Smith, Miller and Grab er(4) state that the maintenance of an efficient

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1 THE SIGNIFICANCE OF THE DIASTOLIC AND SYSTOLIC BLOOD-PRESSURES FOR THE MAINTENANCE OF THE CORONARY CIRCULATION. BY G. V. ANREP AND B. KING. (From the Physiological Laboratory, Cambridge.) IT is generally agreed that the arterial blood-pressure is the main circulatory factor determining the coronary blood flow, but as regards the relative importance of the diastolic and systolic pressures opinions differ. Starling and his co-workers (1,2,3) find that the coronary circulation is within wide limits independent of changes in pulse pressure provided that the mean aortic pressure is kept constant. On the other hand, Smith, Miller and Grab er(4) state that the maintenance of an efficient coronary circulation is fundamentally dependent on the height of the diastolic pressure, and that only in experiments in which the diastolic pressure is reduced to a permanent low level can the coronary blood flow be affected by changes in the systolic pressure. Starling's measurements of blood-pressure were in most cases made with the mercury manometer. Smith, Miller and Graber used a membrane manometer the vibration frequency of which was not stated, but, as can be judged from the tracings given in their paper, it was probably not high. The determination of the relative significance of the systolic and diastolic blood-pressures is of considerable importance for a correct comprehension of the blood supply to the heart muscle. It is especially important in conditions in which the pulse pressure changes without a material alteration in the mean pressure as may occur, for instance, as a result of acceleration of the heart beat or of a reduction in the arterial resistance with a simultaneous increase in the systemic output or in the case of aortic regurgitation. The experiments described below were performed with the object of securing further information on this point. They were performed on the heart-lung preparation, since in this preparation the diastolic and systolic pressures can be easily and independently controlled and maintained constant for any desired length of time.

2 342 G. V. ANREP AND B. KING. The blood-pressure was measured immediately above the aortic valves with an optical manometer, the membrane of which had in the different experiments a vibration frequency of and a sensitivity such as to give, at the magnification used, a deflection of 1 mm. for each mm. Hg change in pressure. The blood flowing from the drained coronary sinus was collected and measured during intervals of 1 min. and was considered constant if five successive measurements differed by not more than i 0.5 c.c. The diastolic and systolic pressures were changed by varying (a) the systemic output or (b) the heart rate which was in all experiments controlled by rhythmic stimulation of the right auricle. The actual experiments proceeded as follows. Optical records of the aortic pressure were obtained after carefully measuring the coronary blood flow and the systemic output of the heart. The output was then increased while the artificial arterial resistance was adjusted so as to maintain (say) the systolic pressure at the level it had during the preceding period of small output. The aortic pressure and the coronary blood flow were again recorded. The observation was then repeated, keeping in this case the diastolic pressure constant. Now, still maintaining a large output, the arterial resistance was adjusted to a level at which the coronary blood flow was within i 0'5 c.c. the same as it had been during the period of the small output, a further set of optical records of the aortic pressure being taken. We thus had four sets of records of the aortic pressures and of the coronary blood flow in each experiment; the first (1) which was taken during the period of small output and the rest (2, 3 and 4) during the period of larger output, (2) with the same systolic pressure, (3) with the same diastolic pressure and (4) with an aortic pressure such that the coronary blood flow during the period of large output was equal to that during the period of small output. In order to determine whether the condition of the coronary blood vessels had undergone a change during the 15 to 20 min. of observation, the output and pressure were again returned to their original values, only those experiments being used in which the coronary blood flow during this control period was equal to that observed before the increase in the output. The above four sets of observations could usually be repeated several times on the same heart-lung preparation. Similar observations were made in experiments in which the pulse pressure was changed by varying the heart rate while the systemic output was maintained constant.

3 CORONARY CIRCULATION THE EFFECT OF CHANGES IN OUTPUT. The results of our experiments with changes in output were concordant in showing that neither the diastolic nor the systolic pressure alone determines the coronary circulation. Thus our observations fail to support the conclusions reached by Smith, Miller and Graber; we find that the mean aortic pressure is in every case a far more significant factor in the coronary circulation. Table I gives the results of a typical experiment. TABLE I. Dog-10 kl.; heart-62 grm. The heart rate was maintained throughout this experiment at 122 beats per min. and the temperature at 370 C. Blood flow Arithmetical from the Systemic Diastolic Systolic mean coronary output in c.c. pressure pressure pressure sinus in c.c. per min. in mm. Hg in mm. Hg in mm. Hg per min. (a) (b) (c) The diastolic pressure is maintained constant k The systolic pressure is maintained constant * The coronary blood flow is maintained constant B *0 The first and the second part of the table show that the coronary outflow is affected by changes in the systolic pressure as well as by changes in the diastolic pressure or, in other words, that it is not determined by either of these pressures singly. The coronary blood flow closely follows the changes in the arithmetical mean pressure, a rise in which has a relatively greater effect as the pressure reaches a higher level: a change in the mean pressure from 99 to 129 mm. increased the coronary flow by 85 c.c., while an equal change from 69 to 99 mm. increased it by only 38 c.c. In the third part of the table the pulse pressure is progressively increased while the aortic resistance is so adjusted as to maintain the coronary outflow constant. It can be seen that the mean aortic pressure had to be dropped by 4 mm. Hg in the case of the largest systemic output. If, in this case, the mean aortic

4 344 G. V. ANREP AND B. KING. pressure had been maintained constant, the coronary blood flow would have been a few cubic centimetres larger. For instance, when after the last observation recorded in Table I (c) the mean pressure was increased from 95 to 99 mm. Hg the coronary blood flow increased from 57 c.c. to 64 c.c. per min. Registration by the hot-wire method (5, 6, 7) shows that the coronary blood vessels are supplied with blood during the whole period of diastole, and that therefore all changes of pressure occurring after the beginning of relaxation of the ventricles must affect the coronary blood flow. The coronary blood flow through the left ventricle is to all evidence completely arrested during systole. It is highly probable, however, that the coronary supply to the right ventricle is not stopped by its less powerful contraction, and if this be the case then it should be expected that not only the post-dicrotic changes in the blood-pressure but also the changes occurring during systole must affect the coronary blood flow. These complex relations are rendered still more difficult of analysis by the fact that the higher the maximum value of the blood-pressure the greater is its effect upon the coronary circulation, and also by the fact that the length of systole and the rate of relaxation of the heart change with alterations in 7 mm.hg Fig. 1. Record of the aortic blood-pressure taken at different systemic outputs and constant coronary blood flows. The average arithmetical pressure is nearly the same in the three cases, while the diastolic pressure is widely different. This fig. shows the method of retracing used in the calculation of the pressures. the output. On account of these complications it is not possible, at present, to evaluate more precisely the significance of changes in the

5 CORONARY CIRCULATION. 345 aortic pressure for the maintenance of the coronary blood flow. Calculating by graphic methods from the areas of the curves the true mean pressures prevailing during the whole cycle or during the period of diastole, we found that these gave no more definite relations to the coronary blood flow than the arithmetical mean pressure. The latter can be, therefore, taken as the one determining the coronary blood flow with such accuracy as our present methods allow. Fig. 1 gives a tracing of the aortic pressure as recorded in one of the experiments; Figs. 2 and 3 are redrawn superimposed tracings of the aortic pressure b a - /7\ ~~~~~~~120- / 100- C20 0 /41 ~~~~10O- a, a ~~~~~~~~~ "' 0-0;2" Fig. 2. Fig. 3. Fig. 2. Redrawn superimposed tracings of the aortic blood-pressure. The systemic output in a, b, and c was 960, 520, and 250 per min. respectively. The blood flow from the coronary sinus was constant at 37.5 c.c. per min. The arithmetical average pressures are 73, 74*5 and 76 mm. Hg in a to c respectively. Fig. 3. Redrawn tracings of the aortic blood-pressure: a systemic output 300 c.c., coronary sinus blood flow 41 c.c. b,, 930 c.c.,,,, 115 c.c. c,, 950 c.c.,,,, 41 c.c. The diastolic pressure is maintained constant in a and b. The coronary blood flow is maintained constant in a and c. THE EFFECT OF CHANGES IN THE HEART RATES. It has been reported on several occasions (1, 2, 3) that in the heart-lung preparation changes in the heart rate have no effect upon the coronary blood flow. Drury (8) has made similar observations in his experiments upon the tortoise heart and Hammouda and Kinosita(g) upon the perfused rabbit's heart. In a recent preliminary communication Miller, Smith and Graber(lo) report that in experiments in which a rapid and regular action of the heart followed the stimulation of the auricle the rate of coronary flow was usually increased, while irregular action with

6 346 G. V. ANREP AND B. KING. premature contractions produced by stimulation did not cause any significant changes in the rate of coronary flow. These workers do not state whether any precautions were taken to maintain the aortic pressure constant; a condition which assumes an especially great importance since their experiments were performed on the whole animal. In view of the stress which these authors place upon the importance of regularity of the heart beat we decided to repeat the experiments upon the effect of heart rate on the coronary blood flow. The experiments were similar to those upon the effect of output. The heart rate was altered by stimulation of the right auricle, while the aortic pressure was adjusted so as to maintain either the diastolic or the systolic pressures or the coronary blood flow constant. Any irregularity of the heart beat could easily be detected on the optical records of the aortic pressure. A typical example of such an experiment is given in Table II, and redrawn superimposed tracings of the aortic pressure taken from the same experiment are given in Fig. 4. TABLE II. Dog-9-5 kl.; heart-56 grm. The systemic output was maintained at 650 c.c. per min. and the temperature at C. 'Blood flow Arithmetical from the Diastolic Systolic mean coronary Heart rate pressure pressure pressure sinus in c.c. per mm. in mm. Hg in mm. Hg in mm. Hg per min. (a) (b) (c) The diastolic pressure is maintained constant i * i 47 The systolic pressure is maintained constant. 100* i k The coronary blood flow is maintained constant. 100* i 47* k k 46*5 * Natural heart rate; the auricle is not stimulated. The results of the experiments upon the effect of heart rate are similar to those upon the effect of output. The relation of the coronary blood flow to the diastolic and the systolic pressures is the same in both cases; the coronary blood flow follows the changes in the mean aortic pressure,

7 CORONARY CIRCULATION. independently of whether the latter is changed by alteration of the systolic or the diastolic pressures. In order to obtain a constant coronary 120- c Fig. 4. The aortic pressure is taken from an experiment in which the heart rate was maintained at 125, 150 and 188 beats per mm., while the coronary blood flow was kept constant at 39 c.c. by adjusting the arterial resistance. blood flow at heart rates varying from 100 to 185 beats per min. the mean pressure has to be maintained constant within a few mm. Hg. The slight increase in the mean pressure which can be seen in Table II (c) has been observed in almost every experiment. It is probably due to the fact that the total time occupied by the number of systole during 1 mn. is longer at the faster heart rates. In the experiment of Table II the ejection time per min. at the rate of 100 beats was 20x8 sec., while at the rate of 185 beats it was 25x2 sec. It must be remembered that the term "mean pressure" represents the arithmetical average between the maximal and the minimal pressure. It is a convenient but often incorrect expression of the summated effects of changes in the aortic pressure occurring within a cardiac cycle. In the heart-lung preparation the diastolic aortic pressure cannot fall rapidly below the externally applied constant pressure which determines the arterial resistance. When the aortic pressure becomes equal to that of the external resistance the outflow of blood is possible only through the coronary arteries. This means that when the heart rate is slow and the output per beat small, there will be a longer or shorter period towards the end of diastole during which the aortic pressure will remain nearly constant at values not far removed from the diastolic pressure. This prolonged maintenance of pressure at low values will not show itself in calculation of the arithmetical average pressure, but will obviously influence the calculation of the true mean pressure on which the coronary circulation ultimately depends. The discrepancy between the arithmetical and the true mean pressure will be greater the slower the heart rate or

8 348 G. V. ANREP AND B. KING. the smaller the output. This effect can be neglected in the experiments so far described in which the aortic pressure never became equal to the external pressure determining the arterial resistance, since neither the output nor the heart rate was excessively diminished. But it does come into evidence in experiments in which the heart beat is reduced to a very slow rate, especially when the output per beat is small so that the pressure in the arterial system quickly falls towards its diastolic value. For example, we have experiments with a small output in which the temperature of the blood was lowered to C., the natural heart rate being reduced in consequence to about beats per min. The heart could be, however, accelerated by stimulation of the auricle to beats per min. In this case, in order to maintain the coronary blood flow constant the arithmetical mean aortic pressure had to be raised at the slower heart rates by a few millimetres. On inspecting the aortic pressure curves it becomes evident that this apparent influence of heart rate is not due to a direct effect but to the fact that the arithmetical mean pressure ceases to give an approximate representation of the true mean pressure prevailing in the aorta. On calculating the true mean pressure it was found to be nearly constant in conditions in which the coronary blood flow was constant (Table III). TABLE III. Dog-9 kl.; heart-52 grm.; Output-200 c.c. per min.; Temperature 330 C. The coronary blood flow is maintained constant. Arithmetical Diastolic Systolic mean True mean Coronary flow Heart rate pressure pressure pressure pressure from sinus in per min. in mm. Hg in mm. Hg in mm. Hg in mm. Hg c.c. per min. 55* * Natural heart rate. The result of the experiments upon the effect of output and of heart rate on the coronary blood flow shows that changes in the strength of contraction of the heart as well as changes in the heart rate have no direct influence upon the coronary circulation. The changes in the coronary blood flow which may be observed under these conditions are brought about indirectly through alteration of the aortic blood-pressure. CONCLUSIONS. 1. The coronary blood flow is not determined by either the diastolic or the systolic aortic blood-pressure singly.

9 CORONARY CIRCULATION The coronary blood flow closely follows the changes in the arithmetical average of the systolic and diastolic aortic pressures, which is in most cases a sufficiently accurate measure of the true mean pressure. 3. Changes in the systemic output and changes of the heart rate have within wide limits no direct effect upon the coronary blood flow. The expenses of this research were defrayed by a grant from the Medical Research Council held by one of us (G. V. A.). REFERENCES. 1. Markwalder and Starling. This Journ. 47. p Nakagawa. Ibid. 56. p Anrep and Segall. Heart, 13. p Smith, Miller and Graber. Archives of Internal Med. 38. p Anrep and Downing. Journ. Sci. Instr. 3. p Anrep, Cruikshank, Downing and Subba-Rau. Heart, Anrep and Stacey. This Joum. 64. p Drury and Smith. Heart, 11. p Hammouda and Kinosita. This Journ. 62. p Miller, Smith and Graber. Amer. Journ. Physiol. 81. p