. of venous reservoir. Ordinates=volume of heart in c.c. those on the tortoise heart, soi have not thought it necessary to quote them here. We thus find that a renewed investigation of the mechanical conditions of the heart beat in cold-blooded animals under the more perfect experimental control possible in these hearts fully confirms the results obtained by an investigation of the warm-blooded heart by means of the heart lung preparation. The wonderful power of the heart to adapt its performance to variations either in the arterial resistance which it has to overcome or to alterations in the amount of blood flowing into it from the venous.system, is shown to be due to the relation which exists between the length of the muscle fibres and the energy evolved during activity. The energy of contraction is thus a function of length or extent of active surface of the muscle fibres rather than of their initial tension.

13 REGULATION OF HEART BEAT. 245 SUMMARY. 1. A study of the isometric contractions of the tortoise ventricle shows that the energy of the contraction, as measured by the tension developed, increases with increase in the volume of the heart, i.e. the length of its muscle fibres, up to an optimum, and then rapidly diminishes. 2. The increase in energy of contraction is not dependent on the initial tension, since this increases but slowly while the energy of contraction is rising to a maximum, and rises rapidly after the optimum length has been surpassed. 3. The systolic size of the heart varies directly with the arterial resistance. The diastolic volume depends on the diastolic filling of the heart. The arterial pressure remaining constant, the output depends solely on the diastolic filling, the systolic volume being independent within wide limits of the diastolic filling. 4. The mechanical regulation of the heart beat is thus effected in virtue of the rule that the energy of contraction is a function of the length of the muscle fibres. W(5. The law of behaviour of the heart deduced from a study of the mammalian heart lung preparation is thus found to apply also to the cold-blooded heart. REFERENCES. (1) Markwalder and Starling. This Journal, xlvii. p Patterson and Starling. This Journal, XLVIII. p Patterson, Piper and Starling. This Journal, XLVm. p (2) Frank. Ztsch. f. Biol. xxxvn. p (3) Rohde. Arch. f. exp. Path. u. Pharm. LXVIII. p (4) Patterson. Proc. Roy. Soc. B. LXXXVI. p